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This is to certify that the
dissertation entitled

OXIDATIVE CLEAVAGE OF OLEFINS MEDIATED BY OSMIUM
TETROXIDE AND EFFORTS TOWARD ELABORATION OF A
PYRROLIDINE SYNTHON DERIVED FROM A TANDEM AZA-

PAYNE HYDROAMINATION REACTION

presented by

Stewart Ross Hart

has been accepted towards fulfillment
of the requirements for the

PhD. degree in Chemistry

 

 

   

'- 41 “N

 

 

m '_ /
Wofessor’s 3W
8 / 24; / 0‘?
Date

MSU is an Afi‘innative Action/Equal Opportunity Employer

OXIDATIVE CLEAVAGE OF OLEFINS MEDIATED BY OSMIUM TETROXIDE
AND EFFORTS TOWARD ELABORATION OF A PYRROLIDINE SYNTHON
DERIVED FROM A TANDEM AZA-PAYNE HYDROAMINATION REACTION
By

Stewart Ross Hart

A DISSERTATION

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

DOCTOR OF PHILOSOPHY
Chemistry

2009

ABSTRACT
OXIDATIVE CLEAVAGE OF OLEFIN S MEDIATED BY OSMIUM TEI‘ROXIDE
AND EFFORTS TOWARD ELABORATION OF A PYRROLIDINE SYNT HON
DERIVED FROM A TANDEM AZA-PAY NE HYDROAMINATION REACTION
By
Stewart Ross Hart

The research described in this thesis can be classified into two areas. The bulk of
the work was done examining an oxidative cleavage of olefins mediated by osmium
tetroxide. The use of hydrogen peroxide as a co-oxidant instead of Oxone, the original
co-oxidant is the discussed in Chapter 2. Mechanistic details are also examined (Chapter
4). The second group of work consists of elaboration of a pyrrolidine synthon with an
enamine, epoxide, and 3 stereocenters derived from a tandem aza-Payne/hydroamination
reaction (Chapter 5).

Most oxidative cleavage of olefin reactions can be classified into two categories;
direct cleavages such as ozonolysis and dihydroxylation of the olefin followed by diol
cleavage such as Johnson-Lemieux type chemistry. The original oxidative cleavage
reaction reported by our lab suggested that the reaction fell into the direct cleavage
category. The placement is correct but not completely. The data suggests that two
pathways are active in the course of reaction, the direct cleavage and a two-step
procedure involving a—hydroxy carbonyl formation followed by a Baeyer-Villiger type
cleavage.

The pyrrolidine synthon elaboration involved hydrogenation of the enamine, two
methods for bromination of the enamine with both geometries accessible, and attempts at

opening of the epoxide. The bromination of the enamine was accomplished by a tandem

bromination/aza-Payne/hydroamination reaction to yield the E isomer and direct
bromination of the pyrrolidine to yield the Z isomer. The substitution of the alkyne
during the tandem aza-Payne/hydroamination was examined and an electron effect was

examined.

For Rachel, who has made my life worthwhile.

For Dad, I wish you had seen this for you made it possible.

ACKNOWLEDGEMENTS

It has been said that we are all standing on the shoulders of giants and I would
like to acknowledge those who have propped me up through this time in graduate school.
It is necessary that those who have help me see this through be given my graditude.

First I must thank my advisor, Dr. Babak Borhan. That is probably only the
second time I’ve used his title and full name. Babak has the ability to make someone he
just met completely comfortable and has always been truly concerned with those whom
life has brought to him. I would like to thank him for giving me the chance to learn, fail,
and succeed in his lab. His influence on my professional career is evident, but his
influence on my life cannot be understated. Thank you for being my advisor and my
friend.

I would also like to thank the other members of my committee, Dr. Robert
Maleczka, Dr. Gregory Baker, and Dr. Merlin Bruening, for their guidance, insight, and
support during my education.

I would like to thank my group members, who have put up with me during my
time here. I have never and will never be with such a diverse group of individuals who
actually enjoy each other company. Thank you to Chrysoula who has been a constant
during my time here, Roozbeh and Xiaoyong who always can make me laugh, Tao and
Jun who made this group feel welcome (even thought they had opposite methods), and
the rest of group.

I would like to thank a few friends in particular. Dan, Adam, and Jason have

made this experience enjoyable by weekly lunches, a few of which turned into afternoon

excursions, weekend get-togethers, and countless conversations about science and
anything else that was relevant. Thanks to Dan and his wife Kristi for making me feel at
home my first few years by allowing me to watch their cable TV and enjoy their
hospitality.

I would like to thank my family for their unwavering support during my life. My
parents always gave me the opportunities to succeed and to go out on my own. My
sisters have kept me grounded and reminded me of what is important.

Last, I would like to thank my wife, Rachel. She has always been supportive of
my education and willing to adapt to our changing lives. Our years together have been
the best of my life and I am excited to see where life will take us. Thank you and I love

you.

VI

TABLE OF CONTENTS

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

LIST OF TABLES IX
LIST OF FIGURES ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, __XI
LIST OF SCHEMES ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Xll
LIST OF CHARTS ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, XIV
Chapter 1: Oxidative Cleavage Reactions: A Brief History ,,,,,,,,,,,,,,,,,,,,,, ,_,1
1 .1: Introduction 1
12: Osmium Tetroxide ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 2
13: Hydrogen Peroxide ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 9
1.3.1: History," ________________________________________________________________________________ 9
1.3.2: Organic Reactions _________________ 11
1.4: Oxidative Cleavage of Olefins 14
1.4.1: Ozonolysis 14
1.4.2: Johnson-Lemieux Type Cleavages ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 17
1.4.3: Other Methods ,,,,,, 20
References _23
Chapter 2: Oxidative Cleavage of Alkenes with Osmium Tetroxide and Hydrogen
Peroxide 30
2.1: Introduction ,,,,,,, _ 3O
22: Cleavage of Aryl Alkenes with Osmium Tetroxide and Hydrogen Peroxide ,,,,,,,,,,,,, 30
2.3: Cleavage of Alkyl Substrates ,,,,,,,,,,,,,,,,,,,,,,,,,,,,, "37
2.4: Urea Hydrogen Peroxide as Co-Oxidant ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 57
2.5: Conclusions ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 60
2.6: Experimental Details __________________________________________________________________________ 61
2.7: NMR Spectra _______________________________________________________________ 69
Reference 32
Chapter 3: Oxidative Cleavage of Olefinic Polymers in an Effort to Reduce Polymer
Waste _________________ 84
3.1: Introduction ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 84
3.2: Polymerizaiton ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 88
3.3: Depolymerization of Polybutadiene ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 90
3.4: Conclustion ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 97
35: Experimental Details ___________________________________________________________________________________________________ 98
3.6: NMR Spectra ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 100
Reference ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 102

VII

Chapter 4: A Kinetic Analysis of the Osmium Tetroxide Mediated-Cleavage of Olefins

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

with Oxone 104
4.1: Introduction ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 104
42: Substrate Choice ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 106
4.3: Effective Quenching Method _________________________________________________________________________________________ 107
4.4: Results and Discussion ,,,,,,,,,,,,,,,,,,,,,, 109
45: Conclusion ____________ 128
4.6: Experimental Details ,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 130
Reference 135
Chapter 5: Attempts at Elaboration of the Tetrasubstituted Pyrrolidine from a Tandem
Aza-Payne/Hydroamination Reaction 138
5.1: Introduction: The Tandem Aza-Payne/Hydroamination 138
5.2: Attempts at Elaboration ,,,,,,,,,,,,,,,,,,,,,, 142
5.2.1: Reduction of the Enamine _________________ 144
5.2.2: Toward Understanding Alkyne Substitution 148
5.2.3: Catalytic Nature of the Aza-Payne/Hydroamination Procedure ,,,,,,,,,,,,,,,,, 153
52.4: Bromination of the Enamine 157
525: Miscellaneous Reactions ________________________________________________________ 161
5.3: Conclusions ____________ 162
5.4: Experimental Details ___________ ' ______________________________________________ 1 63
55: NMR Spectra _____________________ _ _, __ ,,,,, 192
Reference 247

 

 

 

VIII

IMAGES IN THIS THESIS/DISSERTATION ARE PRESENTED IN COLOR

LIST OF TABLES

11-1. Aryl Substrate Solvent Test

34

 

11-2. Aryl Substrate Test for Oxidative Cleavage,"

36

 

 

11-3. Solvent Test for l-Decene

38

 

11-4. Solvent Test for l-Decene (Percent Converstion) ............

11-5. DMF Test for l-Decene

 

11-6. Additive Test for l-Decene

11-7. Alkyl Substrates for Oxidative Cleavage

 

 

11-8. Cis-6-Dodecene Cleavage with Acetic Acid and Pyridine
11-9. S-Methylenenonane Cleavage with Acetic Acid and Pyridine
11-10. Trans-S-Decene Cleavage with Acetic Acid and Pyridine
11-11. 2-Methyl-2-Unadecene Cleavage with Acetic Acid and Pyridine

11-12. Cleavage with Ethereal Hydrogen Peroxide

11-13. Urea Hydrogen Peroxide, Water, and DMF Test for Cis-6-D0decene ..................
11-14. Urea Hydrogen Peroxide, Water, and DMF Test for Trans-S-Decene ..................
11-15. Urea Hydrogen Peroxide, Water, and DMF Test for S-Methylenenonane ............

11-16. Urea Hydrogen Peroxide, Water, and DMF Test for 2-Methyl-2-Unadecene _______

1I-17. Urea Hydrogen Peroxide, Water, and DMF Test for l-Decene _____

8

‘5

42

..43

45

46

46

56

58

58

59

59

60

 

III-1. Energy Outputs of Common Fuel Sources ..............................

 

III-2. Chemical Constituents of a Typical Car Tire ...........................................................

 

III-3. Cleavage of Polybutadiene

 

IV-l. Cleavage of 5-Methylenenonane with 4 equiv of KH805

IX

...86

95

..,111

IV-2. Cleavage of l-Decane with 4 equiv of KHS05 .................................

1V-3. Cleavage of S-Methylenenonane with 8 equiv of KH805 ,,,,,,,,,,,,,,,,

IV-4. Cleavage of l-Decane with 8 equiv of KH805 ,,,,,,,

 

1V-5. Cleavage of Cis-6-Dodecane with 8 equiv of KH305

 

1V-6. Cleavage of Trans-S-Decane with 8 equiv of KHS05

 

IV-7. Cleavage of 2-Methyl-2-Unadecane with 8 equiv of KHSOS

 

1V-8. Isolation Results

 

1V-9. Repeat Time Trial for l-Decene a New Standard Curve and ISTD
V-l. Aziridinol Formation

V-2. Aza-Payne/Hydroamination Results

 

V-3. Hydrogenation Conditions ,,,,,,,,,,,,,,

 

V-4. Attempts at Opening the Epoxide of V-63

 

V-S. Substituted Aziridinol

 

 

V-6. Aza-Payne/Hydroamination of Alkynyl Substituted Aziridinols.

V-7. Results of Hydroamination with Catalytic Amounts of Base ______

 

V-8. Solvent Test with NaH and t-BuOK

 

V-9. Soluble Base Test

V-10. Qualitative Study of the NBS Bromination of the Pyrrolidine ________

112

116

117

119

121

123

126

127

139

I40

145

147

149

152

154

155

156

160

LIST OF FIGURES

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1-1. IR Stretching Bands for Osmate Ester Complex 4
1-2. Ligands for Asymmetric Dihydroxylation ,,,,,,,,,, 7
LB. Common Peracids for Epoxidations _______________________________________________ 12
111-1. Polymer Cleavage Products .......................................... 86
111-2. Succinic Acid Products _____________ 87
111-3. Levulinic Acid Products ________________________________________________________________________ 88
111-4. Wang’s Proposed Oxidation Complex and Os Sulfo Complex ".93
IV-l. HSP90 Inhibitors 104
1V-2. Six Olefin Groups 106
1V-3. Proposed Direct Cleavage Mechanism _____________________________________ 114
1V-4. Lohray Proposed a-Hydroxy Carbonyl Formation ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 115
1V-5. Combined Mechanism _______ 129
V-l. Pyrrolidine Product Potential Elaboration _______________________________ ___________________________________ 144
V-2. nOe on Hydrogenation Product and Suggested Conformation _______ 146
V-3. Enamine Bromination ____________________________ 159
V4. Proposed Piperidine Synthesis _____ 161

XI

LIST OF SCHEMES

I-l. Dihydroxylations of Alkenes with 0804 ,,,,,,

 

1-2. Cycloaddition Debate: [2+2] verses [3+2]

 

1-3. Johnson-Lemieux Oxidative Cleavage of Olefins

 

1-4. The Two Catalytic Cycles for Asymmetric Dihydroxylation ...................................

I-S. AD-Mix Biphasic Conditions

[-6. Common Industrial Hydrogen Peroxide Processesm

 

1-7. Phophotungstate/Hydrogen Peroxide Epoxidationm

_______ 8

9

13

 

1-8. Ozonolysis Mechanism ...............................................................................................

[-9. Standard Ozonolysis Procedures ..............................

 

1-10. Cleavages with Various Metals Systems .................................................................

1-11. Solid Supported Oxidative Cleavage

ooooooooooooooooooooooo

,,,,, 16

_____ 18

19

 

1-12. Ru Catalyzed Cleavages .................................

 

_l9

 

1-13. Noryori’s and Ranu’s Oxidative Cleavage ..............................................................

1-14. Proposed Cleavage Mechanism ................................................................................

II-l. Oxidative Cleavage of Olefins with Oxone to Ketones, Carboxylic Acids, and
Lactones

11-2. Synthesis of (+) Tanikolide

 

 

11-3. Proposed Mechanism for Oxidative Cleavage .........................................................

11-4. Possible Products for l-Decene

11-5. Cleavage of Cis-6-Dodecene .....................................................................................

"-6. Control Experiments for Aldehyde Oxidation .........................................................

II-7. Lohray Proposed a-Hydroxy Carbonyl Formation .............................

20

21

.31

,,,,, 32

54

,55

 

XII

111-1. Proposed Polymerization ______________________________________________________________________________________________ 89

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

111-2. First Attempt at Polymerization ,,,,,,,,,,,,,,, 89
111-3. Oxidative Polymerization ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 90
111-4. Initial Depolymerization ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 9 1
111-5. Initial Polymer Cleavage Reactions ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 9 3
111-6. Cleavage of Polybutadiene to form Dimethyl Succinate,,__ .--.94
III-7. Residue Test for OsO4 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 97
1V-1. Autolytimycin Intermediate ____________________________________ 105
IV-2. Witti g Reaction that Yielded Cis/Trans Mixtures ____________________ 107
1V-3. Synthesis of IV-l4 by McMurry Coupling ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 107
1V-4. Attempt at Cleaving the Tetrasubstitued Olefin ___________ 126
V-l. Mechanism for the Tandem Aza-Payne/Hydroamination Reaction __________________________ 138
V-2. Syn vs. Anti Orientation ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 141
V-3. Synthesis of Compound V-23 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 143
V-4. SN2’ to Form Pyrroles ,,,,,,,,,,,,,,,,,,,,,,, 144
V-S. Synthesis of Aziridinols ________________________________________________________________________________________________ 151
V-6. J¢rgensen’s Alkynyl Bromination 158
V-7. Tandem Alkynyl Bromination Aza—Payne/Hydroaminationm ,,,,,,, 158
V-8. Pyrrolidine Bromination _________________________________________ 159
V-9. Conditions used for Bromination ____________________ 160
V-10. Piperidine Attempt ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 162
V-ll. Ozonolysis of the Pyrrolidine ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 162

XIII

LIST OF CHARTS

 

 

 

 

 

 

 

“-1. Standard Curve for Decane and its Derivatives _________________________________ 33
11-2. Cis-6-Dodecene Product Ratios with No DMF ____________________________________________________________ 4 8
11-3. Cis-6-Dodecene Product Ratios with 0.1 equiv DMF48
11-4. Cis-6-Dodecene Product Ratios with 20 equiv DMF ...........49
11-5. Trans-S-Decene Product Ratios with No DMF49
11-6. Trans-S-Decene Product Ratios with 0.1 equiv DMF __________________________________________________ 5 0
“-7. Trans-S-Decene Product Ratios with 20 equiv DMF 50
11-8. S-Methylenenonane Product Ratios with No DMF ______________________________________________________ 5 1
11-9. S-Methylenenonane Product Ratios with 0.1 equiv DMF 51
11-10. 5-Methylenenonane Product Ratios with 20 equiv DMF ___________________________________________ 52
11-11. 2-Methyl-2-Unadecene Product Ratios with No DMF 52
11-12. 2-Methyl-2—Unadecene Product Ratios with 0.1 equiv DMF," 53
“-13. 2-Methyl-2-Unadecene Product Ratios with 20 equiv DMF ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 5 3
IV-l. Standard Curves for the 1,1-Disubstitured Substrate (IV-13) __________________________________ 110
IV-2. l-Decane Product Ratios for 4 equiv of KH805 _______________________________________________________ 113
IV-3. l-Decane Product Ratios for 8 equiv of KH805 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 118
IV-4. Cis-6-Dodecane Product Ratios for 8 equiv of lKH805 ____________________________________________ 120
IV-S. Trans-S-Decane Product Ratios for 8 equiv of KH805 ____________________________________________ 122
IV-S. 2—Methyl-2-Unadecane Product Ratios for 8 equiv of KH805 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 125

XIV

Chapter 1. Oxidative Cleavage Reactions: A Brief History
1,1 Introduction
The increase of chemical knowledge over the past half century has been

astounding. An ever-present trend of chemistry can be summed up by one of the new
buzzwords in our culture today, namely a push to be “greener”. From a chemical
standpoint this concept has many forms. Chemists are in a never ending quest to make
reactions milder, higher yielding, safer, and cheaper. These goals can be achieved in
several ways, such as reducing solvents, replacing toxic reagents with more benign
compounds, and replacing stoichiometn'c reagents with catalytic alternatives.
Throughout the Ph.D. research discussed herein the main theme is to improve existing

reactions, oxidative cleavages in particular, by making them greener.

A main theme of the group’s research is in various oxidative processes such as
chromium oxidations of alcohol and aldehydes (Jones, PCC, PDC, etc), hydroxylations,
dihydroxylations, aminohydroxylations, epoxidations, aziridinations, metal assisted
oxidative cleavages of alkenes and alkynes, the oxidative cleavage of diols, and
Ozonolysis."lo The importance of these types of reactions cannot be overstated. These
are essential tools for organic chemists when undertaking the synthesis of complex
mOIecules on both a laboratory and industrial scale or for the creation of natural or
unnatural products for commodities and pharmaceuticals.

This interest opened a new tangent of research in the laboratory. It was noticed

that by-products in osmium tetroxide mediated 2,3 ,S-THF diol reactions were oxidized

cleavage products, namely carboxylic acids. Dr. Benjamin Travis took this tangent and
deve10ped an oxidative cleavage of olefins by osmium tetroxide and Oxone
(2KH8050KHSO40K2SO4) to carboxylic acids, esters, or lactones. This also led to a
new , easy purification method for the active oxidant present in Oxone, KHSOS. The
mechanism for this reaction was never examined in detail and is the subject of Chapter 4.
The push to make this reaction more environmentally friendly is examined in Chapter 2,
where Oxone, which can leave large salt streams as by-product, was replaced with

hydrogen peroxide, were the only by-product is water. This modification made the

isolation of aldehydes possible. These reagents, 0304 and H202, have an interesting

history in terms of discovery and utility. This chapter will discuss a brief review of these
two reagents and a look into oxidative cleavage reactions.

12 Osmium Tetroxide

Osmium tetroxide’s main use has been in the cis-dihydroxylation of olefins.”12
This reactivity toward unsaturated species has made osmium tetroxide an essential
reagent in the synthetic toolbox of reagents. The first reported catalytic use of 0804 for
dihydroxylation was by Hoffmann and was mediated by sodium or potassium

chlorate.”‘” Milas elaborated on this work by substituting the chlorates with hydrogen

Peroxide.” (Scheme I-1)

Scheme 1-1. Dihydroxylations of Alkenes with Os04

— 0804 HO OH

R Fl >
1 2 Co-Oxidant R1 R2

 

R1 and R2 = Alkyl, Aryl, etc
Co-Oxidant = KCIO3, H202, t-BuOOH,
NMO, NaClO4, 02, NalO4, K3Fe(CN)6, Oxone

Criegee’s stoichiometric reactions to form diols was the first direct link between
the dihydroxylation pathway and OsO4.'6'l7 His work suggested that the intermediate was
the osmium (VI) ester complex which needed to be hydrolyzed to yield 0503 and release
the diol in a stoichiometric reaction or reoxidized back to the osmium (V 111) ester to
release the diol and continue a catalytic pathway. The osmium (V I) ester complex can be

identified by several infrared bands near 980 cm'1 (Os=O stretch), 580 cm'1 , and 630 cm"
1 (OS-O stretch) (Figure I-1) and is typically green. Three forms of the osmate esters
have been shown to be prevalent by crystal structure, two dimeric monoesters and a
diester. The predominate geometry for these osmate esters is square pyramidal. Tertiary
amines have been shown to increase the rate of osmate ester formation. These produce
brown crystals in octahedral complexes. In these octahedrall complexes the O=Os=O

b0nd is found at 840 cm"1 (Figure I-l). Osmium crystal structures are quite prevalent in

literature with examples of normal dihydroxylation.”19

Figure 1-1. IR Stretching Bands for Osmate Ester Complexes

980 crn'1
580 cm"1
i ii ..
0:... M0 ...n0 0:... ...uO
Coros‘or'os‘oj ofos\oj
H I-2
630 cm'1 840 cm'1
0!... ll ”“0“,“ ”.00 O
[ofos\0/O“s\oj [0% H _,.uL
O 0” ‘L
l-3 H

The formation pathway of the osmate ester has been the subject of great debate in
dihydroxylation chemistry. Two pathways have been suggested for the formation of the
osmate ester; (1) direct [3+2] cycloadditionm' and (II) a [2+2] cycloaddition followed by
a ring expansion mechanism. Sharpless and his group have been on both sides of this
debate. In 1977, he favored the [2+2] cycloaddition pathway based on results that
showed the nucleophilic attack upon carbonyls occurs on the carbon, not the oxygen,
Suggesting that more electropositive osmium center should favor attack (Scheme 1—2)?”3
1ilietallocyclobutanes were well know in olefin metathesis chemistry.”26 The [2+2]
Pathway was thought to explain the different rates of dihydroxylation observed in the
Presence or the absence of tertiary amines. The ligand was thought to promote the
Osmium-carbon bond cleavage and ring expansion. Sharpless favored the {3+2}
lTlechanism twenty years latter when he, Houk, and Singleton completed a high-precision
experimental kinetic isotope effects study with high-level transition structure

calculations. The experimental results match favorably with the [3+2] mechanism not the

[2+2] osmaoxetane and ring expansion.

Scheme 1-2. Cycloaddition Debate: [2+2] verses [3+2]

.3

’/
\\

0°
6/

0 [2+2] 0

> 565:0

Cycloaddition kcly‘o
'5

/..'

0“,, ll
Kort? L

R

0
q 40 [3+2] 0:... H _,.\\L

” 0’) ‘O Cycloaddition > ':0" ”S‘L
O

p +2L

Os

 

l-7

Besides hydrogen peroxide and potassium chlorate, many other co-oxidants have
been shown to be effective at oxidizing the osmate (V I) ester to the osmate (V 111) ester.
These include t-BuOOH, NMO, NaClO4, oxygen, NaIO4, and K2Fe(CN)4 (Scheme 1-
1)-'3“527'35 The main two problems with cis-dihydroxlation are selectivity and over-
oxidation but these can be managed by appropriate choice of oxidant, solvent, and
reaction temperature. The Johnson-Lemieux reaction, which utilizes NaIO4, is the most
Prominent (Scheme I-3).3’637 NaIO4 serves a duel purpose in this reaction. It allows for
the oxidation of the osmate (VI) ester back to osmium (V 111) so the reaction can be
catalytic in osmium. It also cleaves the diol to the corresponding aldehydes. The

PIOblem of over-oxidation can now be considered as useful. The drawback of this

reaction is that NaIO4 is not selective toward the newly formed diol, so other vicinal diols

must be protected. Over oxidations can be a problem because of the oxidation of the

product aldehydes to carboxylic acids.

Scheme 1-3. Johnson-Lemieux Oxidative Cleavage of Olefins

r- 60 m
__ 0504 HO 0“ NalO4 Ho-ll”—\0H o o
n’ R ——” _" o/ o ——” )L
1 2 NalO4 R1 92 R. H R2 H
“1 92

 

 

Over the past twenty years asymmetric reactions have received a large amount of
attention by chemists due to the invaluable contribution to synthesis. The asymmetric
dihydroxylation of olefins has been one of the reactions that has benefited from this area
of research. Numerous ligands have been developed for asymmetric dihydroxylation.12
Many different classes and features have been used for asymmetric dihydroxylation but

the most common feature of the ligands is a tertiary amine (Figure I-2). Tertiary amines
were shown by Criegee’s pyridine and stoichiometric OsO4 reactions to enhance the rate
0f dihydroxylation.”l7 Chiral pyridine derivatives were used by Sharpless and Hentges
early based on the work by Criegee.38 These attempts were fruitless due to the pyridine
derivatives low affinity toward OsO4 but this changed when the Cinchona alkaloids were
Used and became a pillar of Sharpless’ research. Useful enantiomeric excess (>41%)
cOuld be achieved with 1,4-diazabicyclo[2.2.2]octane derivatives. Chiral diamines did

Provide good to excellent enantiomeric excesses, but the bidentate nature was resistant to

hydrolysis due to the stable chelate that was formed. The utility of this was limited due

to stoichiometric amounts of 0804 being required .39“

 

Figure 1-2. Ligands for Asymmetric Dihydroxylation

.~\NR1R2
5612\09 Q

NR1R2
on

 

R = TBDPS R1 = H, R2 = Neohexyl
R1,R2 = Me

The first examples with the Cinchona alkaloids as chiral auxiliaries for
asymmetric dihydroxylation were also stoichiometric in OsO4 and were not useful on
large scale due to cost. NMO was used as co—oxidant and thus eliminated the cost
problem but initially provided lower enantiometric excesses when compared to the
stoichiometric reactions.42 The reason for the decrease in ee was due to a second cycle
involving the bis-osmate that is active in the catalytic system (Scheme I-4). The bis-
OSmate that is active in the second cycle does not allow for the chiral auxiliary to
Participate in the reaction, thus leading to a racemic reaction. The slow addition of
alkene substrate did increase the ee‘” but the breakthrough came when K3Fe(CN)6 was

implemented as the co—oxidant in a biphasic system.44 The second cycle was eliminated
due to the fact that 0804 was only present in the organic phase while the co—oxidant and
the reduced osmium(VI) species was found in the aqueous layer. The final modification
Was to change the osmium source from 0304 to the nonvolatile KZOsO3OHzO which
a“owed for the preparation and sale of a premixed system referred to as “AD-mix”.
Methanesulfonamide was added to greatly increase the reaction times. The reactions ees

remained unchanged or were enhanced by this system (Scheme I-5).29 Another advantage

of this system is the complimentary Cinchona alkaloids that are used as the chiral source.
This allows for dihydroxylation to occur at either the or or [3 face of the molecule which
can be predicted using a reliable mnemonic.”46 The substrate scope for this chiral cis—

dihydroxylation system is very general and numerous examples in the literature can be

found by simple search.”12

Scheme 1-4. The Two Catalytic Cycles for Asymmetric Dihydroxylation

R

 

H0) .9“ H20 ._
R n R
ii 3
_. _...\O “
°“ii"o
o i n
O 0 NMM II ."
:bsf Primary Cycle f‘ L Secondary Cycle °""os-“‘°
0 ‘0 High 99 Low 99 or ‘0
n n
NMO
fl
._ ..... 0
L O—Ols"o
L R
RH
HO OH
R H20

Scheme 1-5. AD-Mix Biphasic Conditions

 

”'20 i s: EOs’:
HO H OH HO II 0
O
on' 2H20
2Fe(CN)63‘ 2Fe(CN)64'
1-3 Hydrogen Peroxide
1.3.1 History

Hydrogen peroxide was first isolated by Thénard in 1818 by reacting barium
Peroxide with nitric acid.“ This method was improved by replacing the nitric acid with
hYdrochloric acid to produce barium chloride as a by-product, then sulfuric acid to
Precipitate barium sulfate. This method was scaled for commercial use sixty years later
and was used throughout the 19th and the first half of the 20th century. A pure sample of
hYdrogen peroxide was not obtained until 1894 by Wolffenstein by a vacuum distillation

Process.48 Earlier attempts had been plagued by the trace amounts of solids and metals

leading to catalytic decomposition or explosion. Thénard’s method could produce 2000

metric tones of hydrogen peroxide from 10,000 metric tones of barium peroxide by the

turn of the 19th century. The major drawbacks of this method was that only 3% m/m

aqueous hydrogen peroxide solution was produced, and due to the large number of

impurities, stability of the solutions were poor. Meidinger improved this method by

using aqueous sulfuric acid in an electrochemical reaction.49 Berthelot was the first to

show that peroxodisulfuric acid was an intermediate in this process50 (Scheme I-6).

3802

BaClz + H2504

8302 + H2304

Thenard's Method

+ 2HC|

Scheme 1-6. Common Industrial Hydrogen Peroxide Processes

 

BaCI +HO 2HO——->H +H
2 22 4 8 2

HZSZOB + H2O ——> H2305 + H2304

 

88304 + 2HC|
H2805 + H20 -——" H202 + H2304

 

BaSO4 + H202 2H20 —~ H202 + H2

 

 

Electrochemical Process
OH 0
Fl R
DOC + 02 0.0 +
OH O
O OH
R Catalyst R
0.0 + ... 000
Pd. Ni, etc.
0 OH

Anthrahydroquinone Autoxidation Process

Manchot’s discovery of hydroquinones or hydroazobenzenes ability to produce

hydrogen peroxide quantitatively by an autoxidation process was a major breakthrough in

the industry .5‘ 52 This method was altered by Walton and Filson53 to use hydrazobenzenes

10

'9‘...“ L..-

to produce H202 and again by Pfleiderer“ in an alkaline auto-oxidation to produce

sodium peroxide, with sodium amalgam to reduce the azobenzene. The main problem,
hydrogenation of azobenzene with sodium amalgam and oxidation of hydrobenzene in
alkaline solution, with autoxidation process with azobenzene were solved by using
anthrahydroquinone (Scheme I-6). This work was based on the research by Reidl and
Pfeiderer and was utilized by BASF between 1935 and 1945.54 The first auto—oxidation
process plant was commissioned in 1953 by E.I. Duponte de Nemours.
The choice of quinone must be carefully made in order to ensure good solubility
of the hydroquinone that is formed, resistance to non-specific oxidation, and easy
availability. Degradation products can be common so their ability to regenerate to active
quinones can dictate the choice. By-products include non-specific hydrogenation,
epoxidation, and tautomerization. The hydrogenation catalyst must also be carefully
Chosen, as they can lead to catalytic decomposition of hydrogen peroxide. Raney nickel,
used by BASF, is a common catalyst but is plagued by its sensitivity to oxygen requiring
Se[)aration before hydrogenation. This problem was alleviated by treatment with
anlmonium formate but the pyrophoric properties of Raney nickel limit its current use for
hB’drogen peroxide formation.54 Most current plants employ a palladium catalyst under
Val'ying conditions to produce hydrogen peroxide.
1 32 Organic Reactions
The use of hydrogen peroxide in organic synthesis is vast and only a brief survey
of reactions will be covered here. This reagent has been used in many vital
transformations such as epoxidations, hydroxylation, and cleavage of olefins, oxidation

0f alcohols, carbonyls, aromatic side-chains, organo-nitrogen, and sulfur compounds, and

11

 

halogenations. Hydrogen peroxide is a more expensive reagent than molecular oxygen
but it frequently is used in fine chemical and pharmaceutical applications due to its ease
of use .55
Epoxidation is one of the more common uses for hydrogen peroxide. The
prevalence of peracids to epoxidize olefins was discovered by Prilezhaev.56 The
mechanism was suggested by Bartlett” to be a concerted process in which the proton on
the transferred oxygen is transferred intramolecularly to the carbonyl oxygen while the st-
bond attacks the oxygen. These peracids are generally formed by reaction of the
carboxylic acid or anhydride with either aqueous hydrogen peroxide or urea hydrogen
peroxide (Figure I-3).5"”‘53 Other uses of hydrogen peroxide call for the in situ generation
of perforrnic or peracetic acid which then epoxidize olefins.

Figure 1-3. Common Peracids for Epoxidations

— —

0 Os

0 O

O ’\
H OH

JLo

F3C o’ ‘H 09
or o

Mg2+ sto

 

 

Peroxytrifluoroacetic acid m-Chloroperbenzoic acid Magnesium monoperoxyphthalate

(PTFAA) (mCPBA) (MMPP)
O
O 0‘
o o 9 O’O‘H
990. H 0
HO _ OH ‘H
. O
Permaleic acid Perbenzoic acid Monoperphthalic acid
(PMA) (PBA) (MPPA)

The pairing hydrogen peroxide with a metal complex can lead to powerful

epoxidation reagent. Extensive work has been done using tungsten complexes with a

12

quaternary ammonium salt in chlorinated solvents. These negatively charged species are
used as cationic phase transfer agents (Scheme I-7).64456 This chemistry is also vast
67-71

including iridium, palladium, platinum, metalloporphrins, titanium, etc.

Scheme 1-7. Phosphotungstate/Hydrogen Peroxide Epoxidation

 

 

_ wo42‘, 9042', H202 o
CeHra F
Aliquat 336 06*“ 3
82%
W042'. P042" “202 0
W0 > WCI
Aliquat 336
80%

The cleavage of olefins and vic-diols are key reactions in organic synthesis.
Cleavage of vic-diols in sugars have lead to chiral synthons. Chromium trioxide,72 lead
tetroxide?3 periodic acid,74 and ozone75 are all well known methods for cleaving olefins.
Rllthenium has been shown to cleave olefins and vic-diols with hydrogen peroxide.7678
The gold standard in hydrogen peroxide cleavage was done by Noyori with a tungsten
Catalyst.79 Adipic acid was produced from cyclohexene mediated by NaZWO4 and 30%
hYdrogen peroxide. These reactions will be discussed in more detail in the subsequent
SeCtion.

Hydrogen peroxide has enjoyed a near ZOO-year history and its importance to the
chemical world has only increased. Hydrogen peroxide is produced from an auto-

OXidation process. On an industrial level it is mainly used as a disinfectant and bleaching

agent with many large scale oxidations being done by molecular oxygen. The diversity

13

comes in the synthesis of fine chemicals and pharmaceuticals where its ease of use and
versatility is utilized.
1.4 Oxidative Cleavage of Olefms
The oxidative cleavage of olefins has a long history in organic chemistry. The
vast majority of cleavages can be summarized into two categories, (i) direct cleavage by
ozonolysis"'753°‘31 and (ii) dihydroxylation followed by cleavage with a suitable reagent,
Johnson-Lemieux chemistry .36 The conditions of these reactions can be tailored to yield
either aldehydes or carboxylic acid derivatives.
l .4.1 Ozonolysis
Ozone and ozonolysis has been an integral part of modern organic chemistry. Its
usefulness can be summarized in a quote by Bentley in 1972: “The reaction of ozone with
double bonds, followed by the decomposition of the resulting products, is one of the
most-reliable procedures for oxidative fission of unsaturated molecules and for
determining the precise location of the unsaturation.”82 C. F. Schdnbein discovered
Clone in 1847.83 He noted that organic molecules behaved different than inorganic
n"101ecules when subjected to ozone. Inorganic molecules were usually taken to the
highest oxidation state, while organic molecules yielded carboxylic acids instead of
component elements such as water and carbon dioxide .84 Before 1900, chemist reported
using ozone on many different crude substances like straw, humus, blood, etc. and
reported obtaining pure compounds. Other examples included the conversion of indigo
‘0 isatin, aromatic compounds like benzene to explosive solids, and ether to peroxides

Without any insight into mechanism.85

14

The “father” of modern ozonolysis was Carl Dietrich Harries and his work was
concentrated in the early 20th century. Ozone was the cause of degradation of rubber
tubing and Harries decided that ozone would be useful in determining the structure of
natural rubber. During his research he published 80 papers on the subject including four
reviewsfmo His early work was not unchallenged and met with resistance by the Italian
chemist Molinari, who tried to claim the field for himself and reported several erroneous
results. Harries responded with a quote “This is the third time that I have had to take the
trouble to check and correct Molinari’s major mistakes,” and later allowed history to

determine his work was correct?4

Ozonolysis is a well-developed reaction that can yield aldehydes and carboxylic
acids upon work-up. The mechanism for ozonide formation is well studied. The first step
0f the reaction is a 1,3-dipolar cycloaddition of ozone to the olefin to form the initial
0Zonide. This is followed by a cascade of fragmentation and cycloaddition that results in
a 1 2,4—trioxolane ozonide (Scheme I-8). The ozonide is either reductively or oxidatively
cleaved to form the final products. The main problem with ozonolysis is the
interrnediates; ozonides and peroxides, in these reactions can be explosive?"94 This has
been a concern for the pharmaceutical industry for large-scale reactions and the paper
l‘S‘vcycling industry for decolorization of recycled paper. Scheme 1-9 shows a survey of
cfinditions used.80 The initial steps of these reactions are all very similar with the

addition of ozone at low temperature. The utility of ozonolysis resides in the variety of
the work-ups. From cyclohexene a large variety of products can be obtained, ranging

from dials, diacids, diesters, acetals, and alcohols.

15

Scheme 1-8. Ozonolysis Mechanism

0
H R 69 o’ ‘o (9 ,0 , o s”
‘ — H O/’O\0e Fri i"H JOL j]: “(v-7‘”
R H R a H H a ° °
Inital Ozonide
Ozonide

Scheme 1-9. Standard Ozonolysis Procedures

0 O
H OR
o o 1) 03, ROH, NaHCO;; 0 OR
W 2) A0201 Et3N W
H OH H OH
1) 03, CH300002M8, ~78'C 1) 03. ROH. TsOH

2) Et3N 2) M628, NaHC03

0 OR

0 O
W /U\/\/\)\

1) 03. CHacocone, 0°C 1) 03, ROH, TsOH
2) PhaP 2) Ac20, EtaN
o o
/\/\/\)(1)\ H W H
”0 H 1) 03, CH3COCOzMe, 43° c

 

1)03, CH300002Me. -7s° c 0 We 2) PhaP
2):.131-14
3) Ph3P H Chile

1) 03. CH3COCOzMe, MeOH -73° C

2) Ph3P

1) 03, MeOH

Q 2) stOH 0 OMe
3) NaHCOa HWOMe
4) M623
16

..fi

1.4.2 Johnson-Lemieux-Type Cleavages

There are few other examples of direct cleavage of olefins other than ozonolysis,

but many examples exist with an intermediate diol. The two most common catalysts used
are ruthenium and osmium based. RuCl3 and RuO4 can catalytically cleavage olefins to
the corresponding aldehydes with varying oxidants, although the mechanism is still in
question.”'°° The direct cleave of olefins, without a diol intermediate, with OsO4 has
been reported with hydrogen peroxide and t-butyl hydrogen peroxide in low yields.1527
Direct cleavage with 0804 and H202 will be discussed in Chapter 2. Our group reported
a direct cleavage of olefins mediated by 0804 and Oxone to carboxylic acids, esters, and
lactones.‘°”°6 The placement of this reaction into one of these two classes of mechanism

will be discussed in Chapter 4.
The Johnson-Lemieux reaction typically uses NaIO4 to cleave the diol, but a

Variety of oxidants have been used. These oxidants can cleave diols that have been

f0l‘med from Os, Mn, Ru, and W oxides. Potassium permanganate (KMnO4) is a cheap

and useful oxidant, but due to its non-specific nature and insolubility in many organic
30] vents its versatility is lacking.""m"” An example of its utility is shown in Scheme I-9,
but it is noted that no other functional group is present in the molecule. There has been a
‘Ot of work to make these reactions more selective and solve the solubility issues by using

Phase transfer catalysts and solid supported reagents but they have failed to provide a

general solution to the problem (Scheme I—10) and are prone to byproducts and low

yields “8,110.112-1 l6

l7

Emmi

Scheme 1-10. Cleavages with Various Metals Systems

KMnO4 (Cat)

NalO4, K2003: RuCI3 3H20 (Cat) HO

 

 

9A0 COQH

QAc
' silicageI-KMnO4 Wain? NalO4
\m Benzene :W CCI42ACN2H20

O C02H O

O O

0304 (Cat)
N 47 N
_>= Jones Reagent _\r—0
0 O

Acetone

 

 

 

 

Sodium periodate (NaIO4), as stated before, is the most common reagent for
cleaving diols.‘5 Its insolubility has led researchers to pursue soluble forms like

quaternary alkyl ammonium periodate,”7'”8

potassium metaperiodate with phase transfer
Catalysts,”9 and silica supported NaIO412° that have increased their solubility and
1' eactivity. These methods are improvements but they still depend on a diol intermediate
that must be isolated. A one-pot catalytic 0304 and NaIO4 has been developed but it

often plagued with formation of byproductsm

Other examples include solid-phase
clteavage using 0504 and NaIO4 in an intermolecular N-acyliminium Pictet-Spengler
reaction (Scheme I-ll).122 The addition of DABCO in this reaction inhibited the
fOl‘mation of the or-hydroxy ketone side-product that had plagued this procedure. These

Cleavage methods work well as long as no other diol is present in the molecule and it

does require more than one step.

