Indian Journal of Chemistry

Vol. 51B, April 2012, pp 653-657

Note

Microwave accelerated synthesis of 2- boiling organic solvents such as 1,4-dioxane and

aminothiophenes in ionic liquid via three dimethylformamide, high reaction temperatures, long
reaction duration, tedious procedure for product
component Gewald reaction isolation, low yields and difficult recovery or
Sunil S Chavan, Yogesh Y Pedgaonkar, Ananda J Jadhav complete loss of catalysts during workup. Hence it is
& Mariam S Degani* relevant to explore a simple, rapid and
Department of Pharmaceutical Sciences and Technology, environmentally friendly method for the synthesis of
Institute of Chemical Technology, N. Parekh Marg, Matunga, 2-aminothiophene derivatives which could lead to
Mumbai 400 019, India number of thieno-fused heterocycles of medicinal
E-mail: [email protected] importance.
Ionic liquids (ILs) are of current interest as an
Received 7 February 2011; accepted (revised) 20 December 2011
environmentally friendly alternatives to conventional
Microwave accelerated synthesis of substituted 2-amino- organic solvents in chemical processes, due to their
thiophenes by a three-component Gewald reaction using a basic physicochemical properties such as negligible vapor
ionic liquid, 1,1,3,3-tetramethylguanidine lactate [TMG] [Lac] as pressure, excellent thermal stability, good solvating
solvent as well as catalyst has been developed. The products are ability, non-flammability and ease of recyclability.
obtained in good to high yields and the ionic liquid is reusable
over several cycles without significant loss in catalytic activity.
Imidazole based ionic liquids such as [Bmim][BF4]
and [Bmim][PF6] have been used as catalysts for the
Keywords: Gewald reaction, 2-aminothiophenes, ionic synthesis of 2-aminothiophenes12. However,
liquid, multicomponent reaction, microwave-assisted imidazole-based ILs containing BF4 and PF6 anions
synthesis are environmentally unsafe as they liberate hazardous
HF gas. In addition, their use in industries is limited,
Substituted 2-aminothiophenes are reported to possess mostly due to the expensive cations and anions used
various biological activities such as phosphatase in their synthesis. In the current research focusing
PTP1B inhibitors1, serotonin receptor subtype 5-HT1A towards the development of mild, economical and
inhibitors2, human leukocyte elastase inhibitors3 and environmentally friendly synthetic protocols, it has
adenosine receptor A3 inhibitors4. They are also used been reported previously that hetero-Michael reaction,
as starting materials for the synthesis of dyes, Knoevenagel condensation, Biginelli reaction under
agrochemicals and conducting polymers5,6. microwave irradiation and Heck reaction can be
The most convergent and well-established classical carried out using cost-effective ionic liquids13-16.
approach for the synthesis of 2-aminothiophenes is Recently, use of microwave energy has become
Gewald’s method, which involves three component popular in organic synthesis in order to improve
condensation of a ketone, aldehyde or β-dicarbonyl yields and reduce the reaction time17-19. This can be
compound, an active nitrile and elemental sulfur in coupled with solvent free reactions or IL mediated
the presence of a base7. The earlier method has reactions, to make the synthesis faster and more
several drawbacks such as long reaction duration, use environment friendly.
of unstable starting compounds such as α-
mercaptoaldehyde or α-mercaptoketone and the need Results and Discussion
for chromatographic purification after work up. Many In the present method, an easily synthesizable and
modifications of this synthesis have been reported cost-effective IL, 1,1,3,3-tetramethylguanidine lactate
recently, including the use of solid support8, Lewis [TMG] [Lac] was used as solvent as well as catalyst
acid catalysis9, heterogeneous catalysis10 and for the three component synthesis of 2-amino-
microwave irradiation combined with soluble polymer thiophene derivatives (Scheme I) using both
support11. However, many of these methods have conventional heating and microwave irradiation.
limitations such as use of hazardous bases such as To optimize the amount of IL in the reaction,
morpholine and piperidine, use of toxic and high several experiments were carried out using cyclo
654 INDIAN J. CHEM., SEC B, APRIL 2012

