I Preparation of N-Sulfonylsulfilimines Via

University of New Hampshire University of New Hampshire Scholars' Repository

Doctoral Dissertations Student Scholarship

Spring 1968

I PREPARATION OF N-SULFONYLSULFILIMINES VIA CYCLOADDITION REACTIONS OF N-SULFONYL ISOTHIOCYANATES AND N-SULFONYL PHOSPHINIMINES WITH SUFOXIDES II ATTEMPT AT PREPARING (METHYLSULFINYL)ALKYL ISOTHIOCYANATES VIA OPTICALLY ACTIVE METHANESULFINATE ESTERS

JOHN BUTLER O'BRIEN University of New Hampshire, Durham

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Recommended Citation O'BRIEN, JOHN BUTLER, "I PREPARATION OF N-SULFONYLSULFILIMINES VIA CYCLOADDITION REACTIONS OF N-SULFONYL ISOTHIOCYANATES AND N-SULFONYL PHOSPHINIMINES WITH SUFOXIDES II ATTEMPT AT PREPARING (METHYLSULFINYL)ALKYL ISOTHIOCYANATES VIA OPTICALLY ACTIVE METHANESULFINATE ESTERS" (1968). Doctoral Dissertations. 2363. https://scholars.unh.edu/dissertation/2363

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O 'B R IEN , John B utler, 1941- I. PREPARATION OF N-SULFONYLSULFILIMINES VIA CYCLOADDITION REACTIONS OF N-SULFONYL- ISOTHIOCYANATES AND N-SULFONYLPHOSPHINI- MINES WITH SULFOXIDES. II. ATTEMPT AT PREPARE ING (METHYLSULFINYL)ALKYL ISOTHIOCYANAT ES VIA OPTICALLY ACTIVE METHANESULFINATE ESTERS. University of New Hampshire, Ph.D.91968 Chemistry, organic

University Microfilms, Inc., Ann Arbor, Michigan

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. I. PREPARATION OF N-SULFONYLSULFILIMINES VIA

CYCLOADDITION REACTIONS OF

N-SULFONYLISOTHIOCYANATES AND

N-SULFONYLPHOSPHINIMINES WITH SULFOXIDES.

II. ATTEMPT AT PREPARING (METHYLSULFINYL)ALKYL

ISOTHIOCYANATES VIA OPTICALLY ACTIVE

METHANESULFINATE ESTERS

JOHN B^fc'BRIEN

B. A., LAFAYETTE COLLEGE, 1963

A THESIS

Submitted to the University of New Hampshire

In Partial Fulfillment of

The Requirements for the Degree of

DOCTOR OF PHILOSOPHY

Graduate School

Department of Chemistry

January, 1968

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. This thesis has been examined and approved.

Qj u i a j j ]// A

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENTS

The author wishes to extend his sincere gratitude

to Dr. Kenneth K, Andersen, whose guidance and encouragement

aided greatly in the completion of this work.

The author would like to thank Dr. Paul R. Jones for

reading the entire thesis and making many helpful suggestions.

Thanks are also due the entire Organic Staff for their co

operation and assistance. Financial support from the National

Institutes of Health is gratefully acknowledged.

The author wishes to dedicate this thesis to his

wife, whose patience and understanding has made the completion

of this work possible#

H i

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Page

L i S t Of T &b l©S®o®®o®®«®eQaa9®«eee®®®o»®®«e»®®»B®®B®o.8a®®9a®«.3CH

L i s t Of F ig\X2?@ Sase.a.aa.QOaB®®.®®®®®®.®®®®®®®®®®®®®®®®®®®®®®®® 3£lV

PART I

INTRODUCTION e®®.®®®®®®©®®.®.®®®®.®®®.®®®®®®®®®®®®®.®®®®®®®®®®©®®^

Early history of sulf ilimines« i •> m>i • ® > • • •®2

St rueture of sulf i1 imineSo®o®®®«8«®a®ofl®®®«a®«®«o®®®®®©®®®®®®®®®3

Mechanism of general sulf ilimine reaction...... *...... ® ®^

Preparation of N-sulfonylsulfilimines...... ® ® ® • ®5

Preparation of N—acylsulfilimines. >•®•«■® ®•«•«®••■®««••® «■® < ® ®•i5

Cycloaddltlon Route to N-sulf onylsulf ilimines...... ©6

Cycloadditlon Route to N-acylsulfilimines.

Preparation of an optically active N-sulf onylsulf ilimine...... 7

Mechanism of the N-sulf inylsulfonamide reaction. • ...... ® ..«••• 8

Purpose of this investigation.o®®®«ee®®e®®®®®o»«®®®®®a««ae®o®®®.8

RESULTS AND DISCUSSION o....oaQo.oflo.fi.8oe«88oa«Ba880o..®eao®o.oo9

Phosphinimine and phosphoramidate route • • • •. •. • ..... 9

Structure and Wittig reaction of phosphlnimines...... 10

Mechanism of phosphinimine reaction...... 11

Reaction of N-jo-toluenesulfonyltriphenylphosphlnlmine with

d ime thy1 sulfoxid6 ^ « i « • s ■* * m m « a > < * >> i • 1 1 * »*•«i *•««»s12

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Reaction of N-^-toluenesulfonyltriethoxyphosphinimine with

dime thyX sulf ox id@« m i « « • • > i « ■ i * > « « * i • m * « i • • * •• < « ■ * *• *12

Reaction of dimethyl N-]D-toluenesulfonylphosphoramidate with

d imethy1 sulfoxlde®*©©8ao®®e«®®aa®®oaaa®*o®®®©«©®®«®a®®®®13

Reaction of N-^-toluenesulfonyltrichlorophosphlnimine with

dIme thy1 SUlfOX ide eo»>a««oao«o 9 e«flo9 i o o a » 0 o « o t o » « o » 4 >fte«i 1^4*

Mechanism of the reaction® ® ®«©see«t®>«® 9 ®g®«®i®s<®®«s®®®®®«®<« ®13

Discussion of effect of substituents on reactivity of

phosphinimines•••••••••••••••■•••••••••••••••••••••••••••13

Possibilities for future work®•••••••t®®®«®®®®®®®«®<®a®®*®®®®®#16

1,2-Cycloaddition route with N-sulfonyl- and

N-acylisothiocyanatesee®®®®®®®®®^^®®®®®®®®®®®®®®®®®®®®®®®16

Reactivity of N-acyl- and sulfonyllsocyanates. •...... 17

Reaction of N-sulfonylisocyanates with sulfoxides®®18

Reactivity of isothiocyanate in terms of structure® ©. • ...... 18

Reaction of N-£-toluenesulfonylisothiocyanate with dimethyl

sulf oxide ©.o®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®©.®®®©©® 19

New preparation for N-jd- toluene sulf onyl isothiocyanate...... 19

Reaction of N-benzoylisothiocyanate with dibenzyl sulfoxide...♦20

Reaction of N-benzoylisothiocyanate with dimethyl sulfoxide.••.20

Possibilities for future work® ®«®®®®®o®®o®®®e®o®e®®®oo®®®®®®®® ®20

DESCRIPTION OF EXPERIMENTS e.®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®*®®®® 21

N-£-Toluenesulf onyltriphenylphosphinimlne •. *...... 22

Attempted reaction of N-jo-toluenesulf onyltriphenylphosphinimlne

Wl th dIme thy1 sulf oxide ee««eaeea«««s«asea®®«®aaso«o®®®ae ® 2 2

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TristhyX phosphite©®©®#©©©©©©®©®©®©©©®®©©©®©®©®®©©©®®®©©®®®®®®®^^

N-jo-Toluenesulfonyltriethoxyphosphlnimine ...... 22

Attempted Reaction of N-jo-toluenesulf onyltrlethoxyphosphinlmine

with dimethyl sulf oxide ©©•©©©©©••©©©©©©©©©©©©©©©•©s©©©©®© 23

Diethyl N-jd-toluene sulf onylphosphoramldate® ...... 23

Dimethyl N-jo-toluene sulf onylphosphoramldate©.. © •...... 23

Attempted reaction of dimethyl N-]D-toluenesulfonylphosphoramldate

with d ime thy1 sulf oxide ©•©©©©•©•©©©■©•©••©©•••©©•oo©*«s©©23

N-g-Toluenesulf onyltrichlorophosphinimine © ©... ©...... 2^

Reaction of N-j>-toluenesulfonyltrichlorophosphinimine with

d ime thy1 sulfoxlde9®®®©®®©©eo9©©©©o©oo©©t©©e®©®©©«®®®©©®©23

Reaction of N-jo-toluenesulfonyltrichlorophosphinimine with

dipheny1 sulf OXlde»©9«e©o»©9o®»«©®o«9®9e»©90©©©®®»©8©®®8o23

N-Benzoy1 is o th1ocyanate ©a©©©©©®©©©©©©©©®©©©®©©©®®®©©©®©®®©®©®©© 26

Potassium N-^-toluene sulf onyl iminodithlocarbonate® ©•..•....©••• 26

N-j>-Toluenesulf onyllsothiocyanate ...... 26

Chlorination of Potassium N-j>-toluenesulfonylimino-

d1th1ocarbonate ©«©©©«©»©©©•©©oo©©©©©©©©©©©©©©©©©©©©©©©©®® 27

Reaction of N-£-toluenesulfonyllsothiocyanate with dimethyl

SUlfOXldeoo©e«©©©©«&oe©9«©©e©©«©o©©©®o«o®o©©Q©©®®o®©®®©®©2d

Reaction of N-£-toluenesulfonylisothiocyanate with alkyl aryl

SUlfOXldeS99©aoofie9©fle©a©o©«e©©©©©©®©«oe©9©©©©©o©©©®©®©©®23

Reaction of N-benzoylisothiocyanate with dlbenzyl sulfoxide.©«.29

Reaction of N-benzoylisothiocyanate with dimethyl sulfoxide..•.29

BIBLIOGRAPH Y ©o©9©«Q©©©©o0©«e©©©8O8Q©oo9®®®©©ae®©©oe©o9e©©®©®®©o3"^*

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PART II

Page

INTRODUCTION 36

Early hIs tory9©©©#®a®©®®®0®®®®®©®«®®®®09®©®®®®9®©©©©©®®®®®®©®®36

Structure of the isothiocyanate glucoside...... *37

Early Isolation. worlc© g®®®®®®®®®®®*©®®®©®®®®®®#©®®®*©®®®©®®®®© «3®

Optical rotatory dispersion studies...... ®>.®>®«39

Reaction of (-)-menthyl arenesulfinate ester with Grignard

reagents 90®©®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®© 40

Optical analog for isothiocyanate sulf oxides«...... 41

X-Ray study on isothiocyanate sulfoxides® •...... • ••*.. ®...... 42

Purpose of this investigation® ©©o©®®©®©®®®®®®®®®®®®®®®®®®®®©© ©43

RESULTS AND DISCUSSION a®®®®®®®®®®®®®®®®®®®®®®®©®®©®*®®®©®®®©® ®44

(4") — Ethy 1 £-toly 1 sulf oxide 9®®®®®®®®®®®®®®®®®®®®®©®®®®®®®©®®®® 44

N-Methyl-N-^3-(methylsulfinyl)-propyl]-aniline.*...... 45

Assignment of absolute configuration. ©...... 46

Asymmetric Synthesis of jo-toluenesulfinate esters...... ®47

(-)-(JL)-Methyl phenyl sulfoxide via menthyl methanesulfinate..48

Purification1of (— )—isoborneol® e®®®®®®®®®®©®.®®®©©©®©©©©©©®©® ®48

( + )-(R_)-Methyl £-tolyl sulfoxide via (-)-hornyl

(db)—me thane sulf1nate9©©o99««ee©©e©o«oo«9e©««9oo©«o©e®®«©49

(+)-(Jj“Methyl phenyl sulfoxide via (-)-isobornyl

(dc)—me thane sulf inate 0®©®®©©©..©®®®©®©.©®®®®®®®®©®©©©©©©® ^0

vii

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( + )-ii-Butyl methyl sulfoxide via (-)-cholesteryl

(i )-methanesulf inate oaoooeoaaooeeeaao.eeaooooeeaaaaaoeooo 5^

Purity Of methaneSUlf inate esters ooeoeoeaaoeeoaaaaeeeeoeooaaoea 51

Infrared speotrae oooaoaooaaaoooeeoa.ee..aaaeooeeoeoooaaoaaoaoea 51

Ultraviolet speotrae oaoeeaae.eeeeeaeaoaoeaaoeeeaaaaeeaooeaoooea 51

Nuclear magnetic resonance spectrao aaaa«*a>0«Q«»aaaaaBO««aaoaaa53

Synthesis of racemic sulfoxide isothiocyanates...... •••53

Hydroboratlon routeeooeeaeeoeoooeeeeeeoeseeeeooeeeoeaoaeeoaeoeo 5^

Hydroboration of allyl methyl sulfoxide.. a a...... 55

Attempted protonation reaction#$© ©..«o o . a . 56

Reaction of allyl phenyl sulfoxide with bis- (3-»methyl-2-butyl)•»

bOrane eeeooeoeoeooooeeoaoeeooeoaeeeoaeooeaeeaeoaaaoeaeeea 57

Reaction of allyl phenyl sulfide with bls-( 3-meth.v 1-2-butyl)-

borane oaeaae.aeeo.o.eaoe.eaoe.aaceaaaaeeoaaaeaaaeaaeaa.ea 57

Disllazane route o ©® ft eooeaeeaoeos. o o o o a o e ooooeeeeoeeoooeoaoeee.5®

Potassium 1,1,1,3»3»3-hexame thyldi s ilazaneaaao.aaaa.aoaoa58

Stability of trimethylsilyl group toward organometallic

reagents aeeQoooeoeoeeeaeeeeooooaoooaoooo.aoaeoaooeaoooe.a 39

N—Butyl“1jl,l»3 »393"hexamethyldi silazane aaaaec.eaaaaoooo0aooe.a6O

Trimethylsilyl and tetrahydropyranyl ether route....o.a.a...... 60

— (Me thy1SUlflny1)—1 —butanolaeaaeeoaaeaoaaaa«eeoaaaaaeoaaaeoeaa6l

Preparation of chloroalkyltetrahydropyranyl ethers ...... 62

3-Me thylsulf inyl-1- (1 ,1-dimethylpropoxy)-propane ...... <63

Possibilities for future work eeoeaaaaaaeoaaeoeB.oaeaoaaoaaoaoaa63

DESCRIPTION OF EXPERIMENTS.aaaaeeaaoaaaoaaaaaaoaaaaaaaeaaaaaeoa73

viii

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Sodium £-toluenesulfinate d Ihydrate . o . . . . ® . ® ...... 7^

£-Toluenesulflny1 chloridet®®*®®®®®®®®®.®®®®®®®®®®®®®®®.®®®®®.. 7^

(— )—Menthy1 (— )—jd—toluene sulf inate*••••«•••.•••••••••••••••»«•• 7^

(+) — (R) “Methyl p— toly 1 sulf oxide

Me thy1 pheny1 SUlf OX ide oo«eo®®®®®«®ee®8®®®*B®e®®®®e®®®B®e®®®®®®75

Me thy1 jd— t oly1 sulf oxide

Bu ty 1 me thy 1 sulf ide i(m»niio(tiinm

Bu ty 1 me thy 1 sulf oxide

Methyl methanesulfinate .0®®®®.®.®®®®®®.®®®®®®®®®®®®®®#®®®®®®®®® 7^

Me thane sulflny1 chlorid 6®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®?^

Methyl p—toluenesulfInate»c®®®®®®®®*®.•«»•«»•••«•■•••••••••••••77

(— )“Menthy1 methanesulfinate•••«••«••••«•••••••••••••«•••«•••••77

(i )“Isoborny1 me thanesulf inate ca*®®®®®®®®®®®®®*®®®®®®®®®®®®®®*® 78

(ab)“Borny1 methane sulf inate•••e®®®®®®®®®®®®*®®®®®®®®®®®®®®®®®®® 79

(■**)“ X SObO me Ol®Q00ooo®ooco®o09o0e«®ooeo®eoa®o®o®0®B®®®.®®o®8®®®79

Purific&fc 1 on of (—)—isoborneOloo®®o®c®o®®®o®®e®®®®<3a®®®®«®oo®®e80

(-)-Isobornyl (± )-me thane sulf inat e (0°reactlon)«...«••••..... ®81

(-)-Isobornyl (± )-me thane sulf inate (-65° reaction)«®... 0...... 81

Lithium trimethoxyaluminohydride• ...... • 82

Attempted reduction of d-oamphor with lithium

trimethoxyaluminohydride .e®®®..®®®.®®..®®..®.®®.®.®®®®®®® 83

Purification of (-)-borneol by column chromatography.•...... 83

jo—Mltrobenzoy1 chloride o®®#®®®®®®®®®®®®®®®*®®®®®®®®®®®®®®.®#®®® 8^

Pur i f1cat ion of (— )—borne oXo®®®.®®®®..®®®®®®.®..®®®®.®®*®®..®®® 8^

(-)-Bornyl (i)-methanesulfinate (0° reaction)®®®®®.o.®•«««•.•®.86

(-)-Borayl (±)-methanesulfinate (-65° reaction)...... 8 6

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(— )-Chole s t ery 1 (— ) —me thane sulf Inate 9®®®®®®®®®®®®®®®*®®*®®$®®®® 86

(-)-(jS)-Methyl £-tolyl sulfoxide via (-)-menthyl

(sfc)“ine thane sulf1nate®®®®®®®®®®®®®®®®*®*®®®®®®®®®®®®®*®®*® 87

(»)_(S)-Methyl phenyl sulfoxide via (-)-menthyl

( i ) -methane sulf Inate 8®oe®®««®®®®®®®e®eBe®®®®ee«®«®o«®*®®® 88

(+)-(R)-Methyl £-tolyl sulfoxide via (-)-isobornyl

(±)-methanesulfinate (-65° reaction®..®«.®.•..**••...... 89

(+)-(R)-Methyl phenyl sulfoxide via (-)-isobornyl

(± )-me thane sulf inate (-65° reaction)««•«.®««.*.®®®®*»®®*®90

(+)-(R)-Methyl phenyl sulfoxide via (-)-bornyl

(i )—me thane sulf inate (0® reac t ion•••••••••«®®®®<«®®®*»*®®91

(+)-(R)-Methyl _g-tolyl sulfoxide via (-)-bornyl

(± ) -me thane sulf inate (-65° reaction) •. • ® •» • • ®91

(-)-(S)-Methyl jD-tolyl sulfoxide via (-)-cholesteryl

(—)—me thane sulf inate a >« m ••••(•••••i ® t (>• i ■ * m n> *91

Optical fractionation experiment® ..... • ® • ®93

Separation of cholesterol from sulfoxides - sulfuric acid

method® ceo®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®®*9 ®93

Separation of cholesterol from sulfoxides - acetronltrile

me t h o d ® ® ® o q ® a ® o a o ® ® « e e o 9 ® 9 o 0 ® ® ® ® ® ® ® ® ® ® o ® ® ® ® ® ® ® ® ® ® ® ® ® ® 9 ® ® ® 9^"

(+)-(S)-n-Butyl methyl sulfoxide via (-)-cholesteryl

(— )—me thane sulfinate s®®®®®®®®®®®®®®®®®®®®®®®*®®®®®®*®®®®® 9^

(-)-(S)-Methyl phenyl sulfoxide via (-)-cholesteryl

(— )—methanesulfinate e®®®®®®®®®®®®®®®®®®®®®*®®®®®®®®®®®®*® 96

Epimerizatlon attempt with (-)-menthyl (±)-methanesulfinate...®97

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Allyl Die thy 1 SUlf ld.6 ■aoaa®aa®0®«a®®oo®0o®®0®®00®©®©0®®®®®oe®°*.®98

A1ly1 Diethy1 sulf oxide ©©©©©©©»9®b©©©®©©so©o©©«©o©o©«®©©*©««®®®9^

Allyl jo-anisyl sulfidee®®®®®®®®®®*®®®®®®®®®®®®®®®®®®®®®®®®®®®*98

Ally1 pheny1 sulf ide •»#Be®«®®o®®®a®®®®e«®®®®®®«®®®®®®®®®®®®®®®98

Ally1 pheny1 sulfoxide s®®®®®®®®®®®®*®®®®®*®®®®®®®®®®®®®®®®®***99

Hydroxylamine—O—sulfonic acid® ••••••••••••••••••a®®*®®*®®**®®•99

N- (3-Bromopropyl) phthalimide ••»••«••..... 100

N-[3-(Methylsulfinyl) propyl]-phthalimide •.®.•••••«...... 100

3" (Me thy 1 th io) —pr opy lamine e*e#e*®®®B®®o®«®®»«®®e®e®®®®®®®®®®®100

3- (Methylsulf inyl)-propylamine • ...... 100

Hydroboration of Allyl Methyl Sulfoxide®...... 100

Attempted preparation of methyl n-propyl sulfoxide via

hydroboration of allyl methyl sulfoxide®. •••••••••101

Bis- ( 3 ““me thy 1—2 —buty 1 ) — borane a®e®®®®osasa®®asss®aasaao>®a®ae®102

Reaction of allyl phenyl sulfoxide with bls-

(3*"®® thy 1—2—butyl) —borane ® ® • • • • ® ® • ® i < ■ • < ® •• ® ■ ® • ® ® • ® • ■ • 1102

Reaction of allyl phenyl sulfide with bls-

(3-methy1—2—buty1)—borane•aasas«®«®ssg®aa®s®8oe®®®®o»e®lO^

Potassium 1,1,1,3»3» 3-hexamethyldlsilazane ...... ®105

Attempted preparation of N-( £ -bromobutyl)-

1.1.1.3.3.3-hexamethyId i s ilazane e®®®®®•«»••t mi «< <105

Attempted preparation of N-(Y-chloropropyl)-

1.1.1.3.3.3-hexamethyIdisilazane•«i•im «))><•® t •><106

Attempted preparation of N-( 6 -bromobutyl)-l,1,1,3»3*3-

hexamethyldisilazane - Grignard method...... 107

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N-Buty1-1,1,1,3,3,3”hexamethyldisIlazane••••n« m •>••••>••»108

4-Chloro-l-butanol©a*®#®©®®*©©©©©©©©©©©©®©©©©©®©©®®©®®®®®©©®®®100

*f-Chlorobutoxytrlmethylsilane© ...... • • «108

ty— (Me thy 1 sulf lny 1) —1—butanol ...... 109

2-Chloroethoxy-2-tetrahydropyran®•»•••« •...... ©..«..... ® •.. • ©110

3-Chloropropoxy-2-tetrahydropyran ...... 110

6-Chlorohexoxy-2-tetrahydropyran...... ©Ill

3-Bromopropoxy-2-tetrahydropyran. ..©••••••...... ©112

3-Bromo-l- (1,1-dlmethylpropoxy) -propane. © © ©...... 112

3-Methylsulf inyl-l-(l, 1-dlme thylpropoxy)-propane© ...... ©113

Attempted cleavage of 3-methylsulflny1-1-(1,1-dlmethyl

propoxy )-propane with sulfuric acid© • © ...... ••••©•• 115

BXBXjXOGrRAPRY e©ooea©©9aofto©ooa©ooe©©o©o©©9OOQ«®o0©oo©dfiO©©0®9®® 116

SUMMARY tllOlltlKIIOtlltdMllltltlOIIIXtttltttdlKMail I il25

xll

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PART I I

Table Page

1. Stereochemical calibration of methanesulfinate

eSterS«e»oo9eoo«oeoeQ&ooooe94OO»oeoo0Q0o*oeooooeQ9Qoo63

2. Ultraviolet absorption data for alkyl

methane sulf inate s»»ee«®®0®»»®o*®«®®®®®®®®®e®®®®®®®®®® 67

xiii

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PART II

Figure Page

1© Ultraviolet spectra of methyl me thane sulf inate ®©««... ®»68

2. Ultraviolet spectra of (-)-bornyl (±)

me thane sulf inate ©©®©®0©«ao0o®©#©«©©®®B«®®o®«®®®«®®o®®©©89

3* Ultraviolet spectra of (-)-Isobornyl

(dfc) me thane sulf inate

Ultraviolet spectra of (-)-menthyl

(i)methane sulf inate•••••••••••••••••••••••••••••••••••• 71

5© Ultraviolet spectra of (-)-cholesteryl

Ii)me thane sulf inate ® © © © ®» • ®«® © ®«® ® ® © ® ® ® • ® © ® ® © ®«® © ® ® ® © ® ® 72

xlv

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ABSTRACT

I. PREPARATION OF N-SULFONYLSULFILIMINES VIA

CYCLOADDITION REACTIONS OF

N-SULFONYLISOTHIOCYANATES AND

N-SULFONYLPHOSPHINIMINES WITH SULFOXIDES

II. ATTEMPT AT PREPARING (METHYLSULFINYL)ALKYL

ISOTHIOCYANATES VIA OPTICALLY ACTIVE

METHANESULFINATE ESTERS

JOHN B. 0 9 BRIEN

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. I. As there have been no reports In the literature

of the reaction between phosphinimines (R^P=NR9) and sulfoxides,

this reaction was investigated as a possible new synthetic

route to sulfilimines (R2S=NR*). Several N-sulfonylphosphinimines

and N-sulfonylphosphoramidates [[RSOgNH^ORjg]] failed to react

with dimethyl sulfoxide, although an N-arylsulfonyltrichloro

phosphinimine (RSOgNsPCl^) did react with dimethyl sulfoxide in

pyridine to give the corresponding sulfilimine in yield*

By analogy with phosphonium ylids, the compounds that were

studied can be classified as "stabilized” ylids. An

N-arylsulfonyllsothiocyanate (RSO^NsCsS) also reacted with

dimethyl sulfoxide to give the desired sulfilimine in 37$

yield. An attempt to expand the scope of this reaction to

include alkyl aryl sulfoxides was unsuccessful. During the

course of this work, a general method for the preparation of

N-arylsulfonylisothiocyanates was developed.

