Chiral Sulfoxides: A Whirlwind Tour Literature Presentation Scott Jarvis April 27 th, 2010

Chiral Sulfoxides: Chiral Sulfoxides: A Whirlwind TourA Whirlwind Tour

Literature Presentation

Scott Jarvis

April 27th, 2010

Characteristics of SulfoxidesCharacteristics of Sulfoxides Sulfoxides have high optical stability, in general the

racemization of sulfoxides only occurs at an appreciable rate at 200oC except Benzyl and allyl sulfoxides whose racemization occurs at lower temperatures, 130-150oC and 50-70oC respectively.

Sulfoxides are accessible in both enantiomeric forms

The large stereoelectronic differences between the three types of substituents (oxygen, electron lone pair, and two alkyl or aryl groups) at the sulfinyl sulfur allow the creation of a well defined chiral environment around the sulfur atom, therefore they are efficient as carriers of chiral information

S

O

Methods to Prepare Chiral Methods to Prepare Chiral SulfoxidesSulfoxides

Oxidative methods ◦ Diastereoselective ◦ Modified sharpless oxidation◦ Salen oxidation◦ Chiral oxaziridines ◦ Chiral epoxides

Nucleophilic substitution methods◦ Andersen Methodology (menthol)◦ Aminosulfites (ephedrine, aminoindane)◦ Sulfites (lactate derivative, sugars)◦ Evans auxillary ◦ Oppolzer’s Sulfinylsultam

Combination◦ Thiosulfinate approach(tert-Butyl-SO-R)

Diastereoselective OxidationDiastereoselective OxidationThe oxidation of sulfur can be directed by a coordinating

atom such as N or O or straight steric bulk

NMe2

S

NMe2

S

O

NaBO3

AcOH78% de

N

S

HN

O

O

O

H

OOH

N

S

HN

O

O

O

H

OOH

OH2O2

DCM90%, 100% de

N

SBr

O

H

OOH

F

N

SBr

O

H

OOH

F O

Quant., 100% deDMD

DCMSynthesis, 1992, 555Tet. Lett., 1993, 7877

Diastereoselective OxidationDiastereoselective Oxidation

Chem. Comm., 1998. 2763

OO

OO

R

R

OR

R

S R'

OO

OO

R

R

OR

R

SR'

:

O

up to 100% de

chirality independant of reagent(NaIO4, MCPBA, Oxone all give same compound)

Chirality of sulfoxide comes fromthe anomeric effect

:

:

Modified Sharpless Oxidation Modified Sharpless Oxidation Mostly relies on steric bulk to gain the selectivity

R1 R2 Yield (%) ee (%) ( R )

Phenyl Me 81 91.2p-Tolyl Me 77 95.6p-anisyl Me 73 92.1o-anisyl Me 72 89.3o-nitrophenyl Me 51 75.0Phenyl CH=CH2 58 55.4p-Tolyl Et 68 78.1p-Tolyl n-butyl 70 25.0o-anisyl phenyl 64 6.2benzyl Me 72 90.3n-octyl Me 69 70.7

Bull. Soc. Chim. Fr., 1996, 1109Synlett, 1996, 404 (Kagan)

O

Ti

O

OO

OO

R

O

[Ti]

H

O O

SRL

RS

:

Modified Sharpless OxidationModified Sharpless OxidationOther diols have been used in place of DET

OH

OHOH

OH

OH

OH

OH

OH OH

OH

Uemura’s Binol VersionUemura’s Binol VersionAr Solvent Method Yield (%) ee (%)

( R )

p-tolyl CCl4 A 65 84

p-tolyl CCl4 B 67 93

p-tolyl CCl4 B a 64 88

p-tolyl CCl4 C 44 96

p-tolyl CHCl3 A 74 23p-tolyl DCM A 84 16p-tolyl DCE A 86 25p-tolyl Toluene A 66 72p-tolyl o-xylene A 88 61p-tolyl cumene A 86 57p-tolyl THF A 46 72p-tolyl Diethyl ether A 32 57

