Highly stereoselective preparation of chiral α-Substituted sulfides from α-Chloro sulfides via 1,2-asymmetric induction

Article abstract of DOI:10.1055/s-0030-1258106

A C-S stereogenic center is created with efficient stereocontrol by 1,2-asymmetric induction due to a vicinal C-O stereogenic center. Propargylic, allylic, and alkyl sulfides are readily prepared in good yield and stereoselectivity from α-chloro sulfides. The allylic sulfide have been converted to the corresponding sulfoxide/sulfilimine/sulfur ylide and subjected to [2,3]-sigmatropic rearrangement. The efficient 1,3-chirality transfer observed in this reaction eventually results in a net 1,4-chirality transfer. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258106

LETTER
1807
Highly Stereoselective Preparation of Chiral a-Substituted Sulfides from
a-Chloro Sulfides via 1,2-Asymmetric Induction
Preparation of Chiral a-Substituted Sulfides
Sadagopan Raghavan,* V. Vinoth Kumar, L. Raju Chowhan
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500007, India
E-mail: sraghavan@iict.res.in
Received 12 February 2010
OP
OP
Abstract: A C–S stereogenic center is created with efficient stereo-
control by 1,2-asymmetric induction due to a vicinal C–O stereo-
genic center. Propargylic, allylic, and alkyl sulfides are readily
prepared in good yield and stereoselectivity from a-chloro sulfides.
The allylic sulfide have been converted to the corresponding sulfox-
ide/sulfilimine/sulfur ylide and subjected to [2,3]-sigmatropic rear-
rangement. The efficient 1,3-chirality transfer observed in this
reaction eventually results in a net 1,4-chirality transfer.
R2M
R2
Ph
S
R1
Ph
R1
S
Cl
1
2
Scheme 1 Diastereoselective preparation of a-substituted sulfides
a-Chloro sulfides are valuable synthetic intermediates as
reactive electrophiles,7 nucleophiles in metal-promoted
carbon–carbon bond-forming reactions1,2,8 and as alde-
hyde or ketone equivalents.9 The reaction of a-chloro sul-
fides with silyl enol ethers10 constitutes an important
method for the regioselective introduction of a thioalkyl
substituent a to the carbonyl group. The reaction of a-
chloromethyl methylsulfide with phenyl Grignard reagent
reported first by Bohme11 has been extended into a general
method for introducing a-alkyl/aryl substituents. Howev-
er, the reactions reported thus far have been carried out on
simple cyclic and acyclic a-chloro sulfides only. There are
no reports on the preparation of a-branched sulfides by the
reaction of a-chloro sulfides with Grignard and other or-
ganometallic reagents.
Key words: a-chloro sulfide, rearrangement, sulfoxide, stereo-
selective synthesis, asymmetric induction
The development of new and highly selective carbon–
carbon and carbon–heteroatom bond-forming processes
are an important topic in organic synthesis. The creation
of stereogenic centers in acyclic systems, as compared to
cyclic systems, is particularly challenging due to the many
available degrees of freedom. Chiral a-branched propar-
gylic and allylic sulfides are versatile building blocks as a
source of epoxy alkynes,1 epoxydiynes,2 allylic alcohols,3
allylic amino derivatives,4 and g,d-unsaturated acids.5
However, the required substrates are not readily available
and are prepared from the chiral-pool starting materials6
thus making one enantiomer more available than the other
while simultaneously limiting the products that can be
prepared. An exception to this is the recent report by
Armstrong and co-workers on the preparation of allylic
sulfides by organocatalysis.4 An alternative approach to
chiral a-branched sulfides would therefore greatly expand
the scope of the process. We disclose herein the results of
our investigation on the stereoselective synthesis of chiral
a-branched sulfides 2 by reacting a-chloro sulfides 1 with
organometallic reagents, via 1,2-asymmetric induction by
an adjacent stereogenic carbon bearing a protected hy-
droxy group (Scheme 1).
The envisaged reaction of the a-chloro sulfide with a basic
organometallic reagent was expected to pose difficulties
because of the other competing reactions like metal–halo-
gen exchange and subsequent b-elimination of the alkoxy
substituent to furnish vinyl sulfide 3, elimination of chlo-
rine to yield enol ether 4 or reduction12 to yield sulfide 5
(Scheme 2).
