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dissertation entitled

OSMIUM TETROXIDE AND OXONE: DEVELOPMENT OF AN

ORGANOMETALLIC OZONOLYSIS REACTION, NOVEL
OXIDATIVE METHODS AND PROGRESS TOWARDS
AMPHIDINOLIDE T1.

presented by

Benjamin Ross Travis

has been accepted towards fulfillment
of the requirements for the

Ph.D. degree in Organic Chemistry

 

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OSMIUM TETROXIDE AND OXONE: DEVELOPMENT OF AN
ORGAN OMETALLIC OZONOLYSIS REACTION, NOVEL OXIDATIVE METHODS
AND PROGRESS TOWARDS AMPHIDINOLIDE T1.

By

Benjamin Ross Travis

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY
Department of Chemistry
2004

ABSTRACT
OSMIUM TETROXIDE AND OXONE: DEVELOPMENT OF AN
ORGAN OMETALLIC OZONOLYSIS REACTION, NOVEL OXIDATIVE METHODS
AND PROGRESS TOWARDS AMPHIDINOLIDE T1.
By
Benjamin Ross Travis

Numerous oxidative and reductive processes are reported in literature. However,
when it comes to oxidatively cleaving olefins to form aldehydes, ketones, carboxylic
acids or esters, there are two primary methodologies, i) Transform the olefin into a 1,2
diol followed by cleavage with NaIO4 (or other oxidants),l’2 or ii) Ozonolysis, in which
the olefin is directly transformed into a variety of functionalized products depending on
the workup conditions.3’4 We have now developed a methodology that mimics
ozonolysis; i.e., directly oxidize and cleave an olefinic bond to yield carbonyl
compounds.

We have pursued this goal using metal catalysts capable of activating the C-C
scission under very mild conditions. Our results to date have been promising in terms of
achieving the set goals. Osmium tetroxide mediated oxidative cleavage of olefins with
Oxone (2KHSOs-KHSO4-KZSO4) as the preferred co-oxidant has led to oxidative
cleavage of vinyl groups to yield aldehydes, carboxylic acids, methyl esters and
lactones.5'6 Additionally, we have investigated the purification of the Oxone triple salt to
KHSOS,7 which has been invaluable for our kinetic studies of the aldehyde oxidation to
prepare carboxylic acids and esters.8 The oxidative cleavage methodology has now been

applied to the total synthesis of tanikolde9 and erythromycin B10 and is currently a key

step in our approach to amphidinolide T1.

10.

References

Kolb, H. C.; Vannieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
Schroder, M. Chem. Rev. 1980, 80, 187.

Criegee, R. Angew. Chem. Int. Ed. 1975, I4, 745.

Bailey, P. S. Chem. Rev. 1958, 58, 925.

Schomaker, J. M.; Travis, B. R.; Borhan, B. Org. Lett. 2003, 5, 3089.

Travis, B. R.; Narayan, R. 8.; Borhan, B. J. Am. Chem. Soc. 2002, 124, 3824.

Travis, B. R.; Ciaramitaro, B. P.; Borhan, B. Eur. J. Org. Chem. 2002, 2002,
3429.

Travis, B. R.; Sivakumar, M.; Hollist, G. 0.; Borhan, B. Org. Lett. 2003, 5, 1031.
Schomaker, J. M.; Borhan, B. Org. Biomol. Chem. 2004, 2, 621.

Hergenrother, P. J .; Hodgson, A.; Judd, A. S.; Lee, W.-C.; Martin, S. F. Angew.
Chem. Int. Ed. 2003, 42, 3278.

For Heather, Matthew, and Lucy

iv

ACKNOWLEDGEMENTS

This dissertation would be incomplete without the mention of all those who
contributed to my successful graduate career. Babak Borhan has been an enthusiastic
advisor who continues to challenge each student to the limits of their ability. Over the
past five years, I have seen Babak grow, change, learn, teach, and get tenure and I know
that I too have done many of the same. He continues to be supportive of my decisions
and has always let me be independent and explore my own ideas. I would also like to
thank Profs. Maleczka, Baker, Smith and Weliky for serving on my committee at various
times along with the advice they have provided over the years.

The friends I have in the group and in the department have been a great source of
support. I would especially like to thank Jim Salvador who carpooled or biked in with
me; Jun Yan who helped me finish a couple projects along with several hours of typing as
it got close to crunch time; and Meena who was an intellectual inspiration. I have greatly
enjoyed the time I spent with Tao, Chryssoula, Courtney, Montse, and Marina who all
worked in close, and I mean close proximity to me for several years. Also the past and
new graduate students, Rhada, Qifei, Rachel, Stuart, Dan, Somnath and Shang were great
colleagues.

I am grateful for the support of my parents and the rest of the family, especially
my loving wife, whom have been crucial to my success. Heather has endured long hours,
grumpy moods, too much fast food, and basically just not seeing me without too much
discontent. She was a constant encouragement every step of the way. Over the past year

she has carried our baby who arrived August 16, 2004 at 5:31 am, just one week afier my

defense. His name is Matthew Ross Travis and is the most precious thing in the world.
My family (Heather, Matthew, and Lucy (the St. Bernard)) is what brings joy into my life

and is the reason I could finish this thesis with my sanity intact.

vi

TABLE OF CONTENTS

LIST OF TABLES ................................................................................... xi
LIST OF FIGURES ................................................................................ xiii
LIST OF SCHEMES ................................................................................ xiv
LIST OF ABBREVIATIONS .................................................................... xvii
Chapter 1. Osmium Tetroxide and Oxone: A Brief Review ..................................... 1
1.1. Introduction .................................................................................. l
1.2. Osmium Tetroxide .......................................................................... 2
1.3. Oxone ......................................................................................... 8
1.3.1. History ................................................................................. 8

1.3.2. Organic Transformations ........................................................... 10
1.3.2.1. Epoxidation of Olefins ...................................................... 11

1.3.2.2. Heteroatom Oxidations ...................................................... 13

Chapter 2. 2,3,5-Trisubstituted Tetrahydrofurans ............................................... 16
2.1. Introduction ................................................................................. 16
2.1.1. Annonaceous Acetogenins ......................................................... 17

2.1.2. Arachidonic Acid Metabolism .................................................... 18

2.1.3. Approaches to 2,3,5-Trisubstituted THF Diols ................................. 22

2.2. Oxidative Cyclization Approach to Trisubstituted THF Core ...................... 26
2.2.1. Initial Results ......................................................................... 29

2.2.2. Improvement Strategies ............................................................. 32

2.2.3. Optimized Reaction Conditions .................................................... 35

vii

2.2.4. Mechanistic Proposal ............................................................... 36

2.2.5. Other Substrates ...................................................................... 41

2.2.6. Final Improvements ................................................................. 42

2.2.7. Conclusions .......................................................................... 42
Chapter 3. Preparation of Purified Oxone and its Soluble Form by Simple and Efficient

Methods ................................................................................................. 44

3.1. Introduction ................................................................................. 44

3.2. Initial Purification Methods ............................................................... 46

3.3. Purification Method Development ....................................................... 47

3.3.1. Preparation of Purified Oxone ..................................................... 47

3.3.2. Preparation of Soluble Oxone (TBA-OX). ...................................... 49

3.3.2.1. Background .................................................................... 49

3.3.2.2. TBA-OX Method Development: Preparation from Oxone ............ 50

3.3.2.3. TBA-OX Method Developnment: Preparation from KHSOs°HzO...51

3.4. Solubility ..................................................................................... 52
3.5. Peroxysulfate Salts as Oxidizing Reagents ............................................. 54
3.6. Work-up Protocols ......................................................................... 55
3.7. Conclusions ................................................................................... 56

Chapter 4. Osmium Tetroxide Promoted Catalytic Oxidative Cleavage of Olefins. An

Organometallic Ozonolysis ......................................................................... 58
4.1. Introduction ................................................................................. 58
4.2. Initial Observations ......................................................................... 62
4.3. Results ....................................................................................... 63
4.4. Mechanistic Proposal ...................................................................... 67

viii

4.5. Other Examples ............................................................................. 69

4.6. Conclusions ................................................................................. 72

Chapter 5. Oxidative Cleavage Extensions ...................................................... 73

5.1. Introduction ................................................................................. 73

5.2. New Oxidative Cleavage Methods ..................................................... 73

5.2.1. Preparation of Aldehydes with KHC03 .......................................... 73

5.2.2. Finding a New Oxidant via OsO4 Complexes ................................... 78

5.2.3. Preparation of Aldehydes with H202 ............................................. 80

5.2.4. Preparation of Esters with KH805 ................................................ 91

5.2.5. Preparation of Lactones with Oxone .............................................. 95

5.3. Conclusions ............................................................................... 102
Chapter 6. Oxidation of aldehydes and a- and B-diones or a-ketoalcohols to provide

carboxylic acids and esters ........................................................................ 103

6.1. Introduction ............................................................................... 103

6.2. Oxidations of Aldehydes ................................................................ 103

6.2.1. Preparation of Carboxylic Acids ................................................ 103

6.2.2. Preparation of Esters .............................................................. 108

6.3. Oxidations of a-diones, B-diones and a-ketols ...................................... 110

6.3.1. Preparation of Esters .............................................................. 111

6.4. Mechanistic Interpretation ............................................................. 116

6.4.1. Aldeyhde Oxidations ............................................................. 116

6.4.1.1. Initial Observations ......................................................... 117

6.4.1.2. Results ........................................................................ 120

6.4.1.2.]. NMR and GC Experiments .......................................... 120

ix

6.4.1.2.1. Kinetics ................................................................ 124

6.4.2. a-Diones, B—Diones and a-Ketols ................................................ 129

6.5. Conclusions ................................................................................ 133
Chapter 7. Experimental Details ................................................................. 135
7.1. General Information ..................................................................... 135
7.1.1. Orgins of Starting Materials ..................................................... 136

7.1.2. List of Compounds that were Compared with the Aldrich Database. 138

7.1.3. List of Compounds that were Compared to Literature Reports ............. 139

7.2. Data for Chapter 2 ....................... . ................................................. 140
7.3. Data for Chapter 3 ........................................................................ 148
7.4. Data for Chapter 4 ........................................................................ 153
7.4.]. Additional Data Related to Chapter 4 ........................................... 160

7.5. Data for Chapter 5 ........................................................................ 161
7.6. Data for Chapter 6 ........................................................................ 166
REFERENCES ...................................................................................... 174

LIST OF TABLES

Table 11-1. Initial attempts to prepare 2,3,5-THF-diol 11-18 .................................. 31
Table 11-2. Solvent effects on the cyclization of ML .......................................... 33
Table 11-3. Co-oxidant effects on the cyclization of ML ...................................... 34
Table 11-4. Temperature and Oxidant Effects of ML Cyclization in DMF ................. 35
Table III-1. Solubility profiles of various XHS05 Salts ....................................... 53
Table 111-2. Oxidation of various functionalities with Oxone and soluble Oxone. . . . . ....55
Table IV-l. Oxidative cleavage of simple olefins ............................................. 64
Table IV-2. Oxidative cleavage of assorted olefins ........................................... 66
Table IV-3. Additional oxidative cleavage examples .......................................... 71
Table V-l. Oxidations of benzaldehyde in the presence of base ............................. 74
Table V-2. Oxidative cleavage of V-l with base ............................................... 75
Table V-3. Oxidative cleavage of aryl olefins to aldehydes .................................. 76
Table V-4. Osmate esters of V-l and V-4 ...................................................... 78
Table V-5. Varying amounts of additive in various solvents ................................. 81
Table V-6. Various oxidants and substrates .................................................... 83
Table V—7. Various osmium tetroxide sources ................................................. 85
Table V-8. Oxidative cleavage with various additives ......................................... 86
Table V-9. Oxidative cleavage of various olefinic substrates with H202 ................... 88
Table V-lO. Oxidations of Alkyl olefins with H202 ........................................... 90
Table V-11. Oxidations of alkyl olefins in the presence of Si02 ............................ 91
Table V-12. Oxidative cleavage of olefins to esters ........................................... 93

xi

Table V-13. Oxidative lactonization of alkenols ............................................... 99

Table VI-l. Oxone oxidations of aromatic aldehydes ....................................... 104
Table VI-2. Oxidation of assorted aldehydes ................................................. 106
Table VI-3. Oxidation of VI-7 to VI-7a in various solvents ................................ 107
Table VI-4. Oxidation of aldehydes to esters ................................................. 109
Table VI-5. Oxidation of a-diones, B-diones and a-ketols in MeOH ..................... 113

Table VI-6. Oxidation of a-diones, B-diones and a-ketols in EtOH and iPrOH.......115

Table VI-7. Rate constants of the oxidation of benzaldehyde by KH805 at 298 K ...... 125
Table VI-8. Temperature effects on rate ....................................................... 126
Table VI-9. Substitutent effect at 298 K ........................................................ 128
Table VI-lO. Equivalents of Oxidant Necessary for Complete Conversion ............... 133

xii

LIST OF FIGURES

Figure [-1. Typical osmate ester structures and typical IR stretching bands ................. 3
Figure 1-2. Ligands for asymmetric dihydroxylation ............................................ 6
Figure I-3. Chiral ketone precursors for dioxirane epoxidations ............................. 13
Figure II-l. Representative examples of Annonaceous acetogenins ......................... 16
Figure II-2. Representative examples of implicated 2,3,5-AA-THF diols .................. 17
Figure II-3. Structure of adriamycin .............................................................. 18
Figure II-4. Bis-metaloxetane intermediate and resultant THF-diol ......................... 37

Figure II-5. Standard and 3-D projections of reactive intermediates II-43 and II-44. ....41

Figure III-1. Extraction of TBA-OX from Oxone into CH2Cl2 with various equiv. of

nBu4NHSO4 .......................................................................................... 51
Figure IV-l. Structure of IV-21b ................................................................ 67
Figure IV-2. Side products from Table IV-3 entry 7 .......................................... 72
Figure IV-3. Desired products from Table IV-3 entries 11, 12 and 13 ..................... 72
Figure V-l. Products from the oxidative cleavage of methylcyclohexene .................. 74
Figure V-2. Proposed structure of one of eight cis complexes ............................... 79
Figure V-3. Structures of isolated products from Table V-lO ................................ 90
Figure VI-l. NMR study of hexanal oxidation ................................................ 123

xiii

LIST OF SCHEMES

Scheme 1-1. Dihydroxylation of olefms with osmium tetroxide ............................... 2
Scheme I-2. Initial cycloaddition—[2+2] versus [3+2] ....................................... 4

Scheme 1-3. Lemieux-Johnson oxidative cleavage of olefins ................................. 5

Scheme I-4. The second catalytic cycle ........................................................... 7
Scheme 1-5. Optimized AD conditions with cinchona alkaloid ligands ...................... 7
Scheme I-6. Known oxidative pathways for Oxone ............................................ 10
Scheme 1-7. Epoxidations with metalloporphyrins and Cqu ................................ 11
Scheme I-8. Iminium salts as epoxidation catalysts ............................................ 12
Scheme 1-9. General catalytic epoxidation with dioxiranes .................................. 13

Scheme I-lO. Generalized Baeyer-Villiger reaction with KHS05 ........................... 14
Scheme I-11. Baeyer-Villiger oxidation of aldehydes ......................................... 14
Scheme I-12. Oxidation of a- and B-diones or a-ketols ....................................... 15
Scheme I-13. Oxidation of a-nitro ketones via the Nef reaction ............................ 15

Scheme II-l. AA metabolites via three different enzymatic pathways ...................... 20
Scheme II-2. Proposed biosynthesis of AA-THF-diols ....................................... 21

Scheme II-3. Regiochemically controlled epoxide openings ................................. 23

Scheme II-4. Regiochemically controlled epoxide openings—competing nucleophiles.24
Scheme II-5. Trimethylsulfoxonium iodide epoxide opening to form oxetanes ........... 24
Scheme II-6. Trimethylsulfoxonium iodide epoxide opening to form THFs ............... 24
Scheme II-7. Conversion of syn diols to epoxides via an orthoester ........................ 25
Scheme II-8. Intramolecular trapping of an orthoester to prepare THFs .................... 25

xiv

Scheme II-9. Oxidative cyclization of 1,5 and 1,6-dienes .................................... 27

Scheme II-lO.

Scheme II-l 1.

Scheme II-12.

Scheme II-13.

Scheme II-14.

Scheme II-15.

Scheme II-16.

Examples of enantioenriched oxidative cyclizations ........................ 27
Preparation of C-21 to C-3O of salinomycin .................................. 28
Synthesis of (+)-anhydro-D-glucitol and D-chitaric Acid .................. 29
Putative oxidative cyclization pathway ........................................ 29
2,3,5-THF diols from bis-epoxides ............................................. 3O
Diols do not oxidatively cyclize ................................................ 36

Proposed KMnO4 oxidative cyclization via an initial [3+2]

cycloaddition ......................................................................................... 38

Scheme II-17.
Scheme II-18.
Scheme II-19.
Scheme II-20.
Scheme II-21.
Scheme III-1.
Scheme III-2.
Scheme III-3.
Scheme IV-l.
Scheme IV-2.
Scheme IV-3.
Scheme IV-4.
Scheme IV-5.
Scheme IV-6.

Scheme IV-7.

Proposed 0504 oxidative cyclization via an initial [3+2] cycloaddition..38
Oxidative cyclization with stoichiometric 0504 and TMEDA ............ 39

Proposed mechanistic pathways for the 1,4 diene oxidative cyclization..40

Oxidative cyclization of 9,12-trans-methyl lineolate ........................ 42
Final improvements of the oxidative cyclization of ML .................... 42

Known oxidative pathways for Oxone ......................................... 44
Anhydrous oxidation of sulfides to sulfones with TBA-0X ............... 45

Selective oxidative deprotections with TPPB-OX ........................... 46
Various pathways of ozonolitic workup ....................................... 59
Reactions with Os, Mn, and Ru oxides ........................................ 60
General periodate oxidations ................................................... 61
Green oxidative cleavage of cyclohexene with Na2W04 .................... 61
Initial 0504—Oxone results ..................................................... 62
Requirement of 0304 for oxidative cleavage of olefms ..................... 62
Selective oxidative cleavage with 0304—Oxone—DMF ................... 63

XV

Scheme IV-8. Diols are not intermediates ...................................................... 68

Scheme IV-9. Proposed catalytic cycle ......................................................... 69
Scheme V-l. Envisioned oxidative cleavage / kinetic resolution ............................ 87
Scheme V-2. One pot oxidative cleavage with two different oxidants ...................... 95
Scheme V-3, Intramolecular trapping of an aldehyde with an alcohol ...................... 95
Scheme V-4. Envisioned one pot oxidative lactonization .................................... 96
Scheme V-5. Oxidative lactonization: proof of concept ....................................... 97
Scheme V-6. Oxidative lactonization with TBA-0X ........................................ 101
Scheme V-7. Total synthesis of (+)-Tanikolide via an intramolecular oxidative

lactonization ........................................................................................ 101
Scheme VI-l. Dakin products from electron rich aromatic aldehydes ..................... 105
Scheme VI-2. Prior studies with Oxone cleavages ........................................... 111
Scheme VI-3. Proposed mechanism of Oxone promoted oxidations ...................... 116
Scheme VI-4. Presumed structures, VI-52, of isolated acetal intermediates .............. 118
Scheme VI-5. Intramolecular epoxidation provides y-lactone .............................. 1 19
Scheme VI-6. Oxone does not epoxidize under identical conditions ...................... 119
Scheme VI-7. 180 Labeled oxidations of benzaldehyde ..................................... 121
Scheme VI-8. Not just a Fischer esterification ................................................ 130

Scheme VI-9. Probable mechanistic routes for the oxidative cleavage of a-diones. . . ..131
Scheme VI-lO. Probable mechanistic routes for the oxidative cleavage of B—diones. . . 131

Scheme VI-l 1. Probable mechanistic routes for the oxidative cleavage of a-
hydroxyketones .................................................................................... 1 32

xvi

3»

aq

CH2C12
CI

CSA

DBU
DCC
DCM
de

DI
DIAD
DIBAL
DIPEA
DMAP

DMDO

LIST OF ABBREVIATIONS
angstrom
arachidonic acid
acetyl
acetonitrile
asymmetric dihydroxylation
Aryl
aqueous
dihydrobispyrazolylborate
dichloromethane
chemical ionization
camphorsulfonic acid
cyclohexyl
1 ,8-diazabicyclo[5,4,0]undec-7-ene
dicyclohexylcarbodiimide
dichloromethane
diasteromeric excess
deionized
diisopropyl azodicarboxylate
diisobutylalurninurn hydride
diisopropylethyl amine
4-(dimethylamino)pyridine

dimethyl dioxirane

xvii

DME
DMF
DMP
DMSO
131350
ee

EI

eq
equiv
FAB

GC

HMPA
HRMS
HWE
IBX
KHMDS
LiHMDS
mCPBA
Mes

mL

ML

mmol

dimethoxyethane
N,N-dimethylformamide
dess-martin periodinane

dimethyl sulfoxide

Effective Dose to 50 percent
enantiomeric excess

electric ionization

equation

equivalent

fast atom bombardment

gas chromatography

hour

hexamethyl phosphoramide

high resolution mass spectrometry
Homers-Wadsworth-Emmons reaction
2-iodoxybenzoic acid

potassium bis(trimethylsilyl)amide
lithium bis(trimethylsilyl)amide
m-chloroperbenzoic acid

mesityl

milliliter

methyl lineolate

millimole

xviii

MS
NaHMDS
NBS
NMM
NMO
NMR
NMP
NOE
0304

Ph

PMB
PPTS
PTSA
RT
TBAF
TBA-OX
TBS
THF
THP
TMEDA

TMS

mass spectrometry

sodium bis(trimethylsilyl)amide
N-bromosuccinimide
n-methylmorpholine
n-methylmorpholine-n-oxide
nuclear magnetic resonance
N-methyl-Z-pyrrolidinone
nuclear Overhauser effect
osmium tetroxide

phenyl

p-methoxybenzyl

pyridinium para-toluenesulfonate
p-toluenesulfonic acid

room temperature
tetrabutylammonium fluoride
tetra-n-butylammonium peroxymonosulfate
t-butyldimethylsilyl
tetrahydrofuran

tetrahydropyran
tetramethylethylenediamine

trimethylsilyl

xix

Chapter 1. Osmium Tetroxide and Oxone: A Brief Review
1.1. Introduction

Over the past twenty-five years in organic chemistry an enormous amount of
progress has been achieved. This includes numerous modifications for existing processes
to make them milder, higher yielding, and cheaper not to mention catalytic and/or
asymmetric. At the outset of the Ph.D. research that will be discussed herein we realized
the obvious, oxidations and reductions are key reactions for organic chemists. In
particular, our laboratory had an interest in oxidative chemistries to prepare 2,3,5-
trisubstituted tetrahydrofuran (2,3,5-THF) diols, which are known metabolites of
arachidonic acid (AA) metabolism. Additionally, an example of a natural product that
contains such a substitution pattern exists in a class of compounds known as the
Anneaceous acetogenins, specifically mucoxin (See Chapter 2).

We were interested in examining various oxidative processes including chromium
oxidations of alcohols and aldehydes (Jones, PCC, PDC, etc), hydroxylations,
dihydroxylations, aminohydroxylations, epoxidations, aziridinations, metal assisted
oxidative cleavage of alkenes and alkynes, the oxidative cleavage of diols, and
ozonolysis.l 1'20 We believed that the importance of these reactions cannot be overstated,
and that the need for new, more efficient, and milder reactions with unique properties
would only increase the repertoire of tools organic chemists could use to tackle the
syntheses of complex molecules on both laboratory and industrial scales or for high
valued commodities and pharmaceuticals. It is with these ambitious aims that we

approach organic synthesis methodology.

The question, however, was with what approach we should tackle our specific
problem: An efficient way to prepare 2,3,5-trisubstitutedtetrahydrofuran diols. Our
answer to this question has led us down a wandering path that has allowed for the
development of methodologies in several areas and focuses on two reagents, osmium
tetroxide (0504) and Oxone® (2KHS05-KHSO4-K2SO4). These reagents, when used in
conjunction, allow unique reactions to proceed with unexpected ease. It is interesting to
note that individually, both 0504 and KH805 (the active peroxysulfate portion of Oxone)
have had an interesting history of discovery and implementation and as such will be
reviewed briefly throughout the remainder of this chapter.

1.2. Osmium Tetroxide

Osmium tetroxide has long been known for its reactivity towards unsaturated
species to provide cis-diols."2 Hofmann first demonstrated this using catalytic 0304 with
sodium or potassium chlorate to dihydroxylate alkenes, and Milas later extended this
work by demonstrating that hydrogen peroxide is also an effective oxidant for this

process (Scheme 1- 1 ).21’23

Scheme l-1. Dihydroxylation of olefins with osmium tetroxide

0804
/=\ HO OH

 

R1
oo-oxidant R R1

F1 and R‘ = numerous possibilities
Co-oxidant = KCIOa, H202, tBuOOH,
NMO, NaCIO,, oxygen, NalO,_ K3Fe(CN)6
Criegee was the first to demonstrate that the dihydroxylation pathway was

directly linked to 0504 by performing stoichiometric reactions to generate diols.2425 He

suggested that osmium(VI) ester complex was an intermediate, which could either be

hydrolyzed directly to yield 0503 or reoxidized to the osmium(VIII) ester. The

osmium(VI) ester complex is generally green and has infrared bands near 980 cm'1
(Os=0 stretching), 580 cm], and 630 cm'l (Os—O stretching) (Figure I-l). Crystal
structures have revealed three predominate forms of osmate esters, two are dimeric
monoesters and the other is a diester. All of these osmate ester forms predominate in a
square pyramidal geometry. The addition of tertiary amines has been shown to increase
the rate of osmate ester formation, and the resultant crystals are typically brown,
octahedral complexes. Here the O=Os=0 asymmetric stretching frequency is typically
near 840 cm’I (Figure I-l). Many related osmium crystal structures, along with numerous

examples of normal dihydroxylation, have now been reviewed in the literature.”27

Figure I-1. Typical osmate ester structures and typical IR stretching bands

980 cm-1

 

 

 

 

 

 

 

o. ..... ......o H ...o__ _o. ......
.......... Os‘” 0:
:O/: \ 0/ \ O_, _/° ‘°’O\
630cm-1 840cm1
o of o
:0. ................... .. _ r—o, ...... jg, ...... .
. o/O L\:/|O|\O_ . '—O/H\L
L=teniaryamine

While the interrnediacy of an osmate ester has not been the subject of debate in
dihydroxylation chemistry, the route by which the osmate is formed has been. The two
schools of thought have been either a direct [3+2] cycloaddition 28 29 or a [2+2]
cycloaddition followed by ring expansion. Sharpless et al in 1977 initially favored the
[2+2] cycloaddition pathway based upon the observation that nucleophilic attack upon
carbonyls occurs on carbon, not oxygen. Thus, by analogy, the more electropositive

osmium center should favor attack (Scheme I-2).3O’3 ‘ Additionally, metallocyclobutanes

are well known in olefin metathesis chemistry?”34

The differences in the two pathways
potentially explain the differences in rate of dihydroxylation in the presence or absence of
a tertiary amine whereby the ligand could potentially promote the osmium-carbon bond
cleavage and the subsequent ring expansion. Twenty years later, Houk, Singleton,
Sharpless et al essentially recounted the [2+2] cycloaddition pathway after comparing
high-precision experimental kinetic isotope effects with high-level transition structure
calculations in which their experimental results match quite favorably with their
calculations with a [3+2] mechanism and not the [2+2] osmaoxetane or the ring
35

expansion.

Scheme l-2. Initial cycloaddition—[2+2] versus [3+2]

 

 

A ——O Zl-
0\ 4’0 [2+2] coco
/ \\ = s
O

o \..||\\o
U . o
/ I-s

 

 

I \\O +L
L \
F6 0
||/\°>//° ...... _ +_o., ,,,,, it .....
AOOSQO +7“- ' LO/||\L
0

1-7
a) Possible route of interconversion from osmaoxetane (I-5) to osmate ester (W)

In addition to hydrogen peroxide and potassium chlorate, various other oxidants
are effective co-oxidants including tBuOOH, NMO, NaClO4, oxygen, NaIO4 and
K3Fe(CN)(, (Scheme I-l).21’22’3M3 Selectivity and over oxidation are known problems of
the cis-dihydroxylation process but can generally be avoided by the appropriate choice of

oxidant, solvent, and reaction temperature. In the case of NaIO4, this over oxidation is

4

most prominent and is referred to as the Lemieux-Johnson reaction (Scheme I-3).44’45

Here, in one pot, the normal resultant diol can independently be oxidatively cleaved into
two respective aldehydes. Unfortunately, the NaIO4 reaction is not selective for just the
newly formed diol but for any diol present in the molecule, making prior protection of
vicinal diols a necessity. In addition, further over oxidation (to carboxylic acids) makes

this reaction less desirable.

Scheme l-3. Lemieux-Johnson oxidative cleavage of olefins

 

 

 

'00
030 cat. NalO H04” OH O O
Rm— ..1 “ ’“0 °” ‘ o/l'to JL + .JL
Naio4 R R‘ >_/’< R H R H

Ft R1

It has been noted that over the last two decades asymmetric reactions have
become an invaluable asset to organic chemists. This has definitely been true for
dihydroxylation chemistry such that numerous ligands have now been developed for
asymmetric dihydroxylation.l Several general features and classes of ligands emerge as
good asymmetric inductors (Figure I-2). The most prominent feature of such ligands is a
tertiary amine. This element is crucial to enhance the rate of the dihydroxylation overall
and was first noted by Criegee utilizing pyridine and stoichiometric amounts of 0304.24’25
Sharpless and Hentges began their asymmetric efforts based on the pyridine observation
using chiral pyridine derivatives.46 However, these attempts failed due to low 0504
affinity, and changing to the chichona alkaloids proved to be essential for their research.46
1,4-Diazabicyclo[2.2.2]octane derivatives failed to give useful enantiomeric excess
(<41% ee). More recently, chiral diamines have provided good to excellent enantiomeric
excesses, but their bidentate nature provides stable chelates which are resistant to

hydrolysis. Therefore stoichiometric oxidative conditions are required.4749

Figure l-2. Ligands for asymmetric dihydroxylation

   

NRR1

...OH fi‘v ...NRR‘
[Nikon CL
OR

 

N R=TBDPS R = H, R‘: neohexyl

H.131: Me
DHQD DHQ

The first examples of chichona alkaloids as chiral auxiliaries for asymmetric
dihydroxylation reaction were also stoichiometric in 0304 and were thus cost prohibitive
to run on large scale. Introduction of NMO as a co-oxidant eliminated this problem but
initially provided lower enantiomeric excesses than with the comparable stoichiometric

5° The problem was found to be a competitive second achiral catalytic cycle

reaction.
involving a bisosmate (Scheme I-4). Slow addition of the olefin substrate helped to
alleviate the second catalytic cycle,51 but the real advance came by using K3Fe(CN)6 as
the co-oxidant in a biphasic system.52 This modification essentially eliminated the
second catalytic cycle because only 0504 remains in the organic phase while the co-
oxidant and the reduced osmium(VI) species are found in the aqueous layer. Finally,
utilization of K20804°2H20 as a nonvolatile source of osmium has allowed for the
preparation and sale of a premixed system conventionally referred to as “AD-mix,” and
the introduction of methanesulfonamide has greatly decreased reaction times.
Additionally, reactions enantiomeric excesses remain unchanged or are even enhanced
(Scheme 1-5).37 Moreover, complementary cinchona alkaloids can selectively
dihydroxylate either the a or B face of the olefin which can be predicted using a reliable

mnemonic.53’54 The substrate scope for this chiral cis-dihydroxylation is very general,

and numerous examples can be found in the literature."2

Scheme 14. The second catalytic cycle

HO;_( OH F1H
Primary Cycle Secondary Cycle g'Os
High ee Low ee 01:

I3

0’?”
O: 's. O
I O

F1>_4 Ft

Scheme l-5. Optimized AD conditions with cinchona alkaloid ligands

 

20H 2H20
2Fe(CN)63‘ 2Fe(CN)e*

1.3. Oxone
1.3.1. History

Caro’s acid (H2805), first reported in 1898, has had an intriguing 100 year
history.55’56 For nearly a decade the constitution of Caro’s acid was not known, and
several references debate various possible formulas, the most probable of which were
H2S209 and H2805. Even after fifty years of research, the constitution of Caro’s acid was
only “generally accepted” as H2S05. However, persistence prevailed, and in 1984 two
independently obtained crystal structures of the potassium salt were published.”8 These
results confirmed not only the constitution of Caro’s acid as H2805 but also the structure
of the KH805 salt as a peroxysulfate unambiguously. Caro’s acid is a potentially
explosive substance that proved to be difficult to isolate, purify, and identify, but it now
exists as a shelf stable triple salt (2KHS050KHSO4-K2SO4) sold under the trademark
name of Oxone.”63

While Oxone is a convenient and cheap triple salt (~810/Kg), there is only ~50%
of active oxidant per mol of the triple salt. Several methods have been developed to
prepare the pure potassium salt of peroxymonosulfate, yet these purified oxidants have
not proven to be synthetically useful, most probably due to the less than convenient
procedures necessary to purify the oxidant. For example, in 1985, Appleman et a1.
isolated and characterized pure KH805 and KHSOs-H2O by passage of sodium
peroxydisulfate (N a2S2Og) through a cationic ion exchange resin followed by hydrolysis
of the peroxydisulfate at 50 °C to yield equal molar peroxymonosulfate and bisulfate.
Adjustment of the pH with KHCO3 and lyophylization yielded the purified

KHSOs-H2O.(’4 The purification of KHSOs°H20 was revisited by Connick et al. in the

early 90's along with a modified method for its preparation.65 Essentially a
straightforward filtration protocol starting from Oxone, followed by evaporation and
crystallization, resulted in the isolation of analytically pure KHS05°H20. Again, this
method received little attention from organic chemists, perhaps due to its limitations upon
scale-up where the removal of large volumes of water is required.

Prior to either Appleman or Connick’s attempts to purify KHSOs, Adam66 in 1979
utilized the bis(trimethylsilyl)peroxymonosulfate prepared from
bis(trimethylsilyl)peroxide with S03 for the Baeyer-Villiger reaction of ketones to esters.
In the mid 80’s, Dehmlow et al. reported a methodology to prepare several tetraalkyl
ammonium salts of Oxone by cationic exchange of Oxone. These include ammonium
peroxymonosulfate, tetra-n-butylammonium peroxymonosulfate (TBA-OX), tetra-n-
pentylammonium peroxymonosulfate, and tetra-n-hexylammonium
peroxymonosulfateffl’68 However, only in 1988 did Trost and coworkers popularize TBA-
OX as an organic soluble form of Oxone that was capable of oxidizing sulfides to
sulfones under anhydrous conditions.68 In 2000, Haj ipour developed a method to prepare
Ph3PBnHSOs (TPPB-OX).69'71 This interesting phosphoniurn salt has been used for the

oxidative deprotection of TMS and THP ethers, among other things.

The active oxidant within the mixture of Oxone, peroxymonosulfate (HSOs'), has

been the subject of study in various fields ranging from atmospheric science to physical,

computational, and organic chemistry. For example, HSOs' is proposed to be an

intermediate in atmospheric oxidation of sulfur, and it is hypothesized that 35% of the
total sulfur species in clouds exist as HSOs'.72’73 The standard electrochemical potential

of HSOs' and the mode of H80; decomposition have also been evaluated, but reaching

“'79 Other physical characteristics

numerical consensus have been issues of contention.
have been less debatable, and in the mid-eighties the molecular and vibrational spectra of
KH305 and KHSOs°H2O in aqueous solution were reported by IR and Raman along with
two independently solved crystal structures.”’58 These data have been revisited and
confirmed by computational experimentation. Organic chemists have also found
peroxymonosulfate to be an intriguing molecule, especially since it has been utilized for
numerous organic transformations.
1.3.2. Organic Transformations

Over the past twenty years, Oxone has become a very popular oxidant for the
preparation of dimethyl dioxirane in situ from acetone and buffered water to epoxidize
olefins.”86 Additionally, Oxone has been quite remarkable for its effective oxidations of
boron, sulfur, nitrogen, and phosphorous.68’87'93 However, the earliest use of the free acid
(Caro’s Acid, H2805), before its constitution was fully understood, was in Baeyer-
Villiger chemistry.66 This area has also grown significantly over recent years and now
includes oxidations of a- and B-ketones, aldehydes, or a-amino acids with Oxone to

name a few.”99

Scheme l-6. Known oxidative pathways for Oxone

69 e
RaN—oo RCO2H R3P=O

 

10

1.3.2.1. Epoxidation of Olefms

There are some examples of epoxidation in which KHS05 is simply the oxygen
donor to an active metal complex that subsequently undergoes epoxidation. Meunier for
one has used iron metalloporphyrins to epoxidize simple olefins where aqueous KH805

”(“02 Copper dihydrobispyrazolylborate (Cqu) With PH 7

was the active oxidant.
buffered Oxone proved to also be an efficient epoxidation protocol however, small
amounts of oxidative cleavage were observed.103

Scheme I-7. Epoxidations with metalloporphyrins and Cqu

KHso5 Cqu o
: /= F + PhCHO
Ph Oxone. pH = 7 Ph
> 85 <5 °/o

70 % isolated

 

 

G)
H, .H
8”: O’EWO

In addition to metal complexes that transfer oxygen, there are several examples
where organic molecules themselves act as the oxygen electrophile. For instance,
oxaziridinium salts are one such example and contain highly electrophilic oxygens that
can be transferred effectively to alkenes or thioethers; however, the isolation of such salts
can be quite difficult. Oxone has been shown to effectively oxidize the requisite
iminium salt to the oxaziridinium salt104 in situ thus allowing the iminium salt to be used
in substoichiometric quantities (10 mol %).1°5"°7 Modifications to prepare chiral
iminium salts do indeed provide epoxidation products with varying levels of

enantiomeric excess (% ee) (Scheme I-8).'08'109

11

The primary role of organic compounds to serve as oxygen donors has been in the
area of DMDO epoxidation. A significant advance in this area was to move away from
the acetone-derived oxidant DMDO and instead prepare dioxiranes of chiral ketones.
Examples include fructose-derived ketones by Shi et al., [3.2.1] chiral ketobicycles by
Armstrong et al., and modified 1,1’-biphenylketones that can now in situ generate chiral
dioxiranes which in turn provide chiral epoxideslm'124 This asymmetric application has
proven general and allows for a wide variety of olefins to be epoxidized with high % ee.

