BF3·Et2O promoted conjugate addition of ethanethiol to electron-deficient alkynes

Article abstract of DOI:10.1016/j.cclet.2012.04.008

An effective method for the synthesis of vinyl thioethers through the conjugate addition of ethanethiol to electron-deficient alkynes promoted by BF₃·Et₂O has been developed. Electron-deficient internal alkynes react with ethanethiol

Full text of DOI:10.1016/j.cclet.2012.04.008

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 639–642
www.elsevier.com/locate/cclet
BF3ꢀEt2O promoted conjugate addition of ethanethiol
to electron-deficient alkynes
*
Qing Fa Zhou , Xue Ping Chu, Shen Zhao, Tao Lu, Wei Fang Tang
*
Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, China
Received 23 December 2011
Available online 14 May 2012
Abstract
An effective method for the synthesis of vinyl thioethers through the conjugate addition of ethanethiol to electron-deficient
alkynes promoted by BF3ꢀEt2O has been developed. Electron-deficient internal alkynes react with ethanethiol in this system to yield
mainly Z-isomer of vinyl thioether adducts, while electron-deficient terminal alkynes afford mainly E-isomer of vinyl thioether
adducts.
# 2012 Qing Fa Zhou. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Vinyl thioether; Electron-deficient alkyne; Conjugate addition; Synthesis
The development of efficient method to multifunctionalize alkenes in stereoselective fashions is an important goal
in organic chemistry [1] and is still being actively explored [2]. Among these alkenes, the vinyl thioethers are
particularly useful for serving as chemically important precursors [3]. Sulfur-containing compounds also exhibit a
wide range of pharmaceutical uses. For example, the dihydrobenzoxanthiin is a selective estrogen receptor modulator
[4], and diltiazem is used as a calcium channel blocker in the treatment of hypertension [5]. Thus, many ways have
been developed for the synthesis of these organosulfur compounds, especially for vinyl thioethers [6].
Owing to simplicity and atom economy, the widely used method is the conjugated addition of sulfur nucleophiles to
electron-deficient alkyne (thia-Michael reaction). Thia-Michael addition of thiols to electron-deficient alkyne is a
convenient way to synthesize vinyl thioethers. Most of these reactions are catalyzed or promoted by bases, such as Et3N
[7a], pyridine [7b], N-methylmorpholine [3a], tributylphosphine [7c], NaH [7d], K2CO3 [7e]. However, few examples of
synthesis of vinyl thioethers in the presence of acidic conditions have been reported, to the best of our knowledge; even
though many reports about the addition of thiols to activated alkenes by activation of the acceptors with Lewis acids have
been known, which included Bi(NO3)3 [8a], Bi(OTf)3 [8b], Cu(BF4)2 [8c], and B(OH)3 [8d]. Here, we wish to report a
facile method for the synthesis of vinyl thioethers through the Michael addition of ethanethiol to electron-deficient
alkynes by use of BF3ꢀEt2O as acid promoter with good to excellent chemical yields and regioselectivity (Scheme 1).
We first chose 1,3-diphenylprop-2-yn-1-one (1a) and ethanethiol as the standard substrates to search for suitable
reaction conditions and the results are shown in Table 1. It was observed that no reaction was found when the reaction
was stirred at room temperature in dichloromethane for 2 days. However, a crude product mixture of Z-2a and E-2a as
* Corresponding authors.
E-mail addresses: zqf@mail.ustc.edu.cn (Q.F. Zhou), twf@cpu.edu.cn (W.F. Tang).
1001-8417/$ – see front matter # 2012 Qing Fa Zhou. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.04.008

