Transesterification of trimethyl orthoacetate: An efficient protocol for the synthesis of 4-alkoxy-2-aminothiophene-3-carbonitriles

Article abstract of DOI:10.1016/j.tetlet.2012.12.090

A facile one-pot method is reported for the synthesis of 4-alkoxy-2-aminothiophene-3-carbonitriles. Transesterification of trimethylorthoacetate technique allowed introducing alkoxy substituents into 2-aminothiophene ring system. Diverse alkoxy substituents could be introduced efficiently by using this methodology. Further the synthesis of some of new 4-alkylamino-2-aminothiophenes is also reported.

Full text of DOI:10.1016/j.tetlet.2012.12.090

Tetrahedron Letters 54 (2013) 1274–1278
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Transesterification of trimethyl orthoacetate: an efficient protocol
for the synthesis of 4-alkoxy-2-aminothiophene-3-carbonitriles
K. Venkata Rao a, C. Balakumar a, B. Lakshmi Narayana a, D. Pran Kishore a, K. Rajwinder a,
A. Raghuram Rao b,
⇑
a Pharmaceutical Chemistry Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160 014, India
b Pharmaceutical Chemistry Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal 506 015, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile one-pot method is reported for the synthesis of 4-alkoxy-2-aminothiophene-3-carbonitriles.
Transesterification of trimethylorthoacetate technique allowed introducing alkoxy substituents into 2-
aminothiophene ring system. Diverse alkoxy substituents could be introduced efficiently by using this
methodology. Further the synthesis of some of new 4-alkylamino-2-aminothiophenes is also reported.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 7 August 2012
Revised 18 December 2012
Accepted 22 December 2012
Available online 31 December 2012
Keywords:
2-Aminothiophenes
4-Alkoxythiophenes
Transesterification
Gewald reaction
Multisubstituted 2-aminothiophenes are privileged structures,
which attracted considerable attention in the design of several bio-
logically active molecules.1 Ample data have been accumulated
highlighting their biological utility as synthons, that is, substituted
2-aminothiophenes and thieno[2,3-d]pyrimidines in the develop-
ment of various interesting molecules. Some of them are known
as kinase inhibitors, namely, receptor tyrosine kinase inhibitors
(RTK1),2 B-Raf kinase inhibitors,3 ErbB-2 kinase inhibitors4, and
epidermal growth factor receptor (EGFR) kinase inhibitors.5 One
such substituted alkoxythiophene 1 (Fig. 1) is currently being ex-
plored for its anticonvulsant potency.6 Further they are also ex-
plored for diverse industrial applications such as new conducting
polymers7 and in the preparations of dyes.8
In pursuance of our modeling studies based on structure-based
drug design of new adenosine kinase inhibitors, 4-amino-5-alkoxy-
thieno[2,3-d]pyrimidine 2 and its precursor 2-amino-4-alkoxythi-
ophene 3 (Fig. 1) were identified as key intermediates. Hence we
focused our attention to introduce diverse 4-alkoxy substituents
into 2-aminothiophene ring system.
CH3
S
O
H
N
O
CH3
O
R
H3C
N
NH2
N
N
R
O
O
O
S
H3C
N
NH2
S
S
N
S
R = alkyl
R = alkyl
1
2
3
Figure 1. Structures of alkoxythiophenes.
The versatility of the Gewald reaction (GR) to prepare 2-amino-
thiophenes with a high degree of functionality is well known.14–22
When GR was employed to synthesize one of the desired 4-
alkoxythiophene 6 (Scheme 1) by condensing a mixture of trime-
thylorthoacetate (4) and malononitrile in the presence of sulfur
in ethanol using morpholine as base, in addition to the desired 6
in 25% yield, 2-amino-4-ethoxythiophene-3-carbonitrile (8, 10%)
and 2-amino-4-morpholinothiophene-3-carbonitrile (11, 40%)
were also isolated.
The formation of the products may be explained by two plausi-
ble ways: acrylonitrile 5 may undergo nucleophilic substitution
reaction with ethanol/morpholine to give the intermediates 7 or
10 which were further converted to the respective thiophenes 8
or 11. The other possibility could be transesterification of 4 result-
ing in triethylorthoacetate (9) which further underwent GR to give
8. In order to delineate the formation of 7 a set of two different
Alkoxythiophenes are usually synthesized by nucleophilic sub-
stitution of halothiophenes with an alkoxide,9,10 or direct oxygen-
ation of thiophenes or metallothiophenes with peroxides.11–13 The
presence of reactive functional groups, such as amines demand
however pre-protection under such conditions.
⇑
Corresponding author.
E-mail address: raghumed@gmail.com (A. Raghuram Rao).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.090

