Efficient synthesis of substituted 2-amino-3-carbethoxythiophenes

Article abstract of DOI:10.1080/00397910701575889

A microwave-assisted method for the synthesis of a variety of thiophene o-aminoesters (2a-l) has been developed, starting from an appropriate aldehyde, methyl ketone or acetoacetate ester with ethyl cyanoacetate in the presence of elemental sulfur. Copyright Taylor & Francis Group, LLC.

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Efficient Synthesis of Substituted
2‐Amino‐3‐carbethoxythiophenes
M. K. Kathiravan a , C. J. Shishoo b , T. S. Chitre c , K. R. Mahadik a &
Professor K. S. Jain c
a Poona College of Pharmacy, Pune, India
b L. M. College of Pharmacy, Ahmedabad, India
c Sinhgad College of Pharmacy, Pune, India
Version of record first published: 10 Dec 2007.
To cite this article: M. K. Kathiravan , C. J. Shishoo , T. S. Chitre , K. R. Mahadik & Professor K. S. Jain
(2007): Efficient Synthesis of Substituted 2‐Amino‐3‐carbethoxythiophenes, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:23, 4273-4279
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Synthetic Communicationsw, 37: 4273–4279, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701575889
Efficient Synthesis of Substituted 2-Amino-
3-carbethoxythiophenes
M. K. Kathiravan
Poona College of Pharmacy, Pune, India
C. J. Shishoo
L. M. College of Pharmacy, Ahmedabad, India
T. S. Chitre
Sinhgad College of Pharmacy, Pune, India
K. R. Mahadik
Poona College of Pharmacy, Pune, India
K. S. Jain
Sinhgad College of Pharmacy, Pune, India
Abstract: A microwave-assisted method for the synthesis of a variety of thiophene
o-aminoesters (2a–l) has been developed, starting from an appropriate aldehyde, methyl
ketone or acetoacetate ester with ethyl cyanoacetate in the presence of elemental sulfur.
Keywords: Gewald, MAOS, microwave, MWI, thiophene o-aminoesters
INTRODUCTION
Thiophene o-aminocarbonyl compounds are present as a part of structures in a
variety of natural products.[1] The Gewald synthesis[2–8] has been the most
preferred method of synthesis, which involves the condensation of
Received in India May 11, 2007
Address correspondence to K. S. Jain, Professor, Department of Pharmaceutical
Chemistry, Sinhgad College of Pharmacy, S. No. 44/1, Vadgaon(Bk), Sinhgad Road,
Pune 411 041, Maharastra, India. E-mail: ks_jain@vsnl.net or kishor.s.jain@gmail.com
4273

4274
M. K. Kathiravan et al.
Scheme 1. Reaction conditions: a) stirring at 25–408C, 3–4 h (32–85%); b) under
microwave irradiation, 350 W, 2–5 min (60–90%).
aldehyde, methyl ketones, or acetoacetate ester and active methylene
compounds such as ethyl cyanoacetate or malanonitrile in the presence of
sulfur and is effected in one or two steps (Scheme 1).
Recent modification of the Gewald synthesis has reported the use of solid
supports[9] as well as microwave irradiation. Herein, we offer a much simpler
technique based on microwave irradiation (MWI) to get a variety of thiophene
o-aminoesters in good yields and purity in just a few minutes.
RESULTS AND DISCUSSION
The traditional Gewald synthesis with aldehyde, methyl ketones or acetoace-
tate ester occurs rather efficiently. But when applied to specific ketones, a two-
step synthetic sequence is needed. To circumvent this issue and force the
Gewald synthesis of active methylene compounds with specific ketones, we
resorted to MWI. Indeed, under MWI, these specific ketones reacted effi-
ciently within a short period of time and afforded good yields of the products.
The Gewald thiophene synthesis of methyl ketones such as cyclopenta-
none (1g), acetophenone (1h), 4-methylacetophenone (1i), 4-chloroacetophe-
none (1j), 4-methoxyacetophenone (1k), propiophenone (1l), and so on
required a two-step process (Scheme 2). However, reaction mixture of these
ketones (1g–l), with ethyl cyanoacetate and a mixture of NH4OAc
(catalytic) and gl acetic acid (catalytic) when irradiated under microwave con-
ditions in a tall glass beaker, gave the corresponding alkylidene intermediate
in a very short time. At this point, sulfur and diethylamine were added and the
reaction mixture further irradiated to obtain the products (2g–l).
Our MWI method employed for the synthesis of the thiophene
o-aminoesters (2a–l) thus reduced the overall reaction time from 15–18 h
to 12–24 min, avoiding isolation of the alkylidine cyanoacetate intermediate.