Scheme l-8. Iminium salts as epoxidation catalysts

KH805
(>3? a?

R
Ph ”‘9
R 1: 30% ee
R 2 I 40°/o 96
+ _.
Br
N‘R
P] h oosoax

m2“ Br— KHso4
I R
)3...Me
R 1 = J R 2 = ’3’.
HO "'Ph

Scheme I-9. General catalytic epoxidation with dioxiranes

O
R1JL R2
Rad/R4
KH805
Ra/\/R4 KHSO4
O-O
R1XR2

3:501 88 is

Shi Yang Armstrong
1.3.2.2. Heteroatom Oxidation
Other advances include selective oxidations of boron, nitrogen, phosphorous, and

68'87'93 Most generally, boronic acids or

sulfur containing compounds (Scheme I-6).
boronic esters are oxidatively hydrolyzed to the corresponding alcohol, while nitrogen,
phosphorous, and sulfur are oxidized to their respective oxides. Interestingly, with extra
oxidant sulfur will fully oxidize to the corresponding sulfones.
1.3.2.3. Ketones, Aldehydes, and Acetals

In the area of oxygen oxidations, first on the scene were Baeyer and Villiger, who
noted Caro’s acid’s ability to convert a variety of ketones to esters.”125 Kennedy and

coworkers126 and Robinson and coworkers127 also contributed to this body of knowledge

utilizing Caro’s acid. In the late 70’s, Adam66 utilized the

13

bis(trimethylsilyl)peroxymonosulfate and noted remarkable reactivity towards ketones
providing esters at low temperature, and in 1991 Hirano demonstrated that cyclic ketones
could be converted to the corresponding lactones by absorbing Oxone onto wet
alumina.128

Scheme l-10. Generalized Baeyer-Villiger reaction with KHSO5

O KHSOS H67 o-Gsoax

0
R1 R2 R. R2 ———. R1JLOR2+KHs04

Work by Baumstark in 1989 has demonstrated that aldehyde oxidations can be
promoted by dimethyl dioxirane (DMDO) to generate carboxylic acids, while Webb’s
group in 1998 also oxidized aldehydes to acids with Oxone in a manner that supposedly
does not generate DMDO in situ.95’96 Related oxidations by Curini in 1999 demonstrated
that acetals could undergo oxidation to esters with Oxone in acetonitrile at elevated
temperature, and Wang demonstrated this again in 2001 utilizing an ethanolic Caro’s acid
solution.129’l30 In a similar sense to an acetal oxidation, THP protected alcohols can be
unmasked by Oxone in acetonitrile as shown by both Curini and Mohammadpoor-

Baltork. 129"”

Scheme l-11. Baeyer-Villiger oxidation of aldehydes

O KHSOS H6) oposoax 0

=2. >< _.
JL R Q) RJLOH +KHSO4

R H

Baeyer-Villiger oxidation of ketones that contain an 01- or [I -heteroatom
substitution tend to promote the oxidative cleavage pathway. Oxidation of a-diones with
Oxone was shown to be feasible in 1988 by Panda, but with a very limited scope.99 A
study by Ashford and Grega94 reported that B-diones could be oxidatively cleaved to the

corresponding one carbon deleted carboxylic acid using

14

Oxone—NaHCO3—acetone—water. Paradkar demonstrated that a-amino acids
oxidatively decarboxylate generally providing a one carbon shorter acid, this oxidative
cleavage is analogous to a-ketols that will be discussed in Chapter 6.98

Scheme l-12. Oxidation of a- and B-diones or a-ketols

X O
M KH805
R n R ——> HCOZH
X = O or OH,H
n = 0,1

Cyclic a-nitro ketones oxidatively cleave to provide diacids or diesters with
Oxone or methanolic Caro’s acid and heat as shown by Ballini.132’133 Again, this process

is analogous to the Nef reaction, which has been performed under milder conditions by

Ceccherelli in a phosphate buffered methanol solution with Oxone.134

Scheme I-13. Oxidation of a-nitro ketones via the Net reaction

0 0
N02 KH805 OH

—>
COZH
OMe OMe

15

Chapter 2. 2,3,5-Trisubstituted Tetrahydrofurans
2.1. Introduction

The development of methodologies to prepare substituted 2,5-disubstituted
tetrahydrofurans (THF’s) stereoselectively has become an area of great interest due to the
increasing reports of their biological activity in areas such as polyether antibiotics and
Annonaceous acetogenins!”136 Comparatively, 2,3,5-trisubstituted THF-diols are fairly
rare subclasses of either the Annonaceous acetogenins or polyether antibiotics and are
therefore much less studied. A notable exception includes the non-classical acetogenin
mucoxin a bis-THF natural product where one THF ring is 2,3,5-trisubstituted.

Figure "-1. Representative examples of Annonaceous acetogenins

o‘“ 0‘“
OH OH

Uvaricin(first isolated Acetogenin) Il-1

   

Mucoxin (nonclassical-
Muconin (nonclassical-THP) Il-2 hydroxylated THF) "-3

Aside from the new reports within the Annonaceous acetogenins and polyether
antibiotics a recent discovery within arachidonic acid (AA) metabolism suggests that
2,3,5-AA-THF-diols may have an important biological function within the cell.137 Here,
the implicated 2,3,5-AA-THF-diols (II-4 to II-6), have as of yet undetermined relative
regiochemistry and stereochemistry (Figure II-2); however, twenty four possibilities can
be envisioned from the three possible vicinal diepoxides. In addition, the biological

response of the AA-THF-diols seems significant (See section 2.1.2). Therefore, our

16

 

interest in 2,3,5-THF diols is promoted on two fronts that have previously been known to
be both biologically rich and diverse: Annonaceous acetogenins and arachidonic acid

(AA) metabolism.

Figure "-2. Representative examples of implicated 2,3,5-AA-THF diols

OH
HOZC _ _ ’ ...0

OH

H020 ’ .0 H020 _ o _

OH OH

2.1.1. Annonaceous Acetogenins

Annonaceous acetogenins are typically found in tropical and sub-tropical regions
and are derived from C32 or C34 fatty acids. Traditionally, extracts of many species
belonging to this family have been used in folk medicines as insecticides, fungicides,
antiparasitics, antimalarials, emetics, antitumor agents, and as a cure for snake bites. The
natural products isolated, purified, and tested from within this family of compounds have
proven to be highly bioactive, to be selectively cytotoxic against a variety of human
tumor cell lines, and to posses sub-nanamolar ICso values. This has culminated in a wide

variety of interest from researchers in chemical, biological, and medicinal sciences.l36"38'

141

Classical acetogenins (II-1) generally contain one or more 2,5-disubstituted THF
rings within the long fatty acid chain. Much less common are the non-classical
acetogenins, which contain THP (II-2) or hydroxylated 2,3,5-trisubstituted THF rings

(II-3).

17

In the early eighties the first acetogenin uvaricin (II-1) was discovered from an
ethanolic root extract of Uvaria accuminata and determined to be a potent antilukemic
(P-388) agentm’143 Upon structural elucidation, a novel C34 scaffold was discovered.
Since then biological studies of over 400 related compounds have allowed the
Annonaceous acetogenins to emerge as a new class of highly potent bioactive
compoundsm'146

Mucoxin (II-3) is the first non-classical acetogenin to contain a 2,3,5-
trisubstituted THF ring. McLaughlin isolated it in 1996 from the bioactive leaf extracts
of Rollinia mucosa. Mucoxin (EDso = 3.7 x 10'3 mg/mL) was found to be more potent
and selective in vitro against MCF-7, a human tumor cell line, as compared to
adriamycinm'149 (II-7) (EDso = 1.0 x 10'2 mg/mL), which is a well studied antitumor
agent. Our interest in this 2,3,5-trisubstituted THF ring scaffold has made this molecule

one of great interest in our laboratory such that we are pursuing its total synthesism’150

Figure "-3. Structure of adriamycin147

ll-7: Adriamycin, Synthesis: Smith 1977

2.1.2. Arachidonic Acid Metabolism
Arachidonic acid (AA) is a C20 polyunsaturated fatty acid that plays an important
role in the production of prostanoids (which include prostacyclins, prostaglandins, and
thromboxanes) and leukotrienes.15 "153 Prostanoids and leukotn'enes have critical roles in

pulmonary and vascular physiology (i.e. pain, fever, and regulation of blood pressure) as

18

4- .
‘5 '56 Prostan01ds and

well as in the onset of inflammation, asthma, and cancer.
leukotrienes are derived from the cyclooxygenase and lipoxygenase metabolic pathways.
They have both been highly scrutinized over the years, and each contains a great number
of compounds that are rich in biological activity and structural diversity. This has
prompted much research focused on the enzymes and receptors involved in AA

metabolism along with the total synthesis of many of these compounds. (Scheme II-l).'57'

160
The third least scrutinized metabolic pathway is that of P-450 epoxgenase
(Scheme II-l). Biologically significant compounds such as 5,6 EET (5,6 epoxide of AA),

a potent stimulator of prolactin release and an effective vasodilator, along with 11,12
DHET (11,12 diol of AA), a Na+/K+ ATPase inhibitor, are just two of the metabolites

that have been well studied and synthesized!“167 The emphasis placed upon the P-450
metabolic pathway, however, has had a narrow focus, specifically on compounds that are
derived from monooxygenation of AA. Metabolites derived from dioxygenation, their
respective hydrolytic metabolites, and their presumed biological relevance have not been
examined in detail.13 7’167'169

Recently, a new class of AA metabolite has been found that appears to be derived
from the hydrolysis of an AA vicinal diepoxide along the P-450 pathway.137 The
resultant compounds are termed arachidonic acid tertahydrofuran diols (AA-THF-diols)
(Figure II-2). Since monoepoxides and their respective diols by way of hydrolysis are

known, it is probable that the hydrolytic products of higher order epoxides exist.

19

Scheme "-1. AA metabolites via three different enzymatic pathways

5-HPETE LTA4
0H
WCOZH
S

HlecozH
LTE4

O
lipoxygenase
_ _ COOH _ _
_ __ W

_ .... COOH

 

 

 

II-8, arachidonic acid

HO OH

jk \ 11,12 DHET
fl ,.\‘\=/\/\ '.
C‘) W001 M‘WCOM
; - / HOZC

cyclooxygenase

 

 

 

_ HO 3
OH OH
PGH2 PGan
0 OH
WE“ : \\=/\/\/COZH
OH OH
PGE1 Txe2

Moghaddarn et al. have demonstrated through in vitro experimentation that, when
AA-monoepoxides are exposed to clofibrate treated mouse liver microsomes, AA-
diepoxides are generated. In addition, synthetically prepared AA diepoxides, when
treated with the same microsomes, can produce AA-THF-diols.137 Here the AA-THF-
diols were compared via derivitization and subsequent GC-MS fragmentation analysis to

an authentic synthetically prepared sample. These in vitro studies in which AA-THF-

20

diols are prepared allow for a reasonable biosynthetic pathway to be proposed (Scheme
II-2). Additionally, AA-THF-diols have now been found in vivo; lipids isolated from
liver extracts of clofibrate treated mice were derivatized similarly to the in vitro
experiments, and the AA-THF-diols were identified unambiguously by GC-MS
fragmentation analysis. 170
Scheme "-2. Proposed biosynthesis of AA-THF-diols

F 1
p.450 (01 o 0

AA, "-3 = o * Hz MR.
epoxygenase R R
2 \/=\/-\/ 1

 

 

 

 

epoxide epoxide

 

 

 

 

 

 

 

hydro/ase hydro/ass
HO OH HO OH 0
R2)‘J\/=\/Rt R2 MR1
[01
HO OH 0 HO OH
R2 MR1 R2 R1
L _J ._ _i
OH OH
92 O 0 R1
5 2 Hi + H2 2 5
3 OH HO 3 :
AA-THF-diols
R1 = 02H4C02H R1 = CsHeCOzH R1 = CaH12C02H
R2 = CgH14CH3 R2 = 06H10CH3 R2 = CaHsCHa

 

 

 

Interestingly, the mixture of synthetic AA-THF-diols (100 mM) also exhibit a

pronounced biological effect in that upon their incubation with rat pulmonary alveolar
epithelial cells, a rapid increase in intracellular Ca+2 ion concentration was observed.170
Notably, this response appears to be close and time dependent. These are significant

results in that intracellular Ca+2 ion levels play a crucial role in controlling physiological

21

processes such as signal transduction and cell homeostasis. Notably, AA and AA-

monoepoxides did not exhibit an increase in intracellular Ca+2 at all while AA-diepoxides

initially showed no increase, but after a few minutes of incubation intracellular Ca+2 ion

levels began to increase with a slow, and transient rise in intracellular Ca+2 levels. This
finding suggests that the AA-diepoxides are not initially active; however, as they are
metabolized AA-THF-diols form by interconversion from the AA-diepoxides, and a
modest level of activity is then detectable. This biological activity along with the unique
structural feature of AA-THF-diols has been the thrust of our research group’s interest in
devising a variety of new ways to prepare substituted THF rings, specifically 2,3,5-
trisubstituted-THF-diols. Included in the next sections is the brief description of three of
our group’s approaches, followed by my own.
2.1.3. Approaches to 2,3,5-Trisubstituted THF Diols

Numerous strategies have been developed to provide quick and facile entry into
2,5-disubstituted THFs, 2,3,5-trisubstituted THFs, and 2,6-disubstituted tetrahydropyrans
(THPs).m'182 183488 Perhaps the most common methods utilize a regiochemically
controlled opening of epoxides (Scheme II-3). Synthetically, this is an excellent
approach because of the relative ease in which innumerable substrates can be prepared in
a chiral fashion. These substrates are generally prepared utilizing a variety of well
precedented asymmetric methods including but not limited to asymmetric

1’2"” A regiochemically defining

dihydroxylation and asymmetric epoxidation.
substituent such as an alkyl or hydroxy group is introduced adjacent to the epoxide such
that a Lewis acid promoted epoxide opening leads to preferential nucleophilic attack at

C-5; therefore, it is possible to direct the path of ring opening in an exo fashion (II-9 to

22

Il-10). Conversely, when substituents such as an allyl, propargyl, or phenyl sulfide
group can be introduced adjacent to the epoxide such that a Lewis acid promoted epoxide
opening leads to preferential nucleophilic attack at C-6; therefore, it is possible to direct
the path of ring opening in an exo/endo fashion (II-11 to II-12). By controlling the
intramolecular regiochemistry in the cyclization of epoxy-alcohols, a very versatile

strategy for stereodefmed THFs and THPs has been established.”"182

Scheme "-3. Regiochemically controlled epoxide openings

 

 

LA
H / y
/\/\/:<(.?/\ PO 1 " O H :0“
PO 1 ; J '
OH 6 6
"-9 "-10
'2‘ /LA U 0 U
W P01 : t \
PO 1 ; 5 6+\ _‘
6U 5’OH
"-11 "-12

Notably, most synthetic strategies have had a single hydroxyl group acting as the
nucleophile, and thus product diversity from competing nucleophiles was not an issue.
Our initial approach to 2,3,5-trisubstituted THFs addresses this issue specifically. Can a
non-differentiated epoxy-diol (II-l3) participate in a selective regiochemically controlled
epoxide opening? Our research has bourne out that this is indeed a viable option to
produce 2,3,5-trisubstituted THFs or tetrahydropyrans (THPs) in good yield with
excellent regio- and stereocontrol (Scheme II-4).l‘90

An alternative approach to THF rings that has been developed in our laboratory
also utilizes a directed epoxide ring opening with trimethylsulfoxonium iodide.

Generally this method is applicable to form oxetane rings (Scheme II-S), but when an

allylic epoxyalcohol is subjected to the same reaction conditions, an initial Payne

23

rearrangement followed by nucleophilic ring opening provides the dianion (Scheme II-6).
Here either alkoxide may attack to displace DMSO intramolecularly, but in these

instances the formation of the THF core proceeds preferentially and in good yield.

Scheme "-4. Regiochemically controlled epoxide openings—competing nucleophiles

OH

O
TBDPSOWX
patha _ H . H

C
\

HO
5—exo

=CH20H. Et. OMe

F‘ OH
b TBDPSO o

M X path b
TBD PSO

HO \/ < 5-exo / 6-endo
"-13 U0 OH
TBDPSOWSH‘
H‘ H

K. "’OH

 

l path c

 

7-endo / 6.exo

Scheme “-5. Trimethylsulfoxonium iodide epoxide opening to form oxetanes

o (CH3)3SOI e K?

o 3.0

a. __, ___> n

R tBuOK/SO'C RM I @—
3d/56—83°/o

oxetane

Scheme "-6. Trimethylsulfoxonium iodide epoxide opening to form THFs

HONQA Base

R Payne
rearrangement

 

 

HO

R" o

 

24

A third approach to THF rings developed in our laboratory again utilizes an
intramolecular ring closure. This particular idea stemmed from dihydroxylation
chemistry where protection of syn diols as their orthoester is utilized as a method to
generate an epoxide in a stereospecific fashion (Scheme II-7). We hoped that placement
of a nucleophilic oxygen four carbons away (II-14) could serve as an intramolecular trap
for the intermediate acetoxonium ion to provide an ester protected THF ring (Scheme 11-
8). Again this method was successful and proved very useful in the construction of the

second THF ring in mucoxin.

Scheme "-7. Conversion of syn diols to epoxides via an orthoester

OM
0“ 2 MeC(OMe)3 X e ,L
o o TMSX oqoo

 

 

 

R‘ )_/
OH PPTS (cat) R, "’92 R, "’82
OAc X
Base -
O ’K/RZ 1' R2
R2 1 + 1
914’ MeOH R x R It:

Scheme "-8. Intramolecular trapping of an orthoester to prepare THFs

HO R? ><OMe
MeC(OMe)a BF3 Et20
OH
HO PPTS(cat.)HO‘(R1_)>§'(:R2 mg;
R1
"-14

R2

R‘ 0,.
OAc

These powerful and compelling results are a definite addition to existing

 

 

 

literature. The directed epoxide Opening methodology and the orthoester method have
both been utilized in the total synthesis of the proposed structure of mucoxin. The ylide

chemistry is currently being used for the preparation of haterumalide NA. However, our

25

underlying interest in these 2,3,5-trisubstituted THF substructures has prompted us to
investigate other alternative routes to 2,3,5-THF-diols, as will be discussed in the
remainder of this chapter.
2.2. Oxidative Cyclization Approach to 2,3,5-Trisubstituted THF Diol Core

In 1965 Klein and Rojhan demonstrated that the oxidation of geranyl acetate with
potassium permanganate (KMnO4) did not provide the expected tetraols but instead
underwent a stereospecific oxidative cyclization to provide the 2,5-bis-
hydroxymethyltetrahydrofiiran II-15 in 70% yield (Scheme II-9).'91 The oxidative
cyclization of other related 1,5-dienes continues to be an intriguing approach for the
synthesis of 2,5-disubstituted THF diols, and its synthetic utility has only gained interest
over the past 40 years. This can be understood due to the excellent relative
stereochemical control and the high degree of oxygenation that occurs in one simple
transformation. Recently, the 1,5-diene oxidative cyclization has been reported with not
only KMnO4,l9"195 but also 050.11%198 and RuO4 199"mas oxidants. The reaction
generally provides the desired THF products in 40-80% yield with excellent
stereoselectivity. A similar methodology has recently been reported for 1,6-dienes in
which RuCl3 mediated oxidation stereoselectively prepares 2,6-disubstituted
tetrahydropyran-diols such as II-16 (Scheme 11.9).199

Interestingly, the asymmetric potential of this reaction had not been explored at
all until very recently. Brown and co—workers206 have demonstrated that the
stoichiometric permanganate mediated oxidative cyclization of 1,5-dienes in the presence
of chiral tertiary ammonium salts affords enantiomerically enriched THF rings (Scheme

II-10). This reaction was substrate specific and required an aryl a,B-unsaturated ketone

26

to undergo a selective reaction. In this system, the degree of enantiomeric excess, was
affected by changing the reaction temperature or solvent. As one may expect more polar
solvents and higher temperatures led to decreases in the enantiomeric excess and the best
conditions were determined to be in DCM at —30 °C with HOAc and mm. Previous
to this study, there were only two reports that achieve control of absolute stereochemistry
through oxidative cyclization of 1,5-dienes containing either Oppolzer’s chiral sultam or
193,207

Evans’ norephedrin based oxazolidone (Scheme II-lO).

Scheme "-9. Oxidative cyclization of 1,5- and 1,6-dienes

OAc
KMnO4, I,“ OH: OH

OAC 0304.
or Ru04
"-15
OH OH
RuCla O
/ \ ——> -“
NalO4
"-16

Scheme "-10. Examples of enantioenriched oxidative cyclizations

O
W KMnO4 (1.6 eq) > W”
Ar 6 HO OH
0 Br
/p@ Ar = p—CSH4F (50%, 72% ee)
BnO

 

 
 

 

 

 

’ I
\N
0 V 1. mm, .. .-
N V \‘. :
MesO _ __ 6:8“ 2. CH30MgBr
O 40%, 931 de
0 )‘O KMnO4 .' ‘. A
N\J~ T Ho ’0‘ i N 0
_ — .- "Ph 0H «.9

Ph
65°/o. 3 31 d6

27

The potential in this field lies in the highly stereoselective nature of the oxidative
cyclization which yields functionalized oxygenated products from simple dienes. In
addition, the added benefit of chiral induction has increased the value of this reaction
tremendously. The popularity of such a 1,5—diene oxidative cyclization reaction can be
seen in its recent utilization in the total synthesis of complex natural products such as
salinomycin (Scheme II-11) and sugar derivatives including (+)-anhydro-D-glucitol and
D-chitaric acid (Scheme II-12). These synthetic efforts demonstrate the utility of the
oxidative cyclization of 1,5-dienes. Our synthetic interests of course lie in the area of
2,3,5-trisubstituted THF diols. We believed an analogous approach utilizing 1,4-dienes

may provide an efficient entry to our desired THF core.

Scheme "-11. Preparation of C-21 to C-3O of salinomycin

 

   

Salinomycin
0 Xe
KMnO4 (\0
540/ ‘I'. O O” 2 "
o ‘ OH / a
Xc = [(1% 30

28

Scheme "-1 2. Synthesis of (+)-anhydro-D-glucitol and D-chitaric acid.
050.,

(98.1 MeaNO 8110 3an H2, Pd-C HO :‘OH
3 CSA 4 o H ElOH i Q ';

OBn DCM HO 9 OH 99% HO H H OH
34%

 

 

(+)-anhydro-D-glucitol

 

BnBr
A920
”$36.? 1. TEMPO
N80102
BnO pan “$3,110 HO ..OH
rzjfi ”Ck—bi
ioi 2.H2,Pd-C io':
HO H H OBn M 90H 0 H H OH

76% . . .
D-chitanc acrd

2.2.1. Initial Results

As previously mentioned we are interested in studying 2,3,5-trisubstituted
tetrahydrofuran-diols (THF-diols) isolated from the oxidative metabolism of arachidonic
acid (AA, II-S) (Scheme II-3).137 This has led us to investigate the feasibility of securing
these structural motifs by the unprecedented oxidative cyclization of 1,4-dienes (Scheme
II-13). As a starting point, we utilized protocols for the 1,5-diene and 1,6-diene systems.
Methyl linoleate (II-17) was chosen as an initial substrate due to its structural similarities
to the desired substrate AA. We believed that methyl linoleate would be an ideal model
system since the THF-diols derived from the bis-epoxides were known. Moreover, the
system is inherently simpler since there are only two oxidizable olefins.

Scheme "-13. Putative oxidative cyclization pathway

OH

 

CH302CH1407'.5:3j/chj-111
KMnO4 or HO
CH3020H1407/LVACSH" 0so4 +OH
11-17 CHaochucv/YZ'CSH”
OH

"-18 and ll-18-regiolsomer

29

Our initial attempts utilized KMnO4 in aqueous acetone (9:1) providing the
desired 2,3,5-trisubstituted THF-diols (II-18 and II-lS-regiosomer) as a 1:1
regioisomeric mixture in a very modest 20% yield (Table 1) (referred to as II-18 only
throughout the remainder of this chapter). Analysis of 1H, '3 C, HMQC, and COSY NMR
identified the products as II-18, and the corresponding peracetylated compounds allowed
the relative ring stereochemistry to be defined as 2-trans-3,5-cis. Similar to other 2,3,5-
trisubstituted THF-diol stereoisomers obtained from linoleic acid oxidation and
cyclization reported previously, these compounds were also inseparable using standard

8 Verification of the ring stereochemistry was also

chromatographic techniques.20
established by simple bis-epoxidation of ML or 9,12-trans ML with mCPBA, subsequent
HClO4 ring closure, and finally peracetylation as described in literaturezos’209 This

provided easy access to all four relative ring stereochemistries either as free hydroxyls or

the acetates as standards (Scheme II-14).

Scheme "-14. 2,3,5—THF diols from bis-epoxides

 

on on
O 0,, ’
CH3OZCH1407 05H“ CHaochuc, . C5H1,
1. mCPBA
M DCM no + no
CH3°2CH1407 CSH” 2 THFH o "-19 R=H + regiosomer ii-20 R=H + regiosomer
".17 ' HCIO42 ll-21 R=Ac + regiosomer "-22 R=Ac + regiosomer
3- AC20. py
OR OR
1. CPB H , O O
310M A C 302CH14C7 .. 05H" CHSOZCH1‘C717ACSH"
CHaochuC‘rM/CsHi 1 +
2. THF-H20 RC R6
"-23 HCIO.
3 A020 py "-18 R=H + regiosomer "-24 R=H + regiosomer
' ’ "-25 R=Ac + regiosomer "-26 R=Ac + regiosomer

Attempts to increase the yield in this system by adjusting the pH were
unsuccessful. However, TsOH-HZO and C02 did not reduce the yield and provided 18%

and 23% respectively. BF3°Et20 did reduce the yield of the cyclized products to 10%

3O

and DIPEA and NaHCO3 produced no cyclized product at all. Other cyclization attempts
were performed with KMnO4 and ML using TsOH-Hzo as an additive in various
solvents, EtOH, DCM, H20, and THF. Unfortunately, no reaction occurred most likely

due to the lack of solubility of KMnO4 (Table II-l).

Table "-1. Initial attempts to prepare 2,3,5—THF—diol ll-18

 

 

Entry Oxidant Solvent Additive Yield "-1 8 (%)
1 KMnO. Acetone-H20 (9:1) 20
2 KMnO4 Acetone-H20 (9:1) CO2 23
3 KMnO, Acetone-H20 (9:1 ) BFa-Etzo 10
4 KMnO4 Acetone-H20 (9:1) DIPEA 0
5 KMnO4 Acetone-H20 (9:1) NaHCO3 0
6 KMnO4 Acetone-H20 (9:1 ) TsOH-HZO 18
7 KMnO4 EtOH TsOH-HZO NR
8 KMnO4 DCM TsOH-H20 NR
9 KMnO4 E120 TsOH-HZO NR
10 KMnO4 THF TsOH-HZO NR
1 1 0504 Acetone-H20 (9:1) NalO4 21
12 RuCla-nHZO EtoAc/ACN/l-120 NalO4 12

 

With promising results we chose to move away from KMnO4, primarily due to the
great amount of excess reagent needed, and shifted our focus toward other metal-0x0
oxidants. Attempts to cyclize ML with catalytic 0304 and NaIO4 did provide II-l8 in
21% yield while oxidative cyclization with catalytic RuCl3 and Nan4 was an inefficient
process, providing only a 12% yield of II-18 (Table II-l).199 Detailed analysis of all of
these initial reactions revealed that 1,2-diols and tetraols were present in the crude
reaction mixture. We suspected that these alcoholic byproducts could have come from a

competitive hydrolytic pathway of the intervening osmate ester. Aldehydes were also

31

found in both MO, and N310; reactions. Such reagents are known to oxidatively
cleave diols to yield the aldehydic products.2 10-212
2.2.2. Improvement Strategies

In an attempt to hinder the hydrolysis of the intermediate osmate ester, numerous
anhydrous solvents were used with 0304 and different co-oxidants. With only a few
exceptions, compound “-18 was formed to no appreciable degree (Table II-2). To
summarize these results, using standard conditions (ML, NaIO4, 0504 1:4:0.05), no
product was observed with CHzClz, toluene, ethyl acetate, diethyl ether, t-BuOH, and
hexanes. In all cases starting material was recovered with trace amounts of diols being
produced. THF and acetonitrile respectively yielded 8% and 10% of the desired product
II-18. Notably, DMF provided compound II-18 in an improved yield of 30%. Two
possible explanations for the modest reactivity of the more polar solvents such as
acetonitrile, THF, and DMF is that there is a charge stabilizing effect, assuming the
mechanism involves a charged species. The higher yield could also be due to better
solvation of the reagents in the more polar solvents.

With 0504 as the oxidant we attempted to vary the co-oxidant in acetone-water.
These results showed that only a few of these provided the desired compounds in greater
than 10% yield (Table II-3). Primarily, the products obtained were diols and/or
aldehydes. NMO with or without TsOH°H20, K103, t-BuOOH, H202, and DMP did not
yield any THF-diol products. Using AD-mix-B in the presence of methanesulfonamide
also did not provide any desired cyclization product. The co-oxidants that did yield
products were KClO3, 2-iodoxybenzoic acid (IBX), K104, and Oxone. Interestingly,

Oxone, a mono potassium peroxysulfate salt, was unique not only because it provided

32

yields comparable to the initial KMnO4 and OsO4-NaIO4 systems, but also this reaction

had fewer number of byproducts, thus making the work-up more facile.

Table "-2. Solvent effects on the cyclization of ML

 

 

Entry Oxidant Solvent Additive Yield "-18 (%)
1 (.3504 NaIO4 Acetone-H20 (9:1) 21
2 030, NalO4 DCM 0
3 0504 NaIO. EtZO O
4 0504 NalO4 t-BuOH 0
5 OsO4 NaIO4 ACN 1 0
6 0504 NalO4 Hexanes O
7 0504 NalO4 EtOAc 0
8 0504 NalO4 Toluene 0
9 OsO4 NalO, DMF 30

1 1 050., NaIO4 THF 8

 

Various other co-oxidant/solvent reactions variations provided no improvement.
For instance when ML was treated with 0504 and Oxone in THF the reaction proceeded
providing II-18 but in only 17%. Using t-BuOH-HZO had no effect on the yield as
compared to standard NaIO4 conditions (Table II-3, entry 1), and changing to a purely
biphasic system (toluene-H20) even with Adogen 464 as a phase transfer catalyst
provided no cyclized product. The rate of addition of the co-oxidant NaIO4 was also
varied from the standard one portion addition. This was achieved by dissolving the co-
oxidant in either DMF or acetone-H20 and then slowly adding the solution via syringe
pump over the course of 10 h. These attempts had absolutely no effect on the yield of the

isolated product, which remained at 30% and 20%, respectively.

33

Table "-3. Co-oxidant effects on the cyclization of ML

 

 

Entry Oxidant Co-oxidant Solvent Additive Yield "-18 (%)
1 0804 NalO4 Acetone-H20 (9:1) 21
2 0304 NMO Acetone-H20 (9:1) 0
3 0504 NMO Acetone-H20 (9:1) TsOH-HZO 0
4 050, t-BuOOH Acetone-H20 (9:1) 0
5 0504 KIO3 Acetone-H20 (9:1) 0
6 0504 KlO4 Acetone-H20 (9:1) 20
7 0804 KCIO3 Acetone-H20 (9:1) 8
8 0504 IBX Acetone-H20 (9:1) 5
9 0504 DMP Acetone-H20 (9:1) 0
1 0 030, Oxone Acetone-H20 (9:1 ) 20
1 1 0504 Oxone THF 17
1 2 0304 Oxone DM F 30
13 0304 AD-mix b t-BuOH-HZO (1 :1) Methane sulfonamide 0
14 0504 NalO4 t-BuOH-Hzo (1 :1 ) 20
15 0804 NaIO4 Toluene—H20 (1 :1) Adogen 464 O
16 050, NaIO4 DMF syringe pump 30
17 0504 NaIO4 Acetone-H20 (9:1) syringe pump 20

 

With DMF as the solvent, Oxone-based reactions also yielded 30% of the desired
oxidatively cyclized products. Changing the temperature in the DMF-Oxone system
with hopes of reducing the rates of competing reactions and to increase the yield of the
desired product II-18 did not result in any improvements (Table II-4). Experiments at
both 0 °C and —40 °C actually lowered the yield of II-l8 providing 20% and 12%,
respectively. Elevating the temperature to 50 °C was also ineffective and lowered the

yield to 13%. Adding 4A molecular sieves reduced the yield to 9%, and other 0804

34

reactions in DMF utilizing IBX or DMP resulted in little or no conversion 10% and 0%,

 

 

respectively.
Table "-4. Temperature and oxidant effects of ML cyclization in DMF
Entry Oxidant Co-Oxidant Solvent Additive Yield "-18 (%)
1 0304 NalO. DMF 30
2 0504 Oxone DMF 30
3 0304 Oxone DMF 4A Sieves 9
4a P-OsO4 Oxone DMF 30
5 050. Oxone DMF -40 °C 14
6 0304 Oxone DMF 0 °C 22
7 0504 Oxone DMF 50 °C 13
8 0504 IBX DMF 10
9 0504 DMP DMF 0

 

a) P-0504: Polymer bound 0304 where the polymer is derived from 4—vinylpyridine

2.2.3. Optimized Reaction Conditions

While the results of our optimization studies did not increase the isolated yield,
we still believe this to be an intriguing reaction since it sets four stereocenters in a simple,
one pot reaction. This prompted us to see if the reaction was scaleable. Using our best
reaction conditions for the oxidative cyclization, i.e., Oxone (4 equiv.) and 0804 (0.05
equiv. 2.5% in t-BuOH) in DMF (0.2 M), we scaled the reaction up to 5 mmol (1.5 g) of
ML. This did indeed provide “-18 in 30% yield. Detailed analysis of the reaction
byproducts in this instance showed no diol or aldehyde products as seen with NaIO4 or
KMn04. Instead, this reaction revealed only the formation of carboxylic acids from
oxidatively cleaved olefins. The 0804 assisted oxidative cleavage of olefins will be

discussed more in subsequent chapters. As a final note the amount of catalyst need not

35

be 5 mol%. Successful reactions were carried out with as little as 0.5 mol%, a ten-fold
decrease in catalyst providing an identical yield of II-18 in 30%.
2.2.4. Mechanistic Proposal

Again noting the potential usefulness of this reaction we felt that it was necessary
to analyze the reaction mechanism as compared to others reported.194"97’2l3'216 A very
simple explanation for the oxidative cyclization could be based on Walba’s research.
Walba reported an oxidative cyclization using a Cr(VI) compound to prepare 2,5-
disubstituted THF rings from 5,6-dihydroxyalkenes.213 Analogous to Walba’s
observations, we thought that the diol of one of the olefins in II-27 might be a possible
intermediate, so it was independently synthesized from the corresponding monoepoxide.
While Walba's mechanism with Cr(VI) might be an alternative explanation for the
observed cyclization in our systems, treatment of II-27 with conditions that yield
oxidative cyclization did not produce any THF-diol product (Scheme II-15). This was
true not only for the DMF-Oxone system but also for the Na104—acetone—H20 system.
This suggests that the diol is not involved as a possible reaction intermediate to the

oxidatively cyclized products II-18.

