Basic Ionic Liquid [bmIm]OH-Mediated Gewald Reaction as Green Protocol for the Synthesis of 2-Aminothiophenes

Article abstract of DOI:10.1080/00397911.2014.951898

A simple, efficient, and environmental friendly procedure was developed based on the Gewald reaction for the synthesis of 2-aminothiophenes using a basic ionic liquid [bmIm]OH as both catalyst and solvent. Besides being a green protocol, the method offers advantages of successful synthesis of a variety of alkyl, aryl, alkoxy, and alkylamino-2-aminothiophenes in good yields.

Full text of DOI:10.1080/00397911.2014.951898

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Basic Ionic Liquid [bmIm]OH Mediated Gewald
Reaction as Green Protocol for the Synthesis of 2-
Aminothiophenes
Venkata Rao Kakia, Raghuram Rao Akkinepallib, Prankishore Deba & Mallikarjuna Rao Pichikaa
a Pharmaceutical Chemistry Division, School of Pharmacy, International Medical University
(IMU), Kuala Lumpur, Malaysia
b Pharmaceutical Chemistry Division, University College of Pharmaceutical Sciences,
Kakatiya University, Warangal, AP, India
Accepted author version posted online: 25 Sep 2014.
To cite this article: Venkata Rao Kaki, Raghuram Rao Akkinepalli, Prankishore Deb & Mallikarjuna Rao Pichika (2014):
Basic Ionic Liquid [bmIm]OH Mediated Gewald Reaction as Green Protocol for the Synthesis of 2-Aminothiophenes,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2014.951898
To link to this article: http://dx.doi.org/10.1080/00397911.2014.951898
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Basic ionic liquid [bmIm]OH mediated Gewald reaction as green protocol for the
synthesis of 2-aminothiophenes
Venkata Rao Kaki1, Raghuram Rao Akkinepalli2, Prankishore Deb1, Mallikarjuna Rao
Pichika1
1Pharmaceutical Chemistry Division, School of Pharmacy, International Medical
2
University (IMU), Kuala Lumpur, Malaysia. Pharmaceutical Chemistry Division,
University College of Pharmaceutical Sciences, Kakatiya University, Warangal, A. P.,
India
Corresponding Address: E-mail: kvenkatrao80@gmail.com
Abstract
A simple, efficient and environmental friendly procedure was developed based on
Gewald reaction for the synthesis of 2-aminothiophenes using a basic ionic liquid
[bmIm]OH as both catalyst and solvent. Besides being a green protocol the method offers
advantages of successful synthesis of a variety of alkyl, aryl, alkoxy and alkylamino-2-
aminothiophenes in good yields.
KEYWORDS: Basic ionic liquid, [bmIm]OH, 2-aminothiophenes, Gewald reaction,
Ionic liquid, 4-alkoxythiophenes
1

INTRODUCTION
Ionic liquids (ILs) have attracted growing interest in the context of green organic
synthesis. Initially they were introduced as alternative green reaction media because of
their unique chemical and physical properties of non-volatility, non-flammability,
thermal stability, and controlled miscibility[1]. They are also referred as ‘‘designer
solvents’’ as their physical and chemical properties could be tailor-made by a careful
choice of cation and anion. Recently, the development of task-specific ionic liquids
(TSILs) with special functions to suit the specific requirements of a reaction has become
an attractive field. Besides their inherent advantages as reusable homogenous supports,
reagents, and catalysts with green credentials, the additional enabling tunable features
made them more popular. These TSILs often serve the dual role of catalyst as well as
reaction media[2].
Multisubstituted 2-aminothiophene scaffolds derived from Gewald reaction (GR)
attracted considerable attention in the design of several biologically active molecules [3].
Ample data has been accumulated highlighting their biological utility as synthons in the
development of atypical antipsychotic agents (Fig 1, 1)[4], antiinflammatory agents (2),
allosteric enhancers of adenosine A1 receptor (3, 5)[5-7], IκB kinase β (IKKβ) inhibitors (4)
[8] and antitubercular agents (6) [9].
A typical GR involves base catalyzed condensation of a ketone with an activated nitrile in
the presence of sulfur to obtain functionalized 2-aminothiophenes [10]. Majority of GR
applications include use of organic bases such as morpholine[11,12], triethylamine [13,14]
,
2

