Download Note Microwave assisted transformation of benzimidazolyl

Indian Journal of Chemistry
Vol. 49B, July 2010, pp. 989-993
Note
Microwave assisted transformation of
benzimidazolyl chalcones into N1-substituted
pyrazolines and evaluation of their
antimicrobial activities
Jayanti Rajora, Janardan Yadav, Ravindra Kumar &
Yogendra K Srivastava*
Synthetic Organic Chemistry Laboratory, Department of
Chemistry, M. P. Govt (PG) College,
Chittorgarh 312 001, India
E-mail: [email protected]
Received 20 April 2009; accepted (revised) 23 April 2010
1-Benzimidazolyl-3-aryl-prop-2-ene-1-ones 2 have been
transformed into N1-substituted pyrazoline derivatives by the
interaction with phenyl hydrazine, thiosemicarbazide and
hydrazine hydrate in the presence of formic acid under solvent
free microwave induced protocol. The structure of newly
synthesized compounds have been confirmed on the basis of their
elemental analysis and spectral data. Newly synthesized
compounds have been evaluated for their antimicrobial activity in
vitro against E. coli, K. pneumonae, P. aeruginosa and B. subtilis
using paper disc method. Some of the compounds have shown
significant activity against the pathogens.
The diverse nature of chemical reactions require
various chemical strategies directed towards
environmentally sound and ecofriendly methods and
envisages minimum hazards as the performance
criteria while designing the new process. One of the
thrust areas for achieving this goal is to explore
alternative reaction conditions to accomplish desired
chemical transformation with elimination of the use of
hazardous conventional solvents. Microwave irradiation (MWI) has gained popularity as a powerful non
conventional tool for rapid, efficient and ecofriendly
synthesis of a variety of compounds, because of
selective absorption of microwave energy by polar
molecules1. The application of MWI to provide
enhanced reaction rate, improved yield and cleaner
products2 is proving quite successful in the formation
of a variety of carbon-heteroatom bonds. The solvent
free solid phase approach involving MWI exposure of
neat reactants is applicable to rapid one pot assembly
of heterocyclic compounds from in situ generated
intermediate3-5. Nitrogen-sulfur containing heterocycles have been exclusively used as important
pharmacophores and in drug designing. Benzimidazoles are important group of heterocycles possessing a
wide spectrum of pharmacological activities6 such as
antifungal7, antihypertensive8, antioxidant9, cardiovascular10, anticonvulsant11, antiviral12, and HIV-IPR
inhibitory activity13. Pyrazoline derivatives have been
explored extensively due to their versatile biological
activities. Antibacterial15, antiamoebic16, antiproliferative17, anticancer18, cox 11SS inhibitory19 and cytoxic
activities20-23 have been reported to be associated with
pyrazoline nucleus. Besides this, due to easy
accessibility and diverse chemical reactivity they are
useful synthons. Therefore these two moieties were
coupled and an attempt was made to synthesize
molecules which may possess enhanced activities.
Results and Discussion
The required synthon 1-benzimidazolyl-3-aryl-2propen-1-one 2 was prepared by Claisen-Schmidt
condensation of 2-acetyl benzimidazole 1 with
substituted aromatic aldehydes in the presence of base
under MWI by Literature method24.
Condensation of 2 with phenyl hydrazine gave
N1-phenyl-3-benzimidazolyl-5-aryl-2-pyrazolines 3 in
80-85% yield. The reaction of 2 with hydrazine
hydrate in the presence of formic acid afforded 3benzimidazolyl-5-aryl-2-pyarzoline-1-carboxaldehyde
4 where as when 2 was condensed with thiosemicarbazide in the presence of anhydrous K2CO3, gave
3-benzimidazolyl-5-aryl-2-pyrazolinyl-1-thiocarbamides 5 (Scheme I). All these transformations were
carried out using solvent less, solid phase neat
reactants under microwave irradiation. The reaction
was completed with in 4-8 min with 80-85% yield.
Above transformation when carried out using
conventional heating method under liquid phase,
required 6-8 hr of heating and yields were 60-65%
indicating the superiority of MWI method over
conventional heating.
The characterization of newly synthesized
compounds was based on their elemental analysis
(Table I) and spectral data. IR spectra of newly
synthesized compound gave absorption bands at
3420-3380 cm-1 (-NH of benzimidazole ring), 14401385 cm-1 (combined vibrations of C=N and N-N
990
INDIAN J. CHEM., SEC B, JULY 2010
Scheme I
grouping), For compounds 4 a sharp peak at 1690
cm-1 for aldehydic group was obtained whereas for
compounds 5 absorption band at 1360-1340 cm-1 for
C=S linkage was observed.
1
H NMR spectra of these compounds gave signals
at δ 3.36-3.38 (double doublet for C4-HA), δ 3.99-4.01
(double doublet C4-HB), and δ 6.18-6.22 (double
doublet C5-HX), confirming the presence of typical
ABX pattern of pyrazoline system. For compounds 4
a sharp high intensity singlet for aldehyde proton was
observed at δ 10.01. Compounds 5 exhibited a sharp
singlet at δ 6.75 for proton of amino group.
(Table II).
The mass spectra of these compounds gave
molecular ion peaks corresponding to their molecular
mass.
