An efficient and facile one-step synthesis of highly substituted thiophenes

Article abstract of DOI:10.1016/j.tet.2004.05.072

An efficient one-step method for the synthesis of fully substituted thiophenes, from thiomorpholides and α-halo ketones, was developed. A mechanism has also been proposed for the course of reaction.

Full text of DOI:10.1016/j.tet.2004.05.072

Tetrahedron 60 (2004) 6085–6089
An efficient and facile one-step synthesis
of highly substituted thiophenes
*
Firouz Matloubi Moghaddam and Hassan Zali Boinee
Department of Chemistry, Sharif University of Technology, P.O. Box 11365-9516 Tehran, Iran
Received 10 November 2003; revised 17 May 2004; accepted 20 May 2004
Available online 15 June 2004
Abstract—An efficient one-step method for the synthesis of fully substituted thiophenes, from thiomorpholides and a-halo ketones, was
developed. A mechanism has also been proposed for the course of reaction.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
restricted by the lack of enough available methods to
construct the desired ring bearing functionality in a
controlled fashion. The most convenient method for
preparing thiophenes with a high degree of functionality is
by the Gewald method in which elemental sulfur is reacted
with an activated acetonitrile and an aldehyde, ketone or
1,3-dicarbonyl compound in the presence of a base
(equimolar quantities of each).4 A modification of the
Gewald method has been reported in which an alkoxy-
acetone is reacted with ethylcyanoacetate, sulfur, and
morpholine producing 5-alkoxy thiophene derivatives in
poor yields (19–39%).5
The synthesis of highly substituted thiophenes has attracted
a great deal of interest over the years due to their presence
in natural products,1 as new conducting polymers2 and
isosteric replacement for phenyl group in medicinal
chemistry.3 Our interest in this class of compound was
based on their use as novel anti-inflammatory and analgesic
drugs having general formula (A).
Thioamides have been used as useful synthons in the
synthesis of heterocycles.6 Thiazole derivatives are pro-
duced by the reaction of primary and/or secondary
thioamides with a-haloketones. But, in contrast to the
primary and secondary thioamides, the nitrogen atom of
However, the synthesis of highly substituted thiophenes is
Scheme 1.
Keywords: Substituted thiophenes.
*
Corresponding author. Tel.: þ98216005718; fax: þ98216012983; e-mail address: matloubi@sharif.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.072

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F. Matloubi Moghaddam, H. Zali Boinee / Tetrahedron 60 (2004) 6085–6089
Table 1. Constraction of highly substituted thiophenes using thiomorpholides
Entry
1
Ar
R1
R2
Product
Reaction time (h)
Temperature
70
Isolated yield (%)
Mp (8)
H
H
7
75
178
2
3
8
7
80
75
58
60
145
153
H
H
4
5
6
7
7
6.5
7
85
75
80
85
63
80
55
62
158
208
214
243
8
8
9
7
6
75
70
69
70
196
105
–CH3
H
tertiary thioamides could not take part in heterocyclization.
However, the tertiary thioamides having an activated
methylene group could react with a-halocarbonyl com-
pounds in the presence of a base leading to the synthesis of
2-aminothiophene derivatives. For example, tertiary thio-
acetamides in benzene react with a-bromoketones in the
presence of DBU yielding 2-amino-3-nitrothiophenes.7
These reactions are restricted to the tertiary nitro thio-
acetamides as starting materials. Earlier we have reported a
simple microwave-induced method for the preparation of
thiomorpholides including aryl thioacetomorpholides.8 The
availability of such thiomorpholides provided a unique
opportunity of examining their synthetic utility. We were
especially intrigued by the possibility of their use in the
synthesis of thiophene containing heterocyclic compounds
especially aryl acetic acids. We hoped that such compounds
would exhibit interesting analgesic and anti-inflammatory
properties. As a preliminary result, recently we have
reported a versatile one-pot synthesis of trisubstituted
thiophenes from thiomorpholides via S-Claisen rearrange-
ment.9 In continuation of our research in this area and
aiming to find new biologically active heterocyclic
compounds, such as 2-aminothiophene derivatives, here
we report our results on the reaction of aromatic
thioacetomorpholides with a-bromoketones (Scheme 1).
When the thiomorpholide 1 was treated with a-bromo-
ketone 2 in toluene and stirred for 6–8 h at 60–80 8C in the
presence of anhydrous K2CO3, the highly substituted
thiophenes were obtained in good yields. Several
examples have been investigated and Table 1 sum-
marizes our results along with the melting points of the
compounds.
A mechanism is proposed for the reaction course and
shown in Scheme 2. Thiomorpholide undergoes first an
S-alkylation with a-haloketone, then subsequent treatment
with base leading to cyclization and formation of thiophene
ring with water elimination.
For confirming the proposed mechanism, one of the model
compounds (3i) was prepared by a reaction pathway for

