Chiral Sulfoxides:
A Whirlwind Tour
Literature Presentation
Scott Jarvis
April 27th, 2010
Characteristics 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, 130150oC 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
O
S
Methods to Prepare Chiral Sulfoxides

Oxidative methods
◦
◦
◦
◦
◦

Nucleophilic substitution methods
◦
◦
◦
◦
◦

Diastereoselective
Modified sharpless oxidation
Salen oxidation
Chiral oxaziridines
Chiral epoxides
Andersen Methodology (menthol)
Aminosulfites (ephedrine, aminoindane)
Sulfites (lactate derivative, sugars)
Evans auxillary
Oppolzer’s Sulfinylsultam
Combination
◦ Thiosulfinate approach(tert-Butyl-SO-R)
Diastereoselective Oxidation
The oxidation of sulfur can be directed by a coordinating atom such as N or
O or straight steric bulk
NMe 2
O
O
NMe 2
AcOH
S
H
N
NaBO 3
78% de
S
O
H
N
H2O2
H
S
O
DCM
N
O
O
S
90%, 100% de
N
O
O
OH
O
Br F H
O
Br F H
S
DMD
N
DCM
O
Synthesis, 1992, 555
Tet. Lett., 1993, 7877
H
O
OH
OH
O
S
Quant., 100% de
N
O
O
OH
Diastereoselective Oxidation
R
R
R
O
O
: S
R'
:
R O
O
R
O
O
R O
O
R
R
O
O
:
R'
S
Chirality of sulfoxide comes from
the anomeric effect
O
up to 100% de
chirality independant of reagent
(NaIO4, MCPBA, Oxone all give same compound)
Chem. Comm., 1998. 2763
Modified Sharpless Oxidation
Mostly relies on steric bulk to gain the selectivity
R1
O
R
O
O
O
H
O
Ti
O
O
O
O
RL
S
:
[Ti]
RS
Bull. Soc. Chim. Fr., 1996, 1109
Synlett, 1996, 404 (Kagan)
R2
Yield (%)
Phenyl
p-Tolyl
p-anisyl
o-anisyl
o-nitrophenyl
Me
Me
Me
Me
Me
81
77
73
72
51
ee (%)
(R)
91.2
95.6
92.1
89.3
75.0
Phenyl
p-Tolyl
p-Tolyl
o-anisyl
benzyl
n-octyl
CH=CH2
Et
n-butyl
phenyl
Me
Me
58
68
70
64
72
69
55.4
78.1
25.0
6.2
90.3
70.7
Modified Sharpless Oxidation
Other diols have been used in place of DET
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Uemura’s Binol Version
Ar
Solvent
Method
Yield (%)
ee (%)
(R)
p-tolyl
CCl4
A
65
84
p-tolyl
CCl4
B
67
93
p-tolyl
CCl4
Ba
64
88
p-tolyl
CCl4
C
44
96
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
CHCl3
DCM
DCE
Toluene
o-xylene
cumene
THF
Diethyl ether
A
A
A
A
A
A
A
A
74
84
86
66
88
86
46
32
23
16
25
72
61
57
72
57
Ph
Ph
CCl4
Toluene
A
A
80
86
65
63
2-Napthyl
CCl4
A
73
51
p-BrC6H4
CCl4
A
62
68
n-octyl
CCl4
B
64
69
JOC, 1993, 4529
O
Ar
S
Me
Ar
Method A: under Ar peroxide in toluene
Method B: under Air, peroxide in water
Method C: Half as much catalyst
Note a: under Argon
S
Me
Modified Sharpless Oxidation
H-Bonding under specific conditions can also give good selectivity (but very
sensitive).
O
N
O
Ti(OiPr)4/(S,S)-DET/H2O
O
O
S
N
N
S
N
H
iPr2NEt
Cumene Peroxide
N
N
H
NH is directing
Tet. Asymm., 2000, 3819
O
92% yield (94% ee)
Salen Oxidation
Typically thought of for chiral epoxidation of olefins but with modifications
they are useful for sulfide oxidations.
R
Cat
R
N Cl N
Fe
O
O
Ph Ph
Catalyst
JACS, 2007, 8940.
S
Cat (2 mol%)
aq H 2O2 (1.5)
O
S
O
O
S
H 2O, 3h, 20o C
ee of
Yield
Yield
sulfoxide
(sulfoxide) (sulfone)
(%)
none
4
0
1
30
2
2
25
3
4
R1
p-MePh
R2
ee of
Yield
Yield
sulfoxide
(sulfoxide) (Sulfone)
(S) (%)
Me
91
9
96
10 ( R )
p-MeOPh Me
92
8
95
2
10 ( S )
p-ClPh
Me
76
24
94
89
5
88 ( S )
o-ClPh
Me
97
<1
96
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
91
9
88
Me
Other Metal Catalyzed Oxidations
X
OH
N
1: X = NO 2
2: X = t-Bu
HO
VO(acac)2 1 mol %
1 1.5 mol %
H2O2
R
S
R'
R
R
R'
R
R'
O
S
VO(acac) 2/2
S
H2O2 (30%)
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, 2640
Synlett, 1998, 1327
S
R
R'
R
R'
Yield
Ph
p-Tolyl
p-Cl-Ph
H
H
H
84
79
87
p-MeO-Ph
o-Br-Ph
o-NO2-Ph
t-Bu
H
H
H
H
60
81
75
67
44 (cis)
Ph
Me
S
S
O
ee (%)
(cis)
85
77
64
57
64
62
46
68
12
37 (trans) (trans)
Chiral Oxaziridine Oxidations
L
O
N
O
S
O O
O
Tet., 1988, 5703
JACS, 1989, 5964
JACS, 1988, 8477
JOC, 1992, 7274
Tet. Asymm., 1992, 629.
R
RT
Cl
Cl
N
S O
O2
Cl
Cl
N
S
O2
S
N
O
SO2
($50/g)
O
Oxaziridine
L
S
R
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
Cl
Cl
N
O
Top view
SO2
Looking down the
pocket between Ph
and camphor
Cl
Cl
N
O
Top view
SO2
Looking down the
pocket between Ph
and camphor
Chiral Peroxides
H
OBn
HO
O
Bn
O
O
OH
O
S
S
25% ee
-20oC
S
Ti(OiPr) 4
Peroxide
O
S
O O
S
-20oC
O
Peroxide =
Yield
Tet., 1997, 185
JOC, 1998, 3423
79% (20% ee)
21%
16% (75% ee)
84%
OH
Summary of Oxidative Methods

