An efficient one-pot synthesis of tri-substituted thiophenes via a multicomponent reaction in water

Article abstract of DOI:10.1080/17415993.2010.496129

An efficient one-pot synthesis of functionalized trisubstituted thiophenes via the reaction of 3-morpholino-3-thioxopropanenitrile, cyclohexyl isocyanide and -haloketones is reported. This method provides a straightforward route to a variety of highly substituted thiophenes not easily accessible by conventional methods.

Full text of DOI:10.1080/17415993.2010.496129

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An efficient one-pot synthesis of
tri-substituted thiophenes via a
multicomponent reaction in water
Firouz Matloubi Moghaddam a , Ghasem Rezanejade Bardajee b &
Maliheh Dolabi a
a Laboratory of Organic Synthesis and Natural Products,
Department of Chemistry, Sharif University of Technology, PO Box
11155-9516, Tehran, Iran
b Department of Chemistry, Payame Noor University, Qazvin
Branch, PO Box 878, Qazvin, Iran
Published online: 28 Sep 2010.
To cite this article: Firouz Matloubi Moghaddam , Ghasem Rezanejade Bardajee & Maliheh Dolabi
(2010) An efficient one-pot synthesis of tri-substituted thiophenes via a multicomponent reaction in
water, Journal of Sulfur Chemistry, 31:5, 387-393, DOI: 10.1080/17415993.2010.496129
To link to this article: http://dx.doi.org/10.1080/17415993.2010.496129
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Journal of Sulfur Chemistry
Vol. 31, No. 5, October 2010, 387–393
An efficient one-pot synthesis of tri-substituted thiophenes via
a multicomponent reaction in water
Firouz Matloubi Moghaddama*, Ghasem Rezanejade Bardajeeb and Maliheh Dolabia
aLaboratory of Organic Synthesis and Natural Products, Department of Chemistry, Sharif University of
Technology, PO Box 11155-9516, Tehran, Iran; bDepartment of Chemistry, Payame Noor University, Qazvin
Branch, PO Box 878, Qazvin, Iran
(Received 25 April 2010; final version received 23 May 2010)
An efficient one-pot synthesis of functionalized trisubstituted thiophenes via the reaction of 3-morpholino-
3-thioxopropanenitrile, cyclohexyl isocyanide and α-haloketones is reported. This method provides a
straightforward route to a variety of highly substituted thiophenes not easily accessible by conventional
methods.
Keywords: amides; cyclization; multicomponent reaction; nitriles; thiophene
1. Introduction
Highly substituted thiophenes have attracted considerable attention in organic synthesis. They
constitute an important class of natural compounds (1), show interesting biological activities
and are used as a monomer in the synthesis of conducting polymers (2), isosteric replacements
for phenyl groups in medicinal chemistry (3), flavor of food stuff comprising and optical chro-
mophores (4). Certain thiophene derivatives occur as plant pigments and other natural products.
For example, antihistamine methapyrilene (Thenylene), Biotin and certain other synthetic phar-
maceuticals contain the thiophene nucleus. For instance, Banminth and Echino-thiophene are
found in natural products (Figure 1) (5). Thus, several methods have been introduced for their
syntheses which often consist of multistep reaction processes (6–15).
Although some methods such as Fisselmane, Gewald, Hinsberg and Paal were introduced
and developed for the synthesis of various derivatives of thiophenes (5), finding new strategies
for the synthesis of these structure motifs is still interesting. Furthermore, new routes for the
functionalization of thiophenes for biological purposes are a challenge in thiophene chemistry.
As one can see, a one step, straightforward and generally applicable reaction procedure for the
synthesis of this functionalized scaffold would find significant utility in organic synthesis.
To the best of our knowledge, there are a few reports for the synthesis of nitrile functionalized
thiophenes (10, 11, 13). Expensive reagents, multistep reaction process and uncommon reagents
*Corresponding author. Email: matloubi@sharif.edu
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2010 Taylor & Francis
DOI: 10.1080/17415993.2010.496129
http://www.informaworld.com

