Efficient preparation of highly substituted thiophenes and thiophene-based arylacetic acids

Article abstract of DOI:10.1080/17415993.2012.733006

An efficient and one-step method for the preparation of highly substituted thiophenes and thiophen-2-yl-acetic acid derivatives was developed. Hence, thioacetomorpholides were smoothly reacted with -bromo carbonyl compounds in [bmim]OH as an efficient dua

Full text of DOI:10.1080/17415993.2012.733006

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Efficient preparation of highly
substituted thiophenes and thiophene-
based arylacetic acids
Hassan Zali-Boeini a & Fatemeh Pourjafarian a
a Department of Chemistry, University of Isfahan, 81746-73441,
Isfahan, Iran
Version of record first published: 01 Nov 2012.
To cite this article: Hassan Zali-Boeini & Fatemeh Pourjafarian (2012): Efficient preparation of
highly substituted thiophenes and thiophene-based arylacetic acids, Journal of Sulfur Chemistry,
DOI:10.1080/17415993.2012.733006
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Journal of Sulfur Chemistry
iFirst, 2012, 1–7
Efficient preparation of highly substituted thiophenes and
thiophene-based arylacetic acids
Hassan Zali-Boeini* and Fatemeh Pourjafarian
Department of Chemistry, University of Isfahan, 81746-73441 Isfahan, Iran
(Received 15 August 2012; final version received 19 September 2012)
An efficient and one-step method for the preparation of highly substituted thiophenes and thiophen-2-yl-
acetic acid derivatives was developed. Hence, thioacetomorpholides were smoothly reacted with α-bromo
carbonyl compounds in [bmim]OH as an efficient dual catalyst-reaction medium to produce the title
compounds in good yields.
Keywords: arylacetic acids; ionic liquids; sulfur heterocycles; thioamides; thiophenes
1. Introduction
There has been considerable interest in the synthesis of highly substituted and functionalized
thiophenes during the years due to their huge applications in medicinal (1–4) chemistry and
industry (5–8). The most known method for the preparation of highly substituted thiophenes
is the Gewald method (9) in which, elemental sulfur is reacted with equimolar amounts of an
activated acetonitrile and a carbonyl compound in the presence of a base. Earlier, we have shown
that a one-pot thio-Claisen reaction and ring closure of thioacetomorpholides with propargyl
bromide leads to trisubstituted thiophenes via an α-allenyl thioacetomorpholide intermediate (10).
Following that we reported an efficient method for the synthesis of fully substituted thiophenes
using thioacetomorpholides (11). However, preparing the desired thiophenes in an unfriendly
solvent (toluene) and in long reaction times (6–8 h) was the main disadvantage of the method.
Herein, we have developed an efficient method for the preparation of highly substituted
thiophenes using [bmim]OH as a task-specific ionic liquid. It was found that the reaction of
*Corresponding author. Email: h.zali@chem.ui.ac.ir
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2012 Taylor & Francis
http://dx.doi.org/10.1080/17415993.2012.733006
http://www.tandfonline.com

2
H. Zali-Boeini and F. Pourjafarian
thioacetomorpholides with α-bromocarbonyl compounds in [bmim]OH proceeds smoothly at
80◦C and produces moderate to excellent yields (58–93%) and in a relatively short time (50 min,
Scheme 1).
Scheme 1. Preparation of highly substituted thiophenes.
2. Results and discussion
Basic ionic liquids are environmentally friendly and recoverable solvents and catalysts with high
activity. In this study, [bmim]OH was used to replace traditional bases such as KOH, NaOH,
K2CO3, NaHCO3, NaOAc, triethylamine, or tetrabutylammonium acetate. Using the traditional
bases generally suffered from disadvantages such as waste production, corrosion, and environ-
mental problems. Basic ionic liquids suggest a new feasibility for developing environmentally
benign basic catalysts due to the combination of the benefits of inorganic bases and the striking
solubilizing power of ionic liquids.
At the outset of our study, phenyl acetomorpholide 1a was used as a test substrate and reacted
with 2-bromo-1-(4-bromophenyl)ethanone 2a in [bmim]OH and at various reaction temperatures
to produce 4-[4-(4-bromophenyl)-3-phenyl-2-thienyl]morpholine 3a. Our investigations revealed
that the reaction proceeds efficiently and cleanly at 80◦C to produce the desired thiophene product
in excellent yield (93%, Table 1).
However, when aryl thioacetomorpholides were reacted with 3-bromo-4-oxo-4-phenylbutanoic
acid derivatives in [bmim]OH, the corresponding thiophen-2-yl acetic acids were produced in fair
to good yields (58–77%).
Table 1. Temperature screening in the synthesis of thiophenes.
Entry
Product
T (◦C)
Yield (%)a
1
2
3
4
3a
3a
3a
3a
60
80
95
71
93
90
120
84b
Notes: aIsolated yields.
bFormation of some tarry and colored materials was observed.