Ph CCl4 A 80 65Ph Toluene A 86 63

2-Napthyl CCl4 A 73 51p-BrC6H4 CCl4 A 62 68

n-octyl CCl4 B 64 69

Method A: under Ar peroxide in tolueneMethod B: under Air, peroxide in waterMethod C: Half as much catalyst

Note a: under Argon

ArS

Me ArS

Me

O

JOC, 1993, 4529

Modified Sharpless OxidationModified Sharpless OxidationH-Bonding under specific conditions can also give good

selectivity (but very sensitive).

Tet. Asymm., 2000, 3819

N

NH

S

N

O O N

NH

S

N

O OOTi(OiPr)4/(S,S)-DET/H2O

iPr2NEtCumene Peroxide

92% yield (94% ee)

NH is directing

Salen OxidationSalen OxidationTypically thought of for chiral epoxidation of olefins but with

modifications they are useful for sulfide oxidations.

JACS, 2007, 8940.

N N

Ph PhO O

Fe

RRCl

SCat S

OCat (2 mol%)aq H2O2 (1.5)

H2O, 3h, 20oC

SOO

Catalyst Yield (sulfoxide)

Yield (sulfone)

ee of sulfoxide

(%)R1 R2

Yield (sulfoxide)

Yield (Sulfone)

ee of sulfoxide

(S) (%)

none 4 0 p-MePh Me 91 9 96

1 30 2 10 ( R ) p-MeOPh Me 92 8 95

2 25 2 10 ( S ) p-ClPh Me 76 24 94

3 89 5 88 ( S ) o-ClPh Me 97 <1 96

4 92 8 96 ( S ) o-MeOPh Me 99 <1 95

Ph Et 78 22 81

1 (R, R): R = H PhCH2 Me 93 7 87

2 (R, R): R = Me n-C8H17 Me 82 18 89

3 (R, S): R = H n-C12H25 Me 82 18 94

4 (R, S): R = Me c-C6H11 Me 91 9 88

Other Metal Catalyzed Other Metal Catalyzed OxidationsOxidations

R R' Yield ee (%)

Ph Me 94 70

Ph iPr 64 62

Ph N-C10H21 77 53

p-NO2Ph Me 55 63

t-Bu Bn 91 65

ACIE, 1995, 2640Synlett, 1998, 1327

RS

R' RS

R'

O

OH

X

N

HO

VO(acac)2 1 mol %1 1.5 mol %

H2O2

S

S

R

R'

S

S

R

R'

O

VO(acac)2/2

H2O2 (30%)

1: X = NO22: X = t-Bu

R R' Yield ee (%) (cis)

Ph H 84 85p-Tolyl H 79 77p-Cl-Ph H 87 64

p-MeO-Ph H 60 57o-Br-Ph H 81 64o-NO2-Ph H 75 62t-Bu H 67 46

Ph Me44 (cis) 68

37 (trans)12

(trans)

Chiral Oxaziridine OxidationsChiral Oxaziridine Oxidations

LS R

LS R

OOxaziridine

RTS

N

OO

O

O

Cl

ClN

OSO2

SO2

N

O Cl

Cl

ON SO2

Tet., 1988, 5703JACS, 1989, 5964JACS, 1988, 8477JOC, 1992, 7274Tet. Asymm., 1992, 629.