18

Vim" 'mfl

Scheme I-ll. Solid Supported Oxidative Cleavage

HN

W0 0 2) TFA:DCM (1:1)

3) 0.1 M NaOH (aq) then 0.1 M HCI (aq)

 

A’ 1) 0so4 (0.01 equiv), DABCO (5 eq)
GW‘O NalO4 (10 equiv), THF:DCM (1 :1)

 

A ruthenium catalyzed oxidative cleavage of olefins to aldehydes has been
reported using RuCl3 and Oxone (Scheme I-12).123 This method was useful for aryl and
alkyl olefins with the diol being the minor by-product. Another report used
Rqu/BaTi409 and NaIO4 to cleave olefins to aldehydes or carboxylic acids. The ratio
of products depended on the amount of catalyst used.124 A report of computational
calculations explored the reasons why olefins are usually cleaved with RuO4 and
dihydroxylated with 0304325 Despite these calculated results our lab has been able to

cleave olefins with 0804.

Scheme 1-12. Ru Catalyzed Cleavages

 

 

RuCl3 (3.5 mol%)
Ph Oxone (1.5 equiv) NaHCOa (4.7 equiv) o
ph ACN/H20 (1.5:1) rt, pH 7-7.5, 0.5 h ' Ph H
85%
MOW Flu02/Ba11409(x mol%) 0 0
. > AcO H AcO OH
OAc ~an v w , EtOAc/H 0 buffer 6.88 W W
4( 9Q“ i 2 ( ) 0 Ac 0A0

98% 87%
X = X = 3
v=4 Y=6

19

 

1 .4.3 Other Methods
Other more “green” methods have included using light and singlet oxygen to
cleave olefins, but in low yields.126 As mention earlier the gold standard has been
Noyori’s work using a Na2W04/H202 system to cleave cylcohexene to adipic acid
(Scheme I-13).79 This methods provides an easy, cheap path for high valued compounds
on large scale, but it is not a general procedure and nor is tolerant of many functional
groups. Ranu’s group has reported an elegant InCl3/t-BuOOH cleavage of varying

alkenes and alkynes.127

Scheme 1-13. Noryori’s and Ranu’s Oxidative Cleavage

Noyori

 

NaWO4, H202 0 OH
O F HOJVVY
Me(n-oct)3NHSO4

 

 

O
Ranu O 0
R1 [R =H
/=< InCI3 (cat) R/lLOH H1/U\OH 2
R F12 _
90°C
R : R R =alkyl
‘ RJLOH FiflkRz 2

Fl, R1, R2 = H /alkyl / aryl

InC|3 (C81)

:<fi: r-BuOOH, H20 T °:<_:

90° c

 

Our laboratory has developed an osmium tetroxide-mediated cleavage of olefins

t - . . . .
o acIds, ester, and lactones wrth Oxonem‘106 This rs a direct cleavage of the olefin, not a

20

 

Johnson-Lemieux type reaction. A mechanism was proposed (Scheme I-14 and will be
discussed further in Chapter 4. This is a mild reaction that accommodated mono, di, 1,1,
and trisubstituted olefins, with only a slight modification for trisubstituted olefins (the
addition of NaHCO3).102 Olefins could be cleaved to esters by substituting the solvent
(DMF) with an alcoholic solvent, while lactones were synthesized by the appropriate

enol.“’3"104 This procedure has been applied in the synthesis of the (+)-tanikolide

 

 

 

lactone.105
Scheme 1-14. Proposed Cleavage Mechanism
0. ,o 0
_ :05: \eeé'seo
Rt Fl2 0304 o o [o] 0’ ‘0 H 0 $09
[3+2] R1 R2 H1 H2
I-6 l-7 I-B l-9
_ _ O 0
e \\ l/0
\9 9890‘AsoeH . . R1)” H 9,)1‘011
O o Oxrdatlve O [O] O
H > g, >
_ R1 F12 ‘ Cleavage Fig/“\H Rz/ILOH
l-10 I-1 1 NZ

These varied approaches show how important oxidative cleavage reactions are to
Organic chemistry. There is still a need to improve existing methods by making then
more economical, more environmentally friendly, and more versatile. The research
discussed in this thesis is keeping with this green theme. The replacement of Oxone, a
“green” reagent but prone to leaving salt streams, with hydrogen peroxide, with water as

the only by-product, is the focus of Chapter 2. This will also give access to the aldehyde

21

oxidation state of the cleavage product. The mechanism for this reaction is the focus of

Chapter 4.

22

 

 

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Noureldin, N. A.; Lee, D. G. J. Org. Chem. 1982, 47, 2790-2792.

Noureldin, N. A.; McConnell, W. B; Lee, D. G. Canadian Journal of Chemistry-
Revue Canadienne De Chimie 1984, 62, 2113-2116.

Santaniello, E.; Ponti, F.; Manzocchi, A. Tetrahedron Lett. 1980, 21, 2655-2656.
Keck, G. E.; Fleming, S. A. Tetrahedron Lett. 1978, 19, 4763-4766.

Kalsi, P. S.; Kaur, P. P.; Singh, J .; Chhabra, B. Chemistry & Industry 1987, 394-
395.

Daumas, M.; Voquang, Y.; Voquang, L.; Legoffic, F. Synthesis 1989, 64-65.
Cainelli, G.; Contento, M.; Manescalchi, F .; Plessi, L. Synthesis 1989, 45-47.
Nielsen, T. E.; Meldal, M. Organic Letters 2005, 7, 2695-2698.

Yang, D.; Zhang, C. Journal of Organic Chemistry 2001, 66, 4814-4818.
Okumoto, H. 0., K.; Banjoya, S Synlett 2007, 20, 3201.

28

(125) Frunzke, J.; Loschen, C.; Frenking, G. J. Am. Chem. Soc. 2004, 126, 3642-3652.
(126) Murthy, R. S. B., M.; You, Y. Tetrahedron Lett. 2009, 50, 1041-1044.
(127) Ranu, B. C.; Bhadra, S.; Adak, L. Tetrahedron Lett. 2008, 49, 2588-2591.

29

Chapter 2: Oxidative Cleavage of Alkenes with Osmium Tetroxide and Hydrogen
Peroxide

2.1 Introduction

Oxidative cleavage of olefins is one of the most prevalent reactions in organic

synthesis. The main two oxidative cleavage methodologies can be summarized as

conversion of olefins to vicinal diols and subsequent cleavage with NaIO4‘, Johnson-

Lemieux,“ or other oxidants and ozonolysis in which the olefin is directly cleaved into
functionalized products depending on workup.” Ozonolysis is quite reliable, but has
always had major safety concerns. Ozone gas is highly toxic and requires specialized

equipment; also the ozonide can be explosive. Examples of alternate reactions to

ozonolysis include Noyori’s8 cleavage of olefins to carboxylic acids with hydrogen

peroxide and NaZWO4, Ranu’s9 lnCl3/t-BuOOH cleavage of alkenes and alkynes to

carboxylic acids, and several gold catalyzed cleavages to carboxylic acids using t-
BuOOH. Paquette and Tsuilo did report a stoichiometric osmium tetroxide cleavage of an
olefin with sodium dithionite. In this chapter an oxidative cleavage of aryl and alkyl
01 efins to the corresponding aldehydes is described.

2-2 Cleavage of Aryl Alkenes with Osmium Tetroxide and Hydrogen Peroxide

Recently, we reported an osmium based catalytic oxidative cleavage of olefins.”

The initial report used a catalytic portion of osmium tetroxide with several equivalents of

0"(One (a triple salt containing two parts KHSOS, one part KHSO4, and one part K2804),

vwhich facilitated the cleavage of a variety of olefins to the corresponding carboxylic
aci(ls (for mono- and vicinal disubstituted alkenes) or ketone (for geminal disubstituted

allllenes) (Scheme II-l). Trisubstituted olefins yielded the acids and ketones with only a

30

minimal modification to the general procedure (addition of sodium bicarbonate). Esters
and lactones were accessible if alcohols were used as solvent or an alcohol was present in

the alkenyl molecule.‘2'l3 This reaction’s utility was highlighted in the efficient total

synthesis of (+)-tanikolide (Scheme 11-2).M

Scheme II-l. Oxidative Cleavage of Olefins with Oxone to Ketones, Carboxylic
Acids, and Lactones

0804 (0.01 equiv)
R1 Oxone (4 equiv)

 

 

 

O O
>—-\_ F
32 F12 DMF (0.1M), FIT R1)L F12 RS/ILOH
"-1 11-2 11-3
0304 (0.01 equiv) o
Oxone (4 equiv)
MO“ > O
n DMF (0.1M), RT
n
n = 1, 2, 3
"-4 "-5
Scheme 11-2. Synthesis of (+) Tanikolide
I) nBu4NHSO5, 0804 (cat) 0
u 7 Steps THF (73%) OH
P 00251 ——> ’ O
(Et0)2’ V -—-—> 2) Pd(OH)2, H2 -.(h)/
EtOAc. RT (87%) 10

 

This methodology allows access to the higher oxidation state carbonyl compounds
(ketones, esters, and carboxylic acids) but direct cleavage to the aldehyde has not been
easily achieved. The reason for this is that the intermediate aldehyde is readily oxidized
to the carboxylic acid in the presence of Oxone. Our proposed mechanism (Scheme 11-3)

inVolves an attack of the KHSO5 anion (II-9) on the osmium (V 111) intermediate (II-8)

followed by fragmentation that releases two aldehydes and regenerates the 0304

31

catalyst.“ We have reported that the aldehyde was accessible, but only with purified

“soluble Oxone” (nBu4NHS05 = TBA-OX) and only alkyl aldehydes (T BA-OX will

oxidize benzaldehyde to benzoic acid).ls In this report, we demonstrate an osmium

tetroxide mediated oxidative cleavage of aryl and alkyl olefins to aldehydes in good to

moderate yields.

Scheme “-3 Proposed Mechanism for Oxidative Cleavage

 

 

 

o. ,o O
,—-\_ :05: \O-QOISTO 9
F11 R2 OsO4 o o [O] 0’ ‘0 H03802
[3+2] H1 H2 R H
"-6 1 2
"-7 "-8 "-9
— o o ._ jl:
O \\ //
330830‘8803H . . F11 H l‘h’lLOH
O 0 Oxrdatlve O [0] 0
—_.> )‘x g, a ——‘>
— R1 R2 — Cleavage RZJLH RZ/ILOH.
Il-1O "-11 "'12

In order to test this methodology quickly and efficiently, gas chromatography was
utilized. An internal standard was chosen and a standard curve was made for each
SUbstrate and product. Two internal standard (ISTD) were used throughout thisproject,
Pentadecane and tetraglyme. Both were chosen for their appropriate retention time (both
appeared away from most products, reactants, and side-products) and their inertness to
the reaction conditions. By-products were also identified on the GC trace but standard
curves were not always constructed for them. Instead, a percent conversion was

calculated for by-product comparisons. Standard reaction conditions were used for each

32

 

 

 

trial. The standard conditions were 0.1 mmoles of substrate, 1 mL of solvent, 50 (LL of
osmium tetroxide solution (1 g/20 mL of toluene), additives, 50 11L of 50% H202 (aq.),

and 0.05 moles of ISTD. This allowed reactions to be run in the GC vials and injected

without transfer. A sample standard curve is shown in Chart II-2 for decene and its

product and by-products. The R2 values for all standard curves were greater than 0.990

or the curves were remade.

Chart II-l. Standard Curve for Decene and its Derivatives

2 ‘y‘-.-13.61x-0.00 y: ll.24x-0.00
1.8‘ R2=0.99 R2=099

1.6 1y=12.73x+0.00 y=9.73x -002
2 = 0.99 R?- =0.99

Ratio (X/PD)

 

 

0.8 / /
0.6 / ~—-/
0.4 y = 8.90x + 0.00
2 -
0.2 ,/ R - 0.99
0 . . . . . . .
0 0.02 0.04 0.06 0.08 0.] 0.12 0.14

 

.Decene 'Nonyl Aldehyde ‘Nonanoic Acid 'l.2-Decanediol .12-Epoxydecane

Initially, the standard reaction conditions were used with only the Oxone being
replaced by 50% hydrogen peroxide (aq.). This gave unsatisfactory results for several

aryl olefins. The DMF was then replaced by a variety of solvents (ACN, Benzene, THF,

MeOH, EtOH, EtzO, cyclohexane, hexane, CHCl3, and DCM) along with 20 equiv of

33

‘ilf
....

DMF. The test olefins were stilbene, styrene, and methyl cinnamate. Stilbene cleaved
well in most solvents (~100% conversion) except with cyclohexane and hexane, which
showed significant amounts of starting material after 24 hours. These two solvents were
not used for the styrene and methyl cinnamate. Table II-l shows that ACN is the most
efficient solvent for electron deficient olefins. For electron neutral olefins (like styrene)
ACN (II-15) works well, though it does not provide the best yield. In order to have a

consistent methodology ACN was chosen as the solvent for the reaction.

Table 11-1. Aryl Substrate Solvent Test
0804 (0.01 equiv) O

\ R Oxone (4 equiv)
0V ,, H
DMF (20 equiv)

ACN (0.1 M), FIT

 

 

 

R = H or COZH
Entry Solvent Styrene Methyl Cinnamate
%PhCHO (PhCOzH) %PhCHO (PhCOzH)

II-13 Benzene 45 -7 (7 -3) ' 75-4 (1 1-0)
11.14 DMF 56.3 (15.0) 68.6 (8.6)
11-15 ACN 50.3 (13.0) 95.2 (4.1)
11.16 MeOH 46.2 (7.3) 82.0 (11.6)
11.17 EtOH 41.6 (6.5) 73.6 (8.6)
11.13 EtZO 43.2 (8.5) 25.5 (5.3)
11.19 DCM 27.0 (5.6) 83.2 (13.3)
11.20 CHCI, 23.9 (5.4) 73.2 (8.8)

\
All reactions were carried out with 0.1 mmol of substrate, 1 mol% OsO4, 4 equiv

of 50% H202 (aq) 20 equiv of DMF, Solvent (0.1M) and 0.05 mmol of dodecene (ISTD).
A“ yields are based on GC.

34

m

..| ..
"I
JUL-...

".3 H
53. U»

1.-.». .

In! ...,

”‘0 L”.
‘5‘ A.“

1. . . ‘-
u‘.(: 1‘]

fi

5“. I
._\r- *1
.\x

 

The end result of these trials were aldehydes with only a minimal amount of
carboxylic acid being detected in most cases (<15%). This differs from our standard
reaction, which yielded only carboxylic acids. This is due to hydrogen peroxide’s is less
able to oxidize the intermediate aldehyde to carboxylic acid under our reaction
conditions, while Oxone readily oxidizes the aldehyde to carboxylic acid (Scheme 2).
The osmate is oxidized by Oxone or hydrogen peroxide. Hydrogen peroxide or KH805
then attacked the oxidized osmate. Fragmentation regenerates 0804 and two aldehydes.‘l

Hydrogen peroxide seems to be too poor a leaving group to allow for the Baeyer—Villiger
oxidation. The cleavage is not due to a Johnson-Lemieux type reaction because cleavage
does not take place when a diol is used as starting material instead of an olefin. The

reaction yields only complete recovery of the starting material.

Several aryl olefins of varying electronic nature were chosen (Table II-2). To
probe the necessity of DMF in solution, reactions were done with 0 and 20 equivalents of
DMF. The electron-poor substrates (II-23, Il-24, II-25) benefited from the addition of
DMF while the other substrates did not receive the same benefit. The electron poor-
Suhstrates exhibited lower yields with cinnamyl aldehyde giving the worst yield in the
Series. These substrates showed a marked increase in the corresponding diol. This
suggested that the cleavage step is slower than the competing hydrolysis reaction. The
electron-rich substrates showed very little of the diol byproduct. The cleavage of a-
methylstyrene (II-29) showed that more substituted olefins can be cleaved successfully in
good yield. The initial product from a-vinylbenzyl alcohol (II-31) should have been an

Q“hydroxy aldehyde, which then must have undergone Baeyer—Villiger type oxidation“5

35

Table II-2. Aryl Substrate Test for Oxidative Cleavage

\ R1
R2

0304 (0.01 equiv) O

Oxone (4 equiv)
) H

 

DMF (20 equiv), 24 h
ACN (0.1M), RT

 

 

Entry R, R2 20 eq. DMF % 0 eq. DMF %
PhCHO (PhCOzH) PhCHO (PhCOzH)
11-21 R‘ = H R2: H 47.9 (4.0) 46.1 (5 .4)
11-22 R‘ = Ph R2: H 76.5 (0.0)a 92.6 (6.8)a
11—23 R‘ = cone R2 = H 71.3 (3.9) 22.8 (0.0)
11—24 R1 = COZH R2 = H 75.6 (23.6) 44.5 (8.4)
11-25 R' = C0211 R2 = CH3 65.8 (8.9) 50.5 (14.5)
II-26 R1: CH0 122: H 28.6 (6.4) 15.0 (14.5)
11-27 R' = CHZOCOMe R2: H 60.6 (8.0) 67.9 (8.3)
II-28 R‘ = CH20H R2 = H 49.9 (7.5) 66.8 (4.7)
II-29 a-Methyl Styrene 78.3 (0.0)b 85.5 (0.0) b
11-30 Dibenzoylethylene 0.0 (93 .2) a 0.0 (94.4) a
11-31 a-Vinylbenzyl Alcohol 64.6 (3.9) 54.0 (11.2)
\

 

All reactions carried out with 0.1 mmol of substrate, 1 mol% 0804, 4 equiv 30%
H202 (aq.), 20 equiv of DMF, ACN (0.1M) and 0.05 mmol of Tetraglyme (ISTD). GC
Yields. aYields represent two equivalent of benzoic acid or benzaldehyde. inelds are of
acetophenone.

to an aldehyde. This was not the case when the initial cleavage yields an a-keto aldehyde

01-30). The cleavage of dibenzoylethylene yielded only benzoic acid in excellent yield.

36

This is assumed to be similar to a cleavage of a and fidicarbonyl to diacids using
KHSOSthat our group reported.16 This proceeded through a Baeyer—Villiger type

mechanism and was efficient for alkyl and aryl or and [3 dicarbonyls and a-hydroxy
carbonyls.
2.3 Cleavage of Alkyl Substrates
The alkyl substrates proved to be a more challenging endeavor. The first
substrate chosen was l-decene and in hindsight this proved to be the worst substrate for
this reaction. When this terminal olefin was subjected to reaction conditions, a complex
mixture was the result (Scheme Il-4). The main product was the diol (II-35)(45%-55%),
with cleavage products (aldehyde (II-34) and carboxylic acid (II-35)) making up only
15% of the mixture. Trace amounts of epoxide (II-37)were also observed along with a
substantial amount of the a-hydroxy ketone (II-36)(30-45%), while the a-hydroxy
ald'l‘vhyde was not observed. The ratio between the a-hydroxy ketone and the diol
depended on the solvent. Table II-3 shows the results of the solvent test. A standard
Cu” e was not completed for the a-hydroxy ketone but it was the only other major peak

obSel‘ved for benzene, DMF, EtOAc, and DCM. It can be suggested that ACN and

Scheme “-4. Possible Products for l-Decene

o o
OsO4, (0.01 equiv) \HfllLOH \(v);U‘H
"-34

 

807 H o (5 uiv)
% ° 2 2 eq , "-33
DMF (20 equiv), 24 H
I- 2
' 3 Solvent (0.1 M), 4°C or RT 0” O 0
%0H Wm W
7 7 7
"-35 "-36 "-37

37

Me0H inhibited the formation of the a-hydroxy ketone so those two solvents were used
for subsequent reactions. Several traces (Entries 1144, 45, 47, and 48) showed over

100% yield which was attributed to on impurity in those samples that eluded with the diol

 

 

 

(ll-35).
. Table lI-3. Solvent Test for l—Decene Cleavage
0504 (0.01 equiv), DMF (20 equiv)
W 30% H202 (4 equiv), Solvent X (0.1M), W0
"-32 8988;289:981" "-34 “
Entry Solvent Method 3:32;“ Tfifigg? 1801;121:1010 Decanzediol Epoxlyfiecane
¥ (II-33) (II-35) (II-37)

11-38 Benzene A Trace 15 .4 7 .3 33 .0 0.2
11-39 Benzene B Trace 15.3 7.0 34.3 0.2
"-40 Benzene C Trace 15.2 6.6 34.2 0.1
Il-41 DMF A Trace 14.2 7.1 32.6 0.1
11-42 DMF 3 Trace 413.2 7.7 30.8 0.1
11-43 DMF . cf ’ Trace 9.1 7.7 75.2 0.1
II~44 ACN A Trace 5.3 7.6 119.7 0.0
II~45 ACN 3 Trace 5 .3 7.9 105.9 0.0
11‘46 ACN (3 Trace 5.3 8.2 91.9 0.0
II~47 MeOH A Trace 4.2 6.3 105.1 0.0
11‘48 MeOH 3 Trace 3.1 4.4 118.4 0.0
II~=39 MeOH C Trace 4.7 10.2 79.9 2.6
11‘50 EtOAc A Trace 7.2 16.2 40.6 5.3
11‘51 EtOAc B Trace 5.7 15.8 38.2 5.1
::‘52 EtOAc (3 Trace 5.1 15.4 37.1 5.1
It ‘53 DCM A Trace 13.4 7.9 34.0 2.5
‘54 DCM 3 Trace 21.4 0.3 31.0 0.0

38

Table “-3. Continued

 

TI-ss DCM c Trace 215 1.0 31.6 0.4

All reactions were carried out with 0.1 mmol of substrate, 1 mol% 0s04, 4 eq.
30% H202 (aq.), 20 eq. of DMF, Solvent (0.1M), 0.05 mmol of Pentadecane (ISTD), A
& C at RT and B at 0° C. GC Yields. 1,2-Decenediol has elevated yields due to overlap
with an unknown byproduct, which accounts for the yields above 100%.

The addition of varying equivalents of DMF, multiple solvents (with MeOH
giving the highest yields), and other additives (acidic: HCI, H2804, & AcOH; basic:

sodium carbonate, sodium bicarbonate, & pyridine) only decreased the amount of
cleavage products at the best and halted the reaction completely at the worst. Table II-4
shows that MeOH was the best solvent albeit the cleavage was in low yield (Entry II-59).
The major products were the diol and the a-hydroxy ketone. The four best solvents
(M6011, Benzene, EtOAc, and DCM) were then tested for equivalents of DMF (Table II-
5)- The cleavage reaction yield increased as the number of DMF equivalents approached
20. but decreased as it approached 40 equivalents. An additives test (Table II-6) showed
that the addition of acids to the reaction pushed the yields toward dihydroxylation
(Entries Il-98-102), but new peaks emerged on the GC trace that were not identified
(aSSUmed to be degradation products). Sodium carbonate and bicarbonate (Entries II-
1()3-107) both showed significant amounts of starting material and the major product was
the (x-hydroxy ketone (II-36). Pyridine (Entries “-108 & 109) was only effective at
shutting the reaction down at higher equivalents, but the major product was still the 01-
ydl’oxy ketone (II-36). These attempts at optimization were mostly fruitless and a new

a
I)Dl‘oach was considered.

39

Table “-4. Solvent Test for l-Decene (Percent Conversion)

o o
0304, (0.01 equiv) ‘Hglk/OH \(~);U‘H

 

 

 

50% H202 (5 equiv) "-36 "_34
W ’ 0H 0
"_32 DMF (20 equiv), 24 h WOH \HJL
MeOH(O.1M), RT 0H
Pentadecane (0.5 equiv) 7 7
"-35 “-33
. 1 ,2- l-hydroxy-
Nonanal Nonan01c l-Decene .
Entry Solvent . Decaned1ol 2-decanone
_ (II-34) Ac1d (II-33) (II-32) (II-35) (II-36)
II-56 Benzene 14.2 6.8 6.9 22.2 44.2
11-57 DMF 3 .8 1.9 - 81.3 13 .0
lI-58 ACN 6.1 7 .3 - 34.8 49.7
Il-59 MeOH 20.0 2 .4 - 22.1 47 .8
“-60 EtOAc 8 .0 7 .6 1 .1 28 .0 51 .4
161 DCM 10.6 5.7 - 38.5 35.4

 

 

GC Conversions Only. No ISTD was used. All reactions were done with 0.1
mmoles of substrate, 1 mol% 0s04, 5 eq. 30% H202 (aq.), 20 eq. of DMF, Solvent
(0.1M). The 1,2-epoxydecane was seen in trace amounts but it was not analyzed for this

 

 

 

data set.
Table II-S. DMF Test for 1-Decene
0804, (0.01 equiv) W \HJLH
% 50°43 H202 (5 GQUiV)’. 7IO|_37 "-034
"-32 DMF (X equiv), 24h}.
Solvent (0.1M), 4°C \H/‘\/OH \HJKOH
Pentadecane (0. 5 equiv)
"-35 "-33
\
N onanoic l ,2- 1 ,2-Epoxy
S 01 Vent Entry 131M: 3:53;; 1:33:13] Acid Decanediol Decane
(II-33) (II-35) (II-37)
h II-62 0 0.2 17.0 1 .0 42.7 0.4
' e011 11-63 5 0.1 18.0 1.0 40.4 Trace
II-64 10 0.1 18.7 1.1 37.8 -
“-65 15 0.1 19.6 1.2 35.6 0.4

40

Table “-5 Continued

 

 

 

MeOH 11-66 20 - 20.6 0.7 33.3 0.9
“-67 25 - 21 .0 0.4 33 .9 0.9

“-68 30 - 21 .4 0.9 34.4 0.8

II-69 35 - 21.6 1.3 33 .6 0.9

¥ 11-70 40 - 21.9 0.8 32.8 0.9
“-71 O - 19.1 9.3 2.6 0.4

11-72 5 - 7.8 3 .8 11.8 0.1

II-73 10 - 15.6 7.6 23.7 0.2

“-74 15 - 15.2 8.1 26.5 Trace

Benzene “-75 20 - 14.9 8.5 29.2 -
11-76 25 - 13.1 9.2 29.8 -

lI-77 30 — 1 1.3 9.8 30.3 -

“-78 35 - 8.9 9.4 30.8 -

k “-79 40 - 6.6 9.1 31.2 -
11-80 0 0.2 19.6 35 68.9 -

II-81 5 - l 1.6 4.7 55.2 -

II-82 10 - 13.6 6.3 41.1 -

11-83 15 - 13.7 6.2 39.2 -

EtOAc 11-84 20 - 13.8 6.2 37.2 -
Il-85 25 - 14.2 6.1 36.1 -

Il-86 30 - 14.6 6.1 35.2 -

lI-87 35 - 9.4 8.2 34.4 -
x “-88 40 - 4.1 10.5 33.4 -
11-89 0 - 19.1 9.3 2.6 0.4

11-90 5 - 7 .8 3 .8 11.8 0.1

II-91 10 - 15.6 7.6 23.7 0.1

lI-92 15 — 15.2 8.1 265 Trace

DCM 11-93 20 - 14.9 85 29.2 -
11-94 25 - 13.1 9.2 29.8 -

“-95 30 - 1 1.3 9.8 30.3 -

II-96 35 - 9.0 9.4 30.8 -
\ Il-97 40 - 6.6 9.1 31.2 -

 

All reactions were carried out with 0.1 mmol of substrate, 1 mol% 0804, 5 equiv

30% H202 (aq), X equiv of DMF, Solvent (0.1M), 0.05 mmol of Pentadecane (ISTD).

C Yields. The a-hydroxyketone product was not analyzed for this data set but did
EIke-up a significant portion of the spectra.

41

0304, (0.01 equiv)

w 50% H202 (5 equiv)

 

"-37

Table II-6. Additive Test for l-Decene

 

 

>
"-32 DMF (X equiv), 2411 OH OH O
Solvent (0.1 M), 4°C \H/‘V \HJLOH
Pentadecane (0.5 equiv) 7 7
"-35
¥ Nonanoic 1 ,2- l-hydroxy-
Entry Additive (eq.) 3:32: 21:11:33? Acid Decanediol 2-decanone
__ (II-33) (II-35) (II-36)
"-98 Acetic Acid (1) - 2.6 2.6 31.9 395
lI-99 Acetic Acid (5) - 5.1 5.1 72.6 20.4
ll-100 HCl (1) - 2.8 2.8 39.2 18.3
Il-lOl HCI (5) - 0.8 0.8 44.9 7 .2
lI-102 H2504 (1) - 2.0 2.0 14.2 12.9
II-103 H2504 (5) - 0.8 0.8 5.0 3.8
II-104 Na2C03 (1) 59.0 2.8 - - 34.2
II-105 Na2C03 (5) 71.9 2.2 - - 29.9
“-106 151ch03 (1) 24.0 5 .0 - 8 .3 51 .6
II-10‘7 Nch03 (5) 25.8 4.3 - 7.8 52.5
11-108 Pyridine (1) 2.3 11.1 - 22.3 69.0
N Pyridine (5) 35.6 4.7 - 10.8 53.7

 

mass balance.

Order alkyl olefins were used and yield of diol decreased to minimum and the yield of
cleavage product increased to an acceptable range (40-90%). Table II-7 shows the

Qleavage results for the four olefins (cis-6-dodecene [CiS], trans-S-decene [Trans], 5-

methylenenonane [1,1 Disub], and 2-methyl-2—unadecene [Tri]).

42

All reactions were carried out with 0.1 mmol of substrate, 1 mol% 0304, 5 equiv
30% H202 (aq). 20 equiv of DMF, MeOH (0.1M), Additve (1 or 5 equiv) 0.05 mmol of
entadecane (ISTD). GC Yields. Unidentified peaks in the spectra would complete a

Only after a change of substrate did the cleavage reaction succeed. Four higher

Table II-7. Alkyl Substrates for Oxidative Cleavage
No DMF 0.1 eq. DMF 20 eq. DMF
Entry Olefin %Ald(Acid) %Ald(Acid) %Ald(Acid)

m
Cis—6-Dodecene 34.1 (0.0) 33 .0 (0 .0) 38.4 (0.0)
“-110

II-ll4

WW
lrans-S-Decene 38.8 (5.2) 41.9 (2.6) 51.7 (2.6)
II-lll

\/\/u\/\/

5-Methylenenonane 65 .1 * 75 .2* 89 .2*
II-112

W
2-Methyl-2-Unadecene 65.5 (2.1) 72.0 (2.7) 64.1 (0.8)
II-113
All reactions were carried out with 0.1 mmol of substrate, 1 mol% 0804, 4 equiv
30% 11202 (aq). X equiv of DMF, ACN (0.1M) and 0.05 mmol of Tetraglym (ISTD).

GC Yields. *Yields are of 5-nonanone.

II—llS

II-ll6

II- 1 17

g

The major by-products for the cis and trans disubstituted olefins and the
triSubstituted olefin were the a-hydroxy-ketone (20-30%) while the diol formation had
been severely inhibited. This trend changed when going to the 1,1 disubstituted olefin

with only a minimal amount of the a-hydroxy aldehyde being observed by GC. The 01-

h3'dl‘oxy aldehyde could be cleaved by a Baeyer-Villiger type mechanism (similar to II-

23) . which could explain the higher yield of the cleavage product for the 1,1 disubstituted
product (Table 11-7).

The formation of the by-product was examined further in order to inhibit their

f0 l"I‘nation. Samples of the a-hydroxy carbonyl and diol were obtained by the addition of

by“ dine (0.1 eq.) to the normal reaction conditions (Scheme lI-5). The diol was also

0
btai ned from the UpJohn procedure.17 This process was done for all four substrates.

43

Scheme “-5. Cleavage of Cis-6-Dodecene

HO O

"-11 8

— 0304 (0.01 equiv) 28 8%
fl 50% H202 (3“) (7.3 equiv) '
>
"-110 Pyridine (0.1 equiv) HO OH

Me0H (0.1 M), RT, 24H

 

Caproic Aldehyde was observed “-119
by GC and TLC but not isolated. 14.0%

Pyridine and acetic acid were then added to the normal reaction (varying in DMF
concentration) conditions at 0.1, 0.5, 1, and 5 equivalents (each reaction was done in
triplicate and averaged) but again only proved to inhibit the reaction or favor one of the
by-products (diol or a-hydroxy ketone) (Fables II-8, 9, 10, & 11). The cleavage product
obtained from the addition of pyridine was the carboxylic acid. It was postulated that the

N-oxide was formed in the presence of osmium tetroxide and hydrogen peroxide.

Table II-8. Cis-6-Dodecene Cleavage with Acetic Acid and Pyridine

0304 (0.01 equiv)

— 50% H202 (aq) (7.3 equiv) 0
» /\/\/u\
/—/—/—L\—\ Additive (0, 0.1, 0.5, or 5 equiv), H
"-110 DMF (0. 0.1. or 20) "-120

MeOH (0.1 M), RT, 24h

 

 

 

\ rb
0.1 eq. DM 20 eq. DMFC
Entry Additive (9(1) (7 HNegalimicid) % Hexanal % Hexanal
\ 0 (Acid) (Acid)
11-121 None 38.9 (5 .2) 41.9 (2.6) 51.7 (2 .6)
11-122 Pyridine (0.1 eq.) 38.2 (6.1) 42.0 (2.6) 48.0 (2.6)
11123 Pyridine (0.5 eq.) 8.6 (17.3) 21.3 (8.5) 18.9 (11.8)

44

"-124
”-125
"-126
“-127
II-128
Il-129

Pyridine (1.0 eq.)
Pyridine (5 eq.)
Acetic Acid (0.1 eq.)
Acetic Acid (05 eq.)
Acetic Acid (1.0 eq.)
Acetic Acid (5 eq.)

Table II-8. Continued

4.0 (15.6)
0.0 (12.9)
36.4 (2.6)
47 .7(2 .6)
45.8 (2.6)
39.6 (2.6)

5.8 (17.7)
0.2 (12.9)
42.5 (2.6)
48.4 (2.6)
46.4 (2.6)
noam

8.9 (15.9)
1.1 (13.3)
50.0 (2.6)
552 (2.6)
58.2 (2.6)
54.1 (2.6)

 

GC Yields (ISTD = Tetraglyme), Reactions were done in triplicate and averaged.

“(e 4% except 11-126, +/- 8%) “(e 2%) °(= 5%, except 11423 +/— 14%) By-products
include diol and a-hydroxy ketone.

Table “-9. 5-Methylenenonane Cleavage with Acetic Acid and Pyridine

0304 (0.01 equiv)
50% H202 (aq) (7.3 equiv) o
4’

V\/u\/V Additive (0, 0.1, 0.5, or 5 equiv), \NK/v

"-112 DMF (0. 0.1. or 20) "-130
MeOH (0.1M), RT, 24h

 

‘

 

 

b

EMU Additive (eq.) No DMF“ 0.2 eq. DMF 20 eq. DMFc

\ % Nonanone % Nonanone % Nonanone
11-131 None 65.1 75 .2 89.2
11-132 Pyridine (0.1 eq.) 70.4 74.1 81.3
II-133 Pyridine (05 eq.) 53.0 56.3 59.2
II-134 Pyridine (1.0 eq.) 41.8 43.1 47.1
“-135 Pyridine (5 eq.) 21.2 21.6 23.0
11-136 Acetic Acid (0.1 eq.) 66.2 70.4 80.2
11-137 Acetic Acid (05 eq.) 53.3 55.9 65.7
“-138 Acetic Acid (1.0 eq.) 47 .9 48.2 59.9
“-139 Acetic Acid (5 eq.) 35.6 34.3 44.8

\

 

GC Yields (ISTD: Tetraglymce), Reactions were done in triplicate and averaged.
ah: 2% except II- 133 8%). b(:1: 6%). c(:1: 7%) By-products include diol and minimal 01-
hYdroxy aldehyde.

45

Table II-10. Trans-S-Decene Cleavage with Acetic Acid and Pyridine

0304 (0.01 equiv)

 

\ 50% H202 (aq) (7.3 equiv) o
\/\/\/\/\ >
Additive (0, 0.1, 0.5, or 5 equiv), WLH
II-111 DMF (0. 0.1. or 20) "-140

MeOH (0.1 M), RT, 24h

 

No DMFa 0.3 eq. DMFb 20 eq. DMF“

 

’i Entry Additive (eq.) % Pentanal % Pentanal % Pentanal
11-141 None 34.1 33.0 38.4
“-142 Pyridine (0.1 eq.) 33.4 27 .0 33.6
“-143 Pyridine (05 eq.) 195 15.6 13.2
“-144 Pyridine (1.0 eq.) 7.1 6.6 8.0
II-145 Pyridine (5 eq.) 0.9 1.0 1.6
II-l46 Acetic Acid (0.1 eq.) 335 31.8 33.0
II-l47 Acetic Acid (05 eq.) 36.8 31.2 33.8
II-l48 Acetic Acid (1.0 eq.) 37.7 32.3 34.5
II-l49 Acetic Acid (5 eq.) 35.5 31.1 35.4

 

GC Yields (ISTD = Tetraglyme), Reactions were done in triplicate and averaged.
“(a 35% except 111-143 10%). b(: 4%). °(a 4% except 111-149 10%). Acid yield was
not determined but was present in the pyridine reactions. By-products include diol and 01-
hYdroxy ketone.

Table II-ll. 2-Methyl-2-Unadecene Cleavage with Acetic Acid and Pyridine
0304 (0.01 equiv)
50% H202 (aq) (7.3 equiv) 0
W } WH
Additive (O, 0.1, 0.5, or 5 equiv),
"-113 DMF (0. 0-1. or 20) "-34
MeOH (0.1M), RT, 24h

 

 

 

\
0.4 eq. DMFb 20 eq. DMFc
E . .
ntry Additive (3C1 -) (7 Niza2211(FAaci d) % Nonanal % Nonanal
TI-15\ 0 (Acid) (Acid)
0 None 65 .5 (2.1) 72.0 (2.4) 64.1 (0.8)
46

LA

Table II-ll. Continued

lI-lSl Pyridine (0.1 eq.) 70.9 (1.7) 65.4 (2.0) 64.0 (0.8)
11-152 Pyridine (0.5 eq.) 59.7 (2.8) 25.3. (5.1) 31.7 (3.2)
“-153 Pyridine (1.0 eq.) 14.3 (2.4) 10.4 (10.8) 11.2 (9.8)
“-154 Pyridine (5 eq.) 0.9 (9.6) 0.7 (9.4) 1.4 (13.3)
Il-155 Acetic Acid (0.1 eq.) 67.1 (2.0) 57.9 (2.5) 56.4 (0.8)
“-156 Acetic Acid (0.5 eq.) 625 (2.8) 59.9 (3.7) 60.1 (0.9)
11-157 Acetic Acid (1.0 eq.) 615 (3.3) 58.8 (4.1) 58.6 (0.8)
lI-158 Acetic Acid (5 eq.) 47 .4. (5 .8) 39.3 (5 .4) 345 (1 .6)

 

*—

GC Yields (ISTD = Tetraglyme), Reactions were done in triplicate and averaged.
a(:1: 4% except “-155, 13%). b(:: 4% except II-lSl, 6% and II-152, 20%). c(:: 4% except
II-152, 20%) By-products include diol and a-hydroxy ketone.

