, 5...
..lv.t.::
it...

“5.11. .3

to.
41...... 3 7...
fl. :1 is?! . ‘

:5. m. .
‘uxg

 

v
Litii:
. .Iirr:x. ?
. , a: ., :35. .
:5. .. 5.1;:

t

(u
5......

 

. , z
1.. ‘ I
2:96..» ,1

E {ii a;

 

 

1..
.1: .. .4. K
.1. [1.3.

 

.. {we}.
‘ .. I:
I“: a.

 

 

 

 

 

 

 

.3...
$9:
a; fit

as...

 

. 2:5
. .x .... .7
Q

 

11.5.5: .54

 

:I.|I.

.0
I Lfi rm?! .

 

 

 

This is to certify that the
dissertation entitled

SYNTHETIC APPLICATIONS OF IRIDIUM-CATALYZED
AROMATIC C—H BORYLATION

presented by

FENG SHI

has been accepted towards fulfillment
of the requirements for the

Ph.D. degree in Chemistry

 

 

Major‘Professor—sWignature

7/(ll01’2009—

Date

l
. “i

MSU is an affinnative-action, equal-opportunity employer

 

-v-ac»-c-u—n-n-n-n-o—n-n-o-u—o—--—--a-a—c--c-.-a-a-sun-o-----u-c-n-o--n-n-.-a--o-o-n------.---.—-o--.--.—-—n-

 

 

LIBRARY
Michigan State
University

 

 

 

PLACE IN RETURN BOX to remove this checkout from your record.
TO AVOID FINES return on or before date due.
MAY BE RECALLED with earlier due date if requested.

 

DATE DUE DATE DUE DATE DUE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

6/07 p:/CIRC/DaleDue.indd-pv1

 

 

SYNTHETIC APPLICATIONS OF
IRIDIUM-CATALYZED AROMATIC C—H BORYLATION

By

Feng Shi

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
DOCTOR OF PHILOSOPHY
Department of Chemistry

2007

 

 

ABSTRACT

SYNTHETIC APPLICATIONS OF
IRIDIUM-CATALYZED AROMATIC C—H BORYLATION

By
Feng Shi

The lr-catalyzed aromatic C—H borylation discovered by our group has been
demonstrated as a powerful tool for direct functionalization of unactivated arenes.
This reaction provides a method for preparation of aryl boronic esters directly
from arenes and bypasses the need for aryl halides precursor. It also comes
with a unique sterics-directed regioselectivity, thus is complementary to
traditional chemistry and able to provide aromatic building blocks with
substitution patterns difficult to access via other routes. The cleanliness of this
reaction allows succeeding reactions performed without isolation and purification
of the boronic ester intermediates.

Through the years, we have successfully demonstrated the utility of this C-H
borylation by combining it with subsequent chemical events in the one-pot
fashion. By doing this, we are able to not only elaborate this reaction into
synthetically useful protocols toward the preparations of many functionalized
aromatic motifs, but also discover new chemistries. Along these lines, we have
been working on both transforrnating the boryl group to other functionalities and
carrying on aromatic substitution with the boronic ester groups intact. We have
established the borylation/oxidation protocol for the preparation of substituted
phenols, the borylation/deuteration protocol for the preparation of specifically

deuterated aromatics, and the borylation/amidation/oxidation protocol for the

preparation of 5-substituted 3-amidophenols. At the same time, we have also
demonstrated the viability to extend the lr-catalyzed aromatic C-H borylation
chemistry from simple arenes to aromatic amino acid substrates and successfully
carried out the borylation/oxidation protocol to prepare hydroxylated
phenylalanine and tryptophan derivatives and analogues. Moreover, we have
discovered that the proto-ldeuterio-deborylation reaction of aryl boronic
acids/esters is an lr-catalyzed reaction and therefore established a thermal, acid-
lbase-free deborylation condition on its own. The borylation/ amidation/oxidation
protocol comes with an undesired Suzuki side-reaction, and we are able to
exploit it not only by utilizing its potential useful products, but also by giving
preliminary success for a possible borylation/amidation/Suzuki protocol that uses
the same Pd catalyst and ligand to promote both the amidation and the Suzuki
reactions.

We are also applying the 0—H borylation chemistry strategically to total
synthesis of natural product autolytimycin. We have been able to demonstrate
that autolytimycin, a new ansamycin superfamily member exhibiting antitumor,
anti-inflammation, and antiviral activities, can potentially be assembled using our
borylation/amidation/oxidation protocol with advanced intermediates. We have
prepared the individual segments, and successfully demonstrated that the
borylation/amidation/oxidation process can be successfully applied to the total
synthesis in the relatively late stage. The completion of the total synthesis can

be expected in the near future.

To my parents, my friends and Chunrui

ACKNOWLEDGEMENTS

“A PhD. is just the beginning.” That’s what I have learned and have
experienced during the past five and a half years here at Michigan State
University. My Ph.D. study and training fulfills me with the true meaning of PhD.
that I will have to spend my entire life to fully understand and realize. A PhD. is
far more than a gain of knowledge and experience. It is a gain of capabilities to
analyze the situation, to find problems and to solve them. It is also a gain of
interest, desire, enthusiasm, and dedication that I will carry with me for my career.
However, none of these could ever be possibly realized, let alone achieved,
without the guildance and supervision of my advisor, Professor Robert E.
Maleczka, Jr. He has been always helpful and suggestive for my research, my
personal growth and my interest in chemistry. Through the years, he has led me
through the murky waters of chemistry, corrected my path, taught me to face
frustration and overcome it, and shaped my love of chemistry as a profession.
He is strict, yet is also patient and tolerant. He allows me to explore chemistry
with freedom and yet is still always ready to help me navigate the difficult area. I
am very fortunate to have him as my dedicated and effective mentor, and I owe
him my lifelong appreciation.

My thanks also go to Professor William D. Wulff, Professor Babak Borhan,
and Professor Milton R. Smith, III for serving on my guidance committee. They
have always been helpful with my research and taught me how to become a

qualified chemical researcher. I would give them my deepest gratitude for

everything they have done to make my Ph.D. more fruitful. A specific thank is
given to Professor Milton R. Smith, III for serving as our collaborator over the
years and bringing research ideas and instructions to me.

I would also like to thank Dr. Jian-Yang Cho, Dr. Daniel Holmes, Dr. Yong
Gong, Dr. Wei He, Dr. William P. Gallagher, Dr. Jennifer M. Schomaker, and Dr.
Yonghong Deng for their help, advice and supervision in the laboratory. It is they
who taught me hand-by-hand how to be a chemist. And nothing I have achieved
would be possible without them.

In addition, I would give specifical thanks to my group members and all my
friends here in this department. Some of them have already graduated and
some are expecting. It is they who have made my life colorful and I enjoy every
minute with them.

I will also give my special thank to my parents back in China and my wife
Chunrui Wu. They are always encouraging me, supporting me and giving me
confidence. I am extremely lucky to have such a warm and encouraging family

and it is their support that leads me this far.

vi

 

 

 

TABLE OF CONTENTS

 

 

LIST OF TABLES .................................................................................................................... x
LIST OF FIGURES ................................................................................................................ XI
LIST OF SCHEMES _____________________________________________________________________________ x n
LIST OF SYMBOLS AND ABBREVIATIONS xv

CHAPTER 1. INTRODUCTION: CATALYTIC AROMATIC C—H BORYLATION
AND ITS POTENTIAL SYNTHETIC APPLICATIONS ,,,,,,,,,,,,,,,,,,,,,,,,, 1
1.1 0-H Activation ............................................................................................................ 1
1.2 C—H Borylation and Its Special Features ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 3
1.3 Potential Synthetic Applications of Catalytic Aromatic C—H Borylation ,,,,,,, 10

 

CHAPTER 2. THE C—H BORYLATION/OXIDATION APPROACH FOR THE

 

 

 

PREPARATION OF META-SUBSTITUTED PHENOLS ,,,,,,,,,,,,,,,,, 13
2.1 Phenols and Their Preparations ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 13
2.2 Applications of Catalytic Aromatic C—H Borylation in Phenol Synthesis and

Initial Studies ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 15
2.3 Substrate Study ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 19
2.4 Mechanistic Investigation of Aryl Boronic Ester Oxidation with Oxone _______ 29
2.5 Conclusions 32

CHAPTER 3. THE C—H BORYLATION/OXIDATION STUDY OF AROMATIC

 

AMINO ACIDS DERIVATIVES AND ANALOGUES ,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 33
3.1 Aromatic Amino Acids and the Potential C—H Borylation Investigation ______ 33
3.2 Study of Substituted Phenylalanine Derivatives and Analogues ,,,,,,,,,,,,,,,,,, 35
3.3 Study of 5-Membered Phenylalanine Analogues ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 4 2
3.4 Study of a Tryptophan Derivative ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 4 5
3.5 Conclusions ______________________________________________________________________________________ _ __ _ _46

 

CHAPTER 4. THE C—H BORYLATION/DEUTERATION APPROACH FOR THE
PREPARATION OF SPECIFICALLY DEUTERATED AROMATICS _______________________ 48
4.1 Specifically Deuterated Aromatics and Their Preparations__ 48
4.2 Applications of Catalytic Aromatic C-H Borylation in the Synthesis of

Specifically Deuterated Aromatics and the Discovery of Ir-catalyzed

 

 

Deuteration of Arylboronic Acids/Esters ____________________________________ 50
4.3 Substrate Study ........................................................................................................ 55
4.4 Attempts to Deuterate Vinyl Boronic Acids/Esters ........................................... 61
4.5 Conclusions 63

vii

CHAPTER 5. THE C—H BORYLATION/AMIDATION/OXIDATION PROTOCOL

 

 

 

 

FOR THE PREPARATION OF 5-SUBSTITUTED 3-AMIDOPHENOLS ................. 65
5.1 5-Substituted 3-Amidophenols and Their Preparations 65
5.2 Applications of Catalytic Aromatic C-H Borylation in the Synthesis of 5-

Substituted 3-Amidophenols 67
5 3 Substrate Study 75
5. 4 Competing Suzuki Side-Reaction during the Amidation Step and Its
Potential UtilitY..._ 80
5.5 Conclusions __ 86

 

 

CHAPTER 6. ATTEMPTED TOTAL SYNTHESIS OF AUTOLYTIMYCIN
UTILIZING THE C—H BORYLATION/AMIDATION/OXIDATION PROTOCOL 87

6.1 Autolytimycin and Ansamycin Family Natural Products 87
6.2 Reported Total Syntheses of Geldanamycin Family Natural Products 91

6.3 Our Strategic Disconnection and Retrosynthetic Analysis for Autolytimycin.

 

 

 

 

 

 

 

 

 

 

 

96

6.4 Synthesis of the Right-hand Segment ________________________________ 100
6.5 Synthesis of the Left-hand Segment _____ 105
6.6 Coupling of Segments in the Late Stage ________________ 113

6 6.1 Choice of the Halides on the Aromatic Starting Material _____________________ 113
6.6.2 Joining the Right-hand Segment with the Aromatic Segment Using
Borylation/Amidation /Oxidation Protocol. 116

6.6.3 Attempted Suzuki Coupling of the Chloride 118
6.6.4 Model Studies of the Suzuki Coupling of the Chloride __ 120

6.7 Conclusions ___________ " 133
SUMMARY ............................................................................................... 134
EXPERIMENTAL SECTION 135

CHAPTER 7. EXPERIMENTAL DETAILS AND COMPOUND
CHARACTERIZATION DATA FOR C—H BORYLATION AND RELATED
REACTIONS 135

7.1 Materials and Methods 135

7.1.1 Materials and Methods For C-H Borylation of Simple Aromatics 135

7.1.2 Materials and Methods For C—H Borylation of Aromatic Amino Acid

 

 

 

 

 

 

 

Substrates _ 1 38

7. 2 Preparation of Non- commercial Starting Materials," 139
7. 2. 1 Preparation of Non- commercial Arene "139
7. 2. 2 Preparation of Non-commercial Aromatic Amino Acid Starting
Materials ,,,,,,,,,,,,,,,,,,,,,,,,,,,, 141

7. 2. 3 Preparation of Aryl Boronic Pinacol Esters from the Corresponding
Boronic Acids , ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 144

7.2.4 Preparation of Non-commercialAmides _____________________ 147

 

.......

 

ooooooooooooooooooooooooooooooooooooooooooooooooooooo

viii

 

7.4 Experimental Details and Compound Data _____________________________________________________ 154

 

7.4.1 Simple Phenols ______________________________________________________________________________________________ 154
7.4.2 Hydroxylated and Borylated Aromatic Amino Acid Derivatives and

Miscellaneous Products ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, .. 168
7.4.3 Deuterated Aromatics ___________________________________________________________________________________ 176
7.4.4 Amidophenols and Miscellaneous Compounds _____________________________________ 184

CHAPTER 8. EXPERIMENTAL DETAILS AND COMPOUND
CHARACTERIZATION DATA FOR ATTEMPTED TOTAL SYNTHESIS OF

 

AUTOLYTIMYCIN .............................................................................................................. 2 05
8.1 Materials and Methods ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 2 05
8.2 Experimental Details and Characterization Data for the Compounds

Related to Total Synthesis __________________________________________________________ 205

8.3 Experimental Details and Characterization Data for the Compounds
Related to the Model Suzuki Coupling ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 272
BIBLIOGRAPHY 284

ooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooo

Table 2.1
Table 2.2
Table 2.3
Table 2.4

Table 3.1

Table 4.1
Table 4.2

Table 4.3

Table 4.4
Table 5.1
Table 5.2
Table 6.1
Table 6.2
Table 6.3

 

 

LIST OF TABLES

Initial study of reaction conditions for oxone oxidation ___________________ 18
C-H Borylation/oxidation protocol for phenol synthesis ________________ 20
C-H Borylation/oxidation protocol for iodinated substrates __________ 27
Solvent study in the oxidation step 30
C-H Borylation/oxidation protocol to phenylalanine derivatives

and analogues _______________________________________________________________ 39
Acid and base-promoted conditions ___________________________________________________ 52
lr-catalyzed conditions ___________________________________________________________________________ 53

C—H Borylation/deuteration protocol for synthesis of deuterated

 

 

 

 

 

 

 

 

aromatics ,,,,,,,,,,,,,,,,,,,,,,,,,,, _ 56
Electronic and steric perturbations _________________________ _ 59
C—H Borylation/amidation/oxidation protocol ___________________________________ 75
Suzuki Side-product formation ___________________ 82
1H NMR analysis of the stereochemistry of 6.34 at C11 ,,,,,,,,,,,,,, 112
Protecting group study ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 126
Use of trifluoroborate in Suzuki coupling ................ _ 131
x

 

Figure 1.1

Figure 2.1

Figure 3.1

Figure 4.1
Figure 5.1
Figure 6.1

Figure 6.2

LIST OF FIGURES
Difficult aromatic substitution tasks for traditional chemistry __________ 9

1H NMR analysis of crude oxidation of 2.2q before and after

 

quench ................................................ 24
Empirical calculation of the 13C NMR chemical shifts and
structural assignment ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 4 6
Vinyl boronic acids/esters as potential substrates __________________________ 62
5-Substituted-3-amidophenol and AHBA __________________________________________ 66
Some ansamycin natural products ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 88
Geldanamycin family members ........................................................... 89
xi

Scheme 1.1
Scheme 1.2
Scheme 1.3
Scheme 1.4

Scheme 1.5

Scheme 2.1

Scheme 2.2

Scheme 2.3

Scheme 2.4

Scheme 2.5

Scheme 3.1
Scheme 3.2
Scheme 3.3
Scheme 3.4
Scheme 3.5
Scheme 3.6

Scheme 4.1

Scheme 4.2
Scheme 4.3

Scheme 4.4

LIST OF SCHEMES
General equation of C—H borylation _____________________________________________________ 3
An example of (Ind)lr(cod)-catalyzed aromatic C—H borylation ,,,,, 5
Proposed catalytic cycle of lr-catalyzed C-H borylation ,,,,,,,,,,,,,,,,,, 5
Comparison of different methods for boronic ester preparation ,,,,, 7

Possible synthetic applications of lr-catalyzed aromatic C—H

borylation ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 11
A traditional preparation of 3-bromo-5-chlorophenol ,,,,,,,,,,,,,,,,,,,,,, 15
Proposed one-pot C—H borylation/oxidation protocol for

preparation of phenols ___________________________________________________________________________ 16
Investigation of the demethylation of 2.1] ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 26

Combining borylation/oxidation with Pd-catalyzed PMHS
reduction: access to more phenols .................................................... 29

The revised mechanism for the oxone oxidation of an aryl boronic

ester ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 31
Literature preparation of 4-fluoro-meta-tyrosine ______________________________ 34
9-BBN-derived 3-chlorophenylalaine and its borylation ................. 37

N-Boc 3-chlorophenylalaine methyl ester and its borylation _________ 37
Borylation of 5-membered phenylalanine analogues ,,,,,,,,,,,,,,,,,,,,, 43
Borylation/oxidation of 5-membered phenylalanine analoguesm44
Boylation/oxidation of a tryptophan derivative ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 45

Proposed one-pot C—H borylation/deuteration protocol for
preparation of specifically deuterated aromatics _____________________________ 51

A putative mechanism for Ir-catalyzed deuteriodeboronation ______ 60
An iodinated substrate for C-H borylation and deuteration .......... 61

Styryl boronic acid/ester in the deuteration reaction ,,,,,,,,,,,,,,,,,,,,,,, 62

xii

Scheme 5.1
Scheme 5.2
Scheme 5.3
Scheme 5.4

Scheme 5.5

Scheme 56

Scheme 5.7
Scheme 5.8

Scheme 5.9

Scheme 5.10

Scheme 5.11

Scheme 6.1
Scheme 6.2
Scheme 6.3
Scheme 6.4
Scheme 6.5

Scheme 6.6

Scheme 6.7

Scheme 6.8

Scheme 6.9

Scheme 6.10

Acylation strategy for the preparation of amidobenzenes ,,,,,,,,,,,,, 67

 

 

Smith total synthesis of trienomycin A _______ __ ______________ 67
Proposed C—H borylation/amidation/oxidation protocol _________________ 69
A related C—H borylation/amination protocol ____________________________________ 69
Desired amidation versus undesired Suzuki ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 70
Stepwise borylation and amidation reactions ___________________________________ 71
The oxdiation of the amidophenyl boronic ester ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 73
Undesired Suzuki side-product formation ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 81
The established C—H borylation/Suzuki protocol _____________________________ 83
The C-H borylation/Suzuki under standard Buchwald amidation

conditions ___________________________________________________________ 85
One-pot borylation/amidation/Suzuki protocol _________________________________ 85
Baker's syntheis of macbecin l ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 92
Evans' syntheis of macbecin I .............................................................. 93
Martin's syntheis of macbecin l ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 93
Martin's C8—C9 olefination approach _________________________________________________ 95
Panek's syntheis of reblastatin, _____ 96

 

Success in the borylation/amidation/oxidation with unsaturated
amide ......................................................................................................... 98

Retrosynthetic analysis for autolytimycin ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 98

First-generation synthesis en route to the right-hand segment 6.5

 

........................................................................................ 101
Second-generation synthesis en route to the right-hand segment
6 5 ............................................................................................................. 103
Recycling of the undesired TBS diol ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 104

xiii

Scheme 6.11
Scheme 6.12
Scheme 6.13

Scheme 6.14

Scheme 6.15

Scheme 6.16
Scheme 6.17
Scheme 6.18
Scheme 6.19
Scheme 6.20
Scheme 6.21

Scheme 6.22
Scheme 6.23
Scheme 6.24

Scheme 6.25

Scheme 6.26

Scheme 6.27

Completion of the synthesis of the right-hand segment 6.5 ........ 105
Retrosynthetic analysis for segment 6.3 _________________________________________ 1 O5

First-generation synthesis en route to the left-hand segment 6.3
.................................................................................................................. 107
Second-generation synthesis en route to the left-hand segment
............................................................................................................. 109
Second-generation synthesis en route to the left-hand segment
6-3 (continued) ....................................................................................... 110

Completion of the synthesis of the left-hand segment 6.3 ,,,,,,,,,, 111

 

 

Amidation/oxidation of dihalobenzenes with tiglic amide ............. 115
Amidation/oxidation protocol for the synthesis of 6.4 ,,,,,,,,,,,,,,,,,,, 117
Attempted Finkelstein halide exchange ___________________________________________ 118
Attempted Suzuki coupling ______________________________________ 120
Control experiments of the Li/l exchange and the boronate

adduct formation ________________________________________________________________ 121
Control experiments of the Suzuki coupling ................................... 123
Suzuki coupling with added Li/I exchange step ,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 124

Improved Suzuki coupling with added Li/l exchange step ,,,,,,,,,, 125

Application of the TIPS-protected phenol in the Suzuki coupling

 

to the real system ______________________________________________________ 129
Preparation of the trifluoroborate ______________________________________________________ 130
Coupling with a bromide ______________________________________________________________________ 132

xiv

 

Ac

AD
ADP
AHBA
AIBN
Anal.
aq.

Ar
ATP
9-BBN
Bcat
Bn
Boc
4-BPA
Bpin
szing
BPS
br
brsm
Bu, ”Bu

'Bu

LIST OF SYMBOLS AND ABBREVIATIONS

angstrom

acetyl

asymmetric dihydroxylation
adenosine 5’-diphosphate
3-amino-5-hydroxybenzoic acid
2,2'-azobis(2-methylpropionitrile)
analysis

aqueous

aromatic group

adenosine 5’-triphosphate
9-bora-bicyclo[3.3.1]nonane
catecholboryl

benzyl

tert-butoxycarbonyl
4-boronophenylalanine
pinacolboryl (4,4,5,5-tetramethyI—[1,3,2]dioxaborolyl)
bis(pinacolato)diboron
tert-butyldiphenylsilyl

broad

based on recovered starting material
n-butyl

tert-butyl

Bz
calcd
cat.

CI

cod

coe
mCPBA
CSA

Cy
DABCO

Davephos

dba
d'bpy
DBU
DCC
d

dec
DIAD
DMAP
DMDO
DME
DMF

dmpe

benzoyl

calculated

catalyst, catalytic amount
chemical ionization

1 ,5-cyclooctadiene
cyclooctene
3-chloroperbenzoic acid
camphorsulfonic acid
cyclohexyl

1 ,4-diazabicyclo[2.2.2]octane

2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-
biphenyl

dibenzylideneacetone
4,4’-di-tert-butyI-2,2’-bipyridine
1 ,8-diazabicyclo[5.4.0]undec—7-ene
dicyclohexylcarbodiimide
doublet

decomposition

di-iso-propyl azodicarboxylate
4-(dimethylamino)pyridine
dimethyldioxirane
dimethoxyethane
N,N-dimethylformamide

bis(dimethylphosphino)ethane

xvi

 

DMSO
dppe
dppf
dr
EITDA
El
equN
Et
ESI

FAB

GC
COSY

h
HmeLX
HBMn
HETCOR
HMDS
HMBC
HMPA
HMQC
HPLC
HRMS

dimethyl sulfoxide
bis(diphenylphosphino)ethane
1,1’-bis(diphenylphosphino)ferrocene
diasteromeric ratio

ethylenediamine tetraacetic acid
electron ionization

equivalent

ethyl

electrospray ionization

fast atom bombardment

gram

gas chromatography

correlation spectroscopy

hour

halogen

pinacolborane

heteronuclear chemical shift correlation
bis(trimethylsilyl)amide

heteronuclear multiple bond correlation
hexamethyl phosphoramide
heteronuclear multiple quantum correlation
high-performance liquid chromatography

high-resolution mass spectrometry

xvii

Hz
II'DzCO
Imid

Ind

LDA
lit

LRMS

um

[AM
Me
mg
MHz
min
mL
mm
mmHg

mmol

hertz

1 ,1 ’-carbonyldiimidazole
imidazole

n5-indenyl

infrared, infrared spectrum
equilibrium constant

liter

microliter

lithium di-iso-propylamide
literature value
low-resolution mass spectrometry
multiplet

micrometer

molar

micromolar

methyl

milligram

megahertz

minute

milliliter

millimeter

millimeter of mercury

millimole

xviii

mol
umol
MOM
mp
MS
nm

NMR

NMO
[0]

OXOI’IG

P (various superscripts)
PCC

Ph

Piv

PMB

PMHS

PPTS

quint

R (various superscripts)

mole

micromole

methoxymethyl

melting point

mass spectrometry, mass spectrum
nanometer

nuclear magnetic resonance, nuclear magnetic
resonance spectrum

N-methylmorpholine-N-oxide
oxidant

triple salt of potassium hydropersulfate,
potassium hydrosulfate, and potassium sulfate

protecting group
pyridinium chlorochromate
phenyl

pivaloyl

4-methoxybenzyl
polymethylhydrosiloxane
pyridinium para-toluenesulfonate
iso-propyl

pyridine

quartet

quintet

substituent

xix

RL. Rs
RCM

Rf

3N2

SAR
SEM
sext

S-phos

TBAF
TBS
TCD

TEA
Tf

TF A
TH F
Tig
TIPS

TNT
ToI

substituent, large and small, respectively
ring-closing olefin metathesis
retardation factor
room temperature
singlet
bimolecular nucleophilic substitution
structure-activity relationship
2-(trimethylsiIyl)ethoxymethy|
sextet
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-bipheny|
triplet
tetrabutylammonium fluoride
tert-butyldimethylsilyl
thermal conductivity detector
triethylamine
trifluoromethanesulfonyl
trifluoroacetic acid
tetrahydrofuran
tiglic (E—2-methyI-but-2-enoyl)
tri-iso-propylsilyl
trimethylsilyl
2,4,6-trimethyltoluene

toluene

XX

TPAP
Tr
Ts
UV
ILW
VV

xa ntphos

tetrapropylammonium perruthenate
trityl (triphenylmethyl)
4-toluenesulfonyl

ultraviolet

microwave

Watt

9,9-dimethyI-4,5-bis(diphenylphosphino)xanthene

xxi

Chapter 1. Introduction: Catalytic Aromatic C—H Borylation and its Potential
Synthetic Applications
1.1 C—H Activation
C—H activation, said by its name, refers to a chemical transformation that
directly functionalizes an otherwise unactivated C—H bond.1 Such a
transformation, ideally, should be a process that replaces the strong, inert C—H
bond with a relatively weaker, more reactive bond. More strictly, C—H activation
should be a process that “activates” a 0—H bond without assistance from its
neighboring functional groups, and a process that avoids the generation of
uncaged reactive intermediates, such as free radicals or carbocations.
Therefore, processes such as acidic C—H bond deprotonation or B-hydride
elimination from a carbon atom are not considered “true” C—H activations.

‘l'he importance of C—H bond activation can be well understood from a
trad itional chemistry point of view. The isolated C—H bond is one of the least
rea ctive bonds in organic reactions. Having a bond dissociation energy close to
100 kcal/mol and lack of polarity, the C-H bond is very inert towards many organic
transformations. In a traditional synthetic perspective, a 0—H bond is not
cor"ISidered as a “functional group". This nature of the C—H bond makes C—H
ac“Vation a highly challenging task from a basic scientific point of view. On the

0ther hand, hydrocarbons, consisting of only 0—H and CC bonds, are the main

Constituents of oil and natural gas, which is feedstock for the chemical industry,
and the starting materials for most chemical products. The transformations of
unactivated C—H bonds, therefore, constitute an extremely important goal for
organic chemists. Discovery and development of selective, mild, and efficient
transformations that utilize C—H bonds to construct other bonds will potentially not
only provide the chemical industry new, more efficient, cost-friendly, and
environmentally benign methods of generating more valuable chemical products
directly from hydrocarbon stock, but also provide synthetic organic chemists
fundamentally novel yet extremely powerful tools for retrosynthetic analysis of
complex molecules as well as rapid and direct synthesis of diversely
functionalized small molecules. Therefore, C—H activation represents one of the
most fundamentally important reactions in organic chemistry.
Since the 1970’s, C—H activation has attracted Significant attention from

"2 A variety of methods that selectively

orQanic and organometallic chemists.
actiVate aliphatic, aromatic or benzylic C-H bonds to construct C—C, C—N, C—0,
and C—B bonds have been reported. These methods represent great success
Iowa rd this fundamentally challenging mission and have provided synthetic
Che I'TIistry new and efficient methods to construct C—C or C—Heteroatom bonds

that are not straightforward by other means. Mechanistically, C—H activation

methods can be roughly divided into two categories: inner-sphere and

outer-sphere.3 The inner-Sphere C—H activations utilize a transition metal for
direct C—H oxidative addition (or o-bond metathesis) and have been used to
construct C—C,4 C—N,5 C—O,6 C—Halogen,7 and C—B (vide infra) bonds. The
outer-sphere mechanism, on the other hand, does not call for a direct interaction
of the metal center to the 0—H bond. It generally utilizes a metal-bound carbene
or nitrene to directly insert into the C—H bond and completes the C—H activation.
It may also involve activation of a small molecule, such as dioxygen, to form a
highly reactive intermediate, which reacts with the C—H bond in a radical H
abstraction/rebound manner. This type of process has also been used to
con struct C—C,8 C—N,9 and C—010 bonds.
1 .2 C—H Borylation and Its Special Features
C—H borylation is a type of C—H activation11 where a C—H bond is transformed
into a C—B bond (Scheme 1.1). So far, C—H borylation follows an inner-Sphere
mechanism which calls for a transition metal, typically Pd, Re, lr or Rh, to directly

”Dd ergo oxidative addition (or o-bond metathesis) to cleave the 0—H bonds.

Scheme 1.1 General equation of C-H borylation

 

I /
—(|3-H 'I' H'B\

Since 1999, when Smith and coworkers demonstrated that C—H borylation
COU Id be catalyzed by some Ir species,12'13 much work has been done to improve

and further develop this reaction”20 in terms of substrate scope, catalyst choice

 

and activity, and reaction conditions. It has been realized that depending on the
catalyst choices, C—H borylations can selectively take place on aromatic,”17
aliphatic,18 benzylic,19 or B-styrylic C—H bonds.20 It has also been discovered
that some of these reactions can be performed in solvents whose C-H bonds are

not reactive under the reaction conditions.14b

For the aromatic C—H borylation,
the discovery of (nS-lndenyl)lr(cod) catalyst (abbreviated as (Ind)lr(cod)). by Smith
and coworkers, was one of the breakthroughs in terms of product cleanliness,

c This catalyst in combination of a bidentate

catalyst activity and turnover.14
phosphine ligand, generally bis(dimethylphosphino)ethane (dmpe) or
bis(diphenylphosphino)ethane (dppe), allows a variety of aromatic substrates to
undergo clean C—H borylation with pinacolborane (HBpin) under relatively mild
Conditions to give aromatic boronic pinacol esters in good yields (Scheme 1.2).
Fur‘ther improvements by Miyaura, IShiyama and Hartwig revealed
['r(I—L2-0Me)(cod)]2 as a more active catalyst (abbreviated as [lr(OMe)(cod)]2).15b
Th is catalyst in combination with a bipyridine ligand
4'4”—di-tert—butyl-2,2’-bipyridine (d'bpy) could allow for reactions at room
temperature with bis(pinacolato)diboron (szinz) and with more functional groups
tolerated. The mechanism of this C—H borylation has been studied, and an

Ir“ I I )llr(V) catalytic cycle involving an oxidative addition (or o-bond metathesis) of

the aromatic C—H bond14°'15a followed by a reductive elimination to afford the

corresponding C—B bond (Scheme 1.3) has been supported.

Scheme 1.2 An example of (Ind)lr(cod)-catalyzed aromatic C-H borylation

 

Cl 2 mol% (lnd)lr(cod)-dppe, CI\
: H8 in —— 02
\ P . ,
\\ //—‘H o > \\ /T B I __ + H2
I—u cyclohexane, 100 C 2 J o/“\
MeOZC 95% MeOzC

Scheme 1.3 Proposed catalytic cycle of lr-catalyzed C-H borylation

Pre-catalysts

l

rL

A H
H E \ ‘\L/IEr\Bpin n\\ r
(E: Hor Bpin)
E Bpin/ i
Ar
/L ,E ’L I E
k /|r\ gIri—H
L H C'- 'EBpin
‘\ /
/'/l
V
Ar—Bpin

Like other C—H activation methods, catalytic C—H borylation increases the
Pool of starting materials to include unactivated hydrocarbons. It also allows for
Imp roved efficiency, economy, and “greenness”. One specific attraction that
drawS the attention of synthetic chemists is its ability to generate a boronic ester
di" e ctly from an unactivated C—H bond with sterics-directed regioselectivity.16d

Boronic acids/esters are versatile intermediates in organic syntheses. They
“Dd ergo a variety of important transformations to make 0-0 or C—Heteroatom
bonds, and therefore are intensively used in organic syntheses. Typical

9x8 mples of such important transformations include, but are certainly not limited

to, Pd-catalyzed Suzuki-Miyaura couplings,21 Rh-catalyzed addition reactions to
alkynes/olefins, COz, carbonyls, or cult-unsaturated carbonyls,22 Petasis
reactions,23 Matteson homologations,” and Cu-mediated cross-coupling
reactions.25 They also serve as functional molecules,26 10B carriers for neutron
capture therapy,27 and biologically active compounds.28 Such uses of boronic
acids/esters keep urging the development of new, mild, easy, and scalable
synthetic protocols for their preparations. Traditionally, boronic acids/esters are
made via a metal/metal exchange step (transmetalation) from the corresponding
lithium or Grignard reagents with trialkyl borate (Scheme 1.4 A).29 Although such
a protocol is commonly used, it obviously has drawbacks. For one, this
app roach calls for the intermediacy of highly reactive organolithium or magnesium
sDecies, resulting in relatively poor functional group compatibility and are
ope rationally inconvenient at large scales. It also necessitates the ready
availability of the corresponding halides, which may not always be the case.
HYd roboration of olefins or alkynes, either catalyzed or uncatalyzed, can minimize
SUCh limitations,30 but aromatic boronic acid/ester preparations via such an
approach is obviously not viable. Recently, Miyaura and Masuda developed a
C'e\/er method to couple aryl halide directly with borane or diboron reagents
”t" 52ing Pd-catalyzed dehydrohalogenative conditions and thus avoid generating

the reactive organolithium or magnesium intermediates (Scheme 1.4 B).31 Such

an improvement greatly expands the scope of aromatic boronic acid/ester
preparations, especially for those with functionalized arenes, but still does not
overcome the need for halogenated starting materials.

C—H borylation, on the other hand, does not require the corresponding halide
as the starting material (Scheme 1.4 C). It uses a C—H bond to form the boronic
ester without generating a highly reactive intermediate. Thus, it has
considerable functional group tolerance. Considering that halides are ultimately
made from the hydrocarbon feedstock, C—H borylation serves as a much more
direct and concise route to prepare boronic esters. Moreover, C—H borylation
not only bypasses the aryl halide precursors, but also tolerates halides as a
functional group. Therefore, the product of the C—H borylation can still possess

a halide for further manipulation, which further expands the utility of this process.

Scheme 1.4 Comparison of different methods for boronic ester preparation

 

 

— 1.Mg°, THF (or BuLi) — .o\
— A, .z A f 29
<\] B' 2. B(OMe)3 \ / 30/ ('e I
3. aq. HCI
4. diol
—- HBpin or szinz, ,O\.L
_ e < B ref31
C} Br Pd cat., base vac/LC ( )

 

_ - _ O\/,
QH lr cat., HBpIn #7 QB j? C (ref 1447)
- O

In addition, C—H borylation has a very unique sterics-directed regioselectivity.
Such selectivity allows for the activation of the C—H bonds that are viewed as

"less reactive" in the traditional chemistry standpoint. For example, C—H

borylation on aliphatic substrates can lead to selective borylation on primary C—H
bonds, leaving secondary and tertiary C—H bonds intact, which is complementary

"“9 This trend is also followed

to traditional electrophilic substitution chemistry.
for aromatic substrates. Traditional aromatic substitution is generally dictated by
electronics. Thus, electron-releasing groups direct the incoming electrophilic
substituent to their ortho/para positions, and electron-withdrawing groups direct
the incoming electrophilic substituent to their meta positions. Under such
guidelines, it is predictable that functionalization of aromatics at positions that are
not favored by existing substituents will be difficult. For example (Figure 1.1 A),
selective substitution of the 5-position of a 1,3-disubstituted benzene is
notoriously hard by traditional chemistry methods, because in order to achieve
such a directing effect, both the existing substitution groups need to be
electron-withdrawing. However, in that case, the aromatic ring is too deactivated
to undergo electrophilic substitution.32 Similarly, substitution of the 5-position of
a 1 ,2,3-trisubstituted benzene (Figure 1.1 B) would require R and R” to be
e'ectron-withdrawing groups. Although in this case R’ could be an
eIectron-releasing group, restoring the reactivity of the aromatic ring towards
electrophilic substitution may not be guaranteed. For another example (Figure

1 - 1 C), traditional functionalization of 1,4-disubstituted benzenes generally occur

at the ortho positions of the stronger electron-releasing group and it is very hard to

twist. This leads to difficulties in functionalizing the ortho positions of sterically
small but electron-withdrawing groups, such as cyano and fluoride. One method
that deviates from this electronics-governed regioselectivity is the
chelation-directed ortho-metallation.3’3 Under such reaction conditions, a
chelating substitutent, regardless of its electronic nature, will direct the incoming
group to its ortho positions, and therefore be able to potentially turn some
traditional meta directors into ortho directors. This complements the traditional
substitution chemistry in some cases, yet still does not provide for access to other

problematic substitution patterns, such as the one shown in Figure 1.1 A.

Figure 1 . 1 Difficult aromatic substitution tasks for traditional chemistry

. R RL
R \./\\\/ R R \ R" ‘\
K/ I / / /’ I \
I i
I RS
A B C

C—H borylation, on the other hand, operates largely with a sterics-directed
r egioselectivity. While the electronic effects of the substituents will affect the rate
of the borylation,14'15'34 borylation of aromatic substrates generally occurs at the
IeFast hindered positions, regardless of the electronic nature of the existing
SUbstitution groups. Therefore, this unique regioselectivity complements both
the traditional substitution chemistry and the ortho-metallation methods, and is

particularly suitable for substitution at the difficult meta/para positions. Taking

the same example into consideration (vide supra), selective substitution of the
5-position of a 1,3-disubstituted benzene is now straightforward (Figure 1.1 A),
because the 5-position is the most sterically accessible position. Selective
functionalization at the 2-position of 4-substituted fluorobenzenes or benzonitriles
is also straightforward (Figure 1.1 C),14d because such positions are relatively less
sterically demanding compared with the other positions. Thus, C—H borylation
can be used to synthesize aromatic chemical products whose substitution
patterns prohibit their traditional syntheses.
1 -3 Potential Synthetic Applications of Catalytic Aromatic C—H Borylation
Synthetically, the activation of aromatic C—H bonds, if used in combination
with subsequent chemical events, may serve as efficient methods for rapid
preparation of diversely functionalized, pharmaceutically important aromatic
building blocks with substitution patterns difficult to achieve by other means. The
SYnthetic utility of this method is highlighted by the functional group compatibility
0f the catalytic aromatic C—H borylation.1“°""15b In fact, ethers, esters, amides,
amines, cyanos, and halides are all well tolerated in the borylation step, allowing
densely functionalized products to be quickly assembled. Moreover, this
'r‘Catalyzed aromatic C—H borylation is generally clean and the only byproduct is
“Yd rogen gas, which allows the subsequent reactions to be performed on crude

rhaterials without isolation and purification of the boronic ester intermediates.

1O

This telescoping-reaction technique can further improve the throughput and the
overall efficiency of the reaction combinations.

There are two ways of applying this catalytic aromatic C—H borylation to the
construction of aromatic building blocks (Scheme 1.5). One way is to borylate a
substituted aromatic substrate, and transform the boronic ester into other

functional groups, thus achieving an overall C—H functionalization. The other
way is to utilize the halide tolerance of this C—H borylation and transform the
pre-existing halide on the aromatic substrates to other groups after the borylation

step. Should the boryl group stay intact in the second elaboration, this method

Scheme 1.5 Possible synthetic applications of lr—catalyzed aromatic C-H borylation

C-D bond formation

 

 

 

 

   
  

 

 

2
CO bond formation R1 j R3 C-C bond formation
1 ' 3 ' / R \ ‘\ .R
R W/R \I/\/
I .
Ar'
OH . . Ideuteration
oxdiation
fin- ,_-, _ Suzuki
R2 l R2 R2
R1\«/~\¥R3 lr cat. AI R \(\«R R3=hal *7 R \WNRZ
\/ HBpin or szinz . \f/J Amination \7
l ' ‘ .
H I Bpin 3_ Bpin
R3=hal R "03' ON bond formation
Sonogashira R3=I Amidation
2 _ .
1\/R\/R C 8 coupling R2
R . \ R2 RK/WNHCOR
i! /I 1 ; f
Bpin . V Bpin
0’6 bond formation Bpin C-N bond formation

C-S bond formation

11

 

 

would allow the rapid formation of highly functionalized aromatic boronic esters

with substitution patterns not straightforward to achieve by traditional chemistry.

12

Chapter 2. The C—H Borylation/Oxidation Approach for the Preparation of
meta-Substituted Phenols
2.1 Phenols and Their Preparations
Phenols and phenolic derivatives, both synthetic and natural, are ubiquitous.35
Phenols serve as resin monomers, surfactants, and antioxidants.36 They have
also gained significant attention for their toxicity, radical scavenging activity, metal
binding activity, and physical organic properties.‘°‘7 Combinatorial libraries have
been built around them,38 synthetic methods use them as starting materials,39 and
the construction of many macromolecules, natural products, and pharmaceuticals
use phenols as synthetic intermediates.40 For these reasons, phenol
preparations have evolved over decades.“42
Traditional phenol preparation methods are vast, ranging from oxidations to
Substitutions, from rearrangements to annulations. Oxidation methods use aryl
metallic species, such as aryl silanes, lithiums, or boronic acids/esters as
Substrates for oxidation.43 These methods necessitate the preparation of
COrresponding precursors ultimately from aryl halides. Thus they are lengthy
and may be limited by the availability of such halides, as well as the problems
associated with the preparation of these precursors such as reactive intermediate

generation and functional group tolerance. Substitution methods use either

diazonium salts or halides for formal hydrolysis.44 Obviously, the former case

13

deals with hazardous materials, and the latter case deals with harsh reaction
conditions. Rearrangement methods include classic examples of benzylic
hydroperoxide rearrangements and Bayer-Villiger rearrangements (followed by
hydrolysis in this case),45 as well as newer cyclodienone rearrangements.46
These methods do not need halides as precursors but certainly need the
presence of other groups. In fact, except for very few examples,” all the
methods mentioned above only transform an existing group to the hydroxyl group
of phenols. Therefore, using these traditional methods, a substituted phenol
must come from a precursor with an equally difficult (or simple) substitution
pattern. Hence, they are limited to the availability of such corresponding starting
materials. As a result, the preparation of some phenols, even those with
seemingly Simple structures, can be unimaginably hard. This is illustrated by the
preparation of 3-bromo-5-chlorophenol (2.3a), a structurally simple molecule.
The only literature preparations traced back about 80 years and called for a
1 O-step route starting from TNT (Scheme 2.1)!48
Understanding these limitations, another class of phenol preparations has
been developed. They start with acyclic molecules and through different
CYCIization-aromatization methods, build up the benzene rings. Such examples
inelude classic cyclization of polyketones or polyketo-esters,41 the Wulff-Dotz

behzannulation“9 and other [m+n+p] annulation methods, as well as

14

electrocyclization methods.‘50 These methods are exceptionally good at
preparing highly substituted phenols and are not confined by the directing effects
of traditional aromatic substitutions. Unfortunately however, they generally

require multiple steps to prepare the precursors and thus are low in overall
throughput and efficiency. Therefore, the demand for a rapid, efficient, scalable,
and operation-friendly method to prepare phenols with difficult substitution
patterns is still high.

Scheme 2.1 A traditional preparation of 3-bromo-5-chlorophenol
Me

 

t o N NO 0 N NH
OZNWNOZTT—T 2 W 21.NaZS.Et0H_ 2 W 2
K? ——> V” 2. HCI ' \7

NO2 OMe OMe

 

O N Br H N Br
Sandmeyer protoccl 2 \l \ Sn, HCl 2 CF H2804

 

/
OMe OMe
H2N \ Br Cl 1| \ Br
k/ Sandmeyer protocoLr l /
’ l
I OH
OH 2.3a

 

2-2 Applications of Catalytic Aromatic C-H Borylation in Phenol Synthesis
and Initial Studies

As mentioned in Chapter 1, the catalytic aromatic C—H borylation is
particularly good at making aromatic building blocks having othenivise difficult

SL1 bstitution patterns, especially all meta-substituted benzenes. In addition, the

15

 

C—H borylation generates a boronic ester group, which are known to be oxidized

to phenols.“3d'e

Therefore, it could be envisioned that treatment of the C—H
borylation product with an appropriate oxidant should be able to afford a hydroxyl
group at a position where the 0—H borylation occurs (Scheme 2.2). Furthermore,
since the borylation step is clean enough to allow subsequent reactions to occur
on crude reaction mixtures, it might be possible to telescope the 0-H borylation
with the oxidation step in the same reaction vessel. This overall process would
constitute a one-pot, highly efficient protocol to convert a substituted benzene to a
substituted phenol with a net hydroxyl group installation at the most sterically
open position. The good functional group tolerance of C—H borylation and the
efficiency to eliminate the intermediate isolation might allow this method to be
extended to high-throughput screening and large-scale processes. Therefore,
this protocol would represent a most direct route to numerous structurally simple
phenols, especially meta-substituted, densely functionalized phenols, whose

practical use may be currently limited by their accessibility.

Scheme 2.2 Proposed one-pot C-H borylation/oxidation protocol for preparation of phenols

2
1 . 3 lr-cat.,|igand, l 1 R 3] 1 32 3
RWw/R HBpin or szinzt RWR ; [o] RWR

 

i
b Borylation ' \/ ‘ Oxidation v
i g .
H |_ Bpin J OH
2.1 2.2 2.3

Literature reveals two practical methods to oxidize aryl boronic acids/esters.

16

One uses hydrogen peroxide as the oxidant43a while the other calls for oxone.43d
We favored the oxone oxidation for a number of reasons. First, the reported
conditions for hydrogen peroxide oxidation do not cover boronic esters, whereas
the oxone oxidation does. Secondly, the reaction time can be shortened from
hours for hydrogen peroxide to minutes for oxone. Lastly, unlike hydrogen
peroxide, oxone is a solid that is easy to handle and poses no storage issues.
However, the reported oxone oxidation conditions were far from being considered
friendly. They use 0.9 equiv oxone in a 0.4 mmol/L EDTA aqueous solution with
10~15% acetone, 1.5 equiv NaOH, and ~42 equiv NaH003 as buffer, at 2 °C for 5
min. The details of this operationally complicated procedure suggest the
involvement of the highly reactive transient oxidant dimethyldioxirane51 (DMDO)
in this process. DMDO, normally generated in situ from the reaction of oxone
and acetone, is a strong oxidant and has been demonstrated as a versatile
reagent for oxidation chemistry. Yet its generation has to be controlled rigorously
at low temperature within a narrow pH range. The oxone oxidation conditions
mentioned above may possibly be needed to insure the generation of DMDO.

As we first demonstrated that the oxidation could be carried out on crude
borylation mixtures and no isolation and purification of the aryl boronic esters
were needed, the literature procedure gave reproducible yields in our hands.

This problem, as well as the complicated procedure and the elaborate oxidation

17

system, triggered us to simplify the reported conditions. EDTA was first found to
be dispensable, and more work was targeted at identifying the necessity for other
additives and controlling factors. As listed in Table 2.1, we found that almost
everything in the reported reaction conditions was unnecessary. The oxidation
did not require EDTA, did not require NaOH, and did not need NaHC03 as buffer.
Temperature control was also unnecessary.52 Interestingly enough, however,

contrary to the literature report, the acetone/water ratio was a critical parameter in

Table 2.1 Initial study of reaction conditions for oxone oxidation

 

 

 

 

2 mol%
C'YVC' “fittings: lC'WC'l W
V neat, 150 °C > £ V } acetone/water, rt> v
H L Bpin J OH
2.1b 2.2b 2.3b
Entry Base Buffer Temperaturec Acetone/water ratio °/o Yieldd
useda used” V/ V
1 Yes Yes 0 °C 0 (0)
2 Yes Yes 0 °C 0221 (43)
3 Yes Yes 0 °C 04:1 (98)
4 Yes Yes 0 °C 0.621 (100)
5 Yes Yes 0 °C 1:1 (100)
6 Yes No 0 °C 0221 (57)
7 Yes No 0 °C 04:1 (94)
8 Yes No 0 °C 1:1 (100)
9 Yes Yes 0 °C 1 :1 81
10 Yes No 0 °C 1:1 78
11 No No 0 °C 1:1 78
12 No No rt 1:1 81

 

All reactions were run in 1 mmol scale. a 1.5 equiv NaOH. b ~42 equiv NaHCOa. ° 15 min for 0
°C reaction, and 7 min for room temperature reaction. d Isolated yields; GC yields (internal
standard) listed in parenthesis.

18

our reactions. In order to reproducibly obtain full conversions, a ratio of at least
0.4:1 of acetone/water is needed. We chose 1:1 as our standard conditions.

In summary, this modified oxidation protocol was greatly simplified and easy
to operate. However, it raised an elementary question regarding to the
mechanism of the oxidation, namely, whether DMDO is indeed generated and
participating in the oxidation. This question will be addressed in Section 2.4.

2.3 Substrate Study53

Having developed the optimized oxidation conditions, we next screened a
variety of substituted arenes in the one-pot C—H borylation/oxidation protocol
(Table 2.2). Our standard procedure involves simply heating the arene and
HBpin with (Ind)lr(cod) catalyst and dmpe to 150 °C (or dppe at 100 °C) to
achieve a complete borylation, and treating the cooled crude mixture with acetone
and an aqueous solution of oxone. Such a procedure is easy and timesaving.
In fact, compound 2.3a, previously made from TNT in 10 steps (Scheme 2.1),
could be quickly prepared via our method from 3-chlorobromobenzene 2.1a in
83% yield in a single day (Entry 1). Moreover, a variety of functional groups were
tolerated in this process, including ethers, esters, amines and halides. Thus a
variety of diversely functionalized phenols could be rapidly prepared. In terms of
substitution patterns, our protocol is amendable to 1,3-disubstituted and

1,2,3-trisubstituted benzene substrates, where hydroxyls are installed selectively

19

at the 5-positions. Compound 2.19, a pyridine derivative, could also undergo the
same reaction sequence with similar regioselectivity (Entry 6). This protocol,
therefore, constitutes a general and unified route for preparation of these
meta-substituted phenols. In fact, quite a few phenols such as 2.3h and 2.3q
(Entries 7, 17) had not been reported in the literature.

Table 2.2 C-H Borylation/oxidation protocol for phenol synthesis

 

 

 

 

R2 cat (lnd)lr(cod)-dmpe/dppe [ R2 1 R2
1 w 3 - . 1 3 1 3
R VWR HBpin _ R \IAY’R l oxone _ R WYR
v neat or cylcohexane, 150 °C' . V! f acetone/water, rt' \Z
H L Bpin 1 OH
2.1 2.2 2.3
Entry Starting arene Borylation conditionsa Phenol % Yield”
1 Cl Br 2 equiv HBpin, Cl Br 83
U 3.5 h, 150 °C \Q/
2.1a OH
2.3a
2 Cl CI 1.5 equiv HBpin, Cl CI 80
\©/ 3.5 h, 150 °C 0
2.1b OH
2.3h
2 Br Br 2 equiv HBpin, Br Br 87
\0 18 h, 100 °C U
2 1c OH
2.3c
3 Me Br 1.5 equiv HBpin, Me Br 81
1:} Q
2.1d OH
2.3d
4 MeO CI 2 equiv HBpin, MeO Cl 79
18 h, 150 °C O
2.19 OH
2.3a

 

20

Table 2.2 Continued

 

 

Entry Starting arene Borylation conditionsa Phenol % Yield"
5 M902C CI 1.5 equiv HBpin, MeOZC Cl 70
U 3 h, 150 °C
2.1f OH
2.3f
6 Cl ,N CI 1.5 equiv HBpin, Cl /N CI 64
\ l 3 h, 150 °C \ '
2-19 OH
2.39
7 Cl 2 equiv HBpin, Cl 85
MBUC' 12 h, 150 °c Mega
2.1h OH
2.3h
8 Me 1.5 equiv HBpin, Me 88
Cl\©Cl 12 h, 150 °C CI\©CI
2.1l OH
2.3l
9 OMe 2.5 equiv HBpin, OH 68
CIWCI 16 h, 150 °c Cl Cl
K)
2.1] OH
2.311
10 Me 2.5 equiv HBpin, Me 72
MGUBF 50 h, 100 °c Mega
2.1k OH
2.3k
11 Br 2 equiv HBpin, Br 80
Cl\©/Cl 3.5 h, 150 °C CIQCI
2.1l OH
2.3l

 

21

Table 2.2 Continued

 

 

Entry Starting arene Borylation conditionsa Phenol °/o Yield”
12 CI 1.8 equiv HBpin, CI 89
Cl\©/Cl 3 h, 150 °C CIVK/Cl
by
2.1m OH
2.3m
13 Br 0.25 equiv HBpin, Br 68
F0 3.5 h, 150 °C FQ (based
2.1n OH on
2.3n HBpin)
14° Br 4.5 equiv HBpin, HO Br 74
F0 53 h, 110 °c FQ
2.1n OH
2.3M
15" F 5 equiv HBpin, 1: 51
Q 63 h, 150 °c HO OH
F F F F
2.10 OH
2.30
16 F3C CI 1.5 equiv HBpin, F3C / 1 Cl 80
3.5 h, 150 °C \I
OH
2.1p 2 3p
17 MezN Cl 2 equiv HBpin, MezNQ/C' 79
18 h, 150 °C
OH
2.1q 2.3q

 

All reactions were run in 1 mmol scale. ‘ Borylation used 2 mol% lr and ligand. The time can be
HBpin-batch dependent. See experimental section for full details. b Isolated yields, average of
two runs. (Note: Most phenols were isolated with contamination of solvents, such as acetone or
ether. However, due to the volatility of these phenols, forcing evaporation led to significant
products loss. Thus in that case, yields were calculated by the total weight of the phenols with
contaminants, and the 1H NMR ratio thereof.) ° 5 mol% lr and ligand. d 3 mol% Ir and ligand.

Other substitution patterns were also possible. Since the borylation is

largely sterically directed, the small size of fluorine could be exploited to achieve a

22

C—H borylation on its ortho position(s).54 This could be further manipulated with
stoichiometry adjustment to achieve a mono hydroxylated phenol or a multiple
hydroxylated phenol from the same starting material (Entries 13-14). It should
be noted that phenols such as 2.3n1 and 2.30 were also prepared here for the
first time.

The one-pot borylation/oxidation approach is generally clean and gives the
desired phenol as the only aromatic product, with no protodeborylation or
overoxidation55 detected. That being said, this one-pot protocol still came with
surprises. For example, the oxidizable nitrogens survived the oxidation and no
N-oxides were detected (Entries 6 and 17). Surprisingly enough, it is known that
both DMDO and oxone can oxidize amines or pyridines to their corresponding
N-oxides.56 It is hardly imaginable that such an oxidation did not occur under our
reaction conditions. However, since the oxone oxidation was quenched by
NaHSO3 before workup, it is possible that such a quenching step reduced the
N-oxide back to the corresponding amine. In order to test this hypothesis, we
performed the oxidation of 2.2q in deuterated solvents and then analyzed the
reaction by 1H NMR before and after the quench (Figure 2.1). The methyl
protons in N,N-dimethylaniline and its oxide and hydroxide have been
characterized and reported.57 Thus by comparison with the literature, it might be

clear whether the N-oxide is generated transiently or not.

23

 

 

Figure 2.1 1H NMR analysis of the crude oxidation of 2.2q before and after quench

 

 

 

 

 

 

 

 

 

 

 

OH
MeZN c1 » M N Cl
/ Me N 92 /
\ I oxone 2g C' NaHSO3 |
5 —--—-——->
DZO/acetond-ds \
an OH OH
2.2q 2.3q
O
*
(a) k
.l 1 l W Le“);
erfiIfi—rrv‘vv11‘VIIVIVYTvavYVTv‘V1YITIVvlrvvxlvvrvrrfifiv[Iriv‘vrfi
7.0 60 5.0 4.0 30 2.0
* O
(D)
W l t i
1 T 1 r 1 1' FT Y—TT S ‘ I I F I l ‘ T r I r I 1 r
7.0 5.0 50 40 3.0 20
O
(C)
All A . L
TYYTIYTTTITFT‘rYI‘TIYTIT‘YIITIIva[ivlevrvxIYIrIIItlTT.IIr‘vv
7.0 6.0 5.0 4.0 3.0 2 0
(d) //
*
TFYYTI'T—YTIYYYYIiY‘TTTYYl‘FYV‘IIVVT[Trl’lTrTI‘IYVVYIYYWTIlYT"E7171
7.0 0.0 6.0 4.0 3.0 2.0

(a) Before quench, pH = 10. * = methyl protons in the N-oxide, o = methyl protons in aniline.

(b) Before quench, pH < 4. * = methyl protons in N-hydroxide, o = methyl protons in protonated
(or hydrogen-bonded) aniline.

(c) After quench, organic layer. 0 = methyl protons in aniline.
((1) After quench, aqueous layer. * = methyl protons in N-hydroxide.

Shown in Figure 2.1 (a) and (b), the crude oxidation mixture, before being
quenched, clearly had two sets of signals with approximately equal amounts.

One of them (labeled as “0”) corresponded to the free amine by the chemical shift

24

of the N-methyl protons. The other set (labeled as “*”) showed a significant pH
dependency. In a basic environment (pH 10), the chemical shift of the N-methyl
protons occurred at 3.50, while in an acidic environment (pH 3-4), these proton
signals shifted to 3.93. The exact chemical shifts are consistent with the
literature values for the methyl protons of N,N—dimethylaniline N-oxide and its
N-hydroxide.57 Moreover, the pKa of a tertiary amine N-hydroxide is ~5,58 which
can also explain the migration of this signal with the change of pH. After
quenching the oxidation with NaHSO3, the signal for the N-oxide or the
N-hydroxide disappeared. Thus, it would appear that the reaction conditions
oxidized the nitrogen to its corresponding N-oxide, and the N-oxide was reduced
back to the amine upon quenching the oxidation with NaH803. Nonetheless, it is
unlikely that the N-oxide intermediate can serve as a competing oxidant to convert
the boronic ester into a hydroxyl. A control experiment using an N-oxide (NMO)
as the oxidant failed in this task. In addition, literature precedence clearly
indicates that amine N-oxide oxidation of boronic esters only occurs slowly at
elevated temperatures.59

Another interesting observation was the demethylation of 2.1j (Entry 9, Table
2.2). As previously mentioned, ethers are well-tolerated functional groups in

14,15

both the borylation and the oxidation steps. In fact, the same methyl ether

group in 2.1e survived the borylation/oxidation protocol quite well (Entry 4, Table

25

2.2). That contrast led us to investigate this specific demethylation. As the
borylation step was carefully monitored by GC and GC-MS, it was realized that
the demethylation occurred only after the borylation (Scheme 2.3). Therefore,
isolation of the normal borylation product 22] could be achieved by stopping the
reaction at an early stage (less than 1 h at 150 °C, see experimental section for
details). Subsequent studies confirmed that the demethylation needed both
HBpin and the Ir catalyst. This is indicative of a demethylation via an 8N2 attack
of the methyl group by some lr-bound nucleophile, such as a hydride.60 The
presence of two chlorine atoms as well as the boryl group may help to stabilize
the negative charge of the oxyanion and make it a better leaving group. Further

studies ruled out the possibility that the demethylation occurred during the

oxidation step, as 221' could be oxidized to afford the 4-methoxyphenol 2.3j in

 

98% yield.
Scheme 2.3 investigation of the demethylation of 2.1]

2 mol% . 1
M .
OMe (Ind)lr(cod)—dmpe, l O eCl {Cl (Replgl .
. 2.5e uivHB in CW , \//\/ l
|\ 1 neat, 150 C \7/ continue ; V l
Bpin 1L Bpin J'

2.1] 2.2) 2.211

oxone
acetone/water, rt
68% from 2.1j

oxone
acetone/water. rt
98%

 

 

OMe OH
Cl Cl Cl Cl
l
OH OH
2.3j 2.3j1
26

 

While the borylation has good functional group tolerance, Smith’s original
catalyst (Ind)lr(cod) does not work well with iodobenzenes.14° By virtue of the
higher reactivity of Miyaura, lshiyama and Hartwig’s [lr(OMe)(cod)]2 catalytic
system, borylation could be achieved at room temperature and iodide tolerance
became attainable. Under such conditions, the borylation/oxidation protocol
could be successfully extended to iodobenzene substrates (Table 2.3). It is
noteworthy that 2.35 (Entry 2) was a starting material in the total syntheses of the
anticancer natural products duocarmycin and yatakemycin. In these cases, the

literature preparation of 2.35 consists of a 6-step process from 4-nitrophenol.‘“"61

Table 2.3 C-H Borylation/oxidation protocol for iodinated substrates

 

 

 

 

 

cat.
R2 [lr(OMe)(cod)]2-d'bpy, I R2 122
R1 “ R3 B P' R1\/'\/R3 R1\/'\/R3
.l \ 2 m2 2 I \1 ‘ oxone > I‘ N
" / alkane solvent, rt Kg acetone/water, rt V7
H I - Bpin J (311
R‘ or R2 or R3=| R1 or R2 or R3=| R‘ or R2 or R3=l
2.1 2.2 2.3
Entry Starting arene Borylation conditionsa Phenol % Yield”
1 l Br 0.6 equiv szinz, l Br 76
U m... (j
2.1T OH
2.3r
2 l 1.0 equiv szinz, l 93
Br\©/Br 3 h, rt Br / l Br
\
2.1s OH
2.35

 

All reactions were run in 1 mmol scale. a Borylation used 3 mol% lr. See experimental section
for full details. b Isolated yields, average of two runs.

27

Although such a process could afford 2.35 in a satisfactory 65% overall yield, our
one-pot procedure is much more concise and high-yielding.

While our one-pot C—H borylation/oxidation protocol is efficient at preparing
meta-substituted phenols or phenols with an ortho fluoride, phenols with different
substitution patterns remain elusive. Since the C—H borylation is directed to the
sterically open sites, substrates with more than one sterically open position could
not be functionalized regioselectively. For example, monosubstituted benzenes
generally afford a statistic mixture of meta and para borylated products.
1,2-Disubstituted benzenes bearing different groups also undergo nonselective
borylation at the 4- and 5-positions. Achieving regioselective monoborylation of
these substrates is not straightforward. Therefore, preparing mono-substituted
phenols with a single meta-substituent or 3,4-disubstituted phenols with different
groups at the 3- and 4-positions is not straightforward. Since the C—H borylation
tolerates halides, it is possible to utilize halides as protecting groups to block
certain positions from being borylated. Such halides could be removed by
subsequent Pd-catalyzed hydrodehalogenation reaction with polymethylhydro-
siloxane (PMHS)62. In this manner, preparing mono-substituted phenols with a
single meta-substituent could start from a meta-substituted halobenzene
(Scheme 2.4 A) and reduce the halide after borylation/oxidation. Similarly,

preparing 3,4-disubstituted phenols with different groups at the 3- and 4-positions

28

could start from a 2,3-disubstituted halobenzene (Scheme 2.4 B) and reduce the
halide after borylation/oxidation. Such a combination could further extend the
utility of the borylation/oxidation protocol. By virtue of the extremely low cost of
PMHS (< $8 per mole hydride), these preparations would still remain economical.
For example (Scheme 2.4 C), compound 2.4 cannot be obtained via simple
borylation/oxidation because borylation of fluorobenzene is not regioselective.
However, PMHS-reduction of the bromide in 2.3n1, previously prepared from
2.1n (Entry 14, Table 2.2), was easy and successful, affording 2.4 in good yield.

Scheme 2.4 Combining borylation/oxidation with Pd-cata/yzed PMHS reduction:
access of more phenols

 

 

1 1
R \H/N/Ha' Borylation _ R1\(\/Ha' cat. Pd, PMHS-KF_ R W

 

 

 

.. - - i 1 A
V Oxrdation v V
H OH OH
R2 R2 R2
1 1
R WW“ Borylation A R1y\/Ha' cat. Pd, PMHS-KF_ R W B
V Oxidation ' V V
H OH (511
HO Br HO
W cat. Pd(OAc)2, KF, PMHi \¢\ 0
PW THF/water ,rt ’ F’V
OH 80% OH
2.3111 2.4

2.4 Mechanistic Investigation of Aryl Boronic Ester Oxidation with Oxone
Mentioned previously in Section 2.2, our oxidation conditions questioned the

literature suggestion43d that the oxone oxidation of an aryl boronic ester involves

the in situ formation of DMDO. In order to examine this question, the oxidation

was performed in solvents other than acetone (Table 2.4). These solvents

29

Table 2.4 Solvent study in the oxidation step

 

 

 

 

O f—
1 $2 3 (lnd)lr2(cr2§)l-gmpe, ; 1 82 31'. 1 R2 3
R WR 1.5 equiv HBpin = i R \l/\/R ; oxone AR WR
Y 150 °C . K/ } solvent/water V
H L Bpin J OH
certainly 2.1 2.2 2.3
Entry Substrate Solventa Product Temperature” % Yieldc
1 Cl Cl THF Cl Cl 0 °C 74
2 U CH3CN O 0 °c 82
3 2.1b Dioxane OH rt 79
4 Diglyme 2.3b rt 80
5 CHC|3 0 °C 0
6 c1 CHZCIZ C, rt 0
7" C' / 0112c:2 CI n 44
8 \ I DMF fl rt 85
2.1t OH
2.3t

 

All reactions were run in 1 mmol scale. a 1:1 to water (V/V). b 15 min for 0 °C reaction, and 7
min for room temperature reaction. C Isolated yields. d 25 mol% Bu4Nl was added as phase
transfer catalyst.

could not be used to make DMDO and a successful oxidation in these solvents
would strongly support our hypothesis that DMDO was not the real oxidant.
Indeed, the results indicated that the oxidation did not have to be run in acetone,
as solvents such as THF, dioxane, and DMF proved well suited for this oxidation.
This result argues against the participation of DMDO in the oxidation. On the
other hand, CHch2 and CHC|3 were not good solvents (Entries 5-7), as the
oxidation failed in these two solvents. Interestingly, it seemed that all the

suitable solvents are polar and water-miscible, whereas the unsuitable solvents

are less polar and not water-miscible. As the aryl boronic esters are sparingly

30

soluble in water, particularly in the highly salted aqueous oxone solution, while at
the same time oxone is insoluble in less polar organic solvents such as CHC|3 and
CH20l2, it is reasonable to imagine that the role of the organic solvent is simply to
bring the two reagents into the same phase. To test this hypothesis, the
oxidation in CHZClz was repeated with a phase transfer catalyst (Entry 7). This
time, considerable conversion was observed within the same period of time to
afford the phenol in 44% yield. Therefore, it is very possible that in the oxidation,
the need for a polar, water-miscible organic solvent is simply a solubility issue.
Thus, the oxidation mechanism probably does not involve DMDO. Instead, the
traditional mechanism involving a nucleophilic attack of the peroxy nucleophile to
the boron atom, followed by an aryl transfer (Scheme 2.5) is very likely at work,

which resembles the hydrogen peroxide oxidation of trialkylborane.

Scheme 2. 5 The revised mechanism for the oxone oxidation of an aryl boronic ester

:OM (Ed 0— so2 c3: _\/OB Ar -so42' A/O

' B- o A H 20 Ar OH
_, r____, _
-H® /\OB‘ so—oi> 7L5 -HOBpin

 

To further probe this hypothesis, the reaction was performed with mCPBA as
the oxidant in THF. Like oxone, mCPBA is another nucleophilic oxidant with an
internal leaving group. As expected, we found that mCPBA could oxidize the
boronic ester intermediate to the corresponding phenol in 69% yield. That again

supports the hypothesized mechanism shown in Scheme 2.5. It should also be

31

noted that distilled DMDO (acetone solution) was unable to perform the oxidation,
which strongly disfavors the involvement of DMDO in the oxidation step.
2.5 Conclusions

In conclusion, we have developed an efficient one-pot C—H
borylation/oxidation protocol to prepare meta-substituted phenols directly from
arenes without isolation of the boronic ester intermediates. This protocol is
complementary to traditional methods, and is particularly suitable for preparation
of phenols with substitution patterns hard to access through traditional methods.

The oxidation does not involve the formation of DMDO.

32

Chapter 3. The C-H Borylation/Oxidation Study of Aromatic Amino Acids
Derivatives and Analogues
3.1 Aromatic Amino Acids and the Potential C—H Borylation Investigation
Aromatic amino acids, including phenylalanine, tyrosine, histidine and
tryptophan, are important building blocks for peptides, natural products and
pharmaceuticals.63 Although bearing different aromatic rings, these molecules
can be viewed as substituted arenes. Therefore, they are interesting substrates
for the C—H borylation chemistry. In fact, certain boronic acids derived from
these amino acids, such as 4-boronophenylalanine (4-BPA), are very important
radiotherapeutical agents64 due to the neutron capture nature of 10B. In addition,
certain hydroxylated amino acids, such as 5-hydroxytryptophan and meta-tyrosine,
are important bioactive compounds.65 Access to these compounds may be
straightfonivard via our C—H borylation (or borylation/oxidation), even though their
efficient preparation with traditional chemistry may be difficult. In fact, the most
efficient preparation of 4-BPA is a multiple-step process from tyrosine.66 The
synthesis involves triflation of the phenol hydroxyl group followed by Pd-catalyzed
borylation of the triflate31 as key steps. The direct preparations of hydroxylated
tryptophans and phenylalanines are also limited.67 Most of the existing methods,
ironically, start from an aromatic precursor and construct the amino acid moiety

later,66‘3‘e instead of modifying an aromatic moiety with the amino acid functionality

33

68 9
d ,6b

pre-installe . For example, 4-fluoro-meta-tyrosine is a biochemical probe of

striatal dopaminergic function and has attracted significant attentionfsg“1 yet its

current synthesis requires arduous multiple-step processessgb'e (Scheme 3.1).

Scheme 3.1 Literature preparation of 4-fluoro-meta-tyrosine

1. TBSCI, Imid

2. sec-BuLi, then B(OMe)3 /
MOH 3 HOAc H202 MOH

. \, Br
I . . , _ H SOBrz, py ¥ U
FM 4. KF, Mel , F / 35% T 1: ./

60% overall OMe OMe

NBoc
COZH
0,08” 1. LDA ML: >48” __> m
0:";8 >‘ \BF%FVO~1OO% FV NHZ

1‘ / OMeO OH
We 78%

 

 

 

F

Due to this limitation, direct and rapid synthesis of those biologically
interesting hydroxylated amino acids for SAR or combinatorial studies is hard to
realize. Therefore, development of a method that can directly functionalize the
aromatic moiety of the amino acids is needed. We proposed that the catalytic
borylation would serve this purpose. Putting this chemistry into practice, we
should gain easy and rapid access to not only the borono/boryl and hydroxyl
aromatic amino acids, but also other diverse functionalized derivatives.

On the other hand, although the C—H borylation has been studied extensively
for simple substituted arenes with various substitution groups and patterns, this
reaction has not been well developed with more complicated substrates such as

these aromatic amino acids. Exactly how the functionalized side chain of the

34

amino acids would respond to the borylation was not known. Should the
borylation of the aromatic amino acids be successful, the scope of C—H borylation
would be significantly expanded and further information on reaction condition
modifications and catalyst designs could be obtained.

3.2 Study of Substituted Phenylalanine Derivatives and Analogues

Since the catalytic borylation has been studied most extensively on
substituted benzenes, our initial plan was to use substituted phenylalanines as
substrates. 3-Chlorophenylalanine was chosen as the test substrate due to its
commercial availability and the presence of an electron-withdrawing group, which
would hopefully accelerate the borylation. We first investigated the protecting
group choice of the amine and carboxylate.

The protection of amino acids has been extensively studied,703 and two main
methods of protection are available. Joint protection of both the amine and the
acid with a single protecting group is one option, and individual protection with two
different protecting groups is another common strategy. An operationally easy
joint protection uses 9--BBN,7°"'c the presence of which is also reported to increase
the solubility of amino acids in organic solvents. Thus, the 9-BBN-derived
3-chlorophenylalanine 3.1a was prepared and subjected to the C—H borylation
conditions using the more reactive [lr(OMe)(cod)]2 catalytic system (Scheme 3.2).

Two problems were quickly realized. First, 3.1a was still not soluble in standard

35

C—H borylation solvents, namely alkanes or cycloalkanes, thus a more polar
solvent such as THF had to be used. Second, the reaction of 3.1a was
extremely sluggish. Mild heating at 45 °C for 14 h did not lead to any observable
borylation with 3 mol% lr catalyst. Compared with simple arene substrates,15b
this behavior could be evaluated as “unreactive”. Since microwave irradiation
can be a much more effective heating method,71 borylation of 3.1a was then
studied under microwave conditions. Still, only low conversion (37%") was
observed with 6 mol% lr catalyst after 20 min of irradiation at 120 °C.