Large R Yield (%) ee (%)

p-Tolyl H 95 >95

p-Tolyl Ph 74 88

2-Napthyl H 84 94

t-Butyl H 84 94

t-Butyl Ph 80 94

n-octyl H 60 45

($50/g)

Cl

Cl

ON SO2

Top view

Looking down the pocket between Ph and camphor

Cl

Cl

ON SO2

Looking down the pocket between Ph and camphor

Top view

Chiral PeroxidesChiral Peroxides

Tet., 1997, 185

JOC, 1998, 3423

O

OBnH

HOO

Bn OOH

S S

-20oC

O

25% ee

S

OS

OOH

Ti(OiPr)4

Peroxide

-20oC

Peroxide =

SOO

Yield 79% (20% ee) 21%

16% (75% ee) 84%

Summary of Oxidative Summary of Oxidative MethodsMethods

In general the oxidative methods require a large steric difference between the two sulfide substituents (ie: Ph vs Me)

H-bonding can give selectivity despite a lack of large steric differences in some cases, though conditions are sensitive and difficult to optimize

The oxaziridine oxidation works if the ‘small’ substituent is a methylene (or equally small such as vinyl) and the ‘large’ is phenyl or tert-butyl

If the molecule is already chiral, diastereoselective oxidation can occur which depending on which isomer is desired could be an aid or a detriment

Andersen’s Nucleophilic Andersen’s Nucleophilic Method Method Oldest method, other secondary carbinols have been used

also Limited to Di-aryl or aryl/alkyl sulfoxides. For the synthesis of dialkyl sulfoxides, the required menthyl

alkanesulfinate esters cannot be prepared enantiomerically pure at sulfur (they cannot be crystallized, since they’re oils).

Tet. Lett., 1962, 93JACS, 1992, 5977JOC, 1984, 4070

OH

Menthol

ArS

O

Cl

OS

Ar OS

Ar

O O

Separated by crystallization, cannot by column

OS

Ar

O

Major

RM

RS

Ar

O"High ee's"

AminosulfiteAminosulfitePioneered by Wudl and Lee using ephedrine as a chiral

auxillary (1973), modified by Snyder and Benson (AlMe3, prevents racemisation).

HO NHMe

Ephedrine

1.2 equiv SOCl2, Et3N

DCM, 0oC, 24h

O NMeS

O

O NMeS

O

9:1

1) Crystallize (70% yield)2) RM, Toluene -40oC

(50-94% yield)

HO N SR

O

O N SR

O

AlMe3

DCMRT

30min

Al

R'MgX

RT5h

RS

R'

O

>99% ee

JACS, 1973, 6349Tet. Lett., 1991, 5885

Kagan’s SulfiteKagan’s SulfiteSuitable for dialkyl, alkyl aryl, and diaryl sulfoxides giving

enantiopure sulfoxides however tedious purifications (auxiliary derived from lactate).

JOC, 1991, 5991 (Kagan)

OHHO

H PhPh

OO

H PhPh

SOCl2/Et3N

-40oCDCM

SOO

H PhPh

S

O O

9:1

OO

H PhPh

S

O

OHO

H PhPh

SO R

OHO

H PhPh

SOR

R1M

R2M

R2M

R1S

R2

O

R1S

R2

O

"100% ee"

"100% ee"

Evan’s AuxiliaryEvan’s Auxiliary It was found that EWG’s on the N facilitate N-S cleavage, so

Evan’s auxiliary was a logical step. Nucleophilic displacement occurs with inversion of

configuration at the sulfur, and N-Sulfinyloxazolidinones are at least 2 orders of magnitude more reactive than Anderson’s menthyl sulfinate.

OHN

O

Bn

n-BuLi

ArSOClON

O

Bn

SAr

O

ON

O

Bn

SAr

O

Major Minor

OLiN

O

Bn

ON

O

Bn

SR

O

ON

O

Bn

SR

O

MajorMinor

R S S

O

O

Ph

ON

O

Bn

SR

mCPBA

R = Me, tBu, Ph

JACS, 1992, 5977

Evan’s AuxiliaryEvan’s AuxiliaryR1

R2

Yield (%) ee (%)

p-Tol Me 90 99p-Tol Et 90 98p-Tol i-Pr 91 97p-Tol t-Bu 88 97p-Tol Bn 86 99Ph Me 87 90t-Bu Me 78 93Bn Me 82 91n-octyl Me 78 100Me t-Bu 92 100n-Bu t-Bu 91 100