640
Q.F. Zhou et al. / Chinese Chemical Letters 23 (2012) 639–642
O
O
EtS
EtSH
BF3.Et2O
2a
1a
Scheme 1.
Table 1
Reaction of 1,3-diphenylprop-2-yn-1-one (1a) and ethanethiol under various conditions.
Entry
BF3ꢀEt2O (mol%)
Solvent
Temperature
Z/E selectivity (%)a
Yield of 2a (%)b,c
1
2
100
100
100
100
100
100
100
100
100
0
CH2Cl2
THF
r.t.
–
Trace
90
98
90
92
90
79
29
74
0
r.t.
85/15
92/8
62/38
84/16
96/4
87/13
88/12
87/13
–
3
Et2O
r.t.
4
Toluene
EA
r.t.
5
r.t.
6
Acetone
CH3CN
EtOH (95%)
EtOH (anhydrous)
Et2O
r.t.
7
r.t.
8
r.t.
9
r.t.
10
11
12
13
14
r.t.
50
Et2O
r.t.
85/15
91/9
86/14
93/7
81
96
80
85
200
100
100
Et2O
r.t.
Et2O
35 8C
0 8C
Et2O
a
Z/E selectivity was estimated by crude 1H NMR determination.
b
c
Yield after purification by silica gel column chromatography.
Unless otherwise noted, reactions were carried out in the presence of 1 equiv. of BF3ꢀEt2O for 48 h.
a diasteromeric ratio of 85:15 in favor of the Z-isomer was formed when THF was used as solvent. The configuration of
the double bond of carbon and carbon in 2a was determined by NOESY spectrum and by comparison of the 1H NMR
data with those of known or related compounds. The yield and the degree of diastereoselective induction increased
from 90% to 98% and 85:15 to 92:8 when ethyl ether (Et2O) was used as solvent. With toluene, ethyl acetate (EA) and
acetone as solvent, the corresponding product 2a was generated in a relatively lower yield. But the selectivity for the Z-
isomer is slightly better in acetone than in ethyl ether. The product 2a was formed in very poor yield, when ethanol
(95%) was used as the solvent; while ethanol (anhydrous) was used as the solvent, the product 2a was obtained in
moderate yield. The amount of BF3ꢀEt2O employed had a significant effect on the reaction rate, but no obvious effect
on the selectivity. No reaction was found when the reaction was carried out in the absence of BF3ꢀEt2O. Reaction was
carried out in the presence of 0.5 equiv of BF3ꢀEt2O, the corresponding product 2a was generated in a relatively lower
yield than that in the presence of 1.0 equiv of BF3ꢀEt2O. When the ethanethiol was increased to 2.0 equiv, the result
was similar to that of 1.0 equiv ethanethiol. An interesting trend was observed when these conditions were examined in
ethoxyethane as solvent: the Z-isomer selectivity gradually increased as the reaction temperature was decreased as
shown in Table 1. Thus, the optimal reaction conditions for this reaction were determined to be: 100 mol% BF3ꢀEt2O
as acid promoter in ethoxyethane at room temperature.
With theses results in hand, a variety of alkynones were first submitted to the reaction; these results are summarized
in Table 2. It was observed that all of electron-deficient internal alkynes reacted with ethanethiol to yield mainly Z-
isomer of vinyl thioether adducts and afforded the corresponding products with good to excellent yields under the
optimized conditions. The substituents on the phenyl ring of the electron-deficient internal alkynes have obvious
effects on the yields of the reaction. For example, the reaction of 1-(4-nitrophenyl)-3-phenylprop-2-yn-1-one or 1,3-
diphenylprop-2-yn-1-one, under the conditions described, gave the corresponding products 2e and 2a in 75% and 98%
yields, respectively.
Electron-deficient terminal alkynes with ethanethiol also proceeded smoothly to generate the corresponding
products with good yields (Table 2, entries 8–10). It was notable that the E-isomer of the addition adducts is main
product. For example, the desired product of vinyl thioether was formed in 76% yield with an E/Z selectivity ratio of

Q.F. Zhou et al. / Chinese Chemical Letters 23 (2012) 639–642
641
Table 2
Reactions of alkyes 1 with ethanethiol.a
O
R2
BF3.Et2O (100 mol%)
Et2O, r.t., 48h
O
EtS
R1
R1
+
EtSH
R2
Entry
R1
R2
Product
Z/E selectivity (%)b
Yield of 2 (%)c
1
2
C6H5
C6H5
2a
2b
2c
2d
2e
2f
92/8
98
90
87
95
75
80
92
70
76
60
48d
64
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
4-F–C6H4
90/10
92/8
3
4-Cl–C6H4
4-Br–C6H4
4
85/15
88/12
80/20
86/14
34/66
16/84
19/81
14/86
27/73
5
4-NO2–C6H4
4-MeO–C6H4
4-MeS–C6H4
C6H5
6
7
2g
2h
2i
8
9
H
2-Cl–C6H4
Me
10
11
12
H
2j
H
OEt
2k
2l
COOMe
OMe
a
Unless otherwise noted, reactions were carried out at r.t. for 48 h.
Z/E selectivity was estimated by crude 1H NMR determination.
Yield after purification by silica gel column chromatography.
35 8C.
b
c
d
O
S
HS
S
SH
O
3
1a
Scheme 2.
84:16, when 1-(2-chlorophenyl)prop-2-yn-1-one was submitted to the reaction. Ethyl propiolate and dimethyl but-2-
ynedionate were also submitted to the reaction. Ethyl propiolate did not react at room temperature. However, when
elevating the temperature to 35 8C, the reaction proceeded smoothly and obtained the product in moderate yield. The
reaction of dimethyl but-2-ynedioate obtained the product in moderate yield and the E-isomer was main product.
We then examined the reaction of 1,2-ethanedithiol in place of ethanethiol with 1,3-diphenyl-2-propyn-1-one. To
our surprise, we obtained only double Michael adduct (1-pheny-2-(2-phenyl-1,3-dithiolan-2-yl)ethan-1-one) in 85%
yield (Scheme 2) [9]. This compound is very important in organic synthesis [10]. Interestingly, only vinyl thioether 2a
was formed, even though in the presence of 2 equiv of ethanethiol.
R2
O
.
BF3 Et2O
O
.
BF3 Et2O
R1
R2
4
1
R1
EtSH
.
R1
S
O
C
BF3 Et2O
O
O
.
S
R2
R1
S
R2
S
H
O
BF3 Et2O
C
H
R2
R1
R2
R1
5'
5
Z-isomer
E-isomer
Scheme 3. Possible mechanism for the BF3ꢀEt2O promoted reaction of ethanethiol with electron-deficient alkynes.

