N-Chlorosuccinimide as a versatile reagent for the sulfenylation of ketones: a facile synthesis of α-ketothioethers

Article abstract of DOI:10.1016/j.tetlet.2008.02.136

The sulfenylation of ketones having α-hydrogens has been achieved using N-chlorosuccinimide (NCS) under mild reaction conditions to produce α-ketothioethers in excellent yields with high selectivity. The use of NCS makes this method quite simple, convenient and practical.

Full text of DOI:10.1016/j.tetlet.2008.02.136

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Tetrahedron Letters 49 (2008) 3015–3018
N-Chlorosuccinimide as a versatile reagent for the sulfenylation
of ketones: a facile synthesis of a-ketothioethers
J. S. Yadav *, B. V. Subba Reddy, Ruchi Jain, Gakul Baishya
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 23 November 2007; revised 21 February 2008; accepted 25 February 2008
Available online 29 February 2008
Abstract
The sulfenylation of ketones having a-hydrogens has been achieved using N-chlorosuccinimide (NCS) under mild reaction conditions
to produce a-ketothioethers in excellent yields with high selectivity. The use of NCS makes this method quite simple, convenient and
practical.
Ó 2008 Published by Elsevier Ltd.
Keywords: Sulfenylation; Ketones; Aromatic thiols; a-Ketothioethers
a-Sulfenylketones are important intermediates1 for the
mono- and dialkylation of ketones2 preparation of 1,2-
diketones by bis-sulfenylation3 alkylation of the less
reactive a-position after bis-sulfenylation4 1,2-carbonyl
transposition5 and for the preparation of a,b-unsaturated
ketones.6 The most common methods for a-sulfenylation
of ketones involve the reactions of enolates7–12 (generated
from ketones using LDA in THF at À78 °C) with various
sulfenylating reagents such as PhSSPh, MeSSMe,
methylmethanthiosulfate (MeSSO2Me) or PhSCl and N-
(phenylthio)phthalimide or N-phenylthiocaprolactam.
Generally, the sulfenylation reactions of preformed eno-
lates13,14 or enamines,15–17 require multi-step sequences
for the preparation of the substrate thiol, strongly basic
conditions and anhydrous conditions. To our knowledge,
no direct method for a-sulfenylation of unmodified ketones
has been reported.
of N-chlorosuccinimide. The reaction went to completion
within 50 min at room temperature and the product, 2-
(phenylthio)cyclohexanone 3a was obtained in 80% yield
(Scheme 1). Similarly, cyclohexanone reacted with p-
chloro- and p-bromothiophenol to give 2-(arylthio)cyclo-
hexanones in good yields (Table 1, entries b and c). This
result provided the incentive to extend this sulfenylation
to other cyclic ketones such as cyclopentanone, dodeca-
none, b-tetralone, a-tetralone and 4-phenylcyclohexanone.
Interestingly, these cyclic ketones reacted efficiently with
p-chlorothiophenol to give the corresponding a-sulfenyl-
ketones (Table 1, entries d–h). Similarly, p-chloropropio-
phenone also underwent smooth a-sulfenylation under
these conditions (Table 1, entries i and j). This method
was successfully applied to a number of acyclic ketones
including 2-butanone, 3-pentanone, methyl isopropyl
ketone, diisopropyl ketone, methyl isobutyl ketone and
2-heptanone (Table 1, entries k–v). In all cases, the reactions
In this Letter, we report a simple, direct and efficient
method for the preparation of a-ketothioethers from
ketones and aromatic thiols.
Initially, we attempted the sulfenylation of cyclohexa-
none (1) with thiophenol (2) using a stoichiometric amount
O
O
SH
S
NCS
+
CH2Cl2, r.t.
3a
1
2
*
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
Scheme 1. Sulfenylation of cyclohexanone.
E-mail address: yadavpub@iict.res.in (J. S. Yadav).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.02.136

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J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 3015–3018
Table 1
NCS-promoted a-sulfenylation of ketones with aromatic thiols
Entry
Substrate
Thiophenol
Producta
Reaction time (min)
48
Yieldb (%)
80
O
O
S
SH
a
O
S
O
O
SH
b
c
d
42
38
45
82
89
78
Cl
Br
Cl
Cl
Cl
Br
O
S
SH
SH
O
S
O
Cl
O
S
O
O
SH
e
40
79
Cl
O
S
SH
SH
f
44
42
80
82
Cl
Cl
Cl
O
O
S
g
Cl
O
O
S
SH
SH
h
i
49
52
75
72
Cl
Cl
Cl
Ph
Ph
O
O
O
O
S
Cl
Cl
Cl
Br
SH
SH
S
j
55
75
Br
Cl
Cl
Cl
O
O
k
l
20
38
25
15
94
89
90
89
S
Cl
O
S
SH
O
O
O
O
S
O
S
SH
SH
m
n
Br
Br

