One-pot green synthesis of 3'-(2-aminobenzimidazolyl)-2-phenyl spiro[4H-benzopyran-4,2'-thiazolidin]-4-ones and acylation using trifluoroacetic anhydride

Article abstract of DOI:10.1080/10426507.2011.557574

An expeditious one-pot synthesis of a novel heterocyclic system, 3'-(2- aminobenzimidazolyl)-2-phenyl spiro[4H-benzopyran-4,2'-thiazolidin]-4-ones, has been accomplished by condensing substituted hydrazinobenzimidazole, flavanone, and mercaptoacetic acid

Full text of DOI:10.1080/10426507.2011.557574

Phosphorus, Sulfur, and Silicon, 186:2086–2095, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.557574
ONE-POT GREEN SYNTHESIS
OF 3ꢁ-(2-AMINOBENZIMIDAZOLYL)-2-PHENYL
SPIRO[4H-BENZOPYRAN-4,2ꢁ-THIAZOLIDIN]-4-ONES
AND ACYLATION USING TRIFLUOROACETIC ANHYDRIDE
Kanti Sharma and Renuka Jain
Department of Chemistry, University of Rajasthan, Jaipur, Rajasthan, India
GRAPHICAL ABSTRACT
6
7
R
R
N
5
Conventional
∆, 4 5 h
8
N
+
4a
8a
N
NHNH2
O
O
4
O
1
N
NHN
R1
2
R1
3
1
2
Ph
3
Ph
Conventional
∆, 8 10 h
[bmim]PF
6
SHCH2COOH
SHCH2COOH
1 h
R
R
N
6
O
N
5´
5
N
O
6
S
1´
4´
3´
N
5´
5
7
(CF3CO)2O
S
1´
4a
4´
3´
2´
7
N
R1
4a
2´
4
0
5°C
8
N
R1
NH
N
4
8a
3
8
COCF3
Dry ether
2
8a
O
3
2
1
O
4
1
Ph
5
Ph
Abstract An expeditious one-pot synthesis of
a
novel heterocyclic system, 3ꢀ-(2-
aminobenzimidazolyl)-2-phenyl spiro[4H-benzopyran-4,2ꢀ-thiazolidin]-4-ones, has been
accomplished by condensing substituted hydrazinobenzimidazole, flavanone, and mercap-
toacetic acid by conventional heating in ethanol or toluene, and in an ionic liquid, viz.,
1-butyl-3-methyl-imidazolium hexafluorophosphate. Excellent yields (85%–90%) and higher
purity are obtained in the ionic-liquid-mediated synthesis as compared with the conventional
procedure (55%–60%). Further, these compounds were acylated with trifluoroacetic
anhydride. The structures of the compounds were confirmed by IR, 1H NMR, 13C NMR, mass
spectral data, and elemental analysis. The compounds, upon evaluation for their antibacterial,
antifungal, and insecticidal activities, exhibited excellent results.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Ionic liquid; 3ꢀ-(2-aminobenzimidazolyl)-2-phenyl spiro[4H-benzopyran-4,2ꢀ-
thiazolidin]-4-ones; trifluoroacetic anhydride; antibacterial; antifungal; insecticidal activity
Received 18 August 2010; accepted 19 January 2011.
One of the authors (KS) is grateful to UGC New Delhi, India, for granting research award. We are also
thankful to the Central Drug Research Institute (CDRI), Lucknow, India, for elemental and spectral analyses.
Address correspondence to Kanti Sharma, Department of Chemistry, University of Rajasthan, JLN Marg,
Jaipur-302055, Rajasthan, India. E-mail: drkanti@gmail.com
2086