388 F.M. Moghaddam et al.
Figure 1. Thiophene containing natural products.
are major disadvantages of the reported methods.As a favorable functional group with the potential
for converting to other biological important moieties such as amides, carboxylic acids and amines,
the synthesis of nitrile-substituted thiophenes in the course of the reaction will be interesting.
Continuing our foregoing efforts in the construction of highly functionalized thiophene deriva-
tives (16, 17), herein we report a new methodology to construct functionalized thiophene
derivatives by applying isocyanides through a one-pot procedure in water.
2. Results and discussion
The approach involved the use of 3-morpholino-3-thioxopropanenitrile (cyanothioacetamide) 2
and cyclohexyl isocyanide followed by the addition of an α-haloketone to produce the desired thio-
phene derivatives in water. This protocol takes advantage of readily accessible starting materials,
one-pot construction of thiophene building blocks and simple procedures. In this regard, cyanoac-
etamide 1 was synthesized by a direct amidation of alkyl cyanoacetates using DBU according
to a recently reported procedure with a little modification (Scheme 1) (18). The thionation of
compound 1 in the presence of P2S5 gave the desired product 2 in good yield (Scheme 1) (8, 12).
To test the feasibility of this reaction, we initially investigated the reaction of cyanothioac-
etamide 2, cyclohexyl isocyanide and phenacyl chloride 3a under various reaction conditions. To
this end, different solvents and bases were examined. While with ethanol, DMSO, acetonitrile,
DMF and diethyl ether low yield of the desired product was obtained, water as a solvent improved
the reaction yield. A base screen (carbonates, sodium methoxide, ammonia and triethyl amine)
revealed that carbonate bases such as potassium and cesium carbonate result in higher reactiv-
ity in this cyclization reaction. Accordingly, when thiomorpholide 2 (0.6 mmol, 1 equiv.) and
cyclohexyl isocyanide (0.6 mmol, 1 equiv.) in water (3 mL) were treated with phenacyl chloride
(0.6 mmol, 1 equiv.) in the presence of K2CO3 (0.7 mmol, 1.2 equiv.) for about 6 h at 60◦C, the
three-substituted thiophene 4a was obtained in 65% yield (Table 1, Entry 1).
Scheme 1. The general route for the synthesis of compound 2.

Journal of Sulfur Chemistry 389
Table 1. One-pot conversion of thiomorpholide 2 to highly functionalized thiophenes 4.
Entry
1
α-Haloketone (3)
Product (4)
Yielda (%)
65
2
3
4
72
74
59
5
6
64
62
7
66
8
9
–
–
–
–
10
65
Note: aIsolated yields.

390 F.M. Moghaddam et al.
We next used these optimal reaction conditions to investigate the scope of the reaction with a
range of α-haloketones. The results showed that a variety of substituents were tolerated under the
reaction conditions. While the para-bromophenacyl bromide 3b and para-chlorophenacyl bro-
mide 3c resulted in the corresponding thiophenes 4b and 4c in 72% and 74% yields, respectively,
the para-methoxyphenacyl bromide 3d afforded product 4d in lower yield (Table 1, Entries 2–4).
This dissimilarity of yields can be attributed to the different abilities of halides and methoxy sub-
stitutions on the phenyl rings in the stabilization of related anions. In continuation, we expanded
the scope of the reaction to include naphthalene rings. Compound, 3e gave the desired product
with a satisfactory yield (64%, Table 1, Entry 5). As well, the possibility of the reaction was inves-
tigated by using the aliphatic partner of α-haloketones 3f and a comparable yield was obtained
1
(Table 1, Entry 6). The structure of the products was confirmed by analytical data, FT-IR, H
NMR and 13C NMR spectra (17).
It was also desirable to test whether α-halonitriles, α-haloamides and α-haloesters could be
applied in the reaction. While with the chloroacetonitrile 3g, comparable results were obtained
(Table 1, Entry 7), 2-chloro-N-phenylacetamide and ethyl-2-chloroacetate failed to take part in
this methodology (Table 1, Entries 8 and 9).
The possible mechanism for this conversion is summarized in Scheme 2. The first step involves
the deprotonation of compound 2 by cyclohexyl isocyanide via an acid–base reaction. Then,
the nucleophilic addition of carbanion to positively charged ion obtained from cyclohexyl iso-
cyanide leads to 6 which easily isomerizes to enamine 7. The S-alkylation of component 7 with
α-haloketone 3 via an SN2 reaction affords the iminium ion 8. Subsequent cyclization followed
by cyclohexylamine elimination affords the corresponding thiophene 4. The improved yield of
the reaction in water can be explained by this mechanism. As the starting materials as well as
the intermediates involving in this reaction are polar compounds in organic chemistry, the more
polarity of water relative to other examined solvents can result in higher homogeneity of the
reaction mixture and in more stability of relating intermediates.
In order to determine whether nucleophilic addition of compound 7 to α-haloketones is the
rate-determining step, phenacyl bromide (3j) was used instead of phenacyl chloride (3a), and no
Scheme 2. The plausible mechanism for the formation of substituted thiophenes.