II. A series of optically active methanesulfinate

esters (CH^OR) were Investigated to determine which ester

would give the corresponding sulfoxide of highest enantiomeric

purity when treated with a Grlgnard reagent. In agreement with

previous work, it was found that in all cases those esters

prepared at -?8° and used without distillation consistently gave

sulfoxides of higher enantiomeric purity,than those prepared

at room temperature and purified by distillation. (-)-Isobornyl

(±)-methanesulfinate gave sulfoxide of 65$ enantiomeric purity

while (-)-cholesteryl (-)-methanesulfinate gave sulfoxide of

80$ enantiomeric purity. Both of these values represent a

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. substantial improvement in enantiomeric purity over values

previously reported in the literature. The use of these latter

two esters also has the advantage of producing the opposite

enantiomeric sulfoxides. During the course of this work, a new

method for the separation of sulfoxides from cholesterol was

developed which utilized the complexing ability of acetonitrile

with sulfoxides. Several different synthetic routes to

(methylsulfinyl) alkyl isothiocyanates were investigated and

included* 1) hydroboration of allyl methyl sulfoxide followed

by amination with hydroxylamine-O-sulfonic acid. 2) coupling

reaction of potassium 1,1,1,3*3*3-hexamethyldisilazane

[tle^Siwith polymethylene dihalides followed by Grignard

formation. 3) the use of trimethylsilyl and tetrahydropyranyl

groups as protecting groups for ehloro- and bromohydrlns

followed by Grignard formation. *0 the use of t,-amyl groups

as protecting groups for bromohydrlns followed by Grignard

formation. As promising results were obtained in the latter

two cases, work in this area is continuing.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PART I

PREPARATION OF N-SULFONYLSULFILIMINES VIA

CYCLQADDITION REACTIONS OF

N-SULFONYLISOTHIOCYANATES AND

N-SULFONYLPHOSPHINIMINES WITH SULFOXIDES.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2

INTRODUCTION

The use of 2, 2. * -dichlorodi ethyl sulfide (I.), commonly

known as mustard gas, by Germany during World 'War I stimulated,

an intensive investigation of this compound in Great Britain, 2 m Raper , in 1917, found that 1 readily condensed with chloramine-T

(2) to give a crystalline compound and used this method in the

characterization of small quantities of 1. Later, Nicolet and

Willard described "a new type of nitrogen-sulfur compound"

from the reaction of chloramine-T with diethyl sulfide.

(c i c h 2c h 2 )2s CH' / \\-S02-N«C1 + Na

Mann and Pope ' studied the action of chloramine-T on

diethyl-, methylethyl-, and dibenzyl sulfides; and the resulting

crystalline compounds were assigned the general structure ^

and called "sulf ilimines". Structure was i-n agreement with 3 the structure previously proposed by Nicolet and Willard where cr X and Y=C2H^. In 192^, Mann and Pope^ suggested that sulfilimines

should be capable of existing in enantiomeric forms but their

attempts at resolution failed. Later, Clarke, Kenyon, and

Phillips were successful in the resolution of the sulfilimine

from the reaction of chloramine-T with dl-m-carboxyphenyl

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3

methyl sulfide.

. +/CH CEf Og-N-S. j COOH ° V f ^ V S02-N=S^

Because of their successful resolution of a sulfilimine,

Phillips and coworkers^ postulated that the sulfur-nitrogen

bond in sulfilinines was a semi-polar double bond as represented

by structure J5 and not a covalent double bond. Recently,

Kucsman and coworkers have stated that resolvability of mixed

sulfilimines Q, X^Y) does not afford evidence concerning the

sulfur-nitrogen bond character and that stereoisomerism based on

the rigidity of the sulfur-nitrogen bond has not been reported

with simple sulfilimines (j)t X=Y). On the basis of infrared 7 studies o n sulfilimines, Kucsman and coworkers suggest covalent

double bond character for the sulfur-nitrogen bond in N-sulfonyl-

sulfilimines 2*

- +/x -SQg-N-S^ o h 3 - \ /- s V ^ 0H3 - V

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Phillips and coworkers" correctly assigned structure

2 to chloraraine-T and viewed the reaction of 2 with sulfides

as proceeding via a two-step mechanism (eq 1) involving a

radical intermediate, later recognized as a sulfonylimido 8 intermediate (nitrene) 6.

(1)

NaCl

Na+ 6

Kucsman and coworkers' have recently postulated an

Sn2-t;ype mechanism (eq 2) for the same reaction based on the

observation that the reaction was facilitated by increasing the

electron density on the sulfur atom. The dotted line represents

the possible delocalization of charge. Since imido intermediates Q (nitrenes) are highly electrophilic , the evidence of Kucsman 9 and coworkers does not seem to preclude the involvement of an

imido intermediate in this reaction.

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Tarbell and Weaver^ developed a new synthesis of

N-sulfonylsulfill mines from the reaction of arylsulfonamides

with sulfoxides in the presence of phosphorus pentoxide or

acetic anhydride (eq 3)«

P 2°5 or R2S-^0 + R R 1 + H 2 0 \ f 50zm z (3) A o 20

The first N-acylsulfilimines 2 were also reported by

Tarbell and Weaver''"’ from the condensation of dichloro- and

trichloroacetamid.es with diethyl sulfoxide in the presence of

a dehydrating agent. Benzami.de did not react with sulfoxides

under these conditions. Several N-acylsulfilimines were later

obtained by Likhosherstov"*’"'" from the reaction of N-chloroacetamide

with sulfides.

R-C-N<-S(C2H5)2 R=CHC12 or GCl^

1 Recently, 1,2-dipolar addition reactions have found

extensive use in the preparation of N-ac.yl-and N-sulf onylsulf il

imines. Isocyanates constitute an example of a cumulative double

bond system which readily undergoes 1,2-dipolar addition reactions.

The tendency of isocyanates to add preferentially across the

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carbon-nitrogen double bond is increased in acyl-and sulfonyl-

isocyanates because of the polarizing effects of the acyl and ip sulfonyl groups. ' King reported the formation of a sulfilimine

from the 1,2-dipolar addition reaction of jo-toluenesulfonyl-

isocyanate (8) with dimethyl sulfoxide (eq 4). As is

characteristic of these reactions, a c?/clic intermediate was

postulated.

N-acylsulfilimines have been prepared recently by " 14 Neidlein and Heukelbach from the 1,2-dipolar addition reaction

of several acylisocyanates with dimethyl sulfoxide (eq 5)•

CH R-C-N=C=0 + ■*HC-JK-S(CH,), + CO," (5) c h ; II 32 y 0

B=CHC12-,CC13-

Since N-sulfinylsulfonamides 2* obtained from

ar.ylsulfonamid.es and thionyl chloride, had been previously 15 reported to undergo 1,2-dipolar addition reactions readily ,

a general synthesis of sulfilimines was developed by Schulz and *1 & Kresze utilizing the reaction of 2 with sulfoxides (eq 6).

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Using a slight -modification of Kresze's^ and Tarbell1 s'*"^ 17 methods, Cram and Day reported a stereospecif'ic synthesis of

an optically active sulfilimine 10 from an optically active

sulfoxide^ (eq 7)® Basic hydrolysis of the sulfilimine gave

optically active sulfoxide whereas acidic hydrolysis gave racemic

sulfoxide, in contrast to previous work reported by Kresze and 19 Wustrow. £-c h 3c 6h ^s o 2n =s =o

NS02-C6HltCH3-£ S-CH P°CH3C6H4S02NH2 CH tS— CH (7)

It was shown from optical rotatory dispersion (ORD)

studies on the sulfoxide and sulfilimine that all three reactions

had proceeded with inversion of configuration. Two moles of

N-sulfinylsulfonamide were implicated in the reaction, and the

following cyclic mechanism (eq 8) was postulated by Cram and D 8 Day. " They stated that similar cyclic or noncyclic mechanisms

could be formulated for the other two reactions.

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CH3 T s o II .CH. ^ GH3 .N- -S. 2TsNS0 •so2 -S— -NTs (8) o ------^ -s: -TsNSO 0 s \c 6h JL|.c h 3-.£ 'C6H4CH3-.£ II C,H. CH -£ NTs 6 4 3

T8*ja-CH3C6H^S02.

This part of the thesis deserines the preparation

of N-ac.yl- and N-sulfonylsulfilimines via c.ycloaddition

reactions utilizing N-acyl- and N-sulfon.ylisothiocyanates

with, sulfoxides and via Wittig-libe reactions between

appropriately substituted phosphinimines (R3P=NR^) and

analogous compounds with sulfoxides.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 9

RESULTS AND DISCUSSION

A » Phos ph ininine and Phosphoramid.ate Route 20 The reaction of phosnhonium ylids with carbonyl

compounds to form olefins and phosphine oxides (eq 1), commonly 21 known as the Wittig re ct.ion , has attained great importance

in preparative organic chemistry, especially in the field of 2 ? natural products.

(c 6h ) f = c h 2 (C/H ) P— CR r c=cn* 6 5 3 | 2 0— CR' (1 )

R»oC = 0 (06h 5)3p= °

Although phosphonium ylids have been reacted with a

variety of compounds containing polarizablo atoms , the reaction

with sulfoxides to form sulfoniu.m ylids has been conspicuously 23 absent from this list. Corey and coworkers have reported the

— -f use of methylsulfinvl cnrbanion (CHoSOCH-Na ) in the preparation J) u. of phosphorus ylids, but the ylid was then reacted with a

carbonyl compound to form the corresponding olefin. Castrillon 2k and Szmant have suggested this type of reaction as a possible

intermediate step in the reduction of sulfoxides by triphenyl-

phosphine and carbon tetrachloride (eq 2).

Ph3P = C C l 2 + RgS^-O Ph^P— 0 + (R2S = C C 1 2 ) (2)

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 10

Phosph3 r i-n Jnos (Iwinophosphorwry: s ) ore of interest to

the organic chemist becuuse of their chemical similarity to

oho:-r>honii:ini y 1. i 1 a (mothy 1 er;ephosohoranes ) * with which they ere 2 '5 iso- lectronic. Pho--phinisri ir.er; can be represented oa resonance

hybrids of the two ccntribu t :i ng structi:r...o la and lb, with the

degree of overlao of the filled nitrogen 2p-orbit°ls(s) with

the vacant phosphorus 3d-orbital(s) determining the nature of the

bonding between the nitrogen and sho ; phorua atoms.

R 0P— N-R’ <------> R ?=K-R* J (a) (b)

26 Standinger and Meyer sere the first to snow that

phosohin inn nes react with carbonyl compounds in a manner analogous p C to that of the Wittig reaction.They found that N-phenyl-

tripheny 1 phosphiniraine (2) reacted with a variety of carbonyl

compounds to give the correspond ing irir.es and triphenyl chosphire

• **•» oxMe (cq 3).

(C6H5 )3P = N C gH5 + (CgH5 )2C = o - »(C6H5)2C=rNC6Hs + ((gHg PO <3)

The mechanism of the reaction between phosphinitiiines and

carbonyl compounds has been recently elucidated by Johnson 27 28 and dong. Betaine formation via, nucleophilic attack of the

nitrogen on the carbonyl carbon was the rate-determining step

(eq b). However, an increase in the electron density on phosph

orus can slow the oxyanion attack to a point, where the second

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steo 'becomes rnte-de termir.1 ng •

+ Ph P— N'Ph Ph„P— N-Ph Ph0P— 0 P j 0— CH-Ph (^)

Ph— C. PhN=CH-Ph H

29 Horner r-'nd Winhl '-r have recently reported that an

optically active N-aryltriarylpb os phin inline reacted, with

nitrosyl chloride and the resulting phosphine oxide was produced

with net retention of configuration accompanied by some

racemizution. The previous mechanism would predict retention of

configuration at phosphorus.

As was the case with phosphoniurn ylids, there has been

no report of reactions between phosphiniinines and sulfoxides.

Since this reaction would serve as a new synthetic route to

su1fillmines (eq 5)» it was investigated uti1izing

N-sulfonylphosphintmines and analogous compounds.

R nP— N-R R-N— SR 1 J w + Q-^-SR 1 + (5)

0 = S R ’ R3p= o 2

However, there was no reaction observed between N-jo-

toluenesulfonyltriphenylphosphinimine (b) and dimethyl sulfoxide

in dry, refluxing benzene (eq 6). The nucleophilicity of

must be decreased to a sufficient extent by the resonance

stabilization of the sulfonyl group to'prevent reaction with

sulfoxides.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. C6H6 (G/Hr)oP=NS0c>C,H,1CH<32 + (CE )oS-*0 NO RiACTION (6) 6 5 3 y 6 h- j *a 2 Reflux

The only instance of an trialbyloxyphosphirimine

undergoing a Wittig-1 ike ruction with carbonyl compounds was 10 reported by Kabachnik and Gilyarov.' They found that

N-phenyltriethoxyuhosphinimine (_£) reacted with carbon disulfide

to give the correspond ing isothiocya.no.te, isolated as a thiourea

derivative (eq 7).

( C?H^O ) PzrrN-C^H ^ + GS. C.H3T— C — S + {C H 0) P = 3 (7) y 6 5 ^ 5 3 C,H,NH0 . 6 5 R

(C.H6 5 NH) 2 C = S

There was no reaction observed between N-jo-toluene-

sulfonyltriethoxyphosphinimine (6) and dimethyl sulfoxide in

refluxing 1,2-dimethoxyetha.ne (eq 8). Once again, the resonance

stabilization of the sulfonyl group is responsible for the

decrease in the nucleophilicity of 6.

DME (C H50)3P=NS02C6H^CH3£ + (c h 3)2s^ o -> NO REACTION (8) Reflux 6

Attention was now turned to N-sulfonylphosphoramidates. 31 Wadsworth and Emmons found that phosphoramidate anions 2. react

with a variety of carbonyl compounds to give the corresponding

imines in high yield (eq 9) • Their method has the advantage

that the diethyl phosphate which is formed precipitated from the

reaction mixture and could be separated much easier than the

triphenylphosphine oxide from the analogous phosphinimine reaction

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 13

Another advantage is the relative ease of obtaining the desired

reagent and its stability compared to many of the phosphir.imines.

,0 NaH _0 R ’CHO (C9H<0)9R ; ------^ (G H 0) Pv ------h R»CH=NR ^ 5 ^ NHR Di/a;lyme ^ 5 2 N-R + (9)

2 <°2W ° 2

As in the previous cases, reactions of phosohoramidate

anions with sulfoxides have not been reported. The reaction

of dimethyl N-jo-toluenesulfonylphosphornmidate (8) with dimethyl

sulfoxide in dry d iglyme (eq 10) gave only unreacted starting

material. As before, resonance stabilization by the sulfonyl

group accounts for the unreactivity of 8.

0 0 f NaH t (CH 0) oPNS0,_,C Hh CH r> ------► (CH 0) PNS0oC H CH £ (10) J ^ I O J D Hi i. glyme v>np 9 ^ ^ o H 8

Diglyme (CH3) s-^o

NO REACTION

The last group of pho^phinimines that were investigated

were the N-arylsulfon.yltrichlorophosphinimines. N-substituted

trichlorophosphinimines, readily obtainable from the amine or

amide and phosphorus pentachloride, undergo reactions similar 32 to those reported for other phosphiniraines. Ulrich and Sayigh

found that heating dimeric N-methyltrichlorophosphinimine (£)

produced the monomeric form which underwent the following

Wittig-like reactions (eq 11).

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Cl P— N-CH, CO 3| | 17 5-180 Cl P— N-CH CH N = C = Q CH„~N— PCI. 3 3 7 C ,H NCO C S h \ > (11) 6 5 I CH3N=:C=S

C^H^N— C— N-CH^

When N-jo-toluene sulf oriyltrichloro phosphinimine (10) was

treated with dimethyl sulfoxide in anhydrous pyridine, an

exothermic re.act.ion occurred with subsequent formation of the

desired sulfilinline (eq 12) in yield. The fact that the

reaction occurred at all is surprising since resonance

stabilization of the ylid by the sulfonyl group is still operatable

and electron-withdrawing groups (e.g. Cl) on phosphorus would

increase the d-orbitai resonance and favor structure (lb) of the

p h o s ph i n i rn i n e .

C H J.N Cl P— NS0oC/H.CHod + (CH ) S-»0 > ^CH C H( SO NarS(CH^) (12) 3 2 6 4 3~ 32 0 3 6 ,+ 2 j> * 10 +P0C1

33 As jLO has been shown to be monomeric , the mechanism

of this reaction is probably similar to that proposed for the 22 Wittig reaction. Nucleophilic addition of the ylid nitrogen

to the postively charged sulfur of the sulfoxide would result in

betaine formation. Because of the great affinity of phosphorus 22 for oxygen and its ability to expand its octet to 10 electrons ,

a P 0 bond would be formed leading to a four-membered ring

compound _11. Intermediate 11 would then collapse to give the

sulfilimine and phosphorus oxychloride (eq 13)*

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3 Betaine Intermediate

(13)

£c h 3c 6h ^s o 2n = s (c h 3)2 Cl P— NSO C,H CH p 3 2643 - + 4 .CH 0— s 3 P0C1 CH Q 3 J 11

In order to determine the scope of this unusual reaction,

N-jD-toluenesulfonyltrlchlorophosphinimine (1C) was reacted with

diphenyl sulfoxide in dry benzene. The only product obtained

from this reaction was n-toluenesulfonamide, the hydrolysis

product of IQ. 2.2 As is the case with phosphonium ylids , the reactivity

of phosphinimines is determined by the distribution of negative

charge in the molecule. This distribution defends upon the

nature of the substituent (R*) attached to nitrogen as well as

the groups (R) on phosphorus (see 1 ). The nucleophilic character

of the phosphinimine will be decreased and the stability increased

if the electron pair on nitrogen is delocalized into the

substituent (R•), as was the case for the compounds studied.

An electron-withdrawing substituent (R1) will thus stabilize the

negative charge and reduce the reactivity of the ylid. The

groups (R) on phosphorus influence the reactivity of the

phosphinimine by either increasing or decreasing the d-orbital

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resonance between nitrogen and phosphorus. Decreased d-orbital

resonance would result in a larger contribution from the ylid

form la and thus in increased reactivity of the phosphinimine.

Electron-withdrawing groups R on phosphorus will increase the

d-orbital resonance and favor the ylene form Fb, while electron

releasing groups will decrease d-orbital resonance and increase

the importance of the ylid form la. On this basis, it is difficult

to explain why the N-arylsulfonyltrichlorophosohinimine reacted

with dimethyl sulfoxide when the other phosphinimine? studied

did not react; unless a solvent effect is operative in this case.

As a result of this study, it would seem profitable to

investigate the reaction of N-aryl-and N-alkylphosphinimines with

sulfoxides, since in these compounds, resonance stabilization

would no longer be a problem. An intensive investigation of the

reaction of N-arylsulfonyltrichiorophosphinimine? with sulfoxides,

with special emphasis on possible solvents effects, won1d help

to explain the anomaly observed with these compounds.

B. 1.2-Cycloaddltlon Route with N-Sulfonyl-and N-Aoyllsothiocyanates 3 4 1,2-Cycloaddition reactions of heterocumulenes-' are of

great Interest to synthetic organic chemists since the addition

often occurs readily under mild conditions and high yields are In frequently encountered*'' Heterocumulenes have been shown to

add readily to a large variety of multiple bond compounds,

giving rise to stable or unstable, four-membered ring cyclo-

adducts. Four-membered ring compounds containing three or four

hetero atoms usually undergo fragmentation to a new double bond

compound and a new heterocumulene (eq 1^).

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R P=N-R8 + RNCO R 0P-j—N R 8 -f- R^PO + RN— C=NR8 (14) 3 3

Isothiocyanates and isocyanates are examples of

heterocumulenes which undergo 1,2-cycloaddition reactions.

The effect of substituents on the reactivity of isocyanates

has been thoroughly Investigated. In general, electron-

withdrawing groups attached to the isocyanate group increase

the electrophilicity of the center carbon atom, while electron- 34 donating substituents reduce its electrophilicity. The

reactivity of the isocyanat© group toward nucleophilic

substitution and cycloaddition reactions is greatly enchanced

in N-acyl- and N-sulfonyllsocyanates 1,2 since the developing

negative charge on the nitrogen atom can be better stabilized by

the acyl and sulfonyl groups. A similar trend in reactivity

would be expected for Isothiocyanates. Because a heterocumulene 34 can act as its own substrate, cyclodimerization often occurs.

In cycloaddition reactions, no tendency of N-sulfonylisocyanates 12 to form dimeric or trimerlc species was observed,

0 0

R-S-N-C=X <- -> R-S=N-C=X II II , 0 (a) 12 0 (b)

Cycloaddition reactions of alkyl and aryl isocyanates 13 with sulfoxides have not been reported? however, King J found

that an N-arylsulfonylisocyanate reacted with dimethyl sulfoxide

at room temperature to form the corresponding sulfllimine. The

generality of this reaction was later demonstrated by Appel

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 18

35 and Rittersbacher » who found that N-sulfonyldiisocyanate

(12) reacted with dimethyl sulfoxide (eq 1 5 ) to form

N,N'-sulfonyIbis £s, S-d ime thy 1 sulf 11 inline] (14).

so2(nco)2 + 2(ch3 )2so ------^ so2[n=s(ch3)2]2 (15)

12, l^

In the cycloaddition reactions of isocyanates, addition

occurs almost exclusively across the C = N bond, while with

isothiocyanates, the C S bond often participates in

cycloaddition reactions®" Addition across the C— S bond in

cycloaddition reactions is best seen in the dlmerization of

N-arylsulfonylisothiocyanates to give the symmetric dimers 36 (eq 16), as reported by Dickore and Kuhle.

/S\ RS02N = C = S ------*RSO N = C V ^C— NSOgR (16) s

The polarization of the NGS grouping is probably

similar to that found In the NCO grouping, the only difference

being the ability of a sulfur atom to better stabilize the

negative charge (15a-c).

- + + - R-N— C— S ------> R-N-C— S ----- : R-N— C-S

(a) (b) (c)

,=L5

As the reaction of N-sulfonylisothiocyanates with

sulfoxides has not been reported, N-jo-toluene sulfonylisothio-

cyanate (16) was reacted with dimethyl sulfoxide at room

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temperature to form the corresponding sulfllimine (eq 1?)

£ - C H oC.H,,S0oN = C = S E-OH^gH^SO^N-C: 3 6 ^ 2 16 (ch3 )2s-o (17)

(c h 3 )2s — o £-CH3c 6Y ° 2N=S(CH3)2 + C02

In an attempt to determine the scope of this reaction,

16 was treated with methyl phenyl sulfoxide and ethyl jo-tolyl

sulfoxide. However, there was no reaction observed in either

case, as only unchanged starting materials were recovered. A

new preparation for 16 was developed during the course of this

work. Although Dickore and Kuhle reported the preparation of

16 from the phosgenation of N-jo-toluenesulfonylimlnodlthio-

carbonate (.12), it was found that good yields of 16 could be

obtained via the chlorination of 1£ during attempts to prepare

N-sulf ony lisocyanlde dichlorides ( R S C ^ N ^ C C ^ ) (eq 18).

SK £-c h 3c 6h ^s o 2n =:c + ci2 > ^ - C H ^ H ^ S O g N — C=rS (18)

n 16

Attention was now turned to N-acylisothiocyanates.

Neldlein and Haussmann^? reported the reaction of dichloro- and

trichloroacetylisocyanates (B^CCONCS) with dimethyl sulfoxide to

form the corresponding N-acylsulfilimlnes, but the analogous

reaction with N-acyllsothiocyanates has not been reported.