piperidine [15], pyridine and diethylamine [16] etc. making it environmental unfriendly
which necessitated us to investigate GR using TSILs. Surprisingly, very few such
attempts were reported in the literature. The application of an IL-ester, prepared by
coupling of DCC with cyanoacetic acid and an imidazolium-based IL as soluble support
in GR was studied by Hu et al., however this methodology lacks versatility [17,18]. For
instance IL-ester cannot be prepared with activated nitriles such as malononitrile and
ethylcyanoacetate. Further product isolation by base-catalyzed hydrolysis and recovery of
IL from alkoxide solution is prohibitively tedious process. Though, a basic ionic liquid
[TMG] [Lac] (1,1,3,3-tetramethylguanidine lactate) has been explored as solvent and
catalyst in synthesis of 4,5-dialkyl-2-aminothiophenes, the utility of the method has not
been studied for 4-aryl and 4-alkoxy-2-aminothiophenes [19]. Hence the development of a
versatile and robust protocol involving TSIL was felt as an urgent need for the synthesis
of functionalized 2-aminothiophenes.
Recently a TSIL [bmIm]OH has been successfully utilized to catalyze Michael addition
of active methylene compounds to conjugated ketones, carboxylic esters and nitriles,[20]
and Markovnikov addition of N-heterocycles to vinyl esters[21] etc. The versatility of this
TSIL as green reaction media and catalyst prompted us to study its utility in GR to get 2-
aminothiophenes.
RESULTS AND DISCUSSION
As our key interest is to develop a multi-component one-pot green protocol, different
alkylketones, activated nitrile, and sulfur was condensed in one-pot using [bmIm]OH as
3

catalyst and solvent (Scheme-1). Interestingly, the yields of 2-aminothiophenes (2a-2j,
Table-1) are better than the reported procedures [22-24]. For example, in the literature 2a
was obtained in 61% yield after 8 h using Calcined Mg-Al hydrotalcite as the base at
60ºC in EtOH, [22] while 2a was obtained in 88% yield in present method, similarly 2g-2j
were also obtained in high yields. Several reviews and papers on the Gewald reaction and
its improvements propose that 2-aminothiophene ring is formed from the aliphatic
ketones such as 1a-j during the multi-step reaction sequence: condensation, base
promoted activation and addition of sulfur and ring closure. Hence it can be presumed
that [bmIm]OH is efficient to catalyze condensation as well as sulfur addition process in
the synthesis of 4,5-alkyl-2-aminothiophenes. The additional advantage of this green
methodology is that the final products are pure enough (>90%) for spectral analysis and
to proceed further reactions.
Encouraged with the results, utility of [bmIm]OH has been studied in the synthesis of 4-
aryl-2-aminothiophenes, 2,3,4,5-tetrasubstitued thiophenes (Scheme-2) and 4-alkoxy-2-
aminothiophenes (Scheme-3). Condensation of acetophenone (3a), activated nitrile, and
sulfur using [bmIm]OH in one-pot resulted in low yield (<40%) of 2-aminothiophene 5a.
Conversely, reaction of ylidene 4a with sulfur using [bmIm]OH as catalyst resulted in
good yield (77%) of 5a. Similarly synthesis of different ylidenes 4b-4g [25, 26] and 7a-7i
[27] by Knoevenagel condensation followed by [bmIm]OH catalyzed cyclisation with
sulfur yielded respective 4-aryl-2-aminothiophenes, 2,3,4,5-tetrasubstitued thiophenes
(Table 2) and 4-alkoxy-2-aminothiophenes (Table-3) in good yields. Demonstrating that
[bmIm]OH is efficient in sulfur addition and cyclisation of ylidenes though not effective
4