ON

O

Bn

SR1

O

SR1

O

R2

R2MgX

-78oCTHF

JACS, 1992, 5977

ON

O

Bn

SR1

O

SR1

O

OR-78oC

ROLi, ROH

Et2NMgBr

-78oCS

R1

O

NEt2

Oppolzer’s SulfinylsultamOppolzer’s Sulfinylsultam

Yields: 83-97%, ee’s 96 to >99% but only p-tolyl used for sulfinylsultam R

The Sultam can be recovered and reused (recovered yields >90%)

SO2

NHDMAP, p-TolSOCl

rt SO2

NS

Ar

ORM

SAr

O

R

R = Alkyl, Bn, vinyl, allyl, alkyne, heteroaryl

Tet. Lett., 1997, 2825.

Combination Approach to Chiral Combination Approach to Chiral SulfoxidesSulfoxides

RS P

O

OO

RS P

O

OO

O

Ti(OiPr)4R-BINOL

Water

TBHP

= Me >98% ee= Et 91% ee= Ph 94% ee

R

R'MgX

RS

R'

O

RR1 Yield (%) ee (%)

Me n-octyl 54 >98%Me n-decyl 46 >98%

Me n-octadecyl 49 >98%Me cyclohexyl 50 9Me t-Bu 15 >98%Me (E)-2-styril 43 >98%Et n-octyl 40 Et p-tolyl 36 91Ph methyl 60 94Ph p-tolyl 42 94

RS

LG

O R'MgX

RS

R'

O

LG's X

X

P

O

OO

X =X OCH3BrCl

Summary of Nucleophilic Summary of Nucleophilic MethodsMethods All nucleophilic methods use chiral auxiliaries that are

available enantiopure and cheap.

Diaryl sulfoxides can be made using: Anderson method, Kagan’s sulfite method, or Oppolzer’s method

Aryl/alkyl sulfoxides can be made using any of the methods

Di-alkyl sulfoxides or alkyl aryl sulfoxides can be made enantiopure using Evan’s auxillary, Snyder/Lee’s method, the ephedrine method or Kagan’s sulfite

Of all the methods, Kagan’s method is the most versatile but least used since it is so tedious for the crystallizations. Evan’s auxiliary method is easy, and versatile giving aryl/alkyl and alkyl/alkyl sulfoxides.

Uses of sulfoxidesUses of sulfoxides

Drug candidates/Natural product synthesis

Ligands in Catalysis◦ Hydrogenation◦ Cyclo-additions (DA)◦ C-C bond formation (Enone addition)

Chiral Auxillaries (Main use)

Chiral reagents ◦ NADH analog

Sulfoxides in DrugsSulfoxides in Drugs

Sulfoxides have a reputation for being potentially metabolically unstable - and they can go either way, being oxidized up to sulfones or reduced back to the parent sulfide.

Sulfoxides have a strange character for drugs, because that oxygen atom is about as close to a naked O-minus as you're going to find in physiological conditions.

The tetrahedral geometry of the sulfur means that this electronegative group is held is a very specific orientation relative to the other parts of your molecule (usually positive for binding to a target).

Also, of course they're chiral. That can either be a bug or a feature, depending on your project and on your view of the world

Examples of Drugs and Natural Examples of Drugs and Natural ProductsProducts

S

O

NH2

O

Armodafinil(analeptic, stimulant)

Fulvestrant(Estrogen hormone treatment)

HO

H

H

H

OH

S

O

CF3

F F

NH

NO

SO

N

O

Esomeprazole(Proton pump inhibitor

ulcers/acid reflux)

O

O

O

OS

H

OH

CH3

O

Podolactone D

Sulfoxides as Ligands for Sulfoxides as Ligands for MetalsMetals Generally metals bind through the oxygen of the sulfoxide,

however the soft metals of the Pt group (Ru, Rh, Os, Ir) can also bind through the sulfur depending on the other ligands of the metal.