642
Q.F. Zhou et al. / Chinese Chemical Letters 23 (2012) 639–642
A plausible mechanism to account for the formation of the vinyl thioethers 2 is presented in Scheme 3. The role of
BF3ꢀEt2O in the thia Michael addition reaction could be envisaged as an electrophilic activation process during which
coordination of BF3ꢀEt2O with the carbonyl oxygen of acetylenic ketones renders it more susceptible to nucleophilic
attack. The intermediate 5 or 50 undergoes proton transfer to give the E-isomer of the product or the Z-isomer of the
product.
In summary, we have developed an effective method for the synthesis of vinyl thioethers through the conjugate
addition of thiols to electron-deficient alkynes promoted by BF3ꢀEt2O in mild conditions [11]. Electron-deficient
internal alkynes react with ethanethiol in this system to yield mainly Z-isomer of vinyl thioether adducts, while
electron-deficient terminal alkynes affords mainly E-isomer of vinyl thioether adducts. This reaction system offers an
alternative way to synthesize vinyl thioethers that could not be incorporated in base conditions.
Acknowledgments
Thanks are due to the National Natural Science Foundation of China (No. 21102179) and Fundamental Research
Funds for the Central Universities (No. JKZ2011011) for the financial support.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/
j.cclet.2012.04.008.
References
[1] (a) M. Bella, K.A. Jørgensen, J. Am. Chem. Soc. 126 (2004) 5672;
(b) B.M. Trost, A.B. Pinkerton, Angew. Chem. Chem. Int. Ed. 39 (2000) 360;
(c) G.M. Barrett, J.M. Hill, E.M. Wallace, J. Org. Chem. 57 (1992) 386.
[2] (a) D.J. Dong, H.H. Li, S.K. Tian, J. Am. Chem. Soc. 132 (2010) 5018;
(b) B.L. Chen, B. Wang, G.Q. Lin, J. Org. Chem. 75 (2010) 941;
(c) Q.F. Zhou, Q.P. Wu, S. Xue, Tetrahedron Lett. 49 (2008) 7027.
[3] (a) M. Journet, A. Rouillard, D. Cai, et al. J. Org. Chem. 62 (1997) 8630;
(b) O.D. Lucchi, V. Lucchini, C. Marchioro, et al. J. Org. Chem. 51 (1986) 1457;
(c) W.D. Rudorf, A. Schierhorn, M. Augustin, Tetrahedron 35 (1979) 551.
[4] T.A. Blizzard, F. DiNinno, H.Y. Chen, et al. Bioorg. Med. Chem. Lett. 15 (2005) 3912.
[5] C. Mordant, C. Can˜o de Andrade, R. Touati, et al. Synthesis (2003) 2405.
[6] (a) M.S. Kabir, M. Lorenz, M.L. Van Linn, et al. J. Org. Chem. 75 (2010) 3626;
(b) B. Subhash, D. Jayanta, S. Swadeshmukul, Tetrahedron Lett. 50 (2009) 124;
(c) C.G. Bates, P. Saejueng, M.Q. Doherty, et al. Org. Lett. 6 (2004) 5005.
[7] (a) O. Arjona, F. Iradier, R. Medel, et al. J. Org. Chem. 64 (1999) 6090;
(b) M.T. Omar, M.N. Basyouni, Bull. Chem. Soc. Jpn. 47 (1974) 2325;
(c) S. Zhao, Q.F. Zhou, J.Z. Liu, et al. Chin. Chem. Lett. 22 (2011) 397;
(d) R. Medel, M.L. Monterde, J. Plumet, et al. J. Org. Chem. 70 (2005) 735;
(e) C. Reuter, F. Vo¨gtle, Org. Lett. 2 (2000) 593.
[8] (a) N. Srivastava, B.K. Banik, J. Org. Chem. 68 (2003) 2109;
(b) M.M. Alam, R. Varala, S.R. Adapa, Tetrahedron Lett. 44 (2003) 5115;
(c) S.K. Garg, R. Kumar, A.K. Chakraborti, Tetrahedron Lett. 46 (2005) 1721;
(d) K.C. Mihir, H. Sahid, J. Mol. Catal. A: Chem. 269 (2007) 214.
[9] K. Tomoko, O. Takeshi, Tetrahedron Lett. 51 (2010) 290.
[10] A.B. Smith III, C.M. Adams, S.A. Lodise Barbosa, et al. J. Am. Chem. Soc. 125 (2003) 350.
[11] Typical procedure: A solution of alkynones (0.2 mmol), ethanethiol (0.22 mmol), and BF3ꢀEt2O (0.2 mmol) in 2 mL of Et2O was stirred for
48 h at room temperature. The reaction was quenched by addition of 10% aqueous NaHCO3 (2 mL). The resulting two phases were separated,
and the aqueous phase was extracted Et2O (3 ꢁ 10 mL). The combined organic layers were then washed with brine, dried over anhydrous
magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (15:1–10:1 PE–EtOAc) to afford the
corresponding products.