Despite the low yields for the cleavage products these two additives did have an

effect on the formation of by-products. Since a standard curve for the diol and 01-
hydroxy carbonyl was not done, the peak area ratios were compared (the peak area of the
substrate divided by the ISTD peak area). This did not give a percent yield but a percent
conversion could be calculated. The results of this comparison are Shown in Charts 11-2-
13 (Py. = Pyridine and Ac. = Acetic Acid). In all case, trace amounts of epoxide was
observed. The profiles of each chart suggest that the addition of ‘ pyridine or acetic acid to
the reaction inhibits formation of the a-hydroxy carbonyl in favor of the diol. The only
exception in this trend was the 1,1-disubstituted substrate, which forms an a-hydroxy
aldehyde instead of an a-hydroxy ketone. The amount of DMF did not have a great effect

on the by -products.

47

Chart II-2. Cis-6-Dodecene Product Ratios with No DMF

' Hexanal
I Hexanoic Acid
' alpha-Hydroxy
' l l ' Diol
1

None Py. Py. Py. Py. Ac. Ac. Ac. Ac.
(0.1) (0.5) (1) (5) (0.1) (0.5) (1) (5)

2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0

 

Chart II-3. C is-6-Dodecene Product Ratios with 0.1 equiv DMF
2.0

' Hexanal
' Hexanoic Acid
' alpha-Hydroxy
' Diol

0. 0

None Py. Py. Py. Ac. Ac. Ac. Ac.
(01) (05) (1) (5) (0-1) (0-5) (1) (5)

   

48

Chart II-4. C is-6-Dodecene Product Ratios with 20 equiv DMF

 

2.0
1.8
1.6
1.4
1.2
1 0 'Hexanal
' ' Hexanoic Acid
0'8 ' alpha-Hydroxy
0.6 'Diol
0.4
0.2
0.0
None Py. Py. Ac. Ac. Ac. Ac.
(01) (0 5) (1y) (5) (0-1) (0-5) (1) (5)
Chart II-S. Trans-S-Decene Product Ratios with No DMF
1.8

1 0 ' Valeraldehyde
' Valeric Acid
' alpha-hydroxy
' Diol
0. 0

None Py Py Py ((51)Py Ac Ac Ac (1 Ac (5
(01) (05) )0-( 1)(0.5)

49

Chart II-6. Trans-S-Decene Product Ratios with 0.1 equiv DMF
1.8

1 6
1 4
1 2
1 ° ' - Valeraldehyde
o 3 ' Valerie Acid
' alpha-hydroxy

O 6 ' Diol
0 4
0 2

0

None Py Py Py(1)Py(5) Ac Ac Ac (1 Ac (5
(0.1) (0.5) (0.1) (O. 5)

Chart II-7. Trans-S-Decene Product Ratios with 20 equiv DMF
1.8

' Valeraldehyde
' Valeric Acid
' alpha-hydroxy
' Diol

O o E ..

None Py Py Py(1)Py(5) Ac Ac Ac (1 Ac (5)
(01) (05) (01) (0 5)

 

   

50

Chart II-8. 5-Methylenenonane Product Ratios with No DMF
2.5

2.0 '
1.5 .
I'5-M--Nonane
'5-Nonanone
1'0 ‘ 'Diol
' alpha-Hydroxy
0.5
0.0 «

None Py Py Py Py Ac Ac Ac Ac
(0.1) (0.5) (1) (5) (0.1) (0.5) (1) (5)

 

Chart II-9. 5-Methylenenonane Product Ratios with 0.1 equiv DMF
2.5

2.0

1

' S-M-Nonane
' 5-Nonanone
1 '0 ' ' Diol
' alpha-Hydroxy
O. 5 -
0. 0

None Py Py Py Py Ac Ac Ac Ac
(0.1) (0.5) (1) (5) (0.1) (0.5) (1) (5)

01

51

 

 

 

 

Chart II-10. 5-Methylenenonane Product Ratios with 20 equiv DMF
3.0

2.5

2.0

1 5 . 'S-M-Nonane

' '5-Nonanone
10 ‘ lDiol

' ' alpha-Hydroxy
0.5 '

0.0
None Py Py Py Py Ac Ac Ac Ac
(0.1) (0.5) (1) (5) (0.1) (0.5) (1) (5)
Chart II-ll. 2-Methyl-2-Unadecene Product Ratios with No DMF
1.8

1.6
1.4
1.2

1 '0 ' Nonanal
' Nonanoic Acid
_ .
0.6 010|
' alpha-Hydroxy

0.4

0.8

0.2

     

0.0

None Py Py Py Py Ac Ac Ac Ac
(0.1) (0.5) (1) (5) (0.1) (0.5) (1) (5)

52

Chart II-12. 2-Methyl-2-Unadecene Product Ratios with 0.1 equiv DMF
1.8

1.6
1.4
1.2

1 '0 ' Nonanal

o_3 ' Nonanoic Acid
0 6 ' Diol

' ' alpha-Hydroxy
0.4
0.2 '
0.0

None Py Py Py Py Ac Ac Ac Ac
(0.1) (0.5) (1) (5) (0.1) (0.5) (1) (5)

       

Chart II-13. 2-Methyl-2-Unadecene Product Ratios with 20 equiv DMF

' Nonanal

' Nonanoic Acid
' Diol

' alpha-Hydroxy

None Py Ac Ac Ac Ac
(01) (05) (P1) (5) (01) (05) (1) (5)

53

As mentioned previously the addition of pyridine favored the over oxidized
cleavage product. The carboxylic acid was thought to be from the formation of the N-
oxide, which can be formed from the amine and hydrogen peroxide. This oxidation has
been observed with Pt catalysts but is not reported with OS.'8 Scheme H-6 shows the
control test. Interestingly the oxidation only occurred in the presence of osmium
tetroxide, hydrogen peroxide, and pyridine. The N-oxide is still the likely oxidizer but its
formation must be from the osmium tetroxide and hydrogen peroxide. Literature
examples Show that amine can be oxidized to the N-oxide in the presence of certain
metals (ex. Pt) and hydrogen peroxide.'8“°

The a-hydroxy carbonyl product has been a common by-product when using
osmium tetroxide and peroxide co-oxidants. Lohray has proposed a mechanism for the

a-hydroxy carbonylm' He proposed that the osmium bisglycolate ester was an

intermediate for the a-hydroxy carbonyl formation because in an asymmetric reaction no

Scheme II-6. Control Experiments for Aldehyde Oxidation

 

 

 

50°/o H202 (7.3 BQUiV)
0 Pyridine (5 equiv)
W H MeOH (0.2M), 24 H OH
Tetraglyme (0.5 equiv)
0804 (001 equiv) NO OXidation By GC
0 50% H202 (7.3 equiv) 0
M/lL ’
H Pyridine (5 equiv) 0”
MeOH (02er 24 H Near Complete
Tetraglyme (0.5 equiv) Oxidation By GC
0304 (0.01 equiv)
0 50% H202 (7.3 equiv)
W
H MeOH (0.2M), 24 H 01"
Tetraglyme (0.5 equiv)

No Oxidation By 60

54

ee was observed for the oi-hydroxy carbonyl product. Lohray proposed that the osmium
bisglycoate ester (II-159) is protonated (II-160), and then one of the hydroxyl groups is
replaced by the peroxide (his work used t-BuOOH). Then either through a radical cage
reaction (II-163) or deprotonation the a-hydroxy carbonyl is formed (II-162 & 162)

(Scheme “-7).

Scheme II-7. Lohray’s a-Hydroxy Carbonyl Mechanism

:IO/Ob 0033/0 ::0”3::

 

     

   
   

 

 

 

 

 

 

 

 

"-159 "-160
t-Bu00H
[0] 0
( H
0H
OH
R R o o R
I%£=k fig:
R O \O R 0 g H F1
"-161 O "' 62 \(PJ
tBu
V RJKf
[- - 0H
0H
RIO\ I /O R .
’03 OH R
R 0 go Fl :I:\o l /0
° {ll/H IOCIDISO
tBu
Solvent Cage "-164
"-163

Cleavage of alkyl olefins was not dependent on water being present in the
reaction. Ethereal hydrogen peroxide was used under anhydrous conditions and the
reaction proceeded, but in lower yields (previous solvent tests showed that ether pushed

the reaction toward diol formation). The reaction rate seemed to be slowed by the

anhydrous conditions because starting material was observed when no water was present

55

(1.71.

In", ‘

n‘ I
Inlm

ail.

Willi”

during the reaction (Table Il-12). The GC yields of cleavage product did not greatly
improve as equivalents of water were added, but when run in larger scale (1 mmol) under
the anhydrous conditions the yields of the a-hydroxy product increased (~35% for the cis
and the trisubstituted olefin and isolation of the a-hydroxy aldehyde from the 1,1
disubstituted olefin). Diol formation was also increased when water was added. These
results suggest that water is not essential for cleavage reaction to occur but if water is not

present then the reaction is slowed or formation of the a-hydroxy carbonyl product

 

 

increases.
Table II-12. Cleavage with Ethereal Hydrogen Peroxide
0304 (0.01 equiv), 24H

92 Ethereal H202 (7.3 equiv) R2

)VRS A
R1 Water (0, 14, 28 equiv) R1 0

DMF (20 equiv), MeOH (0.1 M)
Entry Substrate No H20 14 eq. of H20 28 eq. H20

% Aldehyde % Aldehyde % Aldehyde

 

441:1).—

. 43.9 33.7 32.3
czs-6—Dodecene (t 37 ) (z 27) (:1: 17)
11-165 (R1 = H, R2 & R, = pentyl) ° ° 0
II-110
MM
trans-S-Decene 25 .3 - 28 .7 3 1 .2
11-166 (R2 = H, Rl & R3 = butyl) (:1: 2%) (:1: 1%) (:1: 2%)
II-lll
\/\/U\/\/ a a a
5—Methylenenonane 40'8 41 '7 41 '2
11-167 (R, = H, Rl & R2 = butyl) (t 3%) Gt 1) (a: 1%)
II-112
W
50.6 48.8 49.7
2-Methyl-2-Undecene (:1; 2%) (:1: 1%) (:1: 2%)

11-168 (R1 = CH3, R2 = 0CD", R3 = H)
II-ll3

56

ll-ltli

'- 1 F.
' l"

TWL.,

ui,'.‘

‘l-.‘V
‘ . .

."-u.

in.;

‘1‘“

‘ I
IA‘;1

r'iiuq

 

‘;l:"i
\ I
5‘. ~

3
fit.

‘~‘

01.5 .‘

‘5 .
a“

Table II-12. Continued

 

W

l—Decene 17'9 207 21.6
"-169 (R1 & R, = H, R, =octyl) (* 1%) (t 1%) (i 1%)
11-32

 

All reactions were carried out in triplicate and averaged with 0.1 mmol of
substrate, 1 mol% 0304, 7.3 equiv of ethereal H202, 20 equiv of DMF, MeOH (0.1M)
and 0.05 mmols of Tetraglyme (ISTD). All yields are GC yields. aYields are of 5-
nonanone.

2.4 Urea Hydrogen Peroxide as the Cooxident

Urea peroxide showed interesting results. The cleavage product was not obtained
in very high yield for the cis, trans, and mono substituted olefins (IO-20%), but the major
product of the reaction was the a-hydroxy ketone (30-50%). The 1,1-disubstituted
substrate did provide a small amount of a-hydroxy aldehyde (the only time it was
isolated) and cleavage was still the major product (55%). The trisubstituted olefin
yielded cleavage and the a-hydroxy ketone in similar amounts (25%-35% each). We
postulated that the more stable osmate ester leads to the higher yields of cleavage
products in the trisubstituted olefin and the propensity of the a-hydroxy aldehyde to
undergo Baeyer-Villiger type cleavage leads to the high yield of the cleavage product in
the 1,1 disubstituted olefin.

The large amount of a-hydroxy carbonyl present in these experiments and the
small amount of diol present suggested that urea hydrogen peroxide could be a viable
alternative as a co—oxidant. In an attempt to improve the yield of cleavage product,
anhydrous reactions were attempted in the same fashion as the ethereal hydrogen
peroxide experiments. Unfortunately, adjusting the amount of water in the reaction had

no effect on the yield of the reaction nor did the amount of DMF present (Tables “-13,

57

14, 15, 16, & 17). The trisubstituted and the 1,1-disubstituted substrates showed that the
cleavage product as the the major peak while the other three substrates yielded a-hydroxy
carbonyl as their major product with only diol as the only other significant peak. These
experiments showed that water must play a role in the cleavage reaction but the formation
of the ot-hydroxy ketone is unaffected. The use of urea hydrogen peroxide was an

adequate way to form the a-hydroxy ketone.

Table 1143. Urea Hydrogen Peroxide, Water, and DMF Test for Cis-6-Dodecene

0304 (0.01 equiv)

_ Urea H202 (7.3 equiv) o
> WL
Water (0, 25, 50 pl) H

DMF (0, 0.1, 20 equiv)

 

 

 

""10 MeOH (0.1 M), RT, 24h ""2"
En Water [11L No DMF 0.1 equiv DMF 20 equiv DMF
try (equiv)] % Hexanal (Acid) % Hexanal (Acid) % Hexanal (Acid)
“-170 None 28 .6 (2.6) 26.1 (2.6) 325 (122)
“-171 25 (13.9) 27.8 (2.6) ' 25.5 (2.6) 29.3 (10.1)
II-l72 50 (27 .8) 25 .5 (2.6) 24.5 (2.6) 29.6 (9.7)

 

All reactions were done on a 0.1 mmol scale. GC yields (ISTD =Tetraglyme).
Reactions were done in triplicate and average (:1: 4%). .

II-14. Urea Hydrogen Peroxide, Water, and DMF Test for Trans-S-Decene

0804 (0.01 OQUlV)
Urea H202 (7.3 equiv) o

 

 

W >
Water (0, 25, 50 pl) WLH
DMF (0, 0.1, 20 equiv)
"'111 MeOH (0.1 M), RT, 24h ""40
Entry Water [11L No DMF 0.2 equiv DMF 20 equiv DMF
(equiv)] % Pentanal % Pentanal % Pentanal

 

II-l73 None 25 .0 21 .6 36.7

58

Table II-l4. Continued
II-l74 25 (13.9) 26.0 22.7 35.4
“-175 50 (27.8) 24.2 23.1 35.8

 

All reactions were done on a 0.1 mmol scale. GC yields (ISTD =Tetraglyme).
Reactions were done in triplicate and averaged (:l: 4%).

II-15. Urea Hydrogen Peroxide, Water, and DMF Test for 5-Methylenenonane

0304 (0.01 equiv)

Urea H202 (7.3 equiv) 0
\/\/H\/\/ > W

Water (0, 25, 50 til)
"-1 12 DMF (O, 0.1, 20 equiv) "-130
MeOH (0.1 M), RT, 24h

 

 

 

En Water [11L No DMF 0.3 equiv DMF 20 equiv DMF
try (equiv)] % Nonanone % Nonanone % Nonanone
II-l76 . None 51.4 48.2 60.0
II-l77 25 (13.9) 51.3 51.1 58.2
“-178 50 (27 .8) 50.4 53.7 57.1

 

All reactions were done on a 0.1 mmol scale. GC yields (ISTD =Tetraglyme).
Reactions were done in triplicate and averaged (:1: 4%).
II-l6. Urea Hydrogen Peroxide, Water, and DMF Test for 2-Methyl-2-Unadecene
0304 (0.01 equiv)
W Urea H202 (7.3 equiv) o
/ > ML
Water (0, 25, 50 111) H

DMF (0, 0.1, 20 equiv)

 

 

 

“"13 MeOH (0.1 M), RT, 24H "'34
Tin Water [uL No DMF 0.4 equiv DMF 20 equiv DMF
__ try (equiv)] % Nonanal % Nonanal % Nonanal
Il-l79 None 31.0 28 .5 28.5
“-180 25 (13.9) 31.3 28 .5 27.8
II-181 50 (27.8) 31.9 27 .8 28 .5

 

All reactions were done on a 0.1 mmol scale. GC yields (ISTD =Tetraglyme).
Reactions were done in triplicate and average (:1: 4%).

59

II-l7. Urea Hydrogen Peroxide, Water, and DMF Test for l—Decene

0304 (0.01 equiv)

 

Urea H202 (7.3 equiv) 0
MW ) W\/\/u\
Water (0, 25, 50 111) H
"-32 DMF (0, 0.1, 20 EQUIV) "_34

MeOH (0.1M), RT, 24h

 

 

En Water [ML No DMF 0.5 equiv DMF 20 equiv DMF
try (equiv)] % Nonanal % Nonanal % Nonanal
II-l82 None 13.0 (3 .9) 12.6 (4.4) 15.8 (9.2)
“-183 25 (13.9) 12.0 (4.0) 122 (4.3) 16.7 (6.8)
“-184 50 (27 .8) 10.9 (4.2 11.4 (4.2) 16.7 (7 .0)

 

All reactions were done on a 0.1 mmol scale. GC yields (ISTD =Tetraglyme).
Reactions were done in triplicate and average (:l: 4%).

2.5 Conclusion

This chapter has detailed a procedure for the green cleavage of a variety of
olefins. The aryl olefins cleave in high yields for electron-rich and electron-neutral
olefins, but poor to moderate yields for electron-poor olefins. The alkyl olefins have
proved to be more difficult. Monosubstituted olefins are very poor for this reaction while
cis and trans olefins cleave in moderate yields. The trisubstituted and 1,1 disubstituted
both cleaved in high yields. It was found that 50% aqueous hydrogen peroxide proved to
be the best source of hydrogen peroxide, while ethereal hydrogen peroxide lowered the
yields suggesting that water plays an unknown role in the mechanism. Urea peroxide
provided mainly the a-hydroxy product. The subsequent chapter Shall examine the

mechanism for this reaction with Oxone.

60

2.6 Experimental Details
All commercially available starting materials were used without further
purification. Commercially available starting materials were purchased from Aldrich and

Strem. All of the spectral data for known compound either match those reported by

Aldrich or by comparison to the literature report. 1H, 13C, gCOSY, gHMBC, HMQC,

DEPT, and nOe Spectra were recorded on either a 300 MHz NMR spectrometer
(VARIAN INOVA) or on a 500 MHz Spectrometer (VARIAN VXR). Column

chromatography was performed using SIlicycle (40-60mm) silica gel. Analytical TLC

was done using pre-coated Silica gel 60 F254 plates. GC analysis was preformed using

HP (6890 or 6950 Series) GC system.

Gas Chromatography Method:

An Agilant Technologies 6850 Series 11 Network GC System equipped with an
Agilant Tech. 6850 Series 11 Auto sampler was used for analysis. The column used for
all experiments was an Agilant Tech. J&W Scientific High Resolution Gas
Chromatography Column (190912-413E HP-l) with specifications: Length (m.) 30,
1.D.(mm) = 0.32 widebore, Film (um) = 0.25, and temperature limits = -60 °C to 325 °C
(350 °C). Method: Injection Temp. = 250 °C, Detector Temp. = 250 °C, Makeup gas =
Helium, Mode = Constant Pressure, Detector Temp. = 250 °C, Ramp = 60 °C for 2 min.
then ramped at 10 °C/min. until 300 °C then hold for 5 min.

General Procedure for the Preparation of Standard Curves

Stock solutions of the starting materials, by-products, and internal standard

(ISTD) were made (ranging from 1.0 to 0.1 M depending on solubility). All reaction

61

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were done on 0.1 mmole scale so 0.05 mmoles of ISTD was used for 2:] substrate to
ISTD ratio. In each vial 0.05 mmoles of ISTD was added followed by varying amounts
(covering the range of the reaction = 0.01, 0.02, 0.03,. . ., 0.12 mmoles) of starting
material or by-product. The total volume was taken to 1 mL and injected into the GC.

The peak area ratio (X/ISTD) was then calculated and a line was applied to fit the data.

The R2 values were always greater than 0.990 or the curve was not used.

Standard GC Reaction Conditions

Stock solutions of the substrate were made (ranging from 0.5 to 2.5 M depending
on solubility) and internal standard (ISTD)[either tetraethylene glycol dimethyl ether
(tetraglyme), pentadecane, or dodecane] were made. Then, 0.1 mmoles of substrate were
aliquoted into a 35 mL GC vial followed by 0.05 mmoles of lsTD (a substrate to ISTD

ratio of 4:1). The vials were diluted to 1 mL of solvent and any additives (DMF, Acetic

Acid, Pyridine, etc.) were added. Then, 0.01 eq. (5 ML) of OSO4 (l g/20 mL toluene

solution) was added and stirred for 5 minutes. Depending on substrate and solvent the

solution could or could not darken (indicative of osmium (V 1)). Either 4, 5, or 7.3 eq. of

30%, 50% H202 (aq.), ethereal H202 or urea H202 were added. The solutions were

stirred overnight, after which they were injected into the GC. The Spectra were compared
with a standard curve for analysis.
Purchased Chemicals
Chemicals purchased from Aldrich; Styrene (II-l3), (5)-Stilbene (II-l4), Methyl
Cinnamate (II-15), trans-Cinnamic Acid (II-l6), Methyl-a-Methyl Cinnamate (II-l7),

trans~Cinnamaldehyde (II-18), Cinnamyl Acetate (II-19), Cinnamyl Alcohol (II-20), 01-

62

$3612:

a
l
,u...
l

1111 Ill Ill. ”U H Ill: Ill. . - H. ill] .Illl. [11 l l
it . - l- i
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Methyl Styrene (II-21), trans-Dibenzoylethylene (II-22), a-Vinylbenzyl Alcohol (II-23),

l-Decene (II-42), Tetraglym, Pentadecane, dodecane.

Data for Entries II-l3 thru II-20

Standard GC reaction conditions were used. Single injections only.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Peak Areas for Styrene
Entry Solvent Benzaldehyde Benzoic Styrene Dodecane
Acid
“-13 Benzene 790 77 0 1847
II-l4 DMF 977 219 0 1846
“-15 ACN 835 192 0 1769
II-l6 MeOH 992 96 0 2294
II-l7 EtOH 752 65 0. 1935
II-18 3,0 1 17 3 156 4 2904
II-19 DCM 552 56 0 2215
Il-20 Cl-lCl2 507 52 0 2310
Peak Areas for Methyl Trans Cinnimate
Entry Solvent Benzaldehyde Benzoic Methyl Dodecane
Acid Cinnimate
II-13 Benzene 1550 172 176 2168
II-l4 DMF 988 84 605 1530
II-15 ACN 1776 18 30 1437
II-16 MeOH 1566 174 442 1928
II-17 EtOH 1472 l 16 217 2136
II-l8 Et20 814 84 1656 3147
II-19 DCM 1571 207 45 1872
II-20 CHCl2 1553 127 1 85 2281

 

 

 

 

 

 

 

Standard Curves Slopes: Benzaldehyde (y = 95435x — 0.0083) Benzoic Acid (Y

= 10.0585x - 0.0315), Styrene (y = 13.7110x — 0.0454), Methyl Cinnimate (y = 13.989x -—

0.0152)

All reaction were run under inert atmosphere (nitrogen) unless otherwise noted.

Synthesis of 1,2-Decanediol and l-I-Iydroxy-Z-Decanone22

63

 

 

l-Decene (1 mmol, 140.27 mg) of was dissolved in ACN (10mL, 1 M) and DMF

(20 equiv, 1.5 mL). Then, 0304 (0.01 equiv, 50 ML) (1 g/20 mL toluene solution) was

added and stirred for five minutes. Urea peroxide (5 equiv, 479.4 mg) was added and
stirred overnight. The reaction was quenched with a saturated sodium sulfite solution and
then extracted (3X) with EtOAc and the extracted (3X) with water to yield an oil. A
column was run in 20% EtOAc and hexanes and yielded two fractions. Fraction 1 was

the a-hydroxyketone in 54.9% yield (94.5 mg) and fraction 2 was 1,2-decanediol in

18.6% yield (32.4 mg) which matched the Spectra from Aldrich. a-hydroxyketone 1H

NMR: (CDC13; 300 MHz): 5 4.24 (d, 1 H), 3.10 (t, 1H), 2.40 (t, 2H), 1.63 (pentet, 2H),
1.26 (m, 10H), 0.86 (t, 6H). LRMS (m/z): 172.1 (1%), 141.0 (60%), 71.0 (75%), 57.0
(100%); Diol 1H NMR: (CDCl3; 300 MHz): 6 3.66 (dd, 2H), 3.42 (q, 1H), 1.99 (broad,
2H), 1.40 (m, 12H), 0.85 (t, 3H)

Synthesis of Cis-6-Dodecene (II-102)

Hexyl triphenylphosphonium bromide (1 mmol, 427.36 mg., 1 eq.) was dissolved
in dry THF at 0°C. n-Butyllithium (1.2 equiv of a 2.5 M in hexanes solution) was added
dr0pwise and the solution tumed a dark red color. The solution was stirred for 1 hour at
0°C. Hexanal (1.2 equiv, 103.4 mg) was added dropwise and the mixture stirred

overnight. The solution was extracted (3X) with water (100 mL). A column was run in

5% EtOAc/hexanes to purify the olefin as an oil. This yielded 101.5 mg of the olefin in

60.3 % yield which matched literature spectra.23 1H NMR (CDCl3; 300 MHz): 6 5.32 (m,

2H), 2.01 (m, 4H), 1.24 (m, 12H), 0.87 (t, 6H). l3C NMR(CDC13; 300 MHz): 6 129.88,

31.55, 29.47, 27.17, 22.59, 14.03.

Synthesis of 6,7 -Dodecanediol24 and 7 -hydr0111y-6-Dodecanone23

cis-6-Dodecene (2 mmol, 336 mg) was dissolved in MeOH (0.1M, 20 mL).
Pyridine (0.1 equiv, 15.8 mg) was added followed by Os04 (0.01 equiv, 100 111) (1
gJ20mL toluene solution) was added and stirred for five minutes. Then, 50% hydrogen
peroxide (7.3 equiv, 500 ML) of was added and stirred overnight. The solution was
quenched with saturated sodium sulfite and the aqueous layer extracted (3X) with EtOAc.
The combined organic layers were washed (1X) with water and brine. The solvent was
removed under reduced pressure to yield an oil. A column (20% EtOAc/Hexanes)

yielded two fractions (F1 = 7-hydroxy-6-dodecanone [102.6 mg, 25.6%], F2 = 6,7-

dodecandiol [45.2mg, 11.9%]). The cleavage product (hexanal) was not isolated.

Fraction l: 1H NMR: (CDC13; 300 MHz): 04.13 (t, 1H), 3.48 (d, 1H), 2.41 (octet, 2H),

1.76-1.26 (m, 14H), 0.85 (t, 6H), Fraction 2: 1H NMR: (CDCl3; 300 MHz): 6 3.59 (t,

2H), 1.63-1.20 (m, 16H), 0.87 (t, 6H).
Synthesis of S-Methylenenonane (II-104)

Methyl triphenylphosphonium iodide (1 mmol, 404.22 mg, 1 equiv) was
dissolved in dry THF at 0°C. n-Butyllithium (1.2 equiv) of a 2.5 M in hexanes solution)

was added dropwise and the solution turned a dark red color. The solution was stirred for

1 hour at 0°C. Then, 5-nonanone (1.2 equiv, 168.3 mg) was added dropwise and stirred

overnight. The solution was extracted (3X) with water (100 mL). A column was run in

65

Si BO.

0 .'I 4
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41.411... I

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STD

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10
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5% EtOAc/hexanes to purify the oil in 91% (127.3 mg) yield. The olefin matched a

literature Spectra of the compound that was synthesized by an alternative method .25 1H
NMR (CDCl3; 300 MHz): 0 4.69 (q, 2H), 2.00 (t, 4H), 1.38 (m, 8H), 0.93 (t, 6H). l3C

NMR(CDC13; 300 MHz): 5 150.26, 108.36, 35.83, 30.11, 22.55, 13.97

Synthesis of 2-Buty1-l,2-Hexanediol" and 2-Hydroxyhexanal”
First, 5-methylenenonane (2 mmol, 280.6 mg.) was dissolved in MeOH (0.1 M.,

20 mL.) and DMF (20 equiv, 3 m1.). Pyridine (0.1 equiv 15.8 mg) was added followed

by (0.01 equiv, 100 ML) of 0304 (1 g/20mL toluene solution) was added and stirred for

five minutes. Then, 50% hydrogen peroxide (7 .3 equiv, 500 ML) was added and stirred
overnight. The solution was quenched with saturated sodium sulfite and the aqueous
layer extracted (3X) with EtOAc. The combined organic layers were washed (1X) with
water and brine. The solvent was removed under reduced pressure to yield an oil. A
column (20% EtOAc/Hexanes) yielded three fractions (Fl = S-nonanone [100.4 mg,
35.3%], F2 = 2-hydroxy-2-butylhexanal [74.8 mg, 21.7%], F3 = 2-butyl-1,2-hexandiol
[92.7 mg, 266]). Fraction 1: 1H NMR: (CDC13; 300 MHz): 6 2.37 (t, 4 H), 151 (pentet, 4
H), 1.30 (hextet, 4H), 0.88 (t, 6H), Fraction 2: 1H NMR: (CDC13; 300 MHz): 6 9.46 (s,
1H), 3.75 (s, 1H), 3.14 (d, 1H), 2.02-1.21 (m, 12H) 0.85 (t, 6H), Fraction 2: 1H NMR:
(CDC13; 300 MHz): 0 3.40 (s, 2H), 2.80-2.20 (broad, 2H), 2.00-1.91 (m, 12H), 0.85 (t,
611).
Synthesis of 2-Methyl-2-Unadecene (II-105)28

lsopropyl triphenylphosphonium iodide (20 mmol, 7.7056 g., 1 eq.) of was

dissolved in dry THF at 0°C. n—Butyllithium (1.2 eq. of a 2.5 M in hexanes solution) was

66

added dropwise and the solution turned a dark red color. The solution was stirred for 1
hour at 0°C. Nonanal (1.2 equiv, 2.805 g) was added dropwise and stirred overnight.
The solution was extracted (3X) with water (100 mL). A column was run in 5%
EtOAc/hexanes to purify the oil (first fraction). The reaction yielded 95% (2.66 g) olefin.

1H NMR (CDC13; 300 MHz): 6 5.10 (m, 1H), 1.95 (d, 2H), 1.66 (S, 3H), 1.58 (S, 3H),

1.30 (m, 12H), 0.86 (t, 3H); 13C NMR: (CDCl3; 300 MHz): 6 131.04, 124.98, 31.94,

29.94, 29.59, 29.39, 29.36, 28.07 , 25.69, 22.70, 17.60, 14.08

Synthesis of 2-Methyl-2-Hydr0xy-3-Unadecanone29

First, 2-methyl-2-unadecene (1 mmol, 168 .3 mg) of was dissolved in MeOH
(10ml, 0.1 M). Then, OSO4 (0.01 equiv 50 ML) (1 gJZOmL toluene solution) was added
and stirred for five minutes. Then, 50% hydrogen peroxide (7.3 equiv 05 mL) was
added and stirred overnight. The reaction was quenched with a saturated NaSO4 solution
and then extracted (3X) with EtOAc and the extracted (3X) with water to yield an oil. A

column was run in 20% EtOAc and Hexanes and yielded two fractions. Fraction 1 was

nonanal (47.7 mg, 33.5%), fraction 2 was a mix a-hydroxyketone and the aldehyde (1:1),

and fraction 3 was the pure a—hydroxyketone (30 mg, 16.1%). Fraction 3: 1H NMR:

(CDCl3; 300 MHz): 6 3.85 (broad, 1H). 2.50 (t, 2H), 1.59 (t, 2H), 1.34 (m, 18H), 0.85 (t,

3H).
Synthesis of 2-Methyl-2,3-Unadecandiol for GC Standard (U pJohn)

First, 2-methyl-2-unadecene (1 mmol, 168.3 mg) was dissolved in acetone and

water (9:1, 10mL). 0304 (0.01 equiv, 50uL) (l gJ20mL toluene solution) was added and

67

stirred for 5 min. Then of N-methyl morpholine (NMO) (1.2 equiv, 140.6 mg) was added
and the solution was stirred for 4 hours at RT. The solution was quenched with a sat.
solution of sodium sulfite (2 mL) and then extracted with EtOAc (3X, 20 mL.). The
organic layer was washed (3X, 20 mL) with water and the organic layer was stripped. A

column (40% EtOAc/Hexanes) provided pure product and the yield was not determined.
1H NMR: (CDC13; 300 MHz): 6 3.36 (d, 1H), 1.85 (broad, 2H), 1.5-1.25 (m, 14H), 1.186
(8, 3H), 1.13 (S, 3H), 0.85 (t, 3H)

Synthesis of 6-Hydroxy-5-Decananoe for GC Standard

Trans-S-decene (1 mmol, 140.2 mg) of was dissolved in MeOH (10mL, 0.1 M).

0304 (0.01 equiv, 50 ML) (1 g./20mL toluene solution) was added and stirred for five

minutes. Then, 50% hydrogen peroxide (7.3 equiv 0.5 mL) was added and stirred
overnight. The reaction was quenched with a saturated sodium sulfate solution and then
extracted (3X) with EtOAc and the extracted (3X) with water to yield an oil. A column
was run in 20% EtOAc and Hexanes and yielded one fraction (6—hydroxy-5-decenone)

which matched TCI pure product. A yield was not determined because this was only for

a GC standard. 1H NMR: (CDCI3; 300 MHz): 6 4.12 (m, 1H), 3.49 (broad, 1H), 2.40 (m,

2H), 1.81—1.20 (m, 10H), 0.86 (overlapping t, 6H); 13C NMR: (CDC13; 300 MHz):

6 212.51 , 76.30, 37.48, 33.36, 26.88, 25.62, 22.45, 2227,1381, 13.71.

68

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References

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Pappo, R.; Allen, D. S.; Lemieux, R. U.; Johnson, W. S. J. Org. Chem. 1956, 21,
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Bailey, P. S. Chem. Rev. 1958, 58, 925-1010.
Criegee, R. Angew. Chem. Int. Ed. 1975, 14, 745-752.
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Noyori, R.; Tomino, 1.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem. Soc. 1984, 106,
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Travis, B. R.; Narayan, R. S.; Borhan, B. J. Am. Chem. Soc. 2002, 124, 3824-3825.
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Travis, B. R.; Sivakumar, M.; Hollist, G. 0.; Borhan, B. Org. Lett. 2003, 5, 1031-
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Schomaker, J. M.; Borhan, B. Org. Biomol. Chem. 2004, 2, 621-624.

Travis, B. R.; Ciaramitaro, B. P.; Borhan, B. Eur. J. Org. Chem. 2002, 3429-3434.
Yan, J.; Travis, B. R.; Borhan, B. J. Org. Chem. 2004, 69, 9299-9302.
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Colladon, M. 5., Alessandro: Strukul, Giorgio Green Chem. 2008, 10, 793-798.
Sato, K. U., Yoko Jpn. Kokai Tokkyo Koho 2005, 8.

Lohray, B. B. K., R. K. J Org Chem 1994, 1375-1380.

82

(21)

(22)

(23)
(24)
(25)
(26)

(27)
(23)
(29)

Lohray, B. B.; Bhushan, V. Tetrahedron Lett. 1993, 34 , 3911-3914.

Bang-Chi Chen, P. 2., Franklin A. Davis, Engelbert Ciganek Organic Reactions
2003, 62, No pp. given.

Nishikawa, T.; Shinokubo, H.; Oshima, K. Tetrahedron 2003, 59, 9661-9668.
Fukuzawa, S. F ., Tatsuo; Sakai, Shizuyoshi J. Organomet. Chem. 1986, 299, 179.
Kakiya, H.; Shinokubo, H.; Oshima, K. Tetrahedron 2001, 5 7, 10063-10069.

Criegee, R.; H‘ger, E.; Huber, G.; Kruck, P.; Marktscheffel, F.; Schellenberger, H.
Justus Liebigs Annalen der Chemie 1956, 599, 81-124.

Rodemeyer, G. n.; Klemer, A. Chem. Ber. 1976, 109, 1708-1723.

' Schauder, J. R.; Denis, J. N.; Krief, A. Tetrahedron Letters 1983, 24, 1657-1660.

Katritzky, A. R.; Heck, K. A.; Li, J.; Wells, A.; Garot, C. Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry 1996, 26, 2657 - 2670.

83

Chapter 3. Oxidative Cleavage of Olefinic Polymers in an Effort to Reduce Polymer
Waste

3.1 Introduction

The United States retires from service one tire per year for every citizen in the US
(295,232,364 is the population estimate by US Census Bureau as of Jan. 11, 2005). Two
and a half million tons of tires were scraped each year in North America, 1.5 million tons
in Europe, and 05 million tons in Japan.1 Tires make up 1.8% of the total solid waste in
the US with stockpiles (2001) of 300 million.2 There are few options for disposing tires.
Crumb rubber is an environmentally friendly way to dispose of tires, but only 31 million
tons are used for this every year. Crumb rubber is used for athletics tracts, fillers in
composites, rubber modified asphalt, and soil amendments to improve durability on
athletic fields. Forty million tires are incinerated each year but this has proven to be a
less than ideal fuel due to the relatively low energy output (2800-3700 kJ/kg) and high
levels of pollution. Table III-1 shows the energy output of some common fuels and you
can see that tire waste is well below those common fuels. Landfills are another option
but these are prone to chemical leaching and if ever ignited they can burn for years like
underground coalmines. The European Union has attempted to control its tire waste by
two European Commission Directives: The Waste Landfill Directive (1999) which bans
tires from being deposited in landfills and The End of Life Vehicle Directive (2000)3
which stipulates which tires can be used by vehicle dismantlers and encourages them to
recycling. Clearly there is a need for new technology to help deal with large amount of

tire waste.

84

Table 111-1. Energy Outputs of Common Fuel Sources

 

 

Higher Calorific Value
Fuel (Gross Calorific Value — GCV)
kJ/kg Btu/lb.
Alcohol, 96% 30,000 -
Bituminous Coal 17,000 - 23,250 7,300 - 10,000
Butane 49,510 20,900
Charcoal 29,600 12,800
Coal 15,000 - 27,000 8,000 - 14,000
Coke 28,000-31,000 12,000- 13,500
Diesel 44,800 19,300
Ethanol 29,700 12,800
Ether 43 ,000 -
Gasoline 47,300 20,400
Glycerin 19,000 -
Hydrogen 141 ,790 61,000
Methane 55,530 -
Oils, vegetable 39,000 - 48,000 -
Peat 13,800 - 20,500 5,500 - 8,800
Petroleum 43,000 -
Propane 50,350 -
Tar 36,000 -
Wood (dry) 14,400- 17,400

 

http: //www .engineeringtoolbox .com/fuels-higher-calorific- values- d_ 169 .html

Recycling tires has been impeded due to the complex mixture of chemical species
in tires. Two ways to reduce the volume of scrap tires are masticated (crumb) rubber
(used for resilient surfaces on athletic tracks, fillers in composites, rubber modified
asphalt, and more recently as a soil amendment to improve the durability of athletic
fields) and reCOVering rubber or chemical intermediates from tires. Through pyrolytic
distillation low-molecular-weight (LMW) gases, volatile, and non—volatile heavy oils,
carbon black, and steel are recovered .4 The Kobe process operates in Japan and typically
yields 31% oil, 15% gas, 29% carbon black, 10% steel, 5% sludge, 2% water, and 8%
loss in mass balance.5 Different experimental systems have been used to perform waste
tire pyrolysis. Thermobalance has been used69 to obtain kinetic information, fluidized

bed reactors,”12 batch reactors,” many configurations based on fixed bed reactors, and a

85

few with moving bed reactors.““‘5 In most cases the volatile fraction is consumed during

the process, but a few have isolated the volatile fraction. Limonene and other terpenes

were isolated by pyrolysis but in low yield.1 So, pyrolytic distillation has proven inferior

to crude oil in terms of products recovered.