Given these poor results, a different protection strategy was pursued. The
individual protection method provided an N-Boc amino acid methyl ester 3.1b. .
This substrate was soluble in cyclohexane, the standard solvent for catalytic
borylation. Gratefully, 3.1b reacted much faster than 3.1a, giving full conversion
under the same microwave conditions (Scheme 3.3). The reaction conditions
could be further improved in terms of catalyst loading and reaction times without
impairment of conversion. Thus, conditions with half of the Ir loading (3 mol%)
and half of the microwave irradiation time (10 min) allowed a virtually complete
borylation of 3.1b. Upon isolation, the product was identified as the desired
5-borylated 3.2b. Control experiments demonstrated that the borylation failed
with the unprotected acid, and gave complex mixtures with the unprotected

amine.

36

Scheme 3.2 Q-BBN-den'ved 3-chlorophenylalaine and its borylation

 

0
Cl
CIWfi/COZH 9,33,.) [\ 0
fly NH2 THF.rt ' / H2853?
700/0 -—/\\
3.1a W
o O

Cl

 

CI 1’
0 l ,0
v \ B ' \.
pin
3.1.. 6% 3.2.. W

1.5 mol% [lr(OMe)(cod)]2, 3 mol% d'bpy,
1.5 equiv szinz, THF, 45 °C, 14 h

3 mol% [lr(OMe)(cod)]2, 6 mol% d‘bpy, 37% conversion
1.5 equiv szinz, THF, w, 120 °c, 20 min (see ref 72)

 

No conversion

 

Scheme 3.3 N—Boc 3-chloropheny/alaine methyl ester and its borylation

 

 

 

Cl 1 \. COZH TMSCHN2 : Cl . \. COzMe
K) NHBoc MeOH/PhH. rt v NHBoc
1000/0 3.1b
c1 \ 002Me C'WCOZMe
l >
1 / NHBoc : NHBoc
3.1b Bpin 3.2b
O o t
1 3 mol /0 [lr(OMe)(cod)]2, 6 mol /0 d bpy, 100% conversion
1.5 equiv szinz, CyH, pW, 120 °C, 20 min
0 o t 97% conversion
2 1.5 mol /0 [lr(OMe)(cod)]2, 3 mol /0 d bpy, (see ref 72)

1.2 equiv szinz, CyH, uW. 120 °C. 10 min 80% isolated

 

The successful borylation of 3.1b demonstrated the viability of the borylation
on amino acid derivatives. It also demonstrated the importance of the protecting
group choice on such borylations. On the basis of this success, we investigated
other substituted phenylalanine substrates in the form of N-Boc amino acid methyl

esters.

37

Surprisingly enough, it was quickly realized that the successful borylation
conditions for 3.1b (Entry 2, Scheme 3.3) worked only for 3.1b itself. Other
substrates such as the 3-trifluoromethyl analogue 3.1c and 3-cyano analogue
3.1d (see Table 3.1 for structures) could not be completely borylated under the
same conditions. It was also found that in order to achieve higher conversions, it
was better to increase the loading of Ir catalyst rather than increase the reaction
time. This may be indicative of the catalytic species undergoing some type of
decomposition under the reaction conditions. Unfortunately, when the catalyst
loading, as well as the loading of nginz, increased, isolation and purification of
the corresponding boronic ester products became very difficult. The product tails
significantly on silica gel chromatography, making removal of the szinz
byproducts and the d’bpy ligand hard to achieve. Reverse phase HPLC was also
unsuccessful at this task. However, since the boronic pinacol ester can be
transformed in its crude form to the corresponding, but isolable (by reverse phase
HPLC), boronic acid in the same pot,683'° we believe that this problem of
separation is not without a solution.

Having developed successful borylation conditions, we attempted to further
utilize this reaction, as well as the boronic ester intermediates, toward preparation
of more amino acids derivatives. Our attention then shifted to applying the

one-pot C—H borylation/oxidation, discussed in Chapter 2, to these phenylalanine

38

derivatives to obtain tyrosine derivatives and analogues.

Thus the crude

borylation mixture was treated with acetone and oxone. To our pleasure, the

corresponding hydroxyl phenylalanine derivatives could be generated and

isolated in satisfactory yields for a scope of substrates (.Table 3.1).

The substrate screening revealed valuable information.

As seen in Table 3.1,

the borylation has a reasonable substrate scope for these phenylalanine

derivatives and analogues.

That said, substrates having electron-withdrawing

Table 3.1 C-H Borylation/oxidation protocol to phenylalanine derivatives and analogues

R COzMe R
m cat. [lr(OMe)(cod)]2-d'bpy, szin2‘ 1 m 1

cyclohexane, uW,

NHBoc
Y

 

C02M91

\y NHBoc ’
l

 

 

3'1 120 °C, 10 min 1 Bpin 3.2 1
oxone ~ RmCOZMe
acetone/water, rt 7 \71 NHBoc
OH 3.3
Entry Starting material Borylation Product” %
conditions“ Yield6
1 Cl CO2Me 3 mol% lr Cl CO2Me 7O
NHBoc 1.2 equiv szinz mHBoc
3.1b OH 3.3b
2 F30 002Me 9 mol% lr F30 cone 55
NHBoc 2.0 equiv szinz mHBoc
3.1c OH 3.3c
3 NC COzMe 7 mol% lr NC COzMe 77
NHBoc 1.75 equiv szinz NHBoc
3.1d OH 3.3d
4 F COzMe 8 mol% Ir F COzMe 79
Fjij/\l‘\lHBoc 1.75 equiv szinz FmHBOC
3.1e OH 3.3e

 

39

Table 3.1 Continued

 

 

Entry Starting material Borylation Product” %
conditionsa Yieldc
d
5 F cone 3 mol% lr F COzMe 48
F NHBoc 1.5 equiv szinz F NHBoc
3.1f 0H 3.3f
CO M e
6 2 e 6 mol% Ir . 002MG 44
F NHBoc 1.25 equnv nginz mHBoc
3.19 F
OH 3.39
7 Cl 3 mol% Ir Cl 71
mmzm 1.5 equiv szinz mCOzMe
Cl NHBoc HO Cl NHBoc
3.1h 3.3h
I
8 N \ COzMe 15 mol% ll’ N \ COzMe 36
2. . .
/ NHBoc 0 equw szinz wHBoc
3.1l
0“ 3.31
9
9 Me COZMe 15 ”1.0% Ir. Me COzMe O
mHBoc 2'0 equuv 82pm?" mHBoc
3.1] OH 3.3]

 

All reactions were run in 0.5 mmol scale. a All borylations gave > 90% conversion under the
specific conditions, unless otherwise indicated in experimental section. b The stereochemistry of
products were not determined. ° Isolated yields. ‘9 20% starting material recovered. d 9%
3,5-dihydroxyl product was also isolated. Attempt to obtain this dihydroxyl compound as major
product experienced unsuccessful oxidation. ' Reaction was run in THF and product was isolated
as a TFA salt. " Borylation of this substrate gave 43% conversion at 140 °C, but oxidation on
crude material failed to give any phenolic product.

groups seem to have higher reactivity and likelihood for successful
borylation/oxidation. An electron-releasing group on the aromatic ring, such as
in 3.1], significantly slowed the reaction (Entry 9). Notably, although the

reactions were performed at 120 °C, functional group tolerance was still

40

maintained. Not only did the protected amino acid side chains survive the
reaction, other groups on the aromatic ring, such as the cyano group (Entry 3)
also survived quite well. Regretfully, we did not examine the stereochemistry of
the products, and therefore, the response of the stereogenic centers on the amino
acid side chains to the borylation remains unknown.

The small size of fluorine, again, can be exploited to allow borylation to occur
at its ortho position (Entries 4-6). This reaction could also be applicable to a
B-amino acid derivative such as 3.1f (Entry 5). While most substrates are
3-substituted phenylalanines, a 2,6-disubstituted phenylalanine can be selectively
functionalized at 4-position (Entry 7). Heterocyclic substrates, such as 3.1i
(Entry 8) can also react, albeit under more forcing borylation conditions.
Compound 3.39, a protected version of 4-fiuoro-meta-tyrosine (see Scheme 3.1),
can be readily prepared in acceptable yield directly from commercially available
4-fluorophenylalanine.

In terms of solvents for the borylation, it was found that substrates that are
insoluble in cyclohexane could be successfully borylated in THF (Entry 8).
Although control experiments showed that the same borylation occurs more
slowly in ethereal solvents than in alkane solvents, the introduction of ethereal
solvents to borylation is still beneficial, because our previous solution to the

insoluble substrates was to use fairly expensive HBpin as the solvent.

41

 

3.3 Study of 5-Membered Phenylalanine Analogues

While phenylalanine derivatives and its 6-membered heterocyclic analogue
work well under the C—H borylation conditions, the reactivity of the 5-membered
analogues remained unexplored. Previous literature and experience suggested
that the 5-membered heteroaromatics react faster toward the borylation and are
generally borylated at the oc-positions.17 Thus, a brief survey was conducted to
include various thiophenylalanine, furylalanine derivatives, and etc (Scheme 3.4).

Although the results are very preliminary, the data are interesting. A
thiophene substituted by an a-amino acid side chain at the a-position (3.4a) could
be smoothly monoborylated at the other a—position to afford 3.5a, whereas a
thiophene substituted by a B-amino acid side chain at the B-position (3.4b) could
be smoothly diborylated at both a-positions to afford 3.5b. Somewhat
surprisingly, although crude 3.5a was accompanied with ~10% diborylation
byproduct, pushing the reaction conditions to achieve full diborylation of 3.4a was
not achieved. On the contrary, attempts to stop the borylation of 3.4b at the
monoborylation stage also failed, resulting in the formation of a mixture of starting
material, two monoborylation products, and 3.5b. This difference is more likely
due to the higher reactivity of the a-position of thiophene toward the borylation,
rather than the difference in the amino acid side chains, because 3.4c, having a

B-amino acid side chain at the a-position, could not be fully diborylated either.

42

That being said, for these 5-membered substrates, the significant conversion to
the second borylation, especially on the ortho position of a sterically demanding
alkyl chain, was considerably different from the behavior of the 6-membered
aromatic substrates. The elevated reactivity of thiophene toward the borylation,
as well as the difference in ring sizes,73 may be possible explanations of this

observation that is not seen in 6—membered rings.

Scheme 3.4 Borylation of 5-membered phenylalanine analogues

1.5 mol% [lr(OMe)(cod)]2,
3 co Me 3 mol% d'bpy, 1.1 equiv szinz Bpin co Me
< \/\r 2 ‘ \/\ SW 2

 

 

L4 NHBoc CyH, w, 120 °c, 10 min ' NHBoc
3.4a 79% 3.5a
3 mol% [lr(OMe)(cod)]2.
['MCOZM‘B 6 mol% d‘bpy,1.75 equiv B2pin2 WCOZMe
( NHB ,, X k NHBoc
s) cc CyH uw, 120 c 10min Bpin s 3pm
3.4b 3.5b

7.5 mol% [lr(OMe)(cod)]2.

(SWCOZMe 15 mol% dtbpy. 2-50 equiv 3.29102: 3:7 monoborylation:diborylation

L-J NHBoc CyH, pW, 120 C, 10 min (HPLC, uncalibrated)
3.46

3 mol% [lr(OMe)(cod)]2,

6 mol% d'bpy. 1.5 equiv szinz 7:3 monobo lation:dibo lation
\\ OWYCOZMe _ ry W

 

 

NHBoc CyH, uW, 120 °C, 10 min ' (HPLC, uncalibrated)
3.4d
4.5 mol% [lr(OMe)(cod)]2,
N , 002MB 9 mol% d'bpy, 1.75 equiv szinz‘ _
(s) NHBoc THF, uw, 140 °C, 10 min ’ N0 react'on
3.4a

Nonetheless, it was found that different aromatic structures resulted in
different reactivity. The furan ring in 3.4d was not borylated as selectively as

3.4a and 3.4c. In fact, under the specific conditions shown in Scheme 3.4, 3.4d

43

afforded two isomeric monoborylation products (ca. 1.8:1), as well as a
diborylation product. Such a difference in reactivities between furan and
thiophene had not previously been observed to this extent in simple substrates.
In addition, a thiazole substrate 3.4e did not give any observable product.

The one-pot C—H borylation/oxidation of these heteroaromatic substrates was
even more unexpected (Scheme 3.5). First of all, complete oxidation of 3.5a and
3.5b required more oxone than the oxidation of simple arenes. Using 1 equiv of
oxone simply led to incomplete consumption of 3.5a and 3.5b. Secondly, neither
of these substrates afforded the expected hydroxylated product or its keto
tautomer. Oxidation of crude 3.5a revealed the dimerized 3.6a as the only
observed product by HPLC, while oxidation of crude 3.5b afforded the
overoxidized 3.6b with only small amount of dimer (ca. 8%). We reasoned that
the formation of 3.6a might involve the transient generation of the hydroxyl
intermediate, since 2-boronothiophene was known to be oxidized by hydrogen

t’74a

peroxide to afford the 2-hydroxythiophene produc and at the same time 5-

Scheme 3.5 Borylation/oxidation of 5-membered phenylalanine analogues

 

O S/ COzMe
S COzMe 1 Borylation - -
. . > NHBoc
KW 2. oxone, acetone/water. rt I l_\lHBoc

 

NHBoc .
3.4a 33% 2 steps OASMCOZMe
3.6a
// \ COzMe 1. Borylation _ /_. COZMe
KS ‘ NHBOC 2. oxone, acetone/water, rt OASXONHBOC

3.4b 43% 2 steps 3.6b

44

alkyl-2-hydroxythiophene is also known to undergo the same oxidative
dimerization to generate products resembling 3.6a.74b'c

3.4 Study of a Tryptophan Derivative

Scheme 3.6 Boy/ation/oxidation of a tryptophan derivative

 

/ \ COzH 1. Boc20, NaHCOa, HZO/CHSCN, rt / \\ cone
F , 2. TMSCHNZ, PhH/MeOH, rt F [W
__ ‘\ NH2 :7 m fl NHBOC
N 3. BOCzo, DMAP, CH3CN, rt N
H 3.7a 79% overall 806 3,71:

6 mol% [lr(OMe)(cod)]2, r PinB 7

12 mol% d'bpy, 2 equiv. szinZ; F--- / \ \(COZMe ll NalO4, NH4OAc

 

 

 

CyH, 11W, 120 °C, 10min, i “ j NHBoc l acetone/water, rt ;
76% conversion L B ,N l 43 %
00 3.8a .

OH

“0’3 HO —— COZMe
F- {.7 \ {CO2Me oxone : F / \ ff
\— J NHBoc acetone/water ‘_ N ) NHBOC
.N 80% B ,
Bed 3.3:: °C 3.9

Our attention was then turned to a tryptophan derivative (Scheme 3.6). To our
delight, after global protection of commercially available 6-fluorotryptophan 3.7a,
3.7b could be smoothly borylated, albeit in lowered 76% conversion. Isolation of
3.8a from the crude reaction mixture was not successful, but 3.8a could be
converted into the corresponding isolable boronic acid 3.8b. Oxidation of pure
3.8b successfully afforded the corresponding hydroxyl product 3.9 in good yield.
However, as the 7-position in unprotected indole is also available for

borylation,17"'f the borylation of 3.7b would possibly occur at either the 5-position

45

or the 7-position. Therefore, the unambiguous assignment of regioselectivity of

this borylation remains elusive.”76

A temporary assignment as the 5-borylated
product has been proposed based on the absence of two doublets of doublets in
1H NMR (due to JH-F coupling), as well as the empirical calculation of 13C NMR

chemical shifts (Figure 3.1). Clearly, more work needs to be done with regards

to the structural assignment.

Figure 3.1 Empirical calculation of the 13C NMR chemical shifts and structural assignment

 

HO
COzMe ~ COzMe
——< j NHBoc >1— \ NHBOC Observed
iv HO ,N
Boc Boc
C5 138 110 141
ca 140 140 150
C7 99 127 103

3.5 Conclusions

In conclusion, we have demonstrated that the C—H borylation chemistry can
be extended to aromatic amino acid derivatives, especially phenylalanine and
tryptophan derivatives and analogues, under microwave irradiation conditions.
The one-pot C—H borylation/oxidation protocol is also viable to certain
phenylalanine derivatives and analogues. However, 5-membered phenylalanine
analogues undergo overborylation and overoxidation. As these results are only

preliminary, more work in this area is certainly needed to further understand the

46

chemistry and the behavior of questionable substrates.

47

Chapter 4. The C—H Borylation/Deuteration Approach for the Preparation of
Specifically Deuterated Aromatics
4.1 Specifically Deuterated Aromatics and Their Preparations

lsotopically labeled compounds,77 including those labeled at specific positions,
are widely used as probes for spectroscopy,78 reaction mechanisms,79
phan'nacokinetics, and enzymology.80 Deuterated or tritiated compounds are of
particular interest since they are easier to prepare and relatively less expensive
than the corresponding 13C or 14C-labeled compounds. Deuterium also has a
larger kinetic isotope effect versus hydrogen, compared with 13C versus 12C.81
As the need for specifically labeled compounds grows, ready incorporation of
deuterium atoms at specific positions, on aromatic rings for instance, in good yield
and with high incorporation becomes increasingly important. Ideally, isotopic
incorporation methods would be more attractive if they can be applied at the late
stage of a synthesis. In such cases, however, functional group compatibility and
good regioselectivity become important factors.

Traditional deuteration methods such as acid-, base- or transition

77,82

metal-promoted direct H/D exchange methods often suffer from harsh

conditions, incomplete deuterium incorporation and relatively poor regioselectivity,

and are therefore more useful for global deuteration of insensitive substrates.82d'e

780.79.83

Deuteriolysis of organometallic compounds and reduction of

48

organohalogen compounds84 by deuteride or its equivalents are among the most
important and most used methods to generate site-specifically deuterated
compounds. However, the necessary preparation of the halide precursors and
functional group compatibility retard their use. This is particularly true if the
halide precursor is either equipped with sensitive functional groups or, in case of
an aromatic halide precursor, bearing substitution patterns contrary to the
electronic directing effects. Another drawback of Grignard deuteriolysis is the
lowered deuterium incorporation (~80% is not uncommon), attributed to the partial
H radical abstraction from the solvent by the Grignard reagent.79'83
Consequently, direct H/D exchanges or one-pot deuteration methods without
these drawbacks would be attractive. In this regard, transition metal catalysts,
such as the Felkin-Crabtree catalyst ([Ir(PCy3)(py)(cod)][PF5]) are known to
catalyze the direct H/D exchange of a variety of substrates at the positions that
are accessible to the metal center via an internal coordination.85 Such
chelation-directed metalation methods can be regioselective toward the ortho
positions of the chelating group on the aromatic substrates and also tend to be
tolerant of functional groups. However, the level of deuterium incorporation is
widespread against different substrates and varies significantly from one to

another and can be unpredictable. Deuterated acids and Lewis acidic BF3-Et20

with 020 can promote H/D exchange on aromatic substrates at the ortho/para

49

positions with respect to strong electron-donating groups.86 However, a simple
method to install deuterium atoms at sites that are neither close to a chelating
group nor activated by electronic effects is still lacking. As a result, preparation
of certain deuterated aromatics can be arduous.78c
4.2 Applications of Catalytic Aromatic C-H Borylation in the Synthesis of
Specifically Deuterated Aromatics and the Discovery of Ir-catalyzed
Deuteration of Arylboronic Acids/Esters

Regiochemically, catalytic aromatic C—H borylation, previously mentioned in
Chapters 1 and 2, is shown to be dominated by a sterics-directing effect. Thus it
is complementary in regioselectivity to the existing metal-catalyzed direct H/D
exchange methods and acid-promoted H/D exchanges of electron-rich arenes.
In addition, the C—H borylation generates a boronic ester group, which upon
subsequent deuteriolysis, presumably, would afford the corresponding
deuterium-labeled compounds (vide infra) without suffering the hydrogen atom
abstraction problems of Grignard reagents. The particular capability of the
borylations to tolerate halogens would minimize the problems of regio- or
chemoselectivity of Grignard formation or deuterio-reduction from polyhaloarenes,
and therefore would be beneficial for preparing deuterated arenes with halide
substituents. Thus, a one-pot C—H borylation/deuteration strategy should

constitute a general method to prepare specifically labeled aromatics with

50

 

deuterium, which could possibly be extended to tritium labeling (Scheme 4.1).

Scheme 4.1 Proposed one-pot C-H borylation/deuteration protocol for
preparation of specifically deuterated aromatics

 

2 2
1 F1? 3 lr-cat., ligand, r 1 B 31 1 F32 3
R WR HBpin or szin2 1 R WR g 020 R WR
ll ! B - é? l ' -—-—.—-* j: I
\V orylation V I Deuteration \/
H Bpin g D
2.1 2.2 4.3

Although the protonolysis/deuteriolysis of organoboron compounds is a
well-known process,87 most investigations have employed trialkyl and triaryl
boranes as starting materials.88 Surprisingly, utilization of boronic acids/esters
as starting substrates in this reaction has only been performed as mechanistic
studies or other physical organic investigations.89 Synthetically useful reaction
conditions and the development thereof are still lacking.90

Presented with such a situation, we first sought reaction conditions that would
provide a reliable method for the protonolysis/deuteriolysis of the aryl boronic
esters generated in the borylation reactions. A variety of conditions were tested
on commercially available 3,4-dichlorophenylboronic acid pinacol ester 2.2t
(Table 4.1). In this study, water-soluble solvents, such as THF or DME, were
chosen in order to make the reaction homogeneous.

Much to our disappointment, the desired deuteration reaction proved
unexpectedly difficult. At temperatures as high as 150 °C (sealed tube), the

reaction with pure 2.2t in D20 failed to give the deuterated arene when promoted

51

 

 

by either an acid (Entry 1) or a tertiary amine base (Entry 7). Although an

oxygen base (Entries 2-5) or cesium fluoride (Entry 6) could promote the reaction,

full conversion was not obtained even after extended periods.

This low reactivity

of the boronic acids/esters toward protonolysis/deuteriolysis was obviously an

obstacle that needed to be overcome.

Table 4.1 Acid and base-promoted conditions

Cl

Cl

1
1

 

@C' DZO, reagent _
' 1/ THF or DME '

1\CI
‘/

 

 

Bpin 150 0C 0
2.2t 4.33
Entry Reagent (equiv) Time lh % Conversion8
1 AcOD (1 .0)b 2 trace
2 NaOH (0.11) 2 26%
3 NaOH (1 .1) 2 59%
4 NaOMe (2.2) 1 61%
5 NaOMe (2.2) 5 76%
6 CsF (1 .1) 4° 55%
7 DABCO (1 .1 ) 5 trace

 

All reactions were run in 0.5 mmol scale in 0.25 mL DZO (~23 equiv) and 2 mL DME. " GC area
ratio calibrated with corresponding non-deuterated compound. b 0.5 equiv A020 was actually

used. c 1 h at 150 °C followed by 3 h at 160 °C

Fortunately, but unexpectedly, a control experiment using crude 2.2t

generated from the borylation of 1,2-dichlorobenzene (2.1t) gave full conversion

to the corresponding deuterium-labeled product 4.3a within 1 h at 150 °C. This

reaction was performed without acid or base, and the only “extra additive” in the

reaction mixture was the residual lr catalyst and phosphine ligand that were used

52

during the borylation. This surprising result triggered the thought that the Ir
residue might serve as a catalyst for the deuteriolysis of aryl boronic esters. Of
course, the phosphine residue could also be playing a role. However, it is not

known that phosphine can catalyze such a process.

Table 4. 2 Ir-catalyzed conditions

 

 

 

Cl Cl
N0 020, reagent = (VG
VJ THF or DME ’ /
11311111 150 °C, 30 min D
2.2t 4.3a
Entry lr species” Other species Solvent ConversionC
1 None None THF <1 %
2 None None DME <1 %
3 None dmpe THF <1 %
4 Crude borylation mixture None THF 100%
5 (Ind)lr(cod) None THF 95%
6 (Ind)lr(cod) None DME 97%
7 [lr(OMe)(cod)]2 None THF 98%
8 [lr(PCy3)(py)(cod)][PF6] None DME 100%
10 [erl(cod)]2 None THF 33%
11 IrCI3-3H20 None THF <1 %
12 (C6H6)lr(Bcat)3 None THF <1 %
13 (d'bpy)lr(coe)(Bpin)3 None DME 47%
14 None Pd(P'Bu3)2 THF trace

 

All reactions were run in 1 mmol scale in 0.5 mL DZO (~23 equiv) and 34 mL solvent, arbitrarily for
30 min. b 2 mol% Ir in every case. c GC area ratio calibrated with corresponding non-deuterated
compound.

This hypothesis was then tested. Pure 2.2t, obtained Ir—free either from the

commercial source or prepared from the corresponding boronic acid and pinacol,

was subjected to the deuteration conditions, but this time with an added Ir species

53

(Table 4.2) and without any added acid or base. The reaction proceeded
smoothly when certain lr species were introduced, while the phosphine ligand was
ruled out as a catalyst (Entry 3). Clearly, the reaction is promoted by some
Ir-derived species.

Not all lr species are able to catalyze this reaction. The two Ir catalysts that
were known to promote C—H borylation served quite well as the active catalysts,
or possibly pre-catalysts, in this deuteration reaction (Entries 5-7). The Ir residue
in the crude borylation mixture was also an active promoter (Entry 4).
Surprisingly, however, (d‘bpy)lr(coe)(Bpin)3, the catalyst resting state during the
borylation,15a was found to be a poor promoter for the deborylation (Entry 13),
although significant conversion of 47% was observed. Crabtree’s catalyst,
previously known to promote H/D exchanges, was also capable of affecting this
deuteration specifically at the boronic ester site (Entry 8). It should also be
included that the protodeborylation reaction can be performed in alcohols, such as
1-butanol, instead of water and DME (or THF).

Mechanistically, it should be noted that every reaction here used the Ir
species without any added ligand. Therefore, an active catalytic species
different from the catalytic C-H borylation is possibly in play, so is a catalytic cycle
different from the C—H borylation. However, an in-depth mechanistic study to

identify the active catalytic species and the mechanism has not been performed.

54

Some mechanistic discussion will be presented in Section 4.3.
4.3 Substrate Study91

On the basis of the above study, we noticed that the crude borylation product
could be simply treated with D20 in a suitable solvent, and then heated to 150 °C
in a sealed tube, to obtain the desired deuterated arene. This process .is very
easy and quick to execute. However, for safety concerns, we looked to lower the
reaction temperature. In practice, running the reaction at 100 °C or lower can
still lead to full conversion of the boronic ester, albeit in a longer period of time.92
The Ir catalyst loading could also be lowered to 0.6 mol% while still achieving 97%

conversion of 2.2t.92

We then screened several substrates against this one-pot
C—H borylation/deuteration protocol (Table 4.3).

The overall reactions were very clean, producing the deuterated arenes as
the only aromatic products. High yields were easily achieved for non-volatile
products. More importantly, the level of the deuterium incorporation obtained via
this method was generally more than 95%, which is much higher than the
Grignard deuteriolysis, provided the borylation went to completion and no
atmospheric moisture was introduced into the system during the deuteration
reaction. Of course in cases where the borylations cannot be pushed to

completion, it should be possible to simply isolate the boronic ester intermediate

and then run the deuteration with this pure material plus Ir to achieve a high level

55

 

of deuterium incorporation. 2H and 1H NMR analysis of these reactions indicated
that deuteration occurred selectively at the boron-bearing carbon. Due to the
absence of acid or base in the deuteration step, functional groups such as cyano
group (Entry 6) survived the reaction conditions. Note that 4.3f is not a
straightforward product from Grignard deuteriolysis, because of the incompatibility
of Grignard reagent with the cyano group. On the other hand, this protocol can
also be used in the opposite direction, namely to start from a perdeuterioarene to

a monoprotioarene (Entry 2).

Table 4.3 C-H Borylation/deuteration protocol for synthesis of deuterated aromatics

 

 

 

 

 

1 R2 3 (lnd)lr(codf—Ztmpe/dppe, 1 1 B2 31 1 R2 3
R WR HBpin A R \11/\/R 1 020 g R WR
' ,/r ' : \Kl THfstgroEéME v
H L Bpin _ OH
2.1 2.2 4.3
Entry Starting Borylation Deuteration Product % %
arene conditions" time" Yieldc D"
1 CI 1.4 equiv 0.5 h Cl 75 98
C' HBpin, Cl
3.5 h
2.11 1')
4.3a
2" c: 1.5 equiv 1 h C. 82 N/A'
60' HBpin, / 1 CI
\ 7d“ 3 h $1”
2.1u H
4.3b
3 CI 1.8 equiv 1 h Cl 95 98
Cl CI HBpin, Cl CI
U (j
2.1m D
4.3c

 

56

Table 4.3 Continued

 

 

Entry Starting arene Borylation Deuteration Product % %
conditions time” Yieldc D“
4 Cl ,N CI 1.8 equiv 1 h on /N on 89 96
U HBpin, U
2.19 3.25 h D
4.3d
5 F30 CI 1.8 equiv 1.5 h F3C CI 67 100
o <3
3 h D
2.1p 4.3e
6 NC / Br 1.5 equiv 2 h NC Br 69 99
U HBpin, 0
2.1V 6 h D
4.3f
7 MezN CI 2 equiv 2 by MezN Cl 92 92
o U
211‘. 18 h D
4.39
8 MeO CI 1.5 equiv 1 h MeO CI 88 96
U U
2.1e 12 h (I)
4.3h

 

All reactions were run in 2 mmol scale. a 2 mol % (Ind)lr(cod)-dmpe at 150 °C for all entries
except 6, for which 1.5 mol% [lr(OMe)(cod)]2 and 3 mol% d’bpy at room temperature instead. b
On the crude borylation mixture with 0.5 mL D20 (~11 equiv) and 3-4 mL solvent. ° Isolated yields,
average of two runs. d Determined by MS intensities; see experimental section for method of
calculation. ° The second step was carried out with H20, not D20, and this reaction was not
duplicated. ' Not measured. " Deuteration was carried out with 0.5 equiv A020; see further
discussion for details.

In these reactions, it is not obvious how the electronic nature of the aromatic
ring affects the rate of the deuteration. Considering that all the deuterations
were typically complete in 2 h or less (except Entry 7), it would seem that the

arene electronics have little effect on the deuteration time. However, this is

57

F

 

complicated by the dramatically distinct behavior of 2.2q (Entry 7), whose

deuteration took over 15 h and was not reproducible from run to run.

Nonetheless, adding 0.5 equiv A020, which should generate 1 equiv AcOD under

the reaction conditions, significantly accelerated that reaction to the point where it

was also complete in about 2 h with good reproducibility. It remains unclear'
whether this acceleration is due to the “protonation” of the basic nitrogen, or due

to the introduction of free acetate, or other effects, such as possible acid catalysis.

Nonetheless, this observation piqued our curiosity to further investigate the

electronic and steric perturbations of the rate of the deuteration step.

Two xylylboronic acids were obtained from their commercial sources and the
corresponding boronic esters were prepared (Table 4.4). Compound 4.4b has
the same substitution pattern as 2.2t (Table 4.2). 1 However, by replacing the two
chlorides with more electron-releasing methyl groups, the aromatic ring of 4.4b is
more electron-rich. Boronic esters 4.4b and 4.5b have a similar electronic
nature. However, by moving the para-methyl group to the ortho-position, 4.5b is
more sterically demanding. Upon subjecting these boronic acids and esters to
the deuteration conditions, we observed the following: 1) deuterations of 4.4b and
4.5b took approximately the same time to complete (although monitoring the
reaction before full conversion suggested that 4.4b was somewhat faster than

4.5b); 2) deuterations of 4.4b and 4.5b were slower than that of 2.2t, but not by

58

Table 4.4 Electronic and steric perturbations

 

 

 

R R
NR 2 mol% (Ind)lr(cod), 020: WR
. , ,1 DME, 150 °C 0
\“\BX2 \,\D
Entry Starting Deuteration Product %
arene timea Yield"
1 Me 0.5 h Me 100
©Me ©Me
B(OH)2 D
4.4a 4.68
2 Me 2 h Me 91
Me Me
Bpin D
4.4b 4.6a
3 $:Me 1 h $:Me 94
Me Me
B(OH)2 D
4.58 4.6b
4 Me 2 h Me 93
ElMe Me
Bpin D
4.5b 4.6b

 

All reactions were run in 1 mmol scale. a The time for full conversion, checked at 30 min intervals.
b 60 yields calibrated with corresponding non-deuterated compound.

much; 3) deuterations of the corresponding boronic acids 4.4a and 4.5a took
comparable periods of time compared to 2.2t. These observations, together with
the data in Table 4.3 (except Entry 7), suggested that the electronics and sterics
of the aromatic ring do not have a significant effect on the rate of the deuteration

reaction. Therefore, the behavior of Entry 7 in Table 4.3 remains mysterious.

59

In terms of the reaction mechanism, although we have not performed an _
in-depth investigation, a putative catalytic cycle is given in Scheme 4.2. It calls
for an lr(l) hydroxide (or alkoxide if the reaction is performed in alcoholic solvents)
as the active catalytic species. A subsequent transmetalation step is responsible
for the cleavage of the C—B bond to generate the aryl lr species.
Protonolysis/deuteriolysis of this lr-Ar bond affords the arene and regenerates the
Ir hydroxide. Our major explanations that lr(I), rather than lr(|l|), is the
catalytically active species is based on two reasons. For one, according to Table
4.2, lr(l) species are better catalysts than lr(lll). For the other, this
transmetalation is known for Rh-catalyzed reactions and Rh(|) species are
generally recognized as the active catalysts in these reactions.22 Since Ir is one
row lower in the periodic table than Rh, it is logical to consider that Ir may have a
similar reactivity.93 In addition, we think that those catalytically active lr(lll)
species (Entry 13, Table 4.2) would probably be first reduced to lr(l) prior to
entering the reaction cycle. However, since this mechanistic hypothesis has not
been studied in full details, other possibilities are still open for discussion and

Scheme 4.2 A putative mechanism for Ir-catalyzed deuteriodeboronation
Ir pre-catalyst species

AD lr-OD Ar—BX
r \11/ \ X2=(OH)220r pin

020 A lr~Ar / \ (DOIBX2

60

clearly more work needs to be done to address the related questions.

Although both (Ind)lr(cod) and [lr(OMe)(cod)]2 are good catalysts for the
deuteration, neither of them was found to be able to promote the deuteration for
iodinated substrates. The reaction was much slower and was accompanied with
significant deiodination, even if the deuteration was carried out on isolated
iodoaryl boronic esters. However, Felkin-Crabtree’s catalyst provided
satisfactory resUlts (Scheme 4.3). Compound 4.3i could be isolated in 54% yield
for the deuteration step and 47% yield over 2 steps with no detectible deiodination
by 1H NMR. This success allows for the preparation of iodine-containing
aromatics that are specifically deuterated, which is not always straightforward for
traditional Grignard deuteriolysis. It also allows the potential preparation of 2H

and 131l (or 125I) doubly labeled aromatics for related studies.

Scheme 4.3 An iodinated substrate for C-H borylation and deuteration

1.5 mol% [lr(OMe)(cod)]2.

 

 

Br Br I 4 mol% Crabtree's cat., Br W'
W 3 mol% d'bpy, 1 equiv szinz; \1/j/ 020 11 \.
V heptane. rt. 10 h ' V DME, 150 °c, 4h V
H 86 % Bpin 54%, 90% D D
2.1r 2.2r 4.3i

4.4 Attempts to Deuterate Vinyl Boronic Acids/Esters
The success in deuteration of aromatic boronic acids/esters led us to study
the possible extension of this method to vinyl boronic acids/esters. Two sets of

substrates were considered for this study, trans-styrylboronic acid/ester and

61

trans-1-octenylboronic acid/ester (Figure 4.1).

Figure 4.1 Vinyl boronic acids/esters as potential substrates

mBme

l .- Wmomz
\f/ 4.9a 4.10a
\ \ Bpin
l ; WBpin
/ .
4.9b 4.10b

Although still in the very preliminary stage, surprisingly enough, under the
same reaction conditions (150 °C, 2 mol% (Ind)lr(cod)), those vinyl boronic
acids/esters behave very differently from the aromatic substrates. For
compounds 4.10a and 4.10b, the olefin transposition was a serious competing
reaction. Both 1-octene and 2-octenes (cis and trans) were observed by GC and
GC-MS, together with isomerized starting material. At the same time, deuterium
was observed to be incorporated not only into the vinyl positions, but also

significantly into the aliphatic positions. Therefore, fairly complex mixtures were ~

 

 

generated.
Scheme 4.4 Styryl boronic acid/ester in the deuteration reaction
2 mol °/o (Ind)lr(cod) HID H/D .
\ B(OH) ,, 0% ratio
M 2 DZO/DME, 150 C, 5 h = \ \ H/D 1:1:1:0.5(ring)
V Ma 69 /o (60) I / HIE/D Total 0.7 D
\ , 2 mol % (Ind)lr(cod) H/D .
MEN“ 0 0% ratio
v DZO/DMIE, 150 C. 6 h= (WW0 121,1
4 9b 59 /o (60) V H/D Total 1.0 o

On the other hand, for compounds 4.9a and 4.9b, such olefin transposition

62

 

cannot occur and the reaction mixture was easier to analyze. However, it was
observed that deuterium completely scrambled throughout all the possible vinyl
positions (Scheme 4.4).

First, for the products of the deuteration of 4.9a and 4.9b, the three vinyl
positions were equally deuterated. This was clearly indicated by both 1H NMR
and 2H NMR, as all the residual vinyl 1H’s signals integrated at 1:1:1, and all the
newly formed vinyl 2H’s signals also integrated at 1:1:1. Secondly, using 4.9a as
the starting material also resulted in the introduction of deuterium to the aromatic
ring, albeit to a lesser extent. In contrast, 4.9b did not undergo arene
deuteration. This introduction of deuterium to the aromatic ring is regioselective,
as 2H NMR only showed one single signal for aromatic deuterium. The chemical
shift of this aromatic 2H in 2H NMR, as well as the decrease of the proton
integration in 1H NMR indicated an ortho position deuteration. Thirdly, 1H NMR
analysis revealed a deuterium incorporation of 0.7 D per molecule for deuteration
of 4.9a and 1.0 D per molecule for deuteration of 4.9b. The exact ratio of do, d1,
and d2 compounds remained elusive,94 although they are all present in significant
amounts.

4.5 Conclusions
In conclusion, some Ir species, including the Ir precatalysts for the C—H

borylation, can promote fast protonolysis or deuteriolysis of aryl boronic acids or

63

esters. The reaction is high yielding, clean, facile, and able to incorporate an
extraordinarily high level of deuterium regioselectively on the boron-bearing
carbon. The absence of any need for acids, bases, strong nucleophiles, or
reducing agents in this process affords good functional group tolerance. In
combination with the catalytic C—H borylation, this method can be used to perform
H/D exchanges on specific positions of arenes, with regioselectivity
complementary to the conventional means. Further mechanistic studies and an

investigation of the reactivity of vinyl substrates are also warranted.

64

Chapter 5. The C—H Borylation/Amidationleidation Protocol for the
Preparation of 5-Substituted 3-Amidophenols
5.1 5-Substituted 3-Amidophenols and Their Preparations

5-Substituted 3-amidophenols, with the amido group including ureas and
carbamates (Figure 5.1), are useful structural motifs for pharmaceuticals and
other biologically important compounds.95 Many molecules bearing this
structural motif are recognized as kinase inhibitors, growth regulators,96 etc.
There are also a number of biologically active natural products that can
structurally fall into this category (eg. the ansamycin family, see Chapter 6 for
details). Such natural products, containing 5-substituted 3-amidophenols or
further elaborated aromatic cores within macrolactams, have been reported to be
antitumor agents and antibacterial agents (see Chapter 6 for details).
Biosynthetically, these natural products are derived from
3-amino-5-hydroxybenzoic acid (AHBA, Figure 5.1),97 itself a 5-substituted
3-amidophenol derivative. Due to the interesting biological activities of these
natural products, as well as the vast number of small molecule derivatives of
5-substituted 3-amidophenols,‘*““96 this moiety is a valuable, versatile building
block that can be potentially further elaborated into pharmaceutically interesting

libraries.

65

 

Figure 5.1 5-Substituted-B-amidophenol and AHBA

RCKHVR. HOZCCrNHZ
/ O ./

5H CH
General structure AHBA

However, synthetic paths to such useful structures are quite narrow. Due to
the limitations of traditional aromatic substitution chemistry, generating these
1,3,5-trisubstituted benzene rings having at least two ortho/para directing groups
is very difficult. Reported methods for making AHBA are typified by long routes
and harsh conditions.98 Methods for constructing more complicated structures
generally involve an acylation step as the key reaction (Scheme 5.1),99 namely
the acylation of aromatic amines with acyl chlorides or esters100 (for syntheses of
carboxyamides and carbamates) or the acylation of amines with aromatic

isocyanates101

(for syntheses of ureas). Although such acylations are
straightfonivard, the overall route lacks versatility. They often involve
multiple-step processes and are heavily dependent on the availability of suitable
aromatic components. In fact, due to the limited availability of related aromatic
starting materials, syntheses of the small molecules bearing 5-substituted

3-amidophenol moieties have been limited to molecules bearing only few different

groups at the 5-position.102

66

Scheme 5.1 Acylation strategy for preparation of amidobenzenes

 

 

NH .
\J 2 + R O/CIWX
AR 0
Likewise, syntheses of more complicated 5-substituted

3-amidophenol-containing natural products often count a considerable number of
steps in assembling the aromatic moiety. An illustrative example is the Smith
total synthesis of trienomycin A.103 While the total synthesis of such a
complicated natural product took only 39 steps, 9 out of those 39 steps were
dedicated to generating the aromatic core (Scheme 5.2). With these facts in
mind, we viewed it attractive to establish a new, versatile, and efficient route to
build around this aromatic core, especially if this route could provide a variety of

substituents at the 5-position.

Scheme 5.2 Smith total synthesis of trienomycin A

ms was
\
N02 gsteps l \ O 25 steps i /
l . ———- (R/ N ———> .
Hozc)\7\no2 SOzPh oh ON 0%
H .. .
We 0‘ \ \ \ OMe
OH

f
5 steps / /J\NH
—‘ HO O
H 0‘“ \ \ \ OMe

Cy N K
1; r0 trienomycinA

5.2 Applications of Catalytic Aromatic C—H Borylation in the Synthesis of

67

5-Substituted 3-Amidophenols

We envisioned that some of the obstacles in traditional syntheses of
5-substituted 3-amidophenols could be overcome by our discovery and
development of the sterics-directed C—H borylation and the one-pot protocols
developed thereof. This C—H borylation event, working outside the
electronics-dominated aromatic substitution, is able to position a boronic ester
group at the 5-position of a 1,3-disubstituted benzene, giving us the exact
substitution pattern in question.

A hallmark of the C—H borylation is its compatibility with halides. As
demonstrated by Buchwald and co-workers, aromatic halides can participate in
Cu- or Pd-catalyzed C—N coupling reactions with corresponding amides to form

amidobenzene derivatives.1°""105

By incorporating this chemistry with catalytic
C—H borylation, a different strategy to synthesize these 5-substituted
3-amidophenols can be envisaged. Borylation of a 3-substituted halobenzene,
followed by Buchwald amide coupling, would in theory provide us a 5-substituted
3-amidophenyl boronic ester intermediate. Subsequent oxidation, as discussed
in Chapter 2, should reveal the hydroxyl group in the target molecule (Scheme
5.3). This method would be uniquely efficient for the rapid preparation of these

types of densely functionalized aromatic building blocks, especially if all reactions

could be telescoped into a single reaction vessel.

68

 

 

Scheme 5.3 Proposed C-H borylation/amidation/oxidation protocol

R Hal Ir-cat..|igand. R \ Hal Pd/Cu-cat.,ligand,
O HBpin or szinz _ 7;) amide (5.2), base;

 

 

I Borylation T g . , Amidation
H t Bpin l
2.1 2.2
h R' l R 5' x
R r \ wa Jon—e, W it
" / o Oxidation Ki? 0
Bpin OH
X=C,O,N
5.3 5.4

The viability of such a protocol was further supported by the success in the
establishment of the related borylation/amination protocol, demonstrated by Mr. G.
A. Chotana and Dr. D. Holmes in the group.106 In their process, a crude
borylation mixture of a 3-substituted halobenzene could be subjected to
Pd-mediated amination conditions to afford the 5-substituted 3-aminophenyl
boronic ester (Scheme 5.4). Thus, the related borylation/amidation/oxidation

approach looked very promising.

Scheme 5.4 A related C-H borylation/amination protocol

lr-cat., ligand,

 

 

. 1
R Hal R Hal Pd-cat., ligand, R
W HBpin or szinz | \ 1 amine, base ‘ R \. NR2
\7 Borylation , / J Amination ' I /i
Bpin l .
Bpin

That said, while Buchwald and co-workers have demonstrated the utility and
versatility of the amidation reaction with a wide range of functional groups,
reaction conditions, and coupling partners, to the best of our knowledge, no

examples of aryl halides that bear boronic ester groups have been reported in

69

 

 

such a coupling reaction. The absence of this type of substrates led us to be
concerned that the amidation conditions might instead promote an undesired
Suzuki coupling between the boronic ester group and the halide (Scheme 5.5).
In fact, we had previously demonstrated that polyphenylenes could be generated
by such a Suzuki event.14C Thus, the proposed borylation/amidation method
must deal with the competition between the C—N coupling and the Suzuki reaction
during the second step. Luckily, our related borylation/amination work showed
that this Suzuki coupling could be suppressed if the amination was run under dry
conditions.106 We hoped that suppression of the undesired Suzuki could also be
achieved for the borylation/amidation sequence.

Scheme 5.5 Desired amidation versus undesired Suzuki

 

 

R\ \ Br R.
‘I
Q A Pd, base RWBr Pd, amide, base_ R { \. NTX
d ‘ SUZUki \2 Amidation / O

RMBpin (Undesrred) Bpin (Desrred) Bpin

Initial experiments targeted exclusively on the amidation step using
acetamide as the amide coupling partner. 3-Bromobenzotrifluoride (2.1w) was
chosen to be the standard halide partner for this preliminary study. Due to our
concern over potential Suzuki couplings, our first thought was to avoid the use of
the Pd catalysis for the amidation. Thus, after borylation of 2.1w, the amidation

was attempted using Buchwald’s Cul-catalyzed conditions (Scheme 5.6).

70

Unfortunately, those conditions104 netted little success. Although we were able
to repeat Buchwald’s reported result with simple aryl halide bearing no boronic
ester group, these conditions failed to amidate 2.2w. Instead, we observed high
levels of protodeborylation under these Cu-catalyzed amidation conditions.
Even using purified boronic ester or increasing the Cu loading from 1 mol% to 10
mol% met no success.

To our pleasure, the amidation step could be achieved under Buchwald’s

1OSa-c

Pd-catalyzed conditions (Scheme 5.6). Protodeborylation was not observed

and Suzuki coupling was observed in no more than trace amounts (see Section
5.4 for details). We also increased the catalyst loading so that the amidation
step could be complete in a few hours instead of overnight. It was also delightful
to find that the Pd-catalyzed amidation could be performed on the crude

borylation mixture without isolation of the boronic ester intermediate.

Scheme 5.6 Stepwise borylation and amidation reactions

1. cat. [lr(OMe)(cod)]2-d'bpy, HBpin, then pump down
2. cat. szdba3-xantphos, AcNHz (5.2a), C52C03, dioxane, 74% overall

l l
; cat. Pd dba -xantphos,
cat. [lr(OMe)(cod)]2 AcN2H2, 332003,

F C Br F C NHAc
F3C \ Br -d‘bpy, HBpin 3 dioxane, 78% 3 W
' / 93% or \%
Bpin . cat. CUI- Bpin
2.1“, 2.2w diaminocyclohexane, 5.3a
ACNHz, K2CO3,
dioxane, trace

 

 

 

Having combined the borylation with a subsequent amidation, we next

71

 

attempted to convert the crude amidation mixture to the amidophenol via the
oxone oxidation conditions. We expected the oxidation of this crude
amidophenylboronic. ester to be uneventful, given the results from Chapter 2.

Specifically, although our standard oxidation solvent is acetone, we have
demonstrated that water-miscible ethereal solvents, such as THF and dioxane,
could also be used for successful oxidation. As the amidation was carried out in
THF or DME, oxidation of the crude amidation mixture should not have a problem
with solvent incompatibility. Secondly, although our standard oxidation does not
require base or buffer, we have also demonstrated that the presence of base and
buffer did not hamper the oxidation. As the amidation was carried out in
presence of 032003, it could be expected that the excessive Cszcog, and its
byproducts CsHCO3 and CsBr generated in the amidation, would simply be
viewed as bases or buffer. Thus, we reasoned that the oxidation should not
have a problem with the presence of these inorganic salts, either.

Unfortunately, this hypothesis proved incorrect as all attempts at a strictly
one-pot borylation/amidation/oxidation failed to give any desired phenol. The
only detectable product (GC-MS and 1H NMR) was pinacol. Adding HCI into the
crude mixture to neutralize C52003 thus making the system homogenous did not
help. We were able to determine that this failure stemmed from the catalytic

milieu and not the amidation intermediate, as isolated 5.3a could be uneventfully

72

oxidized to the phenol with oxone in 95% yield (Scheme 5.7). While a one-pot
borylation/amidation followed by purification and then an oxidation would make for
a fairly efficient route to 5-substituted 3-amidophenols, the poor behavior of the
amidophenyl boronic ester on silica gel chromatography makes the purification of
this intermediate unfavorable.

Seeking a compromise between a two-step process with a purification step
and a true one-pot procedure, we filtered the crude amidation mixture through a
pad of silica gel to remove the offending residue. -Gratefully this filtration was
able to “clean” up the crude intermediate to a sufficient level that the filtrate, after
evaporation, could be successfully oxidized with ease.

Scheme 5. 7 The oxdiation of the amidophenyl boronic ester

 

 

Status of 5.3a yield
F3C\/\ NHAc F c NHAc
'l \/ oxone, acetone 3 W crude 0%
V 2 . /= .
, Y purified 95% (69% from 2.1w)
Bpin OH
5.38 5,43 fi'te'ed (63% from 2.1w)

(silica pad)

In order to identify the destructive agent that was removed by this filtration, we
repeated the oxidations on filtered amidation mixtures with different reaction
species added into the oxidation. It was found that the Pd catalyst, the
phosphine ligand, and CszCO3 that are used in the amidation step were all
harmless to the oxidation. Unexpectedly, adding [lr(OMe)(cod)]2. the

pre-catalyst that promoted the borylation, into the oxidation led to the lowest yield

73

for the oxidation step. The qualitative features of this lr-containing reaction, such
as the black color, were identical to those failed reactions that were performed
without such filtration, and were distinctively different from the successful
oxidations with a brownish color. Certainly, this [lr(OMe)(cod)]2 species should
be different from the residual lr species that was present in the crude amidation
mixture, thus it is still not conclusive that it is this lr species that caused the
problems of the unfiltered oxidation. However, lr-retardation of the oxidation was
observed in the study of amino acid borylation/oxidations (see Chapter 3, Entries
6 and 9, Table 3.1), especially when the Ir loadings needed to be extraordinarily
high (> 10 mol%) for successful borylations. The understanding of such
behavior will need more detailed investigations.

Although the filtration solved the problems of oxidizing crude amidation
mixtures, we quickly realized another problem. The oxidation produces a
stoichiometric amount of pinacol. As the desired amidophenol products are
polar, the separation of the desired product from pinacol was sometimes difficult.
To solve this problem, the crude oxidation mixture was stirred over NalO4 for a
period of time (ca. 1 h) to remove pinacol. Thus, the final amidophenol could be
isolated clean without contamination.

Thus our final borylation/amidation/oxidation protocol consists of a catalytic

borylation, subsequent Pd-catalyzed amidation of the crude borylation mixture, 3

74

filtration, oxidation of the evaporated filtrate, and finally a NalO4 workup before
extraction and chromatographic purification. Although requiring a number of
operations, this protocol is still very efficient, as there is only one chromatography
step after three different chemical events. Indeed, the whole procedure can be
finished within two days and is reproducible.
5.3 Substrate Study107

With optimized reaction conditions in hand, we screened a series of
substrates, both halobenzenes and amides, to test the scope of this 3-step
sequence (Table 5.1).

Table 5.1 C-H Borylation/amidation/oxidation protocol

lr-cat., ligand, FR Hal 1 Pd-cat., ligand,
R WHal HBpin or szinz _ \O amide (5.2), has:

V J THF or DMEfi

 

 

 

 

 

IBpin
2.1 2.2
l R' 7 R'
l R H \ “TX ‘ oxone ‘ RWNYX
I \l/ O ! acetone/water, rtr \K O
t Bpin J OH
5.3 5.4
Entry Substrate Amide Product % Yield“
1 F3C Br AcNHz F3C NHAc 63
U 5.2a Q
2.1w OH
5.4:
2 NC Br ACNH2 NC NHAC 68
U 5.2a U
2.1V OH
5.4!)

 

75

Table 5.1 Continued

 

 

Entry Substrate Amide Product % Yield“
3 Cl Br AcNHz Cl NHAc 75
5.2a U
2.1a OH
5.4e
4 Me02C Br AcNHz MeOZC NHAc 60
5.2a Q
2.1x OH
5.4d
5 Me Br AcNH2 Me NHAc 43°”
0 5.2a U
2.1d OH
5.4e
6 MeO Br AcNH2 MeO NHAC 33"“
U 5.2a O
2.1y OH
5.4f
7 F30 Cl AcNH2 F3C NHAc 408
g 5.2. Q
OH
2.1p 5.4a
8 F300 AcNH2 F3C (0)“
CI 5.2a NHAc
2.12 OH
5.49
9 F30 Br BzNH2 F3C NHBz 82
U 5.2..
2.1w OH
5.4h
10 MeOzC Br BocNHz MeOZC NHBoc 469
U 5.2c O
2.1x OH
5.4i
11° F3C Br 0 H 129
0 A FgcA/NTNHPMB (19)“
MW NHPMB “W; o
5.2d OH
5.4]

 

76

Table 5.1 Continued

 

Entry Substrate Amide Product 0/0 Yield“

 

(j HZN N’ F30 N‘n/N‘Bn
2.1w

l
Bn 0
5.4k
13 F3C Br O 469
U Cw F30 N
2.1w 0
I
5.2f OH
5.4l
14 F3C Br 0 H l 37
0 HzN/lk/ F3C N
2.1w 5.29 U 0
OH
5.4m
Cl B
2.1a O
5.2h
OH
5.4n

 

All reactions were run in 2 mmol scale. a See experimental section for details. b Isolated yields
over three steps with NalO4 workup, average for two runs. Welds not duplicated are listed in
parentheses. ‘ No NalO4 workup was performed. d Significant protodeborylation and phenyl
transfer products were observed. 9 Significant protodeborylation side-products were observed.
' Only product isolated was 45% protodeborylation. ‘7 Significant Suzuki side-products were
observed (see Section 5.4 and Table 5.2).

As can be seen in Table 5.1, this 3-step protocol was able to tolerate a range
of functional groups, such as chlorides, cyanos, ethers, and esters. However,
due to the presence of the boronic ester group, side-reactions were present

during the Pd-catalyzed amidation step. Therefore, the substrate scope for a

successful borylation/amidation/oxidation process is narrower than the

77

corresponding substrate scope for the amidation alone demonstrated by
Buchwald.

In general, this 3-step protocol worked best on electron-deficient aromatic
bromides with primary amides (free NH2). In this case, the desired
amidophenols (5.4) could be obtained in high yields. Side-products such as
protodeboylation and Suzuki dimerization (see Section 5.4 for details) were not
observed in significant amounts (Entries 1-4, 9). In contrast, electron-rich
aromatic bromides did not work well in the borylation/amidation/oxidation process
(Entries 5 and 6), although they are a class of “no-problem” substrates in the
Buchwald amidations alone. In that case, while the 3-step protocol produced the
desired products in moderate yields (33-43%), side-reactions took place,
including Suzuki dimerization, protodeborylation and phenyl transfer from the
xantphos ligand. Furthermore, due to the electron-rich nature of the aromatic
rings, the products could not stand the Na|O4 workup utilized to destroy pinacol.
Thus pinacol contamination was observed without a recrystallization or HPLC
separation.

The amidation reaction became very sluggish when a chloride was used
instead of a bromide (Entries 1 and 7). Higher temperature and much longer
reaction times were needed and severe protodeborylation byproduct was

observed. Suzuki dimerization, however, was suppressed, presumably due to

78

 

the lowered reactivity of the chlorides.

Another observation was the effect of ortho su bstituents on the amidation step.
Arene 212 could be borylated ortho to the chloride, but the subsequent amidation
only afforded the protodeborylation product (Entry 8). Therefore, by comparing
entries 7 and 8, it can be seen that sterics indeed have an adverse effect on the
amidation step of our borylation/amidation/oxidation protocol, although Buchwald
demonstrated that certain substrates with ortho substituents but without boronic
ester could be amidated. Therefore, achieving substituted aminophenols with
other substitution patterns unfortunately seems less viable.

On the other hand, the scope of the amide partners proved to be relatively
broad. In addition to carboxyamides, carbamates and ureas (Entries 10-15)
could be used in the borylation/amidation/oxidation process. For example,
BocNHz (5.2c), a carbamate, could be used as a protected form of “NH3” and
product 5.4i, a doubly protected version of AHBA, could be synthesized quickly
from commercially available starting materials in 46% overall yield (Entry 10).
Likewise, 1,1-dibenzylurea (5.2e) could be used as a protected form of urea to
synthesize the urea-analogue of the amidophenol 5.4k (Entry 12). This work
provides an alternative route for the preparation of such molecules without using
isocyanates. Unfortunately, coupling with a guanidine derivative

(1 ,3-bis(t—butoxycarbonyl)guanidine) was not successful.

79

 

 

Lactams and a,B-unsaturated carboxyamides were also useful coupling
partners (Entries 13-15). The use of cull-unsaturated carboxyamides further
demonstrated the functional group compatibility for this protocol. However, with
acrylic amide itself the overall yield was only 37% (Entry 14). This yield could be
increased to a synthetically useful 66% when the olefin was further substituted in
a form of tiglic amide (Entry 15). For a lactam and secondary amide (Entry 13),
the competing Suzuki dimerization during the amidation step became intrusive
(see Section 5.4 for details) and the overall yield for the desired product dropped
accordingly to 46% (Entry 13). Disappointingly, this Suzuki dimerization could
not be suppressed by using 3 equiv amide instead of 1.1 equiv (Entry 13).

5.4 Competing Suzuki Side-Reaction during the Amidation Step and Its
Potential Utility

As discussed previously, the Pd-catalyzed amidation conditions occasionally
promote an undesired Suzuki coupling, leading to the dimerization or further
oligomerization of the borylated halobenzene intermediate (Scheme 5.5). We
originally expected that such a Suzuki coupling could be suppressed given the
anhydrous reaction conditions and the absence of reports using xantphos as a
ligand for Suzuki coupling.108 However, this proved incorrect, as several
examples in Table 5.1 indicated that the amidation reaction was accompanied by

significant Suzuki dimerization side-products. The dimerization products could

80

 

 

 

continue to undergo amidation and oxidation to afford 5,5'-disubstituted
3-amido~3’-hydroxy biphenyls 5.5 (Scheme 5.8), which could be isolated together
with the desired amidophenol product 5.4 at the end of the 3-step

borylation/amidation/oxidation protocol.

Scheme 5.8 Undesired Suzuki side-product formation

RmBr

 

 

. R TrX
RWBr . \
. // Pd, base K) Pd, amide, base $3.2?
\ Suzuki A Amidation m
Bpin I ' \
/ .
R' F—
R \ NYX ) R
i , N x
oxone :2/ O . (\r 71/
OXIdatIon . l V 0
v. \ i
II
R / OH ' Q
5.5 ‘ OH

 

 

5,5'-dlsu bstituted

3-amido-3’-hydroxybiphenyl 3-amldo-3'-hydroxybiphenyl

Table 5.2 lists the formation of 5.5 for several examples. The yields of 5.5
here are just reflective of however much was obtained under the conditions
specified in Table 5.1. In other words, they are by no means optimized for 5.5.
Interestingly, however, this Suzuki side-reaction can be potentially useful.
3-Amido-3’-hydroxybiphenyl (see Scheme 5.8) is a structural motif for bioactive
compounds recognized as vanilloid VR1 receptor antagonists, antiviral agents,

109

etc. However, the corresponding 5,5’-disubstituted variants 5.5 are not known,

presumably because of the difficulty in synthesis. Therefore, this Suzuki event

81

Table 5. 2 Suzuki side-product formation

 

 

 

H
RY/\/Hal 1. lr-cat., ligand, HBpin or szinz 7:: O
V 2. Pd-cat., ligand, amIde (52), base
3. oxone \.
2.1 i,’ /.
R/\/\OH
5.4 5.5
Entry Substrate Amide Product 5.4 Side-product 5.5
(% yield)a (% yield)8
1 MGOZC Br BOCNH2 M6020 NHBOC MeOZC NHBoc

5.2c O

2.1x OH
5.4l O

(46) MeOzC OH
5.51
(18)
2" F3C / Br 0 H
\ ' F30 NYNHPMB F3C N YNHPMB
2.1w H2N NHPMB U 0
5.2d

3 F3C BF 0
0 8+

2.1w

All reactions were run in 2 mmol scale, in the same conditions shown in Table 5.1.
yields over three steps with NalO4 workup, average for two runs.

performed, not duplicated.

OH O};
5.41M/©\

(19)

BC 6) ,3, ,,
O O o

OH

5.4I O

(46) F3C OH

(23)

3 Isolated
b No NalO4 workup was

may provide a quick preparation of 5.5-type small molecules for further

manipulation into biologically interesting compounds.

82

At the same time, the observation of biaryl formation led us to consider the
possible use of the szdbag-xantphos-CszCOg combination to promote a Suzuki
coupling. It should be noted that Dr. D. Holmes in our group has previously
demonstrated the viability of combining the C—H borylation with subsequent
Pd-catalyzed Suzuki couplings of the aryl boronic ester intermediates with

different organohalides (Scheme 5.9)”““110

and has established a one-pot
borylation/Suzuki protocol. Such a protocol allows for quick preparations of a
variety of substituted biaryls. However, in the context of telescoping another

reaction, amidation for example, between the C—H borylation step and the Suzuki

coupling has not been sought.

Scheme 5.9 The established C-H borylation/Suzuki protocol

 

 

1 2 lr-cat., ligand, R1 R2 Pd-cat., ligand,
R \GR HBpin or szinz : [ \CT Ar-Hal. base 5R1WR2
/ Borylation : I/ Suzuki '\/l

Ar

Along these lines, we were specifically interested in developing a one-pot
borylation/amidation/Suzuki protocol to prepare diversely functionalized
amidobiphenyls with structures more versatile than 5.5. Unlike the original
borylation/Suzuki protocol that requires charging the catalytic system (Pd, ligand
and base) in between the two steps, we wanted to use the same catalytic system,

namely the szdbag-xantphos-C52003 combination, to promote both the

83

amidation and the Suzuki coupling without additional loading of any Pd catalyst,
ligand, or base after the amidation step. If successful, this protocol would have a
simple overall operation, high throughput and would be more economical with
respect to the fairly expensive metal catalysts and ligands.

To test this proposal, we first executed a simplified borylation/Suzuki
sequence using bis(trifluoromethyl)benzene as the substrate (Scheme 5.10).
After borylation, the crude reaction mixture was treated with
szdba3-XantphOS-C82C03 combination and phenyl bromide was introduced as
an electrophile. Since our borylation/amination study indicated that Suzuki

reaction could be dramatically facilitated by added water,107

water was also
charged at this point to assist the Suzuki reaction. As no amide was present in
this reaction, the only expected chemical event would be the desired Suzuki
coupling, or the undesired protodeborylation. To our pleasure, the Suzuki
coupling was the favored event and the desired biphenyl product 5.6 was isolated
in 75% yield over 2 steps without optimization. Therefore, the
szdbag-xantphos-CszCoa combination proved to be a good reagent combination
for Suzuki coupling, and luckily enough, the lr-catalyzed, water-promoted
deborylation of the boronic ester intermediate (see Chapter 4) did not occur. A

control experiment showed that the Suzuki coupling could also take place in the

absence of added water, albeit at a much lowered rate (overnight instead of 2 h).

84

 

Scheme 5.10 The C-H borylation/Suzuki under standard Buchwald amidation conditions

F30 \, CF3 -dmpe,HBpin = 032C03,PhBr,H204

 

 

cat. (Ind)lr(cod) [ECWCFj cat. szdbag-xantphos, F3Cm/\/CF3
l

‘ y‘ 150°C . DME.100°C V
Bpin I 75% overall :2

Having obtained this result, the one-pot borylation/amidation/Suzuki protocol
was tested (Scheme 5.11). Compound 2.1w was first subjected to the standard
borylation/amidation conditions. Since both the amidation and the Suzuki
required a stoichiometric amounts of base, we doubled the load of CszCO3, but
we kept the load of Pd catalyst and ligand the same. After completion of the

amidation, the crude mixture was directly treated with phenyl bromide and water.

Scheme 5.11 One-pot borylation/amidation/Suzuki protocol

 

 

 

F3C\/\/Brl cat. szdba3-xantphos,
FsCWBr cat. (Ind)lr(cod)-dmpe, HBpin l I, : ACNH2 (5 2a). 082003
l > I ' / >
V) 150°C V I THF 80°C
2.1w Borylation !L Bpin I Amidation
. I , - 2 _ '
V ' THF, 80 a? (Z 47% overall
I Bpin I Suzuki ph
5.3a 5.7

We noted that this Suzuki could be much more complicated by side-reactions
than that in Scheme 5.10. First, the excessive amide 5.2a might react with
phenyl bromide (amidation). Secondly, 5.3a might also react with phenyl
bromide at the amide nitrogen (amidation). Thirdly, it would still be possible for
the protodeboylation to take place. Despite these potential pitfalls, the desired

product 5.7 was isolated in 47% unoptimized overall yield. However, the

85

 

reaction also produced the deboylation side-product in about 15% yield.
5.5 Conclusions

In conclusion, we have successfully developed a 3-step sequence of C—H
borylation/amidation/oxidation of 3-substituted halobenzenes to afford
5-substituted 3-amidophenols in acceptable yields without intermediate isolation.
This development further expands the utility of the C—H borylation chemistry and
provides an alternative route for preparing these important compounds. The
catalyst combination is also found to be capable of promoting Suzuki couplings
and a borylation/amidation/Suzuki protocol can be expected. Applying this
borylation/amidation/oxidation process in the total synthesis of a natural product

will be discussed in Chapter 6.

86

Chapter 6. Attempted Total Synthesis of Autolytimycin Utilizing the C—H
Borylation/Amidationleidation Protocol
6.1 Autolytimycin and Ansamycin Family Natural Products

Over the past few decades, a series of natural products called the ansamycin

superfamily has been isolated (Figure 6.1).111

Structurally, these natural
products share a similar aromatic moiety called the mCyN unit, which consists of a
benzene core with a carbon, a nitrogen, and an oxygen substituents in an all-meta
relationship. A macrocyclic ring bridges the nitrogen and the carbon through a
macrolactam functionality. The benzene core may be further functionalized,
oxidized, or fused to form a naphthalene or naphthoquinone. The benzenic

103‘” geldanamycin,113 and ansamytocins,114

ansamycins, such as trienomycins,
whose aromatic cores are benzenes or benzoquinones, show significant
cytotoxicity and anticancer activity. The naphthlenic ansamycins, such as

8

naphthomycin,115 rifamycins,116 tolypomycin117 and damavaricin,11 whose

aromatic cores are naphthalenes or naphthoquinones, show antibacterial activity,

“13"” The mC7N unit of these natural

especially towards Gram-positive bacteria.
products is believed to be biosynthetically derived from
3-amino-5-hydroxybenzoic acid (AHBA), as mentioned in Chapter 5.97 Due to

the interesting biological activities and structural features, ansamycin natural

products have attracted significant attention from biological chemists as well as

87

 

synthetic chemists. Intensive total synthesis work on these natural products has
been performed and a number of reports have been published."2'121

Figure 6.1 Some ansamycin natural products

H 0“. OMe

Cy N
1; $0 TrienomycinA

 

Tolypomycin Y

O

  
 

- . MeO C
/\.%‘N /\. 2
. o H -

.~ MeO~K ‘I’OH O OH 1% MNH

 

\
l i II

I , , I
H 0 OH Oflo OR

Geldanamycm Damavaricin D

Rifamycins
Geldanamycin family is a subfamily of ansamycin natural products (Figure
6.2). These compounds all have a 19-membered lactam ansa bridge connecting
the C-substituent and the N-substitutent of the benzenic core. This ansa bridge
is densely functionalized with multiple stereogenic centers, oxygen substituents,

and stereochemically defined olefins. Among these structures, geldanamycin,113

88

herbimycins,119 and macbecins120 have benzoquinone cores, whereas a newer
family member reblastatin121 has a phenolic core. In addition to the difference in
the oxidation state of the benzene moiety, reblastatin also possesses the absence

of the C4,CS-unsaturation of the ansa bridge.

Figure 6.2 Geldanamycin family members

 

 

R‘ R2 R3 R4
HerbimycinA H OMe Me OMe
HerbimycinB H OMe H OMe
HerbimycinC H H H OMe
Macbecinl H OMe Me Me
Geldanamycin OMe H H OMe
I
OH
R ’I \ O
/ NM Reblastatin R=OMe
H Autolytimycin 6.1 R=H
\ OH MeO
be
MeO W OCONH2

Geldanamycin demonstrates its antitumor activity through binding to the
N-terminal ATP/ADP binding domain of Hsp90, a protein responsible of folding
other “client proteins” for conformational maturation. Such a binding leads to the
inhibition of the inherent ATPase activity of Hsp90, which in turn inhibits its
capability to fold its client proteins to their mature form and ultimately disrupts the

cell cycle.122

Reblastatin, in addition, is also reported to exhibit potent inhibitory
activity in the cell-based oncostatin M signaling pathway. Oncostatin M is a

pleiotropic cytokine with pro-inflammatory activity, which upregulates adhesion

89

molecule expression in endothelial cells and synergizes with lL-1 to promote
cartilage degradation. It is present in the synovium and synovial fluid of patients
with rheumatoid arthritis. Therefore, inhibition of oncostatin M can be potentially
important from an anti-inflammation point of view.123a

Autolytimycin (6.1), a new geldanamycin analogue, was first isolated in 2000

and 2001 independently by Stead and Jiang groups through fermentation with

1233,b 123d

Streptomyces. A third isolation was achieved in 2005 by Rascher group.
Autolytimycin also appeared as a hit structure in a patent.123e The structure of
autolytimycin shares an identical ansa bridge with reblastatin and the two natural
products only differ by a methoxy group on the benzene ring. Autolytimycin, like
geldanamycin and reblastatin, also interrupts Hsp90 protein and therefore has

1236 In addition, like

potential to control tumor growth and angiogenesis.
reblastatin, autolytimycin also demonstrates potent inhibition of oncostatin M and
IL-6-driven sPAP production with leo of 0.7 pM in HepGZBG cells and therefore
has potential to serve as an anti-inflammation agentma Moreover, autolytimycin
also exhibits quite interesting antiviral activity against HSV-1, HSV-2, vesicular

stomatitis virus, andcoxakie virus B3, etc.‘23b'C

This spectrum of interesting
biological activity makes autolytimycin highly attractive as a target for total

synthesis and further SAR studies on its structural analogues.

Although geldanamycin, herbimycin A, macbecin I, and reblastatin have all

90

succumbed total synthesis, to the best of our knowledge, autolytimycin has not
been accessed via total synthesis. Total synthesis is unlikely to provide more
material than that which is available from fermentation, which could provide up to
59 mg autolytimycin in a single batch.123d Nonetheless, a synthetic route toward
this interesting molecule would help to confirm its absolute stereochemical
assignment, which is currently based on analogy with other natural products in the
family. Moreover, a total synthesis that lends itself to analogue production could
be used to develop the biological properties of this molecule.
6.2 Reported Total Syntheses of Geldanamycin Family Natural Products

Most of the synthetic strategies for the construction of the geldanamycin
family natural products involve the preparation of the aromatic precursor, followed
by construction of the side chain from the C15 substituent toward C1.
Macrolactamization at the late stage furnishes the macrocyclic ring.

Pioneering work in this area traces back to 1989, when Baker and co-workers

achieved the first asymmetric total synthesis of macbecin |.120C

In their synthetic
strategy, a key epoxide opening was used for construction of the C9—C10 bond
(Scheme 6.1).

Evans and co-workers later achieved a more convergent route for the

120b

asymmetric total synthesis of macbecin | (Scheme 6.2). Although utilizing the

same aromatic starting material as well as the same macrolactamization method,

91

Evans’ total synthesis is highlighted by the strategic disconnection of the
C12—C1 3 bond, which was constructed via an aldol reaction. This disconnection
allows the union of the two segment pieces with similar sizes and complexity, and

therefore makes the overall total synthesis more convergent and favorable.