Scheme "-15. Diols do not oxidatively cyclize

HO OH 0504
R2’ V _ R1 +> ll-18
“-27 Oxone/DMF

R1 = (CH2)7COzCH3
Rz = (CH2)4CH3

Our second hypothesis was based conjointly on the works of Walba, Baldwin, and
Piccialli. In 1979, Walba and coworkers proposed that the 2,6-octadienes they were

working with underwent a double [2+2] cycloaddition of ma; to form II-28, and this

36

putative bis-metaloxetane can rearrange and eliminate to yield diol II-29 (Figure 11-

4).214,215

Figure “-4. Bis-metaloxetane intermediate and resultant THF-diol

fl W
0' M n '0 'IO\‘

0 HO OH
I

-28 "-29
In our case with 0804 we did not discount the bis-metaloxetane theory out of
hand. Several studies by Sharpless were highly in favor of an 0304 [2+2] reaction with

olefins.216

More recently, however, experimental and theoretical calculations by Houk,
Sharpless, and Singleton favored the [3+2] cycloaddition of 0304 to olefins and found
that the [2+2] formation of the osmaoxetane and the subsequent ring expansion are
prohibitively high energy processes (~42 kcal/mol and ~30 kcal/mol, respectively).35
Baldwin’s mechanistic proposal in 1979 was based on an initial Mn04' [3+2]
cycloaddition to II-31 followed by a second [3+2] cycloaddition to provide II-32
(Scheme II-16).194 Hydrolysis would then provide the desired THF diol II-33. Piccialli
and coworkers, using 0304 as a catalyst, also propose a concerted [3+2] cycloaddition to
form the THF diol core. The relative stereochemistry of their products is analogous to
that of 1,5-dienes reported previously (Scheme II-17).197 The first step of their
mechanism involves formation of the isolated oxidized bis-osmate ester II-34. Then a
[3+2] cycloaddition followed by oxidation of the osmate provides II-35. It is postulated
that this intermediate also undergoes a [3+2] cycloaddition to yield II-36, and finally,

hydrolysis of the his osmium complex “-37 yields the cyclized product II-15 and

regenerates 0804 after reoxidation of the metal.

37

Scheme "-16. Proposed KMnO4 oxidative cyclization via an initial [3+2] cycloaddition

H o
o '9 O'M'IQO
'2'” o o l
"-30 "-31

 

o H
D H H + H
H'" o o 0 1° 0
OH ., ‘lyln
HO ’H _o 0
"-33 "-32

Scheme "-17. Proposed 0504 oxidative cyclization via an initial [3+2] cycloaddition

_ 050 Mi : OAc
>—/——>':\7 4 0‘ IO OAC [3+2] W
0Ac 0.0seo
O 0’ ‘0 OAc
\ OAc W
"-34
Wow
0 O z o

 

 

[3+2] : OAC

 

"MW hydrolysis
H
O>05<O
"-15 O OA"
OAc '-

u-37 "-36
More recently Donohoe198 and coworkers have demonstrated that stoichiometric
0804 reactions with TMEDA as a ligand and 1,5-dienes produce an osmate ester that,
upon treatment of this complex with MeOH and HCl, provide high yields of the desired
THF diol (Scheme II-18). In this instance, since there is no additional oxidant, the
cyclization is presumed to occur with an initial 08(VI) species ultimately providing a

reduced 08(IV) species afier hydrolysis.

Scheme "-18. Oxidative cyclization with stoichiometric 0304 and TMEDA

 

H0
0504, TMEDA H0 o
>=/—>=\_ DCM.-78'C
NH :
>rCC|3 then MeOH, ”N
o HCI, RT

0J‘CCI3

In our reactions with 1,4-dienes we have obtained no evidence for or against a
bis-osmate but can find no initial fault with this interpretation. Assuming, however, that
the reaction proceeds in an analogous mechanism to that proposed by Piccialli mono-
osmate, II-38 would be oxidized generating II-39 (Scheme II-19). A [3+2]
rearrangement could provide “-40. At this point hydrolysis, or oxidation followed by
hydrolysis, provide the desired product II-18. We believe that, based on a mono-osmate,
that an alternate mechanism may still exist where intermediate II-39 is further activated
by the co-oxidant Oxone (Scheme II-19). II-41 could then undergo a [3+2]-like
rearrrangement in which the last step is the expulsion of bisulfate. The intermediacy of
II-41 may be responsible for the solvent dependence of the reaction.

Alternatively, Donohoe’s interpetation could be equally as valid whereby II—38
could directly cyclize via a [3+2] in the presence of a coordinating ligand to prepare II-
42. This proposed intermediate could be hydrolyzed, or oxidized and then hydrolyzed, to
provide the desired product II-18 (Scheme II-19). Unfortunately, a similar experiment
conducted with ML did not provide the desired cyclized product but instead cleanly

afforded the normal dihydroxylation product (II-27).

39

Scheme "-19. Proposed mechanistic pathways for the 1,4 diene oxidative cyclization

 

 

 

R
JOSO4
R
(3,01;D O R
R IS§ \ . \
0 Ln. [3+2] -rearrangement \
R /
"-38 ".42
1101 l [0]
0
“,0
303‘: R O
0/ 9 [3+2]- rearrangement Oi .R —
/ ' oaOg—O
R v.
"-39 "-40
KHSOS [0]
0-1940 R
R 98%9 0 03K [3+2]-Iikerearangement 0‘" 0 ..R
o H. = \
': 0=/(/)s\--O
/ ," O \O
R ‘.
"-41 l

 

OH
0 .
RM" R
OH
"-18

Figure II-5 illustrates a three-dimensional representation of two pr0posed reactive
intermediates obtained from a 1,5-diene, II-43, and a 1,4-diene, II-44. The approach of
the olefinic carbon to the osmate ester oxygen, which will eventually become the THF

ring oxygen, is hindered by the neighboring alkyl group. This is not the case with the

1,5-diene in which the neighboring group is a methylene and does not pose a bulky
presence. In the 1,5-diene example, there is good overlap between the olefin and both
oxygen atoms that are incorporated into the 2,5-THF-diol product. However, the strain of
the 1,4-diene, II-44, hinders the approach of the olefinic carbon towards the osmate ester
oxygen and thus could prevent a good overlap of the atoms participating in the
cycloaddition (Figure II-S). The relatively hindered approach and the overcoming of
steric congestion could very well be the cause for the reaction to proceed with 1,4-dienes,

but only in modest yields.

Flgure "-5. Standard and 3-D projections of reactive intermediates "-43 and "-44

 

approach of olefinic carbon
could be hindered due to

 

 

 

 

 

 

 

 

 

 

 

 

the neighboring substituent
effect
Q ’0 R
0=‘Os ’H As compared to 1.5. this
0" ‘0 'H bond has hindered rotation.
\ and thus produces an
/ inherent strain in the
better alignment of 1 5 1 4 approach of the osmate to
atoms with olefinic 0 Q 0 0.. ,9
carbons ”Os“ 0=0s-0
0’ '0 0'
W \
R R R R
"-43 "-44

2.2.5. Other Substrates

Based on the aforementioned [3+2] cycloaddition pathway and the observed
stereoselectivity in the oxidative cyclization of II-l7 we predicted that under the same
reaction conditions 9,12-trans-methyl lineolate, II-23, would produce II-21 with an all
cis relative stereochemistry. This reaction did unambiguously provide the known all-cis

THF-diol 11-21 in a comparable 30% yield (Scheme 11.20).208

41

Scheme "-20. Oxidative cyclization of 9,12-trans-methyl lineolate (ll-23)
\ 0H
— o 0 CH 0 H c o
S 4 3 2C 14 7w05H11
cozue oxg’flfi gm H0
"-23 "-19

 

2.2.6. Final Improvements

During the course of our efforts to improve the selectivity of the oxidative
cleavage of olefins to aldehydes (See chapter 5.2.3) we came across several systems that
we believed were applicable to perform an oxidative cyclization of a 1,4-diene. While
most of these new systems failed or provided no improvement, the utilization of
acetonitrile with DMF, H202, and 0804 provided the desired product in an improved
50% yield (Scheme II-21). Again, attempts to further optimize these conditions did not

increase the yield.

Scheme "-21. Final improvements of the oxidative cyclization of ML

 

0804 (0.01 eq) 0H
/=_-\/=\ ”202 (4 9‘1“”) CH3020H1407.., o
CH302CH14C7 C5H1 1 > C5H11
DMF (20 equiv.)
CH3CN . 4 'c. 50% H0
"-17 "-18

2.2.7. Conclusions

In summary, the oxidative cyclization of 1,4-dienes is a feasible reaction and
proceeds stereoselectively through a predictable [3+2] rearrangement and has both a
solvent and temperature dependence. Currently, a maximum of 50% yield has been
obtained. This result has been attributed to the strain of the proposed transition state of
II-44 and the competing oxidative pathways, notably, the oxidative cleavage of the
olefins, which will be discussed in the subsequent chapters, and the hydroxylations

yielding diols and tetraols. The reaction is amenable to scale up with the oxidative

42

cyclization of II-l7 (1.5 g, 5 mmol) providing a 30% yield of II-l8 following our

initially developed protocol.

43

Chapter 3. Preparation of Purified Oxone and its Soluble Form by Simple and
Efficient Methods

3.1. Introduction
As discussed earlier, Caro’s acid (H2805) has had an intriguing history.”217 A
potentially explosive substance that proved to be difficult to isolate, purify, and identify
now exists as a shelf stable triple salt (2KHSOs-KHSO4-K2804) sold under the trademark
name of Oxone.”63 The focus of this chapter is on the active oxidant within the triple
salt mixture, potassium peroxymonosulfate (KHSOs).

Over the past twenty years, Oxone has become a popular oxidant for the
preparation of dimethyl dioxirane in situ from acetone and buffered water to epoxidize
olefins.80 Other advances include selective oxidations of boron, nitrogen, phosphorous,

and sulfur containing compounds, while it has also been shown to oxidize acetals and

68,87,89-92,95,96,129,218-221 Generally these
9

aldehydes to acids or esters (Scheme III-1).
oxidations are performed in water, methanol, acetone, DMF, or a miscible mixture
including one of the latter solvents. The need for aqueous and/or pH controlled reactions
is perhaps the most significant drawback in the use of Oxone for applications in organic
chemistry.

Scheme Ill-1. Known oxidative pathways for Oxone

0 e
Rani—.0 RCOZH R3P=0

 

 

(RO)3B

To overcome the need for aqueous conditions, several tetraalkyl ammonium salts
of Oxone have been reported. These include ammonium peroxymonosulfate, tetra-n-
butylammonium peroxymonosulfate (TBA-0X), tetra-n-pentylammonium
peroxymonosulfate, and tetra-n-hexylammonium peroxymonosulfate.67’68 In 1985,
Dehmlow and coworkers. reported a methodology to prepare TBA-0X (67.5% w/w) and
other tetraalkyl ammonium salts of peroxymonosulfate by cationic exchange from
Oxone. However, only in 1988 did Trost and coworkers popularized TBA-0X as an
organic soluble form of Oxone that was capable of oxidizing sulfides to sulfones under
anhydrous conditions (Scheme III-2). This reagent was prepared from cationic exchange
of the bulk potassium ions, and thus yielded a soluble version of the triple salt; i.e., tetra-
n-butylammonium salts of sulfate and bisulfate were also formed. The oxidative activity

of this soluble Oxone was 37.5% of the actual weight.

Scheme Ill-2. Anhydrous oxidation of sulfides to sulfones with TBA-0X

 

Oxone
nBu4NHSO4
TBA-OX O
(37.5%» W/W) ll
R1—S‘R2 R1‘§“R2
DCM

A second type of soluble peroxymonosulfate has been recently described by

69‘" The reported benzyltriphenylphosphonium

Hajipour and coworkers.
peroxymonosulfate (TPPB-OX) has the ability to perform some of the oxidative reactions
that are well developed for Oxone (Scheme III-3). These include various oxidations of

alcohols the deprotection of acetals, trimethylsilyl ethers and tetrahydropyranyl ethers to

yield the corresponding alcohols.

45

Scheme Ill-3. Selective oxidative deprotections with TPPB-OX

 

 

o 0THP 0

Ohms TPPB-Ox.DCM; ©)LH GK TPPB-0x.DChL ©/N\
microwave microwave
90% 85%

3.2. Initial Purification Methods

While Oxone is a convenient and cheap triple salt (~$10/Kg), there is only ~50%
of active oxidant per mol of the triple salt. Several methods have been developed to
prepare the pure potassium salt of peroxymonosulfate, yet these purified oxidants have
not been used in synthesis, most probably due to the less than convenient procedures
necessary to purify the oxidant. Appleman and coworkers isolated and characterized
pure KHSOS and KH8050H20 by passage of sodium peroxydisulfate (Na28203) through a
cationic ion exchange resin followed by hydrolysis of the peroxydisulfate at 50 °C to
yield equal molar peroxymonosulfate, KHSOs, and bisulfate, KHSO4. Adjustment of the
pH with KHC03 and lyophylization yielded the purified KHSOs'H20.222 This resulted in
one of two reported crystal structures of KHSOs-H20. Interestingly, both reports were
published within months of each other.”’223 The purification of KHSOs°H20 was
revisited by Connick et al. in the early 90's along with a modified method for its

65 Essentially a straightforward filtration protocol starting from Oxone,

preparation.
followed by evaporation and crystallization resulted in the isolation of analytically pure
KHSOs-H20. Again, this method received little attention from organic chemists perhaps

due to its limitations upon scale-up where the removal of large volumes of water is

required.

3.3. Purification Method Development

We have developed a modified, straightforward, and stepwise procedure for the
preparation of pure KHSOs-H20 (>98% activity) from Oxone that does not require
laborious water removal. Additionally, a method for the preparation of analytically pure
tetra-n-butylammonium peroxymonosulfate (TBA-0X) from KHSOs-H20 has been
developed, along with a one step procedure to purify and solubilize the commercial
Oxone triple salt with nBu4NHSO4. Furthermore, the chemical reactivity of
commercially available Oxone has been compared with that of pure KH805°H20 and two
soluble forms of the oxidant.

3.3.1. Preparation of Purified Oxone.

From a preparative point of view, comparison of the two reported methods to
obtain KHSOs-H20 in pure form favors the method described by Connick et al.‘55 The
procedure is easier since the starting material is Oxone, which contains the active oxidant
and does not lose activity over time. This method provides the desired pure
KHSOs-H20, but requires a laborious removal of water, which is followed by
crystallization of the product. This limits the scale on which the procedure can be
performed easily. In order to satisfy our need for large amounts of purified Oxone, we
have devised a preparative scheme that is not only facile, easy, and reproducible, but also
amenable to large scale production (0.5 mol).

To prepare the purified oxidant, commercially available Oxone was added to
deionized (DI) water (1:1 w/w) and swirled for 5 min until the noticeable fizzing
subsided. Molecular oxygen is the gas evolved during the mixing of Oxone with water.

This was shown by bubbling the gas through a suspension of Cul in aqueous NH4OH.

47

The solution turned blue immediately as Cu+2 was generated through oxidation of Cu+
with oxygen. The overall loss of oxidant is less than 2% (measured via iodometric
titration of the solution after the evolution of gas had ceased), and is probably due to the
decomposition of Oxone by trace metal ions present in the solution?”24

Potassium peroxymonosulfate is more soluble in H20 than the corresponding
sulfate salts and is dissolved preferentially. However, keeping the slurry for a prolonged
time allows the salts to equilibrate and lower yields are obtained. The cold slurry (~10
°C) was filtered and washed with minimal amounts of cold DI H20. The initial pH of this
clear solution was about 1.0. The pH of the filtrate was adjusted to 3.5 using solid
KHC03 while continuously stirring the solution. At the endpoint a noticeable pink color
was observed along with the formation of some precipitate. We found that overshooting
the endpoint resulted in a reduced yield of the purified material. If need be, the pH can
be readjusted with a few drops of concentrated H2804. This pink slurry was filtered and
the solid was washed with MeOH (2 volumes) and combined with the original water
filtrate resulting in the formation of more precipitate. The precipitate was again filtered
and washed with MeOH (1 volume). The slightly cloudy solution containing water and
MeOH (1:3 v/v) was placed in a freezer overnight to crystallize the purified product. The
thick slurry was filtered and washed with Et20 to provide KHSOs-H20 in 45% yield
(based on oxidative equivalence as compared to Oxone). The crop was found to be
99.1% pure after triplicate iodometric titration. A second crop (4%) could be obtained if
the filtrate containing the water, methanol, and ether mixture was again place in the
freezer overnight. This material showed negligible loss of activity over a prolonged

period of time (6 months) when stored on the bench top in an amber bottle. The hydrated

48

pure KH805 can be dried under vacuum at room temperature to yield pure anhydrous
KHSOs. Although we have not had any incidents of rapid decomposition or explosion
with Oxone (triple salt or purified) when heated, the oxidizing activity is lost at 70 °C,
and thus drying the sample should be carried out at room temperature. Also noteworthy
is that dry KH805 does not seem to be a contact explosive. This was tested by repeatedly
hammering a sample on a smooth flat surface. The two major advantages of the latter
procedure are the immediate crystallization of KHS05°H20 that provides analytically
pure product, and the fact that large volumes of water need not be removed via
evaporation. The only limit to perform this procedure effectively on a large scale is the
need for a few large erlenmeyers.

There is a significant advantage for converting the commercially available Oxone
to purified KHSOs-H20 since less weight of salt is required. Oxone's
(2KH8050KHSO40K2SO4) molecular weight of 615 g/mol is equivalent to 307 g/mol of
oxidizing equivalence. This is significantly more than that of KHSOs-H20, 170 g/mol.
Thus, the use of purified Oxone results in more oxidant per mol of salt. This significantly
reduces the amount of oxidant needed, which could be a major factor when doing large-
scale chemistry.

3.3.2. Preparation of Soluble Oxone (TBA-OX).
3.3.2.1. Background

As mentioned previously anNHSOs (TBA-0X) has been prepared by both the
Dehmlow and Trost groups with 61% and 37.5% activity, respectively.“68 While the
preparative methods are similar, it is necessary to explain the differences to better

understand how it has led us to obtain >98% active TBA-0X with only minor

49

modifications. Dehmlow’s procedure requires the preparation of two solutions, a
concentrated aqueous solution of Oxone and a solution of nBu4NHSO4. The latter two
solutions were mixed together overnight and the TBA-0X was isolated by extraction into
CH2C12. In contrast, Trost’s procedure utilizes 5 equiv of nBu4NHSO4 per each equiv of
Oxone. The two reagents are mixed for 30 min in water, which is followed by extraction
into CH2C12 to provide 37.5% active TBA-OX. The recovered activity is less than the
activity of the starting Oxone. The latter two examples yield products with different
activities, probably due to two factors; time of mixing prior to extraction and the ratio of
nBu4NHSO4 and Oxone used for preparation of soluble Oxone. Optimization of both
factors should lead to the isolation of a more pure product with higher activity.

3.3.2.2. TBA-OX Method Development: Preparation from Oxone.

We have found that the solubility of nBu4NH805 in CH2C12 (352 mg/mL) is
higher than the solubility of anNHSO4 in the same solvent (168 mg/mL). Thus, it
should be possible to preferentially extract nBu4NH805 in favor of nBu4NHSO4. It is
plausible that the excess amount of nBu4NHSO4 used in Trost’s extraction procedure
counterbalances the higher solubility of TBA-OX and leads to the extraction of
nBu4NHSO4 along with TBA-0X. To illustrate this point Oxone (1 equiv) and varying ’
amounts of nBu4NHSO4 were used to extract TBA-OX into CH2C12. As can be seen
from Figure III-1, lowering the equivalence of nBu4NHSO4 used in the extraction greatly
enhances the purity of the extracted TBA-0X (range of 35% to 91%), presumably due to
the higher solubility of anNHSOs in CH2C12. Therefore, by utilizing 1 equiv of
nBu4NHSO4 in a single extraction, 88% of the oxidative equivalence is obtained in

soluble form (TBA-0X). Overall, much higher extraction efficiencies are realized with

50

less nBu4NHSO4. Additionally we do not find it necessary to mix the solids for an
extended amount of time, but instead simply mixing both solids in water followed by an
immediate extraction provided reproducible results. We attribute the success of this
procedure to the fact that KHSO5 dissolves preferentially over KHSO4 and K2804, and
that nBu4NHSOs is more soluble in CH2Cl2 as compared to nBu4NHSO4 in the same

solvent.

Figure Ill-1. Extraction of TBA-0X from Oxone into CH2CI2 with various equiv of nBu4NHSO4

”BU4NHSO4 + 2KHSOS'KHSO4'K2504 =—"—-— "BU4NHSOS "l' (I‘BU4N)2SO4
(Oxone)

 

I more soluble in CH2C12]

 

100 .

90«

80‘

704

Activlty (96)
0

4o.

 

 

30 . . . . . .
o 1 2 3 4 5 6
Equlv of nBu4NHSO4
3.3.2.3. TBA-OX Method Development: Preparation from KHSOs-H2O
Utilizing the same extraction technique, the preparation of analytically pure TBA-
OX is feasible simply by extracting pure KHSOs°H2O (1 equiv) with nBu4NHSO4 (1.2
equiv). In fact, single extraction with purified KHSOs-H20 yields >98% active TBA-

OX. The two methods described above use stoichiometric amounts of nBuNHS04 to

easily prepare pure TBA-0X. The highly purified TBA-OX (>98%) has been stable for

51

more than 6 months at room temperature in an amber vial. Moreover, removal of
residual water from the purified TBA-0X under vacuum has met with no problems. This
should allow for the use of TBA-0X in anhydrous form for oxidations in organic solvents
without the necessity for using a great excess of oxidant or mixed tetrabutylammonium
salts. It should be noted that heating of TBA-OX at 70 °C in order to speed up the drying
led to the decomposition of the oxidant (complete loss of activity).

3.4. Solubility

The latter experiments strongly suggest that solubility plays a major role in
obtaining pure nBu4NHSOs. To demonstrate this further we have compared the
solubility of KHSOs-H2O and TBA-0X. KHS05°H20 possesses very poor solubility in
CH2C12 such that a 1:6 (w/w) mixture of KHSOs-H2O and TBA-OX resulted in 99%
recovery of the KHSOs-H20 after filtration. To ensure that the oxidative equivalence
measured by iodometric titrations of the organic phase are not a result of KHSOs°H20’8
partial solubility in CH2C12, purified KHSOs-H2O was vigorously stirred with CH2Cl2
and the filtrate was titrated for oxidizing activity. The iodometric titrations showed less
than 1% activity present in the organic filtrate based on the starting amount of
KHSOs-H2O.

The soluble salt forms of Oxone have a good solubility profile with various
organic solvents, therefore, making it possible to use a large number of organic solvents
for the oxidations (Table 111-1). This is clearly an advantage over traditional Oxone
chemistry, which uses water in a large number of the reported reactions. Oxone (triple
salt) is practically insoluble in all solvents except water, although, the KH805 portion of

Oxone does have solubility in other solvents such as DMF. KHSOs-H2O is also soluble

52

in water, however, it exhibits notable solubility in DMF (100 mg/mL) and slight
solubility in MeOH. TBA-0X is completely soluble in DMF, acetone, water, CHCl3,
CH2C12, CH3N02, CH3CN, and MeOH at 100 mg/mL (this is not to say the solutions are
saturated). Other solvents such as EtOAc, hexanes, CCl4, benzene, THF, and B20 were
not able to dissolve TBA-0X. Comparably, Ph3BnPH805 was soluble only in MeOH,
CHCl3, CH2C12, and DMF and insoluble in all other solvents tested. Since these salts all
exhibit a lack of solubility in solvents such as hexanes or ether, we feel that this could
perhaps be beneficial since it can provide an easy route to remove the oxidant and its by-
products (usually XHSO4) by simple precipitation from the reaction mixture upon

addition of hexanes or ether.

Table Ill-1. Solubility profiles of various XHSO5 salts

 

 

Solvent Oxone KHSOs-HZO TBA-0X TPPB-OX

DMF A B C C
Acetone D D

Water C C C D
CHCIa D D C C
CHZCI2 D D C C
CH3N02 D D C D
CH3CN D D C D
MeOH D B C C
EtOAc D D D D
Hexanes D D D D
Benzene D D D D
CCI. D D A D
THF D D A D
Et20 D D D D

 

A) slightly soluble; B) ~100 mg/mL; C) >100 mg/mL; D) insoluble

53

3.5. Peroxysulfate Salts as Oxidizing Reagents

As discussed above, Oxone is an effective oxidant in many types of
transformations. Having at hand a simple method to secure both pure KHSOs-H20 and
its pure soluble form, TBA-OX, a comparison of their reactivity was pursued. Through a
set of simple experiments Oxone, KHSOs-H2O, TBA-OX, and Ph3PBnH805 (TPPB-OX)
were compared directly in five different reaction manifolds. The results are summarized
in Table 111-2. Essentially, Oxone and KHSOs°H2O showed no significant differences in
reactivity or yield of isolated products in the reactions studied, namely, oxidation of
benzaldehyde to benzoic acid, oxidative cleavage of trans-stilbene to benzoic acid,
oxidation of triphenylphosphine to triphenylphosphine oxide, oxidation of thioanisol to
methylphenylsulfone, and oxidative cleavage of phenylboronic acid to phenol. 0n the
other hand, TBA-0X was ineffective in oxidizing benzaldehyde to benzoic acid and not
very effective in cleaving the OB bond of phenylboronic acid providing phenol in only
40%. However, as reported by others for the less pure TBA-0X, it was efficient in
oxidation of both phosphorous and sulfur. Use of TBA-0X for oxidative cleavage of
olefins was attempted with trans-stilbene. Although, both Oxone and KHSOs-H20
yielded benzoic acid as the oxidation product, TBA-OX led to the isolation of
benzaldehyde as the sole product in 88% yield. Clearly, the soluble form of Oxone has
attenuated activity. This is a beneficial outcome since selectivity can be exercised based
on the oxidant utilized for the reaction. TPPB-OX is a rather poor oxidant for the
reactions illustrated here except for the oxidation of triphenylphosphine, which resulted

in a 98% yield of triphenylphosphine oxide.

54

Table Ill-2. Oxidation of various functionalities with Oxone and soluble Oxone.al

CHO Oxidant C02H O Oxidant
DMF O 0so4 (cat) / DMF

 

 

 

 

Ill-1 Ill-1a Ill-2
Oxidant 0 O Q‘ ICHS
Phap ———-> Ph3P=O OSCHa ’0 am be
THF / MeOH MeOH ,Hzo
Ill-3 Ill-3a III-4 Ill-4a
03“)le Oxidant OOH
NaOH IH20 7
111-5 meme Ill-5a
Substrate Product Oxone KHSOs TBA-0X TPPB-OX
benzaldehyde III-1 benzoic acid Ill-1 a 97% 94% NR." N.R. b
trans-stilbene Ill-2 benzoic acid Ill-1 a 95% 97% 88% ° 25%°
triphenylphosphine III-3 "'pheng'gggsi’mne III-3a 98%" 99% 97% 98%
thioanisol Ill-4 methylphenylsulfone Ill-4a 95%‘1 90% 91 % 52%
phenylboronic acid Ill-5 phenol Ill-5a 86%" 80% 40% 30%

 

a) See experimental for reaction details. b) Starting material was recovered (90% for TBA-0X,
85% for TPPB-0X). 0) Yield of III-1. d)Y1eId reported in literature.

3.6. Work-up Protocols

During the course of our study we found that using purified reagents showed only
minor reactivity differences, and that the work-up was facile for all substrates on a 1
mmol scale. However, extraction and chromatography are more tedious upon scale-up.
To investigate this further we evaluated the oxidation of triphenylphosphine with Oxone,
KHSOs-H2O, anNHSOs (30%, containing other nBu4N-sulfate salts) and anNHSOs
(98%) on a 10 mmol scale. Not surprisingly, the starting material was cleanly converted
to the corresponding triphenylphosphine oxide over a 2 h period with all the oxidants

utilized. In a typical experiment, removal of the organic solvent under reduced pressure

55

by 50% was followed by precipitation of the salts with Et20. The precipitation was
completed upon storing of the filtrate in the freezer for 3 h, and the salts were removed by
filtration to provided excellent yields of the product (>95 % in all cases after removal of
solvent). Oxidation with pure nBu4NH805 led to only 3% of the tetrabutylammonium
salts left over in the final product. However, when 30% active nBu4NH805 was used the
product was contaminated with 35% of tetrabutylammonium salt. Both Oxone and
KHSOs-H2O yielded clean products, but less 320 was required for precipitation and
washing using the purified reagents. Thus, for large-scale reactions it is advantageous to
use purified oxidant to reduce the amount of solvent needed for purification. Also, use of
pure soluble oxidants yields products of higher purity after a simple filtration of the
tetrabutylammonium salts.
3.7. Conclusions

Oxone is a cheap commercially available oxidant that easily oxidizes numerous
functional groups. In this study, we have developed a facile procedure for the preparation
of pure KHSOs-H2O in a straightforward and efficient manner, which is amenable to
large-scale production. An improved procedure for the preparation of nB u4NH805
(soluble Oxone) has also been developed that requires much less nBu4NHSO4 and
delivers high purity in a single extraction from either Oxone or KHSOs-H20. The
purified Oxone (KHSOs-H2O) was as effective as Oxone, but only required half the mass
of oxidant, thus making the reaction work-ups more facile. Column chromatography was
generally not necessary with either Oxone or KHSOs-H2O reactions. The high purity of
TBA-OX led to easier purification since less tetrabutylammonium ions were present.

TBA-0X was also unique in that it does not oxidize aromatic aldehydes, but remained as

56

effective as Oxone in the oxidative cleavage reaction, thus providing an alternate oxidant

for procuring aldehydes instead of carboxylic acids.

57

Chapter 4. Osmium Tetroxide Promoted Catalytic Oxidative Cleavage of Olefms.
An Organometallic Ozonolysis

4.1. Introduction

Oxidative cleavage of olefins is one of the paramount reactions developed in
organic chemistry. Many oxidative pathways discussed in the literature can be
summarized into two main methodologies; i) Transformation of olefins into 1,2-diols
followed by cleavage with NaIO4 or other oxidantsm, or ii) Ozonolysis, in which the
olefin is directly cleaved into a variety of fiinctionalized products depending on the
workup conditions.”226

The standard method for the direct oxidative cleavage of olefins is ozonolysis.
This reaction has been well-developed and yields aldehydes or carboxylic acids upon
reductive or oxidative workup, respectively.226 Simple modification of the workup also
gives rise to terminally differentiated functionality, such as combinations of ester-
aldehydes, acetal-aldehydes, acetal-esters, and carboxylic acids in combination with
acetals and alcohols.”’20

A lingering problem with ozonolysis is the major concern for safety; serious

(1.227'231 Under normal conditions,

accidents due to explosions have been reporte
ozonolysis reactions form ozonides and can also produce peroxides. These by-products
are hazardous and can lead to explosions upon concentration. This has been a point of
concern for the pharmaceutical industry during large-scale reactions, and also the paper

recycling industry, which utilizes ozonolysis during the decolorization process of

recycled paper.

58

Scheme lV-1. Various pathways of ozonolitic workup

0 O

 

4

 

l
(R0)2/\1vrlLon

4

a) 1. 03, CH3C0002Me, -78°C 2. PPha

b) 1. 03, ROH, NaHC03 2. A020, TEA

c) 1. 03, ROH, T80H 2. DMS. NaHCOa

d) 1. 03, ROH, TsOH 2. Ac20, TEA

e) 1. 03, CH300C02Me. -78°C 2. TEA

f) 1. 03, CH300002Me, -78°C 2. LiBH, 3. PPh3

A8 important as ozonolysis has proven to be in synthetic chemistry, there are
relatively few alternate reactions that duplicate the same transformation; i.e., the direct
cleavage of olefins in one step without the intermediacy of 1,2-diols. Ruthenium
catalyzed oxidative cleavage of olefins with RuCl3 or Ru04 to aldehydes with various co-
oxidants has been reported, although it is not clear whether or not diol intermediates are

(1232'234 Direct oxidative cleavage of olefins with 0804, without the

generate
intermediacy of 1,2-diols, has been suggested by using either hydrogen peroxide or (-
butyl hydrogen peroxide as co-oxidants, albeit in low yields.”’36 In these instances

mixtures of over oxidized products such as a-hydroxy ketones, aldehydes, and carboxylic

acids are present.

59

Alternatively, the Lemieux-Johnson reaction, which typically uses NaIO4, and its
variants are widely used for the one pot oxidative cleavage of 1,2-diols, and can be
coupled to the dihydroxylation of olefins with 08, Mn, Ru, and W oxides. Potassium
permanganate (KMnO4), for example, is a cheap and useful oxidant but is not soluble in
many organic solvents and is often non-specific.”’212’235'237 Much work in this area has
focused on the use of various phase transfer catalysts and solid supported reagents to
modify the reactivity and selectivity of permanganate, but while these reactions are all
milder and more selective than permanganate itself, this has not proven to be a general

solution to the problem (Scheme IV-2).236’238'243

Scheme lV-2. Reactions with 08, Mn, and Ru oxides

0H
0 KMno4 (cat) (IDA Nal04 o 0
CG N l0 (:0 H ”OM
a 4 2 RuCl3-3H20 (cat) 3

K2003

 

if
if

QAC QAC COZH

H
‘ silica-geI-KMn04 Ru02, Na104
m Benzene Y ; : H ecu, ACN, H20
0 O C02H o O
O O
0804(081)
N = N
—>= Jones reag —>=0
0 0

Acetone

 

 

ll

 

 

Sodium periodate (Na104) is another useful reagent for oxidations including
cleaving diols.16 This reagent is also limited by its insolubility in organic solvents.

244345 potassium metaperiodate along with phase

Quaternary alkyl ammonium periodate,
transfer catalysts,246 and silica gel supported NaIO42"'7 are reported examples that increase
the solubility and reactivity of the oxidant. These modifications have been successful to

some extent; however, the drawback of these reactions is the necessary intermediacy of

diol precursors to the cleavage. Alternatively, catalytic 0804 and NaIO4 have been used

1 Unfortunately, this

together to oxidatively cleave olefins in a one-pot procedure.21
reaction often produces undesirable byproducts. This fact necessitates that the diol
precursor is independently prepared before a separate periodate cleavage. Ultimately,

this becomes a two-step process instead of a more desirable one-pot method. Also, other

1,2-diols within target molecules need to be protected.

Scheme lV-3. General periodate oxidations

O

8 Ni
/©/\ C 02H ( “)4 O4 2 /©/tLH
Cl dioxane, reflux Cl

..~0H silica gel-Nal04 o o ph 0604 (cat)
0. M /=/ =
4 H Ph Nal04, dioxane

OH DCM H

 

 

 

Noyori and coworkers have also developed a “green” route for the direct
oxidation of olefins to carboxylic acids with catalytic Na2W04 and hydrogen peroxide as
the terminal oxidant (Scheme IV-4). This is an elegant procedure for production of high
valued compounds such as adipic acid from cyclohexene in large quantities using cheap
oxidants, however, it is not very general in its scope and is not tolerant of many
functional groups.248

Scheme lV-4. Green oxidative cleavage of cyclohexene with Na2W04

Nawo,, H202 o o
O T HOMOH

Me(n'OCI)3NHSO4 4
78 °/o

 

Development of the many oxidative cleavage methodologies is a testimony to the
importance of this reaction for synthetic chemists. Ultimately, organic chemists will
utilize the most appropriate conditions for their particular transformation amongst the

large body of possible reaction tools. Thus, it is very important to pursue other reaction

61

manifolds that could be more efficient, milder, and act as a substitute for established
transformations.
4.2. Initial Observations

Our interest in this area stemmed from previous work in the oxidative cyclization
of 1,4-dienes, in which 0804 and various co-oxidants were used to promote the desired
cyclization pathway.249 Low yields of the cyclized products were attributed to a large
number of side reactions including diol and tetrol formation, oxidative cleavage to
aldehydes when Na104 was used as a co-oxidant, and the formation of carboxylic acids
especially when Oxone was used as the co-oxidant (Scheme IV-5). We noted early on
that 0804 was necessary for the cleavage reactions with Oxone because subjecting either
methyl lineolate or its diol to the reaction conditions without 0804 did not provide

oxidized products, but instead returned the starting material untouched (Scheme IV-6).

Scheme IV-5. Initial 0804—Oxone results

 

 

OH
0504, Oxone 0 .R2 1
R1/=\/:R2 > R1 - + R C02H R2C02H
DMF, 3 h \ v J
OH
R1 = (CHzl'ICOzCl'la 3O % ~70 %

R2 = (CH2)4CH3

Scheme lV-6. Requirement of 0804 for the oxidative cleavage of olefins

HO OH
R?- — R‘
xo
or R‘COZH + R2C02H
F, l'I
R1 _ V — R2

R1 = (CH2)7COaCH3
F12 = (CH2)4CH3

Further investigation into the nature of the over-oxidized products and

optimization of that side reaction has led to a selective oxidative cleavage of olefins to

62

yield carboxylic acids using catalytic 0804 and Oxone in DMF (Scheme IV-7). Herein,

we report initial observations on a mild, organometallic alternative to ozonolysis.

Scheme lV-7. Selective oxidative cleavage with 0804—Oxone—DMF

0804 (0.01 equiv)
Oxone (4 equiv)

R1 R2 DMF 3h RT .7 R1C02H + R2C02H

 

4.3. Results

Initially, we investigated the oxidative cleavage of olefins in simple alkyl and
aromatic compounds (Table IV-l). Both cis- and trans-stilbene, IV-l and IV-2, cleanly
provided two equivalents of benzoic acid, IV-l a, in 95% yield. trans-Cinnamic acid IV-
3, styrene IV-4, and methyl cinnimate, IV-5, were also easily converted to IV-la in 97%,
94%, and 96% yields, respectively. Cyclohexene, IV-6, and cyclooctene, IV-7, provided
the corresponding adipic acid, IV-6a, and suberic acid, IV-7a, in good yields.
Additionally, simple alkyl olefins such as l-decene, IV-8, l-nonene, IV-9, and trans-2-
nonene, IV-10, all provided the appropriate alkyl carboxylic acids in 93%, 90%, and
93%, respectively. Similarly, methyl oleate IV-ll, provided a clean conversion to

nonanoic acid, IV-8a, and nonanedioic acid monomethyl ester, IV-lla.

