Phase transfer catalysis assisted thorpe reaction for the synthesis of 3-aminothiophene-2-carboxylates

Article abstract of DOI:10.1155/2011/650501

Thorpe cyclization constructing synthetically important methyl or ethyl 3-amino-4-arylthiophene-2-carboxylates has been studied using eco friendly phase transfer catalysis technique. 3-Amino-4-arylthiophene-2-carboxylates have been synthesized from 3-hydr

Full text of DOI:10.1155/2011/650501

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(1), 368-372
http://www.e-journals.net
Phase Transfer Catalysis Assisted Thorpe Reaction
for the Synthesis of 3-Aminothiophene-2-carboxylates
R D SHAH
Chemistry Department, M. G. Science Institute
Navrangpura, Ahmedabad – 380009, Gujarat, India
drrdshah@yahoo.co.in
Received 30 March 2010; Accepted 24 May 2010
Abstract : Thorpe cyclization constructing synthetically important methyl or
ethyl 3-amino-4-arylthiophene-2-carboxylates has been studied using eco
friendly phase transfer catalysis technique. 3-Amino-4-arylthiophene-2-
carboxylates have been synthesized from 3-hydroxy-2-arylacrylonitriles and
thioglycolates under different solid-liquid phase-transfer conditions.
Keywords: Thorpe reaction, 3-Aminothiophenes-2-carboxylates, Thioglycolate, 3-Hydroxy-2-
arylacrylonitriles, Phase-transfer catalyst.
Introduction
In the chemistry of five member amino heterocycles the intermolecular Thorpe1-3 reaction
and its intramolecular version Thorpe-Zeigler4-6 reactions are one of the most promising
lines. They are base catalyzed and sodium or potassium alkoxide7,8, sodium hydride9,
potassium hydroxide10, lithium hydroxide11 and potassium carbonate1,2 were employed
frequently. Radical alternatives12, solvent free13 strategies as well as iridium hydride
complexes14 also have been applied to intramolecular as well as intermolecular Thorpe
reaction. Yet, a little to our surprise, no much attention was given to employ comprehensive
strategies for Thorpe reaction involving different PT conditions.
Thorpe cyclization is well known for the formation of synthetically important five
membered heterocycles such as furan, thiophene, pyrrazole and many more having adjacent
amino and carbethoxy or nitrile functionalities1,7,15-17. It is very well understood that such
functionalities are constructive moieties when treated with varieties of condensing agents
resulting into various fused heterocycles of almost all kinds of promising biological
interests7,17-19. Strategy to incorporate Thorpe reaction with eco friendly15,20 phase-transfer
catalysis (PTC) technique is always been of great interest to study. Our earlier work
presented Thorpe cyclization for 3-aminopyrazole-2-carboxylates15. Herein, we report
synthesis of important building blocks such as 4-substituted methyl or ethyl 3-amino-4-
arylthiophene-2-carboxylates involving Thorpe reaction from 3-hydroxy-2-aryl
acrylonitriles19 and thioglycolates under different solid-liquid PTC.