Scheme 6.1 Baker's syntheis of macbecin l

 

 

   

   

Q OMe
/ I l
MeO , _ MeO! \ h N \
lactamizatiorL OMe L2
elaboration 7 \\
MerEkOH (OTBS
M90 OC(O)NH2 ‘1. f/ 7 /
‘ 9 5
OTBS
‘.
I epoxide opening
oMe U
OH (PMe l
V (:————— MeO \/'l\ :: ‘,- OMe \ +I / 7 SOTBS
l ' N02 9 ores
OMe M9020 0M3 MeO

{1:0
10 '\

Another strategy involves disconnecting the aromatic segment from C15 in a
nucleophilic addition manner. Such a strategy has been used independently by

"9° (Scheme 6.3) as well as Tatsuta and co-workers119d in

Martin and co-workers
their syntheses of herbimycin A and formal synthesis of macbecin l. Although
these routes required a lengthy linear route to prepare the corresponding ansa

chain, their syntheses demonstrated the viability of preparing the aromatic

segment independently from the side chain and the late-stage coupling of the two

92

subunfis.

Scheme 6.2 Evans' syntheis of macbecin l
OMe

l \

l/ OMe

02N o s
lactamization OMe 13 J’x
'130 H :fi) N MS
1 OMe . ea “3 °" /\ \OMe
H012 I
M60 . OC(O)NH2

 

s ; / 5 N‘OMe
T880 0
l
Maldol
OMe QMe QMe
A 5 steps A
' I C::. __._‘:I'. MeO /\ 4::
VNOZ 12M NO2
OH Hozc e

 

TBSO o

Scheme 6.3 Martin '3 syntheis of macbecin I

 

 

 

Q
h 9,
MeO 15 ‘ '
Wt: Yfi lactamization
o l . i’
\ elaboration
pm \2 /OBPS
MeO .- \ OC(O)NH2 /‘
OTIPS
H nucleophilic addition
0'
OMe /E\15,OH
5ste s '
(l 3:: M MeO 560' OBPS
l N02 “WW
OH
OTIPS

The recent decade has witnessed extensive work on the total syntheses of

93

these natural products. Panek and Andrus have both been heavily involved in

this area 113.119b,1203

Somewhat surprisingly, these more recent efforts have not
brought more novel or convergent disconnection strategies. For example, both
Panek’s and Andrus’ synthetic strategies employed a rather lengthy and linear
construction from C15 to C1. Linearity in the total synthesis of complex
molecules tends to be inefficient and suffers from low overall yields. It also
retards the synthesis of analogous structures. Nonetheless, such total
syntheses can serve to test new synthetic tactics in a challenging environment.

Other retrosynthetic analyses have been put forward,124 such as a
ring-closing metathesis to construct the C4—C5 olefin in the late stage of the
synthesis. However, the successful applications of these strategies to the total
synthesis of these natural products are still pending.

Several bond construction approaches are common among all the reported
syntheses. For example, the amide linkage of the ansa chain to the aromatic
core was almost universally constructed late in the syntheses via Cl—N amide
bond formation. In addition, except very few examples,120c'121a'124b C8—CQ olefin
was almost universally constructed with a Wittig-typed olefination. Establishing
other alternative methods for the assembly of these units would be instructional

and potentially beneficial. For instance, disconnection of the 08-09 olefin

breaks the ansa chain into two pieces with similar sizes and complexity without

94

disruption of the stereogenic centers and the heteroatom substituents along the -
ansa chain. In this regard, Martin has reported an alternative strategy for
construction of 08—09 olefin through a [2,3]-sigmatropic rearrangement.125 In
his report, two advanced intermediates with multiple stereogenic centers could be
successfully coupled to give the trisubstituted olefin with the desired E geometry
in excellent yield (Scheme 6.4). This provides a useful alternative to Julia-typed

olefination methods, which could be often problematic with methyl ketones.126

Scheme 6.4 Martin '3 C8-CQ olefination approach

OMe
*9 9*?”
O3 150 O OH8 O

 

 

OTBS CTBS
SC(O)SMe
1. NaH, C32 9 OMe
2 Mel Bu3SnH,AIBN
3. heat 66% overall 15 O

(was OTBS

In 2005, Panek and co-workers reported the total synthesis of reblastatin with

a much more novel disconnection strategy.121a

Not only did they avoid the
C8—C9 Wittig olefination, but they also introduced the amide N—CAr bond to the
benzene ring via a Buchwald amidation (Scheme 6.5). In addition to their
application of novel chemistry to total synthesis, their overall route is more

convergent and concise than Panek’s original synthesis of herbimycin.11gb

95

Scheme 6.5 Panek's syntheis of reblastatin

 

 

151 / EN 1 / amide coupling 15 / Br
( H 9 H2N O
\ OH MeO elaboration

""">O/\./\/‘ocoui-i2 M80 \ 09M
5‘ ; w“*\//§l\:‘V\Z/'\/i
ores

l nucleophilic addition
elaboration

EtOVO

K

3 steps Meogz

H05 : + OMe

OHC ”W
O

OHCSMBr:

 

6.3 Our Strategic Disconnection and Retrosynthetic Analysis for
Autolytimycin

Autolytimycin 6.1, as discussed previously, has a different structure from all
its cousins (Figure 6.2). Thus a different synthesis strategy is needed to allow a
convergent coupling of highly elaborated segments in the late-stage synthesis
and avoid the linear construction from one end to the other. Another specific
goal of our synthesis is to establish a different and improved synthesis of the
aromatic structure of autolytimycin, which may shed light on the synthesis of
related natural products sharing the same or similar aromatic core structures.

As can be seen, the aromatic core of autolytimycin is a 5-substituted

3-amidophenol structure with three functionalized ortho/para directing groups all

96

in 3 meta relationship. Such a substitution pattern is different from all other
geldanamycin family members, and therefore many methods used to prepare the
aromatic cores of these other natural products are not easily applied to
autolytimycin. Additionally, this 1,3,5—trisubstitution pattern also poses its own
synthetic challenge, as traditional aromatic substitution is not able to provide such '
a structure efficiently. Although preparations of similar 5-substituted
3-amidophenol structures of other natural products, such as trienomycin,103'112
have been achieved, they tend to be lengthy and laborious (see Chapter 5,
Scheme 5.2).

As discussed in Chapter 5, we have established a very attractive, highly
efficient aromatic C—H borylation/amidation/oxidation protocol for the preparation
of 5-substituted 3-amidophenols from simple 3-substituted halobenzenes. Since
the aromatic segment of autolytimycin is a 5-substituted 3-amidophenol, utilization
of this C—H borylation/amidation/oxidation protocol to the total synthesis of
autolytimycin is attractive. Furthermore, we have demonstrated good functional
group tolerance of that protocol, especially the tolerance of the a,B—unsaturation of
the amide partner that resembles the C1-C4 portion of autolytimycin (Scheme
6.6). Therefore, it is very appealing to test the feasibility of applying this

borylation/amidation/oxidation protocol to total synthesis. Should this protocol

succeed, the preparation of the aromatic region of this type of natural products

97

would be dramatically simplified over the existing methods, and the power of C—H

borylation in bringing efficiency and speed of assembly to synthetic chemistry
would be highlighted.

Scheme 6. 6 Success in the borylation/amidation/oxidation with unsaturated amide
1. cat. (Ind)lr(cod)-dmpe, HBpin

 

H 2. cat. szdba3-xantphos, .
A TlgNHz, 052C033, DME _ A O
i " 3. filtration , M 1*
CIM Br 4. oxone acetone Cl um
66% overall

5.4n
However, as mentioned in Chapter 5, the borylation/amidation/oxidation
protocol works best if the aromatic bromide is electron-poor. Therefore, although
preparation of 5.4n (Scheme 6.6) is straightforward, this protocol could be
problematic on a phenyl bromide bearing the C15 alkyl chain of the target

molecule. Therefore, our plan was to apply this borylation/amidation/oxidation

Scheme 6. 7 Retrosynthetic analysis for autolytimycin
OH CH

A 0 K\ 0
15/\/\N*1\/\\ _B_Q_.M 15x wN/Kf/fi Suzuki
__~_—_> K 7 _———"—‘::)

 

 

v._._._ H .____._z___.__.
MeO . MeO
0H9 J\,..0P'
MeO . VOID
OC(O)NH2 V :8
9 6.2
OH 0
Vi . \ O - 'l
\I I / , C-H borylation/ H 1"sz
GB OMe Hal1 N / amidation/oxidaLoq ' I
15 + H 2 '1 \. + M30“
pp/ MeO Hal‘MHalz \* OP
MeO .é V0,, i
6.3 6.4 ‘ 6.5

98

strategy prior to the installation of the C15 alkyl substituent, as illustrated in
Scheme 6.7.

According to this plan, a late-stage ring-closing metathesis will be used -to
construct the C8—CQ olefin from the acyclic precursor 6.2. Such a ring-closing
metathesis has been attempted in the total synthesis of geldanamycin and

resulted in a failurema

However, although Andrus reported that his attempts
included different solvents, concentrations, temperatures, etc., the only catalyst
attempted was the Grubbs’ second generation catalyst. Since olefin metathesis
has been dramatically developed in recent years including the discovery of

microwave-assisted conditions1273

as well as the emergence of new catalysts with
much higher reactivity, such as Hoveyda-Grubbs' catalyst12qu and Grubb’s
fluorinated catalyst,127C the scope of successful metathesis has been considerably
increased. Given this situation, in addition to the higher flexibility of precursor
6.2 compared to Andrus’ precursor of geldanamycin due to the absence of C4—C5
olefin and a less crowded aromatic segment, we viewed our proposed ring-closing
metathesis as a challenge worth pursuing.

Compound 6.2 would arise from the union of the C15 substitutent and the
halobenzene segment 6.4, which would be assembled via our

borylation/amidation/oxidation protocol first. This should avoid the

aforementioned incompatibility of the electron-releasing group with the

99

borylation/amidation/oxidation protocol. In this context, a modified Suzuki
coupling between the corresponding aryl halide 6.4 and a corresponding
B—alkyl-BBN nucleophile 6.3 carrying the C15 alkyl chain was planned. Such
Suzuki couplings have been developed in quite a few laboratories over recent
years, and has proved a versatile strategy for late-stage construction of
C(sp3)—C(sp2) bonds.128 As mentioned previously, halide 6.4 would be prepared
from a dihalobenzene and a fully elaborated amide segment 6.5 via the C-H
borylation/amidation/oxidation protocol. Although our study in Chapter 5
demonstrates the versatility and functional group tolerance of this protocol,
application of this method to a system with such complexity has not been
attempted. Thus, the validation of the borylation/amidation/oxidation for complex,
functionalized substrates would be an important advance in this chemistry.
6.4 Synthesis of the Right-hand Segment

Our synthetic journey began with the construction of the right-hand segment
6.5 (Scheme 6.8). While previous syntheses used different methods to generate

113419421 we decided to build

the two stereogenic centers with oxygen substituents,
this moiety from the chiral pool. (L)—Threonic acid, which structurally resembles
the C5-08 moiety of 6.5, caught our attention. The literature preparations of a

(L)-threonic acid derivative start from vitamin C (6.6). Thus, following literature

procedures,129 the diol of 6.6 was first protected as an acetonide, followed by an

100

oxidative cleavage of the endiol to generate a four-carbon unit, 3,4—isopropylidene
(L)-threonic acid potassium salt 6.8. This salt, without purification, was alkylated
to afford a methyl ester (6.9). Subsequent TBS protection of the free alcohol
followed by a two-fold Grignard attack of the ester yielded the tertiary carb‘inol
6.11a. Dehydration provided the desired methyl olefin moiety in 6.12a.129°'d

Scheme 6.8 First-generation synthesis en route to the right-hand segment 6.5

OH
O>< O /
8H A___c___CI HzOz.K2¢Oa= -0 Mel : o>\
acetone, rt HZO,0°C tort HO H MeCN, reflux HO H

 

 

 

 

 

 

 

 

 

 

H06 60H 86% H06 70H COZK 900/0 2 steps COzMe
6.8 6.9
_0 f0
TBSCI, Imid, DMAP Q>< MeMgX A "O SOCIZ i—O
CH2C|2,rt TBSO‘LH ether, reflux TBSO::H py, 0 °C to rt TBSOTFH
COzMe 83% 2 steps OH 77%
6.103 6.11a 6.12a
r—OH QH QTS
MeOH/TFA eon __ Ho TsCl, TEA 2 3 ch03 _
TBSO- Hi Z c ' o '
rt CH2C12, 0 C to rt MGOH. 0 C
60%, 63% A OTBS 87%, 99% brsm i OTBS 33%
brsm 6.13a 6.14a
o \ \ 3
‘> /MgBr cat CuCN HO NaH, Mel ‘ MeO + TBSOW/
THF, -40 °c to -25 °c THF, 0 °c to rt
VkOTBS 97% OTBS 54% 6.17:: OTBS YOMG
6.15a 6.16a 41% 5-188 6.17a 6.18a

The acetonide protecting group was removed under acidic conditions to give
diol 6.131129“ Although the isolated material from this step clearly indicated the
survival of the TBS group under this reaction condition, the 60% yield was only

moderate, suggesting a significant loss of material. The primary alcohol of 6.13a

101

was tosylated, followed by an intramolecular displacement of the tosylate under
basic conditions to afford epoxide 6.15a. Epoxide opening was achieved with
vinyl Grignard using CuCN as the catalyst,130 generating a secondary alcohol
6.16a. Using other cupper sources such as CuBr and Cul gave inferior results.
Surprisingly, methylation of 6.16a came with significant silyl migration, giving the
desired methyl ether 6.17a and undesired methyl ether 6.18a in a 13:1 ratio.
Although methylation using MeOTf and 4-methyI-2,6-di-tert-butylpyridine gave
isomerially pure 6.17a without silyl migration, the reaction was very slow. In fact,
1.5 days of such methylation only afforded ~50% conversion. We then
reconsidered the choice of TBS as a protecting group. The lack of steric bulk
around the silicon may contribute to the ease of transfer to the neighboring
oxyanion during the methylation. Moreover, the low yield during the acetonide
removal (6.12a to 6.13a) may be partially due to methanolysis of the TBS group
and formation of water-soluble triol. On the basis of these uncertainties,
recourse to the sterically more crowded tri-iso-propylsilyl group (TIPS) was made.

We obtained the TIPS-protected acetonide 6.12b from two routes (Schemes
6.9 and 6.10). One route (Scheme 6.9) mimicked the chemistry shown in
Scheme 6.8, while the other “recycled" the TBS-protected 6.12a and 6.13a to the
desired TIPS variants (Scheme 6.10). Subjecting TIPS-protected 6.12b to the

acidic acetonide removal conditions afforded 84% yield of 6.13b along with 14%

102

Scheme 6.9 Second-generation synthesis en route to the right-hand segment 6.5

o o F0><
£0 TIPSCI, DMAP_ £0 MeMgX n soczi2
HO

t TIPSO+H

 

 

 

 

 

 

 

 

. H DMF, rt v TIPSO H ether, reflux py, 0 °C to rt:
COZMe 86% 002MG 84% OH 92%
6.9 6.10b 6.11b
:_ .0 / OH OH
J— MeOH/TFA‘ fiEOH __ HO TsCl,TEA -
TIPSO ,—H 0 °C to rt ' TIPSO H : CHZCIZ, 0 °C to rt '
A 84%, 98% A . OT'PS 92%, 99% brsm
6.12b brsm 6.13b
OTs o \
& K2003 - Sf ”MgBr cat. oucn = H0
MeOH, 0 °C THF, -40 °c to -25 °c
. OT'PS 93% OT'PS 76%, 95% brsm I OTIPS
6-14b 6.15b 6.16b
\ \
NaH, Mel ‘ MeO + TIPSO
THF, 0 °c to rt '
78% 6.17b OTIPS OMe
19% 6-13" 6.17b 6.18b

recovered starting material. This represented a much improved result compared
with 6.12a, indicating that the use of the TIPS protecting group was beneficial.
The same steps of tosylation, epoxide formation, and Cu-catalyzed epoxide ring
opening led to the secondary alcohol 6.16b. Gratefully, under the same
methylation conditions, 6.16b afforded the desired product 6.17b and the
undesired silyl migration product 6.18b in a much improved 4.2:1 ratio. Although
the amount of side-reaction was still significant, the yield of the desired product

6.17b was sufficient enough to carry out further elaborations (Scheme 6.11).

103

Scheme 6.10 Recycling of undesired TBS diol

 

 

OH MeO OMe O><
EOH cat. CSA, )K _ 0 TBAF _
TBSO H acetone, rt T880241 THF, 0 °C to rt
84% 97%
6.13a 6.12a

~o / ~o
,Lo>\ TIPSCI,DMAPA :0 \
HO""*—H DMF, rt 7 TIPSO l H
A 85% A
6.19 6.12b

 

The two olefins in compound 6.17b were successfully discriminated via an
Rh-catalyzed hydroboration with catecholborane (HBcat). Under those
conditions, the mono-substituted olefin chemoselectively reacted, leaving the
disubstituted olefin intact. This type of selectivity has been reported with similar

substrates.131

A subsequent oxidation with basic hydrogen peroxide furnished
primary alcohol 6.20 in good yield. PCC oxidation of 6.20 generated the desired
aldehyde 6.21, which, without purification, was subjected to a Wittig olefination to
give the cup-unsaturated ester 6.22 in a 13:1 E/Z ratio. Unfortunately, the E and
Z isomers were not separable at this stage. Conversion of the ester group to the
amide group was achieved with a standard Weinreb procedure using NH4CI and
AIMe3,132 which presumably generates an aluminum amide typed nitrogen
nucleophile. Luckily, after this transformation, the E and Z isomers of the

a,B-unsaturated amide could be separated by chromatography, with the desired E

isomer 6.5 obtained in 82% yield.

104

Scheme 6.11 Completion of the synthesis of the right-hand segment 6.5

 

 

 

fl 1. HBcat, Cth(PPh3)3 HO 0HC\
MeOS/ THF, rt MeO Poo/Sio2 MeO\/*
' 2. NaOH, H202 ' CHzClzrt
YOTIPS H20. 0 °C to rt 1 OTIPS 98% as is OTIPS
6.17b 81% 2 steps 6.20 6. 2 1
EtOzC o
EtOZC PPh3 % H “1%
' 2
Y M eOJ pre-mixed NH4CI-AIMe3 _
toluene 110 °C \% benzene, 45-50 °C ' Meofi/
98°/ 13: 1 \ OTIPS 82°/ Eonl ’
o I o y \l/‘OTIPS
6.22 6_5

Thus, the synthesis of the right-hand segment 6.5 was completed in 14 steps
from vitamin C in 22% overall yield. The overall process is efficient and high
yielding, and does not require any asymmetric induction.

6.5 Synthesis of the Left-hand Segment

Having obtained the right-hand segment 6.5, we turned our attention to the
preparation of the left-hand segment 6.3. Its synthesis would require some type
of asymmetric induction, at least for the stereogenic center at C14 (Scheme 6.12).

An asymmetric alkylation with a chiral auxiliary was proposed for this purpose.

Scheme 6.12 Retrosynthetic analysis for segment 6.3

/

K OP H
/ i : s, _crotylation
\/ G BIOMe OP! l' E W; flWfA ~——— ----- >

”We; = OMe: = OMe=
é OMeé

"0
IO

 

 

 

6.3
OP 0 . - OP 0 O
1 AD, oxudation !
I_ H ———— W “.9 XCW : XCIA/
é OMe i 3

Initially we focused on use of the imidazolidinone chiral auxiliary 6.23.133

105

This chiral auxiliary can be easily prepared from ephedrine and has been utilized
in our laboratory’s total synthesis of the proposed structure of amphidinolide A134
Thus, a large stock of 6.24 and the optimized reaction conditions are readily
available.

Following that procedure,134

the enolate of 6.24 underwent an asymmetric
allylation to give the corresponding product 6.25 (Scheme 6.13). Contrary to our
previous experiences, it was observed that LiHMDS worked better than NaHMDS,
giving an improved diastereomeric ratio of 12-15:1 versus 7:1 for NaHMDS.
However, scaling up the LiHMDS allylation (3.7 9 scale) resulted in some
problems such as gel formation during the reaction. Luckily, the two
diastereomers were separable by careful column chromatography. The chiral
auxiliary of 6.25 could be reductively removed by LiBH4 to furnish the alcohol 6.26
in 89% yield with quantitative recovery of 6.23. Our plan was to perform a
Sharpless asymmetric dihydroxylation135 on protected 6.26 to stereoselectively
generate the diol functionality. To our dissapointment, such a dihydroxylation did
not lead to a good stereochemical induction, with either PMB or TIPS protected
alcohol. Diastereomeric ratios of about 3:1 were observed, and the two
diastereomers were not separable, even after protection of the diol as an

acetonide. This twist led us to consider other approaches for the diol generation.

Particular interest was given to systems that could lead to the ready separation of

106

diastereomers, since the Sharpless asymmetric dihydroxylation can sometimes

give unsatisfactory results with unhindered monosubstituted olefins.”5

Scheme 6.13 First-generation synthesis en route to the left-hand segment 6.3

 

 

 

 

 

 

 

0 0 9 o o
\NJKNJK/ LiHMDS, then allyl-I \NANW LiBH4, H20 \NAN'H +oH
> _- > ,f
.- - THF. '73 °C .\—./ EtZO, 0 °C to rt t_J_ W
M; Pb 75% S isomer Mé‘ fph 89% 6.26 Mei. 13h :
6.24 5.25 100% 6-23 5.23 6.26
NaH, PMBCI j_ OPMB / AD-mix-a : 0PMB 9H
THF/DMF, rt 5 HZO/(BUOH, 0 0C
74% - - OH
0“ 6.27a 95%, 3.3:1 dr 5,233
Mi __
6 26 iTIPSCI, Imid, DMAP‘ OT'PS / AD-miX-a = OT'PS 0“
' CHZCIZ, rt ' HZO/tBuOH, 0 °C
90% £3.27!) 85%, 2.8:1 dr 52?:

In seeking for a more facile way to separate such diastereomers, we
considered the formation of a ring so as to turn the linear diastereomers into
hopefully more separable cis and trans isomers. Such a strategy was used in a
related system by Carter and co-workers during their attempt to synthesize
azaspiracid.136 Thus, we sought to reproduce their early-stage results.

This journey began with Evans oxazolidinone chiral auxiliary 6.30,137 which is
conveniently prepared from norephedrine 6.29 by treatment of carbonyl
diimidazole138 (Scheme 6.14). This switch from 6.23 to 6.30 was made simply
because the starting material to prepare 6.23, ephedrine, was no longer

commercially available.

107

Thus, following a literature acylation procedure that gave 6.31,139 the same
allylation was performed, furnishing 6.32 as a single diastereomer as indicated by
crude 1H NMR (> 95:5 dr). The chiral auxiliary was removed via a transacylation
reaction to afford the benzyl ester 6.33 along with quantative recovery of the chiral
auxiliary. Sharpless asymmetric dihydroxylation of 6.33 was accompanied by an
in situ Iactonization of the secondary alcohol to furnish a five-membered lactone
ring. TIPSCI protection of this crude mixture gave the corresponding silyl ethers
6.34a and 6.34b as a pair of cis and trans isomers. These two silyl ethers were
easily separable by column chromatography, giving the desired 6.34a in 52%
yield over the two steps. One drawback of the asymmetric dihydroxylation was
that, due to its heterogeneous nature, a reproducible reaction rate was not
achieved and the percent conversion of starting material varied from run to run.
Best results were obtained by stopping the reaction at 1-1.5 days regardless of
the conversion, since longer reaction times gave significantly lower yields.
Irrespective of when we stopped the reaction, the stereoselectlvity of this process
remained unsatisfactory (3:1). Nonetheless, since Carter and co-workers

‘36 in their synthesis, and since the two diastereomers

reported the same ratio
were separable, this result was deemed acceptable. That said, it would certainly

be useful if we could recycle or utilize the undesired isomer.

108

Scheme 6.14 Second-generation synthesis en route to the left-hand segment 6.3

o 0 O
HO NH ' '
\_/ 2 Im2C0 OAN'H (EtCO)ZO,DMAP,Et3N: Oka/

 

 

 

 

 

 

pg he CHZCI2.rt .L_{ THF.0°C tort _\___/
86% at n. 78% n: n
6.29 6.30 6.31
E: O
LiHMDS, then all l-l 3 ' re-mixed BnOH, BuLi
THF,-78°C \__/ THF,0°C
79% S isomer, 89% brsm PH: Me 97% 6.33 and 97% 6.30
6.32
09/0 .. /OTIPS
1.AD-mix-a, MeSOzNHz, v, ‘
NaHCOa, 'BuOH/HZO 6 34
BnO C / ' a
2 W 2. TIPSCI. DMAP
‘ CHZCl2,rt
52% 6.34a (60% brsm) and L 09,0 OTIPS
6-33 17% 6.34a (19% brsm)
6.34b

Shown in Scheme 6.15, the Iactone ring in 6.34a was reductively opened to
afford diol 6.35a. The primary alcohol in 6.35a could be easily and
chemoselectively protected with either a pivaloyl group140 or a trityl group.141 Mr.
L. A. Sanchez of our group demonstrated that the undesired isomer 6.34b could
undergo a similar process to afford 6.35b. In addition, Mitsunobu inversion of
the secondary alcohol in 6.35b followed by a reduction of the resulted ester gave
the same Tr ether 6.36b as obtained from 6.34a in reasonably good overall yield
(63%). This recycling process minimized the downside of the poor asymmetric
induction during the Sharpless dihydroxylation. However, given this recycling
protocol, the use of a Piv protective group would not be favored due to its

incompatibility with LiBH4 reduction.

109

Scheme 6.15 Second-generation synthesis en route to the left-hand segment 6.3 (continued)

 

 

 

 

 

 

Oio) ..../OT'PS LiBH4, MeOHf QH OT'PS pivc. : 9P” OT'PS
W“; THF. 0 ac to rt 5 DYICHzclz, O 0C to rt :
3 OH 90% 2 steps ' OH
6.34a 6.35a 5353
L TrCI, DMAP ‘ 0“ OT'PS
py. rt
81 %, 98% brsm. 2 steps ‘ 0”
6.36b
1. LiBH4, MeOH, 1- p-N0206H4002H.
Oj’O OTIPS THF, 0 0C to rt wTIPS PPh3, DIAD, THF, rt
2. TrCl, DMAP. ' 5H 2- LiBH4. MeOH.
py, rt THF, 0 °C to rt
634" 82% 2 steps 6'35b 77% 2 steps

Subsequent methylation of the secondary alcohol in 6.36alb was performed.
Under NaH-Mel conditions, methylation of 6.36a was accompanied by multiple
side-reactions. On the other side, the same methylation worked well with 6.36b
to afford 82% 6.39 after desilylation with TBAF (Scheme 6.16). This result
further confirmed the choice of Tr as the protecting group. That said, as
expected, this methylation step, like the methylation of 6.16b. also resulted in a
small amount of silyl migration (15% after silyl deprotection). The silyl migration
problem could be eliminated by using an alternative methylation method.
Treatment of 6.36b with KHMDS in toluene followed by methylation with MeOTi142

furnished pure 6.39 without silyl migration.143

However, the overall yield of 6.39
after desilylation via this route (86%) was not improved.
The primary alcohol in 6.39 was then oxidized to form aldehyde 6.41. This

oxidation was less facile than the oxidation of 6.20. Among different conditions

110

attempted, Swern oxidation proved the best. Other oxidants gave inferior results.
For example, using PCC resulted in epimerization of the a stereocenter, while-
using TPAP-NMO combination led to incomplete conversion.

According to our retrosynthetic plan (Scheme 6.12), the aldehyde functionality
in 6.41 needs to undergo an asymmetric crotylation to elongate the carbon chain
and generate the two stereogenic centers at C10 and C11. This crotylation could
be performed with various reagents.1“4'145 Among them, we chose Leighton’s

crotylsilane145 for that purpose due to its easy preparation and handling. Thus,

Scheme 6.16 Completion of the synthesis of the left-hand segment 6.3

 

 

OTr oTlPs KHMDS' MeOTf on OR‘ TBAF ‘ OTr oR‘
\KY Tol, -78 °C to rt 7 W2 THF, 0 °C to rt’ _ 2
' 0H 91% 6.37 only ‘ OR 94% 6.39 only ' 0R
535” 6.37, R1=TIPS, R2=Me 6.39, R‘=H, R2=Me
6.38, R‘=Me, R2=TIPS 6.40, R‘=Me. R2=H
L 1. NaH, Mel, THF, 0 °C to rt I

 

2. TBAF, THF, 0 °C to rt
82% 6.39 and 15% 6.40 2 steps

pre-mixed (COCI)2-DMSO,

 

 

 

 

 

T OH
3 CHZCIZ, -78 °c to rt ' H CHZCIZ, 0 °C to rt
‘ 0M9 99% as is ' OMe 64% OMe
6.39 6.41 6.43
MOMCI, iPerEt, DMAPA m cat. PPTS ; r Br
CHZCIZ, 0 °C to rt ; \ MeOH. rt ‘ /©/
84%, 91% brsm ' 2:4: 92% l

_.\N\
C137)
‘ N Cl
0“ QMOM l2,PPh3,lmid w 63 1
> ----- '5 . . \
WW CHZCIZ’n 5 ;_ \ I h
/
Br

IIO

 

; OMeé 710/ 5 OMG5 I
6.45 ° 6.46 ( 5-42

 

 

111

crude 6.41 was treated with reagent 6.42. To our pleasure, the desired product
6.43 was isolated in 64% yield as the only diastereomer. To the best of our
knowledge, application of Leighton’s asymmetric crotylation in total synthesis has

only been reported once145d

and utilization of 6.42 in total synthesis has not been
reported. The absolute stereochemistry of 6.43 was confirmed by the modified
Mosher ester analysis developed by Trost146 on the O-methylmandelate esters.
Thus, the secondary alcohol in 6.43 was esterified with both R and S isomers of
O—methylmandelic acid. 1H NMR spectra were recorded for 6.43, 6.47a, and
6.47b, and each proton in the spectra was assigned by its chemical shift, splitting
pattern and gCOSY experiment. The change in the 1H NMR chemical shifts

between 6.47a and 6.47b was consistent with an R-configuration assignment of

stereochemistry at C11 in 6.43 (Table 6.1).

Table 6.1 1H NMR analysis of the stereochemistry of 6.34 at C11

 

 

 

 

O
HO \ Ph 0 Ph
DCC,DMAP, R1 R2 ‘ T Q 1 2
CHZCIZ, rt 0 r R R
70% for 6.47a . . \
75% for 6.47b 5 OMeE
6.43 1 2
assumed stereochemistry 6.47a (R), R =H, R =OMe
6.47b (S), R‘=0Me, R2=H
Proton 15 14 a 13 12 10 9 b
6.43 3.03, 2.93 2.05 1.02 164,126 3.28 2.28 5.67 1.16
6.47b 2.99, 2.91 2.01 0.93 1.61,1.14 3.28 2.24 5.51 0.59
6.47a 2.84, 2.70 1.82 0.84 1.22, 0.92 3.19 2.39 5.63 0.91

A5(S-R) 0.15, 0.21 0.19 0.09 0.39, 0.22 0.09 -0.15 -0.12 -0.32

 

112

Having made the appropriate stereochemical assignments, our synthetic

‘47 of the free alcohol in 6.43 was followed by

journey continued. MOM protection
a mild acidic detritylation to give the free primary alcohol 6.45. The free alcohol
was iodinated128° to afford a primary iodide 6.46, which could be simply treated»
with ‘BuLi followed by B-OMe-BBN to generate 6.3. We favor storing alcohol
6.45 due to its stability, and then preparing and using 6.46 and 6.3 when needed.

In this way, alcohol 6.45, the precursor of 6.3, was synthesized in 14 steps
from norephedrine in 16% overall yield. With recycling of 6.34b, the overall yield
increased to 19%.
6.6 Coupling of Segments in the Late Stage

Having the fully elaborated segments 6.5 and 6.3 both in hand, we next
investigated the coupling of these pieces in the late stage. First, we attempted to
perform the C—H borylation/amidation/oxidation protocol with fully elaborated
right-hand piece 6.5 to prepare 6.4.
6.6.1 Choice of the Halides on the Aromatic Starting Material

As discussed before, the aromatic starting material should be a dihalide
(Scheme 6.7). One halide would be used for the amidation and the other for the
subsequent Suzuki coupling. It should be noted that in our previous studies

(Chapter 5), this type of substrate was purposefully avoided due to the uncertainty

of the reactivity of the second halide during the course of the amidation. The

113

only such substrate tested was 3-bromochlorobenzene 2.1a, which gave no
significant side-reactions because of the low reactivity of chloride towards either
the amidation or the Suzuki. However, this substrate might not be suitable for
this total synthesis due to the questionable reactivity of the chloride in the
successive Suzuki coupling. Hence, the behavior of a dihalide substrate, with
neither halide being chloride, in the borylation/amidation/oxidation protocol had to
be investigated.

Two related aryl dihalides, 1,3-dibromobenzene 2.1c and 1-bromo-3-
iodobenzene 2.1r, were first investigated in the borylation/amidation/oxidation
protocol. We hoped that for 2.1 r, the amidation would selectively occur on the
iodide and leave the bromide for Suzuki coupling. For 2.1c, we hoped that the,
first amidation would introduce enough electronic perturbation to the aromatic ring
so that the second bromide would not be reactive under the amidation conditions.

Unfortunately, our expectations went unmet. Reaction conditions that were
successful with 5.4n (Scheme 6.6) led to only 40-44% yield for 6.48 from isolated
2.2c and tiglic amide (Scheme 6.17), a much inferior result compared with the
formation of 5.4n. Analysis of the crude reaction product revealed that a major
side-reaction was the Suzuki coupling of the residual bromide with the boronic
ester, leading to significant dimer formation with various extent of amidation

coupling. Obviously, our thought that upon amidation, the remaining bromide

114

would be unreactive towards the undesired Suzuki side-reaction was not correct.
Stopping the amidation before consumption of its starting material, to our
disappointment, proved no big improvement.

Scheme 6.17 Amidation/oxidation of dihalobenzenes with tiglic amide

1. cat. szdba3-xantphos,

 

 

Bpin TlgNHz, C32CO3 OH
A DME, 100 °C _ a O
l/ ll 2. filtration r '\ ’L\/\
Br/MBr 3. oxone. acetone Br u i/
2.26 44% 2 steps 5.48
1. cat. szdbaa-xantphos,
Bpin TIQNHz, CSzCO3 OH
DME, 85 °C 0
/ l 2 filtration >
Br \ I 3. oxone, acetone Br [1%
2.2, 20% 2 steps 6.48

Next, we examined the use of 2.2r, hoping that the amidation of iodide would
be fast enough to discriminate against the undesired Suzuki reaction. This
expectation proved incorrect as well, as the yield of 6.48 dropped further to about
20% from isolated 2.2r. At the same time, the amount of Suzuki dimerization
products actually increased, indicating the possibility that the iodide might
participate in both the Suzuki and amidation competitively. The Suzuki
side-reaction was certainly a much bigger obstacle than expected. As a result,
we reconsidered 3-bromochlorobenzene as our starting arene. In this context,
we sought for conditions that would allow the chloride to be employed in a Suzuki

reaction or other equally productive transformations. Over the past several

115

years, Suzuki couplings of chlorides have been witnessed to dramatic

8 Thus we would look to see if some of the newly published

advances.‘4
conditions would be applicable to our synthesis.
6.6.2 Joining the Right-hand Segment with the Aromatic Segment Using
Borylation/Amidation [Oxidation Protocol

Our initial attempts toward using 3-bromochlorobenzene 2.1a in the
borylation/amidation/oxidation protocol to couple with amide 6.5 focused on
understanding the behavior of 6.5 under such conditions compared with tiglic
amide. Thus, boronic ester 2.2a was prepared in 97% yield via the borylation of
2.1a (Scheme 6.18). The amidation was then attempted with 1 equiv amide 6.5.
Two observations were quickly made. For one, amidation of 2.2a with 6.5 was
about three times slower than with tiglic amide. Also, at the end of the reaction
2.2a was fully consumed, but not 6.5. This clearly indicated that there were
side-reactions taking place on 2.2a, such as Suzuki couplings. These two
observations argued against the use of 2.2c or 2.2r as the aromatic substrate,
since the undesired Suzuki would be even more prevalent against the sluggish
amidation. Given that amide 6.5 was obtained via a multiple-step route and thus

more valuable, the amidation was modified to use excess 2.2a instead of excess

amide as described in Chapter 5.

116

Scheme 6.18 Amidation/oxidation protocol for the synthesis of 6.4

 

 

 

 

 

H cat. Irltowlellcodn-d‘bpy. Bpin cat. szdba3-xantphos.
Cl ‘0 Br n-hexane,9r;,°/:hen 70 C Cl Br DME, 95 °C
2.1a 2.2a
l Bpin _ 0H CIWOH
/
fl 9 8hr 0 V
filtration * /K O
\ ' \ '
Cl N / then oxone C'MN / M 9
H = H + Cl N / -
MeO acetone/ MeO H
water, rt MeO
l OTIPS 73% 5-4 OTIPS
L J 16% 6.50 OTIPS
2 steps
6.49 6.4 6.50

Thus, 1.5 equiv of pure bornoic ester 2.2a became the loading of choice for
the amidation/oxidation protocol. However, here a new problem emerged.
Oxidation of the crude amidophenyl boronic ester 6.49 failed to go to full
conversion under our standard operation conditions (1 equiv oxone per boron, 1:1
acetone/water, rt, 10 min). At the same time, the oxidation of the residual 2.2a
was complete. A reasonable explanation of this slower reaction rate of 6.49 was
its poor solubility in the oxidation medium, relative to the simple aryl boronic
esters in Chapter 2. Thus, modified reaction conditions using 1.5 equiv oxone
per boron, in 1.5:1 acetone/water for 40 min were examined. To our delight,
those conditions proved successful. Reaction between 2.2a and 6.5 afforded the
desired amidophenol 6.4 in 73% yield over the two steps. Hence, this
amidation/oxidation protocol proved successful to include even highly

functionalized amide coupling partners, such as 6.5. Compound 6.4 was

117

accompanied by about 16% Suzuki dimerization product 6.50, but the yield of 6.4
was high enough to continue with the synthesis. It should be noted that using
3-chlorobromobenzene (2.1a) in the 3-step one-pot borylation/amidation/oxidation
sequence was successful, but the overall yield dropped to about 48%. For this
reason, we prefer to run the borylation and the amidation/oxidation separately.
6.6.3 Attempted Suzuki Coupling of the Chloride

The success of the amidation/oxidation approach to afford 5-chloro
3-amidophenol 6.4 did not take away our worries. As mentioned previously,
although this amidation/oxidation protocol is highly efficient for preparation of
chloride 6.4, utilizing the same method for preparation of the corresponding
bromide or iodide is not expected. Therefore, the low reactivity of the chlorides
in Suzuki couplings148 has to be overcome. In this regard, we first looked to
transform the chloride in compound 6.4 to a more reactive aryl iodide using a
Finkelstein-type reaction. We tested Buchwald Cul-diamine conditions on model
compound 5.4n (Scheme 6.19).149 To our disappointment, this reaction failed.

No aryl iodide was observed, as only starting material 5.4n was recovered.

Scheme 6.19 Attempted Finkelstein halide exchange

OH Nal, cat. Cul- “:2 OH
2

‘
r

dioxane, 130 °C

0 54 NHTiQ >90% recovered 5.4n ' NHTig
. n

 

118

Therefore, the straightforward Suzuki reaction between the fully elaborated
chloride and the BBN-derived nucleophile (6.3) was attempted. Among different
reaction conditions that can promote Suzuki couplings from aryl chlorides,1‘“"150 a
Buchwald report using S-phos ligand150a caught our attention. Buchwald has
demonstrated a wide range of chlorides as suitable substrates in such Suzuki
couplings, including an example of using a B-alkyl-BBN derivative as nucleophile,
which was very similar to our B—OMe-B-alkyl-BBN coupling partner. Since these
Suzuki conditions utilize CsF as a promoter, the TIPS protecting group in
compound 6.4 became an issue. We worried that fluoride-promoted desilylation
during the reaction might adversely affect the proposed Suzuki reaction. To
avoid this potential complication, the TIPS protecting group was first removed by
TBAF to afford 6.4a as the free alcohol (Scheme 6.20). Previous Suzuki
reactions tolerated free alcohols on the electrophile,128° thus we considered that
the free alcohol in 6.4a would not obstruct the cross-coupling.

In this manner (Scheme 6.20), iodide 6.46 was first subjected to Li/I
exchange151 conditions with tBuLi to obtain a lithium species, which was trapped
with B-OMe-BBN to form the boron adduct 6.3.128 This boronate was then

1503 However,

allowed to react with 6.4a under Buchwald Suzuki conditions.
during this reaction, we observed that the Pd catalyst underwent rapid

decomposition to form Pd black. We attempted to compensate for this

119

decomposition by recharging the reaction with fresh Pd catalyst and ligand every
3 h over 9 h (total 20 mol% Pd). Careful analysis revealed that the desired
Suzuki coupling product 6.2 was formed, but the yield was only ~5%.
Dechlorination side-product was also observed. This result, though not
satisfactory, showed promise for using chlorides, such as 6.4a, as the Suzuki
electrophiles. We thus set out to examine reaction systems in an attempt to
optimize this Suzuki reaction.

Scheme 6. 20 Attempted Suzuki coupling

 

OH OH
l/l ii) Q l?
C' \ 3 ./ l TBAF Cl 3%
MeO THE“ MeO
~100%
OTIPS OH
6.4 6.4a

.' QMOM 1.2.3equivt-BuLi, m Li®
’ l

. ether, -78 °C _ ¢ OM e .
W 2. 2.8 equiv B-OMe-BBN: 9E? QMOM ;

- OMe“ THF. -78°C to rt W -
6.46 (1.15 equiv) = i

 

 

5 mol% Pd(OAc)2-

10 mol% S-phos,
added 4 times every 3 h,

6.4a, 3 equiv CsF

THF, 70 °C
(5%)

 

6.2

6.6.4 Model Studies of the Suzuki Coupling of the Chloride

Since both of the Suzuki coupling partners were obtained in multiple steps, we

120

recognized that it would be synthetically challenging to perform Suzuki
optimization studies using fully elaborated compounds 6.4 and 6.3. Thus, a
model Suzuki system was sought.

Before conducting even a model study, we wanted to insure that the 5% yield
was truly reflective of the low reactivities of the Suzuki coupling partners, rather
than other unforeseen problems. Therefore, we wanted to confirm that (a) Li/l
exchange indeed took place, (b) the boron adduct 6.3 was indeed generated, and
(c) literature Suzuki coupling was reproducible.

Along these lines, pentyl iodide 6.51a was first subjected to the Li/l exchange
conditions and the generated lithium species 6.52a was trapped with an aldehyde
(Scheme 6.21). Crude NMR of this reaction clearly indicated formation of the

desired alcohol. Thus the Li/l exchange step was confirmed.

Scheme 6.21 Control experiments of the Li/l exchange and the boronate adduct formation

QCHO OH
Br / i

 

 

 

 

2.3 equiv ‘BuLi
\/\/\| O a [ \/\/\Li 1 = \}
ether, -78 C warm to rt, 1 h l I
6.51a 6.52a 74% Br /
(1.15 equiv)
2 equiv 'BuLi_ l . l 1.6 equiv B-OMe-BBN_
' ether, -78 °C 1 L'; THF, warm to rt '
6.51a 6.52a
././ (9
l J!\ Li + /B/\/\/
e 6.53a 6.54a

Next, 6.51a was again subjected to the UH exchange condition, followed by

addition of B-OMe-BBN to generate a model boronate 6.53a. 11B NMR of this

121

solution showed two characteristic signals: one signal at 86 ppm, corresponding
to the neutral species 6.54a, and another at 0 ppm, corresponding to the anionic
adduct 6.53a (Scheme 6.21).1283'b These two species are known to exist in an
equilibrium, which lies in the direction of 6.53a with K.q ~ 100.128” Due to this
equilibrium, isolation and quantification of 6.53a or 6.3-type boronate adduct
would be a very tough task. Nonetheless, while not quantitative, this experiment
clearly confirmed the generation of 6.3-type boronate adduct.

Finally, a few Suzuki coupling reactions were carried out to test the
reproducibility of the reported conditions as well as the operational techniques
(Scheme 6.22). Commercial "BuLi 6.52b was treated with B-OMe-BBN, and the
generated boronate adduct 6.53b was allowed to react with 3-chloroanisole under
conditions similar to those reported by Buchwald but using Davephos ligand
instead.150b Contrary to the reaction between 6.3 and 6.4a (Scheme 6.20), the
Pd catalyst did not decompose and only 5 mol% Pd loading was needed to
smoothly carry this reaction to full completion as judged by GC and GC-MS.
These reaction conditions were also found to be compatible with 5.4n without
protection of either the phenol or the amide, giving the desired coupling product in
~53% yield with only slight contamination by unreacted, inseparable starting

material 5.4n (ca 5-7°/o).

122

Scheme 6. 22 Control experiments of the Suzuki coupling
5 mol% Pd(OAc)2-
7.5 mol% Davephos,
3-Chloroanisole, 3 equiv CsFy MGOWBU
' /

 

 

 

 

dioxane, 70 °C
1.3 equiv [ (9 full conversion
_ B-OMe-BBN‘ , Li _
MU THF, rt ' f \ /\/\ 10 mol% Pd(OAc)2-
65“ M 089 15 mol% Davephos, OH
(1.3 equiv) L. e J 54" 3 .
6.53b . , eCIUIV CSF ; A
NMe dioxane, 70 °C 33
2;- >900/ ' BUMNHTIQ
_ / \\ o converSlon
DavePhos - \ /
: >_
(3sz

On the basis of these control experiments, we concluded that the 5% yield of
6.2 via Scheme 6.20 was reflective of the true reactivity of the two coupling
partners under the reaction conditions. The question of what caused the low
reactivity was next to be addressed.

In this regard, the Li/I exchange of the iodide 6.46 was scrutinized. Although
we were sure that the exchange conditions indeed generated the Li species, it
was possible that the Suzuki reaction was adversely affected by the different
solvent system or concentration, or by the Lil by-product that came along with the
UH exchange. To understand the effect of this Li/l exchange on the Suzuki
coupling, the two control experiments in Scheme 6.22 were repeated with material
prepared by a Li/I exchange from an iodide 6.51a (Scheme 6.23).

As seen in Scheme 6.22, the Suzuki coupling between 3-chloroanisole and
6.53b, prepared from 6.52b via a single B/Li exchange, was successful with a full

consumption of the chloride starting material. Yet the Suzuki coupling between

123

3-chloroanisole and 6.53a, prepared from 6.51a via a sequential Li/l and B/Li
exchange, gave only ~30% conversion (GC, uncorrected) of the chloride (Scheme
6.23). The same trend was observed in the Suzuki coupling with 5.4n. With a
single B/Li exchange, 6.53b successfully coupled with 5.4n to give > 90%
conversion, whereas providing the boron adduct 6.53a via a Li/l exchange from
iodide 6.51a completely shut down the Suzuki reaction. In addition to the low
conversion, it was also observed that Pd-catalyst decomposition to Pd black was
severe in these reactions. This failure clearly demonstrated the offensive effect

of the UH exchange step on the Suzuki coupling.

Scheme 6. 23 Suzuki coupling with added Li/I exchange step

1. 2.6 equiv lBuLi
ether, -78 °C A _
\/\/\l . = l
2. 3 equ1v B—OMe-BBN I \/ 8W 5
6°51“ THF, warm to rt 9

l
- I eO l
(1.3 equuv) L 6.538 s

l

 

3-Chloroanisole, 3 equiv CsF
5 mol% Pd(OAc)2-7.5 mol% Davephos Meow n-C5H11
I dioxane, 80 °C 7 ”\y
‘ ~30% conversion

 

”I

5.4n, 3 equiv CsF

l
l

 

 

7.5 mol% Pd(OAc)2-11 mol% DavePhos, OH
added 4 times every 3 h A
dioxane, 70 °C 5

II I
_ M n
no reaction n C5H11 NHT'Q

Although we were not sure exactly why such Li/l exchange step would cause
the Suzuki coupling to fail, we attempted to further manipulate the Suzuki

conditions to be compatible with this exchange step. Along these lines, the

124

Suzuki coupling of 3-chloroanisole with 6.53a, obtained from 6.51a after two
exchanges, was repeated with several different Pd catalysts (Pd(dppf)Cl2 and
Pd(OAc)2), ligands (Davephos, S-phos, (2-biphenyl)P‘Bu2,150C
(2—biphenyl)PCy2,15°C and AsPh3), and promoters (CsF, KF, K3PO4'nH20, and
CszCoa). Both conventional heating and microwave irradiation were examined.
Among all combinations attempted, the best reaction system consisted of
Pd(OAc)2, in conjunction with Davephos or S-phos ligand, promoted by CsF or
K3PO4'anO under conventional heating conditions. Although those
combinations were found to tolerate the UH exchange step, Pd decomposition
remained severe and required recharging of the Pd catalyst and ligand to
compensate for this decomposition. Nonetheless, these combinations all
pushed the Suzuki coupling of 3-chloroanisole to > 90% conversion, with the
fastest reaction (total 9 h) observed with the Pd(OAc)2-S-phos-K3PO4'nHZO
combination (Scheme 6.24).
Scheme 6. 24 Improved Suzuki coupling with added L17! exchange step

1. 2.6 equiv ‘BuLi
W\ ether, -78 °c = Li®
' 2. 3 equiv B-OMe-BBN B/W

6-513 THF warm to rt ' G
- ' MeO 1
(1.3 equw) L 6. 5 33

 

3-Chloroanisole, 2 equiv K3PO4-nHZO
5 mol% Pd(OAc)2-1O mol% S-phos
added 3 times every 3 h _ MeO \ n-Can
THF, 70 °c ' U
> 90% conversion

 

125

Table 6.2 Protecting group study

 

OR‘

‘1

Cl/ ‘C ‘N’Tig

 

 

 

1. ’euLi - \ l ‘2 0R1
! \ R
ether,-78°C l Ll® conditions A
W' 2. B-OMe-BBN ‘ \ W THF, 70 0c 4 A¢\ aTig
65“ THF, warm to rt '89 "'C5H11 N
MeO R2
6.53a
Entry R1 R2 Reaction condition Results3
1 H H Pd(OAc)2-S-phos-CsF no reaction
2 H H Pd(OAc)2-Davephos-CsF no reaction
3 En H Pd(OAc)2-S-phos-CsF no reaction
4 Bn H Pd(OAc)2-S-phos-K3PO4'nHZO no reaction
5 TIPS H Pd(OAc)2-S-phos-K3PO4°nHZO ~30% conversion
6 TIPS H szdbaa-S-phos-K3P04'nHZO trace conversion
no 8 k',
7” TIPS H Pd(OAc)2-S-phos-TIOEt ”Z” '
loss of TIPS
8 TIPS H Pd(OAc)2-S-phos-TI2C03 no reaction
Pd OAc -S- hos-K PO 'nH 0
9C TIPS H ( )2 p 3 4 2 trace conversion
A920
Pd OAc -S- hos-K PO 'nH O
106 TIPS H ( )2 p 3 4 2 no reaction
AngO3
Pd OAc -S- hos-K PO 'nH O
11“ TIPS H ( )2 p 3 4 2 no reaction
AQNO3
no Suzuki,
12 Ac H Pd(OAc)2-S-phos-K3PO4' nHZO
loss of Ac
no Suzuki,
13 AC H szdba3'S'phOS'K3PO4'"H20
loss of Ac
no Suzuki,
14 Ac H Pd(OAc)2-S-phos-CsF
loss of Ac
Suzuki occurred,
1 5 TIPS Boc Pd(OAc)2-S-phos-K3PO4'nHZO ,
complex mixture
16 TIPS SEM Pd(OAc)2-S-phos-K3PO4'nHZO ~30% conversion
no Suzuki,
1 7 Ac Boc Pd(OAc)2-S-phos-CsF ,
loss of Tlg

 

All reactions were run in 0.15-0.25 mmol scale, with 4 times of periodical addition of 5 mol% Pd
catalyst and 10 mol% ligand (7.5 mol% in case of Davephos). 3 equiv bases were used, except
K3PO4'nHZO (2 equiv). See experimental section for a general procedure. ‘ Judged by crude 1H

NMR. b Reaction was run in THF/water 3:1. ° 1 equiv Ag per halide.

126

To our great disappointment and surprise, use of S-phos did not work at the
coupling of 5.4n with 6.53a (Entry 1, Table 6.2). No reaction took place as 5.4n
was left unreacted, as observed by NMR. Up to this point, the failure of the -
Suzuki coupling probably should not be attributed solely to the Li/l exchange,
because such an exchange could be tolerated by the reaction with
3-chloroanisole, yet could not be tolerated by the reaction with 5.4n. Thus the
failure of using 5.4n in the Suzuki coupling is more likely due to a combination of
the Li/l exchange and the intrinsic nature of 5.4n, which might be linked to the
presence of the phenol and the amide functionalities. Such functional groups in
5.4n, in the Li/l exchange milieu, might either destabilize the boron nucleophile, or
destabilize the Pd catalyst, ultimately leading to a failed reaction. Understanding
this problem, the next task was to protect these groups and test the Suzuki
coupling thereafter (Table 6.2).

Disappointedly, protecting the phenol and the amide did not lead to an
improved Suzuki coupling. Protection of the phenol functionality as a benzyl
ether showed no reactivity toward the Suzuki reaction (Entries 34). Protection
as an acetate led to exclusive hydrolysis of the protecting group (Entries 12-14).
Only TIPS-protected phenol, under the Pd(OAc)2-S-phos-K3PO4'nH20 conditions,
gave ~30% conversion (Entry 5). TI bases have previously been shown to

dramatically improve the reactivity of Suzuki reactions.152 Unfortunately,

127

experiments employing Tl bases afforded no success (Entries 7-8). Adding
silver salts, such as AgNO3, Ang03, and A920, into the reaction system to
sequester the halide also had little positive effect (Entries 9-11). Protection of
the amide nitrogen also failed to improve the reactivity. An SEM-protected
amide, for instance, did not couple more effectively than the unprotected amide
(Entries 5 and 16). Protecting the amide nitrogen as an imide only led to
significant hydrolysis during the Suzuki reaction. 11B NMR of these failed Suzuki
couplings showed the absence of the neutral B-alkyl BBN species (86 ppm) as
well as the absence of the anionic B-OMe-B-alkyl BBN adduct (0 ppm). A signal
at 33 ppm did emerge, which was attributed to the decomposition of these two

reactive species.1283

Finally, although the TIPS-protected phenol gave ~30°/o
conversion in this model coupling (Entry 5), it did not work in the real system, as
protection of the free phenol in 6.4 as a TIPS ether resulted in a complete failure
in the coupling with 6.3 (Scheme 6.25).

Due to these negative results and the difficulties in isolating and handling the
B-alkyl BBN species, an approach to the Suzuki coupling that would obviate the
UH exchange milieu had to be considered. One option was to use the
trifluoroborate as the Suzuki coupling partner instead of the 9-BBN adduct. Alkyl

trifluoroborates have been developed in recent years as excellent Suzuki coupling

partners.153 Several advantages, such as no protodeborylation, ease for

128

isolation and purification, no handling and storage issues, and reasonably good
reactivity have been identified for these substrates. Unlike 9-BBN adducts,
which are always in equilibrium with their neutral species following loss of the
methoxide and are therefore difficult to isolate, alkyl trifluoroborates are crystalline
solids and can be purified very easily by crystalization. Therefore, it is possible
to subject a pure boron species to the Suzuki conditions without problems from

the solvent, concentration or Lil contamination.

Scheme 6. 25 Application of the TIPS-protected phenol in the Suzuki coupling to the real system

 

OH OTIPS
A Q l \ 9
ClM\u ./ TIPSCI, DMAP ‘ CI / 14%
v H
100% M90
6.4 OTIPS 6.4b OTIPS

 

1. 3.1 equiv t-BuLi,
| QMOM ether, -78 °C A g OM e
W 2. 2.5 equiv B-OMe-BBN, GB QMOM
‘ OMe‘ THF, -78°C to rt W

6.46 _ OMe; #
(1.5 equw) 6.3

5 mol% Pd(OAc)2-

10 mol% S-phos,
added 4 times every 3 h,
6.4b, 2 equiv K3PO4'nH20

THF, 70 °C '

 

 

 

 

6.2

Thus (Scheme 6.26), the lithium species 6.52a, obtained from 6.51a via Li/l

129

exchange, was treated with triisopropyl borate followed by acid hydrolysis. The
intermediacy of the boronic acid was confirmed by formation of the pinacolate
6.55. Compound 6.55 was then allowed to react with KHF2 under literature
conditions153 to give the desired trifluoroborate 6.56 as a crystalline solid, which
gave clean 1H, 13C and 11B NMR spectra. Pure 6.56 was then subjected to the

Suzuki conditions with 5.4n and its derivatives.

Scheme 6.26 Preparation of the trifluoroborate
'BuLi l l B(O’Pr)s i

 

 

 

 

l
~= . W ' . - W .
' ether, -78 °C L L'j warm to rt |L B(OH)2.
6.51a 6.52a ”
HCI, then pinacoL \/\/\ . KHF2 ‘ \/\/\
ether, rt 5 8pm MeCN/water, rt v BFaK
6-55 51% overall 6.56

To our great frustration, 6.56 turned out to be an even worse coupling partner
than 6.53a. The Pd catalyst decomposed even faster than the reactions in Table
6.2 and no Suzuki couplings were observed (Table 6.3).

To make the situation worse, the loss of the chloride in Entry 1 might suggest
that the problem of the Suzuki coupling is more complicated than we had
expected. Such a dechlorination would likely occur with a successful oxidative
addition followed by a B-H elimination from Pd-bound methoxide. This can be
further supported by the absence of such dechlorination product once the solvent
is switched from methanol to THF/water (Entry 2). Thus the failure of the Suzuki

coupling might lie not in the oxidative addition step, but rather in a later step in the

130

Table 6.3 Use of trifluoroborate in Suzuki coupling

 

 

 

OR‘
JO
CI /’Ime 1
R2 QR
ditions
WBF3K COD : A
solvent, 70 °C I I -
6.56 n-C5H11MN’T'9
R2
Entry R1 R2 Reaction condition Result‘9
1 En H Pd(OAc)2-S-phos-K2CO3, trace Suzuki
MeOH" 82% dechlorination
Pd(OAC)2-S-phOS-C52C03,
2 Bn H o t'
THF/water1021b " reac '0”
Pd OAc -S- hos-K PO 'nH O
3 TIPS H ( )2 p 3 ‘ 2 no reaction

THFC

All reactions were run in 0.12 mmol scale. ’ Judged by crude 1H NMR. b 10 mol% Pd and 20
mol% ligand, 4.5 h, then additional 10 mol% Pd and 20 mol% ligand, 4.5 h. 3 equiv base. ° 5 mol%
Pd and 10 mol% ligand added 4 times every 3 h, then overnight. 2 equiv base.

catalytic cycle.

A bromo version of the Bn-protected phenol was prepared and subjected to
the Suzuki coupling conditions using boron adduct 6.53a as the nucleophile
(Scheme 6.27). Again, the conditions gave no Suzuki coupling. Although this
result may not directly suggest a successful oxidative addition, it is consistent with
our hypothesis that the Suzuki coupling has other problems, and simply changing
the reactivity of the halide may not be sufficient to achieve a success.

We considered that other possibilities leading to a problematic Suzuki

coupling might include (a) a relatively rapid decomposition of the boron coupling

partner, (b) a kinetically sluggish transmetalation, or (c) a relatively rapid Pd

131

Scheme 6.27 Coupling with a bromide

 

 

 

 

OH OB” cat. szdba3-xantphos, OBn
A BnBr, cho3 ; \ TlgNHz, Cs2CO3 4 (l\
M DMF, rt I / dioxane, 100 °C l /:
Br Br quantitative Br Br 61% BrMNHTig
1. 2.8 equiv 'BuLi f

\/\/\ ether, -78 °C ‘ y LI®
' 2. 2.5 equiv B-OMe-BBN V\ W ‘
6-518 THF, warm to rt ’89 .
(1.3 equiv) MeO J

6.53a
OBn 5 mol% Pd(OAC)2-
'\ 10 mol% S-phos
Q added 3 times every 3 h, OB”
/ .
Br NHTig 2 equw K3PO4~nHZO V‘ \
THF, 70 °c "T l

n-C5H11 / NHTig
decomposition. Among these factors, the intrinsic sluggish nature of the
transmetalation seems the least likely, since we were able to couple 6.53b and
5.4n, as shown in Scheme 6.22. The Pd decomposition is also not very
probable, as Mr. L. A. Sanchez in the group demonstrated that the Pd
decomposition issue is more likely caused by air or moisture intrusion, since
running the reaction with extreme care could eliminate the Pd black formation.
Even these dry anaerobic conditions did not lead to a successful Suzuki coupling.
Therefore, the remaining issue, namely the rapid decomposition of the boron
coupling partner, which was supported by 11B NMR, becomes our most likely
explanation. Compared with the success of the coupling between 6.53b and
5.4n (Scheme 6.22), it is possible that organoboron coupling partner

decomposition may be the major harmful effect of the UH exchange milieu. That

132

said, this may be only one of several reasons for the failed Suzuki reactions
(Table 6.2 and Table 6.3). Recent results from Mr. L. A. Sanchez in the group
demonstrated the feasibility of utilizing an isolated alkyl boronic acid in the
coupling with the chloride in the model system.154 The application of such
conditions to the real system is expected.
6.7 Conclusions

While the total synthesis of autolytimycin remains elusive, our efforts
successfully demonstrated the viability of utilizing the C—H
borylation/amidation/oxidation protocol on a fully elaborated amide segment to
synthesize the aromatic core of autolytimycin. However, we have not been able
to use the planned Suzuki coupling to further elaborate the synthesis and couple
the left-hand piece to the aromatic ring. Problems for this Suzuki coupling point
to the UH exchange milieu as well as the presence of the amidophenol
functionality in the electrophile. Although we have not been able to gain enough
understanding to overcome these problems, it appears that the instability of the
organoboron species under the Suzuki conditions may be one of the reasons for

the failed coupling.

133

Summary

Through our work, we have demonstrated that catalytic C—H borylation has a
wide potential to be utilized in organic synthesis. It can not only be used to
prepare aryl boronic esters, but also be used to directly functionalize complicated
substrates, such as amino acid derivatives. In combination with subsequent
oxidation, deuteration, and amidation reactions, it allows for rapid construction of
uncommon but potentially useful synthetic intermediates and building blocks.
We have also demonstrated in the area of total synthesis that a
borylation/amidation/oxidation protocol can be used to include highly
functionalized amide substrates, which could lead to the efficient construction of

the aromatic core structure of autolytimycin.

134

Chapter 7. Experimental Details and Compound Characterization Data for
C-H Borylation and Related Reactions
7.1 Materials and Methods
7.1.1 Materials and Methods For C—H Borylation of Simple Aromatics

Unless otherwise noted, for C—H borylation and the one-pot reactions thereof,
all arene substrates were purified before use. Solid substrates were sublimed
under vacuum. Liquid substrates were refluxed (or stirred if the boiling points are
too high) over Na, CaHz, or molecular sieves (4 A) overnight, and then distilled
and degassed. Pinacolborane (HBpin) was stirred over PPh3, vacuum
transferred into an air—free flask and brought into the glove box. A simple
distillation was also sufficient. Bis(pinacolato)diboron (szinz) was used without
purification. Solvents for the C—H borylation were purified and rigorously dried.
Cyclohexane was washed with concentrated H2804 until the acid layer was
colorless, followed by washes with water and saturated NaHCO3, then dried over
MgSO4, refluxed over Na, distilled, and degassed. n-Hexane, and other alkane
solvents, such as pentane, heptane and octane, were refluxed over Na, distilled,
and degassed. All solvents should pass the Na-benzophenone test inside the
glove box. lr catalysts for C—H borylation were prepared according to literature

155356 Ligands for C—H borylation were obtained from the

procedures.
commercial sources and used without purification.

For the oxidation protocol, oxone was purchased as 2KHSOs-KHSO4-KZSO4
and used as a ~0.3 mol/L aqueous solution. Reagent grade acetone was used

without purification, and technical grade acetone also worked well.

135

For the deuteration protocol, D20 (99.9% D) and acetic anhydride were used
without purification. Commercial boronic acids were used as received and the
corresponding boronic esters were prepared from these boronic acids and
unpurified pinacol (see Section 7.2.3 for details). Crabtree catalyst was used as
received. Ethereal solvents such as THF and DME were distilled over Na.

For the amidation protocol, the amides coupling partners were obtained from
their commercial sources and were used as received. Non-commercial amides
were prepared and used without purification (see Section 7.2.4 for details).
szdbag (Strem) and xantphos ligand were used as received. Cs2003 was dried
by heating at 130-150 °C under high vacuum for 1-2 days before use. Ethereal
solvents such as THF and DME were distilled over Na. Dioxane, obtained as
anhydrous grade (99.8%), could be used directly without purification.

All small-scale borylation reactions were set up under nitrogen atmosphere
inside the glove box, and carried out in oven- or flame-dried thick-walled sealed
air-free flasks, magnetically stirred, and monitored by GC-FID and GC-MS
(standard GC temperature program: 70 °C for 2 min, followed by a 20 °Clmin
ramp to 250 °C, and stay at 250 °C). Large-scale borylation reactions were also
set up in the glove box but were carried out in oven- or flame-dried round-bottom
flasks with vent to nitrogen balloon or nitrogen manifold, and high-temperature
reaction conditions were avoided. Yields refer to isolated, clean materials. In
case of volatile products that could not stand forcing evaporation, yields were
corrected to discount the added weight of the residual solvents. All spectral data

reported were obtained from solvent-free materials, unless specifically noted.

136

Thin-layer chromatography was performed with 0.25 mm pre-coated silica-gel
plates on aluminum. Silica gel was supplied as 60 A (230-400 Mesh). GC-FID
spectra were recorded on a Varian CP-3800 instrument with capillary WCOT
fused silica column (30 m*0.25 mm ID coating CP-SIL 8 CB). GC-MS spectra
were recorded on either a Varian 2200 GC-MS instrument, or a HP 5890 Series II
GC in tandem with a Trio-1 MS instrument. The latter instrument was also used
to record MS spectra with direct-probe inlet. Infrared spectra were obtained on a
Nicolet lR/42 spectrometer. Melting points were measured on a Thomas-Hoover
capillary melting point apparatus and are uncorrected. 1H NMR and 13C NMR
spectra were recorded on Varian Gemini-300, Varian lnova-300, Varian VXR-500,
and Varian Unity-plus 500 spectrometers (300, 500 MHz for 1H, respectively, and
75, 125 MHz for 13c, respectively). Chemical shifts for 1H and 13c were reported
in part-per-million (ppm) values relative to the residue peaks of solvent CDCl3 (8
7.24 for 1H and 77.0 for 13C) or acetone-d6 (8 2.04 for 1H and 29.8 for 13C). 2H
NMR spectra were recorded on Varian Unity-plus 500 spectrometers (500 MHz
for 1H, 76.75 MHz for 2H), with chemical shift relative to acetone-d6 internal
standard (8 2.04 for 2H). 11B NMR spectra were recorded on Varian lnova-300,
Varian VXR-500 and Varian Unity-plus 500 spectrometers (500 MHz for 1H, 160
MHz for 11B), with chemical shift relative to BF3-OEt2 as external standard (8 0.0
for 11B). High-resolution mass spectra were obtained at Michigan State
University Mass Spectrometry Service Center with a JOEL-AX505 mass
spectrometer (resolution 7000), or at the Mass Spectrometry Laboratory of

University of South Carolina. Preparative GC was performed with a Varian 920

137

GC-TCD with packed C18 column. Combustion analyses were performed on a
Perkin Elmer Series II 2400 CHNS/O analyzer.
7.1.2 Materials and Methods For C-H Borylation of Aromatic Amino Acid
Substrates

This part of work was performed at Johnson & Johnson Pharmaceutical
Research and Development, LLC. Due to the differences in laboratory
equipments and requirements, differences in materials, methods and operations
from Section 7.1.1 may exist. The following descriptions only depict what was
performed and may not be the optimal operations.

For this part, all amino acid starting materials were purchased from PepTech
as N-Boc amino acids and methylated using commercial (trimethylsilyl)-
diazomethane reagent (see Section 7.2.2 for detail). Non-commercial amino

157 (see

acid starting materials were prepared according to literature procedures
Section 7.2.2 for detail). The substrates were not purified before use.
Bis(pinacolato)diboron (szinz) and ligand d'bpy were used without purification.
Solvents for borylation, including cyclohexane and THF, were obtained as
anhydrous grade and used as received. Other solvents, such as acetone for
oxidation, benzene and methanol for methyl ester formation, were all obtained as
reagent grade and used as received. Ir catalyst for C—H borylation was prepared
according to literature procedures.156

All borylation reactions were set up in air using think-walled

microwave-adaptive vials that were not dried. Reactions were performed in a

CEM Discover microwave synthesizer (75 W maximum power) equipped with

138

CEM Explorer automated workstation and magnetically stirred. Reactions were
monitored by HP 1100 reverse phase analytical HPLC (water/acetonitrile as
mobile phase) with SUPELCO column (33*4.6 mm, 3 pm) and 214/254 nm dual
UV detectors, and/or Agilent 1100 reverse phase LC-MS (water/acetonitrile as
mobile phase) with SUPELCO column (50*2.1 mm, 3 pm), the latter of which was
also used for mass spectra recording (positive ESI). Column chromatography
was performed on silica gel 60 A (230~400 mesh). Preparative HPLC was
performed on Gilson 215 liquid handler reverse phase HPLC, with YMC HPLC
column (ODS-A, 100*30 mm, S-5 p, 12 nm) and 214/254 nm dual UV detectors
using 0.1% TFA-containing water/acetonitrile as the mobile phase, which was
evaporated by Vlrtis lyophilizer. 1H and 13C NMR spectra were recorded on
Bruker Avance-300 or Bruker Avance-500 spectrometers with chemical shifts
reported relative to TMS (8 0.00 ppm). Melting points were measured on a
Thomas-Hoover capillary melting point apparatus and are uncorrected (Note:
Lyophilized sample do not give reliable melting points. All lyophilized samples
were dissolved in a solvent and then slowly evaporated before measuring the
melting point). IR spectra were recorded on Nicolet 670 FT-IR spectrometer.
Elemental analysis results were obtained from Robertson Microlit Laboratory.
High-resolution mass spectra were obtained at Johnson and Johnson
Pharmaceutical Research and Development, LLC with FAB ionization.

7.2 Preparation of Non-commercial Starting Materials

7.2.1 Preparation of Non-commercial Arenes

1,3-Dibromo-2-iodobenzene (2.13): To 4.0 g 2,6-dibromoaniline (16 mmol)

139

 

I ‘ in a round bottom flask (not dried) was added 6.7 mL concentrated

Br Br
U HCI (80 mmol, 5 equiv) followed by 30 mL water and ~30 9 ice.
2.1s

 

The whole mixture was cooled by an ice bath and a suspension

 

was generated. In a separate beaker, 1.3 g NaNOz (19 mmol, 1.2 equiv) was
dissolved in 10 mL water and also cooled by an ice bath. The cold NaNOz
solution was then introduced dropwise to the vigorously stirred suspension
containing 2,6-dibromoaniline, and the temperature was controlled below 5 °C by
addition of ice. Upon complete addition, the mixture was stirred for another 25
min until a homogenous light greenish-yellow solution was formed. This solution
was filtered through glass fiber to crushed ice. Upon stirring, urea was added by
small portions until gas evolution ceased. To this solution was added dropwise a
solution of 5.3 g Kl (32 mmol, 2 equiv) in 30 mL water. The mixture turned brown
with gas evolution and quickly became a slurry. It was stirred at room
temperature for 1 h and then 45 °C for 45 min, until there appeared a
homogeneous brown solution on the bottom with foams and slurries on top. This
mixture was filtered through glass fiber and cotton to collect the insolubles, which
was further dissolved in ether. The ether layer was washed successively with
NaHSOa, 3 M NaOH, and water, dried over M9804 and evaporated. 5.45 9 dark
brown crystals (94%) were obtained and sublimation under 0.1 mmHg vacuum at
85 °c afforded slightly orange crystals; mp 97 0c (lit158 99-995 °C). 1H NMR (300
MHz, CDCI3): 8 7.54 (d, J = 8.0 Hz, 2 H), 7.05 (t, J = 8.0 Hz, 1 H); 13C NMR (75
MHz, CDCI3): 8 131.3, 131.1, 130.3, 109.4; IR (neat): 3054, 1547, 1418, 1387,

772 cm'1; LRMS m/e 360 (M+), 232, 153, 127, 74.