in Knoevenagel condensation of these ketones. Hence we propose that in the modified
two-step Gewald method i.e., Knoevenagel condensation followed cyclisation with
sulfur, [bmIm]OH can be utilized efficiently for sulfur addition and cyclisation to yield 2-
aminothiophenes.
Remarkably, [bmIm]OH is very promising for the synthesis of 4-alkoxy-2-
aminothiophenes (Scheme 3) in high yields. Since, in our previous experiments[27] use of
organic bases for sulfur addition and cyclisation of ylidenes 7a-i resulted in black color
masses, which consequently necessitated us tedious column purification process.
Whereas with aqueous inorganic bases (aqueous KOH or NaOH), nucleophilic
displacement of 7a with hydroxyl and subsequent formation of 2-amino-4-
hydroxythiophene (9) as the major product. Using [bmIm]OH no such side products were
observed. The final compounds are separated from the IL simply by washing with diethyl
ether or ethyl acetate. The residual ionic liquid was washed with diethyl ether, dried
under vacuum at 90 0C for 2 h to eliminate any water trapped from moisture. Weight of
the ionic liquid lost in the washings was adjusted and reused for subsequent reactions.
The ionic liquid has been reused in 3 runs without loss of activity (Table 1, 2k-l)
highlighting it as a greener approach.
In conclusion, the present study highlights the task-specific basic ionic liquid [bmIm]OH
as an useful environmental-friendly solvent and catalyst in GR. The results delineated in
Table 1-3 demonstrate its versatility for the synthesis of functionalized 2-
aminothiophenes.
5

EXPERIMENTAL DATA
Synthesis of 4,5-alkyl-2-aminothiophenes (2a-2j): general procedures are described as
those of compound 2i.
A mixture of N-benzyl-4-piperidone (1i, 380 mg, 2mmol), malononitrile (132 mg,
2mmol), sulfur (64 mg, 2mmol) and basic ionic liquid (bmIm)OH (380 mg, 2.4 equiv.)
was heated to 60 ºC for 2 h. Reaction mixture cooled to room temperature, washed with
diethyl ether or ethyl acetate (3 x 40 mL) and organic layers concentrated under vacuum
to obtain oily crude product. The crude product was dissolved in ether: hexane (3:1, 50
mL) mixture, insoluble material was decanted; organic layer was concentrated to 1/4 of
the volume and kept in a refrigerator. The precipitate formed was filtered and dried.
2-Amino-6-Benzyl-4,5,6,7-Tetrahydrothieno[2,3-C]Pyridine-3-Carbonitrile (2i)
Red color solid; 1H NMR (400 MHz, CDCl3): δ = 7.31 (m, 5H), 4.68 (s, 2H), 3.69 (s,
2H), 3.40 (s, 2H), 2.80 (t, J = 6.0 Hz, 2H), 2.63 (t, J = 6.0 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ = 160.5, 137.8, 130.9, 129.9, 128.4, 127.3, 117.8, 115.1, 88.2, 61.7, 50.7,
49.5, 24.6. MS (ESI): m/z = 270.1 (M+H)+.
Synthesis of 4-aryl-2-aminothiophenes (5a-g) and 4-alkoxy-2-aminothiophenes (8a-h):
general procedures are described as those of compound 8b.
6

