Reactions of cyclopropenethiones and acetylenedicarboxylates: Synthesis of substituted thioethers and thiocyclobutanones

Article abstract of DOI:10.1016/j.tetlet.2015.07.041

The reaction of cyclopropenethiones and electron-deficient alkynes has been described in this context. The corresponding thioethers and thiocyclobutanones were afforded depending on the reaction conditions and the employed substrates. Ambient water partic

Full text of DOI:10.1016/j.tetlet.2015.07.041

Tetrahedron Letters 56 (2015) 5086–5089
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Tetrahedron Letters
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Reactions of cyclopropenethiones and acetylenedicarboxylates:
synthesis of substituted thioethers and thiocyclobutanones
Wen-Tao Zhao b, Min Shi a,b,
⇑
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
b Laboratory for Advanced Materials & Institute of Fine Chemicals, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of cyclopropenethiones and electron-deficient alkynes has been described in this context.
The corresponding thioethers and thiocyclobutanones were afforded depending on the reaction condi-
tions and the employed substrates. Ambient water participated in the reaction on the basis of deuterium
labeling experiment. In the plausible reaction mechanism, we propose that the reaction might proceed
through an autocatalytic process.
Received 26 June 2015
Revised 12 July 2015
Accepted 14 July 2015
Available online 17 July 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropenethiones
Autocatalytic process
Electron-deficient alkynes
In recent years, cyclopropenones1 have drawn great attention
from organic chemists as a result of their unique structures and
reactivities. Cyclopropenethione, as the thiosulfate product of
cyclopropenone, has similar reactivity as that of cyclopropenone
and is also very important in organic chemistry.2 However, the
application of cyclopropenethiones in organic synthesis remains
undeveloped. Most of cyclopropenethione related reactions are
involved with the ring-opening cycloadditions.3 For example,
Ramamurthy and co-workers4 have demonstrated the regioselec-
for 12 h. We found that thioether (3a) was formed in 42% yield.
The examination of solvents such as dichloromethane, acetonitrile,
1,4-dioxane, diethyl ether, and chloroform revealed that 3a was
formed in the best yield when the reaction was carried out in ace-
tonitrile (Table 1, entries 2, 4–7, and 9). In tetrahydrofuran and
N,N-dimethylformamide, none of 3a could be formed. Conducting
the reaction in a sealed tube did not give better results (Table 1,
entry 10). Raising the reaction temperature or increasing the load-
ing of 2a did not afford 3a in higher yield (Table 1, entries 11–12).
tive
a-cleavage reactions in arylalkylcyclopropenethiones. More
recently, it has been reported that cyclopropenethiones also could
readily react with alkyl halides (Scheme 1a), such as methyl bro-
mide, ethyl iodide, and benzyl bromide, to give the corresponding
cyclopropenium salts, which next underwent cascade to give
cyclized products.5 Moreover, carbon–sulfur double bond can also
take part in the reaction as well. Tokitoh6 reported that treatment
of the selenadiazole with diphenylcyclopropenethione led to a
characteristic and interesting cyclization product (Scheme 1b).
Furthermore, 2,3-diphenyl cyclopropenethione,7 2,3-diamino-8
and 2,3-bis(alkylthio)-substituted ones9 all could undergo intrigu-
ing cyclizations to construct novel structures in organic syntheses.
As for the underdevelopment of cyclopropenethiones, we won-
dered whether cyclopropenethiones would react with electron-
deficient alkynes to give interesting cyclization products. Initially,
we used the cyclopropenethione (1a) and methyl acetylenedicar-
boxylate (2a) as substrates and mixed them together in toluene
X-
S
SR
RX
Et3N
O
O
+
R'
Ph
Ph
Ph
Ph
R' = Me, EtO
RX = CH3Br, EtI,
PhCH2Br
(a)
SR
H
SR
SR
OH
Ph
Ph
Ph
Ph
O
O
O
Me
Ph
Me
R'
Ph
R'
O
R'
O
S
Ph
Ph
Ph
Se
N
S
N
Se
N
S
Se
Ph
Ph
(b)
O
N
O
O
benzene, 80 o
C
Ph
N
N
⇑
Corresponding author. Tel.: +86 21 54925137; fax: +86 21 64166128.
E-mail address: Mshi@mail.sioc.ac.cn (M. Shi).
Scheme 1. (a) Cyclopropenethiones reacted with alkyl halides and next underwent
cascade with ethylacetoacetate. (b) Reaction on carbon–sulfur double bond.
http://dx.doi.org/10.1016/j.tetlet.2015.07.041
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