140

7.2.2 Preparation of Non—commercial Aromatic Amino Acid Starting

 

Materials
' Cl . 2-tert-Butoxycarbonylamino-3-(2,6-dichloropheny|).
mcozm propionic acid methyl ester (3.1h): 6.2 mL commercial LDA
ClNHBoc
3.1h solution (1.8 M in heptane/THF/ethylbenzene, 11 mmol, 2.2

 

 

 

eq) was further diluted with 16 mL THF and cooled to 0 °C by ice bath. To this
solution was added dropwise a solution of 740 pL N-Boc glycine methyl ester (5
mmol) in 5 mL THF over 5 min, followed by another 4 mL THF. The mixture was
stirred at 0 °C for 15 min, and charged with a solution of 2.4 g 2,6-dichlorobenzyl
bromide (10 mmol, 2 equiv) in 3 mL THF. The reaction mixture turned light
yellow. The ice bath was then removed and the reaction was allowed to warm up
to room temperature and kept for 1.5 h. Water was then added and the mixture
was stirred upon slow addition of 1 M HCI until pH ~ 5. Layers were separated
and the aqueous layer was extracted twice with EtOAc. The combined organic
layer was dried over M9804 and evaporated. The crude material was purified by
preparative HPLC (50/50 ——+ 30/70 water/acetonitrile). After lyophilization, 595
mg of 3.1h (34%) was obtained as a yellow oil, which solidified upon storage at
room temperature; mp 69-72 °C. 1H NMR (300 MHz, CDCI3): 8 7.30 (d, J = 8.0 Hz,
2 H), 7.12 (t, J= 8.0 Hz, 1 H), 5.18 (d, J: 8.8 Hz, 1 H), 4.7-4.8 (m, 1 H), 3.74 (s, 3
H), 3.28-3.44 (m, 2 H), 1.33 (s, 9 H); 13c NMR (75 MHz, coch): 8 172.6, 155.3,
136.6, 133.4, 129.0, 128.7, 80.2, 52.9, 52.7, 34.6, 28.6; LRMS (ESI): m/e 292,
248 ([M-Boc+2H]*).

2-tert-Butoxycarbonylamino-3-(6-fluoro-1H-indol-3-yl)—propionic acid

141

 

 

COZMe methyl ester: 880 mg 6-fluorotryptophan (4 mmol) and

F

WW” 673 mg NaH003 (8 mmol, 2 equiv) were suspended in
H

20 mL water and 15 mL acetonitrile To this suspension

 

was added a solution of 1.08 g Boczo (5 mmol, 1.25 equiv) in 5 mL acetonitrile.
The suspension turned to a clear solution upon stirring at room temperature.
After the reaction was judged complete by HPLC, it was treated with 1 M HCI until
pH ~ 4 and directly lyophilized. The crude residue was then dissolved in 21 mL
benzene and 6 mL MeOH. With vigorous stirring, (TMS)diazomethane solution
(2 M in hexanes) was slowly added and the reaction medium was kept slightly
acidic by introduction of 1 M HCI dropwise. After the mixture became sustained
yellow, the solution was evaporated. The residual was extracted with CHzClz,
washed with saturated N3HCO3, water and dried over MgSO4. Chromatography
purification (1:1 heptane/EtOAc) afforded 1.1 g desired product (86% 2 steps) as
a white solid; mp 170-172 °C (dec); 1H NMR (300 MHz, CDCI3): 8 8.05 (br, 1 H),
7.45 (dd, J = 5.3, 8.6 Hz, 1 H), 6.85-7.05 (m, 3 H), 5.05 (br, 1 H), 4.65 (m, 1 H),
3.67 (s, 3 H), 3.25 (br, 2 H), 1.43 (s, 9 H); LRMS (ESI): m/e 695 ([2M+Na]+), 359

([M+Na]+), 281, 237 ([M-Boc+2H]+).

 

CO Me 1 3-(2-tert-Butoxycarbonylamino-2-methoxycarbo
2

F
SN ll NHBoc nyI-ethyl)-6-fluoro-indole-1-carboxylic acid tert-butyl
u Boc 3-7b ester (3.7b): 537 mg (1.6 mmol)

 

 

 

N-Boc-6-fluorotryptophan methyl ester, obtained from the previous reaction, and
21.5 mg DMAP (0.176 mmol, 11 mol%) were suspended in 20 mL acetonitrile.

To this suspension was added a solution of 460 mg Boczo (2.1 mmol, 1.3 equiv)

142

in 5 mL acetonitrile. The suspension gradually turned to a clear solution and the
mixture was kept at room temperature. After being judged complete by HPLC,
the reaction mixture was diluted with EtOAc and washed with brine followed by
water, dried over M9804, and evaporated. Chromatography purification (2:1
heptane/EtOAc) yielded 643 mg of 3.7b (92%) as a gel—like material. 1H NMR
(300 MHz, CDCI3): 8 7.83 (d, J = 8.9 Hz, 1 H), 7.36-7.43 (m, 2 H), 6.98 (dt, J = 2.1,
8.9 Hz, 1 H), 5.15 (d, J: 7.6 Hz, 1 H), 4.6-4.7 (m, 1 H), 3.69 (s, 3 H), 3.1-3.3 (m, 2
H), 1.66 (s, 9 H), 1.43 (s, 9 H); 13C NMR (75 MHz, CDCI3): 8 172.6, 161.4 (d, J =
239 Hz), 155.4, 149.7, 136.0, 127.2, 124.6, 119.9 (d, J= 9.9 Hz), 115.4, 111.1 (d,
J = 24.2 Hz), 103.0 (d, J = 28.3 Hz), 84.5, 80.4, 54.0, 52.7, 32.2, 28.7, 28.5; LRMS
(ESI): m/e 895 ([2M+Na]+), 459 ([M+Na]+), 337 ([M-Boc+2H]*), 281, 237; Anal.
Calcd for szHngNzosz C, 60.54; H, 6.70; N, 6.42. Found C, 60.81; H, 7.00; N,
6.21.

General Procedure for methylation of Other N-Boc-amino Acids:
Commercially available N-Boc—amino acid was dissolved (or suspended if not
soluble) in 3:1 ~ 4:1 benzene/MeOH to make a solution (or suspension) at the
concentration of ~ 0.2 M. (TMS)diazomethane (2 M hexanes) was added via a
syringe dropwise until gas evolution ceased and the yellow color sustained. The
complete methylation could be confirmed by HPLC. The solution was then
evaporated and dried over high vacuum overnight to afford a crude product.
This product normally contained a small amount of MeOH and some TMS residue
but no further purification was necessary as long as no residual benzene was

detected (1H NMR 7.36 ppm). In that case, further purification could be

143

performed by dissolving the material in CH2CI2, washing with saturated NaHC03
and water, drying over MgSO4, evaporating and drying over high vacuum
overnight.
7.2.3 Preparation of Aryl Boronic Pinacol Esters from the Corresponding
Boronic Acids
General Procedure: Aryl boronic acid and 1 equiv pinacol were dissolved in
anhydrous ether and the mixture was stirred at room temperature. The crude
mixture was dried over MgSO4 (not necessary) before being evaporated. The
residue was passed through a silica plug (CH2CI2 or hexanes/CHzClz) to afford the
desired pinacol ester.
T 3,4-Dichlorophenylboronic acid pinacol ester (2.2t): Following
CI

the general procedure, 1.91 g dichlorophenyl boronic acid (10 mmol)

Bpin and 1.2 g pinacol (10 mmol, 1.0 equiv) were dissolved in 50 mL ether
2.2t

 

 

and stirred at room temperature for 1 h. MgSO4 was added and the
mixture was filtered. The filtrate was evaporated and passed through a silica
plug (CHZClz). Evaporation afforded 2.66 g of 2.2t as colorless oil (97%). 1H
NMR (500 MHz, CDCI3): 8 7.84 (d, J: 1.3 Hz, 1 H), 7.57 (dd, J = 1.5, 7.9 Hz, 1 H),
7.42 (d, J = 7.9 Hz, 1 H), 1.32 (s, 12 H); 11B NMR (160 MHz, CDCI3): 8 30.6; 130
NMR (125 MHz, CDCI3): 8 136.6, 135.5, 133.7, 132.3, 130.0, 84.3, 24.8; IR (neat):
2980, 1591, 1383, 1354, 1144, 1096, 845, 666 cm"; LRMS (El) m/e 272 (M*), 257,
186, 83.
3,4-Dimethylphenylboronic acid pinacol ester (4.4b): Following the

general procedure, 1.25 g of boronic acid 4.4a (8.3 mmol) and 1.0 g pinacol (8.3

144

Me mmol, 1.0 equiv) were suspended in 20 mL ether and stirred at room

Me
temperature for 1 h. The mixture quickly turned to a homogeneous

Bpin
4.4b
filtrate was evaporated and passed through a silica plug (CH2CI2). Evaporation

solution. MgSO4 was added and the mixture was filtered. The

 

 

afforded 1.66 g of 4.4b as colorless oil (86%). 1H NMR (500 MHz, CDCI3): 8 7.57
(s, 1 H), 7.53 (d, J: 7.4 Hz, 1 H), 7.13 (d, J: 7.4 Hz, 1 H), 2.26 (s, 3 H), 2.25 (s, 3
H), 1.32 (s, 12 H); 11B NMR (160 MHz, CDCI3): 8 31.4; 13c NMR (125 MHz,
CDCI3): 8 140.0, 135.92, 135.86, 132.4, 129.1, 83.6, 24.8, 20.0, 19.4; IR (neat):
2978, 1615, 1399, 1356, 1148, 1132, 1094, 857, 669 cm"; LRMS (El) m/e 232
(M*), 217, 146, 132.

FT 2,3-Dimethylphenylboronic acid pinacol ester (4.5b):
@Me Following the general procedure, 1.23 g of boronic acid 4.5a (8.2

Bpin
4.5b mmol) and 0.97 g pinacol (8.2 mmol, 1.0 equiv) were suspended in

 

 

 

20 mL ether and stirred at room temperature for 1 h. The mixture quickly turned
into a homogeneous solution. MgSO4 was added and the mixture was filtered.
The filtrate was evaporated and passed through a silica plug (CHZClz).
Evaporation afforded 1.56 g of 4.5b as colorless oil (82%). 1H NMR (500 MHz,
CDCI3): 8 7.59 (d, J = 7.4 Hz, 1 H), 7.19 (d, J = 7.4 Hz, 1 H), 7.07 (t, J = 7.4 Hz, 1
H), 2.45 (s, 3 H), 2.25 (s, 3 H), 1.33 (s, 12 H); 11B NMR (160 MHz, CDCI3); 8 32.0;
13C NMR (125 MHz, CDCI3); 8 143.0, 136.5, 133.5, 132.3, 124.8, 83.4, 24.8, 20.4,
18.4; IR (neat): 2978, 1590, 1379, 1350, 1306, 1140, 1034, 851, 727, 669 cm";

LRMS (El) m/e 232 (W), 217, 175, 132.

145

 

trans-Z-Styreneboronic acid pinacol ester (4.9b):

I©T1J

mmol) and 1.18 g pinacol (10 mmol, 1.0 equiv) were dissolved in 20 mL ether and

Following the general procedure, 1.48 g of boronic acid 4.9a (10

 

stirred at room temperature for 1 h. The reaction was directly evaporated and
the residue was passed through a silica plug (1 :1 CH2Cl2/hexanes). Evaporation
afforded 2.18 g of 4.9b as colorless oil (95%). 1H NMR (500 MHz, CDCI3): 8
7.46-7.48 (m, 2 H), 7.38 (d, J = 18.4 Hz, 1 H), 7.25-7.33 (m, 3 H), 6.15 (d, J =18.4
Hz, 1 H), 1.30 (s, 12 H); 11B NMR (160 MHz, coch); 8 30.5; 130 NMR (125 MHz,
CDCI3): 8 149.5, 137.5, 128.9, 128.6, 127.1, 83.3, 24.8; IR (neat): 2978, 1624,
1387, 1352, 1325, 1211, 1144, 970, 853, 748 cm"; LRMS (El) m/e 230 (M‘), 215,

187, 173, 157, 144, 130, 105, 77.

 

[ trans-1-Octeneboronic acid pinacol ester (4.10b):
WBDID]

4.10b Following the general procedure, 1.01 g of boronic acid
4.10a (6.5 mmol) and 0.77 g pinacol (6.5 mmol, 1.0 equiv) were dissolved in 20
mL ether and stirred at room temperature for 1 h. The reaction was directly
evaporated and the residue was passed through a silica plug (1:2
CHzCI2/hexanes). Evaporation afforded 1.17 g of 4.10b as colorless oil (76%).
1H NMR (500 MHz, CDCI3): 8 6.61 (dt, J = 17.9, 6.5 Hz, 1 H), 5.40 (dt, J = 17.9,
1.6 Hz, 1 H), 2.10-2.15 (m, 2 H), 1.35-1.40 (m, 2 H), 1.22-1.29 (m, 18 H), 0.85 (t, J
= 7.0 Hz, 3 H); 11B NMR (160 MHz, CDCI3): 8 30.1; 130 NMR (125 MHz, CDCI3): 8
154.9, 83.0, 35.8, 31.7, 28.9, 28.2, 24.8, 22.6, 14.1; IR (neat): 2978, 2959, 2928,
2857, 1640, 1399, 1364, 1319, 1148, 972, 851 cm"; LRMS (El) m/e 239 ([M+H]*),

223, 181, 153, 139, 111, 95, 81, 67, 55, 41.

146

7.2.4 Preparation of Non-commercial Amides

 

0 N-(4-Methoxybenzyl)urea (5.2d): 2.74 g

HZNANHPMB

5.2d
containing 1.7 mL concentrated HCI (~20 mmol, 1 equiv). Upon stirring, a

4-methoxybenzylamine (20 mmol) was dissolved in 60 mL water

solution of 2.43 g KOCN (30 mmol, 1.5 equiv) in 20 mL water was added and the
mixture was stirred at room temperature for 18 h, and precipitate formed. The
precipitate was collected by filtration and the cake was dissolved in 40 mL hot
absolute EtOH and recrylstalized. After drying under high vacuum, 1.97 g of
white needle-like crystals (55%) were obtained; mp 159-161 °c (11059 163 °C). 1H
NMR (300 MHz, acetone-d6): 8 7.19-7.22 (m, 2 H), 6.82-6.87 (m, 2 H), 5.93 (br, 1
H), 5.12 (br, 2 H), 4.21 (d, J = 5.8 Hz, 2 H), 3.75 (s, 3 H); 13C NMR (125 MHz,
acetone-d5): 8 159.5, 159.3, 133.8, 129.4, 114.4, 55.4, 43.7; IR (neat): 3426, 3337,
1645, 1601, 1560, 1516, 1248, 1034, 826, 812 cm"; LRMS: m/e 180 (M‘), 136,
121, 106, 77. Anal. Calcd for C9H12N202: C, 59.99; H, 6.71; N, 15.55. Found C,

59.61; H, 6.55; N, 15.43.

 

F o ‘ N,N-Dibenzylurea (5.2e): 9.85 g (50 mmol)
A ,Bn
H2” 3 N,N-dibenzylamine was suspended in 200 mL water containing 4.2
n
5-29 mL concentrated HCI (50 mmol, 1 equiv). Upon stirring, a

 

 

 

solution of 6.1 g KOCN (75 mmol, 1.5 equiv) in 200 mL water was added. The
mixture was stirred at room temperature for 36 h (open flask), during which time a
large amount of white precipitate was formed. The precipitate was collected by
filtration and the cake was dissolved in minimum amount of hot absolute EtOH

and recrystallized. After being dried over high vacuum, 8.5 g of a white

147

needle-like crystalline solid (71%) was obtained, mp 122.5-124 °c (lit160 125-125
°C). 1H NMR (300 MHz, acetone-d5): 8 7.22-7.35 (m, 10 H), 5.55 (br, 2 H), 4.45 (s,
4 H); 130 NMR (75 MHz, acetone-d6): 8 159.7, 139.5, 129.3, 125.2, 127.8, 50.0; IR
(neat): 3410, 3337, 1535, 1595, 1495, 595 cm"; LRMS: m/e 240 (M*), 149, 105,
91, 79, 55. Anal. Calcd for C15H15N20: c, 74.97; H, 5.71; N, 11.55. Found 0,

75.05; H, 6.42; N, 11.51.

Tiglic amide (5.2h): In an oven-dried 100 mL round-bottom

 

 

o
'12?“ka flask (no stirrer bar) topped with a dried air condenser and flushed
5.2h
with nitrogen, 3 g (30 mmol) tiglic acid was heated to 50 °C neat in

 

an oil bath. 2.5 mL (34 mmol, 1.14 equiv) SOCI2 was slowly added followed by
1.5 mL (20 mmol, 0.67 equiv) DMF. The reaction mixture quickly turned into a
liquid. It was kept at this temperature for 30 min and cooled to room temperature.
The residue was slowly added to 150 mL cold (0 °C), concentrated aqueous
ammonia. During the addition, the temperature was kept at 0 °C by addition of
ice. The round-bottom flask containing tiglic acid chloride was rinsed with
aqueous ammonia. Upon complete addition, the resulting aqueous mixture was
extracted three times with EtOAc. Combined organics were dried over M9804
and evaporated. 2.1 g of 5.2h (70%) was obtained as a white crystalline solid,
mp 71.5-73.5 °o (lit.161 77 °C). 1H NMR (300 MHz, acetone-d5): 8 5.1.7.0 (br, 2 H),
6.46 (qq, J = 7.1, 1.4 Hz, 1 H), 1.79 (apparent t, J = 1.4 Hz, 3 H), 1.70 (dq, J = 6.9,
1.1 Hz, 3 H); ”C NMR (75 MHz, acetone-d5): 8 171.2, 132.5, 130.7, 13.9, 12.4; IR
(neat): 3339, 3177, 1667, 1603, 1420, 1123, 625 cm"; LRMS: m/e 99 (W), 82, 55,

44. HRMS (El): m/e calcd for [C5H9NO]+ 99.0683, found 99.0684.

148

7.3 General Procedures for C—H Borylation and Related One-pot Protocols
General Procedure A (C—H Borylation for Isolation of the Boronic Esters):
Small scale: in the glove box, arene, HBpin (1.5-2.5 equiv), (Ind)lr(cod) (2 mol%),
and dmpe/dppe (2 mol%) (or [lr(OMe)(cod)]2 (1.5 mol%) and d'bpy (3 mol%))
were transferred into an air-free flask equipped with a stirrer bar in the following
order: HBpin with lr calatyst, followed by ligand, followed by arene. 0.5-2 mL
(per mmol of arene) solvent (cyclohexane, n-hexane, heptane, or octane) could
be used to help dissolution and transfer. The flask was sealed and brought out
of the glove box and placed in an oil bath heated to 150 °C (for (Ind)lr(cod)-dmpe)
or 100 °C (for (Ind)lr(cod)-dppe), or stirred at room temperature (for
[lr(OMe)(cod)]2-d'bpy) until the reaction was judged complete by GC-FID. (Note:
in the cases of multiple borylations and borylations of sluggish substrates,
periodic cooling and purging of the H2 gas help to maintain an effective rate of
reaction.) At that time the reaction was allowed to cool to room temperature.
Upon stirring, the residue was quenched by dropwise addition of MeOH until gas
evolution ceased. The mixture was concentrated by a gentle nitrogen flow and
the resultant syrup was passed through a silica plug (10-15 cm long, 2 cm wide for
1-2 mmol scale, CHzClz or hexanes/CHzClz) to give the desired boronic ester.
Large scale: in the glove box, arene, HBpin (1.2-2.5 equiv), [lr(OMe)(cod)]2
(0.25-1 mol%) and d’bpy (1 equiv per lr) were transferred into a round-bottom
flask equipped with a stirrer bar in the same order (CAUTION! Mixing HBpin with
large amount [lr(OMe)(cod)]2 may cause significant gas evolution!) 0.5-1 mL

(per mmol of arene) solvent (cyclohexane, n-hexane, heptane, or octane) could

149

be used to help dissolution and transfer. The flask was sealed by a septum and
brought out of the glove box. It was topped with a nitrogen balloon or a nitrogen
line connected to the manifold, and the reaction was stirred at room temperature
until the reaction was judged complete by GC-F ID. In case a full conversion was
not achieved and the reaction had indication of slowing down, the flask could be
topped with a dried condenser and heated to 70 °C. Upon completion, the
reaction was allowed to cool to room temperature and quenched by dropwise
addition of cold MeOH (CAUTION! Quenching a large-scale borylation with
large amount of residual HBpin may cause significant gas evolution and heat
buildup!) until gas evolution ceased. The mixture was concentrated by rotary
evaporation or a gentle nitrogen flow and the syrup was passed through a silica
plug (CH2CI2 or hexanes/CHzClz) to give the desired boronic ester.

General Procedure B (C—H Borylation/Oxidation for Preparation of
Phenols): A borylation reaction with 1 mmol arene was set up according to the
general procedure A and judged complete by GC-F ID. Solvent for this borylation,
if any, was removed by a gentle nitrogen flow. To this residue was added 3.2 mL
acetone, and the mixture was stirred to produce a homogeneous solution. An
aqueous solution of 0.615 g oxone (1.0 mmol, 1.0 equiv) in 3.2 mL water was
introduced dropwise over 2-4 min. Upon complete addition, the reaction mixture
was vigorously stirred for an additional 7 min. At that time the reaction was
quenched with aqueous NaH803 (solid NaH803 also worked). A layer of dark
orange oil was typically observed. The reaction mixture was then extracted

three times with ether or CH2C|2. Combined organics were washed with brine

150

followed by water, and concentrated. The crude material was dissolved in
minimum amount of CH2Cl2 or pentane/ether and passed through a plug of silica
gel. Evaporation afforded the phenol.

General Procedure C (C—H Borylation/Oxidation for Amino Acid
Substrates): A thick-walled microwave vessel was charged with a stirrer bar, 0.5
mmol starting N—Boc-amino acid methyl ester and desired amount of szinz,
[lr(OMe)(cod)]2. and d'bpy in open atmosphere. 2 mL solvent (normally
cyclohexane, some cases THF) was added to the vessel and the system was
flushed by nitrogen before the vessel was sealed. It was then irradiated by
microwave and held at 120 °C for 10 min (lt normally took 5-10 min for the
temperature to increase to 120 °C and this period was not counted in those 10
min). After cooling down to ambient temperature, the solvent was removed by a
gentle nitrogen flow.

If the boronic ester was to be isolated, the reaction was quenched with a few
drops of MeOH, concentrated and passed through a silica plug (ether/CHzClz). lf
oxidation was to be performed, to this sticky residue was added 3 mL acetone and
1 mL water. The mixture was stirrer until no gas was evolving. An aqueous
solution of 400 mg oxone (0.65 mmol, 1.3 equiv) in 2.5 mL water was added to the
above mixture dropwise, and the mixture was stirrer at room temperature for 12
min before quenched with NaHSOa. It was extracted three times with ether,
washed with water, dried over MgSO4, filtered, and evaporated. The crude
product could be purified by column chromatography (CH2CI2/ether) followed by

evaporation and drying over high vacuum. Alternatively, preparative HPLC could

151

also be used for purification. In that case, the combined ether extraction was
directly evaporated and re-dissolved in acetonitrile or THF and the product was
purified by Gilson HPLC followed by lyophilization.

General Procedure D (C—H Borylation/Deuteration for Preparation of
Deuterated Aromatics): A borylation reaction with 2 mmol arene was set up
according to the general procedure A and judged complete by GC-FID. Solvent
for this borylation, if any, was removed by a gentle nitrogen flow. The residue
was placed under high vacuum for a few hours and the flask was back filled with
nitrogen. To the reaction were added 0.5 mL D20 and 3-4 mL dry THF or DME.
The flask was resealed and heated in an oil bath to 150 °C until the reaction was
judged complete by GC-FID. Upon completion, the mixture was poured into
water and extracted with pentane (or CH2CI2 if the product has low solubility in
pentane), dried over M9804, filtered, and evaporated. Column chromatography
(pentane or CH2Clz) afforded the product.

For standing-alone deuteration, 2 mmol aryl boronic acid/ester and the Ir
catalyst (0.02 mmol, 2 mol %) were dissolved in 3-4 mL THF or DME in the glove
box and transferred into an air-free flask equipped with a stirrer bar. The flask
was sealed and brought out of the dry box and charged with 0.5 mL D20. It was
resealed and heated in an oil bath to 150 °C until the reaction was judged
complete by GC-F ID, and worked up as described in the general procedure.

General Procedure E (C-H Borylation/Amidationleidation for
Preparation of Amidophenols): A borylation reaction with 2 mmol arene was set

up according to the general procedure A and judged complete by GC-FID.

152

Solvent for this borylation, if any, was removed by a gentle nitrogen flow. The
residue was placed under high vacuum for a few hours and the flask was
backfilled with nitrogen. Upon returning to the glove box, it was charged with
18.4 mg szdbag (0.02 mmol, 1 mol%), 34.8 mg xantphos (0.06 mmol, 3 mol%),
amide (~2.2 mmol, ~1.1 equiv), 900 mg Cs2C03 (2.8 mmol, 1.4 equiv), and 6 mL
THF or DME. The flask was sealed, taken out of the box, and heated to 80-100
°C until the reaction was judged complete by GC-F ID. At this time, the reaction
mixture (typically a yellow suspension) was cooled to room temperature and
filtered through a silica pad (1-2 cm thick, 4.5 cm wide; ~12 g silica gel) eluting
with acetone until the filtrate showed no UV activity on TLC (ca. 150-200 mL
acetone was used). The acetone was evaporated and the residue was dissolved
back in 6 mL acetone (or more if needed to obtain a homogenous solution). To
that stirred solution was added dropwise a solution of 1.33 g oxone (2 mmol, 1
equiv) in 6 mL water and the reaction was stirred for 10 min at room temperature.
An aqueous suspension of 430 mg NalO4 (1.0 equiv per pinacol) in 2 mL water
was added in a single portion followed by 2 mL acetone. The mixture was further
stirred for 1-2 h before being twice extracted with EtOAc. The aqueous layer
was charged with solid NaHS03, and the mixture was swirled until color appeared
and then diminished. The aqueous phase was then back extracted once or twice
with EtOAc. The combined organics were washed with brine, dried over M9804,
and concentrated. The residue was purified on silica gel chromatography
(CH2Cl2/EtOAc or CH2Cl2/acetone). Evaporation followed by drying under high

vacuum afforded the final product.

153

7.4 Experimental Details and Spectroscopy Data

7.4.1 Simple Phenols

 

3-Bromo-5-chlorophenol (2.3a): General procedure B (page

Cl Br
0 150) was applied to 192 mg 3-bromochlorobenzene (1.0 mmol).

 

 

L 2.33 The borylation step was carried out neat with 250 mg HBpin (1.95

 

mmol, ~2 equiv), 8.3 mg (Ind)lr(cod) (0.02 mmol, 2 mol%) and 3.0 mg dmpe (0.02
mmol, 2 mol %) at 150 °C for 3.5 h. The oxidation step was then carried out as
described in the general procedure, after which the crude material was purified
with a plug of silica gel (CH2CI2). Evaporation of solvent gave 183 mg of a white
solid containing 171 mg of 2.3a (82%) and 12 mg acetone. Compound 2.3a
could be obtained pure by preparative GC at 160 °C as a white solid; mp 66-68 °C
(Iit.483 70 °C). 1H NMR (300 MHz, CDCI3): 8 7.08 (t, J = 1.65 Hz, 1 H), 6.89 (dd, J =
2.2, 1.65 Hz, 1 H), 6.78 (t, J = 2.1 Hz, 1 H), 5.0-5.1 (br, 1 H); 13C NMR (75 MHz,
CDCI3): 8 156.7, 135.6, 124.0, 122.9, 117.9, 115.0; IR (neat): 3293, 1578, 1435,
914, 775 cm"; LRMS m/e 206 (M‘), 127, 99. Anal. Calcd for C5H4BrCIO: C, 34.74;

H, 1.94. Found C, 34.87; H 2.03.

 

fol Cl . 1,3-Dichlorophenol (2.3h): General procedure B (page 150)

was applied to 147 mg 1,3-dichlorobenzene (1.0 mmol). The

0H
2.3;, borylation step was carried out neat with 200 mg HBpin (1.55

 

k

 

mmol, 1.55 equiv), 8.3 mg (Ind)lr(cod) (0.02 mmol, 2 mol%) and 3.0 mg dmpe
(0.02 mmol, 2 mol °/o) at 150 °C for 3.5 h. The oxidation step was then carried
out as described in the general procedure, after which the crude material was

purified with a plug of silica gel (CHzClz). Evaporation of solvent gave 137 mg of

154

 

a white solid containing 127 mg of 2.3b (78%) and 10 mg acetone. Compound
2.3h could be obtained pure by putting under high vacuum (loss of product) as a
white solid; mp 64-66 °C (Aldrich catalogue 65-68 °C). 1H NMR (300 MHz, CDCI3):
8 6.93 (t, J = 1.65 Hz, 1 H), 6.73 (d, J = 1.65 Hz, 2 H), 5.32 (br, 1 H); 13C NMR (75

MHZ, CDCI3): 8 156.6, 135.4, 121.3, 114.5.

 

r ‘ 3,5-Dibromophenol (2.3c): General procedure B (page 150)

Br Br
U was applied to 236 mg 1,3-dibromobenzene (1.0 mmol). The
DH

2-30 borylation step was carried out with 256 mg HBpin (2.0 mmol, 2

 

 

equiv), 8.3 mg (Ind)lr(cod) (0.02 mmol, 2 mol%) and 8.0 mg dppe (0.02 mmol, 2
mol %) in 1.0 mL cyclohexane at 100 °C for 18 h. After removal of cyclohexane,
the oxidation step was then carried out as described in the general procedure,
after which the crude material was purified with a plug of silica gel (CH2CI2).
Evaporation of solvent gave 250 mg of a white solid containing 227 mg of 2.3c
(90%), 12 mg water, and 11 mg acetone. Compound 2.3c could be obtained
pure by sublimation at 55 °C under 0.08 mmHg as a white solid; mp 78-80 °C
(Aldrich catalogue 79-83 °C). 1H NMR (300 MHz, CDCI3): 8 7.23 (t, J = 1.4 Hz, 1
H), 6.94 (d, J = 1.4 Hz, 2 H), 4.82 (s, 1 H); 13C NMR (75 MHz, CDCI3): 8 156.7,
126.7, 123.1, 117.8; IR (neat): 3233, 1576, 1421, 841, 752 cm"; LRMS: m/e 250
(M‘), 171, 143. Anal. Calcd for C6H4Br20: C, 28.61; H, 1.60. Found C, 28.98; H,

1.52.

 

r M B ~ 3-Bromo-5-methylphenol (2.3d): General procedure B (page
e l‘

150) was applied to 171 mg 3-bromotoluene (1.0 mmol). The

OH
2.3d

 

 

 

155

borylation step was carried out neat with 200 mg HBpin (1.55 mmol, 1.55 equiv),
8.3 mg (Ind)lr(cod) (0.02 mmol, 2 mol%) and 3.0 mg dmpe (0.02 mmol, 2 mol %)
at 150 °C for 12 h. The oxidation step was then carried out as described in the
general procedure, after which the crude material was purified with a plug of silica
gel (CHzClz). Evaporation of solvent gave 174 mg material containing 146 mg of
2.3d (78%), 17 mg acetone, and 11 mg CHzClz. Compound 2.3d could be
obtained pure by preparative GC at 150 °C as a white solid; mp 55-57 °C (lit.162 52
°C). 1H NMR (300 MHz, CDCI3): 8 6.89 (s, 1 H), 6.80 (s, 1 H), 6.56 (s, 1 H), 4.67 (s,
1 H), 2.26 (s, 3 H); 13C NMR (75 MHz, CDCI3): 8 156.0, 141.4, 124.7, 122.4, 115.8,
115.0, 21.1; IR (neat): 3297, 1579, 1366, 1273, 822 cm"; LRMS: m/e 186 (M‘),

107, 77. Anal. Calcd for C7H7BrO: C, 44.95; H, 3.77. Found C, 45.21; H, 3.93.

 

‘ ‘ 3-Chloro-5-methoxyphenol (2.3e): General procedure B

MeO Cl
Q (page 150) was applied to 143 mg 3-chloroanisole (1.0 mmol).
OH

2-39 The borylation step was carried out neat with 256 mg HBpin (2.0

 

 

 

mmol, 2 equiv), 8.3 mg (Ind)lr(cod) (0.02 mmol, 2 mol%) and 3.0 mg dmpe (0.02
mmol, 2 mol %) at 150 °C for 18 h. The oxidation step was then carried out as
described in the general procedure, after which the crude material was purified
with a plug of silica gel (CH2CI2). Evaporation of solvent gave 148 mg material
containing 121 mg of 2.3e (76%), 20 mg acetone, and 7 mg CH2CI2. Compound
2.3e could be obtained pure by preparative GC at 170 °C as a white solid; mp
94-96 °C. 1H NMR (300 MHz, CDCI3): 8 6.48 (t, J = 2.2 Hz, 1 H), 6.43 (t, J = 2.2
Hz, 1 H), 5.27 (t, J = 2.2 Hz, 1 H), 4.81 (s, 1 H), 3.75 (s, 3 H); 130 NMR (75 MHz,

CDCI3): 8 161.3, 157.0, 135.4, 108.6, 107.3, 100.4, 55.5; IR (neat): 3378, 1597,

156

1159 cm"; LRMS: m/e 158 (M+), 128. Anal. Calcd for CyHyCIOz: C, 53.02; H, 4.45.

Found C, 52.88; H, 4.81.

 

Methyl 3-chIoro-5-hydroxybenzoate (2.30: General

rMeozc Cl
; procedure B (page 150) was applied to 171 mg
OH

2-3f 3-chlorobenzoate (1.0 mmol). The borylation step was carried

 

 

out neat with 200 mg HBpin (1.55 mmol, 1.55 equiv), 8.3 mg (Ind)lr(cod) (0.02
mmol, 2 mol%) and 3.0 mg dmpe (0.02 mmol, 2 mol %) at 150 °C for 3 h. The
oxidation step was then carried out as described in the general procedure, after
which the crude material was purified with a plug of silica gel (pentane/ether 2:1).
Evaporation of solvent gave 134 mg clean material (72%). Compound 2.3f could
be obtained pure by sublimation at 85 °C under 0.06 mmHg as a white solid; mp
133-135 °C (lit.163 138-139 °C). 1H NMR (300 MHz, acetone-d5): 8 9.2 (brs, 1 H),
7.43 (t, J = 1.7 Hz, 1 H), 7.40 (dd, J = 2.2, 1.7 Hz, 1 H), 7.10 (t, J = 2.2 Hz, 1 H),
3.87 (s, 3 H); 13C NMR (75 MHz, acetone-d5): 8 165.9, 159.3, 135.3, 133.8, 121.0,
120.6, 115.7, 52.7; IR (neat): 3335, 1690, 1591, 1431, 1350, 1242, 768 cm";
LRMS: m/e 186 (W), 155, 127, 99. Anal. Calcd for CaH7Cl03: C, 51.50; H, 3.78.

Found C, 51.78; H, 3.73.

 

Fol N C" 2,6-Dichloro-4-pyridinol (2.39): General procedure B (page
\ I 150) was applied to 148 mg 2,6-dichloropyridine (1.0 mmol). The
OH
2-39 borylation step was carried out with 200 mg HBpin (1.55 mmol,

 

 

 

1.55 equiv), 8.3 mg (Ind)lr(cod) (0.02 mmol, 2 mol%) and 3.0 mg dmpe (0.02
mmol, 2 mol %) in 1 mL cyclohexane at 150 °C for 3 h. After removal of

cyclohexane, the oxidation step was then carried out as described in the general

157

procedure, after which the crude material was purified with a plug of silica gel
(pentane/ether 2:1). Evaporation of solvent gave 145 mg material containing
108 mg of 2.39 (66%) and 37 mg water. Compound 2.3g could be obtained pure
by sublimation at 110 °C under 0.1 mmHg as a white solid; mp 201-202 °C. 1H
NMR (300 MHz, acetone-d5): 8 10.48 (brs, 1 H), 5.88 (s, 2 H); 130 NMR (75 MHz,
acetone-d6): 8 168.3, 151.5, 111.5; IR (KBr): 3200~2500 (br), 1597, 1576, 1554,
1427, 1294, 1211, 1157, 1092, 993, 966, 847 cm"; LRMS: m/e 163 (M‘), 128, 100.
Anal. Calcd for C5H3CI2NO: C, 36.62; H, 1.84; N, 8.54. Found C, 36.63; H, 1.98, N,

8.52.

 

C. ‘ 3,4-DichIoro-5-methylphenol (2.3h): General procedure B

Me Cl
(page 150) was applied to 161 mg 2,3-dichlorotoluene (1.0 mmol).

23: The borylation step was carried out neat with 256 mg HBpin (2.0

 

 

 

mmol, 2 equiv), 8.3 mg (Ind)lr(cod) (0.02 mmol, 2 mol%) and 3.0 mg dmpe (0.02
mmol, 2 mol %) in at 150 °C for 12 h. The oxidation step was then carried out as
described in the general procedure, after which the crude material was purified
with a plug of silica gel (CH2CI2). Evaporation of solvent gave 154 mg material
containing 147 mg of 2.3h (83%) and 7 mg water. Compound 2.3h could be
obtained pure by sublimation at 70 °C under 0.07 mmHg as a white solid; mp
98-100 °C. 1H NMR (300 MHz, CDCI3): 8 6.81 (d, J = 2.2 Hz, 1 H), 6.63 (t, J = 2.2
Hz, 1 H), 4.61 (s, 1 H), 2.34 (s, 3 H); 13C NMR (75 MHz, CDCI3): 8 153.7, 139.1,
133.0, 124.3, 116.4, 115.0, 21.3; IR (neat): 3285, 1580, 1449, 1285, 1151, 886,
646 cm"; LRMS: m/e 176 (M‘), 141, 77. Anal. Calcd for C7H5C|20: C, 47.49; H,

3.42. Found C, 47.72; H, 3.61.

158

 

’ Me ‘ 3,5-Dichloro-4-methylphenol (2.3i): General procedure B

Cl Cl
\éjf was applied to 161 mg 2,6-dichlorotoluene (1.0 mmol). The

OH
2.31

1.55 equiv), 8.3 mg (Ind)lr(cod) (0.02 mmol, 2 mol%) and 3.0 mg dmpe (0.02

borylation step was carried out neat with 200 mg HBpin (1.55 mmol,

 

 

mmol, 2 mol °/o) in at 150 °C for 12 h. The oxidation step was then carried out as
described in the general procedure, after which the crude material was purified
with a plug of silica gel (CH2CI2). Evaporation of solvent gave 176 mg material
containing 156 mg of 2.3i (88%), 14 mg water, and 6 mg acetone. Compound
2.3i could be obtained pure by sublimation at 70 °C under 0.08 mmHg as a white
solid; mp 92-93 °C. 1H NMR (300 MHz, CDCI3): 8 6.79 (s, 2 H), 4.67 (s, 1 H), 2.34
(s, 3 H); 13C NMR (75 MHz, CDCI3): 8 153.5, 135.6, 126.6, 115.2, 16.4; IR (neat):
3333, 1608, 1578, 1238, 947, 839 cm"; LRMS: m/e 176 (M”), 141, 105, 84, 77.

Anal. Calcd for C7HsCI20: C, 47.49; H, 3.42. Found C, 47.65; H, 3.45.

 

OH 2,6-Dichloro-1,4-hydroquinone (2.3j1): General procedure B

l
C' C (page 150) was applied to 177 mg 2,6-dichloroanisole (1.0 mmol).

23": The borylation step was carried out neat with 320 mg HBpin (2.5

 

 

 

mmol, 2.5 equiv), 8.3 mg (Ind)lr(cod) (0.02 mmol, 2 mol%) and 3.0
mg dmpe (0.02 mmol, 2 mol %) in at 150 °C for 16 h. The oxidation step was
then carried out as described in the general procedure, after which the crude
material was purified with a plug of silica gel (pentane/ether 2:1). Evaporation of
solvent gave 140 mg material containing 120 mg of 2.3j1 (67%) and 20 mg water.
Compound 2.3j1 could be obtained pure by sublimation at 90 °C under 0.08

mmHg, or recrystalization from CHzClz, as a white solid; mp 150-151 °C (lit164 154

159

°C). 1H NMR (300 MHz, acetone-d5): 8 8.43 (brs, 1 H), 8.24 (brs, 1 H), 5.83 (s, 2
H); ”C NMR (75 MHz, acetone-d6): 8 150.7, 142.3, 122.3, 115.5; IR (KBr): 349,
1591, 1482, 1213, 953, 791 cm"; LRMS: m/e 178 (M*), 142, 114, 85. Anal. Calcd

for C5H4C|2022 C, 40.26; H, 2.25. Found C, 40.58; H, 2.17.

 

' OMe * 3,5-Dichloro-4-methoxyphenylboronic acid pinacol ester

CI Cl
(2.2j): Following the same procedure mentioned above, the

 

 

2.82?" borylation of 3 mmol 2,6-dichloroanisole was stopped after heating

 

at 150 °C for 20 min. Silica gel chromatography (3:1 hexanes/CHzClz) afforded
273 mg material containing the desired borylation product 2.2] with unreacted
starting material 2.1j (clean otherwise; molar ratio of 2.2j/2.1j ~ 8:1,
corresponding to ~28% yield of 2.2j). Another round of chromatography afforded
pure 2.2j as a white solid; mp 79-81 °C. 1H NMR (300 MHz, CDCI3): 8 7.69 (s, 2
H), 3.89 (s, 3 H), 1.31 (s, 12 H); “B NMR (150 MHz, CDCI3): 8 29.8; 130 NMR
(125 MHz, CDCI3): 8 154.6, 135.1, 129.1, 84.4, 60.7, 24.8; IR (neat): 2980, 1588,
1381, 1350, 1146, 1129, 999, 965, 889, 851, 810, 689 cm"; LRMS m/e 302 (M‘),

287, 216, 202, 85, 41. Anal. Calcd for C13H17BCI203: C, 51.53; H, 5.66. Found C,

 

51.74; H, 5.64.
[ OMe . 3,5-Dichloro-4-methoxyphenol (2.3j): 303 mg 2.2j (1 mmol)
Cl Cl was dissolved in 3 mL acetone. This solution was treated with
23:1 615 mg (1 mmol, 1 equiv) oxone in 3 mL water. The workup was

 

 

 

performed as described in the general procedure B. Silica gel chromatography

(CH2Cl2) afforded 190 mg of 2.3j (98%) as a white solid, mp 121-122 °C. 1H NMR

160

(300 MHz, cook): 8 5.79 (s, 2 H), 4.79 (s, 1 H), 3.82 (s, 3 H); 130 NMR (125 MHz,

CDCI3): 8 151.9, 146.2, 129.5, 116.0, 60.9; IR (neat): 3297, 1603, 1580, 1482,

1447, 1428, 1223, 1186, 986, 953, 878, 849, 804, 768 cm'1; LRMS m/e 192 (M+),

177, 149, 85, 53. Anal. Calcd for C7HsC|202: C, 43.56; H, 3.13. Found C, 43.67; H,

3.14.

 

l

 

I

Me

Me

OH
2.3K

Br

 

 

3-Bromo-4,5-dimethylphenol (2.3K): General procedure B
(page 150) was applied to 185 mg 3-bromo-o—xylene (1.0 mmol).

The borylation step was carried out with 320 mg HBpin (2.5 mmol,

2.5 equiv), 8.3 mg (Ind)lr(cod) (0.02 mmol, 2 mol%) and 8.0 mg dppe (0.02 mmol,

2 mol %) in 1 mL cyclohexane at 100 °C for 50 h. After removal of cyclohexane,

the oxidation step was then carried out as described in the general procedure,

after which the crude material was purified with a plug of silica gel (CH2CI2).

Evaporation of solvent gave 148 mg pure 2.3k (74%) as a white solid; mp 98-99

°C (lit165 101-102 °C). 1H NMR (300 MHz, CDCI3): 8 5.91 (d, J = 2.5 Hz, 1 H), 5.59

(d, J = 2.7 Hz, 1 H), 2.25 (s, 5 H); ”C NMR (75 MHz, CDCI3): 8 153.2, 139.3,

128.3, 125.2, 116.9, 116.2, 21.4, 18.3; IR (neat): 3252, 2919, 1606, 1576, 1477,

1451, 1279, 1119, 839 cm"; LRMS: m/e 200 (M+), 185, 121, 91; HRMS (El): m/e

calcd for [CgHgBrO]+ 199.9837, found 199.9839.

 

l

 

Cl

Br

OH
2.3I

CI

 

4-Bromo-3,5-dichlorophenol (2.3i): General procedure B
(page 150) was applied to 226 mg 1-bromo-2,6-dichlorobenzene

(1.0 mmol). The borylation step was carried out with 256 mg

HBpin (2.0 mmol, 2 equiv), 8.3 mg (Ind)lr(cod) (0.02 mmol, 2 mol%) and 3.0 mg

dmpe (0.02 mmol, 2 mol %) in 1 mL cyclohexane at 150 °C for 3.5 h. After

161

removal of cyclohexane, the oxidation step was then carried out as described in
the general procedure, after which the crude material was purified with a plug of
silica gel (CH2CI2). Evaporation of solvent gave 260 mg material containing 197
mg of 2.3l (81%), 31 mg CHZCIZ, and 32 mg acetone. Compound 2.3i could be
obtained pure by sublimation at 90 °C under 0.3 mmHg as a white solid; mp
117-119 °C. 1H NMR (300 MHz, CDCI3): 8 5.90 (s, 2 H), 4.85 (s, 1 H); 13C NMR
(75 MHz,CDCl3):8154.8, 136.5, 116.2, 114.4; IR (neat): 3366, 1570, 1412, 1129,
845 cm". LRMS: m/e 240 (M+), 162; HRMS (El): m/e calcd for [Cr5H3CI2BrO]+

239.8744, found 239.8751.

 

‘ c. ‘ 3,4,5-Trichlorophenol (2.3m): General procedure B (page 150)
Cl Cl
was applied to 182 mg 1,2,3-trichlorobenzene (1.0 mmol). The

2.3,: borylation step was carried out with 226 mg HBpin (1.8 mmol, 1.8

 

 

 

equiv), 8.3 mg (Ind)lr(cod) (0.02 mmol, 2 mol%) and 3.0 mg dmpe (0.02 mmol, 2
mol %) in 1 mL cyclohexane at 150 °C for 3 h. After removal of cyclohexane, the
oxidation step was then carried out as described in the general procedure, after
which the crude material was purified with a plug of silica gel (CHzClz).
Evaporation of solvent gave 212 mg material containing 176 mg of 2.3m (89%), 4
mg CH2CI2, and 32 mg acetone. Compound 2.3m could be obtained pure by
sublimation at 70 °C under 0.05 mmHg as a white solid; mp 97-99 °C (lit166 101
°C). 1H NMR (300 MHz, CDCI3): 8 5.89 (s, 2 H), 5.04 (s, 1 H); 13C NMR (75 MHz,
CDCI3): 8 154.0, 134.4, 123.3, 116.3; IR (neat): 3312, 1574, 1420, 1144, 947, 818
cm"; LRMS: m/e 196 (M‘), 160, 133, 97. Anal. Calcd for C5H3CI302 C, 36.50; H,

1.53. Found C, 36.73; H, 1.64.

162

 

r—————Bs 5-Bromo-2-fluorophenol (2.3n): General procedure B (page
I'
F 150) was applied to 700 mg 1-bromo-4-fluorobenzene (4.0 mmol, 4

OH
2.3n equiv). The borylation step was carried out neat with 128 mg

 

 

HBpin (1.0 mmol), 8.3 mg (Ind)lr(cod) (0.02 mmol, 2 mol%) and 3.0 mg dmpe
(0.02 mmol, 2 mol %) at 150 °C for 3.5 h. The oxidation step was then carried
out as described in the general procedure, after which the crude material was
purified on silica gel chromatography (CHzclz). The first fraction (~ 500 mg) was
unreacted starting material. Evaporation of the second fraction gave 165 mg
material containing 134 mg of 2.3n (70%, based on HBpin), 14 mg acetone, and
17 mg CH2CI2. Compound 2.3n could be obtained pure by preparative GC at
110 °C as a colorless oil. 1H NMR (300 MHz, CDCI3): 8 7.12-7.16 (m, 1 H),
6.90-6.96 (m, 2 H), 5.29 (s, 1 H); 13C NMR (125 MHz, CDCI3): 8 150.3 (d, J = 239
Hz), 144.4 (d, J =15 Hz), 123.7 (d, J = 6 Hz), 120.6, 116.8 (d, J =19 Hz), 116.8 (d,
J= 3 Hz); IR (neat): 3412, 1611, 1495, 1267 cm"; LRMS: m/e 190 (M), 161, 111,

83. Anal. Calcd for C5H4BrFO: C, 37.73; H, 2.11. Found C, 37.58; H, 2.32.

 

r HO Br; 5-Bromo-2-fluororesorcinol (2.3n1): General procedure B

p (page 150) was applied to 175 mg 1-bromo-4-fluorobenzene (1.0
OH

2-3'" mmol). The borylation step was carried out with 580 mg HBpin

 

 

 

(4.5 mmol, 4.5 equiv), 20.6 mg (Ind)lr(cod) (0.05 mmol, 5 mol %) and 20.0 mg
dppe (0.05 mmol, 5 mol %) in 1 mL cyclohexane at 110 °C for 53 h. After
removal of cyclohexane, the oxidation step was carried out as described in the
general procedure with 6.5 mL acetone, 6.5 mL aqueous solution of 1.24 g oxone

(2 mmol, 1 equiv per boron) at room temperature for 11 min. The crude material,

163

after workup, was purified with a plug of silica gel (pentane/ether 1.5:1) followed
by recrystallization from CHzClz, giving 165 mg of 2.3n1 (76%) as a white solid;
mp 83-86 °C; Rf 0.31 (pentane/ether 2:1). 1H NMR (300 MHz, CDCI3): 8 6.72 (d, J
= 7.1 Hz, 2 H), 5.10 (s, 2 H); 13C NMR (75 MHz, acetone-d5): 8 147.5 (d, J = 11
Hz), 141.4 (d, J = 237 Hz), 115.8 (d, J= 5 Hz), 112.3; IR (KBr): 3128, 1617, 1501,
1431, 1331, 1159, 1047 cm". LRMS: m/e 206 (M‘), 127, 109, 79. HRMS (El): m/e

calcd for [C(5H4FBr02]+ 205.9379, found 205.9378.

 

F 2,4,6-Trifluoroglucinol (2.30): General procedure B (page

HO OH
m 150) was applied to 132 mg 1,3,5-trifluorobenzene (1.0 mmol).
F F

23: The borylation step was carried out with 640 mg HBpin (5 mmol, 5

equiv), 12.5 mg (Ind)lr(cod) (0.03 mmol, 3 mol %) and 4.5 mg dmpe (0.03 mmol, 3

 

 

mol %) in 1 mL cyclohexane at 150 °C for 63 h. The borylation gave a 1:6
mixture of diborylated and triborylated products. After removal of cyclohexane,
the oxidation step was carried out as described in the general procedure with 9
mL acetone, 8.5 mL aqueous solution of 1.74 g oxone (2.8 mmol) at room
temperature for 13 min. The crude material, after workup, was purified with silica
gel Chromatography (pentane/ether 1:1.5) followed by washing with boiling
CH2CI2, and sublimation at 130 °C under 0.1 mmHg, giving 88 mg of 2.30 (49%)
as a slightly yellow solid; mp 260 °C (dec); R; 0.43 (pentane/ether 1:1.5).1H NMR
(300 MHz, acetone-d6): 8 8.66 (br, 3 H); 13C NMR (125 MHz, acetone-d5): 8 137.3
(dt, J = 230, 6 Hz) 131.9 (dt, J= 14, 5 Hz); IR (KBr): 3324, 1510, 1400-1200 (br),
1132, 980 cm"; LRMS: m/e 180 (M*), 151, 104; HRMS (El): m/e calcd for

[C5H3F3O3]+ 180.0034, found 180.0030

164

 

 

 

( F3C Cl ‘ 3-ChIoro-5-trifluoromethylphenol (2.3p): General
procedure B (page 150) was applied to 181 mg

OH
2'39 3-chlorobenzotrifluoride (1.0 mmol). The borylation step was

 

carried out with 200 mg HBpin (1.55 mmol, 1.55 equiv), 8.3 mg (Ind)lr(cod) (0.02
mmol, 2 mol%) and 3.0 mg dmpe (0.02 mmol, 2 mol %) in 1 mL cyclohexane at
150 °C for 3.5 h. After removal of cyclohexane, the oxidation step was then
carried out as described in the general procedure, after which the crude material
was purified with a plug of silica gel (CHZCIZ). Evaporation of solvent gave 185
mg material containing 160 mg of 2.3p (81%) and 25 mg acetone. Compound
2.3p could be obtained pure by preparative GC at 120 °C as colorless oil. 1H NMR
(300 MHz, CDCI3): 8 7.18 (brs, 1 H), 7.01 (brs, 1 H), 6.96 (brs, 1 H), 5.03 (s, 1 H);
13C NMR (75 MHz, CDCI3): 8 156.5, 135.7, 133.1 (q, J = 33 Hz), 123.0 (q, J = 273
Hz), 119.2, 118.5 (q, J = 4 Hz), 111.0 (q, J = 4 Hz); IR (KBr): 3384, 1597, 1455,
1335, 1175, 1134, 936, 704, 693 cm"; LRMS: m/e 196 (M*), 177, 161, 146;

HRMS (El): m/e calcd for [C7H4CIF30]+ 195.9903, found 195.9902.

 

3-ChIoro-5-(dimethylamino)phenol (2.3q): General

rMezN Cl
0 procedure B (page 150) was applied to 156 mg
OH

2-39 3-chloro-N,N-dimethylaniline (1.0 mmol). The borylation step

 

 

was carried out neat with 256 mg HBpin (2.0 mmol, 2 equiv), 8.3 mg (Ind)lr(cod)
(0.02 mmol, 2 mol%) and 3.0 mg dmpe (0.02 mmol, 2 mol %) at 150 °C for 18 h.
The oxidation step was then carried out as described in the general procedure,
after which the crude material was purified with a plug of silica gel (pentane/ether

2:1). Evaporation of solvent gave 155 mg material containing 146 mg of 2.3q

165

 

(85%) and 9 mg ether. Compound 2.3q could be obtained pure by sublimation
at 60 °C under 0.10 mmHg as a slightly colored solid; mp 86-88 °C; Rf 0.30
(pentane/ether, 2:1). 1H NMR (300 MHz, CDCI3): 8 6.28 (brs, 1 H), 6.19 (t, J = 1.6
Hz, 1 H), 6.03 (t, J = 2.2 Hz, 1 H), 5.0-5.3 (brs, 1 H), 2.88 (s, 6 H); 13C NMR (75
MHz, CDCI3): 8 156.8, 152.3, 135.4, 105.6, 104.2, 97.8, 40.4; IR (neat): 3349,
2901, 2812, 1603, 1506, 1443, 1156, 1233, 1019, 916 cm"; LRMS: m/e171 (M‘),
170, 128, 99. Anal. Calcd for CaHmCINO: C, 55.99; H, 5.87; N, 8.16. Found C,
56.12; H, 5.81; N, 8.11.

fi—fi 3-Bromo-5-iodophenol (2.3r): General procedure B (page 150)

I Br
\Q/ was applied to 283 mg 1-bromo-3-iodobenzene (1.0 mmol). The

 

 

23' borylation step was carried out with 154 mg szinz (0.6 mmol, 1.2
equiv boron), 10.0 mg [lr(OMe)(cod)]2 (0.015 mmol, 1.5 mol %), and 8.0 mg d'bpy
(0.03 mol, 3 mol %) in 5 mL n-hexane in dark environment at room temperature
for 11 h. After removal of cyclohexane, the oxidation step was then carried out
as described in the general procedure, except that ether, instead of CH2CI2, was
used for the extraction. The crude material was purified with a plug of silica gel
(CH2CI2). Evaporation of solvent gave 244 mg material containing 236 mg of
2.3r (79%), 5 mg ether, and 3 mg acetone. Compound 2.3r could be obtained
pure by sublimation at 50 °C under 0.09 mmHg as a white solid; mp 83-84 °C
(lit48a 82.5 °C). 1H NMR (300 MHz, CDCI3): 8 7.42 (t, J = 1.4 Hz, 1 H), 7.13 (dd, J =
1.4, 2.2 Hz, 1 H), 6.96 (dd, J: 1.9, 2.2 Hz, 1 H), 4.77 (s, 1 H); 13C NMR (75 MHz,
CDCI3): 8 156.4, 132.4, 123.6, 123.2, 118.6, 94.2; IR (neat): 3268, 3071, 1586,

1566, 893, 885, 664 cm'1; LRMS: m/e 298 (M+), 171, 143. Anal. Calcd for

166

C6H4BrIO: C, 24.11; H, 1.35. Found C, 24.26; H, 1.30.

 

F I . 3,5-Dibromo-4-iodophenol (2.33): General procedure B

B B
r r (page 150) was applied to 362 mg 1,3-dibromo-2-iodobenzene
293': (1.0 mmol). The borylation step was carried out with 254 mg

 

 

 

szinz (1.0 mmol, 2 equiv boron), 10.0 mg [lr(OMe)(cod)]2 (0.015 mmol, 1.5 mol
%), and 8.0 mg d'bpy (0.03 mol, 3 mol %) in 5 mL n-hexane in dark environment
at room temperature for 3 h. After removal of cyclohexane, the oxidation step
was then carried out as described in the general procedure, except that ether,
instead of CH2CI2, was used for the extraction. The crude material was purified
with a plug of silica gel (pentane/ether 2:1). Evaporation of solvent gave 352 mg
pure 2.3s (93%) as a white solid; mp 149-152 °C (lit4° 1535-1539 °C). 1H NMR
(300 MHz, CDCI3): 8 7.12 (s, 2 H), 4.92 (s, 1 H); 13‘C NMR (75 MHz, acetone-d5): 8
159.6, 131.4, 120.0, 96.3; IR (neat): 3289, 3069, 1584, 1561, 1399, 1246, 1219,
853, 748 cm“; LRMS (El): m/e 376 (M"), 249, 143, 127, 91, 62. Anal. Calcd for

C5H33T2IOI C, 19.08; H, 0.80. Found C, 19.62; H, 0.79.

HO Br HO
cat. Pd(OAc)2, KF, PMHSA
F THF/water, rt ' 1:

OH OH
2.3n1 2.4

 

 

2-Fluororesorcinol (2.4): To a solution of 9.0 mg Pd(OAc)2 (0.04 mmol, 5
mol%) in 4 mL degassed THF was added 166 mg of 2.3n1 (0.8 mmol). Upon
stirring, a solution of 93 mg KF (1.6 mmol, 2 equiv) in 1.6 mL degassed water was

added. 240 pL PMHS (240 mg, 3.2 mmol, 4 equiv) was introduced dropwise and

167

the reaction mixture turned black. After 30 min, TLC indicated full conversion.
The reaction was quenched by addition of 4 mL 3 M NaOH, stirred for 6 h, and
diluted with water and washed with ether (discarded). The aqueous layer was
then acidified with concentrated HCI, and then extracted with ether. Combined
ether was dried over M9804 and evaporated. Column chromatography (1.5:1
pentane/ether) followed by sublimation at 70 °C, 0.1 mmHg afforded 82 mg of 2.4
(80%) as a white solid; mp 111-114 °C (lit167 114-115 °C). 1H NMR (500 MHz,
acetone-d5): 8 8.44 (s, 2 H), 6.76 (dt, J = 2.0, 8.3 Hz, 1 H), 6.45 (dd, J = 7.6, 8.1
Hz, 2 H); 13C NMR (125 MHz, acetone-d6): 8 146.8 (d, J = 10.6 Hz), 142.2 (d, J =
235 Hz), 124.3 (d, J = 4.6 Hz), 109.3; IR (neat): 3368, 1615, 1524, 1512, 1478,
1383, 1329, 1210, 1013 cm"; LRMS m/e 128 (W), 57, 43.

7.4.2 Hydroxylated and Borylated Aromatic Amino Acid Derivatives and
Miscellaneous Products

Experiments were following general procedure C (page 151) in this section.

 

. 2-tert-Butoxycarbonylamino-3-[3-chIoro-5-(4,4,5,5-
CI 002MB

NHBoc tetramethyI-[1,3,2]dioxaborolan-2-yl)-phenyI]-propion-
39'" 3.2b

 

ic acid methyl ester (3.2b): Slightly yellow solid; mp 83-86

 

°C. 1H NMR (300 MHZ, CDCI3): 8 7.65 (s, 1 H), 7.43 (s, 1 H), 7.20 (s, 1 H), 5.01 (d,
J = 7.7 HZ, 1 H), 4.5-4.6 (m, 1 H), 3.73 (s, 3 H), 2.9-3.2 (m, 2 H), 1.43 (s, 9 H),
1.33 (s, 12 H); 13C NMR (75 MHZ, CDCI3): 8 172.4, 155.3, 137.9, 134.4, 134.2,
133.5, 132.4, 84.9, 84.5, 80.4, 54.8, 52.6, 38.2, 28.6, 25.3, 25.2; IR (neat): 3365,
2978, 1746, 1717, 1356, 1167, 1144 cm"; LRMS (ESI): m/e 462 ([M+Na]+), 340

([M-Boc+2H]f). Anal. Calcd for C21H31BCIN05: C, 57.36; H, 7.11; N, 3.19. Found C,

168

57.78; H, 7.40; N, 2.98.

2-tert-Butoxycarbonylamino-3-(3-chloro-5-hydro-

 

fl

CI COzMe
mHBOC xy-phenyI)-propionic acid methyl ester (3.3b): A

0“ 3.35 colorless thick gel. 1H NMR (300 MHz, CDCI3): 8 5.75 (s,

 

1 H), 5.57 (s, 1 H), 5.54 (s, 1 H), 5.05 (brs, 1 H), 5.05 (d, J = 7.9 Hz, 1 H), 4.55 (m,
1 H), 3.74 (s, 3 H), 2831 (m, 2 H,), 1.43 (s, 9 H); 13C NMR (75 MHz, CDCI3): 8
172.7, 157.5, 155.9, 139.2, 135.2, 121.8, 115.2, 115.0, 81.1, 54.7, 52.9, 385,285;
IR (neat): 3355, 2978,2931, 1684, 1152 cm"; LRMS (ESI): m/e 581 ([2M+Na]*),
352 ([M+Na]*), 274 ([M-‘Bu+2H]*), 230 ([M-Boc+2H]+). Anal. Calcd for

C15H20C|N05-0.5H202 C, 53.18; H, 6.25; N, 4.13. Found C, 53.04; H, 5.95; N, 4.11.

 

‘ 2-tert-Butoxycarbonylamino-3-(3-trifluoromethyl-

F3C COzMe
mHBOC 5-hydroxy-phenyI)-propionic acid methyl ester (3.3c):
OH 3.3c

 

White solid; mp 94-95.5 °C. 1H NMR (300 MHz, CDCI3): 8

 

6.97 (s, 1 H), 6.91 (s, 1 H), 6.83 (s, 1 H), 6.01 (brs, 1 H), 5.08 (brs, 1 H), 4.57 (m, 1
H), 3.73 (s, 3 H), 3.0-3.2 (m, 2 H), 1.42 (s, 9 H); 13C NMR (125 MHZ, CDCI3): 8
172.2, 156.7, 155.5, 138.6, 131.9 (q, J = 32.5 Hz), 123.8 (q, J = 271 HZ), 119.5,
117.9, 111.3, 80.8, 54.3, 52.5, 38.3, 28.2; IR (neat): 3354, 2981, 1684, 1368, 1171,
1125 cm“; LRMS (ESI): m/e 385 ([M+Na]*), 308 ([M-‘Bu+2H]+), 254
([M-Boc+2H]”). Anal. Calcd for C15H20F3NO5: C, 52.89; H, 5.55; N, 3.86. Found C,

52.67; H, 5.53; N, 3.85.

 

J

2-tert-Butoxycarbonylamino-3-(3-cyano-5-hydro-

NC COzMe
mHBOC xy-phenyl)-propionic acid methyl ester (3.3d): White

OH
3.3d

l

 

 

 

169

solid; mp 104-105 °C. 1H NMR (300 MHz, CDCI3)I 8 7.00 (s, 1 H), 5.97 (s, 1 H),
5.91 (s, 1 H), 5.25 (s, 1 H), 5.08 (brs, 1 H), 4.55 (m, 1 H), 3.75 (s, 3 H), 2932 (m,
2 H), 1.42 (s, 9 H); 13C NMR (75 MHz, CDCI3): 8172.3, 157.3, 155.8, 139.7, 125.1,
121.7, 118.9, 118.0, 113.4, 81.3, 54.5, 53.0, 38.6, 28.6; IR (neat): 3355, 2979,
2231, 1742, 1684, 1358, 1155 cm"; LRMS (ESI): m/e 553 ([2M+Na]*), 343
([M+Na]"), 255 ([M-‘Bu+2H]+), 221 ([M-Boc+2H]"). Anal. Calcd for C15H20N205: C,

59.99; H, 6.29; N, 8.74. Found C, 60.07; H, 6.50; N, 8.92.

 

2-tert-Butoxycarbonylamino-3-(3,4-difluoro-5-hy-

 

F COZMe
F NHBoc droxy-phenyI)-propionic acid methyl ester (3.39):
OH
3'“ Colorless thick oil. 1H NMR (300 MHz, CDCI3): 8 6.45-6.58

 

(m, 2 H), 5.53 (brs, 1 H), 5.09 (d, J = 8.0 Hz, 1 H), 4.5 (m, 1 H), 3.74 (s, 3 H),
2831 (m, 2 H), 1.43 (s, 9 H); 13C NMR (75 MHz, CDCI3): 8 172.5, 155.7, 151.2
(dd, J = 246 Hz, the other J value not clear due to overlapping signal), 145.9 (d, J
= 10 Hz), 139.7 (dd, J= 240, 15 Hz), 132.5, 114.0, 109.4 (d, J= 18 Hz), 81.0, 54.7,
52.8, 38.2, 28.6; IR (neat): 3356, 2980, 1690, 1523, 1368, 1165, 1055 cm"; LRMS
(ESI): m/e 685 ([2M+Na]”), 354 ([M+Na]+), 276 ([M-‘Bu+2H]“), 232 ([M-Boc+2H]”).

HRMS (FAB): m/e calcd for [C15H13F2N05-H]+ 330.1153, found 330.1151.

 

3-tert-Butoxycarbonylamino-4-(3,4-difluoro-5-hy-

F COzMe

NHBoc droxy-phenyI)-butyric acid methyl ester (3.30: The
0“ 3.3r

F

borylation went to 80% conversion. Slightly yellow solid;

 

mp 125-129 °C. 1H NMR (300 MHz, CDCI3): 8 5.50-5.55 (m, 2 H), 5.70 (brs, 1 H),

5.1 (br, 1 H), 4.08 (m, 1 H), 3.70 (s, 3 H), 2.66-2.80 (m, 2 H), 2.42-2.58 (m, 2 H),

170

1.41 (s, 9 H); 13C NMR (75 MHz, CDCI3): 8 172.4, 155.8, ~151.9 (dd, overlapped),
145.8 (d, J = 13 Hz), ~140.2 (dd, overlapped), 134.3, 113.9, 109.5 (d, J = 29 Hz),
80.3, 525,490,403, 38.0, 28.7; IR (neat): 3355,2979, 1719, 1585, 1521, 1358,
1154, 1055 cm"; LRMS (ESI): m/e 713 ([2M+Na]"), 358 ([M+Na]+), 290
([M-'Bu+2H]*), 245 ([M-Boc+2H]"). Anal. Calcd for C16H21F2N205: C, 55.55; H,

6.13; N, 4.06. Found C, 55.94; H, 6.28; N, 4.10.

 

002m 2-tert-Butoxycarbonylamino-3-(4-fluoro-3-hydroxy

F NHB°° -phenyI)-propionic acid methyl ester (3.3g): Colorless
0H 3.39

 

thick oil. 1H NMR (300 MHz, CDCI3): 8 5.95 (dd, J = 8.3,
10.5 Hz, 1 H), 5.78 (dd, J = 8.3, 1.5 Hz, 1 H), 5.5 (m, 1 H), 5.38 (brs, 1 H), 5.07 (d,
J = 7.8 Hz, 1 H), 4.55 (m, 1 H), 3.72 (s, 3 H), 2.931 (m, 2 H), 1.42 (s, 9 H); 13C
NMR (75 MHz, CDCI3): 8 172.7, 155.7, 150.8 (d, J = 235 Hz), 144.0 (d, J = 15 Hz),
133.2, 121.7 (d, J = 5.4 Hz), 118.6, (d, J = 1.7 Hz), 115.9 (d, J = 18 Hz), 80.7, 54.8,
52.7, 381,285; IR (neat): 3355,2979, 1592, 1512, 1155 cm"; LRMS (ESI): m/e
549 ([2M+Na]+), 335 ([M+Na]”), 258 ([M-‘Bu+2H]+), 214 ([M-Boc+2H]+). HRMS

(FAB): m/e calcd for [C15H19FN05-H]+ 312.1247, found 312.1233;

 

2-tert-Butoxycarbonylamino-3-(4-fluoro-3,5-dihy-

 

HO COzMe
F NHBoc droxy-phenyI)-propionic acid methyl ester (3.391.
OH ”91 byproduct of borylation/oxidation of 3.19 due to double

 

borylation): 1H NMR (300 MHz, acetone-d5): 8 6.38 (d, J = 7.3 Hz, 2 H), 4.34 (m, 1
H), 3.68 (s, 3 H), 2.8-3.0 (m, 2 H), 1.38 (s, 9 H), OH and NH protons were not
observed; LRMS (ESI): m/e 681 ([2M+Na]*), 393 ([M+Na+CH3CN]*), 352

([M+Na]+), 274 ([M-tBu+2H]+), 230 ([M-Boc+2H]+). HRMS (FAB): m/e calcd for

171

 

 

 

[C15H19FNOe-H]+ 328.1196, found 328.1201.

 

4 2-tert-Butoxycarbonylamino-3-(2,6-dichloro-4-hyd

 

 

Cl
co M
m 2 e roxIl'PherIyI)-propionic acid methyl ester (3.3h): White
Ho CINHBoc
3'3" crystal; mp 164-165 °C (dec). 1H NMR (300 MHz, CDCI3):

8 5.73 (s, 2 H), 5.30 (d, J = 9.3 Hz, 1H), 454.7 (m, 1 H), 3.78 (s, 3 H), 3135 (m,
2 H), 1.38 (s, 9 H), OH proton was not observed; 13C NMR (75 MHz, CDCI3): 8
172.8, 155.5, 155.9, 135.4, 124.0, 115.2, 81.0, 53.3, 53.0, 34.0, 28.6; IR (neat):
3347, 2979, 1585, 1154 cm"; LRMS (ESI): m/e 749 ([2M+Na]*), 427
([M+Na+CH3CN]*), 385 ([M+Na]+), 308 ([M-‘Bu+2H]*), 254 ([M-Boc+2H]*). Anal.
Calcd for C15H19C|2N05-0.5H202 C, 48.27; H, 5.40; N, 3.75; CI, 19.00. Found C,

48.35; H, 5.27; N, 3.64; CI, 18.62.

 

2-tert-Butoxycarbonylamino-3-(5-hydroxy-pyridin-3-

N \ COzMe
mm”: yI)-propionic acid methyl ester (3.3i, isolated as TFA salt):

OH 3.3i

 

The borylation went to 84% conversion. The workup

 

procedure was slightly different for this compound. Following general procedure
C (page 151), the oxidation step was quenched with NaHSOg. The resultant
solution was directly lyophilized. The residual solid was extracted with MeOH
and concentrated. Preparative HPLC followed by Iyophilization afforded 3.3i as
a slightly yellow gel. 1H NMR (300 MHz, CD3OD): 8 8.22 (s, 2 H), 7.84 (s, 1 H),
4.45-4.50 (m, 1 H), 3.76 (s, 3 H), 3.0-3.1 (m, 2 H), 1.36 (s, 9 H), OH and NH
protons were not observed; 13C NMR (75 MHz, CD300): 8 173.2, 158.5, 158.1,
140.9, 135.2, 134.4, 129.9, 81.4, 55.5, 53.4, 36.0, 29.0; IR (neat): 3600-2400 (br),

3307, 2979, 1683, 1202, 1182 cm'1; LRMS (ESI): m/e 297 (M+H). Anal. Calcd for

172

C15H21F3N207 (TFA salt): C, 46.83; H, 5.16; N, 6.83. Found C, 47.22; H, 5.07; N,

7.14.

 

Bpinmcone 2-tert-Butoxycarbonylamino-3-[5-(4,4,5,5-tetrame-
NHBoc thyl-[1,3,2]dioxaborolan-Z-yI)-thiophen-Z-yll-propionic
3.5a acid methyl ester (3.5a): Slightly yellow gel. 1H NMR
(300 MHz, CDCI3): 8 7.47 (d, J = 3.4 Hz, 1 H), 6.87 (d, J = 3.4 Hz, 1 H), 5.14 (d, J
= 7.8 Hz, 1 H), 4.6 (m, 1 H), 3.75 (s, 3 H), 3.38 (d, J = 4.9 Hz, 2 H), 1.44 (s, 9 H),
1.33 (s, 12 H); 13C NMR (75 MHz, CDCI3): 8 171.9, 155.5, 145.4, 137.8, 128.6,
84.4, 80.5, 54.6, 52.8, 33.0, 28.7, 25.1, 25.1; IR (neat): 3363, 2978, 1747, 1717,
1472, 1358, 1165, 1144 cm"; LRMS (ESI): m/e 434 ([M+Na]*), 356 ([M-‘Bu+2H]*),
312 ([M-Boc+2H]*). Anal. Calcd for C19HgoBSN05: C, 55.48; H, 7.35; N, 3.41.

