A novel one-pot synthesis of fully substituted thiophen-2(3H)-ones using N,N-disubstituted thioamides

Article abstract of DOI:10.1002/hlca.201100517

A new one-step synthesis of highly substituted thiophen-2(3H)-one derivatives was developed. 2-Aryl-1-(morpholin-4-yl)ethanethiones were reacted with 2-chloro-2-phenylacetyl chloride in DMF in the presence of a base to give the title compounds in moderate-to-good yields. Copyright

Full text of DOI:10.1002/hlca.201100517

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A Novel One-Pot Synthesis of Fully Substituted Thiophen-2(3H)-ones Using
N,N-Disubstituted Thioamides
by Hassan Zali-Boeini* and Fatemeh Pourjafarian
Department of Chemistry, University of Isfahan, 81746-73441, Isfahan, Iran
(phone: þ 98-311-7932715; fax: þ 98-311-6689732; e-mail: h.zali@chem.ui.ac.ir)
A new one-step synthesis of highly substituted thiophen-2(3H)-one derivatives was developed. 2-
Aryl-1-(morpholin-4-yl)ethanethiones were reacted with 2-chloro-2-phenylacetyl chloride in DMF in the
presence of a base to give the title compounds in moderate-to-good yields.
Introduction. – There has been considerable interest in the synthesis of highly
substituted and functionalized thiophenes during the past few years due to their
applications in medicinal chemistry [1 – 4] and industry [5 – 8]. The most general
approaches for their preparation is the Gewald method [9], in which elemental sulfur in
the presence of a secondary aliphatic amine is reacted with equimolar amounts of an
activated MeCN and a carbonyl compound. Trisubstituted thiophenes have been
prepared by the thio-Claisen rearrangement of S-propargylated thioacetomorpholides
(¼1-(morpholin-4-yl)ethanethiones) and via the ring closure of an a-allenyl thioace-
tomorpholide intermediate [10]. Also, fully substituted thiophenes have been success-
fully synthesized from the reaction of a-halocarbonyl compounds and tertiary
thioamides in the presence of a base [11].
Here, for the first time, to the best of our knowledge, we report a one-step synthesis
of new fully substituted thiophen-2(3H)-one derivatives.
Results and Discussion. – When a mixture of an 2-aryl-1-(morpholin-4-yl)ethane-
thione 1 and 2-chloro-2-phenylacetyl chloride 2 in DMF in the presence of a base was
heated at 908, fully substituted thiophen-2(3H)-ones 3 were obtained in moderate-to-
good yields (54 – 76%; Scheme 1).
Scheme 1
The study was initiated by running the reaction of 1-(morpholin-4-yl)-2-phenyl-
ethanethione (1a) as a test substrate with 2 in DMF and in the presence of Et3N as a
base. Under these conditions, only small amounts of the corresponding thiophene 3a
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
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(26%) were obtained. Therefore, we decided to examine various reaction conditions to
find the optimal conditions for the highest yield of thiophen-2(3H)-one 3. Hence, in
addition of DMF and Et3N, other solvents and bases were also tested in the reaction
course, and the results are compiled in Table 1.
Table 1. Screening of the Solvent and the Base in the Synthesis of Thiophene 3a
Entry
1
Solvent
Base
Yielda) [%]
DMF
dioxane
MeCN
DBUb)
75
58
61
2
3
DMF
dioxane
MeCN
K2CO3
KOH
39
25
26
DMF
dioxane
MeCN
45
27
31
a) Yields of isolated products. b) DBU ¼ 1,8-Diazabicyclo[5.4.0]undec-7-ene.
The results show that DBU in DMF led to the highest yield of the desired product.
The effect of reaction temperature was also tested, and the results indicated that the
best reaction temperature was 908. At higher temperatures, the reaction mixture was
contaminated with some colored or tarry materials.
After optimizing the conditions, we next examined the generality of these
conditions to other substrates by using several 1-(morpholin-4-yl)ethanethiones
(Table 2).
Table 2. One-Step Synthesis of Highly Substituted Thiophen-2(3H)-ones
Entry
Ar
Producta)
Yieldb) [%]
1
2
3
4
5
6
7
8
Ph
3a
3b
3c
3d
3e
3f
3g
3h
75
69
59
76
64
60
54
70
4-ClꢀC6H4
4-BrꢀC6H4
4-MeꢀC6H4
4-MeOꢀC6H4
4-PhꢀC6H4
Naphthalen-2-yl
Pyridin-4-yl
a) All products were characterized on the basis of their melting points, IR, and 1H- and 13C-NMR spectra.
b) Yields of isolated products.