SYNTHESIS OF 3ꢁ-(2-AMINOBENZIMIDAZOLYL)-2-PHENYL
2087
INTRODUCTION
Benzimidazoles are important in the field of biochemistry and medicine and the
present era has witnessed the increasing use of these compounds in chemotherapy.1 The
benzimidazole scaffold has been reported to exhibit antimicrobial,2,3 antifungal,4 pestici-
dal,5 antiparkinson,6 and anticancer activities.7 Flavanones possess strong antioxidant and
antibacterial activity but only scant data on their chemical modification is available in the
literature.8 The reactions of flavanone with simple hydrazines have been reported9–11 but
no such investigation with hydrazino heterocycles has been carried out. The chemistry
of 4-thiazolidinones has been reviewed12 and found to exhibit antibacterial, herbicidal,
anti-inflammatory, and analgesic activities,13 while some derivatives are potent anti-HIV
agents14 and evaluated as selective human immunodeficiency virus type-1 reverse transcrip-
tase (HIV-1 RT) enzyme inhibitors.15,16 It was hypothesized that the title molecules incor-
porating benzimidazole, thialzolidinone, and flavanone moieties would exhibit enhanced
biological properties. The investigation further appeared interesting as spiro[benzopyran-
4,2ꢀ-thiazolidinone] has not been reported in literature with C-4 of flavanone ring as spiro
carbon and amino benzimidazolyl group as a substituent.
With a view to develop an efficient and extremely fast procedure using a “green chem-
istry” concept, a one-pot three-component (hydrazinobenzimidazoles, flavanone, and mer-
captoacetic acid) synthesis of 3ꢀ-(2-aminobenzimidazolyl)-2-phenyl spiro[4H-benzopyran-
4,2ꢀ- thiazolidin]-4-ones 4 was developed for the first time by conventional method as well as
using ionic liquid, viz., 1-butyl-3-methyl-imidazolium hexafluorophosphate ([bmim] PF6)
as solvent. In the conventional method, first 2-phenyl-[4-benzimidazol-2-yl]benzopyran 3
was prepared by reacting 1 and 2 in ethanol with few drops of glacial acetic acid and then
reacted with mercaptoacetic acid to give 4. The compounds 4 were further acylated with
trifluoroacetic anhydride to give 5 to enhance their biological activity17 (Scheme 1).
RESULTS AND DISCUSSION
The syntheses of 4a–d have been performed employing two methodologies.
Conventional Method
Method A. In this method, 2-hydrazinobenzimidazoles, as synthesized following
the method of Bednyagina et al.,18 were first reacted with flavanone in ethanol with few drops
of glacial acetic acid, for 5 h to give 2-phenyl-4-(benzimidazol-2-yl-hydrazono)benzopyran
3 in 65%–70% yield. The hydrazones 3 were refluxed with mercaptoacetic acid for 8–10 h
in toluene to afford the thiazolidinone derivatives in 45%–55% yield.
Method B. Hydrazones synthesized in method A were not isolated, mercaptoacetic
acid was added in situ, and heated further for 8–10 h at 70 ◦C–80 ◦C to give the thiazolidinone
derivative in 55%–60% yield.
Ionic-Liquid-Mediated Synthesis
Ionic liquids are used as a green solvent because these are environmentally benign
in comparison with the common solvents generally used, which can cause severe hazards
such as benzene is carcinogenic and causes acute leukemia, aplastic anemia, and multiple
myeloma.19 The reactions in ionic liquid are easy to perform and need no special apparatus

2088
K. SHARMA AND R. JAIN
R
N
+
N
NHNH2
O
O
R1
1
2
Ph
Conventional
∆, 4 5 h
6
[bmin]PF6
SHCH2COOH
1 h
7
R
5
8
N
8a
4a
O
1
N
NHN
4
2
R1
3
3
Ph
Conventional
∆, 8 10 h
SHCH2COOH
R
N
O
6
5´
5
S
4´ 1´
3´
N
7
8
4a
2´
N
R1
NH
4
8a
3
2
O
4
1
Ph
0
5°C
(CF3CO)2O
Dry ether
R
N
O
N
6
5´
5
S
4´ 1´
3´
N
7
4a
2´
N
R1
4
8
8a
3
COCF3
2
O
1
Ph
5
Compound
R
R1
Compound
R
R1
H
H
H
H
H
CH3
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
CH3
H
H
CH2Ph
COCF3
CH3
H
CH2Ph
CH3 COCF3
H
H
H
H
H
CH3
CH3
CH2Ph