Found C, 55.70; H, 7.00; N, 3.21.

 

4-[2,5-Bis-(4,4,5,5-tetramethyI-[1 ,3,2]dioxaboro-

. / \ NHBoc
Bpm S Bpm Ian-2-yI)-thiophen-3-yI]-3-tert-butoxycarbonylamino-

3.5b

butyric acid methyl ester (3.5b): Slightly yellow gel. 1H NMR (300 MHz, CDCI3):
8 7.54 (s, 1 H), 5.52 (d, J: 7.7 Hz, 1 H), 4.0-4.2 (m, 1 H), 3.69 (s, 3 H), 3.0-3.2 (m,
2 H), 2.4-2.7 (m, 2 H), 1.32-1.36 (three overlapping s, 33 H); 13C NMR (75 MHz,
CDCI3): 8 172.3, 155.6, 150.0, 140.7, 84.5, 84.5, 79.3, 51.9, 50.0, 40.1, 34.6, 28.7,
25.3, 25.2, 25.1, 25.0; IR (neat): 3383, 2978, 1738, 1715, 1386, 1333, 1167, 1140
cm"; LRMS (ESI): m/e 496 ([M-Boc+2H]*), 452 ([M-Boc+2H]+), 352. HRMS (FAB):
m/e calcd for [C25H44B28N08+H]+ 552.2974, found 552.2986.

2-tert-Butoxycarbonylamino-3-[5'-(2-tert-butoxycarbonylamino-Z-metho

xycarbonyI-ethyI)-2,2'-dioxo-[3,3']-bithiophenyliden-5-yI]-propionic acid

173

 

 

‘ methyl ester (3.6a): Dark purple solid; mp 136 °C (dec). 1H
NMR (300 MHz, CDCI3): 8 7.48 (s, 2 H), 5.25 (d, J = 7.5 Hz,

2 H), 4.6 (m, 2 H), 3.79 (s, 6 H), 3.1-3.3 (m, 4 H), 1.45 (s, 18

 

 

 

 

H); 13C NMR (75 MHz, CDCI3) and DEPT: 8 195.3 (C), 171.4 (C), 155.2 (C), 150.7
(C), 135.2 (C), 1207 (CH), 80.9 (C), 53.3 (CH), 53.2 (CH3), 35.8 (CH2), 28.5
(CH3); cosv (300 MHz with respect to 1H, CDCI3): 7.48-3.1, 5.2545, 4.5-3.1,
4.5-3.3, 3.1-3.3; HETCOR (500 MHz with respect to 1H, CDCI3): H7.48-C120.7,
H4.6-C53.3, H3.79-C53.2, H3.1-C36.8, H1.45-C28.6; HMBC (500 MHz with
respect to ‘H, CDCI3): H7.48-C36.8, H7.48-C53.3, H7.48-C135.2, H7.48-C150.7,
H7.48-C195.3, H5.25-C53.3, H5.25-C171.4, H4.6-C36.8, H4.6-C150.7,
H4.6-C171.4, H3.79-C171.4, H3.1-C53.3, H3.1-C120.7, H3.1-C135.2,
H3.1-C150.7, H3.1-C171.4, H1.45-C80.9; IR (neat): 3340, 2957, 2925, 2855,
1738, 1725, 1578, 1513, 1272, 1155, 1028 cm"; LRMS (ESI): m/e 521 ([M+Na]*),
487 ([M-2'Bu+3H]*), 443 ([M-Boc-'Bu+3H]*). HRMS (FAB): m/e calcd for

[(325I"I33I\I201oSz-I‘I]+ 597.1577, found 597.1586.

0 S C)NHBoc

3.6b

 

3-tert-Butoxycarbonylamino-4-(2,5-dioxo-2,5-dihy-

dro-thiophen-3-yI)-butyric acid methyl ester (3.6b):

 

Yellow thick oil which solidified upon storage, mp 95-98 °C.
1H NMR (300 MHz, CDCI3): 8 6.84 (s, 1 H), 5.26 (d, J: 8.8 Hz, 1 H), 4.2 (m, 1 H),
3.73 (s, 3 H), 2.6-2.9 (m, 4 H), 1.39 (s, 9 H); 13C NMR (125 MHz, CDCI3) and
DEPT: 8 193.1 (C), 190.6 (C), 171.6 (C), 156.4 (C), 155.3 (C), 139.0 (CH), 80.1
(C), 52.0 (CH3), 46.0 (CH), 38.5 (CH2), 32.0 (CH2), 28.2 (CH3); HETCOR (500

MHZ with respect to 1H, CDCI3): H6.84-C139.0, H4.2-C46.0, H3.73-C52.0,

174

H2.9-C32.0, H2.6-C38.5, H1.39-C28.2; HMBC (500 MHz with respect to 1H,
CDCI3): H6.84-C32.0, H6.84-C155.3/156.4, H6.84-C190.6, H6.84-C193.1,
H3.73-C171.6, H2.9-C46.0, H2.9-C139.0, H2.9-C155.3/156.4, H2.9-C193.1,
H2.6-C32.0, H2.6-C46.0, H2.6-171.6, H1.39-080.1; IR (neat): 3357, 2957,2928,
1734, 1590, 1154 cm"; LC-MS (ESI): m/e 352 ([M+Na]*), 274 ([M-'Bu+2H]*), 230

([M-Boc+2H]+). HRMS (FAB): m/e calcd for [C14H19N058]+ 329.0933, found

 

329.0943.
( pH ‘ 3-(2-tert-Butoxycarbonylamino-2-methoxycar-
HO-B
ELQjNCOzMe bonyI-ethyI)-5-borono-6-fluoroindoIe-1-carboxylic
I NHBoc
, acid tert-butyl ester (3.8b): General procedure C
8°C 3.8b

 

 

 

(page 151) was applied to 210 mg of 3.7b (0.5 mmol).
The borylation step was carried out with 254 mg B2pin2 (1.0 mmol, 2 equiv), 20
mg [lr(OMe)(cod)]2 (0.03 mmol, 6 mol%) and 16 mg d‘bpy (0.06 mmol, 12 mol %)
in 2 mL cyclohexane. After removal of cyclohexane, 15 mL acetone and 15 mL
aqueous solution of 90 mg NH4OAc (1.2 mmol, 2.4 equiv) and 1.07 g NaIO4 (5
mmol, 2.5 equiv per Bpin) were added. The reaction mixture turned dark green
with a white precipitation formed. It was stirred at room temperature until
reaction judged complete by HPLC. The reaction was filtered to remove the
precipitate and extracted with CH2CI2. The combined organic layer was
evaporated and the residue was dissolved in acetonitrile and purified by
preparative HPLC (50/50 -—> 70/30 acetonitrile/water) to afford 102 mg (43 %) of
3.8b as a pale yellow solid. 1H NMR (300 MHz, CDCI3): 8 7.85 (d, J = 6.3 Hz, 1 H),

7.74 (d, J = 12.1 Hz, 1 H), 7.31 (s, 1 H), 5.8 (br, 2 H), 5.17 (d, J = 7.5 Hz, 1 H),

175

4.58 (br, 1 H), 3.66 (s, 3 H), 3.16 (m, 2 H), 1.59 (S, 9 H), 1.35 (s, 9 H) (Note: CDCI3
signal was observed at 7.19); LRMS (ESI): m/e 503 ([M+Na]+), 381 ([M-Boc+2H]+),

325 ([M-Boc-'Bu+3H]*), 281 ([M-2Boc+3H]*).

 

r HO . 3-(2-tert-Butoxycarbonylamino-2-methoxycarbo-
CO Me
FWHB; nyl-ethyI)-5-hydroxy-6-fluoroindoIe-1-carboxylic acid
N
Boc’ 3 9 tert-butyl ester (3.9): To a solution of 21 mg of 3.8b (44

 

 

 

pmol) in 400 pL acetone was added a solution of 30 mg oxone (49 pmol, 1.1 equiv)
in 400 pL water. The mixture was stirred at room temperature for 12 min and
quenched with NaH803. The reaction mixture was extracted with EtOAc and
evaporated. It was further dissolved in acetonitrile and purified by preparative

HPLC (50/50 —* 70/30 acetonitrile/water) to afford 16 mg of 3.9 (80%) as a pale

white solid. 1H NMR (300 MHz, CDCI3): 8 7.78 (br, 1 H), 7.24 (s, 1 H), 6.97 (d, J =
8.4 Hz, 1 H), 5.08 (d, J: 7.4 Hz, 1 H), 4.53 (m, 1 H), 3.64 (s, 3 H), 2.9-3.2 (m, 2 H),
1.56 (s, 9 H), 1.36 (s, 9 H) (Note: CDCI3 signal was observed at 7.18); 13C NMR:
(125 MHz, CDCI3): 8 172.7, 155.6, 150.3 (d, J = 233 Hz), 149.6, 140.8 (d, J = 15.6
Hz), 129.1, 127.2, 124.9, 115.1, 105.9, 103.3 (d, J: 26 Hz), 84.3, 80.7, 54.0, 52.9,
28.7, 28.6, 28.3; IR (neat): 3373, 2980, 2934, 1733, 1472, 1395, 1160, 1074 cm";
LRMS (ESI): m/e 475 ([M+Na]"), 353 ([M-Boc+2H]*), 297 ([M-Boc-‘Bu+3H]*), 253
([M-2Boc+3H]*). ‘
7.4.3 Deuterated Aromatics

1,2-Dichlorobenzene-4-d (4.3a): General procedure D (page 152) was

applied to 295 mg 1,2-dichlorobenzene (2 mmol). The borylation step was

176

C; carried out neat with 365 mg HBpin (2.85 mmol, 1.4 equiv), 16.6 mg
CI
(Ind)lr(cod) (0.04 mmol, 2 mol%) and 6.0 mg dmpe (0.04 mmol, 2

 

 

3.33 mol%) at 150 °C for 3.5 h. The crude borylation mixture was
pumped down under high vacuum and charged with 0.5 mL D20 and 3 mL THF.
The deuteration step was then carried out at 150 °C for 30 min and worked up as
described in the general procedure, after which the crude material was purified
with a silica gel Chromatography (pentane) to afford 220 mg of 4.3a (74%) as a
colorless oil. 1H NMR (300 MHz, CDCI3): 8 7.41-7.44 (m, 2 H), 7.16-7.20 (m, 1 H);
2H NMR (75.75 MHz, pentane): 8 7.21; 13C NMR (125 MHz, CDCI3): 8 132.5,
130.5, 130.4, 127.6, 127.4 (t, Jog = 25 Hz); IR (neat): 3063, 1564, 1455, 1385,
1125, 1034, 901, 835, 731, 648 cm"; LRMS (El): m/e 147 (M"), 112, 76. HRMS
(El) m/e calcd for [C(3H2,DCI2]+ 146.9753, found 146.9759.

T 1,2-DichIorobenzene-3,4,6-d3 (4.3h): General procedure D
(:47: (page 152) was applied to 303 mg unpun'fled 1,2-dichlorobenzene-d4

H (2 mmol). The borylation step was carried out neat with 402 mg

4.3!)

HBpin (3.1 mmol, 1.55 equiv), 16.6 mg (Ind)lr(cod) (0.04 mmol, 2 mol%) and 6.0

 

 

mg dmpe (0.04 mmol, 2 mol%) at 150 °C for 3 h. The crude borylation mixture
was pumped down under high vacuum and charged with 0.5 mL H20 and 3 mL
THF. The protonation step was then carried out at 150 °C for 60 min and worked
up as described in the general procedure, after which the crude material was
purified with a silica gel chromatography (pentane) to afford 246 mg of 4.3b (82%)
as a colorless oil. 1H NMR (500 MHz, CDCI3): 8 7.18 (s), a small peak (ca. 10%) at

7.42-7.44 (m) was also present (‘H at ortho positions of the chlorides, presumably

177

because i) the starting material was 98% deuterated, and ii) some borylation
occurred to such positions); 2H NMR (76.75 MHz, pentane): 8 7.49 (s, 2 D), 7.21
(s, 1 D); 13C NMR (125 MHz, CDCI3): 8 132.5, 130.2 (t, Jon = 25 Hz), 130.1 (t, Jon
= 25 Hz), 127.5, 127.3 (t, JC-D = 26 Hz); IR (pentane solution film): 1557, 1418,
1393, 1352, 1157, 1069, 1026, 626 cm"; LRMS (El): m/e 149 (W), 114, 77.
HRMS (El): m/e calcd for [C5HD3CI2]+ 148.9878, found 148.9879.

FT 1,2,3-Trichlorobenzene-5-d (4.3c): General procedure D

CI CI
(page 152) was applied to 364 mg 1,2,3-trichlorobenzene (2 mmol).

D
4.3c

 

The borylation step was carried out neat with 450 mg HBpin (3.6

 

 

mmol, 1.8 equiv), 16.6 mg (Ind)lr(cod) (0.04 mmol, 2 mol%) and 6.0 mg dmpe
(0.04 mmol, 2 mol%) at 150 °C for 3.25 h. The crude borylation mixture was
pumped down under high vacuum and charged with 0.5 mL D20 and 3 mL THF.
The deuteration step was then carried out at 150 °C for 60 min and worked up as
described in the general procedure, after which the crude material was purified
with a silica gel chromatography (pentane) to afford 343 mg of 4.3c (94%) as a
white solid; mp 52-53 °C (53-55 °C for commercial non-deuterated compound). 1H
NMR (500 MHz, CDCI3): 8 7.36 (t, Jpn = 1.1 Hz); 2H NMR (76.75 MHz, pentane):
8 7.14; 13C NMR (125 MHz, CDCI3): 8 134.3, 131.6, 128.6, 127.2 (t, Jon = 25 Hz);
IR (neat): 3071, 1553, 1412, 1385, 1196, 1159, 899, 768, 666 cm"; LRMS (El):
m/e 181 (M), 146, 110. Anal. Calcd for C5H2DCI3: C, 39.50. Found C, 39.06.

2,6-Dichloropyridene-4-d (4.3d): General procedure D (page

152) was applied to 300 mg 2,6-dichloropyridene (2 mmol). The

 

 

 

178

 

borylation step was carried out with 450 mg HBpin (3.6 mmol, 1.8 equiv), 16.6 mg
(Ind)lr(cod) (0.04 mmol, 2 mol%) and 6.0 mg dmpe (0.04 mmol, 2 mol%) in 1 mL
heptane at 150 °C for 3.25 h. After removal of heptane by a gentle nitrogen flow,
the crude borylation mixture was pumped down under high vacuum and charged
with 0.5 mL D20 and 3 mL THF. The deuteration step was then carried out at
150 °C for 60 min and worked up as described in the general procedure, after
which the crude material was purified with a silica gel chromatography (CH2CI2) to
afford 273 mg of 4.3d (92%) as a white solid; 84-86 °C (86-88.5 °C for commercial
non-deuterated compound). 1H NMR (500 MHz, CDCI3): 8 7.25 (t, JH-D = 1.1 Hz);
2H NMR (76.75 MHz, CH2CI2): 8 7.65; 13C NMR (125 MHz, CDCI3): 8 150.6, 140.4
(t, Jon = 25 Hz), 122.7; IR (neat): 3050, 2269, 1559, 1547, 1373, 1136, 986, 901,
739, 702 cm"; LRMS (El): m/e 148 (W), 113. Anal. Calcd for CsH2DNCI2: C,

40.31; N, 9.40. Found C, 40.34; N, 8.80.

 

F30 Cl 3-Chlorobenzotrifluoride-5-d (4.3d): General procedure D
? (page 152) was applied to 363 mg 3-chlorobenzotrifluoride (2
4'“ mmol). The borylation step was carried out with 450 mg HBpin
(3.6 mmol, 1.8 equiv), 16.7 mg (Ind)lr(cod) (0.04 mmol, 2 mol%) and 6.0 mg dmpe
(0.04 mmol, 2 mol%) in 2 mL cyclohexane at 150 °C for 3 h. After removal of
cyclohexane by a gentle nitrogen flow, the crude borylation mixture was pumped
down under high vacuum and charged with 0.5 mL D20 and 3 mL THF. The
deuteration step was then carried out at 150 °C for 90 min and worked up as

described in the general procedure, after which the crude material was purified

with a silica gel chromatography (pentane) to afford 244 mg material containing

179

239 mg of 4.3e (66%) and 5 mg pentane. Continuing evaporation afforded pure
4.3e (some loss of product occurred) as a colorless oil. 1H NMR (300 MHz,
CDCI3): 8 7.60 (br, 1 H), 7.50-7.51 (br, 2 H); 2H NMR (76.75 MHz, pentane): 8
7.45; 13C NMR (125 MHz, CDCI3): 8 135.0, 132.3 (q, JG): = 34 Hz), 131.9, 129.9 (t,
Jon = 25 Hz), 125.7 (q, Jc-p = 4 Hz), 123.3 (q, J04: = 4 Hz), 123.3 (q, J04: = 272
Hz); IR (pentane solution film): 3087, 1576, 1426, 1310, 1175, 1134, 1103, 1161,
887, 708, 677 cm"; LRMS (El): m/e 181 (W), 162, 146. HRMS (El): m/e calcd for

[C7H3DCIF3-Cl]+ 146.0328, found 146.0330.

 

3-Bromobenzonitrile-5-d (4.3f): General procedure D (page

rNC Br
g 152) was applied to 364 mg 3-bromobenzonitrile (2 mmol). The
D

43' borylation step was carried out with 400 mg HBpin (3.1 mmol, 1.55

 

 

equiv), 20.0 mg [lr(OMe)(cod)]2 (0.03 mmol, 1.5 mol%) and 16.0 mg d'bpy (0.06
mmol, 3 mol%) in 2 mL heptane at room temperature for 6 h. After removal of
heptane by a gentle nitrogen flow, the crude borylation mixture was pumped down
under high vacuum and Charged with 0.5 mL D20 and 3 mL THF. The
deuteration step was then carried out at 150 °C for 2 h and worked up as
described in the general procedure, after which the crude material was purified
with a silica gel chromatography (CH2CI2), followed by a sublimation at 45-50 °C
under 0.1 mmHg to afford 257 mg of 4.3f (70%) as a white solid; mp 37-39 °C
(38-40 °C for commercial non-deuterated compound). 1H NMR (500 MHz, CDCI3):

8 7.78 (apparent t, J = 1.6 HZ, 1 H), 7.73 (br, 1 H), 7.59 (br, 1 H); 2H NMR (76.75

MHZ, CHzClz): 8 7.39; 13C NMR (125 MHZ, CDCI3): 8 136.0, 134.7, 130.5, 130.3 (t,

Jc-o = 25 HZ), 122.8, 117.2, 114.2; IR (neat): 3075, 2234, 1553, 1429, 1406, 1186,

180

909, 882, 785, 675 cm'1; LRMS (El): m/e 182 (M+), 103. Anal. Calcd for C7H3DNBr:

C, 45.94; N, 7.65. Found C, 45.70; N, 7.53.

 

3-Chloro-N,N-dimethylaniIine-5-d (4.39): General

M92N CI
0 procedure D (page 152) was applied to 312 mg
D
4.39 3-chloro-N,N-dimethylaniline (2 mmol). The borylation step

 

 

was carried out neat with 512 mg HBpin (4 mmol, 2 equiv), 16.6 mg (Ind)lr(cod)
(0.04 mmol, 2 mol%) and 6.0 mg dmpe (0.04 mmol, 2 mol%) at 150 °C for 18 h.
The crude borylation mixture was pumped down under high vacuum and Charged
with 0.5 mL D20 and 3 mL DME. 102 mg AC2O (1 mmol, 0.5 equiv) was also
added at this time. The deuteration step was then carried out at 150 °C for 2 h
and cooled to room temperature. It was basified with 5% NaOH to pH > 10
before being extracted with CH2CI2. After drying and concentration, the crude
material was purified with a silica gel chromatography (pentane/CH2CI2 3:1) to
afford 292 mg of 4.39 (93%) as a colorless oil. 1H NMR (500 MHz, CDCI3): 8 6.68
(br, 2 H), 5.58 (br, 1 H), 2.93 (s, 5 H); 2H NMR (75.75 MHz, pentane): 8 7.14; 13C
NMR (125 MHz, CDCI3): 8 151.5, 134.9, 129.6 (t, Jon = 24 Hz), 116.1, 112.2,
110.4, 40.3; IR (neat): 3085, 2892, 2807, 2272, 1593, 154, 1491, 1439, 1227,
1113, 986, 972, 675 cm"; LRMS (El): m/e 155 ([M-Hl“). Anal. Calcd for CaHQDNCII

C, 61.35; N, 8.94. Found C, 61.09; N, 8.86.

 

3-ChloroanisoIe-5-d (4.3h): General procedure D (page 152)

MeO CI
0 was applied to 288 mg 3-Chloroanisole (2 mmol). The borylation

o
4.3h step was carried out neat with 400 mg HBpin (3.1 mmol, 1.55

 

 

equiv), 16.6 mg (Ind)lr(cod) (0.04 mmol, 2 mol%) and 6.0 mg dmpe (0.04 mmol, 2

181

mol%) at 150 °C for 12 h. The crude borylation mixture was pumped down
under high vacuum and charged with 0.5 mL D20 and 3 mL THF. The
deuteration step was then carried out at 150 °C for 1 h and worked up as
described in the general procedure, after which the crude material was purified
with a silica gel chromatography (CH2CI2), to afford 258 mg of 4.3h (90%) as a
colorless oil. 1H NMR (300 MHz, CDCI3): 8 6.91 (br, 1 H), 6.88 (t, J= 2.2 Hz, 1 H),
5.77 (br, 1 H), 3.78 (s, 3 H); 2H NMR (75.75 MHz, pentane): 8 7.20; 13C NMR (125
MHz, CDCI3): 8 160.3, 134.9, 129.9 (t, Jon = 24 Hz), 120.7, 114.3, 112.4, 55.3; IR
(neat): 3083, 3007, 2963, 2940, 2834, 1593, 1574, 1458, 1258, 1237, 1044, 679
cm“; LRMS (El): m/e 143 (M+). Anal. Calcd for CyHeDCIO: C, 58.55. Found C,
58.61.

3-Bromo-5-iodophenyl boronic acid pinacol ester (2.2r):

General procedure A (page 149) was applied to 566 mg

 

1-bromo-3-iodobenzene (2.0 mmol). The borylation step was

 

carried out with 510 mg B2pin2 (2.0 mmol, 2.0 equiv boron), 20.0 mg
[lr(OMe)(cod)]2 (0.03 mmol, 1.5 mol %), and 16.0 mg d'bpy (0.06 mol, 3 mol %) in
4 mL heptane in dark environment at room temperature for 12 h. (Note: use 2.0
equiv high-quality HBpin could also be effective) The reaction was carefully
quenched by addition of EtOH and concentrated. The syrup was passed
through a silica plug (CH2CI2) to afford 700 mg of 2.2r (86%) as a white solid; mp
88-92 °C. 1H NMR (300 MHz, CDCI3): 8 8.02 (brs, 1 H), 7.91 (t, J = 1.5 Hz, 1 H),

7.85 (brs, 1 H), 1.31 (s, 12 H); “B NMR (95 MHz, cook): 8 29.5; 13C NMR (75

182

MHZ, CDCI3): 8 142.0, 141.8, 136.6, 122.9, 94.6, 84.5, 24.8; IR (neat): 3058, 2980,
2930, 1537, 1429, 1399, 1372, 1337, 1269, 1167, 1142, 1113, 962, 862, 723, 698
cm'1; LRMS (El): m/e 408 (M+), 393, 322, 309, 181, 133, 116, 101, 83, 58, 41.

Anal. Calcd for C12H1sBrIBO2: C, 35.25; H, 3.70. Found C, 35.39; H, 3.69.

 

1-Bromo-3-iodobenzene-5-d (4.3i): In an air-free flask, 700

I Br l
0 mg of 2.2r (1.7 mmol) was Charged with 55 mg Crabtree’s catalyst

 

 

4-3' (0.058 mmol, 4 mol%) 0.5 mL D20 and 3 mL DME. The
deuteration was carried out at 150 °C for 4.5 h and worked up as described in the
general procedure, after which the crude material was purified with a silica gel
chromatography (pentane), to afford 267 mg of 4.3i (55%) as a colorless oil. 1H
NMR (500 MHz, CDCI3): 8 7.85 (t, J: 1.8 Hz, 1 H), 7.61 (br, 1 H), 7.45 (br, 1 H), a
small peak at 6.95 (t, J = 8.0 Hz) was also present due to non-deuterated
5-position; 2H NMR (75.75 MHz, pentane): 8 5.97; 13C NMR (125 MHz, cook): 8
139.8, 136.0, 131.0 (t, Jon = 25 Hz), 130.7, 123.1, 94.5; IR (neat): 3063, 1549,
1416, 1391, 1105, 864, 700, 673 cm"; LRMS (El): m/e 283 (W), 156, 77. HRMS
(El) m/e calcd for [C7H5DCIO]+ 282.8604, found 282.8612.

Example of Calculating D% Incorporation.

’ C. ‘ A GC-MS spectrum for the non-deuterated 1,2-dichlorobenzene
Cl

was first recorded. The peak intensities for [M-H], M, and [M+H]

233 were observed as such: 145 (M-H), 4.43%; 145 (M), 100%; 147

 

 

(M+H), 12.8%. Therefore, a ratio of [M-H]:M:[M+H] = 4.43:100:12.8 was
obtained. We assume that this ratio also applies for 1,2-dichIorobenzene-d1

(This assumption is true unless the M-H signal in the do compound is due to the

183

 

loss of the specific H that has been replaced by D). Thus, for
1,2-dichlorobenzene-d1, we should expect a ratio of peak intensities for
146:147z148 to be also 4.43:100:12.8.

Next, a GC-MS spectrum of 4.33 (a mixture of do and d1 compounds) was
recorded. The peak intensities were observed as such: 146 (M-H), 6.44%; 147
(M), 100%. If 4.3a is a mixture of x% do compound and y% d1 compound, then

x + y = 100
At the same time, consider that the peak 146 in the mass spectrum of 4.33
consists of two parts: the contributions from the do and d1 compounds,
respectively. We assume that the peak intensities for [M-H]:M:[M+H] as
4.43:100:12.8 hold for both do and d1 compounds. Thus, for x% do (M = 146), the
contribution to the peak 146 (M) in mass spectrum of 4.3a is 100x, where the
number 100 is the relative peak intensity for [M]. Likewise, for y% (I; (M = 147),
the contribution to the peak 146 (M-H) in mass spectrum of 4.3a is 4.43y, where
the number 4.43 is the relative peak intensity for [M-H]. Therefore, the intensity
of 146 for 4.3a can be viewed as (100x+4.43y). Similarly, the intensity of 147 for
4.3a can be viewed as (12.8x+100y). Thus, the ratio of 1461147 can be

re-written as (100x+4.43y)/(12.8x+100y), which is 6.442100 by experiment. So,

1 00x+4.43y
= 0.0544

 

12.8x+100y
On the basis of these two equations, one can obtain the values of x = 2, and y
= 98. Therefore, 4.3a is 98% d1 compound.

7.4.4 Amidophenols and Miscellaneous Compounds

184

 

lF3C NHAC‘ 3-Acetylamido-5-trifluoromethylphenyl boronic acid

pinacol ester (5.3a): General procedure E (page 152) was
Bpin
5-3a applied to 450 mg 3-bromobenzotrifluoride (2 mmol). The

 

 

L

borylation step was carried out with 440 mg HBpin (3.44 mmol, 1.75 equiv), 20.0
mg [lr(OMe)(cod)]2 (0.03 mmol, 1.5 mol%) and 16.0 mg d'bpy (0.06 mmol, 3 mol%)
in 2 mL n-hexane at room temperature for 4 h. After evaporation of hexane, the
crude borylation mixture was pumped down under high vacuum. The amidation
step was then carried out with 18.4 mg Pd2dba3 (0.02 mmol, 1 mol%), 34.8 mg
xantphos (0.06 mmol, 3 mol%), 130 mg acetamide (2.2 mmol, 1.1 equiv), and 900
mg Cs2C03 (2.76 mmol, 1.4 equiv) in 6 mL THF at 80 °C for 3-4 h, resulting in a
yellow suspension. The suspension was filtered to remove the insolubles and
then concentrated. Silica gel chromatography (6:1 —> 3:1 CH2CI2/Et20, 5.3a
significantly tails on silica gel) afforded 507 mg of 5.3a as a pale yellow gummy
solid (~74%) that was contaminated by trace amount of pinacol.
Recrystallization from acetone/hexanes gave pure 5.3a as a cream-colored solid;
mp 175-176 °C. 1H NMR (300 MHz, acetone-do): 8 9.41 (brs, 1 H), 8.32 (s, 1 H),
8.07 (brs, 1 H), 7.64 (apparent t, J= 0.9 Hz, 1 H), 2.14 (s, 3 H), 1.34 (s, 12 H); 13C
NMR (75 MHz, acetone-do): 8 169.4, 140.8, 130.9 (q, J = 32 Hz), 129.1, 125.8 (q,
J = 4.1 Hz), 125.0 (q, J = 272 Hz), 118.7 (q, J= 3.5 Hz), 85.2, 25.1, 24.3; 11B NMR
(96 MHz, acetone-do): 8 31.8; IR (neat): 3306, 2928, 1674, 1566, 1391, 1300,
1167, 1144, 1127, 889, 846, 708, 687 cm"; LRMS (El): m/e 329 (M*), 314, 287,

272, 230, 201, 187, 43.

185

 

fF3C NHAC‘ N-(3-Hydroxy-5-trifluoromethylphenyl)acetamide (5.4a)
(from bromoarene): General procedure E (page 152) was

OH
5.4a applied to 450 mg 3-bromobenzotrifluoride (2 mmol). The

 

 

 

borylation step was carried out neat with 440 mg HBpin (3.44 mmol, 1.75 equiv),
16.6 mg (Ind)lr(cod) (0.04 mmol, 2 mol%) and 6.0 mg dmpe (0.04 mmol, 2 mol%)
at 150 °C for 4 h (these conditions pose no difference from the conditions above).
The crude borylation mixture was pumped down under high vacuum. The
amidation step was then carried out with 18.4 mg Pd2dba3 (0.02 mmol, 1 mol%),
34.8 mg xantphos (0.06 mmol, 3 mol%), 130 mg acetamide (2.2 mmol, 1.1 equiv),
and 900 mg Cs2COo (2.76 mmol, 1.4 equiv) in 6 mL THF at 80 °C for 4 h, resulting
in a yellow suspension. After filtration through a pad of silica, the oxidation and
workup were performed as described in the general procedure. The crude

product was purified on silica gel chromatography (2:1 —> 1.5:1 CH2Cl2/EtOAc) to

afford 282 mg of 5.4a (64%) as a pale orange solid; mp 1545-1555 °C. Rr~0.38
(2:1 CH2CI2/EtOAc). 1H NMR (300 MHz, acetone-do): 8 9.33 (brs, 1 H), 8.97 (s, 1
H), 7.50 (s, 1 H), 7.46 (s, 1 H), 6.79 (s, 1 H), 2.08 (s, 3 H); 13C NMR (75 MHz,
acetone-do): 8 169.8, 159.2, 142.2, 132.1 (q, J = 32 Hz), 125.0 (q, J = 271 Hz),
110.2 (overlapped peak), 107.6 (q, apparent d, J = 3.4 Hz), 24.2; IR (neat): 3345,
3400-2800 (br), 1709, 1671, 1615, 1574, 1364, 1256, 1175, 1156, 1119, 1038,
855, 735 cm"; LRMS (El): m/e 219 (M), 177, 43. Anal. Calcd for CgHoFoNO2-H2O:
C, 45.58; H, 4.25; N, 5.91. Found C, 45.62; H, 4.48; N, 5.82.
N-(3-Cyano-5-hydroxyphenyl)acetamide (5.4h): General procedure E

(page 152) was applied to 364 mg 3-bromobenzonitrile (2 mmol). The borylation

186

 

 

step was carried out with 400 mg HBpin (3.1 mmol, 1.55 equiv),

NC NHAC
0 20.0 mg [lr(OMe)(cod)]2 (0.03 mmol, 1.5 mol%) and 16.0 mg
OH

( 5-4b d'bpy (0.06 mmol, 3 mol%) in 2 mL n-hexane at room

 

 

 

temperature for 3 h. After evaporation of hexane, the crude borylation mixture
was pumped down under high vacuum. The amidation step was then carried out
with 18.4 mg Pd2dba3 (0.02 mmol, 1 mol%), 34.8 mg xantphos (0.06 mmol, 3
mol%), 130 mg acetamide (2.2 mmol, 1.1 equiv), and 900 mg Cs2C03 (2.76 mmol,
1.4 equiv) in 6 mL THF at 80 °C for 3 h, resulting in a yellow suspension. After
filtration through a pad of silica, the oxidation and workup were performed as
described in the general procedure. The crude product was purified on silica gel
chromatography (4.521 -' 2.5:1 CH2Cl2/acetone) to afford 222 mg of 5.4h (63%)
as a pale yellow solid; mp 2645-2665 °C. Rp0.34 (1.5:1 CH2Cl2/EtOAc). 1H
NMR (300 MHz, acetone-do): 8 9.35 (brs, 1 H), 9.09 (s, 1 H), 7.52 (t, J= 2.1 Hz, 1
H), 7.49 (t, J = 1.5 Hz, 1 H), 5.84 (dd, J = 2.2, 1.4 Hz, 1 H), 2.07 (s, 3 H); 13C NMR
(125 MHz, acetone-do): 8 169.4, 159.1, 142.6, 119.2, 114.3, 113.9, 113.8, 111.3,
24.3; IR (neat): 3353, 3200-2800 (br), 2226, 1671, 1599, 1572, 1426, 1331, 885,
858, 822, 770, 694 cm"; LRMS (El): m/e 176 (M‘), 134, 43. HRMS (El): m/e calcd

for [C9H3N202]+ 176.0586, found 176.0586.

 

Cl NHA . N-(3-ChIoro-5-hydroxyphenyl)acetamide (5.4c): General
C
procedure E (page 152) was applied to 383 mg
OH
5.4e 3-bromochlorobenzene (2 mmol). The borylation step was

 

 

carried out neat with 480 mg HBpin (3.75 mmol, 1.9 equiv), 16.6 mg (Ind)lr(cod)

(0.04 mmol, 2 mol%) and 6.0 mg dmpe (0.04 mmol, 2 mol%) at 150 °C for 4 h.

187

The crude borylation mixture was pumped down under high vacuum. The
amidation step was then carried out with 18.4 mg Pd2dba3 (0.02 mmol, 1 mol%),
34.8 mg xantphos (0.06 mmol, 3 mol%), 126 mg acetamide (2.14 mmol, 1.07
equiv), and 900 mg C32003 (2.76 mmol, 1.4 equiv) in 6 mL THF at 80 °C for 3 h,
resulting in a yellow suspension. After filtration through a pad of silica, the
oxidation and workup were performed as described in the general procedure.

The crude product was purified on silica gel chromatography (2:1 .. 1.5:1

CH2CI2/EtOAc) to afford 284 mg of 5.4c (77%) as a white solid; mp 161-162 °C.
Rr~0.31 (1.75:1 CH2CI2/EtOAc). 1H NMR (300 MHz, acetone-do): 8 9.17 (brs, 1 H),
8.75 (s, 1 H), 7.23 (t, J: 1.8 Hz, 1 H), 7.16 (t, J: 1.9 Hz, 1 H), 6.55 (t, J= 2.1 Hz,
1 H), 2.05 (s, 3 H); 13‘C NMR (75 MHz, acetone-do): 8 169.3, 159.4, 142.4, 134.9,
111.1, 111.0, 105.4, 24.3; IR (neat): 3413, 3400-2800 (br), 1663, 1605, 1553,
1426, 1165, 866 cm"; LRMS (El): m/e 185 (M*), 143, 80, 43. Anal. Calcd for

CoHoCINOz: C, 51.77; H, 4.34; N, 7.55. Found C, 51.59; H, 4.46; N, 7.28.

 

M3020 NHAC‘ Methyl 3-acetylamido-5-hydroxybenzoate (5.4d):

General procedure E (page 152) was applied to 430 mg
OH

5.46 methyl 3-bromobenzoate (2 mmol). The borylation step

 

 

was carried out with 515 mg HBpin (4 mmol, 2 equiv), 20.0 mg [lr(OMe)(cod)]2
(0.03 mmol, 1.5 mol%) and 16.0 mg d'bpy (0.06 mmol, 3 mol%) in 2 mL n-hexane
at room temperature for 18 h, during which time the flask was open to a nitrogen
manifold. After evaporation of hexane, the crude borylation mixture was pumped
down under high vacuum. The amidation step was then carried out with 18.4 mg

Pd2dba3 (0.02 mmol, 1 mol%), 34.8 mg xantphos (0.06 mmol, 3 mol%), 133 mg

188

 

 

acetamide (2.25 mmol, 1.13 equiv), and 900 mg Cs2CO2, (2.76 mmol, 1.4 equiv) in
6 mL THF at 100 °C for 2 h, resulting in a yellow suspension. After filtration
through a pad of silica, the oxidation and workup were performed as described in
the general procedure. The crude product was purified on silica gel
chromatography (2.5:1 —» 2:1 CH2CI2/acetone) to afford 262 mg (contaminated
by ~2% pinacol) of 5.4d (~56%) as a pale yellow solid; mp 230-232 °C. Rr~0.53
(2:1 CH2CI2/acetone). 1H NMR (300 MHz, acetone-do): 8 9.21 (brs, 1 H), 8.66 (s, 1
H), 7.66 (t, J = 1.7 Hz, 1 H), 7.62 (t, J: 2.2 Hz, 1 H), 7.15 (dd, J= 1.5, 2.2 Hz, 1 H),
3.83 (s, 3 H), 2.07 (s, 3 H); 13C NMR (125 MHz, acetone-do): 8 169.1, 167.0, 158.6,
141.8, 132.4, 112.1, 111.6, 111.3, 52.3, 24.3; IR (neat): 3343, 3300-2900 (br),
1713, 1669, 1655, 1605, 1568, 1433, 1329, 1252, 874, 766 cm"; LRMS (El): m/e
209 (M"), 178, 167, 136, 109, 68, 43. Anal. Calcd for C1oH11NO4: C, 57.41; H, 5.30;

N, 6.70. Found C, 57.11; H, 5.54; N, 6.38.

 

r . N-(3-Hydroxy-5-methylphenyl)acetamide (5.4e):
Me NHAC
0 General procedure E (page 152) was applied to 342 mg
OH
54,, 3-bromotoluene (2 mmol). The borylation step was carried

 

 

 

out neat with 510 mg HBpin (4 mmol, 2 equiv), 16.6 mg (Ind)lr(cod) (0.04 mmol, 2
mol%) and 6.0 mg dmpe (0.04 mmol, 2 mol%) at 150 °C for 12 h. The crude
borylation mixture was pumped down under high vacuum. The amidation step
was then carried out with 18.4 mg Pd2dba3 (0.02 mmol, 1 mol%), 34.8 mg
xantphos (0.06 mmol, 3 mol%), 134 mg acetamide (2.27 mmol, 1.14 equiv), and
900 mg Cs2C03 (2.76 mmol, 1.4 equiv) in 6 mL DME at 120 °C for 3.5 h, resulting

in a yellow suspension. After filtration through a pad of silica, the oxidation and

189

workup were performed as described in the general procedure but without the
NaIO4 workup. The crude product was purified on silica gel Chromatography

(1.25:1 - 0.75:1 CH2CI2/EtOAc). Two fractions were isolated. The first

fraction (69 mg) at R)~0.5 (2:1 CH2Cl2/EtOAc) was an inseparable ~2:1 mixture of
3-methylacetanilide (protodeborylation) and acetanilide (phenyl transfer from
phosphine ligand). The second fraction (292 mg) at Rr~0.23 (2:1 CH2CI2/EtOAc)
contained desired 5.4e and substantial amount of pinacol (molar ratio of 5.4e to
pinacol ~1 :1 .5). Pinacol was removed by stirring the crude material in 2 mL CCI4
for ~3 h and then decanting off the liquid (repeat if needed). The remaining
orange solid was dried under vacuum to afford 150 mg of 5.4e (46%); mp
1355-1365 °C. 1H NMR (300 MHz, acetone-do): 8 8.96 (brs, 1 H), 8.19 (s, 1 H),
7.16 (s, 1 H), 6.81 (s, 1 H), 6.35 (s, 1 H), 2.18 (s, 3 H), 2.02 (s, 3 H); 13C NMR (125
MHz, acetone-d5): 8 168.7, 158.5, 141.3, 139.9, 111.7, 111.6, 104.4, 24.3, 21.5;
IR (neat): 3306, 3400-3000 (br), 1665, 1626, 1605, 1559, 1426, 1373, 1281, 1156,
837, 687 cm"; LRMS (El): m/e 165 (W), 123, 43. HRMS (El): m/e calcd for

[C9H11N02]+ 165.0790, found 165.1787.

 

r . N-(3-Hydroxy-5-methoxyphenyl)acetamide (5.4f):
MeO NHAC

General procedure E (page 152) was applied to 375 mg

OH
54f 3-bromoanisole (2 mmol). The borylation step was carried

 

 

L

out neat with 510 mg HBpin (4 mmol, 2 equiv), 16.6 mg (Ind)lr(cod) (0.04 mmol, 2

 

mol%) and 6.0 mg dmpe (0.04 mmol, 2 mol%) at 150 °C for 10 h. The crude
borylation mixture was pumped down under high vacuum. The amidation step

was then carried out with 18.4 mg Pd2dba3 (0.02 mmol, 1 mol%), 34.8 mg

190

 

xantphos (0.06 mmol, 3 mol%), 136 mg acetamide (2.3 mmol, 1.15 equiv), and
900 mg Cs2C03 (2.76 mmol, 1.4 equiv) in 6 mL DME at 120 °C for 4 h, resulting in
a yellow suspension. After filtration through a pad of silica, the oxidation and
workup were performed as described in the general procedure but without the
NaIO4 workup. The crude product was purified on silica gel chromatography (1 :1

_. 0.7:1 CH2CI2/EtOAC). Two fractions were isolated. The first fraction (62 mg)

at Rp0.59 (1:1 CH2CI2/EtOAc) was an inseparable ~1:1 mixture of
3-methoxyacetanilide (protodeborylation) and acetanilide (phenyl transfer from
phosphine ligand). The second fraction (274 mg) at Rr~0.37 (1 :1 CH2Cl2/EtOAc)
contained desired 5.4f and substantial amount of pinacol (molar ratio of 5.4f to
pinacol ~1:0.4, corresponding to ~36°/o 5.4f). Pinacol was removed by
recrystallization from hexanes/acetone. Drying over high vacuum afforded pure
5.4f as a white solid, mp 139.5-143 °C (dec). 1H NMR (300 MHz, acetone-do): 8
9.08 (brs, 1 H), 8.44 (s, 1 H), 6.93 (t, J = 1.8 Hz, 1 H), 6.72 (t, J = 1.9 Hz, 1 H),
5.12 (t, J = 2.2 Hz, 1 H), 3.58 (s, 3 H), 2.05 (s, 3 H); 13C NMR (75 MHz,
acetone-d5): 8 169.2, 161.9, 159.5, 141.9, 99.8, 97.25, 97.22, 55.3, 24.3; IR (neat):
3316, 3400-3000 (br), 1669, 1611,1559, 1505, 1428, 1281, 1196, 1154, 837, 683
cm'1; LRMS (El): m/e 181 (M*), 139, 110, 43. HRMS (El): m/e calcd for

[C9H11N03]+ 181.0739, found 181.0730.

 

FFaC NHAC; N-(3-Hydroxy-5-trlfluoromethylphenyl)acetamide (5.4a)
(from chloroarene): General procedure E (page 152) was

OH
5.4a applied to 360 mg 3-chlorobenzotrifluoride (2 mmol). The

 

 

 

borylation step was carried out with 400 mg HBpin (3.1 mmol, 1.55 equiv), 16.6

191

mg (Ind)lr(cod) (0.04 mmol, 2 mol%) and 6.0 mg dmpe (0.04 mmol, 2 mol%) in 2
mL n-hexane at 150 °C for 4 h. After removal of hexane, the crude borylation
mixture was pumped down under high vacuum. The amidation step was then
carried out with 18.4 mg Pd2dba3 (0.02 mmol, 1 mol%), 34.8 mg xantphos (0.06
mmol, 3 mol%), 132 mg acetamide (2.2 mmol, 1.1 equiv), and 900 mg Cs2C03
(2.76 mmol, 1.4 equiv) in 6 mL THF at 100 °C for 27 h, resulting in a yellow
suspension. After filtration through a pad of silica, the oxidation and workup
were performed as described in the general procedure. The crude product was
purified on silica gel chromatography (2:1 CH2CI2/EtOAc) to afford first a fraction
of 172 mg (42%) protodeborylation product at Rr~0.63, followed by a trace
amount of the presumed Suzuki byproduct, and then a fraction of 175 mg of 5.4a

(40%) at Rr~0.38.

 

F30 NHAC Protodeboylatlon product: pale yellow SOIId, mp 100-102
0 °C (commercial sample 103-104 °C), Rr-0.63 (2:1

 

 

CH2CI2/EtOAC). 1H NMR (300 MHz, acetone-do): 8 9.43 (brs, 1 H), 8.15 (s, 1 H),
7.78 (d, J = 7.7 Hz, 1 H), 7.50 (t, J = 8.0 Hz, 1 H), 7.36 (d, J = 7.7 Hz, 1 H), 2.11 (s,
3 H); 13C NMR (125 MHz, acetone-do): 8 169.5, 141.2, 131.2 (q, apparent d, J =
32 Hz), 130.5, 125.2 (q, apparent d, J = 272 Hz), 123.1, 120.2 (q, apparent d, J =
3.6 Hz), 116.2 (q, apparent d, J = 4.1 Hz), 24.2; LRMS (El): m/e 203 (M*), 161,43.
Anal. Calcd for CgH8F3NOI C, 53.21; H, 3.97; N, 6.89. Found C, 53.34; H, 3.89; N,
6.69.

N-(2-Hydroxy-4-triquoromethyIphenyl)acetamide (5.49): General

procedure E (page 152) was applied to 722 mg 4-chlorobenzotrifluoride (4 mmol,

192

 

F ‘ 2 equiv). The borylation step was carried out with 256 mg

F30
QNHAC HBpin (2 mmol), 16.6 mg (Ind)lr(cod) (0.04 mmol, 2 mol%) and
OH

5-49 6.0 mg dmpe (0.04 mmol, 2 mol%) in 2 mL n-hexane at 150 °C

 

 

for 4 h. After removal of hexane, the crude borylation mixture was pumped down
under high vacuum. The amidation step was then carried out with 18.4 mg
' Pd2dba3 (0.02 mmol, 1 mol%), 34.8 mg xantphos (0.06 mmol, 3 mol%), 132 mg
acetamide (2.2 mmol, 1.1 equiv), and 900 mg Cs2C03 (2.76 mmol, 1.4 equiv) in 6
mL DME at 110 °C for 12 h, resulting in a yellow suspension. After filtration
through a pad of silica, the oxidation and workup were performed as described in
the general procedure. The crude product was purified on silica gel
chromatography (2:1 CH2CI2/EtOAc), which afforded 184 mg protodeborylation

product (45%). No 5.49 was detected.

 

Protodeboylation product: pale solid, mp 148.5-150 °C

 

F3C.
ONHAC] (commercial sample 151-152 °C), Rr~0.54 (2:1

 

CH2CI2/EtOAc). 1H NMR (300 MHz, acetone-do): 8 9.47 (brs, 1 H), 7.84 (apparent
d, J = 8.5 Hz, 2 H), 7.61 (apparent d, J = 8.5 Hz, 2 H), 2.11 (s, 3 H); 13C NMR (125
MHz, acetone-do): 8 169.5, 143.9, 126.7 (q, J = 4.0 Hz), 125.4 (q, apparent d, J =
271 Hz), 125.0 (q, J=33 Hz), 119.7, 24.3; LRMS (El): m/e 203 (M*), 161, 43. Anal.

Calcd for C9H3F3NOI C, 53.21; H, 3.97; N, 6.89. Found C, 53.09; H, 3.76; N, 6.78.

 

(F C NHBZ: N-(3-Hydroxy-5-trifluoromethylphenyl)benzamide
3
(5.4h): General procedure E (page 152) was applied to 450
OH
5,411 mg 3-bromobenzotrifluoride (2 mmol). The borylation step

 

 

 

was carried out neat with 440 mg HBpin (3.44 mmol, 1.75 equiv), 16.6 mg

193

(Ind)lr(cod) (0.04 mmol, 2 mol%) and 6.0 mg dmpe (0.04 mmol, 2 mol%) at 150
°C for 4 h. The crude borylation mixture was pumped down under high vacuum.
The amidation step was then carried out with 18.4 mg Pd2dba3 (0.02 mmol, 1
mol%), 34.8 mg xantphos (0.06 mmol, 3 mol%), 281 mg benzamide (2.32 mmol,
1.16 equiv), and 900 mg C32003 (2.76 mmol, 1.4 equiv) in 6 mL THF at 80 °C for
4 h, resulting in a yellow suspension. After filtration through a pad of silica, the
oxidation and workup were performed as described in the general procedure.
The crude product was purified on silica gel chromatography (10:1 CH2Cl2/EtOAc)
to afford 382 mg of 5.4h (80%) as a pale yellow solid; mp 154-156 °C. R)~0.36
(12:1 CH2CI2/EtOAc). 1H NMR (300 MHz, acetone-do): 8 9.69 (brs, 1 H), 9.02 (s, 1
H), 7.97-8.01 (m, 2 H), 7.77 (s, 1 H), 7.70 (s, 1 H), 7.48-7.62 (m, 3 H), 6.88 (s, 1H);
13C NMR (75 MHz, acetone-do): 8 166.7, 159.1, 142.3, 135.8, 132.6, 132.2 (q, J=
32 Hz), 129.3, 128.4, 125.1 (q, J: 271 Hz), 111.1, 108.7 (q, J= 4.6 Hz), 108.0 (q,
J= 3.4 Hz); IR (neat): 3310, 3400-2800 (br), 1655, 1615, 1557, 1451, 1439, 1354,
1254, 1175, 1127, 696 cm"; LRMS (El): m/e 281 (M*), 105, 77. Anal. Calcd for
C14H1oF3NO2: C, 59.79; H, 3.58; N, 4.98. Found C, 59.70; H, 3.81; N, 4.85.

Methyl 3-tert-butoxycarbonylamino-5-hydroxy-

 

IMeOZJC \ NHBoc
I / benzoate (5.4i): General procedure E (page 152) was
0H
54. applied to 430 mg methyl 3-bromobenzoate (2 mmol).

 

 

 

The borylation step was carried out with 510 mg HBpin (4 mmol, 2 equiv), 20.0 mg
[lr(OMe)(cod)]2 (0.03 mmol, 1.5 mol%) and 16.0 mg d'bpy (0.06 mmol, 3 mol%) in
2 mL n-hexane at room temperature for 18 h, during which time the flask was

open to a nitrogen manifold. After evaporation of hexane, the crude borylation

194

mixture was pumped down under high vacuum. The amidation step was then
carried out with 18.4 mg Pd2dba3 (0.02 mmol, 1 mol%), 34.8 mg xantphos (0.06
mmol, 3 mol%), 260 mg tert-butylcarbamate (2.22 mmol, 1.11 equiv), and 900 mg
Cs2003 (2.76 mmol, 1.4 equiv) in 6 mL THF at 100 °C for 2.5 h, resulting in a
yellow suspension. After filtration through a pad of silica, the oxidation and
workup were performed as described in the general procedure. The crude
product was first passed through a silica gel column (8:1 -> 4.5:1 CH2CI2/EtOAc),
and then purified by a second round of chromatography (1.6:1 _. 1.2:1
hexanes/EtOAc). The first fraction at R,~0.33 (2:1 hexanes/EtOAc) contained
246 mg of 5.4i (46%), and the second fraction at R,~0.23 (2:1 hexanes/EtOAc)
contained 76 mg of impure Suzuki product 5.5i (~19%).

Desired product 5.4i: White solid; mp 149-150.5 °C (dec). 1H NMR (300 MHz,
acetone-do): 8 8.61 (s, 1 H), 8.51 (brs, 1 H), 7.72 (t, J = 1.6 Hz, 1 H), 7.39 (t, J =
2.2 Hz, 1 H), 7.12 (dd, J = 1.6, 2.2 Hz, 1 H), 3.83 (s, 3 H), 1.48 (s, 9 H); 13C NMR
(75 MHz, acetone-do): 8 167.1, 158.6, 153.6, 142.0, 132.5, 111.4, 110.9, 110.4,
80.2, 52.2, 28.4; IR (neat): 3349 (br), 2982, 1700 (with a shoulder 1726), 1605,
1547, 1435, 1368, 1329, 1248, 1159, 872, 772 cm"; LRMS (El): m/e 267 (M*),
211, 167, 136, 109, 57. HRMS (El): m/e calcd for [C13H17N05]* 267.1107, found

267.1100.

 

[ Suzuki product 5.5i: White solid (recrystallized from
MeO2C NHBoc
0 acetone/hexanes) mp 179-181 °C (dec). 1H NMR (300

0 MHz, acetone-do): 8 8.92 (s, 1 H), 8.75 (brs, 1 H), 8.30 (m,

MeO2C OH

 

5.5i

 

 

195

 

1 H), 8.12 (t, J = 1.8 Hz, 1 H), 7.89 (t, J = 1.55 Hz, 1 H), 7.78 (t, J = 1.5 Hz, 1 H),
7.51 (dd, J =1,4,2.5 Hz, 1 H), 7.38 (dd, J =1.8,2.3 Hz, 1 H), 3.91 (s, 3 H), 3.90 (s,
3 H), 1.51 (s, 9 H); 13C NMR (125 MHz, acetone-do): 8 155.95, 155.90, 158.9,
153.7, 142.5, 141.7, 141.5, 133.2, 132.4, 122.2, 121.5, 119.8, 119.05, 119.02,
115.3, 80.6, 52.49, 52.45, 28.4; IR (neat): 3353 (br), 2980, 1701 (with a shoulder
1725), 1597, 1547, 1439, 1357, 1294, 1233, 1159, 1005, 872, 770 cm"; LRMS
(El): m/e 401 (M*), 345, 327, 301,295,270, 120, 105,77, 59, 57. HRMS (El): m/e

calcd for [C21H23NO7]+ 401.1475, found 401.1473.

 

F . 1-(3-Hydroxy-5-trifluoromethylphenyI)-3-(4-meth
H
F3C Nm/NHPMB oxybenzy|)-urea (5.4j): General procedure E (page 152)
0
OH 5.41 was applied to 450 mg 3-bromobenzotrifluoride (2 mmol).

 

 

 

The borylation step was carried out neat with 436 mg HBpin (3.44 mmol, 1.75
equiv), 17.5 mg (Ind)lr(cod) (0.042 mmol, 2.1 mol%) and 6.4 mg dmpe (0.042
mmol, 2.1 mol%) at 150 °C for 3 h. The crude borylation mixture was pumped
down under high vacuum. The amidation step was then carried out with 18.4 mg
Pd2dba3 (0.02 mmol, 1 mol%), 34.8 mg xantphos (0.06 mmol, 3 mol%), 398 mg
4-methoxybenzylurea (2.24 mmol, 1.12 equiv), and 900 mg Cs2003 (2.76 mmol,
1.4 equiv) in 6 mL THF at 100 °C for 2 h, resulting in a yellow suspension. After
filtration through a pad of silica, the oxidation and workup were performed as
described in the general procedure, but without NalO4 workup. The crude

product was purified on silica gel chromatography (6.5:1 —> 1.5:1 CH2CI2/EtOAc).

The first fraction at Rr~0.69 (4:1 CH2CI2/EtOAc) contained 115 mg of Suzuki

product 5.5j (24%) and the second fraction at R,~0.35 (4:1 CH2CI2/EtOAc)

196

 

contained 130 mg of desired product 5.4j (19%).

Desired product 5.4j: White solid; mp 194-196.5 °C. 1H NMR (300 MHz,
acetone-do): 8 8.80 (s, 1 H), 8.18 (brs, 1 H), 7.37 (s, 1 H), 7.31 (s, 1 H), 7.24-7.27
(m, 2 H), 685-6.89 (m, 2 H), 6.67 (s, 1 H), 6.19 (br, 1 H), 4.32 (d, J= 6.0 Hz, 2 H),
3.76 (s, 3 H); 13C NMR (75 MHz, acetone-do): 8 159.7, 159.1, 155.8, 143.6, 132.9,
132.1 (q, J= 32 Hz), 129.5, 125.2 (q, J: 271 Hz), 114.5, 108.8, 106.5 (q, J= 4.0
Hz), 105.7 (q, J= 4.0 Hz), 55.4, 43.6; IR (neat): 3341 (br), 1657, 1613, 1584, 1514,
1441, 1375, 1250, 1175, 1125, 696 cm"; LRMS (El): m/e 340 (M*), 203, 177, 136,
121, 78. Anal. Calcd for C15H15F3N2O3: C, 56.47; H, 4.44; N, 8.23. Found C, 56.61;
H, 4.40; N, 8.20.

r - Suzuki product 5.5j: White solid (recrystallized from

 

H
PMB
F3C O NTOKNH acetone/hexanes) mp 185 °C (dec). 1“ NMR (300 MHZ.

O acetone-do): 8 9.21 (s, 1 H), 8.42 (brs, 1 H), 8.01 (s, 2 H),
F3C OH

 

 

l

H), 7.16 (s, 1 H), 685-6.90 (rn, 2 H), 6.37 (br, 1 H), 4.36 (d, J = 6.0 HZ, 2 H), 3.76

55] 7.52 (s, 1 H), 7.45 (s, 1 H), 7.38 (s, 1 H), 7.26-7.30 (m, 2

(s, 3 H); 13C NMR (125 MHz, acetone-d5): 8 159.8, 159.3, 155.9, 143.2, 143.1,
141.8, 132.84, 132.80 (q, J = 28 Hz), 132.0 (q, J = 32 Hz), 129.5, 125.2 (q
apparent d, J = 272 Hz), 125.0 (q apparent d, J = 272 Hz), 120.6 (apparent d, J =
1.2 Hz), 118.5, 117.0 (q, J = 3.6 Hz), 115.5 (q, J = 4.0 Hz), 114.8 (q, J = 4.0 Hz),
114.5, 112.4 (q, J = 4.0 Hz), 55.4, 43.7; IR (neat): 3341 (br), 1655, 1607, 1564,
1514, 1387, 1335, 1264, 1244, 1171, 1125, 864, 702 cm"; LRMS (El): m/e 484
(M), 347, 328, 321, 250, 163, 136, 121. Anal. Calcd for C23H18F6N203: C, 57.03;

H, 3.75; N, 5.78. Found C, 56.96; H, 4.11; N, 5.41.

197

 

 

1 ,1-DibenzyI-3-(3-hydroxy-5-trifluoromethylphenyl)

I H ,Bn
F3C NYNBn urea (5.4k): General procedure E (page 152) was applied
0
OH to 450 mg 3-bromobenzotrifluoride (2 mmol). The
5.4k

 

 

 

borylation step was carried out neat with 440 mg HBpin
(3.44 mmol, 1.75 equiv), 17.5 mg (Ind)lr(cod) (0.042 mmol, 2.1 mol%) and 6.3 mg
dmpe (0.042 mmol, 2.1 mol%) at 150 °C for 4 h. The crude borylation mixture
was pumped down under high vacuum. The amidation step was then carried out
with 18.4 mg Pd2dba3 (0.02 mmol, 1 mol%), 34.8 mg xantphos (0.06 mmol, 3
mol%), 529 mg N,N-(dibenzyl)urea (2.2 mmol, 1.1 equiv), and 900 mg Cs2C03
(2.76 mmol, 1.4 equiv) in 6 mL THF at 100 °C for 1.5 h, resulting in a yellow
suspension. After filtration through a pad of silica, the oxidation and workup
were performed as described in the general procedure. The crude product was

purified on silica gel chromatography (15:1 —> 7.521 CH2Cl2/EtOAc) to afford 420

mg of 5.4d (53%) as an orange solid; mp 1465-1485 °C. Rr~0.38 (15:1
CH2CI2/EtOAc). 1H NMR (300 MHz, acetone-do): 8 8.81 (s, 1 H), 8.16 (s, 1 H),
7.45 (apparent t, J: 1.9 Hz, 1 H), 7.41 (s, 1 H), 7.24-7.39 (m, 10 H), 6.72 (s, 1 H),
4.63 (s, 4 H); 13C NMR (75 MHz, acetone-d5): 8 158.9, 156.2, 143.5, 138.8, 131.8
(q, apparent d, J = 32 Hz), 129.4, 128.2, 128.1, 125.2 (q, apparent d, J: 271 Hz),
110.1, 108.1 (q, apparent d, J = 4.6 Hz), 106.3 (q, apparent d, J = 4.6 Hz), 50.1;
IR (neat): 3283, 3400-2900 (br), 1647, 1612, 1547, 1453, 1362, 1240, 1169, 1125,
696 cm"; LRMS (El): m/e 400 (M*), 309, 132, 106, 91, 77; HRMS (El): m/e calcd

for [C22H19F3N202]+ 400.1399, found 400.1403.

198

 

 

1-(3-Hydroxy-5-trifluoromethylphenyl)piperidin-2-one

50$"? (5.4l): General procedure E (page 152) was applied to 450
0
OH

mg 3-bromobenzotrifluoride (2 mmol). The borylation step

 

5.4I

 

was carried out neat with 440 mg HBpin (3.44 mmol, 1.75
equiv), 17.5 mg (Ind)lr(cod) (0.042 mmol, 2.1 mol%) and 6.3 mg dmpe (0.042
mmol, 2.1 mol%) at 150 °C for 4 h. The crude borylation mixture was pumped
down under high vacuum. The amidation step was then carried out with 18.4 mg
Pd2dba3 (0.02 mmol, 1 mol%), 34.8 mg xantphos (0.06 mmol, 3 mol%), 220 mg
8-valerolactam (2.2 mmol, 1.1 equiv), and 900 mg C32003 (2.76 mmol, 1.4 equiv)
in 6 mL THF at 100 °C for 2 h, resulting in a yellow suspension. After filtration
through a pad of silica, the oxidation and workup were performed as described in
the general procedure. The crude product was purified on silica gel
chromatography (1.75:1 -> 0.75:1 CH2CI2/EtOAc) to afford two fractions. The
first fraction at R,~0.52 (2:1 CH2CI2/EtOAc) contained 94 mg of Suzuki product
5.5I (23%), and the second fraction at Rr~0.22 (2:1 CH2CI2/EtOAc) contained 247
mg of desired product 5.4i (48%).

Desired product 5.4I: Pale gray solid, mp 167.5-169.5 °C. 1H NMR (300 MHz,
acetone-do): 8 9.14 (s, 1 H), 7.13 (brs, 1 H), 7.04 (t, J= 1.8 Hz, 1 H), 6.94 (brs, 1
H), 3.71 (t, J = 5.0 Hz, 2 H), 2.44 (t, J = 5.3 Hz, 2 H), 1.86-2.00 (m, 4 H); ”C NMR
(125 MHz, acetone-d6): 8 170.5, 159.1, 146.6, 132.0 (q, J = 32 Hz), 124.9 (q, J =
271 Hz), 118.1 (q, overlapped), 114.6 (q, J = 4 Hz), 110.6 (q, J = 3.8 Hz), 51.8,
33.5, 24.0, 21.8; IR (neat): 3171, 2955, 3400-2800 (br), 1632, 1605, 1458, 1366,

1258, 1167, 1125, 702 cm'1; LRMS (El): m/e 259 (M+), 202, 190, 55. Anal. Calcd

199

for C12H12F3NO3: C, 55.60; H, 4.67; N, 5.40. Found C, 55.74; H, 4.70; N, 5.34.

 

7 Suzuki product 5.5I: White solid (recrystallized from

F C N
3 O :0; hexanes/acetone) mp > 205 °C (dec). 1H NMR (300 MHz,

0 acetone-do): 8 9.25 (s, 1 H), 7.94 (s, 1 H), 7.82 (s, 1 H), 7.74
F3C OH

(8, 1 H), 7.49 (s, 1 H), 7.38 (t, J = 1.8 Hz, 1 H), 7.15 (s, 1H),

 

 

L 5.5l
3.85 (t, J = 5.9 Hz, 2 H), 2.50 (t, J = 5.5 Hz, 2 H), 1.92-2.03 (m, 4 H); 13C NMR

 

(125 MHz, acetone-do): 8 170.4, 159.3, 145.2, 142.5, 142.0, 132.8 (q, J = 32 Hz),
131.9 (q, J = 32 Hz), 129.4, 125.0 (q, J = 272 Hz), 124.95 (q, J = 272 Hz), 123.5 (q,
J = 3.9 Hz), 121.8 (q, J = 3.9 Hz), 118.7, 115.7 (q, J = 3.9 Hz), 112.5 (q, J = 3.7
Hz), 51.7, 33.5, 24.1, 22.0; IR (neat): 3189, 2955, 3400-2900 (br), 1532, 1501,
1455, 1385, 1331, 1254, 1157, 1125, 866, 704 cm"; LRMS (El): m/e 403 (Mr),
374, 334,235, 188, 82, 70, 55. Anal. Calcd for C19H15F6NO2: C, 55.58; H, 3.75; N,

3.47. Found C, 56.61; H, 4.04; N, 3.61.

 

fi H | . N-(3-Hydroxy-5-trifluoromethylphenyl)acrylamide (5.4

r: c N?
3 o m): General procedure E (page 152) was applied to 450 mg
52m 3-bromobenzotrifluoride (2 mmol). The borylation step was

 

 

 

carried out neat with 440 mg HBpin (3.44 mmol, 1.75 equiv), 17.5 mg (Ind)lr(cod)
(0.042 mmol, 2.1 mol%) and 6.3 mg dmpe (0.042 mmol, 2.1 mol%) at 150 °C for 4
h. The crude borylation mixture was pumped down under high vacuum. The
amidation step was then carried out with 18.4 mg Pd2dba3 (0.02 mmol, 1 mol%),
34.8 mg xantphos (0.06 mmol, 3 mol%), 258 mg acrylic amide (2.23 mmol, 1.11
equiv), and 900 mg Cs2003 (2.76 mmol, 1.4 equiv) in 6 mL THF at 80 °C for 3.5 h,

resulting in a yellow suspension. After filtration through a pad of silica, the

200

oxidation and workup were performed as described in the general procedure.
The crude product was purified on silica gel chromatography (2:1 CH2CI2/EtOAc)
to afford 171 mg of 5.4m (37%) as a pale-white solid; mp 118-120 °C. Rrv0.60
(2.5:1 CH2CI2/EtOAc). 1H NMR (300 MHz, acetone-do): 8 9.50 (brs, 1 H), 9.01 (s,
1 H), 7.57 (s, 2 H), 6.84 (s, 1 H), 6.31-6.48 (m, 2 H), 5.74 (dd, J= 3.3, 9.1 Hz, 1 H);
13C NMR (125 MHz, acetone-do): 8 164.4, 159.2, 142.1, 132.4, 132.2 (q, J = 32
Hz), 127.9, 125.0 (q, J = 272 Hz), 110.4, 108.0 (q, J = 4.4 Hz), 107.9 (q, J = 3.5
Hz); IR (neat): 3293, 3400-2900 (br), 1671, 1615, 1561, 1445, 1370, 1354, 1223,
1173, 1127, 860, 696 cm"; LRMS (El): m/e 231 (M*), 177, 55. Anal. Calcd for

C1oHoF3N02: C, 51.96; H, 3.49; N, 6.06. Found C, 51.58; H, 3.54; N, 5.70.

 

, . (E)-2-MethyI-but-2-enoic acid (3-chIoro-5-hydroxy
H
Cl him/E phenyl) amide (5.4n): General procedure E (page 152) was
0
OH 54" applied to 385 mg 3-bromochlorobenzene (2 mmol). The

 

 

 

borylation step was carried out with 430 mg HBpin (3.4 mmol, 1.7 equiv), 16.6 mg
(Ind)lr(cod) (0.04 mmol, 2 mol%) and 6.0 mg dmpe (0.04 mmol, 2 mol%) In 0.5 mL
n-hexane at 150 °C for 3.5 h. After removal of hexane, the crude borylation
mixture was pumped down under high vacuum. The amidation step was then
carried out with 18.4 mg Pd2dba3 (0.02 mmol, 1 mol%), 34.8 mg xantphos (0.06
mmol, 3 mol%), 216 mg tiglic amide (2.18 mmol, 1.1 equiv), and 900 mg Cs2003
(2.76 mmol, 1.4 equiv) in 6 mL THF at 100 °C for 1.5 h (or at 80 °C for 8 h),
resulting in a yellow suspension. After filtration through a pad of silica, the
oxidation and workup were performed as described in the general procedure.

The crude product was purified on silica gel chromatography (7:1 _. 3:1

201

CH2CI2/EtOAc) to afford 298 mg of 5.4m (65%) as a pale yellow solid; mp
131.5-1335 °C. Rr~0.41 (7:1 CH2CI2/EtOAc). 1H NMR (300 MHz, acetone-do): 8
8.97 (brs, 1 H), 8.73 (s, 1 H), 7.32 (t, J = 1.8 Hz, 1 H), 7.30 (t, J = 2.1 Hz, 1 H),
6.56 (t, J = 2.1 Hz, 1 H), 6.47 (qq, J = 1.4, 6.9 Hz, 1 H), 1.86 (apparent t, J = 1.4
Hz, 3 H), 1.75 (dq, J = 6.9, 1.1 Hz, 3 H); 13C NMR (125 MHz, acetone-do): 8 168.6,
159.3, 142.6, 134.8, 133.9, 131.4, 111.7, 111.2, 106.1, 14.0, 12.5; IR (neat): 3299,
3500-2900 (br), 1663, 1599, 1536, 1429, 1289, 1179, 839, 675 cm"; LRMS (El):
m/e 225 (M"), 143, 136, 105, 83, 77, 55. Anal. Calcd for C11H12CINO2: C, 58.54; H,

5.36; N, 6.21. Found C, 58.44; H, 5.38; N, 6.04.

 

 

A s
F F
F3C CF3 1. cat. (Ind)lr(cod)-dmpe, HBpin, 150 °C_ 30 C 3
2. cat. szdbaa-xantphos, Cs2C03, 7
PhBr, H20, DME, 100 °C p).
5.6

 

 

 

3,5-Bis(trifluoromethyl)biphenyl (5.6): Following general procedure E (page
152), 215 mg 1,3-bis(trifluoromethyl)benzene (1 mmol) was borylated with 217
mg HBpin (1.7 mmol, 1.7 equiv), 8.4 mg (Ind)lr(cod) (0.02 mmol, 2 mol%) and 3.0
mg dmpe (0.02 mmol, 2 mol%) in 0.5 mL n-hexane at 150 °C for 3.5 h. After
removal of hexane, the crude borylation mixture was pumped down under high
vacuum. The flask was returned to the glove box and charged with 9.2 mg
Pd2dba3 (0.01 mmol, 1 mol%), 17.4 mg xantphos (0.03 mmol, 3 mol%), 234 mg
phenyl bromide (1.5 mmol, 1.5 equiv), 450 mg Cs2C03 (2.76 mmol, 1.4 equiv),
and 3 mL DME. After being taken out of the glove box, the reaction mixture was

charged with 27 pL water (1.5 mmol, 1.5 equiv) and heated at 100 °C for 2 h

202

(control experiment showed a much slower reaction in the absence of water).
After concentration, the crude product was purified on silica gel chromatography
(hexanes) to afford 217 mg of 5.6 (75%) as a colorless oil. 1H NMR (500 MHz,
CDCI3): 8 8.00 (s, 2 H), 7.84 (s, 1 H), 7.58-7.61 (m, 2 H), 7.42-7.52 (m, 3 H); 13C
NMR (125 MHz, CDCI3): 8 143.4, 138.3, 132.1 (q, J = 33 Hz), 129.3, 128.9,
127.24, 127.21 (m), 123.4 (q, J = 273 Hz), 120.9 (sept, apparent quint, J = 3.7 Hz);
IR (neat): 3071, 1466, 1383, 1280, 1177, 1132, 1063, 897, 764, 706, 683 cm";
LRMS m/e 290 (M*), 220, 200, 151, 134, 56, 43. Anal. Calcd for C14HoFo: C, 57.94;

H, 2.78. Found C, 58.12; H, 2.71.

