One-pot approach for the regioselective synthesis of β-keto sulfones based on acid-catalyzed reaction of sulfonyl chlorides with arylacetylenes and water

Article abstract of DOI:10.1016/j.tetlet.2004.10.176

Reaction of sulfonyl chlorides with arylacetylenes and water in the presence of a catalytic amount of sulfonic acid in THF provided β-keto sulfones in good yields with excellent regioselectivity.

Full text of DOI:10.1016/j.tetlet.2004.10.176

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 513–515
One-pot approach for the regioselective synthesis of b-keto
sulfones based on acid-catalyzed reaction of sulfonyl chlorides
with arylacetylenes and water
*
Chunbo Lai, Chanjuan Xi, Yanfeng Jiang and Ruimao Hua
Key Laboratory for Bioorganic Phosphorus Chemistry of Ministry of Education, Department of Chemistry,
Tsinghua University, Beijing 100084, China
Received 10 August 2004; revised 25 October 2004; accepted 28 October 2004
Available online 7 December 2004
Abstract—Reaction of sulfonyl chlorides with arylacetylenes and water in the presence of a catalytic amount of sulfonic acid in THF
provided b-keto sulfones in good yields with excellent regioselectivity.
Ó 2004 Elsevier Ltd. All rights reserved.
Sulfone compounds have drawn increasing attention
in organic synthesis. Among their derivatives, b-keto
sulfones display a broad range of synthetic versatili-
R1
O
R2
Cat.H+
THF
R1
1
R2 Cl SO R3 H O
2
2
SO R3
2
1
,2
3
ties and some exhibit fungicidal activity. Considering
the importance of b-keto sulfones, the development of
synthetic methodology for b-keto sulfones is of great
interest. The existing approach includes: (i) acylation
2
R = Aryl, R =H
1
Scheme 1.
4
of a-sulfonyl carbanions; (ii) alkylation of metallic
1
0
5
tion, we investigated the reaction of phenylacetylene
with p-toluenesulfonyl chloride (TsCl) and water in the
presence of a catalytic amount of p-toluenesulfonyl acid
TsOH) in THF at 50 °C. Interestingly, 1-phenyl-2-(p-
toluenesulfonyl) ethanone 1a was formed in good iso-
lated yield with excellent regioselectivity (Scheme 2).
Besides the desired compound 1a, styryl-p-tolyl-sulfone
a was also obtained in 10% isolated yield. These two
products 1a and 2a could be easily separated by using
column chromatography. It is noted that the result is
dependent on which solvent was used. Using CHCl or
3
DMSO solvent instead of THF, no product 1a was ob-
tained. In addition, using alcohols such as MeOH,
arene sulfinates; (iii) oxidation of b-keto sulfides, b-keto
6
sulfoxides or b-hydroxy sulfones; (iv) reaction of sulfo-
nyl chlorides with silyl enol ethers catalyzed by a ruthe-
7
(
nium(II) complex; (v) reaction of diazo sulfones with
8
aldehydes catalyzed by SnCl ; (vi) free-radical rear-
2
1
1
9
rangement of enol sulfonates. However these methods
are deficient in some aspects such as the use of strong
base, strict reaction conditions, complicated procedures
or unavailable starting materials. The most attractive
one seems to be the direct hydroxyl sulfonylation of
alkynes, in which C–S and C–O bond also formed in a
one-pot procedure. To the best of our knowledge, reac-
tion of sulfonyl chlorides with alkynes resulting in b-
keto sulfones has not been reported so far. Herein we
would like to report a one-pot procedure for the synthe-
sis of b-keto sulfones via the reaction of sulfonyl chlo-
rides with arylacetylenes and water in the presence of
a catalytic amount of sulfonic acid (Scheme 1).
2
BuOH or PhCH OH instead of water, the same product
2
was also obtained.
Ph
O
Ph
+
TsOH 30%
Encouraged by our previous study of preparation of b-
hydroxyl sulfones based on the acid-promoted reac-
Ph
+TsCl +H
O
2
o
Ts
Ts
THF, 50 C, 48h
1
a
2a
*
Corresponding author. E-mail: cjxi@tsinghua.edu.cn
Scheme 2.
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.176

