Gewald-type reaction of double activated 2,3-diarylcyclopropanes with elemental sulfur for synthesis of polysubstituted 2-aminothiophenes

Article abstract of DOI:10.1016/j.tetlet.2014.01.043

A new synthetic procedure for the polysubstituted 2-aminothiophenes was developed via Gewald type ring-opening reaction of 1,1-dicyano-2,3- diarylcyclopropanes with elemental sulfur in N,N-dimethylformamide in the presence of morpholine as base.

Full text of DOI:10.1016/j.tetlet.2014.01.043

Tetrahedron Letters 55 (2014) 1441–1443
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gewald-type reaction of double activated 2,3-diarylcyclopropanes
with elemental sulfur for synthesis of polysubstituted
2-aminothiophenes
⇑
Ying Han, Wan-Quan Tang, Chao-Guo Yan
College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new synthetic procedure for the polysubstituted 2-aminothiophenes was developed via Gewald type
ring-opening reaction of 1,1-dicyano-2,3-diarylcyclopropanes with elemental sulfur in N,N-dimethyl-
formamide in the presence of morpholine as base.
Received 8 October 2013
Revised 5 January 2014
Accepted 13 January 2014
Available online 18 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Thiophene
Cyclopropane
Sulfur
Gewald reaction
Ring-opening reaction
The donor–acceptor-substituted cyclopropanes are widely used
as the versatile three carbon building blocks for the synthesis of
versatile functionalized molecules.1,2 Through the ring-opening
reactions of the donor–acceptor cyclopropanes with various chem-
icals, for example electrophiles, nucleophiles, and radicals, such as
aldehydes, imines, isocyanate, nitrones, acetylenes, and nitriles
have been demonstrated to form valuable five-membered hetero-
cycles, especially furan and pyrroles.3–7 At present the direct trans-
formation of the activated cyclopropanes to functionalized
skeleton of thiophene with sulfur-containing reagents still remains
a challenging subject mainly due to their low nucleophilicity.
Reissig and co-workers8 firstly reported the synthesis of
2-aminothiophene by reaction of cyanoacetates, elemental sulfur,
and methyl 2-siloxycyclopropanecarboxylates, which were used
as equivalents of carbonyl compounds. Chandrasekaran and
co-worker9 developed the regioselective ring-opening of cyclopro-
panes with tetrathiomolybdate as the sulfur transfer reagent to
give dihydrothiophenes in excellent yield. Recently, Dong and
co-workers10 successfully developed a domino reaction of dime-
thylaminopropenoyl cyclopropanes initiated by Lawesson’s
reagent for convenient synthesis of 2,3-dihydrothieno[3,2-c]pyri-
dines. On the other hand, 2-aminothiophene is arguably one of
the most typical functionalized molecules in the present-day
chemical and medical research of thiophene.11 In 1965 Gewald
et al. reported the synthesis of substituted 2-aminothiophenes
via condensation of carbonyl compounds with methylene active
nitriles and elemental sulfur in the presence of organic bases.12
Since then this novel multicomponent reaction turned out to be-
come a universal method for the synthesis of substituted 2-amino-
thiophenes and has gained prominence in recent years.13,14 Under
this background, and as also in the context of our investigations to
develop more efficient ring-opening reactions for the sterically
hindered polysubstituted cyclopropanes,15 herein we wish to
report the preliminary results on the Gewald-type reactions of
1,1-dicyano-2,3-diarylcyclopropanes with elemental sulfur for
the synthesis of polysubstituted 2-aminothiophenes.
To optimize the reaction conditions, we examined the reaction
of 1,1-dicyano-2-phenyl-3-p-nitrophenylcyclopropane15a 1a with
elemental sulfur in the presence of different bases and solvents.
When pyridine, triethylamine, diethylamine, or piperidine were
used as base, nearly no reaction was observed in refluxing metha-
nol, but when morpholine was used, the product 1a was obtained
in about 20% yield. If the reaction was carried out in refluxing eth-
anol, triethylamine, diethylamine, and morpholine resulted in the
products in 10%, 25%, and 20% yields, respectively. When DMF
was used as solvent, triethylamine gave a complicate mixture of
products, diethylamine and piperidine still gave low yields of prod-
uct. The highest yield of product 1a (73%) was obtained in the pres-
ence of morpholine as base. This result was concordance with the
known facts that morpholine had been proved to be the most suit-
able base for the activation with sulfur and the subsequent sulfur
⇑
Corresponding author. Tel.: +86 514 87975531; fax: +86 514 87975244.