Journal of Sulfur Chemistry 391
variation in yield was observed (Table 1, Entry 10). This result suggests that the conversion of
intermediate 7 to 8 is not the rate-determining step which is attributed to the steric and mainly to
electronic effects (19).
3. Conclusion
In summary, we have developed a straightforward and general one-pot approach to highly func-
tionalized thiophenes using readily accessible α-haloketones and cyanothioacetamide. We have
investigated the possibility of this methodology for the construction of these structural patterns
not easily available by other methods. Expansion of the derived methodology for the preparation
of similar functionalized heterocycles is under investigation.
4. Experimental
4.1. Synthesis of cyanoacetamide 1
Compound 1 was synthesized according to a recently reported method with a little modifica-
tion (16). DBU (1.73 mL, 11.48 mmol) and morpholine (2.00 mL, 22.96 mmol) were added to
tetrahydrofuran (8 mL) and the reaction temperature was maintained at 40◦C. Ethyl cyanoacetate
(4.89 mL, 45.91 mmol) was added and the mixture was stirred for 4 h. The mixture was concen-
trated and purified by column chromatography (SiO2; 2% methanol in methylene chloride) to
give of an off-white crystalline solid (62%).
4.2. Synthesis of thiocyanoacetamide 2
Cyanothioacetamide 2 and α-halocarbonyl compounds 3 were prepared according to previously
reported procedures (8, 12, 20, 21). In a typical procedure for the synthesis of cyanothioacetamide
2, certain amount of P2S5 (0.05 mol) was added gradually to a stirring mixture of cyanoacetamide
1 (0.1 mol) in dichloromethane (250 mL) at room temperature. In continuation, the mixture was
refluxed for 5 h, and after cooling to room temperature, it was subsequently triturated with water
in an efficient fume hood. After stirring overnight, the organic layer was separated, dried with
CaCl2 and concentrated in vacuum. The solid product was triturated with methanol and isolated
by filtration and stored in a refrigerator for further reactions.
4.3. Typical experimental procedure for the synthesis of substituted thiophenes (4)
In a round-bottomed flask equipped with a magnet and a condenser, cyclohexyl isocyanide
(0.6 mmol, 1 equiv.) was added to a stirred suspension of cyanothioacetamide 2 (0.6 mmol,
1 equiv.) in H2O (3 mL). The reaction mixture was stirred at 60◦C for 8 h. After completion
of the reaction, α-halocarbonyl compound 3 (0.6 mmol, 1 equiv.) in acetonitrile (2 mL) and
K2CO3 (0.7 mmol, 1.2 equiv.) was added to the mixture. The reaction mixture was stirred at
60◦C for further 6 h. The course of the reaction was monitored using TLC on silica gel with
dichloromethane as an eluent. After completion of the reaction, the mixture was extracted with
CH2Cl2 (2 × 10 mL). The combined organic extracts were dried with MgSO4 and concentrated.
The residue was subjected to column chromatography on SiO2 (dichloromethane) to obtain pure
products. Representative analytical data: Compound 4a: Oil; 1H NMR (500 MHz, CDCl3) δ 3.50
(t, J = 5.0 Hz, 4H), 3.92 (t, J = 5.0 Hz, 4H), 6.61 (s, 1H), 742 (d, J = 6.8 Hz, 2H), 747 (m, 2H),