When N-benzoylisothiocyanate (18) was reacted with dlbenzyl

sulfoxide in anhydrous tetrahydrofuran (eq 19 )t & white solid

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thought to be the corresponding sulfilimine, as claimed by

Llkhosherstov-^, was obtained, Briscoe-^ has shown that this

compound was In fact a 1«1 molecular complex of dibenzyl

sulfoxide and benzamide.

0 || THF C^H^CNxxC~S + (C^H^CHgJgS—>*0 ------>-lil molecular complex (19)

N-benzoylisothiocyanate (18) did react with dimethyl

sulfoxide at room temperature to give a solid product which was

shown via Infrared not to be the desired N-acyl-sulfilimine

(eq 20), The structure of the compound is currently being

Investigated, and preliminary results (infrared data) suggests

a 1»1 molecular complex.

0 II. ? C^H-CN— C= S + (CHo )oS->0 ------> 1 s 1 molecular complex (20) 6 5 3 2 18

Pyridine was not tried as a solvent since

Isothiocyanates have been reported to form Itl complexes with 12 it. Further work in this area should be concentrated on the

reaction of N-sulfonylisothiocyanates with sulfoxides. If

optimum conditions could be found for the reaction, the yields

could be substantially Increased.

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N-jo-Toluenesulfonyltriphenylphosphinimine was prepared 40 according to the procedure of Kirsanov and Nekrasova from the

reaction of N-jo-t°luenesulfonyltrichlorophosohinimine with

phen.ylmagnesium bromide. The desired product was obtained as a

white crystalline solid (:Ji'% yield) which, after recrystallization

from 95% ethanol, melted at 186.5-187•5°i lit.**® mp 185-187°»

An ir.fr red spectrum (solution, CHGl^) showed a strong band at

1265 cm-1 (P— N).

React ion of N-jo-Toluenepu 1 fony 11ripheny 1 p h o s ph i. n im in e

with Dimethyl Sulfoxide. - N-jo-Toluenesulfonyltriphenylphosphinimine

failed to react with dimethyl sulfoxide ir refluxing benzene, as

only the unreacted starting materils were obtained. Because of

the aopsrent unre' ctivity of this compound, N-jo-toluenesulf onyl-

triphenylphosphinimine would be classified as a "stabilized" 22 ylid .

Tr1ethy1 Phosdhlie was prepared according to the

procedure of Ford-Moore and Ferry from the reaction of phosphorus

trichloride with ethanol in the presence of N,N-diethylaniline.

The desired compound was obtained as a colorless liquid (^k%

yield), bp 55-57° (16 mm), lit.**'*’ bp 57-58° (16 mm), by

fractionation through a 15-cra Vigreux column.

N-jd-Toluenesu 1 fony 11ri ethoxy phos phin im ine was prepared 42 according to the procedure of Cadogan and Moulden from the 43 reaction of anhydrous chloramine-T J with triethyl phosphite.

The desired compound was obtained as a colorless viscous liquid

(68^ yield), bp 181-182° (0.65 mm), lit. bp 159-160° (0.01 mm).

An infrared spectrum (neat) showed strong bn ds at 1260 cra"^

(P=N), 1155-1150 cm”1 (P-OCgH^) and 1055-1050 cm"1 (P-OAlkyl).

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 23

Reaction of N-jo-Toluenesulfon.yltriethoxyphosphinimine

with Dimethyl Sulfoxide. - There was no reaction observed in

refluxing (24 hr) 1,2-dimethoxyethane between excess dimethyl

sulfoxide and N-£-toluenesulfonyltriethoxyphosphinimine.

Because of the unreactivity of this compound, N-£-toluenesulfonyl

triethoxyphosphinimine would be classified as a "stabilized"

ylid.22

Diethyl N-o-Toluenesulfonylphosphoramidate was prepared 44 according to the procedure of Kirsanov and Shevchenko from the

reaction of N-jo-toluenesulfonyltrichlorophosphinimine with

sodium ethoxide followed by hydrolysis and acidificiation of the

intermediate salt. The desired compound was obtained as a white ^ o LlLl ,o solid (97% yield), mp 98-100 , lit. tup 105-106 , after one

recrystallization from carbon tetrachloride. An infrared

spectrum (solution, CHCl^) showed a medium band at 3350 cm (N-H),

and strong bands at 1225-(P 0), 1165-(P-OC^H^)» and 1025-cm

(P-OAlkyl).

Dimethyl N-p-Toluenesulfonylphosphoramidate was prepared 44 according to the procedure of Kirsanov and Shevchenko from the

reaction of N-jc-toluenesulfonyltrichlorophosphinimine with sodium

methoxide followed by hydrolysis and acidification of the

intermediate salt. The desired compound was obtained as a white

solid (70% yield), mp 107-108°, lit.^ mp 110-111°, after

being dried in a vacuum desiccator. An infrared spectrum (solution,

C'HCl^) showed a medium band at 3350 cm ^ (N-H), and strong bands

at 1225-(P 0), 1164-(P-0CH^), and 1035-cm'1 (P-OAlkyl).

Reaction of Dimethyl N-jo-Toluenesulf onylphosphoramidate

with Dimethyl Sulfoxide. - Diglyme (dimethyl ether of diethylene

glycol) was purified by stirring with sodium hydride (50% in

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 24

mineral oil) at room, temperature for twelve hours. The diglyme was

decanted into a distilling flask and sufficient lithium aluminum

hydride was added to ensure an excess of active hydride. J

The diglyme was then distilled from the lithium aluminum hydride

under aspirator pressure. A solution of dimethyl N-jo-

toluenesulfonyIphosohoramidate (13*96 g» 0.05 mole) in dry

diglyme (80 ml) was added dropwise under nitrogen with mechanical

stirring to a slurry of $0% sodium hydride (2.4 g, 0.05 mole)

in dry diglyme (100 ml). When the addition was completed, the

reaction mixture was heated to 70° for one hour. After cooling

to room temperature, dry dimethyl sulfoxide (15.62 g, 0.2 mole)

in dry diglyme (10 ml) was added dropwise at room temperature

to the light yellow reaction mixture. When the addition was

completed, the mixture was heated to 80° for two hours then

stirred at room temperature for eight hour0. The diglyme was

removed in, vacuo and the residue dissolved in water (40 ml) and

acidified with 20% hydrochloric acid. A white solid formed

which was collected by filtration and washed with water. After

being dried in a vacuum desiccator, the solid had a mp of 110- o LlIl o . . 112 , lit. mp 110-111 , and an infrared spectrum (solution)

identical to that of the starting material. Because of the

apparent unreactivity of the N-sulfonyIphosphoramidates toward

sulfoxides, these compounds can be classified as '*stabilized" 22 ylids.

N-jo-Toluenesulfonyltrichlorophosphinimine was prepared 46 according to the procedure of Kirsanov and Egorova from the

reaction of jc-toluenesulfonamide with excess phosphorus

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 25

pentachloride. After sublimation under reduced pressure to

remove the phosphorus pentachloride, the desired compound was

obtained as a hygroscopic white solid (95$ .yield) which was

ground to a fine white powder in a drybox under nitrogen.

S ,S-Dimethyl N-£-Toluenesulfonylsulfilimine from

N-jo-Toluenesulfonyltrichlorophosphinimine. ~ A solution

of anhydrous dimethyl sulfoxide (15.63 g» 0*2 mole) in anhydrous

pyridine (20 ml) was added with mechanical stirring and cooling

(ice bath) to a solution of N-jD-toluenesulfonyltrichloro

phosphinimine (18.62 g, 0.0607 mole) in a anhydrous pyridine

(100 ml). When the addition was completed, the mixture was

stirred 0.5 hr at ice-bath temperature. After the mixture was

cooled in an ice-bath, a tan solid formed which was collected

by filtration. This solid was dissolved in hot 50$ ethanol;

the solution clarified with Norit A, and upon cooling, the

desired sulf ilimine was obtained as a white solid yield),

mp 158-159°, lit.^^ mp 158.5-159°. An infrared spectrum (mull)

showed a strong band at 9^5 era"''', characteristic of sulfilimines.

Reaction of N-jo-Toluenesulfonyltrichlorophosphinimine

with Diphenyl Sulfoxide. - A solution of diphenyl sulfoxide

(7*68 g, 0.038 mole) in dry benzene (60 ml) was added dropwise

with mechanical stirring to a solution of N-jo-toluenesulfonyl

trichlorophosphinimine (II.76 g, 0.038 mole) in dry benzene

(125 ml) cooled in an ice-water bath. When the addition xvas

completed, the reaction mixture was stirred for one hour at

ice-water bath temperature. As no precipitate formed (the

expected product S,S-diphenyl-N-jo-toluenesulfonylsulfilimine is

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 26

insoluble in benzene), the benzene was removed _in vacuo leaving

a viscous brown liquid which solidified upon standing. The

tarry brown solid was extracted with hot $0% aqueous ethanol

solution, and then clarified with Norit A. After filtration

and concentration, light yellow crystals formed.

Recrystallization of these crystals from ^0% aqueous ethanol

yielded white crystals, mo 136-1.3^*5°» lit. ^ mp 137* 5°» An

infrared spectrum (mull) of these crystals was identical to

that of jo-toluenesulf onamide, the hydrolysis product of N-jo-

toluenesulf onyltricholorophosphinimine.

Benzoy1isothiocyanate was prepared according to the if 9 procedure of Smith and Kan from the reaction of benzoyl

chloride with lead thiocyanate. The desired product was obtained o as a light yellow liquid (75% yield), bp 7^-71 (0.2 mm), lit.

bp Id-3° (20 mm). An infrared spectrum (neat) showed a broad -1 -1 band in the region 2000-1920 cm and a strong band at 1700 cm ,

characteristic of acyl isothiocyanates and carbonyl respectively.

Potassium N-jo-Toluenesulfonyliminodithiocarbonate was

prepared according to the procedure of Gompoer and Hagele-^

from the reaction of jd-toluenesulfonamide with carbon disulfide

and potassium hydroxide. The desired compound was obtained as a

yellow solid (86% yield) which was washed thoroughly with ether

and acetone to remove traces of carbon disulfide and dried in a

vacuum desiccator.

2 -Toluenesulfonylisothiocyanate was prepared according to

the procedure of Dickore and Kuhle from the reaction of

potassium N-jo-toluenesulfonyliminodithiocarbonate with phosgene.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2?

The desired compound was obtained as a light yellow liquid

{70% yield), bp 127-121° (0.7 mm), lit.*56 bp 109° (0.4- mm). - 1 An infrared spectrum (neat) showed a strong band at 1900 cm ,

characteristic of sulfonylisothiocyanates.

Chlorination of Potassium N-o-Toluenesulfonyliminodithio-

carbonate. - Potassium N-n-toluenesulfonyliminodithiocarbonate

(87.2 g, 0.27 mole) was suspended in anhydrous carbon tetrachloride

(350 ml) and dry chlorine gas (125 g, 1.7^ mole) passed over

the solution with the temperature held below 25° (ice-water

\ bath). When the addition was completed, the orange reaction

mixture was stirred at room temperature for four hours and

then cooled in an ice-bath. The white salt was collected by

filtration under nitrogen and washed with anhydrous carbon

tetrachloride. Removal of the carbon tetrachloride and sulfur

dichloride rn vacuo left an orange liquid which upon vacuum

distillation gave a light yellow liquid (32.2 g, 56$ yield),

bp 104- 105° (0.19 mm), lit.^6 bp 116-118° (0.01 mm). An infrared

spectrum (neat) showed a strong band at 1900 cm \ characteristic

of sulfon.ylisothiocyanat.es, and two strong bands at 1370- and

1170-cm \ characteristic of the sulfonyl group. As N-jd-

toluenesulfonylisothiocyanate has been prepared recently from

the reaction of potassium N-p-toluenesulfonyliminodithiocarbonate

with phosgene, the above reaction may have synthetic value in the

preparation of sulfonylisothiocyanates. A second trial in

which the chlorine gas was bubbled, into the solution also gave

the N-sulfonylisothiocyanate, instead of the expected

N-sulfonylisocyanide dichloride.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 28

S , S-Dimethyl-N-]o-Toluenesulf on.ylsulf ilimine via £-

Toluenesulfonylisothiocyanate. - ^-Toluenesulfonylisothiocyanate

(15•7 S» 0.073 mole) was added dropwise with magnetic stirring

at room temperature to dry dimethyl sulfoxide (17*2 g, 0.22 mole).

The reaction was exothermic with the evolution of a pungent gas

(COS). When the addition was completed, the reaction mixture

was stirred at room temperature for one hour. Water was added

to precipitate the sulfilimine and the mixture stirred for two

hours. The yellow precipitate was collected by filtration,

dissolved in 50/° ethanol, and. the solution clarified with

Norit-A. Uoon cooling, white crystals formed which were collected

by filtration and dried in a vacuum desiccator. Aqueous sodium

hydroxide was added to the white crystals to remove any

sulfonamide and after stirring for three hours, the white

crystals were collected by filtration and again recrystallized

from 50$ ethanol. The desired sulfilimine was obtained as

white crystals (37$)t nip 156-157°, l i t ^ mp 1 58. 5-159°. An

infrared spectrum (mull) showed a strong band at 9^-1 cm \

characteristic of sulfilimines .

Reaction of jD-ToTuenesulfonylisothiocyanate with Alkyl

Aryl Sulfoxides. - ^-Toluenesulfonylisothiocyanate failed to

react with ethyl jo-tolyl sulfoxide at room temperature giving

only unreacted starting material and p-toluenesulfonamide, the

hydrolysis product of the isothiocyanate. There was also no

reaction Twith methyl phenyl sulfoxide in refluxing benzene, as

only the unreacted starting materials were obtained. Hence this

method of preparing sulfilimines was abandoned for more fruitful

procedures.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 29

Reaction of Benzoylisothiocyanate with Dibenzyl

Sulf oxide. - A solution of -benzoylisothiocyan&te (2.5 S> 0.15

mole) in anhydrous tetrahydrofuran (15 ml) was added at room

temperature with magnetic stirring to a solution of dibenzyl

sulfoxide (3.5 g, 0.015 mole) in anhydrous tetrahydrofuran

(60 ml). When the addition was completed, the yellow reaction

mixture was stirred at room temperature for two hours, refluxed

on a steam-bath for four hours, then cooled tc room temperature.

As there was no evolution of gas, it was assumed that the reaction

did not occur. However, when most of the tetrahydrofuran had

been removed in vacuo and the resulting solution cooled in an

ice bath, a white solid formed. When tills solid was recrystallized

from dry acetone, it melted at lib.5-115°» lit.^ mp 115 • An

infrared spectrum (double mull) did not show the desired sulf11-

imlne bard but a medium band at 3375 cm \ and a strong band

at 1010 cm -1 . Briscoe 39 has shown that this compound is a lsl

molecular complex of dibenzyl sulfoxide and benzamide and not OQ the sulfilimine as previously claimed by LiVnosherstov.

As the sulfur oxygen band for the sulfoxide is shifted to

1010 cm-^', complexation must be through the oxygen atom. ^

Reaction of Benzoy11sothiocyanate with Dimethyl

Sulfoxide. - The benzoylisothiocyanate was redistilled, bp 6b-

65° (0,25 mm), before being used. Benzoylisothiocyanate

(12.9 g , 0.08 mole) was added dropwise with magnetic stirring

at room temperature to dry dimethyl sulfoxide (12.5 g, 0.1.6

mole). A vigorous reaction occurred and the odor of a pungent

gas (COS) was evident. When the addition was completed, the

orange reaction mixture was stirred at room temperature for two

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 30

hours. A stream of nitrogen was passed over the reaction

mixture while it was heated in a water bath (65°) for 0.5

hour. After the reaction mixture had cooled to room temperature,

it was stirred for six hours. Chloroform (300 ml) was added

to the viscous orange liquid and after removal of the

chloroform in vacuo, a yellow solid (5•0 g) was obtained. The

product could not be forced out of ether by the addition of

3 0 - 6 0 ° petroleum ether, as described by Briscoe.After the

ether was removed in vacuo, long white needles of mp 1*4-6-147°

remained. The solid was not water soluble as is the expected

product (S,S-dimethyl-N-benzoylsulfillmlne)« An infrared

spectrum (KBr) showed strong bands at 3235-(N-H), 1700-(C=O), -1 / 1225-» 1115-s and 1022cm (S-0?), The structure of this

compound is currently being investigated and preliminary results

suggest a 1*1 molecular complex of benzamide and dimethyl sulfoxide.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 31

BIBLIOGRAPHY

1. F. Challenger in N. Kharasch, "Organic Sulfur Compounds",

Pergamon Press, New York, N. Y., 1961, Ch. 29, p. 339 and

references cited therein.

2. H. S. Raper, Reports to the British Chemical 'Warfare Depart

ment, Vol. 4-0 (I917)l F. G. Mann and W. J. Pope, J. Chem.

Soc. , 121, 10.52 (1922) .

3 . B. H. Nicolet and J. Willard, Science, _52, 2.17 (1921).

4-. F. G. Mann and W. J. Pope, J. Chem. Soc., 121, 1052 (1922).

5. F. G. Mann and W. J. Pope, ibid., 125, 911 (1924).

6. S. G. Clarke, J. Kenyon, and H. Phillips, ibid., 188 (1927)*

7 . A. Kucsman, F. Ruff, and I. Kapovits, Tetrahedron, 22,

1575 (1966).

8 0 R. A. Abramovitch and B. A. Davis, Chem. Rev., 64, 169 (1964-) »

9. A. Kucsman, I. Kapovits, a.nd M. Ba.lla, Tetrahedron, 18,

75 (1962).

10. D, S. Tarbell and C. Weaver, J. Amer. Chem. Soc., 6.2*

2939 (1941).

11. M. V. Likhosherstov, J. Gen. Chem. U. S. S. R. , 12, 14-77

(1947); Chem. Abstro, 4^, 172d (1949).

12. H. Ulrich, Chem. Rev., 6£, 374 (1965).

13. C. King, J. Org. Chem., 2£, 352 (I960).

14. R. Neidlein and E. Heukelbach, Arch. Pharm., 299, 64 (1966).

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 32

15. G . Kresze, A. Maschke, R. Albrecht, K. Bederke, H. P.

Patzschke, H. Smalla, and A. Trede, Angew. Chem., 74.

135 (1962).

16. G. Schulz and G. Kresze, idId. , 7 5, 1022 (1963).

17. J. Day and D. J, Cram, J. Amer. Chem. Soc., 84-398

(1965)•

18. K. K. Andersen, Tetrahedron Letters, 93 (1962).

19. G. Kresze and B. Wustroxe, Chem. Ber., 2652 (1962).

20. A. W. Johnson, "Ylid Chemistry", Academic Press Inc.,

New York, N. Y., 1966, po 132-189. Johnson defines an

"Ylid" as a substance in which a carbanicn is attached

directly to a heteroatom carrying a high degree of positive

charge (e.g. R C X ),

21. G. Wittig and G, Geissler, Ann., 530, 44 (1953).

22. A. Maercker in "Organic Reactions", Vol. 14, R. Adams, Ed.,

John Wiley & Son, Inc., Nei\r York, N. Y., 1965, Chapter 3»

23. E. J. Corey and M. Chaykcvsky, J. Amer. Chem. Soc.., 84,

866 (1962); R. Greenwald, M. Chaykovskv, and E. J. Corey,

J. Ora. Chem., 28, 1128 (1963).

24. J. P. A. CastrilIon and H. H. Szmant, ibid., JO, 1338

(1965)•

25. A. W. Johnson, "Ylid Chemistry", Academic Press Inc.,

New York, N. Y., 1966, p. 217; G. Singh and H. Zimmer,

Organomet. Chem. Rev., 2, 279 (1967).

26. H. Staudinger and J. Meyer, Helv. Chim. Acta, 2, 619 (1919).

27. A. W. Johnson and S. C. K. Wong, Abstracts, 151-st National

Meeting of the American Chemical Society, Pittsburgh, Pa.,

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 33 March 1966, No. K 50. 20 28. Johnson defines a "betaine" as a doubly but oppositely

charged species in which the formal charges are not on

adjacent atoms, such as the zwitterionie form of amino

ac id s.

29. L. Horner and H. Winkler, Tetrahedron Letters, 175 (1964).

30. M. I. Kobachnik and V. A. Gilyarov, Izv. Akad. Nauk

SSSR, 799 (1956); Chem. Abstr., ^1, 18231 (1957).

31. W. S. Wadsworth, Jr., and W. D. Emmons, J. Org. Chem.,

22, 2816 (1964).

32. H. Ulrich and A, A. R. Sayigh, Angew. Chem., 2l> 900

(1962) .

33. I. N. Zhmurova and A. V. Kirsanov, Zh. Obshch. Khim. , 30,

3044 (I960); Chem. Abstr., 23» 175501 (1961).

34. H. Ulrich, ,6Cycloaddition Reactions of Heterocumulenes,M

Academic Press Inc., New York, N. Y . , 1967, pp 1-36.

Ulrich defines a "heterocumulene" as a cumulative system

(e.g.. H2C ~ C = C H 2) In which one or more of the atoms are

hetero atoms (S,Ne0,P etc.)

35® S. Appel and H. Rlttersbacher, Chem. Ber., 97. 852

(1964).

360 K. Dlckore and E. Kuhle, Angew. Chem. Int. Ed. Engl.,

4, 430 (1965).

37® S. Neldlein and W. Haussmann, ibid.» 4, 708 (1965)®

38 . M. V. Likhosherstov, Zh. Obshch. Khim., 17 . 1478 (1947),

Chem. Abstr., 4^, 172d (1949).

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3^

39° P« A. Briscoe, Ph.D. Thesis, University of Leeds (1953)*

We would like to thank Dr. Briscoe for providing us with

unpublished information concerning this reaction.

40. A. V. Kirsanov and Z. D. Nebrasova, Zh. Obshch. Khim.,

26, 903 (1956)? Chem. Abstr., £0, 14631b (1956).

41 A. H. Ford-Moore and B, J. Perry, Org. Syn., 31, 111 (1951)»

42. J. I. G. Gadogan and H. N. Moulden, J. Chem. Soc., 3079

(1961).

43. Chloramine-T was dried by heating in a vacuum oven at

100-110° for three hours. WarningJ Ghloramine-T may

explode if heated above 130-140° under normal pressure.

44. A. V. Kirsanov and V. I, Shevchenko, Zh. Obshch. Khim.,

24. 474, 882 (1954)? Chem. Abstr., 4 9 . 6l64a, 8l68d (1955)•

45. H® G. Brown and G. Zweifel in "Organic Reaction," Vol. 13,

R. Adams, Ed., John Willey & Sons, Inc., New York, N. Y . ,

1963» Chapter 1.

46. A. V. Kirsanov and N. L. Egorova, Zh. Obshch. Khim., 25.

187 (1955)i Chem. Abstr., £0, 16471 (1956).

47. M. Vecera and J. Petranek, Chem. Llsty, 50. 240 (1956)?

Chem. Abstr., 50. 773^JI (1956).

48. Handbook of Chemistry and Physics, 4lst ed»C. D, Hodgman,

Ed., Chemical Rubber Publishing Co., Cleveland, Ohio,

I960, p 1252.

49. P® A® S. Smith and R. 0. Kan, J. Org. Chem®, 29. 2261

(1964).

50. R. Gompper and W. Hagele, Angew. Chem., 753 (1962).

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PART II

ATTEMPT AT PREPARING (METHYLSULFINYL)ALKYL

ISOTHIOCYANATES VIA OPTICALLY ACTIVE

METHANESULFINATE ESTERS

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 36

INTRODUCTION

The occurrence of pungent principles in numerous higher

plants, especially those belonging to the family Crueiferae, has

been recognized since ancient times and has motivated the

extensive use of such plants in several parts of the world as 1 potherbs, condiments, and remedies. Over a century ago, the

sulfur-containing compounds responsible for the production of

the biting principles of black and white mustard were isolated in

crystalline form. Several decades later they were recognized

as glucosides, undergoing enzymic hyrolysis to isothiocyanates

(mustard oils), glucose, and sulfate. 2 Gadamer , in 189?, proposed structure 1 which, until

recently, was the generally accepted structure for the glucosides.

R - N = C ^ 6 1 1 5+ 'OSO^” x

As several experimental observations were not easily re- 3 concilable with the Gadamer structure, Ettlinger and Lundeen , on

the basis of conclusive experimental evidence, proposed the

general structure 2 for the isothiocyanate glucosides.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 37

s-c— B

OH HO OH 2

In a subsequent paper, Ettlinger and Lundeen left no

doubt as to the correctness of their proposed structure, when

they reported the first synthesis of an isothiocyanate glucoside.

Their structure was compatible with the view that the enzyme

attacks only one site in the glucoside with the subsequent

steps proceeding nonenzymically.