Journal of Sulfur Chemistry
3
Table 2. Efficient synthesis of highly substituted thiophenes.
Entry
1
Ar1
Ph
Ar2
R
H
Producta
Yieldb (%)
93
O
4-BrC6H4
N
S
3a
Br
O
2
3
4
4-ClC6H4
2-Naphthyl
4-PhC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
H
H
H
85
87
83
N
S
Cl
3b
Br
O
N
S
3c
Br
O
N
S
3d
Br
O
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
90
81
84
S
3e
O
4-BrC6H4
4-MeOC6H4
2-Naphthyl
N
S
Br
3f
O
N
S
MeO
3g
O
80
N
S
3h
(Continued)

4
H. Zali-Boeini and F. Pourjafarian
Table 2. Continued.
Entry
9
Ar1
Ph
Ar2
Ph
R
Producta
Yieldb (%)
77
O
CH2COOH
N
COOH
S
3i
O
10
11
12
13
14
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-MeC6H4
4-PhC6H4
Ph
Ph
Ph
Ph
Ph
CH2COOH
CH2COOH
CH2COOH
CH2COOH
CH2COOH
65
58
60
78
73
N
COOH
S
Cl
3j
O
N
COOH
COOH
COOH
COOH
S
Br
3k
O
N
S
MeO
3l
O
N
S
Me
3m
O
N
S
3n
O
15
Ph
4-MeC6H4
CH2COOH
71
N
COOH
S
3o
Me
(Continued)

Journal of Sulfur Chemistry
5
Table 2. Continued.
Entry
16
Ar1
Ar2
R
Producta
Yieldb (%)
68
O
4-MeC6H4
4-MeC6H4
CH2COOH
N
S
COOH
Me
3p
Me
O
17
4-PhC6H4
4-MeC6H4
CH2COOH
69
N
COOH
S
3q
Me
O
18
19
2-Naphthyl
2-Naphthyl
Ph
CH2COOH
CH2COOH
67
62
N
COOH
S
3r
O
4-MeC6H4
N
COOH
S
3s
Me
Notes: aAll products were characterized by IR, 1H NMR, and CHNS elemental analysis.
bAll yields refer to pure isolated products.
The generality of the method has been confirmed by successful synthesis of 19 different
thiophene derivatives in moderate to excellent yields (58–93%), and Table 2 summarizes our
results.
To assess the feasibility of applying this method on a preparative scale, we carried out the
reaction of thioamide 1a with 2-bromo-1-(4-bromophenyl)ethanone 2a on a 40-mmol scale. It
was found that the reaction proceeded smoothly, similar to the case in a smaller scale (Table 2,
Entry 1), and the requested thiophene 3a was obtained in 89% isolated yield.
3. Conclusions
In conclusion, we have developed an efficient method for the preparation of highly substituted
thiophenes using a task-specific ionic liquid, which plays the role of a basic catalyst as well
as the solvent. Easy work-up, isolation, purification of product, mild reaction conditions, short
reaction time, and high yield of product are salient futures of the method. It is also expected
that the synthesized thiophen-2-yl acetic acids show potential anti-inflammatory and/or analgesic
properties.

