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)