1. cat. (Ind)lr(cod)-dmpe, HBpin, 150 °C r g
2. cat. Pd2dba3-xantphos, AcNH2 (5.2a), F3C NHAc

FsC Br Cs2C03, THF, 80 °c _
O 3. PhBr, H2O, THF, 80 °C '
2.1w Ph

5.7

 

 

 

 

 

N-(5-TrifluoromethyI-biphenyl-3-yI)-acetamide (5.7): General procedure E
(page 152) was applied to 450 mg 3-bromobenzotrifluoride (2 mmol). The
borylation step was carried out neat with 432 mg HBpin (3.4 mmol, 1.7 equiv),
17.6 mg (Ind)lr(cod) (0.042 mmol, 2.1 mol%) and 6.3 mg dmpe (0.042 mmol, 2.1
mol%) at 150 °C for 3 h. The crude borylation mixture was pumped down under
high vacuum. The amidation step was then carried out with 18.4 mg Pd2dba3
(0.02 mmol, 1 mol%), 34.8 mg xantphos (0.06 mmol, 3 mol%), 130 mg acetamide
(2.2 mmol, 1.1 equiv), and 1.6 g Cs2C03 (5 mmol, 2.5 equiv) in 6 mL THF at 80 °C
for 3.75 h, resulting in a yellow suspension. To this suspension was added 470

mg phenyl bromide (3 mmol, 1.5 equiv) and 40 pL water (2.2 mmol, 1.1 equiv)

203

and the mixture was heated at 80 °C for 2 h, turning into a pale gray suspension.

The resulting mixture was concentrated and purified by chromatography (1 .4:1 _.

1:1 hexaneletOAc). The first fraction (~46 mg) at Rrv0.51 (1.5:1
hexanes/EtOAc) contained what was assigned as a m-terphenyl structure:
N-(5,5'-bis-trifluoromethyl-[1 ,1 ';3', 1 "]terphenyI-3-yl)-acetamide. The second
fraction (260 mg) at Rr~0.41 (1.5:1 hexanes/EtOAC) contained the desired product
5.7 (47%). The third fraction (61 mg) at Rrr0.34 (1.5:1 hexanes/EtOAC)
contained the deborylation product N-(3-trifluoromethylphenyl) acetamide.
Desired product 5.7: Yellow solid; mp 84.5-87 °C. 1H NMR (500 MHz,
acetone-d5): 8 9.51 (br, 1 H), 8.12 (s, 2 H), 7.66-7.69 (m, 2 H), 7.61 (s, 1 H),
7.48-7.51 (m, 2 H), 7.40-7.43 (m, 1 H), 2.14 (s, 3 H); 13C NMR (125 MHz, CDCI3):
8 169.5, 143.6, 141.8, 140.2, 131.9 (q, J= 32 Hz), 129.9, 129.1, 127.8, 125.2 (q,
apparentd, J: 272 Hz), 121.5, 118.7 (q, J= 4.1 Hz), 115.1 (q, apparentd, J=4.1
Hz), 24.3; IR (neat): 3287, 1673, 1617, 1566, 1466, 1451, 1364, 1282, 1167, 1125,
878, 764, 700 cm"; LRMS m/e 279 (W), 237, 43. HRMS (El) m/e calcd for

[C(5H12F3NO]+ 279.0871, found 279.0868.

204

Chapter 8. Experimental Details and Compound Characterization Data for
Attempted Total Synthesis of Autolytimycin
8.1 Materials and Methods

Unless othenlvise noted, all commercial compounds were used as received.
Solvents for the reactions were purified as indicated in Chapter 7, unless
otherwise noted. All reactions, except those performed in aqueous conditions
and/or in unpurified solvents, were performed in oven- or flame-dried glassware
and monitored by TLC. \fisualization was achieved by UV lamp or
phosphomolybdic acid stain.

Optical rotation was measured with Perkin-Elmer 341 polarimeter. Other
instrumental analysis was performed as indicated in Chapter 7 (page 137).
8.2 Experimental Details and Characterization Data for the Compounds

Related to the Total Synthesis

OH o><
OH O
ngo AcCl, acetone ; liefo

HO OH HO OH
6.6 6.7

 

To a stirred solution of 105 g vitamin C (0.6 mol) in 600 mL acetone (no
purification or drying needed) was added 10 mL acetyl chloride (11 g, 0.14 mol,
~23 mol%). The reaction was sealed with a septum and stirred overnight. A

precipitate formed and was collected by suction filtration and washed with cold

205

acetone to remove the yellow color. The combined mother liquor was
concentrated to about 200 mL and a second crop of precipitate was collected and
washed. The combined mother liquor was again concentrated to about 100 mL
and a third crop of precipitate was collected and washed. The combined solid
was dried over high vacuum to afford 110.5 g of crude 6.7 (~86%) as a white solid,
mp (crude) 204 °C (dec) (lit163 217-222 °C, dec); [8:120D +153 (0 0.95, EtOH); 1H
NMR (500 MHz, acetone-do): 8 ~96 (br, 1 H), ~7.6 (br, 1 H), 4.71 (d, J: 3.3 Hz, 1
H), 4.35 (dt, J = 3.3, 5.7 Hz, 1 H), 4.17 and 4.00 (d of ABq, 3J = 6.8 Hz, JAB = 8.5
Hz, 2 H), 1.29 (s, 3 H), 1.28 (s, 3 H), some impurities at 4.71 and 3.7; 13C NMR
(125 MHz, acetone-do): 8 171.1, 151.1, 120.0, 110.2, 75.4, 75.0, 66.0, 26.2, 25.8;
LRMS (El): m/e 216 (M*), 201, 141, 101, 85, 73, 60, 44. This crude product was

used directly in the next step without further purification.

 

O O
O>< 1. H202, K2003 O
O O 7

2. Mel, MeCN 'Ho H

M

HO OH 002 e
5.7 5.9

To a solution of 110 g of 6.7 (0.51 mol) in 750 mL water was added 138 g
K2C03 (1 mmol, 2 equiv) and the resultant solution was cooled by an ice-water
bath. To this solution was added 200 mL cold (by ice bath) 30% H202 (~1.94 mol,
~4 equiv) slowly. Ice was also added so that the internal temperature did not

exceed 30 °C. Upon complete addition, the ice-water bath was removed and the

206

 

reaction was stirred at room temperature in the open flask for about 15 h. Water
was removed by rotary evaporation in a 60-65 °C water bath. The remaining
water was removed by co-evaporation with EtOH and then drying under high
vacuum. The residual solid was suspended in 500 mL EtOH at refluxing
temperature to extract the organic salt. The insoluble inorganic salt was
removed by careful filtration of the hot supernatant through cotton. This
extraction was repeated 3 times, and the combined EtOH was evaporated.

This crude solid was then suspended in 600 mL acetonitrile (no purification or
drying needed). To that suspension was added 45 mL Mel (103 g, 0.72 mol,
1.45 equiv, purified by passing through neutral alumina). With vigorous stirring,
the whole mixture was heated to reflux for 1 day, during which time the reaction
mixture became a slightly yellow-brown solution. After being cooled to room
temperature, it was evaporated to ~ 200 mL and 300 mL CH2CI2 was added to
precipitate Kl. The KI was filtered off and washed with CH2CI2 and the combined
filtrate was evaporated. Column chromatography (1:1 —> 1:1.5 hexanes/EtOAc)
afforded 87 g of 6.9 (90% over 2 steps) as a colorless oil; R)~0.5 (1:1
hexanes/EtOAC); [comD +200 (c 1.14, acetone); 1H NMR (500 MHz, cock): 8
4.37 (dt, J = 1.8, 6.7 Hz, 1 H), 4.10 (d, J = 2.8 Hz, 1 H), 4.07 and 3.99 (d ofABq, 3J
= 6.7 Hz, JAB = 8.4 Hz, 2 H), 3.80 (s, 3 H), ~2.9 (br, 1 H), 1.40 (s, 3 H), 1.33 (s, 3

H); 13C NMR (125 MHZ, CDCI3): 8 172.5, 110.0, 76.2, 70.3, 65.6, 52.7, 26.1, 25.3;

207

 

LRMS (El): m/e175([M-Me]+), 133, 115, 101,43.

0 o
o TBSCI, Imid, DMAP‘ 0
HO H CH2CI2 ' TBSO H

C02Me C02Me
6.9 6.10a

 

Small scale: to a solution of 1.9 g of 6.9 (10 mmol) in 25 mL CH2CI2 were
added 122 mg DMAP (1 mmol, 10 mol%) and 0.88 g imidazole (13 mmol, 1.3
equiv). Upon stirring, 1.8 g TBSCI (12 mmol, 1.2 equiv) was added in one
portion. The reaction was sealed with a septum and topped with a nitrogen
balloon and stirred at room temperature overnight. Upon completion, the
reaction mixture was poured into half saturated (by mixing saturated solution with
equal volume of water) NaHC03, and extracted with CH2CI2. After drying over
M9304 and evaporation, the crude product was purified by column
chromatography (4:1 hexanes/ether) to yield 2.92 g of 6.10a (96%) as colorless
oil; R,~O.41 (4:1 hexanes/ether); [dimD +332 (c 1.25, EtOH); 1H NMR (500 MHz,
CDCI3): 8 4.29433 (m, 1 H), 4.21 (d, J = 5.1 Hz, 1 H), 4.02 and 3.95 (d of ABq, 3J
= 6.6 and 6.1 Hz, JAB = 8.5 Hz, 2 H), 3.73 (s, 3 H), 1.38 (s, 3 H), 1.32 (s, 3 H), 0.89
(s, 9 H), 0.08 (s, 3 H), 0.05 (s, 3 H); 13C NMR (125 MHz, CDCI3): 8 171.6, 109.8,
77.1, 73.1, 65.5, 51.9, 26.2, 25.7, 25.3, 18.3, -5.0, 53; IR (neat): 2988, 2955,
2932, 2892, 2859, 1761, 1474, 1381, 1372, 1256, 1215, 1157, 1074, 839, 781

cm"; LRMS (El): m/e 289 ([M-Me]+), 247, 204, 189, 161, 101, 89, 73, 59, 43;

208

 

HRMS (Cl, methane) m/e calcd for [C14H2305SI+H]+ 305.1784, found 305.1785.
Large scale: to a solution of 32.5 g of 6.9 (0.17 mol) in 350 mL CH2CI2 were
added 2.1 g DMAP (17 mmol, 10 mol%) and 14.0 g imidazole (0.205 mol, 1.2‘
equiv). Upon stirring, 28.4 g TBSCI (0.19 mol, 1.1 equiv) was added in one
portion. The reaction was sealed with a septum, topped with a nitrogen balloon,
and stirred at room temperature overnight. Precipitate formed. Upon
completion, the precipitate was filtered off and washed with CH2CI2. The
combined filtrate was washed with half saturated NH4CI and then half saturated
NaCI, dried over MgSO4 and evaporated. The resultant crude oil (55 g) was

obtained and used directly in next reaction without further purification.

 

0%
o
I O/ MeMgX _ O
TBSOjEH ether ' TBSO H
co M
2 8 0H
6.10a 5.11a

Small scale: commercial MeMgCI solution (12.8 mL, 3 M in THF, 38.4 mmol, 4
equiv) was diluted with 35 mL anhydrous ether (some white precipitate was
observed). To this Grignard solution was added a solution of 2.92 g of 6.10a (9.6
mmol) in 35 mL ether via cannula. Upon complete addition, the mixture was
refluxed for 1 h and then cooled to room temperature. It was then quenched with
saturated NH4CI and poured into half saturated NH4CI and extracted with ether.

The combined organics were dried over K2C03, evaporated, and purified by

209

column Chromatography (5:1 CH2CI2/ether) to afford 1.81 g of 6.11a (62%) as
colorless oil; Rr~0.5 (5:1 CH2CI2/ether); [81200 -3.5 (c 1.05, EtOH); 1H NMR (500
MHz, CDCI3): 8 4.02-4.07 (m, 1 H), 3.96 (dd, J = 6.1, 8.3 Hz, 1 H), 3.68 (t, J = 8.5
Hz, 1 H), 3.47 (d, J = 7.3 Hz, 1 H), 2.25 (s, 1 H), 1.39 (s, 3 H), 1.32 (s, 3 H), 1.18 (s,
3 H), 1.16 (s, 3 H), 0.90 (s, 9 H), 0.12 (s, 3 H), 0.09 (s, 3 H); 13C NMR (125 MHz,
CDCI3): 8 108.0, 80.0, 77.3, 72.4, 66.8, 27.0, 26.6, 26.2, 25.44, 25.42, 18.5, -3.6.
-4.6; IR (neat): 3470, 2986, 2957, 2932, 2897, 2859, 1472, 1370, 1254, 1101,
1059, 860, 837, 775 cm"; LRMS (CI, methane): m/e 289 ([M-Mej“), 247, 187, 171,
145, 131, 101; HRMS (CI, methane) m/e calcd for [C15H3204SI+H]+ 305.2148,
found 305.2142.

Large scale: commercial MeMgI solution (200 mL, 3 M in ether, 0.6 mol, 3.5
equiv) was placed in a round-bottom flask topped with a refluxing condenser and
heated to 50 °C in an oil bath. In a separate round-bottom flask, 55 g of crude
6.10a (0.17 mol) was dissolved in 250 mL ether. This ethereal solution was
transferred into the Grignard solution over 30 min via cannula, after which the
mixture was refluxed for another 30 min before being cooled to room temperature.
TLC indicated full consumption of the starting material. While stirring, the
reaction was carefully quenched with saturated NH4CI (CAUTION!) and significant
precipitation occurred. The supernatant of this mixture was transferred into a

separation funnel and washed with saturated NH4CI and water. The slurry was

210

diluted with ether and stirred over 200 mL saturated sodium potassium tartrate for
a few hours until it was no longer milk-like. The mixture was filtered and the
filtrate was extracted with ether. This ether extraction was combined with the
previous ether supernatant, and dried over Na2SO4 and evaporated. After
column chromatography, 46 g of 6.11a was obtained (83% over 2 steps) as a

slightly yellow oil.

 

 

F0 0
*0 SOCI2 o><
TBSO::H py > TBSCiH
OH
6.11a 6.12a

Small scale: a solution of 1.8 g of 6.11a (5.9 mmol) in 30 mL pyridine (no
purification or drying needed) was cooled in an ice-water bath. To this solution
was added 860 pL S0Cl2 (1.4 g, 11.8 mmol, 2 equiv) via syringe and the reaction
mixture quickly turned yellow-orange. It was then warmed to room temperature
and stirred for 1 h. Upon completion, it was quenched with half saturated
Na2C03 at 0 °C and diluted with ether. The layers were separated and the
aqueous layer was extracted with ether. Combined organics were washed with
water, followed by 5% CuSO4 until the aqueous phase was no longer purple, and
then again water. The organics were dried over K2C03, evaporated, and purified
by column chromatography (12:1 hexanes/ether or 1:1 hexanes/CH2CI2) to yield

1.33 g of 6.12a (79%) as a clear, slightly yellow oil; R,~0.39 (1 :1 hexanes/CH2CI2);

211

 

 

 

[o]2°o -2.1 (01.27, EtOH); 1H NMR (500 MHz, CDCI3): 8 5.03 (m, 1 H), 4.93 (quint,
J = 1.5 Hz, 1 H), 4.34 (d, J = 8.1 Hz, 1 H), 3.75-3.82 (m, 2 H), 3.67 (dd, J = 4.2,
11.2 Hz, 1 H), 1.76 (m, 3 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 0.88 (s, 9 H), 0.051 (s, 3
H), 0.046 (s, 3 H); 13C NMR (125 MHz, CDCI3): 8 142.1, 113.9, 108.9, 81.1, 80.0,
62.9, 27.08, 27.06, 25.9, 18.4, 17.4, -5.3, 55; IR (neat): 2988, 2955, 2932, 2859,
1653, 1474, 1464, 1379, 1370, 1254, 1146, 1086, 837, 777 cm"; LRMS (El): m/e
271 ([M-Mel"), 171, 141, 75; HRMS (CI, NH3) m/e calcd for [C15H3003Si+H]"
287.2042, found 287.2045.

Large scale: a solution of 46 g of 6.11a (0.15 mol) in 480 mL pyridine was
cooled to 0 °C. To this solution was added 22 mL SOCI2 (35.7 g, 0.3 mol, 2
equiv) via a pressure-equalized addition funnel over 25 min. The reaction
quickly turned dark and cloudy with some precipitate formed. The ice bath was
removed after complete addition and the reaction was stirred at room temperature
for 1 h 20 min. Upon completion, it was cooled to 0 °C and quenched by slow
addition of saturated Na2C03 (CAUTION!) until gas evolution ceased. After
extraction with ether, the organic layer was washed with saturated Na2C03, water,
followed by 5% CuS04 until the aqueous phase was no longer purple, and then
half saturated NH4CI before being dried over K2C03 and evaporated. Column

chromatography afforded 33.3 g of 6.12a (77%) as a slightly yellow oil.

212

 

 

o>< 0H 0”
o MeOH,TFA A OH HO
TBSO H ' TBSO H E

ores

6.12a 6.13a

To a solution of 1.43 g of 6.12a (5 mmol) in 30 mL MeOH (no purification or
drying needed) was added 8 mL TFA slowly. 20 min later, the reaction was
quenched with saturated Na2C03 and extracted six times with EtOAc.
Combined organics were dried over Na2SO4 (MgSO4 was avoided due to its
partial solubility in the solvent) and evaporated. The crude material was purified
by column chromatography (2:1 hexanes/EtOAc). Along with ~80 mg of
recovered 6.12a (~5%), 0.74 g of 6.13a (60%) was isolated as a white solid;
Rr~0.18 (3:1 hexanes/EtOAc); mp < 35 °C (it quickly melted when the vial was
held in hand); [842°D +19.8 (c 1.24, CHCI3); 1H NMR (500 MHz, CDCI3): 8 4.95 (m,
1 H), 4.91 (quint, J = 1.5 Hz, 1 H), 4.03 (d, J = 5.6 Hz, 1 H), 3.57-3.61 (m, 2 H),
3.47-3.51 (m, 1 H), 2.27 (br, 2 H), 1.70 (m, 3 H), 0.89 (s, 9 H), 0.07 (s, 3 H), 0.03
(s, 3 H); 13C NMR (125 MHz, CDCI3): 8 144.5, 114.1, 77.1, 73.0, 53.3, 25.8, 18.2,
17.6, -4.6, -5.2; IR (neat): 3409, 2955, 2930, 2859, 1649, 1472, 1254, 1084, 837,
777 cm"; LRMS (Cl, methane) : m/e 247 ([M+H]*), 229, 213, 201, 185, 171, 159,
133, 115; HRMS (Cl, methane) m/e calcd for [C12H2603$i+H]* 247.1729, found
247.1726.

This procedure can be performed up to 6 9 scale. Beyond that scale the

213

workup became problematic, although the yield remained the same.

 

0H 0Ts
:3]: TsCl, TEA _ H0
, OTBS CH2C'2 OTBS
6.13a 5.145

A solution of 2.99 g of 6.13a (12.2 mmol) in 40 mL CH2CI2 was cooled to 0 °C. .
To this solution was added 17 mL EtoN (12.3 g, 122 mmol, 10 equiv) followed by
2.8 g TsCI (14.6 mmol, 1.2 equiv, no recrystallization needed). The reaction was
stirred overnight allowing the ice bath to slowly melt. The reaction was then
quenched with saturated NaHCOo and diluted with CH2CI2. The layers were
separated and the aqueous layer was extracted with CH2CI2. The combined
organics were dried over Na2SO4 and evaporated. Column chromatography
purification (3:1 —> 1:1 hexanes/ EtOAc) afforded 360 mg of recovered 6.13a
(12%) and 4.24 g of 6.14a (87%) as oil. This material deteriorates over time and
thus should be quickly used in the next step; Rr~0.55 (3:1 hexanes/EtOAc); [odzoo
-8.1 (c 1.18, EtOH); 1H NMR (500 MHz, CDCI3): 8 7.77-7.79 (m, 2 H), 7.32 (m, 2
H), 4.94 (m, 1 H), 4.90 (quint, J = 1.5 Hz, 1 H), 4.04 (d, J = 4.9 Hz, 1 H), 3.98 and
3.92 (d of ABq, 3J = 5.4 and 5.7 Hz, JAB = 10.3 Hz, 2 H), 3.69 (dddd, J = 4.9, 5.6,
5.6, 5.6 Hz, 1 H), 2.43 (m, 4 H, overlapping signal), 1.67 (br, 3 H), 0.85 (s, 9 H),
0.03 (s, 3 H), 0.00 (s, 3 H); 13C NMR (125 MHz, CDCI3): 8 144.9, 143.9, 132.9,

129.8, 128.0, 114.1, 75.5, 70.5, 69.9, 25.7, 21.6, 18.1, 18.0, -4.7, -5.3; IR (neat):

214

 

3544, 2955, 2930, 2859, 1364, 1190, 1179, 1098, 980, 837, 779, 667 cm’1; LRMS
(CI, methane): m/e 401 ([M+H]+), 383, 343, 329, 313, 287, 269, 229, 213, 185,

171; HRMS (Cl, methane) m/e calcd for [C19H3202,SSI+H]+ 401.1818, found

 

401 .1818.
0Ts 0
I ores M60” OTBS
6.14a 6.15a

To a stirred solution of 2.0 g of 6.14a (5 mmol) in 25 mL MeOH (no purification
or drying needed) was added 1.2 g K2C03 (8.7 mmol, 1.7 equiv) at 0 °C in one
portion. The suspension was stirred at 0 °C for 2 h and poured into half
saturated NaCl and extracted with CH2CI2. The combined organics were dried
over Na2SO4 and evaporated. Column chromatography purification (1:1
hexanes/CH2CI2) afforded 0.95 g of 6.15a (83%) as a colorless oil; Rr~0.42 (1 :1
hexanes/CH2CI2); [dimD -25 (c 1.00, EtOH); 1H NMR (500 MHz, CDCI3): 8 4.99 (m,
1 H), 4.86 (m, 1 H), 3.69 (d, J = 6.2 Hz, 1 H), 2.95 (ddd, J = 2.7, 4.0, 6.1 Hz, 1 H),
2.76 (dd, J = 4.2, 5.0 Hz, 1 H), 2.59 (dd, J = 2.7, 5.0 Hz, 1 H), 1.75 (m, 3 H), 0.89
(s, 9 H), 0.08 (s, 3 H), 0.03 (s, 3 H); 13C NMR (125 MHz, CDCI3): 8 144.6, 111.9.
78.1, 55.5, 44.9, 25.8, 18.8, 18.3, -4.9, 51; IR (neat): 2957, 2930, 2859, 1653,
1474, 1252, 1092, 937, 837, 777 cm“; LRMS (CI, MeOH): m/e 229 ([M+H]+), 221,

199, 185, 171, 81; HRMS (Cl, methane) m/e calcd for [C12H2402SI+H]+ 229.1624,

215

found 229.1622.

 

0 \
”MgBr CuCN H0
OTBS THF OTBS
6.15a 6.16a

To a solution of 1.14 g of 6.15a (5 mmol) in 25 mL THF was added 45 mg
CuCN (0.5 mmol, 10 mol%). The mixture was cooled to -40 °C and 10 mL of a
vinyl Grignard solution (1 M in THF, 10 mmol, 2 equiv) was added via syringe
pump over 45 min. Upon complete addition, the reaction was kept at that
temperature for 20 min before being warmed up to -25 °C and stirred overnight.
The reaction was quenched with saturated Na2C03 and detoxified with saturated
Na2S203 before being extracted with ether. The combined organics were dried
over Na2SO4 and evaporated. Column chromatography (1:1 hexanes/CH2CI2)
afforded the 1.24 g of 6.16a (97%) as a colorless oil; Rr~0.41 (1:1
hexanes/CH2CI2); [812% +105 (c 1.08, CHCI3); 1H NMR (500 MHz, CDCI3): 8 5.87
(dddd, J = 6.8, 6.8, 10.0, 17.1 Hz, 1 H), 5.04-5.10 (m, 2 H), 4.92 (m, 1 H), 4.89
(quint, J = 1.6 Hz,1 H) 3.85 (d, J = 6.3 Hz, 1 H), 3.55 (ddd, J = 4.2, 6.3, 8.1 Hz, 1
H), ~2.5 (br, 1 H), 2.06-2.24 (m, 2 H), 1.69 (m, 3 H), 0.89 (s, 9 H), 0.07 (s, 3 H),
0.02 (s, 3 H); 13C NMR (125 MHz, CDCI3): 8 144.9, 135.1, 116.9, 114.0, 80.0, 72.3,
37.4, 25.8, 18.2, 17.6, -4.6, -5.2; IR (neat): 3582, 3077, 2955, 2930, 2859, 1643,

1473, 1254, 1067, 837, 777 cm'1; LRMS (El): m/e 239 ([M-OH]+), 199, 185, 129,

216

 

107; HRMS (Cl, methane) m/e calcd for [C14H2oO2Si+H]+ 257.1937, found

257.1936.
\ \ \
H0 MeO + TBSO
OTBS OTBS OMe
6.16a 6.17a 6.18a

Method 1 (NaH, Mel): in a round-bottom flask, ~58 mg NaH (60% dispersion
in mineral oil, ~1.45 mmol, ~3 equiv) was suspended in 3 mL dry THF to remove
the mineral oil and the supernatant was removed. The remaining slurry was
dried under high vacuum. This purified NaH was suspended in 1 mL THF and
the mixture was cooled to 0 °C. To this mixture was added 130 pL Mel (purified
by passing through neutral alumina, 300 mg, 2.1 mmol, 4 equiv) via syringe
followed by a solution of 136 mg of 6.16a (0.53 mmol) in 1 mL THF. The ice bath
was removed and the reaction was allowed to warm to room temperature and
stirred for 19 h. The reaction was then quenched with saturated NH4CI and
extracted with ether. The combined organics were dried over M9304 and
evaporated. Column chromatography (6:1 hexanes/CH2CI2) afforded two
fractions. The first fraction at Rr~0.40 contained 59 mg of 6.18a (41%) as a
colorless oil and the second fraction at Rr~0.23 contained 78 mg of 6.17a (54%)
as a colorless oil.

Method 2 (MeOTf, 4-methyl-2,6-di-tert-butylpyridine): to a solution of 128 mg

217

of 6.16a (0.5 mmol) in 2 mL dry CH2CI2 was added 359 mg 4-methyI-2,6-di-tert-
butylpyridine (1 .75 mmol, 3.5 equiv) in one portion followed by dropwise addition
- of 140 pL MeOTf (205 mg, 1.25 mmol, 2.5 equiv). The reaction was stirred at
room temperature for 38 h, but was not complete. Nonetheless, it was poured
into saturated NaHC03 and extracted with CH2CI2. After drying over Na2SO4
and evaporation, the crude product was purified by column chromatography (2:1
hexanes/CH2CI2) to yield 64 mg of recovered 6.16a (50%) and 66 mg of 6.17a

(49%).

 

(—

“fl Desired product 6.17a: R)~0.23 (6:1 hexanes/CHzCI2); [00200

1\2

M90 4 3
' 78?: +5.8 (0 1.08, EtOH); 1H NMR (500 MHz, CDCI3): 8 5.85 (dddd, J =
6 5 OTBS

. 8 7.1, 7.1, 10.3, 17.3 Hz, 1 H), 4.99-5.05 (m, 2 H), 4.88 (m, 1 H),

 

 

4.83 (m, 1 H), 4.01 (d, J = 6.6 Hz, 1 H), 3.43 (s, 3 H), 3.14 (ddd, J = 3.4, 6.6, 8.5
Hz, 1 H), 2.17-2.23 (m, 1 H), 1.97-2.04 (m, 1 H), 1.70 (m, 3 H), 0.88 (s, 9 H), 0.05
(s, 3 H), 0.01 (s, 3 H); 13C NMR (125 MHz, CDCI3): 8 145.3, 135.7, 116.4, 113.1,
84.0, 78.9, 59.4, 35.4, 25.8, 18.2, 18.1, -4.9, 50; IR (neat): 3077, 2955, 2930,
2859, 1642, 1471, 1464, 1252, 1109, 1088, 902, 862, 837, 775 cm'1; LRMS (Cl,
methane): m/e 269 ([M-H]+), 255, 229, 213, 185, 159, 107; HRMS (Cl, methane)
m/e calcd for [C15H3o02Si1-H]+ 271.2093, found 271.2087. The positions of Me
and TBS were assigned by HMQC and HMBC in a selected region: H on C4 (ddd)

had HMBC correlation to CH30, so had the CH30 to C4. Such a correlation was

218

 

not observed between H on C5 (d) and CH30, or between CH30 and C5. This

concludes that MeO is on C4, not C5.

 

r "—1;2‘o Silyl migration product 6.18a: Rr~0.40 (6:1 hexanes/CH2CI2);
\
SO
TE: V3 [842°D +235 (c 0.90, EtOH); 1H NMR (500 MHz, CDCI3): 8 5.84
J 6 5 OMe
t a (dddd, J = 7.1, 7.1, 9.5, 15.8 Hz, 1 H), 4.95-5.01 (m, 3 H), 4.91 (m,

 

 

1 H), 3.69 (dt, J = 4.2, 7.1 Hz, 1 H), 3.33 (d, J = 7.3 Hz, 1 H), 3.17 (s, 3 H),
2.16-2.22 (m, 1 H), 2.00-2.06 (m, 1 H), 1.63 (m, 3 H), 0.87 (s, 9 H), 0.05 (s, 3 H),
0.04 (s, 3 H); 13C NMR (125 MHz, CDCI3): 8 142.2, 135.6, 116.7, 115.4, 89.4, 73.3,
56.2, 38.3, 26.0, 18.4, 17.7, -4.1, -4.8; IR (neat): 3077, 2953, 2930, 2857, 1647,
1472, 1454, 1252, 1117, 1101, 1019, 907, 835, 777 cm"; LRMS (Cl, methane):
269 ([M-H]+), 255, 239, 229, 213, 185, 107; HRMS (Cl, methane) m/e calcd for
[C15H3o02Si-H]+ 269.1937, found 269.1941. The positions of Me and TBS were
assigned by HMQC and HMBC in a selected region: H on 05 (d) had HMBC
correlation to CH30, so had the CH30 to 05. Such a correlation was not
observed between H on C4 (dt) and CH30, or between CH30 and C4. This
concludes that MeO is on C5, not C4. By comparison of 1H NMR spectra of this
pair of isomers, it was also noted that the H on the C bearing OTBS always had a

higher chemical shift than the H on the C bearing OMe.

219

 

0 0
£0 TIPSCI, DMAP; o><
H0 H DMF TIPSO H

002MB 002MB
6.9 6.11“)

To a solution of 1.75 g of 6.9 (10.2 mmol) in 15 mL DMF (distilled over MgSO4)
was added 2.49 g DMAP (20.4 mmol, 2 equiv). Upon stirring, 3.27 mL TIPSCI
(2.95 g, 15.3 mmol, 1.5 equiv) was added dropwise. The flask was sealed with a
septum, topped with a nitrogen balloon, and stirred at room temperature for 1 day.
White precipitate formed. Upon completion, the reaction mixture was poured
into half saturated NaHC03 and extracted with CH2CI2. Combined CH2CI2 was
washed with water and dried over M9804 and evaporated. Column
Chromatography (1.5:1 hexanes/CH2CI2) afforded 2.86 g of 6.10b (85%) as a
colorless oil; Rr~0.42 (5:1 hexanes/ether); [a]2°o +107 (5 1.27, EtOH); 1H NMR
(500 MHz, CDCI3): 8 4.43 (d, J = 5.4 Hz, 1 H), 4.28 (q, J = 6.1 Hz, 1 H), 4.08 and
4.00 (d of ABq, 3J = 6.1 Hz, JAB = 8.8 Hz, 2 H), 3.72 (s, 3 H), 1.36 (s, 3 H), 1.32 (s,
3 H), 0.99-1.11 (m, 21 H); 13C NMR (125 MHz, CDCI3): 8 171.5, 1097.771, 73.3.
65.2, 51.8, 26.2, 25.1, 17.81, 17.78, 12.2; IR (neat): 2946, 2869, 1756, 1464,
1372, 1256, 1204, 1156, 1073, 884, 826, 683 cm"; LRMS (ESI): m/e 410
([M+MeCN+Na]"), 385, 369, 307, 289; HRMS (ESI) m/e calcd for [C17H3405Si+K]+

385.1813, found 385.1822.

220

—-O

 

 

g>< MeMgX A —0

TIPSO H ether TIPSO::H
C02Me 0H

6.10b 6.11b

Commercial MeMgl solution (13.4 mL 3 M in THF, 40 mmol, 3.2 equiv) was
diluted with 30 mL anhydrous ether. To this Grignard solution was added a 40
mL ethereal solution of 4.33 g of 6.10b (12.5 mmol) via cannula. Upon complete
addition, the mixture was refluxed for 45 min and the allowed to cool to room
temperature, after which it was quenched with water. The resultant slurry was
treated with saturated sodium potassium tartrate and vigorously stirred until all the
solid dissolved (ca. 30 min). After separation of the layers, the aqueous layer
was extracted four times with ether. The combined organics were dried over
M9804 and evaporated. Column chromatography purification (1:1
hexanes/ether) afforded 3.64 g of 6.11b (84%) as white wax-like solid; Rio-0.47
(1:1 hexanes/ether); mp 74-755 °C; [812% -5.9 (c 1.19, EtOH); 1H NMR (500 MHz,
CDCI3) 8 3.60-3.65 and 3.95-4.04 (m, 4 H), 2.26 (s, 1 H), 1.37 (s, 3 H), 1.31 (s, 3
H), 1.19 (s, 3 H), 1.16 (s, 3 H), 1.15-1.22 (m, 3 H), 1.06-1.08 (m, 18 H); 13‘C NMR
(125 MHz, CDCI3): 8 107.7, 80.8, 77.5, 72.3, 66.9, 26.6, 25.4, 25.3, 18.4, 13.4
(There is one overlapped signal); IR (neat): 3472, 2946, 2869, 1466, 1369, 1244,
1129, 1059, 884, 866, 814, 679 cm"; LRMS (CI, MeOH): m/e 329 ([M+H-H20]+),

311, 271, 229, 115, 101; HRMS (FAB) m/e calcd for [C13H3304SI+H]+ 347.2618,

221

found 347.2617.

 

 

—o
r—o
r-O sool2 A ' o
“’30::‘1 py ' TIPSOiH
0H
5.11b 5.12b

A solution of 3.54 g of 6.11b (10.2 mmol) in 80 mL pyridine (no purification or
drying needed) was cooled to 0 °C by an ice-water bath. To this solution was
added 1.5 mL SOCI2 (2.45 g, 20.5 mmol, 2 equiv) dropwise via syringe and the
mixture quickly turned yellow-orange. The reaction was then warmed to room
temperature and stirred for 1 h. Upon completion, the reaction was quenched
with half saturated Na2C03 at 0 °C and diluted with ether. The layers. were
separated and the aqueous layer was extracted with ether. The combined
organics were washed with water, followed by 5% CuSO4 until the aqueous phase
was no longer purple, and then water before being dried over MgSO4. After
evaporation, the crude material was purified by column chromatography (1.1:1
hexanes/CH2CI2) to yield 3.09 g of 6.12b (92%) as a clear, slightly yellow oil;
R,~0.57 (1:1 hexanes/CH2CI2); [81200 -2.0 (c 1.12, EtOH); 1H NMR (500 MHz,
CDCI3) 8 4.91 (m, 1 H), 4.86 (quint, J = 1.7 Hz, 1 H), 4.10-4.21 (m, 2 H), 3.83 and
3.62 (d of ABq, 3J = 6.4 and 7.6 Hz, JAB = 8.5 Hz, 2 H), 1.73 (m, 3 H), 1.37 (s, 3 H),
1.32 (s, 3 H), 1.01-1.08 (m, 21 H); 13C NMR (125 MHz, CDCI3): 8 144.8, 113.3,

109.4, 78.5, 78.4, 65.9, 26.5, 25.4, 18.3, 17.99, 17.98, 12.4; IR (neat): 3075, 2944,

222

 

 

2859, 1547, 1454, 1379, 1370, 1252,1211, 1159, 1108, 1057, 884, 830, 581 cm'1;
LRMS (El): m/e 328 (M*), 313, 285, 227, 185, 157, 101; HRMS (FAB) m/e calcd '

for [C1oH36038i]+ 328.2434, found 347.2440.

 

i—OH MeO OMe r—O><
.r—CH CSA, )K ‘ I—O
TBSO l H acetone 7 TBSO I H
6.13a 6.128

To a solution of 8.58 g of 6.13a (34.9 mmol) and 25 mL 2,2-dimethoxypropane
(21 g, 202 mmol, 5.8 equiv) in 150 mL acetone (dried over Drierite) was added
810 mg racemic camphor-10-sulphonic acid (3.5 mmol, 10 mol%). The solution
was stirred at room temperature for 3 h and then quenched with saturated
NaHC03. The mixture was extracted with CH2CI2 and dried over MgSO4.
Column Chromatography purification (1:1 hexanes/CH2CI2) afforded 8.37 g of

6.12a (84%).

 

O>< O><
f0 TBAF ‘ PO
T830 1 ---H THF ' HO—t—H

A

6.12a 6.19

To a solution of 8.36 g of 6.12a (29.2 mmol) in 150 mL THF at 0 °C was slowly
added 48 mL TBAF (1 M in THF, 48 mmol, 1.64 equiv). Upon complete addition,
the reaction was allowed to warm to room temperature and stir for 2.5 h. Upon

completion, the reaction was quenched with water and concentrated to about half

223

of its original volume. The solution was partitioned between saturated NaH003
and ether, and layers separated. The aqueous layer was extracted further with
ether. Combined organics were dried over Na2SO4 and concentrated. Column
chromatography purification (3.5:1 hexanes/EtOAc) afforded 4.88 g of 6.19 (97%)
as colorless oil; Rr~0.45 (3:1 hexanes/EtOAC); [a]2°o +119 (0 1.50, acetone); 1H
NMR (500 MHz, CDCI3): 8 5.00 (m, 1 H), 4.92 (m, 1 H), 4.14 (q, J = 6.3 Hz, 1 H),
3.94 (d, J = 6.6 Hz, 1 H), 3.95 and 3.73 (d of ABq, 3J = 6.6 Hz, JAB = 8.6 Hz, 2 H),
2.40 (br, 1 H), 1.75 (s, 3 H), 1.44 (s, 3 H), 1.35 (s, 3 H); 13C NMR (125 MHz,
CDCI3): 8 143.8, 113.8, 109.8, 77.3, 76.7, 66.3, 26.8, 25.3, 18.1; IR (neat): 3474,
3079, 2988, 1653, 1456, 1372, 1254, 1214, 1157, 1071, 905 cm‘; LRMS (CI,
MeOH): m/e 155 ([M+H-H20]+), 101, 69, 59; HRMS (CI, NH3) m/e calcd for

[C9H1503+H]+ 173.1178, found 173.1177.

0 0
F0 TIPSCI, DMAP A [:0

.L

HOAH DMF ' TIPSOAH

6.19 6.12b

 

To a solution of 2.85 g of 6.19 (15 mmol) in 45 mL DMF (distilled over MgS04)
was added 5.5 g DMAP (45 mmol, 3 equiv). Upon stirring, 6.5 mL TIPSCI (5.8 g,
30 mmol, 2 equiv) was added dropwise. The reaction was sealed with a septum,
topped with a nitrogen balloon, and stirred at room temperature for 16 h. Upon

completion, the reaction mixture was partitioned between half saturated NaHCOo

224

 

and ether. The layers were separated and the aqueous layer was further
extracted with ether. The combined organics were dried over M9804 and
evaporated. Column chromatography (5:1 hexanes/ether) afforded 4.45 g of

6.12b (86%) as a colorless oil.

 

o>< 0H 0H
0 MeOH, TFA A OH HO
TIPSO H ' TIPSO H E
OTIPS
5.12b 5.13b

To a solution of 10.5 g of 6.12b (32 mmol) in 190 mL MeOH (no purification or
drying needed) at 0 °C was added 64 mL TFA over a few minutes. The ice bath
was removed and 35 min later, the reaction was quenched with saturated N32003
until gas evolution ceased. This quench generated precipitate. The reaction
mixture was concentrated to about half of its original volume and extracted with
EtOAc (At the beginning of extraction, some water or saturated NaHCOo could be
used to help separate layers). The combined organics were dried over Na2SO4
(MgSO4 was avoided due to its partial solubility in the solvent) and evaporated.
The crude material was purified by column chromatography (2.5:1
hexaneletOAc). Along with 1.5 g of recovered 6.12b (14%), 8.0 g of 6.13b
(containing 0.24 g EtOAc, 84% yield discounting the added weight of EtOAc) was
isolated as a very thick oil; Rr~0.47 (2.5:1 hexanes/EtOAc); [(11200 -9.1 (c 1.04,

EtOH); 1H NMR (500 MHz, CDCI3): 8 4.98 (m, 1 H), 4.92 (quint, J = 1.6 HZ, 1 H),

225

 

 

 

4.19 (d, J = 5.5 Hz, 1 H), 3.59-3.55 (m, 2 H), 3.45-3.51 (m, 1 H), 1.6-2.8 (br, 2 H),
1.73 (dd, J = 0.9, 1.5 Hz, 3 H), 1.04-1.10 (m, 21 H); 130 NMR (125 MHz, CDCI3): 8
144.7, 114.4, 77.5, 73.4, 53.0, 18.05, 18.01, 17.5, 12.4; IR (neat): 3414, 2945,
2869, 1454, 1385, 1092, 1055, 1015, 884, 581 cm"; LRMS (ESI): m/e 311 '
([M+Na]+), 289, 271, 245, 198, 115; HRMS (ESI) m/e calcd for [C15H32038i+Na]+

311.2018, found 311.2025.

 

0H 0Ts
HOV TsCl, TEA _ H0
Yonps CHZCIZ OTIPS
6.13b 6.14b

To a solution of 9.44 g of 6.13b (32.8 mmol) in 100 mL CH2CI2 at 0 °C was
added 45 mL Et3N (32.7 g, 323 mmol, ~10 equiv) followed by 7.02 g TsCl (36.8
mmol, 1.12 equiv, no recrystallization needed). The reaction was stirred
overnight allowing the ice bath to slowly melt. The reaction was quenched with
saturated NaHC03 and diluted with CH2CI2. The layers were separated and the
aqueous layer was extracted with CH2CI2. The combined organics were dried
over Na2SO4 and evaporated. Column chromatography purification (4.5:1 —> 1:1
hexanes/ EtOAc) afforded 0.67 g of recovered 6.13b (7%) and 13.55 g of 6.14b
(containing 0.24 g EtOAc, 92% discounting the added weight of EtOAc) as oil.
This material deteriorates over time and thus should be quickly used in the next

step; R2053 (4:1 hexanes/ EtOAc); [(11200 -24.9 (c 1.05, EtOH); 1H NMR (500

226

MHz, CDCI3): 8 7.77 (m, 2 H), 7.32 (m, 2 H), 4.94 (m, 1 H), 4.90 (quint, J = 1.5 Hz,
1 H), 4.19 (d, J = 5.7 Hz, 1 H), 4.06 and 3.94 (d of ABq, 3J = 4.2 and 6.1 Hz, JAB =
10.3 Hz, 2 H), 3.73 (dt, J = 4.2, 5.9 Hz, 1 H), 2.43 (s, 3 H), 1.68 (m, 3 H), 0.99-1.03
(m, 21 H) (OH not ovserved); 13C NMR (125 MHz, CDCIo): 8 144.8, 144.0, 132.9,
129.8, 128.0, 114.5, 76.3, 71.2, 70.2, 21.6, 17.98, 17.96 (17.96 is an overlapping
signal for 2 C’s. HMQC confirmed its correlation to both the Me’s in TIPS and
the allylic Me), 12.4; IR (neat): 3540, 2946, 2869, 1599, 1464, 1366, 1190, 1179,
1098, 980, 667 cm"; LRMS (ESI): m/e 460 ([M+NH4]+), 443 ([M+H]*), 269, 198,

97; HRMS (ESI) m/e calcd for [C22H3805SSi+H]+ 443.2287, found 443.2281.

0Ts 0

 

HO ch03 A \f
OTIPS MeOH OTIPS
I l
6.14b 5.15b

To a stirred solution of 14.5 g of 6.14b (containing 0.2 g EtOAc,
corresponding to 14.3 g of pure 6.14b, 32.4 mmol) in 150 mL MeOH (no
purification or drying needed) at 0 °C was added 7.6 g K2C03 (55 mmol, 1.7 equiv)
in one portion. The suspension was stirred at 0 °C for 2 h and poured into half
saturated NH4CI before being extracted with CH2CI2. The combined organics
were dried over Na2SO4 and evaporated. Column chromatography purification
(1 .5:1 hexanes/CH2CI2) afforded 8.16 g of 6.15b (93%) as a colorless oil; Rrv0.5

(1 .5:1 hexanes/CH2CI2); [(11200 -10.5(c1.01, EtOH); 1H NMR (500 MHz, CDCI3): 8

227

4.98 (m, 1 H), 4.86 (apparent quint, J = 1.5 Hz, 1 H), 3.79 (d, J = 6.3 Hz, 1 H), 3.00
(ddd, J = 2.7, 4.2, 6.3 Hz, 1 H), 2.76 (dd, J = 4.2, 4.9 Hz, 1 H), 2.57 (dd, J = 2.7,
4.9 Hz, 1 H), 1.77 (m, 3 H), 1.02-1.10 (m, 21 H); 13C NMR (125 MHz, CDCI3): 8
144.8, 112.2, 78.6, 56.0, 44.9, 18.7, 17.95, 17.90, 12.3; IR (neat): 2946, 2869,
1653, 1464, 1100, 1069, 936, 884, 832, 681 cm"; LRMS (Cl, methane): m/e 271
([M+H]+), 253, 227, 197, 185, 157, 145; HRMS (Cl, methane) m/e calcd for

[C15H30028i+H]+ 271.2093, found 271.2091.

 

o \

\> /\ MgBr CuCN: Ho '
VOTIPS THF fiIonps

5.15b 5.15b

To 3.07 g of 6.15b (11.4 mmol) and 153 mg CuCN (1.7 mmol, 15 mol%) was
added 55 mL THF. The mixture was cooled to -40 °C and 28 mL of a vinyl
Grignard solution (1 M in THF, 28 mmol, 2.5 equiv) was introduced via syringe
pump over 45 min. Upon complete addition, the reaction was kept at -40 °C for
20 min before being warmed to -25 °C and then stirred overnight. The reaction
was quenched with saturated Na2C03 and detoxified with saturated Na2S203.
The mixture was then extracted with ether and the combined organics were dried
over M9804 and evaporated. Column chromatography (2:1 hexanes/CH2CI2)
afforded 0.62 g of recovered 6.15b (20%) and 2.58 g of 6.16b (76%) as a

colorless oil (6.15b and 6.16b are not easily separable and use of large amount of

228

 

silica gel is suggested); R,~0.4 (1.5:1 hexanes/CH2CI2); [or]2°o -18.0 (c 1.02,
EtOH); 1H NMR (500 MHz, CDCI3): 8 5.88 (dddd, J= 6.6, 7.6, 10.3, 17.1 Hz, 1 H),
5.04-5.10 (m, 2 H), 4.93 (m, 1 H), 4.90 (quint, J = 1.6 Hz,1 H), 4.00 (d, J = 7.1 Hz,
1 H), 3.55 (ddd, J = 3.7, 7.3, 8.5 Hz, 1 H), ~2.6 (br, 1 H), 2.01-2.27 (m, 2 H), 1.71
(m, 3 H), 1.02-1.09 (m, 21 H); 13C NMR (125 MHz, CDCI3): 8 144.7, 135.2, 116.9,
114.5, 80.5, 72.5, 37.0, 18.08, 18.03, 17.6, 12.4; IR (neat): 3584, 3077, 2946,
2869, 1642, 1464, 1385, 1092, 1063, 905, 884, 681 cm"; LRMS (CI, methane):
m/e 299 ([M+H]*), 281, 255, 227, 213, 201, 185, 175, 157, 131, 107; HRMS (CI,

methane) m/e calcd for [C17H3402Si+H]+ 299.2406, found 299.2403.

\ \ \
H0 NaH, Mel ; Meo + TIPSO
THF '
OTIPS OTIPS OMe

6.16b 6.17b 6.18b

 

To a suspension of 887 mg NaH (60% dispersion in mineral oil, not washed,
corresponding to 532 mg pure NaH, 22.2 mmol, 1.6 equiv) in 35 mL THF was
added 2.76 mL Mel (purified by passing through neutral alumina, 6.3 g, 44.4 mmol,
3.2 equiv) via syringe. A solution of 4.13 g of 6.16b (13.86 mmol) in 35 mL THF
was then added via syringe. The reaction was stirred at room temperature for 20
h. Upon completion, it was quenched with saturated NH4CI and extracted with
ether. The combined organics were dried over M9804 and evaporated.

Column chromatography (6:1 hexanes/CH2CI2) afforded two fractions. The first

229

fraction at R,~O.60 contained 0.8 g of 6.18b (18.5%) as a colorless oil and the
second fraction at R,~O.37 contained 3.37 g of 6.17b (78%) as a colorless oil.

F—,““"’—‘ Desired product 6.17b: R2037 (5:1 hexanes/CH2CI2); [812%

 

. s2

; M60 4 ‘3 -1.9 (c 0.97, EtOH); 1H NMR (500 MHz, CDCI3): 8 5.87 (dddd, J =
l 7 6 5 OTIPS

I 3 7.1, 7.1, 10.2, 17.3 Hz, 1 H), 5.04 (dq, J = 17.3, 1.7 H2, 1 H)‘, 5.00

 

(dddd, J = 1.2, 1.2, 2.2, 10.2 Hz, 1 H), 4.93 (m, 1 H), 4.89 (quint, J = 1.6 Hz, 1 H),
4.26 (d, J = 6.1 Hz, 1 H), 3.42 (s, 3 H), 3.26 (ddd, J = 2.9, 6.1, 8.8 Hz, 1 H),
2.05-2.32 (m, 1 H), 1.93-2.00 (m, 1 H), 1.72 (m, 3 H), 1.02-1.08 (m, 21 H); 13C
NMR (125 MHz, CDCI3): 8 144.9, 136.0, 116.3, 113.1, 84.4, 76.8, 58.8, 34.7, 18.9,
18.06, 18.03, 12.4; IR (neat): 3077, 2946, 2869, 1642, 1464, 1111, 1067, 903.
884, 681 cm"; LRMS (Cl, methane): m/e 311 ([M-H]*), 281, 269, 227, 157, 145,
139, 107; HRMS (CI, methane) m/e calcd for [C1oH3502Si-H]+ 311.2406, found
311.2404. The positions of Me and TIPS were assigned by HMQC and HMBC in
a selected region: H on C4 (ddd) had HMBC correlation to CH30, so had the
CH30 to C4. Such a correlation was not observed between H on C5 (d) and
CH30, or between CH30 and C5. This concludes that MeO is on C4, not C5.

Silyl migration product 6.18b: Rr~0.60 (6:1

 

f

1 TIPSO

\

hexanes/CH2CI2); [042"D +42.8 (c1.12, EtOH); 1H NMR (500 MHz,
[ OMe '

 

CDCI3): 8 5.90 (dddd, J = 5.5, 7.5, 10.5, 17.1 Hz, 1 H), 4.95-5.01

 

(m, 3 H), 4.92 (m, 1 H), 3.87 (ddd, J = 5.5, 5.5.7.8 Hz, 1 H), 3.35 (d, J = 7.8 Hz, 1

230

 

H), 3.13 (S, 3 H), 2.22-2.28 (m, 1 H), 2.02-2.09 (m, 1 H), 1.61 (m, 3 H), 1.03-1.10
(m, 21 H); 13C NMR (125 MHz, CDCI3)I 8 142.2, 135.1, 116.8, 115.8, 89.4, 72.8,
55.8, 38.5, 18.3, 17.4, 12.8; IR (neat): 3077,2944, 2867, 1647, 1464, 1103, 1017,
907, 884, 577 cm"; LRMS (Cl, methane): m/e 311 ([M-Hr), 281, 259, 227, 157,
145, 117, 107; HRMS (Cl, methane) m/e calcd for [C1oH3502Si-H]+ 311.2406,

found 311.2397.

 

\ H0
Meo 1. HBcat, CIRh(PPh3)3, THFA MeO
OTIPS 2' NaOH’ H202 OTIPS
5.17b 5.20

To a solution of 4.94 g of 6.17b (15.8 mmol) and 439 mg Wilkinson’s catalyst
(0.475 mmol, 3 mol%) in 150 mL THF was added 47.5 mL commercial
catecholborane solution (1 M in THF, 47.5 mmol, 3 equiv) via syringe. The
reaction mixture turned dark and was stirred for 50 min at room temperature
before being cooled to 0 °C. The reaction was then quenched by the slow
addition of 32 mL of 1:1 water/T HF. Gas evolution was observed. A pre-cooled
(via ice bath) mixture of 32 mL 2 M NaOH (64 mmol, 4 equiv) and 32 mL 30%
H202 (310 mmol, ~20 equiv) was added into the reaction mixture slowly. Ice was
also added to the reaction so that the internal temperature never exceeded 30 °C.
Upon complete addition, the mixture was stirred for 25 min at 0 °C and another 25

min after the ice bath was removed. The reaction was then partitioned between

231

 

brine and ether. The layers were separated and the aqueous layer was
extracted with ether. The combined organic were washed with 1 M NaOH until
the wash was colorless. After being dried over M9304 and evaporated, the
crude residue was purified by column chromatography (3:1 hexanes/EtOAc) to
afford 4.24 g of 5.20 (81%) as oil; R2043 (3:1 hexanes/EtOAc); [r1120D -12.8 (c
1.01, EtOH); 1H NMR (500 MHz, CDCI3): 8 4.94 (m, 1 H), 4.87 (quint, J = 1.6 Hz, 1
H), 4.30 (d, J = 6.0 Hz, 1 H), 3.60 (t, J = 6.1 Hz, 2 H), 3.45 (s, 3 H), 3.18 (ddd, J =
2.1, 6.0, 8.5 Hz, 1 H), 1.75-1.80 (br, 1 H), 1.72 (m, 3 H), 1.62-1.68 (m, 3 H),
1.22-1.29 (m 1 H), 1.02-1.10 (m, 21 H); 13C NMR (125 MHz, CDCI3): 8 144.9,
113.0, 84.8, 76.6, 63.1, 58.7, 29.3, 26.6, 18.9, 18.07, 18.04, 12.4; IR (neat): 3366.
2946, 2869, 1464, 1101, 1067.901, 884, 681,656 cm'1; LRMS (CI, NH3): m/e 331
([M+H]+), 299, 255, 228, 174, 157, 125; HRMS (CI, methane) m/e calcd for

[C1oH33038i+H]+ 331.2668, found 331.2661.

OHC

 

H0
CH2CI2
OTIPS OTIPS
l
5.20 5.21

To a solution of 4.24 g of 6.20 (12.85 mmol) in 150 mL CH2CI2 was added 9.42
g solid-supported PCC (4.71 g PCC, 21.8 mmol, 1.7 equiv, ground together with
4.71 g of silica gel). The resulted purple-brown suspension was stirred at room

temperature for 2.5 h and then filtered through a pad of silica gel (~2 cm thick,

232

~4.5 cm wide). The silica pad was further eluted with ether. The filtrate was
evaporated and 4.25 g of crude 6.21 (containing 0.1 g CH2CI2. 98% as is,
discounting the added weight of CH2CI2) was obtained. This product was Clean
enough by NMR to be used in the next reaction without further purification; [a]20[)
-20.4 (crude, c 0.97, acetone); 1H NMR (500 MHz, CDCI3): 8 9.69 (t, J = 2.0 Hz, 1
H), 4.95 (m, 1 H), 4.89 (quint, J = 1.7 Hz, 1 H), 4.27 (d, J = 5.9 Hz, 1 H), 3.38 (s, 3
H), 3.16 (ddd, J = 3.0, 5.9, 9.0 Hz, 1 H), 2.43-2.47 (m, 2 H), 1.87 (dddd, J = 3.2,
7.1, 7.1, 14.4 Hz, 1 H), 1.73 (m, 3 H), 1.57 (dddd, J = 7.1,7.1,9.2,14.4 Hz, 1 H),
1.03-1.05 (m, 21 H), some impurity at 3.45; 13C NMR (125 MHz, CDCI3): 8 202.5,
144.8, 113.2, 83.9, 76.9, 58.7, 40.6, 23.1, 19.0, 18.06, 18.02, 12.4; IR (neat):
2946, 2869, 2720, 1728, 1464, 1098, 1067, 903, 884, 679 cm"; LRMS (El): m/e
285 ([M-‘Pr]+), 253, 227, 185, 157, 145, 117, 101, 89, 75, 59; HRMS (FAB) m/e

calcd for [C18H35033i-H]+ 327.2356, found 327.2350.

 

EtOC
OHC EtO2C\rPPh3 2 /
MeO 4' MeO
toluene
1 OTIPS OTIPS
6.21 6.22

To a solution of 4.25 g of crude 6.21 obtained from the previous reaction
(~12.6 mmol) in 120 mL dry toluene was added 9.12 g of Wittig reagent (25.2
mmol, 2 equiv). The suspension was heated to 110 °C and stirred overnight.

The Wittig reagent dissolved to give a Clear, light yellow solution initially, and as

233

 

 

the reaction proceeded, a white precipitate formed. After cooling the reaction to
room temperature, the solvent was removed by rotary evaporation, followed by
co-evaporation with EtOAc (For ease of operation, the white precipitate could be
filtered off before evaporation and chromatography). Chromatography
purification (10:1 hexanes/EtOAC) afforded 4.80 g of a 13.821 E/Z mixture of 6.22
(93%) as a colorless oil. (Another run gave 98% of a 12.721 E/Z mixture) Rr~0.59
(10:1 hexanes/EtOAC); [ajzoo -10.8 (12.7:1 E/Z mixture, 01.04, EtOH); 1H NMR
(500 MHz, CDCI3): 8 6.72 (ddq, J = 7.1, 8.2, 1.5 Hz, 1 H, the B-proton of the
cup-unsaturated ester moiety in the E isomer. The corresponding proton for the
Z isomer appears at 5.87), 4.94 (m, 1 H), 4.88 (quint, J = 1.6 HZ, 1 H), 4.30 (d, J =
5.6 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 3.43 (s, 3 H), 3.15 (ddd, J = 2.8, 5.7, 9.0 Hz.
1 H), 2.20-2.28 (m, 2 H), 1.81 (d, J = 1.2 Hz, 3 H), 1.72 (br, 3 H), 1.64 (dddd, J =
2.8, 7.6, 9.0, 14.1 Hz, 1 H), 1.34 (dddd, J = 5.7, 8.2, 9.2, 14.0 Hz, 1 H), 1.27 (t, J =
7.1 Hz, 3 H), 1.03-1.07 (m, 21 H); 13C NMR (125 MHz, CDCI3): 8 168.2, 145.0,
142.1, 127.9, 112.9, 84.0, 76.3, 60.4, 58.7, 28.8, 25.0, 19.2, 18.07, 18.03, 14.3,
12.4, 12.3; IR (neat): 2946, 2869, 1713, 1464, 1275, 1260, 1113, 883, 683 cm”;
LRMS (El): m/e 412 (M"), 369, 337, 227, 185, 157, 145, 75, 59; HRMS (Cl,

methane) m/e calcd for [C23H3304Si]+ 412.3009, found 412.3006.

234

 

 

Et02C /
/
M NH4CI, AlMe3 H2”
e0 :
benzene MeO
OTIPS OTIPS
6.22 6.5

To a suspension of 1.13 g NH4CI (21.2 mmol, 3 equiv) in 20 mL dry benzene
at 0 °C was slowly added 10.6 mL of AIMe3 solution (2 M in toluene, 21.2 mmol, 3
equiv) via syringe. Gas evolution was observed. The cold reaction mixture was
stirred for a few minutes and then warmed to room temperature. After being
stirred for another 30-35 min, gas evolution ceased and all the solid NH4CI had
dissolved (More AlMe3 could be added if NH4CI was not completely dissolved).
This clear solution was transferred via cannula to another flask containing 2.91 g
of 6.22 (7.06 mmol, 12.721 E/Z mixture) in 70 mL dry benzene. Upon complete
addition, the flask was topped with a condenser and the mixture was heated to
45-50 °C. After ~9.5 h, another 1.13 g NH4CI (21.2 mmol, 3 equiv) and 10.6 mL
AlMeo solution (2 M in toluene, 21.2 mmol, 3 equiv) were mixed in the same way
described above and transferred into the reaction vessel. The reaction
continued overnight. After being cooled to room temperature, the reaction was
quenched carefully with 1 M HCI until no more gas evolved. The mixture was
then stirred over saturated sodium potassium tartrate for 30 min until a clear
solution was obtained. Extraction with EtOAc was followed by drying over

M9804 and evaporation. Column chromatography separation (1:1

235

hexanes/EtOAC) afforded a small amount of Z isomer (Fer-0.41, 1:1
hexanes/EtOAc) and 2.21 g of the desired E isomer (82%) as a white solid;
R,~0.29 (1:1 hexanes/EtOAC); mp 52-55 °C; [81200 -13.2 (c 1.14, acetone); 1H
NMR (300 MHz, acetone-do): 8 6.67 (br, 1 H), 6.39 (to, J = 7.5, 1.5 Hz, 1 H), 6.18
(br, 1 H), 5.01 (m, 1 H), 4.90 (m, 1 H), 4.38 (d, J= 6.0 Hz, 1 H), 3.45 (s, 3 H), 3.25
(ddd, J = 3.1, 6.2, 8.8 Hz, 1 H), 2.20-2.28 (m, 2 H), 1.81 (m, 3 H), 1.76 (m, 3 H),
1.64 (dddd, J = 2.9, 7.3, 9.2, 13.9 Hz, 1 H), 1.32 (dddd, J = 6.6, 8.0, 8.0, 14.5 Hz,
1 H), 1.07-1.15 (m, 21 H); 13C NMR (75 MHz, acetone-do): 8 171.0, 146.3, 136.2,
131.9, 113.1, 84.6, 77.6, 58.8, 29.9, 25.1, 19.3, 18.47, 18.44, 13.2, 12.7; IR (neat):
3350, 3196,2946, 2889, 1667, 1636, 1603, 1377, 1111, 884, 681 cm“; LRMS (El):
m/e 340 ([M-‘Pr]+), 308, 253, 227, 185, 157, 115, 89, 75, 59; Anal. Calcd for

C21H41NO3Si: C, 65.75; H, 10.77; N, 3.65. Found C, 66.00; H, 10.89; N, 3.86.

 

0 o 0 o
\NJLNJK/ LiHMDS,alIyI-I= \NJKNJW
.\—J. THF .L—./ 5
M5 Ph Me‘ inn
5.24 5.25

A solution of 15.7 mL commercial LiHMDS (1 M in THF, 15.7 mmol, 1.05 equiv)
was further diluted with 10 mL THF and cooled to -78 °C. To this solution was
added a solution of 3.69 g of 6.24 (15 mmol) in 25 mL THF via syringe pump at a
rate of 0.77 lemin. Upon complete addition, the mixture was stirred at -78 °C

for 1 h. A solution of 1.65 mL (3.04 g, 18.1 mmol, 1.2 equiv) allyl iodide in 10 mL

236

THF was added via syringe pump at a rate of 0.77 mL/min. This process may
cause a large amount of precipitate or gel formation, so occasionally stopping the
addition and warming the mixture to dissolve this precipitate may be needed.
The mixture was stirred at -78 °C overnight. Upon completion, the reaction was
quenched with water and warmed to room temperature. It was partitioned
between brine and ether. The layers were separated and the aqueous layer was
extracted with ether. The combined organics were dried over M9804 and
evaporated. 1H NMR of the crude material showed a diastereomeric ratio of
~12:1. Two rounds of column Chromatography (2:1 hexanes/EtOAc) afforded a
small amount of the undesired R isomer (Rr0.51) and 3.21 g of the desired S
isomer (75%) as a white solid; inf-0.43 (2:1 hexanes/EtOAc); mp 71-73 °C; [81200
-43.6 (C 1.06, acetone); 1H NMR (500 MHZ, CDClo): 8 7.23-7.30 (m, 3 H),
7.11-7.13 (m, 2 H), 5.65 (dddd, J = 6.5, 7.6, 10.3, 17.0 Hz, 1 H), 5.28 (d, J = 8.7
Hz, 1 H), 4.89-4.95 (m, 2 H), 4.00 (sext, J = 6.8 Hz, 1 H), 3.87 (dq, J = 8.7, 6.6 Hz,
1 H), 2.81 (s, 3 H), 2.42 (dtt, J = 13.9, 1.3, 6.3 Hz, 1 H), 2.04 (dtt, J = 13.9, 1.2, 7.4
Hz, 1 H), 1.09 (d, J = 5.7 Hz, 3 H), 0.78 (d, J = 5.5 Hz, 3 H); 130 NMR (75 MHz,
CDCI3): 8 176.0, 155.7, 136.8, 135.7, 128.4, 128.0, 127.1, 116.6, 59.4, 53.8, 38.1,

37.3, 28.2, 15.3, 15.0; LRMS (El): m/e 285 (M“), 189, 132, 59, 58.

237

 

 

0 o 0
. OH
LBH , H O .
\NJLNW | 4 2 > \NXN H + W
.\__{ Et20 L4
Mé Ph Me Ph '
6.25 6.23 6.26

To a solution of 2.86 g of 6.25 (10 mmol) in 100 mL dry ether was added 0.2
mL water (200 mg, 11.1 mmol, 1.1 equiv). The solution was cooled to 0 °C and 6
mL LiBHa solution (2 M in THF, 12 mmol, 1.2 equiv) was added via syringe. The
reaction quickly turned cloudy and a white precipitate formed. The mixture was
stirred for 1 h at 0 °C followed by another 2 h at room temperature before being
quenched with saturated NH4CI. While stirring, 10 mL water and 10 mL glycerol
were added and the mixture was stirred overnight. The layers were separated
and the aqueous layer was extracted with ether. The combined organics were
dried over Na2SO4 and evaporated. Column chromatography (1.5:1
hexaneslether) afforded 895 mg of 6.26 (89%) as the first fraction. Further
elution with 1:1 EtOAc/acetone afforded 1.88 of g 6.23 (quantitative). Alcohol
5.25: Rr~0.32 (1 .5:1 hexaneslether); [0t]2°o -2.5 (c 1.10, EtOH); 1H NMR (500 MHz,
CDCI3): 8 5.79 (dddd, J = 7.3, 7.3, 10.3, 17.3 Hz, 1 H), 4.98-5.05 (m, 2 H), 3.50
and 3.44 (d of ABq, calculated vA at 3.494 ppm, vs at 3.440 ppm, 3J = 5.1 Hz, JAB
= 10.7 Hz, 2 H), 2.12-2.19 (m, 1 H), 1.89-1.96 (m, 1 H), 1.72 (sext, J = 6.8 Hz ,1
H), 1.40-1.43 (br, 1 H), 0.90 (d, J = 6.8 Hz, 3 H); 13C NMR (125 MHz, CDCI3): 8

137.0, 116.1, 67.9, 37.8, 35.6, 16.3; LRMS (El): m/e 99 ([M-H]+), 83, 67.

238

OH NaH, PMBCI OPMB

W F W

_ THF/DMF
6.26 6.27a

 

To a suspension of 528 mg NaH (60% dispersion in mineral oil, not washed,
corresponding to 317 mg pure NaH, 13.2 mmol, 1.5 equiv) in 9 mL DMF was
added a solution of 882 mg of 6.26 (8.8 mmol) in 18 mL THF. The mixture was
stirred at room temperature for 30 min before 1.44 mL PMBCI (1.67 g, 10.7 mmol,
1.2 equiv) was added via syringe. The mixture was stirred overnight and then
quenched with diethylamine. After stirring the mixture for another 10 min, water
was added until gas evolution ceased. The mixture was diluted with saturated
NH4CI and extracted with ether. The combined organics were dried over K2C03
and evaporated. Column chromatography (12:1 hexaneslether) afforded 1.43 g
of 6.27a (74%) as a colorless oil; Rr~0.32 (10:1 hexaneslether); [ajzoo +0.9 (01.05,
EtOH); 1H NMR (300 MHz, CDCI3): 8 7.25 (m, 2 H), 6.86 (m, 2 H), 5.76 (dddd, J =
6.8, 6.8, 10.5, 17.1 Hz, 1 H), 4.95-5.03 (m, 2 H), 4.41 (s, 2 H), 3.79 (s, 3 H), 3.29
and 3.22 (d of ABq, calculated vA at 3.282 ppm, ya at 3.228 ppm, 3J = 6.1 Hz, JAB
= 9.0 Hz, 2 H), 2.15-2.24 (m, 1 H), 1.77-1.94 (m, 2 H), 0.90 (d, J = 6.3 Hz, 3 H);
13C NMR (75 MHz, CDCIo): 8 159.1, 137.0, 130.8, 129.1, 115.9, 113.7, 75.0, 72.6,
55.3, 38.0, 33.3, 16.8; IR (neat): 3075,2955, 2838, 1612, 1514, 1249, 1092, 1038,
820 cm'1; LRMS (Cl, MeOH): m/e 219 ([M-H]+), 121; HRMS (Cl, methane) m/e

calcd for [C14H2oOz]+ 220.1463, found 220.1464.

239

 

 

 

OH / TlPSCl,lmid,DMAPA OT'PS

5 CHch2 :
6.26 6.27b

/

 

To a solution of 258 mg of 6.26 (2.5 mmol) in 7.5 mL CH2CI2 was added 30 mg
DMAP (0.25 mmol, 10 mol%) followed by 204 mg imidazole (3 mmol, 1.2 equiv).
While stirring, 640 pL TIPSCI (580 mg, 3 mmol, 1.2 equiv) was added via syringe.
The reaction flask was sealed with a septum, topped with a nitrogen balloon, and
stirred overnight at room temperature. Upon completion, the reaction mixture
was poured into half saturated NaHCOo, and extracted with CH2CI2. After drying
over MgSO4 and evaporation, the crude product was purified by column
chromatography (hexanes) to yield 600 mg of 6.27 (90%) as colorless oil; Rr~0.53
(hexanes); loo?"D -2.5(c1.10, EtOH); 1H NMR (500 MHz, CDCIo): 8 5.78 (dddd, J
= 7.1, 7.1, 10.3, 17.1 Hz, 1 H), 4.95-5.02 (m, 2 H), 3.51 and 3.48 (d of ABq,
calculated W, at 3.509 ppm, vs at 3.481 ppm, 3J = 5.1 Hz, JAB = 9.5 Hz, 2 H),
2.18-2.24 (m, 1 H), 1.83-1.89 (m, 1 H), 1.68 (octet, J = 6.6 Hz, 1 H), 1.02-1.10 (m,
21 H), 0.88 (d, J = 6.6 Hz, 3 H); 13C NMR (125 MHz, CDCI3): 8 137.5, 115.6, 68.0.
37.7, 36.0, 18.0, 16.4, 12.0; IR (neat): 3079, 2944, 2867, 1642, 1105, 993, 884,
793, 681 cm"; LRMS (El): m/e 213 ([M-’Pr]+), 171, 143, 131, 103, 75, 61; HRMS

(Cl, methane) m/e calcd for [C15H320Si1-H]+ 257.3201, found 257.2304.

240

 

 

O
HO NH2 ImzCO
L_/ L- CAN-H
CH2CI2 \__/
P5 ’e
6.29 6.30

 

P5 Me

A mixture of 12.08 g norephedrine (80 mmol) and 14.6 g carbonyldiimidazole
(90 mmol, 1.12 equiv) was dissolved in 300 mL dry CH2CI2 and stirred at room
temperature for 2 h. Upon completion, the mixture was evaporated and the
residue was directly purified by column chromatography (1 :4 hexaneletOAc) to
afford 12.2 g of 6.30 (86%) as a white solid; mp 115-118 °C (commercial material
118-121 °C); [812°D +1534 (0 2.03, CHCI3); 1H NMR (500 MHz, CDCI3): 8
7.26-7.39 (m, 5 H), ~6.2 (br, 1 H), 5.69 (d, J = 8.0 Hz, 1 H), 4.16-4.22 (m, 1 H),
0.79 (d, J = 6.6 Hz, 3 H); 13C NMR (125 MHz, CDCI3): 8 159.5, 134.8, 128.47,

128.44, 125.9, 81.0, 52.4, 17.5; LRMS (El): m/e 177 (M+), 107, 79.

 

ii 0 °
EICO O, DMAP, TEA
.' L THF .' "
Ph Me Pit Me
6.30 6.31

To a solution of 12.2 g of 6.30 (68.9 mmol) in 40 mL THF were added 210 mg
DMAP (1.72 mmol, 2.5 mol%) and 11.6 mL EtoN (8.35 g, 82.7 mmol, 1.2 equiv).
The mixture was then cooled to 0 °C. 15 mL propionic anhydride (15.2 g, 117
mmol, 1.7 equiv) was added dropwise via syringe and the reaction was allowed to

warm up to room temperature and stirred for 1 h 35 min. The mixture was

241

 

 

poured into half saturated NaHC03 and extracted with EtOAc. After drying over
Na2S04 and evaporation, the crude product was purified by column.
Chromatography (4:1 hexanes/EtOAc) to first afford 12.59 g of 6.31 (78%) as a .
very thick oil. Further elution with 100% EtOAc afforded 2.70 g of recovered
5.30 (22%). Compound 5.31: R,~0.4 (4:1 hexanes/EtOAc); [comD +429 (c 2.08,
CH2CI2); 1H NMR (500 MHz, CDCI3): 8 7.27-7.41 (m, 5 H), 5.65 (d, J = 6.7 Hz, 1
H), 4.74 (quint, J = 6.7 Hz, 1 H), 2.98 and 2.90 (q of ABq, 3J = 7.3 Hz, JAB = 17.8
Hz, 2 H), 1.16 (t, J = 7.3 Hz, 3 H), 0.87 (d, J = 6.6 Hz, 3 H); 13C NMR (125 MHz,
CDCI3): 8 173.8, 153.1, 133.3, 128.71, 128.67, 125.6, 79.0, 54.7, 29.3, 14.5, 8.3;

LRMS (El): m/e 233 (M*), 115, 107, 91, 70, 57.

