Direct sulfanylation of 4-hydroxycoumarins with thiols in water

Article abstract of DOI:10.1016/j.tetlet.2009.03.004

The direct sulfanylation of 4-hydroxycoumarins with thiols via C-OH bond activation in water under mild conditions is described, which afforded the corresponding 4-sulfanylcoumarins in good yields.

Full text of DOI:10.1016/j.tetlet.2009.03.004

Tetrahedron Letters 50 (2009) 2405–2406
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Tetrahedron Letters
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Direct sulfanylation of 4-hydroxycoumarins with thiols in water
*
Yi-Yuan Peng , Yanfang Wen, Xuechun Mao, Guanyinsheng Qiu
Key Laboratory of Green Chemistry, Jiangxi Province and Department of Chemistry, Jiangxi Normal University, Nanchang, Jiangxi 330027, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The direct sulfanylation of 4-hydroxycoumarins with thiols via C–OH bond activation in water under
mild conditions is described, which afforded the corresponding 4-sulfanylcoumarins in good yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 10 January 2009
Revised 26 February 2009
Accepted 3 March 2009
Available online 6 March 2009
As a privileged scaffold, coumarin shows interesting biological
properties.1 The prominence of coumarin in natural products and
biologically active molecules has promoted considerable efforts to-
ward their synthesis.2 Recently, it was found that 4-sul-
fanylcoumarins showed promising anti-HCV activity.3 The
discovery of promising lead antivirus compounds and their moder-
ate activity warranted the development of efficient and rapid syn-
theses and evaluations of analogous structures in the search for
better inhibitors. Although 4-sulfanylcoumarins have been synthe-
sized either for biological evaluation or as key intermediates in
generation of complex molecules, their syntheses usually suffer
from multiple synthetic steps, harsh reaction conditions (such as
utilizing toxic reagents often under high temperatures), and poor
substituent tolerance.4 Thus, it is highly desired to develop general
and efficient methods for the synthesis of 4-sulfanylcoumarins,
especially in a green process.
Initially, a set of experiments were carried out using 4-hydroxy-
coumarin 1a and 4-methylbenzenethiol 2a as model substrates.
We conceived that the presence of arenesulfonyl chloride would
enable an in situ activation of 4-hydroxycoumarin substrates.7
Thus, the reactions were performed in water at room temperature
in the presence of different bases and p-toluenesulfonyl chloride
(Scheme 1). Gratifyingly, we observed the formation of the desired
product 3a (30% yield) when the reaction occurred in the presence
of sodium bicarbonate. Further screening of bases (including inor-
ganic and organic bases) revealed that triethylamine was the best
choice. Under this condition, the desired 4-sulfanylcoumarin 3a
was isolated in 76% yield. Similar yield was generated while adding
surfactant in the reaction. No product was detected without addi-
tion of base. The reaction could not proceed in the absence of p-tol-
uenesulfonyl chloride. It is also noteworthy that this reaction could
be carried out under air atmosphere without loss of yield.
Recently, palladium-catalyzed cross-coupling reactions via C–
OH bond activation of tautomerizable heterocycles with arylbo-
ronic acids using phosphonium salts as activation reagent were
disclosed. In this Letter, Kang et al. described that phosphonium
salts enabled an in situ activation of tautomerizable heterocycles,
as well as their subsequent palladium-catalyzed cross-coupling
reactions of arylboronic acids.5 Subsequently, Ackermann reported
that phenols could be employed as proelectrophiles in ruthenium-
catalyzed dehydrative direct arylations, and p-toluenesulfonyl
chloride was utilized for the C–OH bond activation.6 Prompted
by the results, we envisioned that 4-hydroxycoumarin might be
utilized as starting material for synthesis of 4-sulfanylcoumarins
in the presence of p-toluenesulfonyl chloride as C–OH bond activa-
tor. Meanwhile, considering the green process, it is of importance
to perform this reaction in water since water is environmentally
benign and potential advantages of using water as a solvent are
its low cost, safety, and ease of use. Thus, to verify the practicability
of this projected route, we started to investigate the possibility of
this transformation.
The scope of this reaction was then investigated under this pre-
liminary optimized conditions (TsCl, Et3N, H2O, rt, air), and the re-
sults are summarized in Table 1. For all cases, 4-hydroxycoumarin
1 reacted with thiols 2 leading to the corresponding products 3 in
good yields. For instance, reaction of 4-hydroxycoumarin 1a with
benzenethiol 2b under the standard conditions gave rise to the de-
sired product 3b in 80% yield (Table 1, entry 2). Similar yield was
obtained when 4-fluorobenzenethiol 2c was utilized as the reac-
tion partner (Table 1, entry 3, 83% yield).
Reactions of 4-hydroxycoumarin 1a and benzenethiols with
electron-withdrawing group attached on the aromatic ring pro-
ceeded well to afford the desired products 3 in good yield (Table
1, entries 3–5). It seems that the groups attached on the aromatic
OH
O
SC6H4p-Me
SH
TsCl, base
H2O, rt
+
O
Me
O
O
2a
3a
1a
* Corresponding author. Tel.: +86 791 8120386; fax: +86 791 8120386.
E-mail address: yiyuanpeng@yahoo.com (Y.-Y. Peng).
Scheme 1. Screening conditions for reaction of 4-hydroxycoumarin 1a with 4-
methylbenzenethiol 2a.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.004