Substituted 2-Amino-3-carbethoxythiophenes
4275
Scheme 2. Reaction conditions: a) 8–18 h reflux in toluene; b) 7–24 min, MWI at
350 W; c) 6–8 h stirring at 508C (50–78%); d) 2 min, MWI in ethanol (60–80%).
In conclusion, this MWI method is efficient, clean, and quick for the
synthesis of 2-amino-3-carbethoxythiophenes variously substituted at 5 and
6 positions, and gives better yields and substantially reduces the reaction
time over the previously reported conventional methods.
EXPERIMENTAL
Melting points were determined in open capillaries using a Veegow (India)
electronic melting-point apparatus and are uncorrected. Thin-layer chromato-
graphy (TLC) was performed on silica-gel 60 F254 (Merck) plates using
benzene as the solvent system. The compounds were detected by UV light
absorption and also by exposing the TLC plates to iodine vapors. For the
synthesis, MWI was carried out using a domestic microwave oven (1000-W
output power) at 2450 MHz. To control the reactions, irradiations were
carried out continuously for a period of 5–10 min at a stretch with intermittent
1-min cooling times in between. However, the total time of irradiation
excluding the cooling time is given in Table 1.
IR spectra were recorded on a Perkin-Elmer BX2 FT-IR spectrometer in
1
potassium bromide disks. H NMR spectra were recorded on NMR Varian-
Mercury 300-MHz spectrometer. Chemical shifts (d) are given in parts per
million (ppm) relative to TMS as internal standard. Mass spectrum was
obtained on an electron-impact mass spectrometer with a 70-eV ionizing
beam and using a direct insertion probe.
General Procedure
Synthesis of thiophene 2-amino-3-carbethoxy esters (2a–e) under
Microwave Irradiation: General Procedure A
An appropriate ketone (0.05 mol), sulfur (1.6 g; 0.05 mol), ethyl cyanoacetate
(5.8 g; 0.05 mol), and diethylamine (3.65 g; 0.05 mol) were mixed together in
methanol (4 ml) in a 100-ml open tall glass beaker. The beaker was irradiated

Table 1. Physical data of 2-amino-3-carbethoxythiophenes
Conventional method
Mirowave-assisted method
Yield (%) Time (min)
Mol formula
solvent of
Sr. no.
R1, R2
recrystallizationꢀ
Yield[Ref] (%)
Mp (8C)[Ref]
Time (h)
(method)
Mp (8C)
350 W
2a
2b
2c
2d
-(CH2)4-
CH3, CH3
CH3, COOC2H5
C11H15NO2S (E)
C9H13NO2S (E)
C11H15NO4S (B)
C17H20N2O2S (E)
80[3], 82[4,6]
39[5,6], 49[5,6]
32[5,6]
115[3,4,6]
91–92[5,6]
108–109[5,6]
98–100
3
3
2
5
90 (A)
60 (A)
70 (A)
70 (A)
113–115
92–94
2
2
4
5
107–108
98–100
68
2e
2f
2g
2h
2i
-(CH2)5-
H, C2H5
-(CH2)3-
C12H17NO2S (E)
C9H13NO2S (B)
C10H13NO2S (E)
C13H13NO2S (E)
C14H15NO2S (E)
C13H12ClNO2S (E)
C14H15NO3S (E)
C14H15NO2S (E)
85[7]
75[5,6]
52[4]
62[5,6]
78[8]
69
88–89[7]
73[5,6]
3
80 (A)
72 (A)
67 (B)
68 (B)
80 (B)
70 (B)
60 (B)
65 (B)
88–90
72–74
91–92
5
2
4
91[4]
15–18
15–18
15–18
15–18
15–18
15–18
10 þ 2
7 þ 2
12 þ 2
24 þ 2
14 þ 2
12 þ 2
C6H5, H
98[5,6]
98–99
4-CH3C6H4, H
4-ClC6H4, H
4-CH3OC6H4, H
C6H5, CH3
101–103[8]
102–104
96–99[8]
93[5,6]
101–103
102–104
98–100
92–94
2j
2k
2l
69[8]
50[5,6]
ꢀSolvent of recrystalliation, B ¼ benzene, E ¼ ethanol.

