A mild protocol for the deoxygenation of α-hydrogen-containing sulfoxides to the corresponding sulfides

Article abstract of DOI:10.1016/j.tetlet.2004.05.049

A mild method for the deoxygenation of α-hydrogen-containing sulfoxides to sulfides is reported. This synthetically useful and operationally simple protocol derives mechanistically from the Swern oxidation methodology.

Full text of DOI:10.1016/j.tetlet.2004.05.049

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5193–5195
A mild protocol for the deoxygenation of a-hydrogen-containing
sulfoxides to the corresponding sulfides
Gurpreet S. Bhatia and Piotr P. Graczyk*
Department of Medicinal Chemistry, EISAI London Research Laboratories,
University College London, Bernard Katz Building, London WC1E 6BT, United Kingdom
Received 5 March 2004; revised 4 May 2004; accepted 11 May 2004
Abstract—Amild method for the deoxygenation of a-hydrogen-containing sulfoxides to sulfides is reported. This synthetically
useful and operationally simple protocol derives mechanistically from the Swern oxidation methodology.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Chiral sulfoxides have gained widespread use as auxil-
iaries in asymmetric synthesis. Their ability to control
the formation of stereogenic centres mainly in carbon–
carbon bond forming reactions is well documented.1
After stereoinduction the sulfinyl moiety may be
removed by deoxygenation to sulfide followed by the
elimination of sulfur.
required, nondiscrimination against other functionalities
present or the problematic removal of toxic and heavy
metal by-products. In this context, an alternative deoxy-
genating protocol was sought.
The popularly used Swern reaction15 [DMSO–(COCl)2–
Et3N reagent system] employed for the oxidation of
alcohols to aldehydes and ketones involves the con-
comitant reduction of DMSO to Me2S. We reasoned
that the replacement of DMSO with another sulfoxide
and the use of a sacrificial alcohol under Swern-like
conditions would afford the desired sulfide. We now
report work towards this goal with our initial model
system of 1-bromo-4-methanesulfinylbenzene 1 and the
application of our findings to a number of other sys-
tems.
We recently required a very mild method to generate
sulfides from the corresponding sulfoxides for our bio-
logical screening programmes. Examination of the lit-
erature revealed a plethora of reviews concerning this
subject.2;3 Among the numerous reagents reported for
this task were hydrogen halides (HCl, HBr, HI),4 sulfur
compounds (H2S, PhSH, MeCOSH),5 phosphorus
compounds (PBr3, POCl3, P4S10),6 silicon compounds
(HSiCl3, Si2Cl6),7 boranes,8 metal hydrides (LiAlH4,
DIBAL-H, RedAl),9 low-valent metal ions (TiCl3,
CrCl2, VCl2)10 and other miscellaneous systems (carb-
enes, acid chlorides, metalloporphins and Grignard
reagents).3 More recent research in this area has dem-
Treatment of sulfoxide 1 with oxalyl chloride (1 equiv)
at )78 ꢁC for 1 h followed by the addition of methanol
(1.4 equiv) and then after a further 1 h triethylamine
(2 equiv) led to only a small conversion of 1 (Table 1,
entry 1, 12%)16 into the relevant sulfide 2. As expected,
increasing the excess of reagents resulted in additional
amounts of 2 being generated (entry 2). However, sub-
sequent attempts to improve the yield of 2 by further
increasing the amounts of reagents (entry 3) or by
inclusion of 2% of DMAP (entries 4–5), led to little
improvement.
11
onstrated the use of NaBH4/I2 and TiCl4/In12 for
deoxygenation of sulfoxides and the Lawesson’s
reagent13 for similar systems. Unfortunately none of the
current methods available were amenable to our sensi-
tive classes of compounds14 due to either the elevated
temperatures involved, large excesses of reagents
As the observed degree of conversion might depend on
the efficiency of formation of the alkoxysulfonium ion 4
(Scheme 1) and breakdown of ylide 5 into aldehyde/
ketone R0RC@O and sulfide 6, we decided to examine
Keywords: Sulfoxides; Sulfides; Deoxygenation.
* Corresponding author. Tel.: +44-20-7413-1147; fax: +44-20-7413-
1121; e-mail: piotr_graczyk@eisai.net
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.049