63

Table IV-1. Oxidative cleavage of simple olefinsa

 

 

 

050., (0.01 equiv) o
H/VR t
Oxone (4 equiv) H 0”
DMF. 3 h, RT
Entry Substrate Product Yieldb (%)

1 cis-stilbene, lV-1 benzoic acid, lV-1 a 95

2 trans-stilbene, lV-2 lV-1a 95

3 trans-cinnamic acid, IV-3 IV-1 a 97

4 styrene, lV-4 lV-1a 94

5 methyl cinnimate, lV-5 lV-1 a 96

6 cyclohexene, IV-6 adipic acid, lV-6a 50 (94)c
7 cyclooctene, IV-7 suberic acid, lV-7a 82 (92)c
8 1-decene, IV-8 nonanoic acid, IV-8a 93

9 1-nonene, lV-9 octanoic acid, lV-9a 90
1 0 2-trans-nonene, IV-1 0 heptanoic acid, lV-10a 93
1 1 methyl oleate, lV-1 1 IV-8a + lV-11a 80 (93)c

 

a) All reactions were performed with olefin (1 equiv), Oxone (4 equiv), and 080, (0.01 equiv) in
DMF for 3 h at RT. b) Isolated yields. 0) G0 yield.

A number of mono-substituted, 1,1-disubstituted, 1,2-disub8tituted, tri-substituted,
and tetra-substituted olefins containing a variety of functional groups were also subjected
to the oxidative cleavage (Table IV-2). In most cases a yield of 80% or greater of the
desired ketene or carboxylic acid was obtained.

Acetate IV-12 reacted smoothly to provide the carboxylic acid IV-12a in 93%
yield. (-)-Isopulegol, IV-13, was oxidized to furnish the desired hydroxyketone IV-l3a
and formate IV-13b in 78% total yield. The formate could be easily hydrolyzed with
base; therefore, it is clear that the alcohol functionality is immune to oxidation. The
benzyl-protected isopulegol IV-14 provided 80% of the desired ketone IV-14a.

Substituted stilbenes, IV-15 and IV-16 were also cleanly converted into the

corresponding acid products, IV-15a and IV-l6a without difficulty in 91% and 95%
yield, respectively.

Interestingly, (Jr-methyl cinnamic acid, IV-l8, and l-methyl cyclohexene, IV-l9,
(examples of trisubstituted olefins) did not deliver the desired product in high yields
under standard conditions. Seemingly, the hydrolysis of the osmate intermediate leads to
the formation of the observed diol side product, presumably as a result of the acidity of
Oxone. However, addition of solid NaHCO; to the reaction substantially improved the
results, leading to high yields of the oxidatively cleaved trisubstituted olefins IV-l8 and
IV-l9. Cleavage of the tetrasubstituted olefin IV-20 in presence of NaHCO; was also
successful in yielding acetophenone, IV-20a.

a,[3-Unsaturated systems pose an interesting case since their cleavage would yield
an a-dicarbonyl functionality. Oxidation of 2-cyclohexenone (Table IV-2, entry 6)
provided pentanedioic acid, most probably via the a-dicarbonyl intermediate which
decarboxylates under the oxidative conditions. Baeyer-Villiger like oxidative cleavage of
a-dicarbonyls have been reported previously with peroxy compounds, and is likely the
operative route in the latter oxidation.”250 1,2-Cyclohexanedione, subjected to the same
reaction conditions (without 0804) was also oxidized to adipic acid (See Chapter VI),
thus demonstrating the lability of the a-dicarbonyl functionality. In a similar fashion,
(+)-pulegone, IV-21, yielded the dicarboxylic acid IV-21a via the intermediacy of an a-
diketone along with small amounts of lV-21b (16%), the simple hydrolyzed Baeyer-

Villiger product.

65

Table IV-2. Oxidative cleavage of assorted olefinsa

 

 

 

0804 (0.01 equiv) O
R/VR >
Oxone (4 equiv) R
DMF, 3 h, RT
Entry Substrate Product Yield (%)b
1 MOM Iv-12 AcO/WcozH lV-12a 93
0
2 ”'13 IV-13b R=CHO 34
OR
0% °
3 IV-14 ”W Iv-14a so
an
080 °
4 O \ IV-15 D/KOH IV-15a 91
N02 0
5 O \ O lV-16 Dim IV-16a 95
02N O2N
0
6 lV-17 HOZCMCOZH lV-17a 92
\ C02H C02H
7 m IV-18 O IV-1a 82
0
v- -
8 I 19 M002“ IV 19a 80
Ph 0
9 )—(Ph lV-20 Q/K IV-20a 85
H0 C
10 IV-21 2 \AfcozH IV-21a 67
0
11 M22 m IV-22a 60
' o
12 MOM 1v-23 Recovered SM lV-23 96

 

8All reactions were performed with olefin (1 equiv), Oxone (4 equiv), and 080, (0.01 equiv) in
DMF for 3 h at RT. bIsolated yields.

Figure lV-1. Structure of IV-21 b
0
W0,
0 lV-21b

Treatment of nootkatone, IV-22, containing dissimilar olefins under standard
conditions furnished ketone, IV-22a, showing that selectivity in oxidation is also
obtainable. Lastly, alkyne IV-23 was subjected to the cleavage conditions, however, it
proved immune to oxidation and starting material was recovered, thus indicating
selectivity for alkenes vs. alkynes.

4.4. Mechanistic Proposal

Oxone, a mono potassium peroxysulfate salt, is known to be an effective oxidant
for numerous transformations. For instance, Oxone is well known to prepare sulfones or
sulfoxides from sulfides, oxides of both phosphorous and nitrogen, and several reports
have shown that Oxone can also be used to oxidize aldehydes to carboxylic acids.68’87'
92’95’963'8’221’25 I We believe that in this system Oxone functions in three distinct oxidizing
roles: I) oxidizes the initially formed osmate back to 08(VIII), 2) promotes the oxidative
cleavage to an intermediate aldehyde, and 3) independently oxidizes the aldehyde to the
carboxylic acid.

We are not certain as to the mechanism of the oxidative cleavage, however, we do
propose the intermediacy of an osmate ester, which undergoes the cleavage. We do not
believe that the 1,2-diol is an intermediate of this reaction for two reasons: i) The
oxidation of olefins with the 0804-Oxone system proceeds just as well under anhydrous
conditions; i.e, there is no hydrolysis of the osmate ester. ii) Submission of 1,2-diols to

this reaction does not yield products, and in fact starting diol is recovered quantitatively.

67

To highlight the fact that 1,2-diols do not oxidize under our reaction conditions to
yield product, and thus are not intermediates during the cleavage, two test reactions were
performed with both styrene glycol and methyl 9,10-dihydroxyoctadecanoate. In both
cases, their corresponding olefin counterparts: i.e. styrene and methyl 9,10-octadecanoate
were also subjected to the oxidative cleavage reaction simultaneously [Oxone (2 equiv),
0804 (0.01 equiv), 3 h, RT]. The reactions were monitored by 1H NMR, TLC and GC
and clearly showed that the olefins were cleanly oxidized to their corresponding
carboxylic acids; however, the diols in both cases remained untouched and were
recovered in quantative yields.

0804 does not cleave 1,2-diols independently either. From the latter experiment
and literature precedent it is clear that Oxone also does not cleave or oxidize alcohols or
1,2-diols without other co-factors present. Thus it is reasonable to assume that this
oxidative cleavage proceeds without the formation of an intermediate 1,2-diol, and in fact

the osmate ester is activated for the direct cleavage of the C-C bond.

Scheme lV-8. Diols are not intermediates

 

 

 

 

OH
GA 0804, Oxone OCOZH 0W9
DMF, 3 n M C 3 0H
94 % (SM 96 °/.)
0804, Oxone B‘COZH Os ,O ne HO? OH
1— R2 > + : R1l—<R2
R DMF, 3 h RZCOZH W

93 °/. (SM 99 %)
R1 = (CHzlfiocha
R2 = (CH2)4CH3
Scheme IV-9 depicts our proposed mechanism, in which osmate IV-24 is

oxidized by Oxone to furnish IV-25, which is subsequently attacked by the same to yield

68

intermediate IV-26. Fragmentation of IV-26 regenerates 0804 and produces two

aldehydes, which can undergo further oxidation to yield carboxylic acids.

Scheme lV-9. Proposed catalytic cycle

9%
”97,08 06803K
0 ) 0
R R
RCHO + KHso. N-26
1,0, k0
o....o o
o Ds'</\ --
\ o ' - ,O-S-OK
RCOZH ,\0s” 0 0 Ho 5
0’ \\
R R
lV-25
o, ’0 mm,
.08.’
o o
R R
lV-24

To highlight the utility of this reaction, the oxidative cleavage of IV-2 was
successfully scaled to 50 mmol (9 g) and the amount of 0804 required was greatly
reduced from 1 mol % to 0.02 mol % (5000 turnovers). The isolated yield of this
reaction remains high at 95%; 88% after crystallization from chloroform.

4.5. Other Examples

Since our initial publication in this area, several new substrates have been
examined. In general we continued to be interested in aromatic olefins, which had
different functionalities on one side of the olefin and various other alkyl olefins (Table
IV-3). Trisubstituted olefin, IV-27, underwent clean reaction with the addition of
NaHCO3 as previously seen in 98%. The conjugated ketone IV-28 and the long chain

alkyl aromatic IV-29 provided reasonable yields at 83% and 90% respectively. Table IV-

69

3, entry 4, which contains a conjugated diene, has been reported to be problematic for
complete oxidative cleavage, but in this instance there were no complications and
provided IV-la in 93% yield. Cinnamyl aldehyde, IV-3l, did not oxidatively cleave very
well providing a modest 41% yield. There is no seemingly good explanation because
even if cinnamyl aldehyde underwent a Michael addition of KH805 instead of direct
osmium assisted oxidative cleavage the resultant 1,3-ketol should still be able to progress
to benzoic acid (See Chapter 6). Cinnamyl alcohol, IV-32, and 1-bromo-5-phenyl-4-
pentene, IV-33, however, proceeded in 84% and 98% yield without incident.

The trisubstituted cyclic olefin careen, IV-34, proved to be a very difficult
substrate to oxidatively cleave. Addition of NaHC03 continued to be necessary, but the
best attainable yield was 44% of the desired acid product IV-34a. Analysis of the
reaction byproducts demonstrated that the diol, IV-34b, and the formylated diol, IV-34c,
were the major byproducts (Figure IV-2).

The allylic alcohol IV-35 was subjected to normal oxidative cleavage conditions,
but the resultant product was not the expected a-hydroxyacid but instead an even further
oxidized product where the a-hydroxyacid functionality cleaved and provided the simple
acid product IV-35a in 95% yield. This cleavage could be stopped by protection as the
acetate providing a-acetoxyacid, IV-36a, in 86% yield. We had some hope that the
homoallylic alcohol might serve as an intramolecular trap to provide the acid-ester IV-
37b, but this product was not seen at all and the only isolable product was pentanoic acid
in 98% yield (Figure IV-3). The last two examples were pursued because we had
previously reported that alkynes do not undergo oxidative cleavage with our

DMF—OsO4—0xone system. We hoped to be able the isolate the alkynyl acid from the.

70

 

 

ml

Table IV-3. Additional oxidative cleavage examplesa

 

 

 

0s04 (0.01 equiv) o
[RA/R >
Oxone (4 equiv) R 0”
DMF, 3 h, RT
Entry Substrate Product Yield (%)”
\
1 m IV-27 benzoic acid lV-1a 93
o
2 GM lV-28 benzoic acid lV-1 a 83
\
3 W Iv-29 benzoic acid lV-1a 9o
4 lV-30 benzoic acid IV-1 a 93
O
5 WH IV-31 benzoic acid IV-1 a 41
\ 0H
6 W IV-32 benzoic acid IV-1 a 34
7 We lV-33 benzoic acid lV-1a 98
r
o
8 W lV-34 lV-34a 44
0 0H
0H 0
9 \ lV-35 IV-35a 95
W1 HOJLMM
OAC OAC
_ 0
10 W1 IV 36 W1 iv-36a 86
OH
11 HOW IV-37 pentanoic acid IV-37a 98
0H 0
12 M was HOJLM/ mm: 93
/ 1 1 11
0Ac 0
13 M lV-39 H0164? Iv-35a 97

11

alAll reactions were performed with olefin (1 equiv), Oxone (4 equiv), and 0804 (0.01 equiv) in
DMF for 3 h at RT. bIsolated yields.

71

left hand portion of the eneyne, but this product could not be found for either the free
alcohol, IV-38, or the acetate, IV-39, yet the long chain acid, IV-35a, was recovered in

good yield for both substrates, 93 % and 97 % respectively

Figure IV-2. Side products from Table lV-3 entry 7
0H 0
0%..
IV-34b lV-34c

Figure lV-3. Desired products from Table IV-3 entries 11, 12 and 13

\Vfl\;i0/\/kUH >‘;=.%)

HO OH

R = H, Ac
4.6. Conclusions
During the course of our investigation we have been able to show that a simple,
mild, and efficient oxidative cleavage of olefins takes place with 0804 and Oxone in
DMF, to provide ketones or carboxylic acids. Modification of the reaction to deliver
aldehydes exclusively is in progress. This reaction can be considered as an

organometallic alternative to ozonolysis

72

Chapter 5. Extension of the Oxidative Cleavage Methodology

5.1. Introduction

In the ozonolysis of olefins, aldehydes, carboxylic acids, and esters can be
obtained depending on the work-up procedure. In our previous studies on the oxidative
cleavages of olefins, carboxylic acids were obtained exclusively by using an
0804—Oxone—DMF system (See Chapter 4).6 Our laboratory was interested in
developing a suitable oxidative cleavage system that would provide easy access to

aldehydes, esters, and lactones as well. These attempts are described below.

5.2. New Oxidative Cleavage Methodologies
5.2.1. Preparation of Aldehydes with KHCO3

In the oxidations of olefins with 0804—Oxone—DMF we noted that the
immediate products of oxidation were aldehydes, which could be observed via GC.6
However, the reactions did not stop at the aldehyde oxidation state and simply reducing
the amount of Oxone to less than equivalent amounts did not provide the aldehydes
either. Instead carboxylic acids were the major products. We believed that by increasing
the rate of the oxidative cleavage of the intermediate osmate ester that we may overcome
the facile oxidation of aldehydes, thus being able to isolate the desired aldehyde products.
One way we thought to promote the rate of oxidative cleavage was through the use of
additives. This idea came about from the fact that the addition of NaHCO; to tri and tetra

6In

substituted olefins had improved the yield of the desired acid cleavage reactions.
those instances we believed that the problem was also the oxidative cleavage rate because

the major byproducts were the hydrolyzed osmate and the structurally related formylated

diol (Figure V-l). Additionally, additives such as methanesulfonamide and pyridine are

73

frequently used in dihydroxylation reactions to increase the rate of hydrolysis of the

intermediate osmate ester.l

Figure V-1 . Products from the oxidative cleavage of methylcyclohexene

0804
o
O/ CEOH + OH + /u\/\/\
KHSOsDMF 0H 0CHO COZH

For an initial screen we wanted to know if simply adding enough base as an

 

additive would prevent the oxidation of benzaldehyde, V-la to benzoic acid V-lb.
When we added 1 to 4 equiv of NaHC03 and 1 equiv of Oxone to benzaldehyde in DMF
the over-oxidation was not prevented and clean conversion to V-lb occurred.
Interestingly, by changing the additive to KHC03 (1 to 4 equiv), a majority of the starting
material could be maintained overnight with using 4 equiv of base (Table V-l).

Table V-1. Oxidations of benzaldehyde in the presence of base‘I

 

 

Entry Substrate Solvent Base Equivalents V-1 a” V-1 b"
1 Benzaldehyde, V-1 a BM F NaHCO3 1 0 100
2 V-1a DMF Ncho3 2 o 100
3 V-1 a DMF NaHCO3 3 0 100
4 V-1a DMF NaHCO3 4 0 100
5 V-1a DMF mm, 1 o 100
6 V-1a DMF KHco, 2 o 100
7 V-1a DMF KHco3 3 20 80
3 V-1a DMF mm, 4 33 17

 

a) All reactions were performed with olefin (1 equiv), Oxone (1.2 equiv), Base and 080, (0.01
equiv) in DMF (0.1 M) for 18 h at RT. b) Conversions determined as compared to the relative
areas of all peaks from a GC analysis.

With this result we chose to now directly investigate the oxidative cleavage of
trans-stilbene, V41 with KHC03 and NaHCO3. Using KHCO3 as an additive, no
carboxylic acid products could be detected in the reactions with one or more equivalents

of base. With half an equivalent, however, the reaction showed a majority of the acid

74

product. Reactions with NaHC03 again showed no carboxylic acid products, but lower
conversions. The success with KHC03 could not be extended to the alkyl olefin, 1-
decene, V-2, where a mixture of the starting material, nonanal, V-2a, and nonanoic acid,

V-2b, were obtained (Table V-2 entry 14).

Table V-2. Oxidative cleavage of V-1 with base‘3

 

 

Entry Substrate Solvent Base Equivalents V-1 b V-1a" V-1 b”
1 trans-stilbene. V-1 DM F None — 23 ND 77
2 V-1 DM F KHC0a 0.5 15 5 80
3 V-1 DMF KHC03 1 ND 100 ND
4 V-1 DMF KHCO3 2 ND 100 ND
5 V-1 DMF KHC03 3 ND 100 ND
6 V-1 DMF KHC03 4 ND 100 ND
7 V-1 DM F KHC03 5 ND 100 ND
8 V-1 DMF NaHC0a 2.5 12 88 ND
9 V-1 DM F NaHCO3 5 45 55 ND

10 V-1 DM F Me803NH 1 2 98 ND
1 1 V-1 MeOH None — 40 ND 60c
1 2 V-1 MeOH KHCO3 5 400 60 ND
13 V-1 MeOH MeS03NH2 1 20 98 ND
1 4 1 -decene, V-2 DM F KHC0a 5 1 4 9 77
15 V-2 DMF MeSOaNH 1 10 13 77

 

a) All reactions were performed with olefin (1 equiv), Oxone (1.2 equiv), Base and 0804 (0.01
equiv) in the appropriate solvent (0.1 M) for 18 h at RT. b) Conversions determined as compared
to the relative areas of all peaks from a GC analysis. 0) 60 % refers to methyl benzoate.

A few of other additives were also tried with mixed success. The choice of these
additives, methanesulfonamide and imidazole, was based on Shi’s observation that the
Baeyer-Villiger decomposition of their ketone catalyst is prevented under basic
conditions.”8’120 While methanesulfonamide provided V-la for aryl olefins, it was again
not successful in stopping the cleavage of V-2 at the aldehyde stage. Imidazole proved to

be more basic or reactive than desired and decomposed the active KHSOs very rapidly

75

resulting in no oxidative cleavage at all. It is plausible that the imidazole was oxidized to
the corresponding N oxide.

Oxidations of various substrates under our optimized conditions provided
benzaldehyde in varying yields. Trans-stilbene, styrene, methyl cinnimate and V-5,
provided high yields of the desired product at 96%, 92%, 94%, and 94%, respectively.
V-9 and V-10 along with cinnamyl aldehyde and cinnamyl alcohol provided somewhat
lower yields at 70%, 68%, 80%, and 73%, respectively. In the third subgroup, however,
the yields drop off precipitously providing only 56% and 60% product from the two
cinnamic acid derivatives, and only a 45 % and 47 % yield from 1,4-diphenylbutadiene,

V-ll, and the long chain alkyl-aryl olefin, V-12.

Table V-3. Oxidative cleavage of aryl olefins to aldehydes
0804 (0.01 equiv) 0
R2 Oxone (1.2 equiv)
\ 4 H
R R3 dodecane(1 equiv) R‘
101003 (1.2 equiv)
DMF, 1.5 11. RT

 

.A

 

Entry Substrate Product 00 Yield (%)b

O V-1 V-1 a 1 00

\
2 ©/\ v-3 V-1a 92
O

3 WOMe V-4 V-1a 94
\ O V-5 V-5a 94

O
5 WH V-6 V-1a 30
6 W0” v-7 V-1a 73

 

76

Table V-3. cont'd.

 

 

Entry Substrate Product GC Yield (%)°

0
7 Wm V-8 V-1 a 56

o
8 Wm V-9 V-1a 60

\
9 m v-1o V-1a 7o
/
1 0 V-1 1 V-1 a 68
Br

0

V-1 2 V-1 a 47°

11 O \ \
\
12 W v-13 V-1a 45

a) All reactions were performed with olefin (1 equiv), Oxone (1.2 equiv), KHCOa (1.2 equiv),
dodecane (1 equiv) and 0804 (0.01 equiv) in DMF (0.1M) for 18 h at RT. b) Welds determined as
compared to a GC standard curve with dodecane as an internal standard. c) Oxone (2.4 equiv)
and KHC0a (2.4 equiv) were added in for this substrate

Currently, we attribute the differences in the selectivity between aryl and alkyl
olefin cleavages to a difference in the relative rates between the 0804 promoted cleavage
and Oxone promoted oxidation of aldehydes. We think that for alkyl olefins the rate of
oxidation of the aldehyde is much faster than the rate of cleavage of the osmate ester.
The exact role of KHC03 in preventing the over-oxidation of aryl aldehydes is not clear
at present but possibly the slightly increased bacisity, due to the added KHCO3, slows
down the Baeyer-Villiger oxidation. Overall, we feel that Oxone is well suited for the
complete oxidation of olefins to carboxylic acids, but may generally be less suited for the
preparation of aldehydes. This has led us to study and search for other oxidants to affect

an oxidative cleavage and this is discussed in subsequent sections of this chapter.

77

5.2.2. Finding a New Oxidant via OsO4 Complexes

Our initial strategy to find a new oxidative cleavage oxidant was to prepare a few
stoichiometric osmium complexes of t-stilbene.23'27’252 This was easily accomplished at
low temperature in THF with 0s04, t-stilbene, and an appropriate ligand (none, DMF or
pyridine) (Table V-4).

Table V-4. Osmate esters of V-1 and V-4'

 

 

Entry Substrate Ligand Product Weld (%)"
Ph Q ,0
1 v-1 — I 9s; v-14 95°
Ph‘“ 0 0
Ph 0
2 V-1 DMF Ph“.&g;gs-DMF V-15 64
P“ o
_ o. .. .Py _
3 V1 Py PM. 0,9,“ V 16 36
0
Ph 0
,o O 6

 

a) All reactions were performed with substrate (1 equiv), ligand (3 equiv) in THF (0.2 M) at 0 °C
and then precipitated at —20 °C. b) Isolated yields. c) 1H NMR yield

The ligand free complex was not isolable, but could be identified by UV and
NMR. This complex showed good stability as a cold solution, but upon warming it
decomposed to provide benzaldehyde as the sole product. The DMF complex could be
isolated under nitrogen as a brown solid and was determined to contain only one DMF
ligand by NMR. However, when stored under nitrogen the solid compound remained
stable either cold or at room temperature. When left to stand in an air atmosphere the
brown solid turned to a black solid and no complex remained, only benzaldehyde. The
DMF complex was also stable as a cold solution, but decomposed slowly when left at
room temperature. The pyridine complex showed two pyridine ligands for every one

stilbene by NMR and this isolable brown solid was stable in air and in solution at room

78

me

016

be

Oli

(J

temperature. All three complexes could be cleaved via addition of KH805 to a solution
of the complex in DCM providing only benzaldehyde. Furthermore, the DMF complex
could very quickly and cleanly be converted to benzaldehyde with NMO, H202, or even
air. These intriguing results provided our first insight into the fact that other oxidants
may be suitable for the desired oxidative cleavage reaction and in various solvents.

In addition to the complex with trans-stilbene we also prepared a complex of
methyl cinnimate with DMF. After isolating the pure complex of methyl cinnimate the
1H NMR was recorded. Interestingly, it showed eight distinctive doublets for both
olefinic protons (H4 and Hb) and eight doublets (Mec) for the methyl ester, which we
believe could suggest a cis conformational relationship between a bidentate DMF and the

olefin. We have no evidence for the structure drawn in Figure V-2, however this picture

Figure V-2. Proposed structure of one of eight cis complexes

IIIIIII

could potentially describe why there are eight different doublets and eight different
methyl groups. The reasoning is as follows: there are two distinct rotations for the olefin,
two distinct faces of the olefin and two rotations for a bidentate DMF, this would provide
23 possibilities which is eight. There are of course alternatives including a bisosmate, or
dimeric/polymeric osmate, but they are perhaps as unlikely as our proposal. To
investigate this further a stable DMF containing osmium complex needs to be prepared

and crystallized. A possible substrate for this work would be 4-nitro-methyl cinnimate.

79

Again our complex, V-17, was susceptible to oxidative cleavage with a variety of
oxidants including NMO, H202, and air.
5.2.3. Preparation of Aldehydes with H202

A drawback of the earlier described Oxone/DMF system to promote oxidative
cleavage is its utility in large-scale synthesis. The need to remove large volumes of DMF
together with the large amounts of inorganics will result in the system being unattractive
for the isolation of products at the end of the reaction especially in the case of small
molecules. To circumvent this problem, several modifications were attempted with the
hope to develop a more convenient and suitable system for the use in a large-scale
preparation. We also wanted to see if the direct oxidative cleavage of the osmate ester
intermediate was a unique property of the Oxone—DMF combination or if the cleavage
would be promoted by other oxidants as well. This section describes the results of our
modifications on the Oxone/DMF system.

As can be seen from Table V-S, our test reaction with H202—DMF with methyl
cimmimate at RT led to the recovery of starting material. We surmised that this was
most probably due to the rapid decomposition of H202 in the presence of 0804 and DMF,
which was observed as the evolution of oxygenm’254 Cooling to 0 “C did not prevent
decomposition completely but did provide a 27% conversion to benzaldehyde.
Encouraged by this result, we decided to carry out the cleavages in ACN at 0 °C. We
reasoned that ACN would be more convenient to use and facilitate easy work-up
protocols. In the case of ACN at 0 °C, an 18% conversion to benzaldehyde was observed

while the remaining was unreacted starting material (Table V-5).

80

To improve the yield of the oxidative cleavage, the reaction was carried out in
varying amounts of DMF. ACN would remain the primary solvent, DMF would now be
considered as the “additive” and H202 would be used at a slight excess to gauge the
reaction outcome. As can be seen from Table V-5, addition of DMF up to 20 equiv
steadily improved the percent conversion of the benzaldehyde product. More surprising
was the decrease in conversion when the amount of DMF was further increased to 100
equiv. We surmised that the decomposition of H202 again became rapid with the
increased equivalents of DMF and thusly provided a decrease in conversion.

Since the addition of a relatively small amount of DMF seemed to promote the
cleavage effectively, different commonly used organic solvents with varying amounts of
DMF were pursued. These results are summarized in Table V-5. Thus, all the solvents
showed appreciable amounts of benzaldehyde, although, the best results were observed in
DCM or ACN. In most cases increasing DMF beyond 20 equiv proved to be detrimental,

therefore, we decided to carry out further cleavages with 20 equiv. of DMF in ACN.

Table V-5. Varying amounts of additive in various solvents‘

 

 

Entry Solvent DM F SM" Aldehyde”
1 DM F — 1 00° ND
2 DMF — 73 27
3 Acetonitrile 0 46 54
4 Acetonitrile 1 64 36
5 Acetonitrile 5 1 1 89
6 Acetonitrile 1 0 1 3 87
7 Acetonitrile 20 4 96
8 Acetonitrile 50 6 94
9 Acetonitrile 1 00 56 44
10 DCM 5 59 41.
11 DCM 10 45 55
1 2 DCM 20 4 96

 

81

Table V-5. cont’d.“

 

 

Entry Solvent DM F SMb Aldehydeb
1 3 DCM 50 ND 1 00
1 4 DC M 1 00 ND 1 00
1 5 Hexanes 20 47 46
1 6" Hexanes 50 1 97
17d Hexanes 100 48 17
18° EtOAc 20 51 45
1 9e EtOAc 50 65 3O
20 EtOAc 1 00 97 3
21 Toluene 20 14 86
22 Toluene 50 34 66
23 Toluene 1 00 53 47

 

a) All reactions were performed with methyl cinnimate, V-4, (1 equiv), H202 (3 equiv), DMF (0-
100 equiv), and 030, (0.01 equiv) in solvent (0.1M) for 18 h at 0—4 ’0. b) Conversions
determined as compared to the relative areas of all peaks from a GC analysis. c) Reaction
carried out at RT d) Diol contaminant: entry 16, 2%; entry 17, 35 % e) Acid contaminant: entry
18, 4%; entry 19, 5 %

We had observed the best cleavage reactions for our model system in ACN with
20 equiv. DMF and 3 equiv. H202 at 0 °C, and therefore, this system was chosen as our
standard reaction condition. We preferred this to DCM and toluene where the reactions
were biphasic and very efficient stirring was necessary. In fact, we observed
significantly different conversions for the same reaction in DCM based on the stirring
rate.

We next decided to screen a series of oxidants other than H202 to affect the
cleavage in ACN with 20 equiv DMF. The oxidants chosen were NMO, AcOOH,
tBuOOH, urea H202, KHSOs, and NaIO4. Some of these were chosen in order to keep
the system completely anhydrous. We felt that in an anhydrous system the potential

hydrolytic pathway would be shut down resulting in exclusive oxidative cleavage. Here

82

in addition to our standard methyl cinnimate we also chose four other olefins to do
simultaneous comparisons.

As can be seen in Table V-6, KH805 and tBuOOH led mostly to over oxidation
providing the carboxylic acid, while NMO was not generally a very efficient oxidant and
yielded unreacted starting material or diol. AcOOH, urea H202, NaIO4, and H202 were
also evaluated in this system and again gave mixed results. All four oxidants provide
significant amounts of aldehyde for the aromatic olefins tested, V-3, V-4, and V-17. The
alkyl cases, V-2 and V-18, remained most difficult except for NaIO4, but distinguishing
an osmate oxidative cleavage from in iodate oxidative cleavage would be difficult.
Otherwise, only H202 looked promising for alkyl aldehyde production. Hence we chose

H202 as the oxidant of choice for further studies.

Table V-6. Various oxidants and substrates

 

 

Entry Oxidant Substrate SM Aldehyde Acid Diol
1 30% H202 V-3 28 72 ND ND
2 30% H202 V-7 ND 100 ND ND
3 30% H202 V-4 ND 100 ND ND
4 30% H202 V-2 4 19 6 71
5 30% H202 V-18 ND 26 17 56
6 AcOOH V-3 ND 100 ND ND
7 AcOOH V-7 ND 1 00 ND ND
8 AcOOH V-4 ND 100 ND ND
9 AcOOH V-2 14 10 26 50
10 AcOOH V—18 33 ND ND 67
11 tBu00H V-3 ND 28 72 ND
12 tBu00H V-7 23 9 7 61
13 lBu00H V—4 ND ND 100 ND

14d tBu00H V-2 94 ND ND ND
15 tBu00H V-18 93 ND ND 7

16 urea H202 V-3 ND 70 30 ND
17 urea H202 V-7 ND 100 ND ND

 

83

Table V—6. cont’d.

 

 

Entry Oxidant Substrate SM Aldehyde Acid Diol
18 urea H202 V-4 ND 100 ND ND
19 urea H202 V-2 28 ND ND 72
20 urea H202 V-18 30 ND ND 70
21 KHSO5 V-3 ND 26 74 ND
22 KHSO5 V-7 ND 46 54 ND
23 KHSO5 V-4 ND 86 14 ND
24 KHSO5 V-2 5 ND 95 ND
25 KHSO5 V-18 ND ND 100 ND
26 NMO V-3 ND 70 30 ND
27 NMO V-7 50 30 20 ND
28 NMO V-4 100 ND ND ND
29 NMO V-2 20 ND ND 80
30 NMO V-18 7 ND ND 93
31 NaIO, V-3 ND 100 ND ND
32 Nal04 V-7 ND 100 ND ND
33 NaIO, V-4 ND 100 ND ND
34 NaIO, V-2 ND 58 16 26
35 Nal04 V-1 8 ND 38 15 47

 

a) All reactions were performed with substrate (1 equiv), oxidant (3 equiv), DMF (20 equiv) and
0804 (0.01 equiv) in ACN (0.1M) for 18 h at 0—4°C. b) Conversions determined as compared to
the relative areas of all peaks. c) V-18 is 2-trans-nonene. d) Epoxide contaminant: entry 14, 6%.

With several factors clearly scoped out, i.e. solvent, amount of DMF, and oxidant,
we chose to investigate the source of osmium that may promote cleavage (Table V-7). If
effective, OSC13 and K20804-H20 would prove to be cheaper and easier to handle
sources of osmium. Additionally polymer bound 0804 would facilitate an easier work-
up. As seen in Table V-7 when our previous oxidative conditions were used
(DMF—Oxone), all reactions behave well providing the desired carboxylic acid V-lb or
V-2b. However, with the modified conditions (ACN—DMF—H2O2) only OSCl3 was
effective in the cleavage of methyl cinnimate as compared to the original 0804.

However in the oxidative cleavage of decene 0803 and 0804 provided mixtures of

84

products while potassium osmate and polymer bound 0804 provided no cleaved products
and returned only starting material. With these results we felt that using other osmium
sources for the oxidative cleavage reaction was potentially valuable but not worth

pursuing further at this time.

Table V-7. Various osmium tetroxide sources

 

 

Entry Substrate Osmium Source Conditions“ Product Yield (%)°
1 V4 K2080, ° 2H20 A V-1 b 87
2 V4 08Cl3 A V-1 b 90
3 v.4 Pyridine polymer A V-1 b 88
4 v.4 0804 A V-1 b 96
5 v.4 K20804 - 2H20 B — NR
6 v.4 08Cl3 B V-1a 100°
7 v.4 Pyridine polymer B — NR
3 v.4 030, B V-1a 100c
9 v-2 K2080, - 2H20 A V-2b 72
1 0 V-2 OsCl3 A V-2b 83
11 v-2 Pyridine polymer A V-2b 72
12 v-2 0804 A V-2b 93
13 V-2 K20804 - 2H20 B - NR
14 V-2 08CI3 B _ _d
15 v-2 Pyridine polymer B — NR
16 v.2 OsO. B — —“

 

a) Condition A: All reactions were performed with substrate (1 equiv), Oxone (4 equiv), and
osmium source (0.01 equiv) in DMF (0.1M) for 3 h at RT. B: All reactions were performed with
substrate (1 equiv), H202 (3 equiv), DMF (20 equiv) and osmium source (0.01 equiv) in ACN
(0.1 M) for 18 h at 0—4 °C. b) Isolated Yields 0) Yields of aldehydes determined as compared to
a GC standard curve with dodecane as an internal standard. d) Conversions determined as
compared to the relative areas of all peaks and the reactions provided a comparable mixture of
products as Table V-6 entry 4.

The only other variant that needed to be explored before testing the standard
condition as an alternative to the initial Oxone/DMF system was to change the “additive”
which as previously mentioned in this section is DMF. We chose to study other amide
based ligands as the exact role of DMF in these reactions was not clear. However, our

previous results on solvent changes demonstrated that several amide based solvents

85

promoted either oxidative cleavage or aldehyde oxidation. The results were compared in
ACN and can be seen in Table V-8. A much smaller amount of ligand (0.4 equiv) was
chosen to determine if there was indeed a ligand effect. Additionally, the reactions were
carried out using methyl cinnimate as the model substrate and H202 (3 equiv) as the

oxidant. We observed what does appear to be a ligand effect and in fact several ligands

Table V-8. Oxidative cleavage with various additives“

 

 

Additive Conversion (%) Additive Conversion (%)"
0 CN
\NJLH 12 O 3
|
o i
Cl \/lL NH2 1 0 \T 1 8
CN 0
4 \ 1 9
.. é
o 0
HzNM/YNHZ 6 HN 28

I2

Cg.
C)
3;

O 0
(Dim? 17 WED 31
0
0
\/IL 23 NH 5
NH2
0
0
NH 7
0

 

a) All reactions were performed with V-4 (1 equiv), H202 (3 equiv), ligand (0.4 equiv) and 080,
(0.01 equiv) in ACN (0.1 M) for 18 h at 0—4 °C. b) Conversions determined as compared to the
relative areas of all peaks.

performed equal to or better than DMF. However, when the “better” ligands (v-
caprolactam and pyrolidinone) were evaluated with varying amounts of ligand the

reaction did not proceed cleanly to the aldehyde and instead carboxylic acids began to

86

form. This is an intriguing area to investigate because of its potential to start an oxidative
cleavage / kinetic resolution project. For instance, if an appropriate chiral ligand, perhaps
amide based, could bind to 0804 and then create a preference for the face of attack, a

kinetic resolution / oxidative cleavage may be realized (Scheme V-l).

Scheme V-1. Envisioned oxidative cleavage I kinetic resolution

0504, Oxone O
2 HOMOH
chiral Ligand i 0

solvent

 

Based on all of the above considerations a system comprising of ACN (0.1 M),
DMF (20 equiv), H202 (2 — 3 equiv.) and 0804 (0.01 equiv.) at 0 — 4 °C was chosen to
study the cleavage of various types of olefins (Table V-9).