According to the model of Davies sulfoxide coordination through O induces a decrease in the S=O bond order while the opposite occurs for coordination through S. Therefore, the bond length of the S-O lengthens for oxygen coordinated complexes and decreases for sulfur coordinated complexes.

The difference in bond length can be observed by IR (thus one can determine the mode of bonding), with the typical IR frequencies for SO being 1080-1150 for DMSO-S and 890-95- for DMSO-O.

The binding mode also affects the 1H NMR, with coordination through O induces small downfield shifts (max 0.5ppm) and coordination through S induces larger downfield shifts (0.5-1.1ppm).

Chem. Rev., 2004, 4203

Catalytic HydrogenationCatalytic Hydrogenation First work was by James and coworkers in 1976 using (+)-

methyl p-tolyl sulfoxide with disappointing results. Followed up by McMillan in 1977 using a diastereomic mixture of sulfoxides which gave low ee’s.

J. Mol. Catal., 1976, 439Can. J. Chem., 1977, 3927

HO

HO

H

HS

O

SO

O

O

H

HS

O

SO

bdios ddios

McMillan's Ligands

OH

O

HO

O

Ligand

H2 (40 PSI), 55oC(49%yield)

OH

O

HO

O

(25.2% ee)

Catalytic HydrogenationCatalytic Hydrogenation

JOC, 2000, 3010

Temp (oC) Conversion (%) ee (%)

60 99 6540 38 6720 57 80

S

NH2

OH

S

NH2

OH

S

NH2

OH

O

O

H2O2

A

BS-Bn-Cysteinol

Ligand Preparation

OIr, Ligand B

HCO2HR R

OH

OIr, Ligand B

HCO2HR R

OH

OH

99%65% ee

OH

82%73% ee

OH

99%52% ee

Cl

OH

95%65% ee

O

OH

99%79% ee

OH

99%70% ee

OH

98%55% ee

at 60oC

JOC, 2000, 3010

Chiral Lewis Acid Catalyst for Chiral Lewis Acid Catalyst for Diels-AlderDiels-AlderThough not sulfoxides, the bis(sulfinyl)imidoamidine shown

below gave moderate to excellent diastereoselectivity and enantioselectivity.

JACS, 2001, 1539

S

O

N N NS

O

Ligand prepared in 3 steps

n

+ R

O

N O

OCu(SbF6)2

Ligand

DCM-78oC

R

NO O

O

n

R = H, CH3, Ph, CO2Et, Acrolein

65-96% yield32-98% ee94-98% de

Chiral Lewis Acid for Hetero-D.A.Chiral Lewis Acid for Hetero-D.A.

JACS, 2001, 3830

O

O

O

N NS S

O O

Ligand

5 mol % Ligand5 mol % Cu(TfO)2

MS 4ADCMRT

O CO2Et

H

81% yield98% ee99:1 endo:exo

Diethylzinc Addition to Diethylzinc Addition to BenzaldehydeBenzaldehyde

Tet. Asymm., 1993, 727

JOC, 2002, 1346

S

OHO HOS

O

35% ee 45% ee

Fe

S

NHS

O

OO

80% ee

Ligands

O OHLigand

Et2ZnToluene

0oC

Enone AdditionEnone Addition

JACS, 2010, 4552

JACS, 2008, 2172

ACIE, 2009, 2768

S

S

O

O

99% yield98% ee (R)

S

S

O

O

98% yield>99% ee (S)

SO

SO

96% yield98% ee (R)

Ligands

O

PhB(OH)2

[Rh(C2H4)2Cl]2Ligand

40oC

O

Ph

JACS, 2010, 4552

SO

SS

O

1) n-BuLi, -78oC

2)

SO

SO

45% yieldenantiopure

Ligand Preparation

O

96% yield98% ee

O

97% yield97% ee

F

O

99% yield97% ee

Cl

O

95% yield95% ee

O

87% yield97% ee

O

97% yield96% ee

O

90% yield96% ee

O

93% yield92% ee

O

98% yield92% ee

O

98% yield94% ee

O

95% yield93% ee

O

O

87% yield94% ee

O

97% yield98% ee

O

O

75% yield>99% ee

Sulfoxides as Chiral Sulfoxides as Chiral AuxilliariesAuxilliaries “The reduction of beta-ketosulfoxides has been the most

extensively investigated and used reaction involving the asymmetric induction of chiral sulfoxides.”