2406
Y.-Y. Peng et al. / Tetrahedron Letters 50 (2009) 2405–2406
Table 1
were generated as expected with good yields (Table 1, entries
13–18). In this transformation the conditions are extremely mild,
since the reactions are performed using water as the solvent at
room temperature. For the mechanism of this reaction, we rea-
soned that the presence of p-toluenesulfonyl chloride enabled an
in situ activation of 4-hydroxycoumarin. The generated intermedi-
Direct sulfanylation of 4-hydroxycoumarin 1 with thiol 2 in water
OH
SR2
TsCl, Et3N
R1
+
R2 SH
R1
H2O, rt
O
O
O
O
ate enol tosylate in
a,b-conjugated system subsequently reacted
with thiol via 1,4-addition and elimination8 to afford the expected
4-sulfanylcoumarin. We believed the results presented here not
only represented a green process but also provided a facile and no-
vel route for the synthesis of 4-sulfanylcoumarins.
Entry
1
R
R2
Product
Ya (%)
OH
4-MeC6H4 (2a)
3a
76
In conclusion, we have described a green, efficient, and novel
route for the synthesis of 4-sulfanylcoumarins via direct sulfanyla-
tion of 4-hydroxycoumarins with thiols. This transformation is
highly effective which is performed in water at room temperature
under air atmosphere. The efficiency of this method combined
with the operational simplicity of the present green process makes
it potential attractive for library construction.
O
O
1a
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
C6H (2b)
3b
3c
3d
3e
3f
80
83
70
80
65
63
64
4-FC6H5 (2c)
2-ClC6H5 (2d)
4-ClC6H5 (2e)
C6H5CH2 (2f)
CH3CH2CH2(2g)
HOCH2CH2 (2h)
3g
3h
Acknowledgment
OH
Financial support from National Natural Science Foundation of
China (No. 20862009) and the Natural Science Foundation of Jiang-
xi province is gratefully acknowledged.
9
4-MeC6H4 (2a)
3i
3j
71
72
O
O
1b
1c
References and notes
OH
O
1. Murray, R. D. H.; Méndez, J.; Brown, S. A. The Natural Coumarins: Occurrence,
Chemistry, and Biochemistry; Wiley: New York, 1982.
10
4-MeC6H4 (2a)
O
2. For selected examples, see: (a) Zhang, L.; Meng, T.; Fan, R.; Wu, J. J. Org. Chem.
2007, 72, 7279; (b) Wu, J.; Zhang, L.; Gao, K. Eur. J. Org. Chem. 2006, 5260; (c) Wu,
J.; Wang, X. Org. Biomol. Chem. 2006, 4, 1348; (d) Wu, J.; Zhang, L.; Xia, H. G.
Tetrahedron Lett. 2006, 47, 1525; (e) Wu, J.; Zhang, L.; Luo, Y. Tetrahedron Lett.
2006, 47, 6747; (f) Murakami, A.; Gao, G.; Omura, M.; Yano, M.; Ito, C.;
Furukawa, H.; Takahashi, D.; Koshimizu, K.; Ohigashi, H. Bioorg. Med. Chem. Lett.
2000, 10, 59; (g) Maier, W.; Schmidt, J.; Nimtz, M.; Wray, V.; Strack, D.
Phytochemistry 2000, 54, 473; (h) Garcia-Argaez, A. N.; Ramirez Apan, T. O.;
Delgado, H. P.; Velazquez, G.; Martinez-Vazquez, M. Planta Med. 2000, 66, 279;
(i) Zhou, P.; Takaishi, Y.; Duan, H.; Chen, B.; Honda, G.; Itoh, M.; Takeda, Y.;
Kodzhimatov, O. K.; Lee, K. H. Phytochemistry 2000, 53, 689; (j) Khalmuradov, M.
A.; Saidkhodzhaev, A. I. Chem. Nat. Compd. 1999, 35, 364; (k) Kamalam, M.;
Jegadeesan, M. Indian Drugs 1999, 36, 484; (l) Tan, R. X.; Lu, H.; Wolfender, J. L.;
Yu, T. T.; Zheng, W. F.; Yang, L.; Gafner, S.; Hostettmann, K. Planta Med. 1999, 65,
64; (m) Vlietinck, A. J.; Bruyne, T. D.; Apers, S.; Pieters, L. A. Planta Med. 1998, 64,
97; (n) Silvan, A. M.; Abad, M. J.; Bermejo, P.; Villar, A.; Sollhuber, M. J. Nat. Prod.
1996, 59, 1183; (o) Yang, Y. M.; Hyun, J. W.; Sung, M. S.; Chung, H. S.; Kim, B. K.;
Paik, W. H.; Kang, S. S.; Park, J. G. Planta Med. 1996, 62, 353.
11
12
1c
1c
C6H (2b)
4-FC6H5 (2c)
3k
3l
73
76
OH
O
F
13