The study was initiated with racemic sulfide13 6. On treat-
ment of 6 with an equivalent amount of N-chlorosuccin-
imide (NCS) in benzene at ambient temperature a-
chlorosulfide 7 was formed. The a-chlorosulfide 7 was
used without isolation, being added to 1-octynylzinc bro-
mide (8a), that was prepared from 1-octynylmagnesium
chloride and anhydrous zinc bromide14 in THF. Work up
OP
OP
OP
and/
or
and/
S
S
S
S
Ph
R
Ph
R
or
Ph
R
Ph
R
Cl
1
3
4
5
Scheme 2 Possible side reactions
SYNLETT 2010, No. 12, pp 1807–1810
x
x
.x
x
.2
0
1
0
Advanced online publication: 30.06.2010
DOI: 10.1055/s-0030-1258106; Art ID: S00910ST
© Georg Thieme Verlag Stuttgart · New York

1808
S. Raghavan et al.
LETTER
of this mixture afforded propargyl sulfide 9a as a 9:1 mix- Similarly reaction of 7 with the organozinc bromide 8b
ture of diastereomers in 86% yield15 (Table 1).
prepared from propargyl silyl ether afforded a 9:1 mixture
of diastereomers. A bulky TMS substituent in 8c, howev-
er, led to the isolation of a single product in 90% yield.
The alkenyl organozinc reagents were prepared from the
corresponding Grignard reagents which were either com-
mercially available or prepared.16 The reaction of mono-,
di-, and trisubstituted alkenylzinc bromides with 7 pro-
ceeded very stereoselectively to afford a single diastereo-
mer in good yield (Table 1). Likewise the reaction of 7
with primary and secondary alkylzinc bromides proceed-
ed very stereoselectively, to afford the products in moder-
ate yield though, as a consequence of some reduction to
sulfide 6 and elimination to afford vinyl sulfide of the type
4.17
Table 1 Stereoselective Synthesis of Racemic a-Substituted Sul-
fidesa
OTBS
Ph
RZnBr, THF
OTBS
Ph
8
S
R
Ph
X
S
Ph
6 X = H
7 X = Cl
9
NCS, PhH
Entry
Organozinc reagent (RM)
Product, yield (%)b
(ratio syn/anti)c
M
9a, 86
(9:1)
4
1
2
8a
M
We next explored the preparation of optically active prod-
ucts. Acetonide 10, prepared from L-tartaric acid in four
steps, was converted to a-chloro sulfide 11 and reacted
with a variety of organozinc bromides (Table 2). An in-
9b, 76
(9:1)
OTBS
8b
9c, 90
(>95:<5)
M
TMS
3
4
Table 2 Stereoselective Synthesis of Chiral a-Branched Sulfidesa
8c
OP2
OP2
P1O
P1O
9d, 80
(>95:<5)
RZnBr, THF
M
8
OBn
OBn
8d
PhS
R
X
SPh
d
5
6
–
10 P1, P2 = C(Me2); X = H
11 P1, P2 = C(Me2); X = Cl
13 P1 = P2 = TBS; X = H
14 P1 = P2 = TBS; X = Cl
12 P1, P2 = C(Me2)
15 P1 = P2 = TBS
M
8e
M
NCS, PhH
NCS, PhH
9f, 90
(>95:<5)e
Entry
Organozinc reagent Chlorosulfide Product, Yield (%)b
(RM)
(ratio syn/anti)c
8f
M
9g, 72
1
2
8a
11
11
11
11
11
11
11
14
14
14
12a, 76
(3:1)
7
(>95:<5)f
8g
M
8d
8f
12d, 78
(>95:<5)
9h, 76
(>95:<5)
8
9
3
12f, 80
(>95:<5)
8h
M
9i, 60
(>95:<5)
4
8h
8i
12h, 86
(>95:<5)
5
5
8i
5
12i, 66
(>95:<5)
9j, 60
(>95:<5)
10
11
12
M
6
8k
8l
12k, 60d
(>95:<5)
8j
9k, 64g
(>95:<5)
M
8k
7
12l, 60d
(>95:<5)
9l, 60g
(>95:<5)
M
8
8a
8f
15a, 70
(98:2)
8l
a All reactions were carried out on a 0.5 mmol scale.
b Yield refers to isolated yield.
9
15f, 80
(98:2)
c Ratios determined by examination of crude 1H NMR.
d Reagent polymerization during organozinc bromide preparation.
e 1.5:1 mixture of geometrical isomers.
10
8k
12a, 60d
(98:2)
f 5:1 ratio of geometrical isomers.
g 10% of vinyl sulfide of type 4 and sulfide observed.
a All reactions were carried out on a 0.5 mmol scale.
b Yield refer to isolated yield.
c Ratios determined by examination of crude 1H NMR.
d 10% of sulfide and vinylsulfide of type 4 observed.