Table 111-2. Chemical Constituents of a Typical Car Tire

 

 

Compound Name Mass %

Polyisoprene (natural rubber) 41
Polybutadiene (synthetic rubber) 12
Carbon Black 30
Aromatic hydrocarbon oil 45
Zinc oxide (activates vulcanization accelerators) 3
Stearic acid/ org. zinc salts (activates vulcanization accelerators) 1.4
Antioxidants l .7
Anti-ozone wax 0.99
Mercaptobenzothiazole (vulcanization accelerator) 0.34
Tetramethylthiuram monosulfate (accelerator buster) 0.07
Belts (steel or polymer fabric) 5

 

Figure III-l. Polymer Cleavage Products

_ Oxidative O
___>
n Cleavage HO 0
Polybutadiene Succinic Acid
III-1 Ill-2
1 1 Oxidative O
_ ,
HO 1
n Cleavage O
Polyisoprene Levulinic Acid
III-3 Ill-4

86

Figure III-2. Succinic Acid Products

 

 

  
 
     

 

O
O 0
WOW \}5,
O O
n
O Polyester
< 7 H2NOC~CONH2
Tetrahydrofuran succinamide

O

J—L CO H

HO C/\/ 2
2-Pyrrolidone Succinic Acid 1,4-Diaminobutane
O
( , ’ CN
N-MethyI-Z-Pyrrolidone succinonitrile
0
Alkyl Succinate
< O
T HO\/\/\0H
y-Butyrolactone 1 ,4-Butanediol

 

[ 1 n
Polybutadiene
(mix of cis & trans)

 

 

 

Tires are complex mixtures of materials (Table 111-2) designed to provide traction,
resilency, and long life over a large range of temperature and mechanical stresses.'7 The
interesting thing about tires is that over 50% (by weight) is two olefinic polymers. If
these polymeric olefins were oxidatively cleaved, then small molecules could potentially
be recovered, thus reducing the mass of tire waste. The osmium tetroxide mediated
oxidative cleavage reaction developed in our lab could facilitate the depolymerization.
The products produced (Figure III-1) by these polymers are succinic acid (esters) and
levulinic acid (esters). These molecules are starting materials for many small molecule

building blocks (Figures 2 & 3) for organic synthesis and feedstocks.

87

Figure III-3. Levulinic Acid Products

0 H020

O O B-Acetylacrlic Acid O 0
v HO OH

y-Valerolactone Diphenolic Acid

&/ o 0028 0
HO { ‘ f > H 020M

1 ,4-Pentanediol

 

 

Alkyl Levulinate fi-Acetylacrylic Acid

0 0 t 0
U H2N\)J\/\COZH

Angelilactone w / 1’4.Diam11'1obutane

Levulinic Acid

\LO) T H020“

2-Methylletrahydrofuran Acrylic Acid
1 1n

Polyisoprene

 

 

 

 

 

Currently, succinic acid is made by overproduction of diacids from the Krebs
cycle, a biotransfonnation. Levulinic acid is currently made from the catalyzed
dehydration and decomposition of cellulosics and sugars. This method was not meant to
compete with these established procedures in terms of scale or cost, but only as a way of
recovering a useful product for an abundant waste source.

3.2 Polymerization

The synthesis of esters by the group cleavage method is easily accomplished by
replacing DMF with an alcoholic solvent (usually methanol or ethanol).““9 This fact let
our group postulated that polyesters could also be obtained from cyclohexene and a diol
using our oxidative cleavage reaction. If cyclohexene was cleaved in the presence of a

diol then a polyester would be the result (Scheme III-1). The initial experiment was done

88

with 1,3-propanediol and cyclohexane. The results yield one major product, the diacetal,
albeit in low yield (<20%) (Scheme III-2). This was confirmed by synthesis of the
diacetal by an alternative method (periodate cleavage of cyclohexene followed by acetal
formation). Interesting, this could allow for the isolation of the aldehydic oxidation state
of the carbonyl instead of the carboxylic acid. This area was not pursed since results
discussed in chapter 2 also yielded aldehydes. For the goal of polymerization, this result
suggested that the polymerization would not be facile. This was thought to be due to the
stable cycloacetal that was formed so a different diol would have to be chosen that would
not form a stable cycloacetal.

Scheme III-l. Proposed Polymerization

0804 (0.01 equiv) O
KHSO4 (8 equiv) .
O HOAH’SH > 0W0 0&1.
. DMF (0.1 M) O O
n

Polyester

 

Scheme III-2. First attempt at Polymerization

 

O A KHSO5 (5 equiv) H M H
OH OH > 0 0
Solvent (0.1 M) V
III-5 III-6 (None, DMF. DCM) Ill-7

In order to test the validity of this method, a model conpound was chosen. First

1,6-hexanedial (III-8) was synthesized by periodate cleavage of cyclohexenxe and

subjected to KHSOS in the presence of 1,5-pentanediol. It was thought that the acetal

formation would be inhibited due to the kinetics of forming a large cycloacetal. The
reaction only yielded a small oligomer (3 trimers) (Scheme III-3). No acetal was

observed by NMR or GC-MS. The low amount of polymerization was discouraging but

89

an oxidative cleavage polymerization was attempted (Scheme III-3). This reaction only
produced an oligomer of four subunits (similar to the model), so it was assumed that the
propagation step was the main problem. This process is a step-growth polymerization

and the tetramers formed did not participate in subsequent cleavage reactions to form
larger oligomers. Heating the reactions higher than 70° C is not possible because KH805
will degrade at higher temperatures. The continued isolation of tetramers led to the

abandoning of this method in order to focus on a depolymerization procedure.

Scheme III-3. Oxidative Polymerization

O HO(CH2)5OH (III-9) (1 equiv) O
/ KHSO5 (5 equiv)
(I > are 05..
\O DCM (1 M) O o 3

 

 

Ill-8 Ill-10
HO(CH2)5OH (III-9)(1 equiv) O
KHSO5 (5 equiv)
O > %ro ‘V’h
DMF or ACN (1 M) O O 3
Ill-5 III-10

3.3 Depolymerization of Polybutadiene

Polybutadiene, the main component in car tires, is a clear solid or viscous liquid at

room temperature depending on the number-average molecular weight (Mn). The first

reaction was run to test the concept of the reaction. This was done with a solid block of

polybutadiene (High-Density = ~420,000 Mn = HDPD), which was subjected to the

standard oxidative cleavage reaction conditions of DMF with osmium tetroxide (0.01

equiv) and 4 equiv of KHSOS (equiv refers to number of olefins) (Scheme III-5) to test

for the loss of mass.20 Another solid sample of equal weight was placed in DMF for a

90

control experiment. Both reactions were stirred for 36 hours, but the polymer never

dissolved. The reaction was quenched and the solid samples washed with DMF, dried,

and the weight recorded. The sample exposed to osmium tetroxide and KH805 lost

significant weight (50 mg out of 250 mg) while the control lost only minimal weight (<10

mg out of 250 mg). The experimental sample also turned black, which suggested that the

Os (III) was sequestered in the remaining material. This result suggested that the

depolymerization was possible but impractical with this procedure. A solvent to

solublize the polymer was needed to keep the reaction from only occurring at the surface.
Scheme III-4. Initial Depolymerization

0804 (0.01 equiv) O

l ,—\__ I KH305 (4 equiv)

" DMF 0

 

The problem that presented itself was how to keep the polymer soluble under the
reaction conditions. Benzene, toluene, and cyclohexane are good solvents for dissolving

polybutadiene, but unfortunately they are poor solvents for the oxidative cleavage

reaction partly due to the limited solubility of Oxone or KHS05 (active oxidant in

Oxone). A biphasic system was needed for this reaction. The second major problem was
the isolation of products. Succinic acid is moderately water—soluble (1 g/13 mL of cold
water) and it would be difficult to isolate from the water-soluble sulfate salts that are left
after the oxidation. The choice of co-solvent was the answer to both problems. If an

alcohol, like methanol or ethanol, was used the product would not be the diacid but the

diester, which are much less soluble in water (0.2 g/ 100 mL of water at 25° C for diethyl

succinate). Also, the oxidant is partially soluble in these alcohols. Due to this partial

91

solubility it was decided to limit the amount of salt in the reaction by using KH805

(152.17 g/mol oxidant) instead of Oxone (614.76 g/2 mol of oxidant), which reduced the

salt weight by half. Another option was to use “soluble” Oxone (Bu4NHS05, TBX)21 but

this path was lead to isolation problems due the excess amount of Bu4N in solution that

hide the product on GCMS. Also, TBX generally yielded aldehydes as products.

Initial experiments were done in a toluene/MeOH and analyzed by gas
chromatograph/mass spectroscopy (GC—MS) (Scheme 111-5). The GC—MS showed a
large number of peaks with some corresponding to aryl products. The complexity of
spectra did not allow for identification dimethyl succinate (DMS) but it could be seen in

the crude NMR. The GC results suggested a benzylic oxidation of toluene by the

reaction conditions (KH805 and 0804). This is not an unprecedented reaction, albeit it

is with osmium and Oxone. Wang22 has reported a similar oxidation using Ozone over

Ce02 promoted by sulfated T102 and others have used Iron (11)23 and Iron (III)24

complexes. These reports showed low yields (<10%) and usually yielded higher
oxidation state compounds were isolated, like benzaldehyde and/or benzoic acid. Wang’s
report suggested that a bridged bidentate or chelating bidentate catalyst facilitated the
oxidation, which could be a similar catalyst in the oxidation observed (Figure III-4).
These complexes have not been reported for osmium but bridged systems have been
reported with sulfo osmium complexes.25 These oxidation products were not pursued and
toluene was no longer used as a solvent for the depolymerization reaction in order to limit

the by-products in NMR and GC-MS analysis.

Scheme III-5. Initial Polymer Cleavage Reactions
0so4 (0.01 equiv) o
KHSO5 (4 equiv)
W F HscOMOCHa ©/\OH
n MeOH/Toluene (1 :2) 0
(HDPD) RT, 48 H
Ill-12 Ill-13 Ill-14

 

Product (III-l3) peaks observed in crude NMR but not isolated. III-l4 observed
by GC-MS.

Figure III-4. Wang’s Proposed Oxidation Complex and Os Sulfo Complex

US$30
’0 H O (I) 0 (I) OH
033’ Mb Dis/011;) H20:OIS:_ 1318:0142
/ , ’
0/ \ —M O \O/ \O 2 0‘ ’0 2
\0 1,89
- O O
Bridged Bidentate Chelating Bidentate Sulfo Osmium Complex
III-15 III-16

The remaining experiments were done using benzene or cyclohexane to dissolve
the polybutadiene. The first choice for the co-solvent was methanol, but as will be
explained this led to isolation problems. The dimethyl succinate (DMS) produced in the
reaction could be observed by GCMS, but not by TLC. Several methods attempted to
isolate product, unfortunately none of these proved to be effective. The product could not
be isolated by either column or distillation. A major problem with this isolation was due
to the water extraction that was done to remove the salts from the mixture, but
unfortunately the dimethyl ester was lost during this work-up procedure due to the
moderate solubility of the DMS (Scheme III-6). Other work-up procedures included
evaporation of the solvent, dilution with diethyl ether, followed by filtration, removal of
the ether, and distillation of the residue. This failed to yield product. It was thought to be

lost during the removal of benzene or cyclohexane/methanol solution. Both cylohexane

93

and benzene showed product by GCMS. It was thought that the small nature of dimethyl
succinate led to these isolation problems, so a new co-solvent was needed.

Scheme III-6. Cleavage of Polybutadiene to form Dimethyl Succinate

 

OSO4 (0.01 eq.) 0
KHSO5 (4 eq.)
W + H3COJWOCH3
ll MeOH/Benzene or O
(HDPD) Cyclohexane (1 :4)
Ill-12 RT, 1-6 days III-17

No product isolated by extraction or distillation.

A simple solution was the substitution of methanol with ethanol. Also, the water
extraction was no longer used due to the partial solubility of the diester. This allowed the
diethyl succinate (DES) to be isolated by Kugelrohr distillation, albeit in low yields
(Table 111-3). The higher density polybutadiene (solvent ratio 4:1, benzene or
cyclohexanezethanol) cleavage yielded more product than the lower density
polybutadiene (solvent ratio 1:1, benzene or cyclohexane:ethanol) despite the more
unfavorable solvent ratio (the reaction standard cleavage reaction slowed in benzene and
cyclohexane) except in GC yields. The best-isolated yield (Entry III-21) came in
cyclohexane with a long reaction time (72 hours). Even after this long reaction time
oxidant was still present as shown in a positive test with NaI. Reaction times in excess of
72 hours (4 days to 1 week) did not lead to higher product yield. These longer time

frame experiments yielded no product during the distillations. It was thought that raising

the temperature would increase the yield but KI-lS05 will degrade above 70° C. Entries

III-23 and 24 (the product was not purified for this reaction and the yield reported is were
run at 50° C) did not lead to an increase yields of pure product. Two additives were tired,

sodium bicarbonate and sulfonamide. Sulfonamide has been shown to help osmylation

94

but the addition did not increase the yield of cleavage product (Entry III-25). The
addition of sodium bicarbonate was used in our literature report to cleave trisubstituted

olefins.20 The addition of sodium bicarbonate (Entry III-26) did not increase the yield of

 

 

 

 

 

DES.

Table III-3. Cleavage of Polybutadiene
0304 (0.01 equiv) O
KH305 (8 equiv)

m > EIOMOEt
n EtOH/Benzene or 0
(HDPD) Cyclohexane (1:4)
Ill-12 RT. 1-6 days
Benzene/EtOH (1:1) Cyclohexane/EtOH (1:1)
Entry mm” % Yield DES % Yield DES

III-18 LDPB 7.8% -

III-19° LDPB 4.8% 0.2%
III-20 LDPB 22.5% (GC Yield) 21.7% (GC Yield)
Ent Pol mer Benzene/EtOH (4: 1) Cyclohexane/EtOH (4:1)

'y y % Yield DES % Yield DES

III-21 HDPB 14.2% 9.4%

III-22" HDPB 13.0% 22.3%
111.23c HDPB 50.3% 61.1%

III-24" HDPB 11.3% -
III-25° HDPB - 12.0%
III-26' HDPB - 37.9%

 

All reactions were carried out with 250 mg of polymer, 0.01 equiv of 0304, 8 eq.

of KHSOS, at room temperature unless otherwise stated. a1 g of polymer used. bReaction

time was 72 hours °50° C reaction temperature and based on crude weight. NMR showed

less than 50% purity. ‘150° C reaction temperature. el equiv of sulfonamide used. I:5

equiv of NaHCO3, the yield is based on crude weight. NMR showed less than 50%
purity.

In all reactions a large amount of a black tar-like substance was recovered. Since
NaI tests showed that oxidant was present at the end of the reaction, the low oxidation

state osmium could have been sequestered in the polymer after a period of time or the

95

olefins of the polymer were no longer present. This material could be dissolved in
benzene or cylcohexane/ethanol solutions and subjected to the reaction condition
(KHSOS) minus the osmium tetroxide but the system would not yield any cleavage
product, diethyl succinate. It was first postulated that the olefins in the remaining
polymer had been dihydroxylated and/or converted to ot-hydroxy ketones. The presence
of a-hydroxy ketones was discounted due to KHSOS’s ability to cleave these functional
groups by a Baeyer-Villiger type oxidative cleavage .26 The subsequent acids would then
be converted to ester in the alcoholic solvent. If the olefins had been dihydroxylated then
they would be inactive under these reaction conditions. It was then necessary to
determine if the 0304 was still active in the residue material. This was done by a control
reaction on the black “tar” residue that remained after distillation (Scheme III-7). A
sample of this residue was added to a standard cleavage reaction of stilbene with H202
but without 0304. The reaction was analyzed by GC and it was found that the olefin in
stilbene had been cleaved to yield only benzaldehyde. A control experiment was run
without the polymer residue and only starting material remained. This showed that 0304
was still active and could still participate in an oxidative cleavage reaction. It was then
assumed that the olefins in the polymer had been made inactive by some oxidative

procedure during the course of the reactions.

96

Scheme III-7. Residue Test for 0804

Residue Tar (20 mg) 0 O
0 H202 (30% aq) (5 equiv)
\ ’ H OH
DMF (20 equiv), ACN (0.1 M)
RT, 24H
Ill-26 Ill-27 Ill-28
57% 42%

The reaction was analyzed by GC. Yields are percent conversion. No stilbene
was seen in the GC trace.

 

3.4 Conclusion

This chapter showed that a pure sample of polybutadiene could be cleaved in low
yield. The fact that ~25%. diester could be obtained showed that the cleavage was
catalytic, but the yield suggests that polymer effects the cleavage (likely due to the steric
bulk). The sequestering of the osmium in the polymer could be major problem in terms
of reducing waste. The toxicity of osmium tetroxide is due to its volatile nature, which
makes the handling more difficult when compared to other transition metals (Ru, Mn, or
Cr). The catalytic nature of osmium tetroxide allows for small quantities to be used. The
by-product “tar” would then have to treated as hazardous waste due to the osmium

content. A system for removal the osmium would have to be devised before the disposal

of the waste, which has been done on other systems. This catalyst (0504) has been used

in industrial scale to produce pharmaceuticals with no detectable levels of osmium in the
product. For example, Rhodia used this chemistry in a synthesis of an anti-diabetic agent
(CL-316,243) in 4000 L reactors. So the removal of the osmium on an industrial scale
has been achieved.

Another concern with this process was the volume of solvent per gram of

polymer. The need for this reaction to be run in a liquid phase with a co-solvent is

97

prohibitive. A method for isolation of the diacids would solve most of the solvent
problem. This could be achieved by deprotonation of the diacids to make them water-
soluble. Then the acids could possible be isolated by extraction. This process was
abandoned due to the platitude of the yield on a pure sample making the likelihood of a
complex mixture (like that in tires) yielding product is low.
3.5 Experimental Data
Synthesis of the Diacetal (III-7)27

First, cyclohexene (III-S) (1 equiv, 05 mmol, 41 mg) was added along with of

1,3-propandiol (III-6) (2.5 mL). This solution was diluted with DCM (0.1 M). Then,

0804 was added (0.01 equiv, 50 11L of a l g/20UmL of toluene solution) and the solution

darkened. Then, KH805 (4 equiv, 340 mg) was added and the solutions was stirred

overnight at room temperature. The solution was quenched with sodium sulfite and
extracted (3X) with EtOAc. The combined organics were washed with water and brine

and the solvent was removed under reduced pressure. Scaled-up procedure (1 g) with
DCM was run and the diacetal isolated. 1H NMR (CDC13; 300 MHz): 6 4.4 (t, 2h), 4.1
(m, 8H), 1.6 (m, 4H), 1.3 (m, 8H)

Synthesis of a tetramer from a dial (III-9)

First, 1,6-hexanal (111-8) (1 mmol, 114 mg, 1 equiv) and 1,5-pentane diol (104

mg, 1 equiv) were diluted in DCM (0.5M, 5 mL). Then, KH805 (5 equiv, 851 mg) was

added and the suspension was stirred overnight at room temperature. The reaction was
quenched with water and extracted (3X) with DCM. The combined organics were

washed with water and brine. The solvent was removed under reduced pressure to yield a

98

viscous oil. NMR showed a trimer by integration. 1H NMR (CDCl3; 300 MHz): 5 4.0

(Broad, 4H), 3.6 (Broad, 1H), 2.3 (Broad, 4H), 1.6 (Broad, 8H), 1.4 (Broad, 2H)
Synthesis of a 4-mer from cyclohexene (III-10)

Cyclohexene (III-5) (1 equiv, 82 mg, 1 mmol) and of 1,5-penandiol (1 equiv, 104

mg) (III-6) was diluted in of DMF (A) or ACN (B) (5 mL). OsO4 (0.01 eq) was added

(50 11L of a 1g/20mL of toluene). The solution for all three flasks darkened. KH805 (4

equiv, 851 mg) was added the solutions stirred overnight. The reactions were quenched
with sodium sulfite and extracted (3X) with EtOAc. The combined organics were
washed with water and brine and the solvent removed under reduced pressure. NMR
showed the same compound as (III-9).

Standard Polymer Cleavage Reaction

The polymer (250 mg, 54 g/olefin, 4.6 mmol of olefin) was dissolved in benzene

or cyclohexane (12 mL). Methanol or ethanol (4 mL) was added dropwise. KH805 (4-8

equiv, 3.131 or 6.262 g) was added and the suspension was stirred vigorously. Then,

0304 (0.01 equiv, 50 11L of a 1g/20mL of toluene) was added along with any additives.

The solution was stirred for 24—72 hours. A solution of NaI was used to test for the
presence of oxidant by adding an aliquot of the reaction to a saturated aqueous solution of
Nal. If oxidant was present the solution changed from clear to purple. The suspension
was filtered (to remove any undissolved sulfate salts) and the solvent was removed under
reduced pressure. The residue was redissolved in diethyl ether, filtered again, and the
solvent was removed. The black, viscous liquid was then distilled at 218° C to yield

diethyl succinate. The distillate was a black tar-like substance.

99

3.6 NMR Spectra

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o no 0. m... o.~ 3 3 on 3 3. 3 we. 3 no on 2 o...

. _ . _ .
111» r... ....»ltrt....»L.i ..-..e. 1.111.111.1{11 .. .p:le.rirE1:--.Lll1L1rlt...:ltl1litruliltelutLl......rLllreubrr. .rl...1.pi..l.-. .l-1..r.11-al..l.....)...r...i..irll1
., .. ... .. . .. rl Hllu
. v
t . .9

 

 

.14 €11,111llfi ..... 13:11-1... 3.1

 

 

Diethyl Succinate. 1H NMR

”.5

 

 

 

8.2321824. .-....w

101

(1)
(2)

(3)
(4)
(5)

(6)

(7)
(8)
<9)
' <10)

(11)

(12)
(13)

(14)
(15)
(16)
(17)

(13)

References

Stanciulescu, M.; Ikura, M. J. Anal. Appl. Pyrolysis 2006, 75 , 217-225.

Murillo, R.; Aranda, A.; Aylon, E.; Callen, M. S.; Mastral, A. M. Ind. Eng. Chem.
Res. 2006, 45, 1734-1738.

Marrno, L. Waste Manage. (Oxford) 2008, 28, 685-689.

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Dufton, P. W. RAPRA Technology Ltd., 1987.

Aylon, E.; Callen, M. S.; Lopez, J. M.; Mastral, A. M.; Murillo, R.; Navarro, M.
V.; Stelmach, S. J. Anal. Appl. Pyrolysis 2005, 74, 259-264.

Chen, F. 2.; Qian, J. L. Waste Manage. (Oxford) 2003, 23, 463-467.
Senneca, O.; Salatino, P.; Chirone, R. Fuel 1999, 78, 1575-1581.

Leung, D. Y. C.; Wang, C. L. J. Anal. Appl. Pyrolysis 1998, 45, 153-169.
Wu, S. Y.; Su, M. F.; Baeyens, J. Powder Technol. 1997, 93, 283-290.

Araki, T.; Niikawa, K.; Hosoda, H.; Nishizaki, H.; Mitsui, S.; Endoh, K.;
Yoshida, K. Conservation & Recycling 1979, 3, 155-164.

Conesa, J. A.; Font, R.; Marcilla, A. Energy & Fuels 1996, 10, 134-140.

Laresgoiti, M. F.; Caballero, B. M.; de Marco, 1.; Torres, A.; Cabrero, M. A.;
Chomon, M. J. J. Anal. Appl. Pyrolysis 2004, 71, 917-934.

Napoli, A.; Soudais, Y.; Lecomte, D.; Castillo, S. J. Anal. Appl. Pyrolysis 1997,
40-1 , 373-382.

Diez, C.; Sanchez, M. E.; Haxaire, P.; Martinez, 0.; Moran, A. J. Anal. Appl.
Pyrolysis 2005, 74, 254—258.

Gonzalez, .1. F.; Encinar, J. M.; Canito, J. L.; Rodriguez, J. J. J. Anal. Appl.
Pyrolysis 2001 , 58 , 667-683.

Effects of Waste Tires, W. T. F., and Waste Tire Projects on the Environment

yruaEduxuufl0s2Lg031EhflbutathunflEhuuié32£EflLhishut

Travis, B. R.; Sivakumar, M.; Hollist, G. 0.; Borhan, B. Org. Lett. 2003, 5, 1031-
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Schomaker, J. M.; Borhan, B. Org. Biomol. Chem. 2004, 2, 621-624.

Travis, B. R.; Narayan, R. S.; Borhan, B. J. Am. Chem. Soc. 2002, 124, 3824-
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Travis, B. R.; Ciaramitaro, B. P.; Borhan, B. Eur. J. Org. Chem. 2002, 3429-
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Wang, B. M., W.; Ma, H. Ind. Eng. Chem. Res. 2009, 48, 440-445.

Mori, K.; Kagohara, K.; Yamashita, H. Journal of Physical Chemistry C 2008,
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Huang, G.; Cai, C. C.; Luo, J.; Zhou, H.; Guo, Y. A.; Liu, S. Y. Canadian Journal
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Zhilyaev, A. N. F., T. A.; Katser, S. B. Zhurnal Neorganischeskoi Khimii 1998,
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Fumiss, A. I. V. B. S. Vogel's Textbook of Practical Organic Chemistry,
including Qualitative Organic Analysis.; 4th ed.; Burnt Mill: Harlow, Eng, 1987.

103

Chapter 4: A Kinetic Analysis of the Osmium Tetroxide Mediated-Cleavage of
Olefins with Oxone

4.1 Introduction:
Oxidative cleavage of olefins is an essential tool in organic chemistry. The

oxidative cleavage of olefins can be summed up into two classes: (1) conversion of the

olefin into 1,2-diol followed by cleavage with NaIO4 or other oxidantsl or (2) ozonolysis

where the olefin is cleaved directly and then converted to a variety of functionalized
products which can be controlled by the work-up.“ In 2002, the group proposed a
mechanism for the oxidative cleavage of olefins using osmium tetroxide and Oxone that
suggested a third alternative; the direct oxidative cleavage of the osmate ester
intermediate. During these reactions the timescale remained the same (24h). By
allowing the reaction to run to completion, the mechanism could not be probed. The

selectivity of the reaction was not examined either. This was not probed by our group

Figure IV-l. HSP90 Inhibitors

   

R1 & R2 = OCH3, R3 = H; Geldanamycin (IV-1) Autolytimycin (IV-6)
R1 = H, R2 = OCH3, R3 = CH3; Herbimycin A (IV-2)

R1 81 R3 = H, R2 = OCH3; Herbimycin B (IV-3)

R1 = H, R2 = OCH3, R3 = H; Herbimycin C (IV-4)

R1 = H, F12 = CH3, R3 = CH3; Macbecin I (IV-5)

104

until Prof. R. Maleczka’s lab in the department had an interesting result while utilizing
our oxidative cleavage.

Autolytimycin (IV-6) exhibits HSP90 (Heat Shock Protein) inhibition at
nanomolar levels.5 Inhibition of HSP90 has been suggested as an important therapeutic
mechanism for cancer treatment because of its antiproliferative activity against cancer
cells in various models that are dependent on reductive activation to the hydroquinone by
the enzyme NAD(P)H/quinone oxidoreductase l (NQOl)?25 Autolytimycin is a
nonbenzoquinone ansamycin, which may differ in mechanism from the benzoquinone
ansamycins like geldanamycin (IV-l), herbimycin (IV-2,3,4), macbecin (IV-5), and
derivatives.5 Monica Norberg in her efforts to synthesize autolytimycin used the
osmium-mediated cleavage reaction (Scheme IV-l). She sought to oxidatively cleave a
terminal olefin while leaving a 1,1 disubstituted olefin untouched (IV-7). This happened
with good selectivity and in moderate yield (IV-8).26 The question that presented itself
was whether the selectivity observed was inherent to the olefin order or due the steric
hindrance of the 1,1-disubstituted olefin contained within this particular substrate. A GC

kinetic study of the cleavage of simple olefins could tell us if there is selectivity based on

Scheme IV-l. Autolytimycin Intermediate

 

0H
_ O
I 0504 (0.01 eq.) I
O Oxone (4 eq.) 0
)
OTIPS DMF. 40 min OTIPS
IV-7 IV-8
60%

105

the order of the olefin or if the result depicted in Scheme IV-l is due to neighboring
group effects.
4.2 Substrate Choices

Six substrates that represented the six basic (mono-substituted, cis, trans and 1,1
(ii-substituted, tri-substituted, and tetra-substituted) types of olefins were chosen (Figure
IV-2). The substrates were the same used for the olefin cleavage mediated with osmium
tetroxide and hydrogen peroxide that was discussed in Chapter 2. Due to the number of
standard curves that were required a simplification was attempted by altering the olefins

to yield the same acids. This approach failed but did show an interesting result that is to

follow.
Figure IV-2. Six Olefin Groups.
W W
lV-9 lV-1 0 lV-1 1
lV-1 2 lV-1 3 lV-14

To try and limit the number of compounds that had to be analyzed a new cis
olefin was considered. Two compounds were chosen, cis-S-decene and cis-2-unadecene.
If cis-5-decene was used the analysis would be the same for cis and trans (IV-ll) olefins,
likewise if cis-2-unadecene were used its analysis would be similar to the tri-substituted
product (same cleavage product). A Wittig reaction using hexanal and hexyl triphenyl

phosphonium bromide was used for the synthesis of cis-6-dodecene (IV-ll), with only

one isomer seen on 1H NMR, so a similar procedure was proposed to work for the other

106

Scheme IV-Z. Witti g Reactions that Yielded Cis/Trans Mixtures

1) nBuLi (1.1 eq.)

-73° c to RT THF
BfPh3P—/ > W

2) Nonanal (1.1 eq.)
RT to Reflux 12H
IV-15 IV-16
65%
3:1 cis:trans

 

1) nBuLi (1.1 eq.)

-78° C to RT THF -—
IPhaP/V\/\ >

2) Hexanal (1.1 eq.)

RT to Reflux 12H
. lV-18
IV 17 70%
4:1 cis:trans

compounds. The two Witti g reactions in Scheme IV —2 yielded olefins, but unfortunately

 

in a mixture of cis/trans isomers. It was interesting that only one extra carbon on each
side led to complete regiochemical control of the olefin geometry. Olefins IV-9 and 10
were purchased from Aldrich. Olefins IV-ll, 12, and 13 were formed from a Wittig

reaction. IV-14 was formed from a McMurry coupling (Scheme IV-3).2"'29

Scheme IV-3. Synthesis of IV-l4 by McMurry Coupling

o 1) ZQ (10 equiv), TiCl4 (5 equiv)
WW -5 C to RT, 3 hours, THF 1
>

2) Cooled to -5° c, Pyridine (2.5 equiv)
”'19 Ketone (2 equiv), RT to Reflux, 12h ”'14

 

4.3 Effective Quenching Method

Before the timed experiments could be done several technical factors had to be
overcome. The first technical issue was the development of an effective way to quench

the reaction. An ideal quenching reagent for this study should immediately halt the

107

reaction and have a small footprint in the GC when analyzed. The first quenching
reagent used was saturated sodium sulfite (aq). This was our previously reported
quenching method. This did not work well at neutralizing the excess oxidant. The
reaction continued to completion even after it was added. Two other quenching reagents
were then tried, dimethyl sulfide and triphenyl phosphine. Both of these were effective at
halting the reaction but the footprint of dimethyl sulfide was much smaller (it only
yielded DMSO as a by-product), while the by-product of triphenyl phosphine
(triphenylphosphine oxide) produced a large broad peak at a retention time that interfered
with the reagent and product peaks of the reaction. For the sake of the column and for
analysis dimethyl sulfide was used.

The second technical issue was the choice of oxidant. In the reported procedures
Oxone was exclusively used but this presents a problem in terms of reproducibility with

respect to the GC experiments. Oxone has a high molecular weight (614.76 g/2 mol of

oxidant, remembering it is a triple salt containing two parts KHSOS, one part KHSO4,

and one part K2804). The literature reactions were run with 4 equiv of Oxone (8 eq. of

oxidant), which is a large amount of salt per reaction (a 0.1 mmol scale reaction would
have 245.9 mg of salt).30 These salts can accumulate in the GC leading broader peaks

and cause unnecessary wear on the column. It was decided that for this study purified

KH805 (152.17 g/mol oxidant) would be used.31 The amount of salt in the reaction

would be decreased by over half (using KH805 a 0.1 mmol scale reaction would have

121.7 mg of salt if 8 equiv were used).

108

In order to further limit the amount of salt, filtering of samples before injection
was tested for reproducibility. This was not successful. The 5-methylenenonane was

used as a test reaction because it produced few by-products that can complicate the GC.

Also 4 equiv of KH805 was used initially in hopes of slowing the reaction but as is

shown in the results section this was abandoned in order to make the reactions more
consistent with the literature conditions. The reactions were filtered through several
materials (sand, silica, celite, and several combinations) after quenching. The filtering
process greatly diminished the reproducibility of the results. The ratio of products to
IST D changed depending on when the reaction was injected (before filtering compared to
after filtering). The ratios were not consistent form injection to injection. If the samples
were injected multiple times without filtering the ratio did not change significantly (2
1%). Due to these results the samples were injected into the GC without filtering because
the results were reproducible. The cause behind the filtering inconsistency was not
completely understood. It was thought that the internal standard and the starting material
and products were eluding from these pipet columns at difference rates. This was curious
because this happened at with all filtering material including sand, which is not generally
thought to separate materials in solution.
4.4 Results and Discussion

In order to test this methodology quickly and efficiently, gas chromatography was
utilized. An internal standard was chosen and a standard curve was made for each
substrate and product. Two internal standards (ISTD) were used throughout this project,
pentadecane and tetraglyme. Both were chosen for their appropriate retention time (both

appeared away for most products, reactants, and side-products) and their inertness to the

109

reaction conditions. By-products were also identified on the GC trace but Standard
curves were not always constructed for them. Instead, a percent conversion was
calculated from by-product comparisons. Standard reaction conditions were used for

each trial. The Standard conditions were 0.1 mmoles of substrate, 1 mL of solvent, 50 11L

of osmium tetroxide solution (1 g/20 mL of toluene), additives, 68.1 mg of KHS05 (4

equiv) or 136.2 mg (8 equiv), and 0.05 mmoles of ISTD. This allowed reactions to be
run in the GC vials for a predetermined time, quenched with dimethylsulfite, and injected

without transfer or filtering. A sample standard curve is shown in Chart IV-l for the 1,1-

disubstituted olefin and its cleavage product. The R2 values for all standard curves were

above 0.990.

Chart IV -1. Standard Curves for the 1,1 Disubstituted Substrate (IV-l3)

7.0 ., ---... _ - .. . .--_. ... . .. .--. .. ..-.--.-..-._....-... --...- .- --.-

9‘
o

y = 59.2687x + 0.0001
R2 = 0.9998

9"
o

P
o

y = 45.837Sx - 0.0279

 

Peak Area Ratios (Sub/ISTD)
w
0

 

R2 = 0.9998
2.0 4
1 0 i
’ f
I
0.0 - ‘ r 2 . r . i
0.00 0.02 0.04 0.06 0.08 0.10 0.12

mmols of Substrate

0 S-Methylenenonane I S-Nonanone

110

The first two sets of experiments were done with only 4 equiv of KHSOS. A

sample of 5-methylenenonane was the first subjected to the timed experiments (T able IV-
1). The reaction was complete in less than 80 min. (Entry IV-28), but the overall yield
was only moderate. A small peak was observed for the diol and ol-hydroxy aldehyde by-
products but not in any significant amounts. The a-hydroxy aldehyde would be cleaved

very quickly by a Baeyer-Villager type mechanism if formed.

Table IV-l. Cleavage of S-Methylenenonane with 4 equiv of KH805

0804 (0. 01 equiv)
KHSO5 (4 equiv)
VJVV + VV‘lL/V
DMF (0.1), Time (X)

“(.13 Tetraglyme (0. 25 equiv), RT “(.19

 

 

Entry RX“. Time (Mill) Olefin (% Detected)a 5-Nonanone (% Yield)b

 

IV-20 1 90.2 0.3
IV-21 10 370C 1.3 °
rv-22 20 -d 3.4
IV-23 30 68.3 8.9
1v-24 40 47.6 21.2
rv-2s 50 17.9 36.9
IV-26 60 10.6 44.5
rv-27 70 1.3 51.2
rv-2s 80 0.6 535
[v.29 90 0.6 54.2

 

All reactions were done in triplicate and averaged. All reaction used 0.1 mmol of
substrate with 0.01 equiv of 0304, 4 equiv of KHSOS, and 0.25 equiv of tetraglyme
(ISTD) in DMF (0.1M). The reactions were run for a certain time interval and quenched
with Me2S (8 equiv) and analyzed by GC. a(:l: 10%). b(:l: 4%). 6Done in duplicate only.
(I . . . .

Olefin peak merged With an impurity in the sample.

111

Table IV-2. Cleavage of l-Decene with 4 equiv of KH805

0804 (0.01 equiv)

 

KHSO5 (4 equiv) 0H
W -> W
DMF (0.1), Time (X) 0
lV-9 Tetraglyme (0.25 equiv), RT lV-30

 

Entry Rxn. Time (Min.) Olefin (% Detected) Nonanoic Acid (% Yield)

 

IV-3l l 93 .8 -
IV-32 10 75.8 1.1
IV-33 20 52 .8 5 .9
IV-34 30 32.7 14.2
IV-35 40 18.4 24.5
IV-36 50 10.6 28.1
IV-37 60 7.7 29 .2
IV-38 7O 3 .2 36.2
IV-39 80 3 .3 40.3
IV-40 90 0.4 395

 

All reactions were done in triplicate and averaged (:l: 4%). All reactions used 0.1
mmol of substrate with 0.01 equiv of 0304, 4 equiv of KHSOS, and 0.25 equiv of
tetraglyme (ISTD) in DMF (0.1M). The reactions were run for a certain time interval and
quenched with MeZS (8 equiv) and analyzed by GC.

Table IV -2 shows the results for the cleavage of 1-decene. The reaction was over
in less than 90 min. and again in lower than expected yields. This substrate did show
significant by-product formation so they were analyzed by peak area ratios (no standard
curve for the by-products was made) (Chart IV-2). Interestingly, a significant portion of
the material was converted to the a-hydroxy ketone (verified by injecting a pure sample).
These results suggested that two pathways are active in this reaction. The two pathways
are the direct cleavage reaction mechanism (Figure IV-3) and the oxidation to the or-
hydroxy ketone (Figure IV-4)32 followed by a Baeyer—Villager type oxidative cleavage .33

This data suggest that the selectivity observed by the Maleczka group was not due to the

112

order of the olefin but to the Sterics of the substrate. In order for selectivity to be achieved
between olefin classes, the rate of osmlyation must be different for each olefin. This
preliminary data Shows the Starting material being consumed at nearly the same rate.
Nonetheless, the Study was continued due to the higher than expected amount of or-
hydroxy ketone being produced during the cleavage reaction but the amount of oxidant
was raised to 8 equiv to make the condition more inline the reaction in which selectivity

was observed.

Chart-IV-Z. l-Deccne Product Ratios for 4 equiv of KH805

 

 

 

 

8.0 1
70 1Q
A 6.0 1
e 6
E 5.0 1 1
5
94.0 : 1
O
'5
g 3.0 .
3 Q ‘ 0 A 9 0
2 2.0 ‘ ‘ . ‘
31.0
R- . . . : . . . ‘ .
0.0 . 0 i t . t
0 20 40 60 80 100
Time (min)
. l -Dcccnc INonanal ‘Nonanoic Acid .alpha-l l) droxy

The group’s proposed mechanism was suggested due to two factors (Figure IV-3).

First, the oxidation of olefins with the OsO4/Oxone system proceeded just as well under

113

anhydrous conditions, making hydrolysis of the osmate ester as part of the cleavage
reaction impossible?0 Second, subjecting a 1.2-diol like 1,2-decanediol to the reaction
conditions does not yield cleavage products, as opposed to the Johnson-Lemieuxms type
cleavage of diol. This data supports this mechanism because of the appearance of
cleavage product early in the reaction. Also, diol is never observed in any significant
yield. The appearance of the a-hydroxy carbonyl product suggests that Lohray’s
suggested mechanism is active (Scheme IV—4).3236 Lohray suggests that the a-hydroxy
carbonyl results from the bisglycolate (IV-48). With t-butyl hydrogen peroxide (T BHP),

Lohray reported a mixture of diol and a-hydroxy carbonyl that varied depending on

conditions. With KHSOS, the diol pathway must be cut off leaving only the a—hydroxy

carbonyl. The a-hydroxy carbonyl can be readily cleaved in a Baeyer-Villiger type

oxidative cleave .33

Figure IV-3. Proposed Direct Cleavage Mechanism

 

 

 

0“ ’10 x I
R/=\R Os ‘2‘ u ’0
1 2 0804 0’ ‘0 [01 o’ ‘o
) ( a } { H03802
[3+2] R1 Hz R1 92
lV-41 lV-42 lV-43 IV-44
_ _ O 0
9 Q ,9
\9‘,OS,3°‘8303H . . R11 H R1/ILOH
o o Oxndatwe O [0]
——> > )L ——> i
Cleava e
__ Fi1 R2 J g Fl2 H R2 OH
lV-45 IV-46 lV-47

114

Figure IV-4. Lohray’s a-Hydroxy Ketone Formation

::I‘°”’::I :IOPS I:

03:5

 

 

lV-48 IV-49
t-BuOOH

ll

[0]

 

 

 

 

133.3121:
0 O
0 HR

9' 0 v

tBu

L. _

Solvent Cage IV-53
IV-52

Next, S-methylenenonane was subjected to the reaction conditions, but now with

 

 

 

8 equiv of KHSOS. Table IV-3 shows the percent yield at different time intervals. The

cleavage of IV-l3 was complete in 40 minutes, which was the timeframe of the
autolytimycin intermediate reaction. If selectivity was based on olefin order than
compound IV-l3 should have been largely untouched in that time interval. Since it was
complete in the 40-minute timeframe, this data suggest that the selectivity observed in the

autolytimycin intermediate cleavage is based on a factor other than olefin order.