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 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).
Ar
O
S
Cl
O
O
OH
S
O
Ar
O
S
Ar
Major
Menthol
Separated by crystallization, cannot by column
O
O
Tet. Lett., 1962, 93
JACS, 1992, 5977
JOC, 1984, 4070
S
O
RM
Ar
R
S
"High ee's"
Ar
Aminosulfite
Pioneered by Wudl and Lee using ephedrine as a chiral auxillary (1973),
modified by Snyder and Benson (AlMe3, prevents racemisation).
O
HO
NHMe
O
S
1.2 equiv SOCl2, Et3N
O
S
NMe
O
NMe
9:1
DCM, 0oC, 24h
Ephedrine
1) Crystallize (70% yield)
2) RM, Toluene -40oC
(50-94% yield)
O
R
S
R'MgX
R'
>99% ee
JACS, 1973, 6349
Tet. Lett., 1991, 5885
RT
5h
Al
O
O
N S
R
O
AlMe3
DCM
RT
30min
HO
N S
R
Kagan’s Sulfite
Suitable for dialkyl, alkyl aryl, and diaryl sulfoxides giving enantiopure
sulfoxides however tedious purifications (auxiliary derived from lactate).
H
HO
Ph
Ph
SOCl2/Et 3N
H
-40oC
DCM
OH
O
Ph
Ph
S
O
H
9:1
O
O
H
O
S
O
Ph
Ph
Ph
Ph
S
O
O
R 2M
OH
O
R1
S
R2
R
"100% ee"
H
O
Ph
Ph
S
R1M
O
O
H
Ph
Ph
HO
R
JOC, 1991, 5991 (Kagan)
O
S
O
R2M
R1
O
S
R2
"100% ee"
Evan’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.
O
HN
O
O
n-BuLi
Ar
ArSOCl
Bn
O
O
S N
O
Ar
Major
O
LiN
O
R
Bn
S N
Bn
R = Me, tBu, Ph
JACS, 1992, 5977
O
O
mCPBA
O
S N
O
Bn
Bn
O
R S S Ph
O
Minor
O
R
O
O
S N
Bn
Minor
O
R
O
S N
O
Bn
Major
Evan’s Auxiliary
R1
O
R1
O
S N
O
Bn
-78oC
THF
R1
S
R2
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
Ph
t-Bu
Bn
n-octyl
Me
n-Bu
O
R2MgX
R2
O
R
Me
Et
i-Pr
t-Bu
Bn
Me
Me
Me
Me
t-Bu
t-Bu
O
S N
1
Yield
(%)
90
90
91
88
86
87
78
82
78
92
91
ee (%)
99
98
97
97
99
90
93
91
100
100
100
ROLi, ROH
O
o
-78 C
R1
O
S
OR
Bn
Et 2NMgBr
JACS, 1992, 5977
o
-78 C
R1
O
S
NEt2
Oppolzer’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%)
R = Alkyl, Bn, vinyl, allyl, alkyne, heteroaryl
O
DMAP, p-TolSOCl
N
NH
S
O2
Tet. Lett., 1997, 2825.
rt
S
O2
S
RM
Ar
R
O
S
Ar
Combination Approach to Chiral
Sulfoxides
LG's
R
O
S
R'MgX
LG
R
O
S
X
X
X = OCH3
Br
Cl
X
R'
O
P O
O
R
R
S
O
O
P
O
Ti(OiPr)4
R-BINOL
Water
TBHP
O
S
R
O
O
P
O
R = Me >98% ee
= Et 91% ee
= Ph 94% ee
R'MgX
R
O
S
Me
Me
R1
n-octyl
n-decyl
Me
Me
Me
Me
Et
Et
Ph
Ph
n-octadecyl
cyclohexyl
t-Bu
(E)-2-styril
n-octyl
p-tolyl
methyl
p-tolyl
Yield (%)
ee (%)
54
46
>98%
>98%
49
50
15
43
40
36
60
42
>98%
9
>98%
>98%
R'
91
94
94
Summary of Nucleophilic Methods