The enzymic hydrolysis involves an intramolecular

rearrangement (eq l) analogous to the Lossen rearrangement of

hydroxamic acids. Because of the similarity in mechanism of this

rearrangement with that found in the Hofmann-Curtius-Beckmann-

Lossen types, it seems highly probable that the sulfate and the

migrating group R are located anti to each other.

N-OSO “ X+ N-OSOo” X+ R-NCS II Enzyme , || _ > (1) r -c -s -c 6h 11o 5 r -c -s *s o 4=

Schmid and Karrer^, in 19^8, isolated from the enzymic

hydrolysis of radish seed extracts the first natural product

in which optical activity was due exclusively to an asymmetric

sulfoxide grouping. This compound, sulforaphene (j))» can be

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 38

viewed as a representative for an extensive series of natural

mustard oils having in common an unbranched ca.rbon chain

terminally substituted with a methylthio grouping in various

oxidized stages. Special interest was centered on sulforaphene

and other sulfoxide mustard oils ^ in attempts to determine the

absolute configuration at the asymmetric sulfur atom.

CH^SOCH^CHCHgCHgNCS CH^SO (GHg ) nNCS

1 i£

Sulforaphane, the saturated derivative of 2 » was

synthesized by Schmid and Karrer in both racemic and optically

active form. After the relative configuration of the

levorotatory isomer of sulforphane had been correlated with

naturally occurring, levorotatory sulforphene u>. the latter was

suggested as an arbitrary standard of relative configuration at

the asymmetric sulfoxide grouping for other naturally occurring *7 8 sulfoxide mustard oils Karrer and coworkers ’ synthesized

other homologs of 2. where n=2,3i and 5 along with some

unsaturated derivatives whose configurations were related to 2°

Many of these mustard oils, which have in common an optically

active meth.ylsulfinyl group, were later isolated in the 9 laboratories of A. Kjaer,

The first example of the determination of absolute

configuration of an optically active sulfoxide was recorded by 10 , . , . Hine and Rogers using X-ray analysis on (+)-(S )-methyl-L-

cysteine sulfoxide (_£). In this same paper, Klyne suggested

that the configuration of other naturally occurring sulfoxides

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 39

could, be tentatively assigned by comparison with

Identical configuration around the asymmetric sulfur

atom in the homologous series of naturally occurring sulfoxide

mustard oils was suggested to Kjaer and Gaielin^ by the fact that

the optical rotations at 589 mu of the isothiocyanates and

their thiourea derivatives were all negative and of comparable 12 magnitude. Klyne, Day, and Kjaer found that various phenyl-

urea, phen.ylthiourea, and thiourea derivatives 6 of the sulfoxide

mustard oils gave negative plain optical rotatory dispersion

(ORD) curves between 600 and 300 mu which were very similar

and, in some cases, almost superimposable. This was interpreted

to mean that the absolute configurations were identical for all

of these compounds.

0 X = 0 S or S

CH S(CH_) NHCXNHY Y=HS or C.H-CH 3 2 n 0 5 o 3 2 6 n = 3* 5» 8s 9s or 10

13 Recently, Andersen obtained optically active sulfoxides

of high optical purity from the reaction of Grignard reagents

with optically active sulfinate esters (eq 2). This method

proved to be of great value in the prediction of the absolute

configuration of the naturally occurring, levorotatory sulfoxide

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 40

mustard oils

RMgX J (2) 0 Aryl

Aryl H

14 As Herbrandson and Gusano had tentatively assigned

the (S)-configuration'*’^ to the asymmetric sulfur atom in (-)-jo-

iodobenzenesulfinate (j£) on the basis of kinetic and thermodynamic

data, Andersen assumed that (-)-menthyl (-)-jo-toluenesulfinate

(8) also had the (S)-configuration at the asymmetric sulfur

atom, since "para-methyl and -iodo groups would not be expected

to change the sign of rotation of the powerfully rotating 16 17 sulfinate ester group". Mislow and coworkers * later proved

these assignments to be correct by X-ray studies on 2 anc^-

chemical correlation reactions on 8.

0 0

p-ICgHjj,

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 41

The reaction of Grignard reagents with optically 13 active sulfinate esters was assumed by Andersen to have

proceeded with Inversion of configuration at sulfur* This

assumption was based upon reported inversions at sulfur in the 1, alcoholysis of optically active alkyl jo-toluenesulfinate esters 19 + and the basic hydrolysis of alkoxysulfonlum salts , R0SB2 *

In each instance, a nucleophilic attack on sulfur was involved*

Further evidence for the inversion mechanism was provided by 20 Mlslow and coworkers from optical rotatory dispersion studies

on optically active alkyl jo-tolyl sulfoxides. With the

utilization of Andersen9s method, absolute configurations can be

assigned to sulfoxides derived from optically active sulfinate

esters.

Since it had been previously shown by Klyne, Day, and 12 Kjaer that a change in value of n does not affect the sign

and scarcely the shape of the optical rotatory dispersion curves

of the sulfoxide mustard oils 4, the functional groups at the

terminal position of the alkyl chain must have very little, if

any, influence on the sulfoxide chromophore. On this basis,

Andersen21 chose N-methyl-N-[3-(methylsulflnyl)propyl] aniline

(£) as a suitable model compound for the naturally occurring

sulfoxide mustard oils.

0 CH I 3 CH SCHLCH CH J-C,H 3 2 2 2 6 5

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 42

2 1 Andersen devised a synthetic scheme by which the

configuration at sulfur in £ could be related to that of (-)-

menthyl (-)-jo-toluenesulfinate (8). Inherent in these correlations

was the assumption that the ratio of diastereomers in the

starting material accurately reflects the ratio of enantiomers in 17 the product, later proven unequivocally by Mislow and coworkers.

The (Reconfiguration was assigned to the asymmetric sulfoxide 21 grouping in 2 an(i Andersen predicted the (R)-configuration

at sulfur for the levorotatory sulfoxide mustard oils 4. Later, 22 Mislow and coworkers arrived at this same conclusion from

optical rotatory dispersion studies with optically active

dialkyl sulfoxides. Both these conclusions proved to be correct 23 when Kjaer, Sim, and Cheung determined the absolute configuration

of the asymmetric sulfur atom in the phenylthiourea derivative

(10) of (-)-iberin by X-ray analysis.

0 |pi88Bg»‘— C H ^ ) ^NHCNH C c 6h 5 CH, CH 10

The (R)-configuration was assigned to the asymmetric

sulfoxide grouping in _10 and, on the basis of previous optical

rotatory dispersion studies, the (R)-configuration was assigned

to all naturally occurring, levorotatory sulfoxide mustard oils

4, as well as to the glucosides from which they are derived.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 4 3

This portion of the thesis describes the partial

resolution of methanesulfinyl chloride via optically active

methanesulfinate esters. Several attempts to prepare racemic 13 sulfoxide mustard oils utilizing Andersen’s method are also

described.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. kk

RESULTS AND DISCUSSION

Recently, a new method for the preparation of optically

active sulfoxides of high optical purity from the reaction

of an optically active sulfinate ester with an organoraagneslum

halide was described by Andersen®He found that (-)-menthyl

(-)-£-toluenesulfinate (1) gave (+)-ethyl jo-tolyl sulfoxide

(2) and assumed the reaction had proceeded with inversion of

configuration of sulfur (eq 1).

:--v-Si [A C2H5MSI > -.-"A ° A (1), £n-CH^CrH 3 6 4 u S £ \

Andersen and coworkers showed the reaction was general

and proceeded with a high degree of stereospecificlty, e.g., 2 c the above reaction proceeds with 96% inversion and k% retention. 13 Andersen assigned the (S)-configuration to 1 and, assuming

Inversion, the (R)-configuration to 2. Both of the assignments l6 17 were later proven correct by Mislow and coworkers. '

Because the absolute configuration at sulfur for a

series of naturally occurring sulfoxide isothiocyanates 2 was p "I unknown, Andersen chose N-methyl-N-[3-(methylsulfinyl)-propyl]-

aniline (k) as an optical analog for 2*

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. k5

o 0 CH 1 I 3 CH3S(CH2 )nNCS

The configuration of ** was related to that of 1 by 21 the synthetic scheme shown below (eq 2). Andersen suggested

that the configuration of the two predominating enantiomers,

(+)-methyl phenyl sulfoxide (_£) and ( - should be the same

since they both resulted from the predominant dlastereomer of

the (-)-menthyl (±)-methanesulfinate (6) mixture.

0 OSCH + CH^SCl i 6 C-H JlgBr 6 o

(2)

CH C/-H (E) 3 6 5

o 0

(s) C rH CH (S) 3 65 3 1

R^S R^S

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 46

Andersen^ had previously assigned the (R)-configuration 20 to 2 derived from and Mislow and coworkers later showed

from optical rotatory dispersion (ORD) studies that all (+)-

alkyl j>-tolyl sulfoxides derived from 1 had the same configuration. 14 Because the (S)-configuration had been assigned to the

asymmetric sulfur in 1, the (R)-configuration was assigned to 21 (+)-2 and (-)-4® On the basis of the ORD curve for 4, Andersen

tentatively assigned the (R)-configuratlon to the asymmetric

sulfur atom in the levorotatory sulfoxide isothiocyanates® This 17 22 same conclusion was reached later by Mislow and coworkers ’

from the ORD study of (+)-dialkyl sulfoxides®

Because assignments of configuration from the sign of 26 the Cotton effect in an ORD curve can sometimes lead to 27 erroneous conclusions , it vxas decided to develop a chemical 13 correlation sequence utilizing the Grignard method for jL

Since the sequence would involve reactions of known stereochemical

consequence, the configuration of the asymmetric sulfur atom

in 2 could be correlated with that of 1. During the course of

this work® the absolute configuration at the asymmetric sulfur 23 atom in 2 (n=3) was determined by X-ray analysis J and was shown

to be (R) for the levorotatory enantlomer.

The resolution of methanesulfinyl chloride (j£) via

optically active methanesulfinate esters was studied in order

to ascertain which ester would give the corresponding sulfoxide 28 of highest optical purity® Mislow and coworkers have recently

reported a highly stereoselective method for the configurational

correlation of alcohols via asymmetric synthesis of £-toluene-

sulfinate esters (eq 3)«

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 4?

M I 0 ! i : C .H N g-CH^CgH^SCl + 5 5 dlastereomeric mixture of -78° i i jo-toluenesulfinate esters i OH CH^Mgl (3) 8

CH3 c6H4GV £ £“GH3C6h4 CH3 (R) £ (s)

The sign of the predominant enantiomer of methyl £-

tolyl sulfoxide (£) was uniquely related to the absolute

configuration of the inducing alcohol 8® Since Mislow and 17 coworkers had previously shown that the ratio of enantiomeric

sulfoxides produced in the Grlgnard reaction equals the ratio

of dlastereomeric sulfinate precursor, the high optical yields

observed in this reaction accurately reflect the high

stereoselectivity of the asymmetric esterificatlons® 29 Jacobus and Mislow have recently reported a 21 modification of Andersen®s procedure for the preparation of

(-)-menthyl (±) methanesulfinate (6), which led to an ester of

higher dlastereomeric purity* Andersen had distilled 6 while 29 Jacobus and Mislow 7 used 6 in the crude stage® Results in

this laboratory (Table l) agree with the findings of Jacobus

and M i s l o w . ^ They also reported that 6 slowly eplmerlzes over

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 48

a period of time and suggested that stereochemical calibrations

be run coincident with sulfoxide preparations. Similar results

have been observed in this laboratory} e.g., a six-month-old

sample of distilled 6 gave (-)-(S)-methyl phenyl sulfoxide

(eq 4)} hence the configuration at sulfur in the predominant

diastereomer of 6 must be (S).

0 i 0 1 •» (4) CgHJGgBr CH, 0' CH G6H 5 (+)-(s)-6 (-)-(s)-2

&x]D -S.47(

Other optically active alcohols, besides (-)-menthol,

were investigated as their methanesulfinate esters. As the

(-)-lsoborneol used in the preparation of (-)-isobornyl (a )-

methanesulfInate (14) was contaminated with (+)-borneol (10), it

was purified according to the o-nitrobenzoate method (eq 5)» 30 as described by Jackman and coworkers. The pure (-)-isoborneol 31 (11) was sublimed from the (+)-bornyl £-nitrobenzoate (12)

This same procedure can be used to purify borneol that is

contaminated with isoborneol, since the bornyl o-nltrobenzoate 32 can be hydrolyzed to borneol with alcoholic potassium hydroxide.

H c 5h 5n > ^ " ^°H ' 'S ^

Cl 11 12 Sublime 0

jOH

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ip 9

(+)-(R)-Methyl jo-tolyl sulfoxide (<£) was obtained

from the dlastereomeric mixture of (-)-bornyl (±)-methanesulfInate

(13)5 hence the predominant diastereomer of 13 must have the

(R)-configuration at sulfur (eq 6)»

£ .CH3C6H,M s Br >. I (16) Et^O ^ 2 c h 3 c 6h 5c h 3-£

(+) - ( r ) ~_2

[ ]D + 27,0°

When a dlastereomeric mixture of (-)-isobornyl

(±)-methanesulfinate (14;) was treated with phenylmagnesium

bromide* (+)-(R)-methyl phenyl sulfoxide was obtained (eq 7)

with an enantiomeric purity of 65<>2/6o-^ The highest enantiomeric

purity for 2. prepared from 6 was 30«7$» reported by Jacobus

and Mislow*2^ Because of the ease of separation of (-)-isoborneol

from the corresponding sulfoxide-^, 14 seems ideally suited as a

precursor for the organic synthesis of the naturally occurring

sulfoxide isothiocyanates» The predominant diastereomer of 14

must have the (R)-configuration at sulfur* as was the case for 13»

C6H MgBr (17)

CH. C 6H 5 (R)-l4 (+)-(R)-2

[ ]D +97.1'

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 50

(-)-Cholesteryl (-)-methanesulfinate (15) was purified

by fractional recrystallization from methanol. When 1^ was

treated with phenylmagnesium bromide, (-)-(S)-methyl phenyl

sulfoxide was formed (eq 8) with an enantiomeric purity of

Although this value exceeds that obtained with 14, the

purification procedure was more tedious.

y \ (8) C.H CH 6 5 3 (-)-(s)-2

■9908* [a]Q - 119.5C [a]'D

Treatment of 1^ with n-butylmagnesium bromide gave

( + )-(,S)-n-butyl methyl sulfoxide (16) with an enantiomeric 3 5 purity of 76.5$ (ecl 9). On the basis of these results, the

(S)-configuration is assigned to the predominant diastereomer

of 15. Since (-)-(R)-16 could be synthesized from 14. both

isomers of the naturally occurring sulfoxide isothiocyanates

can now in principle be prepared.

0 I BuMgBr y \ Et 0 Bu CH (9) 2 ( + M S ) - 1 6 (~MS)-1£ La ]D +68. V1 La.]]-) -85.0(

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In all of the examples studied, those methanesulfinate

esters used without distillation gave sulfoxides of consistently

higher enantiomeric purity (Table 1) than esters that had been 2 9 distilled, in agreement with the results of Jacobus and Mislow,

Esters that were prepared at Dry Ice-acetone temperature also

gave sulfoxides of higher enantiomeric purity than those

prepared at 0°. ^ The fact that 14; gave sulfoxides of higher

enantiomeric purity than those prepared from is consistent 2 8 with previous results obtained by Mislow and coworkers , who

studied jo-toluene sulf inate esters. It is noteworthy that the

highest enantiomeric purity (80$) for a sulfoxide from the

precursor methanesulfinste ester was obtained in the (-)-S-l5

case. The high enantiomeric purity reflects the high dlastereomeric

ratio (90* 10) for 15. Further purification of 3J> may eventually

lead to the formation of enantlomerically pure sulfoxide. As

the (-)-borneol used in the preparation of 1^ was found to be

Impure-^, the value for pure 1^ would probably give results 29 comparable to those observed by Jacobus and Mislow with 6.

This would be consistent with work previously reported by Mislow 28 and coworkers.

Infrared Spectra. - All the sulfoxides and sulfinate

esters show the characteristic sulfoxide and sulfinate SO

streching bands in the 1070-1030 cm”'*' and Il4'0-1125 c m ” '*' regions,

respectively.

Ultraviolet Spectra. - The ultraviolet spectral data

for the methanesulfinate esters are listed in Table 2. Mislow

and coworkers'1'^ have shown that the absorption spectra of

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jo-toluene sulfinate esters exhibit behavior which closely

parallels that of alkyl jo-tolyl sulfoxides, including solvent

dependence. They suggested that the electronic transition

responsible for the primary band in £-toluenesulfinate esters

was closely similar and comparable to the corresponding transition

in alkyl jo-tolyl sulfoxides. By analogy, the absorption spectra

of the methanesulfinate esters can be discussed profitably in

terms of their relation with saturated dlalkyl sulfoxides.

Saturated dialkyl sulfoxides have been shown to exhibit shoulders

at ca« 210-220 mp (ethanol),37*38 use 0f other solvents, 17 Mislow and coworkers observed well defined maxima at shorter

wave lengths (near or below 210 mp), in addition to the shoulders

previously observed. Because of the intensity of the absorption

(log e ca. 3.5-3.6), an allowed singlet-singlet transition, 1 2 1 39 3.7 probably the (3sp^)---5>-(3sp )(3d-) transition^ , was suggested.

This assignment was supported by the fact that blue shifts itO were observed, suggestive of an n-^rP transition , with a change

to more polar solvents. As seen from Table 2, these same blue

shifts are observed with the methanesulfinate esters, identifying

this transition as involving promotion of the sulfur lone-pair

electrons to an anti-bonding orbital of the sulfinate group 37 (n“»rr^ transition). The similarity in the intensity (log e

ca. 3-35-3«^7) for the absorption of the methanesulfinate

esters lends further support for the comparison with saturated

dialkyl sulfoxides.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 53 21 Nuclear Magnetic Resonance Spectra. - Andersen had

previously reported that the nuclear magnetic resonance (nmr)

spectrum of 6 showed two partially separated, very sharp signals

of about equal intensity at 7*30 and 7 , These were assigned

to the protons of the two methanesulflnyl groups in 6, although

the possibility of long-range splitting by the axial proton was

not ruled out. The nmr spectrum of 12 showed a sharp singlet

at 7<>45t} when the spectrum was enlarged, the singlet was

partially separated into two sharp signals of about equal

intensity. As in the previous case, these were assigned to

the protons of the two methanesulfinyl groups in 13. Similarly,

14 showed a sharp singlet at 7»50t which was resolved into two

partially separated signals of unequal intensity upon enlargement

of the spectrum. This unequal ratio of diastereomers is

reflected in the improved enantiomeric purity of the sulfoxide

obtained from 14 compared to that of 1J> (Table 1). The high

dlastereomeric purity of 1*[ is reflected in the fact that it

showed a sharp singlet at 7•50'1' which was not further resolved

into a doublet upon enlargement of the spectrum. As before,

this singlet was assigned to the methanesulfinyl protons of 15 .

Synthesis of Racemlo Sulfoxide Isothlooyanates. -

Before attempting the preparation of some naturally occurring-

sulfoxide isothlooyanates, racemic 3-(methylsulfinyl)-

propylamlne (12) was synthesized according to the procedure of 7 Karrer, Scheitlin, and Siegrist as shown below (eq 10).

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 54

-(CH ) Br + CH„SNa i-(c h 2 )3s c h 3

NH2NH2 «H20 (10)

I v h 2°? c h 3s (g h 2 )3n h 2 <--- CH3S(GH2 )3NH2 11

Hydroboration Route. - Hydroboration has become an 41 extremely useful synthetic tool for the organic chemist. ko Brown and Subba Rao reported that a slow reaction occurred

between dimethyl sulfoxide and diborane in ether solvents at

25°. However, McAchran and Shore^ later reported that dimethyl

sulfoxide in methylene chloride was cleaved by diborane at -78°.

It was hoped that addition of diborane to the double bond of an

unsaturated sulfoxide would be faster than reduction of the

sulfoxide group (eq 11). ^

0 0° RS(CH.) CH=CH_ + B H/ > [RS(CH ) CH CHp]_B (11) 2 n 2 2 6 Diglyme 2 n 2 2 3

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 55

A|4 Brown and coworkers found that organoboranes react

readily with chloramine or hydroxylamine-O-sulfonic acid to form

the corresponding amines. Application of this reaction (eq 12)

to the organoborane derived from the hydroboration of allyl

methyl sulfoxide (18) would give 17 .

0 0 I B?H, | CH SCH0CH=CH~ >- (CH_S (CH ) _~) _B 3 2 2 Diarlvme 3 2 3 3 18 N ^ O S C ^ H (12)

c h 3s (c h 2 )3n h 2

Although the hydroboration of 18 was attempted in various

ether solvents (e.g.. tetrahydrofuran, diglyme, and triglyme),

17 was never successfully Isolated. Gas liquid partition

chromatography (glpc) could not be used in the analyses of these

reactions because of the sensitivity of alkyl sulfoxides to ^5 heat, 46 Brown and Murray reported that the intermediate

trialkylborane, obtained from the hydroboration of the olefin,

could be protonated with propionic or octanoic acid to give the

corresponding hydrocarbon. When this reaction was applied to

18. no sulfur containing product was found. It is possible that

the product, methyl propyl sulfoxide (19) was formed but

pyrolyzed to 1-propene and methanesulfinlc acid under the reaction

conditions (eq 1 3 )*

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CH3SCH2CH=CH2 (c h 3s c h 2c h 2GH 2 )3b Triglyme

CH (CH ) COOH (13) 0 3 ^ 6

CH 1-H + CH =CH-CH c h 3s c h 2c h 2c h 3 2 3 12

Because of the difficulty previously encountered with

the Isolation of a liquid product 17. the hydroboration of

allyl phenyl sulfoxide (20) was studied in order to obtain a Ixn solid product. Brown and Zweifel had previously shown that

highly substituted olefins, e.g., 2-methyl-2-butene (21) undergo

hydroboration rapidly to the dialkylborane stage 22. with

further reaction to the trialkylborane stage being relatively

slow (eq 1*0.

H,C CH o h 3 3 I 1 3 h 3G\ / Fast J c=c + BH — ------> H-C-C BH H-C' xH 3 I 1 3 h 3c h 2 21 22 (1*0 [h ^C CH 1 HoC CH H~C CH 3 | 1 3 3 I 1 3 3 I 1 3 Slow H-C-C -J B ■«tT . ..s> 1 i H-C-C-— — BH + C=C / I 1 1 1 1 1 H C H 3 H C H 2 H C H 3 L 3 _ 3 22

Compound 22 was shown by these workers to exhibit

considerable sensitivity to the sterio environments of different

double bonds, thus allowing a greater degree of selectivity

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than that exhibited by diborane. When 20, was allowed to react

with bis- ( 3-meth.vl-2-but.yl)-borane (22), a sulfur-containing

product was obtained which gave a negative test for sulfoxides

(eq 15)o The structure of this compound has not yet been

identified, but preliminary results suggest a sulfide.

0 CHo I 3 Diglyme c 6h 5s c h 2c h =c h 2 + (CH3)2CH-CH- .BH

20 22 (15)

0 CH. HgNOSO^H Sulfur-containing C6H5SCH2CH2CH2-B c h (c h 3 )2 - > Compound

When allyl phenyl sulfide (2^) was treated under

analogous conditions, a sulfur containing semisolid was obtained

which could not be identified.

For the hydroboration reaction of ,18 and 20, nonterminal

addition of diborane would be expected because of the electron-

withdrawing effects of S— 0 and C^H^S— 0, respectively. Although

there have been no studies on the directive effects of sulfoxides h O in hydroboration reactions, Brown and Cope reported 22$ addition

to the 2-posltion for the hydroboration of 2jl with diborane

(eq 16). When bis-(l-methvl-2-butyl)-borane [disiamylborane]

was used, there was no addition to the 2-posltlon.

THF H 2°2 c 6h 5s c h 2c h = c h 2 + b 2h 6 — - ^ C.H^SCHoCHoCHo0H O p 2 2 2 o h ” 65% (1 6 )

C^HgSCH^CH-CHo 6 5 2 1 3 22% OH

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As it appeared from the previous work that reduction

of the sulfoxide to the sulfide was occurring, other possible

routes were investigated.

Dlsllazane Route. - 1,1,1,3,3» 3-Hexamethyldlsllazane

(24) is ideally suited as a reagent for trimethylsllylatlon of

appropriately substituted organic compounds since the only 49 by-product of the reaction is ammonia. Although the N-H

bond of 24 has been described as inert because of its stability

to sodium at 125° and to sodium in liquid ammonia*^, it did

react with methylmagnesium iodide to give 88-94$ yields of

methane. ^ Ruhlmann-^ found that 24 would react with sodium

or potassium in the presence of styrene. The intermediate

potassium compound ) was coupled with alkyl halides and the

trimethylsilyl group removed by mild acid hydrolysis to give the

corresponding amines (eq 1?).

