An efficient preparation of 1-phenylsulfonylindolyl methyl sulfoxides using KF/m-CPBA

Article abstract of DOI:10.1016/j.tetlet.2005.04.067

A variety of 1-phenylsulfonylindolylmethyl sulfides are selectively oxidized to the corresponding sulfoxides using a hitherto unexplored KF/m-CPBA system. A major advantage is the absence of over-oxidation.

Full text of DOI:10.1016/j.tetlet.2005.04.067

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4231–4233
An efficient preparation of 1-phenylsulfonylindolyl methyl
sulfoxides using KF/m-CPBA
Arasambattu K. Mohanakrishnan* and Neelamegam Ramesh
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu, India
Received 9 March 2005; revised 7 April 2005; accepted 12 April 2005
Available online 3 May 2005
Abstract—A variety of 1-phenylsulfonylindolylmethyl sulfides are selectively oxidized to the corresponding sulfoxides using a hith-
erto unexplored KF/m-CPBA system. A major advantage is the absence of over-oxidation.
ꢀ 2005 Elsevier Ltd. All rights reserved.
In general, sulfoxides are invariably prepared via the
oxidation of the corresponding sulfides and several ways
of achieving this transformation have been explored.1
Despite the plethora of reagents that are available for
sulfoxidations, most require careful quantitative control
of oxidant to avoid the formation of the over-oxidation
product, namely sulfones.
Next, we turned our attention to hypervalent oxidizing
reagents. Very recently, oxidation of sulfide to the corre-
sponding sulfoxide using hypervalent iodine has been
comprehensively reviewed.7 Sha and coworkers8 utilized
NaI/m-CPBA for iodination of silyl enol ethers. We
wondered if the same system could also be used for sul-
foxidation, however, the use of NaI/m-CPBA led to the
selective sulfoxidation of 1a but only in low yields. The
reaction was slow and the product was always contam-
inated with starting material despite the use of 2 equiv of
NaI/m-CPBA. We noted a recent report which described
an easy conversion of azides into nitro compounds using
HOFÆCH3CN.9 The oxygen atom of HOFÆCH3CN
being electrophilic was also used for the oxidation of
sulfides into sulfones,10,11 so we therefore decided to ex-
plore a KF/m-CPBA system. The interaction of KF and
m-CPBA in acetonitrile–water followed by the addition
of sulfide 1a led to the isolation of sulfoxide 2a in 91%
yield (Scheme 1).
In an ongoing project, we required an array of indolyl-
methyl sulfoxides for annelation studies.2 Additionally,
the indolylmethyl sulfoxides and sulfones have been ex-
plored as potential reverse transcriptase inhibitors.3
Gray et al. reported a novel synthesis of indolylmethyl
sulfoxides involving a tandem sigmatropic rearrange-
ment/Michael addition.4
We initiated our oxidation study with sulfide 1a. All our
attempts using one equiv of m-CPBA led to the forma-
tion of sulfoxide 2a along with the corresponding
sulfone in an appreciable amount (15–20%). Slow
addition of m-CPBA to a solution of substrate in
DCM at 0 ꢁC also led to the formation of the sulfone
as a minor product. The oxidation of sulfide was also at-
tempted using Oxone5 in moist chloroform but without
success. The oxidation of 1a using IBX adopting condi-
tions published by Akamanchi and co-workers6 led to
recovery of starting sulfide 1a. Thus, under all the con-
ditions tried, incomplete oxidation of sulfide or the for-
mation of sulfone was observed as a side product.
We tested the KF/m-CPBA methodology with various
indolylmethyl sulfides (Table 1). In all cases, we ob-
tained the corresponding sulfoxides in good yields
CN
KF/m-CPBA
CN
O
S
0-10 0C
SPh
Ph
N
CH3CN-H2O (5 : 1)
N
SO2Ph
SO2Ph
Keywords: Indolylmethyl sulfide; Sulfoxidation; KF/m-CPBA; Indo-
lylmethyl sulfoxides.
30 min
91%
1a
2a
*
Corresponding author. Fax: +91 44 22352494;
mohan_67@hotmail.com
e-mail:
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.067