K. Venkata Rao et al. / Tetrahedron Letters 54 (2013) 1274–1278
1275
CH3
reacted with different alcohols (3 equiv) followed by Knoevenagel
condensation of ‘higher’ orthoacetate esters with malononitrile to
give the new acrylonitrile intermediates 15a–o (Scheme 3).
H3C
O
O
O
O
H3C
O
O
CH3
CH3
H3C
CH3
CH3
4
To generate the desired 4-alkoxythiophenes in high yields we
further attempted to optimize the reaction conditions. In order to
identify the ideal base for the synthesis of the desired product 6
different inorganic (Table 1, entry 1–6) and organic bases (entry
7–10) were exploited. A perusal of the results presented in Table 1
indicates that aqueous reaction conditions coupled with inorganic
bases could be the best bet for completion of the reaction (entry
10). However, in addition to NaHCO3, triethylamine was also found
to be superior by giving higher yields (67%). The reaction was also
investigated at 3 different temperatures (entry 3–6). At room tem-
perature (35 °C), reaction rate was slow and moderate yield was
obtained. At a high temperature (80 °C), although the reaction
was spontaneous with the addition of base, the yield was low. This
may be due to the decomposition of the product. Highest yield of
the product was obtained at 60 °C. In the optimized procedure,
1 equiv of triethylamine or aqueous NaHCO3 is added for 15 min
to a stirring mixture of sulfur and ylidene 5 in THF at 60 °C.
Under the above optimized reaction conditions, using triethyl-
amine as base GR of the acrylonitriles 15a–o (Scheme 3) provided
respective 4-alkoxy-2-aminothiophene-3-carbonitriles smoothly
(16a–o, Table 2). The results shown in Table 2 illustrate the versa-
tility of the reaction. The nature of alcohol was found to exhibit a
decisive bearing on the yield of the reaction. Transesterification
reactions proceeded smoothly with primary alcohols; as is evident
from high yields of 4-alkoxythiophenes (16a–i). Secondary
alcohols, aryl alcohols, and alkoxyethanols underwent sluggish
interchange reactions, leading to moderate to low yields of
4-alkoxythiophenes (16j–l, n, and o) respectively. Whereas with
tertiary alcohol (16 m) no exchange occurred as no methanol
was formed during the reaction. Conversely, reaction of
trimethyl orthoacetate and malononitrile in tert-butanol resulted
in 2-amino-4-methoxythiophene as the only product suggesting
that the reaction is not proceeding either by transesterification
process or by nucleophilic substitution. The mechanistic pathway
of alkoxythiophene formation could be explained in similar lines
as that of GR (Supplementary data-2). The compounds (16a–o)
9
a
a
N
N
N
N
N
N
H3C
N
CH3
O
H3C
O
H3C
O
CH3
5
10
7
N
N
N
O
H3C
O
N
O
H3C
NH2
NH2
NH2
S
S
S
11 (40%)
8 (10%)
6 (25%)
Scheme 1. Gewald reaction of trimethylorthoacetate; reagents and conditions: (a)
(i) CH2(CN)2 (1 equiv), S8 (1 equiv) morpholine (1.2 equiv), EtOH, 80 °C.
reactions were conducted (Scheme 2). In one set acrylonitrile 5 was
heated to 80 °C in n-pentanol, and in the other n-pentyl orthoace-
tate (12) (synthesized by transesterification of trimethylorthoace-
tate) was reacted with malononitrile. Interestingly both methods
gave identical acrylonitrile intermediate 13 which could be
isolated and characterized by spectroscopic studies. Under GR
conditions 13 was further converted into 2-amino-4-pentyloxythi-
ophene-3-carbonitrile 14 smoothly in 81% yield.
To explore and further exploit transesterification protocol in the
present synthetic study, a detailed investigation was taken up.
According to the literature no such attempts were made for the syn-
thesis of functionalized thiophenes. Further it was also observed
that the purity profile and yield of 13 was noticeably high by transe-
sterification methodology (87%) as compared to nucleophilic sub-
stitution (58%). These observations prompted us to explore this
strategy to introduce a variety of alkoxy groups into the 2-amino-
thiophene ring system. Thus ‘higher’ orthoacetate esters were syn-
thesized following a transesterification procedure described by
Alexander et al.23 and others.24 Trimethyl orthoacetate (4) was
summarized in Table
2 were synthesized according to the
procedure illustrated under the preparation of 2-amino-4-pentyl-
oxythiophene-3-carbonitrile (16e).25
It is noteworthy that, acrylonitrile 5 undergoes nucleophilic
substitution reaction with secondary amines, such as morpholine
N
N
N
N
b
a
O
O
O
CH3
O
CH3
H3C
O
nucleophilic
substitution
3
CH3
CH3
13
5
4
87% by transesterification
58% by nucleophilic substitution
c
a
Transesterification
b
N
O
R
O
O
R
O
3
H3C
NH2
S
R
CH3
14
12
R = pentyl
Scheme 2. Synthesis of 4-pentyloxy-2-aminothiophene 14 and precursor 13 by transesterification of trimethylorthoacetate; reagents and conditions: (a) CH2(CN)2, 60 °C,
3 h; (b) n-pentanol, 24 h, 80 °C; (c) S8, triethylamine, 60 °C, 15 min.