Having chosen ACN—DMF—0804—H202 as the standard system we subjected
a series of aryl and alkyl olefins to cleavage under these conditions (Table V-9). The
reactions were primarily monitored by GC. Most aryl olefins showed benzaldehyde in
quantitative yield (measured with an internal standard) except styrene, V-3, and cinnamyl
aldehyde, V-6, which provided 72% and 55% of benzaldehyde, respectively. In cases
where the disubsituted olefin contained mixed aryl and alkyl components (Table V-9,
entries 10,12 and 15) the 1H NMR spectra of the crude reaction showed a 1:1 mixture of
benzaldehyde and the corresponding alkyl aldehyde. This was an interesting finding
because alkyl olefins did not work well in this system previously. Alternatively,
significant amounts of diol resulting from the hydrolysis of alkyl olefins were observed.
We felt that the hydrolysis of alkyl osmate esters was a facile reaction and overshadows
the desired cleavage process. On the other hand, in the case of aryl olefins the cleavage

process seems to be more facile than hydrolysis and hence the water present in the 30%

87

H202 had no deleterious effect on the cleavage process of aryl and mixed aryl-alkyl

 

 

 

olefins.
Table V-9. Oxidative cleavage of various olefinic substrates with H202“
0504 (0.01 equiv) 0
F12 H202 (3 SQUIV)
\ = H
R, R3 dodecane, ACN R,
DMF (20 equ1v)
13 h, o - 4 '0
Entry Substrate Product GC Yield (%)“
1 O \ O V-1 V-1a 97
\
2 GA v-3 v-1 a 72
o
3 WOMe v-4 v-1 a 100
4 0 \ O V-5 V-5a 100
o
5 ©/Vum V-6 V-1 a 55
6 Wm V-7 V4" 100
o
7 Wm v-3 V-1a 100
o
3 Won v-9 “1“ 100
\
9 m v-1o v-1 a 100
/
10 V-11 V-1a 100
Br
11 O \ \ O V-12 V-1a 50°
\
12 W v-13 V-1a 96

 

88

Table V-9. cont’d.“

 

Entry Substrate Product GC Weld (%)b

13 w v-19 V-1a 100
\
14 ©/\/ v-2o V-1a 1oo
\
15 (:va v-21 V-1a 70

a) All reactions were performed with olefin (1 equiv), H202 (3 equiv), DMF (20 equiv), dodecane
(1 equiv) and 080., (0.01 equiv) in ACN (0.1 M) for 18 h at 0-4 °C. b) Yields determined as
compared to a GC standard curve with dodecane as an internal standard. 6) H202 (6 equiv) was
added in for this substrate.

 

Not unexpectedly, alkyl olefins performed poorly under these conditions (Table
V-10) providing a mixture of oxidized products. An interesting result, however, was the
reaction with cyclohexene V-22, and cyclooctene V-23 (Table V-10, entry 3,4). In the
reaction with V-22 the observed products were the (it-hydroxyketone (15%) and the dione
(85%) (Figure V-3). Notably, V-25 was isolated as its dimer and V-26 was isolated in
good yield. There was no observable cleavage to adipaldehyde. Cyclooctene, V-23, and
methylcyclohexene, V-24, again provided the (it-hydroxyketone, V-25, and the a-dione in
good yield (Table V-10 and Figure V-3).

In an attempt to stop the hydrolysis process we exchanged DMF for silica in
hopes that it would be an effective absorbent and ligand simultaneously (Table V-l 1).
Additionally, we thought that silica supported peroxide may be a stronger oxidant than
peroxide itself because the silica would provide a large oxophilic leaving group and that
the resultant water would then stay bound to the silica. Under these conditions V-22
afforded the (Jr-hydroxyketone V-25 exclusively in 95 % yield. A control experiment

without silica or DMF provided only 8 % of V-25 along with starting material.

89

Table V-10. Oxidations of Alkyl olefins with H202“:b

 

 

Entry Substrate SM Aldehyde Acid Diol Hydroxyketone Dione Epoxide
1 M V-2 4 19 6 71

2 WI; we 26 17 56

3 O V-22 15 (12)“ 85 (80)c

4 O v-23 4 73 (70)c 1o (7)c 3

a) All reactions were performed with olefin (1 equiv), H202 (3 equiv), DMF (20 equiv), dodecane
(1 equiv) and 080, (0.01 equiv) in ACN (0.1 M) for 18 h at 0-4 °C. b) Conversions determined as
compared to the relative areas of all peaks from a GC analysis. c) Numbers in parenthesis
represent isolated yields.

Flgure V-3. Structures of isolated products from Table V-10

6003 (I:

V-25 V-26
O O
V-27 V-28

Noting that the conversion of cyclohexene to V-25 could be achieved easily
without DMF we subjected a number of alkyl olefins to these new oxidative conditions
ACN—OsO4—H202—Si02 (Table V-11). It was observed that cyclopentene, V-30,
could be cleanly cleaved to glutaraldehyde, V-30a, but was isolated in only 50% yield,
while the higher order cyclic olefins again provided good yields of the (it-hydroxyketone
and or-dione. The selectivity for the cleavage of linear alkyl olefins was not improved

with the silica modification (Table V-l 1, entry 1 and 2).

Table V-11. Oxidations of alkyl olefins in the presence of Si02

 

Entry Oxidant Substrate SM Aldehyde Acid Diol Hydroxyketone Dione Epoxide

 

1 M V-2 32 15 52

2 W v-13 33 12 54

3 O v-22 100 (95)°

4 O v-23 4 53 (55)c 26 (20)c 12
5 0/ M4 100 (97)c

6 6 V-30 100 (50)c

 

a) All reactions were performed with olefin (1 equiv), H202 (3 equiv), Si02 (1 g/mmol) and 080,
(0.01 equiv) in ACN (0.2 M) for 18 h at 0-4 °C. b) Conversions determined as compared to the
relative areas of all peaks from a GC analysis. 0) Numbers in parenthesis represent isolated
yields.

5.2.4. Preparation of Esters with KHSOs

Prior investigations in our laboratory have successfully used Oxone coupled with
0804 to oxidatively cleave olefins to prepare carboxylic acids. We have also
demonstrated that Oxone can effectively oxidize aldehydes to carboxylic acids or esters
by a simple change in the solvent. Additionally, we have developed practical methods to
prepare analytically pure KHS05 or n B u4NHS05, which simplify mechanistic
undertakings, and we have since realized the added advantage of differences in reactivity
between the two purified salt forms. We felt that we could further expand our oxidation
chemistry by coupling the esterification and oxidative cleavage reactions to perform an
oxidative cleavage / esterfication in one pot.

As stated earlier, our observation that MeOH effectively transformed aldehydes
into esters allowed us to consider the possibility of oxidatively cleaving an olefin in
MeOH to an ester. To this end under standard reaction conditions (0804 (1 mol %),

KHS05 (6 equiv), MeOH), V-l and V-3, were cleanly converted to the corresponding

91

esters in 90% and 72%, respectively. Other aromatic olefins were successfully
transformed into the corresponding aryl ester without difficulty (Table V-12, entries
4,5,7-12). Analysis by 1H NMR and GC/MS showed that the alkyl portions for V-ll and
V-l3 were cleanly converted to their corresponding esters in a 1:1 ratio as compared to
methyl benzoate, but these compounds were not isolated. Surprisingly t-cinnamic acid,
V-8, did not cleave, instead it provided an 80% yield of methyl 2-hydroxy-3-methoxy-3-
phenylpropionate, V-31. Interestingly, only starting material was obtained when V-8 was
subjected to identical conditions without 0804. Methyl cinnimate, V-4, was again
surprising in that it did not react even at elevated temperatures. Currently we do not
understand the significant reactivity differences with the latter two aromatic olefins.
Primary alkyl olefins such as V-2 and IO-acetoxy-l-decene, V-32, subjected in
the same way were also cleanly converted into alkyl esters in 70% and 68% yield,
respectively. Notably the acetate was hydrolyzed off during the reaction affording V-33.
However, attempts to broaden the scope were met with limited success. Cyclooctene, V-
23 only provided 26% of the desired diester. Reaction with 2-nonene or methyl oleate
provided no oxidatively cleaved product, but instead analysis by NMR showed that the
products were the regioisomeric hydroxy-methoxy 1,2 addition products, V-34a/b and V-

36alb.

Table V-12. Oxidative cleavage of olefins to esters“

 

 

0s04 (0.01 equiv) 0
\ R2 KH805 (6 equiv)
, 0Me
Wm MeOH, 13 11, RT 11‘
Entry Substrate Product Weld (%)b

 

/
O
f

1 O V-1c 90
\
2 @ v-3 V-1c 72
O
3“ Waive V-4 V-4 —
o
4 WH V-6 V-1c 69
5 m0” v-7 V-1c 74
OMe 0
0
Ph OM
6 WOH v-3 0,, ° 30c
v-31
0
7 Wm V-9 V-1 c 83
\
3 m v-1o V-1c 73
/
9 v-11 V-1c 66
Br
10 O \ \ O V-12 V-1c 66°
\
11 W v-13 V-1c 90
O
12 W v-19 V-1c 7o
MeOZCMCOZMe
13 O v-23 6 26
V-23c

 

93

Table V-12. cont’d.

 

 

Entry Substrate Product Yield (%)b
M302C
M v_2 H:
14 V-2c 70
Mom MeochOH
15 7 V32 63
V-33
OMe 0H
16“ v-13 0H 0Me 30°
V-34a 34b
OMe 0H
— M30 0 MeOsz
17d F4377 V'35 2 W 6 7 52°
M902C OH 0M6
V-366 V-36b

 

a) All reactions were performed with olefin (1 equiv), KHSOS (6 equiv), and 0804 (0.01 equiv) in
MeOH (0.1 M) for 18 h at RT. b) Isolated yields. c) No reaction was seen even when the
reaction was elevated to 50 °C. d) Regioisomeric mixtures of the hydroxy and methoxy.

Attempts to do the oxidative cleavage / esterification on alkyl substrates in mixed
solvents i.e. DMF/MeOH resulted in a mixture of products including carboxylic acids,
esters and the hydroxy-methoxy addition product. Additional studies in this area are
ongoing to determine if the cleavage reaction can be accelerated in alcoholic solvents
such that the addition byproduct is minimized.

As an alternative strategy, one could oxidatively cleave the olefin to prepare
aldehydes and then modify the oxidation state by adding the appropriate solvent and an
additional amount of oxidant. A proof of concept experiment was performed along this
line where methyl cinnimate, which notably did not react under the latter cleavage
conditions, was converted to the aldehyde with nBu4NHS05 and 0804 in DCM.

Subsequent dilution with MeOH and addition of KHS05 cleanly provided the desired

94

methyl benzoate (Scheme V-2). This modification is currently not applicable to alkyl
olefins because their selective oxidation to aldehydes has not been accomplished.

Scheme V-2. One pot oxidative cleavage with two different oxidants

0

0 0
KHSO
WORM 0504 Q/ILH 5 G/IKOMG
TBA-0X MeOH, 94%

DCM

 

 

5.2.5. Preparation of Lactones with Oxone

Previously we had noted that the oxidative cleavage of (-) isopulegol in
Oxone—DMF furnished formate ester, V-37, along with the desired hydroxyketone, V-
38. By performing this reaction in d7-DMF we were able to unambiguously establish that
the formate of V-37 did not come from the solvent. Therefore, the formate must be
obtained from an intramolecular formate transfer reaction and by a presumed hemiacetal
oxidation (Scheme V-3).6 In Scheme V-3 please note that the label on the olefinic carbon

is for carbon tracking purposes and not a 13 C labeling of that carbon.

Scheme V-3, Intramolecular trapping of an aldehyde with an alcohol

C'Hz cso4 (0.01 equiv) 9 9
Han : ’C: + Ith-
. H H .

a Oxone (4 equiv) 3
0” erMF, 3 h, RT 0”

 

 

 

The formation of hemiacetals and their subsequent oxidation to esters has also
been observed in the low temperature NMR experiments of oxidation of benzaldehyde to

methyl benzoate with Oxone in d4-Me0H (See Chapter 6). These observations led us to

95

believe that suitably positioned hydroxyolefins could be converted to their corresponding
lactones by an intramolecular trapping of the intermediate hemiacetals. The envisioned

reaction is shown in Scheme V-4 (direct conversion of V-39 to V-40).

Scheme V-4. Envisioned one pot oxidative lactonization

 

0
0804 (cat)
M0” = O
n Oxone / solvent
V39 V-40

Other methods that have been reported for the conversion of hydroxy olefins to
lactones via oxidative cyclization require stoichiometric chromium or permanganate
reagents. Schlecht and Kim”5 have used chromium trioxide in acetic acid/acetic
anhydride and Chandrasekaran and co-workersm’257 have used a pentavalent
(BiPyH2)Cr0C15 reagent to effect the transformation of various y- and 6-hydroxy olefins
to the corresponding lactones. However, these particular sets of reaction conditions are
only useful for hydroxy olefins containing a tertiary alcohol group, otherwise, oxidation
of the alcohol to the corresponding carboxylic acid or ketone is a major problem.

Chandrasekaran and co-workers soon devised a solution to this problem in the
form of cetyltrimethylammonium permanganate, which can be used in the oxidative
cyclization of primary, secondary, or tertiary alkenols to the corresponding lactones.258
Chandrasekaran also reported the use of MO; in the presence of copper sulfate and a
small amount of water as effective in the oxidative cyclization of w-hYdl'OX)’ alkenes to

259 We wish to report on our success in developing a

(D-laCIOI'lCS under mild conditions.
new and mild system for effecting this transformation involving catalytic 0804 in the

presence of Oxone as the oxidant.

96

Our initial efforts centered on the proof of concept depicted in Scheme V-5. Bis-
(hydroxymethyl) biphenyl V-41 was mono-protected and the free hydroxyl was oxidized
to yield aldehyde V-42. Upon treatment of V-42 with either Oxone in DMF or in MeOH,
in situ deprotection of the silyl group occurred concomitantly with oxidation of the
hydroxy aldehyde intermediate to the lactone V-44. Olefination of V-42 to deliver V-43
provided the prerequisite silyl-protected alkenol poised for a tandem oxidative
cleavage/oxidative lactonization to deliver V-44. Treatment of V-43 with catalytic 0804
(1 mol %) and Oxone in DMF led to the isolation of V-44 in good yields, thus
demonstrating the intramolecular trapping of the unmasked hydroxyl upon oxidative

cleavage of the olefin.

Scheme V-5. Oxidative lactonization: proof of concept

“0 1. TBDMSCI (1 eq) CHO
Imw/DMF
O 2. TPAP I NMO O
OH ores

v-41 CHZC'“ v-42

or
Oxone / DMF l MeOH /0xone

 

 
 
   
 

PhaPCstr

nBuLi/THF 4h/rt 18h/rt

76°43 73%»

\ O o
O 0804 / Oxone
O DMF/ 45 min 6 b
0TBS 75%
V-44

V-43

 

DMF was chosen as the initial solvent to study due to fast reaction times and
higher yields of product as compared to other solvents. It was found that the use of a 0.1
M solution of the alkenol in DMF with 4.0 equivalents of Oxone and 1.0 mol % 0804
was effective at converting primary, secondary, and tertiary alcohols to the corresponding

lactones in good yields (Table V-l 3).

Subsequent experiments focused on the conversion of alkenols to their
corresponding lactones. The remainder of the work presented here regarding oxidative
lactonizations has been performed by Jennifer Schomaker, a graduate student in our
laboratory, and is being shown and discussed for completeness of the oxidative story.
Specifically, the conversion of 4-penten-l-ol and 5-hexen-1-ol to butyrolactone and
valerolactone were initially investigated (Table V-13, entries 1 and 2). These lactones
were obtained in good yields, thus demonstrating that alkyl-substituted olefins can also
undergo the lactonization in preference to oxidation to carboxylic acids.

While the formation of five- and six-member lactones was facile as expected, the
yield dropped precipitously on formation of caprolactone (Table V-l3, entry 3). Longer
chain alken-l-ols gave no discemable amounts of lactone, and the carboxylic acids were
isolated as the sole products. This is likely due to the small equilibrium presence of the
cyclized hemiacetals for larger rings. Therefore, following oxidative cleavage, the
oxidation of the intermediate aldehyde to carboxylic acids predominates. The yield of
seven-member lactones could be improved provided conformational freedom was
restricted (Scheme V-5 and Table V-13, entry 4). Attempts to form an eight-member
lactone (Table V-13, entry 5) was unsuccessful and led only to the carboxylic acid
product V-49a, albeit in good yield. We were disappointed with these results, since we
had hoped that this protocol could be extended to the formation of macrocyclic ring
systems, thus providing the opportunity for masking a carboxylic acid as an alkene during
the course of a synthesis. While this might still prove a viable strategy for more highly
substituted systems with preferred conformations that could increase the cyclic

hemiacetal intermediate necessary for lactonization, another route to larger macrocycles

98

can be pursued by tethering an alcohol functionality to an endocyclic double bond (Table
v-13, entry 6).260

Table V-13. Oxidative lactonization of alkenols

 

 

Entry Substrate Product Yield (%)“

o

1 MOH v-45 g0 V-45a 73°
0 o

2 Mon V-46 U V-46a 63°
0 o

3 M0“ v-47 U V-47a 42°

.1“W '0‘
4 V-48 V-48a 59
OH 0 o

/ co H
2
5 W0” v-49 @NOH V-49a 69
O
OH
6 m V50 (:12? v-soa 45
O
/\></
/

0 0
OH v-51 g V-51a 34°
OH O 0
V52 )0? V-52a 35°

HO \
9 V was 000%.. V-53a 73

10 V54 O‘O)=o V-54a 32

OH
OTBS O
1 1 / v-55 v-553 76
0
0H 0H
12 KIA v-56 V-56a 52
\ COZH
ores
13 m v-57 Girl V-57a 65
/ o o
ores
1 4 V-58 o o V-57a 76d
CHO

 

a) Isolated yields, unless specified otherwise. b) 60 yields determined by using 1,2,3,4-
tetramethylbenzene or dodecane as an internal standard. c) NMR yields. d) The reaction
conditions are the same except for omitting 0804.

99

Entries 7 and 8 in Table V-13 illustrate the effect of substitution on the yield of
lactonization. The anticipated Thorpe-Ingold effect261 for alkenol V-Sl did result in
higher yields of V-Sla. However surprisingly, the tertiary alcohols V-52 and V-53 with
steric crowding of the hydroxyl groups reacted efficiently to yield V-52a and the
spirolactone V-53a, respectively. Fused 5/6 and 6/7 ring systems V-54a and V-48a
could be obtained in good isolated yields (Table V-13, entries 10 and 4). Protected
benzylic alcohol V-55 with an olefinic appendage was also lactonized under the same
reaction conditions. However, phenolic systems such as V-56 did not undergo oxidative
lactonization, presumably because of the tempered nucleophilicity of the hydroxyl group
(Table V-13, entry 12). Oxidative lactonization of the silyl-protected alkenol V-57
yielded V-58a, once again demonstrating the in situ deprotection/lactonization sequence
under the reaction conditions. Aldehyde V-59, presumably the intermediate in the
oxidative lactonization of V-58, also yields V-58a in good yields upon treatment only
with Oxone.

The use of a soluble form of Oxone (nBu4NHS05)7 was briefly studied.
Difficulty in separating excess oxidant and oxidation by-products from highly polar
products was not trivial, and thus, nBU4NHS05 is not recommended for use with water-
soluble lactones. However, nBu4NHSO5 is a convenient reagent for more non-polar
substrates and, unlike the Oxone/DMF system, allows for silyl groups to be retained
during the lactonization (Scheme V-6). The reason for the observed difference in
reactivity between nBu4NH805 and Oxone is not apparent, however, it could be a result
of Oxone’s much higher water content and its inherent acidity that could lead to the

hydrolysis of silyl ethers. Previous report by Sabitha and co-workers has demonstrated

100

the ability of Oxone to deprotect TBDMS groups in aqueous MeOH.262 As such, the
tandem oxidative cleavage/oxidative lactonization of the tertiary alcohol V-60 with
nBu4NHS05 in dichloromethane provided lactone V—61 in good yields without the

deprotection of the TBS group.

Scheme V-6. Oxidative lactonization with TBA-0X

 

cs0, (2.5 %) 0
H0 nBu4NH805 (4.4 equiv) 0
MOTBS >
CH20|2 / reflux / 12 n OTBS
64%
V-60 V-61

The oxidative lactonization has now been applied in an eight step total synthesis
of (+)—Tanikolide. This elegant synthesis, which was executed by Jennifer Schomaker,
begins with alkylation of the ylide V-62 to prepare V-63. HWE reaction and DIBAL-H
reduction provide the alcohol V-64. SAE, benzyl protection and a copper mediated
grignard addition provide V-66. This substrate is now poised for the oxidative
lactonization to prepare V-67 in 70% yield. Hydrogenation affords the desired natural

product (+)-Tanikolide (Scheme V-7).9

Scheme V-7. Total synthesis of (+)-Tanikolide via an intramolecular oxidative lactonization

\
(EIO)20P/\COZEI NaH /THF > 1% 1. K2003 lCHzO 4;
2. DIBAL-H

 

 

 

 

MBr (510)201D 00251
V-62 V-63,88%
L-DET/Ti(i0Pr)4 AA/E), 1. NaH/BnBr
M0,, tBuOOH/CHZCIZ : / .. 0H Bu4Nl/Tl-IF :
4AMSI-23'C , 2. CionngBr
V-64, 71 % V35, 94% (93% ee) LizCuCl4 ITHF

 

1

0 0
0804 (1 %)I DMF 60’ H2/ EtOH ESQ»
Oxone (4 eq) T 08" Pd /C OH
M 91% M

OBn . .
V-66, 78% V-67, 70% (+)-Tanikolide

 

101

5.3. Conclusions

In our initial study (See Chapter 4) we found that Oxone is an excellent oxidant
for the oxidation of aldehydes, for the re-oxidation of 08(VI) to 08(VIII) and that the
solubility of Oxone in DMF played a key factor in the overall process. We have now
seen throughout this chapter that small changes (i.e. KHCO3 or MeOH) in our initial
reaction conditions can provide different products selectively such as aldehydes or esters.
Additionally, appropriate placement of an oxygen nucleophile can successfully prepare
lactones. Furthermore we have now determined that successful oxidative cleavage does
not require Oxone or DMF specifically, but that the reaction can be successful with H202
in ACN utilizing small amounts of a coordinating ligand. All of these conditions are mild
and use environmentally friendly co-oxidants and small amounts of 0804 (as little as 0.02

mol %) such that large-scale reactions are feasible.

102

Chapter 6: Oxidation of Aldehydes and a- and B-Diones or a-Ketoalcohols to
Provide Carboxylic Acids and Esters.

6.1. Introduction

Carboxylic acids and esters may seem to be fairly innocuous targets for novel
synthetic methodology given the numerous methods already available. However, with
our intent to pursue “green oxidations” we believe there still is a lot of room for potential
growth. Oxone is a mild and green oxidant that is useful for numerous synthetic
transformations.80’87’89‘90‘”’95’97’'29’220’22I’240‘263’264 We have found that it is quite effective
in complete oxidative cleavage of olefins to carboxylic acids in one pot.8265 Our data
suggests the intermediacy of aldehydes in this oxidation, and thus we began to probe the
aldehyde oxidation independently.

We have now completed the optimization of this aldehyde oxidation to carboxylic
acids and in the process have also discovered a new route for the direct conversion of
aldehydes, or- or B-diones and or-ketols to esters.5’6‘8’249 The scope and limitations for
these oxidative processes and our current mechanistic understanding are presented.
These methods are quite attractive, since as opposed to most methodologies that utilize
Cr, Mn, Re, Ru, or other transition metal oxides, the environmentally benign reagent
Oxone mediates these highly efficient oxidations.263’266'273
6.2. Oxidations of Aldehydes
6.2.1. Preparation of Carboxylic Acids

Initially, oxidation of aryl aldehydes to carboxylic acids with Oxone in DMF were
investigated, the results of which are summarized in Table VI-l. In most cases the
desired carboxylic acids were obtained in >85% yield. Electron withdrawing (N02, CF3,

and CN) and electron neutral (C02Me, Ph, Me, H) benzaldehdyes were oxidized

103

efficiently (Table VI-l , entries 1-10). Halogenated benzaldehydes, including both Br and

C1, were also oxidized effortlessly to their corresponding halogenated benzoic acids in

good yields (Table VI-l, entries 9-11). However, electron rich substrates such as 4-

hydroxybenzaldehyde and p-anisaldehyde provided the formate esters VI-l3b and VI-

15b as the major products in 62% and 58% yield, respectively (Scheme VI-l). This is

consistent with previous observations for the oxidation of electron rich aromatic rings

that are presumed to undergo a Baeyer-Villiger reaction where the phenolic or Dakin

products were obtained. Conversely, the electron rich p-acetoxybenzaldehyde VI-14

proceeds smoothly to the desired carboxylic acid (Table VI-l , entry 14) in 90% yield.

Table VI-1. Oxone oxidations of aromatic aldehydes“

I \ CHO Oxone O/COZH
XI/ DMF //

 

 

 

x

Entry X Product Weld (%)b
1 2-N02 V” VI-1a 90
2 34102 v1-2 Vl-2a 95
3 4-No2 v1-3 Vl-3a 95
4 4-CF3 v1-4 Vl-4a 95
5 4-CN VI-5 VI-5a 85
6 4-002Me Vl-6 VI-68 95
7 H VI-7 VI-7a 97
8 4-Me VI-8 Vl-8a 97
9 2-Cl VI-9 VI-98 90
1 0 4-Cl Vl-10 VI-1 08 97
1 1 3-Br VI-11 VI-11a 97
1 2 3-OH VI-12 Vl-123 63
1 3 4-OH VI-13 Vl-13a 1 9°
1 4 4-OAC VI-1 4 VI-1 4a 90
1 5 4-0Me VI-15 VI-158 31 d
1 6 Ph VI-16 Vl-1 68 90

 

a) Aldehyde (1 equiv), Oxone (1 equiv), DMF (0.2 M), 3 h, RT. b) Isolated yields. c) 62% yield of
VI-13b. d) 58% yield of VI-15b.

104

Scheme VI-1. Dakin products from electron rich aromatic aldehydes

 

CHO
OCH0 3V. 0 hydrolysis OOH
R oxidation R O R
VI-13, H = OH VI-13b, R = OH Vl-18, R = OH
VI-15, Fl = OMe VI-15b, R = OMe VI-19, Fl = OMe

The potential scope of this method was evident when the protocol was extended
to simple aliphatic aldehydes (Table VI-2, entries 1-7). In most cases the oxidation
proceeds with high efficiency and yields of greater than 90% were obtained. While
affording clean reactions, smaller aliphatic aldehydes (Table VI-2, entries 3 and 4),
provided low yields due to isolation difficulties from DMF. 1,2,3,4-
tetrahydrobenzaldehye, which contains a double bond, oxidized effectively to VI-26a in
93% yield. Conversely, cis-4-decenal, VI-27, which also contains a double bond, was a
unique substrate in that in addition to providing the desired acid, (V I-27a, 53%) a
significant amount of the y-lactone (VI-28, 32%) was isolated (Table Vl-2, entry 8).
Oxidation of the electron rich aldehydes VI-29 and VI-31 again provided primarily the
Dakin products (Table VI-2, entries 9 and 10). Interestingly, the oxidation of 5-(4-
bromophenyl)-furfural VI-3l leads to the 1,4-dicarbonyl system VI-33 through a simple
oxidative process upon hydrolysis of the dehydrolactone VI-32 (>70% yield).

A key feature of the oxidation protocol to carboxylic acids is its inherent
simplicity. A mixture of the aldehyde (1 equiv) and Oxone (1 equiv) in DMF (0.1 - 1.0
M) is stirred for 3 h at RT. There is no need for rigorous exclusion of air or moisture in
order to affect a clean oxidation, however, the reactions continue to work even with these
added precautions. In most cases, a simple pass through a plug of silica is enough to

obtain highly pure products.

105

Table VI-2. Oxidation of assorted aldehydes“

 

 

 

o Oxone (1 equiv) 0
FIJLH DMF,3 n. RT 7 RJLOH
Entry Substrate Product Yield (%)“
1 “HfHO vr-2o Vfoz” VI-20a 99
2 177°” VI-21 117°C?” VI-21a 97
CHO CO H
3 \r v1-22 Y "’ Vl-22a 33
CHO CO H
4 >1” vr-23 >r 2 Vl-23a 47
5 OHCHfHO v1-24 ”02°11’92“ Vl-24a 34
CHO COZH
6 0’ was 0’ VI-25a 97
CHO C02H
7 U Vl-26 U VI-26a 93
O
”0 VI-27a 53
4 _
8 MCHO Vl-27 o
4
O
' v1-23 32
4
OH
O
0 W002“ VI-29a 34
CH0
9 W mm 8
O OH
W Vl-30 52
0
Br
v1-32 42
Br %0
10 ‘0/ CH0 v1-31 8,
W002“ was 30
O

 

a) Aldehyde (1 equiv), Oxone (1 equiv), DMF (0.2 M), 3 h, RT. b) Isolated yields.

Previous reports concerning the oxidation of aldehydes with Oxone were

performed in aqueous acetone or acetonitrile. However, we have found that DMF is also

effective for the oxidation; and in some cases superior to aqueous conditions. To test the

106

range of solvents that may promote this oxidation, a number of cyclic and linear
hydrocarbons, ethers, esters, and amides were screened against benzaldehyde, VI-7
(Table VI-3). Surprisingly, very few solvents provided the desired carboxylic acid
product even after extended reaction times of up to 36 h. The absence of reactivity is not
attributed to the lack of solubility of Oxone because a comparable study using TBA-0X
(nBu4NHSOs), a soluble version of Oxone, provided similar results. Interestingly, other
amide based solvents such as NMP, HMPA, and DMA were as effective as DMF in the

oxidation of VI-7 with Oxone providing >96% yield of VI-7a in all cases.

Table VI-3. Oxidation of Vl-7 to Vl-7a in various solvents“'“

 

 

 

o Oxone (1 equiv) 0
RJLH Solvent, 18 h, RT 7 F1 011
Entry Solvent Weld (%)°
1 DMF 97
2 HMPA 99
3 NMP 97
4 DMA 96
5 tBuOH 99
6 MeOH 96°
7 H20 85
8 Acetonitrile 52
9 DCM 20
1 0 Et20 0
1 1 THF 0
1 2 Benzene 0
1 3 Hexane 0
1 4 EtOAc 0

 

a) Vl-7 (1 mmol), Oxone (1 mmol), solvent (5 ml), RT b) Reactions were run for 6 h and checked
by GC. Reactions that still showed Vl-7 were then checked after 18 h and 36 h. All reactions
were then worked-up according to the standard procedure and the yield of VI-7a (or Vl-7b entry
6) was calculated. c) Isolated yields d) Isolated product was Vl-7b not Vl-7a.

107

6.2.2. Preparation of Esters

As a fortuitous extension of the solvent study, the oxidation of aldehydes with
Oxone in alcoholic solvents cleanly provided high conversion to esters. Thus, the
oxidation of benzaldehyde in methanol did not yield the expected carboxylic acid, but
instead the methyl ester was obtained (Table VI-4 entry 1). This oxidative pathway
complements other known methods that directly convert aldehydes to esters such as
oxidation in presence of alcohol with Br2 or 12, NBS/AIBN, PDC, HCN/Mn02 or
performed electrochemically.274'278 Additionally, we found that other alcohols such as
ethanol, propanol, and isopropanol could also provide esters in excellent yields, although
tert-butanol exclusively provided the acid product (Table Vl-4, entries 1-9).

The direct oxidation of a variety of aryl and alkyl aldehydes to their
corresponding methyl esters is also listed in Table VI-4 (entries 10-21). In the case of
electron rich aromatic substrates, as with the oxidations to carboxylic acids in DMF
(Scheme VI-l), the Dakin products were observed. Thus, 4-hydroxybenzaldehyde, VI-
13, and p-anisaldehyde, VI-l3, provided primarily phenols VHS and VI-19 in 77%
yield (Scheme VI-l, Table VI-4) for both along with small amounts of the corresponding
esters (Table 4, entries 14 and 15). Additionally, VI-31 provided 75% yield of the 1,4-
dicarbonyl ester product, VI-34 (methyl ester of VI-33). On the other hand, electron
withdrawing substituents showed slow conversion to the esters (Table VI-4, entries 10
and 11) initially providing mixtures of the presumed monomethyl and dimethyl acetals in
addition to the ester products. The identity of the acetals was proven to be incorrect and

will be discussed later in this chapter. However, by heating the reactions to reflux

108

overnight the observation of incomplete reaction was overcome and clean conversion to

the desired methyl esters VI-3b and VI-Sb occurred.

Table Vl-4. Oxidation of aldehydes to esters“

 

 

 

Q Oxone (1 equiv) O
RJLH R‘OH, 13 11.31 R 091
Entry Substrate Solvent Product Weld (%)“
1 VI-7 MeOH VI-7b 96
2 Vl-7 EtOH VI-7c 90
3 VI-7 n-PrOH Vl-7d 94
4 VI-7 i-PrOH Vl-7e 95
5 VI-7 t-BUOH Vl-7a 98
6 VI-20 MeOH Vl-20b 93
7 VI-20 EtOH VI-2OC 95
8 VI-2O i-PrOH VI-206 90
9 Vl-20 f-BUOH VI-ZOa 98
1 0 VI-3 MeOH Vl-3b 98°
1 1 Vl-5 MeOH VI-5b 98°
1 2 VI-8 MeOH VI-8b 94
1 3 Vl-10 MeOH Vl-10b 98
14 VI-13 MeOH VI-13b 9d
1 5 VHS MeOH VI-14b 1 9°
1 6 VI-21 MeOH VI-21 b 92
1 7 VI-22 MeOH VI-22b 91 °
1 8 Vl-23 MeOH VI-23b 76°
1 9 VI-24 MeOH Vl-24b 98
20 VI-25 MeOH Vl-25b 98
21 Vl-31 MeOH VI-34f 75

 

a) Aldehyde (1 equiv), Oxone (1 equiv), ROH (0.2 M), 18 h, RT. b) Isolated yields. c) These
reactions were carried out at 50 °C for 18 h. d) The phenol products VI-18 (77%) and VH9
(77%) were isolated as the major products for entries 14 and 15. e) 00 yield. 1) Methyl ester of
Vl—33.

Noteworthy, is the fact that iso-propyl esters are made with ease. However, as
mentioned above, tert-butyl esters cannot be accessed, most probably due to the sterics of
the bulky alcohol. Although at this time conversion of aldehydes to esters proceed best if

the reaction is performed in the alcoholic solvent (in order to prevent the formation of

109

carboxylic acids), studies are underway with mixed solvents and show promising
indications that the oxidation to carboxylic acids could be retarded in favor of
esterification. Thus it could be possible to lessen the amounts of alcohol used in the
oxidation.
6.3. Oxidations of a-Diones, B-Diones and a—Ketols

We have further extended our esterification protocol to include substrates such as
a-diones, B-diones and a-ketols which represent a common structural motif in organic
molecules. We noted that oxidative cleavage of a-ketoalcohols, or-diones, and B-diones
to their corresponding dicarboxylic acids is a well precedented process with reagents such
as calcium hypochlorite, sodium percarbonate, copper perchlorate, basic peroxide,
bisthmuth and rhenium and in Ashford and Grega’s report, B-diones could be oxidatively
cleaved to the corresponding one carbon deleted carboxylic acid using Oxone-NaHC03-
acetone-H2O.94°66'27“279 Additionally vanadium based systems have been reported to
convert a-ketoalcohols or or-diones into the corresponding methyl or ethyl esters in
presence of the appropriate alcohol (Scheme VI-2).280‘28'

Our own results in the related area of oxidative cleavage of olefrns indicated that
neither 01,8-unsaturated carbonyls nor or-hydroxyolefins provided the expected or-
ketoacids or or-hydroxyacids, but instead the one carbon deleted product. Moreover, 1,2-

cyclohexanedione when treated with Oxone—DMF provided adipic acid exclusively

(Scheme VI-2).

110

Scheme VI-2. Prior studies with Oxone cleavages

 

 

 

O
0504 (cat)
> HOZCMCOZH
Oxone/DMF
OH 0504(081.) HO O
\ = 2
W Oxone/DMF I“):
O
O Oxone
DMF
O o Oxone/NaHCOa
M > R1CO2H + R2C02H
R1 Rz acetone/water

Since the data suggested that oxidative conversion of ot-ketoalcohols, ct-diones,
and B-diones to carboxylic acids was well precedented there was little need for our group
to pursue it further, but the preparation of esters seemed to be less general. We thought
that these same classes of molecules may provide the corresponding diesters using ROH
as an interactive solvent. We have now developed a methodology to effectively
oxidatively cleave ot-diones, B-diones and a-ketols to diesters in one simple
transformation using the environmentally benign reagent KHSOs, prepared easily from
Oxone,

6.3.1. Preparation of Esters

To test this hypothesis we have now subjected several a-diones or B-diones and
or-hydroxyketones to our oxidative protocol. Under normal conditions, the oxidations
were performed in the chosen alcoholic solvent at RT for 18 h with the purified (>95%)
dry version of Oxone, KHS05 (4 equiv). It should be noted that even though KH805 was
used in all the studies cited in this report, similar reactivity and yield were obtained if

Oxone (triple salt containing KHSOs) was utilized.