514
C. Lai et al. / Tetrahedron Letters 46 (2005) 513–515
To investigate the reaction further, we mixed TsCl,
phenylacetylene and water together in the absence of
H in THF for 48 h at 50 °C, however no desired prod-
uct 1a was obtained. This indicated that sulfonic acid
was necessary to initiate the reaction. Moreover, to
confirm the desired product did not derive from direct
reaction of TsOH with alkynes, we mixed TsOH, phen-
ylacetylene and water in THF at 50 °C for 48 h. No
product 1a was formed. This result indicated that the
role of sulfonic acid was a catalyst and unlikely to be
a reactant.
Table 1 showed several representative examples of sulf-
onic acid catalyzed reactions of sulfonyl chlorides with
various arylacetylenes and water affording b-keto sulf-
ones under mild condition. Using methanesulfonyl chlo-
ride (MsCl) or TsCl and terminal alkynes, the
regioselectivity of product was always favouring intro-
duction of sulfone group to the terminal carbon of alky-
nes and the oxo group to the benzylic position. Besides
the desired product of b-keto sulfones, corresponding
vinyl sulfones have been detected as side products in
10% to 20% isolated yields (entries 1, 2, 4, 5 and 6)
+
Table 1. Reaction of sulfonyl chlorides with arylacetylenes and water
a
Entry
Arylacetylenes
Sulfonyl chloride
Reaction time (h)
48
Product
Yield (%)
O
Ts
Ts
1
TsCl
49
1
a
O
2
TsCl
48
48
Me
Me
1
b
O
Ts
3
4
5
TsCl
TsCl
MsCl
72
72
48
55
54
53
1
1
c
O
S
S
Ts
d
O
O
Ms
1
e
Ms
6
MsCl
48
45
Me
Me
1
f
O
Ms
7
8
MsCl
MsCl
72
72
51
49
1
1
g
h
O
S
S
Ms
a
Yield of isolated pure products after column chromatography on silica gel.

C. Lai et al. / Tetrahedron Letters 46 (2005) 513–515
515
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O
Cl
1
6
5
Scheme 3.
and a trace amount of 2h was detected by GC–MS (en-
try 8). For the reaction of sulfonyl chlorides with 1-ethy-
nyl-naphthalene, compound 1c or 1g was obtained as
the sole product (entry 3 and 7). However, when termi-
nal aliphatic alkynes such as 1-hexyne and internal alky-
nes such as 1-phenyl propyne were used, only trace
desired products were detected by GC–MS even with
the increased reaction temperature and prolonged reac-
tion time. The possible reason is that aliphatic alkyne is
not so active as arylacetylene and in the case of internal
alkyne, the hindrance of substituted group could also re-
tard the reaction.
3
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Based on the above results, a stepwise mechanism for
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1
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3
. In the presence of protic acid, electrophile 2, that is
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7
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4
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1
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5
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3
205.
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1. Representative procedure for sulfonic acid catalyzed reac-
tion of sulfonyl chloride with alkyne and water: Preparation
of 1-phenyl-2-(p-toluenesulfonyl) ethanone (1a): p-Tolu-
enesulfonyl chloride (228 mg, 1.2 mmol) and p-toluene-
sulfonic acid (52 mg, 0.30 mmol) were dissolved in 5 mL
THF. To the solution was added phenylacetylene
1
1
1
In conclusion, we have developed a new method for the
synthesis of b-keto sulfones. The advantages of this
method over previous ones include simple procedure,
mild condition and readily available starting materials.
The investigations into the mechanism of the formation
of side products and expansion of the reaction scope are
now being undertaken in this laboratory.
2
(116 mL, 1.0 mmol) and H O (22 mL, 1.2 mmol) at
ambient temperature. The mixture was warmed up to
5
0 °C and stirred for 48 h. Then it was quenched with H
2
O
and the aqueous layers were extracted with ethyl acetate
(20 mL) for 3 times and the combined organic layers were
Acknowledgements
2 4
dried over Na SO . The extract was evaporated and the
This work was supported by the National Natural Sci-
ence Foundation of China (20172032, 20372041).
crude product was purified by column chromatography on
silica gel (EtOAc/petroleum ether = 1:4) to afford com-
pound 1a (134 mg) as white solid in 49% isolated yield. H
1
NMR (CDCl
7.43 (m, 5H), 7.69 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 7.2 Hz,
3 4
, SiMe ): d 2.36 (s, 3 H), 4.65 (s, 2H), 7.22–
References and notes
1
3
2
128.8 (2C), 129.3 (2C), 129.8 (2C), 134.3, 135.8 (2C),
3 4
H); C NMR (CDCl , SiMe ): d 21.7, 63.6, 128.6 (2C),
1
. (a) Zhao, G.; Hu, J.; Qian, Z.; Yin, W. Tetrahedron:
Asymmetry 2002, 13, 2095–2098; (b) Gotor, V.; Rebolledo,
+
145.4, 188.2; ESI-MS: 281(M+Li ).