(Me„Si)0N-H + C/'HirCH=:GHc> + K ------> (Me,Si) N-K 3 2 8 5 2 3 2 24 2£

R-X (1?)

H„0+ R-NH2 <--- 2----- (Me^Si J^N-R

The stability of the dlsllazane linkage toward

organometallic reagents is shown in the preparation of

2-aminobenzoic acid (26) from jg-bromoanlline (27) utilizing 52 trimethylsilyl groups to protect the amino function (eq 18).

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. n-BuLi

(CH^Si /SKCH^ NH,

HoO COr <■

c o 2h LI 22 We had visualized the route shown (eq 19)» which

seemed ideal because of the ease with which the trimethylsilyl

group can be removed (e.g., heating in methanol),

(Me3Si)2N-K + X(CH2 )nX ------> (Me3Si)2N-(CH2 )nX

25. 26 (19)

Mg, Et20)

CH S(CEL) NH_ (Me3Si)2N-(CH2 )nMgX 3 2 n 2 3-hexamethyldisilazane (25)

was treated with several polymethylene dihalides, the correspond

ing halosubstituted dlsllazane derivative 26 was never

successfully isolated. As a control, 2% was allowed to react

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with 1-bromobutane to give the corresponding-N-butyl derivative

of 2k In 38^ yield (eq 20).

K (Me^Si)0N-H + C H CH =CH ------> (Me Si) N-K 3 ^ 6 5 2 2 Dioxane 3 2 2k n-C^H Br (20)

As Sauer and Hasek*^ and later Wannagat and Kuckertz^

had reported that 2k reacts with alkyl Grignard reagents, the

following scheme (eq 21) was triedj but only unchanged halide

was recovered. Attention was now turned to other protecting

groups.

Et^O (Me^SDgN-H + CgH^MgBr ------>- (Me^SiJ^N-MgBr

(21) xs Br(CH2 )^Br

(Me3Si)2N-(CH2 )^Br

Trimethylsilyl and Tetrahydropyranyl Ether Route. -

Trimethylsilyl groups are being used widely as protecting groups

for alcohols because the corresponding ethers are readily prepared,

are thermally stable and resistant to oxidation, and the

trimethylsilyl groups are easily removed,-’ Speier^-' found

that chlorohydrins react with trimethylsilyl chloride or 2k

to give the corresponding ohloroalkoxytrimethylsllanes, which

then react with magnesium to give the Grignard reagents (eq 22).

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HQ(CHo) Cl + (Me.Sl) N-H -> Me„S10(CH ) Cl ^ n 3 2 3 2 n 24 (22) (Mg, EtgO)

Me~S10(CHo) MgCl 3 2 n

We prepared the Grignard reagent from 4-chloro-

butoxytrimethylsllane (27) and treated It with methyl

methanesulflnate to give the corresponding sulfoxide (eq 23)»

The low yield encountered in this reaction led us to Investigate

other possible routes.

Et20 Me,Si0(CHo ). Cl + Mg ■> Me3S10(CH2)^MgCl 3 *-4 2£ CH^SOCH^

(23)

c h 3s (c h 2 )^o h

Primary, secondary, and even tertiary alcohols have been

added to 2,3-dihydro-4-pyran (29) in the presence of acid to

give high yields of mixed acetals, commonly known as tetrahydro 56 pyranyl (THP) ethers (eq 24) The THP ethers are very stable

toward alkali and organometallic reagents but can be hydrolyzed 54 easily by aqueous mineral acid at room temperature.

+ HOH (24) OB

THP ether

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Mazerolles-^ has recently reported that

chloroalkyltetrahydropyranyl ethers react with magnesium In

tetrahydrofuran to give the corresponding Grignard reagents

(eq 25).

H+ HO(CH ) Cl + Cl(CH2)n0 ^ o 2 n ^0'

Mg ltl THF (25)

n=4,5 ClMg(CH2)n-0-l^0

We have prepared a series of the chloroalkyltetrahydro

pyranyl ethers (n=2„3,6) and found that when n=6, Grignard

formation was successful in tetrahydrofuran but not ether. The

Grignard reagent reacted with methyl methanesulfinate to give the

corresponding sulfoxide (eq 26)®3® Further Investigation of the

above reactions is now being carried out in this laboratory®

c i (c h 2 )6-o - ClMg(CH )5-0

C H oS0CH •'T 3 I 3 (26) 0

CH3S(CH2 )6-0-i\.o

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added to 2-methyl-2-butene (J|0) in the presence of acid to

give the corresponding bromo ether which reacted readily with

magnesium in ether* Reaction of Jd in this laboratory with

methyl methanesulfinate gave the corresponding sulfoxide % 2

(eq 2 7 ).

CH- HpSOj, I J Br(CH2 )3OH + CH3C=CHCH3 ---- -— Br(CH^) ^O-G-GH^GH^

CH„ CH, 3 3 JO (Mg, EtgO) (2?) 0 0 CH« I y CH~ | | J CH SOCHo V CH3S(CH2)30-C-CH2GH3 4 2----- d— BrMg(CH2 )30-C-CH2CH3

c h 3 c h 3

Jis. 22i

As the conditions normally used for cleavage of the

jt-amyl ether group (heat to 130-1500 with jd-toluene sulfonic acid)

were considered too vigorous, cleavage was attempted with 20$

aqueous sulfuric acid. After the sulfoxide had been stirred at

room temperature for 2 k hours, it was recovered unchanged* If

mild conditions could be found for this cleavage, the use of

t-amyl ethers would be preferable as protecting groups for the

alcohol portion of the molecule. Because some promising results

have been obtained via the haloether route, work is continuing

in this area. The final route to the sulfoxide lsothiocyanates

to be attempted is shown below (eq 28)*

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CH^SOR + RO(CH2 )nMgX -> GH S(CH ) OR 3 2 n

TosG l CH_S(CH_) OTos ■<------CH S(CH ) OH 3 2 n C„H 3 2 n (28) 5 5 K-N(SiMe3 )2 0

->CH3S(CH2 )nNH2 CH~S(CH9)3 2 n N(SiMe 3 ).2

CH3S(CH2 )nNCS

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Os V_r\ ___ %

9.29 8.01 14.6 10.6 18.0 17.3 16.0 65.2 62.6 61.4 44.39 41.06 45.68 ^ r i t y , Enantiomeric

0 +23.8 +12.5® +91.5 + 22.8 +13.85® +16.56® +97.1 +97.6® +66.15 +71.27® + 27.0 +61.19 r-P + 26.8 (ethanol) 0 — — ;; + 91.9 + 15.6 + 11.8 + 96.0 + 90,5 + 13.7 + 6 5 .^ + 67.3 + 60.5 (acetone) w D («)

3-£ 2, & 2, c h TABLE 1

j 5 5 h h 6 6 s o c s o c 3 3 6 3 3 3 6 5 3 6 5 3 3 6 5 3 3 6 5 3 3 6 4 3 3 3 6 5 CH3SOC6H2fCH3-2 CH S0C6H CH -£ CHoS0CrH^ CH-SOC.H. CH3S0C6H5CH3-2 C H oS0C.Hc c h CH SOC.H^ c h Sulfoxide CH SOC^H,. ch3soc6h4ch3-£ CH SOCxH CH -p CH ,H. SOC Me thanesulfinateMe Esters (CH SOR)

-6.0? -22.2 -- __ — +1.62 Oft OS Oft -34.5 + 1.62 (acetone) W D (°) 3»2 s* jl.4 i1 ’2 I1 ’2 I3,2 I1 ’* I3 ?^ b B 1 ^ B 1 ’^ B 3 ’^ B 1 *2 B 3 »2 B 1 ’2

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. o\ CK

_ %

5.84 5.68 80.0 30.3 15.67 — 30.7

recrystallization Purity, Enantiomeric

(°) d -119.5 -9.11 -8.47 — +78.7 76.5 +47.2 +23.36® +45.8 (ethanol) See reference 29 M ^Obtained via fractional ■“■Rotation in isooctane■“■Rotation **See reference 21 (-)-cholesteryl

(°) -114.3° -8*58 — +68.4* «»«■ d (acetone) M Calculated value 3-£ h

6V s o c 3 3 6 , 3 3 6 5 3 6 5 ✓ C H ^ O B u CH S0C,H CH3SOC6HitCH3-£ CH_S0C.He CH3SOC6Hi!fCH3-£ CH^OCgH^* +23.0 c h CH S0C,H * Sulfoxide

(0> -85.0 -99.8 -77.2 ““ — -99.0 (acetone) [ a ] D of ester, crude a Temperature of formation of ester,-78 Temperature of formation of ester, 0 1,4 1,2 1,2 SI :1,4 ;5 .5 .5 lB,(-)-bornyls I, (-)-lsobornyl; M, 'Optical fractionation (-)-menthyl; C, was shown to'Purity have occurred -^Purity -^Purity of ester, distilled 2 2 o A o TABLE 1 (Continued.)

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 67

TABLE 2

Ultraviolet Absorption of Alkyl Methanesulflnates

0 ( q "h E in CH^SOR Solvent Absorption Characteristics

(-)-Menthyl E 211.6 (2245)

H 220.3 (2253)

(-)-Bornyl E 212.4 (2439)

H 220.4 (2287)

(-)-Isobornyl E 211.2 (2529)

H 220.5 (2239)

(-)-Cholesteryl E O O B D

H 219.0 (2980)

Methyl E 213.1 (1727)

H 221.2 (1898)

(±)-Bornyl E 212.3 (2565)

H 220,2 (2381)

(±)-Isobornyl E 210.3 (2014)

H 220.4 (1945)

aE, 95% ethanoli H 5 hexane.

^Wave lengths in m|i; molecular extinction coefficients (e) in

parentheses*

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hexane

20 e Q~~

16.0-

200 2^0 230 240 250 260 nU

Fig, 1 - Ultraviolet spectra of methyl methanesulfinate

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 69

28,0--

-- hexane

o x 1 6.0- kJ

12.Q--

200 230 m|ji

Fig. 2 - Ultraviolet spectra of 1-bornyl (±) methanesulflnate

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 70 hexane 250 3) 230 mu 220

- -

0 0 . . 200 (-)-lsobomyl (±) methanesulflnate (Fig. 12 28 Of x 3 Reproduced with permission ofthe copyright owner. Further reproduction prohibited without permission. 71

28®0L 95% EtOH

hexane

20 , 0-

X W

200 230 m|i

Pig, ^ - (-)-menthyl (±) methanesulfinate

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 72

hexane

i o x

12.0-

200

Fig. 5 - (- )-cholesteryl (±)-methanesulfinate

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DESCRIPTION OF EXPERIMENTS

The infrared absorption spectra were determined with

a Perkin-Elmer Model 337 grating infrared spectrophotometer.

All nuclear magnetic resonance spectra were determined with

a Varian Model A-60 nuclear magnetic resonance spectrometer.

The ultraviolet absorption spectra were measured with a Cary-

Model 14 recording spectrophotometer.

The optical rotations at the sodium D line were

determined with a Franz Schmidt and Haensch polarimeter. The

average deviation was recorded for each optical rotation

determined.

Microanalyses were determined by Schwarzkopf

Microanalytical Laboratory, Woodside, N. Y, The boiling

points and melting points are in degrees centigrade and are

uncorrected.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. y b

Sodium jo-Toluenesulf inate Dihydrate was prepared

according to the procedure of Whitmore and Hamilton by the

zinc dust reduction of jo-toluenesulfony1 chloride. The desired

compound was obtained as white crystals (90% yield) which were

air-dried.

_2-Toluenesulfiny1 Chloride was prepared according to

the procedure of Kurzer^ from the reaction of sodium

jo-toluenesulf inate dihydrate with excess thion.yl chloride. The

desired product was obtained as a brown yellow liquid (92%

yield) and was used without further purification.

(-)-Menthyl (-)-jo-Toluenesulfinate was prepared 62 according to the procedure of Herbrandson and Dickerson from

the reaction of jo-toluenesulfiny1 chloride and (-)-menthol.

The desired ester was obtained as white crystals (60% yield.)

with mp lQd-10 5o , lit.^ mp 106-10?°, and -200.6 ± 1°

(c 1 .89b, acetone), lit.^ [ci]q^ -199.2° (c 2.0, acetone).

(+)-(R)-Methyl jo-Tolyl Sulfoxide. The Grignard reagent

prepared from methyl iodide (22.b g, 0.2 mole) and oven-dried

magnesium turnings (d-,86 g, 0.2 g-atom) in anhydrous ether

(75 ml) was added dropwise with mechanical stirring and cooling

(ice salt-bath) to a solution of (-)-menthyl (-)-jo-toluene-

sulfinate (^2.6 g, 0.1^4- mole) in anhydrous ether (^00 ml).

After stirring for one hour at ice-bath temperature, the reaction

mixture was hydrolyzed with saturated aqueous ammonium chloride

(U-00 ml). The layers were separated and the aqueous layer

saturated with sodium chloride. After extraction of the aqueous

layer with three 100-ml portions of ether, the combined ether

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 75

layer was dried over anhydrous magnesium sulfate. The ether

was removed In vacuo; the solid residue was dissolved in

anhydrous ether. After concentrating the ether solution, it

was cooled in a Dry Ice-acetone bath and the light yellow crystals

that formed were collected by filtration. The crystals were

dissolved in a. small volume of ether. The solution was clarified

with Norit A; and, upon cooling, white crystals formed which were

collected by filtration. The desired sulfoxide (9*5 S, o 2 yield) was dried in a vacuum desiccator, mp 75• 0-7.5• 5 ; [a]]}-

+139*9 ± 0.7° (c 1.98, acetone) [lit.17 mp 73-79.5°. [o.]D

+195.5° (acetone)].

Methyl Phenyl Sulfoxide was previously prepared in this

laboratory65 from the _t-butyl hypochlorite oxidation^ of methyl

phenyl sulfide. The desired sulfoxide was obtained as a colorless

liquid, bp 89° (0.25 mm), lit.65 bp 109-105° (0.7 mm).

Methyl jo-Tolyl Sulfoxide was previously prepared in this 6 7 69 laboratory J from the _t-butyl hypochlorite oxidation of methyl

jo-tolyl sulfide. The desired sulfoxide was obtained as a white

solid, mp 92-93°, lit.66 92-93°.

Butyl Methyl Sulfide was prepared according to the 67 procedure of Bordwell and Boutan from the reaction of

butylmagnesium bromide with methyl disulfide. The desired

sulfide was obtained as a colorless liquid (52^ yield), bp

121-123°, lit.^ bp 122.5 (761 mm), by fractionation through a

15-cm Vigreux column. 69 Butyl Methyl Sulfoxide. - ;t-Butyl hypochlorite

(20.2 g, O.I87 mole) was added dropwise with magnetic stirring

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to a solution of butyl methyl sulfide (19*3 g* 0,187 mole)

in methanol (150 ml) cooled, by means of a Dry Ice-acetone

bath. When the addition was completed, the reaction mixture was

stirred for one hour at Dry Ice-acetone temperature, then for

six hours at room temperature. Solid sodium carbon,ate was

added and after the salt was collected by filtration, the

methanol was removed in vacuo. The residual oil was dissolved

in ether and. the ethereal solution dried over anhydrous magnesium

sulfate. Removal of the ether _in vacuo and vacuum distillation

of the residual yellow liquid gave a colorless liquid (70%

yield), bp 7^-75° (1.25 mm), ]it.6 8 bp 51.5° (0.01 mm). An

infrared spectrum (neat) showed a strong bsnd at 1038 cm ^ ,

characteristic of sulfoxides. A thin-layer chromatogram using

Silica Gel G (Brinkmann Instruments) as adsorbent and chloroform

as the eluent showed the presence of only one spot for the

sulfoxide when visualized by the iodine stain method.

Methyl Methanesulfinate was prepared according to the 70 procedure of Douglass from the reaction of methanesulfinyl

chloride with anhydrous methanol. The desired ester was obtained

as a colorless liquid (75% .yield), bp.38-39° (11 mm), lit.*^

by 9'2-9'3° (18 mm), after fractionation through a 15-cm Vigreux

column. An infrared spectrum (neat) showed a strong band at

1132 cm \ characteristic of sulfinate esters.

Methanesulfinyl chloride was prepared according to the 71 procedure of Douglass and Farah from the chlorination of methyl

disulfide in acetic acid. The desired compound was obtained as

a light yellow liquid (85% yield), bp 36-37° (15 mm); n^^’^D

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 77

1,5041 bp 48° (22 mm), 1,5038], after fractionation

through a 15-cm Vigreux column. An infrared spectrum (neat)

showed a strong band at 1144 cm .

Methyl o-Toluenesulfinate. - A solution of anhydrous

methanol (12.8 g, 0.40 mole) and anhydrous pyridine (31*6 g,

0.4 mole) in anhydrous ether (50 nil) was added dropwise vjith

mechanical stirring and cooling (ice bath) to a solution of

jo— toluenesulfiny1 chloride (6l>5 g, 0.35 mole) in anhydrous

ether (60 ml). When the addition was completed, the mixture was

stirred, at ice-bath temperature for one hour and at room temperat

ure for one hour. Ether (50 nil) was added followed by water

to dissolve the pyridinium hydrochloride. The layers were

separated and the ether layer washed with 100-ml portions of

cold 6% hydrochloric acid until the washings were acidic, with

cold, aqueous sodium bicarbonate until the washings were basic,

and finally with cold water. After the ether layer had been

dried over anhydrous magnesium sulfate, the ether was removed

in vacuo, leaving an orange-red liquid. Vacuum distillation

gave the desired ester as a colorless liquid, bp 75-76° (0.2.4 ram), 72 o lit. bp 135 (14 mm). An infrared spectrum (neat) showed a

strong band at 1133 cm~\ characteristic of sulfinate esters.

(-)-Menthy1 (±)-Methanesulfinate. - A solution of

methanesulf iny 1 chloride (86'. 3 g, 0.875 mole) in anhydrous ether

(200 ml) xtfas added dropwise with mechanical stirring and cooling

(ice bath) to a solution of (-)-menthol (136.7 g* 0.875 mole)

and anhydrous pyridine (69-2 g, 0.875 mole) in anhydrous ether

(200 ml). When the addition was complete, the mixture was stirred

at ice-bath temperature for one hour and then hept in a ice bath

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 78

overnight. Ether (100 ml) was added followed by cold water

(250 ml) to dissolve the pyridinium hydrochloride. The layers

were separated and the ether layer washed with 100-ml portions

of cold 10$ hydrochloric acid until the washings were acidic,

with cold, aqueous sodium bicarbonate until the washings were

basic, and finally with cold water. After drying the ether

layer over anhydrous magnesium sulfate, the ether was removed

in vacuo to give the crude ester as a light yellow liquid.

Fractionation through a 15-cm Vigreux column gave (-)-menthyl

(±) -methanesulf inate (165.9- g* 87$ yield) as a colorless liquid, 22 7 bp 92-93° (0.6 mm); [a]D -118.9 ± 0.7° (c 2.19-5, acetone)

[lit.^ bp 88-89° (0.9- mm), [sL~ ^ > -99 ± 1° (c 2.29* acetone)].

An infrared spectrum (neat) showed a strong band at 1138 cm \

characteristic of sulfinate esters.

(±)-Isobornyl Methanesulfinate. - A solution of (±)-

isoborneol (27-7 g* 0.18 mole) and anhydrous pyridine (16.6 g,

0.21 mole) in anhydrous ether (60 ml) was added dropwise with

mechanical stirring and cooling (ice bath) to a solution of

methanesulfinyl chloride (20.6 g, 0.21 mole) in anhydrous ether

(50 ml). When the addition was completed, the reaction mixture

was stirred at ice-bath temperature for two hours and at room

temperature for one hour. Ether (100 ml) was added followed by

cold water (150 ml) to dissolve the pyridinium hydrochloride.

The layers were separated and the ether layer washed with 100-ml

portions of cold, 3% hydrochloric acid until the washings were

acidic, with cold, aqueous sodium bicarbonate until the washings

were basic, and finally with cold water. After drying the ether

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 79

layer over anhydrous magnesium sulfate, the ether was removed

in vacuo to give the crude ester as a yellow liquid.

Fractionation through a 15-cm Vigreux column gave a colorless o liquid (35 St 90% yield), bp 72-7^ (0.11 mm). An infrared

spectrum (neat) showed a strong band at 1136 cm \ characteristic

of sulfinate esters.

(±)-Borny1 Methanesulf inate. - A solution of (±)~

borneol (64.8 g, 0.42 mole) and anhydrous pyridine (35*6 g, 0.45

mole) in anhydrous ether (200 ml) was added dropwise with

mechanical stirring and cooling (ice bath) to a solution of

methanesulf inyl chloride (43.8 g, 0.44 mole) in anhydrous ether

(70 ml). When the addition was completed, the reaction mixture

was stirred at ice-bath temperature for two hours and at room

temperature for one hour. Ether (100 ml) was added followed

by cold water (250 ml) to dissolve the pyridinium hydrochloride.

The layers were separated and the ether layer washed with 100-ml

portions of cold 10$ hydrochloric acid until the washings were

acidic, with cold, aqueous sodium bicarbonate until the washings

were basic, and finally with cold water. After drying the

ether layer over anhydrous magnesium sulfate, the ether was

removed _in vacuo to give the crude ester as a yellow liquid.

Vacuum distillation gave a colorless liquid (80.3 g* 89$ yield),

bp 83-84° (0.44 mm). An infrared spectrum (neat) showed a

strong band at 1133 cm \ characteristic of sulfinate esters.

(-)-Isoborneol was obtained as a 90il0 mixture with

(+)-borneol from the lithium aluminum hydride reduction of

d-camphor as described by Noyce and Denney. 73 A white solid was

obtained in 96.5$ yield which, after being air-dried, melted at

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 80

*2 ^ ^ o 73 186-188°; [oJ q -25.96 ± 0.2 (c 10.21, ethanol) [lit.

[o.]q ^ -26.00° (_c 10, ethanol)].

Purlfication of (-)-Isoborneol. - A solution of

o-nitrobenzo yi chloride (?.0 g, Q.O38 mole) in anhydrous ether

(30 ml) was added dropwise with mechanical stirring and cooling

(ice bath) to a solution of the isoborneo'l-borneol mixture

(38.5 St 0.25 mole) and anhydrous pyridine (20 ml) in anhydrous

ether (150 ml). This procedure is a modification of one 30 described by J.acbman, Macbeth, and Mills. When the addition was

completed, the mixture was stirred at ice-bath temperature for

three hours and at room temperature for two hours. Ether (100 ml)

was added follovjed by cold water (100 ml) to dissolve the

pyridinium hydrochloride. The layers were separated and the

ether layer washed with 100-ml portions of cold, 3% hydrochloric

acid until the washings were acidic, with cold, aqueous sodium

bicarbonate until the washings were basic, and finally with cold

water. After drying the ether layer over anhydrous sodium

sulfate, the ether was removed in vacuo, leaving a light yellow 31 solid (To g). Sublimation of this solid under reduced pressure

(15 Tim) at 80-90° (oil-bath temperature) gave a white solid

(28.9 g), while the yellow (+)-borneol o-nitrobenzoate (10.9 g,

9-T$ yield) did not sublime. Since a nuclear magnetic reasonance

(nmr) spectrum of the isoborneol showed traces of borneol present,

the above procedure was repeated assuming r7% borneol to be present, _ _26 0 The white solid (27.1 g) obtained had Ld.Jp) -31.8 l 0.1 (c_ 10.235,

ethanol). Repetition of the above procedure gave (-)-isoborneol o ?3 as a white solid (21.6 g), mp 20T-205 ; [aj^ -33*^ ± 0.1°

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 81

(c 11.08, ethanol) [lit.-^ up 214 , l i t . La Iq ~33*5 (£ 8.044,

ethanol)].

(-)-Isobornyl (zfc)-Methanesulfinate (0° reaction) was

prepared by the same procedure as that used for (±)-isobornyl

methanesulfinate except that cooling was effected by an ice-salt

bath and stirring was maintained for three hours at ice-salt- bath temperature and two hours at room temperature. The crude nh ester was obtained as a light orange liquid (23.4 g, 103$ yield' ).

Vacuum distillation of a portion of this liquid gave a colorless

liquid containing some white solid (isoborneol), bp 67-72°

(0.05 mm). The solid was removed by sublimation under reduced

pressure (0.04 mm) at 40° (oil-bath temperature) and the liquid

redistilled to give a colorless liquid, bp 64-66° (0.05 mm); 2 5,3 [a ]~ * -34.5 ±0.5° (c 2.0, ethanol). An infrared spectrum

(neat) showed a strong band at 1135 cm characteristic of

sulfinate esters.