115

Table IV-3. Cleavage of S—Methylenenonane with 8 equiv of KHSOS

0304 (0.01 equiv)

KH805 (8 equiv) O
\A/u\/\/ > V\/U\/\/
DMF (0.1), Time (X)

 

 

 

IV-13 Tetraglyme (0.25 equiv), RT “(.19

Entry RX“. Time (Milt) Olefin (% detected)al 5-Nonanone (% Yield)b
IV-54 1 99.8 0.9
IV-55 5 95.0 1.6
IV-56 10 87.7 4.1
IV-57 15 8 l .6 7 .5
IV-58 20 68 .7 14.1
IV-59 30 13 .0 41 .9
IV-60 40 2.0 55.7
IV-61 50 2.1 59.2
IV-62 60 2.2 59.0

 

All reactions were done in triplicate and averaged. All reactions used 0.1 mmol
of substrate with 0.01 equiv of 0304, 8 equiv of Kl-ISOS, and 0.25 equiv of tetraglyme
(ISTD) in DMF (0.1M). The reactions were run for the time interval and quenched with
MeZS (16 equiv) and analyzed by GC. fl: 4%) ”(a 3%).

Subsequently l-decene (IV-9) was retested to see if the trend matched the 1,1-

disubstitued olefin (IV-13). Table IV-4 shows that the cleavage is much faster (complete

in under 30 min.) with 8 equiv of KHSOS, which is consistent with the cleavage of the

terminal olefin in the autolytimycin intermediate. Unlike the 1,1-disubstituted substrate a
significant amount of a-hydroxy ketone was observed by GC and the peak slowly
disappeared after time. It has been shown that an a-hydroxy ketone can be cleaved by a
Baeyer—Villiger type reaction so the disappearance of this peak in proceeding through this
process. As the a-hydroxy ketone peak disappears the carboxylic acid peak increases.
At 10 min (Chart IV-3), the ratio between acid and a-hydroxy ketone was about 2:1, with

only a minimal amount of IV-9 present in the reaction. With the staring material

116

consumed the increase in acid formation must be due to the cleavage of the a-hydroxy
ketone, which takes place over a 20—30 minute period. This suggests that the acid
concentration at 10 minutes could not be solely due to the cleavage of a—hydroxy ketone,

but must be due to the suggested mechanism in the original work in 2002.30

Table IV-4. Cleavage of l-Decene with 8 equiv of KH805

0304 (0.01 equiv)

KH805 (8 equiv) OH
W + W
DMF (0.1), Time (X) 0
IV-9 Tetraglyme (0.25 equiv), RT lV-30

 

 

Entry RXD- Time (Mitt) Olefin (% Detected)a Nonanoic Acid (% Yield)b

 

IV-63 1 100.3c o.o°
IV-64 5 725 3.1

IV-65 10 25.9 23 .9
IV-66 20 2.9 515
IV-67 30 1.0 54.1
IV-68 40 0.0 575
IV-69 50 — 59.7
mm 60 - 59.8
rv-71 7o — 59.4

 

All reactions were done in triplicate and averaged. All reactions used 0.1 mmol of
substrate with 0.01 equiv of 0304, 8 equiv of KHSOS, and 0.25 equiv of tetraglyme
(ISTD) in DMF (0.1M). The reactions were run for the time interval and quenched with
Me2S (16 equiv) and analyzed by GC. 8 (:1: 6%) b (:1: 3%) chelds are from an average of
two runs.

117

Chart IV-3. l-Decene Product Ratios for 8 equiv of KH805

9.0 “i ' 1i
8.0 “Q

A

O 7.0 «

is

{6.0 .
a

5
(05.0 ‘
v

0
54.0 'i ‘ ‘ ‘ ‘
“3.0 ‘

(2.0 ‘
8

n
g 1.0

0.0 4|“ 3 I I i I I
o 10

20 30 40 50 60 70 80
Time (min)

Ol-Decene lNonanal ANonanoic Acid Oalpha-Hydroxy

 

0’0

1
1
1

 

 

 

With the data presented it is a good assumption that the selectivity observed for
the cleavage of IV-7 is due to the sterics around the olefin and not the olefin order
because both substrates were consumed in the same timeframe. However, the data also
suggest that the proposed mechanism for the cleavage is not complete, because of the
significant amount of a-hydroxy ketone produced in the terminal olefin cleavage (Table
VI-4, Chart VI-3). The immediate appearance of acid product in the cleavage of the
terminal olefin suggests the reaction may proceed through two pathways. The 1,1-

disubstitued substrate (IV -l3) did not show significant amounts or-hydroxy aldehyde. It

was thought to be formed by the reaction but quickly cleaved by KH805 due to the

reduced sterics. Further evidence of this will be shown below.

118

The other substrates were analyzed to show that the a-hydroxy ketone is an
alternative pathway for the other olefins orders. The cis and trans disubstituted olefins
were next to be examined. Table lV-S showed the percent yield for the cleavage of cis-6-
dodecene. The starting material was consumed in less than an hour (Entry IV-83) and the

reaction was complete (the a-hydroxy ketone was consumed) in 80 min (Chart IV-4).

Table IV-S. Cleavage of C is-6-Dodecene with 8 equiv of KHS05

0304 (0.01 equiv)

 

 

 

_ KHSO5 (8 equiv) ’ MOI-1
DMF (0.1), Time (X) 0

IV-1 1 Tetraglyme (0.25 equiv), RT IV-72

Entry Time (Min.) Olefin (% Detected) a Hexanoic Acid (% Yield) b

IV-73 1 96.4 0.3

IV-74 5 93 .3 0.6

IV-75 10 86.6 1.2

IV-76 1 5 78 .0 3 .4

IV-77 20 65.2 5.6

IV-78 25 62.5 8.3

IV-79 30 36.4 15.1

IV-80 40 10.4 3 1 .0

lV-8l 50 4.1 42.0

IV-82 55 6.5 42.9

IV-83 60 0.3 53 .5

IV-84 65 0.7 53 .6

1V-85 70 - 59.9

IV-86 75 — 1 53.2

IV-87 80 - 62.1

IV-88 90 - 62.2

119

Table IV-S. Continued

IV-89 100
IV-90 1 10

- 62.8
- 62.4

 

All reactions were done in triplicate and averaged. All reactions used 0.1 mmol of
substrate with 0.0] equiv of 0304, 8 equiv of KHSOS, and 0.25 equiv of tetraglyme
(ISTD) in DMF (0.1M). The reactions were run for the time interval and quenched with
MeZS (16 equiv) and analyzed by GC. a (a: 5%) b (:t 3%).

p—_-._—.__.__.. __ ”—.. . . .._.

(Sub/ISTD)
.9 .m 9 N 9°
C O O O O
L J l l I

i1

a

Peak Area Ratio
E" 9"
o o
I

...a
O
l
’

 

u" '
onto—‘3. ,

Chart IV-4. C is-6-Dodecene Product Ratios for 8 equiv of KH505

 

0 20 40

O Hexanoic Acid

 

Q Q
‘ Q
‘ A
i
. ‘ O ‘
LEI—H4 i i
60 80 100 120
Time (min)
IOIefin Aalpha-Hydroxy

The cleavage of trans-S-decene showed a similar profile when compared to the

cis-6-dodecene. Table IV-6 shows that the reaction is only marginally slower (~10 min.)

for trans olefins. Substrate was consumed in 55 min. while the a-hydroxy ketone

lingered until the 90 min. mark. The data is consistent with the trend of having two

mechanistic pathways.

120

Table IV-6. Cleavage of Trans-S-Decene with 8 equiv of KHSOS

0804 (0.01 GQUlV)

 

 

 

MM KHSO5 (8 equiv) > WOH
DMF (0.1), Time (X) 0
W40 Tetraglyme (0.25 equiv), RT lV-91
Entry Time (Min.) Olefin (% Detected) a Hexanoic Acid (% Yield) b
IV-92 1 91 .5 -
IV-93 5 86.5 —
IV-94 10 80.9 0.9
IV-95 20 73 .9 7.6
1V-96 25 66.6 10.0
IV-97 35 51.1 15.3
IV-98 40 41.6 20.3
IV-99 50 1 5 .7 32 .0
IV-100 55 3 .8 39.7
IV-lOl 75 - 54.9
IV-102 9O - 58.1
IV-103 105 - 61.0
IV-104 120 - 63 .8
IV-l05 135 - 63 .7

 

All reactions were done in triplicate and averaged. All reactions used 0.1 mmol of
substrate with 0.01 equiv of 0804, 8 equiv of KHSOS, and 0.25 equiv of tetraglyme
(ISTD) in DMF (0.1M). The reactions were run for the time interval and quenched with
Me2S (l6 equiv) and analyzed by GC. a (:1: 6%) b (:1: 4%).

121

Chart IV -5. Trans-S-Decene Product Ratios for 8 equiv of KH805

6.0
o
O
5.0 ’
a o
'—
w4.o ’ . o .
S e
a o
93.0 °
.2. ° .
$2.0 o
3
o
(1.0 o :A
x e. A‘ A
a A e A
Q A
0.0.0 at. ~ o o 6 6 o
0 10 20 30 4O 50 60 70 80 90100110120130140
Time(Min.)

’ Valeric Acid ’ t-5-Decene ‘ alpha-Hydroxy

The next substrate, 2-methyl-2-unadecene (IV-12), took much longer for the
reaction to go to completion. No substrate was observed after 90 min. (Entry IV-lll),
but there was little product (24.0%) formed during that time. As the reaction time more
product was formed. Chart IV-6 shows that the ratio of the a-hydroxy ketone equaled
that of acid product. As expected, the a-hydroxy ketone product underwent the Baeyer-
Villager type oxidative cleavage very slowly over 640 minutes at its maximum

concentration at 90 minutes (Entries IV-112-l39). The slow rate was due the steric

congestion around the a-hydroxy ketone, which would inhibit the attack of KH805 on

the carbonyl. This data set gives the best evidence that both mechanisms are present.

The formation of the a—hydroxy ketone and the initial acid product were at a similar rate

122

for the first 90 min. or until the olefin was consumed. Then the acid formation proceeded
slowly and in a similar rate to the disappearance of the a-hydroxy ketone. This suggests
that another pathway is responsible for the initial “fast” formation of cleavage product
and a-hydroxy ketone while olefin is present and the “slow” formation of acid product in

the absence of olefin, which is solely due to Baeyer-Villager type oxidative cleavage.

Table IV-7. Cleavage of 2-Methy1-2-Unadecene with 8 equiv of KHS05

0504 (0.01 equiv)

KH305 (8 equiv) OH
. DMF (0.1), Time (X) 0

 

 

 

~42 Tetraglyme (0.25 equiv), RT IV _30
Entry Time (Min.) Olefin (% Detected) Nonanoic Acid (% Yield)

IV-106 15 83.7 0.0 '
IV-107 30 73.9 2.2
IV-108 45 54.2 6.0
IV-109 60 30.0 1 l .3
IV-110 75 7 .2 17.8
IV-lll 90 0.4 24.0
IV-112 105 - 24.5
IV-ll3 120 - 25.3
IV-ll4 135 - 26.1
IV-115 150 - 26.9
IV-ll6 165 - 27.7
IV-ll7 180 - 28.7
lV-ll8 195 - 29.5
IV-l 19 210 - 30.7
lV-120 225 - 30.6
IV-121 240 - 32.2
IV-122 255 - 32.5

123

Table lV-7. Continued

IV-123 270 - 32.6
IV-124 300 - 32.7
IV-125 330 - 35 .1
IV-126 360 - 34.8
IV-127 390 - 35 .4
IV-128 420 - 37 .l
IV-129 450 - 38 .0
IV-l30 480 - 38 .9
IV-l3l 510 - 39.8
IV-l32 540 - 41 .1
IV-l33 570 — 51 .8
IV-l34 600 - 51 .3
IV-l35 630 - 52.0
IV-136 660 - 52.2
IV-l37 690 - 54.2
IV-138 720 - 55.1
IV-l39 750 - 57 .0

 

All reactions were done in triplicate and averaged (:1: 3%). All reactions used 0.1
mmol of substrate with 0.01 equiv of OsO4, 8 equiv of KHSOS, and 0.25 equiv of
tetraglyme (ISTD) in DMF (0.1M). The reactions were run for the time interval and
quenched with Me2S (16 equiv) and analyzed by GC.

124

Chart IV-6. 2-Methyl-2-Unadecene Product Ratios for 8 equiv of KH805
6.0 .._2_._-, -*-- -- ~ - - — , . .- . 2 _ ___

Peak Area Ratio (Sub/ISTD)
E" 9" 5‘ .U‘
o o o o
O

i“
o
J

 

 

A
‘W
0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800
Time (min)

OOIefln lNonanoic Acid Aalpha-Hydroxy

.0
0

Interestingly, the cleavage of the trisubstituted olefin proceeded without the need
for base (in the literature conditions sodium bicarbonate was used”). A preliminary
study was done with the trisubstituted olefin and 4 eq. of sodium bicarbonate. The GC
traces were messier with several of the key peaks doubling at several time periods and
several new unidentified peaks appeared. The rate did not seem to be effected (the
numbers were similar at intermediate time ranges, 240 min.). Base was also added to a
sample of the cis disubstituted olefin and the reaction slowed by almost half in the same
time period. This was not pursed any further due to the increased complexity of the GC
traces and the slow down of the reaction in the cis substrate.

The final substrate tested was the tetrasubstituted olefin (IV-l4). Due to the
extended reaction time for the trisubstituted olefin (IV -12), a sample reaction was run to

try to gauge the length of the reaction. The tetrasubstituted olefin yielded only starting

125

material after 48 hours (Scheme IV -3). This was not surprising considering the stability
of the osmate ester formed from a tetrasubstituted olefin. This substrate was abandoned
for this study due to its inability to either form the a-hydroxy ketone or oxidatively

cleave.

Scheme IV-4. Attempt at Cleaving the Tetrasubstituted Olefin
0so4 (0.01 equiv)
KH805 (8 equiv) O
m ’ W
DMF (0.1), 48h
Tetraglyme (0.25 equ1v), RT No: Jog? ed

 

IV-‘l4

The yields of the GC cleavage reactions were lower than expected. An isolation
study was done to verify the yield of the cleavage reaction (Table 1V-8). The isolation
yield for the cis olefin was the only substrate that was lower than the GC data, but it was
suspected that some of the small acid product was lost during the work-up and
purification steps. The isolation yields were higher for the mono, trans, and trisubstituted
systems. The main question now was why the GC yields were significantly lower. The
first hypothesis was that the product acids were precipitating out of solution as
carboxylates. This does not seem to be the case because the addition of strong acids (HC1

and H2SO4) did not improve the yields. The reaction media is acidic in nature (KH805 is

 

 

 

isolated at 3 .O pKa).
Table lIV-8. Isolation Results
080 (0.01 equiv)
R, 4 . o o
KHSO 8 UN
’_‘ 5(eq ) > n )LOH or RJLR
”2 ”3 DMF(O.1),RT,24h "3 ‘ 2
Entry Olefin % Yield
W
IV-l40 85%
IV-9

126

Table IV-8. Continued

W

IV-14l 63%
1v-1o

IV-l42 /—/—/—\j—\ 38%
lV-11

mm VVUVV 78%
1v-13

W

IV-144 >95%

Iv-12

 

All reactions were done with 1 mmol of olefin, 0.01 equiv of 0804, and 8 equiv
of KHSOS.

Due to the discrepancy between the GC and the isolated yield, the accuracy of the
standard curve was tested. The curves were not run with KHSOS in the vials and it was
thought this might change the ratio of products. A new curve was run with a new ISTD
(pentadecane) and the addition of KHSOS, but this did not change the results of a new
time trial (Table IV-9). This did not improve the yields of the reactions (IV-l45-153)
greatly (<5%) when compared to Table IV—4. The residual solid was then thought to be a
problem, so the reactions from Entries IV-l45-153 were decanted and then reinjected into
the GC (Entries IV-154-l62). The peak ratios were within 12% of the original injection
so the solid KHSO4 does not seem to affect the product ratio.

Table IV-9. Repeat Time Trial for l-Decene a New Standard Curve and ISTD

0304 (0.01 equiv)

KHSO5 (8 equiv) OH
W F W
DMF (0.1), Time (X) 0
lV-9 Pentadecane (0.25 equiv), RT IV-30

 

127

Table IV-9. Continued

 

 

 

Entry Time (min) % Olefin % Nonanoic Acid
IV-l45 5 56.4 9.2
IV-l46 10 20.2 33.0
IV-147 15 9.3 49.6
IV-148 20 5.5 56.6
IV-l49 25 4.2 57.5
IV-150 3O 3 .3 61.2
IV-lSl 35 2.4 65 .7
IV-152 40 2.1 64.3
IV-153 50 1 .8 63 .2
IV-154 5 54.0 . 9.1
IV-ISS 10 19.8 34.2
IV-156 15 9.0 51.5
IV-157 20 5.4 57.2
IV-158 25 4.1 58.0
IV-159 30 3.2 63.2
IV-160 35 2.4 64.1
IV-161 40 2.1 65.8
IV-162 50 1.8 64.6

 

All reactions were done in triplicate and averaged (:1: 3%). All reactions used 0.1
mmol of substrate with 0.01 equiv of OsO4, 8 equiv of KHSOS, and 0.25 equiv of
pentadecane (ISTD) in DMF (0.1M). The reactions were run for a certain time interval
and quenched with MeZS (16 equiv) and analyzed by GC. Entries IV-154-l62 were
decanted and reinjected.

4.5 Conclusion
This project started with a question about the selectivity of an oxidative cleavage
reaction in an autolytimycin intermediate and as that was being answered some insight

into the mechanism of the reaction was revealed. From the data presented in this chapter

128

it is clear that the selectivity of the autolytimycin intermediate (Scheme IV—l) was due to
either the steric hindrance of the molecule or neighboring group effects and not due to the
substitution pattern of the olefins (1,1—disubstistited verses monosubstituted). A 1,1-
disubstituted olefin (IV-13) and a terminal olefin (IV-9) were both consumed in nearly
same time period (under 30 minutes). This data suggests that the proposed mechanism

(Figure IV -3) is not the only pathway active in the reaction. A significant portion of the

Figure IV-5. Combined Mechanism

 

 

05 2,0
_ IOS\
”1 F12 OsO4 o o
_—’
[3+2] R1 F12
W41 W42
$101
/ ""\ 0.8.0 0
R1 R2 ‘09’ HO so6 1
I \ 3 2 H
n o 0 R 1v-41 0 0 R1
11 ((1) I/Oj: ‘ H M44 0
S +———
R o’ ‘o R R1 Ra Oxidative )L
”.43 2 IV 43 Cleavage F12 H
IV-46
Lohray’s
a-hyroxy [01
Mechanism
0
O Baeyer-Villiger-Type R1/IL0H
R F12 >
1 Oxidative Cleavage 0
IV-54 OH )L
F12 OH
lV-47

129

olefin substrate is converted to an a—hydroxy ketone and then cleaved through a Baeyer-
Villiger type reaction. The new proposed mechanism is presented in Figure IV-S. The
1,1-disubstituted olefin (IV-13) did not show a significant amount of a-hydroxy aldehyde
product. The Baeyer-Villiger pathway is likely active in this substrate but the a-hydroxy
aldehyde would cleave very quickly and is probably just not observed. The a-hydroxy
ketone is preferred over the a-hydroxy aldehyde in the monosubstituted olefin (IV-9) as
it is the only one observed in isolation reaction and by GC. The trisubstituted olefin gave
best evidence that the two pathways are independent of each other due to the
simultaneous formation of a-hydroxy ketone and acid product followed by the slow
consumption of the a-hydroxy ketone that yielded acid.
4.6 Experimental Details

All commercially available starting materials were used without further
purification. Commercially available starting materials were purchased from Aldrich and

Strem. All of the spectral data for known compounds either match those reported by
Aldrich or by comparison to the literature report. 1H, 13C, gCOSY, gHMBC, HMQC,
DEPT, and nOe spectra were recorded on either a 300 MHz NMR spectrometer

(VARIAN INOVA) or on a 500 MHz spectrometer (VARIAN VXR). Column

chromatography was performed using SIlicycle (40-60mm) silica gel. Analytical TLC

was done using pre-coated silica gel 60 F254 plates. GC analysis was preformed using
HP (6890 or 6950 Series) GC system.
Gas Chromatography Method:

An Agilant Technologies 6850 Series 11 Network GC System equipped with an

Agilant Tech. 6850 Series 11 Auto sampler was used for analysis. The column used for

130

all experiments was an Agilant Tech. J&W Scientific High Resolution Gas
Chromatography Column (19091Z-413E HP—l) with specifications: Length (m.) 30,
1.D.(mm) = 0.32 widebore, Film (um) = 0.25, and temperature limits = -60 °C to 325 °C
(350 °C). Method: Injection Temp. = 250 °C, Detector Temp. = 250 °C, Makeup gas =
Helium, Mode = Constant Pressure, Detector Temp. = 250 °C, Ramp = 60 °C for 2 min.
then ramped at 10 °C/min. until 300 °C then hold for 5 min.

General Procedure for the Preparation of Standard Curves

Stock solutions of the starting materials, by-products, and internal standard
(ISTD) were made (ranging from 1.0 to 0.1 M depending on solubility). All reactions
were done on 0.1 mmole scale so 0.05 mmoles of [ST D was used for a 4:1 substrate to
ISTD ratio. In each vial 0.05 mmoles of ISTD was added followed by varying amounts
(covering the range of the reaction = 0.01, 0.02, 0.03,. . ., 0.12 mmoles) of starting
material or by-product. The total volume was taken to 1 mL and injected into the GC.

The peak area ratio (X/ISTD) was then calculated and a line was applied to fit the data.

The R2 values were always greater than 0.990 or the curve was not used.

Standard GC Reaction Conditions

Stock solutions of the substrate (ranging from 0.5 to 2.5 M depending on
solubility) and internal standard (ISTD) (tetraglyme) were made. Then, 0.1 mmoles of
substrate were aliquotied into a 3.5 mL GC vial followed by 0.05 mmoles of ISTD (a
substrate to ISTD ratio of 4:1). The vials were diluted to 1 mL with DMF. 0.01 eq. (5
11L) of OsO4 (1 g/20 mL toluene solution) was added and stirred for 5 minutes.

Depending on substrate and solvent the solution may darken (indicative of osmium (V 1)).

131

11131131

10:13]

Next, 4 to 8 eq. of KH805 or Oxone was added and the time recorded. The solutions
were stirred a predetermined time period (1, 5 , 10, etc. . . min.) and quenched with
dimethylsulfide (2X eq. compared to the eq. of oxidant). The solutions would heat up
and foam. They were allowed to cool and the solid settle, after which they were injected

into the GC. The spectra were compared with a standard curve for analysis.

Purchased Chemicals

Chemicals purchased from Aldrich: l-decene (IV-9), trans-S-decene (1V10),
nonanone (IV-l9), nonanoic acid (IV-30), hexanoic acid (IV-72), penanoic acid (IV-91),
nonanal , hexanal, tetraglyme.

Synthesis of Cis-6-Dodecene (IV-11)

Hexyl triphenylphosphonium Bromide (1.0 mmol, 427.36 mg, 1 equiv) was

dissolved in dry THF at 0°C. n-Butyllithium (1.2 equiv of a 2.5 M in hexanes solution)

was added dropwise and the solution turned a dark red color. The solution was stirred for

1 hour at 0°C. Hexanal (1.2 equiv, 103 .4 mg) was added dropwise and stirred overnight.

The solution was diluted with diethyl ether and the solid was removed by filtrated and

discarded. The solution was extracted (3X) with water (100 mL). A column was run in

5% EtOAc/hexanes to purify the oil (first fraction). This yielded 1015 mg (60.3%). 1H
NMR (CDCI3; 300 MHz): 6 5.32 (m, 2H), 2.01 (m, 4H), 1.24 (m, 12H), 0.87 (t, 6H). 13C

NMR (CDC13; 75 MHz): 5 129.88, 31.55, 29.47, 27.17, 22.59, 14.03.

Synthesis of S-Methylenenonane (IV-l3)

132

in dr}
11an

i.

T‘ .
lllt‘:

.,
31x11}

1'393 1

n --
-3}

Methyl triphenylphosphonium iodide (1.0 mmol, 404.22 mg., 1 eq.) was dissolved
in dry T HF at 0°C. n-Butyllithium (1.2 equiv of a 2.5 M in hexanes solution) was added
dropwise and the solution turned a dark red color. The solution was stirred for 1 hour at

0°C. Then, 5-nonanone (1.2 equiv, 168 .3 mg) was added dropwise and stirred overnight.

The solution was diluted with diethyl ether and the solid was removed by filtrated and

discarded. The solution was extracted (3X) with water (100 mL). A column was run in

5% EtOAc/hexanes to purify the oil and the yield was 91% (127.3 mg). 1H NMR
(CDCI3; 300 MHz): 6 4.69 (q, 2H, J] = 0.9, 12 = 1.8), 2.00 (t, 4H, J, = 6.6), 1.38 (m, 8H),

0.93 (t, 6H, 11 =11.4). 13C NMR (CDC13; 75 MHz): 5 150.26, 108.36, 35.83, 30.11,

2255, 13 .97 .
Synthesis of 2-Methyl-2-Unadecene (IV-12)

lsopropyl triphenylphosphonium iodide (20.0 mmol, 7.70 g, 1 equiv) of was

dissolved in dry THF at 0°C. n-Butyllithium (1.2 eq. of a 2.5 M in hexanes solution)

was added dropwise and the solution turned a dark red color. The solution was stirred for

1 hour at 0°C. Nonanal (1.2 equiv, 2.805 g) was added dropwise and stirred overnight.

The solution was extracted (3X) with water (100 mL). A column was run in 5%

‘H

EtOAc/hexanes to purify the oil (first fraction). The reaction yielded 95% (2.66).
NMR(CDC13; 300 MHz): 6 5.10(tq,1H, J, = 1.2, 12 = 2.7, J3 = 5.4),1.95(d, 2H, J] =

6.6), 1.66 (s, 3H), 1.58 (s, 3H), 1.30 (m, 12H), 0.86 (t, 3H, 11 = 6.3); 13c NMR: (C00,;

133

75 MHz): 6 131.04, 124.98, 31.94, 29.94, 29.59, 29.39, 29.36, 28.07, 25.69, 22.70, 17.60,
14.08.

Synthesis of 5,6-Dibutyl-S-Decene (IV-14) by a McMurry Couplingfl'”

A 2-neck roundbottom flask equipped with a reflux condenser was filled with

THF (40 mL, dry) and zinc (24 mmoles, 1.6 g, 10 equiv) and it was cooled to -5°C

(MeOH and Ice). TiCl4 (12 mmoles, 2.18 g, 5 equiv) was added slowly (the solution

turned black and produced a yellow smoke). The solution was allowed to warm to RT
for 30 min. and was refluxed for 2.5 hours. The solution was again cooled to -5°C and
pyridine (6 mmoles, 483 u], 2.5 eq.) was added and stirred for 10 min. Then, S-nonanone
(2.4 mmoles 413.2 uL), dissolved in THF (5 mL), was added slowly, and then warmed to

RT. The solution was refluxed overnight. The solution was allowed to cool to RT and

quenched with 10% KZCO3/HZO solution. The aqueous layer was extracted with DCM

(3X). The organic layer was washed with brine and dried over anhydrous sodium sulfate.

The solvent was removed under reduced pressure and the oil purified by column

chromatography (hexanes). The reaction yielded 212.1 mg (70%) product. 1H NMR
(CDCI3; 300 MHz): 8 1.9 (m, 4H), 1.5 (m, 4 H), 1.3 (m, 16H), 0.9 (t, 12H); 13c NMR:

(CDC13; 75 MHz): 5 133.4, 78,7, 35.4, 31.5, 31.3, 26.8, 23 .7, 23.0, 14.1.

134

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Travis, B. R.; Ciaramitaro, B. P.; Borhan, B. Eur. J. Org. Chem. 2002, 3429-
3434.

Lohray, B. B.; Bhushan, V. Tetrahedron Lett. 1993, 34 , 3911-3914.
Yan, J.; Travis, B. R.; Borhan, B. J. Org. Chem. 2004, 69, 9299-9302.
Lemieux, R. U.; Johnson, W. S. Can. J. Chem. 1955, 33, 1714.

Pappo, R.; Allen, D. S.; Lemieux, R. U.; Johnson, W. S. J. Org. Chem. 1956, 21,
478-479.

136

(36) Wolfe, 8.; Ingold, C. F.; Lemieux, R. U. J. Am. Chem. Soc. 1981, 103, 938-939.

137

Chapter 5: Attempts at Elaboration of the Tetrasubstituted Pyrrolidine from a
Tandem Aza-Payne/Hydroamination Reaction
5.1 Introduction: The Tandem Aza-Payne/Hydroamination

The aza-Payne and hydroamination reactions were combined in our lab by Dr.
Jennifer Schomaker as an extension to her work with trimethylsulfoxonium iodide ylide
chemistry.” She reported a mild, tandem Aza-Payne/Hydroamination reaction of
aziridinols mediated by dimethylsulfoxonium methylide which yielded a highly
functionalized pyrrolidine ring in one-pot at ambient temperatures (Scheme V-l). These
substrates seem like attractive starting material for the synthesis of tetrasubstituted
pyrrolidines in natural products.

Scheme V-l. Mechanism for the Tandem Aza-Payne/Hydroamination Reaction

0

H
—m
I

Aza-Payne

‘
r

 

 

 

The aziridinols were synthesized from the corresponding aziridinals by Grignard
addition in good yields and usually good diastereomeric ratio (Table V-l). An R group

syn to the carbonyl caused the distereoselectivity to deteriorate (V-5 and V-l9). A trans

138

disubstituted aziridine gave only moderate dr. A 2,2,3—trisubstitued aziridine aldehyde
yielded the syn aziridinols in extremely high yields.

Table V-l Aziridinol Formation

 

 

 

 

 

R‘Tso 5: 31301184 121361494
Ra’lfl/IL 4 R M93' 2K1/‘\ 2%
H R § R §
83 F15 F13 R5
1 2
Syn Anti

Entry R1 R2 R3 R4 R5 Yield 1:2
V-S CH3 CHZOBn H H H 56% 1:1
V-6 H 0711, 5 H H H 67% 2.8:]
V-7 H (311203“ H H H 71% -
V-8 H CHZOBn CH3 H H 96% >95:S
V-9 11 Ph CH3 H H 90% >95:5
V-10 H pMeOPh CH3 H H 67% >95:5
V-ll H CH3 H H 93% >95:5
V-12 H CHZOBn CH3 H CH3 92% >95:5
V-13 H CHZOBn CH3 H Ph 91% >95:5
V-l4 H CHZOBn CH3 CH3 H 89% >95:5
V-lS 1H CHZOBn CH3 CH3 Ph 84% >95:5
V-l6 H CHZOBn CH3 H TMS 90% >95:5*
V-17 H CHZOBn CH3 H TIPS 98% >95:5*
V-18 H CHZOBn CH3 CZH H 80% -
V-l9 nBu CH3 CH3 H H 73% 1.2:1

 

A 0.028 M solution of the aldehyde in DCM was cooled to -78° C and treated
with 5 equiv of the Grignard reagent. *Lithium acetylide was used to prepare the
alcohol.

Table V-2 shows Dr. Schomaker’s results of the aza-Payne/hydroamination of the

synthesized aziridinols. Most proceeded in good yield but notable exceptions exist. If a

139

substituent other than phenyl or TMS was present at R5 the reaction only yielded the aza-

Payne rearranged product. Substitution at R], R2, and R3 seemed to have little effect on

the tandem process.

Table V-2. Aza-Payne/Hydroamination Results

 

 

 

0 F15
R‘ OH 4 _ "_ 1 I,
R2 .,\\R\\ _? ‘ gébif’
95 DMSO Ra " " 4
Entry R1 R2 R3 R4 R5 Yield
V-20 CH3 CHZOBn H H H 72%a
V-21 H 071115 H H H 82%
V-22 H CHZOBn H H H 73%a
V-23 H CHZOBn CH3 H H 76%
v.24 H Ph CH3 H H 71%
v-zs H pMeOPh CH3 H H 71%
V-26 H CH3 H H 65%
v.27 H CHzan CH3 H CH3 0%
63%
“28 H CHZOB“ CH3 H P“ 2:15 145:1
V-29 H CHzan CH3 CH3 H 64%
69%
V-31 H CHZOBn CH3 H TMS 68%
V-32 H CHZOBn CH3 H TIPS O%*
V-33 H CHZOBn CH3 02H H 28%
V-34 nBu CH3 CH3 H H 57%

 

The aziridinols (0.1 M

in DMSO) were treated with 4.0 equiv of
dimethylsulfoxonium methylide (prepared from Me3SOI and NaH in DMSO) and stirred
at rt. aYield starting from the epoxy amine.

140

This tandem process only worked with syn aziridinols, with the anti yielding only
the epoxyamines. This was thought to be due to a favorable orientation of the syn
substrate (Scheme V-2). This orientation is essential for the hydroamination reaction to
occur. The failure of reaction in the third line of Scheme V-2 shows that without a
functionality to restrict the orientation of the alkyne the reaction fails to undergo
hydroamination.

Scheme V-2. Syn vs. Anti Orientation

 

 

 

 

 

Ts
ESOH ,{l
BI'IO —'> ——> BDO
Q BnO .' ..
Me H L Me U
V-8 V-35 V-23
339+. TSWGED Ts\N|_b
BnO ’ ——> BnO ——> Bno
% Q %
Me H ’L Me H Me H
V-36 V-37 V-38
S?
=?— IDMSO
TSHNW > No Reaction
H or NaH ITHF
V-39

This chapter will focus on utilizing the product of this process to further
functionalize the pyrrolidine. Compound V-23 will be the standard compound used for

the remaining reactions.

141

C...
I a
H"-

“h

m

m:

ilSIiL

5.2 Attempts at Elaboration

The synthesis of compound V-23 is shown in Scheme V—5. The synthesis started
with the commercially available (Z) 3-methyl-2-propene-1-ol (V-40), which underwent a
benzyl protection of the alcohol .3‘5 This was followed by an allylic oxidation mediated
by selenium dioxide, which yielded a mixture of aldehyde and alcohol products. This
mixture was reduced using NaBH4. All these reactions were done without purification
until a column that was run to isolate compound V-4l. The allylic oxidation was
changed from Dr. Schomaker’s method and the method used was altered from the
literature procedure, which required the reaction to be run at room temperature for 2-3
days. This yielded a lower amount of desired products (mixture of alcohol and aldehyde)
(45-65%) and a significant amount of over-oxidized products. The other steps in the
sequence were high yielding (>95%) so improving the oxidation was the only way to
improve the yield of the sequence. Other selenium oxidations procedures called for t-
BuOOI-I/toluene under anhydrous conditions and at lower temperatures or aqueous t-
BuOOH at room temperature. A combination of these procedures resulted in an allyic
oxidation being set-up in a cold room (4° C) and run at different time intervals (3, 5, 7, or
9 days). The yield of the reaction increased when run for 5-7 days. It was also noted that
less over-oxidized product was formed. The reaction was also helped by the equivalents
of t-BuOOH being added over the time period (3 eq. to start and then an equivalent every
day). This change in the procedure allowed for improved yield and easier purification

after the reduction.

142

Scheme V-3. Synthesis of Compound V-23

1) NaH (1 equiv), 0°C to reflux

 

 

 

 

 

1 hour
2) Benzyl Bromide (<1 equiv), OBn Chloramine T
Y\/OH 0°C to reflux overnight HO/\I/\’ (1.1 equiv)
> +
V .40 3) $902 (30 mol%), tBuOOH V-41 NBS (20 mol%)
(3-7 equiv), (aq) 4' C, 5-7 days 55-75% ACN, overnight Fit
4) NaBH4, (<1 equiv), MeOH
(>o.2 M), -2o°C, 3h
T N - H Ts
S OBn PYSO3 (3-4 OQUIV), N .
H0/\'>\/ CH2C|2 (7 ml/mmol), OBn Ethynyl MgBr (5 equw)
> O ,
v.42 DMSO (dry. 2 ml/mmol). CH2012 (35 ml/mmol),
o, Et N 4 . , 0°C, 2 h V-43 -78’C. 4 h
4585/ 3 ( 6(1) 85-95%
0” Ts E8
N 1) NaH (4 equiv), (CH3)3$OI (4 equiv)
// DMSO (1 M) so min., RT BnO
OBn > 3' c.-
2) Aziridinol, DMSO (0.1 M) ’ ‘
V .44 RT, overnight _
85'950/0 7g.azsacy°
dr = 9515

Compound V-41 was aziridinated using chloramine T and NBS. This reaction
varied greatly in terms of yield and purity. A by-product of the reaction was sulfonamide
and if it was formed in significant yield, it would co-elute with aziridine product (V-42).
The yield of reaction depended on the purity and dryness of the chloramine T and the
NBS. The resulting aziridinol (V-42) was oxidized to the aziridinal (V-43) with a Parikh-
Doering oxidation.6 Compound V-44 was the result of an alkynyl Grignard addition to
the aziridinal (V-43) with the same dr as reported.1 The final pyrrolidine was then
subjected to the tandem aza-Payne/hydroamination conditions to yield compound V-23.

Compound V-23 is an interesting molecule in terms of stereochemistry and
functional group diversity. It contains an enamine, an epoxide, and 3 stereocenters that

result from the configuration of the materials used. Figure V-l illustrates the possible

143

chemistry that could be used to elaborate the pyrrolidine. These points of reactivity will
be examined in the rest of this chapter.
Figure V-l. Pyrrolidine Product Potential Elaboration
Hydrogenation

Ts
N / “SNZ' Chemistry
BnO/jfx, , Iminium Chemisty

’\

O
Epoxide Opening

5.2.1 Reduction of the Enamine
The hydrogenation of the enamine in a stereoselective fashion was the first

reaction attempted on this structure. This was necessary due to the propensity of the

substrate to undergo SN2’ type reactions which after internalization of the enamine led to
pyrrole formation by elimination the resulting hydroxyl group (Scheme V-4) or
completely degrade under stronger nucleophilic systems. The pathway destroys the

stereochemistry set up by the reaction. It could have potential for forming

tetrasubstituted pyrroles but that was not pursued.
Scheme V-4. SN2’ to Form Pyrroles

Ts Ts Nu Ts

 

 

N . N Nu
B O Nucleophrle B O / Dehydration N
n > n =
.3 ... (Nu) BnO \ /
" ’OH

With relative stereochemistry already present in the molecule it was hoped that an
achiral catalyst would reduce the enamine selectively. Several catalysts were tried with
minimal success (Table V-3). The first catalyst tried was Pd/carbon but this only

provided a complicated mixture of products (presumably benzylated and debenzylated

144

diastereomers)(Entries V-45 and V-46).7B Next, Crabtree’s iridium catalyst was tried but
this reaction failed to reduce the enamine and yielded only starting material (Entry V-
48).““1 The failure of Crabtree’s catalyst was thought to be the steric bulk of the catalyst.
It was thought that the steric hindrance around the enamine might demand more forcing
conditions to facilitate reduction. Platinum (IV) oxide was used in acetic acid but these
conditions proved to be too severe for this molecule and lead to decomposition (Entry V-
47).‘2 Hydride reductions with sodium cyanoborohydride only lead to complex mixtures

that were inseperable or starting material (Entries V-49 and V-50).