1276
K. Venkata Rao et al. / Tetrahedron Letters 54 (2013) 1274–1278
N
H3C
O
N
N
R
R
O
c
O
a
O
b
O
R
O
O
NH2
H3C
CH3
R
R
S
CH3
H3C
O
CH3
16 a-o
15 a-o
4
R = alkyl, benzyl, alkoxy
Scheme 3. Synthesis of 4-alkoxy-2-aminothiophenes (16a–o); reagents and conditions: (a) R-OH (3 equiv), 24 h, 80 °C; (b) CH2(CN)2, 60 °C, 3 h; (c) S8, triethylamine
(1 equiv), 60 °C, 15 min.
Table 1
and piperidine to give the new intermediates 17a–c. The GR of
17a–c provided 4-alkylamino-2-aminothiophene-3-carbonitriles
Yield of 2-amino-4-methoxythiophene-3-carbonitrile with different bases
N
18a–c in moderate to good yields (Scheme 4). Although the limited
results available using a few amines indicate a good scope of this
methodology to synthesize 4-alkylamino-2-aminothiophenes, a
more generalized extension of this methodology for the synthesis
of other analogues like 4-aryl/heteroarylamino-2-aminothioph-
enes needs further investigation.
H3C O
N
N
Table-1
H3C
NH2
S
O
CH3
6
5
Entry
Base (1 equiv)
Solvent
Temp (°C)
Time
Yield (%)
In conclusion, a facile method was developed by expanding the
application and scope of transesterification protocol for the syn-
thesis of 2-amino-4-alkoxythiophenes. The utility of the method
lies in its suitability to introduce diverse alkoxy substituents into
2-aminothiophene ring system by GR. Besides being a one-pot syn-
thetic protocol, it distinctly adds enough advantage in pursuit of
higher yields. Further studies on nucleophilic substitution of 5 by
different arylamines, heterocyclic amines, and thiols could have
potential in combinatorial chemistry for generating diverse library
of 4-alkoxy/alkylamino-2-aminothiophenes.
1
2
3
4
5
6
7
8
9
10
NaOH (aqueous)
NaHCO3
THF
THF
THF
THF
60
60
35
60
80
60
35
35
35
60
30 min
4 h
3 h
15 min
15 min
45 min
4 h
1
2 h
15 min
31c
21a
36a
53c
22c
38a
32c
15a
54a
67c
b
NaHCO3 (aqueous)
b
NaHCO3 (aqueous)
bNaHCO3 (aqueous)
THF
b
NaHCO3 (aqueous)
EtOAC
Pyridine
EtOH
THF
Pyridine
Diethylamine
Triethylamine
Triethylamine
THF
a
b
c
Conversion into 6 by GC.
7.3% Aqueous NaHCO3.
Isolated yields.
Table 2
Yields of 4-alkoxy-2-amino-thiophene-3-carbonitriles
Compd No.b
Alcohol/Orthoester (R-OH)/CH3(OR)3
Acrylonitrile 15a–o
4-Alkoxythiophene 16a–o
Yield (%)
74
mp (°C)
N
O
N
N
7
(OCH3)3C–CH3
193–194
CH3
N
NH2
N
S
H3C
N
O
O
O
O
O
16a
(OC2H5)3C–CH3
CH3–CH2–CH2–OH
84
67
131–132
220–221
NH2
S
H3C
N
N
N
N
O
16ba
NH2
N
S
H3C
N
H3C
O
2
16c
16d
CH3–(CH2)2–CH2–OH
(CH3)2CH–CH2–OH
76
55
84–85
CH3
2
NH2
S
H3C
N
N
N
N
N
O
103–104
NH2
S
H3C
N
O
O
O
N
H3C
O
3
16e
16f
CH3–(CH2)3–CH2–OH
81
61
76–78
CH3
3
NH2
S
H3C
N
N
O
(CH3)2CH–CH2–CH2–OH
190–191
NH2
S
H3C