A mixture of 2-(1-ethoxyethylidene)malononitrile [27] (7b, 272 mg, 2mmol), sulfur (64
mg, 2 mmol) and basic ionic liquid (bmIm)OH (380 mg, 2.4 mmol) were allowed to stir
at 60 °C for 4 h. Reaction mixture cooled to room temperature, washed with diethyl ether
or ethyl acetate (3 x 30 mL), organic layers concentrated to 1/4 of the volume and kept in
a refrigerator. The precipitate formed was filtered and dried.
2-Amino-4-Ethoxythiophene-3-Carbonitrile (8b)
Brown colour solid; Mp 134 ºC (lit. [27] 134 ºC); IR (KBr): 3439, 3320, 3213, 2972, 2199,
1631, 1557 cm-1.; 1HNMR (400MHz, CDCl3): δ = 5.18 (s, 1H), 4.79 (s, 2H, NH2), 4.01
(q, J = 6.8 Hz, 2H), 1.40 (t, J = 6.8 Hz, 3H). 13C NMR (100MHz, CDCl3): δ = 160.4,
154.2, 113.9, 82.6, 78.9, 59.0, 15.1; MS (ESI+): m/z = 169.1 (M+H).
SUPPLEMENTARY MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
ACKNOWLEDGEMENTS
# Part of the work has been submitted as Ph.D. thesis to Panjab University (PU).
The authors thank the Chairman, UIPS, (PU), Chandigarh for providing the facilities.
KVR thank CSIR, New Delhi for awarding Senior Research Fellowship. (Sanction No:
09/135/0628/2011/EMR-I).
7

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10

Table 1. Yields of 4,5-alkyl-2-aminothiophenes using [bmIm]OH as catalyst
S.No.
2a
2b
2c
2d
2e
2f
R1
R2
X
%yield
88
Ref.
22
22
--
CH3
CH3
CN
COOEt 72
CN 85
COOEt 67
CN 88
COOEt 88
CN 87
COOEt 86
CH2 -N(CH2 PH)-CH2 CN 92
(CH2)3
(CH2)4
(CH2)5
23
23
23
24
24
--
2g
2h
2i
2j
COOEt 90
88a
85b
--
2k
2l
(CH2)4
CN
--
--
asecond recycling of IL, Ref. = Reference
bthird recycling of IL
11

Table 2. Yields of 4-aryl-2-amino/2,3,4,5-tetrasubstituted thiophenes using [bmIm]OH as
catalyst
S.No. R1
R2
R3
R4
H
X
%yield Ref.
5a
5b
5c
5d
5e
Ph
CH3
CH3
CH2 Ph
CH3
CH3
Ph
CN
CN
CN
CN
CN
77
62
74
69
67
25
26
26
25
--
4-MeOPh
Ph
4-MeOPh
Ph
H
Ph
H
4-BrPh
3,4-
4-BrPh
3,4-
H
(OCH3 )2 Ph
CH3
(OCH3 )2 Ph
5f
CH2 COOEt CH3
CH2 COOEt CH3
COOEt CN
86
--
5g
CH3
COOEt COOEt 84
17
12

Table 3. Yields of 4-alkoxy/alkylamino-2-aminothiophenes using [bmIm]OH as catalyst
S. No. R1
%yield
72
8a
8b
8c
8d
8e
8f
O-CH3
O-CH2 CH3
84
O-(CH2)2 -CH3
O-(CH2)3 -CH3
O-CH2 -CH(CH3 )2
68
74
72
O-CH2 -CH2 -CH(CH3 )2 76
8g
8h
8i
O-(CH2)7 - CH3
O-CH2 - Ph
82
35
91
13

Figure 1. 2-aminothiophene analogues in clinics (1&2) or in preclinical development (3-
6)
14

Scheme 1. Synthesis of 4,5-alkyl-2-aminothiophenes: Reagents and conditions; a) 1equiv.
S8, 1.2 equiv. [bmIm]OH, 60 ºC, 2h.
15

Scheme 2. Synthesis of 4-aryl-2-amino/2,3,4,5-tetrasubstituted thiophenes: Reagents and
conditions; a) NH4OAc, toluene, reflux.; b) 1equiv. S8, 1.2 equiv. [bmIm]OH, 60 ºC, 4h.
16

Scheme 3. Synthesis of 4-alkoxy/alkylamino-2-aminothiophenes: Reagents and
conditions: a) i) R-OH (3 equiv.), 24 h, 80 °C; (ii) CH2(CN)2, 60 °C, 3 h; [27] b) 1equiv. S8,
1.2 equiv. [bmIm]OH, 60 ºC, 4h; c) CH2(CN)2, 60 °C, 3 h; d) 1equiv. S8, 1 equiv.KOH
(aqueous), 60 °C, 15 min.
17