(-)-Isobornyl (±)-Methanesulfinate (-65° reaction). -

A solution of (-)-isoborneol (21.6 g, 0.14 mole) in anhydrous

pyridine (40 ml) was added dropwise with mechanical stirring

at such a rate that the temperature could be maintained below

-65° to a solution of methanesulfinyl chloride (15.8 g, 0.16

mole) in anhydrous ether (100 ml) cooled to -70° (Dry Ice-acetone

bath). Pyridinium hydrochloride precipitated from the reaction

mixture during the course of the addition. When the addition , o was completed, stirring was continued for three hours at -65 >

then the reaction mixture was warmed to room temperature over a

period of two hours. Water (100 ml) was added to dissolve the

pyridinium hydrochloride, and the layers were separated. The

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 82

ether layer was washed with 100-ml portions of cold water, with

cold, y% hydrochloric acid until the washings were acidic, with

cold aqueous sodium bicarbonate until the washings were basic,

and finally with cold water. After drying the ether layer over

anhydrous magnesium sulfate, the ether was removed in vacuo

at room temperature to give the crude ester as a yellow-orange

liquid (29.7 g, 98% yield). Vacuum distillation of a portion

of this liquid gave a colorless liquid containing some solid

material, bp ?l-73° (0.09 mm). The solid (isoborneol) was removed o by sublimation under reduced pressure (0.05 mm) at 50 (bath

temperature) and the liquid was redistilled to give a colorless 2 2 2 liquid, bp 65-67° (0.04 mm), [a ~ ~ -22.2 ± 0.6 (c_ 2.57>

acetone), 75 Lithium Trimethox.yaluminohyd ride . - Tetrahydrofuran

(Fisher Chemical) was stirred with calcium hydride for 12 hours

then refluxed with anhydrous stannous chloride for five hours

to remove peroxides. The tetrahydrofuran was decanted into a

distilling flask to which was added sufficient lithium aluminum 41 hydride to ensure an excess of active hydride. After the

tetrahydrofuran had been distilled from the lithium aluminum

hydride, a small amount of sodium borohydride was added to inhibit

peroxide formation. Absolute methanol was prepared according 76 to the procedure of Vogel.

The apparatus used was flame-dried under a stream of

nitrogen. Anhydrous methanol (9*6 g, 0.3 mole) was slowly

added to 100 ml of a 1 M solution of lithium aluminum hydride

(0.1 mole) in tetrahydrofuran with mechanical stirring at 0°

(ice-salt bath). A viscous white solid formed, and the reaction

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 83

mixture was warmed to room temperature with stirring.

Attempted Reduction of d-Camphor with Lithium Trimethoxy-

alum.inohydr.id e . -r The hydride in tetrahydrofuran was cooled, to

0° (Dry Ice-acetone bath) and a solution of d-camphor (9.13 S»

0.06 mole) in dry tetrahydrofuran (35 ml) was added with mechanical

stirring at such a rate that the temperature could be maintained,

at 0°. When the addition was completed, tetrahydrofuran (25 ml)

was added and the reaction mixture stirred at 0° for one hour,

then at room temperature for one hour. By this time the reaction

mixture had assumed a jelly consistency. Residual hydride was

destroyed by the slow addition of water and the mixture

transferred to a separatory funnel. Ether (150 ml) was added 75 followed by a saturated solution of disodium tartrate (150 ml).

The organic phase was separated and the aqueous layer extracted

with three 100-ml portions of ether. After drying the combined

ether layers over anhydrous magnesium sulfate, the ether was

removed in vacuo leaving a white solid (8.6 g) which 'was dried

in a vacuum desiccator. The solid, mp 172-17^°, had an spectrum

identical to that of d-canphor, mp 176-177°. A second trial

produced the same result. A possible explanation is that the

molarity of the lithium aluminum hydride had changed

significantly and lithium tetramethoxyalurninohydride was being

formed which would not reduce the d-camphor. 77 Purification of L-Borneol by Column Chromatography. '' «. 21 L-Borneol was obtained from K & K Laboratories, M d -20.6 ±

0.1° (£9.96, ethanol). L-Borneol (10 g) was dissolved in

chloroform (35 ml) and placed on a 3^+ x 580 mm neutral alumina

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 84

column (400 g) . Two liters of petroleum ether (bp 50-70°)

were used to develop the chromatogram and the isoborneol

eluted with petroleum ether. Benzene followed by ether was

used to elute the l_-borneol. After the solvents had been

removed in vacuo, the l_-borneol obtained was purified by

sublimation under reduced pressure. The fraction of highest

purity amounted to 3-5 rap 203-205°; LaJ^ -2-7.6 ± 0.1°

(c 10.2, ethanol) [lit.78 mp 204°, La]^° -36.2° (c 3.068,

ethanol) ], The total amount of product recovered was 8 g

(80% recovery). Because of the poor separation by this

procedure, the o-nitrobenzoate method was attempted.

o-Nitrobenzo.yl Chloride was prepared according to the

procedure of Loclenann and Rein7^ from the reaction of 79 o-nitrobenzoic acid with excess phosphorus pentachloride. The

desired compound was obtained as a light yellow liquid (59%

yield), bp 91-92° (0.2 mm). The compound is a liquid at room

temperature but solidifies to a white solid upon refrigeration.

Purification of L-Borneol. - The _l-borneol (K & K 2 ? 5 Laboratories) used had -21.1 ± 0.2° (c. 9.99, ethanol),

lit.-^ [a -36.22° (c 8.068, ethanol), and was shown to be

contaminated with isoborneol by nuclear magnetic resonance fin (nmr). Assuming 90% borneol and 10/6 isoborneol, a solution

of o-nitrobenzoyl chloride (43.2 g, 0.233 mole) in anhydrous

ether (60 ml) was added dropwise at ice-salt-bath temperature

to a solution of 1-borneol (40 g, 0.26 mole) in anhydrous ether

(200 ml). When the addition was completed, the reaction

mixture was stirred at room temperature for two hours. Water

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 85

(100 ml) was added to dissolve the pyrldlnium hydrochloride

and the layers were separated. The ether layer was washed

with two 100-ml portions of cold 3/“ hydrochloric acid, with

cold aqueous sodium bicarbonate, and finally with two 100-ml

portions of cold water. After, the ether layer had been dried

over anhydrous magnesium sulfate, the ether was removed _in vacuo

to give an orange-yellow solid (60.9 g). Vacuum sublimation

at 0.05 mm (oil bath 70°) gave a waxy white solid (10.7 g)

which was shown to be a mixture of borneol and isoborneol from

its rot • tion, [a -d.93 ± 0.].° (c 10.035, ethanol). The D residual orange-yellow solid was recrystallized three times from

35-60° petroleum ether to -ive light yellow platelets, mo

111.5-112.5°, [a ]2^ -59.^ ± 0.4° (c 2.09, ethanol), [lit. 3°

mp 109°, [a “ +6 7 (c 2.0, toluene) for ( + ) -bornyl

o-nitrobenzootej. Nuclear magnetic resonance (nmr) showed the

presence of ir.obornyl o-nitrober:zoate. 32 The procedure of Alder and Winde-nuth for the hydrolysis

of (-)-born.yl o-nitrobenzonte was followed, (-)-Bornyl

o-nitrobenzoate (33*^ S» 0.11 mole) was heated at reflux for

three hours with 15$ methanolic potassium hydroxide solution

(112 g, 0.3 mole). Water (150 ml) was added and the reaction

mixture was steam distilled. After extraction of the aqueous

layer with ether, the aqueous layer was saturated with sodium

chloride, then extracted with two 200-ml portions of ether.

The combined ether extracts were dried over anhydrous magnesium

sulfate; the e ;her was removed in vacuo to leave a yellow-white 81 solid (15-0 g, 89$ yield). The solid was purified by vacuum

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8 6

sublimation at 0.4 mm (cil bath 65°) to give a pure white

solid, mp 203-204°; fa"]21 -30.4 * 0.17° (c 10.20, ethanol) D [lit.36 mp 204°, [a]20 -36.2 (c 8.068, ethanol)].

(-)-Bornyl (±)-Methanesulfinate (0° reaction). - 22.0 The (-)-borteol mas obtained from K & K Laboratories, LoO q ^*’"'

-21.1 ± 0.2° (c 9.99, ethanol) • The same procedure as that

used for (-)-isoborry1 (i)-methanesulfinate was utilized except

that stirring was for two hours at ice-buth temperature and one

hour at room temperature. The crude ester was obtained as a 74 yellow liquid (44 g, 10072 yield ). Vacuum distillation of a Q portion of the crude ester gave a colorless liquid, bp 67-68

(0.08 mm); [a]^ -6.07 i 0.6° (c 1.975* acetone). An infrared

spectrum (neat) showed a strong band at 1134 cm , characteristic

of sulfinate esters.

(-)-Bornyl ( d.)-Me thanesulf inate (-65° reaction). -

The same procedure as that used for (-) - isoborn.yl ( ±) -mothanesulf-

inate was utilized. The crude ester was obtained as a .yellow

liquid (80 g, 102% y i e l d ^ ) . Vacuum distillation of a portion

of the crude ester gave a colorless liquid, bp 75-77° (0,0'? mm);

La +1.62 ± 0.5° (c 1.85» acetone). An infrared spectrum

(neat) showed a strong band at 1135 cm , characteristic of

sulfinate esters.

(- )-Cholesteryl (-)-Methanesulfinate. - The (-)-

cholesterol was obtained from Fisher Chemical, A solution of

(-)-cholesterol (201 g, 0.52 mole) and anhydrous pyridine

(350 ml) in anhydrous ether (100 ml), was added dropwise with

mechanical stirring and cooling (ice bath) to a solution of

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8?

me thane sulf iny'l chloride (53»6 g, 0,54 mole) in anhydrous

ether (200 ml). When the addition was completed, anhydrous

ether (100 ml) was added to the mixture which then was stirred

for two hours at ice-bath temperature and for four hours at

room temperature. Water (4-00 ml) was added to dissolve the

pyridinium hydrochloride and the layers were separated. The

ether layer was washed with 150-ml portions of cold water,

with cold, yfo hydrochloric acid until the washings were acidic,

with cold, aqueous sodium bicarbonate until the washings were

basic, and finally with cold water. After drying the ether

layer over anhydrous magnesium sulfate, the ether was removed

in vacuo to give the crude ester as a yellow solid (245*9 S»

105$ y i e l d ^ ). The yellow solid was dissolved in hot methanol;

the solution was clarified with Norit A and several crystals of o ^ (-)-cholesteryl (-)~methanesuIfinste (Ca]gj -100.9°) were

added to the hot solution. Upon cooling, a white solid formed

which was filtered and dried in a vacuum desiccator. Fractional

recrystallization from methanol using the above seed crystals < o ,--.20 gave white needle-like crystals, mp 126-127 ; a -101,0 ± D 0.6° (c 2.01, chloroform) after eight recrystallizations. An

infrared spectrum (solution, CHCl^) showed a strong band at

1120 cm \ characteristic of sulfinate esters.

(-)-(S )-Methyl jo-Tolyl Sulfoxide from (-)-Menthyl

(±)-Methanesulfinate. - A solution of six-month-old (-)-menthyl

(±)-methanesulfinate (5=46 g, 0.025 mole) in anhydrous ether

(15 ml) was added at such a rate that vigorous refluxing

occurred to the Grignard reagent prepared from jo-bromotoluene

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 88

(9.95 S> 0.026 mole) and oven-dried magnesium turnings (O.63 S»

0.026 g-atom) in anhydrous ether (50 ml). When the addition

was completed, the reaction mixture was stirred magnet1cally

at room temperature for 20 minutes before hydrolysis with

saturated aqueous ammonium chloride. The layers were separated,

and the ether layer was extracted with four 50-ml portions of

water. The combined aqueous extracts were extracted with three

50-ml portions of 39-60° petroleum ether*^ and then saturated

with sodium chloride. After extraction of the aqueous phase with

four 60-ml portions of chloroform, the combined chloroform

extracts were dried over anhydrous magnesium sulfate. Removal

of the chloroform in. vacuo and vacuum distillation of the

remaining yellow liquid gave the desired sulfoxide as a colorless

liquid, bp 97-98° (2.29 mm), which solidified to a white solid o (1.9 g, 36% yield), mp 92.5-93*5 ! [a ]D " -S.58 ± 0.5 (c 2.0k,

0 -2 . 99.5 acetone) [calculated value ^ [oOd -9*11 (ethanol); 89 enantiomeric purity of 5•89$].

(-)-(S )-Meth;yl Phenyl Sulfoxide from (-)-Menthyl (±)-

Methanesulf inate . - A solu' ion of six-month-old (-)-menth.yl

(i)-methanesulfinate (5*96 g, 0.025 mole) in anhydrous ether

(20 ml) was added at such a rate that vigorous refluxing

occurred to the Grignard reagent prepared from bromobenzene

(9.08 g, 0.026 mole) and oven-dried magnesium turnings (O.63 g»

0.026 g-atom) in anhydrous ether (90 m l K When the addition

was completed, the reaction mixture was stirred magnetically

at room temperature for 20 minutes before hydrolysis with

saturated aqueous ammonium chloride. The layers were separated,

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 89

and. the ether layer was extracted with four 50-ml portions of

water. The combined aqueous extracts were extracted with

three 50-m.l portions of 39-60 petroleum ether' and then

saturated with sodium chloride. After extraction of the aqueous

phase with four 60-ml portions of chloroform, the combined

chloroform extracts were dried over anhydrous magnesium sulfate.

Removal of the chloroform in vacuo gave the desired sulfoxide

as a colorless liquid (2.14 g, 61% yield), bn 66-67° (0.05 mm);

[oJq^ -8.38 ± 0.,° (c 2.271 acetone) [calculated value®^ [ "

-8.''47°; enantiomeric purity 5• 6 8 $ ] . An infrared spectrum

(neat) was identical with that of authentic material.

( + )- (R)-Methyl _p-Tolyl Sulfox:ide from ( - )-Isoborny 1

(±)-Methanesulfinate (-65°reaction. - A solution of crude (-)-

isobornyl (±)-methanesulf inate (5»^ St 0,025 mole) in anhydrous

ether (20 ml) was added at such a rate that vigorous refluxing

occurred to the Grignard reagent prepared from D-bromotoluene

(^.45 gt 0.026 mole) and oven-dried magnesium turnings (O.63 g,

0.026 g-atom) in anhydrous ether (50 ml). The solution became

cloudy during the addition. When the addition was completed,

the reaction mixture was magnetically stirred at room temperature

for 20 minutes before hydrolysis with saturated aqueous ammonium

chloride. The layers were separated and the ether layer extracted

with four 5'9-ml portions of water. The combined aqueous extracts

were extracted with three 5'9-ml portions of 30-60° petroleum

ether and then saturated with sodium chloride. After

extraction of the aqueous pho.se with four 59-ral portions of

chloroform, the combined chloroform extracts were dried over

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 90

anhydrous magnesium sulfate. The chloroform was removed in

vacuo at room temperature to give a yellow liquid which upon

vacuum distillation gave the desired sulfoxide as a colorless

liquid which solidified to a white solid (1.39 g* 36% yield),

bp 78-30° (9.05 mm), mp 6-1--66°; +98.8 ± 0.7° (c. 1.895» Oh ethanol); enantiomeric purity 63*4$. A. thin-layer

chromatogram using Silica Gel G (Brinkmann Instruments) as

adsorbent and chloroform as the eluent showed only one spot for

the sulfoxide when visualized by the iodine stain method.

(+)-(R)-Methyl Phenyl Sulfoxide from (-)-Isobornyl

( ±)-Methanesulfinate (-65° reaction). - A solution of crude

(-)-isobornyl (±)-methanesulfinate (5*4 g* 9.025 mole) in anhydrous

ether (20 ml) was added at such a rate that vigorous refluxing

occurred to the Grignard reagent prepared from bromobenzene

(4.08 g, 0.026 mole) and oven-dried magnesium turnings (O.63 g,

0.026 g-atom) in anhydrous ether (40 ml). The solution became

cloudy during the addition. When the addition was completed,

the reaction mixture was stirred magnetically at room temperature

for 20 minutes before hydrolysis with saturated aqueous ammonium

chloride. The layers were separated and the ether layer

extracted with four 50-ml portions of water. The combined

aqueous extracts were extracted with three 5'3-ml portions of

30-60° petroleum ether-^ and then saturated with sodium chloride.

After extraction of the aqueous phase with four 50-ml portions

of chloroform, the combined chloroform extracts were dried over

anhydrous magnesium sulfate. The chloroform was removed in vacuo

and the remaining yellow liquid vacuum distilled to give the

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 91

desired sulfoxide as a colorless liquid (1.7 g, yield),

bo 63.5-64.5 (0,051 mm); [

this liquid was identical to that of authentic material• A

thin-layer chroma to gram using Sil lea Gel G (Brinbmsnn

Instruments) as adsorbent and chloroform as the eluent showed

only one spot for the sulfoxide when vl.su'"ill.sed by the j.od ir.e

stain method,

(+)-(R) -Methyl Phenyl Sulfoxide from ( - )-Bornyl. (+)-

Methanesulf inn te (C° reaction). - The desired sulfoxide was

prepared according to the same proc- dure used in the previous o - 26.5 o e x pe r 1 m en t, b p 67-6° ' (9,05 mm); [ a]^ +13*7 a s , A ( c , 2 . 2 6 , _ O q _ 2 6 5 o acetone ) [_ calculated value' J [ a] " *+13.85 (ethanol.) ; enantiomeric

pu r i t y 9.2 9%]»3 3

(+)-(R)-Methyl £-Toly.l Sulfoxide from (-)-Bornyl U)-

Me thane sulfinate (-65° reaction). -- The desired sulfoxide was

prepared according to the same procedure used In the previous o Q experiment, bp 7^-75° (9.055 mm), mo 43-44°; [a]r)'~ +27*0 ±

0.6° (o 1.83, ethanol); enantiomeric purity 17*3$

(-)-(S)-Methyl jo-Tol.yl Sulfoxide from ( - )-Cholesteryl

(±)-Methanesulfinate. - The Grignard reagent was prepared from

£-brcmotoluene (5.13 S* n•03 mole ) and oven-dried magnesium

turnings (0.73 g, °.03 g-atom) in anhydrous ether (9-5 ml). The

reagent was added, with mechanical stirring at ice-bath

temperature to (-)-cholesteryl (-)-methanesulfinate (10.4 g,

0.023 mole) of -77• 2 ± 0*5° (c 2.015, chloroform) in

anhydrous ether (90 ml). When the addition was completed, the

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 92

cloudy, white reaction mixture "as stirred at ice-wster-b'th

temperature for one hour, then at room temperature for one hour.

Hydrolya is was accomplished by the dropwj.se addition of aqueous

saturated ammonium chloride solution until there was no

precipitate formed upon the addition of a drop of ammonium

chloride solution. The white precipitate was collected by

filtration and washed with anhydrous ether. The ether washings

were combined with the original ether layer and dried, over

anhydrous magnesium sulfate. The ether was concentrated in vacuo

and the cholesterol collected by filtration and washed with

absolute ethanol. After the alcohol was removed In vacuo,

the residue was vacuum distilled to give a colorless liquid, . o , . bp 116-117 (0.07 mm), which solidified at room temperature.

The desired sulfoxide was hygroscopic and hence difficult to

weigh accurately for rotation. The semi-solid sulfoxide had 21 [a.]p -69.1 ±0.6° (c 1.99, acetone). A thin-layer chromatogram

using Silica Gel G (Brinhmann Instruments) as adsorbent and.

chloroform as the eluent showed three spots, one of which was

identified as cholesterol, when visualized, by the iodine stain

method. Bedistillation of the sulfoxide gave a colorless liquid,

bp 103-105° (0,6 mm), which solidified as before. Thin-layer

chromatography showed one intense spot for the sulfoxide and a

second barely visible spot. The solid sulfoxide was dissolved

in a small volume of anhydrous ether. Upon cooling the ethereal

solution in a Dry Ice-acetone bath, light yellow crystals formed

which were collected by filtration. These crystals melted at

73-7^°, [cc]^ -19-3.8 ±0.7° (c 2.01, acetone). Purification of

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 93

these crystals by the anhydrous ether method gave white crystals,

mp 7^. 5~7 5 • 5°! -l’+A.S + 1" (c 2.01, acetone), |]lit2^

mp 73-7^.5°* Lo-Iq + 1^5»5° (acetone)]. A thin-layer chromatogram

showed only one spot for the sulfoxide. Although the rotation

for (-)-(S)-methyl o-tolyl sulfoxide corresponds to an

enantiomeric purity of 99.2#, the po°sibility of optical

fractionation must be considered.

Optical Fractionation Experiment with (+)-(R)-Methyl

p-'Tolyl Sulfoxide. - As optical fractionation was suspected

in the formation of (-)-(S)-methyl jo-tolyl sulfoxide from(-)-

cholesteryl (-)-methanesulfinate, the following experiments

were run. A small sample of (+)-(R)-methyl £-tolyl sulfoxide 2 2 with [a Id"' +98.8 -1 0.7° (c 1.895* ethanol) was dissolved in

anhydrous ether (less than 10 ml). The ethereal solution was

cooled in a Dry Ice-acetone bath and the white crystals which

formed were collected by filtration and dried in a vacuum

desiccator. The sulfoxide melted at 72-73°* L°2d" '" +1^.7 +

0.7° (,c 1.935* ethanol). Similarly, sulfoxide of [ a ] ^ ”' +70.0 ±

0.7° (o 2,0, ethanol) gave white crystals, mo 65-67°; [ ]q^

+93.5 + 0.8° (c_ 1.865* ethanol). In both cases optical

fractionation occurred, but the ether method of purification

may prove advantageous in obtaining optically pure methyl

jo-tolyl sulfoxide from optically impure sulfoxide.

Separation of Cholesterol from Sulfoxides - Sulfuric

Acid Method. - An ethereal solution of n-butyl methyl sulfoxide

(3.63 g* 0.03 mole) and 1-cholesterol (11.6 g, 0.03 mole)

was evaporated _in vacuo. Gold 5% sulfuric acid was added

and the 1-cholesterol collected by filtration and washed with

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 94

cold 5% sulfuric acid. The 1-cholesterol was dissolved in

chloroform and washed with several portions of cold $% sulfuric

acid. The combined acidic washings were neutralized with sodium

carbonate; the aqueous layer was concentrated, then saturated

with sodium chloride. After extraction of the aqueous solution

with three 100-ral portions of chloroform, the combined chloroform

extracts were dried over anhydrous magnesium sulfate. Removal

of the chloroform _in vacuo left a brown liquid from which methyl

n-butyl sulfoxide (2.05 S» 56$ recovery) was obtained by

vacuum distillation.

Separation of Cholesterol from Sulfoxides - Acetonltrlle

Method. - Since sulfoxides have been reported®-* to form complexes

with acetonitrile and. cholesterol is insoluble in this solvent,

the following method was devised. Methyl phenyl sulfoxide

(3*22 g, 0.02.3 mole) was dissolved in acetonitrile (50 ml)

and 1-cholesterol (8.89 g» 0.023 mole) was added to this

solution. Acetonitrile (20 ml) was added and the mixture

stirred magnetically for 0.5 hour. The mixture was cooled in

an ice bath and the 1-cholesterol collected by filtration and

washed with cold acetonitrile. Removal of acetonitrile in

vacuo and vacuum distillation of the remaining liquid gave the o sulfoxide (2.5 g» 7Qf° recovery) as a colorless liquid, bp 67-68

(0.05 mm), lit.®^ bp 104-105° (0.7 mm).

(+)-(S )-n-Buty1 Methyl Sulfoxide from (-)-Cholesteryl

(-)-Methanesulfinate, - The Grignard reagent was prepared

from n-butyl bromide (3*25 g> 0.023 mole) and oven-dried magnesium

turnings (0.56 g, 0.023 g-atom) in anhydrous ether (40 ml).

The dark Grignard reagent was stirred at room temperature for

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two hours at which time all of the magnesium had reacted. A

solution of (-)-cholesteryl (-)-methanesulfinate (9*90 g, .. 21 _ o . . 0.21 mole) of [_a]o -S5«0 ± 0.8 (c 1.955» chloroform) in

anhydrous ether (12.5 ml) was added dropwise with mechanical

stirring n.t ice-bath temperatures to the Grignard reagent.