 

0 o 0 o
OANJK/ LiHMDS, allyl-l; OANW
1.4 THF t_J_
P5 Me Pfi MB
5.31 5.32

A solution of 50 mL commercial LiHMDS (1 M in THF, 50 mmol, 1.1 equiv, the
solution in hexanes also worked) was further diluted with 40 mL THF and cooled
to -78 °C. To this solution was added a solution of 10.5 g of 6.31 (45 mmol) in 90
mL THF via syringe pump at a rate of 0.67 mL/min. Upon complete addition, the
mixture was stirred at -78 °C for 1 h and a solution of 6.2 mL allyl iodide (11.4 g,
67.9 mmol, 1.5 equiv) in 30 mL THF was added via syringe pump at a rate of 0.67

mL/min. This process may cause a large amount of precipitate or gel formation

242

 

so occasionally stopping the addition and warming the mixture to dissolve this
precipitate may be needed. The mixture was stirred at -78 °C for 1 day. The
reaction was quenched with half saturated NaCl and warmed up to room
temperature. It was partitioned between brine and ether. The layers were .
separated and the aqueous layer was extracted with ether. The combined
organics were dried over Na2SO4 and evaporated. 1H NMR of the crude material
showed a single diastereomer (> 95:5 dr). Conversion of the reaction might vary
from run to run. Column chromatography (5:1 hexanes/EtOAc) afforded 9.64 g
of 6.32 (79%) as a wax solid, along with 1.15 g of 6.31 (11%). Compound 6.32:
ref-0.47 (5:1 hexanes/EtOAc); mp 54-55 °C (lit169 59-70 °C); [c.1200 +459 (c 2.02,
CH2CI2); 1H NMR (500 MHz, CDCI3): 8 7.27-7.41 (m, 5 H), 5.77 (dddd, J = 7.0, 7.0,
10.1, 17.1 Hz, 1 H), 5.64 (d, J = 7.4 Hz, 1 H), 4.98-5.05 (m, 2 H), 4.76 (quint, J =
6.7 Hz, 1 H), 3.86 (sext, J = 6.8 Hz, 1 H), 2.43-2.49 (m, 1 H), 2.16-2.22 (m, 1 H).
1.17 (d, J = 6.8 Hz, 3 H), 0.83 (d, J = 6.6 Hz, 3 H); 13C NMR (125 MHz, CDCI3): 8
176.2, 152.7, 135.2, 133.3, 128.69, 128.64, 125.6, 117.1, 78.7, 54.8, 37.9, 37.1,

16.5, 14.6; LRMS (El): m/e 273 (M+), 258, 230, 178, 156, 134, 118, 107, 97, 70,

 

42.
9 O ' )3 H B O C
OANW BnOH,BULI AV 0 N- + n 2 N
(_) THF LI 2
P6 Me P“ e
6.32 6.30 6.33

243

 

To a solution of 6.1 mL BnOH (6.4 g, 59.2 mmol, 1.8 equiv, no purification
needed) in 160 mL THF at 0 °C was added 28.5 mL of commercial BuLi solution
(titrated to be 1.5 M in hexanes, 42.8 mmol, 1.3 equiv) dropwise. The mixture
was stirred at 0 °C for 20 min before a solution of 9.0 g of 6.32 (32.9 mmol) in 35
mL THF was added. The mixture was stirred at 0 °C for another 40 min before-
being quenched with water and diluted with saturated NH4CI. The layers were
separated and the aqueous layer was extracted with ether. The combined
organics were dried over M9804 and evaporated. Column chromatography
purification (12:1 hexane/ether) afforded 6.60 g of 6.33 as oil (97%). Further
elution with 100% EtOAc afforded 5.62 g of 6.30 (97%). Ester 6.33: Rr~0.46
(10:1 hexanes/ether); [0420D +2.5 (c 4.23, CHCIo); 1H NMR (300 MHz, CDCIo): 8
7.31-7.36 (m, 5 H), 5.73 (dddd, J = 7.0, 7.0, 10.3, 17.1 Hz, 1 H), 5.11 (s, 2 H),
4.98-5.07 (m, 2 H), 2.58 (sext, J = 7.1 Hz, 1 H), 2.38-2.48 (m, 1 H), 2.14-2.25 (m,
1 H), 1.17 (d, J = 7.1 Hz, 3 H); 13C NMR (75 MHz, CDClo): 8 175.8, 135.1, 135.3,

128.5, 128.08, 128.04, 116.9, 66.1, 39.2, 37.7, 16.5; LRMS (El): m/e 204 (M+),

 

130, 91, 69,41.
1. AD-mix-a, NaHCO3,
BnOZCN t-Bu0H/H20 : oi)?“ + o o
E 2. TIPSCI. DMAP, CH2CI2 \
6.33 6.343 6.34b

A suspension of 46.7 g commercial AD-mIX-Ot, 13.5 g NaHCOo (160 mmol, 4.8

244

 

 

 

equiv), and 3.17 g MeSO2NH2 (33.4 mmol, 1 equiv) in 170 mL water and 170 mL
t-Bu0H was vigorously stirred at room temperature until both layers were clear.
The mixture was then cooled to 5-10 °C and 6.81 g of 6.33 (33.4 mmol) was
added. The reaction was then warmed to room temperature and stirred for 22 h.
A batch of 12.3 mg K20s02(0H)4 (~33 umol, 0.1 mol%) was added at this time
(This is not necessary if the conversion is good). The reaction continued for 16 h
and was quenched with saturated Na2803. The conversion of this
dihydroxylation reaction is not very consistent. It is advised to quench the
reaction at ~1.5 days even if incomplete. After being diluted with water, the
mixture was extracted with ether, dried over M9804, and evaporated. The
residue showed about 80% conversion by 1H NMR and was taken in the next
reaction without further purification.

The residue obtained from the above reaction was diluted with 70 mL dry
CH2CI2. To this solution was added 11.0 g DMAP (90 mmol) followed by
dropwise addition of 15.2 mL TIPSCI (13.7 g, 71 mmol). The reaction was stirred
at room temperature for 2.5 h before being poured into half saturated NaHC03.
The mixture was extracted with CH2CI2, dried over M9804, and evaporated.
Column chromatography purification (7:1 hexanes/EtOAc) afforded 0.89 g of
recovered 6.33 (13%), 1.63 g of 6.34b (containing 0.04 g ether, 17% discounting

the added weight of ether), and 4.94 g of 6.34a (clean, 52%).

245

 

Desired cis-isomer 6.34a: R)~0.38 (5:1 hexanes/EtOAc);

 

0 1 0 fi/
1] 5 [or]200 +5.3 (c 3.45, CHCI3); 1H NMR (500 MHz, CDCI3): 8 4.41

 

 

(dddd, J = 3.8, 3.8, 6.1, 9.9 Hz, 1 H), 3.90 and 3.78 (d of ABq,
3J = 3.8 Hz, JAB = 11.1 Hz, 2 H), 2.62-2.70 (m, 1 H), 2.36 (ddd, J = 6.2, 9.0, 12.5
Hz, 1 H), 1.84 (dt, J = 9.9, 12.0 Hz, 1 H), 1.25 (d, J = 7.1 Hz, 3 H), 1.01-1.08 (m,
21 H); 13C NMR (125 MHz, CDCI3): 8 179.5, 78.3, 64.2, 35.4, 31.9, 17.85, 17.84,
15.4, 11.8; IR (neat): 2944, 2867, 1777, 1462, 1171, 1130, 884, 683 cm"; LRMS
(El): m/e 243 ([M-’Pr]*), 185, 173, 131, 103; HRMS (Cl, methane) m/e calcd for
[C15H2,0038i+H]+ 287.2042, found 287.2040. The stereochemistry was assigned

by n0e experiment: H4 and H2 showed n0e to each other.

 

01f)”
2‘! 5
\‘c 3

MHZ, CDCI3): 8 4.51 (dddd, J = 2.9, 2.9, 2.9, 8.9 HZ, 1 H), 3.91 and 3.74 (d of ABq,

OTIPS Undesired trans-isomer 6.34b: R)~0.45 (5:1
hexanes/EtOAc); [8erD 45] (c 3.25, CHCI3); 1H NMR (500

 

3J = 3.4 and 3.0 Hz, JAB = 11.0 Hz, 2 H), 2.80 (tq, J = 9.4, 7.3 Hz, 1 H), 2.43 (ddd,
J = 2.8, 9.5, 12.5 Hz, 1 H), 1.93 (dt, J: 12.7, 8.9 Hz, 1 H), 1.24 (d, J = 7.4 Hz, 3 H),
1.01-1.07 (m, 21 H); 13C NMR (125 MHz, CDCI3): 8 180.4, 77.7, 55.3, 34.2, 32.1,
17.87, 17.85, 15.4, 11.8; IR (neat): 2924, 2867, 1779, 1452, 1381, 1171, 1125,
884, 583 cm"; LRMS (El): m/e 243 ([MJ’Prr), 185, 173, 131, 103; HRMS (CI,
methane) m/e calcd for [C15H30038I+H]+ 287.2042, found 287.2038. The

stereochemistry was assigned by n0e experiment: H4 and H2 showed no nOe to

246

 

 

each other.

/0T|PS UBHM MeOH 0H OTIPS

 

O O .1 >
jj THF = OH
6.34a 6.35a

To a solution of 5.00 g of 6.34a (17.5 mmol) in 90 mL dry THF was added 820
pL MeOH (640 mg, 20 mmol, 1.14 equiv). This solution was cooled to 0 °C and
stirred for 10 min before 10.95 mL of commercial LiBH4 solution (2 M in THF, 21.9
mmol, 1.25 equiv) was added dropwise. The reaction was stirred for 1 h at 0 °C
followed by 2 h at room temperature before being quenched with saturated NH4CI
(CAUTIONI). To the mixture were then added 20 mL water and 15 mL glycerol.
The mixture was stirred overnight before being partitioned between brine and
EtOAc. The layers were separated and the aqueous layer was extracted with
EtOAc. The combined organics were dried over Na2S04 and evaporated. The
resulted 5.76 g residue was directly used in the next reaction without purification.
[a]2°o -28.6 (c 1.48, EtOH); 1H NMR (500 MHz, CDClo): 8 3.73-3.78 (m, 1 H),
3.37-3.66 (2 overlapping d of ABq, can be approximated into 4 dd at 3.64 (dd, J =
3.8, 9.6 Hz, 1 H), 3.54 (dd, J = 4.3, 11.0 Hz, 1 H), 3.44 (dd, J = 8.3, 9.6 Hz, 1 H),
and 3.39 (dd, J = 7.3, 11.0 Hz, 1 H)), 3.16 (s, 2 H), 1.78-1.88 (m, 1 H), 1.29-1.39
(m, 2 H), 1.02-1.08 (m, 21 H), 0.90 (d, J = 6.8 Hz, 3 H); 13C NMR (125 MHz,

CDCI3): 8 71.2, 68.7, 67.8, 38.2, 34.6, 18.1, 17.9, 11.9; LRMS (FAB): m/e 291

247

 

([M+H]*), 247.

 

OH OTIPS OPlv OTIPS
PivCl '
6.35a 6.36a

To a solution of 554 mg of 6.35a (1.94 mmol) in 2.5 mL pyridine (no
purification or drying needed) and 2.5 mL dry CH2CI2 at 0 °C was added dropwise
250 uL PivCI (245 mg, 2.04 mmol, 1.05 equiv). The ice bath was removed 5 min
after complete addition and the reaction was allowed to stir at room temperature
overnight. The mixture was diluted with water and extracted with CH2CI2. The
combined organics were washed with 5% CuSO4 and water before being dried
over M9804 and evaporated. Column chromatography (6:1 hexanes/EtOAc)
afforded 656 mg of 6.36a (90%) as a colorless oil; Rr~0.42 (6:1 hexanes/EtOAc);
[81200 -24.1 (c 1.08, EtOH); 1H NMR (500 MHz, CDCIo): 8 3.95 and 3.88 (d of ABq,
3J = 5.7 and 6.5 Hz, JAB = 10.7 Hz, 2 H), 3.75 (dddd, J = 3.3, 3.3, 7.0, 10.4 Hz, 1
H), 3.68 (dd, J = 3.4, 9.6 Hz, 1 H), 3.46 (dd, J = 7.2, 9.6 Hz, 2 H), ~2.44 (br, 1 H),
2.06-2.12 (m, 1 H), 1.52 (ddd, J = 4.5, 9.8, 14.0 Hz, 1 H), 1.18 (s, 9 H), 1.03-1.09
(m, 21 H), 0.96 (d, J = 6.7 Hz, 3 H); 13C NMR (125 MHz, CDCI3): 8 178.5, 69.6,
69.4, 68.0, 38.8, 36.4, 29.4, 27.2, 17.9, 16.5, 11.9; LRMS (CI, MeOH): m/e 375

([M+H]*), 357. 331. 229, 99, 57.

248

H TIP
0 O S T rCI, DM AP OTr OTIPS

 

‘
v

0H py 3 0H

6.35a 6.36b

To a solution of 1.23 g trityl chloride (4.4 mmol, 1.1 equiv) and 12 mg DMAP
(0.1 mmol, 2.5 mol%) in 4 mL pyridine (no purification or drying needed) was ,
added a solution of 1.19 g of 6.35a (4 mmol) in 3 mL pyridine. The mixture was
stirred at room temperature for 2.5 days and quenched with water. The mixture
was partitioned between water and CH2CI2. The layers were separated and the
aqueous layer was extracted with CH2CI2. The combined organics were dried
over M9804 and evaporated. Column chromatography (9:1 hexanes/EtOAc)
afforded 1.76 g of 6.36b (containing 0.03 g ether, 81% discounting the added
weight of solvent) as an oil. Further elution with 1:1 hexanes/EtOAc afforded
192 mg of recovered 6.35a (17%). Trityl ether 6.36b: Rr~0.43 (9:1
hexanes/EtOAc); [81200 -13.8 (c 1.08, EtOH); 1H NMR (500 MHz, CDCI3): 8
7.45-7.48 (m, 6 H), 7.22-7.32 (m, 9 H), 3.72-3.78 (m, 1 H), 3.68 (dd, J = 3.8, 9.6
Hz, 1 H), 3.51 (dd, J = 7.6, 9.6 Hz, 1 H), 2.95-3.01 (m, 2 H), 2.57 (d, J = 3.5 Hz, 1
H), 2.03-2.10 (m, 1 H), 1.59 (ddd, J = 4.8, 9.4, 14.0 Hz, 1 H), 1.23 (ddd, J = 3.5,
9.2, 13.4 Hz, 1 H), 1.07-1.12 (m, 21 H), 1.01 (d, J = 6.7 Hz, 3 H); 13C NMR (125
MHz, CDCI3): 8 144.4, 128.7, 127.7, 126.8, 86.2, 69.7, 69.0, 68.0, 37.2, 30.5, 18.0,
17.2, 11.9; IR (neat): 3476, 2976, 2928, 2867, 1448, 1383, 1121, 1074, 708 cm'1;

LRMS (ESI): m/e 555 ([M+Na]*), 291, 243; HRMS (ESI) m/e calcd for

249

 

 

[C34H4802.Si+Na]+ 555.3270, found 555.3259. This compound does not store

well in CDC/3.

 

 

0Tr OTIPS _ 0Tr 0R1 TBAF 0Tr 0R1
5 ' 2 THF , 2
- 0H - 0R - 0R
535" 5.37, R1=TIPS, R2=Me 5.39, R‘=H, R2=Me
6.38,R1=Me, R2=TIPS 5.40, R‘=Me, R2=H

Method 1 (NaH, Mel): to a suspension of 1.16 g NaH (60% dispersion in
mineral oil, not washed, corresponding to 0.70 9 pure NaH, 29 mmol, 1.7 equiv) in
70 mL THF at 0 °C was added 3.2 mL Mel (purified by passing through neutral
alumina, 7.28 g, 51.3 mmol, 3.0 equiv) via syringe. A solution of 9.5 g of 6.36b
(17.1 mmol) in 90 mL THF was added next via syringe. The ice bath was
removed and the reaction was stirred at room temperature for 1 day. Upon
completion, the reaction was quenched with half saturated NH4C| and briefly
concentrated. The mixture was extracted with ether, dried over M9804 and
evaporated. The resultant material was a mixture of two inseparable isomers
(6.37 and 6.38) and was used directly in the next step.

The crude residue from the previous reaction was diluted with 35 mL THF and
cooled to 0 °C. To this solution was added dropwise 25.7 mL of TBAF solution
(1 M in THF, 25.7 mmol, 1.5 equiv based on 100% yield of the previous reaction).
Upon complete addition, the reaction was warmed to room temperature and

stirred for 3 h. Water was added and the reaction was diluted with saturated

250

 

NaHC03 and extracted with ether. The combined organics were dried over
M9804 and evaporated. Column chromatography (2:1 hexanes/EtOAc)-
afforded 1.01 g of 6.40 (containing 0.03 g EtOAc, 15% discounting the added,
weight of EtOAc, 2 steps) and 5.26 g of 6.39 (containing 0.16 g EtOAc, 82%

discounting the added weight of EtOAc, 2 steps) as a colorless oil.

 

(97, OH Desired primary alcohol 6.39: Rr~0.32 (2:1 hexanes/EtOAc);

. oMe [842°D +2.9 (0 0.95, CHCI3); 1H NMR (500 MHz, CDCI3): 8 7.45-7.47

 

(m, 6 H), 7.23-7.33 (m, 9 H), 3.65-3.70 (m, 1 H), 3.43-3.47 (m, 1 H), 3.36 (s, 3 H),
3.29-3.33 (m, 1 H), 3.00 and 2.95 (d of ABq, calculated V): at 2.994 ppm, ya at
2.951 ppm, 3J = 6.0 Hz, JAB = 8.8 Hz, 2 H), 1.92 (sext, J = 6.8 Hz, 1 H), 1.87 (br, 1
H), 1.73 (ddd, J = 5.9, 7.3, 13.7 Hz, 1 H), 1.21 (ddd, J = 5.4, 7.8, 13.7 Hz, 1 H),
1.03 (d, J = 6.6 Hz, 3 H); 13C NMR (125 MHz, CDCI3): 8 144.3, 128.7, 127.7,
126.8, 86.2, 79.4, 68.4, 64.1, 57.0, 34.9, 30.7, 17.9; IR (neat): 3389, 3059, 2928,
1491, 1449, 1090, 764, 747, 709, 633 cm"; LRMS (ESI): m/e 413 ([M+Na]+), 243;
HRMS (ESI) m/e calcd for [C2oH30034-Na]+ 413.2093, found 413.2085. The
structure was assigned through HMQC and HMBC analysis: the carbon bearing
OMe is a methine, not a methylene. This compound does not store well in

CDC/3.

 

( on QMj Undesired secondary alcohol 6.40 via silyl migration:
0H

 

Rr~0.43 (2:1 hexanes/EtOAc); [81200 -1.0 (c 1.15, EtOH); 1H NMR

251

(500 MHz, CDCI3): 8 7.42-7.45 (m, 6 H), 7.20-7.30 (m, 9 H), 3.83-3.88 (m, 1 H),
3.36 (s, 3 H), 3.33 and 3.23 (d of ABq, can be approximated as 2 dd, 3.33 (dd, J =
3.4, 10.4 Hz, 1 H), 3.23 (dd, J = 7.6, 9.5 Hz, 1 H)), 2.98 and 2.95 (d of ABq,
calculated vA at 2.978 ppm, vs at 2.954 ppm, 3J = 6.0 Hz, JAB = 8.9 Hz, 2 H), 2.51
(d, J= 2.9 Hz, 1 H), 1.98-2.08 (m, 1 H), 1.51 (ddd, J: 5.2, 9.5, 14.0 Hz, 1 H), 1.22
(ddd, J = 3.4, 8.5, 13.9 Hz, 1 H), 0.95 (d, J = 5.8 Hz, 3 H); 13C NMR (125 MHz,
CDCI3): 8 144.3, 128.7, 127.7, 126.8, 86.4, 77.5, 69.1, 68.2, 59.0, 37.7, 30.7, 17.4;
IR (neat): 3460, 2977, 2919, 2851, 1491, 1449, 1383, 1121, 1073, 764, 747,708,
633 cm"; LRMS (ESI): m/e 454 ([M+MeCN+Na]”), 429 ([M+K]*), 413 ([M+Na]"),
243; HRMS (ESI) m/e calcd for [C25H3o03+Na]+ 413.2093, found 413.2088. The
structure was assigned through HMQC and HMBC analysis: the carbon bearing
OMe is a methylene, not a methine. This compound does not store well in
CDC/3.

Method 2 (KHMDS, MeOTf): a solution of 7.2 g of 6.36b (13.5 mmol) in 60 mL
dry toluene was cooled to -78 °C. To this solution was added 80 mL of
commercial KHMDS solution (0.5 M in toluene, 40 mmol, 3 equiv) via syringe
pump at the rate of 0.77 mL/min. The reaction mixture gradually turned into a
slurry. After the mixture was stirred at -78 °C for 15 min, 7.5 mL MeOTf (11 g, 67
mmol, 5 equiv) was added dropwise. The reaction mixture was stirred overnight,

during which time the dry ice-acetone bath gradually warmed up, letting the

252

 

 

reaction warm up to room temperature. If the sluny became hard to stir, the cold
bath could be removed right away. The reaction was quenched with saturated
NaHC03 and extracted with ether. The combined organics were dried over
M9804 and evaporated. Column chromatography (3:1 —> 1:1 hexanes/CH2CI2)
afforded 6.74 g of pure 6.37 (91 %) as a colorless oil.

The TBAF desilylation was carried out via the same procedure mentioned

above.

 

hexanes/CH2CI2); [or]200 —10.0 (c 1.00, CH2CI2); 1H NMR (500

CT, OTIPS Silyl migration intermediate 6.37: Rp0.35 (2:1
OMe

 

 

MHz, CDCI3): 8 7.46-7.48 (m, 5 H), 7.22-7.32 (m, 9 H), 3.74 and 3.50 (d of ABq, 3J
= 5.5 and 5.0 Hz, JAB = 10.1 Hz, 2 H), 3.42 (s, 3 H), 3.27-3.32 (m, 1 H), 3.01 and
2.92 (d of ABq, 3J = 5.5 and 5.5 Hz, JAB = 8.8 Hz, 2 H), 2.00-2.05 (m, 1 H), 1.55
(ddd, J = 4.5, 9.3, 13.0 Hz, 1 H), 1.35 (ddd, J = 3.7, 9.3, 13.2 Hz, 1 H), 1.07-1.11
(m, 21 H), 1.03 (d, J = 5.5 Hz, 3 H); 13C NMR (125 MHz, CDCI3): 8 144.5, 128.8,
127.5, 125.7, 86.0, 80.0, 68.8, 55.1, 58.1, 35.2, 30.5, 18.0, 17.4, 11.9; IR (neat):
3059, 2942, 2867, 1449, 1103, 1071, 705 cm"; LRMS (ESI): m/e 585 ([M+K]*),
559 ([M+Na]"), 243; HRMS (ESI) m/e calcd for [C35H5o03Si+Na]+ 559.3427, found

569.3427. This compound does not store well in CDC/3.

ORV/YOH (C0Cl)2, DMSO, TEA 0“ O

CH I ;
OMe 2C 2 = OMe

6.39 6.41

 

H

253

A solution of 0.90 mL oxalyl chloride (1.31 g, 10.3 mmol, 1.2 equiv, freshly, ,
distilled) in 30 mL dry CH2CI2 was cooled to -78 °C. To this solution was added
dropwise a solution of 1.46 mL DMSO (1.61 g, 20.5 mmol, 2.4 equiv, freshly
distilled) in 60 mL CH2CI2. The mixture was stirred for 5 min before a solution of
3.4 g of 6.39 (containing 0.1 g EtOAc, 8.5 mmol discounting the added weight of
EtOAc) in 11 mL CH2CI2 was added dropwise, during which time a precipitate was
observed. The mixture was stirred cold for another 10 min before 5.95 mL Et3N
(4.32 g, 43 mmol, 5 equiv, freshly distilled) was added dropwise. The reaction
was warmed to room temperature, and judged complete after 1.5 h. The
reaction was quenched with saturated NaHCOo and extracted with CH2CI2. The
combined organics were dried over Na2S04 and evaporated. The residue (3.81
9, containing 0.40 g CH2CI2 and 0.13 9 DMSO, ~99% as is discounting the added
weight of solvents) was used in the next step without purification; [ajzoo -42.9 (c
0.78, CH2CI2, crude); 1H NMR (500 MHz, CDCI3): 8 9.64 (d, J = 2.0 Hz, 1 H),
7.45-7.47 (m, 6 H), 7.23-7.33 (m, 9 H), 3.61 (ddd, J = 2.2, 4.2, 9.8 Hz, 1 H), 3.41
(s, 3 H), 2.99 (cl, J = 5.9 Hz, 2 H), 2.03-2.10 (m, 1 H), 1.79 (ddd, J = 4.6, 9.5, 14.2
Hz, 1 H), 1.44 (ddd, J = 2.4, 7.3, 12.0 Hz, 1 H), 1.02 (d, J = 6.8 Hz, 3 H); 13C NMR
(125 MHz, CDCI3): 8 203.9, 144.3, 128.7, 127.7, 126.9, 86.3, 84.0, 68.2, 58.2,
33.7, 30.2, 17.0; IR (neat): 3058, 2930, 2874, 1734, 1449, 1071, 764, 747, 708.

533 cm"; LRMS (ESI): m/e 429 ([M+MeCN+H]*), 411 ([M+Na]*); HRMS (ESI) m/e

254

 

calcd for [C25H2803+Na]+ 411.1936, found 411.1929. This compound does not

store well in CDC/3.

HSiCI3, Pd(PPh3)4 _
fl = msrco

 

Butadiene gas was condensed into a round-bottom flask in a dry ice-acetone
bath. A portion of 8.7 mL such liquid butadiene (5.39 g, 0.1 mol) was taken by a
syringe and quickly injected into an air-free flask containing 350 mg Pd(PPh3)4
(0.3 mmol, 0.3 mol%) that was placed in another dry ice-acetone bath. While '
stirring, 10 mL trichlorosilane (13.4 9, ~01 mol) was added into the air-free flask
via syringe and the reaction turned black. The flask was sealed with a Teflon
screw cap and the cold bath was removed. The reaction was stirred at room
temperature overnight. Distillation at 140-142 °C (1 atm) afforded 15.2 g of the
desired product (79%) as a colorless oil. 1H NMR showed a 96:4 Z/E ratio; 1H
NMR (300 MHz, CDCI3): 8 5.67-5.74 (m, 1H), 5.38-5.42 (m, 1 H), 2.33 (ddq, J =
1.7, 8.0, 0.6 Hz, 2 H), 1.65 (ddt, J = 1.7, 6.8, 1.0 Hz, 3 H), minor E isomer at 2.24

and 1.70; 13c NMR (125 MHz, cock): 8 128.3, 118.6, 24.7, 13.0.

OBT INKS/Br
a“: Ct
NH2 CH2C|2

 

255

To a flask containing 9.0 g of the diamine (78.9 mmol), 29.2 g of the aldehyde
(157 mmol, 2 equiv), and 15 g freshly activated molecular sieves (4 A) was added
200 mL CH2CI2. The mixture was stirred at room temperature for 1 day before
being filtered through a pad of celite. The celite pad was washed with CH2CI2
and the filtrate was evaporated. This crude material contained a small amount of
unreacted aldehyde. Thus it was suspended in hexanes with vigorous stirring.
Solid (product) was collected by filtration and washed with minimum amount of
hexanes. The mother liquor was evaporated and the residual solid was again
suspended in hexanes and a second crop of solid (product) was collected. A
third crop was obtained in the same manner. The combined solids were dried
under high vacuum to yield 33.8 g of a white solid (95%), mp 122-123 °C (lit17o
124-125.5 °C); [81200 +253.1 (01.19, CHCI3); 1H NMR (300 MHz, CDCI3): 8 8.09
(s, 2 H), 7.43 (br, 8 H), 3.37 (br, 2 H), 1.78-1.86 (m, 5 H), 1.43-1.49 (m, 2 H); 13C
NMR (75 MHz, CDCI3): 8 159.7, 135.1, 131.6, 129.3, 124.6, 73.7, 32.8, 24.4; IR
(neat): 2930, 2857, 1644, 1590, 1485, 1069, 1011, 818 cm"; LRMS (El): m/e 446
(M*), 265, 184; HRMS (El) m/e calcd for [C2oH2oBr2N2]+ 445.9943, found

445.9978.

256

 

 

/ l Br Br
II
J] MeOH NH
'l
/ Br Br

To a solution of 7.17 g of the diimine (16 mmol) in 80 mL MeOH (no ‘

 

purification or drying needed) and ~10 mL ether (no purification or drying needed)
at 0 °C was added 1.46 g NaBH4 (38.4 mmol, 2.4 equiv) delivered in small
portions. Gas evolution was observed and the reaction was allowed to warm to
room temperature and stir for 19 h. The reaction was quenched with water and
the suspension was extracted with CH2CI2. The combined organics were dried
over K2003 and evaporated to afford 7.25 g of the desired product (100%) as a
slightly yellow oil; [81200 +384 (0 1.14, CHCIg); 1H NMR (500 MHz, CDCIg): 8
7.40-7.42 (m, 4 H), 7.16-7.18 (m, apparent d, 4 H), 3.86 and 3.62 (ABq, JAB = 13.5 _
Hz, 4 H), ~2.31 (m, 2 H), 2.11-2.14 (m, 2 H), 1.71-1.73 (m, 2 H), 1.07-1.24 (m, 4 H)
(NH protons not observed); 13c NMR (125 MHz, CDCIo): 8 139.9, 131.4, 129.7,
120.5, 60.8, 50.1, 31.4, 24.9; IR (neat): 2926, 2853, 1487, 1455, 1071, 1011, 799
cm“; LRMS (El): m/e 450 (M*), 281, 184, 169, 96, 90; HRMS (El) m/e calcd for
[C2oH248r2N2]+ 450.0306, found 450.0286. This product was used directly in the

next step without further purification.

257

 

 

Br

 

T), Wu

To a solution of 2.09 g trichlorocrotylsilane (weighed in a syringe, 11 mmol, 1.1
equiv) in 20 mL CH2CI2 in an air-free flask was added 3.3 mL DBU (3.34 g, 22
mmol, 2.2 equiv, freshly distilled) at 0 °C. A solution of 4.5 g of the diamine in 10
mL CH2CI2 was introduced via syringe pump at the rate of 0.6 mL/min. The
air-free flask was sealed with a Teflon screw cap and the reaction was warmed to
room temperature and stirred overnight. The reaction mixture was pumped
down under high vacuum to remove the solvent, and a white syrup was obtained.
It was taken into the glove box and 30 mL dry pentane was added. A large
amount of precipitate was formed. The flask was sealed and this precipitate was
aged with vigorous stirring overnight. The mixture was filtered and the cake was
washed with pentane. The combined filtrate was concentrated to ~18 mL and
stored in -20 °C freezer inside the glove box (no precipitation was formed after 2
days in freezer). This solution was used directly in the crotylation reaction
without isolation of the reagent.

Determination of the concentration: a solution of 1.0 mL of the crotylsilane

reagent was diluted with 9 mL CH2CI2. To this solution was added 185 mg

258

”1

 

4-bromobenzaldehyde (1.0 mmol) in one portion. The reaction flask was sealed
with a Teflon stopper and the reaction was stirred at room temperature for 19 h,
before being quenched with saturated NaHCOo and extracted with CH2CI2. After
drying over M9804 and evaporation, the crude material was analyzed by 1H NMR.
The ratio of the residual aldehyde vs. crotylation product was determined to be
1:0.6. Therefore, the conversion was 37%. The concentration of the solution

obtained above was 0.37 M (corresponding to ~65% yield of 6.42).

0Tr 0 0Tr 0H

 

W 6.42 T W

. H v 3 a

OMe CH2C'2 i OMei
6.41 6.43

A solution of 6.42 (9.5 mL, 0.37 M determined above, ~3.5 mmol, 1.17 equiv)
was diluted with 40 mL CH2CI2 and cooled to 0 °C. Upon stirring, a solution of
1.32 g of crude 6.41 (containing DMSO and CH2CI2, 3.0 mmol discounting the
added weight), made via a Swern oxidation of 1.17 g of 6.39 (3.0 mmol), in 7 mL
CH2CI2 was added dropwise. The reaction was warmed to room temperature
and stirred for 1.5 days before being quenched with saturated NaHC03. After
being stirred for 15 min, the mixture was extracted with CH2CI2, dried over
Na2S04 and evaporated. Column chromatography (5:1 hexanes/EtOAc)
afforded 0.87 g of 6.43 as a single diastereomer (containing trace amount of

EtOAc, 64% discounting the added weight of EtOAc). Further elution with

259

t

1:1:0.1 hexanes/EtOAc/Eth afforded 1.61 g of the chiral diamine ligand (100%).
Alcohol 5.43: ref-0.35 (5:1 hexanes/EtOAc); [c.1200 -13.7(c1.05, CH2CI2); 1H NMR .
(500 MHz, CDCI3): 8 7.48-7.50 (m, 5 H), 7.24-7.34 (m, 9 H), 5.57 (ddd, J = 8.5,
10.3, 17.1 Hz, 1 H), 5.04-5.10 (m, 2 H), 3.53-3.55 (m, 1 H), 3.35 (s, 3 H), 3.28 (dt,
J = 10.5, 2.7 Hz, 1 H), 3.03 and 2.93 (d of ABq, 3J = 5.4 and 5.8 Hz, JAB = 8.5 Hz,
2 H), 2.24-2.31 (m, 1 H), 2.15 (s, 1 H), 2.01-2.08 (m, 1 H), 1.54 (ddd, J = 3.9, 10.5.
14.2 Hz, 1 H), 1.25 (ddd, J = 2.4, 10.0, 14.4 Hz, 1 H), 1.15 (d, J = 5.5 Hz, 3 H),
1.02 (d, J = 5.8 Hz, 3 H); 13C NMR (125 MHz, CDCI3): 8 144.5, 140.1, 128.8,
127.5, 125.7, 115.1, 85.1, 80.0, 734,591, 55.9, 40.3, 31.4, 30.4, 17.2, 17.1; IR
(neao:3457,3059,2959,2928,1491,1449,1088,1032,915,754,741,708,533
cm“; LRMS (ESI): m/e 457 ([M+Na]*), 243; HRMS (ESI) m/e calcd for

[C3oH3503+Na]+ 467.2562, found 467.2551. This compound does not store well

 

in CDC/3.
L 0
Ph
0" 9H DCC, DMAP, 5M3 0Tr OAK:

. \ CH Cl 7 i we

— OM65 2 2 i r. \
= 0Me=
5.43 6.47b

To a solution containing 34 mg of 6.43 (77 pmol), 13.1 mg of the chiral acid
(77 pmol, 1.0 equiv), and 17.8 mg DCC (84 pmol, 1.1 equiv) in 1 mL CH2CI2 was

added one crystal of DMAP. The reaction was stirred at room temperature

260

 

 

overnight, before being quenched with saturated NaHCOo, extracted with CH2CI2,
dried over MgS04 and evaporated. Column chromatography (5:1
hexanes/EtOAc) afforded 34 mg of 6.47b (75%, containing trace EtOAc); Rr~0.39
(5:1 hexanes/EtOAc); [0t]200 +145 (c 1.00, CHCI3); 1H NMR (500 MHz, CDCI3):
(Due to the large number of aromatic protons, the residual peak of CDC/3 was not
observed. Therefore, the chemical shift in this spectrum was referenced to the
residual peak of acetyl methyl protons of EtOAc at 2. 05 ppm): 8 7.46-7.49 (m, 6 H),
7.41-7.43 (m, 2 H), 7.28-7.33 (m, 9 H), 7.23-7.26 (m, 3 H), 5.51 (ddd, J = 8.5, 10.3,
16.9 Hz, 1 H), 5.08 (dd, J = 3.2, 9.3 Hz, 1 H), 4.90-4.94 (m, 2 H), 4.75 (s, 1 H),
3.40 (s, 3 H), 3.29 (s, 3 H), 3.28 (dt, overlapped peak, 1 H), 2.99 and 2.91 (d of
ABq, 3J = 5.6 and 6.8 Hz, JAB = 8.5 Hz, 2 H), 2.20-2.27 (m, 1 H), 1.98-2.03 (m, 1
H), 1.61 (ddd, J = 3.9, 10.7, 14.4 Hz, 1 H), 1.14 (ddd, J: 2.0, 10.0, 13.7 Hz, 1 H),
0.93 (d, J = 5.5 Hz, 3 H), 0.59 (d, J = 5.8 Hz, 3 H); 13C NMR (125 MHz, CDCI3): 8
170.3, 144.4, 139.1, 136.5, 128.8, 128.6, 128.5, 127.6, 127.3, 126.8, 115.6, 86.0.
82.4, 78.3, 75.2, 68.9, 57.2, 57.0, 39.2, 32.5, 30.3, 16.7, 16.3; IR (neat): 3061,
2930, 2826, 1752, 1491, 1449, 1198, 1179, 1100, 1075, 747, 708, 698, 633 cm";
LRMS (ESI): m/e 615 ([M+Na]+), 243, 83; HRMS (ESI) m/e calcd for
[C39H4405+Na]+ 615.3086, found 615.3073. This compound does not store well

in CDC/3.

261

'L‘]

 

 

0
Ph 0

 

H0 Ph
OT’ 9“ DCC, DMAP, OMe or O
. : \ CH Cl 7 r 0M9
3 OMei 2 2 i i \
5 OMeE
5.43 6.47a

The same operation procedure was applied to 34 mg of 6.43 (77 pmol), 13.1
mg of the chiral acid (77 umol, 1.0 equiv), and 17.8 mg DCC (84 pmol, 1.1 equiv)
in 1 mL CH2CI2 with one crystal of DMAP. The reaction afforded 32 mg of 6.47a
(containing 1 mg ether, ~70% discounting the added weight); Rr-0.43 (5:1
hexanes/EtOAc); [81200 -19.9 (c 1.00, CHCIo); 1H NMR (500 MHz, CDCIo): (Due to
the large number of aromatic protons, the residual peak of CDC/3 was not
observed. Therefore, the chemical shift in this spectrum was referenced to the
residual peak of acetyl methyl protons of EtOAc at 2. 05 ppm): 8 7.43-7.46 (m, 6 H),
7.38-7.40 (m, 2 H), 7.29-7.32 (m, 6 H), 7.23-7.26 (m, 3 H), 7.17-7.21 (m, 2 H),
7.09-7.12 (m, 1 H), 5.63 (ddd, J = 8.5, 10.3, 17.3 Hz, 1 H), 5.06 (dd, J = 3.2, 8.5
Hz, 1 H), 5.00-5.05 (m, 2 H), 4.74 (s, 1 H), 3.41 (s, 3 H), 3.19 (dt, J= 10.7, 2.7 Hz,
1 H), 3.16 (s, 3 H), 2.84 and 2.70 (d of ABq, 3J = 5.4 and 7.3 Hz, JAB = 8.8 Hz, 2 H),
2.35-2.43 (m, 1 H), 1.78-1.85 (m, 1 H), 1.22 (ddd, J = 3.6, 10.7, 14.1 Hz, 1 H),
~0.92 (ddd, overlapped peak, 1 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.84 (d, J = 6.8 Hz, 3
H); 130 NMR (125 MHz, CDCI3): 8 170.5, 144.5, 139.3, 136.3, 128.8, 128.5, 128.3,
127.6, 127.3, 126.8, 115.7, 86.0, 82.7, 78.3, 75.6, 68.9, 57.4, 56.8, 39.0, 32.4,

30.1, 16.7, 16.5; IR (neat): 3061, 2930, 2826, 1752, 1734, 1491, 1449, 1177,

262

._ h,

 

 

1103, 747, 708, 698, 633 cm'1; LRMS (ESI): m/e 615 ([M+Na]*), 243; HRMS (ESI)
m/e calcd for [C39H4405+Na]+ 615.3086, found 615.3088. This compound does

not store well in CDC/3.

 

OT’ 9” M0MC|,'Pr2NEt,DMAP 0Tr 9M0”
: \ CH2CI2 ' . , \

OMe: 0Me=

5.43 5.44

To a solution of 1.71 g of 6.43 (3.84 mmol) and 50 mg DMAP (0.41 mmol, ~10
mol%) in 15 mL CH2CI2 was added 2.0 mL diisopropylethylamine (1.48 g, 11.5
mmol, 3 equiv, freshly distilled). The mixture was cooled to 0 °C and dropwise
Charged with 580 pL MOMCI (615 mg, 7.64 mmol, 2 equiv). The reaction was
allowed to warm to room temperature and stir for 1.5 days. Conversion of this
reaction varied from run to run. The reaction was quenched with saturated
NaHC03, extracted with CH2CI2, dried over M9804 and evaporated. Column
chromatography (8:1 hexanes/EtOAc) afforded 1.58 g of 6.44 (84%) and 135 mg
of recovered 6.43 (~8%). MOM acetal 6.44: Rr~0.30 (8:1 hexanes/EtOAc); [a]200
+182 (5 1.00, CH2CI2); 1H NMR (500 MHz, CDCI3): 8 7.42-7.44 (m, 6 H),
7.18-7.28 (m, 9 H), 5.67 (ddd, J = 8.5, 10.3, 17.1 Hz, 1 H), 4.96-5.02 (m, 2 H),
4.78 and 4.59 (ABq, JAB = 6.6 Hz, 2 H), 3.57 (dd, J = 2.0, 8.3 Hz, 1 H), 3.37 (s, 3
H), 3.26 (s, 3 H), 3.27 (dt, overlapped peak, 1 H), 2.99 and 2.84 (d of ABq, 3J =

5.4 and 7.3 HZ, JAB = 8.7 HZ, 2 H), 2.22-2.29 (m, 1 H), 1.95-2.02 (m, 1 H), 1.59

263

 

 

(ddd, J = 3.9, 105,144 Hz, 1 H), 1.19 (ddd, J = 20,100,142 Hz, 1 H), 1.09 (d, J
= 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H); 13C NMR (125 MHz, CDCI3): 8 144.5,
141.1, 128.8, 127.5, 125.7, 114.8, 97.4, 86.1, 80.7, 79.5, 59.1, 55.9, 55.0, 40.5,
33.3, 30.7, 17.4, 17.2; IR (neat): 3058, 2919, 1449, 1095, 1032, 918, 754, 747,
708, 533 cm‘1; LRMS (ESI): m/e 511 ([M+Na]*), 243; HRMS (ESI) m/e calcd for

[C32H4o04+Na]+ 511.2824, found 511.2825. This compound does not store well

 

in CDC/3.
OTr QMOM PPTS, MeOH OH QMOM
: : \ t ; s \
5 OMei 5 OMei
6.44 6.45

To a solution of 2.42 g of 6.44 (4.92 mmol) in 35 mL MeOH (no drying or
purification needed) was added 617 mg PPTS (2.46 mmol, 0.5 equiv) at room
temperature in one portion. The reaction was stirred for 21 h and then quenched
with saturated NaHCOo. Extraction with ether was followed by drying over
M9804 and evaporation. Column chromatography (1:2 hexanes/EtOAc)
afforded 1.11 g of 6.45 (92%); RrrO.50 (1:2 hexanes/EtOAc); [0t]200 +8.2 (5 1.29,
CHCI3); 1H NMR (500 MHz, CDCI3): 8 5.66 (ddd, J = 8.8, 10.3, 17.1 Hz, 1 H),
4.98-5.03 (m, 2 H), 4.81 and 4.62 (ABq, JAB = 6.6 Hz, 2 H), 3.63 (dd, J = 1.5, 8.8
Hz, 1 H), 3.49 and 3.39 (d of ABq, 3J = 5.2 and 5.9 Hz, JAB = 11 Hz, 2 H), 3.39 (s,

3 H), 3.33 (s, 3 H), ~3.31 (dt, overlapped peak, 1 H), 2.24-2.32 (m, 1 H), 2.23 (br,

264

 

 

 

1 H), 1.74 (sext, J = 5.4 Hz, 1 H), 1.50 (ddd, J = 5.5, 10.0, 15.1 Hz, 1 H), 1.37 (ddd,
J =1.5,7.1, 14.9 Hz, 1 H), 1.11 (d, J = 5.5 Hz, 3 H), 0.91 (d, J = 6.8 Hz, 3 H); 13C
NMR (125 MHz, CDCI3): 8 140.9, 115.1, 97.3, 82.2, 78.6, 58.5, 55.5, 55.0, 40.9,
33.8, 33.4, 17.7, 17.5; IR (neat): 3443, 2932, 1542, 1458, 1381, 1145, 1098,1034,
918 cm"; LRMS (CI, MeCH): m/e 247 ([M+H]*), 215, 197, 183, 153, 129; HRMS

(CI, methane) m/e calcd for [C13H2504+H]" 247.1909, found 247.1918.

 

. _ \ T \

: a CH Cl ; ;;

= 0Me= 2 2 = 0Me=
6.45 6.46

To a solution of 262 mg PPho (1 mmol, 2 equiv) in 5 mL CH2CI2 was added 82
mg imidazole (1.2 mmol, 2.4 equiv) followed by 272 mg l2 (1.07 mmol, 2.14 equiv).
The mixture turned to a yellow suspension upon stirring, which became red after a
few minutes. A solution of 121 mg of 6.45 (0.5 mmol) in 2 mL CH2CI2 was added
to the mixture, which was then stirred in dark environment for 2 h. The reaction
mixture was concentrated and purified by chromatography (6:1 hexanes/EtOAc).
The fractions collected were contaminated with l2 and therefore were stirred over
solid Na2S203 before evaporation to afford 125 mg of 6.46 (71%) as slightly yellow
oil (This reaction unexpectedly resulted in some epimerization at C14171 and an
optical rotation value of pure sample needs to be updated); Rr~0.48 (6:1

hexanes/EtOAc); 1H NMR (500 MHz, CDCI3): 8 5.55 (ddd, J = 8.8, 10.3, 17.2 Hz,

265

 

 

1 H), 5.03 (ddd, J = 1.0, 1.6, 17.2 Hz, 1 H), 4.98-5.01 (m, 1 H), 4.81 and 4.62 (ABq,
JAB = 6.7 Hz, 2 H), 3.60 (dd, J = 2.0, 8.8 Hz, 1 H), 3.40 (s, 3 H), 3.30 (s, 3 H),
3.25-3.28 (m, 2 H), 3.14 (half of d of ABq, can be viewed as dd, 3J = 6.3 Hz, JAB =
9.5 Hz, 1 H), 2.23-2.31 (m, 1 H), 1.68-1.74 (m, 1 H), 1.65 (ddd, J = 3.7, 10.4, 14.2
Hz, 1 H), 1.29 (ddd, J = 2.0,9.4,13.9 Hz, 1 H), 1.10 (d, J = 6.7 Hz, 3 H), 0.93 (d, J
= 6.6 Hz, 3 H); 13C NMR (125 MHz, CDCI3): 8 140.8, 115.0, 97.4, 80.9, 78.8, 57.0,
56.1, 40.7, 36.1, 31.4, 20.0, 19.0, 17.6; IR (neat): 2961, 1642, 1458, 1379, 1196,
1154, 1101, 1034, 918 cm"; LRMS (CI, MeOH): m/e 325 ([M-MeOHi-Hj“), 301,
239, 227, 185, 169, 129; HRMS (CI, NH3) m/e calcd for [C12,H25|03+H]+ 357.0927,

found 357.0930.

 

. , Bpin
Q HBpln, [lr(OMe)(cod)]2-d bpy l
Cl / B pentane Q
r Cl Br
2.1a 2.28

Following general procedure A outlined in Chapter 7 (page 149), 705 pL of
2.1a (1.15 g, 6 mmol) was borylated with 1.75 mL HBpin (1.54 g, 12 mmol, 2
equiv), 20 mg [lr(OMe)(cod)]2 (0.03 mmol, 0.5 mol%) and 16.1 mg d‘bpy (0.06
mmol, 1.0 mol%) in 6 mL pentane at room temperature for 18 h (open to nitrogen)
and then 70 °C for 2 h (sealed tube). After being cooled to room temperature,
the reaction was carefully quenched with MeOH and concentrated. The residual

was passed through a silica plug (CH2CI2) to afford 1.85 g of 2.2a as colorless oil

266

 

.‘c,

 

(97%), which solidified upon standing at room temperature; mp 52-54 °C; 1H NMR
(300 MHz, CDCIg): 8 7.78 (dd, J = 0.8, 1.9 Hz, 1 H), 7.67 (dd, J = 0.8, 1.9 Hz, 1 H),
7.57 (t, J = 1.9 Hz, 1 H), 1.32 (s, 12 H); 13C NMR (125 MHz, CDClo): 8 135.6,
134.9, 133.8, 133.1, 122.6, 84.5, 24.8; IR (neat): 2980, 1551, 1404, 1339, 1144,

868, 770, 700 cm"; LRMS (El): m/e 315 (M*), 301, 230, 215, 85, 58,41.

 

 

 

0H
Bpin 1. Pd2dbag, xantphos, 6.5 0 O
A Cs2C03, DME Cl N’j/j
. l . . = H
I 2. Filtration MeO
CIM Br 3. oxone, acetone
2.2a 6.4 OTIPS

Following general procedure E outlined in Chapter 7 (page 152), the
amidation was performed with 1.15 g of 2.2a (3.6 mmol, 1.5 equiv), 920 mg of 6.5‘
(2.4 mmol), 44 mg Pd2dba3 (0.048 mmol, 2 mol%), 83 mg xantphos (0.144 mmol,
6 mol%) and 1.10 g Cs2C03 (3.36 mmol, 1.4 equiv) in 9 mL DME at 95-100 °C for
5 h. After filtration through a silica pad and eluting with acetone, the oxidation
was performed with a solution of 3.3 g oxone (5.36 mmol, 2.24 equiv) in 16 mL
water and 24 mL acetone for 40 min, and worked up as described. Column
Chromatography (12:1 —> 6:1 CH2Cl2/EtOAc) afforded 0.24 g of the Suzuki
dimerization product (16%) as well as 0.90 g of the desired 6.4 (73%).

Desired product 6.4: White solid, mp 106.5-108 °C; Rr~0.42 (9:1

CH2CI2/Et0Ac); [04200 -12.7° (c 1.02, acetone); 1H NMR (500 MHz, acetone-do): 8

267

 

I /OH 8.94 (br, 1 H), 8.69 (s, 1 H), 7.30 (t, J = 1.8 Hz, 1 H),
l , \\ O

,crAv/Aum 7.28 (t, J = 2.0 Hz, 1 H), 5.55 (t, J = 2.0 Hz, 1 H), 5.42
I MeOJ

i (tq, J = 7.5, 1.5 Hz, 1 H), 5.02-5.03 (m, 1 H), 4.91492
Vows

 

(m, 1 H), 4.40 (d, J = 5.9 Hz, 1 H), 3.45 (s, 3 H), 3.27 '

(ddd, J = 3.0, 5.9, 8.5 Hz, 1 H), 2.25-2.32 (m, 2 H), 1.88 (br, 3 H), 1.77 (br, 3 H),

 

1.67 (dddd, J = 3.2, 7.3, 9.0, 14.2 Hz, 1 H), 1.33 (dddd, J = 6.3, 8.5, 8.5, 14.6 HZ,

1 H), 1.05-1.12 (m, 21 H); 13C NMR (125 MHz, acetone-do): 8 168.5, 159.3, 145.2,

 

142.5, 137.0, 134.8, 132.9, 113.1, 111.8, 111.2, 105.2, 84.6, 77.4, 58.8, 29.7,
25.3, 19.4, 18.47, 18.45, 13.2, 12.8; IR (neat): 3200-3300 (br), 2944, 2867, 1551.
1501, 1539, 1429, 1098, 884, 579 cm"; LRMS (El): m/e 455 ([MJ’Frr), 434, 253,
227, 157, 115, 89, 75, 59. Anal. Calcd for C27H44CIN04SI: C, 53.55; H, 8.59; N,

2.75. Found C, 63.45; H, 8.83; N, 2.64.

 

Suzuki dimerization product: slightly yellow solid,

 

r J

CIWOH
l 0 mp 133-135 °C; ref-0.57 (9:1 CH2CI2/Et0Ac); in)?"D
/\ o
. Cl Mn ' / -122 (c 0.95, acetone); 1H NMR (500 MHz, acetone-do):
I H
I M60 8 9.17 (br, 1 H), 9.00 (s, 1 H), 7.95 (t, J = 1.9 Hz, 1 H),
I OTIPS
l 7.89 (t, J =19 Hz, 1 H), 7.33 (t, J =19 Hz, 1 H), 7.13 (t,

 

 

J = 1.7 Hz, 1 H), 7.04 (dd, J = 1.7, 2.2 Hz, 1 H), 5.90 (t, J = 2.0 Hz, 1 H), 5.51 (tq, J
= 7.3, 1.2 Hz, 1 H), 5.02-5.03 (m, 1 H), 4.91-4.92 (m, 1 H), 4.40 (d, J = 5.9 Hz, 1

H), 3.47 (s, 3 H), 3.28 (ddd, J = 2.9, 5.9, 8.8 Hz, 1 H), 2.29-2.35 (m, 2 H), 1.92 (br,

268

3 H), 1.77 (br, 3 H), 1.57 (dddd, J = 2.5, 7.0, 9.0, 13.7 Hz, 1 H), 1.33 (dddd, J = 5.1,
8.2, 8.2, 14.1 Hz, 1 H), 1.05-1.12 (m, 21 H); 13c NMR (125 MHz, acetone-do): 8
158.5, 159.7, 145.3, 143.3, 142.4, 142.3, 137.5, 135.7, 135.2, 132.8, 1221,1197,
118.9, 117.5, 115.9, 113.5, 113.1, 84.7, 77.3, 58.8, 29.8, 25.3, 19.4, 18.48, 18.45,
13.2, 12.8; IR (neat): 3300 (br), 2945, 2867, 1551, 1598, 1574, 1535, 1431, 1107.
884, 843, 685 cm"; LRMS (El): m/e 575 ([M-‘Pr]*), 544, 392, 334,253,227, 157,

145, 115; HRMS (El) m/e calcd for [033H47CI2NO48i]+ 619.2651, found 619.2678.
OH OH

CVi::1\Nti%x\ CVJ::1\N():/

l TBAF

H . = H
Meo THF MeO
5.4 OTIPS 6.4a OH

To a solution of 0.99 g of 6.4 (1.94 mmol) in 6 mL THF at 0 °C was added

 

dropwise 4 mL of commercial TBAF solution (1.0 M in THF, 4 mmol, ~2 equiv).
After 2.5 h, 2 mL of additional TBAF solution (1.0 M in THF, 2 mmol, ~1 equiv)
was added and the reaction continued overnight. The reaction was judged
complete after 16.5 h. The reaction was then quenched with saturated NaHC03
and extracted with EtOAc. The combined organics were washed with 5% CuS04
followed by 1 M HCI before being dried over M9804 and evaporated. Column
chromatography (1:1.5 hexanes/EtOAc) afforded 0.69 g of 6.4a as a glass-like

material (100%); R)~0.38 (1 :1 .5 hexanes/EtOAc); [alzoo +3.6 (c 1.14, acetone); 1H

269

 

in

 

NMR (500 MHz, acetone-do): 8 8.99 (br, 1 H), 8.72 (s, 1 H), 7.31 (t, J = 1.7 Hz, 1

H), 7.28 (t, J = 2.0 Hz, 1 H), 5.55 (t, J = 2.0 Hz, 1 H), 5.41 (tq, J = 7.3, 1.5 Hz, 1 H),

4,99 (m, 1 H), 4.84 (m, 1 H), 4.04 (m, 1 H), 3.75 (d, J = 4.2 HZ, 1 H), 3.42 (s, 3 H), '

3.28 (ddd, J = 4.2, 5.1, 7.8 Hz, 1 H), 2.24-2.30 (m, 2 H), 1.88 (br, 3 H), 1.73 (br, 3
H), 1.57 (dddd, J = 4.2, 5.5, 9.5, 13.9 Hz, 1 H), 1.45 (dddd, J = 5.3, 7.8, 9.0, 14.2
Hz, 1 H); 13C NMR (125 MHz, acetone-do): 8 168.6, 159.3, 145.8, 142.5, 136.8,
134.8, 133.0, 112.5, 111.8, 111.3, 105.2, 83.2, 77.4, 58.6, 30.2, 25.0, 18.5, 12.8;
IR (neat): 3297 (br), 2932, 1551, 1597, 1539, 1429, 1289, 1159, 1098, 839, 577
cm"; LRMS (El): m/e 353 ([MJ’Prr), 282, 224, 143, 95; HRMS (El) m/e calcd for

[C1oH24CINO4]+ 353.1394, found 353.1392.

 

OH
ll \ O
1. t-BuLi, ether / /
' QMOM 2. B-OMe-BBN, THF 9 H
W 3. Pd(0Ac)2, S-phos,CsF V “ MeO
; 0Me= 6.4a M00 .oOMOM
6.46 “v": OH
)
6.2

The iodide 6.46 (120 mg, 0.34 mmol, 1.15 equiv) was first dried by pumping
down from benzene before being dissolved in 2 mL dry ether. After being cooled
to -78 °C, the solution was charged with 0.42 mL t-BuLi (titrated to be 1.6 M in
pentane, 0.68 mmol, 2 equiv per iodide) via syringe. After a few minutes, 0.82

mL B-OMe-BBN (1 M in hexanes, 0.82 mmol, 2.8 equiv) was added, followed by 2

270

 

mL THF (precipitate formation). The mixture was stirred at -78 °C for a few
minutes and warmed to room temperature (precipitation dissolved). To this
mixture were sequentially added ~150 mg CsF (~1 mmol, 3.4 equiv), 104 mg of
6.4a (0.294 mmol, 6.4a was not very soluble), ~3.5 mg Pd(OAc)2 (15.6 pmol, 5.3
mol%), 12.7 mg S-Phos (31 pmol, 10.5 mol%), and 2 mL THF. The reaction was
heated to 70-75 °C. Every 3 h, an additional batch of ~3.5 mg Pd(OAc)2 (15.6
pmol, 5.3 mol%) and 12.7 mg S-Phos (31 pmol, 10.5 mol%) was added. This
re-addition was repeated 3 times so that the total loads of Pd and ligand were 20
mol% and 40 mol%, respectively. After the last addition of Pd and ligand, the
reaction was allowed to stir overnight. The reaction mixture was cooled to room
temperature and diluted with saturated NaHC03 before being extracted with
EtOAc. The combined organics were dried over M9804 and evaporated.
Column chromatography (1:1.5 hexanes/EtOAc) recovered ~77 mg of impure
6.4a (estimated to be ~45—50% recovery) at Rr~0.41. A lower fraction at Rr~0.29
was re-chromatographed (1.221 —+ 1:1 hexanes/acetone) to afford ~8 mg of
impure 6.2 (~5%) as a glass; R)~0.46 (1 .2:1 hexanes/acetone). 1H NMR (500 MHz,
acetone-d5): 8 8.78 (br, 1 H), 8.13 (s, 1 H), 7.28 (t, J = 2.0 Hz, 1 H), 6.90 (t,
overlapping, 1 H), 6.37-6.41 (m, 2 H), 5.77 (ddd, J = 8.8, 10.3, 17.4 Hz, 1 H),
496-5.06 (m, 3 H), 4.84 (apparent t, J = 1.6 Hz, 1 H), 4.75 and 4.56 (ABq, JAB =

6.3 Hz, 2 H), 4.04 (t, J = 5.2 Hz, 1 H), 3.75 (d, J = 4.5 Hz, 1 H), 3.82 (dd, J = 2.2,

271

 

 

 

 

8.6 Hz, 1 H), 3.43 (s, 3 H), 3.36 (dt, J= 10.5, 2.2 Hz, 1 H), 3.32 (s, 3 H), 3.29 (s, 3
H), 3.26-3.30 (m, 1 H), 2.53 (half of d of ABq, can be viewed as dd, 3J = 5.9 Hz,
JAB = 13.2 Hz, 1 H), 2.24-2.31 (m, 4 H), 1.88 (br, 3 H), 1.73 (br, 3 H), 1.67 (ddd, J
= 3.4, 10.2, 14.2 Hz, 1 H), 1.58-1.64 (m, 1 H), 1.43-1.51 (m, 1 H), 1.25-1.30 (m, 1
H), 1.23 (ddd, J = 2.5, 10.3, 14.3 Hz, 1 H), 1.08 (d, J = 6.7 Hz, 3 H), 0.80 (d, J =
6.6 Hz, 3 H); 13C NMR (125 MHz, acetone-d5): 8 168.3, 158.2, 146.9, 143.7, 142.5,
141.3, 135.9, 133.3, 114.9, 112.6, 112.5, 112.1, 105.4, 97.8, 83.2, 81.5, 79.7,
77.4, 58.6, 57.0, 56.0, 45.5, 41.5, 37.0, 32.0, 30.2, 25.0, 19.2, 18.6, 17.9, 12.9;
LRMS (anionic ESI): m/e 1192, 1094 ([2M-H]'), 644, 582 ([M+Cl]'), 546 ([M-H]'),
450, 352; HRMS (anionic ESI) m/e calcd for [C31H49N07]' 547.3509, found
547.3514.

8.3 Experimental Details and Characterization Data for the Compounds

Related to the Model Suzuki Coupling

 

OH OBn
D o BnBr, K2003 _ O 0
C1 NV DMF Cl NM
H H
5.4n

To a solution of 158 mg of 5.4n (0.7 mmol) in 3 mL DMF (distilled over M9804)
was added 106 mg K2C03 (0.77 mmol, 1.1 equiv) followed by 129 mg BnBr (0.74
mmol, 1.05 equiv). The reaction was stirred at room temperature overnight.

TLC indicated incomplete consumption of 5.4n. Thus another 50 mg K2CO3

272

 

(0.36 mmol, 0.5 equiv) and 65 mg BnBr (0.38 mmol, 0.54 equiv) were added.
After another 2 h at room temperature, 5.4n was completely consumed. The
reaction was quenched with saturated Na2C03 and stirred for 30 min. The
mixture was poured to saturated NaHCOa and extracted with EtOAc. The
combined organics were dried over M9804 and concentrated. Column
chromatography (5:1 hexanes/EtOAc) afforded 210 mg of the desired product as
colorless oil (93%); R)~0.18 (5:1 hexanes/EtOAc). 1H NMR (500 MHz, acetone-d5):
8 7.31-7.41 (m, 6 H), 7.30 (t, J = 2.0 Hz, 1 H), 7.09 (t, J = 1.8 Hz, 1 H), 6.71 (t, J =
2.1 Hz, 1 H), 6.49 (qq, J = 1.5, 6.8 Hz, 1 H), 5.02 (s, 2 H), 1.91 (br, 3 H), 1.80 (dq,
J = 6.8, 1.0 Hz, 3 H); 13c NMR (125 MHz, CDCI3): 8 187.5, 159.8, 140.0, 136.3,
135.0, 132.6, 131.8, 128.6, 128.1, 127.5, 112.5, 111.3, 104.7, 70.2, 14.1, 12.5; IR
(neat): 3303, 1663, 1601, 1536, 1456, 1426, 1277, 1175, 844, 735, 696 cm'1;

LRMS (El): m/e 315 (M+), 232, 91, 83, 55.

 

oH OTIPS
I '\ o TIPSCI,DMAP_ o
' ll ' I
CI / NV DMF cu NV
H H
5.4n

To a solution of 125 mg of 5.4n (0.55 mmol) in 2 mL DMF (distilled over
MgSO4) was added 101 mg DMAP (0.83 mmol, 1.5 equiv). While stirring, 0.13
mL TIPSCI (117 mg, 0.61 mmol, 1.1 equiv) was added dropwise. The reaction

was stirred at room temperature overnight before being partitioned between half

273

 

 

saturated NaHC03 and EtOAc. The layers were separated and the aqueous
layer was extracted with EtOAc. The combined organics were dried over M9804
and evaporated. Column chromatography (8:1 hexanes/EtOAc) afforded 197
mg of the desired product (containing 4 mg acetone, corresponding to 92%
discounting the added weight of acetone) as a white solid; mp 82-83 °C; Rr-0.34
(8:1 hexanes/EtOAc). 1H NMR (500 MHz, CDCI3): 8 7.29 (brs, 1 H), 7.14 (t, J = 2.0
Hz, 1 H), 7.09 (t, J = 2.0 Hz, 1 H), 6.60 (t, J = 2.1 Hz, 1 H), 6.48 (qq, J = 1.4, 6.8
Hz, 1 H), 1.91 (quint, apparent t, J = 1.2 Hz, 3 H), 1.79 (dq, J = 6.8, 1.0 Hz, 3 H),
1.22-1.28 (m, 3 H), 1.07-1.09 (m, 18 H); 13c NMR (125 MHz, CDCl3): 8 187.4,
157.2, 139.8, 134.6, 132.7, 131.7, 115.9, 112.6, 109.75, 109.68, 17.9, 14.1, 12.6.
12.5; IR (neat): 3299, 2946, 2869, 1663, 1599, 1586, 1539, 1449, 1426, 1287,
1183, 1015, 884, 768, 685 cm"; LRMS (El): m/e 381 (W), 338, 310, 83, 55.

HRMS (El): m/e calcd for [ConngISINOzsi]+ 381.1891, found 381.1888.

 

OH OAc
D o NaOH,Ac20_ m 0
Cl / NV ’PrOH/water CI / NV
H H

5.4n

A solution of 40 mg of NaOH (1 mmol, 2 equiv) in 0.7 mL water was mixed
with a solution of 115 mg of 5.4n (0.5 mmol) in 3.4 mL iso-propanol (no distillation
or drying needed). To this mixed solution was added dropwise 140 mg Ac20

(1.37 mmol, 2.7 equiv). The mixture was stirred at room temperature for 30 min

274

 

 

before being partitioned between half saturated NaHCOa and EtOAc. The layers
were separated and the aqueous layer was extracted with EtOAc. The
combined organics were dried over M9804 and evaporated. Column
chromatography (3:1 hexanes/EtOAc) afforded 138 mg of the desired product
(containing 15 mg EtOAc, corresponding to 92% discounting the added weight of
EtOAc) as oil. Rr~0.26 (3:1 hexanes/EtOAc), 1H NMR (500 MHz, CDCI3): 8 7.46
(brs, 1 H), 7.40 (t, J: 1.8 Hz, 1 H), 7.35 (t, J = 2.0 Hz, 1 H), 6.83 (m, 1 H), 6.48 (qq,
J = 1.5, 6.9 Hz, 1 H), 2.26 (s, 3 H), 1.89 (br, 3 H), 1.79 (dq, J = 6.8, 0.7 Hz, 3 H);
13C NMR (125 MHz, CDCI3): 8 168.9, 167.4, 151.3, 139.8, 134.8, 132.5, 132.1,
117.6, 117.2, 111.6, 21.0, 14.1, 12.4; IR (neat): 3320, 2926, 1771, 1667, 1597.
1534, 1458, 1419, 1204, 1159, 1020 cm"; LRMS (El): m/e 267 (M”), 225, 143,83,

55. HRMS (El): m/e calcd for [C13H14CIN03]+ 267.0662, found 287.0883.

 

OTIPS OTIPS
Q o Boc20, DMAP Et3N 03:
H

To a solution of 380 mg of starting material (1 mmol) and 120 mg DMAP (1
mmol, 1 equiv) in 23 mL CH2CI2 was added 102 mg Eth (1 mmol, 1 equiv).
While stirring, 330 mg Boc20 (1.5 mmol, 1.5 equiv) was added in one portion.
The reaction was stirred at room temperature overnight. Upon completion, the

reaction was poured into water. The layers were separated and the aqueous

275

 

 

layer was extracted with EtOAc. The combined organics were dried over MgSO4
and evaporated. Column chromatography (10:1 ——> 7:1 hexanes/EtOAc) afforded
400 mg of the desired product (83%) as thick oil. R)~0.52 (7:1 hexanes/EtOAc).
1H NMR (500 MHz, CDCI3): 8 6.78 (t, J = 2.1 Hz, 1 H), 6.74 (t, J = 1.9 Hz, 1 H),

6.53 (t, J = 2.0 Hz, 1 H), 6.32 (qq, J = 1.5, 7.1 Hz, 1 H), 1.88 (quint, apparent t, J =

1.2 Hz, 3 H), 1.77 (dq, J = 7.1, 1.2 Hz, 3 H), 1.41 (s, 9 H), 1.18-1.25 (m, 3 H),

1.08-1.09 (m, 18 H); 13c NMR (125 MHz, CDCI3): 8 173.9, 158.9, 152.9, 140.6,
134.9, 134.4, 133.1, 120.4, 119.3, 117.8, 83.1, 27.8, 17.9, 14.0, 13.1, 12.6; IR
(nea0:2948,2869,1740,1692,1595,1580,1445,1291,1250,1154,884,683
cm‘1; LRMS (El): m/e 381 ([M-Boc+H]+), 338, 282,83, 57. HRMS (El): m/e calcd
for [C25H40CINO4Si]* 481.2415, found 481.2415.

OTIPS OTIPS
o NaH. SEMCI A o

H SEM

To a suspension of 30 mg NaH (95%, 1.2 mmol, 1.2 equiv) in 20 mL THF was

 

slowly added a solution of 380 mg of starting material in 15 mL THF. Upon being
cooled to 0 °C, 183 mg SEMCI (1.1 mmol, '1 .1 equiv) was added dropwise. The
ice bath was removed and the reaction mixture was allowed to warm to room
temperature. After 5.5 h, another ~30 mg NaH (95% dry, 1.2 mmol, 1.2 equiv)

and 183 mg SEMCI (1.1 mmol, 1.1 equiv) were introduced and the reaction

276

“it

 

 

continued overnight. Water was added to quench the reaction, and the product
was taken into EtOAc. The combined organics were dried over M9804 and 1
evaporated. Column chromatography (10:1 —» 7:1 hexanes/EtOAc) afforded 392
mg of the desired product (77%) as thick oil along with 39 mg of impure starting
material (< 10%). Product: Rr-0.45 (7:1 hexanes/EtOAc). 1H NMR (500 MHz,
CDCl3): 8 6.80 (t, J = 1.8 Hz, 1 H), 6.74 (dd, J = 1.8, 2.2 Hz, 1 H), 6.57 (t, J = 2.0
Hz, 1 H), 5.85 (qq, J = 1.6, 7.0 Hz, 1 H), 5.07 (s, 2 H), 3.58-3.61 (m, 2 H), 1.62
(quint, apparent t, J = 1.2 Hz, 3 H), 1.53 (dq, J = 7.0, 1.2 Hz, 3 H), 1.17-1.24 (m, 3
H), 1.05-1.08 (m, 18 H), 0.90-0.94 (m, 2 H), -0.02 (s, 9 H); 13c NMR (125 MHz,
CDCI3): 8 173.4, 156.9, 145.2, 134.6, 132.3, 131.8, 119.4, 118.7, 116.9, 77.8.
66.0, 18.1, 17.8, 13.9, 13.5, 12.5, -1.4; IR (neat): 2950, 2869, 1669, 1593, 1576,
1447, 1306, 1250, 1073, 860, 837, 762,693 cm"; LRMS (El): m/e 511 (M+), 453,
438, 410, 336, 280, 83, 73, 55. HRMS (El): m/e calcd for [Cst46CIN038i2]+
511.2705, found 511.2696.

OAc OAc

Q 0 BOCzo, DMAP, Et3N‘ m 0

| ' l

CI NV CH2CI2 C. / NV
H

300

 

To a solution of 147 mg of starting material (0.55 mmol) and 81 mg DMAP
(0.66 mmol, 1.2 equiv) in 10 mL CH20l2 was added 67 mg Et3N (0.66 mmol, 1.2

equiv). While stirring, 218 mg Boc20 (1.0 mmol, 1.8 equiv) was added in one

277

portion. The reaction was stirred at room temperature overnight before being
poured into water. The layers were separated and the aqueous layer was
extracted with EtOAc. The combined organics were dried over M9804 and
evaporated. Column chromatography (9:1 —’ 3:1 hexanes/EtOAc) afforded 130
mg of desired product (64%) as thick oil. Rr—0.50 (3:1 hexanes/EtOAc). 1H NMR
(500 MHz, CDCI3): 8 7.07 (t, J = 2.0 Hz, 1 H), 7.03 (t, J = 1.9 Hz, 1 H), 6.86 (t, J =
2.0 Hz, 1 H), 6.35 (qq, J = 1.5, 7.1 Hz, 1 H), 2.25 (s, 3 H), 1.89 (br, 3 H), 1.77-1.80
(m, 3 H), 1.42 (s, 9 H); 13c NMR (125 MHz, CDCI3): 8 173.9, 188.4, 152.8, 151.1,
140.5, 134.9, 134.5, 133.6, 124.9, 121.0, 119.3, 83.6, 27.8, 21.0, 14.1, 13.0; IR
(neat): 2923, 1773, 1738, 1690, 1591, 1445, 1370, 1244, 1198, 1152 cm“; LRMS
(El): m/e 311, 267 ([M+H-Boc]+), 225, 211, 169, 83, 55. HRMS (Cl, NH3): m/e

calcd for [C18H22CINO5+H]+ 368.1265, found 368.1255.