F. Matloubi Moghaddam, H. Zali Boinee / Tetrahedron 60 (2004) 6085–6089
6087
Scheme 2.
Scheme 3.
which the mechanism was known (Scheme 3).9,10 Both
reactions gave the same compound with fixed substitutes in
thiophene ring.
step and good chemical yields (Scheme 4). Table 2 resumes
our results.
Surprisingly this reaction proceeded more conveniently in
a polar solvent such as isopropanol in the presence of
anhydrous Na2CO3 as base compared to the toluene/
K2CO3 system. In toluene, the reaction proceeded
sluggishly with low yield. These new aryl acetic acid
In order to obtain new aryl acetic acid derivatives, it was
also found that the thiomorpholides could react with
functionalized a-haloketones such as b-bromo-b-benzoyl
propionic acid to give fully substituted thiophenes in one
Scheme 4.
Table 2. One-step synthesis of thiophene acetic acid derivatives
Entry
Ar
Product
Reaction time (h)
Temprature
65
Isolated yield (%)
Mp (8)
1
6
58
172
2
3
4
7
7
6
65
60
55
52
50
48
228
190
185

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F. Matloubi Moghaddam, H. Zali Boinee / Tetrahedron 60 (2004) 6085–6089
derivatives have promising analgesic and anti-inflammatory
effect.
Compound 3b: white powder (EtOH), mp: 145 8C, 1H
NMR (CDCl3, 500 MHz) 7.36 (d, J¼8.4 Hz, 2H), 7.26
(d, J¼8.5 Hz, 2H), 7.18 (d, J¼8.5 Hz, 2H), 6.95 (d,
J¼8.4 Hz, 2H), 6.87 (s, 1H), 3.68 (t, J¼4.6 Hz, 4H), 2.86
(t, J¼4.6 Hz, 4H); IR (KBr) 3050, 2953, 1584, 1500, 1123,
830 (cm21).
In conclusion we have developed a new general efficient and
simple method for the preparation of highly substituted
thiophenes. The generality of the method has been
demonstrated by the successful conversion of twelve
substrates into tri or tetra substituted morpholino thiophenes
in good yields. The base is rather cheap and readily
available in all chemistry laboratories. The method was
easily extended to the synthesis of thiophenes (see Table 2)
bearing an acetic acid unit at position 5. These materials
especially 2-morpholino-5-acetic acid substituted thio-
phenes have the potential to be used as analgesic and
anti-inflammatory drugs. The methodology described here
seems to be the simplest one for the one-step synthesis of
these compounds.
Compound 3c: light yellow crystals (EtOH), mp: 153 8C, 1H
NMR (CDCl3, 500 MHz) 7.65 (d, J¼8.2 Hz, 2H), 7.55 (d,
J¼8.0 Hz, 2H), 7.46 (t, J¼7.6 Hz, 2H), 7.36 (t, J¼8.1 Hz,
1H), 7.34 (d, J¼8.1 Hz, 2H2), 7.31 (d, J¼8.0 Hz, 2H), 7.01
(d, J¼8.2 Hz, 2H), 6.88 (s, 1H), 3.70 (t, J¼4.4 Hz, 4H), 2.91
(t, J¼4.5 Hz, 4H); IR (KBr) 3060, 2845, 1638, 1500, 1123,
830 (cm21).
Compound 3d: yellow powder (EtOH), mp: 157 8C, 1H
NMR (CDCl3, 500 MHz) 7.83 (d, J¼7.3 Hz, 1H), 7.77,
(d, J¼8.5 Hz, 1H), 7.72 (d, J¼8.5 Hz, 1H), 7.70 (s, 1H),
7.45–7.50 (m, 2H), 7.41 (d, d, J¼8.4, 1.5 Hz, 1H), 7.29 (d,
J¼8.5 Hz, 2H), 6.98 (d, J¼8.5 Hz, 2H), 6.90 (s, 1H), 3,64 (t,
J¼4.5 Hz, 4H), 2.89 (t, J¼4.5 Hz, 4H); IR (KBr) 3110,
2950, 1610, 1445, 1123, 700 (cm21).
2. Experimental
The compounds gave satisfactory all spectroscopic data. FT
IR spectra were recorded as KBr pellets on a Nicolet
spectrometer (Magna 550). A Bruker (DRX-500 Avance)
NMR was used to record the 1H NMR spectra. All 1H NMR
spectra were determined in CDCl3 at ambient temperature.
Melting points were determined on a Bu¨chi B540 apparatus.