SYNTHESIS OF 3ꢁ-(2-AMINOBENZIMIDAZOLYL)-2-PHENYL
2089
or methodologies. Also, the ionic liquids can be recycled indefinitely and this leads to a
reduction of the costs of the process. The ionic liquid [bmim] PF6 is water stable and forms
a triphasic mixture with water and heterocyclic compounds at the time of separation of
product, which makes it useful for clean synthesis.
A one-pot synthesis of 4 has been accomplished by taking hydrazinobenzimidazoles,
mercaptoacetic acid, and flavanone in ◦an ionic liquid, viz., [bmim] PF6.20 The reaction
◦
has been carried out by heating at 60 C–70 C for 1 h that gives 4 in 85%–90% yield
(Table 1).
Synthesis of Compounds 5a–d
Thiazolidinone derivatives 4, prepared by either method, were reacted with trifluo-
roacetic anhydride taking advantage of its high reactivity where it replaced both >NH of
compounds 4 to give >NCOCF3 derivatives 5 in 90%–95% yield (Table 1).
Characterization
The structures of the compounds have been established from their spectral data. The
IR spectrum of 3a (where R and R1 = H) showed characteristic bands at 3200, 3000,
and 1620 cm−1 for >NHN=, >NH, and >C N stretching vibrations respectively with a
disappearance of the peak due to >C O of flavanone at 1680 cm−1. 1H NMR shows peaks
at δ 2.85 (dd, 1H, J = 16.8, 2.6 Hz) for Heq and 3.11 (dd, 1H, J = 16.8, 12.9 Hz) for Haxial
at C-3. Peaks at δ 5.57 (dd, 1H, J = 12.9, 2.6 Hz) appeared for the C-2 axial proton. A
multiplet at δ 6.92–7.94 and singlets at δ 9.02 and 10.44 also appeared for aromatic, >NH,
and >NHN=, respectively. In 13C NMR, a peak appeared at δ 164.6 for >C N while the
peak due to flavanoyl >C O at δ 180 disappeared. Further, the mass spectrum shows M+
at m/z 354.
The formation of thiazolidinone 4 was confirmed with the appearance of peak due to
>C O at 1720 cm−1 in the IR spectra and a peak at δ 3.81 ppm for –CH2– of thiazolidinone
ring in the 1H NMR spectra. 13C NMR spectra showed peaks at δ 46.0 and 182.6 ppm for
–CH2COS– and –CH2COS– respectively. Further, mass spectrum shows M+ at m/z 428
(4a).
Acylation of 4 to >NCOCF3 derivatives 5 was confirmed by disappearance of peak
1
due to >NH in both IR and H NMR spectra and appearance of peaks in 13C NMR at
δ 117.6 and 188.4 ppm due to –CF3 and –COCF3 respectively. Further, mass spectrum
shows M+ at m/z 620 (5a) (Table 2).
ANTIMICROBIAL AND INSECTICIDAL ACTIVITY
Compounds 3, 4, and 5 have been screened for their antifungal activity against
Aspergillus niger, Aspgerillus flavus, Fusarium oxysporum, and Trichoderma viridae at
two different concentrations (100 and 500 ppm) and antibacterial activity against Bacillus
subtilis, Escherichia coli, Klebsiella pneumonia, and Staphylococcus aureus (50 and 100
ppm) by filter paper disc diffusion plate method.21,22 Standard antifungal drug, griseofulvin,
and antibacterial drug, streptomycin, have also been screened under similar conditions for
comparison (see Supplemental Materials, Tables S1–S3).
Examination of the results of the biological activity of compounds 3, 4, and 5 shows
that compounds 3a, 3b, 4a, 4b, and 5a–d are highly active against both selected bacteria

2090

2091

2092

SYNTHESIS OF 3ꢁ-(2-AMINOBENZIMIDAZOLYL)-2-PHENYL
2093
and fungi (having zone of inhibition 19–24 mm) and the rest of the compounds have shown
good to moderate activity (having zone of inhibition 11–18 mm).
For insecticidal activity,23,24 Periplaneta americana was taken and the knock down
(KD) value of synthesized heterocyclic derivatives was compared with the control drug
(Cypermethrin).
It was observed that compounds having >COCF3 group exhibited better insecticidal
activity (KD value is 3–4 min) in comparison with standard drug (KD value is 5–7 min).
The rest of the compounds have significant to moderate activity (KD value is 7–10 min).
Thus, it is concluded that the synthesized compounds are capable to act as good
antimicrobial agents and insecticidals. They may prove to be helpful to render the services
to the humanity.
CONCLUSION
The one-pot, multicomponent condensation of 2-hydrazinobenzimidazoles 1, car-
bonyl compound, i.e., flavanone 2, and mercaptoacetic acid afforded the product, thiazo-
lidinone 4, which were prepared by adopting two different methodologies: (i) conventional
method: yield 55%–60%, takes long time (8–10 h), and use of solvent is hazardous and (ii)
using ionic liquid: yield 85%–90%, shorter reaction time (1 h), and economical as ionic
liquid recycled for further use.
Therefore, the environmentally benign green synthesis, using ionic liquid, is the better
way for this synthesis.
Further, trifluoroacetic anhydride is a very reactive compound and used for acylation
reaction, as it replaces both the >NH of compound 4 to give 5 with enhanced antimicrobial
and insecticidal activity.1
EXPERIMENTAL
The uncorrected melting points were taken in open glass capillaries using a Gal-
lenkamp melting point apparatus. The IR spectra were recorded on a Nicolet Magna IR
spectrometer Model 550 in KBr pellets and band positions are reported in wave numbers
(cm−1). 1H NMR and 13C NMR spectra were recorded on a JEOL 300 MHz using CDCl3
at 300.15 and 74.46 MHz, respectively, and chemical shifts (δ) are given in ppm. TMS
was used as internal reference. The mass spectra were recorded on a JEOL SX 12 (FAB).
The mass spectra and elemental analyses were performed at the Central Drug Research
Institute, Lucknow, India, while other spectra in the Department. Solvents were purified
by standard procedures.25,26 Commercially available (ACROS) flavanone was used for the
reactions.
Synthesis of Compounds 4a–d by Conventional Method
Method A. 2-Phenyl-4-[Benzimidazol-2-Yl-Hydrazono]Benzopyran 3a. A mixture
of 2-hydrazinobenzimidazole 1 (10 mmol) and flavanone 2 (10 mmol) in equimolar amount
was dissolved in ethanol (50 mL), and then a few drops of acetic acid were added and
refluxed for 5 h. On cooling, crystals appeared that were filtered and washed with water. It
was further recrystallized from ethanol to give 3a in 70% yield; mp 192 ◦C–193 ◦C.
Compounds 3b–d have been prepared similarly and their characterization and spectral
data are recorded in Tables 1 and 2, respectively.

