A versatile one-pot synthesis of 2,3,5-tri-substituted thiophenes from thiomorpholides

Article abstract of DOI:10.1016/S0040-4039(03)01548-X

An efficient method for the preparation of 2,3,5-trisubstituted thiophenes in a one-pot synthesis from thiomorpholides via the thio-Claisen rearrangement was developed.

Full text of DOI:10.1016/S0040-4039(03)01548-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6253–6255
A versatile one-pot synthesis of 2,3,5-tri-substituted thiophenes
from thiomorpholides
Firouz Matloubi Moghaddam* and Hassan Zali-Boinee
Sharif University of Technology, Department of Chemistry, PO Box 11365-9516 Tehran, Iran
Received 19 April 2003; revised 7 June 2003; accepted 20 June 2003
Abstract—An efficient method for the preparation of 2,3,5-trisubstituted thiophenes in a one-pot synthesis from thiomorpholides
via the thio-Claisen rearrangement was developed.
© 2003 Elsevier Ltd. All rights reserved.
Highly substituted thiophenes have attracted a great
deal of interest, due to their presence in natural prod-
ucts,1 as novel conducting polymers,2 isosteric replace-
ments for phenyl groups in medicinal chemistry3 and as
optical chromophores.4 The thio-Claisen rearrangement
has been an excellent method for the formation of CꢀC
bonds and is useful for the construction of heterocyclic
ring system.5 In continuation of our recent work on
microwave-assisted Claisen rearrangement of propargyl
naphthyl ethers to pyrans and furans,6 here we report a
simple and one-pot method for the preparation of
substituted thiophenes.
type of Claisen rearrangement. A mechanism has been
proposed for this type of transformation and is shown
in Scheme 2. Thiomorpholides undergo an initial eno-
lization, then S-propargylation followed by Claisen
rearrangement.
Several further examples have been investigated and
Table 1 summarizes our results along with the melting
points of the compounds. In conclusion, this is a facile
one-pot synthesis of substituted thiophenes. The gener-
ality of the method has been demonstrated by the
successful conversion of six substrates (2a–f) into 2-
morpholinothiophenes (3a–f) in good isolated yields.
These materials have the potential to be used as drugs.7
The methodology described here seems to be the sim-
plest one for the synthesis of these compounds.
When the thiomorpholide 2a as a model was treated
with propargyl bromide in the presence of anhydrous
K2CO3 in o-dichlorobenzene and heated at 120–130°C
for about 4 h, the three-substituted thiophene 3a was
obtained in 76% yield (Scheme 1). o-Dichlorobenzene
was found to be a versatile solvent for conducting this
Experimental
The substrates (2a–f) were prepared from substituted
styrenes8 or arylketones9 by our previously published
procedures.
General procedure for the one-pot preparation of substi-
tuted thiophenes: To
a
stirred solution of
thiomorpholide (2 mmol) in o-dichlorobenzene (4 ml),
anhydrous K2CO3 (0.552 g, 4 mmol) was added. Then,
freshly distilled propargyl bromide (0.36 ml, 4 mmol)
was added dropwise during about 15 min. The reaction
mixture was heated to 60°C for 1 h and was then raised
to 120–130°C for 4 h. The progress of the reaction was
monitored by TLC. After the necessary time, the reac-
tion mixture was filtered, washed with water (3×5 ml)
and dried over anhydrous MgSO4. The solvent was
removed and the crude reaction mixture was purified by
Scheme 1.
* Corresponding author. E-mail: matloubi@sharif.edu
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01548-X

6254
F. Matloubi Moghaddam, H. Zali-Boinee / Tetrahedron Letters 44 (2003) 6253–6255
Scheme 2.
Table 1. One-pot conversion of thiomorpholides to three-substituted thiophenes
column chromatography (silica gel, eluent: ethyl ace-
tate:hexane, 1:4).
Hz, 4H), 2.94 (t, J=4.6 Hz, 4H), 2.48 (s, 3H);
IR (KBr) 2964, 2907, 2860, 1643, 1501, 1429, 1117
(cm−1).
Spectroscopic data for Compound 3a: white powder
(EtOH); mp: 105°C; 1H NMR (CDCl3, 500 MHz)
7.79 (d, J=7.7 Hz, 2H), 7.41 (t, J=7.7 Hz, 2H),
7.27 (t, J=7.6 Hz, 1H), 6.79 (s, 1H), 3.81 (t, J=4.6
1
Compound 3b: yellow crystals (EtOH); mp: 119°C; H
NMR (CDCl3, 500 MHz) 7.71 (d, J=6.6 Hz, 2H),
7.37 (d, J=6.6 Hz, 2H), 6.71 (s, 1H), 3.77 (t, J=4.6

F. Matloubi Moghaddam, H. Zali-Boinee / Tetrahedron Letters 44 (2003) 6253–6255
6255
Hz, 4H), 2.89 (t, J=4.6 Hz, 4H), 2.44 (s, 3H); IR (KBr)
IR (KBr) 2964, 2846, 2805, 1619, 1511, 1443, 1116
(cm−1).
2964, 2856, 2825, 1501, 1441, 1117 (cm−1).
Compound 3c: light yellow crystals (EtOH); mp: 135°C;
1H NMR (CDCl3, 500 MHz) 7.64 (d, J=8.5 Hz, 2H),
7.49 (d, J=8.5 Hz, 2H) 6.71 (s, 1H), 3.77 (t, J=4.5 Hz,
4H), 2.89 (t, J=4.5 Hz, 4H), 2.45 (s, 3H); IR (KBr)
2954, 2912, 2845, 1563, 1501, 1444, 1114 (cm−1).
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Compound 3d: light yellow crystals (EtOH); mp: 75°C;
1H NMR (CDCl3, 500 MHz) 7.69 (d, J=8.7 Hz, 2H),
6.92 (d, J=8.7 Hz, 2H), 6.72 (s, 1H), 3.85 (s, 3H), 3.77
(t, J=4.6 Hz, 4H), 2.90 (t, J=4.6 Hz, 4H), 2.44 (s, 3H);
IR (KBr) 2949, 2846, 1650, 1393, 1120 (cm−1).
1
Compound 3e: yellow powder; (EtOH); mp: 139°C; H
NMR (CDCl3, 500 MHz) 7.86 (d, J=8.2 Hz, 2H), 7.66
(d, J=7.5 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.47 (t,
J=7.5 Hz, 2H), 7.37 (t, J=7.2 Hz, 1H), 6.81 (s, 1H),
3.81 (t, J=4.6 Hz, 4H), 2.95 (t, J=4.6 Hz, 4H), 2.47 (s,
3H); IR (KBr) 2959, 2912, 2851, 1640, 1511, 1449, 1115
(cm−1).
8. Matloubi Moghaddam, F.; Ghaffarzadeh, M.; Dekamin,
M. J. Chem. Res. (S) 2000, 228.
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mun. 2001, 31, 317.
Compound 3f: light brown crystals (MeOH); mp:
128°C; 1H NMR (CDCl3, 500 MHz) 8.01 (s, 1H),
7.65–7.85 (m, 3H), 7.35–7.50 (m, 3H), 6.89 (s, 1H), 3.86
(t, J=4.6 Hz, 4H), 2.94 (t, J=4.6 Hz, 4H), 2.49 (s, 3H);