Scheme I — Ionic liquid mediated synthesis of 2-aminothiophenes

N HO
H N N CH3
OOC
H
H OH
O N HO
R1
R1 X CN CH3
X CN HN N HOOC
R2
R2

R1 X
N
HO H
R2 S NH2 R1 X
R2

-H2O

R1 X N
s s
R1 s s
H
R2 NH X s s
S R2 s s
H

N
R1 X
R1
H -S7H
X
R2 S N R2
s s
s s
s s
s s
Scheme II — Proposed reaction mechanism for the synthesis of 2-aminothiophenes in [TMG] [Lac]
 NOTES 655

Table I — Effect of amount of [TMG] [Lac] on yield of the catalyst. Microwave irradiation reduced the reaction
productsa time dramatically from 4-7 hr to 4-8 min as shown in
Table II. Also, isolated yields of the compounds were
Amount of Time (hr) Yields (%)b
[TMG] [Lac] (g) slightly improved.
The recycling performance of [TMG] [Lac] in the
- 8 NR
same model reaction was also explored (Table III).
0.3 3 26
After the completion of reaction, the ionic liquid was
0.6 3 41 recovered by removing water under reduced pressure
0.9 3 60 and could be recycled at least three times without
1.2 3 72 appreciable decrease in the yield. The proposed
1.5 3 84 reaction mechanism for [TMG] [Lac] catalyzed
1.8 3 84 synthesis of 2-aminothiophenes could be explained by
2.0 3 84 the formation of hydrogen bonding of [TMG] [Lac]
1.2 6 76 with the reactants (Scheme II). This facilitates the
1.5 4 88 nucleophilic attack of activated nitrile on ketone
1.5 6 88 yielding a Knoevenagel condensation product, which
a
Reaction conditions: Cyclohexanone (10.18 mmol), ethyl is then thiolated at methylene group with elemental
cyanoacetate (10.18 mmol), elemental sulfur (10.18 mmol) and sulfur, followed by ring closure to give 2-amino-
ionic liquid at 80°C. thiophene.
b
Isolated yield
NR: No reaction
Experimental Section
hexanone, ethylcyanoacetate and elemental sulfur as Melting points of all the synthesized compounds
the substrate and the results are summarized in were determined on a Kofler melting point apparatus
Table I. No product formation was observed in the and are uncorrected. The ionic liquid [TMG] [Lac]
absence of [TMG] [Lac]. When the reaction was was prepared by previously reported method without
performed with 0.3 g [TMG] [Lac], the reaction any modification and characterized by FTIR and
proceeded with a yield of 26%. The yield improved 1
H NMR spectroscopy20. Commercially available
from 26% to 84% with increasing amount of [TMG] “Discover Benchmate” system of CEM Corporation,
[Lac] from 0.3 g to 1.5 g and reached maximum with with appropriate temperature and pressure control was
1.5 g of [TMG] [Lac]. Better yield was obtained when used for the microwave experiments. All the
the reaction time was increased from 3 to 6 hr. Further synthesized compounds are known and identified
increase in reaction time did not improve the result to from their spectroscopic data. FTIR spectra were
a greater extent. Variation of temperature from RT to obtained on a Perkin-Elmer infrared spectrometer
110°C resulted in identification of 80°C as the with KBr discs and 1H NMR spectra were recorded in
optimum temperature for this reaction. Thus, the CDCl3 or DMSO-d6 on a Jeol 300 MHz spectrometer
optimum reaction conditions, resulting in yield of with TMS as internal standard.
88% included use of 1.5 g [TMG] [Lac] and 4 hr
heating at 80°C. Typical procedure for synthesis of ethyl-2-amino-
With these optimized parameters, reactions of 4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate
structurally diverse ketones with various active under conventional heating
methylene compounds and elemental sulfur were
carried out in [TMG] [Lac] (Scheme I). The results of In a typical experiment, cyclohexanone
[TMG] [Lac] mediated Gewald reactions are (10.18 mmol), ethylcyanoacetate (10.18 mmol),
presented in Table II. Yields obtained using malono- elemental sulfur (10.18 mmol) and ionic liquid (1.5 g)
nitrile as substrate were between 60 to 90% (isolated were charged to a 100 mL round-bottom flask with a
yields) using conventional heating. In the case of magnetic stirring bar. Reaction mixture was stirred at
ethylcyanoacetate and cyanoacetamide, yields 80°C for 4 hr as mentioned in Table I. during which
obtained were slightly lower as compared to time a yellow solid precipitated. The progress of the
malononitrile. reaction was monitored by TLC. After the completion
Gewald reaction was also studied under microwave of reaction, cold water (5 mL) was added to the
irradiation using [TMG] [Lac] as solvent as well as reaction mixture and stirred for 5 min. The
656 INDIAN J. CHEM., SEC B, APRIL 2012