When the addition was completed, ether (100 ml) was added and

the reaction mixture stirred at room temperature for four hoursr

Hydrolysis was accomplished by the dropwise addition of aqueous

saturated ammonium chloride solution until no precipitate

formed. The ether was decanted and the solid washed thoroughly

with ether. After drying the combined ether layer over anhydrous

magnesium sulfate, the ether was removed in vacuo leaving a

yellow solid to which acetonitrile (80 ml) was added and the

resulting mixture stirred at room temperature for one hour. The

solid was collected by filtration and washed with cold

acetronitrile. Removal of the acetonitrile in vacuo left a

yellow liquid containing some solid which was stirred for 12

hours with aqueous potassium hydroxide. The solid was

collected by filtration and washed with cold water. After

saturating the aqueous solution with sodium chloride, it was

extracted with four 190-ml portions of chloroform. The combined

chloroform extracts were dried over anhydrous magnesium sulfate,

and removal of the chloroform in vacuo left a yellow liquid

which, upon vacuum distillation, gave a colorless liquid,

bp 36-38° (0.1 mm); [a]^° +68.^ ± 0.6° (c l.S'4-5, isooctane), 2 0 o [a]}} +78.7 ± 0.5 (c 2.25> ethanol). A thin-layer chromatogram

using Silica Gel H (Brinkmann Instruments) as adsorbent and

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 96 chloroform as the eluent showed only one spot when visualized

by the iodine stain method. An infrared spectrum (neat) was

identical to that of authentic material.

(-)-(S)-Methyl Phenyl Sulfoxide from (-)-Cholesteryl

(-)-Methanesulfinate. - The Grignard reagent was prepared from

bromobenzene (^.08 g, 0.02.6 mole) and oven-dried magnesium

turnings (0.63 g» 0.026 g-atom) in anhydrous ether. (-)-Cholesteryl

(-)-Methanesulf inate (11.2 g, 0.025 mole) of -99*8° ±

0.6° (c 2.385, chloroform) in anhydrous ether (130 ml) was

added with magnetic stirring at ice-bath temperature to the above

Grignard reagent. The solution turned cloudy during the addition;

the white reaction mixture was stirred at ice-bath temperature

for two hours and at room temperature for two hours. Saturated

aqueous ammonium chloride was added dropwise until no precipitate

formed; the ether layer was decanted and the white solid thorough

ly washed with two 100-ml portions of ether. The combined

ether layer was dried over anhydrous magnesium sulfate and

the ether removed in vacuo leaving a white solid. Acetonitrile

(50 ml) was added and the mixture stirred magnetically for 0.5

hour, then cooled in ice. The solid was collected by filtration

and washed with cold acetonitrile. Removal of the acetonitrile

in vacuo left a yellow liquid which was vacuum distilled to give

a light yellow liquid (1.85 g)» bp 66-67° (0.11 mm). Thin-

layer chromatography (tic) using Silica Gel H (Brinkmann

Instruments) as adsorbent and chloroform as the eluent showed

three spots. Water (^0 ml) was added and, after filtration,

the aqueous solution was saturated with sodium chloride and

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 97 extracted with four 60-rnl portions of chloroform. The combined

chloroform extracts were dried over anhydrous magnesium sulfate.

After the chloroform was removed in vacuo, the yellow residue

was vacuum distilled to give a colorless liquid, bp 64-65°

(0.11 mm). Thin-layer chromatography showed two poorly

se parated s pots.

As the impurity was thought to be unchanged sulfinate

ester, the sulfoxide was stirred with dilute sodium hydroxide

for five hours. After filtration, the aqueous solution was

saturated with sodium chloride, then extracted with four 60-ml

portions of chloroform. After drying the combined chloroform

extracts over anhydrous magnesium sulfate, the chloroform was

removed i_n vacuo and the residual liquid vacuum distilled to

give a colorless liquid, bp 70-71° (0.15 mm)j [ a ] ^ -119.5 -

0.8° (c, 1.4 5 5» ethanol); enantiomeric purity 80$. An infrared

spectrum was identical to that of authentic material, and thin-

layer chromatography showed one very intense spot and one barely

visible spot. The sulfoxide was redistilled to determine 21 whether the distillation had any adverse effect, [_a. -118.2 ±

0.4° (c 2.725. ethanol). Epimerizat ion Attempt with ( - ) -Menth.yl ( ±)-

Methanesulfinate. - Dry hydrogen chloride gas, generated from

anhydrous calcium chloride and concentrated sulfuric acid, was

passed into a solution containing a few crystals of

tetraethylammonium chloride and (-)-menthyl ( i)-methanesulfinate

([a]^'^ -118.9 ±0.7°) in anhydrous ether cooled in a Dry

Ice-acetone bath. As no crystals formed, the solution was

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allowed to warm to room temperature and the ether removed In

vacuo. The remaining liquid was vacuum distilled to give a

clear liquid, bp 66-67° (0.1 mm); -100.9 d 0»d3° (£ 2.3>

acetone).

Allyl Methyl Sulfide was prepared according to the

procedure of Price and Gillis®^ from the reaction of sodium

methyl sulfide with allyl bromide. The desired sulfide was

obtained as a colorless liquid ($6% yield), bp 92-94°, 1it.

bo 92.2-92.4°.

Allyl Methyl Sulfoxide was prepared according to the

procedure of O ’Conner and Lyness®? by the hydrogen peroxide

oxidation of allyl methyl sulfide. The desired sulfoxide was

obtained as a colorless liquid {73% yield), bp 62-63° (0.9 mm),

lit.®? bp 48-50° (0.25 mm), by fractionation through a 15-cm

Vigreux column. An infrared spectrum (neat) showed a strong

band at 1040 cm-\ characteristic of sulfoxides.

Allyl jo-Anisyl Sulfide. - The desired sulfide was 88 prepared according to the procedure of Hurd and Greengord

from the reaction of allyl bromide with sodium n-anisyl sulfide.

Allyl jo-anisyl sulfide was obtained as a light yellow liquid.

(90% yield), bp 77-78° (0.3 mm), after fractionation through

a 15-cm Vigreux column. Attempts to oxidize the sulfide to the

corresponding sulfoxide with sodium metaperiodate and 30%

hydrogen peroxide in glacial acetic acid proved unsuccessful.

This procedure was thus abandoned in favor of preparing the

known allyl phenyl sulfoxide.

Allyl Phenyl Sulfide was prepared according to the

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 99

Q Q procedure of Hurd and Greengard from the reaction of sodium

phenyl sulfide with allyl bromide. The desired sulfide was

obtained as a colorless liquid (S$% yield), bo 83-8^' (5.0 mm),

lit.88 bp 10'■‘--106° (25 mm).

Allyl Phenyl Sulfoxide was prepared according to the

procedure of Cope, Morrison, and Field8^ by the hydrogen peroxide

o rid at .i on of allyl phenyl sulfide. The desired sulfcxide was

obta.ined as a 1 ight yellow 1 iquid (7?.% yield), bp 86-87° (0.19

mm), lit bp 103-lQil-0 (0.36 mm), by fract.1 onat ion* through a

15-cm Vigreux column. An infrared spectrum (ne--t) of this

liquid showed a strong band •~'t 10^0 cm , characteristic of

sulfoxides.

H.yd r oxy lam ine - 0 sulfon :1 c Ac id . - A modification of 91 the orocedure of Sommer, Schulz, and iapsau7 was used.

Chlorosulfonic acid (300 ml) was added cautiously to hydroxylamine

sulfate (190 g, 1.1-5 mole) in a one-liter fla.sk equipped with a

drying tube and base trap for the escaping hydrogen chloride.

When the addition was completed, the flask was he--ted on a

steam b”th for ten hours at which time the mixture was a smooth

paste. After cooling to room temperature, the mixture was

cautiously added to ice-cooled anhydrous ether, then

tritu.roted thoroughly with ether. The product was collected by

filtration rapidly and washed several times with anhydrous

ether and anhydrous tetrahydrofuran. The resulting ’white powder

was stored in a vacuum desiccator. As the product was found

to be impure, it was purified by the procedure of Matsuguma

an d Aucl. r i e th . ^2

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 100

N - ( 3 - 2 r o oi o o r o py 1) p h t h a 11 m 1 rl. e was prepared according to 93 the procedure of lug and Manske7-' from the reaction of potar.slum

ohthal in 1/1 o with excess 1, 3~r1ibromopropnr.e . The desired compound

was obtained as a white solid (17;" yield), mp 72-73°» 1 i t

mp ?2°.

N-j 3- (Methylsulfi n.yl) pro pyll-phthal imide was pre pa red 7 according to the procedure of Karrer, Scheitlin, and Siegrist'

from the reaction of N-(3-bromopropyl)phthalimide and sodium

methyl sulfide. The desired compound was obtained as a white

solid (70$ yield), mp 56-57°, lit. ^ mp 56 »

3-(Methylthio)-propylamine was prepared according to the 7 procedure of Karrer, Scheitlin, and Siegrist from the reaction

of N-[3-(methyl 5-ulf inyl) oropylJ-phthal imide with hydrazine

hydrate. The desired sulfide was obtained as a clear liquid

(821 yield), bp 12 3-12/4° (15 mm, lit. 7 bp 1.69° (?60 mm).

3-(Methy1su1finy1)-propy1am1ne was prepared according

to the procedure of Karrer, Scheitlin, and Siegrist 7 from the

hydrogen peroxide oxidation of 3-(methylthio )-prop.ylamtne .

The desired sulfoxide was obtained as a light yellow liquid

(60$ yield), bp 113-11/4° (0.6 mm), lit. 7 bp 90-91° (0.0d mm),and

showed, a strong band at 1031 cm \ characteristic of sulfoxides.

Hydroboratlon of Methyl Allyl Sulfoxide. - 33 ml of a

1 M solution of diborane (0,033 mole) in tetrahydrofuran was

added with mechanical stirring and cooling (ice-bath) to methyl

allyl sulfoxide (10.1/4- g, 0.097 mole) in dry triglyme. When

the addition was completed, the cloudy reaction mixture was

stirred at ice-bath temperature for one hour and at room

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 101

temperature for two hours® Hydroxylamine-O-sulfonic acid

(10.9 St 0,097 mole) was added and the reaction mixture heated

at reflux (120°) with mechanical stirring for three hours.

After cooling to room temperature, 15% hydrochloric acid (50 ml)

was added to dissolve the red oil. The aqueous solution was

extracted with two 150-ml portions of ether, then made strongly

basic with sodium hydroxide. After extraction of the basic

solution with two 200-ml portions of ether and chloroform, the

combined extracts were dried over anhydrous magnesium sulfate®

The chloroform and ether were removed jLn vacuo and the residual

liquid vacuum distilled to give a colorless liquid, bp 52-53°

(0.15 mm), identified by infrared spectroscopy as triglyme.

Because the expected product is water-soluble, phenylisothio-

cyanate was added but no derivative was isolated. The aqueous

solution was concentrated and extracted continuously with ether

over a period of several days. This procedure also proved

unsuccessful. As the diborane solution was in tetrahydrofuran,

the use of mixed solvents may exert a detrimental effect on the

hydroboratlon reaction.

Methyl n-Propyl Sulfoxide via Hydroboratlon of Allyl

Methyl Sulfoxide. - 21 ml of 1 M solution (0.021 mole) of

diborane in tetrahydrofuran was added as rapidily as possible

with mechanical stirring and the temperature maintained at o , V 0 (ice-salt bath) to a solution of methyl allyl sulfoxide

(6.52 g, O.O625 mole) in dry triglyme (30 ml). When the

addition was completed, the reaction mixture was stirred at

ice-water temperature for one hour, then at room temperature

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 102

for one hour. Octanoic acid. (10.53 g» 0.073 mole) was added

and the temperature Increased to reflux and maintained there

for one hour while the tetrahydrofuran was distilled from the

reaction mixture. After cooling to room temperature, the

mixture was vacuum distilled to give a colorless liquid, bp 58-

59° (0«06 mm), shown via infrared spectroscopy to be triglyme.

If methyl n-propyl sulfoxide was formed by the protonation

reaction, it probably pyrolyzed to methanesulfinic acid and

1-propene under the reaction conditions.

As the use of mixed solvents (THF-triglyme) was thought

to have an adverse effect on the hydroboratlon reaction,

diglyme was used and the diborane generated externally.

Attempted protonation of the intermediate borane with propionic

acid proved unsuccessful.

Preparation of Bis-(3-Methyl-2-butyl)-borane. • *»

90 ml of a 1 M solution of sodium borohydrlde in dry diglyme

and 2-methyl-2-butene (16,8 g, 0.24 mole) were placed in a

250-ml three-necked flask equipped with an addition funnel and

mechanical stirrer. After immersing the flask in an ice-bath,

boron trifluoride etherate (17»0 g, 0.12 mole) was added

dropwise with mechanical stirring. When the addition was

completed, the reaction mixture was stirred at 0° for two

hours, then placed in an ice-salt bath.

Reaction of Allyl Phenyl Sulfoxide with Bis- (3-methyl-

2-butyl)-borane• - A solution of allyl phenyl sulfoxide (16.6 g,

0.1 mole) in dry diglyme (20 ml) was added as rapidily as

possible with mechanical stirring to the above borane while the

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temperature was maintained at 0-10°• When the addition was

completed, the reaction mixture was stirred at 0-10° for one

hour, then permitted to warm to room temperature.

Hydroxylamine-0-sulfonic acid (13*6 g, 0.12 mole) in dry

diglyme (75 ml) was added to the cloudy reaction mixture

followed by heating to 100® for three hours. After cooling

the solution, the diglyme was removed in vacuo. leaving a gummy

orange solid to which was added dilute hydrochloric acid

(170 ml). The aqueous solution was extracted with two 100-ml

portions of ether to remove any boronic acid, then made strongly

basic (j)H=10) with sodium hydroxide. Extraction of the basic

solution with three 100-ml portions of ether and removal of the

ether _in vacuo left a light yellow liquid shown by Infrared

to be diglyme. The original ether extracts were evaporated

in vacuo leaving an orange liquid which upon vacuum distillation

gave diglyme and a light yellow liquid, bp 109-110^ (0.3 ram).

The liquid solidified and the resulting white solid (2.0 g)

had mp 58.5-59*5° after two recrystallizations from 30-60°

petroleum ether. The solid gave a positive test for sulfur

(sodium fusion method), but a negative test for sulfoxides

(Dragendorff solution). An infrared spectrum (KBr) showed

medium bands at 11^7- and 1073 cm”1 and strong bands at

1023-(?), 737- and 687 cm”1 (1,^-substitution)« Nuclear magnetic

resonance (nmr) spectrum showed a complex multiplet at 2.37-

2.97 (aromatic protons). The structure of this compound is

currently being investigated.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 10b

Reaction of Allyl Phenyl Sulfide with Bis-(3-methyl-

2-buty1)-borane» - The bis- (3-methyl-2-butyl)-borane was

prepared as previously describede A solution of allyl phenyl

sulfide (30.0 g, 0.2 mole) in dry diglyme was added as rapidily

as possible to a solution of bis- (3-methyl-2-butyl)-borane in

dry diglyme (180 ml) while the temperature was maintained at

0-10°« When the addition was completed, the reaction mixture

was stirred at ice-bath temperature for one hour, then warmed

to room temperature. Hydroxylamine-O-sulfonic acid (22.6 g,

0.2 mole) in dry diglyme (100 ml) was added and the reaction

mixture heated to 100° for three hours with mechanical

stirring. After cooling to room temperature, the diglyme was

removed in vacuo, leaving a white semi-solid to which dilute

hydrochloric acid was added. The acidic solution was extracted

with two 200-ml portions of ether, then made strongly basic

(joH=10) with sodium hydroxide. After extraction of the basic

solution with two 250-ml portions of ether, the combined ether

extracts were dried over anhydrous magnesium sulfate. The ether

was removed .in vacuo leaving a liquid shown by infrared

spectroscopy to be diglyme. The ether from the acidic extraction

was removed in vacuo and the residual liquid vacuum distilled

to give a viscous, light yellow liquid at 56-57° (0.1 mm).

An attempt to derivatize the liquid with phenylisothiocyanate

proved unsuccessful. This liquid solidified to a semisolid

which could not be purified further by trituration,

recrystallization from various solvents, or redistillation.

The solid gave a positive test for sulfur (sodium fusion method).

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 105

As the expected product, C^H^S(GH^is a liquid, lit.^^

bp 125-126° (^.0 mm), this work was discontinued.

N-Potasslum-1.1.1.3.3. 3-hexameth,vldlsilazane. -

Dloxane was refluxed over anhydrous stannous chloride until a Q6 negative test for peroxides-7 was obtained. After the dioxane

had been distilled from the stannous chloride, it was stored

over potassium hydroxide pellets for Zk hours. The dioxane

was decanted from the potassium hydroxide and refluxed over

excess sodium for six hours at which time the sodium surface

remained bright. Distillation from sodium under anhydrous 97 conditions gave pure peroxide-free anhydrous dioxane. A

mixture of styrene (15«2 g, 0.1^6 mole) and 1,1,1»3»3*3-

hexamethyldisilazane (28.3 g, 0.175 mole) was added with

mechanical stirring to potassium metal^6.6 g, 0.1? g-atom)

in dry, refluxing dioxane (80 ml). When the addition was

completed, the reaction mixture was stirred under reflux

until all the potassium had dissolved, then allowed to cool to

room temperature.

Attempted Preparation of N-(6-Bromobutyl)-1.1.1.3.3.3-

hexamethvldlsllazane. - 1,^-Dlbromobutane (213 g» 0.99 mole)

in anhydrous dioxane (80 ml) was added dropwise with mechanical

stirring at room temperature to the previously prepared

N-potassium 1,1,1,3,3» 3**hexamethyldlsilazane. An exothermic

reaction occurred; and when the addition was completed, the

reaction mixture was refluxed for two hours. After cooling,

the salt was collected by filtration and washed with anhydrous

ether. The ether and dioxane were removed in vacuo and the

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 106

liquid residue vacuum distilled to give 1,4— dlbromobutane

(170 g), bp 35-37° (0.20 mm), a colorless liquid, bp 78-79°

(0.12 mm) and a light yellow liquid, bp 108-110° (0.20 mm)

which solidified at room temperature. The white solid melted

at 52-53°. lit.99 mp 52-53°. after recrystallization from

95% ethanol and was subsequently shown by infrared and nuclear

magnetic resonance spectra to be 1 , diphenylbutane. The

colorless liquid did not contain trlmethylsilyl groups as

evident from its nmr and ir spectra? and thus no attempt was

made to determine its structure.

Attempted Preparation of N-Cy-Chloropropyl)-

1.1.1.3.3.3-hexamethyldlsllazane. - Potassium

1.1.1.3.3.3-hexamethyldisilazane was prepared as previously

described. l-Bromo-3-chloropropane (2^6.2 g, 1.56 mole) was

added to potassium 1,1,1,3.3.3-hexamethyldisllazane (0.15 mole)

with mechanical stirring and cooling (ice-water bath). When

the addition was completed, the yellow reaction mixture was

heated to reflux for four hours. After cooling to room temperature,

the white precipitate was collected by filtration and washed

with anhydrous ether. The ether and dioxane were removed in

vacuo and the orange yellow residue was fractionally distilled

through a Vigreux column under reduced pressure to give l-bromo-3-

chloropropane as a colorless liquid, bp 3^-35° (12 mm). The

dark red residue which remained gave a clear liquid, bp 96-

97° (0.05 mm), upon vacuum distillation. The liquid solidified

at room temperature and was shown by infrared spectroscopy to

be 1,4-diphenylbutane. A light tan solid formed in the

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 107

l-bromo-3-chloropropane fraction upon standing, was collected

by filtration, washed thoroughly with anhydrous ether and dried

in a vacuum desiccator. The tan solid was water-insoluble and

did not melt up to 270°. An infrared spectrum (KBr) and an

ignition test showed this compound to be inorganic.

Attempted Preparation of N-(6-Bromobutyl)- <53 1.1.1. 3. 3. 3-hexame thyldisllazane. - Since Wanna gat and Kuckertz"^

reported that l,l,l,3t3»3-hexamethyldisilazane reacts with

ethyl magnesium bromide to form the corresponding Grignard

reagent, the following procedure was attempted. A solution of

ethyl bromide (13®0 g, 0.12 mole) in anhydrous ether (50 ml)

was added dropwise with mechanical stirring to oven-dried

magnesium turnings (2.92 g, 0.12 g-atom) in anhydrous ether

(50 ml). When the addition was completed, the dark reaction

mixture was stirred at room temperature for two hours.

The previously prepared Grignard was added with

mechanical stirring at ice bath temperature to

l,l,l,3»3»3-hexamethyldisilazane (16.1 g, 0.1 mole) in anhydrous

ether (50 ml). When the addition was completed, the dark

reaction mixture was allowed to stir at ice-water bath

temperature for two hours, then at room temperature for one

hour. This solution was added dropwise at ice bath temperature

to 1,4-dlbromobutane (12^.3 g> 0.58 mole) in anhydrous ether

(100 ml). After the addition, the reaction mixture was stirred

at ice-bath temperature for one hour then at room temperature

for four hours. Aqueous saturated ammonium chloride solution

was added until no precipitate formed upon the addition of a

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 108

drop of ammonium chloride solutions The precipitate was

collected and washed thoroughly with anhydrous ether. The

ether was removed in vacuo and the remaining yellow liquid

vacuum distilled to give a colorless liquid (119 g)» bp 36-38°

(0.^ mm), which was shown by Infrared spectroscopy to be

1,^-dlbromobutane»

N-Butyl-hexamethyldlsllazane was prepared according

to the procedure of Ruhlmann^ from the reaction of potassium

l,l,l,3,3»3-hexamethyldisllazane with 1-bromobutane. The

desired compound was obtained as a colorless liquid (38$

yield), bp 76-77° (8 mm), lit.51 bp ^0° (0.6 mm), after

fractionation through a 15-cm Vigreux column. Gas liquid

partition chromatography (glpc) showed only one peak for this

liquid. An Infrared spectrum (neat) showed strong bands at

1250- and 835-cm"”1 , characteristic of a trimethylsilyl group.

^-Chloro-lbutanol was prepared according to the

procedure of Servigne, Szarvasi, and Neuvy1^^from the reaction

of tetrahydrofuran and dry hydrogen chloride gas in the presence

of a trace of ZnClg, The desired product was obtained as a T AT colorless liquid (^8$ yield), bp 83»5-8iK5 ° (15 mm), lit.

bp 81-82° (1^ mm), after fractionation through a 15-cm Vigreux

column.

^-Chlorobutoxytrlmethylsllane was prepared according

to the procedure of Speier55 from the reaction of

1,1,1,3,3» 3-hexamethyldlsilazane (Aldrich Chemical) with

4— chloro-l-butanol. The desired compound was obtained as a

colorless liquid (82$ yield) bp 72-73° (1^ mm), lit.55 bp 81°

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 109

(2^- mm), after fractionation through a 15-cm Vigreux column.

(Methylsulfinyl)-1-butanol. - A small amount of

ethylene dlbromide was added to oven-dried magnesium turnings

(2.38 g» 0.008 g-atom) in anhydrous ether (90 ml) to initiate

reaction. When the reaction was completed, ^-chlorobutoxy-

trimethylsilane (16.8 g, 0.093 mole) was added rapidly to the

cloudy reaction mixture with magnetic stirring. When the

addition was completed, the clear reaction mixture was stirred

at room temperature for four hours, then at reflux for one

hour. After cooling to room temperature, the mixture was stirred

at room temperature for an additional three hours.

Methyl methanesulfinate (8.75 g? 0.093 mole) in

anhydrous ether (15 ml) was added at such a rate that vigorous

refluxing occurred. When the addition was completed, the

cloudy reaction mixture was stirred at room temperature for two

hours. Hydrolysis was accomplished by the dropwise addition

of aqueous saturated ammonium chloride until no precipitate

formed upon the addition of a drop of ammonium chloride

solution. The solid was collected by filtration and washed

thoroughly with ether. After drying the ether over anhydrous

magnesium sulfate, the ether was removed JLn vacuo and the

residual yellow liquid vacuum distilled to give a colorless

liquid, bp 51-52° (0.05 mm). Because of the small yield,

several trials were run and the products combined and distilled

to give a colorless liquid, bp ^>6-^7° (0.05 mm). An infrared

spectrum (neat) showed a strong band at 1060 cm” (SO strech)

and no trlmethylsilyl bands. Each time the reaction was

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 110

repeated, very small yields of product x

2-chloroethanol (Eastman Organic) and the 2,3-dihydro-4— pyran

(Eastman Organic) were redistilled through a 15-cm Vigreux

column before being used. 2-Chloroethanol (16.10 g, 0.20 mole)

was added dropwise with magnetic stirring at room temperature

to 2,3-dihydro-^-p.yran (17*36 g, 0.206 mole) and three drops

of concentrated hydrochloric acid. When the addition was completed,

the light yellow reaction mixture was stirred at room temperature

for four hours. Ether (250 ml) was added and the ether layer

washed with 100-ml portions of water until the washings were

neutral. After drying the ether layer over anhydrous sodium 103 sulfate , the ether was removed in vacuo leaving a light yellow

liquid which upon fractional distillation through a 15-cm

Vigreux column gave the desired compound as a colorless liquid

(69% yield), bp 81-82° (7 mm). Gas liquid partition chromatography

(glpc) on a Silicone SE-30 column showed one major component

to be present. The halide failed to react with magnesium in

anhydrous ether. 102 3-Chloropropoxy-2-tetrahydropyran. - The

3-chloro-l-propanol (Aldrich Chemical) and 2,3-dihydro-^-pyran

were redistilled through a 15-cm Vigreux column before use.