Compound 3e: white powder (EtOH), mp: 208 8C, 1H NMR
(CDCl3, 500 MHz) 7.13–7.24 (m, 13H), 6.96 (d, d, J¼7.4,
1.8 Hz, 2H), 3.61 (t, J¼4.6 Hz, 4H), 2.88 (t, J¼4.6 Hz, 4H);
IR (KBr) 3090, 2970, 1620, 1500, 1123, 700 (cm21).
Compound 3f: yellow powder (EtOH), mp: 214 8C, 1H
NMR (CDCl3, 500 MHz) 7.14–7.23 (m, 8H), 7.10 (d, J¼
8.7 Hz, 2H), 6.97 (d, d, J¼7.3, 2 Hz, 2H), 6.79 (d, J¼
8.7 Hz, 2H), 3.62 (t, J¼4.6 Hz, 4H), 2.89 (t, J¼4.6 Hz, 4H);
IR (KBr) 3120, 2845, 1600, 1507, 1123, 753 (cm21).
2.1. General procedure for the one-pot preparation of
compounds (a–i)
To a stirred solution of thiomorpholide (4 mmol) in toluene
(5 ml), anhydrous K2CO3 (0.552 g, 4 mmol) was added.
Then a solution of bromoketone (4 mmol) in toluene
(,3 ml) was added dropwise over 10 min. The reaction
mixture was heated at 75 8C for about 7 h. The solvent was
evaporated to half volume. After cooling a precipitate was
appeared. The precipitate was filtered and crystallized from
a suitable solvent.
Compound 3g: light yellow powder (EtOH), mp: 243 8C, 1H
NMR (CDCl3, 500 MHz) 7.75 (d, J¼7.7 Hz, 1H), 7.65 (d,
J¼8.5 Hz, 1H), 7.60 (d, J¼7.8 Hz, 1H), 7.58 (s, 1H), 7.40–
7.43 (m, 2H), 7.38 (d, J¼8.5 Hz, 1H), 7.13–7.23 (m, 5H),
7.07–7.11 (m, 3H), 6.96 (d, J¼6.5 Hz, 2H), 3.64 (t, J¼
4.4 Hz, 4H), 2.93 (t, J¼4.4 Hz, 4H); IR (KBr) 3097, 2807,
1607, 1500, 1253, 836 (cm21).
2.2. General procedure for the one-pot preparation of
compounds (j–l)
Compound 3h: light yellow crystals (EtOH), mp: 196 8C, 1H
NMR (CDCl3, 500 MHz) 7.1–7.18 (m, 8H), 7.06 (d, J¼
8.6 Hz, 2H), 6.93 9m, 2H), 6.71 (d, J¼8.6 Hz, 2H), 3.79 (s,
3H), 3.69 (t, J¼4.4 Hz, 4H), 2.94 (t, J¼4.5 Hz, 4H); IR
(KBr) 3090, 2856, 1597, 1502, 1125, 830 (cm21).
To a stirred solution of thiomorpholide (4 mmol) in 2-pro-
panol (3 ml), b-bromo-b-benzoyl propionic acid (4 mmol)
was added. Then reaction mixture was heated to 70 8C for
about 1 h. Then, anhydrous Na2CO3 (0.212 g, 2 mmol) was
added and stirred overnight. The solvent was removed under
vacuum and the residue was dissolved in ether (20 ml),
washed with 2£5 ml NaOH (5%). The aqueous solution was
acidified with HCl (5%) and extracted with diethyl ether.
The solvent was evaporated and the solid residue was
recrystallized from ethanol.
Compound 3i: white crystals (EtOH), mp: 105 8C, 1H NMR
(CDCl3, 500 MHz) 7.79 (d, J¼7.7 Hz, 2H), 7.41 (t, J¼
7.7 Hz, 2H), 7.27 (t, J¼7.6 Hz, 1H), 6.79 (s, 1H), 3.81 (t,
J¼4.6 Hz, 4H), 2.97 (t, J¼4.6 Hz, 4H), 2.48 (s, 3H); IR
(KBr) 2964, 2907, 2860, 1643, 1505, 1117, 837 (cm21).
Compound 3j: white powder (EtOH), mp: 172 8C, 1H NMR
(CDCl3, 500 MHz) 9.45 (s, 1H), 7.24 (m, 3H), 7.11–7.19
(m, 5H), 7.05 (m, 2H), 3.72 (s, 2H), 3.67 (t, J¼4.5 Hz, 4H),
2.89 (t, J¼4.5 Hz, 4H); IR (KBr) 3738, 3050, 2923, 1707,
1446, 1253, 759 (cm21).
2.3. Spectroscopic data for compounds (3a–3m)
Compound 3a: white powder (EtOH), mp: 178 8C, 1H NMR
(CDCl3, 500 MHz) 7.33 (d, J¼8.2 Hz, 2H), 7.29 (d, J¼
9.4 Hz, 2H), 7.27 (t, J¼5.4 Hz, 1H), 7.23 (t, J¼5.4 Hz, 2H),
6.96 (d, J¼8.2 Hz, 2H), 6.86 (s, 1H), 3.67 (t, J¼4.3 Hz, 4H),
2.87 (t, J¼4.3 Hz, 4H); IR (KBr) 3100, 2915, 1645, 1500,
1123, 830 (cm21).
Compound 3k: light yellow powder (EtOH), mp: 228 8C, 1H
NMR (CDCl3, 500 MHz) 9.52 (s, 1H), 7.26 (m, 3H), 7.15 (d,
J¼8.5 Hz, 2H), 7.1 (d, J¼8.5 Hz, 2H), 7.02–7.04 (m, 2H),