1. 'BuLi, ether, -78 °c

2. l3(o"l=r)3 A W ' Kl-ll=2 A W
3. HCl, then pinacol ' 655 Bp'" MeCN/water 656 BF3K

 

 

6.51 a

To a solution of 0.42 mL pentyl iodide (636 mg, 3.2 mmol) in 17 mL ether at
~78 °C was dropwise added 4 mL 'BuLi (titrated as 1.6 M in pentane, 6.4 mmol, 2
equiv). The mixture was stirred at -78 °C for 20 min before 0.74 mL B(O’Pr)3
(600 mg, 3.2 mmol, 1 equiv) was added dropwise. The mixture was stirred at -78

°C for 20 min and then warmed to room temperature. To this mixture was added

278

 

20 mL 1 M HCI and the mixture was stirred for a few minutes. The layers were
separated and the organic layer was charged with 380 mg pinacol (3.22 mmol, 1
equiv). After being stirred for another few minutes, the mixture was dried over
M9804 and concentrated. GC-MS analysis indicated formation of 6.55. LRMS
(El): m/e 183 ([M-Mel"), 129, 112, 99, 85, 57. It was used directly in the next
reaction without purification.

Crude 6.55 obtained from the previous reaction was dissolved in 19 mL
acetonitrile (no purification or drying needed) in a Teflon vial. To this solution
was added 750 mg KHF2 (9.6 mmol) followed by 2.5 mL water. The reaction
was stirred at room temperature for 1.5 h and the yellow suspension quickly
turned to a bright-yellow clear solution. Solvents were evaporated and the
residue was taken into hot acetone. The supernatant was decanted and
charged with ether. The precipitate was collected by filtration and dried over
high vacuum to afford 290 mg of 6.56 (51 % overall from 6.51 a) was obtained as a
white solid. 1H NMR (500 MHz, acetone-d6): 8 1.20-1.27 (m, 6 H), 0.83 (t, J = 7.0
Hz, 3 H), 0.08-0.14 (m, 2 H); 13C NMR (125 MHz, acetone-d5): 8 36.8, 26.1, 23.6,
14.8; “B NMR (160 MHz, acetone-d5): 8 8.9 (q, apparent d, J = 58 Hz); IR (neat):

3438 (moisture), 2955, 2919, 2849, 1853, 1074, 972, 889 cm".

OBn szdbaa-xantphos, OBn

OH
BnBr, K2CO3‘ TigNHZt CS2003 A \
DMF ' dioxane tl /
Br Br Br Br Br NHTi9

279

 

 

 

To a solution of 1.21 g of 3,5-dibromophenol (4.8 mmol) in 20 mL DMF
(distilled over M9804) was added 1.66 g K2C03 (12 mmol, 2.5 equiv). While
stirring, 1.15 mL BnBr (1.64 g, 9.6 mmol, 2 equiv) was added via syringe. The
mixture was stirred at room temperature overnight. The reaction was quenched
with aqueous Na2C03 and stirred to destroy excess BnBr before being extracted
with CH2Cl2. Drying over M9804 was followed by chromatography purification
(9:1 hexanes/EtOAc) to afford 1.65 g of 3.5-dibromophenyl benzyl ether as a
colorless oil (containing 0.02 g ether, quantitative); Rr-0.50 (8:1 hexanes/EtOAc).
1H NMR (500 MHz, CDCl3): 8 7.31-7.40 (m, 5 H), 7.25 (t, J = 1.6 Hz, 1 H), 7.06 (d,
J = 1.5 Hz, 2 H), 5.01 (s, 2 H); 13c NMR (75 MHz, cock): 8 159.9, 135.7, 128.7,
128.4, 127.5, 126.7, 123.1, 117.3, 70.5; IR (neat): 3077, 3032, 1582, 1577, 1435,
1418, 1377, 1254, 1227, 1013, 873, 744,694,666 cm"; LRMS (El): We 91. Anal.
Calcd for C13H1oBr20: C, 45.65; H, 2.95. Found C, 45.68; H, 3.00.

A round-bottom flask was charged with 246 mg of the benzyl ether (0.72
mmol, 1.2 equiv), 11 mg szdbag (0.012 mmol, 2 mol%), 21 mg xantphos (0.036
mmol, 6 mol%), 60 mg TigNHz (0.6 mmol), and 390 mg Cs2003 (1.2 mmol, 2
equiv). The mixture above was suspended in 2.5 mL dioxane and heated to 100
°C. (The reaction system developed a leak and solvents evaporated after 1.5 h.
Thus an addition 2.5 mL of dioxane was added and the reaction continued for 30

min.) The reaction mixture was cooled to room temperature and poured into 1 M

280

HCI, before being extracted with EtOAc and dried over MgSO...
Chromatography (4.5:1 hexanes/EtOAc) afforded 136 mg of the desired product
(61%) as a thick oil; Rr~0.31 (4.5:1 hexanes/EtOAc). 1H NMR (500 MHz, C00,»): 8
7.30-7.41 (m, 7 H), 7.22 (t, J = 1.7 Hz, 1 H), 6.87 (t, J = 1.9 Hz, 1 H), 6.49 (qq, J =
1.5, 6.8 Hz, 1 H), 5.02 (s, 2 H), 1.91 (br, 3 H), 1.80 (dq, J = 7.1, 1.0 Hz, 3 H); 13C.
NMR (125 MHz, CDCl3): 8 167.5, 159.9, 140.2, 136.3, 132.6, 131.8, 128.6, 128.1,
127.5, 122.7, 115.3, 114.2, 105.3, 70.3, 14.1, 12.5; IR (neat): 3303, 1663, 1597,
1532, 1455, 1422, 1275, 1175, 1046, 845, 735, 696 cm'1; LRMS (El): m/e 359

(M), 91, 83, 55. HRMS (El): m/e calcd for [C13H1gBrN02]* 359.0521, found

 

359.0517.
oH OTIPS
l‘:
C' / l: / TIPSCI,DMAP . _ CI {:11 /
Meo DMF MeO
6.4 OTIPS OTIPS

To a solution of 184 mg of 6.4 (0.36 mmol) in 1.8 mL DMF (distilled over
MgSO4) was added 66 mg DMAP (0.55 mmol, 1.5 equiv). While stirring, 0.09 mL
TIPSCI (80 mg, 0.42 mmol, 1.17 equiv) was added dropwise. The reaction was
stirred at room temperature overnight, and then poured into water and extracted
with EtOAc. The combined organics were dried over M9804 and evaporated.

Column chromatography (10:1 hexanes/EtOAc) afforded 247 mg of product

281

(containing 5 mg ether and 7 mg hexane, corresponding to 98% discounting the
added weight) as an oil; R)~0.43 (10:1 hexanes/EtOAc); [81200 -10.3 (c 1.05,
CHCI3). 1H NMR (500 MHz, CDCI3): 8 7.29 (br, 1 H), 7.14 (t, J = 2.0 Hz, 1 H), 7.07
(t, J = 1.8 Hz, 1 H), 6.60 (t, J = 2.0 Hz, 1 H), 6.32-6.36 (m, 1 H), 4.95 (m, 1 H), 4.89
(quint, apparent t, J = 1.7 Hz, 1 H), 4.31 (d, J = 5.6 Hz, 1 H), 3.44 (s, 3 H), 3.18
(ddd, J = 2.7, 5.6, 8.8 Hz, 1 H), 2.20-2.34 (m, 2 H), 1.91 (br, 3 H), 1.73 (br, 3 H),
1.67 (dddd, J = 2.9, 7.1, 9.5, 14.2 Hz, 1 H), 1.33 (dddd, J = 6.6, 9.0, 9.0, 14.4 Hz,
1 H), 1.22-1.28 (m, 3 H), 1.03-1.10 (m, 39 H); 13C NMR (125 MHz, CDCl3): 8
167.5, 157.2, 144.9, 139.8, 136.9, 134.6, 131.9, 115.9, 112.9, 112.5, 109.7, 84.3,
76.2, 58.7, 30.0, 25.0, 19.2, 18.07, 18.04, 17.9, 12.8, 12.6, 12.4; IR (neat): 3300
(br), 2946, 2869, 1661, 1601, 1586, 1537, 1450, 1426, 1096, 884, 683 cm'1;
LRMS (El): m/e 622 ([M-‘Pr]+), 590, 460, 438, 380, 253, 227, 157, 115, 75, 59.
HRMS (El): m/e calcd for [C35H64CINO4Si2]+ 665.4062 found 665.4064.

General Procedure for Suzuki Coupling with Lill Exchange Step:

A solution of 0.23 mmol pentyl iodide (1.5 equiv) in 1 mL dry ether was cooled
to -78 °C. ‘BuLi (freshly titrated, 0.46 mmol, 2 equiv per iodide) was added via
syringe. After being stirred at -78 °C for 15 min, 0.37 mmol B-OMe-BBN (1 M in
hexanes, 2.5 equiv) was added followed by 1 mL THF. The mixture was stirred
at -78 °C for 15 min and warmed to room temperature. CsF (0.45 mmol, 3 equiv)

or K3PO4-nH20 (0.3 mmol, 2 equiv) was added followed by 0.15 mmol chloride.

282

Pd(OAc)2 (5 mol%) and S-Phos (10 mol%) were introduced next (either as solids
or as a THF solution) together with 1 mL THF. The reaction was stirred at 70-75
°C. Every 3 h, additional 5 mol% Pd(OAc)2 and 10 mol% S-Phos were charged.
This re-addition of Pd and ligand was repeated 3 times so that the total loads of
Pd and ligand were 20 mol% and 40 mol%, respectively. After the last addition
of Pd and ligand, the reaction was stirred overnight before being cooled to room
temperature. The mixture was then diluted with saturated NaHC03 and
extracted with EtOAc. The combined organics were dried over MgSO4,
evaporated, and analyzed by NMR. The results of the model studies are listed in

Table 6.2 (page 126).

283

 

Bibliography

1

For comprehensive reviews, see: (a) Shilov, A. E.; Shul’pin, G. B. Chem. Rev.
1997, 97, 2879-2932. (b) Goldberg. K. l.; Goldman, A. S. (Eds) Activation
and Functionalization of C—H Bonds, Vol. 885; American Chemical Society:
Washington, D. C., 2004.

(a) Ittel, S. D.; Tolman, C. A.; English, A. D.; Jessen, J. P. J. Am. Chem. Soc.
1976, 98, 6073-6075. (b) Shilov, A. E.; Shteinman, A. A. Coord. Chem. Rev.
1977, 24, 97-143.

Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439-2463.

(a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc.
2005, 127, 7330-7331. (b) Murai, S.; Kakiuchi, F.; Sekine, 8.; Tanaka, Y.;
Kamatani, A.; Sonoda, M.; Chatani, N. Nature 1993, 366, 529-531. (c) Murai,
S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N.
Pure Appl. Chem. 1994, 66, 1527-1534. (d) Pastine, S. J.; Gribkov, D. V.;
Sames, D. J. Am. Chem. Soc. 2006, 128, 14220-14221 and references
therein. (e) Dyker, G. Angew. Chem. Int. Ed. 1999, 38, 1698-1712. (f) Ritleng,
V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731-1769. (9) Tan, K. L.;
Park, S.; Ellman, J. A.; Bergman, R. G. J. Org. Chem. 2004, 69, 7329-7335.
(h) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. J. Org. Chem.
2005, 70, 6775-6781. (i) Godula, K.; Sames, D. Science 2006, 312, 67-72.

(a) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128,
9048-9049. (b) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 14560-14561.

(a) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141-1144. (b)
Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126,
9542-9543. (c) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 2300-2301. For reviews, see: (d) Arakawa, H.; Aresta, M.; Armor,
J. N.; Barteau, M. A.; Beckman, E. J.; Bell, A. T.; Bercaw, J. E.; Creutz, C.;
Dinjus, E.; Dixon, D. A.; Domen, K.; DuBois, D. L.; Eckert, J.; Fujita, E.;
Gibson, D. H.; Goddard, W. A.; Goodman, D. W.; Keller, J.; Kubas, G. J.;
Kung, H. H.; Lyons, J. E.; Manzer, L. E.; Marks, T. J.; Morokuma, K.;
Nicholas, K. M.; Periana, R.; Que, L.; Rostrup-Nielson, J.; Sachtler, W. M. H.;
Schmidt, L. D.; Sen, A.; Somorjai, G. A.; Stair, P. C.; Stults, B. R.; Tumas, W.
Chem. Rev. 2001, 101, 953—996. (e) Sen, A. Acc. Chem. Res. 1998, 31,

284

1O

11

12

13

14

550-557.

(a) Kalyani, 0.; Dick, A. R.; Anani, W. 0.; Sanford, M. S. Org. Lett. 2006, 8,
2523-2526. (b) Hull, K. L.; Anani, W. 0.; Sanford, M. S. J. Am. Chem Soc.
2006, 128, 7134-7135. (c) Kalyani, D.; Dick, A. R.; Anani, W. 0.; Sanford, M.
S. Tetrahedron 2006, 62, 11483-11498. (d) Wan, X.; Ma, 2.; Li, B.; Zhang, K.;
Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006, 128, 7416-7417.

For reviews in this area, see: (a) Davies, H. M. L.; Beckwith, R. E. J. Chem.
Rev. 2003, 103, 2861-2903. (b) Davies, H. M. L.; Antoulinakis, E. G. J.
Organomet. Chem. 2001, 617-618, 47-55.

(a) Kim, M.; Mulcahy, J. V.; Espino, C. G.; DuBois, J. Org. Lett. 2006, 8,
1073-1076. (b) Espino, C. G.; Fiori, K. W.; Kim, M.; DuBois, J. J. Am. Chem.
Soc. 2004, 126, 15378-15379. For reviews, see: (0) Davies, H. M. L.; Long,
M. S. Angew. Chem. Int. Ed. 2005, 44, 3518-3520. (d) DuBois, J. Chemtracts
2005, 18, 1-13. (9) Espino, C. G.; DuBois, J. Modern Rhodium-Catalyzed
Organic Reactions, Wiley: Weinheim, 2005; pp 379.

For reviews, see: (a) Karasevich, E. l.; Kulikova, V. S.; Shilov, A. E.;
Shteinman, A. A. Russ. Chem. Rev. 1998, 67, 376-398. (b) Mansuy, D.
Coord. Chem. Rev. 1993, 125, 129-142. (c) Meunier, B. Chem. Rev. 1992,
92, 1411-1456. (d) Dolphin, D.; Traylor, T. G.; Xie, L. Y. Acc. Chem. Res.
1997, 30, 251-259.

For a general review, see: lshiyama, T.; Miyaura, N. J. Organomet. Chem.
2003, 680, 3-11.

lverson, C. N.; Smith, M. R., Ill J. Am. Chem. Soc. 1999, 121, 7696-7697.

This C—H borylation can occur without catalyst in certain substrates, see: (a)
Laaziri, H.; Bromm, L. O.; Lherrnitte, F.; Gschwind, R. M.; Knochel, P. J. Am.
Chem. Soc. 1999, 121, 6940-6941. (b) Bromm, L. O.; Laaziri, H.; Lhermitte,
F.; Harms, L.; Knochel, P. J. Am. Chem. Soc. 2000, 122, 10218-10219. (c)
Varela, J. A.; Pena, D.; Goldfuss, B.; Polborn, K.; Knochel, P. Org. Lett. 2001,
3, 2395-2398. (d) Goldfuss, B.; Knochel, P.; Bromm, L. O.; Knapp, K. Angew.
Chem. Int. Ed. 2000, 39, 4136-4139.

For aromatic C—H borylation developments from the Smith group, see: (a)
Cho, J.-Y.; lverson, C. N.; Smith, M. R., Ill J. Am. Chem. Soc. 2000, 122,

285

 

 

 

15

16

17

18

12868-12869; (b) Tse, M. K.; Cho, J. Y.; Smith, M. R., lll Org. Lett. 2001, 3,
2831-2833. (c) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith,
M. R., lll Science 2002, 295, 305-308. (d) Chotana, G. A.; Rak, M. A.; Smith,
M. R., Ill J. Am. Chem. Soc. 2005, 127, 10539-10544.

For aromatic C—H borylation developments from the Hartwig, lshiyama and
Miyaura groups, see: (a) Boller, T. M.; Murphy, J. M.; Hapke, M.; lshiyama, T.;
Miyaura, N.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 14263-14278. (b)
lshiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew. Chem. Int. Ed.
2002, 41, 3056-3058. (c) lshiyama, T.; Takagi, J.; lshida, K.; Miyaura, N.;
Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390-391. (d)
Waltz, K. M.; Muhoro, C. N.; Hartwig, J. F. Organometallics 1999, 18,
3383-3393.

For aromatic C-H borylation developments from other groups, see: (a)
Mkhalid, l. A. l.; Conventry, D. N.; Albesa-Jove, D.; Batsanov, A. 8.; Howard,
J. A. K.; Perutz, R. N.; Marder, T. B. Angew. Chem. Int. Ed. 2006, 45,
489-491. (b) Lam, W. H.; Lam, K. C.; Lin, 2.; Shimada, S.; Perutz, R. N.;
Marder, T. B. Dalton Trans. 2004, 1556-1562. (c) Mertins, K.; Zapf, A.; Beller,
M. J. Mol. Catal. A 2004, 207, 21—25. For a special aromatic C—H borylation
with ortho selectivity, see: (d) Ben-Ari, E.; Gandelman, M.; Rozenberg, H.;
Shimon, L. J. W.; Milstein, D. J. Am. Chem. Soc. 2003, 125, 4714-4715.

For aromatic C—H borylation for heteroaromatics, see: (a) lshiyama, T.;
Takagi, J.; Yonekawa, Y.; Hartwig, J. F.; Miyaura, N. Adv. Synth. Gate]. 2003,
345, 1103-1106. (b) Takagi, J.; Sato, K.; Hartwig, J. F.; lshiyama, T.; Miyaura,
N. Tetrahedron Lett. 2002, 43, 5649-5651. (c) lshiyama, T.; Nobuta, Y.;
Hartwig, J. F.; Miyaura, N. Chem. Commun. 2003, 2924-2925. (d) Ref 16c. (e)
Paul, S.; Chotana, G A.; Holmes, D.; Reichle, R. C.; Maleczka, R. E., Jr.;
Smith, M. R., Ill J. Am. Chem. Soc. 2006, 128, 15552-15553. (f) Lo, W. F.;
Kaiser, H. M.; Spannenberg, A.; Beller, M.; Tse, M. K. Tetrahedron Lett. 2007,
48, 371-375.

For aliphatic C—H borylation, see: (a) Murphy, J. M.; Lawrence, J. D.;
Kawamura, K.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
13684-13685. (b) Hartwig, J. F.; Cook, K. S.; Hapke, M.; Incarvito, C. D.; Fan,
Y.; Webster, C. E.; Hall, M. B. J. Am. Chem. Soc. 2005, 127, 2538-2552. (0)
Lawrence, J. D.; Takahashi, M.; Bae, C.; Hartwig, J. F. J. Am. Chem. Soc.
2004, 126, 15334-15335. (d) Webster, C. E.; Fan, Y.; Hall, M. B.; Kunz, D.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 858-859. (e) Kawamura, K.;

286

 

 

 

19

20

21

22

23

24

25

Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 8422-8423. (f) Waltz, K. M.;
Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 11358-11369. (9) Chen, H.;
Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287, 1995-1997. (h)
Chen, H.; Hartwig, J. F. Angew. Chem. Int. Ed. 1999, 38, 3391-3393. (i)
Waltz, K. M.; Hartwig, J. F. Science 1997, 277, 211-213.

For benzylic C—H borylation, see: (a) lshiyama, T.; lshida, K.; Takagi, J.;
Miyaura, N. Chem. Lett. 2001, 1082-1083. (b) Shimada, S.; Batsanov, A. 8.;
Howard, J. A. K.; Marder, T. B. Angew. Chem. Int. Ed. 2001, 40, 2168-2171.

For B-styrylic C—H borylation, see: Murata, M.; Watanabe, S.; Masuda, Y.
Tetrahedron Lett. 1999, 40, 2585-2588.

For a comprehensive review, see: Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457-2483.

(a) Hayashi, T. Synlett 2001, 11, 879-887. (b) Ukai, K.; Aoki, M.; Takaya, J.;
lwasawa, N. J. Am. Chem. Soc. 2006, 128, 8706-8707. (c) Zou, G.; Wang, Z.;
Zhu, J.; Tang, J. Chem. Commun. 2003, 2438-2439. (d) Takaya, Y.;
Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998,
120, 5579-5580. (e) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103,
169-196.

(a) Follmann, M.; Graul, F.; Schaefer, T.; Kopec, S.; Hamley, P. Synlett 2005,
15, 1009-1011. (b) Jourdan, H.; Gouhier, G.; Van Hijfte, L.; Angibaud, P.;
Piettre, S. R. Tetrahedron Lett. 2005, 46, 8027-8031. (c) Koolmeister, T.;
Sodergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5969-5970. (d)
Koolmeister, T.; Sodergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43,
5965-5968. For a review, see: Petasis, N. A.; Zavialov, l. A. Advances in
Boron Chemistry, The Royal Society of Chemistry: Cambridge, 1997; pp 179.

For reviews, see: (a) Matteson, D. S. Tetrahedron 1998, 54, 10555-10607.
(b) Matteson, D. S. J. Organomet. Chem. 1999, 581, 51-65.

(a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K. M.; Chan,
D. M. T.; Combs, A. Synlett 2000, 10, 674-676. (b) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J. Winters, M. P.; Chan, D. M. T.; Combs, A.
Tetrahedron Lett. 1998, 39, 2941-2944. (c) Chan, D. M. T.; Monaco, K. L.;
Wang, R.-P.; Winters, M. P. Tetrahedron Left. 1998, 39, 2933-2936. (d)
Lengar, A.; Kappe, C. O. Org. Lett. 2004, 6, 771-774. (e) Kusturin, C. L.;

287

 

 

26

27

28

29

30

31

32

33

Liebeskind, L. S.; Neumann, W. L. Org. Left. 2002, 4, 983-985. (f) Liebeskind,
L. S.; Srogl, J. Org. Left. 2002, 4, 979-981. (g) Savarin, C.; Srogl, J.;
Liebeskind, L. S. Org. Lett. 2001, 3, 91-93.

(a) de Vries, J. G.; Hubbard, S. A. J. Chem. Soc., Chem. Commun. 1988,
1172-1173; (b) lshihara, K.; Yamamoto, H. Eur. J. Org. Chem. 1999, 527-538;
(c) Takeuchi, M.; lkeda, M.; Sugasaki, A.; Shinkai, S. Acc. Chem. Res. 2001,
34, 865-873. (d) Shinkai, S.; lkeda, M.; Sugasaki, A.;Takeuchi, M. Acc. Chem.
Res. 2001, 34, 494-503.

(a) Soloway, A. H.; Tjarks, W.; Barnum, B. A.; Rong, F.-G.; Barth, R. F.;
Codogni, I. M.; Wilson, J. G. Chem. Rev. 1998, 98, 1515-1562; (b)
Hawthorne, M. F.; Maderna, A. Chem. Rev. 1999, 99, 3421-3434.

Broad, L. M.; Braun, F.-J.; Lievremont, J.-P.; Bird, G. S. J.; Kurosaki, T.;
Putney, J. W., Jr. J. Biol. Chem. 2001, 276, 15945-15952.

(a) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic Press:
London, 1988. (b) Nesmeyanov, A. N.; Sokolik, R. A. Methods of
EIemento-Organic Chemistry, Vol 1; North-Holland: Amsterdam, 1967.

(a) Brown, H. C. Hydroboration; Benjamin: New York, 1962. (b) Zaidlewicz,
M. In Comprehensive Organometallic Chemistry, Vol 7; Wilkinson, 6.; Stone,
F. G. A.; Abel, E. W. (Eds); Pergamon: Oxford, 1982, pp 143. (c) Smith, K.;
Pelter, A. In Comprehensive Organic Synthesis, Vol 8; Trost, B. M. (Ed.);
Pergamon: Oxford, 1991, pp 703.

(a) lshiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508-7510.
(b) lshiyama, T.; Miyaura, N. J. Organomet. Chem. 2000, 611, 392-402. (c)
Murata, M.; Oyama, T.; Watanabe, 3.; Masuda, Y. J. Org. Chem. 2000, 65,
164-168.

In some extremely rare cases, sterics can override electronics in traditional
chemistry, see: Voronenkov, A. V.; Aliev, A. A.; Kutrakov, A. V.; Voronenkov, V.
V. Russ. J. Org. Chem. 1999, 35, 305-307.

(a) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P., Angew. Chem. Int. Ed.
2004, 43, 2206-2225 and references therein. (b) Snieckus, V. Chem. Rev.
1990, 90, 879-933. (c) Many Pd-catalyzed inner sphere C—H activation
methods that results in C—C, C—N, C-O, C—Halogen bond formation utilize

288

 

 

34

35

36

37

38

39

40

41

the ortho chelation to direct the position of new bond construction, see ref
4-7.

There is some additional chelation or electronic perturbations in the
regioselectivity in the borylation. It is more significant for heteroaromatic
substrates.

Tyman, J. H. P. Synthetic and Natural Phenols; Elsevier: New York, 1996.

(a) For an example of antioxidant, see: Bolotin, A.; Pipiraite, P. Liefuvos Fiz.
Z. 1996, 36, 362-364. (b) For an example of surfactant activity, see:
Takayanagi, T.; Motomizu, S. Bull. Chem. Soc. Jpn. 2001, 74, 2083-2089.

(a) For an example of radical scavenging activity, see: Owen, R. W.; Giacosa,

A.; Hull, W. E.; Haubner, R.; Spiegelhalder, B.; Bartsch, H. Eur. J. Cancer
2000, 36, 1235-1247. (b) For examples of physical organic properties, see:
Liptak, M. D.; Gross, K. C. J. Am. Chem. Soc. 2002, 124, 6421-6427, and (c)
Feng, Y.; Liu, L.; Fang, Y.; Guo, Q.-X. J. Phys. Chem. A 2002, 106,
11518-11525.

(a) Liao, Y.; Reitman, M.; Zhang, Y.; Fathi, R.; Yang, Z. Org. Left. 2002, 4,
2607-2609. (b) Gentles, R. G.; Wodka, D.; Park, D. C.; Vasudevan, A. J.
Comb. Chem. 2002, 4, 442-456. (c) Grabowska, U.; Rizzo, A.; Farnell, K.;
Quibell, M. J. Comb. Chem. 2000, 2, 475-490. (d) Martin, E. J.; Critchlow, R.
E. J. Comb. Chem. 1999, 1, 32-45.

For examples, see: (a) Kobayashi, K.; Arisawa, M.; Yamaguchi, M. J. Am.
Chem. Soc., 2002, 124, 8528-8529. (b) Kobayashi, K.; Yamaguchi, M. Org.
Lett. 2001, 3, 241-242. (c) Trost, B. M.; Toste, F. D.; Greenman, K. J. Am.
Chem. Soc., 2003, 125, 4518-4526.

For example, Yamada, K.; Kurokawa, T.; Tokuyama, H.; Fukuyama, T. J.
Am. Chem. Soc. 2003, 125, 6630-6631.

For comprehensive summary of traditional methods, see: (a) Whiting, D. A.
In Comprehensive Organic Chemistry, Vol. 1; Stoddart, J. F. (Ed.); Pergamon:
Oxford and New York, 1979, Part 4.2. (b) Fyfe, C. A. In The Chemistry of the
Hydroxyl Group, Vol. 1; Patai, S. (Ed); Wiley lnterscience: New York, 1971,
pp 83.

289

 

42

43

44

45

46

47

48

49

For recent examples, see: (a) Hoarau, C.; Pettus, T. R. R. Synlett 2003, 13,
127-137. (b) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc.
2000, 122, 11553-11554. (0) Marchueta, l.; Olivella, S.; Sola, L.; Moyano, A.;
Pericas, M. A.; Riera, A. Org. Lett. 2001, 3, 3197-3200. (d) A review of the
non-traditional method: George, T.; Mabon, R.; Sweeney, G.; Sweeney, J. B.;
Tavassoli, A. J. Chem. Soc., Perkin Trans. 1 2000, 2529-2574.

(a) Julia, M.; Saint-Jalmes, V. P.; Verpeaux, J. N. Synlett1993, 3, 233-234. (b)
Lewis, N. J.; Gabhe, S. Y.; DeLaMater, M. R. J. Org. Chem. 1977, 42,
1479-1480. (c) Sato, K.; Kira, M.; Sakurai, H. Tetrahedron Lett. 1989, 30,
4375-4378. (d) Webb, K. S.; Levy, D. Tetrahedron Left. 1995, 36, 5117-5118.
(e) Simon, J.; Salzbrunn, S.; Surya Prakash, G. K.; Petasis, N. A.; Olah, G A.
J. Org. Chem. 2001, 66, 633-634.

(a) For a review of nucleophilic aromatic substitution, see: Bunnett, J. F.;
Zahler, R. E. Chem. Rev. 1951, 49, 273-412. (D) For reactions on Cr(CO)3
coordinated arenes, see: Semmelhack, M. F. In Comprehensive
Organometallic Chemistry II, Vol. 12; Hegedus, L. S. (Ed.); Pergamon: Oxford
and New York, 1995, Part 9.1. (c) A new Pd-catalyzed halide displacement:
Anderson, K. W.; lkawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am. Chem. Soc.
2006, 128, 10694-10695.

Boger, D. L.; Coleman, R. S. J. Org. Chem 1986, 51, 5436-5439 and
references therein.

Guo, Z.; Schultz, A. G. Org. Lett. 2001, 3, 1177-1180 and references therein.

For example, direct or indirect arene oxidation: (a) Taylor, E. C.; Altland, H.
W.; Danforth, R. H.; McGillivray, G. J. Am. Chem. Soc. 1970, 92, 3520-3522.
(b) Prakash, G. K. S.; Krass, M; Wang, Q.; Olah, G. A. Syn/eff1991, 1, 39-40.
(c) Olah, G. A.; Ernst, T. D. J. Org. Chem 1989, 54, 1204-1206, and other
articles in that series.

(a) Hodgson, H. H.; Wignall J. S. J. Chem. Soc. 1926, 2077-2079. (b) For
alternative possibilities, see: (b) Wedemeyer, K.; Koppelmann, E.; Evertz, W.
Ger. Offen. DE 2344926, 1975; and (c) Kiel, W.; Wedemeyer, K.; Evertz, W.
Ger. Offen. DE 2344925, 1975.

(a) Dotz, K. H. Angew. Chem. Int. Ed. 1975, 14, 644-645. (b) Wulff, W. D.;
Tang, P. C. J. Am. Chem. Soc. 1981, 103, 7677-7678. (c) Dotz, K. H.;

290

5O

51

52

53

54

55

56

57

58

Tomuschat, P. Chem. Soc. Rev. 1999, 28, 187-198.

(a) Serra, S.; Fuganti, C.; Moro, A. J. Org. Chem. 2001, 66, 7883-7888 and
references therein. (b) Gevorgyan, V.; Yamamoto, Y. J. Organomet. Chem.
1999, 576, 232-247.

(3) Adam, W.; Hadjiarapoglou L. In Topics in Current Chemistry, Vol. 164;
Herrmann, W. A. (Ed); Springer-Verlag: New York, 1993, pp 45. (b) Murray, R.
W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847-2853. (c) Murray, R. W.
Chem. Rev. 1989, 89, 1187-1201. (c) Webb, K. S.; Ruszkay, 'S. J.
Tetrahedron 1998, 54, 401-410. (d) Curci, R.; Fiorentino, M.; Troisi, L. J. Org.
Chem. 1980, 45, 4758-4760.

Interestingly, Webb reported in ref 2.9d that oxidation above 15 °C gave
lower yields.

Maleczka, R. E., Jr.; Shi, F.; Holmes, 0.; Smith, M. R., I” J. Am. Chem. Soc.
2003, 125, 7792-7793.

It is also known that borylation can occur ortho to chlorine and cyano group,
if such positions are the most sterically open ones, see ref 1.14d and 1.15b.

It is known that DMDO can oxidize phenols to orthoquiones. Crandall, J. K.;
Zucco, M.; Kirsch, R. S.; Coppert, D. M. Tetrahedron Lett. 1991, 32,
5441-5444.

(a) Ferrer, M.; Sénchez-Baeza, F.; Messeguer, A. Tetrahedron 1997, 53,
15877-15888. (b) Fields, John D.; Kropp. Paul J. J. Org. Chem. 2000, 65,
5937-5941.

(a) The chemical shift of the methyl protons of N,N-dimethylaniline
N-hydroxide is 4.05 ppm: Smith, J. R. L.; Linford, J. M.; McKeer, L. 0.; Morris,
P. M. J. Chem. Soc, Perkin Trans. 2, 1984, 6, 1099-1105. (b) The chemical
shift of the methyl protons of N,N-dimethylaniline N-oxide is 3.57 ppm: ref
2.21a. (c) The chemical shift of the methyl protons of N,N-dimethylaniline is
2.89 ppm.

The pKa of the N-hydroxide of trimethylamine is approximately 5.5, see:
http://daecr1.harvard.edu/pdf/evans_pKa_table.pdf, as indicated on 1/29/07.

291

 

59

6O

61

62

63

64

65

66

 

(a) Kabalka, G. W.; Hedgecock, H. C. J. Org. Chem. 1975, 40, 1776-1779. (b)
Soderquist, J. A.; Najafi, M. R. J. Org. Chem. 1986, 51, 1330-1336.

Literature precedents of such 8N2 attack of methyl aryl ether by hydride exist,
see: Majetich, G.; Zhang, Y.; Wheless, K. Tetrahedron Left. 1994, 47,
8727-8730.

Okano, K.; Tokuyama, H.; Fukuyama T. J. Am. Chem. Soc. 2006, 128,
7136-7137.

Rahaim, R. J., Jr.; Maleczka, R. E., Jr. Tetrahedron Lett. 2002, 43,
8823-8826.

For example, vancomycin and taxol both contain modified aromatic amino
acid segments.

Kageharu, T.; Nagahiro, N.; Nakagawa, Y. Ann. Rev. Shinkei2005, 170-178.
(b) Sjoberg, S.; Carlsson, J.; Ghaneolhosseini, H.; Gedda, L.; Hartman, T.;
Malmquist, J.; Naeslund, C.; Olsson, P.; Tjarks, W. J. Neuro-Oncol. 1997, 33,
41-52. (c) Miyaura, N. Sci. Synth. 2004, 6, 257-300.

For selected references of 5-hydroxytryptophan, see: (a) del Corral, P.;
Pacak, K. Encyclopedia of Dietary Supplements 2005, 349-355. (b)
Upadhyay, S. N. J. Indian Chem. Soc. 2003, 80, 619-621. (c) Van Praag, H.
M. Neuropharmacology 1983, 22, 433-440. (d) Byerfey, W. F.; Judd, L. L.;
Reimherr, F. W.; Grosser, B. I. J. Clin. Psychophannacol. 1987, 7, 127-137.
(e) Beck, 0.; Helander, A. Addiction 2003, 98, 63-72. For selected
references of other hydroxytryptophan and general reviews, see: (f) Walther,
D. J.; Peter, J.-U.; Bader, M. Cancer 2002, 94, 3135-3140. (9) Maskos, 2.;
Rush, J. D.; Koppenol, W. H. Arch. Biochem. Biophys. 1992, 296, 4-20. (h)
Zhelyazkov, D. K.; Levitt, M.; Udenfriend, S. Mol. Pharmacol. 1968, 4,
445-451. (i) Ek, A.; Witkop, B. J. Am. Chem. Soc. 1953, 75, 500-501. (j)
Walther, D. J.; Bader, M. Ger. Oti'en. DE 10112882, 2002. For selected
references for meta-tyrosine, see: (k) Minsker, D. H.; Stokes, A. L.
Experientia 1974, 30, 1051-1053. (I) Ungerstedt, U.; Fuxe, K.; Goldstein, M.;
Battista, A.; Ogawa, M.; Anagnoste, B. Eur. J. Pharmacol. 1973, 21, 230-237.

(a) Nakamura, H.; Fujiwara, M.; Yamamoto, Y. J. Org. Chem. 1998, 63,

7529-7530 and references therein. (b) Nakamura, H.; Fujiwara, M.;
Yamamoto, Y. Bull. Chem. Soc. Jpn. 2000, 73, 231-235. Other methods

292

 

67

68

69

7O

71

72

exist, see: (c) Malan, C.; Morin, C. J. Org. Chem. 1998, 63, 8019-8020 and
references therein. (d) Park, K. C.; Yoshino, K.; Tomiyasu, H. Synthesis 1999,
2041-2044. (e) Malan, C.; Morin, C. Synlett1996, 167-168.

Fermentation methods are actually available, see: (a) Dugave, C. J. Org.
Chem. 1995, 60, 601-607. (b) Liu, W. US Patent 5981239, 1999.

There are limited examples of such modification, see: (a) Mager, H. I. X.; Tu,
S.-C. Tetrahedron 1994, 50, 6759-6766. (b) Blanchard, M.; Bouchoule, C.;
Djaneye-Boundjou, G.; Canesson, P. Tetrahedron Left. 1988, 29, 2177-2178.
(c) Lei, H.; Stoakes, M. S.; Herath, K. P. B.; Lee, J.; Schwabacher, A. W. J.
Org. Chem. 1994, 59, 4206—4210.

(a) Melega, W. P.; Perlmutter, M. M.; Luxen, A.; Nissenson, C. H. K.; Grafton,
S. T.; Huang, 8. C.; Phelps, M. E.; Barrio, J. R. J. Neurochem. 1989, 53,
311-314. (b) Monclus, M.; Masson, C.; Luxen, A. J. Fluon'ne Chem. 1995, 70,
39-44. (c) Barrio, J. R.; Huang, S.-C.; Yu, D.-C.; Melega, W. P.; Quintana, J.;
Cherry, S. R.; Jacobson, A.; Namavari, M.; Satyamurthy, N.; Phelps, M. E. J.
Cerebral Blood Flow Metab. 1996, 16, 667-678. (d) Namavari, M.;
Satyamurthy, N.; Phelps, M. E.; Barrio, J. R. Appl. Radiat. lsot. 1993, 44,
527-536. (e) Chirakal, R.; Schrobilgen, G. J.; Firnau, G.; Gametti, S. Appl.
Radiat. lsot. 1991, 42, 113-119.

(a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis;
Wiley: New York, 1999. (b) Dent, W. H., Ill; Erickson, W. R.; Fields, S. G;
Parker, M. H.; Tromiczak, E. G. Org. Lett. 2002, 4, 1249-1251. (c) Walker, W.
H., IV; Rokita, S. E. J. Org. Chem. 2003, 68, 1563-1566.

(a) Romanova, N. N.; Gravis, A. G.; Zyk, N. V. Russ. Chem. Rev. 2005, 74,
969-1013. (D) de la Hoz, A.; Diaz-Ortiz, A.; Moreno, A. Chem. Soc. Rev. 2005,
34, 164-178. (c) Hayes, B. L. Aldrichimica Acta 2004, 37, 66-77. (d) Kappe, C.
O. Angew. Chem. Int. Ed. 2004, 43, 6250-6284. There are even three
journals focusing on microwave-assisted reactions: Microwave Assisted
Organic Synthesis, Microwaves in Organic Synthesis, and Microwave
Enhanced Chemistry.

This conversion is based on the uncalibrated HPLC integration ratio of the
product versus the unreacted starting material. Under the analytical HPLC
conditions, the product shows two signals, corresponding to the boronic ester
and acid, respectively. Thus, the integration of the product is obtained by

293

 

73

74

75

76

77

78

79

addition of the integration of both boronic ester and acid.

In a pure geometric point of view, a substituent in a 5-membered aromatic
ring can occupy more space than the same substituent in a 6-membered
aromatic ring, and therefore be more flexible to adopt a conformation that .
frees more space of its ortho position.

(a) Pascual, A. J. Prakf. Chem. 1999, 341, 695-700. (b) Wilhelm, 8.; Fritz, T.
Ann. 1939, 540, 1-7. (c) Kosak, A. |.; Palchak, R. J. F.; Steele, W. A.; Selwitz,
C. M. J. Am. Chem. Soc. 1954, 76, 4450-4454. It is even known that the
bridging olefin has a trans geometry.

This work was performed at Johnson & Johnson Pharmaceutical Research
and Development, LLC. Circumstances did not allow for full compound
characterizations. Moreover, owing to corporate reorganization, hard copy
spectra and synthetic materials are unavailable.

The 1H NMR of unprotected form of 3.9 is reported, see: (a) Chanut, E.;
Trouvin, J. H.; Bondoux, D.; Gardler, A.; Launay, J. M.; Jacouot, C. Biochem.
Pharmacol. 1993, 45, 1049-1057. (b) Chirakal, R.; Sayer, B. G.; Firnau, G.;
Garnett, E. S. J. Labeled Compd. Radiopharrn. 1988, 25, 63-71 and
references therein.

For books about isotopically labeled compounds and applications, see: (a)
Muccino, R. R. Synthesis and Applications of lsotopically Labeled
Compounds; Elsevier: Amsterdam, New York, 1985. (b) Buncel, E.; Jones, J.
R. Isotopes in the Physical and Biomedical Sciences; Elsevier: Amsterdam,
New York, 1987. (c) Pleiss, U.; Voges, R. (Eds) Synthesis and Application of
lsotopically Labeled Compounds, Vol. 7; John Wiley: Chichester, New York,
2001.

(a) Eaton, V. J.; Steele, D. J. Mol. Spectrosc. 1973, 48, 446-458. (b) Onda,
M.; Atsuki, M.; Yamaguchi, J.; Suga, K.; Yamaguchi, I. J. Mol. Struct. 1993,
295, 101-104. (c) Foust, R. 0., Jr.; Ford, P. C. J. Am. Chem. Soc. 1972, 94,
5686-5696.

(a) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry, Harper and Row: New York, 1987. (b) Zoltewicz, J. A.; Bunnett, J.
F. J. Am. Chem. Soc. 1965, 87, 2640-2647. (c) Dunn, D. E.; Krueger, P. J.;
Rodewald, W. Can. J. Chem. 1961, 39, 180-191.

294

80

8

_\

82

83

84

85

86

87

Fitzpatrick, P. F. J. Am. Chem. Soc. 1994, 116, 1133-1134.

(a) Brecker, L.; Kogl, M. F.; Tyl, C. E.; Kratzer, R.; Nidetzky, B. Tetrahedron
Lett. 2006, 47, 4045-4049 and references therein. (b) Singleton, D. A.
Thomas, A. A. J. Am. Chem. Soc. 1995, 117, 9357- 9358. (c)Singleton, D. A.;
Merrigan, S. R. Org. Lett. 1999, 1, 327- 330.

(a) Fischer, 0.; Puza, M. Synthesis 1973, 4, 218-220. (b) Werstiuk, N. H.;
Kadai, T. Can. J. Chem. 1976, 54, 2201-2212, and 1974, 52, 2169-2171. (c)
Junk, T.; Catallo, W. J. Chem. Soc. Rev. 1997, 26, 401-406. For recent
examples of metal-catalyzed H/D exchanges, see: (d) Yung, C. M.; Skaddan,
M. B.; Bergman, R. G. J. Am. Chem. Soc. 2004, 126, 13033-13043. (8) Klei,
S. R.; Tilley, T. D.; Bergman, R. G. Organometallics 2002, 21 , 4905-4911.

Weldon, L. H. P.; Wilson, C. L. J. Chem. Soc. 1946, 235-239.

(a) Bosin, T. R.; Raymond, M. G.; and Buckpitt, A. R. Tetrahedron Lett. 1973,
14, 4699-4700. (b) Neumann, W. P.; Hillgartner, H. Synthesis 1971, 2,
537-538. (c) Muller, J. P. H.; Parlar, H.; Korte, F. Synthesis 1976, 7, 524-525.
(d) Kakinami, T.; Eguchi, H. Jpn Kokai Tokkyo Koho JP 06228014, 1994.

(a) Gibson, J. 8.; Herbert, J. M. J. Labeled Compd. Radiopharm. 2003, 46,
531-537. (b) Salter, R.; Bosser, l. J. Labeled Compd. Radiopharm. 2003, 46,
489-498. (c) Valsborg, J. S.; Sorensen, L.; Foged, C. J. Labeled Compd.
Radiopharm. 2001, 44, 209-214. (d) Ellames, G. J.; Gibson, J. 8.; Herbert, J.
M.; McNeill, A. H. Tetrahedron 2001, 57, 9487-9497. (e) Heys, R. J. Chem.
Soc., Chem. Commun. 1992, 680-681. (f) Shu, A. Y. L.; Chen, W.; Heys, J. R.
J. Organomet. Chem. 1996, 524, 87-93. (f) Shu, A. Y. L.; Saunders: D.;
Levinson, S. H.; Landvatter, S. W.; Mahoney, A.; Senderoff, S. G.; Mack, J.
F.; Heys, J. R. J. Labeled Compd. Radiopharm. 1999, 42, 797-807.

(a) Banijamali, A. R.; Charalambous, A.; Van der Schyf, C. J.; Makriyannis, A.
J. Labeled Compd. Radiopharm. 1987, 24, 1479-1482. (b) Charlton, J. L.;
Kostyk, B.; Lei, H. K. Can. J. Chem. 1974, 52, 3577-3580.

(a) Lappert, M. F. Chem. Rev. 1956, 959-1064, and references therein. (b)

Toporcer, L. H.; Dessy, R. E.; Green, S. l. E. J. Am. Chem. Soc. 1965, 87,
1236-1240.

295

88

89

9O

91

92

93

94

(a) Brown, H. C.; Murray, K. J. Tetrahedron 1986, 42, 5497-5504. (b)
Rondesvedt, C. S.; Scribner, R. M.; Wulfrum, C. E. J. Org. Chem. 1955, 20,
9-12. (c) Domaille, P. J.; Druliner, J. D.; Gosser, L. W.; Read, J. M., Jr.;
Schmelzer, E. R.; Stevens, W. R. J. Org. Chem. 1985, 50, 189-194. (d) Brown,
H. C.; Hebert. N. C. J. Organomet. Chem. 1983, 255, 135-142.

(a) Florentin, D.; Foumie-Zaluski, M. C.; Callanquin, M.; Roques, B. P. J.
Heferocycl. Chem. 1976, 13, 1265-1272. (b) Kuivila, H. G.; Reuwer, J. F., Jr.;
Mangravite, J. A. J. Am. Chem. Soc. 1964, 86, 2666-2670. (c) Kuivila, H. G.;
Reuwer, J. F., Jr.; Mangravite, J. A. Can. J. Chem. 1963, 41, 3081-3090. (d)
Nahabedian, K. V.; Kuivila, H. G. J. Am. Chem. Soc. 1961, 83, 2167-2174. (e)
Kuivila, H. G.; Nahebedian, K. V. J. Am. Chem. Soc. 1961, 83, 2164-2166. (f)
Kuivila, H. G.; Nahebedian, K. V. J. Am. Chem. Soc. 1961, 83, 2159-2163. (9)
Snyder, H. R.; Wyman, F. W. J. Am. Chem. Soc. 1948, 70, 234-237. (h)
Challenger, F.; Richards, 0. V. J. Chem. Soc. 1934, 405-411. (i) Ainley, A. D.;
Challenger, F.; J. Chem. Soc. 1930, 1271-1280. (j) Beckett, M. A.; Gilmore, R.
J.; ldrees, K. J. Organomet. Chem. 1993, 455, 47-49.

The protodeboronation is a common side-product for a number of boronic
acid participated reactions, see ref 21-25.

Shi, F.; Smith, M. R., III; Maleczka, R. E., Jr. Manuscript in preparation.

For example, 2.2t could be fully converted to 4.3a with 2 mol% Ir at 150 °C in
40-50 min. At 100 °C with 2 mol% Ir, it took 8 h. With 0.6 mol% Ir at 150
°C, it took 2 h. Further lowering the Ir loading led to incomplete conversion.

Such similarities in the reactivity between Ir and Rh have been observed and
reported, see: (a) Nishimura, T.; Yasuhara, Y.; Hayashi, T. Angew. Chem. Int.
Ed. 2006, 45, 5164-5166. (b) lmIinger, N.; Mayr, M.; Wang, D.; Wurst, K.;
Buchmeiser, M. R. Adv. Synth. Cafal. 2004, 346, 1836-1843.

(a) Such quantification using MS analysis is not expected to be reliable,
because the MS analysis (see Section 7.4.3 for details) is based on the
assumption that the M-H signal in the do compound is NOT due to the loss of
the specific H that has been replaced by D. This assumption is questionable
for styrene. (b) This analysis is based on the decrease of the integration of
vinyl protons versus the aromatic protons. For example, the 1H NMR
spectrum of the deuteration product of 4.9b shows a 0.65 integration of each
vinyl protons, a loss of 35%. This suggests that each vinyl position has 0.35

296

95

96

97

98

99

D, which brings the total deuterium incorporation 1.05.

Over 7000 hit structures in about 800 references per Scifinder Scholar, as
indicated on 1/29/07.

Kinase inhibitor activities: (a) Thaimattam, R.; Daga, P.; Rajjak, S. A.;
Banerjee, R.; Iqbal, J. Bioorg. Med. Chem. 2004, 12, 6415-6425. (b) Wityak,
J.; Das, J.; Moquin, R. V.; Shen, 2.; Lin, J.; Chen, P.; Doweyko, A. M.; Pitt, 8.;
Pang, 8.; Shen, D. R.; Fang, 0.; de Fex, H. F.; Schieven, G. L.; Kanner, S. B.;
Barrish, J. C. Bioorg. Med. Chem. Lett. 2003, 13, 4007-4010. Bacteria growth
inhibitor activities: (c) Kane, J. L.; Hirth, B. H.; Liang, B.; Gourlie, B. B.; Nahill,
8.; Barsomian, G. Bioorg. Med. Chem. Lett. 2003, 13, 4463-4466. (d) For an
example of VEGF receptor antagonist: Saito, 8.; Suga, Y.; Sato, M.; Shibuya,
M. PCT Int. Appl. WO 2003055847, 2003. Plant growth regulator activities: (e)
Bollinger, F. G.; D'Amico, J. J. US Patent4146386, 1979, and (f) Bollinger, F.
G.; D'Amico, J. J.; Hansen, D. J. Ger. Offen. DE 2757111, 1978.

For reports of related biosynthesis, see: (a) Kibby, J. J.; Rickards, R. W. J.
Antibiot. 1981, 34, 605-607. (b) Kibby, J. J.; McDonald, l. A.; Rickards, R. W.
J. Chem. Soc., Chem. Comm. 1980, 768-769. (d) Anderson, M. G.; Kibby, J.
J.; Rickards, R. W.; Rothschild, J. M. J. Chem. Soc., Chem. Comm. 1980,
1227-1228.

(a) Becker, A. M.; Rickards, R. W. Tetrahedron 1983, 39, 4189-4192 and
references therein. (b) Herlt, Anthony J.; Kibby, Jeffrey J.; Rickards, Rodney
W. Aust. J. Chem. 1981, 34, 1319-24. (c) For a synthetic library built around
AHBA, see: Dankwardt, S. M.; Phan, T. M.; Krstenansky, J. L. Mol. Diversify
1996, 1, 113-120.

There are rare examples that do not require such acylation. For example, a
regioselective nitration of 3-substituted phenols on the 5 position is reported,
see: Gu, 8.; Jing, H.;Wu, J.; Liang, Y. Synth. Commun. 1997, 27, 2793-2797.

100 Angeles, E.; Santillan, A.; Martinez, I.; Ramirez, A.; Moreno, E.; Salmon, M.;

Martinez, R. Synth. Commun. 1994, 24, 2441-2447.

101 Shah, M. N.; Joshi, V. Indian J. Heterocycl. Chem. 1994, 4, 59-62.

102 Most structure hits found in Scifinder search have either CF3 or OMe at

5-position.

297

 

103 Smith, A. 3., III; Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem. Soc. 1996,
118, 8316-8328.

104 For Cu-catalyzed amidation, see: (a) Klapars, A.; Antilla, J. C.; Huang, X.;
Buckwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727-7729. (b) Klapars, A.;
Huang, X.; Buckwald, 8. L. J. Am. Chem. Soc. 2002, 124, 7421-7428.

105 For Pd-catalyzed amidation, see: (a) Yln, J.; Buchwald, S. L. Org. Lett. 2000,
2, 1101-1104. (b) Yin, J.; Buchwald, 8. L. J. Am. Chem. Soc. 2002, 124,
6043-6048. (c) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buckwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653-6655. (d) For a method
developed not by Buchwald, see: Shakespeare, W. C. Tetrahedron Left. 1999,
40, 2035-2038.

106 Holmes, D.; Chotana, G. A.; Maleczka, R. E., Jr.; Smith, M. R., lll Org. Left.
2006, 8, 1407-1410.

107 Shi, F.; Smith, M. R., III; Maleczka, R. E., Jr. Org. Left. 2006, 8, 1411-1414.

108 (a) In rare cases, it has been reported that xantphos can promote undesired
Suzuki-couplings as side-reactions, see: Lightfoot, A. P.; Twiddle, S. J. R.;
Whiting, A. Org. Biomol. Chem. 2005, 3, 3167-3172. (b) For a general review
about the utilities of xantphos, see: Kamer, P. C. J.; van Leeuwen, P. W. N.
M.; Reek, J. N. H. Acc. Chem. Res. 2001, 34, 895-904.

109 (a) Codd, E.; Dax, 8.; Flores, C.; Jetter, M.; Youngman, M. PCT Int. Appl.
WO 2006102645, 2006. (b) Yura, T.; Mogi, M.; Ikegami, Y.; Masuda, T.;
Kokubo, T.; Urbahns, K.; Lowinger, T. B.; Yoshida, N.; Freitag, J.; Meier, H.;
Wittka-Nopper, R.; Marumo, M.; Shiroo, M.; Tajimi, M.; Takeshita, K.;
Moriwaki, T.; Tsukimi, Y. PCT Int. Appl. WO 2003014064, 2003. (c) Beaulieu,
P. L.; Fazal, G.; Goulet, 8.; Kukolj, G.; Poirier, M.; Tsantrizos, Y. S. PCT Int.
Appl. WO 2003007945, 2003. (d) Poupart, M.-A.; Cameron, D. R.; Chabot, C.;
Ghiro, E.; Goudreau, N.; Goulet, 8.; Poirier, M.; Tsantrizos, Y. S. J. Org.
Chem. 2001, 66, 4743-4751. (e) Epperson, J. R.; Yevich, J. P. PCTInt. Appl.
WO 9738682, 1997. (f) Fontaine, F.; Pastor, M.; Zamora, l.; Sanz, F. J. Med.
Chem. 2005, 48, 2687-2694.

110 (a) Smith, M. R., III; Maleczka, R. E., Jr. US Patent 6867302 BZ, 2005. (b)
Holmes, D.; Chotana, G. A.; Smith, M. R., III; Maleczka, R. E., Jr. Manuscript

298

 

in preparation.

111 (a) Yu, T.-W.; Muller, R.; Muller, M.; Zhang, X.; Draeger, G; Kim, C.-G.;
Leistner, E.; Floss, H. G. J. Biol. Chem. 2001, 276, 12546-12555. (b) Kim,
C.-G.; Kirschning, A.; Bergon, P.; Zhou, R; Su, E.; Sauerbrei, B.; Ning, 8.;
Ahn. Y.; Breuer, M.; Leistner, E.; Floss, H. G. J. Am. Chem. Soc. 1996, 118,
7486-7491. (c) Floss, H. G Nat. Prod. Rep. 1997, 14, 433-452, and the
references cited therein. (d) Snader, K. M. AnticancerAgents Nat. Prod. 2005,
339-356. (e) Bryskier, A. Antimicrob. Agents Chemother. 2005, 906-924. (f)
Ogilvie, A.; Kersten, W. Antibiotics 1979, 5, 243-263.

112 (a) Kim, W.-G.; Song, N.-K.; Yoo, l.-D. J. Antibiot. 2002, 55, 204-207 and
references therein. (b) Funayama, 8.; Okada, K.; Komiyama, K.; Umezawa, I.
J. Antibiot. 1985, 38, 1107-9. (c) Komiyama, K.; Hirokawa, Y.; Yamaguchi, H.;
Funayama, 8.; Masuda, K.; Anraku, Y.; Umezawa, |.; Omura, S. J. Antibiot.
1987, 40, 1768-72. (d) Smith, A. 3., III; Wood, J. L.; Wong, W.; Gould, A. E.;
Rizzo, C. J.; Barbosa, J.; Funayama, 8.; Komiyama, K.; Omura, S. J. Am.
Chem. Soc. 1996, 118, 8308-8315 and references therein.

113 (a) Andrus, M. B.; Meredith, E. L.; Hicken, E. J.; Simmons, B. L.; Glancey, R.
R.; Ma, W. J. Org. Chem. 2003, 68, 8162-8169 and references therein. (b)
Rinehart, K. L., Jr.; Sasaki, K.; Slomp, G.; Grostic, M. F.; Olson, E. C. J. Am.
Chem. Soc. 1970, 92, 7591-7593.

114 (a) Benechie, M.; Delpech, B.; Khuong-Huu. Q.; Khuong-Huu, F.
Tetrahedron 1992, 48, 1895-1910. (b) Cassady, J. M.; Chan, K. K.; Floss, H.
G.; Leistner, E. Chem. Phann. Bull. 2004, 52, 1-26, and references therein. (c)
Higashide, E.; Asai, M.; Ootsu, K.; Tanida, 8.; Kozai, Y.; Hasegawa, T.; Kishi,
T.; Sugino, Y.; Yoneda, M. Nature 1977, 270, 721-722.

115 (a) Lee, J. P.; Tsao, S.-W.; Chang, C.-J.; He, X.-G.; Floss, H. G. Can. J.
Chem. 1994, 72, 182-187, and references therein. (b) Mochizuki, J.;
Kobayashi, E.; Furihata, K.; Kawaguchi, A.; Seto, H.; Otake, N. J. Antibiot.
1986, 39, 157-161. (c) Mukhopadhyay, T.; Franco, C. M.; Reddy, G. C.;
Ganguli, B. N.; Fehlhaber, H. W J. Antibiot. 1985, 38, 948-951.

116 Floss, H. G.; Yu, T.-W. Chem. Rev. 2005, 105, 621-632, and references
therein.

117 (a) Kishi, T.; Asai, M.; Muroi, M.; Harada, 8.; Mizuta, E.; Terao, 8.; Miki, T.;

299

Mizuno, K. Tetrahedron Lett. 1969, 10, 91-95. (b) Kishi, T.; Harada, 8.; Asai,
M.; Muroi, M.; Mizuno, K. Tetrahedron Lett. 1969, 10, 97-100.

118 (a) Roush, W. R.; Coffey, D. 8.; Madar, D. J. J. Am. Chem. Soc. 1997, 119,
11331-11332, and references therein. (b) Chemler, S. R.; Coffey, D. 8.;
Roush, W. R. Tetrahedron Left. 1999, 40, 1269-1272. (c) Rinehart, K. L., Jr.;
Antosz, F. J.; Deshmukh, P. V.; Kakinuma, K.; Martin, P. K.; Milavetz, B. l.;
Sasaki, K.; Witty, T. R.; Li, L. H.; Reusser, F. J. Antibiot. 1976, 29, 201-203.

119 (a) Okabe, M.; Uehara, M. Leukemia & Lymphoma 1993, 12, 4149. (b)
Carter, K. D.; Panek, J. S. Org. Lett. 2004, 6, 55-57. (c) Martin, S. F.; Dodge,
J. A.; Burgess, L. E.; Limberakis, C.; Hartmann, M. Tetrahedron 1996, 52,
3229-3246. (d) Nakata, M.; Osumi, T.; Ueno, A.; Kimura, T.; Tamai, T.;
Tatsuta, K. Bull. Chem. Soc. Jpn 1992, 65, 2974-2991. (e) Uehara, Y.;
Murakami, Y.; Suzukake-Tsuchiya, K.; Moriya, Y.; Sano, H.; Shibata, K.;
Omura, S. J. Antibiot. 1988, 41, 831-834. (f) Omura, 8.; Nakagawa, A.;
Sadakane, N. Tetrahedron Lett. 1979, 20, 4323-4326. (9) Mahon, T. M.;
O'Neill, L. A. J. J. Biol. Chem. 1995, 270, 28557-28564.

120 (a) Panek, J. 8.; Xu, F.; Rondon, A. C. J. Am. Chem. Soc. 1998, 120,
4113-4122. (b) Evans, D. A.; Miller, S. J.; Ennis, M. D. J. Org. Chem. 1993,
58, 471-485. (c) Baker, R.; Castro, J. L. J. Chem. Soc., Chem. Commun.
1989, 378-381. (d) Muroi, M.; Haibara, K.; Asai, M.; Kamiya, K.; Kishi, T.
Tetrahedron 1981, 37, 1123-1130. (e) Muroi, M.; lzawa, M.; Kosai, Y.; Asai,
M. J. Antibiot. 1980, 33, 205-212. (f) Belardi, J. K.; Micalizio, G. C. Org. Lett.
2006, 8, 2409-2412 and references therein.

121 (a) Wrona, l. E.; Gabarda, A. E.; Evano, G; Panek, J. S. J. Am. Chem. Soc.
2005, 127, 15026-15027, and references therein. (b) Takatsu, T.; Ohtsuki, M.;
Muramatsu, A.; Enokita, R.; Kurakata, S. I. J. Antibiot. 2000, 53, 1310-1312.

122 (a) Drysdale, M. J.; Brough, P. A.; Massey, A.; Jensen, M. R.; Schoepfer, J.
Curr. Opin. Drug Discovery Dev. 2006, 9, 483-495. (b) Gooljarsingh, L. T.;
Fernandes, C.; Yan, K.; Zhang, H.; Grooms, M.; Johanson, K.; Sinnamon, R.
H.; Kirkpatrick, R. B.; Kerrigan, J.; Lewis, T.; Arnone, M.; King, A. J.; Lai, Z.;
Copeland, R. A.; Tummino, P. J. Proc. NatlAcad. Sci. 2006, 103, 7625-7630.
(c) Uehara, Y. Curr. Cancer Drug Targets 2003, 3, 325-330.

123 (a) Stead, P.; Latif, 8.; Blackaby, A. P.; Sidebottom, P. J.; Deakin, A.; Taylor,
N. L.; Life, P.; Spaull, J.; Burrell, F.; Jones, R.; Lewis, J.; Davidson, l.; Mander,

300

T. J. Antibiot. 2000, 53, 657-663. (b) Li, M. G.; Wu, 8. H.; Zhao, L. X.; Zhang,
0.; Li, W. J.; Cui, X. L.; Xu, L. H.; Wu, D. G.; Jiang, C. L. Chin. Chem. Lett.
2001, 12, 903-906. (c) Jiang, C.; Xu, L.; Zhao, L. Faming Zhuanli Shenqing
Gongkai Shuomingshu CN 1313281, 2001. (d) Rascher, A.; Hu, 2.;
Buchanan, G. 0.; Reid, R.; Hutchinson, C. R. Appl. Environ. Microbiol. 2005,
71, 4862-4871. (e) Onodera, H.; Hamano, M.; lchimura, M.; lkeda, 8.-I.;
Suzuki, M.; Kanda, Y. PCT Inf. Appl. WO 2005061461, 2005.

124 (a) Lemarchand, A.; Bach, T. Tetrahedron 2004, 60, 9659-9673. (b)
Centonze-Audureau, 8.; Poree, F.-H.; Betzer, J.-F.; Brion, J.-D.; Pancrazi, A.;
Ardisson, J. Synlett 2005, 981 -985.

125 Martin, S. F.; Limberakis, C.; Burgess, L. E.; Hartmann, M. Tetrahedron
1999, 55, 3561-3572, and references therein.

126 For examples, see: (a) Hirama, M.; Nakamine, T.; Ito, 8. Tetrahedron Left.
1988, 29, 1197-1198. (b) Marko, I. E.; Murphy, F. Dolan, S. Tetrahedron Left.
1996, 37, 2089-2092 and references therein.

127 (a) Mayo, K. G.; Nearhoof, E. H.; Kiddle, J. J. Org. Lett. 2002, 4, 1567-1570.
(b) For a comprehensive review, see: Hoveyda, A. H.; Gillingham, D. G.; van
Veldhuizen, J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J. 8.; Harrity, J. P. A.
Org. Biomol. Chem. 2004, 2, 8-23. (c) Ritter, T.; Day, M. W.; Grubbs, R. H. J.
Am. Chem. Soc. 2006, 128, 11768-11769.

128 (a) FIJrstner, A.; Seidel, G. Tetrahedron 1995, 51, 11165-11176. (b) For
comprehensive review, see: Chemler, S. R.; Trauner, D.; Danishefsky, S. J.
Angew. Chem. Int. Ed. 2001, 40, 4544-4568. (c) For a recent example of
utilizing this reaction in total synthesis, see: Yuan, Y.; Men, H.; Lee, C. J. Am.
Chem. Soc. 2004, 126, 14720-14721.

129 (a) Jung, M. E.; Shaw, T. J. J. Am. Chem. Soc. 1980, 102, 6304-6311. (b)
Wei, C. C.; De Bernardo, 8.; Tengi, J. P.; Borgese, J.; Weigele, M. J. Org.
Chem. 1985, 50, 3462-3467. (c) Kuroda, H.; Miyashita, M.; Irie, H.; Ueno, T.
Chem. Phann. Bull. 1994, 42, 1328-1330. (d) Irie, H.; Matsumoto, K.;
Kitawaga, T.; Zhang, Y. Chem. Phann. Bull. 1990, 38, 1451-1461.

130 Tobia, D.; Rickborn, B. J. Org. Chem. 1989, 54, 778-782.

131 Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114,

301

 

9434-9453.
132 Levin, J. |.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989-993.

133 Cardillo, G.; D’Amico, A.; Orena, M.; Sandri, S. J. Org. Chem. 1988, 53,
2354-2356.

134 Terrell, L. R.; Ward, J. 8., III; Maleczka, R. E., Jr. Tetrahedron Lett. 1999, 40,
3097-3100.

135 For a comprehensive review, see: Kolb, H. C.; VanNieuwenhze, M. 8.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483-2547.

136 Carter, R. G.; Graves, D. E.; Gronemeyer, M. A.; Tschumper, G. S. Org. Lett.
2002, 4, 2181-2184.

137 Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104,
1737-1739.

138 Cutugno, 8.; Martelli, G.; Negro, L.; Savoia, D. Eur. J. Org. Chem. 2001,
517-522.

139 Ager, D. J.; Allen, D. R.; Schaad, D. R. Synthesis 1996, 1283-1285.
140 Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 453-461.

141 Mulzer, J.; Kirstein, H. M.; Buschmann, J.; Lehmann, C.; Luger, P. J. Am.
Chem. Soc. 1991, 113, 910-923.

142 Anderson, E. A.; Alexanian, E. J.; Sorensen, E. J. Angew. Chem. Int. Ed.
2004. 43, 1998-2001.

143 Ms. A. M. Norberg demonstrated that this method could also be applied to
methylation of a substrate similar to 6.16b without silyl migration.

144 For examples, see: (a) Brown, H. C.; Bhat, K. J. Am. Chem. Soc. 1986, 108,
5919-5923. (b) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339-6348.

145 (a) Hackman, B. M.; Lombardi, P. J.; Leighton J. L. Org. Left. 2004, 6,

302

4375-4377. (b) Zhang, X.; Houk, K. N.; Leighton, J. L. Angew. Chem. Int. Ed.
2005, 44, 938-941. (c) Kubota, K.; Leighton, J. L. Angew. Chem. Int. Ed. 2003,
42, 946-948. (d) Bolshakov, 8.; Leighton, J. L. Org. Left. 2005, 7, 3809-3812.

146 (a) Trost, B. M.; Belletire, J. L.; Godleski, 8.; McDougaI, P. G.; Balkovec, J.
M. J. Org. Chem. 1986, 51, 2370-2374. For original Mosher ester analysis,
see: (b) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38,
2143-2147. (c) Ohtani, l.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092-4096.

147 Stork, G.; Takahashi, T. J. Am. Chem. Soc. 1977, 99, 1275-1276.

148 For an excellent review, see: Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed.
2002, 41, 4176-4211.

149 Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844-14845.

150 (a) For S-phos ligand, see: Walker, 8. D.; Barder, T. E.; Martinelli, J. R.;
Buchwald, S. L. Angew. Chem. Int. Ed. 2004, 43, 1871-1876. (b) For
Davephos ligand, see: Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1998, 120, 9722-9723. (c) For other biphenyl-based ligands, see: Wolf,
J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
9550-9561.

151 Bailey, W. F.; Brubaker, J. 0.; Jordan, K. P. J. Organomet. Chem. 2003, 681,
210-214.

152 (a) Uenishi, J.; Beau, J.M.; Armstrong, R. W.; Kishi, Y. J. Am. Chem. Soc.
1987, 109, 4756-4758. (b) Sato, M.; Miyaura, N.; Suzuki, A. Chem. Left. 1989,
1405-1408. (c) Frank, 8. A.; Chen, H.; Kunz, R. K.; Schnaderbeck, M. J.;
Roush, W. R. Org. Left. 2000, 2, 2691-2694.

153 (a) Molander, G. A.; Yun, C.-S.; Ribagorda, M.; Biolatto, B. J. Org. Chem.
2003, 68, 5534-5539. (b) Vedejs, E.; Chapman, R. W.; Fields, S. 0.; Lin, 8.;
Schrimpf, M. R. J. Org. Chem. 1995, 60, 3020-3027. (c) Barder, T. E.;
Buchwald, S. L. Org. Lett. 2004, 6, 2649-2652.

154 Kataoka, N.; Shelby, 0.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002,
67, 5553-5566.

303

 

155 For preparation of (Ind)lr(cod) complex, see: (a) Merola, J. 8.; Kacmarcik, R.
T. Organometallics 1989, 8, 778-784. (b) Crabtree, R. H.; Quirk, J. M.; Felkin,
H.; Fillebeen-Khan, T. Synth. React. Inorg. Met-Org. Chem. 1982, 12,
407-413. (c) Naderer, H.; Siebel, E. Fischer, R. D. J. Organomet. Chem.
1996, 518, 181-187. This material is now commercially available from
Strem (catalogue number 77-0950).

156 For preparation of [lr(OMe)(cod)]2 complex, see: Uson, R.; Oro, L. A.;
Cabeza, J. A. Inorg. Synth. 1985, 23, 126-130. This material is now

commercially available from Strem (catalogue number 77-1100).

157 De Nicola, A.; Einhorn, J.; Luche, J.-L. Tetrahedron Lett. 1992, 33,
6461-6464.

158 Bolton, R.; Sandall, J. P. B. J. Chem. Soc., Perkin Trans. 21977, 2, 278-280.

159 Moschel, R. C.; Hudgins, W. R.; Dipple, A. J. Org. Chem. 1986, 51,
4180-4185.

160 Bakibaev, A. A.; Tignibidina, L. G.; Filimonov, V. D.; Gorshkova, V. K.;
Saratikov, A. 8.; Pustovoitov, A. V.; Dobychina, N. 8.; Pechenkin, A. G.
Khim.-Farm. Z. 1991, 25, 31-35.

161 Kirmse, W.; Rode, J.; Rode, K. Chem. Ber. 1986, 119, 3672-3693.

162 Brittain, J. M.; De la Mare, P. B. D.; Newman, P. A. J. Chem. Soc., Perkin
Trans. 21981, 1, 32-41.

163 Takahashi, K.; Shimizu, 8.; Ogata, M. Heferocycles1985, 23, 1483-1491.

164 Kulkarni, M. G.; Kate, S. D. J. Chem. Soc., Perkin. Trans. 1 2000,
4242-4244.

165 Fischer, A.; Henderson, G. N. Can. J. Chem. 1983, 61, 1045-1052.
166 From AccuStandard.

167 Sun, W.-C.; Gee, K. R.; Klaubert, D. H.; Haugland, R. P. J. Org. Chem. 1997,
62, 6469-6475.

304

 

168 Jackson, K. G. A.; Jones, J. K. N. Can. J. Chem. 1969, 47, 2498-2501.
169 Sibi, M. P.; Rheault, T. R. J. Am. Chem. Soc. 2000, 122, 8873-8879.

170 Brethon, A.; Moreau, J. J. E.; Man, M. W. C. Tetrahedron: Asymmetry 2004,
15, 495-502.

171 Mr. L. A. Sanchez demonstrated that this epimerization is partially attributed
to the excessive iodine and exposure to light during workup. Thus running
the reaction with 1.3 equiv l2 and performing all workup under dark
environment could eliminate the epimerization.

305