4232
A. K. Mohanakrishnan, N. Ramesh / Tetrahedron Letters 46 (2005) 4231–4233
Table 1. Preparation of indolylmethyl sulfoxides with KF/m-CPBA
Entry Sulfide13
Sulfoxide14
CN
Yield (%)
(mp ꢁC)
Entry Sulfide13
Sulfoxide14
Ph
Yield (%)
(mp ꢁC)
CN
O
S Ph
SPh
S
SPh
1
91 (142)
9
89 (132)
O
N
N
SO2Ph
1a
SO2Ph
N
N
2a
SO2Ph
SO2Ph
1i
2i
CO2Me
CO2Me
SPh
O
S Ph
O
S
Ph
N
N
2
3
91 (124–126) 10
82 (liquid)
94 (118)
N
N
PhS
COPh
COPh
SO2Ph
SO2Ph
2b
2j
1j
1b
CO2Et
CO2Et
O
SPh
S
O
SP h
SPh
Ph
84 (136)
11
N
N
N
N
SO2Ph
SO2Ph
SO2Ph
SO2Ph
1c
2c
1k
2k
Br
OPh
OPh
Br
O
O
SPh
SPh
S Ph
S Ph
4
5
87 (120)
93 (142)
12
13
87 (145)
N
N
N
N
SO2Ph
SO2Ph
SO2Ph
2d
Me
SO2Ph
1d
1l
2l
O
Me
S
O
S Ph
S
SPh
95 (182–184)
N
N
N
N
PhO2S
O
SO2Ph
O
PhO2S
SO2Ph
1m
2e
1e
2m
MeO
MeO
COMe
CO2Et
O
COMe
SPh
CO2Et
SPh
O
S Ph
S Ph
6
7
8
90 (130)
91 (118)
88 (182)
14
15
16
92 (94–96)
88 (120)
92 (94)
N
N
N
N
SO2Ph
SO2Ph
SO2Ph
SO2Ph
1f
2f
1n
2n
O
S
O
SPh
SPh
CO2Et
SO2Ph
S
Ph
N3
N3
Ph
N
N
CO2Et
N
N
SO2Ph
SO2Ph
SO2Ph
1g
1o
2g
2o
O
O
S
Br
Br
SPh
Me
SO2Ph
N
N
S
S
Ph
N
N
N
N
N
Me
H
H
N
SO2Ph
SO2Ph
SO2Ph
1h
1p
2p
2h
without any trace of sulfones. Several of these sulfox-
ides 2a, 2b, 2d, 2f, 2g and 2k are regarded as potential
bidentate synthons and they may be useful for the syn-
thesis of biologically important carbazoles. The sulfox-
ides of relatively unexplored indolyl-4-methyl and
indolyl-7-methyl systems were also prepared (entries 9
and 10).
dole and benzimidazole skeletons was prepared in 75%
yield without any trace of the corresponding sulfone.
In contrast to the HOFÆCH3CN system,9 using our sys-
tem an azide survived (entry 15) and only sulfoxidation
occurred. Moreover, oxidation stopped at the sulfoxide
stage as opposed to the sulfone obtained with
HOFÆCH3CN.11
Pantoprazole, which has promising anti-ulcer activity,
has a sulfoxide unit bridging pyridine and benzimidazole
heterocycles. Large-scale production12 of this compound
via sulfoxidation of the corresponding sulfide always
proceeds to give sulfone as a minor impurity. Using
our methodology, sulfoxide 2p (entry 16) containing in-
In summary, we have synthesized several indolylmethyl
sulfoxides via sulfoxidation using a combination of KF
and m-CPBA with good selectivity. The unravelling of
the synthetic utility of these sulfoxides is currently in
progress. Further exploitation of the selective oxidative
behaviour of KF/m-CPBA will also be explored.