Phase Transfer Catalysis Assisted Thorpe Reaction
369
Conventional method for the synthesis of methyl or ethyl 3-amino-4-arylthiophenes-2-
carboxylates involved the treatment of 3-hydroxy-2-arylacrylonitriles and methyl or ethyl
thioglycolate with hydrochloric acid followed by sodium methoxide or ethoxide under
heating condition where reaction time was 30 min and yield16,19 was 35-60%. To set
improved protocol the same reaction was assisted by PTC, where compounds methyl or
ethyl 3-amino-4-arylthiophenes-2-carboxylates were synthesized from 3-hydroxy-2-
arylacrylonitriles, thioglycolates and HCl using different solid-liquid phase-transfer
conditions. All reactions were carried out at RT, potassium hydroxide along with 18-crown-
6 was choice of catalyst, where as acetonitrile was used as solvent (Scheme 1).
R
NH2
R
CN
R
CN
1. HSCH2COOR1,HCl
2.KOH, AcCN,18-C-6,
60-70 0C
COOR1
S
H
OH
1a-f
H
S
COOR1
3a-f
Scheme 1
To optimize PT condition the same reaction was carried out using different PT catalysts in
solid-liquid and liquid-liquid PTC (Table 1).
Table 1. Comparison of PTC assisted synthesis of 3-amino-4-arylthiophene-2-carboxylates (3a-f)
Liquid-liquid
Solid-liquid PTC c
PTC a
TBHSO4
Yield %
58
M.P,
0C
Entry
R
R1
18-Crown-6
Yield %
3a*
3b
3c
3d
3e
3f
C6H5
COOCH3
COOCH3
COOCH3
COOCH3
80
75
73
80
77
70
69
111
115
90
4-OCH3CH4
benzo[b]furyl-2
Thienyl-2
56
55
60
59
51
dimethyl-2,5-thienyl COOCH3
C6H5 COOC2H5
137
73
*PTC = Phase-transfer catalyst, a = CH2Cl2 / KOH (aq. 50 % w/v),
TBHSO4= Tetrabutylammoniumhydrogensulfate; c = 18-crown-6, KOH (solid), CH3CN
Scheme 2 shows probable mechanism for Thorpe cyclization for the synthesis of 3-amino-4-
arylthiophene-2-carboxylates 3, in which 3-hydroxy-2-arylacrylonitriles 1 were believed to
undergo reaction with thioglycolates 2 in presence of HCl resulting in situ generation of
uncyclized thioglycolates, followed by addition of active methylene to nitrile forming compound 3.
N
R
C
R
CN
S
R
CN
Base
C
C
C
C
C
C
H
HCl, HSCH2COOR1
Base
S
COOR1
COOR1
H
OH
H
H
1
R
NH
H
R
NH2
COOR1
S
COOR1
S
3
Scheme 2

370
R D SHAH
The IR spectra of 3 showed bands at 3500-3140 cm-1 for amino and 1680-1670 cm-1 for
C=O of ester functionality. Table 2 shows physical constants and 1H NMR spectral data.
Table 2. Physical constants of 3-amino-4-arylthiophene-2-carboxylates (3a-f)
% C
%H
%N
Mol. Formula
(MW)
1H NMR (δ ppm)
Entry
Calcd Calcd Calcd
(Found) (Found) (Found)
3a*
C12H11NO2S
(233.39)
61.80
(61.35)
4.75
(4.59)
6.01 (s, 5H, 7.0) Ar-H; (s, 1H, 6.75);
(5.86) Ar-H at C4, (m, 2H, 5.3) NH2; (s,
3H, 3.6) CH3
3b** C13H13NO2S
(263.31)
59.31
(59.59)
4.98
(4.81)
5.32 (d, 2H, 7.3) Ar-H; (d, 2H, 6.9)
(5.19) Ar-H; (s, 1H, 7.05) Ar-H at C4;
(m, 2H, 5.5) NH2; (s, 3H, 3.95)
OCH3; (s, 3H, 3.8) CH3
3c*
C14H11NO3S
(273.31)
61.56
(61.94)
4.06
(3.91)
5.13 (m, 5H, 7.1-7.6) Ar-H; (s, 1H,
(4.85) 6.7) Ar-H at C4;(m, 2H, 6.1)
NH2, (s, 3H, 3.75) CH3
3d*
C10H9NO2S2
(239.32)
50.21
(49.81)
53.93
3.79
(3.67)
4.90
5.86 (m, 4H, 6.9-7.3) Ar-H; (m, 2H,
(5.69) 5.7) NH2; (s, 3H, 3.75) CH3
5.24 (s, 1H, 6.95) Ar-H at C4, (s, 1H,
(5.11) 6.5) Ar-H; (m, 2H, 5.5) NH2; (s,
3H, 3.75), CH3 of ester; (s, 3H,
2.45) CH3 at C2’; (s, 3H, 2.35)
CH3 at C5’
3e*
C12H13NO2S2
(267.37)
(53.66)
(4.85)
3f*
C13H13NO2S
(247.07)
63.13
(63.01)
5.30
(5.34)
5.66 (s, 5H, 7.1) Ar-H; (s, 1H,6.8) Ar-
(5.53) H at C4; (m, 2H, 5.3) NH2; (q,
2H, 4.3) CH2; (s, 3H, 3.6) CH3;
(t, 3H, 1.29) CH3 of ester
Solvent used for crystallization *ethanol and **benzene:ether mixture (5:5)
Experimental
Melting points were determined by electro thermal method in open capillary tube and are
uncorrected. The IR spectra were recorded (in cm-1 for KBr pellets) on Buck-500
spectrophotometer. The 1H NMR spectra were recorded on Bruker 300 MHz
spectrophotometer in CDCl3 using TMS as internal standard and the chemical shifts are
expressed in δ ppm. MS spectra were recorded on JEOL/ SX-102 mass spectrophotometer
under electron-impact (EI) ionization. Elemental analyses were performed on a Carlo Erba
1108 microanalyzer or Elementar’s Vario EL III microanalyzer. The purity of the compounds
was routinely checked by TLC using silica gel G and spots were exposed in iodine vapour.
General method for Synthesis of methyl or ethyl 3-amino-4-arylthiophene-2-
carboxylates (3a-f)
Method 1
Solid-liquid PTC: A well stirred solution of toluene or MeCN (20 mL), powdered KOH
(840 mg, 15 mmol) and 18-crown-6 (0.132 g, 0.5 mmol) was added with 3-hydroxy-2-
arylacrylonitriles (1, 5 mmol) and thioglycolates (2, 5 mmol) and 2 drops of concentrated
HCl. Thereafter the reaction mixture was stirred for 20 min at room temperature (35-40 0C).
The solvent was distilled under reduced pressure and the reaction mixture was poured onto