E-mail address: cgyan@yzu.edu.cn (C.-G. Yan).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.043

1442
Y. Han et al. / Tetrahedron Letters 55 (2014) 1441–1443
Table 1
Synthesis of polysubstituted 2-aminothiphenes 2a–2na
O
E
R
R
N
H
E
CN
NH2
S
S8
+
DMF, 60
ഒ
O2N
NO2
Entry
Compd
R
E
Yieldb (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
CN
CN
CN
CN
CN
CN
CN
CN
CN
63
63
56
53
48
81
68
70
78
p-CH3
p-OCH3
o-OCH3
p-OPh
p-F
p-Cl
m-Cl
p-Br
9
10
11
12
13
14
2j
2k
2l
2m
2n
H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
83
79
71
80
78
Figure 1. Molecular structure of compound 2c.
m-CH3
p-CH3
p-Cl
p-Br
a
Reaction conditions: cyclopropane (1.0 mmol), sulfur (1.5 mmol), morpholine
(1.0 mmol), DMF, 60 °C, 48 h.
b
Isolated yields.
addition in Gewald reaction.16 Thus, we established the optimal
conditions for the reaction of polysubstituted cyclopropanes 1 with
elemental sulfur in DMF with morpholine as the base for about
48 h.17
Under these optimized reaction conditions,
a series of
1,1-dicyano-2-aryl-3-p-nitrophenylcyclopropanes were used in
the reaction. The results are summarized in Table 1. It can be seen
that 2-aryl substituents bearing with electron-withdrawing fluoro,
chloro, bromo groups in cyclopropanes gave higher yields of
products than that of 2-aryl substituents with electron-donating
methyl, methoxy, and phenoxy groups (Table 1, entries 1–9). The
reactions of ethyl 1-cyano-2-aryl-3-p-nitrophenyl-cyclopropyl-
1-carboxylate also reacted efficiently to afford polysubstituted
2-aminothiophenes 2j–2n in good yields (Table 1, entries 10–14).
These results showed that this reaction was quite general and
had a very broad scope of substrates. The structures of the
prepared polysubstituted 2-aminothiophenes 2a–2n were fully
characterized by 1H and 13C NMR, MS, IR spectra. The single crystal
structures of compound 2c and 2l were determined by single-
crystal X-ray diffraction (Figs. 1 and 2).18 It is clear to see that
the most stronger electron-withdrawing p-nitrophenyl group
exists on the ortho-position of the newly-formed thiophenyl ring,
while the aryl groups orient on the 3-position. This result indicated
that the cyclopropyl ring was opened between the carbon atom
with the p-nitrophenyl group and the carbon atom with the cyano
group, which also suggested that this reaction was a highly regio-
selective reaction.
Figure 2. Molecular structure of compound 2l.
reaction with morpholine and 1,3-H shift process. Then carbanium
ion was preferably formed on the carbon atom bearing with the
electron-withdrawing p-nitrophenyl group, which consequently
also determined the regioselective ring-opening of the cyclopropyl
ring. Thirdly, the reaction of carbanion with elemental sulfur gave
intermediate (C). Then the intramolecular addition of the sulfur to
the cyano group yielded the ring intermediate (D). Finally, through
the imine-enamine tautomerization and elimination of excess sul-
fur atom, the intermediate (D) was transformed to 2-aminothioph-
ene 2 as the final product.
In conclusion, an efficient synthetic procedure for the polysub-
stituted 2-aminothiophenes was developed by Gewald-type
reaction of the donor–acceptor cyclopropanes with elemental sul-
fur. This protocol not only provides an effective methodology for
the preparation of functionalized pyrroles, but also provides new
examples of the Gewald reaction in organic synthetic chemistry.
The potential uses of this reaction in synthetic and medicinal
chemistry might be quite significant. Further expansion of the
reaction scope and synthetic applications of this methodology are
in progress in our laboratory.