Synlett 2010, No. 12, 1807–1810 © Thieme Stuttgart · New York

LETTER
Preparation of Chiral a-Substituted Sulfides
1809
spection of Table 2 reveals that the reaction of 11 with corresponding sulfoxide 16 which underwent a [2,3]-sig-
alkynylzinc bromide proceeded with modest stereocontrol matropic rearrangement upon warming to furnish the al-
(entry 1). The reaction with alkenylzinc bromides, howev- lylic alcohol 17. Reaction with (R)- and (S)-methoxy
er, proceeded with excellent stereoselectivity to afford a mandelic acid afforded esters 18 and 19, respectively
single product in good yield. As with 7, the yield of the (Scheme 3). A comparison of the chemical shifts19 led to
products in the reaction of 11 with alkylzinc reagents were an unambiguous assignment of S-configuration20 to the
less due to side reactions. It is worthwhile to note that the carbinol and therefore R-configuration at sulfur-bearing
reaction of 8a with the chloro sulfide 14, prepared from carbon in 12i since it is well precedented that the rear-
di-OTBS ether 13,18 proceeded with excellent stereoselec- rangement proceeds with excellent transfer of chirality.21
tivity (Table 2, entry 8).
The structure of other products were assigned based on
analogy.
The configuration of the new stereogenic centre in sul-
fides 9 were assigned based on the J value of the methine The observed stereoselectivity can be rationalized by in-
proton. The observed coupling constant for the benzylic voking a model depicted in Scheme 4 wherein the nucleo-
methine proton of the major isomer (6.6 Hz) and minor phile attacks the sulfenium ion from the side opposite to
isomer (5.1 Hz) in 9a is in full agreement1 of a syn rela- the phenyl group.
tionship between OR and SPh substituents in the major
The products are versatile synthons with many applica-
isomer. Since the earlier study1 pertained to hydroxy sul-
tions in organic synthesis. A recent report details the use
fides, and conformational preferences could be different
of propargylic sulfides for the enantioselective prepara-
for the hydroxy sulfides and the corresponding silyl
tion of allenamides.22 Also they can be partially reduced
ethers, 9a was desilylated to afford an inseparable mixture
to stereoselectively yield either the cis- or the trans-allylic
of hydroxy sulfides. The J value of the methine proton
sulfides or completely reduced to the alkyl sulfides. An
was 8.7 and 3.9 Hz, respectively, for the major and minor
added advantage is that the sp-hybridized nucleophiles are
isomers thus unambiguously confirming the structural as-
less basic compared to others, thereby side reactions are
minimized and the reagent used in excess can be recov-
ered and reused. The usefulness of allylic sulfide was
demonstrated in the stereoselective preparation of the 1,4-
signment. The structure was assigned to compounds 9b–l
based on analogy. The configuration at the newly created
center in 12i was assigned by conversion to mandelate es-
ters 18 and 19. Thus 12i was oxidized with MCPBA to the
diol derivative 17, a subunit present in annonaceous ace-
togenins,23a oxylipins,23b etc. In a similar fashion, 9j on
treatment with MCPBA in dichloromethane followed by
O
O
O
O
R
R
MCPBA, CHCl3
H
addition of triethylphosphite and warming the reaction
mixture furnished allyl alcohol 20 in excellent yield.
Treatment with anhydrous chloramine-T afforded the al-
lyl amino derivative 21.24 Thus a hydroxy/amino substit-
uent can be introduced stereoselectively at C4 relative to
the alkoxy substituent via consequtive 1,2- followed by
1,3-aymmetric induction resulting in a net 1,4-induction.
Also the double bond in 17, 20, and 21 further provides a
useful handle for functionalization. It is noteworthy that
from an appropriate trisubstituted alkenyl zinc reagent,
quaternary stereogenic centers could in principle be creat-
ed by the [2,3]-sigmatropic rearrangement. The in situ for-
mation of sulfur ylide by treatment of 9j with ethyl
diazoacetate in the presence of catalytic amounts of
R
PhS
then P(OEt)3,
MeOH, 80%
S
O
H
Ph
OBn
OBn
4
5
12i
16
O
O
O
O
R2
acid
H
R
R1
OH
O
DCC, CH2Cl2
80%
S
OMe
S
4
5
OBn
BnO
H
O
18 R1 = Ph, R2 = H
19 R1 = H, R2 = Ph
17
Scheme 3 Assignment of configuration
25
Rh2(OAc)4 and subsequent rearrangement yielded a
mixture of isomeric dienes26 22 instead of the desired
SH
OTBS
SPh
TBSO
RM
R
Ph
product (Scheme 5).