111

As can be seen from Table IV-5, oxidation of ot-hydroxyketones, and 01- and [3-
diones in methanol provided good to excellent yields of the desired dimethyl esters. For
instance ketoalcohols, (Table IV-S, entries 1 and 2) provided products in 98% and 69%
yield, respectively, and cyclic or-diones (Table IV-5, entries 3 and 4) convert efficiently
to their corresponding dimethyl esters. Various other cyclic B-diones afforded the
desired dimethyl esters in 78-99% yield. or-Branching did not affect the reaction (Table
IV-5, entry 6); however, his (it-branching in the 1,3-dione IV-41 did hinder the reaction
significantly providing the tertiary ketoalcohol IV-4la in a modest 65% yield.
Interestingly, IV-4la does not undergo further oxidation without heating, presumably due
to steric constraints that hinder nucleophilic attack of the oxidant at the carbonyl carbon.
Heating the reaction to 50 °C, however, did initiate the oxidative cleavage, but with poor
conversion leading to only 54% of the desired diester with 22% of the starting material
being recovered (Table IV-5, entry 16). The structurally related cyclic tertiary
hydroxyketone, IV-50, reacted at room temperature providing an inseparable 4:1 mixture
of the dimethyl ester and the keto ester in a modest 50% yield. Benzil and benzoin (IV-
46 and IV-47) were also notable because they required heating to 50 °C for a facile
reaction. Additionally, the a-dione IV-48 did not yield the expected diester, providing
anhydride IV-48a in 98% yield, while IV-49 did not provide the diester exclusively
affording both the dimethyl and monomethyl esters in 19 and 64% yield, respectively.
Conversion of IV-48 to the cyclic anhydride IV-48a and not the diester (and conversely
the oxidation of IV-49 to IV-49a and IV-49b) is probably related to the observations
made by Blanc in acetylation of 1,5 and 1,6-dicarboxylic acids, and in particular the

differences in the reaction of the latter two compounds.282283

112

Reactions in EtOH and iPrOH (Table IV-6) proved to be quite reluctant to yield
diesters exclusively, and instead a reproducible mixture of mono- and di- esters were
obtained. Notably, the overall yield of these products remains high (51-86%). Benzil
and benzoin (IV-46 and IV-47) again proved to be more difficult substrates requiring
heating to 50 °C. Generally the yield of diethyl esters were higher than the corresponding
diisopropyl esters, however, significant amounts of monoesters were isolated in all
reactions. Reactions with tBuOH provided the diacid exclusively. This is in agreement
with our previous observations, which demonstrated that oxidation of aldehydes in
tBuOH with Oxone provided carboxylic acids without any trace of the desired ester.8

Table Vl-5. Oxidation of a-diones, B-diones and a-ketols in MeOH“

O KHso5

)n L Meozc’ tvrficoznne
r MeOH, 13 11, RT
m( l O

 

 

Entry Substrate Product Weld (%)“
O
1 (I611 VI-3s M°O°°Mf°°M° VI-35a 93
(dimer)
0
2 Ci Vl-36 M°O°°WEO°M° VI-36a 69
OH
0 M60 C CO Me
3 CE v1-37 2 M, 2 Vl-35a 90
O
O
4 CI v1-33 MeOZCMfOWe VI-36a 79
O
O
5 b“) VI-39 M°°2°M2°O°M° VI-39a 35
O
6 6:0 v1.40 M°°°°MEO°M° Vl-39a 30
O O
7 0 mm 002MB VI-41a 65
HO
O
3 W Vl-42 ”02°56‘32”“ VI-42a 36

 

113

Table VI-5. cont’d.

 

 

R=0Mma=4fl

Entry Substrate Product Yield (%)b
O 0 M30 0 co Me
9 U vr-43 2 M, 2 VI-42a 99
o o M3020 cognac
10 864 v1.44 M, VI-42a 36
O O
1 1 a VI-45 M°O2°MfO2M° VI-35a 73°
0
12 FMS/P“ Vl-46 Pocozue Vl-46a 73
OH
O
13 Ph/lkn/ph Vl-47 PhCO2M9 VH7“ 77
O
O O O O O
14 E'E Vl-48 O c Vl-48a 93
O C02Me
0 O Vl-49a R=Me 19
.5 a. v... O
0 R020 VI-49b R=H 64
0 M90 C 00 Me VI—43a 54
16 COZMe VI-49a 2 H; 2
Ho Vl-49a 22
O OH MeOZCHCOR
17 6L/ WM 4 Vl-35a:VI-51 50

 

a) Dione (1 equiv), KHSO5 (4 equiv), MeOH (0.2 M), 18 h, RT. b) Isolated yields.

reactions were carried out at 50 °C for 18 h.

114

c) These

Table Vl-6. Oxidation of a-diones, B-diones and a—ketols in EtOH and iPrOH“

o
KH
)1" 805 fig H‘ozc”tvtn?cozn2
m(°l 0 ”011130“ b: R‘=Et, 1:12:51 d:R‘=’Pr,R2=’Pr

 

 

 

c:R‘=Et,R2=H e:R‘=’Pr,R2=H
Entry Substrate Solvent (ROH) Product Yield (%)“
1 Vl-35 EtOH VI-35b: VI-35c 49:25
2 VI-37 EtOH VI-35b: Vl-35c 44:28
3 VI-39 EtOH Vl-39b: VI-39c 61 :25
4 Vl-4O EtOH Vl-39b: Vl-39c 42:38
5 VI-44 EtOH VI-42b: Vl-420 61 :1 4
6 VI-45 EtOH VI-35b: VI-350 35:48
7° Vl-46 EtOH VI-46b: VI-46c 25:37°
8° VI-47 EtOH Vl-46b: VI-46c 44:37°
9 Vl-48 EtOH V1488 98
1 0 Vl-35 i-PrOH VI-35d: Vl-356 34:45
1 1 Vl-37 i-PrOH VI-35d: Vl-356 33:18
1 2 VI-39 i-PrOH VI-39d: Vl-39e 31 :31
1 3 VI-4O i-PrOH VI-39d: VI-396 30:38
14 VI-44 i-PrOH Vl-42d: VI-42e 24:45
1 5 Vl-45 i-PrOH Vl-35d: VI-356 40:43
1 6° VI-46 i-PrOH Vl-46d: V1466 15:51
1 7° VI-47 i—PrOH Vl-46d: VI-46e 38:43
1 8 Vl—48 i-PrOH VI-48a 90

 

a) Aldehyde (1 equiv), KHSO5 (4 equiv), ROH (0.2 M), 18 h, RT. b) Isolated yields. c) These
reactions were carried out at 50 °C for 18 h.

115

6.4. Mechanistic Interpretation
6.4.1. Aldehyde Oxidations

Studies in our laboratory demonstrated Oxone’s effectiveness in the oxidative
transformations of aldehydes to carboxylic acids and esters. While related studies had
been conducted for the preparation of carboxylic acids from aldehydes, or esters from
acetals our modified protocols now easily provids carboxylic acids or esters directly from
aldehydes. Interestingly, the focus of prior work provides little insight into the oxidative
role of Oxone.

Baumstark demonstrated that the aldehyde oxidation was promoted by dimethyl
dioxirrane (DMDO), which could be either distilled away from Oxone or made in situ,
and proceeded through a radical process.” Webb’s oxidative protocol of aldehydes was
said not be able to generate DMDO in situ; therefore, he attributed the oxidation purely to
Oxone.9° Additionally, Curini demonstrated that acetals could undergo oxidation to
esters with Oxone but provided no mechanistic insight.129 Herein, we discuss several
experiments that allow us to propose a singular putative mechanism for the oxidation of

aldehydes to their corresponding carboxylic acids or esters.

Scheme VI-3. Proposed mechanism of Oxone promoted oxidations

 

H0;<0G803K i
R H A —" R OH +KHSO4
KHso5 11
KHSO
O 5 H0 OMe MeO OMe
R H R><H RXH
MeOH
(0803K

 

116

6.4.1.1. Initial Observations

Several empirical observations were key in pursuing the mechanistic studies of
the oxidation process. Firstly, we observed phenolic products from the oxidation of
aldehydes possessing electron donating substituents, i.e p-anisaldehyde. Baumstark
demonstrated that if the oxidation proceeds through a radical based mechanism the
phenolic products could be avoided by the exclusion of light and air.95 In our oxidations
of p-anisaldehyde with Oxone in DMF the product ratio did not change in the absence of
light and oxygen, thus suggesting that radicals are not generated in these reactions.

Secondly, oxidation of aldehydes with electron withdrawing substituents such as
4-nitrobenzaldehyde, VI-3, in the presence of methanol provided a mixture of unknown
acetals, VI-52. These acetals were not the monomethyl or dimethylacetal as confirmed
by NMR experiments and are suspected to be peroxysulfate acetals. Elevating the
reaction temperature in these cases from 20 °C to 50 °C cleanly provided the desired
ester, VI-3a. Additionally, subjecting the mixture VI-52 to MeOH at 50 °C did produce
the desired ester along with some starting material VI-3. Noting that the 1H NMR of VI-
52 looked like two distinct acetals we attempted to separate them by crystallization,
which was unsuccessful. We found that careful chromatography could provide two
distinct acetals VI-52a and VI-52b in small quantities along with a majority of aldehyde
VI-3 due to hydrolysis of VI-52. Treatment of those two compounds at 50 °C in MeOH
showed clean conversion to the ester for VI-52a while VI-52b converted in a 1:1 ratio of
SM and ester. IR and 1H NMR analysis also revealed that VI-52a contained an OH
group while VI-52b did not. The lR’s of these compounds also showed characteristic

signals for nitro and sulfate. Raman spectroscopy was uninforrnative and attempts to

117

obtain single crystals were unsuccessful. The 1H NMR shift of the benzylic methyne
proton in the proposed peroxysulfate acetal is in agreement with that of known peroxy
acetalsm’285 and therefore we propose that VI-52b is the potassium salt while VI-52a is
the free base. An alternative structure to VI-52a could be the inverted peroxysulfate
acetal VI-52c, however, we believe that compound VI-52c should not undergo clean
conversion to VI-3a. We suspect that the electron withdrawing nitro group prevents the

peroxysulfate acetal from undergoing a facile Baeyer-Villiger conversion.

Scheme VI-4. Presumed structures, VI-52, of isolated acetal intermediates

 

 

 

O r— .—
H Oxone M60 OOSOSK M90 0080311
= H + H
02N MeOH, 50'0
02N can
v1-3
\ Vl-52a Vl-52b j
v1-52
0 M80 oso,H
Of“
OMe
OA 2
02” VI-52c
Vl'3a _. .__a

 

 

Our third observation was that the conversion of cis-4-decenal yielded significant
amounts of the y-lactone side product (Scheme IV-5). The side product VI-28 was
curious and we subsequently investigated its origins. It was determined that Oxone is not
an epoxidizing reagent under the utilized reaction conditions, as evident by the lack of
reactivity of the olefin moiety in oxidation of 1,2,3,6-tetrahydrobenzaldehyde VI-26
(Scheme VI-6). Additionally, subjecting 2-nonene to Oxone under identical reaction

condition did not yield any epoxide and the starting olefin was recovered quantitatively.

118

Furthermore, epoxides were not observed in the oxidation of hexanal with t-stilbene

present as a scavenger,

Scheme Vl-5. Intramolecular epoxidation provides y-Iactone

0H 0
HO S’O‘O
mCHO Oxone 3 __> H0
DMF 4 — 4 —

VI-27 l VI-278, 53%
O l
9
° <——- M00211
4 O
OH
VI-28, 32%

While, the lactone VI-28 is most probably derived from the intramolecular ring
opening of an intermediate epoxide (based on the stereochemistry of the product, which
was determined by decoupling experiments), it certainly is not derived from an
intermolecular epoxidation event. We hypothesize that an intermediate peroxy species
could intramolecularly epoxidize the olefin (Scheme VI-S), as has been observed in

unsaturated fatty peroxyacids.286

Scheme Vl-6. Oxone does not epoxidize under identical conditions

0 o
Oxone
H DMF 0”
Vl-26

 

VI-26a
Oxone
M M
5 DMF 5
MCHO + PhA/ Ph Oxone ‘MCOZH ... PhA/ Ph
4 DMF 4
v1-2o V1420!I

119

6.4.1.2. Results
6.4.1.2.1. NMR and GC Experiments

To better understand the mechanism of the two reactions discussed here,
preparation of carboxylic acids and esters from aldehydes, the oxidation of 18O-labeled
benzaldehyde to benzoic acid and methyl benzoate were studied and the products were
analyzed by mass spectrometry. 18O-Labeled aldehyde was obtained with case from
H2180 and benzaldehyde, and was used in oxidative studies with 1 equiv of anhydrous
KHSOs. Scheme VI-7 depicts the possible routes for the oxidation of an aldehyde to
carboxylic acid (routes a, b and c) and ester (routes d and e). In short, if the oxidation to
benzoic acid involves either the formation of a dioxirane (route c) or the gemdiol of the
aldehyde (route b), the isolated product would contain 50% of the original 18O-Iabel.
However, the nucleophilic attack of Oxone in route a and subsequent Baeyer-Villiger
rearrangement of intermediate VI-53 will lead to benzoic acid with full retention of the
label. The isolated benzoic acid, obtained from the oxidation of the labeled benzaldehyde
in DMF, was analyzed by GC/MS and was shown to have fully retained the oxygen label,
thus suggesting route a as the path to carboxylic acids.

Similarly, the oxidation of benzaldehyde to methyl benzoate was investigated
with the 18O-labeled aldehyde. In the oxidations with MeOH, as in the previous
examples, the intermediacy of a dioxirane would lead to the product with 50% of the
original 18O-label (route e, Scheme VI-7). However, formation of the hemi-acetal, and
either the direct conversion to peroxide VI-54, or its formation through the dimethyl
acetal, followed by a Baeyer-Villiger rearrangement would yield the product with no

retention of the label (route d). The oxidation of 18O-labeled benzaldehyde was

120

performed with 1 equiv of KHSOs in dry methanol, and the isolated methyl benzoate was

analyzed by GC/MS. The product did not exhibit any [M+2]+ peak, thus suggesting that

route d was operative in this reaction.

Scheme Vl-7. 1"0 labeled oxidations of benzaldehyde

 

 

 

 

 

 

' 1 180H 0
180-0 0 0H_’
C H _, OH
)——>
50% 1‘20
’- 18 7 O
H 0 0H
6 ©><H 00803K Ho 00803K ©JL0H
' ‘ 1°0H
H186) 0p0803K
i» m ——> —> @011
v1 .53 100% 12‘0
180
KHSOSUeq) GAO},
150 / DryDMF m/Z=IM+2I* 0

©JLH\__’ KHso5 (1 eq)

 

@OMe
Gloria 0% 1‘30
m/z= [M]+

 

 

 

 

 

 

Further proof for

temperature NMR studies.

Dry MeOH T
(6303K QDMe
“‘80 0M9 M30 OMe Meo’) c')
o H ©><H ©><H on
I = —*
v1-54 f
,8 ”PH o
0—0 180’0H 0MB 6 OMe ©A0Me
e
.__>
50% 180

0x

the suggested mechanisms are provided through low

Oxidation of benzaldehyde and hexanal in d7-DMF and d4-

MeOH at 10 °C were carried out using purified anhydrous KHSOs. Figure VI-2 depicts a

series of NMR traces collected during the oxidation of hexanal in d7-DMF. As expected,

the evolution of product signals is counterbalanced with the disappearance of resonances

121

from hexanal. However, also present are a set of transient signals H1, and Hc that buildup
in concentration as the reaction progresses. The transient resonance at 6 5.51 (H4) is
assigned to the hemiacetal proton of intermediate peroxy species. The chemical shift of
this proton correlates well with the expected shift for hemiacetals.287 The transient signal
H1, (Figure VI-l) also falls within the expected region for a methylene neighboring a
hemiacetal.287 The upfield shift of 11,-9H1, is indicative of the loss of the carbonyl
functionality within the putative intermediate. The downfield shift of Hb-+Hd signifies
the regeneration of the carbonyl group, which in this case is the carboxylic acid. As
expected the integration ratio of H1,:Hc is 2:1.

A similar transient signal was observed in the oxidation of benzaldehyde in d7-
DMF at 6 6.63, which was assigned to the benzylic proton of the corresponding peroxy
hemiacetal. Since the oxidation in benzaldehyde is facile, there was little accumulation
of the intermediate species as can be seen by the low intensity of the signal at 6 6.63. On
the other hand, aromatic substrates with electron withdrawing groups such as 4-
nitrobenzaldehyde showed slower conversion to product, therefore, we carried out the
oxidation of this substrate in d7-DMF and pure KHS05 at 10 °C. A transient signal at 6
6.77 was observed which was significantly stronger as compared to that in benzaldehyde
suggesting accumulation of the putative reactive intermediate as a result of KHS05
addition to the aldehyde.

Oxidation of benzaldehyde and hexanal to their corresponding methyl ester in d4-
MeOH also exhibited transient signals at 6 5.67 and 6 4.69, respectively. These
resonances were assigned as the intermediate peroxy methylacetals corresponding to

structure VI-54 in Scheme VI-7. The signals for intermediate hemiacetal and dimethyl

122

acetal of both aldehydes were also present in the spectra, although, by the end of the
reaction only the signals of the product could be observed.

Figure VI-1. NMR study of hexanal oxidation“

 

O HO O-OSOaK 0
W14 —"> Hc —> OH
Ha H,a Hb Hb Hd Hd

 

 

 

 

ppm

a) Oxidation of hexanal in d7-DMF with Oxone at 10 °C (10 min elapsed between each spectrum)
exhibits transient signals b and c that are assigned to the a-methylene and the hemiacetal proton
of the boxed intermediate, respectively.

123

6.4.1.2.2. Kinetics

Emperical observations and subsequent analytical evidence have lead us to
conclude that there is an initial nucleophilic attack with KHSOs on the aldehydic
functionality which further promotes a Baeyer-Villiger rearrangement to yield the
corresponding carboxylic acids or esters. Furthermore, by using KHSOs in its pure form
we can reasonably suggest that neither radicals nor dioxiranes are involved in this
mechanistic process.

The empirical evidence here supports a Baeyer-Villiger type of mechanism and to
verify that conclusion we undertook a kinetic study of this oxidation using our most
straightforward example with benzaldehyde. We found significant limitations when
trying to employ GC or UV methods and found that for the kinetic study of this oxidation
reaction an iodometric initial rate method was most desirable where pseudo first order
kinetics were maintained by keeping a large excess of the aldehyde relative to KHSOS.
All work related to the kinetics of the KHS05 promoted aldehyde oxidation were
performed by Jun Yan, a graduate student in the Borhan laboratory, in collaboration

with myself.

124

Table Vl-7. Rate constants of the oxidation of benzaldehyde by KHSO5 at 298 K

 

 

[PhCHO], M 1021KH8051, M [H2804], M 10°k,, s"
2.46 0.33 1.00 5.51
2.46 1.27 1.00 5.34
2.46 1.63 1.00 5.33
2.46 2.19 1.00 5.69
2.46 2.79 1.00 5.33
0.49 1.50 1.00 0.74
0.93 1.50 1.00 2.03
1.43 1.50 1.00 2.32
2.02 1.50 1.00 4.13
2.46 1.50 1.00 5.33
2.46 1.00 0.30 4.33
2.46 1.00 0.50 4.71
2.46 1.00 0.75 4.47
2.46 1.00 1.00 5.12
2.46 1.00 1.25 5.00
2.46 1.00 1.50 5.52

 

Analysis of Table VI-7 allows one to see that the oxidation of benzaldehyde by
KH805 is first order in both substrate and KH805 and zero order in acid concentration.
It is therefore in accordance with the following observation, that the rate law for the
disappearance of KHS05 is given as follows:

-d[KHS05] / dt = k [PhCHO][KHS05]
where k is a second order rate constant.

A temperature study between 261 K and 327 K revealed a marked increase in rate
as the temperature was raised. Higher temperatures were not evaluated due to the
inherent lack of stability of KH805 at elevated temperatures. Analysis of the rate

constants at various temperatures allowed us to determine both the enthalpy of activation

125

and entropy of activation. Table VI-8 depicts the rate constant at various temperatures
along with the plot of -In (kr/T) versus III".
The enthalpy of activation (AHI) was calculated from the slope of the plot:
the slope of the plot = AH¢/R
4H2 = R * (the slope) = 3.76713103 * 3.314 = 3131913103 J morl
4H2 = 31.319 KJ mol'l

followed by the calculation of entropy of activation (ASI) from the intercept of the plot:

the intercept of the plot = AS¢IR + 1n (h/k)

482 = R[ln (h/k) - the intercept of the plot]

= 8.314 [ln(6.626e—34/1.386—23) + 1.564]

= -184.5 J morl K"

Table VI—8. Temperature effects on rate

 

Temperature (K) 103 Rate Constant (8")

 

261 0.72
273 1.03
297 5.32
306 7.97
327 12.70

 

[KHSOS] = 0.010 M; [PhCHO] = 2.5 M;
[H2804] = 1.0 M

13.5 -
13.0 -
12.5 1
12.0 '1
11.5 i
11.0 '1
10.5 '1
10.0 -1
9.5 r r r r r
2.9E-03 3. l E-03 3.3E-03 3 513-03 3.7E-03 3.9E—03

l/T

-ln(kr/T)

 

 

 

126

The magnitudes of AHgé and AS;6 reflect the transition-state structure. In
particular, the reacting bonds will be both partially formed and partially broken. The
energy required for bond reorganization is reflected in the higher potential energy of the
activated complex and corresponds to the enthalpy of activation, AH‘. The entropy of
activation is a measure of the degree of order produced in the formation of the activated
complex. If the number of translational, vibrational, or rotational degrees of freedom is
reduced by proceeding from the transition state to the product, there will be an overall
decrease in the total entropy of the system.

Here, the temperature effect, studied in the range of 261-327 K, shows a relatively
low positive AH¢ term demonstrating that bond making accompanies bond breaking.
Additionally, a negative entropy of activation is observed, which reveals that the initially
neutral reagents generate a charged intermediate speciesm’289 In comparison to other
reported Baeyer-Villiger oxidations, which have small positive enthalpies of activation
between 6 and 16 kcal mol'1 and negative entropies of activation between - 46 and - 171 J
mol“1 K", this reaction has very similar trends, with an enthalpy of activation at 31.32 K]
mol" or 7.48 kcal mol'1 and a slightly more negative entropy of activation at -184.5 J
mol'1 K'l. These results are in accordance with the known Baeyer-Villiger oxidation
mechanism.290

The pseudo-first order rate constant was determined by using benzaldehyde and
various substituted benzaldehydes under comparable conditions (Table VI-9). Since
some of the substituted aldehydes did not have very good solubility in DMF they did not
all have the same initial concentration. Even though the starting concentrations were

different, by maintaining the concentrations of aldehydes in great excess over KH805 the

127

observed rate constant (kobs) could be determined and could then be converted to a
comparable rate constant (k,) thus eliminating the effect of the starting concentrations of
aldehydes (kr = kobs / [aldehyde] [H2804]).

Table Vl-9. Substitutent effect at 298 Kal

 

 

substrate 103 km (s“) [aldehyde], M 103 Rr (3") Iog(k,/ko) op

H 5.32 2.46 2.16 0 0
p-Me 3.28 2.05 1.55 -1.46E-01 -0.14
p-Ph 4.68 1 .99 2.35 3.59E-02 0.05
p-Cl 6.80 2.00 3.39 1 .95E-01 0.24
p-CH3OOC 4.33 0.80 5.40 3.98E-01 0.44
p-CF3 14.92 2.06 7.25 5.25E-01 0.53

 

a) [KHSOS] = 0.010 M; [11230,] = 1.0 M

0.6 -
0.5 -
0.4 -
0.3 -
0.2 -
0.1 -

|og(k./ko)

 

~0.2 -O.l 0.2 0.4 0.6
-0.2

We found that the Hammett relatronsh1p that can be obta1ned from the subsututent
effect data is well correlated with Up but poorly with 0+ or 0', suggesting less importance
of resonance effect in a transition state (Table VI-9). The slope of the Hammett plot
about 0p provides a r value of 0.97. Further inspection of the Hammett equation shows
that reactions, which are favored by electron-donating groups, result in a positive p value.

Additionally, the p value is not particularly large suggesting that the reaction is not very

128

sensitive to substituent effects and furthermore implies that there is a relatively small
redistribution of charge in the transition state. Again, as in comparison to known Baeyer-
Villiger oxidation data, p has a typical value of 1.1-1.8 when a hydrogen migration
occurs, which compares favorably to our p value of 0.97. Alternatively, Baeyer-Villiger
oxidations provide negative p values when other groups migrate.
6.4.2. a—Diones, B—Diones and a-Ketols

The mixed products observed during the oxidation in ethanol and isopropanol
prompted a mechanistic study for their origins. Of interest was to ascertain whether
diesters are generated via Fisher esterification of monoesters; i.e., monoesters or
dicarboxylic acids are the product of the oxidation, or different and competing
mechanisms lead to mono and diesters. To address these two differing mechanistic
interpretations adipic acid was treated with KHS05 or KHSO4 in both MeOH and iPI'OH.
KHSO4, the byproduct of the oxidative reaction, can be utilized in general acidic Fisher
esterifications, but generally under heated or microwave assisted conditions?”293
Incubation of adipic acid for 18 h in iPrOH with either KHS05 or KHSO4 did not lead to
any detectable amounts of esterified product as analyzed by GC. Alternatively, adipic
acid in MeOH and KHSO4 led to the generation of dimethyl adipate in 1 h, however, the
same reaction with KHS05 did not yield any esterified product within 5 h. Conversion to
the diester was observed after 9 h, presumably due to the auto-decomposition of KHSOs
to KHSO4 in the wet alcoholic solvent. The presumed auto-decomposition was verified
by iodometric titration6 indicating that simply stirring MeOH and KHSOs for 9 h led to a
1% loss in oxidative activity, thus slowly generating the more acidic KHSO4 that could

be responsible for catalyzing the esterification. Moreover, addition of adipic acid (0.25

129

equiv) led to increased decomposition of KHS05 (4%) during the 9 h span. Considering
the fact that the oxidation of cyclohexanedione VI-37 to dimethyl adipate is nearly
complete in 3 h, it seems unlikely that VI-37 is converted to adipic acid, which in turn is
esterified under the reactions conditions. More evidence of the latter is realized with
experiments that demonstrate neither KHS05 nor KHSO4 can convert simple acids to
isopropyl esters, but yet mono and diisopropyl esters are isolated upon oxidation of 01- or
B-diones and 01- hydroxyketones. Although it is not possible to present a detailed
mechanistic picture from these experiments, it seems likely that the oxidative cleavage of
the functional groups presented here is faster than Fischer esterification of their
corresponding carboxylic acids, and that the mechanism for the formation of the isolated
mono and diesters most probably occurs via different mechanisms. In other words, one
can imagine diesters can originate directly from the oxidation without the intermediary of
monoesters, although it can not be ruled out (at least for the generation of dimethyl
esters) that some supplementary Fischer esterification of monoesters to diesters is
occurring.

Scheme VI-8. Not just a Fischer esterification

 

 

 

 

 

 

MeOH IPI'OH
M902C 002MB < H02C C02H
M4 KHSO4 101804 ”4
1h 18 h
_ HOZC COZH _
M4
MeOH IPI'OH
MGOZCMCOQMG HOszC02H
4 4
KH805 KHso5
9h 18 h

Schemes VI-9 — VI-11 depict possible routes to both monoesters and diesters
from a-diones, B-diones and a-ketoalcohols. The route to monoesters would most
probably involve the intermediacy of a peroxyhemiacetal, which upon Baeyer-Vinegar

like rearrangment would lead to the carboxylic acid functionality of the monoesters. This

130

is shown for a-diones and a-hydroxyketones (intermediates VI-56 and VI-65), which
upon oxidative rearrangement lead to either the monoester VI-58 or the aldehyde VI-67.
Further oxidation of the aldehyde VI-67 with Oxone in the alcoholic solvent would lead
to the monoester VI-58. Conversely, the intermediacy of a peroxyacetal such as VI—60
or VI-69 could lead to the isolation of the diesters without the need for esterification of a
monoesters and proceed to the diester VI-63 directly. In a similar manner, B-diones
could also lead to either mono or diesters. Presumably, (it-hydroxyketone VI-78 is
produced as an intermediate to the final product, although we have not observed this via
NMR spectroscopy. Subsequent Baeyer-Villiger oxidation could provide monoester VI-

80 or diester VI-82 (Scheme VI-l 1).

Scheme Vl-9. Probable mechanistic routes for the oxidative cleavage of a-diones

O O 0
EV ROH
......» HOZC CO R
645030;“ —>U W 2

 

5%0

 

V1l-55 Avril Vl-57 was
0 o 53>
09 BV / ‘R ROH 0 0 OR ROH ROC co R
IIsooosoaK ' OR ' 2 W 2
was v1-151 VI-62 VI-63

Scheme Vl-10. Probable mechanistic routes for the oxidative cleavage of B-diones

8V HO O O OHC CO H [O] ROZC CO H
——>
OOSO3K—> U W 2 ROH W 2

Vl-66 Vl-67 Vl-58

 

 

 

5%“—
11 T1109

HOH
OR
Vl-68

 

8V HO O ’0 R_. OHC co R —>[01 R020 co R
2
oosoax—> W 2 ROH W

Vl-69 v1-70 v1-71 Vl-63
Finally, it was shown that a minimum of 2 equiv of KHS05 for an a-

hydroxyketone VI-35 and 1 equiv of KH805 for a-dione VI-44 in EtOH was necessary

131

for their oxidation to yield the ratios of products listed in Table VI-lO (entries 1 and 2).
Increasing the amount of oxidant did not change the ratio of the mono and diester
products isolated. However, B-dione VI-44 required a minimum of 3 equiv of KH805 to
yield consistent product ratios listed in Table VI-10 (entry 5). These observations are

inline with the postulated mechanism depicted in Scheme VI-8 to Scheme VI-10.

Scheme Vl-11. Probable mechanistic routes for the oxidative cleavage of a-hydroxyketones

 

 

VI-75 Vl-72
OR OH
O O
00803K ~ 2 00803K
Vl-76 VI-73
1 EV 1 EV
G) H
O O
Vl-77 Vl-74

AH

H O/\n/\/C02R

O

/

/ v1-7a
K03800 OR K03800 OH
H = H
R020 0 Roac/\)</O
v1-e1 v1-79
BV CHZO BV
ROH
co R [0] co R
Rope/V 2 Hozc’\/ 2
mm VI-ao
CHOzR

132

Table Vl-10. Equivalents of oxidant necessary for complete conversion

 

 

Entry Substrate Equiv Product Yield(°/e)
Vl-35 2 Vl-35b:Vl-35c 51 :20
2 VI-37 1 VI-35b: Vl-35c 42:33
3 VI-44 3 Vl-44b: Vl-44c 61 :08

 

Summarily, we feel that the oxidative cleavage of 01- or B-diones and or-
ketoalcohols to esters with KHS05 is a valuable addition to the oxidative arsenal of
Oxone chemistry. These results demonstrate a new methodology aimed at the direct
synthesis of esters without the intermediacy of carboxylic acids from readily available 01-
or B-diones and a-ketoalcohols.

6.5. Conclusions

In conclusion, we have demonstrated a simple and effective one-pot protocol to
oxidize aldehydes directly to carboxylic acids or esters. These reactions are facile, high
yielding, and easy to work up (most do not require chromatography) and should provide a
mild oxidative alternative for organic chemists. The oxidative cleavage of 01- or B-diones
and a-hydroxyketones to esters with KHS05 is also a valuable addition to the oxidative
arsenal of Oxone chemistry. These results demonstrate a new methodology aimed at the
direct synthesis of esters from 01- or B-diones and a-hydroxyketones.

As demonstrated throughout this chapter, empirical observation, analytical
experimentation and kinetic measurement provide sound support for a Baeyer-Villiger
oxidation. An initial nucleophilic attack with KH805 on the aldehydic functionality
provides either carboxylic acids or esters depending simply on the solvent. This method
is unique in that comparably harsh metal mediated processes can be replaced with the

environmentally benign peroxysulfate salt KHSO5. Furthermore, by using KHS05 in its

133

pure form we can reasonably suggest that dioxiranes are not involved in this mechanistic

process.

134

Chapter 7. Experimental Details
7.1. General Information

All commercially available starting materials were used without further purification.
Commercially available starting materials were obtained from Aldrich, Fisher, Nu-Chek-
Prep, and Lancaster (Table VIII-1). Some compounds were prepared as previously
reported (Table VIII-1). All of the spectral data for known compounds either match
those reported by Aldrich or by comparison to the literature report. Compounds that
were analyzed by comparison to the Aldrich spectroscopic database are listed below and
their data is not tabulated further in the experimental (Table VIII-2). 1H, 13C, gCOSY,
gHMBC, DEPT and nOe spectra were recorded on either a 300 MHz NMR spectrometer
(VARIAN INOVA) or on a 500 MHz NMR spectrometer (V ARIAN VXR). IR spectra
were recorded on Nicolet IR/42 spectrometer using NaCl cells. Column chromatography
was performed using Silicycle (40-60 mm) silica gel. Analytical TLC was done using
pre—coated silica gel 60 F 254 plates. GC analysis was performed using HP (6890 series)

GC system (Column type-AltechSE-54, 30 m x 320 mm x 0.25 mm).