6
H. Zali-Boeini and F. Pourjafarian
4. Experimental
4.1. General procedure for the preparation of highly substituted thiophenes
Aryl thioacetomorpholide (2 mmol) and α-bromocarbonyl compound (2 mmol) were dissolved in
[bmim]OH (1 ml) and heated to 80◦C for 50 min. After that, the reaction mixture was cooled to
room temperature and poured in water (10 ml). Then, the precipitated compound was filtered and
the solid residue was stirred for 10 min in cold MeOH (5 ml). The off-white thiophene precipitate
was filtered and dried in a vacuum desiccator. For further purification, the solid was redissolved
in the minimum amount of THF and reprecipitated with cold MeOH to obtain the pure product
as white powder.
4.2. General procedure for the preparation of highly substituted thiophen-2yl-acetic acids
Thioacetomorpholide (2 mmol) and α-bromo-β-aroylpropionic acid derivative (2 mmol) were
dissolved in [bmim]OH (1 ml) and heated to 80◦C for 50 min. After that, the reaction mixture
was cooled to room temperature, poured into dilute HCl (5%, 10 ml), and the precipitated product
was filtered. Then, the semi-solid residue was dissolved in diethyl ether (20 ml) and extracted
with NaOH (1 M, 2 × 10 ml). The aqueous layer was separated and treated with HCl (1 M, 22 ml)
and the resulting precipitate was filtered, washed with water (2 × 5 ml), and dried in a vacuum
desiccator to obtain thiophen-2-yl-acetic acids as white to light yellow solids.
The compounds (3a–3l) are known materials (11):
(3m): m.p.: 179–181◦C; 1H NMR (400 MHz, DMSO): δ 11.35 (s, 1H), 7.14–7.21 (m, 3H), 7.05
(d, J = 6.4 Hz, 2H), 6.94–6.99 (m, 4H), 3.53 (t, J = 4.3 Hz, 4H), 3.21 (s, 2H), 2.73 (t, J = 4.3 Hz,
4H), 2.21 (s, 3H); Anal. Calcd for C23H23NO3S: C, 70.20; H, 5.89; N, 3.56; S, 8.15. Found: C,
70.45; H, 5.73; N, 3.64; S, 8.03.
1
(3n): m.p.: 107–109◦C; H NMR (400 MHz, DMSO): δ 11.47 (s, 1H), 7.65 (d, J = 6.5 Hz,
2H), 7.52 (d, J = 6.5 Hz, 2H), 7.32–7.42 (m, 3H), 7.13–7.19 (m, 7H), 3.56 (t, J = 4.2 Hz, 4H),
3.22 (s, 2H), 2.77 (t, J = 4.2 Hz, 4H); Anal. Calcd for C28H25NO3S: C, 73.82; H, 5.53; N, 3.07;
S, 7.04. Found: C, 74.01; H, 5.36; N, 3.02; S, 6.98.
(3o): m.p.: 180–182◦C; 1H NMR (400 MHz, CDCl3): δ 11.32 (s, 1H), 7.18 (t, J = 7.3 Hz, 2H),
7.02–7.12 (m, 3H), 6.99 (d, J = 7.7, 2H), 6.95 (d, J = 7.7, 2H), 3.52 (t, J = 4.3 Hz, 4H), 3.20
(s, 2H), 2.72 (t, J = 4.3 Hz, 4H), 2.24 (s, 3H); Anal. Calcd for C23H23NO3S: C, 70.20; H, 5.89;
N, 3.56; S, 8.15. Found: C, 70.36; H, 5.79; N, 3.77; S, 8.08.
(3p): m.p.: 256–258◦C; 1H NMR (400 MHz, DMSO): δ 11.28 (s, 1H), 6.98–6.94 (m, 8H), 3.53
(t, J = 4.4 Hz, 4H), 3.18 (s, 2H), 2.72 (t, J = 4.4 Hz, 4H), 2.24 (s, 3H), 2.22 (s, 3H); Anal. Calcd
for C24H25NO3S: C, 70.73; H, 6.18; N, 3.44; S, 7.87. Found: C, 70.91; H, 6.06; N, 3.62; S, 7.80.
(3q): m.p.: 127–129◦C; H NMR (400 MHz, DMSO): δ 11.41 (s, 1H), 7.65 (d, J = 7.4 Hz,
1
2H), 7.52 (d, J = 8.2, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.18 (d, J = 8.2 Hz,
2H), 7.01 (m, 4H), 3.55 (t, J = 4.3 Hz, 4H), 3.44 (s, 2H), 2.76 (t, J = 4.3 Hz, 4H), 2.23 (s, 3H);
Anal. Calcd for C29H27NO3S: C, 74.17; H, 5.80; N, 2.98; S, 6.83. Found: C, 74.36; H, 5.69; N,
3.09; S, 6.72.
1
(3r): m.p.: 279–281◦C; H NMR (400 MHz, DMSO): δ 11.57 (s, 1H), 7.79 (d, J = 7.2 Hz,
1H), 7.70 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.57 (s, 1H), 7.37–7.43 (m, 2H), 7.30 (d,
J = 8.3 Hz, 1H), 7.11–7.17 (m, 5H), 3.52 (t, J = 4.2 Hz, 4H), 3.50 (s, 2H), 2.77 (t, J = 4.2 Hz,
4H); Anal. Calcd for C26H23NO3S: C, 72.70; H, 5.40; N, 3.26; S, 7.47. Found: C, 74.76; H, 5.25;
N, 3.37; S, 7.51.

Journal of Sulfur Chemistry
7
(3s): m.p.: 227–229◦C; 1H NMR (400 MHz, CDCl3): δ 11.51 (s, 1H), 9.52 (s, 1H), 7.26 (m,
3H), 7.15 (d, J = 8.5 Hz, 2H), 7.1 (d, J = 8.5 Hz, 2H), 7.02–7.04 (m, 4H), 3.71 (s, 2H), 3.68 (t,
J = 4.4 Hz, 4H), 2.88 (t, J = 4.4 Hz, 4H), 2.22 (s, 3H); Anal. Calcd for C27H25NO3S: C, 73.11;
H, 5.68; N, 3.16; S, 7.23. Found: C, 72.96; H, 5.55; N, 3.32; S, 7.15.
Acknowledgements
We are grateful to University of Isfahan research council for the financial support of this work.
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