Either stereoisomer can be obtained from the same beta-ketosulfoxide depending on the presence or absence of a lewis acid (ie: ZnCl2).

Sulfoxides are cleaved under ‘mild conditions’.

Tetrahedron, 2006, 5559Synth. Commun., 2000, 4467.

S

O O

S

O OHS

O OH

DIBAL DIBALZnCl2

Perkin Trans. 1, 2000, 3143

Tet., 2001, 8469

S R

O

O

DIBAL

THF OO S

R

Al

i-Bu

i-Bu

S R

O

OH

R = Ph: 93%, de = 90%Me: 96%, de = 96%Et: 92%, de = 92%

SO

O SO

OHDIBAL 96%

94% de

There are few examples of gamma-ketosulfoxides being reduced selectively

Unconjugated Addition Unconjugated Addition ReactionsReactions Sulfoxides have the ability to stabilize a negative charge on

an adjacent carbon Deprotonation of the alpha carbon of the sulfoxide requires

a strong base (ie: LiNH2, LDA, n-BuLi, LiHMDS, etc.)

High stereoselectivity usually requires steric hindrance in the vicinity of the alpha carbon and the use of an electrophile with a bulky group. If optically active sulfoxides give a poor diastereoselectivity the presence of another function such as an ester, sulfide or amide which can have a chelating effect in the transition state can improve the selectivity.S

O

R

S

O

R

R'

OH

R'

S

O

R

R'

OH

R'

1) LDA

2) R2'CO

syn anti

R = TMS, R' = Me, 88%, 96:4 syn/antiR = SiMePh2, R' = Me, 73%, >98:2 syn/antiR = CH2TMS, R' = Me, 93%, 73/27 syn/antiR = CH2TMS, R' = (CH2)5, 88%, 84/16 syn/anti

JOC, 2000, 469

O

SCl

O1) LDA

2)

OH SO

Cl 82%

KOtBu

O

SO

HO

S

OH

3:1

93% yield of two isomers

N

HR

R'S

O

LDA

THF

S

O

R

R'HN

R = R' = Ph, 87%, 68% deR = Ph, R' = 2MeO-C6H4, 82%, 62% deR = 4-MeO-C6H4, R' = Ph, 92%, 84% deR = t-Bu, R' = 2-MeO-C6H4, 92%, >99% de

Tet, 2006, 5559

A combination of the chemistry of oxidation and alkylation can be useful for synthesis, such as that shown below which was used for a drug candidate program.

N

NS

O

N

NS

O

OTi(Oi-Pr)4D-DET LDA

ICl

N

NS

O

O

Cl

71% yield98-99% ee

NH

N S

ON

N

>99% ee

Chem. Rev., 2003, 3651

Conjugated AdditionConjugated Addition(Michael Addition)(Michael Addition)

Tet, 2007, 5559

JOC, 2000, 1758

OL, 2001, 29

S

O

TMS

1) LDA2)

3) Electrophile

S

O

TMS

O

OR

E

R O

O

R Electrophile Yield (%) de (%)

H MeI 21 >96

Me MeI 59 >96

Ph MeI 75 >96

Ph BnBr 74 >96

Ph i-PrCHO 90 >96

Ph PhCHO 98 >96

O

O

SO

SO

OO

SO

OO

71% 0%

LDA

Conjugate Addition to Vinyl Conjugate Addition to Vinyl SulfoxidesSulfoxidesVinyl sulfoxides can act as Michael acceptors for a variety of

nucleophiles (cuprates, enolates, malonates, amines, thiols, etc.) and due to the chirality can induce chirality at the beta-carbon, but at least creates diastereomers which can be separated with standard techniques.