135

7.1.1. Orgins of Starting Materials

Materials obtained from Aldrich: benzaldehyde (III-l, V-la, VI-7), trans-stilbene
(III-2 , IV-2, V-l), triphenylphosphine (III-3), methylphenysulfide (III-4),
phenylboronicacid (III-5), cis-stilbene (IV-1), trans-cinnamic acid (IV-3, V-8), styrene
(IV-4, V-3), methyl cinnimate (IV -5, V4), cyclooctene (IV-7, V-23), 1-decene (IV-8, V-
2), l-nonene (IV-9), 2-trans-nonene (IV—10, V-18), (-)-isopulegol (IV-13), 4,4‘-
dimethylstilbene (IV-15, V-S), 4,4‘-dinitrostilbene (IV-16), 2-cyclohexeneone (IV-l7),
a-methyl cinnamic acid (IV-18, V-9) l-methylcyclohexene (IV-l9), (+)-pulegone (IV-
21), 4-phenyl-3-buten—2-one (IV-28, V-19), 1,4—diphenyl-1,3-butadiene (IV-30, V-12),
cinnamyl aldehyde (IV-31, V-6), cinnamyl alcohol (IV-32, V-7), 3-carene (IV-34), 3-
octene-l-l-ol (IV-37), 2,2‘-biphenylmethanol (V -4l), 4-pentene-1-ol (V-45), 5-hexene-
l-ol (V-46), 6-heptene-1-ol (V -47), 2-allylphenol (V-56), 2-nitrobenzaldehyde (VI-1), 3-
nitrobenzaldehyde (V I-2), 4-nitrobenzaldehyde (VI-3), 4-trifluoromethylbenza1dehyde
(VI-4), 4-cyanobenzaldehyde (VI-5), methyl 4-formylbenzoate (VI-6), 4-
methylbenzaldehyde (VI-8), 2-chlorobenzaldehyde (VI-9), 4-chlorobenzaldehyde (VI-
10), 3-bromobenzaldehyde (VI- 1 1), 3 -hydroxybenzaldehyde (V I - 12), 4-
hydroxybenzaldehyde (VI-13), 4-acetoxybenzaldehyde (V I-l4), 4-methoxybenzaldehyde
(VI-15), 4-phenylbenzaldehyde (VI-16), hexanal (VI-20), nonanal (VI-21), iso-
butyraldehyde (VI-22), 2,2,2-trimethylacetaldehyde (VI-23), cyclohexanecarboxaldehyde
(VI-25), 1,2,3,6-tetrahydrobenzaldehyde (VI-26), cis-4-decenal (VI-27), 6-ethyl-4-oxo-
4H-chromene-3-carbaldehyde (VI-29), 5-(4-bromophenyl)furan-2-carbaldehyde (VI-31),
2-hydroxy-cyclohexanone (V I - 3 5 ), 1,2-cyclohexanedione (V I -3 7), 1,3-

cyclopentanedione (VI-39), 2-methyl-1,3-cyclopentadione (VI-40), 2-

136

acetylcyclopentanone (VI-42), 1,3-cyclohexanedione (VI-43), 2-methyl-1,3-
cyclohexanedione (V I-44), 2-acetylcyclohexanone (VI-45), benzil (V I-46), benzoin (V I-
47), acenaphtyl-l,2-dione (VI-48), phenanthrene-9,10-dione (VI-49),

Materials obtained from Fischer: cyclohexene (IV -6),

Materials obtained from Nu-Chek-Prep: methyl lineolate II-17, 9,12-trans-methyl
lineolate II-23, methyl oleate (IV-11, V-35),

Materials obtained from Lancaster: nootkatoone IV-22,

Materials prepared according to literature preparation: (IV-12, V-32),294 IV-14295,
1v--20,296 Iv-23,297 (IV-27, v.10),298 (IV-29)299 (Iv-33, v-11),3°°;3°' Iv-35,3°2 IV-36,3°3
was,”4 v.20,305 v.21,306 (v-27, VI-36)3°5 (V-28, Vi-38),3°7 V-48,3°8 v-so,309 v-51,3"0

v-52 3“ v-53 3‘2 v-54 3‘3 v-55 3” v-57 3‘5 V-58 3“" V-60 3” VI-41 3‘8 VI-50 ‘86

137

7.1.2. List of Compounds that were Compared with the Aldrich Database

Benzoic acid (III-la, IV-la, V-lb, VI-7a, VI-46c), triphenylphosphine oxide
(III-3a), methylphenylsulfone (III-4a), phenol (III-5a), adipic acid (IV -6a), suberic acid
(IV-7a), nonanoic acid (IV-8a, VI-19a), octanoic acid (IV-9a), heptanoic acid (IV-10a),
4-methylbenzoic acid (IV-15a, VI-6a), 4-nitrobenzoic acid (IV-16a, VI-3a), glutaric acid
(IV-17a), acetophenone (IV-20a), and 3(R)-methyladipic acid (IV-21a), tn'decanoic acid
(IV-35a), pentanoic acid (IV-37a), benzaldehyde (V-la), methyl benzoate (V -lc, VI-7b,
VI-46a), methyl nonanoate (V-2 c, VI-Zlb), 4-methylbenzaldehyde (V-5a),
dirnethylsuberate (V-23c, VI-36a), y-butyrolactone (V-45a), y-valerolactone (V-46a), y-
caprolactone (V -47a), 2-hydroxyphenylacetic acid (V-56a), 2-nitrobenzoic acid (VI-la),
3-nitrobenzoic acid (VI-2a), 4-nitrobenzoic acid (V I-3a), methyl-4-nitrobenzoate (VI-
3b), 4-trifluoromethylbenzoic acid (VI-4a), 4-cyanobenzoic acid (VI-5a), methyl-4-
cyanobenzoate (VI-5b), mono-methyl terephthalate (VI-6a), ethyl benzoate (VI-7c, V1-
46 b), n-propyl benzoate (V I-7d), 4-methylbenzoic acid (VI-8a), methyl 4-
methylbenzoate (VI-8b), 2-chlorobenzoic acid (VI-9a), 4-chlorobenzoic acid (VI-10a),
methyl 4-chlorobenzoate (VI-10b), 3-bromobenzoic acid (VI-11a), 3-hydroxybenzoic
acid (VI-12a), 4-hydroxybenzoic acid (VI-13a), methyl 4-hydroxybenzoate (VI-13b), 4-
acetoxybenzoic acid (VI-14a), 4-methoxybenzoic acid (VI-15a), methyl 4-
methoxybenzoate (VI-15b), 4-phenylbenzoic acid (VI-16a), hexanoic acid (V I-20a),
methyl hexanoate (VI-20b), ethyl hexanoate (VI-20c), nonanoic acid (VI-21a), iso-
butyric acid (VI-22a), 1,1,1-trimethylacetic acid (VI-23a), adipic acid (VI-24a), dimethyl
adipate (VI-24b, VI-35a), cyclohexanoic acid (V I-25a), methyl cyclohexanoate (VI-

25b), diethyl adipate (VI-35b), adipic acid monomethyl ester (VI-35c), diisopropyl

138

adipate (VI-35d), dimethyl succinate (VI-39a), diethyl succinate (VI-39b), dimethyl
glutarate (VI-42a), diethyl glutarate (VI-42b), 1,8—naphthalic anhydride (VI-48a)
7.1.3. List of Compounds that were Compared to Literature Reports

[149308309 1140308209 1141308309 11423082091147?” IV-12a,299 IV-l3a,320
mm,321 mm),322 Iv-zza,323 Iv-34a,324 Iv-34b,325 v1--35d,132 v1.39c,32°, VI-39d,327

v1-39e,328 VI-42c,329VI-42e,330 VI-46d8 V1-49a,331 VI-49b,332

139

7.2. Data for Chapter 2

 

OH
KM"°4°' CH 0 CH c, O
CH3020H1407/2W05H11 3 2 14 7 .. C5H11
0804 H0
"-17 "-18

Methyl (2-trans-3,5-cis)-8-(3-hydroxy-5-(1-hydr0xyhexyl)-tetrahydrofuran-2-
yI)octanoate (II-18):

Acidic KMnO4: II-17 (200 mg, 0.68 mmol, 1 equiv) was dissolved in an
acetone/1120 (9:1) (20 mL) mixture and then stOH (117 mg, 0.68 mol, 1 equiv) was
added. Next, KMnO4 (644 mg, 4.08 mol, 6 equiv) was added in three portions over 20
min and stirred for 4 h. The reaction was then filtered through celite and washed with
EtOAc. The organic layer was separated and the aqueous phase was extracted with
EtOAc (10 mL x 2). The combined organics were washed with 1N HCl (30 mL) and
brine (30 mL) and then dried over N32804. The reaction was filtered and then evaporated
under reduced pressure. Silica gel flash chromatography in 40% EtOAc/hexanes
provided “-18 (40 mg, 18%).

Basic KMnO4: II-l7 (50 mg, 0.17 mmol, 1 equiv) was dissolved in an
acetone/1120 (9:1) (SmL) mixture and cooled to 0 °C. C02 was continuously bubbled
through the solution followed by the addition of MO; (81 mg, 0.51 mol, 3 equiv) in
one portion. The reaction was stirred for 30 min at 0 °C, warmed to room temperature,
and continued the C02 stream and stirring for 1 h. The reaction was then filtered through
celite and washed with EtOAc. The organic layer was separated and the aqueous phase
was extracted with EtOAc (5 mL x 2). The combined organics were washed with 1N

HCl (15 mL) and brine (15 mL) and then dried over Na2804. The reaction was filtered

140

and then evaporated under reduced pressure. Silica gel flash chromatography in 40%
EtOAc/hexanes provided II-18 (13.5 mg, 23%).

General Cyclization Protocol with 0804 and Various Co-oxidants: II-l7 (50
mg, 0.17 mol, 1 equiv) was dissolved in acetone/1120 (9:1) (5 mL) followed by the
addition of 0804 (4% in H20, 0.017 mmol, 0.1 equiv). After 5 min. the co-oxidant was
added (0.68 mol, 4 equiv) and stirred for 6 h. The reaction was quenched with Na2S03
(300 mg) and stirred for l h. The reaction was then extracted with EtOAc (5 mL) and the
aqueous phase was washed with EtOAc (5 mL x 2). The combined organics were
washed with 1N HCl (15 mL) and brine (15 mL) and then dried over Na2SO4, filtered and
evaporated under reduced pressure. The reactions were purified by Silica gel flash
chromatography in 10-80% EtOAc/hexanes.

General cyclization protocol with OsO4, NaIO4 and varying solvents: II-l7
(50 mg, 0.17 mol, 1 equiv) was placed in a flame dried flask and dissolved in the
appropriate solvent (5 mL). 0804 (2.5% in t-BuOH, 0.0085 mmol, 0.05 equiv) was
added and stirred for 5 min under N2. NaIO4 (0.68 mol, 4 equiv) was tehn added and
stirred for 6 h. The reaction was quenched with Na2SO3 (300 mg) and stirred for 1 h.
The reaction was then extracted with EtOAc (5 mL) and the aqueous phase was washed
with EtOAc (5 mL x 2). The combined organics were washed with 1N HCl (15 mL) and
brine (15 mL) and then dried over Na2SO4, filtered and evaporated under reduced
pressure. The reactions were purified by silica gel flash chromatography in 10-80%
EtOAc/hexanes.

Optimized preparation with OsO4 and Oxone in DMF: “-17 (1.5g, 5.01

mol, 1 equiv) was dissolved in DMF (50 mL) and 0304 (2.5% in tBuOH, 0.0085 mmol,

141

0.05 equiv) was added and stirred for 5 min followed by the addition of Oxone (20.37
mol, 4 equiv), which was stirred for 3 h. The reaction was quenched with Na2SO3 (9 g)
and stirred for 1 h. CH2C12 (150 mL) was then added and subsequently filtered through a
pad of celite to remove the salts. The celite was further washed with CH2Cl2 (25 mL x
3), and then extracted with H20 (200 mL x 2), IN HCl (200 mL) and brine (200 mL).
The combined organics were dried over NazSO4, filtered and evaporated under reduced
pressure to afford a brown oil. Silica gel flash chromatography in 30% EtOAc/hexanes
provided II-18 (535 mg, 30% yield). 1H NMR (CDC13, 300 MHz): 6 4.05 (m, 1H), 3.98
(m, 1H), 3.93 (m, 1H), 3.78 (m, 1H), 3.63 (s, 3H), 2.26 (t, 2H, J = 7.4Hz), 2.21-2.12 (m,
1H), 1.83 (bd, 1H, J = 3.9Hz), 1.59-1.22 (b, 20H), 0.85 (s, 3H) l3C (CDCl3, 75
MHz): 6 174.2, 87.3, 80.2, 74.5, 71.9, 51.3, 33.9, 33.3, 32.9, 32.6, 31.6, 29.2, 29.0, 28.9,
25.8, 25.6, 24.7, 22.4, 13.9; HRMS (CI) calcd. for C19H3705, 345.2641 m/z (M+H),
observed, 345.2638 m/z; IR (neat, NaCl, cm’l) 3460, 2930, 2861, 1742, 1456, 1442, 1254,

1117, 1066, 1029.

1 CPBA OH 9“
m .
' H 0 H 0:.
_ — DCM CH3OZC 1407 C5H11 C 3020H14C7 , C5H11
CH3020H14C7 CSHH _—’
2. THF-H20 HO + H0 V
11-17 ”0'04 11-19 11-20

Methyl (2, 3, 5-cis)-8-(3-hydr0xy-5-(1-hydr0xyhexyl)-tetrahydrofuran-2-yl)octanoate (II-
19) and Methyl (2,3 -cis-5-trans)-8-(3 -hydroxy-5-(1 -hydroxyhexyl)-tetrahydrofuran-2-
yl)octanoate (II-20): 208’209

II-17 (110 mg, 0.373 mmol, 1 equiv) was dissolved in CH2CI2 (15 mL). mCPBA
(1.120 mol, 3 equiv) was then added in one portion and the reaction was stirred for l h.

The reaction was diluted with hexanes (50 mL) and filtered. The reaction was evaporated

under reduced pressure to afford a white solid (residual meta-chlorobenzoic acid).

142

Additional hexanes (20 mL) were added, the solid was filtered and the organics were
evaporated. This was repeated three times until a clear oil was obtained. This crude oil
was dissolved in THF-——H2O—5% HClO4 (3:1:1) (10 mL) and stirred for 3 h. The
reaction was diluted with EtOAc (50 mL) washed with 5% NaHCO3 (30 mL x 2) and
brine (30 mL). The reaction was dried over Na2SO4, filtered and evaporated under
reduced pressure to a clear oil. Silica gel flash chromatography in 30% EtOAc/hexanes
provided II-l9 (40 mg, 31% yield) and II-20 (44 mg, 35% yield). VII-l9 1H NMR
(CDCl3, 300 MHz): 0 4.00 (m, 1H), 3.91 (m, 1H), 3.63 (s, 3H), 3.60 (m, 1H), 3.43 (m,
1H), 2.36 (m, 1H), 2.27 (t, 2H, J= 7.8 Hz), 1.83 (dd, 1H, J: 13.2, 4.1 Hz), 1.58 (m, 6H),
1.28 (b, 14H), 0.86 (t, 3H, J = 6.0 Hz) 13c (0001,, 75 MHz): 0 174.9, 84.7, 84.6, 79.6,
74.3, 51.9, 39.1, 34.7, 32.5, 32.2, 30.0, 29.8, 29.6, 29.5, 26.6, 25.4, 25.3, 23.1, 14.5; IR
(neat, NaCl, cm") 3396, 2929, 2856, 1739, 1457, 1437, 1253, 1197, 1076, 1034. VII-20
1H NMR (CDC13, 300 MHz): 0 4.20 (m, 1H), 4.00 (q, 1H, J = 8.8 Hz), 3.70 (m, 1H), 3.63
(s, 3H), 3.33 (m, 1H), 2.26 (t, 2H, J= 7.7 Hz), 1.96 (dd, 1H, J= 12.4, 7.1 Hz), 1.82 (m,
1H), 1.58 (m, 6H), 1.28 (b, 14H), 0.85 (t, 3H, J = 6.0 Hz) 13C (CDC13, 75 MHz): 5 174.9,
82.9, 80.7, 74.5, 73.7, 51.9, 38.4, 33.6, 32.5, 32.3, 30.0, 29.4, 29.3, 266,257, 25.4, 25.3,
23.0, 14.5; IR (neat, NaCl, cm") 3470, 2931, 2858, 1740, 1457, 1437, 1252, 1120, 1070,

1026.

143

OH OH

1.mCPBA CHO H c., O CHOCH C 0
DCM 3 2C 14 7 Sj/kCSH" 3 2 14 7 05H"
+

2. THF-H20 “0 Ho“
HC'O‘ 11-10 11-24

 

CH302CH14C7MC5H11

11.23
Methyl (2-trans-3,5-cis)-8-(3-hydr0xy-5-(1-hydroxyhexyl)-tetrahydr0furan-2-
yl)octanoate (II-18) and Methyl (2,5-cis-3-trans)-8-(3-hydroxy-5-(1-hydr0xyhexyl)-
tetrahydrofuran-Z-yl)octanoate (H-24):

“-23 (150 mg, 0.51 mmol, 1 equiv) was dissolved in CH2C12 (20 mL). mCPBA
(1.120 mol, 3 equiv) was then added in one portion and stirred for 1 h. The reaction
was diluted with hexanes (50 mL) and filtered. The reaction was evaporated under
reduced pressure to afford a white solid (residual meta-chlorobenzoic acid). Additional
hexanes (20 mL) were added, the solid was filtered and the organics were evaporated.
This was repeated three times until a clear oil was obtained. This crude oil was dissolved
in THF—H2O—5% HClO4 (3:1:1) (10 mL) and stirred for 3 h. The reaction was diluted
with EtOAc (50 mL) and washed with 5% NaHCO3 (30 mL x 2) and brine (30 mL). The
reaction was dried over Na2SO4, filtered and evaporated under reduced pressure to a clear
oil. Silica gel flash chromatography in 30% EtOAc/hexanes provided II-18 (51 mg, 30%
yield) and II-24 (62 mg, 35% yield). Methyl (2, 5-cis-3-trans)-8-(3-hydroxy-5-(1-
hydroxyhexyl)-tetrahydr0furan-2-yl)octanoate “-24: 1H NMR (CDCl3, 500 MHz): 5
4.1 1-4.01 (m, 2H), 3.82 (m, 1H), 3.73 (m, 1H), 3.64 (s, 3H), 2.27 (t, 2H, J= 7.3 Hz), 2.05
(m, 2H), 1.69-1.26 (br, 20H), 0.86 (t, 3H, J=6.3Hz). l3C (CDCl3, 125 MHz):6 174.3,
86.6, 80.8, 76.4, 70.8, 51.4, 34.2, 34.0, 33.2, 32.4, 31.8, 29.3, 29.1, 29.0, 25.8, 25.6, 24.9,
22.5, 14.0; HRMS (CI) calcd. for C19H37O5, 345.2641 m/z (M+H), observed, 345.2642

m/z; IR (neat, NaCl, cm'l) 3400, 2927, 2859, 1741, 1453, 1438, 1251, 1201, 1078, 1031.

144

OH OAc

CH3020H,,C7,,_ O 0511,, ”‘20; ”Y CH302CH14C72. O 0511,,
90%

HO A00
"-18 "-25

 

Methyl (2-trans-3, 5 -cis)-8- (3 -acet0xy-5 -( I -acet0xyhexyl)-tetrahydrofuran-2-yl)octanoate
(II-25):

II-18 (150 mg, 0.45 mmol, 1 equiv) was dissolved in pyridine (3 mL). A020
(1.35 mol, 3 equiv) was then added and the reaction was stirred for 6 h at RT. The
reaction was quenched with 1N HCl and diluted with EtOAc (15 mL). The organics were
washed with 1N HCl (10 mL x 3) and brine (10 mL) dried over Na2SO4, filtered and
evaporated under reduced pressure to a clear oil. Silica gel flash chromatography in 10%
EtOAc/hexanes provided “-25 (386 mg, 90% yield). 1H NMR (CDCl;;, 300
MHz): 84.99-495 (m, 1H), 4.88-4.85 (m, 1H), 3.98-3.89 (m, 2H), 3.63 (s, 3H), 2.36-
2.23 (m, 1H and t, 2H, J = 7.5Hz), 2.02 (s, 6H), 1.82-1.80 (m, 1H), 1.79-1.25 (b, 20H),
0.84 (t, 3H, J= le). 13(: (CDC13, 75 MHz): 0 174.2, 170.8, 170.5, 83.3, 78.1, 77.8,
74.6, 51.4, 33.9, 33.4, 32.7, 31.6, 30.9, 29.2, 29.0, 28.9, 25.4, 25.2, 25.0, 24.8, 22.4, 21.1,
13.9. HRMS (CI) calcd. for C23H4107, 429.2844 m/z (M+H), observed, 429.2849 m/z; IR

(neat, NaCl, cm'l) 2931, 2859, 1741, 1457, 1436, 1369, 1238, 1174, 1085, 1024.

145

OH OAc

CH302CH14C75, O C5H11 ACZO' py CH302CH14C7,,_ 0 (351111
90%

HO A00
"-18 "-25

 

Methyl (2, 5 -cis-3 -trans)-8- ( 3 -acet0xy-5 -( 1 -acet0xyhexyl)-tetrahydrofitran-2-yl)octanoate
(II-26):

“-24 (50 mg, 0.145 mmol, 1 equiv) was dissolved in pyridine (1 mL). AC20
(0.435 mol, 3 equiv) was added and the reaction was stirred for 6 h at RT. The reaction
was quenched with 1N HCl and diluted with EtOAc (15 mL). The organics were washed
with 1N HCl (10 mL x 3) and brine (10 mL) dried over Na2SO4, filtered and evaporated
under reduced pressure to a clear oil. Silica gel flash chromatography (10%
EtOAc/hexanes) provided II-26 (55 mg, 88% yield). 1H NMR (CDCl;, 300
MHz): 0 5.04-5.02 (m, 1H), 4.99-4.90 (m, 1H), 4.11-4.04 (m, 1H), 3.84-3.82 (m, 1H),
3.63 (s, 3H), 2.27 (t, 2H, J = 7.4Hz) 2.03 (s, 6H), 2.15-1.83 (bm, 2H), 1.57-1.02 (b, 20H),
0.85 (t, 3H). 13c (CDC13, 75 MHz): 0 174.3, 170.7, 170.5, 84.3, 79.4, 78.3, 73.9, 51.5,
34.2, 34.0, 33.0, 31.7, 31.6, 30.8, 29.2, 29.1, 29.0, 25.3, 25.1, 24.9, 22.5, 21.1, 14.0.
HRMS (CI) calcd. for C23H41O7, 429.2844 m/z (M+H), observed, 429.2840 m/z; IR (neat,

NaCl, cm'l) 2932, 2861, 1738, 1458, 1437, 1366, 1241, 1176, 1086, 1023.

146

HO OH

 

1, mCPBA CH302CH14C7 — Can
DCM
011302014,407/:\/=\c51111 +
2. THF-H o
HCIO 2 HO 0”
11.17 4 __
CH302CH14C7 05H1 1
11-27

(Z)-Methyl 9,10-dihydr0xy0ctadec-1 2-en0ate and (Z)-Methyl 1 2,13—dihydr0xy0ctadec-9-
enoate (II-27):“9

II-l7 (150 mg, 0.51 mol, 1 equiv) was dissolved in CH2C12 (20 mL). mCPBA
(0.56 mmol, 1.1 equiv) was then added in one portion and stirred for 1 h. The reaction
was diluted with hexanes (50 mL) and filtered. The reaction was evaporated under
reduced pressure to afford a white solid (residual meta-chlorobenzoic acid). Additional
hexanes (20 mL) were added, the solid was filtered and the organics were evaporated.
This was repeated three times until a clear oil was obtained. This crude oil was dissolved
in THF—H2O—5% HClO4 (3:1 :1) (10 mL) and stirred for 3 h. The reaction was diluted
with EtOAc (50 mL) and washed with 5% NaHCO3 (30 mL x 2) and Brine (30 mL). The
reaction was dried over Na2SO4, filtered and evaporated under reduced pressure to a clear
oil. Silica Gel flash chromatography in 30% EtOAc/hexanes provided II-27 (118 mg,
71% yield). II-27: 1H NMR (CDC13, 300MHz): 6 5.53 (m, 1H), 5.36 (m, 1H), 3.60 (s,

3H), 3.55 (m, 2H), 2.41-2.08 (m, 6H), 1.97 (m, 2H) 1.58-1.16 (br, 18H), 0.84 (t, 3H)..

147

7.3. Data for Chapter 3

2KHSOs'KHSO4K2804 KHSOs'H20 ——> KHSOS

 

Potassium peroxymonosulfate:

Preparation of KHSOs-H2O. Commercially available Oxone (307 g, 0.5 mol)
was placed into a 2 L erlenmeyer. DI H20 (307 mL) was added and swirled for 5 min
until the noticeable fizzing subsided (internal temperature 10 °C). The slurry was filtered
and washed with cold D1 H20 (30 mL). With the aid of a pH meter, the pH of the filtrate
was adjusted to 3.5 using solid KHCO3 (~75 g) with stirring. The initial pH of this clear
solution was about 1.0 and at the endpoint a pink color is observed. We found that
overshooting the endpoint resulted in a reduced yield of the purified material. If need be,
the pH can be readjusted with a few drops of concentrated H2804. The pink slurry was
filtered and the solid was washed with MeOH (2 x 307 mL) into the original water filtrate
resulting in the formation of more precipitate in the filtrate. This precipitate was again
filtered and washed with MeOH (307 mL). The slightly cloudy solution containing water
(337 mL) and MeOH (921 mL) was placed in the freezer overnight to crystallize the
purified product. The thick slurry was filtered and washed with 320 (4 x 200 mL) to
yield 76.88 g, 45% yield of KHSOS°H2O and found to be 99.1% pure after triplicate
iodometric titration. A second crop (6.52 g, 4% yield) could be obtained if the filtrate
containing the water, methanol, and ether mixture was again place in the freezer
overnight. The second crop was found to be 98.9% pure after iodometric titration.

Iodometric Titration of KHSOs-HzO. The iodometric titrations for purified
KHSOs-H2O were all performed in triplicate. KHSOs°H2O (250.6 mg) was dissolved in

D1 H20 (75 mL), 25% (w/w) KI (10 mL), and 10% (v/v) st04 (15 mL). The dark

148

brown solution was immediately titrated with 0.1003 M Na2S2O3 to a slightly yellow
endpoint. This method was adopted from the procedures developed by DuPont, Inc., and

can be found at the following website:

http://www.dupont.com/oxone/techinfo/index.htmL.

nBu4NHSO4

 

KH805 nBu4NHSOS

Tetra-n-butylammonium peroxymonosulfate:

Preparation of nB u4NHSOs (Method A, using KHSOs-H2O). P u r e
KHSOsoH2O (15 g, 88.2 mmol) was dissolved in D1 H20 (50 mL) and placed into a
separatory funnel. A slight excess of nBu4NHSO4 (31.4 g, 92.6 mmol) was added to the
separatory funnel and the slurry was extracted with CH2C12 (4 x 100 mL). The combined
organics were dried over Na2SO4, and the solvent was removed under reduced pressure
providing nBu4NHSOs (31.5 g, 96% yield based on nBu4NHSO4, 98.6% activity) as a
white solid.

(Method B, using Oxone). Oxone (2 g, 3.25 mmol) was dissolved in D1 H20 (20
mL) and placed into a separatory funnel. anNHSO4 (0.25 _. 6 equiv) was added to the
funnel and the slurry was extracted with CH2Cl2 (6 x 50 mL). The combined organics
were dried over Na2SO4, and the solvent was removed under reduced pressure to provide
nBu4NHSOs in 90 -—> 99% yield based on nBu4NHSO4 and ranged in activity from 35 —»
91% activity based on triplicate iodometric titration.

Iodometric Titration of nBu4NHSOs.68 The assay was performed in triplicate
using the following procedure. nBu4NHSOs (200.3 mg) was dissolved in glacial acetic

acid (2 mL), 10% (w/w) Na] (4 mL), and diluted with distilled THF (14 mL). The dark

149

brown solution was immediately titrated with 0.1276 M Na2S2O3 to reach the slightly
yellow endpoint.
CHO Oxidant COZH
O T 0
111-1 III-1a
Benzoic Acid (III-la):

III-1 (100 mg, 0.94 mmol, 1 equiv) was dissolved in DMF (0.1 M). The
appropriate HSOs‘ salt (1.1 equiv) was added in one portion and the reaction was stirred
at RT for 18 h. 1N HCl (10 mL) was then added along with B20 (20 mL) to extract the
products. The organic layer was washed with 1N HCl (10 mL x 3) and brine (10 mL),
dried over Na2SO4, and the solvent was removed under reduced pressure. The reaction
with Oxone and KHSOs-H2O yielded benzoic acid (III-la) in 97% (111 mg) and 94%
(108 mg), respectively. The products were analytically pure and did not required
additional purification. Oxidation with TBA-OX and Ph3PBnHS05 led to the isolation of
starting material III-1. The products of the latter two reactions were purified by column

chromatography with CH2C12 as the eluant.

O Oxidant
\ > III-1 a
O 0904 (cat) IDMF

III-2

 

Benzoic Acid (III-la):

III-2 (100 mg, 0.55 mol, 1 equiv) was dissolved in DMF (0.1 M), and OsO4
(0.01 equiv, 2.5% in tBuOH) was added and stirred for 5 min. The appropriate H805‘
salt (4.4 equiv) was added in one portion and the reaction was stirred at RT for 18 h.

Na2SO3 (2 equiv) was added and stirred for an hour or until the solution became dark

brown/black to reduce the remaining Os(VIII) species. 1N HCl (10 mL) was then added

150

 

along with B20 (20 mL) to extract the products. The organic layer was washed with 1N
HCl (10 mL x 3) and brine (10 mL), dried over Na2SO4, and the solvent was removed
under reduced pressure. Oxidation with Oxone and KHSOs°H2O yielded III-1a in 95%
(128 mg), and 97% (131 mg), respectively. The products were analytically pure and did
not required additional purification. TBA-OX and Ph3PBnHSOs oxidation of III-2
provided III-1 in 88% (104 mg) and 25% (29 mg) yield, respectively. The products of

the latter two reactions were purified by column chromatography with CH2C12 as the

eluant.
Oxidant
Ph3P ___.. Ph3P=O
THF / MeOH
Ill-3 Ill-3a

Triphenylphosphine oxide (III-3a):

III-3 (300 mg, 1.14 mol, 1 equiv) was dissolved in THF/MeOH (1:1, 0.1 M).
The appropriate HSOs' salt (1.1 equiv) was added in one portion and the reaction was
stirred at RT for l h. The solvent was removed under reduced pressure and the products
were purified by column chromatography with CH2Cl2 as the eluant. Oxidation of III-3
with KHSOs-H2O, TBA-OX, and PthBnHSOs led to the isolation of triphenylphosphine
oxide III-3a in 99% (325 mg), 97% (318 mg), and 98% (107 mg), respectively.

O\\S,CH3

\\

SCH3 Oxidant
———->

MeOH IHZO
Ill-4 Ill-4a

Methyl phenylsulfone (III-4a):
Oxidation with KHSOs: III-4 (347 mg, 2.8 mol, 1 equiv) was dissolved in
MeOH/H2O (1:1, 0.1 M). KHSOs-H2O (524 mg, 3.1 mmol, 1.1 equiv) was added in one

portion and the reaction was stirred at RT for 4 h. The solvent was diluted with CH2Cl2

151

 

(20 mL) and water (20 mL). The aqueous fraction was washed with CH2C12 (20 mL x 3)
and the combined organic extract was washed with brine, dried over Na2SO4, and the
solvent was removed under reduced pressure to obtain methylphenylsulfone (III-4a)
(90%, 393 mg).

Oxidation with TBA-OX: III-4 (347 mg, 2.8 mol, 1 equiv) was dissolved in
CH2C12 (0.1 M). TBA-OX (1.1 g, 3.1 mmol, 1.1 equiv) was added in one portion and the
reaction was stirred at RT for 3 days. The reaction was absorbed onto silica gel and was
purified by column chromatography with CH2C12 as the eluant to obtain III-4a (91%, 398
mg).

Oxidation with PthBanosz The procedure outlined above for TBA-OX was
used and led to the isolation of III-4a (52%, 75 mg).

NaOH / H20

Ill-5 “391°“ Ill-5a

 

Phenol (III-5a):

III-5 (100 mg, 0.82 mol, 1 equiv) and NaOH (50 mg) were stirred for 5 min in

H20 (3 mL). NaHCO3 (8.2 mmol, 10 equiv), the appropriate HSOS' salt (1.1 equiv), 400
mM EDTA (4 mL), and acetone (1 mL) were added at 0 °C and stirred for 15 min. The
reaction was quenched with sat. sodium bisulfite (10 mL) and extracted with EtOAc (20
mL). The organic extract was washed with 1N HCl ( 10 mL x 2), H20 (10 mL), brine (10
mL), and then dried over Na2SO4. The solvent was removed under reduced pressure to
obtain the crude product, which was purified by column chromatography with CH2Cl2 as
the eluant. Oxidation with KHSOs-H2O, TBA-OX, and Ph3PBnHSOs yielded phenol

(III-5a) in 80% (62 mg), 40% (31 mg), and 30% (23 mg), respectively.

152

7.4. Data for Chapter 4

OsO4 (0.01 equiv)
Oxone (4 equiv)
Fi‘ _ ‘Rz DMF 3h RT = R‘COZH + R2C02H

 

General Procedure for the Oxidative Cleavage of Mono and Disubstituted
Olefins (Condition A): The olefin (1 equiv) was dissolved in DMF (0.2 M), and 0504
(0.01 equiv, 2.5% in tBuOH) was added and stirred for 5 min. Oxone (4 equiv) was
added in one portion and the reaction was stirred at RT for 3 h or until the solution
becomes colorless. This usually marks the completion of the reaction, which was
verified by TLC or GC. Na2303 (6 equiv w/w) was then added, to reduce the remaining
Os(VIII), and stirred for an additional hour or until solution became dark brown / black.
1N HCl was then added along with EtOAc to extract the products. The organic layer was
washed with 1N HCl (3x) and brine, dried over Na2SO4, and the solvent was removed
under reduced pressure to obtain the crude product. Products were purified by silica gel
column chromatography.

General Procedure for the Oxidative Cleavage of Tri and Tetrasubstituted
Olefins (Condition B): The olefin (1 equiv) was dissolved in DMF (0.2 M), and 0504
(0.01 equiv, 2.5% in tBuOH) was added and stirred for 5 min. A solid mixture of Oxone
(4 equiv) and NaHCO3 (4 equiv) was then added in one portion and the reaction was
stirred at RT for 3 h. or until solution becomes colorless. This usually marks the
completion of the reaction, which was verified by TLC or GC. Na2803 (6 equiv w/w)
was then added, to reduce the remaining Os(VIII), and stirred for an additional hour or
until solution became dark brown / black. 1N HCl was then added along with EtOAc to

extract the products. The organic extract was washed with 1N HCl (3x) and brine, dried

153

over Na2SO4, and the solvent was removed under reduced pressure to obtain the crude

product. Products were purified by silica gel column chromatography.

0
Condition A
O \ —_—_—_—_. OH

1v-2 lV-1a
Benzoic Acid (IV-1a), Large scale preparation: IV-2 (9 g) was dissolved in DMF (250
mL), and OsO4 (0.2 mL, 2.5% in tBuOH) was added and stirred for five minutes. Oxone
(123 g) was then added slowly via a solid addition funnel over 2 h. The reaction was
stirred at RT for 6 h followed by addition of Na2SO3 (54 g) and stirred for an additional
hour. The reaction was diluted with 320 (750 mL) and stirred for 10 min. The solid was
filtered off and washed with B20 (75 mL x 3). The organic extract was washed with 1N
HCl (200 mL x 3) and brine (200 mL) and dried over Na2SO4. The solvent was removed
under reduced pressure to obtain the IV-la (11.60 g, 95%). The final product was
crystallized from hot chloroform to obtain IV-la (10.74 g, 88%). Lit mp = 121-123 °C.

obs. mp = 120-122 °C.

A920. 911
new new

 

9—Decenyl acetate (IV-12, V-32):294 To a solution of 9-decene-1-ol (500 mg, 3.2 mmol)
in pyridine (10 mL) was added acetic anhydride (0.91 mL, 9.6 mmol). The mixture was
stirred and heated for 3 h at 60 °C. The reaction was then extracted with EtOAc (25 mL)
and washed with 1N HCl (25 mL x 5) and brine (25 mL). The organic layer was dried
over Na2SO4 and concentrated under reduced pressure to provide a crude, slightly yellow
oil. Column chromatography (5% EtOAc/hexanes) provided IV-12 (630 mg, 99% yield).

1H NMR (CDC13, 300 MHz): 6 5.74-5.83 (m, 1H), 4.89-4.99 (m, 2H), 4.03 (1, 2H, J= 6.9

154

Hz), 2.02 (s, 3H), 2.01-2.07 (m, 2H), 1.56-1.62 (m, 2H), 1.27-1.38 (m, 10H); 13C NMR
(CDCl;, 75 MHz): 6 171.2, 139.0, 114.1, 64.6, 33.7, 29.3, 29.1, 28.9, 28.7, 28.5, 25.8,
20.9; IR (neat, NaCl, em") 3077, 2927,2856, 1741, 1641, 1242; LRMS (70 ev, EI) m/z

138 [M-OAc]+.

Cond'ti A
Aco/‘(\’)’7\ ' on Aco/‘(V)’6\cozH

IV-12 lV-128

 

9-Acetoxy nonanoic acid (IV-12a):299 1H NMR (CDC13, 300 MHz): 6 4.02 (t, 2H, J= 6.9
Hz), 2.32 (t, 2H, J= 7.4 Hz), 2.02 (s, 3H), 1.56-1.61 (m, 4H), 1.29 (bs, 8H); 13C NMR
((313013, 75 MHz): 6 179.6, 171.4, 64.5, 33.9, 29.0, 289,288, 28.4, 25.7, 24.5, 20.9; IR
(neat, NaCl, cm") 3455, 2931, 2856 1739, 1737, 1242; LRMS (70 eV, EI) m/z 199 (M-

H20]+, 157 [M-OAc]+.

0
1111.04 CODdltionA ' .. : : E0 Hon-W
", ‘3 + 6
OH OH o=(
H

lV-13 lV-13a, 44% lV-13b, 34%

(IR, 2R, 5R)-2-Acetyl-5-methyl cyclohexanol (Iv-13a):320 1H NMR (CDCl3, 300
MHz): 6 3.80 (ddd, 1H, J: 4.4, 9.6, 11.1 Hz), 2.27 (ddd, 1H, J = 3.6, 9.6, 12.9 Hz), 2.17
(s, 3H), 1.91-2.00 (m, 2H), 1.68-1.74 (m, 1H), 1.38-1.52 (m, 1H), 1.22-1.27 (m, 1H),
0.91-1.03 (m, 1H), 0.92 (d, 3H, J= 6.3 Hz); 130 NMR (CDC13, 75 MHz): 6 212.9, 70.4,
58.5, 42.2, 34.0, 31.1, 29.2, 27.5, 22.0; IR (neat, NaCl, em") 3417, 2952, 2927, 2869,
1705; LRMS now, 131) m/z 156 M, 138 [M-Hzor‘, 95 [M-H2O-C(O)Me]+.

(1 R, 2R, 5R)-2-Acetyl-5-methyl cyclohexanylformate (IV-13b): 1H NMR (CDC13, 300
MHz): 6 7.95 (s, 1H), 5.06 (ddd, 1H, J= 4.4, 9.6, 11.2 Hz), 2.59 (ddd, 1H, J= 6.9, 8.9,

14.5 Hz), 2.15 (s, 3H), 2.11-2.13 (m, 1H), 1.93 (qd, 1H, J= 3.9, 6.9 Hz), 1.68-1.77 (m,

155

1H), 1.50-1.62 (m, 1H), 1.27-1.41 (m, 1H), 0.87-1.06 (m, 4H); 13C NMR (CDC13, 75
MHz): 6 209.4, 160.3, 73.1, 55.2, 39.3, 33.3, 30.0, 29.3, 27.8, 21.7; IR (neat, NaCl, cm!)
2952, 2929, 2869, 1728, 1178; LRMS (70 eV, EI) m/z 185 (M+H]+, 149 [M-HCO2H]+;

HRMS [MT Calcd for C10H16O33 184.1099 III/Z . Observed 184.1095 "l/Z .