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 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 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
Products
HO
O
S
O
O
NH2
O
N
O
S
N
H
Armodafinil
(analeptic, stimulant)
H
H
H
N
Esomeprazole
(Proton pump inhibitor
ulcers/acid reflux)
OH
Fulvestrant
(Estrogen hormone treatment)
O
H
O
OH
O
O
Podolactone D
S
O
S
O
CH3
CF3
F F
Sulfoxides as Ligands for Metals

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 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.
McMillan's Ligands
HO
H
S
O
O
H
S
O
O
HO
OH
O
HO
H
O
S
O
bdios
J. Mol. Catal., 1976, 439
Can. J. Chem., 1977, 3927
H
S
ddios
O
O
Ligand
HO
H2 (40 PSI), 55oC
(49%yield)
OH
O
(25.2% ee)
Catalytic Hydrogenation
Ligand Preparation
S
O
S
OH
OH
A
OH
B
NH2
H2O2
NH2
S
O
S-Bn-Cysteinol
O
OH
Temp (oC)
Ir, Ligand B
R
JOC, 2000, 3010
HCO2H
R
60
40
20
NH2
Conversion
ee (%)
(%)
99
38
57
65
67
80
O
OH
Ir, Ligand B
R
HCO2H
R
at 60oC
OH
OH
OH
Cl
82%
73% ee
99%
65% ee
JOC, 2000, 3010
O
99%
52% ee
OH
99%
79% ee
OH
OH
99%
70% ee
95%
65% ee
OH
98%
55% ee
Chiral Lewis Acid Catalyst for Diels-Alder
Though not sulfoxides, the bis(sulfinyl)imidoamidine shown below gave
moderate to excellent diastereoselectivity and enantioselectivity.
O
+
n
R
O
N
Cu(SbF6)2
Ligand
n
R
65-96% yield
32-98% ee
94-98% de
O
O
DCM
-78oC
O
N
O
R = H, CH3, Ph, CO2Et, Acrolein
O
S
N
N
N
O
S
Ligand prepared in 3 steps
JACS, 2001, 1539
Chiral Lewis Acid for Hetero-D.A.
O
O
O
5 mol % Ligand
5 mol % Cu(TfO)2
MS 4A
DCM
RT
H
O CO2Et
81% yield
98% ee
99:1 endo:exo
Ligand
O
S N
JACS, 2001, 3830
O
N S
Diethylzinc Addition to Benzaldehyde
O
Ligand
OH
Et2Zn
Toluene
0oC
Ligands
HO
O
S
35% ee
Tet. Asymm., 1993, 727
JOC, 2002, 1346
HO
O
S
45% ee
Fe
S O
NH O
S
O
80% ee
Enone Addition
[Rh(C2H4)2Cl] 2
Ligand
O
O
PhB(OH)2
40oC
Ph
Ligands
S
S
O
O
99% yield
98% ee (R)
JACS, 2010, 4552
JACS, 2008, 2172
ACIE, 2009, 2768
S
S
S
O
O
98% yield
>99% ee (S)
S
O
O
96% yield
98% ee (R)
Ligand Preparation
1) n-BuLi, -78oC
S
S
O
2)
O
S
O
96% yield
98% ee
O
O
O
O
O
Cl
99% yield
97% ee
O
45% yield
enantiopure
S
O
F
97% yield
97% ee
S
O
O
97% yield
96% ee
95% yield
95% ee
O
O
O
90% yield
96% ee
O
O
87% yield
97% ee
O
O
O
93% yield
92% ee
98% yield
92% ee
JACS, 2010, 4552
98% yield
94% ee
95% yield
93% ee
87% yield
94% ee
97% yield
98% ee
75% yield
>99% ee
Sulfoxides as Chiral Auxilliaries