Substituted 2-Amino-3-carbethoxythiophenes
4277
with MW at 350 W for 2–5 min (Table 1). On chilling, the reaction mixture
produced the desired product, which was filtered, washed with chilled aq.
ethanol, and dried.
Data
2-Amino-3-carbethoxy-4,5,6,7-tetrahydrobenzo(b)thiophene (2a): Yield
1
10.48 g, 90%; mp 113–1158C; IR (KBr) cm21: 3414 (NH); 1649 (CO); H
NMR (CDCl3) d ppm: 1.34, 3H, t, CH3 at 3; 1.62, 2H, s, CH2 at 5 & 6;
2.61, 4H, s, CH2 at 4 & 7; 4.2, 2H, s, NH2; 4.32, 2H, q, CH2 at 3.
2-Amino-3-carbethoxy-4,5-dimethylthiophene (2b): Yield 6.3 g, 60%; mp
1
92–948C; IR (KBr) cm21: 3425, 3312 (NH); 1657 (CO); H NMR (CDCl3)
d ppm: 1.32, 3H, t, CH3 at 3; 2.2, 4H, s, CH2 at 4 & 5; 4.2, 2H, q, CH2 at
3; 4.36, 2H, s, NH2.
2-Amino-3,5-dicarbethoxy-4-methylthiophene (2c): Yield 5.9 g, 70.0%;
mp 107–1088C; IR (KBr) cm21: 3408.5, 3294 (NH); 1660.8 (CO); 1H
NMR (CDCl3) d ppm: 1.32, 6H, s, CH3 at 3 & 5; 2.2, 3H, s, CH3 at 4; 4.32,
4H, s, CH2 at 3 & 5; 4.4, 2H, s, NH2.
2-Amino-6-benzyl-3-carbethoxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2d):
Yield 7.5 g, 70.2%; mp 98–1008C; IR (KBr) cm21: 3412, 3306 (NH); 1665
(CO); H NMR (CDCl3) d ppm: 1.32, 3H, t, CH3 at 3; 2.65, 4H, t, CH2 at 4
1
& 5; 3.62, 4H, s, CH2 at 7; 4.12, 2H, s, NH2, 4.32, 2H, q, CH2 at 3;
7.2–7.4, 5H, m, ArH; MS m/e: 317.0 (Mþ), 303.2, 224.0, 198.0, 120.2.
2-Amino-3-carbethoxy-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene (2e):
Yield 9.8 g, 80%; mp 88–908C; IR (KBr) cm21: 3420, 3316 (NH); 1642
(CO); 1H NMR (CDCl3) d ppm: 1.20, 6H, m, CH2 at 5,6,7; 1.34, 3H, t, CH3 at
3; 1.62, 2H, s, CH2 at 5 & 6; 2.5, 4H, s, CH2 at 5 & 8; 4.0, 2H, s, NH2; 4.2,
2H, q, CH2 at 3.
2-Amino-3-carbethoxy-5-ethylthiophene (2f): A reaction mixture of
n-butanal (3.6 g; 0.05 mol), sulfur (1.6 g; 0.05 mol), ethyl cyanoacetate
(5.7 g; 0.05 mol), and triethylamine (5.0 g; 0.05 mol) in DMF was irra-
diated with microwaves in a similar fashion for 4 min. The reaction
mixture on cooling to room temperature was poured on an ice-water
mixture. The crystals obtained were washed with 20 ml of chilled 50%
aqueous ethanol. The product (72% yield) with a mp of 72–748C was
characterized as 2-amino-3-carbethoxy-5-ethylthiophene (2f). IR (KBr)
cm21: 3408, 3306 (NH); 1660 (CO); 1H NMR (CDCl3) d ppm: 1.22,
3H, t, CH3 at 5; 1.34, 3H, t, CH3 at 3; 4.2, 2H, q, CH2 at 3; 6.6, 1H,
s, H at 4; 4.2, 2H, s, NH2.