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 3015–3018
3017
Table 1 (continued)
Entry
Substrate
Thiophenol
SH
Producta
Reaction time (min)
18
Yieldb (%)
O
O
o
p
98
90
Cl
S
Cl
O
O
SH
32
S
Cl
Cl
O
S
O
O
SH
SH
SH
q
r
s
24
26
35
84
87
85
Br
Cl
Cl
Br
Cl
O
S
O
O
O
S
Cl
O
SH
t
98
49
S
HO2C
O
COOH
SH
O
O
S
u
35
40
78
79
Br
Cl
Br
O
S
SH
v
Cl
a
All products were characterized by 1H NMR, IR and mass spectrometry.
Yield (wt %) refers to pure products after chromatography.
b
O
proceeded smoothly at room temperature under the influ-
ence of 1.1 mol equiv N-chlorosuccinimide. No additives
or acidic promoters were required for the reaction to
proceed. However, a trace amount of diphenyldisulfide
was detected by LC–MS as a side product. The reagent is
readily available at low cost and is highly efficient in pro-
moting sulfenylations. All the products were characterized
O
SCl
O
SH
Cl
N
HN
+
+
O
O
O
S
SCl
+
-HCl
Scheme 2. A plausible reaction mechanism.
1
by H NMR, IR and mass spectrometry and by compari-
son with known samples.7–12 The effects of various solvents
such as THF, diethyl ether, acetonitrile and dimethoxyeth-
ane were screened for this reaction. Of these solvents,
dichloromethane gave the best results. Mechanistically, it
is known that NCS reacts rapidly with an aromatic thiol
to generate a sulfenyl chloride18,19 which subsequently
interacts with ketones to give a-sulfenylketones. A plausi-
ble reaction mechanism is depicted in Scheme 2.
the absence of acid, the reaction was very sluggish.20,21
The scope of this method is demonstrated with respect to
various ketones and aromatic thiols and the results are pre-
sented in Table 1.22
In summary, we have developed a simple, efficient, selec-
tive and metal-free approach for the direct a-sulfenylation
of ketones using N-chlorosuccinimide as a safe and envi-
ronmentally friendly promoter. In addition to its efficiency,
The a-halogenation of ketones with N-halosuccinimide
was previously reported only under acidic conditions. In