Table V-3. Hydrogenation Conditions

 

 

 

T
1.3 NS
3.10/y Hydrogenation ’ Eng/pf
"a, 5" Conditions "a, s"
O
V-34
Entry Conditions Yield Selectivity
Pd) EtOAc (2.5M), RT, 12h
V -46 H2 (1 atm), Pd/C (20 wt% 0% N / A

Pd) EtOAc (2.5M), RT, 12H
Pt20 (20mol%) H2 (1 atm)

V-47 Acetic AcidzTFA (85: 1 5), 0% N/A
RT, 12h (Degraded Material)
1:(con)(py)(pr3)+ (5
V'43 mol%), H2 (1 atm), DCM 0% N/A
(1M) RT, 12h (SM- only)
_ NaCNBH3 (1 eq.) MeOH 0%
V 49 (0.1M) pH = 3.4 (Degraded Material) N/A
V-50 NaCNBH3 (1 eq) MeOH 0% N / A
(0.1M) (S.M. only)

145

Table V-3. Continued
V-Sl (Ph3P)RuCl (5 mol%), H2 70% 3:1
(1 atm). DCM, RT,4h
V-52 (Ph3P)RuCl (10 mol%), H2
(1 atm), DCM,RT,4h

84% 95:5

 

After these failures, another catalytic system was chosen, Wilkinson’s Catalyst
[(Ph3P)3RuCl|.l3 The first reaction was run with 5 mol% of catalyst and the result was an
inseparable 3:1 mixture of product and starting material (Entry V-51). The reaction was
repeated with 10 mol% of catalyst which provided only one diastereomer by NMR in
84% yield. The relative stereochemistry was determined by nOe experiments. In Figure
6, hydrogen 1 shows nOe to the methylene next to the O-Benzyl group, while the methyl
hydrogens do not show any nOe to the same methylene. Both show nOe to the hydrogen
alpha to the nitrogen but that is not uncommon for five-membered rings. Presumably, the
methylene alpha to the nitrogen forces the tosyl group on the nitrogen to be in a trans
relationship. The tosyl then blocks off the bottom face of the molecule, which only
allows the hydrogenation catalyst to come from the top face of the molecule.

Figure V-2. nOe on Hydrogenation Product and Suggested Conformation

Hydrogenation
Approach

 

146

With enamine hydrogenated and the possibility of SN2’ reaction eliminated, it
was thought that opening the epoxide would be quite facile. Table V-4 shows that it was
not an easy task. A large variety of Grignard reagents and lithium reagents were used but
were not effective at opening the epoxide (Entries V-53-72). The less substituted side of
the epoxide does not appear to be blocked by the new methyl group but it still is
unreactive to nucleophilic attack under these basic conditions. Two Lewis acids (SnBr4
and BF3-EtzO) were used in hopes of activating the epoxide but this also failed to yield
product with only starting material being recovered (V-73-78). When protic reagents

were used the molecule fell apart (V-80 and V-9l). This area of research is still ongoing

 

 

 

147

in the lab.
Table V-4. Attempts at Opening the Epoxide of V-63
Ts Ts
N Nucleophile (5 equiv) N
3.10/j) Additive (X equiv) BnO/j—Z
'. .' > '.
30$ THF (0.31M), Overnight OH Nu
-78 C to RT
V-52
Entry Nucleophile Additive Result
V-53 nBuMgBr None N o Rxn
V-54 MeMgl None No Rxn
V-SS PhLi None No Rxn
V-56 VinylMgBr None No Rxn
V-57 EthynylMgBr None No Rxn
V-58 CH3CCMgBr None No Rxn
V-59 PhMgBr None No Rxn
V-60 MeLi None No Rxn
V-61 EtMgBr None No Rxn

V-62 IsopropenylMgBr None No Rxn
V-63 nBuMgBr CuI (lOmol%) No Rxn
V-64 MeMgI Cul (lOmol%) No Rxn
V-65 PhLi CuI ( 10mol%) No Rxn
V-66 VinylMgBr Cul (lOmol%) No Rxn
V-67 EthynylMgBr CuI (lOmol%) No Rxn
V-68 CH3CCMgBr Cul (lOmol%) No Rxn
V-69 PhMgBr CuI (lOmol%) No Rxn
V-70 MeLi CuI (lOmol%) No Rxn
V-7l EtMgBr CuI (lOmol%) No Rxn
V-72 IsopropenylMgBr CuI (lOmol%) No Rxn
v.73a PhMgBr SnBr4 (lSmol%) No Rxn
v.74a EthynylMgBr SnBr4(15mol%) No Rxn
v--75a EtMgBr SnBr4(15mol%) No Rxn
V-76" PhMgBr BF3-OEt2(10mol%) No Rxn
v.77a EthynylMgBr 1313-01312 (lOmol%) No Rxn
v-7s“ EtMgBr BF3°OEt2(10mol%) No Rxn
v-79a NaCNBH3 13133-01512 (30mol%) No Rxn
V-80b TFA None Degraded
V-81c Perchloric Acid None Degraded

Table V-4. Continued

 

All the reactions were done with 0.13 mmol of 8M. All Grignards and Lithium
reagents were purchased. 3The reactions were done with 0.065 mmol of 8M. bThe
reaction was done in THFzHZO (1:1, 0.1M). cThe reaction was done in THFzflzO (1:1,
0.1M), 5 drop of perchloric Acid was used at 40° C.

5.2.2 Toward Understanding Alkyne Substitution
A limiting factor for the aza—Payne/hydroamination reaction is that the enamine
cannot be substituted except with a phenyl or TMS group (Table V-2, Entries V-28, V-

30, and V-31). All other substituents attempted (methyl and TIPS) yielded only the aza—

148

Payne product (Entries V-27 and V-32).l An electronic argument could explain this so a
series of aziridinols were synthesized to test the electronic requirrnents of the reaction.
Due to the inability of the methyl substituted alkynyl aziridinol to undergo
hydroamination a series of substituted aziridinols were synthesized (Table V—S). The
styrene derivatives were synthesized from a lithium-halogen exchange reaction(Entries
V-82 and V-83). The [Si-styrene starting material was a mixture of cis/trans isomers
which produced an inseparable mixture of the 4 possible isomers and the only pure
product was V-13 from an elimination/rearrangement reaction. The alkynyl ester (V-82)
was deprotonated with t—butyl lithium but the addition to the aziridinal only led to a small
amount of product and mostly side reactions presumably from Michael additions.”15 The
four para substituted aromatics (V-85-88), the cyclohexenyl and the methylcyclopentyl
all provided product in good yield (except the nitro and amino substituted substrate) by
deprotonation of the alkyne with n-butyl lithium. The para substituted alkynes used for
nucleophilic addition were synthesized by a Sonogashira coupling.'6"7 The
trifiuoroalkyne proved more demanding but was synthesized by the method in Scheme V-
7.18 Compound V-91 underwent an elimination and subsequent deprotonation to yield the
trifluoroethynyl anion. The aziridinal was added and the addition occurred in good yield.

Table V-S. Substituted Aziridinol

 

 

 

Ts Ts
O N Nucleophile(5 eq.) HO N
H)K}>\/03n , Xxx/OBn
0 R1
THF, 78 C, 5-12 h
V-43 V-82
Entry Rl Method Yield (symanti)
P“ ‘5: Lithium/Halogen .
V-83 \fl Exchange 60% (95.5)

149

V-85

V-86

V-87

V-88

V-89

V-90

V-9l

V-92

aYielded only V-l3 and an inseparable mixture of diastereomers

Table V-S. Continued

Ph/\":

0
MGOK’:

p-MeOPhenylethynyl
p-NOzPhenylethynyl
p-MePhenylethynyl

p-MezNPhenylethynyl

 

F3C : g-

032—}:-
0%:-

150

Lithium/Halogen

Exchange

Alkynyl
Deprotonation

Alkynyl
Deprotonation
Alkynyl
Deprotonation
Alkynyl
Deprotonation
Alkynyl
Deprotonation
Alkynyl
Deprotonation
Alkynyl
Deprotonation
Alkynyl
Deprotonation

14%a

42% (95:5)
79% (27:1)
25% (2:1)
73% (4:1)
50% (95:5)
72% (95:5)
81% (95:5)

86% (95:5)

-. .‘Qs'l'fi Ur"

 

Scheme V-S. Synthesis of Aziridinols

OH Ts

 

 

F30 1) LDA (2 equiv), -78°C, 10 min N
> T /
B, 2) Aziridinal (1 equiv) -78°C / OBn
Overnight, N2, THF (0.5M) F30
V-92 V-90
o T5 1) nBuLi (5 equiv), THF, OH Ts
N -78 C, x (5 equiv) N
OBn R
H >-
2) Aziridinal (V43), RT, 12 h OBn
V43 Fi _ I
X = a-methyistyrene or B-bromostyrene (52 mix) _ ©/\ : /\\“l.:.
Ts OH Ts

 

o '1‘ 1) LDA (3 equiv), -78° C N
OBn Alkyne (3 equiv), THF A
H

2) Aziridinal (V43), HT, 12 h
V43

R = (p)MeOPh, (p)MePh, (p)MezNPh, (p)N02Ph
MeOCO, CpCHz, 11-Cyclohexenyl

The aziridanols in Table V-S were reacted under the standard aza-
Payne/hydroamination procedure. The results are listed in Table V-6. It shows that the
electronic nature of the aromatic ring can greatly effect the hydroamination reaction in
this tandem process. The electron withdrawing nitro group pushes the reaction
completely to the hydroamination product (Entry V-93) but in lower yield due to an
unknown degradation mechanism. Presumably, the para nitro phenyl group stabilizes the
intermediate alkenyl anion. This presumption is further verified by the electron donating
groups, which slowed down the hydroamination allowing for isolation of the aza-Payne
product. The weakly donating methyl group (Entry V-96) provides a 4:5 mixture of

products while the strongly donating methoxy group (Entry V-94) slows the reaction

151

down even further. The dimethyl amino group lead to decomposition of the material for
reasons not understood.
Table V-6. Aza-Payne/Hydroamination of Alkynyl Substituted Aziridinols

1) NaH (4 equiv), RT ,Ts

 

 

0“ Ts (CH3)3SOI (4 equiv) TS “1 “N
N DMSO (1 M) so min. N / 0 can
/ —> BnO
/ 0311 2) Aziridinol, DMSO (0.1 M) //
91 RT, overnight ‘0“ R
1
A B
Entry R1 Yield A/B

 

v-93 ozu—Qg- 45% 95:5
v-94 Meo—Qg- 95% 1:3
v.95 MezN—Qg- 0%3 _
V-96 HacOi— 50% 5:4
V-97 Q;— 92% 1: 17.5

911 ,
V-98 \lf‘t 63% 5:95
V-99 Meoac-g— 0% a -

V-100 Fac-E— 0% a -

H2
v-ror O—c - - 62% 5:95

 

All reactions were run with 4 equiv of the ylide (NaH and (CH3)3SOI combined
for 30 min) in dry DMSO. The reactions were run overnight at RT under N2. aReaction
degraded completely. No product starting material or by-products could be isolated.

With the electronic effect outlined in the aryl case, a trifiuoromethyl group should
have undergone the aza-Payne-hydroarnination, but this reaction only decomposed the
starting aziridinol. This was interesting because the electron withdrawing trifiuoromethyl
group was thought to be able to stabilize the alkenyl anion much like the nitro substituted

aryl group but this was not the case. A conjugative alkyne (Entry V-97) was then tested

152

but only trace amounts of hydroamination product were observed by NMR and a pure
sample could not be isolated.

These results show a clear electronic effect in the aryl cases. Electron
withdrawing groups will lead to only hydroamination products while electron-donating
groups will lead to sluggish reaction and isolation of mixtures of aza-Payne and
hydroamination products. Other substitutions are still as unclear as before. The

trifluororomethyl substrate did not lead to product as expected, so an electronic effect for

non-aryl substituents is not clear at this time. The steric ramifications of a carbon sp3

center at the alkyne could interfere with the reaction (the TMS substrate proceeded in
good yield but it was removed during the reaction) but if that were only the case the
conjugated cyclohexenyl substrate (Entry V-97) should have under gone the
hydroamination but failed to do so. Attempts to add substituents to this position after the
tandem aza-Payne/hydroamination will be discussed in subsequent sections.

5.2.3 Catalytic Nature of the Aza-Payne/Hydroamination Procedure

The proposed mechanism for this reaction suggests that the ylide is acting as a
proton shuttle, deprotonating the aziridinol and protonating the resulting vinyl anion
(Scheme V-3). A question presents itself, is the ylide necessary for the reaction to occur
and if so why are four equivalents necessary. The first experiment to probe this

mechanism was to confirm that the ylide is shuttling the proton or if it is just acting like a

base. DMSO-D6 was used as solvent in the aza-Payne/hydroamination reaction. The

reaction proceeded normally with the pyrrolidine product exhibits no incorporation of

deuterium in the enamine portion of the molecule. This suggests that the proton source is

153

the ylide or the aziridinol itself, thus supporting assumption that the ylide is acting as a
proton shuttle.

The sulfoxonium ylide is an interesting choice of base. Is the proton shuffling
ability of the ylide necessary for completion of the reaction? A catalytic amount of base
should start the proton shuffling process. The first bases that was chosen was a catalytic
amount of ylide, sodium hydride, and potassium tert-butoxide. The results are listed in
Table V-7. The reaction worked extremely well on a small scale (Entries V-103, 105,
106, and 108) but failed to give satisfactory yields on scale-up (Entry V-104).
Interestingly, one full equivalent of base provided excellent yield of the hydroamination
product so the protonation of the vinyl anion may occur in the work up. The ylide is not
needed for small-scale reaction nor is sodium hydride the only effective base. The
reaction also works well on small scale with a catalytic amount of ylide is used (Entry V-
107). The reactions with potassium tert-butoxide gave the product but with a small
amount of an unidentifiable and inseparable by-product (Entry V-108).

Table V-7. Results of Hydroamination with Catalytic Amounts of Base

 

 

 

0H ES Base (X mol%) NS 0 HN’TS
mos. 5:125:55? ’ ”if we...
' 2' e // .
V114 V-823 V-1c02
Entry Base (Xmol%) Additive (Ymol%) Yield (A:B:C)
V-103 NaH (25%) None 84% (B)
v-104a NaH (25%) None 43% (B) 43% (0:45)
V-105 NaH (50%) None 80% (B)
V-106 NaH (100%) None 89% (B)

154

Table V-7. Continued
V-107 NaH (25%) Me3SOI (25%) 87% (B)
V-108 t-BuOK (25%) None 80% (B)

 

All reactions were run with 100 mg of starting material. a 200 mg of starting
material used.

The next question addressed was the solvent. In all other reactions, DMSO (dry)
was the only solvent that provided the tandem reaction. A list of four solvents (DCM,
benzene, diethyl ether, and THF) were used for the reaction. Table V-8 shows that all
four solvent were ineffective at the tandem process with only the starting material
isolated. Solubility of the base was questioned because the lack of aza-Payne product.
DMSO was shown to be the optimai solvent so soluble bases were then considered for
the reaction (Table V-9). These reactions lead to products but only mixtures of aza-
Payne and starting material were isolated. The product ratios show that the aza-Payne
reaction is catalytic. Interestingly, the product ratio was always around a 3:2 mixture of

SM. and aza-Payne (AZPY) product.

Table V-8. Solvent Test with NaH and t-BuOK

 

 

 

T
OH NS Base (X mol%), N2, NS 0 HN,Ts
fib
m Solvent (0.1M), 12h Bro/if N03"
OBn ,2 5'
a s //
V44 V43 v-1o2
Entry Solvent Base Result
V-109 THF NaH No Rxn
V-110 DCM NaH No Rx“
V-lll Et20 NaH No Rxn

155

Table V-8. Continued

V-112 Benzene NaH No Rxn
V-113 THF t-BuOK No Rxn
V-114 DCM t-BuOK No Rxn
V-l 15 Et20 t-BuOK No Rxn
V-ll6 Benzene t-BuOK No Rxn

 

All reactions were done with 200 mg of starting material. The lack of reaction
was confirmed by crude NMR and TLC.

Table V-9. Soluble Base Test

0” Ts

 

 

 

T
N Base (x mol%), N2, NS 0 NHTS
—>
MOB" DMSO (01 M), 12h lam/1f Moon
15
V44 V-23 V-102
A B 0
Entry Base (X mol%) Result (A:C)
V-117 nBuLi (5%) 60:40
V-118 nBuLi (10%) 60:40
V-119 nBuLi (25%) 60:40
V-120 MeMgl (5%) 64:38
V-121 MeMgI (10%) 66:35
V-122 MeMgI (25%) 65:44

 

All reactions were run with 100 mg of starting material.

The catalytic process for the tandem aza-Payne hydroamination works well on a
small scale, but the process fails on scale-up. The solvent needs to be DMSO for the aza-
Payne rearrangement to take place. Also, the Grignard reagents and lithium reagents are
catalytic for the aza-Payne rearrangement but will not undergo hydroamination. The base

is not as important (the ylide, NaH, and t-BuOK work well) as the solvent (DMSO is the

156

only one that allows the reaction to occur). Other DMSO soluble bases might let the
reaction proceed without the need for the ylide.

5.2.4 Bromination of the Enamine

With the failure of the reaction to accommodate substituents at the enamine
position of the pyrrolidine, a new approach was needed to achieve substitution other than
hydrogen, phenyl, and TMS. Bromination of the enamine could be a powerful handle
due to the sheer number of coupling reaction available. Two options present themselves
in terms of bromination, (1) brominating the alkyne before the tandem aza-
Payne/hydroamination and (2) direct bromination of the enamine. It will be shown in this
section that both methods were successful in yielding a brominated pyrrolidine but
fortuitously with opposite geometry.

Jorgensen had reported an easy alkynyl bromination procedure in his study of or-
alkynylation of cyclic [:"i-ketoesters.1920 Scheme V-6 illustrates Jorgensen’s procedure.
Since the stability of alkynyl bromides is a question, it was decided that this method
should be tried in tandem with the aza-Payne/hydroamination. Scheme V-7 illustrates
this 3-step process. Compound V-123 was not isolated or purified, but simply the solid
was filtered though silica and the solvent removed before proceeding with aza-
Payne/hydroamination. These reactions proceeded in good yield but with a mixture of
compounds V-124 and V-23. The best reaction yielded a 2:1 mixture of V-124 and V-23
in a yield of 90%. A complete conversion to the brominated pyrrolidine could not be
accomplished by this method so an alternate method was pursued. The geometry of

compound V-124 was confirmed by crystal structure by Aman Kulshrestha.

157

Scheme V-6. Jorgensen’s Alkynyl Bromination

NBS, AgNO3 (10 mol%)
E—COzMe 6 Br : 002Me
acetone, RT, quant.

 

 

Scheme V-7. Tandem Alkynyl Bromination Aza—Payne/Hydroamination

 

 

 

AgN03 (0.1 equiv) OH
OH 115 NBS (1.1 equiv) (£18
>
// Acetone RT 3h //
' ' OBn
OBn Br A
we ‘ v-123

1) NaH (4 equiv), RT

(CH3)3SOI (4 equiv) NS /3' {,8
DMSO (1 M) 30 min. > Bn 01-7/1 Bro/17¢
2) Aziridinol, DMSO (0.1 M) '6‘ 90:

RT, overnight

 

V-124 V-23

A report in 1991 outlined a procedure for successful bromination of an enamine
(Figure V-3).21 They then go on to exchange the bromide for a lithium for Michael
additions. These mild conditions should not interfere with the other functional groups of
the pyrrolidine. The non-selective nature of this reported reaction was a concern, but it
was hoped that the present rigidity of the molecule would allow for selective
bromination. The reaction was run and after some slight optimization (Scheme V-8) the
reaction was successful on small scale (80% yield on 100 mg scale). The amount of
bromine added is important, excess bromine caused the reaction to fail due to the
inability to adequately purify the product. Interestingly, the regiochemistry of the
bromine changed (confirmed by crystal structure). This process gave access to the E
isomer. The regiochemistry is not unprecedented as Wittig reaction of exocyclic

protected enamines gives the same geometry.

158

Figure V-3. Enamine Bromination

1. Br2, Et20 -60° c,

NR21 30 min, then RT B
R2J\ > R2544 r
2. Et3N, Et20

-20° C to RT Ft"

 

Scheme V-8. Pyrrolidine Bromination

Ts . TS
N 1) Bra (1.5 GQUIV), Etzo

N
2) Et3N (2 equiv) "a

-20°C to RT, then I

overnight in freezer
V-23 V-125

 

’I

The bromination worked well with molecular bromine, but it was thought that
another source of bromine would improve the reaction work-up procedure. The most
common source of bromine is NBS, which has several advantages over bromine. NBS is
a stable solid that is easy to purify by recrystallization. Also, the temperature
requirement for the reaction in Scheme V-7 might be averted by the change in bromine
source.

A qualitative test of this reaction was done to determine the validity of the

approach (Table V-lO). The quenching agent, either water or Et3N, had little (effect on

the result of the reaction. Triethylamine was used to crystallize the triethylamine
hydrobromide by-product. More than 1.5 eq of NBS caused the product or starting
material to degrade. it was decided that 1.1 equivalents of NBS would be ideal for
pushing the reaction to completion and to allow the brominated product to be isolated by
a simple filtration. A 1 mol reaction proceeded in 68-75% yield with only a filtration
(Scheme V-9). It should be noted that repeating this reaction with NCS did not yield

product, only the recovery of starting material.

159

Table V-10. Qualitative Study of the NBS Bromination of the Pyrrolidine

TS TS

 

 

 

N NBS (x equiv) N
8,9 (0.1 M) , ,
" ~‘ Quench (3 equiv) ,0:
V-23 V-125
Entry NBS (X eq) Quenching Agent Qualitative Results
V-126 1 Et3N ' Pure V-125
Complete
“127 1 '5 Et3N Conversion
No SM,
V428 2 5‘3” Minimal V-125
V-129 S Et3N No SM, No Product
V-130 1 H20 Pure V-125
V-l3l 1.5 H20 Pure V-125
No SM,
V432 2 “20 Minimal v.125
V-132 5 H20 No SM, No Product

 

All reactions were run with 50 mg of V-34 dissolved in 1.5 ml of dry Et20 with X
eq of NBS. The solution was stirred overnight at RT under N2. The solutions were
quenched with either Et3N or H20 placed in the freezer for 6—8 h and filtered. The

solvent was dried with Na2804 and the solvent removed. The residue was analyzed by
lHNMR. No yields were determined.

Scheme V-9. Conditions used for Bromination

T8 T8

 

N 1) NBS (1.1 equiv), Eth (0.1 M) N
BID/if RT' N2’ 12“ BnO/jfBr
.. .' V, .0 I.
'3 2) EtaN (3 equiv). -20° C, 7-8h ,0.
then filtered
V'23 was

With access to both the E (V-125) and Z (V-124) isomers a large amount of

coupling reaction can be considered to further elaborate the pyrrolidine. Aman

160

Kulshrestha has continued this research and has used these brominated structures in Stille
and Heck couplings.

5.2.5 Miscellaneous Reactions

Dr. Jennifer Schomaker showed that the structural rigidity provided by the
epoxide and the relative stereochemistry is necessary for the reaction toproceed. One
question was if the alkyne is spaced by a methylene will the reaction proceed to form a
piperidine structure or not. This would provide a new synthon for piperidine containing
natural products.

Figure V-4. Proposed Piperidine Synthesis

 

OH 1) Na” (4 equiV). (CH3)3SOI (4 equiv) T8
T3 DMSO (1 M) 30 min., RT B o N
W 2) Aziridinol. DMSO (0.1 M) a .
OBn RT, overnight \.
v-133 v-134

Figure V-4 illustrates the proposed method. The aziridinol (V-124) could be
synthesized from the aziridinal (V-43) by a Grignard addition of propargyl bromide
(Scheme V-lO). Unfortunately, the reaction of the V-124 under the aza-
Payne/hydroamination conditions did not yield the desired piperidine. Only compound
V-135 could be isolated. This compound is the result of an aza-Payne rearrangement
followed by the elimination of the resulting hydroxyl. The extra degrees of freedom
afforded by the methylene must result in an unfavorable conformation that places the
alkyne too far from the nitrogen anion for hydroamination to occur. If the methylene
could be substituted it could limit the rotations around that bond and limit the

conformations.

161

Scheme V-10. Piperidine Attempt

 

O Ts 1) Propargylbromide, Mg \ OH Es

W03" HgCl (20 mol%), Et20 W
H >
2) Aziridinal (v-54), DCM 03"

v.43 -78 C 75% v.133

1) NaH (4 equiv), (CH3)3SO| (4 equiv) mHTs
DMSO (1 M) 30 min., RT \\ 0 OBn

> /

 

2) Aziridinol, DMSO (0.1 M)
RT, overnight V-135

Another avenue of study utilized to elaborate the pyrrolidine was to oxidatively
cleave the enamine to the lactam. Dr. Schomaker utilized a diol cleavage method
(conversion of the olefin to a diol then an oxidative cleavage). Ozonolysis proved to be
an easier way to access the lactam (Scheme V-l 1). Unfortunately, the lactam epoxide
was as difficult to open with the pyrrolidine. Several Grignards (PhMgBr, VinylMgBr,
ethynylMgBr, and phenylethynylMgBr) and nBuLi yielded only degraded material with
no product or starting material visible by TLC or NMR.

Scheme V-ll. Ozonolysis of the Pyrrolidine

Ts Ts

 

N N o
1) 03, DCM, -78° C 10 min
BnO > 8110
3,, g 2) Zn dust (2 equiv), ‘s,’ g
Acetic Acid, Quantitive O
v.23 V-136

5.3 Conclusion

The functionalization of the pyrrolidine synthon is still in its infancy. The reason
for the inability to hydroaminate with an alkynyl substituent (other than phenyl, bromine,
or TMS) is an unresolved issue for the scope of the reaction. This problem has been

addressed in an indirect fashion. The successful bromination of the enamine, with both

162

regiochemistries available, has opened the door to a host of coupling possibilities (ex.
Stille, NHK reaction, Negishi, etc) that is still being pursued in the lab. The oxidation of
the enamine to the lactam has also been achieved by dihydroxylation followed by
cleavage or directly by ozonolysis. The most glaring deficiency for functionalization is
the lack of success in working with the epoxide functionality. This must be achieved to
show the usefulness of this synthon. It has become obvious that the epoxide is quite
stable and standard Grignard additions will not be successful. More reactive nucleophiles
such as zinc reagents could be the answer. Also, acid methods have been shown to react
with the epoxide, albeit in either a non-selective or destructive fashion. Lewis acid
mediated epoxide opening is another option for functionalization of the molecule.
5.4 Experimental Details

All reaction were run under nitrogen unless otherwise stated.

Drying of DMSO

in a 1000 mL round-bottom flask, 10-20 g of CaH was added followed by 500 mL
of DMSO. The flask was attached to a simple distillation head equipped with a
thermometer. A 100 ml. of round-bottom flask was attached to the collection arm. The
system was attached to a vacuum pump and the pressure reduced to less than 100 mTorr.
The 1000 mL flask was heated until the DMSO started to collect in the 100 mL flask.

When the collection flask was three fourths full it was removed and replaced with a 500

mL round-bottom with 4~Angstrom molecular sieves. The DMSO from the 1St fraction

was discarded because water will azeotrop with DMSO. The distillation continued until
the collection flask contained 350—400 mL of DMSO. The collection flask was purged

with nitrogen and sealed. The distillation apparatus was allowed to cool and was exposed

163

to atmosphere. The remaining DMSO and CaH was cooled in an ice bath and the CaH
was quenched slowly with water.
Benzylation of 3-Methyl-But-2—en-l-ol (V-40)l
\l/\/OH %OBn
V-40

First, sodium hydride of 60% in mineral oil (4.04 g 60% in mineral oil, 100 mmol)
was dissolved in THF (35 ml) and 3-methylbut-2-en-l-ol (8.613 g, 100 mmol) was added
to the solution dropwise at 0° C. The solution was then warmed to reflux for 1 hour. The
solution was cooled to 0° C and benzyl bromide (18.813 g, 100 mmol) was added. The
solution was then refluxed overnight. The reaction was quenched with water, the THF
was removed through reduced pressure, and the residue was dissolved in ethyl acetate.
The organics were washed with saturated sodium bicarbonate (1X), water (IX), and brine
(1X). The product was purified by column (10% EtOAc/Hexanes) in 95% yield (3 .348.8
g). 1H NMR (300 MHz, CDCI3) 6 7.4 (m, 5H), 5.5 (m, 1H), 4.6 (s, 2H), 4.1 (d, 2H), 1.8
(s, 3H), 1.7 (s, 3H); l3CNMR (75 MHz, CDCl3) 6 138.5, 137.0, 128.2, 127.6, 127.4,

121.0, 72.0, 66.5, 25.7,18.0.

Selenium Oxidation of the Allylic Benzyl Ether (Benzyl V-4l) and Reductionl

OH

OBn
——> YVOBn

\KVOB"
(i
OBn
/
YV v-41

First, selenium oxide (2.838 g, 25.7 mmol) and t-butyl hydrogen peroxide (30 mL
of a 70% aqueous solution) was dissolved in DCM (100 mL) and stirred for 30 min.
Then, 3-methyl-2-buten-1-ol benzyl ether (16.743 g, 95 mmol) was added to the solution
and the mixture was stirred for 22 hours at room temperature. The reaction was
quenched with sodium bisulfite, diluted with DCM, washed with saturated sodium
bicarbonate (1X, 100 mL), water (1X, 100 mL), and brine (1X, 100 mL). The combined
organics were dried in sodium sulfate and the solvent was removed under reduced
pressure to yield a 3:1 aldehyde to alcohol ratio. The crude mixture was reduced without
further purification (265% of mixture). The crude 3:1 mixture of aldehyde and alcohol
was dissolved in methanol and cooled to 0°C. Sodium borohydride (0.6 eq, 2.156 g, 57
mmols) was added slowly to the solution. The color of the solution changed rapidly
(brown to yellow to clear) and the solution boiled violently. The solution was stirred for
two hours and then quenched with aqueous acetone. The methanol was stripped and the
residue was dissolved in ethyl acetate, washed with water (2X, 50 mL), and the organics

were dried with sodium sulfate. The solvent was removed and the product was purified

by column (20% EtOAc/Hexanes) to yield 9.612 g (50% from the benzyl ether). 1H NMR
(300 MHz, CDCl3) 6 5.6 (t, 1H), 4.5 (s, 2H), 4.05 (d, 2H), 3.95 (d, 2H), 3.05 (t, 1H), 1.6

(s, 3H); 13C NMR (75 MHz, CDCI3) 6 139.3, 138.0, 128.1, 127.6, 127.4, 120.6, 72.0,

67.3, 66.0, 13.6.

Protection, Oxidation, and Reduction of Allylic Alcohol (V-40 to V-41)l

16S

 

OH
%OH ———-> %OBn
V-40 V-41

Sodium hydride (4.04 g 60% in mineral oil, 101 mmol) was dissolved in

50 mL of THF and 3-methylbut-2-en-1-ol (8.699 g, 101 mmol) was added to the solution

dropwise at 0° C. The solution was then warmed to reflux for 1 hour. The solution was
cooled to 0° C and benzyl bromide (17.103 g, 100 mmol) was added. The solution was

then refluxed overnight. The reaction was quenched with water, the THF was removed
through reduced pressure, and the residue was dissolved in ethyl acetate. The organics
were washed with saturated sodium bicarbonate (1X), water (IX), and brine (1X). The
crude product was added to a premixed solution (30 min.) of selenium oxide (30 mol%)

and t—butyl hydrogen peroxide (2.5 eq, 60% in water) in DCM (200 mL). The solution
was stirred for 5-7 days at 4° c. It was then diluted with DCM and washed with
saturated sodium bicarbonate (1X), water (IX), and brine (1X). The organic layer was

dried with sodium sulfate and the DCM removed under reduced pressure. The residue ‘

was dissolved in methanol (250 mL) in a round bottom flask equipped with a water

condenser and cooled to -20° C (ice/methanol bath). Sodium borohydride (0.8 boron eq)

was added in small portions over the course of an hour. The reaction was stirred for 3
hours. The methanol was stripped and the residue redissolved in ethyl acetate and

washed with water (IX) and brine (1X). The product was purified by column (60%

EtOAc/Hexanes) in a 62.3% yield (17.283 g). 1H NMR (300 MHz, CDCl3) 6 5.6 (t, IR),

166

4.5 (s, 2H), 4.05 (d, 2H), 3.95 (d, 2H), 3.05 (t, 1H), 1.6 (s, 3H); 13C NMR (75 MHz,

CDC13) 6 139.3,138.0,128.1, 127.6, 127.4, 120.6,72.0,67.3,66.0, 13.6.

Aziridation of V-41 to Aziridinol (V-42)l

OH

TsN
YVOB" ’ HOAb/OBn

V-41 V-42

 

The allylic alcohol (9.612 g, 50 mmol, 1 eq) was placed in 175 mL of acetonitrile.

Anhydrous Chloramine-T (15.492 g, 55 mmol, dried under vacuum for 12 hours at 70°

C) and N-bromosuccinimide (0.895 g, 0.1 eq) were added successively and the light
yellow slurry allowed to stir overnight. The reaction mixture was quenched with water
and extracted 3x with portions of ethyl acetate. The combined organics were washed
with brine and dried over sodium sulfate. The solvent was removed under reduced

pressure and a white solid was purified by column chromatography in 64% yield (1.1566
g). 1H NMR (300 MHz, CDC13) 6 7.8 (d, 2H , J = 8.2 Hz), 7.1-7.4 (m, 7H), 4.4 (s, 2H),
4.0 (d, 2H,J = 6.7 Hz), 3.6 (dd, 1H, J =10.4, 4.9 Hz), 3.5 (t, 1H, J = 7.0 Hz), 3.4 (t, 1H, J
= 4.9 Hz), 3.2 (t, 1H, J = 7.0 Hz), 2.4 (s, 3H),1.4(s, 3H); 13C NMR (75 MHz, CDC13) 6
143.9, 137.5, 137.1, 129.4, 129.3, 128.3, 128.2, 127.6, 127.4, 72.9, 67.0, 65.2, 562,484,

21.4, 16.1.

Parikh-Doering Oxidation of Aziridinol (V-42) to Aziridinal (V-43)l

Ts
TsN H N
H OAFVOBn _> 02%08n
V42 V43

167

The alcohol (1.583 g, 4.38 mmol, 1.0 eq) was dissolved in 35 mL of dry

dichloromethane and cooling to 0° C. Triethylamine (2.41 mL, 17.5.0 mmol, 4.0 eq) was

added, followed by a solution of Parikh-Doering reagent (SO30Py) (2.09 g, 13.1 mmol,

3.0 eq) dissolved in DMSO (dry, 10 mL). The reaction was stirred for 30 min and the
solution diluted with 30 mL of diethyl ether and 60 ml. of hexane. The combined
organics were washed with saturated sodium bicarbonate, then 1 M sodium phosphate,
monobasic. The water layers were back-extracted with hexane/diethyl ether and the
combined organics washed were with brine, dried over sodium sulfate and the volatiles
were removed by rotary evaporation. The residue was purified by column

chromatography (9:1 hexanes/ethyl acetate) to give the desired aldehyde in 85% yield
(1.338 g). 1H NMR (300 MHz, CDCl3) 6 9.5 (s, 1H), 7.8 (d, 2H, J = 8.4 Hz), 7.1-7.4 (m,
7H), 4.4 (s, 2H), 3.8 (dd, 1H, J = 6.8, 5.1 Hz), 3.6 (dd, 1H,J =10.8, 5.1 Hz), 3.5 (dd, 1H,
J = 10.8, 6.9 Hz), 2.4 (s, 3H), 1.4 (s, 3H); 13C NMR (75 MHz, CDC13) 6 194.3, 144.7,

137.3, 136.1, 129.7, 128.4, 127.9, 127.57, 127.52, 126.43, 73.2, 66.5, 56.6, 48.9, 21.6,

11.9.

Gridnard addition to Aziridinal (V-43) to Aziridinol (V-44)l

 

Ts OH Ts
H I N
N OBn /
OM / OBn
V-43 V-44

The aldehyde (0.359 g, 1 mmol, 1.0 eq) was dissolved in 35 mL of dry

dichloromethane and cooled to -780 C. Ethynyl magnesium bromide (10 mL of a 0.5 M
solution in THF, 5.0 mmol, 5.0 eq) was added dropwise over 10 min and the reaction

168

stirred for 2 h. Saturated ammonium chloride was added and the aqueous mixture
extracted 3x with portions of dichloromethane. The combined organics were washed
with brine and dried over sodium sulfate. The crude product was purified via column

chromatography (9:1 hexanes/ethyl acetate) to give the aziridinol in 85% yield (327.7
mg). 1H NMR (300 MHz, CDC13) 6 7.8 (d, 2H, J = 8.0 Hz), 7.1-7.3 (m, 5H), 4.9 (dd,
1H, J = 2.5, 25 Hz), 4.45 (d, 1H, J = 11.8 Hz), 4.35 (d, 1H, J = 11.8 Hz), 3.66
(overlapping signals, 2H), 3.4 (overlapping signals, 2H), 255 (d, 1H, J = 0.9 Hz), 2.4 (s,
3H), 1.5 (s, 3H); 13C NMR (75 MHz, CDC13) 6 144.2, 137.5, 136.8, 129.6, 129.4, 128.2,

127.6,127.3,127.1, 80.2,74.5,72.7,66.7,64.9, 57.8,48.8, 21.5,12.9.

Hydroamination of Aziridinol (V44) to Pyrrolidine (V-23)1

Ts
OH Ts N
N
m ———> my
/ OBn '2 5'
WM v-23

Dimethylsulfoxonium methylide was prepared by treating NaH (0.42 g as a 60%
dispersion in mineral oil, 10.4 mmol, 4.0 eq) in 26 mL of dry DMSO with portions of
trimethylsulfoxonium iodide (2.3 g, 10.4 mmol, 4.0 eq). Once the addition of the
trimethylsulfoxonium iodide was complete, the milky-white suspension was stirred for an
additional 30 min. The aziridinol (1.0 g, 2.6 mmol, 1.0 eq) dissolved in 1 mL of DMSO
was added and the reaction was stirred overnight at rt. The reaction mixture was
quenched with water and extracted 3x with portions of ethyl acetate. The combined
organics were washed with brine and dried over sodium sulfate. The crude product was

purified via column chromatography (9:1 hexanes/ethyl acetate) to give the pyrrolidine

169

product in 80% yield (801.8 mg). 1H NMR (300 MHz, CDC13) 6 7.6 (d, 2H, J = 8.1 Hz),

7274 (m, 7H), 5.4 (d, 1H, J = 0.9 Hz), 4.8 (d, 2H, J = 0.9 Hz), 4.6 (d, 1H, J = 12 Hz),
4.5 (d, 1H, J = 12 Hz), 4.0 (br m,1H), 3.8 (2 overlapping d, 2H), 3.4(d,1H, J = 0.9 Hz);

13C NMR (75 MHz, CDC13) 6 144.0, 142.4, 137.8, 134.4, 129.3, 128.4, 127.7, 127.6,

99.0, 73.8, 70.7, 65 .4, 62.7, 62.4, 21.6, 14.2.

Hydroamination to the Pyrrolidine (V-23) using Deuterated DMSO

Ts
OH Ts N
N
/ two/1f
/ OBn "a c“
v-44 V-23

Dimethylsulfoxonium methylide was prepared by treating NaH (0.42 g as a 60%
dispersion in mineral oil, 10.4 mmol, 4.0 eq) in 26 mL of dry DMSO-D6 with portions of
trimethylsulfoxonium iodide (2.3 g, 10.4 mmol, 4.0 eq). Once the addition of the
trimethylsulfoxonium iodide was complete, the milky-white suspension was stirred for an
additional 30 min. The aziridinol (1.0 g, 2.6 mmol, 1.0 eq) dissolved in 1 mL of DMSO-
D6 was added and the reaction stirred overnight at rt. The reaction mixture was quenched
with water and extracted 3x with portions of ethyl acetate. The combined organics were
washed with brine and dried over sodium sulfate. The crude product was purified via
column chromatography (9:1 hexanes/ethyl acetate) to give the pyrrolidine product in

78% yield (781.8 mg). The NMR of the product showed no deuterium incorporation.