392 F.M. Moghaddam et al.
760 (d, J = 7.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 52.0, 66.6, 91.4, 109.0, 117.1, 128.1,
128.7, 129.1, 134.7, 142.8, 169.0, 189.1; IR (KBr) 3086, 2201, 1514, 1382 cm−1; Anal. Calcd
for C16H14N2O2S: C, 64.41; H, 4.73; N, 9.39; S, 10.75. Found: C, 64.62; H, 4.86; N, 9.54; S,
1
10.83. Compound 4b: Yellowish crystals; mp 151–153◦C; H NMR (500 MHz, CDCl3) δ 3.51
(t, J = 4.9 Hz, 4H), 3.93 (t, J = 4.9 Hz, 4H), 6.59 (s, 1H), 746 (d, J = 8.4 Hz, 2H), 760 (d,
J = 8.4 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 51.9, 66.5, 109.1, 116.9, 123.0, 129.7, 130.5,
132.3, 132.5, 133.6, 144.1, 184.3; IR (KBr) 3044, 2922, 2207, 1670, 1497 cm−1; Anal. Calcd
for C16H13BrN2O2S: C, 50.94; H, 3.47; N, 7.43; S, 8.50. Found: C, 51.02; H, 3.64; N, 7.58; S,
8.62. Compound 4c:Yellowish crystals; 1H NMR (500 MHz, CDCl3) δ 3.60 (t, J = 4.9 Hz, 4H),
3.91 (t, J = 4.9 Hz, 4H), 6.90 (s, 1H), 744 (d, J = 8.6 Hz, 2H), 789 (d, J = 8.6 Hz, 2H); 13C
NMR (125 MHz, CDCl3) δ 55.1, 68.7, 113.3, 117.2, 127.7, 129.1, 130.5, 131.2, 131.3, 134.0,
140.6, 193.4; IR (KBr) 3055, 2964, 2209, 1683, 1502 cm−1; Anal. Calcd for C16H13ClN2O2S: C,
57.74; H, 3.94; N, 8.42; S, 9.63. Found: C, 57.86; H, 4.08; N, 8.60; S, 9.77. Compound 4d: Oil;
1H NMR (500 MHz, CDCl3) δ 3.57 (t, J = 5.0 Hz, 4H), 3.86 (s, 3H), 3.94 (t, J = 5.0 Hz, 4H),
6.48 (s, 1H), 6.92 (d, J = 8.7 Hz, 2H), 794 (d, J = 8.7 Hz, 2H); 13C NMR (125 MHz, CDCl3)
δ 54.7, 56.2, 68.4, 111.6, 113.6, 114.5, 115.4, 127.8, 128.8, 129.4, 131.5, 164.2, 193.3; IR (KBr)
3042, 2958, 2188, 1656, 1512 cm−1; Anal. Calcd for C17H16N2O3S: C, 62.18; H, 4.91; N, 8.53;
S, 9.76. Found: C, 62.34; H, 4.75; N, 8.51; S, 9.87. Compound 4e: Yellowish crystals; 1H NMR
(500 MHz, CDCl3) δ 3.56 (t, J = 5.0 Hz, 4H), 3.94 (t, J = 5.0 Hz, 4H), 6.63 (s, 1H), 754 (m,
2H), 785 (m, 4H), 8.12 (s, 1H ); 13C NMR (125 MHz, CDCl3) δ 52.2, 68.3, 110.8, 116.6, 124.0,
125.5, 125.8, 126.4, 126.8, 127.9, 128.8, 129.2, 129.5, 131.3, 132.5 134.7, 141.3, 187.5; IR (KBr)
3059, 2965, 2206, 1675, 1512, 1453 cm−1; Anal. Calcd for C20H16N2O2S: C, 68.94; H, 4.63; N,
8.04; S, 9.20. Found: C, 69.12; H, 4.79; N, 8.21; S, 9.36. Compound 4f: Oil; 1H NMR (500 MHz,
CDCl3) δ 2.31 (s, 3H, CH3), 3.44 (t, J = 4.9 Hz, 4H), 3.88 (t, J = 4.9 Hz, 4H), 6.22 (s, 1H); 13
C
NMR (125 MHz, CDCl3) δ 30.1, 51.6, 66.5, 107.4, 117.0, 130.1, 138.3, 164.1, 203.2; IR (KBr)
3086, 2968, 2205, 1716, 1502 cm−1; Anal. Calcd for C11H12N2O2S: C, 55.91; H, 5.12; N, 11.86;
S, 13.57. Found: C, 56.10; H, 5.24; N, 11.73; S, 13.74. Compound 4g: Oil; 1H NMR (500 MHz,
CDCl3) δ 3.20 (t, J = 5.0 Hz, 4H), 3.69 (t, J = 5.0 Hz, 4H), 5.54 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 49.6, 66.2, 95.5, 110.4, 115.6, 129.8, 141.3, 157.6; IR (KBr) 3086, 2968, 2205, 1716,
1502 cm−1; Anal. Calcd for C10H9N3OS: C, 54.78; H, 4.14; N, 19.16; S, 14.62. Found: C, 54.89;
H, 4.18; N, 19.34; S, 14.74.
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