Ph
H
H
H
H
In summary we have disclosed a very versatile method for
the synthesis of chiral a-branched propargylic, allylic, and
Scheme 4 Model to rationalize the stereoselectivity
OTBS
OTBS
Ph
OTBS
Ph
EtO2CCHN2,
Rh2(OAc)4,
CH2Cl2
MCPBA, CH2Cl2
then P(OEt)3,
MeOH, 80%
S
EtO2C
Ph
Ph
X
or
NaNTsCl,
CH2Cl2, 78%
5
5
5
Me
Me
Me
22
9j
20 X = OH
21 X = NTs(SPh)
Scheme 5 Preparation of allyl alcohols/amines by [2,3] sigmatropic rearrangement
Synlett 2010, No. 12, 1807–1810 © Thieme Stuttgart · New York

1810
S. Raghavan et al.
LETTER
(15) The reaction of chloro sulfide 7 with 1-octynylmagnesium
chloride proceeded to afford the product in lower yield
(50%), while reaction with 1-lithio octyne did not yield any
desired product.
(16) (Z)-1-Octenylmagnesium bromide was prepared from (Z)-1-
bromo octene and Mg turnings while (E)-1-octenyl-
magnesium chloride was prepared from (E)-1-iodo octene
by halogen–metal exchange, see: Ren, H.; Krasovskiy, A.;
Knochel, P. Org. Lett. 2004, 6, 4215.
alkyl sulfides. The methodology would be useful for the
synthesis of natural products possessing a 1,4-diol, 1,4-
amino alcohol subunits, tetrahydrofuran, pyrrolidine, pyr-
an, and piperidine rings from appropriate starting materi-
als. The application of this methodology for the synthesis
of bioactive target molecules is under investigation and
the results would be reported in due course.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(17) General Experimental Procedure
To a solution of 1-octyne (165 mg, 1.5 mmol) in dry THF
(0.8 mL) cooled at –10 °C was added i-PrMgCl·LiCl (1 mL,
1.5 mmol, 1.5 M in THF) and stirred for 30 min at the same
temperature. To the so generated Grignard reagent, ZnBr2
(1.1 mL, 1.65 mmol, 1.5 M in THF) was added at 0 °C and
stirred for 30 min. To the organozinc reagent maintained at
0 °C was added a solution of chloro sulfide (0.5 mmol) in
benzene (5 mL), the reaction mixture stirred gradually
allowing it to attain r.t., and stirred further for a period of 7
h when TLC examination indicated complete consumption
of the chloro sulfide. The reaction mixture was cooled to
0 °C and quenched by the addition of an aq sat. NH4Cl
solution. It was allowed to warm to r.t. and diluted with
Et2O (5 mL), the layers were separated and aqueous layer
extracted with Et2O (3 × 10 mL). The combined organic
layers were washed with H2O (5 mL), brine (5 mL), dried
over Na2SO4, and the solvent evaporated under reduced
pressure to afford a crude compound which was purified by
column chromatography using hexanes as the eluent to
afford the pure product 9a (192 mg, 0.43 mmol) in 86% yield
as a liquid. TLC: Rf = 0.34 (hexanes). IR (KBr): 3445, 3063,
2954, 2928, 1586, 1463, 1384, 1253, 1094, 827, 837, 777,
695 cm–1. 1H NMR (200 MHz, CDCl3): d = 7.60–7.30 (m, 10
H), 4.91 (d, J = 6.8 Hz, 1 H), 4.16 (td, J = 2.3, 6.8 Hz, 1 H),
2.16 (dt, J = 2.3, 6.8 Hz, 2 H), 1.50–1.15 (m, 8 H), 1.00–0.90
(m, 12 H), 0.20 (s, 3 H), 0.0 (s, 3 H). 13C NMR (75 MHz,
CDCl3): d = 142.00, 135.62, 132.11, 128.58, 127.82, 127.69,
127.36, 126.89, 87.32, 77.45, 48.91, 31.45, 28.51, 28.47,
25.89, 22.62, 18.35, 14.20, –4.55, –4.83. ESI-MS: m/z 469
[M + NH4]+. ESI-HRMS: m/z calcd for C28H40ONaSiS:
475.2467; found: 475.2466.
Acknowledgment
S.R. is thankful to Dr. J. M. Rao, Head, Org. Div. I and Dr. J. S.
Yadav, Director, IICT for constant support and encouragement.
V.V.K is thankful to UGC, New Delhi and L.R.C is thankful to
CSIR, New Delhi for fellowship. Financial assistance from DST
(New Delhi) is gratefully acknowledged. We thank Dr. A. C.
Kunwar for the NMR spectra.
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