Although no detailed mechanism and experimental investiga-
tion were carried out in this Letter, a plausible reaction course
for the formation of 2-aminothiophene is proposed in Scheme 1
on the basis of the established ring-opening reaction of the
donor–acceptor substituted cyclopropanes and Gewald reac-
tion.3,14 Firstly, the double activated cyclopropane (1) underwent
ring-opening to give an ionic intermediate (A) on heating. Sec-
ondly, an allylic carbanion (B) was formed by elimination

Y. Han et al. / Tetrahedron Letters 55 (2014) 1441–1443
1443
O
E
E
R
R
R
N
C
N
S8
E
C
N
H
CN
- BH
NO2
NO2
NO2
1
(A)
(B)
E
E
E
R
H
BH
-B
R
R
-S7
NH2
C
N
NH
S
S
S
S
S
S6
S6
O2N
O2N
NO2
(C)
(D)
2
Scheme 1. The proposed formation mechanism of 2-aminothiophene.
15. (a) Wang, Q. F.; Song, X. K.; Chen, J.; Yan, C. G. J. Comb. Chem. 2009, 11, 1007; (b)
Fu, Q.; Yan, C. G. Tetrahedron Lett. 2011, 52, 4497; (c) Han, Y.; Fu, Q.; Tang, W.
Q.; Yan, C. G. Chin. J. Chem. 2012, 30, 1867.
16. (a) Kanbara, T.; Kawai, Y.; Hasegawa, K.; Morita, H.; Yamamoto, T. J. Polym. Sci.:
Part A:Polym. Chem. 2003, 39, 3739; (b) Zavarzin, I. V.; Yarovenko, V. N.;
Shirokov, A. V.; Smirnova, N. G.; Es´kov, A. A.; Krayushkin, M. M. ARKIVOC 2005,
13, 205.
Acknowledgments
This work was financially supported by the National Natural
Science Foundation of China (Grant No. 21172190) and the Priority
Academic Program Development of Jiangsu Higher Education Insti-
tutions. We are also grateful to the Analysis and Test Center of
Yangzhou University for providing necessary instruments for
analysis.
17. Typical procedure:
A mixture of polysubstituted cyclopropane (1.0 mmol),
elemental sulfur (1.5 mmol), and morpholine (1.0 mL) in 10 mL of N,N-
dimethylformamide was stirred at 60 °C for 48 h. Then the reaction was
quenched by adding water. The resulting precipitates were collected by
filtration and subjected to preparative thin-layer chromatography with
light petroleum and ethyl acetate (V/V = 3:1) as developing agent to give
pure product for analysis. 2-Amino-5-(4-nitrophenyl)-4-phenylthiophene-3-
carbonitrile (2a): Orange solid, 63%, mp 172–174 °C; 1H NMR (600 MHz,
CDCl3) d: 8.03 (d, J = 9.0 Hz, 2H, ArH), 7.39 (m, 3H, ArH), 7.29–7.28 (m, 2H,
ArH), 7.21 (d, J = 9.0 Hz, 2H, ArH), 5.22 (s, 2H, NH2); 13C NMR (150 MHz, DMSO-
d6) d: 165.2, 162.3, 145.1, 134.0, 138.5, 133.8, 129.1, 129.0, 128.6, 128.1, 123.8,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.
043.
116.5, 115.6, 88.0; IR (KBr) m: 3723, 3314, 3217, 2211, 1627, 1589, 1511, 1339,
1234, 1107, 853, 743, 699; HRMS (ESI) Calcd for C17H11N3NaO2S ([M+Na]+):
344.0464, Found: 344.0466. 2-Amino-4-(2-methylphenyl)-5-(4-nitrophenyl)-
thiophene-3-carbonitrile (2d): Orange Solid, 53%, mp 184–186 °C; 1H NMR
(600 MHz, DMSO-d6) d (ppm): 8.03 (d, J = 9.0 Hz, 2H, ArH), 7.70 (s, 2H, ArH),
7.44 (t, J = 7.8 Hz, 1H, ArH), 7.20 (d, J = 9.0 Hz, 2H, ArH), 7.16 (d, J = 8.4 Hz, 1H,
ArH), 7.08 (d, J = 7.2 Hz, 1H, ArH), 6.98 (s, J = 7.8 Hz, 1H, NH2), 3.69 (s, 3H,
OCH3); 13C NMR (150 MHz, DMSO-d6) d (ppm): 164.4, 156.8, 144.9, 140.4,
135.8, 130.7, 130.5, 127.1, 123.9, 122.6, 120.9, 117.1, 115.5, 112.1, 89.0, 55.4;
References and notes
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m
: 3399, 3318, 3218, 2209, 1641, 1590, 1513, 1341, 1234, 1187, 847,
754; HRMS (ESI) Calcd for
C
18H13N3NaO3S ([M+Na]+): 374.0570.