Hydrogenation of the pyrrolidine (V-23) with Wilkinson’s Catalyst (Entry V-52)

170

Ts Ts

N N ,m

’\ ’\

 

V-23 V-52

First, the pyrrolidine (V-23) (100 mg, 0.2594 mmol) and Wilkinson’s catalyst (24
mg< 10 mol%) were dissolved in of DCM (2.5 mL). The solution was put under an
atmosphere of hydrogen gas and stirred for 4 hours at rt. A column isolated one fraction,
which was product (V-52). This yielded 84.3 mg of product (83.9%). 1H NMR (500
MHz, CDCl3) 6 7.7 (d, 2H, J = 85 Hz), 7.3-7.2 (m, 7H), 4.5 (ABQ, 2 H, 1J = 12 Hz, 2J =
54), 4.1 (dd, 1H, ’J: 3, 21 =10.5),4.1 (s, 1H), 4.0 (q, 2H, ‘1: 6.5 Hz, 21 = 27,31: 20),
3.7 (d, 1H, J = 10.5), 2.3 (s, 3H), 1.5 (s, 3H), 1.3 (d, 3H, J = 65); 13C NMR (125 MHz,
CDC13) 6 142.6, 140.4, 138.0, 129.3, 128.3, 127.6, 127.4, 126.5, 73.5, 71.1, 65.8, 65.6,

61.9, 57.0, 21.4, 14.6, 14.5; HRMS - [M-l-H] = 388.18 (cal. 388.16)

a-Methylstyrene addition to the Aziridinal (V-43) to form Aziridinol (V-83)

H TS 0'" Ts
OBn
V-43 V-83

First, a-methylstyrene (108 uL, 3 eq.) was dissolved in THF (15 mL). The

solution was cooled to -78° C. Then, nBuLi (600 uL of 2.5M in hexanes, 5 eq) was

added dropwise and the solution turned a yellow color. The aziridinal was dissolved in 1

mL of THF and added dropwise to the solution. The solution was stirred at -78° C for 1

hour and then warmed to room temperature (the solution turned black). The reaction was

171

quenched with sat. ammonium chloride and extracted (3X) with DCM. The organics
were washed with brine, dried with sodium sulfate, and the solvent was removed under

reduced pressure. A column produced (10% EtOAc/Hexanes) produced pure product in

60% yield (66.8 mg). 1H NMR (300 MHz, CDCl,) 6 7.8 (d, 2H, J = 8.1 Hz), 7.1-7.4 (m,
5H), 6.9 (m, 2H), 5.6 (t, 1H J = 1.5), 5.3 (t, 1H, J = 1.5), 5.1 (t, 1H, J = 2.1) 4.0 (ABq,
2H, 1J = 12.3, 21 = 17.7), 3.9 (d, 1H, J = 2.4), 3.0 (m, 2H), 2.7 (dd, 1H,1J = 2.4, 2J =
9.9), 2.3 (s, 3H), 1.2 (s, 3H); 13C NMR (75 MHz, CDCl3) a 147.4, 143.9, 140.2, 137.6,

137.3, 129.4, 128.5, 128.1,127.9,127.6,1275,1272,115.0, 74.2,72.4, 66.8, 57.6, 50.7,

21.5. 12.6, Melting Pt.=110—114 °C.

Hydroamination of alkenyl aziridinol (V-83) to aza-Payne Product (V-98)

OH Ts
N O NHTs
OBn OBn
V-83 V-98

First, trimethylsulfoxionium iodide (457.6 mg, 2.08 mmols, 4 equiv) and of
sodium hydride (83.2 mg, 2.08 mmol, 4 equiv, 60% in mineral oil) was dissolved in
DMSO (dry, 5 mL) and stirred for 30 minutes. Then, aziridinal (244 mg, 0.52 mmol)
dissolved in DMSO (dry, 1 mL) was added and the solution was stirred overnight under
nitrogen at room temperature. The solution was quenched with water (15 ml) and
extracted (3X) with EtOAc. The organics were washed with brine and dried with sodium
sulfate. The solvent was removed under reduced pressure. Column chromatography

(20% EtOAc/Hexanes) purified 152 mg (62.3%) of the aza-Payne product. No trace of

hydroaminated product was detected. 1H NMR (300 MHz, CDC13) 6 7.3 (m, 12H), 7.0

172

(d, 2H, J = 6 Hz), 5.6 (d, 2H, J =15 Hz), 5.3 (d, 1H, J = 7.2 Hz), 5.0 (t, 1H, J :12 Hz),
4.3 (ABq,2H,1J = 11.7, 2J = 31.2 Hz), 3.6 (m, 2H), 3.3 (m, 2H), 2.3 (s, 3H), 1.6 (s, 3H)
13C NMR (75 MHz, CDCl3) a 161.0, 143.0, 141.4, 137.5, 137.4, 136.9, 129.2, 128.3,
128.2, 128.1, 127.7, 127.5, 127.0, 126.3, 112.7, 73.1, 69.3, 65.8, 64.1, 50.6, 21.4, 19.8,
Melting Pt. = 68-73 °C.

Addition of methyl propiolate to the Aziridinal (V-43) to Aziridinol (V-85)""15

TS OH Ts
H I N
N B
OBn
M3020
V-43 V-85

First, diisopropylamine (215.8 (1L, 1.4 mmol) was dissolved in THF (dry, 3 mL)

and cooled to -78° C. Then, nBuLi (560 (1L, 1.4 mmol of 25M in hexanes) was added
and the solution was warmed to -20° C for 30 minutes. The slightly yellow solution was

cooled to -78° C and diluted with THF (dry, 25 mL). Methyl propiolate (116.8 11L, 1.4

mmols) was added dropwise and the solution was stirred for 70 min. Then, aziridinal

(359.5 mg, 1 mmol) dissolved in of THF (dry, 1 mL) was added dropwise to the solution

and stirred for 24 hours at -78° C under nitrogen. TLC showed only two spots, one of
which was starting material so the solution was warmed to -40° C for 1 hour and then to

0° C for 1 hour. The solution was quenched with 1 mL of a 50% aq. HCI solution and

allowed to warm to room temperature. The solution was extracted with EtOAc (3X) and

the combined organics were washed with brine and dried over sodium sulfate. The

173

solvent was removed and the residue was purified by column chromatography (10%

EtOAc/Hexanes). Two fractions were obtained. Fraction one was starting aziridinal

(18.5%, 65 mg.). Fraction two was product aziridinol (110 mg, 24.8%). 1H NMR (300
MHz, CDCI3) a 7.8 (d, 2H, J = 1.8 Hz), 7.3—7.1 (m, 7H), 5.0 (s, 1H), 4.4 (ABq, 2H, 1J =
12 Hz, 2J = 19.2 Hz), 3.7 (s, 3H), 3.6 (m, 2H), 3.4 (m, 2H), 2.4 (s, 3H), 1.5 (s, 3H); 13C

NMR (75 MHz, CDC13) 6 153.2, 1445, 1375, 136.6, 129.5, 128.3, 127.7, 127.4, 127.3,

83.1,77.3,72.8,66.6,65.0,57.1,52.8,48.6,21.6, 13.3.
p-Ethynylanisole Addition to Aziridinal (V-43) to Aziridinol (V-86)

Ts OH Ts
N

N]
0W ——» c a

V-43 M90 v-as

To a solution of LDA (3 eq) at -78° C in THF (05M), p-ethynylanisole (107 11L,
0.83 mmol) in 1 ml of THF was added dropwise and stirred for 70 min. Then, aziridinal
(100 mg, 0.27 mmol) dissolved in THF (dry, 1 mL) was added dropwise. The solution
was stirred for 12 hours at -78° C, -40° C for 1 hour, 0° C for 1 hour, and then room
temperature for 24 hours. The THF was removed and the residue was dissolved in
EtOAc and washed with water and brine. Two spots appeared .on TLC (10%
EtOAc/Hexanes) and both were UV active. Both spots were isolated by column
chromatography (10% EtOAc/Hexanes). Fraction one was a complex mixture. Fraction
two was the product (115 mg, 85%, 27:1 symanti mixture). 1H NMR (300 MHz, CDCl,)

(syn product) 6 7.9 (d, 2H, J = 6.6 Hz), 7.5-7.2 (m, 9H), 6.9 (d, 2H, J = 6.9 Hz), 5.2 (d,

174

1H, J = 2.1 Hz), 45 (ABq, 2H, 1J = 11.7 Hz, 21 = 19.2 Hz), 4.4 (s, 3H), 3.9 (m, 4H), 3.5
(s, 3H), 1.6 (s, 3H); HRMS — [M+Na] = 514.1664 (cal. 514.1660).

Hydroamination of anisolylaziridinol (V-86) to pMeOPh Pyrrolidine (V-94)

OMe

 

M90 V416 V414

Dimethylsulfoxonium methylide was prepared by treating NaH (38.4 mg as a
60% dispersion in mineral oil, 0.96 mmol, 4.0 eq) in DMSO (dry 1 mL) with portions of
trimethylsulfoxonium iodide (211.2 mg, 0.96 mmol, 4.0 eq). Once the addition of the
trimethylsulfoxonium iodide was complete, the milky-white suspension was stirred for an
additional 30 min. The aziridinol (115 mg, 0.24 mmol, 1.0 eq) dissolved in DMSO (dry,
1 mL) was added and the reaction stirred overnight at rt. The reaction mixture was
quenched with water and extracted 3x with portions of ethyl acetate. A column at 20%
EtOAc/Hexanes yielded 42 mg (37%) of an isomeric mixture (1:4, hydroaminationzAza-
Payne). The mixture could not be resolved under any solvent system used.

Sonagashira Coupling of p-bromonitrobenzene for Entry V-9722

Br—O—N02 ——> :—-<;>—No2

To a mixture of trimethylsilyacetylene (1.18g, 12 mmols) and p-
bromonitrobenzene (2.02 g, 10 mmol) in triethylamine (40 mL)

bis[triphenylphosphine]palladiumdichloride (114mg, 0.2 mmol) and copper (I) iodide (10

175

mg, 0.1 mmol) was added. The reaction mixture was stirred at room temperature for 4
hours under nitrogen. The solvent was removed and the green-black residue was
dissolved in water and EtOAc. The water layer was extracted (3X) with EtOAc and the
combined organics were washed with brine. The solution was dried with sodium sulfate
and the solvent was removed. The residue was washed through a silica gel plug with
EtOAc (to remove the palladium) and the solvent was removed. The residue was
dissolved in methanol and 10 mL of 1N KOH and stirred for 1 hour. The methanol was
removed under reduced pressure and the residue was dissolved in diethyl ether and

washed with water and brine. The black solid was purified to a white solid on silica gel

column (5% EtOAc/Hexanes). The reaction yielded 1.3 g. (88%) of product. 1H NMR

(300 MHz, CDC13) 6 8.2 (d, 2H,J = 9.3 Hz), 7.6 (d, 2H,J = 9 Hz), 3.3 (s, 1H)

p-Nitroethynylbenzene Addition to Aziridinal (V -43) to Aziridinol (V-87)

OH Ts

    

OBn

V43 02” v-s7

To a solution of LDA (2 eq) at -78° c in THF (05M), p-nitroethynylbenzene (309

mg, 2 mmol) in THF (dry, 10 mL) was added dropwise and stirred for 70 min. Then,

3595 mg (1 mmol) of aziridinal dissolved in 1 mL of dry THF was added dropwise. The

solution was stirred for 12 hours at -78° C, -40° C for 1 hour, 0° C for 1 hour. The THF

was removed and the residue was dissolved in EtOAc and washed with water and brine.

Two spots appeared on TLC (10% EtOAc/Hexanes) and both were UV active. Both

176

spots were isolated by column chromatography (10% EtOAc/Hexanes). Fraction one was

the excess p-nitroethynylbenzene. Fraction two was product (139 mg, 27.4%, dr symanti

2:1), but was a distereomeric mixture. 1H NMR (300 MHz, CDC13) (Fraction 2, major
isomer) 6 7.8 (d, 2H, J = 8.4), 7.3-7.1 (m, 7H), 4.9 (d, 1H, J = 3.6), 4.4 (ABq, 2H, 1J =
12.3, 2J =16.2), 3.8(s,1H), 3.5 (m, 2H), 3.4 (m, 2H), 2.4 (s, 3H),1.4(s, 3H)

Hydroamination of p-Nitroaziridinol (V-87) to pNOZPh Pyrrolidine (V-93)

 

02N v-e7 v-93

Dimethylsulfoxonium methylide was prepared by treating NaH (43.8 mg as a
60% dispersion in mineral oil, 1.09 mmol, 4.0 eq) in DMSO (dry, 10 mL) with portions
of trimethylsulfoxonium iodide (2412 mg, 1.09 mmol, 4.0 eq). Once the addition of the
trimethylsulfoxonium iodide was complete, the milky-white suspension was stirred for an
additional 30 min. The aziridinol (139 mg, 0.274 mmol, 1.0 eq) dissolved in DMSO
(dry, 1 mL) was added and the reaction stirred overnight at room temperature. The
reaction mixture was quenched with water and extracted 3x with portions of ethyl acetate.

Column chromatography (20%EtOAc/Hexanes) isolated one spot (UV-active) as a white

solid (59 mg, 42.4%) which was all hydroamination product. 1H NMR (300 MHz,

CDCI3) a 7.7 (d,2H,J= 8.1),7.3-7.2 (m, 12H),6.0 (s, 1H),4.5 (ABq,2H, ‘J: 12.3, 2J:

177

18.6), 4.1 (t, 1H, J = 3.3), 3.7 (d, 2H, J = 3.3), 3.5(s,1H), 2.4 (s, 3H),1.4(s, 3H); 13C
NMR (75 MHz, CDC13) 6 143.9, 138.5, 137.7, 135.5, 129.1, 128.3, 128.0, 127.6, 127.5,

108.1 , 73.6, 70.0, 65.7, 62.1, 61.7, 21 .6, 13.9, Melting Pt. = 154—156° C; HRMS — [M+H]

= 507.1597 (cal. 507.1590).

p-Ethynyltoluene Addition to Aziridinal (V-43) to Aziridinol (V-88)

Ts 0“ Ts
H I N
N 08” ———> /
O / OBn
v-43 ”39 v-ae

To a solution of LDA (3 equiv) at -78° C in THF (05M), p-ethynyltoluene (109
11L, 0.83 mmol) in THF (dry, 1 mL) was added dropwise and stirred for 70 min. Then,
aziridinal (100 mg, 0.278mmol) dissolved in lml of dry THF was added dropwise. The

solution was stirred for 12 hours at -78° C, -40° C for 1 hour, 0° C for 1 hour, and then

room temperature for 24 hours. The THF was removed and the residue was dissolved in
EtOAc and washed with water and brine. Two spots appeared on TLC (10%
EtOAc/Hexanes) and both were UV active. Both spots were isolated by column

chromatography (10% EtOAc/Hexanes). Fraction one was a complex mixture. Fraction

two was the product (65 mg, 49%, 4:1 symanti mixture). 1H NMR (300 MHz, CDC13)
(syn product) 6 7.9 (d, 2H, J = 8.4 Hz), 7.5-7.1 (m, 11H), 5.2 (d, 1H, J = 3.0 Hz), 45
(ABq, 2H , 1J = 12.0 Hz, 2J = 18.9 Hz), 3.7 (m, 2H), 3.6 (m, 2H), 2.5 (s, 3H), 2.4 (s, 3H),

1.7 (s, 3H); HRMS — [M+Na] = 498.1715 (cal. 498.1710).

178

Hydroamination of Toluenylaziridinol (V-88) to pMethylPh Pyrrolidine (V-96)

  

OH Ts

N
/ _"
$013" Bno
H3C v-ae

Dimethylsulfoxonium methylide was prepared by treating NaH (22.1 mg as a

V-96

60% dispersion in mineral oil, 055 mmol, 4.0 eq) in DMSO (dry, 1 mL) with portions of
trimethylsulfoxonium iodide (121.4 mg, 0.55 mmol, 4.0 eq). Once the addition of the
trimethylsulfoxonium iodide was complete, the milky-white suspension was stirred for an
additional 30 min. The aziridinol (65 mg, 0.138 mmol, 1.0 eq) dissolved in DMSO (dry,
1 mL) was added and the reaction stirred overnight at rt. The reaction mixture was
quenched with water and extracted 3x with portions of ethyl acetate. A column at 20%
EtOAc/Hexanes yielded 64 mg (98.5%) of an isomeric mixture (1:1,
hydroaminationzAza-Payne). These two spots were separated by column
chromatography (40%Hexanes/35%DCM/5%EtOAc). Fraction 1 was the

hydroamination product (32 mg, 49%, white solid) and fraction 2 was the Aza-Payne

product (32 mg, 49%, green-yellow solid). 1H NMR (300 MHz, CDC13) (Fraction 1,
Hydroamination) a 7.6 (dd, 2H, 'J = 2.4 Hz, 2J = 8.1 Hz), 7.4—7.2 (m, 7H), 7.15 (d, 2H, J
= 3.1 Hz), 6.3 (s, 1H), 4.6 (ABq, 2H, 1J = 12 Hz, 2J = 25.8 Hz), 4.0 (t, 1H, J = 3.6 Hz),
3.9 (ddd, 2H, 1J = 3.3 Hz, 2J = 10.2 Hz, 3J = 24.6 Hz), 3.5 (s, 1H), 2.4 (s, 3H), 2.3 (s,
3H), 1.4 (s, 3H); 13C NMR (75 MHz, CDCl3) 6 143.6, 137.6, 137.3, 134.9, 134.6, 132.6,

179

129.0, 128.5, 128.2, 127.8, 120.8, 103.9, 73.8, 70.7, 64.9, 63.7, 62.0, 21.6, 21.4, 14.1;
Melting Pt. = 146-152° C; 1H NMR (300 MHz, CDC13) (Fraction 2, Aza-Payne) 6 7.7 (d,
2H,J = 8.1 Hz), 7.4—7.2.5 (m, 7H), 7.2 (d, 2H,J = 8.4 Hz), 7.0 (d, 2H,J= 8.4 Hz), 5.3 (d,
1H,6.9),4.5(ABq,2H,1J = 11.7 Hz, 2J = 23.7 Hz), 3.8 (dd, 1H, 1J = 4.5 Hz, 2J = 9.3

Hz), 3.7 (ddd, 1H, 1J = 4.2 Hz, 21 = 6.9 Hz, 3J = 8.7 Hz), 3.5 (dd, 1H, 1J = 4.2 Hz, 2J =

9.3 Hz), 3.4 (s, 1H), 2.4 (s, 3H), 2.3 (s, 3H), 1.4 (s, 3H); ”C NMR (75 MHz, CDCI3) a
143.1, 139.1, 137.3, 137.1, 131.9, 129.5, 128.5, 127.9, 127.6, 127.3, 118.8, 875, 83.0,
73.3, 692, 63.4, 54.0, 53.3, 21 .5, 21 .4, 18.6; Melting Pt. = 95-96° C

l-Ethynylhexene Addition to Aziridinal (V-43) to form Aziridinol (V-92)

OH Ts
H ls N
N OBn /
can —’ / OBn
v-43 v-92

To a solution of LDA (2 equiv) at -78° C in THF (0.5M), l-ethynylhexene (106.2
mg, 1 mmol) in 15 mL of THF was added dropwise and stirred for 70 min and 180 mg
(0.5 mmol) of aziridinal dissolved in 1 mL of dry THF was added dropwise. This
solution was added dropwise to the aziridinal in 15 ml of THF. The solution was stirred
for 12 hours at -78° C, -40° C for 1 hour, 0° C for 1 hour. The THF was removed and
the residue was dissolved in EtOAc and washed with water and brine. One spot appeared
on TLC (10% EtOAc/Hexanes. The spot was isolated by column chromatography (10%

EtOAc/Hexanes). The fraction was product (193 mg., 82.5% yield). 1H NMR (500 MHz,

180

(313013) a 7.8 (d, 2H, J = 8.5 Hz), 7.3-7.1 (m, 7H), 6.1 (quintet, 1H, 1J = 2 Hz, 21 = 4 Hz),
5.0(d,1H,J = 3.5 Hz), 4.4 (ABq, 2H, 1J = 115 Hz, 21 = 30.5 Hz), 3.6 (dd, 1H, 1J = 5.5
Hz, 21 = 11 Hz), 3.5 (d, 111,]: 3.5 Hz), 3.4 (dd, 1H, 1J = 7 Hz, 2J = 11 Hz), 3.3 (dd, 1H,
1J = 5 Hz, 2J = 7 Hz), 2.4 (s, 3H), 2.0 (m, 4H), 1.6 (m, 4), 1.5 (s, 3H); 13C NMR (125
MHz,CDC13)6144.1,137.6,137.1,135.9,1294,1282,127.5,127.3,127.1,119.7,88.1,

82.7, 72.6, 66.8, 65.6, 58.6, 48.8, 28.8, 25.5, 22.0, 21 .5, 21.3,13.1.

p-N,N-Dimethylaminoethyny1benzene Addition (V-43) to Aziridinal (V-89)

Ts OH Ts
H I N
N OBn —> /
O / OBn
v-43 (MelzN V-89

To a solution of LDA (2 eq) at -78° C in THF (0.5M), p-N,N-

dimethylaminoethynylbenzene (145.2, 1 mmol) in THF (dry, 05 mL) was added

dropwise and stirred for 70 min and 180 mg (0.5 mmol) of aziridinal dissolved in 10 mL

of dry THF was added dropwise. The solution was stirred for 12 hours at -78° C, -40° C

for 1 hour, 0° C for 1 hour. The THF was removed and the residue was dissolved in

EtOAc and washed with water and brine. Column chromatography

(20%EtOAc/Hexanes) isolated product in 54.3% yield (137 mg) in a 10:1 syn to anti

diasterameric mixture. 1H NMR (500 MHz, CDC13) 6 7.8 (d, 2H, J = 8.5 Hz), 7.3-7.1 (m,
9H), 65 (d, 2H, J = 8.5 Hz), 5.0 (d, 1H, J = 2.5 Hz), 4.5 (ABq, 2H, 1J = 11.5 Hz, 2J =
30.5 Hz), 3.7 (dd, 1H, 1J = 4.0 Hz, 2J = 10.5 Hz), 3.6 (d, 1H, 1J = 2.3 Hz), 3.4 (m, 2H),

181

2.9 (s, 6H), 2.4 (s, 3H), 1.6 (3H) ); 13C NMR (125 MHz, CDC13) 6 150.2, 144.0, 137.4,

137.0,132.8,129.4,1282,127.5,127.3,127.1,111.5,108.6, 87.3, 83.1,72.6,66.8, 65.8,
58.7,48.9,40.0,21.5,13.2.

Synthesis of Trifluoromethylaziridinol (V-90) from Aziridinal (V-43)

OH Ts
H Ts N
N OBn ___, /
0M / OBn
F3C
V43 V-90

First, 3,3,3-trifluoro-2-bromo-l-propene (256 mg, 1.46 mmol) was added

dropwise to a solution of LDA (2 eq) in THF (0.5M, 3 mL) at -78° C. The solution

turned a purple color and was stirred for 10 min and then the aziridinal (577.3 mg, 1.1

mmol) dissolved in of THF (dry, 2 mL) was added to the solution (the purple color

dissipated) and the solution was stirred overnight at —78° C. The solution was quenched

with 1 N HCl and extracted with EtOAc (3X). The combined organics were washed with

brine and the solvent was removed under reduced pressure. Column chromatography

(20%EtOAc/Hexanes) yielded 255.3 mg (72.2%) of product as a yellow solid.‘8 1H NMR
(500 MHz, CDC13) 6 7.8 (d, 2H, J = 8 Hz), 7.3-7.2 (m, 5H), 7.2 (d, 2H, J = 8.5 Hz), 5.0
(s, 1H), 4.4 (ABq, 2H, 1J =12 Hz, 21 = 205 Hz), 3.8 (d, 2H, J = 3 Hz), 3.6 (dd, 1H, 1J =
4.5 Hz, 2J = 10.5 Hz), 3.4 (dd, 1H, 1J = 7 Hz, 2J = 10.5 Hz), 3.3 (t, 1H, J = 6.5 Hz), 2.4
(s, 3H), 1.5 (s, 3H); 13C NMR (125 MHz, CDCI3) 6 144.7, 129.6, 128.3, 127.7, 127.4

127.3, 113 (q, 1J = 256.9 Hz, 2J = 513.6 Hz), 73.0 (q, 1J = 53.1 Hz, 2J = 106.1 Hz), 72.9,

182

 

66.5, 64.7, 64.7, 56.7, 48.4, 21.5, 13.1; Melting Point = 74760 C; HRMS — [M+H] =

454.1295 (cal. 454.1300).

3-Cyclohexylpropyne Addition to Aziridinal (V -43) to Aziridinol (V-9l)

OH Ts
H ls N
N OBn /
0% ——’ / OBn
V-43 V-91

To a solution of LDA (2 eq) at -78° C in THF (0.5M), 3-cyclohexy1propyne

(108.2 mg, 1 mmol) in THF (dry, 10 mL) was added dropwise and stirred for 70 min and

then the aziridinal (180 mg, 05 mmol) dissolved in of THF (dry, 1 mL) was added

dropwise. The solution was stirred for 12 hours at -78° C, -40° C for 1 hour, 00 C for 1
hour. The THF was removed and the residue was dissolved in EtOAc and washed with
water and brine. Column chromatography isolated 189.3 mg (80.9%) product. 1H NMR

(500 MHz, CDC13) 6 7.8 (d, 2H, J = 8.0 Hz), 7.3-7.2 (m, 7H), 4.8 (s, 1H) 4.4 (ABq, 2H,

1J =12.0 Hz, 2J = 25.0 Hz), 3.6 (dd, 1H, 1J = 5.0 Hz, 2J = 11.0 Hz), 3.5 (d, 1H, 'J = 3.0
Hz), 3.4 (m, 1H), 3.3 (m, 1H), 2.4 (s, 3H), 2.2 (m, 2H), 2.0 (m, 1H), 1.7 (m, 2H), 1.5 (m,
7H), 1.2 (m, 2H); ”C NMR (125 MHz, CDC13) a 144.1, 137.5, 137.1, 129.4, 128.2,

127.6, 127.3, 127.1, 86.7, 76.7, 72.6, 66.8, 65.3, 58.6, 48.9, 38.6, 31.8, 25.1, 24.3, 21.5,

13.0.

Hydroamination of Cyclopenylaziridinol (V-91) to aza-Payne Product (V-101)

183

OH Ts
N

// OBn

 

V-91 Not Formed V-101

Dimethylsulfoxonium methylide was prepared by treating NaH (65.6 mg as a
60% dispersion in mineral oil, 1.60 mmol, 4.0 eq) in DMSO (dry, 5 mL) with portions of
trimethylsulfoxonium iodide (360.8 mg, 1.6 mmol, 4.0 eq). Once the addition of the
trimethylsulfoxonium iodide was complete, the milky-white suspension was stirred for an
additional 30 min. The aziridinol (189.3 mg, 0.400 mmol, 1.0 eq) dissolved in DMSO
(dry, 1 mL) was added and the reaction was stirred overnight at room temperature. The
reaction mixture was quenched with water and extracted 3x with portions of ethyl acetate.
The solvent was removed and a column (20%EtOAc/Hexanes) purified 121.5 mg
(61.4%) of the aza-Payne product. No trace of the hydroaminaion product was seen. 1H
NMR (500 MHz, CDCl3) 6 7.8 (d, 2H, J = 8 Hz), 7.3-7.2 (m, 7H), 5.3 (d, 1H,J = 7 Hz),
4.4 (ABq, 2H, 1J = 12 Hz, 21 = 365 Hz), 3.7 (dd, 1H, 1J = 4.5 Hz, 2J = 95 Hz), 3.6 (m,
1H), 3.1 (s, 1H), 2.3 (s, 3H), 2.2 (m, 2H), 2.0 (m, 1H), 1.7 (m, 2H), 15 (m, 5H), 1.3 (s,
3H), 1.2 (m, 2H); 13C NMR (125 MHz, CDC13) 6 143.2, 137.4, 129.4, 128.3, 127.8,
1275, 127.2, 885, 74.6, 73.2, 69.3, 62.6, 53.5, 53.2, 38.6, 32.0, 32.0, 25.1, 24.7, 21.5.

18.9; HRMS -— [M+Na] = 468.2200 (cal. 468.2209).

l-Ethynylhexene Addition to Aziridinal (V-43) to Aziridinol (V-92)

184

HTS

N
013
0% ” ——' // OBn

V-43 V-92

OH Ts
N

To a solution of LDA (2 eq.) at -780 C in THF (0.5M), l-ethynylhexene (106.2 mg,
1 mmol) in THF (dry, 15 mL) was added dropwise and stirred for 70 min and then the
aziridinal (180 mg, 05 mmol) dissolved in THF (dry, 1 mL) was added dropwise. This
solution was added dropwise to the aziridinal in THF (dry, 15 mL). The solution was
stirred for 12 hours at -78° C, -40° C for 1 hour, 0° C for 1 hour. The THF was removed
and the residue was dissolved in EtOAc and washed with water and brine. One spot
appeared on TLC (10% EtOAc/Hexanes. The spot was isolated by column
chromatography (10% EtOAc/Hexanes). The fraction was product (102.4 mg, 44%
yield). 1H NMR (500 MHz, CDC13) 6 7.8 (d, 2H, J = 8.5 Hz), 7.3-7.1 (m, 7H), 6.1
(quintet, 1H, 1J = 2 Hz, 21 = 4 Hz), 5.0 (d, 1H, J = 35 Hz), 4.4 (ABq, 2H, 1J = 11.5 Hz,
2J: 30.5 Hz), 3.6 (dd, 1H, 1J = 5.5 Hz, 2] =11 Hz), 3.5(d,1H,J = 3.5 Hz), 3.4 (dd, 1H,
1J = 7 Hz, 21 = 11 Hz), 3.3 (dd, 1H, 1J = 5 Hz, 2J = 7 Hz), 2.4 (s, 3H), 2.0 (m, 4H), 1.6
(m, 4), 1.5 (s, 3H); 13C NMR (125 MHz, CDCl3) 6 144.1, 137.6, 137.1, 135.9, 129.4,
128.2,1275,127.3,127.1,119.7, 88.1 , 82.7, 72.6, 66.8, 65.6, 58.6, 48.8, 28.8, 255, 22.0,

21 .5, 21.3, 13.1; HRMS — [M+H] = 466.2055 (cal. 466.2052).

Hydroamination of the eneyne Aziridinol (V-92) to Aza-Payne (V-97)

185

 

0“ Ts

 

N 0 NHTs
// OBn —_> BnO // OBn
V-92 Trace V-97

Dimethylsulfoxonium methylide was prepared by treating NaH (66.4 mg as a
60% dispersion in mineral oil, 1.66 mmol, 4.0 eq) in DMSO (dry, 5 mL) with portions of
trimethylsulfoxonium iodide (365 mg, 1.66 mmol, 4.0 eq). Once the addition of the
trimethylsulfoxonium iodide was complete, the milky-white suspension was stirred for an
additional 30 min. The aziridinol (193 mg, 0.415 mmol, 1.0 eq) dissolved in DMSO
(dry, 1 mL) was added and the reaction was stirred overnight at room temperature. The
reaction mixture was quenched with water and extracted 3x with portions of ethyl acetate.
Column chromatography purified a UV active spot as a white solid (177 mg, 91.7%),

which was the Aza-Payne product with a small amount of the hydroamination (175:1).

'H NMR (500 MHz, CDC13) a 7.7 (d, 2H,J = 8 Hz), 7.3-7.2 (m, 7H), 6.2 (m, 1H), 5.4 (d,-
1H, J = 7 Hz), 4.4 (ABq, 2H, 1J =12 Hz, 2J = 32.5 Hz), 3.7 (dd, 1H, 1J = 5 Hz, 2J = 9.5
Hz), 3.6 (ddd, 1H, 1J = 4.5 Hz, 2J = 7.5 Hz, 3J = 9 Hz), 3.4 (dd, 1H, 1J = 45 Hz, 2J = 9.5
Hz), 3.3 (s, 1H), 2.4 (s, 3H), 2.1 (m,4H), 1.6 (m,4H), 1.3 (s, 3H) ; 13c NMR (125 MHz,

CDC13) 6 143.0,137.5,137.3,136.6, 1293,1282, 127.7, 127.5, 127.2, 119.6, 89.2, 80.9,

73.1, 69.3, 63.0, 60.2, 53.7, 53.2, 29.5, 28.6, 25.6, 22.1, 21.4, 21.3, 18.7, 14.0; HRMS —
[M+Na] = 488.1872 (cal. 488.19).

Bromination of the Aziridinol (V-43) followed by an Aza-Payne/Hydroamination

186

 

Ts Br

m ' BnO . .
/ OBn " ~"

$s

O
V44 V-124

First, the aziridinol (200 mg, 0.518 mmol), silver nitrate (8.8 mg, 0.1 mol%), and
NBS (100.2 mg, 1.1 equiv) were dissolved in of acetone (8 ml). The solution was stirred
at room temperature for 3 hours. The solution was filtered through a silica gel plug and
the solvent was removed under reduced pressure. The residue was dissolved in 1 mL of

DMSO (dry) and added to a solution of the sulfoxonium ylide (82.8 mg of NaH and

455.8 mg of Me3SOI stirred in 2.5 mL of DMSO for 30 min). The solution was stirred

overnight at room temperature under an atmosphere of nitrogen. The solution was
quenched with water and extracted (3X) with ethyl acetate (10 mL). The combined
organics were washed with brine and dried with sodium sulfate. The solvent was
removed and two fractions were isolated by column chromatography

(20%EtOAc/Hexanes). Fraction 1 was starting material with a recovery of 31% (62 mg).

Fraction 2 was the brominated pyrrolidine isolated in 68% yield (165 mg). 1H NMR
(500 MHz, CDC13) 6 7.7 (d, 2H, J = 8 Hz), 7.3-7.2 (m, 7H), 6.1 (s, 1H), 4.5 (ABq, 2H,1J
= 12.5 Hz, 21 = 29 Hz), 4.1 (t, 1H, ]J = 3,5 Hz,2J = 6.5 Hz), 3.7 (d, 2H, J = 3.5 Hz), 3.5

(s, 1H), 2.4 (s, 3H), 1.4 (s, 3H); 13C NMR (125 MHz, CDC13) 6 144.0, 141.4, 137.7,

135.4, 129.2, 128.4, 128.2, 127.7, 127.5, 109.7, 95.9, 73.8, 70.1, 65.6, 62.8, 61.6, 21.6,

14.0; HRMS (ESI) (m/z): [M+H] calculated for [C21H23NO4BrS]+ 464.0531, found

464.0535.

187

Bromination of the Pyrrolidine (V-23) to Entry V-125 with Br2

Ts Ts
N

limo/j—7¢ ——> Brio/1V Br
V-23 V-125

First, bromine (62.1 mg, 1.5 eq) was added directly to a solution of pyrrolidine
(100 mg, 0259 mmol) in diethyl ether (4 mL) at -60° C (the solution turned a yellow
color). The solution was stirred for 30 min and then warmed to rt. The solution was
cooled to -20° C and then triethylamine (54 11L, l5 eq) was added and the yellow color
dissipated. It was warmed to RT and then stored in the freezer overnight. The solid was
filtered off and the solvent removed. The residue was run through a silica gel column
(20% EtOAc/Hexanes) and one fraction was isolated. This fraction was the brominated
product, isolated in 80% yield (97 mg). 1H NMR (500 MHz, CDC13) 6 7 .6 (d, 2H, J = 8
Hz), 7.3-7.2 (m, 7H), 6.6(s,1H), 4.6 (ABQ, 2 H, ]J =12 Hz, 2J = 40.5), 4.0 (t, 1H, J = 3,
2J = 6), 3.9(s,1H), 3.8 (m, 2H), 2.4 (s, 3H),1.4(s, 3H); 13C NMR (125 MHz, CDC13) 6
144.4,1395, 137.7,134.2,129.5,128.4, 127.8, 127.6, 127.5, 94.1, 73.8,70.4,65.7, 62.2,
61.2, 21.6, 14.1; HRMS (ESI) (m/z): [M+H] calculated for [C21H23NO4BrS]+ 464.0531 ,

found 464.0535.

Bromination of the Pyrrolidine (V-23) to Entry V-125 with NBS

188

Ts
N
Bno/j—f ——> Bnoy Br

I

’l
\\
’I

V-23 V-125
First, pyrrolidine (1 mmol, 285.5 mg) was dissolved in E120 (10 mL). Then NBS

(186.8 mg, 1.1 eq) was added and the solution stirred overnight at room temperature.

The solution was quenched with Et3N (2 eq) and placed in a freezer for 6-8 hours. The

solid was removed by filtration and discarded. The solution was removed under reduced
pressure. The solid residue was purified by column chromatography in 75%. 1H NMR
(500 MHz, CDC13) 6 7.6 (2H, d, J = 8), 7.3 (8H, m), 6.6 (1H, s), 4.6 (2H, ABq, 1.] = 12,
2J = 405), 4.0 (1H, t, J = 3), 3.9 (1H, s), 3.8 (2H, t, J =1), 2.4 (3H, s), 1.4 (3H, s); 13C

NMR (125 MHz, CDC13) 6 144.4, 139.5, 137.7, 134.2, 129.5, 128.4, 127.8, 127.6, 127.6,

94.0, 73.8, 70.4, 65.7, 62.1, 61.2, 21 .6, 14.1.

Addition of propargylmagnesium bromide to Aziridinal (V-43) to Aziridinol (V-133)

TS

H [1‘ OH Ts
0%an ——> W-
OBn
V-43 V-133

First, propargyl bromide (3.8 mmols, 561 mg, 80% by wt. in toluene) was added
to a solution of magnesium tumings (91.7 mg, 3.8 mmols) and mercury chloride (20
mol%, 204 mg, 0.755 mmols) in ethyl ether (2 mL) at 0°C. The solution was stirred for 1
hour (boiled spontaneously so a reflux condenser was equipped to the flask). The liquid

was decanted and added to a solution of the aziridinol (271.3 mg, 0.755 mmol) in DCM

189

(30 mL) at —78° C. The solution was stirred of 4 hours and then warmed to room

temperature. The reaction was quenched with saturated ammonium chloride and
extracted with DCM (3X, 30mL). The combined organics were washed with brine (2X,
50 mL), dried with sodium sulfate, and the solvent was removed under reduced pressure
to yield a yellow oil. The product was purified by a column (20% EtOAc/Hexanes) to

yield 229 mg (75% yield) of product of a white solid (8 mixture of diastereomers) and

some SM. This was used without any other purification in the hydroamination. 1H NMR

(300 MHz, CDC13) 6 7.8 (d, 2H, J = 8.1), 7.2-7.3 (m, 7H), 4.4 (s, 2H), 4.2 (m, l H), 3.7
(m, 2H), 3.4 (dd, 1H, J = 3.3, 8.4), 3.3 (1H, dd, J = 84,108), 2.6(m,1H)2.4(m, 4 H),
1.9 (t, 1H, J = 2.7), 1.3 (s, 3H). Melting Pt. = 68-74° C; ; HRMS — [M+H] = 400.1580

(cal. 400.1583).

Hydroamination of Aziridinol (V-143) to form a 6-membered ring

 

0” Ts NS NHTs
w > If W—
03” 6\" OBn
v-133 v-134 V435

Not Formed
First, NaH (55 mg) and (CH3)3SOI (502 mg) was stirred in DMSO (dry, 10 mL)

for 30 min. Then the aziridinol dissolved in DMSO (dry, 2 mL) was added to the
solution was stirred overnight. It was quenched with saturated ammonium chloride,
extracted (3X, 10 mL) with ethyl acetate, the combined organics was washed (2X, 20ml)
with brine, dried with sodium sulfate, and the solvent was remove under reduced

pressure. One fraction (99 mg) was eluded from a column (20% EtOAc/Hexanes). This

190

was not the hydroamination product but an elimination product from the aza-Payne

rearrangement. The reaction yielded 43% (393.7 mg) of the elimination product. 1H

NMR (300 MHz, CDC13) a 7.7 (d, 2H,J = 8.1), 7.2 (m, 7H), 6.2 (d, 1H, J = 15.9), 5.8 (d,
1H,J=16.2),5.3(d,1H,J= 8.7),4.3 (q, 2H,J= 11.7, 15.3), 3.5 (d, 1H,J: 7.8), 3.4 (s,
1H), 3.3 (t, 2H, J = 10.5), 2.9 (s, 1H), 2.4 (s, 3H), 1.0 (s, 3H); ”C NMR (75 MHz,
CDC13) a 148.4, 143.4, 138.0, 136.5, 129.6,1285,1282,127.8,126.9,1082,815,78.5,

76.0, 73.9, 70.7, 58.7, 25.3, 21.5; Melting Pt. = 122-125° C; HRMS — [M+Na] =
406.1459 (cal. 406.1453).