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J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 3015–3018
(1.1 mmol) was added at 0 °C and the reaction was allowed to stir
at room temperature for the appropriate time (Table 1). After
completion of the reaction, as indicated by TLC, the reaction mixture
was quenched with water and extracted with dichloromethane
(2 Â 10 mL). Removal of the solvent followed by purification on
silica gel using ethyl acetate/n-hexane (1:9) as eluent afforded the pure
a-sulfenylketone. The by-product succinimide was isolated from the
aqueous layer by lyophilization. The reaction was also carried out on
large scale (1 g) following this procedure. Spectral data for selected
products:
simplicity and mild reaction conditions, this method pro-
vides excellent yields of products with high a-selectivity.
Acknowledgement
R.J. and G.B. thank CSIR, New Delhi for the award of
fellowships.
References and notes
(e) 2-(4-Chlorophenylthio)cyclododecanone: Liquid, IR (KBr): mmax
2932, 2860, 1705, 1472, 1441, 1340, 1149, 1093, 1012, 819 cmÀ1 1H
.
1. (a) Trost, B. M. Chem. Rev. 1978, 78, 363; (b) Trost, B. M. Acc. Chem.
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Soc. C 1971, 19.
5. Kane, V. V.; Singh, V.; Martin, A.; Doyle, D. L. Tetrahedron 1983,
39, 345. and references cited therein.
NMR (CDCl3, 200 MHz): d 7.38 (m, 4H), 3.60 (dd, J = 3.6, 11.7 Hz,
1H), 2.53–2.46 (t, J = 5.8 Hz, 2H), 2.10–1.65 (m, 4H), 1.60–1.21 (m,
14H); 13C NMR (75 MHz, CDCl3 ): d 207.9, 137.6, 133.6, 131.9,
129.2, 55.6, 40.2, 35.8, 25.6, 25.9, 24.7, 24.5, 24.1, 23.7, 23.6, 22.1. LC–
MS: m/z: 325 (M+1)+. HRMS calculated for C18H25OSClNa
(M+Na+): 347.1213. Found: 347.1212.
(i) 1-(4-Chlorophenyl)-2-(4-chlorophenylthio)propan-1-one: Liquid,
IR (KBr): (mmax): 2978, 2935, 1687, 1590, 1481, 1400, 1349, 1217,
1091, 1010, 951, 739 cmÀ1 1H NMR (CDCl3, 200 MHz): d 7.53 (m,
.
6. Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976, 98,
4887.
7. Scholz, D. Synthesis 1983, 944.
8. Seebach, D.; Teschner, M. Tetrahedron Lett. 1973, 5113.
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10. Groenewegen, P.; Kallenberg, H.; van der Gen, A. Tetrahedron Lett.
1979, 20, 2817.
11. Coates, R. M.; Pigott, H. D.; Ollinger, J. Tetrahedron Lett. 1974, 15,
3955.
12. Huang, C.-H.; Liao, K.-S.; De, S. K.; Tsai, Y.-M. Tetrahedron Lett.
2000, 41, 3911.
13. Murai, S.; Kuroki, Y.; Hasegawa, K.; Tsutsumi, S. Chem. Commun.
1972, 946.
14. Foray, G.; Pefliiory, A. B.; Rossi, R. A. Tetrahedron Lett. 1997, 38,
2035.
15. Kuehen, M. E. J. Org. Chem. 1963, 28, 2124.
16. Kumamoto, T.; Kobayashi, S.; Mukaiyama, T. Bull. Chem. Soc. Jpn.
1972, 45, 866.
17. Wang, W.; Li, H.; Wang, J.; Liao, L. Tetrahedron Lett. 2004, 45,
8229.
18. Emde H.; Homberg, N. Patent DE804572, 1949, 8; Chem. Abstr.
1952, 46, 529i.
19. Schlosser, K. M.; Krasutsky, A. P.; Hamilton, H. W.; Reed, J. S.;
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20. Meshram, H. M.; Reddy, P. N.; Sadashiv, K.; Yadav, J. S.
Tetrahedron Lett. 2005, 46, 823.
6H), 7.28 (m, 2H), 4.00 (q, J = 6.6 Hz, 1H), 2.02 (d, J = 6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3 ): d 199.2, 139.1, 136.1, 135.1, 133.8,
130.0, 129.3, 129.1, 128.8, 45.9, 16.6. LC–MS: m/z: 311 (M+1).
HRMS calculated for C15H13OSCl2Na (M+Na+): 311.0068. Found:
311.0064.
(m) 2-(Naphthalen-2-ylthio)pentan-3-one: Solid, mp 123–126 °C, IR
(KBr): mmax 3052, 2975, 2932, 1708, 1624, 1585, 1498, 1451, 1345,
1129, 1069, 813, 743 cmÀ1. 1H NMR (CDCl3, 300 MHz): d 7.73–7.63
(m, 4H), 7.48–7.31 (m, 3H), 3.86 (q, J = 6.7, 1H), 2.63 (q, J = 7.5 Hz,
2H), 1.40 (d, J = 6.7 Hz, 3H), 1.08 (t, J = 7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 208.5, 136.5, 131.7, 130.4, 129.8, 128.9, 127.9,
127.7, 126.9, 126.7, 125.9, 51.5, 32.6, 16.7, 8.4. LC–MS: m/z: 267
(M+23)+. HRMS calculated for C15H16OSNa (M+Na+): 267.0818.
Found: 267.0819.
(o) 2-(4-Chlorophenylthio)pentan-3-one: Liquid, IR (KBr): mmax 2970,
2927, 1710, 1573, 1470, 1382, 1093, 1011, 819 cmÀ1 1H NMR
.
(CDCl3, 300 MHz): d 7.24 (m, 4H), 3.69 (q, J = 7.5 Hz, 1H), 2.73–
2.60 (dq, J = 6.7, 14.3 Hz, 2H), 1.38 (d, J = 7.5 Hz, 3H), 1.05 (t,
J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 208.1, 134.5, 129.6,
129.5, 129.4, 51.3, 32.5, 16.3, 8.3. LC–MS: m/z: 229 (M+1)+. HRMS
calculated for C11H13OSClNa (M+Na+): 251.0279. Found: 251.0273.
(r) 2-(4-Chlorophenylthio)-2,4-dimethylpentan-3-one: Liquid, IR
(KBr): mmax 2972, 2932, 2872, 1699, 1572, 1471, 1384, 1092, 1033,
822 cmÀ1. 1H NMR (CDCl3, 200 MHz): d 7.26 (m, 4H), 3.40 (m, 1H),
1.40 (s, 6H), 1.15 (d, J = 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3): d
211.6, 136.8, 135.4, 130.1, 129.0, 56.4, 34.1, 24.5, 21.0. LC–MS: m/z:
257 (M+1). HRMS calculated for
279.0584. Found: 279.0586.
C
13H17OSClNa (M+Na+):
21. Toutchkine, A.; Aebisher, D.; Clennas, E. L. J. Am. Chem. Soc. 2001,
123, 4966.
22. General procedure: To a stirred solution of ketone (1 mmol) and thiol
(1.2 mmol) in dichloromethane (10 mL), N-chlorosuccinimide