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Found: 374.0570. 2-Amino-4-(3-chlorophenyl)-5-(4-nitrophenyl)-thiophene-3-
carbonitrile (2h): Orange solid, 70%, mp 242–244 °C; 1H NMR (600 MHz,
DMSO-d6) d: 8.08 (d, J = 7.8 Hz, 2H, ArH), 7.84 (s, 2H, NH2), 7.72 (d, J = 7.2 Hz,
1H, ArH), 7.51 (d, J = 7.2 Hz, 1H, ArH), 7.47 (t, J = 7.2 Hz, 3H, ArH), 7.39 (s, 1H,
ArH), 7.24 (d, J = 7.8 Hz, 2H, ArH); 13C NMR (150 MHz, DMSO-d6) d: 165.3,
145.3, 139.6, 136.5, 135.8, 133.5, 131.7, 130.8, 128.8, 128.6, 128.3, 128.1, 124.0,
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123.8, 117.2, 115.5, 87.7; IR (KBr) m:3721, 3416, 3317, 3217, 2209, 1644, 1591,
1513, 1324, 1109, 848, 779, 750; HRMS (ESI) Calcd for C17H10ClN3NaO2S
([M+Na]+): 378.0074, Found: 378.0075. Ethyl 2-amino-4-(3-methylphenyl)-5-
(4-nitrophenyl)-thiophene-3-carboxylate (2k): Red solid, 79%, mp 158–160 °C;
1H NMR (600 MHz, CDCl3) d (ppm): 7.94 (d, J = 8.4 Hz, 2H, ArH), 7.19 (t,
J = 7.2 Hz, 1H, ArH), 7.14 (d, J = 7.2 Hz, 1H, ArH), 7.10 (d, J = 8.4 Hz, 2H, ArH),
7.00 (s, 1H, ArH), 6.94 (d, J = 7.2 Hz, 1H, ArH), 6.40 (s, 2H, NH2), 3.95 (s, 2H,
CH2), 2.32 (s, 3H, CH3), 0.82 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (150 MHz, CDCl3) d
(ppm): 165.7, 163.4, 145.3, 141.1, 140.1, 137.5, 137.2, 130.3, 128.3, 128.1,
128.0, 126.7, 123.5, 118.0, 108.9, 59.6, 21.4, 13.5; IR (KBr)
2982, 1668, 1580, 1526, 1484, 1331, 1266, 1108, 850; HRMS (ESI) Calcd for
20H18N2NaO4S ([M+Na]+): 405.0879, Found: 405.0881. Ethyl 2-amino-4-(4-
m: 3695, 3452, 3337,
C
bromophenyl)-5-(4-nitrophenyl)-thiophene-3-arboxylate (2n): Red solid, 78%,
mp 144–146 °C; 1H NMR (600 MHz, DMSO-d6) d: 8.02 (d, J = 8.4 Hz, 2H, ArH),
7.85 (s, 2H, NH2), 7.53 (d, J = 8.4 Hz, 2H, ArH), 7.14 (d, J = 8.4 Hz, 4H, ArH), 3.88
(q, J = 7.2 Hz, 2H, CH2), 0.81 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (150 MHz, DMSO-
d6) d: 164.7, 164.3, 144.9, 140.7, 138.0, 136.5, 131.8, 130.8, 128.3, 123.7, 120.5,
9. Gopinath, P.; Chandrasekaran, S. J. Org. Chem. 2011, 76, 700.
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116.4, 106.0, 58.9, 13.4; IR (KBr)
1524, 1493, 1412, 1338, 1244, 1109, 1013, 849; MHRMS (ESI) Calcd for
19H15BrN2NaO4S ([M+Na]+): 468.9828, Found: 468.9834.
m: 3528, 3443, 3390, 3329, 1667, 1644, 1586,
C
18. Single crystal data for compound 2c (CCDC 965174), 2l (CCDC 965174) have
been deposited in the Cambridge Crystallographic Data Center. These data can
be obtained free of charge via www.ccdc.ac.ck./data_request/cif.