W.-T. Zhao, M. Shi / Tetrahedron Letters 56 (2015) 5086–5089
5087
Table 1
Preliminary screening of the reaction conditions
O
Ph
CO2Me
S
Ph
S
MeO2C
+
Solvent, 12 h
Ph
Ph
CO2Me
CO2Me
2a
1a
3a
Entrya
Solvent
Conversionb (%)
Yield (%)/3ac
1
2
3
4
5
6
7
8
Toluene
DCM
THF
MeCN
DCE
1,4-Dioxane
Et2O
77
73
32
66
73
66
70
32
68
66
82
59
42
43
n.d.
54
39
9
42
Trace
20
30
12
32
DMF
9
CHCl3
MeCN
MeCN
MeCN
10d
11e
12f
a
Conditions (unless otherwise specified): 1a (0.2 mmol), 2a (0.3 mmol), and
solvent (2 mL) were added into schlenk tube under argon, and the reaction mixture
was stirred for 12 h.
b
Isolated yield.
Isolated yield.
c
d
1a (0.2 mmol), 2a (0.3 mmol), and solvent (2 mL) were added into a sealed tube
under argon, and the reaction mixture was stirred for 12 h.
e
The reaction mixture was stirred at 60 °C.
The loading of 2a was 0.4 mmol.
f
By slow addition of 2a into the solution of 1a in acetonitrile
with a syringe pump, we found that 3a was obtained in 38% yield
along with another product, 4a, in 21% yield (Table 2, entry 1). 4a
could not be formed when 1a was slowly added by a syringe pump
(Table 2, entry 2). Lengthening and shortening the reaction time
did not give better results (Table 2, entries 3 and 4). Adding some
Figure 1. ORTEP drawings of 3a and 4a.
additives such as H2O, 4 Å MS, PPh3, DABCO, and silica gel into the
reaction system (Table 2, entries 5–8, and 11–12), 4a could not be
formed as well. When 1.5 equiv of sulfur (S) was added, 4a was
formed in 29% yield along with 3a in 24% yield and 5% of starting
materials 1a was recovered (Table 2, entry 6). Increasing S to
3 equiv, the yield of 4a decreased to 16% (Table 2, entry 7). Thus,
finally, we established the optimal reaction conditions: slow addi-
tion of 2 by a syringe pump in 2 h and carrying out the reaction in
MeCN for 12 h at room temperature.
Table 2
Further screening of the reaction conditions
O
Ph
O
CO2Me
CO2Me
S
MeCN
additive, 12 h
S
Ph
MeO2C
O
+
+
S
Ph
Ph
CO2Me
2a
CO2Me
Ph
Ph
4a
1a
3a
Entrya
Additive/(mol %)
Conversionb (%)
Yield (%)/3ac
Yield (%)/4ad
1
—
—
—
—
95
70
80
75
39
55
75
66
38
29
18
46
33
22
24
39
24
30
38
21
21
2e
3f
4g
5
Trace
Trace
Trace
Trace
Trace
Trace
Trace
29j
Table 3
Scope of the reaction using 2a as the model substrate
R1
O
H2O/0.5
H2O/1.0
4 Å MS
Silica gel
S/1.5
S/3.0
PPh3/0.2
DABCO/0.2
O
CO2Me
CO2Me
S
6
O
MeCN
R2
S
7h
8i
9
MeO2C
+
S
+
R1
r.t., 12 h
R1
R2
CO2Me
CO2Me
R2
1
4
95
2a
3
10
11
12
100
100
100
16
Trace
Trace
Entrya Substrate R1
R2
Yieldb (%)/3 (E/Z) Yieldb (%)/4 (E/Z)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ph
Ph
3a, 38 (>20:1)
4a, 21 (>20:1)
4b, 53 (1:1)
4c, 52 (6:1)
n.d.
n.d.
n.d.
a
Conditions (unless otherwise specified): 1a (0.2 mmol) and solvent (2 mL) were
2-MeC6H4 2-MeC5H4 n.d.
3-MeC6H4 3-MeC6H4 n.d.
added into schlenk tube under argon. Then, 2a (0.3 mmol) was added by a syringe
in 2 h, and the reaction mixture was stirred for 12 h.
4-MeC6H4 4-MeC6H4 3d, 43 (4:1)
3-ClC6H4 3-ClC6H4 3e, 37 (10:1)
4-ClC6H4 4-ClC6H4 3f, 43 (10:1)
Me
Bu
b
Isolated yield.
Isolated yield.
Isolated yield.
1a was added by a syringe.
Reaction time was 18 h.
Reaction time was 6 h.
200 mg 4 Å MS was added.
20 mg silica gel was added.
c
d
1g
1h
Ph
Bu
n.d.
n.d.
4g, 43 (3:1)
n.d.
e
f
a
g
Conditions (unless otherwise specified): 1 (0.2 mmol) MeCN (2 mL) was added
into schlenk tube, 2a (0.3 mmol) was added by a syringe in 2 h, and the reaction
mixture was stirred for 12 h.
h
i
b
j
Isolated yield.
5% of 1a was included.