A. K. Mohanakrishnan, N. Ramesh / Tetrahedron Letters 46 (2005) 4231–4233
4233
13. All the required sulfides 1a–p were prepared using the two-
step procedure as described below:
Acknowledgements
A.K.M. thanks the UGC (F.12-140/2001 SR-1), New
Delhi, for financial support. Financial support to the
Department from DST-FIST is also acknowledged.
CH2SPh
Me
CH2Br
NBS/CCl4
NaH/PhSH
N
N
PG
(C6H5COO)2
N
PG
PG
References and notes
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14. All the sulfoxides 2a–p gave satisfactory spectroscopic and
analytical data.Typical experimental procedure for 2a: To
a solution of KF (0.63 g, 10.84 mmol) in acetonitrile–
water (40 mL, 8 mL), 70% m-CPBA (1.87 g, 10.84 mmol)
was added and the mixture stirred at 0 ꢁC for 30 min. To
this, 1-phenylsulfonyl-2-phenylthiomethyl-3-cyanoindole
1a (2.21 g, 5.46 mmol) was added and stirring was
continued for an additional 30 min. The reaction mixture
was then poured into saturated aq NaHCO3 solution,
extracted with ethyl acetate (2 · 40 mL) and the extracts
dried (Na2SO4). Removal of solvent followed by crystal-
lization from MeOH afforded 2a as pale yellow crystals
(2.1 g, 91%).
3. (a) Williams, T. M.; Ciccarone, T. M.; MacTough, S. C.;
Rooney, C. S.; Balani, S. K.; Condra, J. H.; Emini, E. A.;
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Spectroscopic data for selected sulfoxides: For 2a: mp
1
142 ꢁC; IR (KBr) mmax: 2221, 1380, 1181, 1083 cmÀ1. H
NMR (500 MHz, CDCl3): d 4.71 (s, 2 H), 7.26 (d,
J = 7.9 Hz, 1H), 7.51 (m, 8H), 7.65 (d, J = 8.4 Hz, 2H),
7.88 (d, J = 8.0 Hz, 2H), 8.07 (d, J = 8.0 Hz, 1H). MS(EI)
m/z (%): 404 (M-16, 9%), 231 (35), 154 (39), 141 (28).
Elemental anal. calcd for C22H16N2O3S2: C, 62.84; H,
3.84; N, 6.66, S, 15.25%. Found: C, 62.83; H, 3.98; N,
6.51; S, 15.17%.
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For 2k: mp 118 ꢁC; IR (KBr) mmax: 1690, 1360, 1160,
1040 cmÀ1 1H NMR (200 MHz, CDCl3): d 1.35 (t,
.
J = 7.4 Hz, 3H), 4.25 (q, J = 7.4 Hz, 2H), 4.45 (d,
J = 14.0 Hz, 1H), 4.65 (d, J = 14.0 Hz, 1H), 6.45 (d, J =
16.0 Hz, 1H-vinylic a-H), 7.75 (m, 15H). MS(EI) m/z (%):
477 (M-16, 16%), 361 (38). Elemental anal. calcd for
C26H23NO5S2: C, 63.27; H, 4.70; N, 2.84, S, 12.99%.
Found: C, 63.19; H, 4.85; N, 2.73; S, 12.87%.
For 2p: mp 94 ꢁC; IR (KBr) mmax: 3165, 1370, 1160,
9. Rozen, S.; Carmeli, M. J. Am. Chem. Soc. 2003, 125,
8118–8119.
1060 cmÀ1 1H NMR (400 MHz, CDCl3): d 5.15 (d,
.
J = 13.6 Hz, 1H), 5.29 (d, J = 13.6 Hz, 1H), 7.55 (m,
11H), 7.78 (d, J = 7.6 Hz, 2H), 8.07 (d, J = 8.4 Hz, 1H).
MS(EI) m/z (%): 496 (M-16, 12%), 367 (7), 285 (15), 144
(22). Elemental anal. calcd for C22H16BrN3O3S2: C, 51.37;
H, 3.14; N, 8.17; S, 12.47%. Found: C, 51.31; H, 3.21; N,
8.06; S, 12.48%.
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11. Rozen, S. Acc. Chem. Res. 1996, 243–248.
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