“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’.
O
S
DIBAL
O
S
Tetrahedron, 2006, 5559
Synth. Commun., 2000, 4467.
OH
O
DIBAL
ZnCl2
O
S
OH
There are few examples of gamma-ketosulfoxides being reduced selectively
O
S
R
O
i-Bu
DIBAL
O
S
R
Al
i-Bu
THF
O
O
R
OH
S
R = Ph: 93%, de = 90%
Me: 96%, de = 96%
Et: 92%, de = 92%
S
Perkin Trans. 1, 2000, 3143
Tet., 2001, 8469
O
O
DIBAL
S
O
OH
96%
94% de
Unconjugated Addition Reactions



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.
O
S
1) LDA
R
O
S
2) R2'CO
OH
R'
R'
O
S
R'
R'
R
R
syn
OH
anti
R = TMS, R' = Me, 88%, 96:4 syn/anti
R = SiMePh2, R' = Me, 73%, >98:2 syn/anti
R = CH2TMS, R' = Me, 93%, 73/27 syn/anti
R = CH2TMS, R' = (CH2)5, 88%, 84/16 syn/anti
JOC, 2000, 469
N
R
R'
O
S
R'HN
LDA
H
R
THF
O
S
R = R' = Ph, 87%, 68% de
R = Ph, R' = 2MeO-C6H4, 82%, 62% de
R = 4-MeO-C6H4, R' = Ph, 92%, 84% de
R = t-Bu, R' = 2-MeO-C6H4, 92%, >99% de
Cl
O
S
OH
1) LDA
2)
O
S
Cl
82%
O
KOtBu
S
O
S
H
O
3:1
93% yield of two isomers
Tet, 2006, 5559
O
H
O
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
S
N
N
Ti(Oi-Pr)4
D-DET
O
S
N
LDA
N
I
O
Cl
O
71% yield
98-99% ee
N
O
S
NH
>99% ee
Chem. Rev., 2003, 3651
N
Cl
O
N
N
O
S
Conjugated Addition
(Michael Addition)
R
1) LDA
2)
O
S
R
TMS
H
O
O
S
O
3) Electrophile
O
R
O
O
E
TMS
LDA
Yield (%) de (%)
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
S
Electrophile
S
S
O
O
Tet, 2007, 5559
JOC, 2000, 1758
OL, 2001, 29
O
O
O
71%
O
0%
Conjugate Addition to Vinyl Sulfoxides
Vinyl 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.
O
O
O
R
S
R'
Cl
LDA
THF
O
O
O
S
R
R'
Cl
R, R' = BnCH 2 , Me, H
86-91% yield
99% de
O
O P
O
O
S
O
O P
O
O
S
O
S
O
O
Tet. Asymm., 2005, 665
Tet. Lett., 2002, 3061
O
91%
89:11 dr
Sulfoxides as Chiral Auxillaries 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.
O
O
S
CN
O
CN
S(O)p-Tol
DCM
PhI(OAc) 2
O
O
O
O
37%
Tet., 2006, 5559
S(O)p-Tol
CN
28%
OH
O
HO
O
O
S
60% yield
97% ee
O
O
O
O
O
S
CN
O
O
CN
O
CN
DCM
PhI(OAc)2
SO
O
O
71%
92% ee
Chem. Eur. J., 2000, 288
O
O
21%
88% ee
Chiral Reagents
(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.
O
S
O
S
O
S
N
N
O
O
O
Heterocycles, 1998, 261
N
Polymer
O
O
S
N
Polymer
OH
O
2.5 Mg(ClO4)2
ACN/Benzene
12 hours
RT
O
100% yield
>96% ee
O
S
N
Polymer
Pummerer Reaction
(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.
O
R
O
S
R'
R
O
S
O
O
O
R'
R
O
S
O
O
O
R
R'
O
S
R'
H
O
O
O
O
O
R
O
S
O
R'
R
O
S
Nu
R'
R
S
R'
R
S
R'
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
O
S
Ph
Ac 2 O
NaOAc
125 oC
OTBS HO
H
OTBS HO
then H 2O
37%
RO
O
S
H
O
S
Ph
OH
RO
O
H
H
TFAA/TFA
(3 equiv)
OTMS
O
Ph
S
N
H
H
80 oC
N
O
O
2hr
63% yield
O
S Ph
H
o
-25 C to -5 C
90 min
N
O
O
H
o
O
O
OTBS
RO
TMSOTf
(3 equiv)
DCM
O O
S Ph
O
Ph
N
O
O
TBAF
H
THF
-5 oC
20 min
H
H
O
N
Raney-Ni
H
H
N
O
O
O
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)