5088
W.-T. Zhao, M. Shi / Tetrahedron Letters 56 (2015) 5086–5089
respectively (Table 3, entry 1). When R1 = R2 = 2-MeC6H4 or 3-
Table 4
Scope of the reaction using 2b as the model substrate
MeC6H4, the corresponding products 4b and 4c were obtained in
53% and 52% yields (E/Z = 1:1 and 6:1), respectively, but without
the formation of thioether products, presumably due to the steric
effect (Table 3, entries 2 and 3). As for substrates 1d, 1e, and 1f,
in which R1 = R2 = 4-MeC6H4 or 3-ClC6H4 or 4-ClC6H4, only
thioether products 3d–3f were produced without the formation
of thiocyclobutanone products 4, presumably due to the electronic
effect (Table 3, entries 4–6). In the case of substrate 1g, in which
R1 = Me, R2 = Ph, 4g was formed exclusively in 43% yield
(E/Z = 3:1) (Table 3, entry 7). As for substrate 1h (R1 = R2 = Bu), no
reaction occurred (Table 3, entry 8).
To gain more insights into the substrate scope of the reaction,
2b was used as the substrate to react with a variety of substrates
1 under the standard conditions and the results are summarized
in Table 4. We found that no matter R1 = R2 = are electron-poor
or electron-rich aromatic rings, the reaction proceeded smoothly
to exclusively give the corresponding product 5a–5f and 5i in
35–76 yields (E/Z >20:1), perhaps due to that the ethyl group in
2b is sterically more bulky than that of methyl group in 2a
(Table 4, entries 1–5 and 8). As for 1g, the desired product 5g
was obtained in 50% yield (E/Z = 1:1) (Table 4, entry 6). In the case
of 1h, no reaction occurred (Table 4, entry 7).
To figure out whether water participated in the reaction, we
examined the deuterium labeling experiment with the addition
of D2O (5.0 equiv). As shown in Scheme 2, under the standard con-
ditions, 5.0 equiv of D2O was added and mixed into the reaction
system and the corresponding product 5a was afforded in 74%
yield along with the deuterium incorporation at the two olefinic
protons in 77% and 73% D contents, respectively, suggesting that
ambient water was indeed involved in the reaction.
Based on the above investigations, we proposed a plausible
reaction mechanism in Scheme 3. The nucleophilic addition of 1a
to another molecule of 1a affords zwitterionic intermediate A.
Then intermediate B is formed by nucleophilic addition of A to
2a and subsequent capture of the proton from ambient water.
The newly generated hydroxide anion (OH-) attacks intermediate
B to give intermediate C and release one molecule of 1a. Herein,
the reaction can be divided into two possible pathways: path a,
R1
O
O
CO2Et
S
CO2Et
O
MeCN
r.t., 12 h
S
R2
EtO2C
+
+
S
R1
R1
R2
CO2Et
CO2Et
R2
1
6
2b
5
Entrya Substrate R1
R2
Yieldb (%)/5 (E/Z) Yieldb (%)/6 (E/Z)
1
2
3
4
5
6
7
8
1a
1b
1d
1e
1f
Ph
Ph
5a, 76 (>20:1)
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
2-MeC6H4 2-MeC5H4 5b, 50 (>20:1)
4-MeC6H4 4-MeC6H4 5d, 56 (>20:1)
3-ClC6H4 3-ClC6H4 5e, 35 (>20:1)
4-ClC6H4 4-ClC6H4 5f, 59 (>20:1)
1g
1h
1i
Me
Bu
2-FC6H4
Ph
Bu
5g, 50 (1:1)
n.d.
5i, 40 (>20:1)
2-FC6H4
a
Conditions (unless otherwise specified): 1 (0.2 mmol) and MeCN (2 mL) were
added into schlenk tube, 2b (0.3 mmol) was added by a syringe in 2 h, and the
reaction mixture was stirred for 12 h.
b
Isolated yield.
O
Ph
CO2Et
S
S
Ph
D (77%)
CO2Et
5a, 74%
EtO2C
MeCN, D2O (5.0 eq)
r.t., 12 h
+
(73%) D
Ph
Ph
CO2Et
1a
2b
Scheme 2. Deuterium labeling experiment.
The structures of 3a and 4a were unambiguously determined by
X-ray diffraction. Their ORTEP drawings are shown in Figure 1 and
the CIF data are presented in the Supporting information.10
Next, with the optimized conditions in hand, we investigated
the substrate scope of the reaction and the results are summarized
in Table 3. By using 2a as the model substrate, substrates 1 with
different R1 and R2 substituents were tested. As can be seen from
Table 3, as for R1 = R2 = Ph, the reaction proceeded smoothly to give
the products 3a and 4a in 38% and 21% yields (E/Z >20:1),
H
CO2Me
O
Ph
O
OMe
S
O
CO2Me
S
H+
Ph
S
Ph
a
MeO
b
MeO2C
a
O
b
Ph
CO2Me
S
Ph
O
Ph
3a
D
H
C
S
O
Ph
Ph
CO2Me
1a
Ph
Ph
1a
O
Ph
S
H
4a
CO2Me
Ph
Ph
S
MeO2C
S
Ph
Ph
+
S
Ph
OH
+
S
Ph
Ph
A
H
OH
Ph
Ph
B
CO2Me
H2
O
MeO2C
Ph
CO2M
e
S
MeO2C
Ph
+
2a
S
Ph
Ph
Scheme 3. A plausible reaction mechanism.