K. Venkata Rao et al. / Tetrahedron Letters 54 (2013) 1274–1278
1277
Table 2 (continued)
Compd No.b
Alcohol/Orthoester (R-OH)/CH3(OR)3
Acrylonitrile 15a–o
4-Alkoxythiophene 16a–o
Yield (%)
72
mp (°C)
N
N
N
N
N
H3C
H3C
H3C
O
O
O
4
16g
16h
16i
CH3–(CH2)4–CH2–OH
CH3–(CH2)5–CH2–OH
CH3–(CH2)6–CH2–OH
124
CH3
4
NH2
S
S
S
H3C
N
O
O
O
N
5
69
76
119–120
82–83
CH3
5
NH2
H3C
N
N
6
CH3
6
NH2
H3C
N
N
N
N
O
16ja
16k
(CH3)2CH–OH
48
26
178
NH2
N
S
H3C
N
O
O
O
OH
O
100–102
NH2
S
S
H3C
N
OH
N
N
O
16l
28
98
—
NH2
H3C
N
O
O
16m
(CH3)3–CH–OH
—
NR
NH2
S
N
N
N
N
O
OH
16n
16o
32
112
NH2
N
S
H3C
N
O
OH
O
O
32
48
93–95
S
NH2
O
H3C
O
N
N
N
OH
O
O
O
16p
124–125
O
H3C
O
S
NH2
a
5 equiv of alcohol was used, mp = melting point.
Compound no, NR = no reaction.
b
O
R
N
N
R
N
NR2 =
Yield
N
N
R N
b
a
N
H
N
H
N
H
H3C
NH2
N
R
CH3
S
O
CH3
18c) 42%
18a) 82%
18b) 44%
18a-c
17a-c
5
Scheme 4. Synthesis of 4-alkylamino-2-aminothiophene-3-carbonitriles; reagents and conditions: (a) HNR2 (1.5 equiv); (b) S8 (1 equiv), triethylamine (1 equiv), THF, 60 °C,
4 h.
Acknowledgements
Supplementary data
The authors thank the Chairman, University Institute of
Pharmaceutical Sciences (UIPS), Panjab University (PU), Chandi-
garh for providing facilities. Authors thank Sri Avatar Singh,
SAIF, Central Instrumentation Laboratory, PU for recording
NMR spectra. K.V.R. thanks CSIR, New Delhi for awarding a Se-
nior Research Fellowship (Sanction No: 09/135/0628/2011/
EMR-I).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.12.
090.
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