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One of the advantages of the presented method is the simple isolation of the
product. After completing the reaction (TLC), the mixture was poured in H2O (except
for 3g), and the resulting precipitate was filtered and washed with MeOH to obtain
pure compounds as white or light-yellow solids. To evaluate the scope of the reaction,
the quite different thioamide 1i was also used and reacted with 2 to obtain the sterically
congested thiophen-2(3H)-one 3i in low yield (35%; Scheme 2).
Scheme 2
A proposed mechanism for the reaction is outlined in Scheme 3. It seems likely that
the S-acylated thioamide salt 4, formed by the reaction of thioamide 1 with 2-chloro-2-
phenylacetyl chloride 2 is the key intermediate in the reaction. This intermediate
undergoes HCl elimination to give the next intermediate 5, which undergoes
cyclization to form the salt 6, and 6 is finally transformed to the corresponding
thiophen-2(3H)-one 3 via elimination of another HCl molecule.
Scheme 3
Conclusions. – We have developed for the first time a simple one-step method for
the preparation of highly substituted thiophen-2(3H)-ones using N,N-disubstituted
thioamides. Being a one-step reaction, requiring an easy workup and isolation of the
product, and utilizing a general organic base for the reaction course are salient futures
of the presented method.
We are grateful to University of Isfahan Research Council for financial support of this work.
Experimental Part
General. All solvents used were dried and distilled before use according to standard procedures.
Anal. TLC: silica gel (SiO2; Merck 60 F254) coated on aluminum plates; visualization with UV and aq.