W.-T. Zhao, M. Shi / Tetrahedron Letters 56 (2015) 5086–5089
5089
ring-opening of the cyclopropene, and the subsequent attacks of
References and notes
the ester carbonyl group delivers intermediate D, which then kicks
out OMeÀ to give product 4a; path b, ring-opening of cyclopropene
and the subsequent protonation to afford product 3a.
On the basis of this reaction mechanism, it is quite clear that the
production of 3 and 4 is favored if the concentration of intermedi-
ate A can be maintained at higher levels. This is why the reaction
procedure is that substrate 2 was added slowly by a syringe into
1 in MeCN.
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Rev. 2003, 103, 1371; (d) Greenberg, A.; Tomkins, R. P. T.; Dobrovolny, M.;
Liebman, J. F. J. Am. Chem. Soc. 1983, 105, 6855; (e) Korner, O.; Gleiter, R.;
Rominger, F. Synthesis 2009, 19, 3259; (f) Kohler, K.; Piers, W. E. Can. J. Chem.
1998, 76, 1249.
2. (a) Matsumura, N.; Okumura, Y.; Yagyu, Y.; Mizuno, K. Recent Res. Dev. Org.
Chem. 2002, 6, 709; (b) Yoneda, S.; Hirai, H.; Yoshida, Z. Chem. Lett. 1976, 1051;
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A.; Yanagi, K.; Minobe, M. J. Am. Chem. Soc. 1985, 107, 5801; (e) Yoneda, S.;
Ozaki, K.; Tsubouchi, A.; Kojima, H.; Yanagi, K. J. Heterocycl. Chem. 1988, 25,
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1988, 100, 597; (g) Yoshida, H.; Shimizu, J.; Ogata, T.; Matsumoto, K. Bull. Chem.
Soc. Jpn. 1985, 58, 2445; (h) Matsumoto, K.; Uchida, T.; Yagi, Y.; Tahara, H.;
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1990, 27, 1597; (j) Eicher, T.; Krause, D. Synthesis 1986, 899; (k) Musicki, B. J.
Org. Chem. 1991, 56, 110.
3. (a) Potts, K. T.; Baum, J.; Houghton, E. J. Org. Chem. 1976, 41, 818.
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1982, 47, 3550; (b) Singh, S.; Ramamurthy, V. J. Org. Chem. 1985, 50, 3732.
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Chem. Lett. 1983, 155.
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315.
In conclusion, we have developed
a novel reaction of
cyclopropenethiones and electron-deficient alkynes to give the
corresponding thioethers or thiocyclobutanones in moderate
yields depending on the reaction conditions and the employed
substrates. Ambient water participated in the reaction on the basis
of deuterium labeling experiment. In the plausible reaction mech-
anism, we propose that this reaction might undergo an autocat-
alytic process due to that the sulfur atom in cyclopropenethione
is quite nucleophilic and therefore, cyclopropenethione itself can
serve as a catalyst for the reaction proceeding. This finding may
enrich the chemistry of cyclopropenones and cyclopropenethiones
and further investigation on the mechanistic insights is ongoing in
our laboratory.
Acknowledgments
We thank the National Basic Research Program of China
(973)-2015CB856603, and the National Natural Science
Foundation of China (20472096, 21372241, 21361140350,
20672127, 21421091, 21302203, 21102166, 21372250 and
20732008).
8. (a) Yoshida, Z.; Konishi, H.; Ogoshi, H. Isr. J. Chem. 1981, 21, 139; (b) Nakasuji,
K.; Nishino, K.; Murata, I.; Ogoshi, H.; Yoshida, Z. Angew. Chem., Int. Ed. 1977, 16,
866.
9. Yoneda, S.; Ozaki, K.; Inoue, T.; Sugimoto, A. J. Am. Chem. Soc. 1985, 107, 5801.
10. The crystal data of 3a and 4a have been deposited in CCDC with numbers
1006533 and 994199.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.07.
041.