3-Chloro-l-propanol (62,^ g, 0.65 mole) was added at room

temperature with magnetic stirring to 2,3-dlhydro-i»—pyran

(56.1 g, 0,67 mole) and three drops of concentrated hydrochloric

acid. When the addition was completed, the reaction mixture was

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Ill

stirred at room temperature for five hours. Ether (300 ml)

was added and the ether layer washed with 100-ml portions of

water until the washings were neutral. After drying the

ether layer over anhydrous sodium sulfate, the ether was removed

in vaouo and fractional distillation of the residue through a

15-cm Vigreux column gave the desired compound as a colorless

liquid, (95.^ &> 82# yield), bp 9^-95° (6 mm), lit.10*1' bp 103°

(1^ mm). Gas liquid partition chromatography on a Silicone

Se-30 column showed one major component to be present, 102 6-Chlorohexoxy-2-tetrahydropyran» - The

6-chloro-l-hexanol (Aldrich Chemical) and 2,3-dihydro-if-pyran

were redistilled through a 15-cm Vigreux column before being

used, 6-Chloro-l-hexanol (^5»1 S* 0-33 mole) was added dropwlse

at room temperature with magnetic stirring to 2,3-d.ihydro-^-pyran

(30.1 g, 0,36 mole) and three drops of concentrated

hydrochloric acid. When the addition was completed, the reaction

mixture was stirred at room temperature for ten hours. Ether

(300 ml) was added and the ether layer washed with water until

the washings were neutral. After drying the ether layer over

anhydrous sodium sulfate, the ether was removed in vaouo and

the residual liquid fractionally distilled through a 15-cm

Vigreux column to give the desired product as a colorless liquid

(6l«7 g, 8^# yield), bp 97-98° (0,62 mm). However, gas liquid

partition chromatography (glpc) on a Silicone SE-30 column

showed the presence of three major components. As one of the

contaminants was identified as 6-chloro-l-hexanol, the

tetrahydropyranyl ether was dissolved in ether (200 ml).

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 112

The ethereal solution was washed with two 100-ral portions of

aqueous 15$ potassium hydroxide and one 100-ml portion of water.

After drying the ethereal solution over anhydrous sodium

sulfate, the ether was removed .in vaouo and the resulting

6-chlorohexyloxy-2-tetrahydropyran redistilled. The halide

now reacted with magnesium in tetrahydrofuran to give the C-O corresponding Grignard reagent.

3-Bromopropoxy-2-tetrahydropyran. - 3-Bromo-l-propanol

(76.^ g, 0.55 mole) was added dropwise at room temperature with

magnetic stirring to 2,3-dlhydro-;4— pyran (^-8.1 g, 0.57 mole)

and three drops of concentrated hydrochloric acid. When the

addition was completed, the yellow reaction mixture was stirred

at room temperature for ten hours. Ether (250 ml) was added

and the ethereal solution washed with 100 ml portions of

water until the washings were neutral. After drying the ether

layer over anhydrous sodium sulfate, the ether was removed in

vacuo and the residual liquid fractionally distilled through a

15-cm Vigreux column to give a colorless liquid (97*6 g, 80$

yield), bp 67-68° (0.8 mm). This halide failed to react with

magnesium in anhydrous ether. However, gas liquid partition

chromatography (glpc) on a Silicone SE-30 column showed the

presence of three major components. 59 3-Bromo-l~(1.1-dlmethylpropoxy)-propane. -

3-Bromo-l-propanol (9^.2 g, 0.68 mole) was mixed with 2-methyl-2-

butene (119.2 g, 1.7 mole) and the heterogeneous mixture

mechanically stirred at reflux using a water bath maintained

at ^0-^5°• Concentrated sulfuric acid (0.8 ml) was added and

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. U 3

the stirring and heating continued for five hours with

occasional addition of sulfuric acid (4 ml total) to maintain

the two phases. The orange-red bottom layer was separated and

discarded while the upper layer was dissolved in ether (150 ml).

The ethereal solution was washed with 100-ml portions of water,

aqueous 25% potassium hydroxide, aqueous sodium bicarbonate,

and water. After drying the ethereal solution over anhydrous

potassium carbonate, the ether and excess 2-methyl-2-butene were

removed in vacuo and the residual light yellow liquid fractionally

distilled through a 15-cm Vigreux column to give a small

fore-run up to 65° (6 mm). The desired product was obtained

as a colorless liquid, bp 65-71° (6 mm), 112.6 g (79% yield).

This fraction was redistilled and the fraction boiling at 66-69°

(5 mm), lit.*^ bp 70-74° (10 mm), collected. Gas liquid

partition chromatography (glpc) on a Silicone SE-30 column

showed this liquid to be essentially pure 3-bromo-l-(1,1-dimethyl-

propoxy)-propane. An Infrared spectrum (neat) showed a strong

band at 1090 cm“\ characteristic of aliphatic ethers.

3-Methvlsulflnvl-1- (1,l-dlmethvlpropoxv) -propane. -

A solution of 3-'bi,omo-l-(l,1-dimethylpropoxy)-propane

(4l,8 g, 0.2 mole) in anhydrous ether (125 ml) was added dropwise

with mechanical stirring at room temperature to oven-dried

magnesium turnings (4.86 g, 0.2 g-atom) in anhydrous ether

(30 ml). Gentle refluxing occurred; and when the addition was

completed, the dark reaction mixture was stirred at room

temperature for four hours. A solution of methyl methanesulfinate

(18.82 g, 0.2 mole) in anhydrous ether (25 ml) was added dropwise

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 114

with mechanical stirring at room temperature to the Grignard

reagent* Vigorous refluxlng occurred; and when the addition

was completed, the gray reaction mixture was stirred for 0*5

hour* Because a pasty material formed, the stirring was

discontinued and the reaction mixture left at room temperature

for two hours* Ether (100 ml) was added; and after the layers

were separated, the aqueous layer was saturated with sodium

chloride and extracted with three 150-ml portions of chloroform.

The chloroform extracts and the original ether layer were combined

and dried over anhydrous potassium carbonate. Removal of the

chloroform and ether in vaouo left a light yellow liquid which

upon vacuum distillation gave a colorless liquid (13*4 g»

35^ yield), bp 85-91° (0*15 nun). Because of the range in the

boiling point, this fraction was redistilled to give a colorless

fraction, bp 77-81° (0.11 mm), and a second colorless fraction

bp 81-83° (0.12 mm), n2^D 1.4650. Infrared spectra of both

were Identical and showed strong bands at 1089- and 1038-cm""^,

characteristic of aliphatic ethers and sulfoxides, respectively.

A thin-layer chromatogram using Silica Gel H (Brinkmann

Instruments) as adsorbent and chloroform as the eluent showed

one intense spot and one light spot for the sulfoxide when

visualized by the iodine stain method* Nuclear magnetic

resonance values (neat) are inr-unitss triplet, 6.60, J=6

cps (Q-CHg)j multlplet» 7-14-7-40 (-CH^-SO-); singlet, 7»52

(CH3-S0-); multlplet, 7-90-8*70 (-CHg-Cf^) (-CHg-CH^CH^);

singlet, 8*92 (CH^-C-GH^); triplet, 9*17» J=7 cps (-CHg-CH^),

The nmr assignments were made by comparison with the spectrum

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 115

of 3-bromo-l-(l ii 1-dimethylpropoxy)-propane® The compound gave

a positive test for sulfoxides with Dragendorff solution

(orange spot).^^^

Attempted Cleavage of 3-Methylsulflnyl-1-(1,1-dlmeth.vl-

propoxy)-propane with Sulfuric Acid. The sulfoxide (6.12 g,

0.03 mole) and 20$ sulfuric acid (63*5 St 0.13 mole) were stirred

at room temperature for Zk hours. As the mixture was still

heterogeneous, it was neutralized with sodium hydroxide, then

saturated with sodium chloride. The aqueous layer was extracted

with three 100-ml portions of chloroform. After drying the

combined chloroform extracts over anhydrous magnesium sulfate,

the chloroform was removed in vacuo and the residual liquid

vacuum distilled to give a colorless liquid (1.9 g)» bp 7^-76°

(0.1 mm), whose infrared spectrum (neat) was identical to that

of the starting sulfoxide.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 116

BIBLIOGRAPHY

1* A. Kjaer in N. Kharasch, "Organic Sulfur Compounds",

Pergamon Press, New York, N. Y., 1961, ch. 3',+ » P* ^09

and references cited therein.

2. J. Gadamer, Arch. Pharm., 23 5. kk (lp>97)»

3 . M, G. Ettlinger and A. J. Lundeen, J. Amer. Chem. Soc.,

28, 4172 (19 56).

M. G. Ettlinger and A. J. Lundeen, ibid., 79. 176^ (1957)*

5» H. Schmid and P. Karrer, Helv. Chim. Acta, j^l, 1017 (19^8).

6 . H. Schmid and P. Karrer, ibid., 31, 1^97 (19^8).

7. P. Karrer, E. Scheitlin, and H. Siegrist, ibid., 33, 1237

(I.950) .

8 . P. Karrer, N. J. Antia, and R. Schwyzer, ibid., 21* 1392

(195D.

9. B. W. Christensen and A. Kjaer, Acta Chem. Scand., 17. 8^-6

(1963), and references cited therein.

10. R. Hine and D. Rogers, Chem. Ind. (London), lkZ8 (19 56).

11. A. Kjaer and R. Gmelin, Acta Chem. Scand., 10, 1100 (1956).

12. W. Klyne, J. Day, and A. Kjaer, ibid., I k , 215 (i960).

13. K. K. Andersen, Tetrahedron Letters, 93 (1962),

1^. H. F. Herbrandson and C. M. Cusano, J. Amer. Chem. Soc.,

82, 2.12k (1961).

15* R» S. Cahn and C. K. Ingold, J. Chem. Soc., 612 (1951);

R, S. Cahn, C. K. Ingold, and V. Prelog, Experientia, 12,

81 (1956).

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 117

16. E. B. Fleischer, M. Axelrod, M. M . Green, and K. Mislow,

J. Amer. Chem. Soc., 86, 3395 (1964).

17. K. Mislow, M. M. Green, P. Laur, J. T. Melillo, T. Simmons,

and A. L. Terna.y, Jr., Ibid. , 87, 1958 (1965)*

18. H. Phillips, J. Chem. Soc., 122, 2552 (1927).

19. C, R. Johnson and D. McCants, Jr., J. Amer. Chem. Soc.,

82, 5404 (1965).

20. K. Mislow, A. L. Ternay, and J. T. Melillo, ibid., 85,

2330 (1963).

21. K. K. Andersen, J. Org. Chem., 2_2, 1953 (1964).

22. K. Mislow, M. M, Green, P. Laur, and D. R. Chisholm,

J. Amer. Chem. Soc., 82, 665 (1965)."

23. A. Kjaer, G, A. Sim, and K. K. Cheung, Chem. Commun.,

100 (1965).

24s K, K. Andersen, W. Gaffield, N. E . Papanikolaou, J. W.

Fole.y, and R» I. Perkins, J. Amer. Chem. Soc., 86. 5637

(1964).

25. A. C. Cope and E. A. Caress, ibid.. 88. 1711 (1966), report 25 a value of [a]D +203.2° for (+)-ethyl jotolyl sulfoxide.

26. P. Crabbe, "Optical Rotatory Dispersion and Circular

Dichroism in Organic Chemistry," Holden-Day, Inc.,

San Francisco, Calif., 1965, PP 13-14.

27» D. L. Dull and H. S. Mosher, J. Amer. Chem. Soc., 8 9 .

4230 (1967).

28. M, M. Green, M. Axelrod, and K. Mislow, ibid., 8 8 . 861 (1966).

29. J • Jacobus and K. Mislow, ibid., 8 9 . 5228 (1967)•

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 118

30. L. M. Jackman, A. K. Macbeth, and J. A. Mills, J. Chem.

Soc., 2644 (1949).

31. We have found sublimation under reduced pressure to be & preferable to the steam distillation method described by 30 Jackman and coworkers.

32. K. Alder and E. Wlndemuth, Ann., 543. 49 (1939).

33. Calculated from the rotation of optically pure methyl 29 phenyl sulfoxide, for which Jacobus and Mislow report

+149° (ethanol).

34. Jacobus and Mislow^ reported that petroleum ether (30-60°)

will quantitatively remove traces of menthol and other

side products from the aqueous phase when the sulfoxide

is water soluble. We have extended this procedure to

remove traces of borneol and isoborneol from the aqueous

phase.

35« Mislow and coworkers^ report a value of [a]D +*2°

(Isooctane) for n-butyl methyl sulfoxide which corresponded

to an optical purity of 47$. Using this value, (+)-l6

would have an enantiomeric purity of 76.5$.

36. The (-)-borneol was obtained from K & K Laboratories

l 4 2 -5 -21.1 ± 0.2° (o 9*999 ethanol). W. Huckel, Ann.,

549. 176 (1941) reports a value of -36.22° (c, 8.068,

ethanol) for the pure compound.

37. C. C. Price and S. Oae, '’Sulfur Bonding,” The Ronald Press

Co., New York, N. Y., 1962, Chapter 4 j H, H. Jaffe and

M. Orchln, "Theory and Applications of Ultraviolet

Spectroscopy," John Wiley and Sons, Inc., New York, N. Y.,

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 119

1962, pp 491-496.

38. H. P. Koch, J. Chem. Soc., 2892 (1950)1 P® Karrer, N. J.

Antia, and B. Schwyzer, Helv. Chim. Acta, 34, 1392 (1951)®

39® G. Leandrl, A. Mangini# and E. Passerlni, J. Chem. Soc.,

1386 (1957)®

40. M. Kasha, Discussions Faraday Soc., No. 9, 14 (1950)}

H. McConnell, J. Chem. Phys., 20, 700 (1952)5 G. J. Brealey

and M. Kasha, J. Amer. Chem. Soc., 77. 4462 (1955)®

4-1. H. C. Brown, "Hydroboratlon," W, A. Benjamin, Inc., New York,

N. Y., 19625 G. Zwelfel and H. C. Brown In “Organic

Reactions," 13. R. Adams, Ed., John Wiley & Sons, Inc.,

New York, N. Y., 1963, Chapter 1.

4-2, H. C. Brown and B. C. Subba Rao, J. Amer. Chem. Soc., 82.

681 (I960).

43® G. F. McAchran and S. G. Shore, Inorg. Chem., 4, 125 (1965).

4-4-. H. C. Brown, W. R. Heydkamp, E. Breuer, and W.S. Murphy,

J. Amer. Chem. Soc., 86, 3565 (1964)5 M, W. Rathke, N. Inoue,

K. R. Varma, and H. C. Brown, ibid., 88. 2870 (1966).

4-5® C. Walling and L. Bollyky, J . Org. Chem., _2£, 2699 (1964)1

I. D. Entwlstle and R. A. W. Johnstone, Chem. Commun.,

29 (1965)®

4-6 o H. C. Brown and K. Murray, J. Amer. Chem. Soc., 81, 4108

(1959).

4-7. H. C, Brown and G. Zweifel, ibid., 8jl, 486 (1961).

4-8. H. C. Brown and 0. J . Cope, ibid., 86. 1801 (1964),

49. C. Eaborn, "Organosllicon Compounds," Butterworths Scientific

Publications, London, i960, Chapter 11s L. Birkofer and A.

Ritter, Angew. Chem. Int. Ed. E n g . , 4, 417 (1 965)•

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 120

50. R, 0. Sauer and R. H. Hasek, J. Amer. Chem. Soc., 68.

241 (1946).

51. K. Ruhlmann, Chem. Ber., 94. 2311 (1961).

52. W. Broser and W. Harrer, Angew. Chem. Int. Ed, Eng., 4,

1081 (1965).

53= U. Wannagat and H, Kuckertz, Angew, Chem., 95 (1963).

54. J. F, W. McOmle in "Advances in Organic Chemistry/'

Interscience Publishers, New York, N. Y,, 1963, P® 218.

55. J. L. Speier, J. Amer. Chem. Soc., 74 ^1044 (1952).

56. G. F. Woods, and D. N. K ra m e r, J. Amer. Chem. Soc., 6 %,

2246 (194?)} S. P. Barton, D. Burn, G. Cooley, B. Ellis,

and V. Petrow, J. Chem. Soc., 1957 (1959)? D* N.

Robertson, J. Org. Chem., 2 5. 931 (I960).

57. P. Mazerolles, Bull. Soc. Chim. France, 464 (1965)? Chem.

Abstr., 62, 13308h (1965).

58. Unpublished results of M. Cinquinl, Univ. of New Hampshire,

1967®

59. W, B. Renfrow, D. Oakes, C, Lauer, and T. A Walter, J . Org.

Chem., 26. 935 (1961).

60. F. Whitmore and F, H. Hamilton, Org. Syn., Coll. Vol. I,

492 (1941).

61. F. Kurzer, Org. Syn,, 34. 93 (1954).

62. H. Herbrandson and R. T, Dickerson, Jr., J. Amer. Chem.

Soc., 81, 4103 (1959)? H. Herbrandson, R. T. Dickerson,

Jr., and J, Weinstein, Jr., ibid.. 78. 2576 (1956).

63. R. A. Strecker, Ph.D. Thesis, The University of New

Hampshire, 1966.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 121

6^0 P. S. Skell and M. F. Epstein, Abstracts, l^th. National

Meeting of the American Chemical Society, Philadelphia,

Pa., April 1964, p 26N.

65. C. C. Price and J. J. Hydock, J. Amer. Chem. Soc., 7*K

19^3 (1952).

66. A. Cerniani and G, Modena, Gazz. Chim. Ital., 89. 8^3

(1959)? Chem. Abstr., (I960).

67. F. G. Bordwell and P. J. Boutan, J. Amer. Chem. Soc.,

22, 717 (1957).

68. L. Bateman, J. I. Cunneen, and J. Ford, J. Chem. Soc.,

3056 (1956).

69. The J;-butyl hypochlorite was prepared according to the

procedure of H. M. Teeter and E. W. Bell, Org. Syn.,

32. 20 (1952) by the chlorination of _t-butyl alcohol in

basic solution.

70. I® B. Douglass, J. Org® Chem., 30. 63^ (1965).

71. I® B. Douglass and B. S. Farah, Org. Syn., ^0, 62 (i960)•

72. F. Arndt and A. Scholz, Ann., 510. 70 (193^)* For

ultraviolet data on this compound see H. Bredereck, G. Brod,

and G® Haschele, Chem. Ber., 88. V38 (1955).

73. D® S. Noyce and D® B. Denney, J. Amer. Chem. Soc., 72.

57^3 (1950).

7^® The yield of crude ester exceeds 100$ because excess

methanesulfInyl chloride was used to ensure complete

conversion to the ester.

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 122

75. H. C. Brown and H. R. Deck, Ibid.. 8£, 5620 (1965)1

H 9 C» Brown and C. J. Shoaf, Ibid., 86. 1079 (196*0.

76. A. I. Vogel, "A Textbook of Practical Organic Chemistry,"

3rd ed, Longmans, Green and Co., London, 1961, p 169.

77« Be Gastamblde, Ann. Chim. (Paris),

Abstr., 42, 9568h (1955).

78. Merck Index, 7th ed, Merck & C o . , Inc., Rahway, N. J.,

I960, p 162.

79* G. Lockermann and H. Rein, Chem. Ber., J30, 485 0-9*0?

Chem. Abstr., 4^, 1345b (1949). They found that

o-nitrobenzoyl chloride could be purified by vacuum

distillation in the presence of excess phosphorus

pentachloride without any danger of explosion.

80. The nmr spectrum of isoborneol shows a multlplet at

6 .17-6.50Y while that of borneol shows a multiplet at

5.89-6.20T.

81® Some of the product was lost because of Incomplete

condensation of the steam. The yield should be almost

quantitative.

82. The seed crystals were obtained from a pervious experiment.

83. As the rotation of the enantiomerlcally pure sulfoxide

was only reported in ethanol, the rotation in ethanol was

calculated from the rotation in acetone.

84. Calculated from the rotation of optically pure methyl

jo-tolyl sulfoxide, for which K. Mislow, M. Axelrod, D. R.

Rayner, G. Gotthardt, L. M. Coyne, and G. S. Hammond, J. Amer.

Chem. Soc., 82, 4958 (1965), report l_a]^ + 156° (ethanol).

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 123

85* C. D. Ritchie and A. L. Pratt, ibid,, 86. 1571 (1964).

86. C. C. Price and R. G. Glllls, ibid.. 23* 4750 (1953).

87. D. E. 0*Conner and W. I. Lyness, ibid.. 86, 3844 (1964).

88. C. D. Hurd and H. Greengard, ibid., 52. 3356 (1930).

89. A. C. Cope, D. E. Morrison, and L. Field, ibid., 72.

59 (1950).

90. A. Nickon and A. S. Hill, ibid., 86, 1157 (196*0.

91. F. Sommer, 0. F. Schulz, and M. Nassau, Z, Anorg. Allg.

Chem., 142, 142 (1925).

92. H, J. Matsuguma and L. Audrieth, Inorg. Syn., £, 122 (1957).

93® H. R. Ing and R. H, F. Manske, J. Chem. Soc., 2348 (1926).

94. Because of the difficulty encountered in making up a 1 M

solution, the reaction was run using a slurry of sodium

borohydride in diglyme.

95* H« L. Wehrmeister, J. Org. Chem., ,28, 2589 (1963)®

96. See reference 76 , p 163®

97® See reference 7 6 , p 177*

98, The potassium metal was cut under anhydrous xylene in a

nitrogen atmosphere.

99® F. Flchter and H. Stenzl, Helv. Chlm. Acta, 22. 970

(1939)5 Chem. Abstr., 21* 85084 (1939). 100. M. Servigne, E. Szarvasi, and L. Neuvy, Compt. Rend.,

241. 963 (1955)5 Chem. Abstr., £0, 10639& (1956).

101. D, Starr and R. M. Hixon, Org. Syn., 17. 84 (1937).

102. Similar procedure to that used by F, Bohlmann and U.

Niedballa, Chem. Ber., 100. 1936 (I967 ).

103. D. M. Robertson, J. Org. Chem., 25. 931 (i960) states

that magnesium sulfate was sufficiently acidic to reverse

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. the addition in only a few hours.

104. W. E. Parham and E. L. Anderson, J. Amer. Chem. Soc

20, 4188 (1948).

105* L. Suchomelova, V. Horak, and J. Zyka, Microchem. J

196 (1965)j Chem. Abstr., 6^, 9062b (1965).

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SUMMARY

I. The reaction of N-jD-toluenesulfonyltrichloro-

phosphinimine with dimethyl sulfoxide in pyridine gave the

corresponding sulfilimine. This is the first example of the

reaction of a phosphinlmine with a sulfoxide. The use of pyridine

as a solvent has a beneficial effect on this reaction.

N-jo-Toluenesulfonylisothlocyanate also reacted with dimethyl

sulfoxide to give the corresponding sulfllimine but in lower

yield than the N-sulfonylisocyanate case, A new preparation for

N-jo-toluenesulfonylisothiocyanate from the chlorination of

potassium N-j>-toluenesulfonyliminodithlocarbonate was developed

during the course of this work.

II, A series of optically active methanesulfinate

esters were investigated and (-)-isoborneol (± )-methanesulfinate

and (-)-cholesteryl (-)-methane sulf inate were found to give the

corresponding sulfoxides of highest enantiomeric purity

(65 and 8 0 respectively). As the by-products from the

(-)-isobornyl (±)-methanesulfinate are easily removed* this

constitutes the preferable route to sulfoxide isothiocyanates.

Several possible routes to the sulfoxide Isothiocyanates were

attempted* a) Hydroboration of methyl allyl sulfoxide followed

by amination with hydroxylamine-O-sulfonlc acid, b) Coupling

reaction between potassium 1*1,1,3»3»3-hexamethyldlsilazane and

polymethylene dihalides, c) The use of trimethylsilyl groups

as protecting groups for chlorohydrlns which were then reacted

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 2 6

with magnesium in ether, d) The use of tetrahydropyranyl groups

as protecting groups for chlorohydrins which were then reacted

with magnesium in THP. e) The use of jfc-amyl groups as

protecting groups for bromohydrins which were then reacted with

magnesium in ether. Of all the routes explored, d and e seem

to show the greatest promise and are currently being

investigated.

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