R'

R S

Cl

OO

O

LDATHF

R'

R

O O

Cl

S

O

86-91% yield99% de

R, R' = BnCH2, Me, H

SP

O

OO

O

S

O

O

SP

O

OO

O

OO

91%89:11 dr

Tet. Asymm., 2005, 665Tet. Lett., 2002, 3061

Sulfoxides as Chiral Auxillaries Sulfoxides as Chiral Auxillaries for D.A.for D.A. “The sulfinyl group as, equally, become one of the most

interesting chiral inductors in asymmetrics Diels-Alder reactions, due to: (a) its ability to differentiate between diastereotopics faces of neighboring double bonds, (b) the ease of chemical transformations in to different functional groups including its clean removal under mild conditions and (c) the existence of several efficient methods that allow the preparation of enantiomerically pure sulfoxides.”

The substituents and lewis acid used to catalyze the reaction have a strong influence on which product is formed.

Tet., 2006, 5559

O

O

S

O

CN

CN

O

OS(O)p-Tol

S(O)p-Tol

O

OCN

DCM

PhI(OAc)2

37% 28%

Chem. Eur. J., 2000, 288

O

O

HO S

O O

O

OH

60% yield97% ee

O

O

S

O

CN

O

DCM

PhI(OAc)2

O O

O

CN

SO

O O

O

CN

71%92% ee

21%88% ee

Chiral Reagents Chiral Reagents (NADH analog)(NADH analog)

A chiral NADH polymer supported reagent was prepared and shown to enantioselectively reduce the activated carbonyl shown below to an alcohol, and this reagent could be recycled using 1-propyl-1,4,-dihydronicotinamide.

N

S

O

N

S

O

ON

S

O

Polymer

O

O

ON

S

O

Polymer

N

S

O

Polymer

O

O

OH

100% yield>96% ee

2.5 Mg(ClO4)2

ACN/Benzene12 hours

RT

Heterocycles, 1998, 261

Pummerer ReactionPummerer Reaction(can be used for cleavage of a sulfoxide)(can be used for cleavage of a sulfoxide) Sulfoxides with an alpha Hydrogen when reacted with an

activating group (ie: Ac2O, TFAA, TMSOTf, etc.) rearrange to give alpha substituted sulfides.

This reaction allows the conversion of a sulfoxide to a carbonyl, or can transfer the sulfoxide chirality to the alpha carbon creating a chiral sulfide.

RS

O

R' RS

O

R'

OO

O

RS

O

R'

O

O O

RS

O

R'

O

O

O

H

RS

O

R'

O

RS

O

R'

O

RS R'

O

O

RS R'

Nu

Nu

Nu = OH, O-alkyl, O-aryl, O2CR, F, Cl, Br, SR, NR2

Strategic Applications of Named Reactions in Organic Synthesis, 2005, L. Kurti and B. Czako

N

OO

NSPh

O

H H

N

OO

NHS

Ph

H

N

OO

NH

HRaney-Ni

TFAA/TFA(3 equiv)

80oC2hr

63% yield

RO

HOS

PhO

OTBS

RO

HOS

Ph

OTBSOH

RO

OOTBSOAc2O

NaOAc125oC

then H2O37%

OO

O

S PhO

H H

TMSOTf(3 equiv)

DCM

-25oC to -5oC90 min

OO

O

S Ph

H H OTMS

TBAF

THF-5oC

20 min

OO

OH H

O

H

O

Some good reviews if interested◦ Chem. Rev., 2010, ASAP (synthesis of

sulfoxides)◦ Chem. Rev., 2003, 3651 (synthesis of

sulfoxides)◦ Chem. Rev., 2004, 4203 (SO bonding to Pt

metals)◦ Tetrahedron, 2006, 5779 (as chiral

auxilliaries)◦ Chem. Rev., 2007, 5133 (asymmetric

catalysis)