Ozonolysis of Pyrrolidine (V-23) to Lactam (V-136)l

 

Ts Ts
N N o
BnO/jf > BnO/jf
v-23 V-136

First, the pyrrolidine (148.6 mg) was dissolved in DCM (30 mL). The solution
was cooled to -78° C. Ozone was then bubbled through the solution (~5 min) until it
remained blue for 5 min. Zinc dust (100mg) and 1-2 drops of acetic acid were added and
the solution was stirred at —78° C for 10 min and allowed to warm to room temperature.

The solution was filtered through celite and the DCM was removed under reduced
pressure. TLC showed all SM was gone and only one other spot existed. The NMR had

slight impurities so a column (20%EtOAc/Hexanes) was run and the product was isolated
in 90% yield (134.4 mg). 1H NMR (300 MHz, CDC13) 6 7.8 (d, 2H, J = 8.1), 7.3 (m, 5H),
7.1 (d, 2H, J = 6), 4.3 (m, 2H), 3.9(m,1H), 3.7(m,1H), 3.3 (s, 1H), 2.3 (s, 3H),1.5(s,

191

 

3H); 13C NMR (75 MHz, CDC13) 6 169.0, 145.1, 137.0, 135.3, 133.2, 129.6, 129.5,

127.9, 1275, 73.5, 67.5, 62.9, 59.5, 57.3, 52.6, 52.6, 50.9, 21 .5, 13.4; HRMS — [M+H] =

388.1212 (cal. 388.1219).

192

 

5.5 NMR Spectra

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... - 1W1 11W... MW.1_Wz--.....-Jfl . . 1--.. .. JWifii..- 111...; 1 .13.- - - 1.5-.- -1.~..)_W.W .- 3.1%--

 

 

 

 

 

 

 

V-86. 1H NMR

 

 

cmO

 

9 ”72931.59? 11m

208

SRHIV—ST-CSOOAn—F 1

 

V-86. 13C NMR

 

 

c
CD
0

 

 

 

 

 

 

 

MeO

 

 

 

 

 

209

8

' 13.22
14.06

,1 20.88
-_ 21.46

16

24

32

40

48

’48.?9

"”5515

* 58.53
x60.23

:6672
66.82

42.69
[76.74
$76.99
77.24

$84.15
“86.17

56

64

88 80

96
Chemical Shift (ppm)

104

112

“1' 113.79
L114.06

T‘V'Y'T'Y‘TTYTTI'TTYW F'T‘? "Trf‘rnrfiflrrnfitvmfirfit WT? HWY”? 'Wv1m11wmmn *TrrTY'rr "Ir-W ”'11 "r rm n Y‘T'TT’WT'T‘YT’"! Wm TTI?""1‘71

120

1127.17;
127.23%
127.545 3

R“128.19: '-
~129.42_£
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«437.0332
“437.54

—144.14E i

y
F

152

IT! 'Y’YYYTY'Y '7?!

*159.79

9
P

’77 T"'Y

V-87. 1H NMR

E53 5% .3565

o 0.0 o.—. m.—. ON m.N o...” v.0 0.? mi 06 min 0.0 m6 OK m8 0d
rffLLer 1L.» rrbL. rffrtrir. FLFEtfrrhpthth E2FE.»LLLLL¢LLLLL rLrtEer ELL}: [frrhrFrLrer-rrrrft 1E1...r. Egg». r.l _>.1 r. ..L r C FE» -L 1E
.. d «”2 _.- 2 7.1. 1 1+ .2 _.H. 3%. z“ 2. .112 al-1112 1.11.272 21]..
L. L. 9 3 .Ir 0 .0 .Ir .0 .6 .0 ”L .0 .Ir

.89 .0 V3.9 1.9 8 3881. 8

3...... ...2- 1 - 1:13.. ,1.
1 __ .. ..2 . .

 

' ac.—
HIP-1‘-

 

 

 

 

 

 

 

 

 

 

 

 

26

:mo of

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Ngwétmm

210

 

E53 55 .8265

m6 o.—. mé 0N mN QM m.» 06 m6 Qm m.m 0.0 mac os mg. 06

L.rt-rIILIF-11Ivl_!bt rrvt FTTVF. p1erf.r1v1»11_rbL.fL; . . »L .1 .- .. pout... r3..v0>..p . IvE-l1kurrrtlrLlL1rE116FLr11h-r. rnrr .11» rt.L1.F.:Lf,91L.L lrlrLl» .L LL11.» ftbLfo r Tr. . . » ..1 1.... . . .L116L1» vblrb
. u u ..1 . 1. v.1... «11.1-.1. 7111.. n L .... . . I . u u ._
. _ . 4 2 _ ._ _ _ . L 2 .
”L .9 we 7v .3 Z .l .0 V 0 3
Ir 0 8 9 I. 9 0 Z a 9 0
1- III 1 1|!!! 1|} 1‘11 11’; 1111‘) 6‘11
:- ?

 

2 ...
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.

11.1111 111}, 1. 1321111411... 2. ....1-1l11141111.... .11 .. 14.... ...-111.111.15-41
_ .

 

 

 

 

V-88. 1H NMR

 

on:

 

50 on: 80
\

 

 

Io
Nuéom 1-8 "...—ram

211

 

 

 

£53 55m 3665
o no 3 3 ON 3 o.” 3 3 3. 9m 3 3 3 o.“ 3 o.» 3

2::2...._u2_...__...2....2:...r2...._.:_.L.L._5:2...222:2»:_._:_22.._.»LL....:C:1::f..2..::C..22.2....~.m.2;.2-::..2_.:22L»_.2..._:2.._2_..__.22.....2..-__2.:2_h.:
2.2 2. 2 2 .2 2 .__.. . ..1. 2 2 .92 a 2 2
.6 .6 .9 .z z .3 ... .z .6 2
I7 7v 9 Ir 0 Ir 0 7v [- 0

1111 1 111 ‘11

 

 

.2...

. . H21
2 .2 ..2 .... .2
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. . 2

I . I 1.11 .11111/22511111114111/11'11}... 111.1 I 11.1 . .11 111.11 ._.‘o...ll -. (1 1.2%! 1 I 11 Illl '111 I11}... m1:l1vl|1llll.2 a “.11l-(J‘1-.. l 1111 .11 .111

2 2 2 2.2 -2

2
2

L
:—
-2fl- i
u

 

 

 

V-89. 'H, 13c NMR

2...»:

cm0

 

 

pu-c<oom;vm.>_1mm

212

SRHlV-54-C500An-F 1

c
(D
O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

213

 

 

 

"foV

»—-13.19 _

"_‘YYYYYY"11

16

"21.46

24

32

v'r'vrIT~I'~ou

39.97

4O

48

‘48.94

56

' 58.70 ;

1‘17'
64

- 65.82 :
66.80

172.58
_ 76.74
=~-—77.oo
— 77.25

* 83.13
87.34

"I 171 7' '71'7’7
88 80 72
Chemical Shift (ppm)

r'IV—trT'TY"I‘7"1

96

'7'"‘."7""7‘

104

108.55?
11147;;2‘

120

427.10:
. 127.25;
1127.47:
3128.15‘
129.38;
432.79;
5137.01;
437.52;

136 128

144

144.06%

~150.16i_

52

1

 

 

 

 

 

 

223 25 .3265
o md 04 mé ON m.N Cd 06 9v m6 Qm Wm 06 md 0.5 m5 0d
vay. .2111? r. . .. ..rrrLFILLL 11.. . ...2rrrkrr1..rLlrFr»

l. rrv...>». r.s..[1..r1r1.2 ..1>1...»...»

 

.L.r:.:.r11»r:1p rrhk1.1»!rpr..1r111».1:.tL1_1-L>Lr-rr.

LLLvMLrLLP.r.yt».».->.1.»r.yL>p_.fr
2w. _ v.. 2. .1 .. ..fi rhlhu “.1111.” 1 1111.. .2 . .1. .. . ..
.8 .8. .Z .L .z .1. .1. z
Ir Ir Iv 0 0 0 7w 0

, .
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2
2
2 2
\A \ 1|\\

gili- 3.2\11<i.1.1.111.- 41111....114 .11.-..11 1 111122-233‘11 14 1.112.311..- 111 1.2.2.... 11111 1.111.111. 1111111111111. 11.11 112.. V111. 11.1-[1111.1 ..
l2
2.

 

 

 

v-90. ‘H, 13c NMR

on”.
.50

 

 

 

punc<oom118.>_1mm

214

SRHlV-86-C500An-F1

OBn

F 3C

v.90. 13C NMR

—1

 

 

 

 

‘1
——-1
~-1

 

 

215

 

 

'r**"1'"—711‘1‘
8

213.14

16

—21.53

40 32 24

' Tfi‘TW "F'IY’Y'Ff‘T‘ T’T‘ Y'Y TT‘T‘I 1'7”] T T‘Tfi‘ rV‘W‘"

48

~ 48.38

‘7‘1'.

1~4~177

64

,. 64.67
266.50
{72.84
1172.92
\-73.26
1 76.74
c~76.99
\7724

72

80
Chemical Shift (ppm)

"'r'fT'rTer'Tw-rj'r'fi'rr V W W 771'? 1'-

88

_ 17"1'7'21-11'
.

8

PL
«410.6855;

“112.74_ 1-
"114.80E

“416.85g?-

r127.31 E

127.331
:1» 127.73: 8
‘9128.31? "

129.58 E

jr136.43E— (‘9)
—137.42 L ‘-

104

~144.63?Ԥ
1.
t

 

 

 

 

v-91. 1H NMR

 

 

Egg :5 .8....20
o no 3 3 3. an S m." 3. m... 3 3 one 3 S 3 own 3 ca

. _ , ‘ 7 , , .
FbrrfL..Cerrs1rrC.r. FuvLLFII Cir!» C?! > L7; .ttk. .ers CbrL . F .11 -FL- rpprrrrLEEFrEt> Eptktrt ....LLLPrrr. .Lbkrft: :7». o FIT . .rrL - 1.. t .11» . 1L » . Fry rrrrt .7%». #11er Yr!

«HI. I. .817. .. \ 11-. I11: . .u 1 H n11 I I 11; Pruvll v 0”“ w .Vfl1luw , . . u
_ : fl 2 a H w _ J a J 2 .
.v m ... 7. .v .r z .o u .z
0 I 9 9 Ir 9 7 6 m0 0

w

 

 

 

cmO

 

 

 

wu§16m5imm

216

v-91. 13(: NMR

 

 

 

 

 

OBn

‘Irs
N

OH
H3C

 

 

 

 

 

 

 

 

SRHIV-53-CSOOAn-F 1

 

217

'7 "r r-"r'TT1 1 TTTV‘Y

8

“13.00

16

121.46
Jr24.33
~25.09

24

“31.81

32

* 38.65

40

48

—48.91

56

”58.64

64

: 65.34
‘ 66.81

1 72.63
r 76.68
‘1’ 76.74

72
Chemical Shift (ppm)

80

L77.25

* 86.65

1 04 96 88

'r‘yT-Vvvww Yvr'YfiT-vr"Tfi-Y~ YIVWWW rm T‘rTj-v—v’ wfi—qvm-I 'VF"'““’T‘TTYTT'T'I T'VT‘T rT'V—y, WI Wm TT‘TW‘Y‘TFY 'T '1‘

112

f

b

120

muck
4127.25E
36127.59.
128.17{
L129.37: :9,
(137.04; ‘ ...
137.52:

128

~144.05;” 3

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F

 

 

v-91. 13c NMR

-— -~ -—— -— ~- -—13.ooi

 

5:9
r2146 3
‘24.33 .- v
‘7 N

 

 

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WNW1

—31.81

 

VTY’F’Y‘VTY'TH‘ 1'7

“ " *fl” ‘“ 38.65

40

 

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48

 

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OBn
56

 

458.64

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66.81 g 3
-. 95
. 72.63 LN:
776.68 “”2
{ -... 176.74 E §
‘77.00 « E
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L77. , w
25.?- 5

— - “86.65 in

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{8

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127.10?

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128.1 75

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437.04;-

137.52:

 

128

 

136

144

444.055

217

 

o md

FLLLFLIYFLLLLLILL LL LLLL LLLLLLLLLL'LLLLH L 1H1! L1L.L_1

7.1.

v.92. 'H NMR

m.—.

a 1
.

 

ON

L LLL. LLFLLIFLLLLLL L... 1.1.1. LLL1LL1LL L FlkLlLllLLLLIrLerLLL1 rrLL1LL.LL.1.L1.LL1..LLLLL1rLLLrL11r r FLLLLL .L. ILL-1r» .LL1L. ..11L. _-.1L1. -r L. ..--11?. LLLLL.
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c

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m. 6

md 06

W

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A

0.0

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m11U

L.

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L

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2 a

 

 

 

pu§81$n$imm

218

SRHIV-BG-CSOOAn-F1

c
an
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v.92. 13C NMR

 

 

 

 

 

 

 

 

 

 

 

 

219

 

0

8

“13.09

16

121.26
$21.45

~22.04
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“28.79

24

32

40

48

' 48.80

56

64

“65.62
“66.79

72

“72.62
5 76.74
77.00
“77.25

“82.74

80
Chemical Shift (ppm)

88

“88.05

104 96

112

“119.69

1127.131
1427.282
1127.541
“1128.17;

429.39?

{135.963
7137.07:

6

“137.56%

T’T’m‘TT"'° 1 'T ’ NWT'WV TIT VWWTWWWT "1 TT'T'Y‘VT” T‘Y " 1' YW‘V'Y T‘ "'1 WWW'TI‘TY'W 'Y‘I

128 120

36

1

~-144.07f: 3

P

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v.92. 13C NMR

0

8

 

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r2126

 

 

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F'zq—mrlmafl‘

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l
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1.: :. - 477.00

~77.25

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1'7'11 VYYTY

l
72

 

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1
80

Chemical Shift (ppm)

TY'TI'YI

 

88

~ . “88.05 *

96

104

 

112

~ ~—-» . “119.69

1127.13
f127.28

120

 

 

SRHlV-SG-CSOOAn-F 1

 

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~129.39

128

 

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L
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144

 

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219

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.. L .11

_ _ .
1rlL1L1rL-L11frkrir L 1-LL1LL1LLLLH1L11LL1LL11LLLL1 LLLLLLLL LL1rL-1L1rrr1L1riL L lLLLL... ...» 1r rLlthllLlrvaLtirLirLLL
11 . q 4 1 - :11.-
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v.93. 1H NMR

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~02

..uéloonrfln F1>.Imm

220

SRHlV-1 5—C300Ra-F 1

 

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c
m

v.93. 13c NMR

 

H3C

 

 

 

 

 

 

 

221

 

6

8

-13.94

16

“'21.62

48 40 32 24

56

W' ' firrfi r' T11 Tr] T1 Y'T { T1" mT‘r'rTrT'VVTYTTTVT‘P‘I'T' W rm anw'vv-n

64

r/”\~\
s: V
P‘. 9"
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80 72

88
Chemical Shift (ppm)

104 96

Y rTYTV"""“ Y “-1'717YTYYTT“ 7

”108.12

p.

112

O

r127.47< 9.1
127.66

I 128.09g
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429.17

[135.49
4437.71.
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136 128

I
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160

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2% = 1.x...)
_.

 

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7]
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E
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222

SRHlV-S-C300-F1A-HYAM

 

 

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c
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v-94. 1H, 13c NMR

 

 

 

 

 

 

 

 

 

 

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223

 

0

8

“14.15

16

if 21.42
‘21.66

24

32

40

48

56

63.73
“64.91

64

[70.74
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576.58
1577.01

,:‘1
t
72

88

80
Chemical Shift (ppm)

96

"Y’Y‘; ~ 7111"! Y-'~"1‘.TY'T‘7'1 rr'rfi flTfiYT’TY‘YWTmVW‘TT'T Y'Y‘T‘f‘ Tr? Y"”‘F’"T‘F‘"'Tmmmmr mT'V'T'T'T'Y'T‘r—T“

104

112

"Hm-WVTTYHY-‘r—

120

"120.80

[127.75%
“128.18;
428.36: “
1. 128.57 ‘
129.07
1132.62
‘137.62

M 143.61

711‘

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136

144

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152

Y'Y'YTrT-TYTTY‘Y 1‘"
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m - n . a. 7‘14‘- 111‘ * 1AM a d— — «1“ 1 .
.7 .I. .Z .3. 7v .1. .3 .I. Z
17 L v 9 9 Z 7v 9 0
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v-95. 1H NMR

 

 

on:

 

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224

SRHlV-S-C300-F1B-AZPY

15
11’ o
I
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v.95. 13C NMR

 

 

 

 

 

 

 

 

H3C

 

 

225

 

 

0

11 Y 1 IV'YW‘YTTY'TTT‘1fi
10

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—18.66 _
21.46 3
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20

 

30

40

53.29
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"77.42

70

80

Chemical Shift (ppm)

—83.08
" 87.57

100

110

”118.85

r127.29
127.63
427.90
L128.47
. 129.05
IL129.45
"1131.96 -
L137.31
-- 143.15

150 140 130 120

.yTvrT—v . 171 T-Tuy-g-W—v-r-rnw-o—g WTW‘T "'YT’Y”T‘TT""*-TT'YT“FT VWWW WWW ‘YTTTT Y'Tf'17‘1'T‘T‘Y'T'T“f 7 v 117 1

160

T7
1

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o no 3 3 o.~ 3.. ed on o... m... Qm no o5 no 3 mg

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712 4. j 01 :11}: TI 4 L_ “L. 3 ...u _. _ .1 :1 2..
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9 9 9 I. 9 9 9 L I. l I. O 0

 

 

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V-96. 1H NMR
226

Can

 

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cmO

 

«....-oongZIKw

223 55 .8220
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r 1.1) L— "..11.1.lo 1 7 14— _Pl . d WI :2 1111111111 . 9.1.14. — 1 ”“11“.ulllfl I T I b .n. L T H .fi. o . I1‘Hw “ .‘IIIJ
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1.11-11! J2 22.1/3. . 211. 11.11.1722...1121211. 114111-121: ,- 1.23.1-1 11 2.117-122.1111..- 1.71;..31751- 1111.,.l.1..
. : .2
_

 

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2

 

 

 

 

 

 

227

 

v-97. 1H, 13C NMR

 

50 £0 \

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Puoz<oomI1oYZImm

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v.97. 13C NMR

 

 

 

 

 

 

 

 

 

 

 

SRHIV-40-C500AN-F1

228

 

 

 

to
F
E
1L”
[14.05
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£21.28
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153.19
53.66 ~3g
260.19 _
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1137.31[
”37'"?
‘-142.981«§_
@-
:t 8

Chemical Shifl (ppm)

V-98. 121,130 NMR

22$ 55 .825
no 3 3 o.~ ma 3” men o... m... 3 3 0.5 no as m...

 

. .tLPC-rrgL- 2 ...FICL .- :-:~r :+ . h...»-_.p_ .25»: .2»0H2.:.:»E»2.F Fry-rfrrrnrtlrhifi-rtrirf1-rL).rLL11pLLiLL.-._L1rf-.LLC1-rL1FE11...Lk1-.. erLerL-ri
w _ H 1 a 1111i 1 LIN .1 ill) 111 . - m IL —.- 2 «)1 L
- 2 - 2 — J 2T A 2 . _ 2 A A1 . _ . 2 IV
.8 T. .3 3 3 l .l I. 3 l
7 3 9 3 8 .L l L 0 .6

2

- - - - - .A 2_ 222.

- 1. A.;-2.142.... A---11-,A1 . 1 )A)-1.3.111 -- 2:32.11 . ...A-1.J..A_-__1111A1111 ---11-22‘11-12? ...-W111-
2 2 2 e w e

 

 

«:0

50 ”5

ca

mhllIZ O

 

0:00. wu18mI1an1EI¢m

229

SRt-IIII-wZ-CaOO-F‘l-aonc

NH—Ts

OBn

CH3

CH2

V-98. 13C NMR

 

 

 

 

 

 

 

 

 

230

—19.80
\2139

V‘mT'TT' V 1' 1 TW‘r'V'V-TT‘r—r‘ry r1 1’TT‘7‘TT"’—VTTI7‘

"‘Y"'*‘"V1 —v v

I

‘ 50.62

,r64.18
—65.82
«69.33
.—73.14
,~76.58
{777.01
.7143

Y‘V‘TTT—Y'V‘W V1 ‘ FTV'T 1" 7 '

-w'

1" Y

'firrrvrrr‘f'

90
Chemical Shift (ppm)

412.73;
426.30)

126.98}
] 127.48;

YYTfiT‘T‘rY’TTY' "T‘TYT " ’ ’

110

427.71:
.- 12806:;
128.33:

~129.23E

- 136.87g
‘ 137.37;
.‘-137.45:
1441.411

443.071;

2.
...

1

r

‘V-I‘T—F""Y "

30 20 10 0

40

70 60

80

100

150 140 130 120

160

2E3. ...Em .3520
o no 3 3 ca 3 ed on o... m... o.» 3 ed 3 3 ms

. . . . . . . . .
.r; T» 8 21.2: r; r» 1 pl: THE »L 1L»L111. F. r. . . . w r. r- 11. 1 T» .-.... r s 1--. .pl» 2... Frlr.¥1r»lr.?$-r12 {rulrrtllbnrrklr LL . . . pk » .ri 1..» phi-1» 21?,» . . Fr» . Frurbe-LLL1LL-1rrmL-1 .[fphloLL 11L .LL . .2 .111»; 1 . > .2 rr
- .

...-1.. .-- .. .12.... . t. 1.11- .- 2 .2 _. 2 :.
.9 .1. .1. .7. .8 .L .8 . Z ... .L .0
8 9 8 8 8 0 .7 3 0 6 Z
11.111111111- 1 11.1-J. ...-.222. .12 ...-1)._-w1yc1-.;_...1.1-1.1- 4.2.1.111. 2:2... ...2-111114432213111-11111141111. 1.211 1111. .1! 1-.|1..- .... _ «111111123111-

...2 2..2 2.2. 2 2 .. . .2 .. 2 2
’22 .....2. 22 _. 2 .- u ___—
2 . .22 .2 .2 2 . _

. 22
... 2 2 2
\ 2. _2 ,__2

2 22 2 2
_ _

 

 

 

v-101. 1H, NMR

 

50 .”:0 \

m-PIIIZ O

 

Pu.afioomI.oo.>_Imm

231

SRHIV-fiQ-CSOOMu-H

Ts

NH

OBn

CH3

v-101. 13C NMR

 

 

 

 

 

 

 

 

 

 

232

 

“11‘1‘1'11'11v'rr'1'1’1Y"
8 0

16

118.87
.x 21.48
J’ 24.73
x25.12

24

' 32.02

‘ 38.64

VT‘W‘HTWW . ‘fijfiVVTrfivv'
32

40

48

«WWW-1771”

, 53.20
. 53.49

56

- 62.57

64

J 69.32
[73.19
374.55
f 76.74
77.00
77.25

80 72
Chemical sum (ppm)

88

- 88.50

V111 VV'V-TT‘T“V'TTVY‘TV‘WYT‘TIWT’T’VTVTYTT‘I'T‘YY} 'YY'Y‘TT‘I“"‘T'

Yw-o

104

(1 7‘»on v11- wV-Ir-rr' 9v

o md 09 w... o.N

 

s'e '

mN

E63 55 28.565
men

 

 

 

0.6 md 0.x. m.» ow

 

. 2 . _
E‘.L + r» h > w -— . h f bb’hllrlL5lr’"LI[rf1'r'-.rLlrt.r£Lr .LFF h Lr—rn rhhb ~L Pr? L,’|t[frf.frttr91b.n| _» thithEkbbL. P.>’VFFPFF>LLLL v.59 ibbrk' Unifylr.r

«1 . .1 . a. fi . a. u “.1.
. _ 2
8 Ir 7v Ir 8 Z

n a a n a .
8 Ir lv 0 Ir 0

r _ .

 

v-124. 1H, NMR

 

.211

 

2

 

 

 

12fi J). 2x11IJ-2111lll

 

 

 

 

 

0cm

 

2 ~u$8mz-8->_xmm

233

SRHN-QZ-CSOOAn—F2

v.124. 13C NMR

 

 

 

 

 

 

 

 

O
c
m

 

 

 

 

 

234

 

—13.96

21.65

'Y'V’YW 1-T7—-—-¢T"'1vv

V

,x-61.64
- 62.79 t
—65.55 F
«70.09 ‘
473.77 -
‘1’ 76.74 :5—

'—77.00 ;
- 77.25

1‘11

' 1

‘ 95.88

109.74

"YY""7- -fiTv-rywcyv.-o

88

1”XI|1’

' ' ' try-r"

104

24 16

32

40

72

80
Chemical Shift (ppm)

128 120 112

136

 

 

Crystal Structure

fill?) o

 

012) “3‘

fl, '
3.)

Crystal data and structure refinement for V-124.

Identification code
Empirical formula
Formula weight
Temperature
Wavelength

Crystal system
Space group

Unit cell dimensions

Volume
Z

Density (calculated)

Absorption coefficient
F(OOO)

bb33

C21 H22 Br N 04 s

464.37

173(2) K

1.54178 A

Orthorhombic

Pca21

a = l9.2685(8) A a: 90°.
b = l3.3773(6) A b= 90°.
c = 7.7786(4) A g = 90°.
2005 .02(16) A3
4

1.538 Mg/m3

4.002 mrn'l
952

235

Crystal data and structure refinement for V-124. Continued

Crystal size 0.29 x 0.14 x 0.06 mm3

Theta range for data collection 3.30 to 67 .27 °.

Index ranges -17<=h<=22, -15<=k<=14, -7<=l<=9
Reflections collected 7246

Independent reflections 2795 [R(int) = 0.1059]

Completeness to theta = 67 27° 96.1 %

Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.7923 and 0.3858

Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 2795/ l / 255

Goodness-of-fit on F2 1.065

Final R indices [I>2sigma(l)] R1 = 0.0733, wR2 = 0.1554
R indices (all data) R1 = 0.1260, wR2 = 0.1802
Absolute structure parameter -0.01(6)

Largest diff. peak and hole 1.156 and -0533 eA'3

Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Azx
103) for V-124. U(eq) is defined as one third of the trace of the orthogonalized Uij
tensor.

 

 

x y z U(eq)
Br(1 ) 7839(1) 1456(1) 4978(2) 42(1)
5(1) 9208(2) 3466(2) 5825(4) 30(1)
0(1) 8251(4) 5210(6) 3437(1 1) 42(2)
0(2) 10104(4) 3020(7) 1629(1 1) 50(3)
0(3) 8643(4) 3492(6) 6982(1 1) 38(2)
0(4) 9715(4) 4237(5) 5887(1 1) 33(2)
N(l) 8884(5) 3428(7) 3864(12) 25(2)
C(l) 9176(6) 4085(10) 2506(16) 36(3)
C(2) 8567(6) 4747(9) 1939(16) 34(3)
0(3) 7941(6) 4316(8) 2676(18) 37(3)
C(4) 8138(6) 3422(9) 3645(16) 36(3)
C(S) 9502(6) 3536(10) 1056(19) 50(4)
C(6) 8579(6) 5353(8) 363(13) 35(3)
C(7) 7672(6) 2691(9) 4050(16) 36(3)
C(8) 10611(5) 2918(10) 382(16) 44(4)
0(9) 1 1228(6) 2401(8) 1 158(15) 30(3)

236

Atomic Coordinates Continued

C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
C(17)
C(18)
C(19)
C(20)
C(21)

1 1770(7)
12347(7)
123 84(8)
1 1846(8)
1 1260(6)

9640(5)
10294-(6)
10663(6)
10400(7)

9738(6)

9374(6)
10790(8)

2977(9)
2531(11)
151 1(11)
951(11)
1389(9)
2329(8)
2184(8)
1331(9)
592(9)
758(10)
1624(9)
-358(11)

1770(17)
2550(20)
2720(20)
2080(20)
1 343( 16)
6209( 14)
5432( 16)
58 17( 1 8)
6867( 17)
7624( 17)
7272( 16)

7290(20)

41(3)
53(4)
50(4)
56(4)
39(3)
26(3)
35(3)
42(3)
40(3)
39(3)
39(3)
63(4)

 

Bond lengths [A] and angles [°] for V-124.

 

Br( 1)-C(7)
3(1)-0(3)
S(l)-0(4)
S(l)-N(l)
S(1)-C( l 5)
0(1)-C(2)
0( 1 )-C(3)
0(2)-(3(3)
0(2)-C(5)
N ( 1)-C(4)
N(1)-C(l)
C(1)-C(5)
C(1)-C(2)
C( 1 )-H( 1 )
C(2)-C(3)
C(2)-C(6)
C(3)-C(4)
C(3)-H(3)
C(4)-C(7)

1.832(12)
1.413(8)
1.421(7)
1.649(9)
1.758(11)
1.454(15)
1.461(14)
1.383(14)
1.421(14)
1.447(14)
1.485(16)
1.486(17)
1.533(16)
1.0000
1.455(17)
1.470(15)
1.463(17)
1.0000
1.365(16)

237

Bond lengths Continued

C(5)-H(5A)
C(5)-H(5B)
C(6)-H(6A)
C(6)-H(6B)
C(6)-H(6C)
C(7)-H(7)
C(8)—C(9)
C(8)-H(8A)
C(8)-H(8B)
C(9)-C(l4)
C(9)-C(10)
C(10)-C(1 1)
C(10)-H(10)
C(l 1)-C(12)
C(l 1)—H(1 1)
C(12)-C(13)
C(12)-H02)
C(13)-C(14)
C(13)-H(13)
C(14)-H04)
C(15)-C(20)
C(15)-C(16)
C(16)-C(17)
C(16)-H(16)
C(17)-C(18)
C(17)-H(17)
C(18)-C(19)
C(18)-C(21)
C(19)-C(20)
C(19)-H09)
C(20)-H(20)

C(21)-H(21A)
C(21)-H(21B)
C(21)-H(21C)
0(3)-S(1)-0(4)

0.9900
0.9900
0.9800
0.9800
0.9800
0.9500
1 .502( 15)
0.9900
0.9900
1 .363( 15)
1 .381(16)
1 .400(19)
0.9500
1 .372( 19)
0.9500
1 .37(2)
0.9500
1 .394-(17)
0.9500
0.9500
1 .356(16)
1 .41 1(15)
1 .379(15)
0.9500
1 .379(18)
0.9500
1 .422(17)
1 513(17)
1 .381(16)
0.9500
0.9500
0.9800
0.9800
0.9800

119.3(5)

238

 

Bond lengths Continued

 

 

O(3)-S(1)-N(1) 107.3(5)
O(4)-S(1)-N(1) 108.3(5)
O(3)-S(l)-C(15) 106.1(5)
O(4)-S(1)—C(15) 107.3(5)
N(l)-S(1)-C(15) 108.1(5)
C(2)-O(1)-C(3) 59.9(7)
C(8)-O(2)-C(5) 113 .9(10)
C(4)-N(1)-C(1) 107.2(9)
C(4)-N(1)-S(1) 119.0(8)
C(1)-N(1)-S(1) 119.8(8)
N(1)-C(1)-C(5) 114.1(11)
N ( l)-C(1)-C(2) 104.9(9)
C(5)-C(1)—C(2) 113.0(11)
N(1)-C(1)-H(l) 108.2
C(5)-C(1)-H(1) 108 .2
C(2)-C( l)-H(1) 108 .2

O( 1)-C(2)-C(3) 60.3(7)
O( 1)-C(2)-C(6) 116.1(10)
C(3)-C(2)-C(6) 124.1(11)
O( 1)—C(2)-C(1) 109.7(10)
C(3)-C(2)-C(1) 107 .0(10)
C(6)-C(2)-C(1) 123.1(10)
C(2)-C(3)-C(4) 108.1(10)
C(2)-C(3)-O( 1) 59.8(7)
C(4)—C(3)-O( l) 110.7(10)
C(2)-C(3)-H(3) 121 .0
C(4)-C(3)-H(3) 121.0

0( 1)-C(3)-H(3) 121.0
C(7)-C(4)-N( 1) 129.1(11)
C(7)-C(4)-C(3) 122.3(10)
N (1)-C(4)-C(3) 108.3(10)
O(2)-C(5)-C( 1) 110.4(12)
O(2)-C(5)-H(5A) 109.6
C(1)-C(5)-H(5A) 109.6
O(2)-C(5)-H(5B) 109.6

239

Bond lengths Continued

C( l )-C(5)-H(SB)
H(SA)-C(5)-H(SB)
C(2)-C(6)-H(6A)
C(2)-C(6)-H(6B)
H(6A)—C(6)-H(6B)
C(2)-C(6)-H(6C)
H(6A)-C(6)-H(6C)
H(6B)-C(6)-H(6C)
C(4)-C(7)-Br( 1 )
C(4)-C(7)-H(7)
Br(1)-C(7)-H(7)
O(2)-C(8)-C(9)
O(2)-C(8)-H(8A)
C(9)-C(8)-H(8A)
O(2)—C(8)-H(SB)
C(9)-C(8)-H(8B)
H(8A)-C(8)—H(8B)
C(14)-C(9)-C( 10)
C( 14)-C(9)-C(8)
C(10)-C(9)-C(8)
C(9)-C( 10)-C( 1 1)
C(9)-C(10)-H(10)
C(l 1)-C( 10)-H(10)
C(12)-C(1 1)-C(10)
C(12)-C(11)—H(1 1)
C(10)-C(11)-1-I(1 1)
C(1 l)-C(12)-C( l3)
C(l 1)-C(12)-H(12)
C(13)-C(12)-H(12)
C(12)-C(13)-C( 14)
C(12)-C(13)-H(13)
C(14)-C(13)-H(13)
C(9)-C( 14)-C( 13)
C(9)-C(14)-H(14)
C(13)-C(14)-H(14)

109.6
108.1
109.5
109.5
109.5
1095
1095
1095
128.5(9)
115.8
115.8
108.8(10)
109.9
109.9
109.9
109.9
108.3
118.9(11)
122.4(11)
118.7(11)
120.8(12)
119.6
119.6
120.4(13)
119.8
119.8
117.9(14)
121.1
121.1
122.1(13)
119.0
119.0
119.8(11)
120.1
120.1

240

Bond lengths Continued

C(20)-C(15)-C(16)
C(20)-C(15)-S(1)

C(16)-C(15)-S(1)

C(17)-C(16)—C(15)
C(17)-C(16)-H(16)
C(15)-C(16)-H(16)
C(18)-C(17)-C(16)
C(18)-C(17)-H(17)
C(16)-C(17)-H(17)
C(17)-C(18)-C(19)
C(17)-C(18)-C(21)
C(19)-C(18)-C(21)
C(20)-C(19)-C(18)
C(20)-C(19)-H(19)
C(18)-C(19)-H(19)
C(15)-C(20)-C(19)
C(15)-C(20)-H(20)
C(19)-C(20)-H(20)

C(18)-C(21)-H(21A)
C( 1 8)-C(21)-H(21 B)
H(21A)-C(21)-H(ZIB)
C(18)-C(21)-H(21C)
H(21A)-C(21)—H(21C)
H(21B)-C(21)-H(21C)

120.2(10)
121.8(9)
117.9(8)
118.8(11)
120.6
120.6
122.2(11)
118.9
118.9
1175(11)
123.3(12)
119.1(12)
120.3(12)
119.8
119.8
120.9(12)
119.6
119.6
109.5
109.5
109.5
1095
109.5
109.5

 

241

gm

 

v-125. 1H NMR

 

 

A666. :zm 8.820

W.” O v mi 0 m mh 06 mb 0 5 ms 0 m

. F69>ir ». 1 ..1»! MI- .. ... .n. p... r» . l.»?>ire.b»»c 3r}. Yp.»,.».... . p . . .. ... .Pi— ......
nJflv. “11-.-... a. .. 2. 2
..Z .1 .7. ... B Z
Z z 9 o 0 0

 

 

 

 

 

 

 

 

 

 

 

 

 

Ocm

uni—(081$ T>Imm

242

 

v-125. 13C NMR

 

 

£83 55 8.520
o w mp VN Nm 0% Q? on #0 NR 8 mm 0m 3w NS. GNP wNP mar 32.
(Lirrri . t Err-» [Fruits rrithrrrttttfit. Erik...» .11 1:2» Ctr.» . . FEL>hwr1pririirrLF~ h i .LriFFLiCLFLrLLF—EFLFLEE»LrL r- r.
3 2 4 1 O 7 7 2 7
1 5 573 2w4m5 7 7. 6.7.4.5....65. a
1. e. ...mv. mam .m o. m nnmwuww u
T- 5 r [.15. . _ [<11 2 :

 

 

 

 

 

 

 

 

 

243

 

 

 

 

 

 

0.5

L. ..-_.£t:-.<=a-.3.z-: -—_—-._-

 

- fair-.57.;

 

Nugqh Tim—w

:83 £5 3520
o no 3 3 ed m.~ ad ad a... m... 3.. an 90 We 3 ms

. .. . . a . . _ . . .
Esp FFDIFFlvlrLuBLIEL rlrlwlrkfftlri PthIPLILIFFLFbli.r> I brw r.» t u hilwlp .vabnfiL.r rLL iv > vEAPFFlrFttLt D uLiFl—ILIrihtrLibi. Chi—.1111 >17? riff p 5.1%. s rPFLiL t p.» ..v >L|PLIP viii»... DOLL..— t r pith p .L I will”

T... T. .2 J 1-111 «1...... 1. min; .714... a--- .1; 1, ._
.7 .L. .l .9 .... .L .L z. L .8 _ Z
8 6 9 0 9 9 c 9 0

 

 

1

F

 

31. 3111.142) 3;

 

 

 

 

 

 

 

v-133. 1H NMR

 

.50 of

   

fl...

 

§¥~méo¢=1¢w

E8. 55 .3820
o no 3 3 o.~ 3 9m 6.... o... m... o6 3 od 3 o.»
_ L . . _

 

mg 0.6

h 1.1.1.0

1L kt frrrrbiifptir» ...rervckLLitLLLL CtLLyr..oiprf.r.rer.ifh.r. r.FOL....~ yyyyy _p . p » ErferrprtLiryLuth». r- ..Yr.. p... .iLikiu...LLF.F>.L .r.frr1F..P.»v.r».:i.vL .rtblrivi..ci r?..>1.--> L.»
flHW. Vhilb. _F \ wltiln. ... H a I. I .I. .11. J .‘ililiii! 111111“ .—.-.i r. L a *— _hH 31111.“ T: . I 1 11.14 .11
.v .7 .0 .9 7... 1. 1 l .9
cc 0 9 v 9 Z 0 Ir 6
II iii/)2 \ \axi _ /. 3.5111(3)) 3sz a. .\111/ .‘\\. 7.. \ \.. .1 I x I m J .1 iil/ 4.x“
. . .._.. ._ .. t . _ .. . . .x . .... A 4.. 1‘ ... ... . \
... x)... . _. ._ .. . D a... J . a 1. .... E . .. ..
. . ‘_ 5.. __ r q . H . ._ _ ._ . ..
.__... ...u E: __ K .i W.; a“ .7 _ ..__.
_ .. _. n 1 _. u .. _
r . h m _ V g., _ 1. r _ a N . .. .
4 .: f . . fl : _ _ . .. _
_ _. .. l _ on _. m _ i;
0 -1 b m ... _ . _
1\ .
:2... . _fl
7
7
..
A

 

v-135. ‘H NMR

£0

.50

2:
fl

 

 

§I-Nu:~bu=_Imm

245

SRHIII—67-F2-C300

//

HC

OBn

v-135. 130 NMR

 

V-145

CH3

 

“21.47

Tfi'P"

.-rvr

-25.26 g

40

FT

. ”_Y'

'V‘V

‘ 58.65 I

, 70.74
73.88

476.57
-.-76.99 t
77.42 ;

‘ 78.46

81.47

‘-

—108.15'ZL‘

1126.92?

1

1' 127.81;
1 128.18;

‘ 128.57 L

‘- 129.641

* 136.51 ,1;

—- 143.40;

—~148.41f_

'-

r
f .

11“ W‘T'Y‘T

20

100
Chemical Shift (ppm)

160

-20

60

80

120

140

180

200

220

(1)

(2)

(3)
(4)
(5)

(6)
(7)
(8)
(9)
( 10)

(11)
(12)
(13)
(14)

(15)

(16)
(17)
(18)
(19)

(20)

References

Schomaker, J. M.; Geiser, A. R.; Huang, R.; Borhan, B. J. Am. Chem. Soc. 2007,
129, 3794.

Schomaker, J. M.; Bhattacharjee, S.; Yan, J .; Borhan, B. J. Am. Chem. Soc. 2007 ,
129, 1996-2003.

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