5194
G. S. Bhatia, P. P. Graczyk / Tetrahedron Letters 45 (2004) 5193–5195
Table 1. Effect of varying amounts of (COCl)2, MeOH, Et3N and DMAP on deoxygenation of 1
Br
Br
(COCl)2, DCM
Me
S
O
SMe
MeOH, Et3N
-78 oC
1
2
Entry
(COCl)2 equivalents
MeOH equivalents
Et3N equivalents
DMAPa equivalents
Conversionb (%)
1
2
3
4
5
1.0
1.3
2.0
3.0
4.0
1.4
2.0
2.0
3.0
0
12
61
68
69
68
0
3.0
8.0
4.0
0
10.0
12.0
0.02
0.02
10.0
a Added to the starting sulfoxide 1.
b Based on the 1H NMR (CDCl3) spectrum of the reaction mixture after work-up.
R2
R2
H
(1.5–1.1 equiv; entries 3–4) and addition of DMSO
(1 equiv; entry 5) showed no beneficial effect.
H
1. (COCl)2
R1
R'
R
Cl
S
O
H
H
S
O
R1
2. R'RCHOH
As the breakdown of intermediate ylide 5 could be
further accelerated by increasing steric interactions be-
tween R0 and R (Scheme 1), the use of a more hindered
scavenger alcohol was considered as another avenue to
improve the yield of the deoxygenation product 6. In-
deed, utilization of propan-2-ol afforded almost quan-
titative conversion (Table 2, entry 6) with 75% isolated
yield of sulfide 2.17
3
4
base
R2
R2
H
R1
R'
R
H
- R'RC=O
S
S
O
R1
6
5
In accordance with the mechanism presented in Scheme
1, only sulfoxides containing a-hydrogen atom(s) would
be amenable to the aforementioned protocol. Thus, at-
tempts to deoxygenate a sulfoxide not bearing an a-
hydrogen such as diphenyl sulfoxide resulted in recovery
of unreacted starting material. However, a number of
commercially available sulfoxides bearing an a-hydro-
gen atom could be deoxygenated in high yield (Table 3).
Scheme 1. Swern oxidation/sulfoxide reduction mechanism.
the effect of alcohol R0RCHOH and solvent on the
deoxygenation reaction.
Employment of ethanol (2 equiv) as the scavenger
alcohol and Et3N (3 equiv) in dichloromethane
improved the conversion by about 5% (Table 2, entry 1,
67%; cf. Table 1, entry 2, 61%).
In conclusion, we have developed a new protocol for the
deoxygenation of a-hydrogen-containing sulfoxides to
their corresponding sulfides. This technology comple-
ments those currently known for this transformation by
virtue of its extremely mild ()78 ꢁC) reaction conditions
and its expected tolerance of a wide variety of functional
groups.
Replacement of dichloromethane with THF and a fur-
ther increase in the amount of Et3N (5 equiv) allowed
88% of 1 to be deoxygenated (Table 2, entry 2). How-
ever, further variations in the amount of oxalyl chloride
Table 2. Effect of alcohol and solvent on deoxygenation of 1
Br
Br
(COCl)2, solvent
Me
R'RCHOH (2eq)
Et3N, -78 oC
S
O
SMe
1
2
Entry
R0RCH
(COCl)2 equivalents
Et3N equivalents
Solvent equivalents
Conversiona (%)
1
2
3
4
5
6
7
Et
Et
1.3
1.3
1.5
1.1
1.3
1.3
1.3
3.0
5.0
5.0
5.0
5.0
5.0
5.0
CH2Cl2
THF
THF
THF
THFb
THF
THF
67
88
87
78
82
99
99
Et
Et
Et
Me2CH
Me2CH
a Based on the 1H NMR (CDCl3) spectrum of the reaction mixture after work-up.
b Contains DMSO (1 equiv).