4-MeC6H4 (2a)
3m
77
O
1d
14
15
1d
1d
C6H (2b)
4-FC6H5 (2c)
3n
3o
75
71
OH
Cl
16
4-MeC6H4 (2a)
3p
76
3. a Wu, J.; Yang, Z.; Fathi, R.; Zhu, Q.; Wang, L. US Patent 6,703,514, 2004.; b Wu,
J.; Yang, Z.; Fathi, R.; Zhu, Q. US Patent 7,148,253, 2006.
O
O
4. For selected examples, see: (a) Majumdar, K. C.; Ghosh, S. K. Tetrahedron Lett.
2002, 43, 2115; (b) Shepard, M. S.; Carreira, E. M. Tetrahedron 1997, 53, 16253;
(c) Shepard, M. S.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 2597; (d) Wu, J.
Chem. Lett. 2006, 35, 562; (e) Wang, W. Z.; Ding, Q. P.; Fan, R. H.; Wu, J.
Tetrahedron Lett. 2007, 48, 3647.
17
18
1e
1e
C6H (2b)
4-FC6H5 (2c)
3q
3r
78
80
a
Isolated yields based on 4-hydroxycoumarin.
5. Kang, F.-A.; Sui, Z.; Murray, W. V. J. Am. Chem. Soc. 2008, 130, 11300.
6. Ackermann, L.; Mulzer, M. Org. Lett. 2008, 10, 5043.
7. General procedure for direct sulfanylation of 4-hydroxycoumarins with thiols: A
mixture of 4-hydroxycoumarin 1 (0.2 mmol) and triethylamine (0.6 mmol) in
water (1 ml) was stirred for several minutes. Then, 4-methylbenzenesulfonyl
chloride (0.3 mmol) was added to the mixture. The mixture was stirred at room
temperature for 1–2 h. After completion of the reaction as indicated by TLC,
thiophenol 2 (0.34 mmol) was added to the mixture. The mixture was stirred at
room temperature for 16–30 h. After completion of the reaction as indicated by
TLC, the reaction mixture extracted with EtOAc (3 Â 10 mL), washed with
saturated aqueous NaCl (10 mL), dried (Na2SO4), and filtered. Evaporation of the
solvent followed by purification on silica gel provided the corresponding
product 3. Selected example: 4-(p-tolylthio)coumarin, 76% yield. 1H NMR
(400 MHz, CDCl3) d 2.44 (s, 3H), 5.63 (s, 1H), 7.30–7.35 (m, 4H), 7.46 (d,
J = 8.0 Hz, 2H), 7.57 (s, 1H), 7.85 (dd, J = 1.2, 8.0, Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 21.4, 108.2, 117.1, 117.9, 122.6, 123.7, 124.1, 131.2, 132.2, 136.0, 141.4,
152.3, 158.4, 159.6.
8. (a) Mazal, C.; Jonas, J. Collect. Czech. Chem. Commun. 1993, 58, 1607; (b)
Bernasconi, C. F.; Ketner, R. J.; Chen, X.; Rappoport, Z. J. Am. Chem. Soc. 1998, 120,
7461; (c) Schio, L.; Chatreaux, F.; Loyau, V.; Murer, M.; Ferreira, A.; Mauvais, P.;
Bonnefoy, A.; Klich, M. Bioorg. Med. Chem. Lett. 2001, 11, 1461; (d) Saito, T. J.
Chem. Soc., Perkin Trans. I 1988, 3065; (e) Majumdar, K. C.; Sarkar, S. Synth.
Commun. 2004, 34, 2873; (f) Majumdar, K. C.; Sarkar, S. Tetrahedron Lett. 2002,
43, 2119.
ring of benzenethiol 2 do not effect the reaction markedly. The ali-
phatic thiol (such as benzyl thiol and n-propyl thiol) employed in
the reaction also worked well although the yield was lower (Table
1, entries 6 and 7). It is noteworthy that the hydroxy group in the
thiol is also tolerated under the conditions (Table 1, entry 8). Other
4-hydroxycoumarins were also examined. 4-Hydroxy-6-methyl-
coumarin 1b reacted with 4-methylbenzenethiol 2a leading to
the desired product 3i in 71% yield (Table 1, entry 9). 72% yield
of 4-sulfanylcoumarin 3j was generated when 6,7-dimethyl-4-
hydroxycoumarin 1c was utilized as substrate in the reaction of
4-methylbenzenethiol 2a (Table 1, entry 10). Reaction of 6,7-di-
methyl-4-hydroxycoumarin 1c with benzenethiol 2b or 2c also
proceeded well to give rise to the corresponding product 3k or 3l
in good yields (Table 1, entries 11–12). 6-Fluoro-4-hydroxycouma-
rin 1d and 6-chloro-4-hydroxycoumarin 1e were good substrates
in this kind of transformation, and the corresponding products