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KMnO4 soln. M.p.: Stuart SMP3 melting-point apparatus; uncorrected. IR Spectra: UR-20 spectrometer;
KBr pellets; ˜n in cmꢀ1. 1H- and 13C-NMR Spectra: Bruker AMX-400 spectrometers; in CDCl3; d in ppm
rel. to Me4Si as internal standard, J in Hz.
Caution: All experiments should be conducted in an efficient hood to avoid exposure to very
corrosive vapors of 2-chloro-2-phenylacetyl chloride.
General Procedure for the Preparation of Highly Substituted Thiophenes 3. 2-Aryl-1-(morpholin-4-
yl)ethanethione 1 (1 mmol) and 2-chloro-2-phenylacetyl chloride (2; 1.2 mmol, 228 mg) were dissolved
in DMF (1 ml), and DBU (1.06 mmol, 160 mg) was added dropwise. Then, the mixture was heated at 908
for 120 min. After completion of the reaction (TLC), the mixture was cooled to r.t. and poured in H2O
(10 ml). Then, the precipitated compound was filtered, and the solid residue was stirred for 10 min in
warm (458) MeOH (5 ml). The off-white thiophene precipitate was filtered and dried in vacuum
desiccators. For the further purification, the solid was redissolved in a small amount of THF and
reprecipitated with cold MeOH to obtain the pure product as white powder.
5-(Morpholin-4-yl)-3,4-diphenylthiophen-2(3H)-one (3a). IR: 3045, 1689, 1631, 1126. 1H-NMR
(400 MHz, CDCl3): 7.23 – 7.40 (m, 10 H); 5.32 (s, 1 H); 3.69 (t, J ¼ 4.4, 4 H); 2.93 (t, J ¼ 4.4, 4 H).
13C-NMR (100 MHz, CDCl3): 165.3; 136.8; 134.9; 134.3; 129.6; 129.3; 129.0; 128.6; 128.4; 127.9; 120.2;
62.0; 58.7; 52.9.
4-(4-Chlorophenyl)-5-(morpholin-4-yl)-3-phenylthiophen-2(3H)-one (3b). IR: 3011, 1693, 1629,
1122. 1H-NMR (400 MHz, CDCl3): 7.15 – 7.41 (m, 9 H); 5.31 (s, 1 H); 3.68 (t, J ¼ 2.4, 4 H); 2.90 (t, J ¼ 2.4,
4 H). 13C-NMR (100 MHz, CDCl3): 165.8; 133.0; 131.4; 130.3; 129.4; 128.9; 128.8; 128.7; 128.0; 127.4;
127.3; 66.5; 58.6; 52.3.
4-(4-Bromophenyl)-5-(morpholin-4-yl)-3-phenylthiophen-2(3H)-one (3c). IR: 3011, 1688, 1640,
1134. 1H-NMR (400 MHz, CDCl3): 7.23 – 7.90 (m, 9 H); 5.36 (s, 1 H); 3.74 (t, J ¼ 2.4, 4 H); 2.96 (t, J ¼ 2.4,
4 H). 13C-NMR (100 MHz, CDCl3): 165.0; 134.7; 133.1; 129.3; 129.1; 128.9; 128.7; 128.5; 128.1; 127.3;
127.1; 66.6; 58.7; 52.2.
4-(4-Methylphenyl)-5-(morpholin-4-yl)-3-phenylthiophen-2(3H)-one (3d). IR: 3044, 1691, 1643,
1150. 1H-NMR (400 MHz, CDCl3): 6.94 – 7.29 (m, 9 H); 5.20 (s, 1 H); 3.58 (t, J ¼ 4.8, 4 H); 2.82 (t, J ¼ 4.8,
4 H); 2.29 (s, 3 H). 13C-NMR (100 MHz, CDCl3): 165.3; 140.5; 136.8; 134.9; 129.6; 129.3; 129.0; 128.6;
128.4; 127.9; 120.2; 62.0; 56.5; 52.6; 20.9.
4-(4-Methoxyphenyl)-5-(morpholin-4-yl)-3-phenylthiophen-2(3H)-one (3e). Light-yellow powder.
IR: 3022, 1701, 1631, 1110. 1H-NMR (400 MHz, CDCl3): 7.53 (d, J ¼ 8.9, 2 H); 7.32 – 7.41 (m, 5 H); 7.12 (d,
J ¼ 8.9, 2 H); 5.23 (s, 1 H); 3.72 (s, 3 H); 3.54 (t, J ¼ 4.4, 4 H); 2.88 (t, J ¼ 4.4, 4 H). 13C-NMR (100 MHz,
CDCl3): 165.3; 140.5; 136.8; 134.9; 129.6; 129.3; 129.0; 128.6; 128.4; 127.9; 120.2; 69.2; 62.0; 56.5; 52.6.
4-(1,1’-Biphenyl-4-yl)-5-(morpholin-4-yl)-3-phenylthiophen-2(3H)-one (3f). IR: 3043, 1689, 1635,
1122. 1H-NMR (400 MHz, CDCl3): 7.36 – 7.89 (m, 9 H); 7.08 – 7.25 (m, 5 H); 5.24 (s, 1 H); 3.65 (t, J ¼ 4.3,
4 H); 2.94 (t, J ¼ 4.3, 4 H). 13C-NMR (100 MHz, CDCl3): 166.3; 144.0; 133.7; 129.1; 128.7; 128.6; 127.9;
127.8; 127.6; 127.3; 127.2; 126.0; 121.6; 66.6; 58.6; 52.2.
5-(Morpholin-4-yl)-4-(naphthalen-2-yl)-3-phenylthiophen-2(3H)-one (3g). IR: 3053, 1688, 1633,
1101. 1H-NMR (400 MHz, CDCl3): 7.23 – 7.66 (m, 12 H); 5.33 (s, 1 H); 3.71 (t, J ¼ 4.4, 4 H); 2.97 (t, J ¼
4.4, 4 H). 13C-NMR (100 MHz, CDCl3): 165.0; 139.7; 131.6; 131.0; 129.3; 128.9;128.8; 128.7; 128.1; 127.5;
127.4; 127.3; 127.2; 127.0; 126.9; 66.5; 58.7; 52. 32.
5-(Morpholin-4-yl)-3-phenyl-4-(pyridin-4-yl)thiophen-2(3H)-one (3h). Light-yellow crystals. IR:
1
3033, 1698, 1648, 1106. H-NMR (400 MHz, CDCl3): 7.16 – 7.35 (m, 9 H); 5.23 (s, 1 H); 3.61 (t, J ¼ 4.4,
4 H); 2.80 (t, J ¼ 4.4, 4 H). 13C-NMR (100 MHz, CDCl3): 164.2; 131.7; 131.6; 130.5; 129.4; 128.9; 128.8;
128.0; 127.4; 127.1; 66.5; 58.6; 50.9.
5-(Diphenylamino)-3,4-diphenylthiophen-2(3H)-one (3i). Light-yellow powder. IR: 3015, 1690,
1641, 1156. 1H-NMR (400 MHz, CDCl3): 6.96 – 7.36 (m, 20 H); 4.86, (s, 1 H). 13C-NMR (100 MHz,
CDCl3): 171.1; 135.1; 134.7; 129.1; 128.9; 128.8; 128.7; 128.4; 128.2; 127.8; 127.7; 127.6; 126.7; 123.0; 122.4;
53.1.

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Received December 27, 2011