2094
K. SHARMA AND R. JAIN
3ꢀ-(2-Aminobenzimidazolyl)-2-Phenyl Spiro[4H-Benzopyran-4-2ꢀ-Thiazolidin]-4-
One 4a. Hydrazone 3a (5 mmol) in dry toluene (10 mL) was taken in a round bottom flask
and mercaptoacetic acid (10 mmol) was added and refluxed for 8–10 h using a Dean-Stark
apparatus to remove the water formed azeotropically. The solvent was then evaporated
in vacuum and the residual solid mass was treated with water and neutralized with 10%
sodium bicarbonate solution. The solid thus obtained was filtered. It was further purified
by recrystallization from ethanol to give 4a in 55% yield; mp 160 ◦C–162 ◦C.
Compounds 4b–d have been prepared similarly and their characterization and spectral
data are recorded in Tables 1 and 2, respectively.
Method B. To the hydrazone synthesized by method A, mercaptoacetic acid
(10 mmol) was added in situ, refluxed further for 8–10 h [as checked by thin layer chro-
matography (TLC)], and worked up as earlier in method A to give 4a in 55%–60% yield.
Compounds 4b–d have been prepared similarly and their characterization and spectral
data are the same as in method A.
Ionic-Liquid-Mediated One-Pot Synthesis of 4a–d
A mixture of 2-hydrazinobenzimidazole (3 mmol), flavanone (3 mmol), mercap-
toacetic acid (6 mmol), an◦d ionic◦liquid [bmim] PF6 (5 mL) was taken in a round bottom
flask. It was heated at 60 C–70 C for 1 h. The progress of the reaction was monitored
by TLC. After completion of the reaction, the contents were neutralized by 10% aqueous
sodium bicarbonate solution and extraction was carried out with ethyl acetate (three times,
10 mL). The solvent was removed under reduced pressure. The pasty mass thus obtained
was extracted with diethyl ether (three times, 10 mL), dried over anhydrous sodium sul-
fate, and ether distilled off. The product so obtained was purified by crystallization with
ethanol/column chromatography to give 4a–d in 85%–90% yield. The ionic liquid layer
was washed with water (three times, 5 mL) and kept for 2 h at 80 ◦C–85 ◦C under reduced
pressure. It was recycled for use in further synthesis.
The characterization and analytical data are identical to those prepared by the con-
ventional methodology.
3ꢁ-(1-Trifluoroacetyl-2-Trifluoroacetylamino Benzimidazolyl)-2-Phenyl
Spiro[4H-Benzopyran-4,2ꢁ-Thiazolidin]-4-One 5a
3ꢀ-2(aminobenzimidazolyl)-2-phenyl spiro[4H-benzopyran-4,2ꢀ-thiazolidin]-4-one
4a (2 mmol) was dissolved in dry ether (10 mL◦) and trifluoroacetic anhydride (4 mmol) in
◦
dry ether (5 mL) was added with stirring at 0 C–5 C. It was further stirred for 15 min.
The ether was distilled under reduced pressure and water (10 mL) was added to it. The
solid obtained was filtered after some time and recrystallized from ethanol to give 5a, yield
95%; mp 196 ◦C–198 ◦C.
Compounds 5b–d have been prepared similarly and their characterization and spectral
data are recorded in Tables 1 and 2 respectively.
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