Table II — Ionic liquid mediated Gewald reaction under conventional heatingc and microwave irradiationd

Ketone X Conventional Microwave Referencese

Time (hr) Isolated yields (%) Time (min) Isolated yields (%)

CN 6 61 7 64 10 (b)

COOEt 7 58 6 62 10 (b)

CN 4 90 4 92 10 (b)

COOEt 4 88 4 90 10 (b)

CONH2 5 81 4 84 7 (a)

CN 5 78 7 80 10 (b)

COOEt 5 80 6 83 10 (b)

CN 6 60 8 62 10 (b)

COOEt 7 57 8 60 10 (b)

COOEt 7 70 6 73 7 (a)

c
Conventional heating at 80°C.
d
Microwave irradiation at 120 W and 80°C.
e
All the compounds are known and identified by spectroscopic data.

Table III — Results for recyclability of ionic liquid [TMG] runs. All the products are reported in the literature and
[Lac]
identified by comparison of their physical and spectral
Cycle number Yields (%) data with the previously reported data.
1 88
2 87
Typical procedure for synthesis of ethyl-2-amino-
4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate
3 86
under microwave irradiation
4 86
Cyclohexanone (10.18 mmol), ethylcyanoacetate
precipitated yellow solid was filtered, washed with (10.18 mmol), elemental sulfur (10.18 mmol) and
water (5 mL) and dried to afford corresponding 2- ionic liquid (1.5 g) were added to the reaction vessel
aminothiophene (2.01 g, 88%). The ionic liquid was of the microwave reactor (Discover Benchmate, CEM
recovered by removing water under reduced pressure Corp., open vessel). Reaction was programmed to 120
and stored in a desiccator for its reuse in subsequent W at 80°C for 4 min. The progress of the reaction was
 NOTES 657

monitored by TLC. After the completion of reaction, Isolation of product was simple and did not require
cold water (5 mL) was added to the reaction mixture chromatographic purification. The ionic liquid was
and the mixture was stirred for 5 min. The recycled several times without any significant loss in
precipitated yellow solid was filtered, washed with catalytic activity. Use of cost-effective ionic liquid
water (5 mL) and dried to afford the corresponding 2- with microwave energy makes this method a rapid
aminothiophene (2.06 g, 90%). The ionic liquid was and environmentally friendly alternative to the
recovered by removing water under reduced pressure conventional base catalyzed thermal processes.
and stored in a desiccator for its reuse in subsequent
runs. Acknowledgment
Authors are thankful to the Department of
IR and 1H NMR spectral data for selected
Pharmaceutical Sciences and Technology, Institute of
compounds
Chemical Technology, for providing research
Ethyl 2-amino-5,6-dihydro-4H-cyclopenta[b]thio- facilities and SSC thanks UGC (SAP) for financial
phene-3-carboxylate support.
m.p. 90-92°C; IR (KBr): 3395, 3300, 1649, 1592
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