F. Matloubi Moghaddam, H. Zali Boinee / Tetrahedron 60 (2004) 6085–6089
6089
2. Press, J. B.; Pelkey, E. T. Progress in Heterocyclic Chemistry;
Gribble, G. W., Gilchrist, T. W., Eds.; Pergamon: New York,
1997; Vol. 9, p 77.
3.71 (s, 2H), 3.68 (t, J¼4.4 Hz, 4H), 2.88 (t, J¼4.4 Hz, 4H);
IR (KBr) 3610, 3110, 2961, 1710, 1446, 1262, 707 (cm21).
Compound 3l: light yellow crystals (EtOH), mp: 190 8C, 1H
NMR (CDCl3, 500 MHz) 9.58 (s, 1H), 7.25 (m, 3H), 7.08
(d, J¼8.6 Hz, 2H), 7.05 (m, 2H), 6.72 (d, J¼8.6 Hz, 2H),
3.79 (s, 2H), 3.68 (t, J¼4.5 Hz, 4H), 2.89 (t, J¼4.5 Hz, 4H);
IR (KBr) 3446, 2923, 1692, 1592, 1261, 769 (cm21).
3. Jarvest, R. L.; Pinro, I. L.; Ashamn, S. M.; Dabrowsky, G. E.;
Fernandez, A. V.; Jenning, L. G.; Lavery, P.; Tew, D. G.
Bioorg. Med. Chem. Lett. 1999, 9, 443.
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5. Pinto, I. L.; Jarvest, R. L.; Serafinowska, H. T. Tetrahedron
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Compound 3m: yellow crystals (EtOH), mp:185 8C, 1H
NMR (CDCl3, 500 MHz) 9.50 (s, 1H), 7.22–7.27 (m, 3H),
7.08 (d, J¼8.7 Hz, 2H), 7.05 (d, J¼7.7 Hz, 2H), 6.72 (d,
J¼8.7 Hz, 2H), 3.77 (s, 3H), 3.71 (s, 2H), 3.68 (t, J¼4.5 Hz,
4H), 2.89 (t, J¼4.5 Hz, 4H); IR (KBr) 3455, 2937, 1702,
1595, 1257, 748 (cm21).
6. Jagodzinski, S. T. Chem. Rev. 2003, 103, 197–227.
7. Reddy, K. V.; Rajappa, S. Heterocycles 1994, 37(1), 347.
8. (a) Matloubi Moghaddam, F.; Ghaffarzadeh, M.; Dekamin, M.
J. Chem. Res. (S) 2000, 228. (b) Matloubi Moghaddam, F.;
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References and notes
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