G. S. Bhatia, P. P. Graczyk / Tetrahedron Letters 45 (2004) 5193–5195
Table 3. Sulfoxide deoxygenation examplesa
5195
R1
R1
R2
S
R2
(COCl)2, Me2CHOH
Et3N, THF, -78 o
S
O
C
3
6
Entry
R1
R2
GC retention timesb (min)
Conversion (%)
GC
3/6
NMRc
1
2
3
4
5
6
7
p-BrC6H4
p-BrC6H4
Ph
Me
Me
Me
Me
Ph
30.21/25.70
30.21/25.70
25.25/19.84
27.70/21.80
38.26/33.56
22.76/10.50
26.30/19.42
100
100d
99
100
97
100
100
86
p-MeC6H4
PhCH2
100
e
CH2CH2CH2
n-C4H9
99
e
100
88
n-Pr
a Deoxygenation carried out in THF following the standard protocol17 unless specified otherwise. Products were identified by reference to the
corresponding commercially available sulfides.
b GC analysis of the crude reaction mixtures before work-up was performed on a gas chromatograph Perkin–Elmer 8500, 30M BPX5 0.32 mm I.D.
wide bore capillary column; oven conditions: initial 50 ꢁC hold for 8 min, ramp 8 ꢁC/min, final 250 ꢁC hold for 12 min.
c
1H NMR (400 MHz, CDCl3 or C6D6).
d Reaction carried out in CH2Cl2.
e Impossible to estimate due to co-elution of interfering peaks.
Sherwin, P. F. J. Am. Chem. Soc. 1976, 98, 5715–5717; (c)
Kabalka, G. W.; Baker, J. D.; Neal, G. W. J. Org. Chem.
1977, 42, 512–517.
Acknowledgements
We thank the Rooney Laboratories, Windsor, Berk-
shire, UK for performing the GC analysis of all crude
reaction mixtures.
9. (a) Brown, H. C.; Weissman, P. M.; Yoon, N. M. J. Am.
Chem. Soc. 1966, 88, 1458–1463; (b) Yoon, N. M.;
Gyoung, Y. S. J. Org. Chem. 1985, 50, 2443–2450; (c)
Ho, T. L.; Wong, C. M. Org. Prep. Proced. Int. 1975, 7,
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References and notes
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14. This data will be presented elsewhere.
1. (a) Walker, A. J. Tetrahedron: Asymmetry 1992, 3, 961–
998; (b) Posner, G. H. In The Chemistry of Sulfones and
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In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic:
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1
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17. Representative protocol for sulfoxide deoxygenation: To a
stirred and cooled ()78 ꢁC) solution of commercially
available sulfoxide 1 (497 mg, 2.27 mmol) in THF (4 mL)
under a nitrogen atmosphere was added oxalyl chloride
(0.26 mL, 2.95 mmol). After 1 h, propan-2-ol (0.35 mL,
4.54 mmol) was added dropwise. The reaction mixture was
stirred for a further 1 h and Et3N (1.58 mL, 11.35 mmol)
was added. After 3 min, the mixture was removed from the
solid CO2/acetone bath, allowed to warm to room
temperature and partitioned between CHCl3 and brine.
The aqueous layer was extracted with CHCl3 (2·). The
combined organic solutions were dried (MgSO4) and
concentrated. The crude product was an 87:1 mixture of
the sulfide 2 and sulfoxide 1 (based on the signals at d 2.46
and 2.68 in the 400 MHz 1H NMR spectrum). Purification
by silica gel chromatography [hexane–propan-2-ol (100:1)]
afforded 2 (343 mg, 75%) identical with a commercially
available material.