Phase Transfer Catalysis Assisted Thorpe Reaction
371
crushed ice, neutralized with acetic acid (50% v/v). The products thus obtained were filtered,
washed with water, dried and crystallized from respective solvents.
Method 2
Liquid-liquid PTC: A stirred mixture of CH2Cl2 (15 mL), KOH solution (5 mL, 50% w/v),
and TBHSO4 (1.69 g, 5 mmol) was added with 3-hydroxy-2-arylacrylonitriles (1, 5 mmol)
and thioglycolates (2, 5 mmol) and 2 drops of concentrated HCl. Thereafter the reaction
0
mixture was stirred for 20 min at room temperature (35-40 C). The solvent was distilled
under reduced pressure and the reaction mixture was poured onto crushed ice, neutralized
with acetic acid (50% v/v). The products thus obtained were filtered, washed with water,
dried and crystallized from respective solvents.
Results and Discussion
In the synthesis of compound 3 there was significant improvement in the reaction time (20 min),
room temperature and yields (70-80 %) and the workup was clean compared to the reported
methods so far16,19. However any alteration made in molar quantities of the catalyst resulted
in to undesire by products and similar observation was made for the solvent.
To optimize the synthesis of compound 3, different phase-transfer catalysts and solid-liquid
and liquid-liquid phase-transfer conditions were examined. For liquid-liquid phase-transfer
conditions CH2Cl2 / KOH (aq. 50% w/v), low or lack of reactivity was observed in the presence
of catalysts such as tetrabutylammonium bromide (TBAB) and triethylbenzyl- ammonium
chloride (TEBA), results also showed concomitant decomposition of both reactants after
prolonged reaction time and even under heating conditions (24 h, 60-70 OC). Employing
tricaprylmethylammonium chloride (Aliquat®) was also unsuccessful. However, under similar
conditions, tetrabutylammonium hydrogen sulfate (TBHSO4) proved to be a better catalyst and
compounds 3 were obtained in varying yields of 50-60% (c.f. Table 1). Reducing the catalyst
loading or changing the solvent resulted in a significant decrease in the yields. Increasing the
temperature above (50 °C) had little effect on the yields. Finally, in solid-liquid phase-transfer
conditions the use of 18-crown-6, KOH along with acetonitrile or toluene as a solvent resulted in
the formation of the product 3a-f, however in acetonitrile the yields were excellent.
Conclusions
In conclusion, we have described a simple, cleaner and convenient synthesis of methyl or
ethyl 3-amino-4-arylthiophene-2-carboxylates, which are important building blocks for the
construction of various fused heterocycles. A comparison of conventional method, liquid-
liquid PTC and solid-liquid PTC suggests that the solid-liquid PTC conditions using
18-crown-6 is the method of choice with excellent yields. The ease with which phase-
transfer catalyst reacts, presents new opportunities for expanding Thorpe reaction for the
synthesis of other heterocycles that remains almost unexplored with PTC.
Acknowledgment
We wish to thank the Regional Sophisticated Instrumentation Center, Central Drug Research
Institute, Lucknow and Chandigarh, India for 1H NMR and mass spectral analysis,
University Grant Commission for funding the project and Principal M. G. Science Institute,
Ahmedabad for providing the facility to carry out this work.
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