4278
M. K. Kathiravan et al.
Synthesis of Thiophene 2-Amino-3-carbethoxy esters (2g–l) under
Microwave Irradiation: General Procedure B
Step 1.
A reaction mixture consisting of the appropriate ketone (0.05 mol), ethyl
cyanoacetate (5.7 g; 0.1 mol), glacial acetic acid (3–5 drops), and ammonium
acetate (0.4 g; 0.05 mol) in 5 ml of ethanol was irradiated in a tall 100-ml
beaker with MW at 350 W for 7–24 min. The water formed in situ got
evaporated and deposited on the top of the inner walls of the beaker, which
were wipped off dry with an absorbent tissue paper. The alkylidene ethyl cya-
noacetate formed was thiolated as such without isolation in the next step.
Step 2.
The crude alkylidene ethyl cyanoacetate formed was dissolved as such in
ethanol (4 ml) and to this sulfur (1.6 g; 0.05 mol) and diethylamine (3.67 g;
0.63 mol) were added. The reaction mixture was irradiated for 2 min at
350 W. On chilling, the flask produced the desired product, which was
filtered, washed with chilled aq. ethanol, and dried.
Data
2-Amino-3-carbethoxy-5,6-dihydro-4H-cyclopenta[b]thiophene (2g):
Yield 7.0 g, 67%; mp 91–928C; IR (KBr): 3414, 3296 (NH), 1649 (CO); 1H
NMR (CDCl3) d ppm: 1.30, 3H, t, CH3; 1.95, q, 2H, CH2 at 4; 2.5, m, 4H, CH2
at 4 & 5; 4.0, H, s, NH2; 4.29, 2H, q, CH2 at 3.
2-Amino-3-carbethoxy-4-phenylthiophene (2h): Yield 8.4 g, 68%; mp 98–
998C; IR (KBr) cm21: 3425, 3314 (NH); 1661 (CO); 1H NMR (CDCl3) d ppm:
1.30, 3H, t, CH3; 4.0, 2H, s, NH2; 4.29, 2H, q, CH2; 7.32–7.41, 4H, ArH.
2-Amino-3-carbethoxy-4-(4-methyl)phenylthiophene (2i): Yield 9.14 g,
1
80%; mp 101–1038C; IR (KBr) cm21: 3414, 3300 (NH); 1659 (CO); H
NMR (CDCl3) d ppm: 1.30, 3H, t, CH3; 4.0, 2H,s, NH2; 4.29, 2H, q, CH2;
6.3, s, 1H at 5; 2.35, 3H, s, CH3; 7.2–7.42, 4H, ArH.
2-Amino-3-carbethoxy-4-(4-chloro)phenylthiophene (2j): Yield 5.0 g,
1
70%; mp 102–1048C; IR (KBr) cm21: 3450, 3333 (NH); 1660 (CO); H
NMR (CDCl3) d ppm: 1.30, 3H, t, CH3; 2.35, 3H, s, CH3; 4.29, 2H, q,
CH2; 4.0, 2H, s, NH2; 6.3, s, 1H at 5; 7.3–7.5, 4H, ArH.
2-Amino-3-carbethoxy-4-(4-methoxy)phenylthiophene (2k): Yield 6.0 g,
1
60%; mp 98–1008C; IR (KBr) cm21: 3464, 3339 (NH); 1666.7 (CO); H
NMR (CDCl3) d ppm: 1.30, 3H, t, CH3; 3.73, 3H, s, CH3; 4.0, 2H, s, NH2;
4.29, 2H, q, CH2; 6.3, s, 1H at 5; 7.32–7.52, 4H, ArH.

Substituted 2-Amino-3-carbethoxythiophenes
4279
2-Amino-3-carbethoxy-5-methyl-4-phenylthiophene (2l): Yield 5.65 g,
65%; mp 92–948C; IR (KBr) cm21: 3404, 3300 (NH); 1649 (CO); 1H
NMR (CDCl3) d ppm: 1.30, 3H, t, CH3; 2.35, 3H, s, CH3; 2.41, s, 3H, CH3;
4.0, 2H, s, NH2; 4.29, 2H, q, CH2; 6.3, s, 1H at 5; 7.32–7.4, 4H, ArH.
ACKNOWLEDGMENT
The authors thank the Indian Council of Medical Research (ICMR), New
Delhi, for providing research grants to M. K. Kathiravan to carry out the
research.
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