, THF, 0 'c - RT ,
OH 88°/o OBn

lV-13 lV-1 4

 

(1R, 2S, 5R)-(2-Isoprenyl-5-methyl-cyclohexyl) benzyl ether (IV-l4):295 Sodium hydride
(68 mg, 60% dispersion in mineral oil, 1.7 mmol) was suspended in dry THF (9 mL). The
reaction was cooled to 0 °C and isopulegol (200 mg, 1.3 mmol) dissolved in dry THF (1
mL) was added and stirred for 30 min. Benzyl bromide (289 mg, 1.7 mmol) and K1 (63
mg, 1.7 mmol) were added sequentially at 0 0C. The reaction mixture was allowed to
warm to RT and stirred for an additional 3 h, after which it was quenched with water and
sat. NH4C1, and then extracted into EtOAc (20 mL x 2). The combined organics were
washed with water (40 mL) and brine (40 mL), dried over Na2SO4, and the solvent was
removed under reduced pressure to obtain a slightly colored oil. Column
chromatography (10% EtOAc/hexanes) provided the desired benzyl ether (278 mg, 88%).
lH NMR (CDC13, 300 MHz): 6 7.25-7.43 (m, 5H), 4.83 (s, 2H), 4.61 (t, 1H, J=11.5 Hz),
4.52 (d, 1H, J=11.8 Hz), 3.31 (dt, 1H, J= 4.1, 10.7 Hz), 2.11 (m, 2H), 1.71 (s, 3H), 1.64
(m, 2H), 1.28-1.45 (m, 2H), 0.95-1.06 (m, 5H); 13C NMR (CDC13, 75 MHz): 6 147.8,
139.1, 128.3, 128.1, 127.7, 127.6, 127.2, 110.9, 79.1, 70.3, 51.7, 40.2, 34.3, 31.5, 31.0,
22.3, 20.0; IR (neat, NaCl, cm'l) 2923, 2867, 1106; LRMS (70 eV, EI) m/z 243 [M-H]+,

138 [M-OBn]+.

156

W Condition A C O

OBn an
IV-14 W-1 4:

(IR, 2R, 5R)-(2-AcetyI-5-methylcyclohexyl) benzyl ether (IV-14a): 1H NMR (CDC13, 300
MHz): 6 7.21-7.32 (m, 5H), 4.56 (d, 1H, J = 11.3 Hz), 4.37 (d, 1H, J=11.3 Hz), 3.6 (dt,
1H, J: 6, 10.4 Hz), 2.53 (ddd, 1H, J= 3.8, 10.1, 12.6 Hz), 2.16 (s, 3H), 2.12-2.19 (m,
1H), 1.75 (qd, 1H, J: 3.6, 10.2 Hz), 1.64-1.70 (m, 1H), 1.25-1.52 (m, 2H), 0.93 (d, 2H, J
= 3.3 Hz); l3C NMR(CDC13, 75 MHz): 6 212.3, 138.5, 128.2, 127.6, 127.4, 79.1, 70.9,
56.6, 39.4, 33.5, 30.9, 30.8, 27.7, 22.1; IR (neat, NaCl, cm“) 2950,2927, 2867, 1739,
1712; LRMS (70 eV, E1) m/z 228 [M-H2O]+, 140 [M-OBnr'; HRMS [M+H]* Calcd. for

C16H22O2: 246.1620 m/z. Observed 246.1631 m/z .

Condition B O
———’ COZH

lV-19 lV-19a
6-0xyheptanoic acid (IV-l9a):32' ‘H NMR (CDCl3, 300 MHz): 6 2.41-2.45 (m, 2H),
2.31-2.36 (m, 2H), 2.11 (s, 3H), 1.56-1.62 (m, 4H); 13C NMR (CDC13, 75
MHz): 6 208.8, 179.1, 43.2, 33.7, 29.9, 24.0, 22.9; IR (neat, NaCl, eni') 3455, 2939,
1714; LRMS (70 eV, EI) m/z 144 M", 126 [M-H2O]+.

O
/ Condition 8 H O O O
———-r OH + 01-1

0 O
lV-21 lV-21 a, 67% lV-21 b, 1 6%

(10-3, 7-DimethyI-6-0xo-octan0ic acid (Iv-2111):322 ‘H NMR(CDC13, 500 MHz): 6 2.57
(p, 1H, J= 7.0 Hz), 2.46 (dt, 1H, J: 6.2, 9.1 Hz), 2.32 (dd, 1H, J: 6.0, 15.3 Hz), 2.16
(dd, 1H, J: 6.9, 15.3 Hz), 1.93 (sept, 1H, J: 6.6 Hz), 1.63 (m, 1H), 1.48 (m, 1H), 1.07

(d, 6H, J = 6.8 Hz), 0.95 (d, 3H, J= 6.7 Hz); 13C NMR (CDC13, 125 MHz): 6 214.5,

157

178.3, 41.2, 40.9, 37.8, 30.2, 29.8, 19.5, 18.3; IR (neat, NaCl, cm'l) 3164, 2964, 2933,

1706, 1384, 1465; LRMS (70 eV, EI) m/z 186 M, 168 [M-H2O]+, 143 [M-C3H7]+.

O
0m condition A m
: = i - o
lV-22

lV-22a
(4S, 40R, 6R)-6-Acetyl-4, 4a-dimethyl-4,4a,5, 6, 7,8-hexahydro-3H-naphthalen-2-one (IV-
2211):323 'H NMR (c0013, 300 MHz): 6 5.72 (s, 1H), 2.71 (m, 1H), 2.33-2.48 (m, 2H),
2.20—2.25 (m, 2H), 2.1 (s, 2H). 1.94-2.06 (m, 4H), 1.40 (m, 1H), 1.21 (t, 1H, J= 12.5
Hz), 1.06 (s, 3H), 0.93 (dd, 3H, J: 6.6, 1.9 Hz); 13C NMR (CDC13, 75 MHz): 6 10.4,
199.2, 168.5, 125.1, 46.6, 41.9, 40.1, 39.8, 38.8, 31.9, 28.4, 28.1, 16.6, 14.8; IR (neat,

NaCl, cm'l) 2966, 2939, 2883, 1708, 1668, 1617; LRMS (70 eV, EI) m/z 220 M+, 177

[M-COMe]+.
Condition 8 o v OH OH
—_. .V-. + OH + O O
C02H Y
H
lV-34 lV-34I, 44% IV-34b, 10% IV-34c, 23%

2-((1R,3S)-2,2-Dimethyl-3-(2-0x0propyl)cyclopropyl)acetic acid (IV-34a): ”“25 1H
NMR (CDC13, 300 MHz): 6 2.38-2.34 (m, 2H), 2.28-2.23 (m, 2H), 2.15 (s, 3H), 1.1 (s,
3H), 0.90-0.92 (m, 2H) 0.90 (s, 3H); 13C NMR (CDC13, 75 MHz): 6 208.7, 178.9, 39.3,
30.0, 29.6, 28.4, 21.4, 21.1, 17.2, 14.9; IR (neat, NaCl, cm") 3164,2948, 1714, 1168;
LRMS (70 eV, EI) m/z 184 (M)+, 166 (M-H2O)+.

(IR, 6S)-4-Hydroxy-4, 7, 7-trimethylbicyclo[4. 1.0]heptan-3-ylf0rmate (IV -34c): 1H NMR
(CDC13, 300 MHz): 6 8.08 (s, 1H), 4.59 (t, 1H, J= 9.1 Hz), 2.15 (br, 1H), 1.71-1.99 (m,
2H), 0.07-1.68 (m, 13H); 13C NMR (CDC13, 75 MHz): 6 161.3, 77.8, 71.5, 34.0, 28.4,

25.5, 20.5, 20.2, 19.6, 17.8, 15.8.

158

 

OAc

 

OAc Condition A
11 OH ‘1
N-36 M3611

2-Acet0xytetradecan0ic acid (Iv-3611):333 'H NMR (CDC13, 300 MHz): 6 8.5-8.2 (br,
1H), 4.97 (1, 1H, J: 6.3 Hz), 2.11 (s, 3H), 1.85 (m, 2H), 1.40 (m, 1H), 1.23 (b, 20H),
0.85 (1, 3H, J= 6.0 Hz); 13C NMR (CDC13, 75 MHz): 6 176.3, 170.9, 72.1, 32.1, 31.2,

29.9, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 25.3, 22.9, 20.7, 14.3.

CH OAc

A020. py
/ 96% /
1 1 1 1

lV-38 lV-39

 

(E)-0ctadec-5-en-3-yn-2-yl acetate (IV-39): To a solution of IV-38 (132 mg, 0.5 mmol)
in pyridine (5 mL) was added acetic anhydride (102 mg, 1 mmol). The mixture was
stirred and heated for 3 h at 60 °C. The reaction was then extracted with EtOAc (25 mL)
and washed with 1N HCl (15 mL x 5) and brine (25 mL). The organic layer was dried
over Na2SO4 and concentrated under reduced pressure to provide a crude, slightly yellow
oil. Column chromatography (5% EtOAc/hexanes) provided the desired acetate (630 mg,
96% yield). lH NMR(CDC13, 300 MHz): 6 6.15 (dt, 1H, J = 15.9, 7.1 Hz), 5.45 (m, 1H),

2.08 (m, 2H), 1.47 (d, 3H, J= 6.6 Hz), 1.49-1.23 (b, 20H), 0.85 (t, 3H, J= 6.0 Hz).

159

 

7.4.1. Additional data related to Chapter 4
0
g ”OM
_——’ OH
O
O
O

Oxidation of 1,2-Cyclohexanedione to Adipic acid

1,2-Cyclohexanedione (1 equiv) was dissolved in DMF (0.2 M), and Oxone (4
equiv) was added in one portion. The reaction was stirred at RT for 3 h and an aliquot
was removed and diluted with EtOAc for GC analysis. This showed an 80% conversion

to adipic acid.

160

7.5. Data for Chapter 5

0804 (0.01 equiv) 0

F12 Oxone (1.2 equiv)
\ : H
R‘ F13 dodecane(1 equiv) Fi‘
KHC03 (1.2 equiv)
DMF, 1.5 h, RT

 

General Procedure for the Oxidative Cleavage to Aldehydes with KHC03
(Condition A): The olefin (1 equiv) was dissolved in DMF (0.2 M) followed by the
addition of dodecane (lequiv), the internal standard, and OsO4 (0.01 equiv, 2.5% in
tBuOH). After 5 min. KHCO3 (1.2 equiv) and Oxone (1.2 equiv) were added
sequentially and the reaction was stirred at RT for 1.5 h. Reaction progress was

monitored by GC and the data analyzed against a standard curve.

 

0so4 (0.01 equiv) o
92 H202 (3 equiv)
\ = H
R‘ F13 dodecane, ACN R‘
DMF (20 equiv)
18 h, 0 - 4 C

General Procedure for the Oxidative Cleavage to Aldehydes with H202
(Condition B): The olefin (1 equiv) was dissolved in ACN (0.2 M) followed by the
addition of DMF (20 equiv), dodecane (1 equiv) and OsO4 (0.01 equiv, 2.5% in tBuOH).
The reaction was cooled to 0 °C and then H202 (3 equiv) was added and the reaction was
stirred at 4 °C for 18 h. or until the solution becomes colorless. Reaction progress was

then monitored by GC and the data analyzed against a standard curve.

OsO4 (0.01 equiv) 0
R2 KH805 (6 equiv)
\ ; OMe
R, R3 MeOH, 18 11, RT R,

General Procedure for the Oxidative Cleavage to Esters in MeOH (Condition

 

C): The olefin (1 equiv) was dissolved in MeOH (0.2 M), and OsO4 (0.01 equiv, 2.5% in

tBuOH) was added and stirred for 5 min. KH805 (6 equiv) was added in one portion and

161

 

the reaction was stirred at RT for 18 h. Na2S03 (6 equiv w/w) was then added, to reduce
the remaining Os(VIII), and stirred for an additional hour or until solution became dark
brown / black. 1N HCl was then added along with EtOAc to extract the products. The
organic layer was washed with 1N HCl (3x) and brine, dried over Na2SO4, and the
solvent was removed under reduced pressure to obtain the crude product. Products were

purified by silica gel column chromatography.

0
MOH > E O

n Oxone, solvent

 

General Procedure for the Oxidative Cyclization Yielding Water-Soluble
Products (Condition D): A 0.1 M solution of the appropriate alkenol was prepared in
dimethylforrnamide that had been dried over calcium sulfate. Oxone (4.0 equiv) was
added in one portion, followed by 1.0 mol% of 0804 as a 0.2 M solution in tBuOH or
dichloromethane. An internal standard could be added either prior to or immediately
following reaction to determine the in-pot yield. Both 1,2,3,4-tetramethylbenzene and
dodecane were used in this capacity. The reaction was stirred at room temperature, and
progress monitored by either TLC or GC. In a few cases, the reactions were also
performed in deuterated DMF and the NMR was compared to that of an authentic sample
of the lactone in deuterated DMF prior to isolation using benzene as an internal standard.

General Procedure for the Oxidative Cyclization Yielding Water-Insoluble
Products (Condition E): A 0.1 M solution of the appropriate alkenol was prepared in
dimethylforrnamide that had been dried over calcium sulfate. Oxone (4.0 equiv) was
added in one portion, followed by 1.0 mol% of 0804 as a 0.2 M solution in tBuOH or

dichloromethane. The reaction was stirred at room temperature, and progress monitored

162

 

by either TLC or GC. After completion of the reaction, an equal volume of water was
added and the solution was saturated with NaCl. It was then extracted with 3x portions
of ethyl acetate. The combined organics were washed 1x with NaHCOg, dried over
Na2SO4 and evaporated under reduced pressure. The resultant lactones could be purified
by column chromatography using 1:1 petroleum ether/diethyl ether.

Ph
THF -7 . O
\ O ' 8 C O, H

———> ‘Os-DMF
0 mo, DMF P“ 0'5
86%

V45
(V-15): THF (1 mL) and DMF (17 mg, 0.236 mmol) were cooled to -—78 °C. 0804 (20
mg, 0.078 mmol) was then added and stirred for 5 min. followed by the addition of t-
stilbene (14 mg, 0.078 mmol) in THF (0.5 mL). The reaction was warmed to 0 °C and
stored in the freezer overnight. The precipitate was filtered, washed with B20 and dried
under vacuum to provide VII-15 (25 mg, 64%). 1H NMR (CDC13, 500 MHz): 6 7.99 (s,

1H), 7.46-7.11 (m, 10H), 5.98-5.56 (m, 2H), 2.94 (s, 3H), 2.87 (s, 3H).

 

O THF, -78 'c P" o
\ . $01681 FY
0304. py Ph‘ 0' 6 'Py
86%
V-1B

3-195(V-l6): THF (1 mL) and pyridine (18 mg, 0.236 mmol) were cooled to —78 °C.
0504 (20 mg, 0.078 mmol) was then added and stirred for 5 min. followed by the
addition of t-stilbene (14 mg, 0.078 mmol) in THF (0.5 mL). The reaction was warmed
to 0 °C and stored in the freezer overnight. The precipitate was filtered, washed with

B20 and dried under vacuum to provide VII-16 (40 mg, 86%).

163

0

Ph 0
THF, -78'C 0 i0: " _
\ OMe : y“ ,%s DMF
OSO4_ DMF ’0

86% V-17

 

(V-17): Toluene (1 mL) and DMF (15 mg, 0.2 mmol) were cooled to —78 °C. 0504 (25
mg, 0.1 mmol) was then added and stirred for 5 min. followed by the addition of methyl
cinnimate (16 mg, 0.1 mmol) in toluene (0.5 mL). The reaction was warmed to —0 °C
and then stored in the freezer overnight. The precipitate was filtered, washed with 320
and dried under vacuum to provide VI-17 (25 mg, 64%). 1H NMR (CDC13, 500 MHz): 6
8.02 (s, 1H), 7.43-7.41 (m, 5H), 6.28-6.01 (111“, 1H) [‘1 eight doublets 6.28 (d, J = 4.9),
6.25 (d, J = 5.3), 6.24 (d, J = 5.9), 6.18 (d, J = 7.1), 6.07 (d, J= 5.3), 6.05 (d, J= 6.6),
6.02 (d, J = 4.9), 6.01 (d, J = 4.6)], 5.65-5.43 (m‘z, 1H) [‘2 eight doublets 5.64 (d, J =
4.6), 5.63 (d, J: 5.5), 5.59 (d, J= 5.9), 5.52 (d, J = 7.1), 5.47 (d, J= 5.3), 5.46 (d, J =
6.6), 5.45 (d, J: 5.6), 5.44 (d, J= 5.3)], 3.86-3.78 (m‘3, 3H)[‘3 eight singlets 3.86. 3.85,

3.83, 3.82, 3.81, 3.80. 3.78, 3.78], 2.95 (s, 3H), 2.88 (s, 3H).

 

O 0MB 0
\ OH Condition L PhMOMe
OH
v.3 V-31

Methyl 2-hydr0xy-3-methoxy-3-phenylpr0pan0ate (V -3l):3 34 lH NMR (CDC13, 300
MHz): 6 7.34 (b, 5H), 4.53 (d, 1H, J= 3.2 Hz), 4.25 (dd, 1H, J= 6.6, 3.2 Hz), 3.77 (s,
3H), 3.26 (s, 3H) 2.97 (d, 1H, J= 6.6); 13C NMR (CDC13, 75 MHz): 6 172.2, 136.9,

128.6, 126.7, 113.9, 83.1, 74.5, 57.0. 52.2.

164

 

Condition C M60 (3
M0 AC 4 2 WOH
V-32 V-33

Methyl 3-hydroxypr0pan0ate (v.33);335 1H NMR (0130,, 300 MHz): 6 3.64 (s, 3H),
3.60 (1, 2H, J= 6.6 Hz), 2.27 (1, 2H, J = 7.5 Hz), 1.65-1.41 (m, 4H), 1.36-1.16 (b, 8H);

13C NMR (CDC13, 75 MHz): 6 174.3, 62.8, 51.4, 34.0, 32.6, 29.1, 28.9, 25.6, 24.7.

Condition C W W
W i 5 5

3-Meth0xynonan-2-ol (V-34a) and 2-Methoxynonan-3-ol (V-34b): 1H NMR (CDC13, 500

 

MHz): 6 3.35 (s, 3H), 3.34 (s, 1H), 3.10 (p, 1H, J= 6.4 Hz), 2.56 (br, 1H), 1.51-1.42 (m,
2H), 1.36-1.24 (br, 8H), 1.09 (1, 3H, J = 6.3 Hz), 0.86 (1, 3H, J = 6.3 Hz); 13C NMR

(CDC13, 125 MHz): 6 80.5, 74.9, 56.6, 32.8, 31.8, 29.4, 2.5, 22.6, 14.8, 14.0.

OH OH

 

fl condition c ~ MeOZCwVW + MeOZCM/YLM/

6 1 7 ' 6 7 6 7

Me02C OMe OMe
V-35 V468 V461)

Name (V-34a) and Name (V-34b): 1H NMR (CDC13, 300 MHz): 6 3.61 (s, 3H), 3.42 (m,
1H), 3.35 (s, 3H), 2.94 (q, 1H, J = 5.4 Hz), 2.25 (1, 2H, J = 7.4 Hz), 1.63-1.17 (br, 26H),
0.83 (1, 3H, J = 6.8 Hz); 130 NMR (CDC13, 125 MHz): 6 174.2, 84.3, 72.5, 58.0, 51.3,

34.0, 33.3, 31.8, 29.9, 29.7, 29.5, 29.4, 29.2, 29.1, 29.0, 25.6, 25.0, 24.8, 22.6, 13.98.

For data regarding the oxidative cleavage / lactonization please refer to the original

reference.5

165

7.6. Data for Chapter 6

General Procedure for Oxidation of Aldehydes to Carboxylic Acids
(Condition A): The aldehyde (1 equiv) was dissolved in DMF (0.1 M). Oxone (1 equiv)
was added in one portion and stirred at RT for 3 h. The reactions were monitored by
TLC and GC analysis. 1N HCl was used to dissolve the salts and EtOAc was added to
extract the products. The organic extract was washed with 1N HCl (3 x) and brine, dried
over Na2SO4, and the solvent was removed under reduced pressure to obtain the crude
product. Products were purified by silica gel column chromatography.

General Procedure for Oxidation of Aldehydes to Esters (Conditon B): The
aldehyde (1 equiv) was dissolved in the appropriate alcoholic solvent (0.1 M). Oxone (1
equiv) was added and stirred at RT for 18 h. The reaction was monitored by TLC and
GC analysis. 1N HCl was used to dissolve the salts and EtOAc was added to extract the
products. The organic extract was washed with 1N HCl (3x) and brine, dried over
Na2SO4, and the solvent was removed under reduced pressure to obtain the crude
product. Products were purified by silica gel column chromatography.

General Procedure for Oxidation of a- or 8-Diones and a—Ketoalcohols with
Oxone (Conditon C): The substrate (1 equiv) was dissolved in the appropriate solvent
(methanol, ethanol, or isopropanol (0.2 M)). Dry KHS05 (95% pure, 4 equiv) was added
to the solution in one portion and stirred at room temperature for 18 h. The reactions
were monitored by TLC, GC or NMR analysis. After the substrate had been consumed
the reaction was diluted with B20 and 10% (v/v) HCl solution. The layers were
separated and the aqueous layer was extracted with Et2O (x 3). The combined organic

layers were collected and dried over anhydrous Na2SO4 or MgSO4. After filtration of the

166

drying agents, the solvent was removed under reduced pressure to yield the crude

product. Products were purified by silica gel column chromatography.

0
Git—7’ GM
VI-7 VI-7e
Iso-propyl benzoate (VI-7c):336 'H NMR(CDC13, 300 MHz): 6 8.02 (m, 2H), 7.43 (m,
3H), 5.24 (sept, 1H, J: 6.3 Hz), 1.34 (d, 6H, J: 6.3 Hz); 13C NMR (0130,, 75

MHz): 6 175.2, 132.2, 130.4, 129.0, 127.8, 67.9, 21.5; IR (neat, NaCl, cm!) 2981, 2938,

1716, 1276, 1103, 711; LRMS (70 eV, EI) m/z 164 [M]+, 122 [M-C3H6r, 105 [M-

OC3H7]+.
CHO
HO HO HO
VI-13 Vl-13b, 62% VI-13a, 19%

4-Hydr0xyphenylf0rmate (VI-13b);337 lH NMR(CDC13, 300 MHz): 6 8.27 (s, 1H), 6.98

(d, 2H, J= 9.0 Hz), 6.78 (d, 2H,J= 8.9 Hz), 5.35 (bs, 1H); mp = 56-58 °C, [111. 57 "(3].337

 

CHO
MeO M60 M60
Vl-15 V1-15b,58% Vl-158,31%

4-Meth0xyphenylformate (VI-15b):95’338’339 'H NMR(CDC13, 300 MHz): 6 8.26 (s, 1H),
7.03 (d, 2H, J: 9.0 Hz), 6.89 (d, 2H, J = 8.9 Hz), 3.78 (s, 3H); mp = 31-33 °C, [111. 32-34

6C].338

167

O
NVCHO WLo/k
VI-20

VI-200
i-Propyl hexanoate (VI-20c):340 lH NMR(CDC13, 300 MHz): 6 5.04 (m, 1H), 2.30 (m,
2H), 1.12-1.54 (m, 12H), 0.86 (bs, 3H); 13(3 NMR (CDC13, 75 MHz): 6 186.6,50.9, 34.7,
31.7, 29.8, 22.6, 21.8, 14.0, 13.9; IR (neat, NaCl, cm") 2956, 2930, 1729, 1457, 1375,
1176, 1108; LRMS (70 ev, 131) m/z 158 [M]+, 116 [M-CsH6]+, 99 [M-OC3H7]+.

UCHO UCOZH

Vl-26 VI-26a
1, 2, 3, 6-Tetrahydr0benzoic acid (VI-26a):34"342 1H NMR (CDC13, 300 MHz): 6 5.63-5.7
(m, 2H), 2.54-2.64 (m, 1H), 2.24-2.27 (m, 2H), 1.98-2.15 (m, 3H), 1.62-1.76 (m, 1H);
130 NMR(CDC13, 75 MHz): 6 182.6, 126.7, 124.9, 39.1, 27.1, 24.8, 24.3; IR (neat, NaCl,

cm") 3027, 2926, 1705, 1438, 1306, 1238; LRMS (70 eV, E1) m/z 126 [M]+, 108 [M-

O
WCOZH ‘ M5

OH
VI-27 Vl-278, 53% Vl-28, 32%

H2O]+, 81 [M-CO2H]+.

 

WCHO

Cis-4-decanoic acid (VI-2711):343 lH NMR(CDC13, 300 MHz): 6 5.28-5.45 (m, 2H),
2.30-2.40 (m, 4H), 1.99 (bs, 2H), 1.26 (bs, 6H), 0.85 (bs, 3H); 130 NMR(CDC13, 75
MHz):6 179.4, 131.9, 126.9, 34.1, 31.4, 29.2, 27.1, 22.5, 14.0; IR (neat, NaCl, cm“)
3139,2958, 2930,2872, 1711, 909, 734; LRMS (70 eV, EI) m/z 170 [M]+.

5, 6-trans-5-(1-hydr0xyhexyl)-dihydr0furan-2-one (VI-28):344 1H NMR (CDC13, 300

MHz): 6 4.36-4.42 (m, 1H), 3.50-3.56 (m, 1H), 2.49-2.62 (m, 2H), 2.05-2.27 (m, 3H),

168

1.49 (bs, 3H), 1.28 (bs, 5H), 0.84 (bs, 3H); l3C NMR (CDC13, 75 MHz): 6 177.3, 83.0,

73.6, 32.8, 31.6, 28.7, 25.1, 24.0, 22.5, 13.9; mp = 40-42 °C, [11142-44 °C].3‘“

O O 0

CH0 _ COZH + on
I | |
o o o

Vl-29 VI-29a, 34% V1-30, 52%

 

6-ethyl-4-0x0-4H-chr0mene-3-carboxylic acid (VI-29a): 1H NMR (CDCl3, 300
MHz): 6 13.50 (bs, 1H), 8.98 (s, 1H), 8.11 (s, 1H), 7.68 (dd, 1H, J= 2.2, 8.5 Hz), 7.55 (d,
1H, J= 8.8 Hz), 6.80 (bs, 1H), 2.72 (q, 2H, J: 7.7 Hz), 1.24 (1, 3H, J = 7.7 Hz); 13(2
NMR (CDC13, 75 MHz): 6 179.4, 164.3, 163.6, 155.1, 144.0, 136.3, 124.2, 122.7, 118.6,
112.7, 28.4, 15.3; IR (neat, NaCl, cm'l) 3073, 2961, 2924, 2869, 1734, 1616, 1478, 1436,
1310; LRMS (70 eV, E1) m/z 218 [M]+; HRMS (CI) calcd for C12H1004: 218.0579 m/z
[M]+, observed 218.0580 m/z; mp = 133-135 °C.

6-ethyl-3-hydr0xychromene-4-0ne (VI-30): 1H NMR (CDC13, 300 MHz): 6 8.03 (d, 1H,
J=2.2), 7.97 (s, 1H), 7.47 (dd, 1H, J=2.2, 8.8), 7.36 (d, 1H, J=8.8), 6.80 (bs, 1H), 2.72 (q,
2H, J=3.4), 1.24 (t, 3H, J=3.6); 13C NMR (CDC13, 75 MHz):6 173.4, 154.7, 141.7,
140.8, 138.7, 133.9, 123.3, 121.7, 118.2, 28.2, 15.4; IR (neat, NaCl, cm") 3276, 2959,
1610, 1408, 1204, 1170; LRMS (70 eV, E1) m/z 190 [M]+; HRMS (CI) calcd for

C11H1003: 190.0630 m/z [M]+, observed 190.0627 m/z; mp = 119-121 °C.
O

31' Br OH
O > O +
CH0 0 0
l / 1

Br
Vl-31 Vl-32, 42% VI-33, 30%

 

5-m-Br0m0phenyl)-2(3H)-furan0ne (VI-32):345 lH NMR(CDC13, 300 MHz): 6 7.51 (d,
2H. J= 8.5 Hz), 7.49 (d, 2H, J: 8.2 Hz), 5.78 (1, 1H, J= 2.7 Hz), 3.49 (d, 2H, J: 2.7

Hz); 13C NMR (CDC13, 75 MHz): 6 175.4, 153.0, 131.9, 131.6, 127.2, 126.2, 123.7, 98.3,

169

34.7, 14.2; IR (neat, NaCl, cm") 2916, 2848, 1780, 1673; LRMS (70 eV, EI) m/z 238
[M]+, 240 [M+2]+; HRMS (CI) calcd for C10H7O2Br: 237.9630 m/z [M]: observed
237.9631 m/z; mp = 124-127 °C, [111. 126-130 "c1.“5

4-(p-Bromophenyl)-4-0xobutanoic acid (VI-33):346 1H NMR (CDCl3, 300MHz): 6 7.83
(d, 2H, J: 8.5 Hz), 7.59 (d, 2H, J: 8.7 Hz), 3.26 (1, 1H, J: 6.4 Hz), 2.81 (d, 2H, J: 6.4
Hz); 13(3 NMR (CDC13, 75 MHz):6196.8, 178.5, 132.0, 131.9, 131.7, 130.3, 129.6, 33.1,
27.9; IR (neat, NaCl, cm") 3425, 3091, 2958, 2925, 1694, 1678, 1585, 1339, 1229;
LRMS (70 eV, E1) m/z 256 [M]+, 183 [M-C3H502]+; mp = 144-146 °C, [111 148-150

6C].346

Br OMe

 

Br
Vl-31 v1.34

Methyl 4-(p-brom0phenyl)-4-oxobutan0ate (VI-34)?”349 lH NMR (CDC13,
300MHz): 6 7.80 (d, 2H, J = 2.2 Hz), 7.77 (d, 2H, J = 2.0 Hz), 3.65 (s, 3H), 3.22 (t, 2H, J
= 6.6 Hz), 2.49 (t, 2H, J= 6.6 Hz); 13C NMR (CDC13, 75 MHz): 6 197.0, 173.2, 135.1,
131.9, 129.5, 128.4, 51.8, 33.2, 27.8; IR (neat, NaCl, cm") 3024, 2952, 2916, 2848, 1736,
1688, 1586, 1218, 1171, 1070, 757; LRMS (70 eV, EI) m/z 270 [M]+, 183 [M-C4H7O2]+;

HRMS (CI) calcd for C11H1103Br: 269.9892 m/z [M]+, observed 269.9896 m/z; mp = 48-

E‘ j 0 EtOAc, 97°/o E‘ j 0

Vl-41

50°C.

 

2-methyl-2-propylcyclopentane-I,3-dione (VI-41):318 To a RT solution of 2-allyl-2-

methyl-1,3-cyclopentadione (89 mL, 0.6 mmol) in EtOAc (6 mL) was added 10% Pd-C

170

 

(4.6 mg, 5% by wt). A hydrogen filled balloon was attached and the system was purged
under vacuum and replaced with hydrogen gas. The reaction was stirred at RT for 15 h.
The Pd-C was then filtered and washed with EtOAc. The solvent was removed under
reduced pressure providing VI-41 (90 mg, 97% yield) and did not require additional
purification. VI-41: 1H NMR (300 MHz, CDC13): 6 2.68 (s, 4H), 1.54-1.49 (m, 2H), 1.12-
1.04 (m, 2H), 1.02 (s, 3H), 0.76 (t, 3H, J= 7.1 Hz).

0
ofig/ : Mom
0
HO

O
Vl-41 VI-41a

 

Methyl 5-hydroxy-5-methyl-4-ox00ctanoate (VI-41a): KH805 (547 mg, 3.6 mmol) was
added in one portion to a solution of diketone VI-41 (145 mg, 0.9 mmol) in methyl
alcohol (8 mL) at RT. The reaction was stirred at RT for 18 h, after which it was diluted
with B20 and 10% (v/v) HCl (15 mL). The layers were separated and the aqueous layer
was extracted with H20 (10 mL x 3). The combined organic layers were dried over
anhydrous MgSO4, the salt was filtered and the organics were concentrated under
reduced pressure. The product was purified by silica gel column chromatography (20%
EtOAc / hexanes) to furnish ester VI-41a as a colorless oil (58 mg, 65% yield). VI-41a:
1H NMR (300 MHz, CDC13): 6 3.63 (s, 3H), 2.87-2.72 (m, 2H), 2.61-2.56 (m, 2H), 1.66-
1.60 (m, 2H), 1.32 (s, 3H), 1.09-0.97 (m, 2H), 0.85 (1, 3H, J = 7.1 Hz); 13C NMR (75
MHz, CDC13): 6 212.8, 172.9, 78.7, 51.8, 41.8, 30.8, 27.6, 25.5, 16.5, 14.2; IR (thin film)
3400, 2961, 1741, 1713, 1441, 1373, 1242, 1173, 1047 cm'l;LRMS (70 ev, EI) m/z 202
[M]+, 184 [M-H2O]+, 171 [M-CH3O]+; HRMS (CI) calcd for C10H1904: 203.1283 m/z

[M+H]+, observed 203.1283 m/z.

171

 

CEO 5 AoMok + *oj‘lvrfOZH

O
Vl-37 Vl-35d, 34% VI-350, 45%

6-Isopropoxy-6—ox0hexanoic acid (VI-35e): KHS05 (608 mg, 4 mmol) was added in one
portion to a solution of diketone VI-37 (112 mg, 1 mmol) in isopropanol (10 mL) at RT.
The reaction was stirred at RT for 18 h, after which it was diluted with B20 and 10%
(v/v) HCl (15 mL). The layers were separated and the aqueous layer was extracted with
320 (10 mL x 3). The combined organic layers were dried over anhydrous MgSO4, the
salt was filtered and the organics were concentrated under reduced pressure. The product
was purified by silica gel column chromatography (20% EtOAc / hexanes) to firrnish
esters VI-35d (70 mg, 33%) and VI-35e (32 mg, 18%) as colorless oils. VI-35e: 1H NMR
(300 MHz, CDC13): 6 11.05 (br, 1H), 4.95 (sept, 1H, J = 6.32 Hz), 2.32 (t, 2H, J = 6.87
Hz), 2.25 (t, 2H, J = 7.14 Hz), 1.67-1.57 (m, 4H), 1.17 (d, 6H, J= 6.04 Hz); 13C NMR
(75 MHz, CDC13): 6 179.6, 172.9, 67.6, 34.2, 33.6, 24.3, 23.9, 21.7; IR (thin film) 3210,
2982, 2939, 1730, 1729, 1375, 1242, 1182, 1109, 1047, 939, 822 cm]; LRMS (70 ev, EI)
m/z 170 [M-H2O]+, 129 [M-OCH(CH3)2]+; HRMS (CI) calcd for C9H17O4: 189.1127 m/z

[M+H]+, observed 189.1128 m/z.

35F" -— 4.1-51.x 4.4.8.

VI-44 VHZd, 24% V1420, 45%

 

Diisopropyl glutarate (V I-42d): KHS05 (608 mg, 4 mmol) was added in one portion to
a solution of diketone VI-44 (126 mg, 1 mmol) in isopropanol (10 mL) at RT. The
reaction was stirred at RT for 18 h after which it was diluted with B20 and 10% (v/v)
HCl (15 mL). The layers were separated and the aqueous layer was extracted with B20

(10 mL x 3). The combined organic layers were dried over anhydrous MgSO4, the salt

172

was filtered and the organics were concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography (20% EtOAc / hexanes) to
furnish esters VI-42d (51 mg, 24%) and VI-42e (77 mg, 45%) as colorless oils. VI-42d:
1H NMR (300 MHz, CDC13): 6 4.96 (sept, 2H, J = 6.32 Hz), 2.27 (t, 4H, J = 7.14 Hz),
1.88 (p, 2H, J = 7.14 Hz), 1.18 (d, 12H, J = 6.32 Hz); 13C NMR (75 MHz, CDC13): 6
172.5, 67.6, 33.6, 21.8, 20.2; IR (thin film) 2982, 2934, 1732, 1375, 1256, 1202, 1181,
1109, 1057, 1011, 970, 933 cm‘l; LRMS (70 ev, El) m/z 216 [M]+, 157 [M-
OCH(CH3)2]+; HRMS (CI) calcd for C11H2104: 217.1440 m/z [M+H]+, observed

217.1440 W2.

0

H Oxone M80 oosoax M60 OOSO3H
= H + H
0211 MeOH, 50 '0
02111 o2N

Vl-3

 

Vl-52a V1—52b

4-Nitrobenzaldehyde-methyl-potassiumperoxysulfate acetal (V I-52a): 1H NMR (3 00
MHz, CDCl3): 6 8.22 (d, 2H, J = 9.1 Hz), 7.66 (d, 2H, J = 9.0 Hz), 5.76 (s, 1H), 3.65 (s,
3H); 13C NMR (75 MHz, CDC13): 6 148.2, 142.7, 127.9, 123.3, 105.6, 56.7; IR (thin
film) 3117, 2939, 1510, 1353, 1315, 1200, 1097, 980, 854.

4-Nitr0benzaldehyde-methyI-peroxysulfate acetal (VI-52b): 1H NMR (300 MHz, CDC13):
6 8.22 (d, 2H, J: 8.4 Hz), 7.66 (d, 2H, J= 7.14 Hz), 5.80 (s, 1H), 3.70 (s, 3H); 13C NMR
(75 MHz, CDC13): 6 142.5, 131.0, 128.1, 123.5, 106.2, 56.5; IR (thin film) 3420, 3115,

3082, 2940, 2842, 1523, 1349, 1205, 1097, 1013, 854.

173

10.

ll.
12.

13.

14.

15.

16.

17.
18.
19.

20.

21.

22.

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