Experimental Section
The melting points reported were determined in
open capillary and are uncorrected. The IR spectra
were taken on a Perkin-Elmer spectrometer using KBr
pellets (ν cm-1). 1H NMR were recorded on a Brucker
DRX-300 spectrometer (Chemical shift δ ppm,CDCl3)
and mass spectra (FAB) were recorded on Jeol-Sx102/DA 600 mass spectrometer using m-nitro benzyl
alcohol as matrix . The matrix peaks were observed at
m/z 136, 137, 154, 289 and 307. The purity of
products and progress of reaction was checked by
TLC using ethyl acetate:benzene (1:9) as eluent and
silica gel G as adsorbent. All the transformation were
carried out in domestic microwave oven (Samsung
1630N, output energy 800 watt, frequency 2450 MHz.
NOTES
991
Table I ― Physical data of synthesized compounds
Compd
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
Ar
phenyl
4-OMe phenyl
3,4-diOMe phenyl
3,4,5-triOMe phenyl
4-Cl phenyl
4-NMe2 phenyl
phenyl
4-OMe phenyl
3,4-diOMe phenyl
3,4,5-triOMe phenyl
4-Cl phenyl
4-NMe2 phenyl
phenyl
4-OMe phenyl
3,4-diOMe phenyl
3,4,5-triOMe phenyl
4-Cl phenyl
4-NMe2 phenyl
Mol.Formula
(Mol. wt.)
C22H18N4 (338)
C23H20N4O (368)
C24H22N4O2 (398)
C25H24N4O3 (428)
C22H17N4Cl (372.5)
C24H23N5 (381)
C17H14N4O (290)
C18H16N4O2 (320)
C19H18N4O3 (350)
C20H20N4O4 (380)
C17H13N4OCl (324.5)
C19H19N5O (333)
C17H15N5S (321)
C18H17N5SO (351)
C19H19N5SO2 (381)
C20H21N5SO3 (411)
C17H14N5SCl (355.5)
C19H20N6S (364)
m.p.
ºC
203
260
140
142
283
237
230
210
245
255
204
190
238
175
156
154
190
198
Yield %
80
82
80
84
83
80
85
82
80
84
83
83
85
84
86
82
81
81
Reaction time
(min)
4.0
4.0
5.0
4.5
4.0
5.5
4.0
3.5
3.0
4.0
3.0
3.0
6.0
6.0
6.0
6.5
6.5
6.0
%N Calcd
(Found)
16.86 (16.80)
15.21 (15.48)
14.07 (14.40)
13.08 (13.00)
15.0 (14.89)
18.37 (18.07)
19.31 (19.22)
17.5 (17.31)
16.0 (15.48)
14.73 (14.56)
17.25 (17.09)
21.02 (20.87)
21.8 (21.66)
19.94 (19.89)
18.37 (18.30)
17.03 (16.88)
19.69 (19.48)
19.23 (19.11)
Table II ― Spectral data of synthesized compounds
IR (KBr,υ cm-1)
1
MS (FAB, m/z %)
3a
3022-2892 (CH str), 1590-1492
(C=N, N-N combined vib)
338M+(75), 339M+1(100),
227(4)
3b
3058-2837 (CH str), 1594-1498
(C=N, N-N combined vib)
3e
2974-2890 (CH str), 1590-1450
(C=N, N-N combined vib)
5a
3415 (NH), 3252 (NH2), 30572927 (CHstr), 2362 (C=S) 15431468 (C=N, N-N combined vib)
3375 (NH), 3275 (NH2), 29322833 CH str), 2364 (C=S), 15171465 (C=N, N-N combined vib)
3305 (NH), 3252 (NH2), 29332830 (CH, 2360 (C=S), 15991465 (C=N, N-N combined vib)
3061-2960 (CH str), 1596-1495
(C=N, N-N combined vib)
2940-2841 (CH str), 1595-1410
(C=N, N-Ncombined vib)
2932-2893 (CH str), 1596-1490
(C=N, N-N combined vib)
2939-2875 (CHstr), 1510-1434
(C=N, N-N combined vib)
3.14-3.22 (dd, 1H, C4-HA), 4.03-4.10 (dd, 1H, C4-HB)
5.59-5.65 (dd, 1H, C5-HX), 12.88 (s, 1H, NH
benzimidazole)
3.35-3.47 (dd, 1H, C4-HA), 3.97-4.07 (dd, 1H, C4-HB),
5.31-5.37 (dd, 1H, C5-HX), 10.20 (s, 1H, NH
benzimidazole)
3.33-3.41 (dd, 1H, C4-HA), 4.01-4.11 (dd, 1H, C4-HB),
5.38-5.44 (dd, 1H, C5-HX), 12.35 (s, 1H, NH
benzimidazole)
3.46-3.52 (dd, 1H, C4-HA), 4.01-4.05 (dd, 1H, C4-HB),
5.05-5.10 dd, 1H, C5Hx), 7.028.20(m, 9H, Ar), 7.30 (s, 2H,
NH2), 12.3 (s, 1H, NH benzimidazole)
3.40-3.50 (dd, 1H, C4-HA), 3.84-3.99 (dd, 1H, C4- HB),
5.99-6.02 (dd, 1H, C5HX), 7.78 (s, 2H, NH2, 11.83 (s, 1H,
NH benzimidazole)
3.40-3.52 (dd, 1H, C4-HA), 3.92-4.01 (dd, 1H, C4- HB),
5.99-6.02 (dd, 1H, C5-HX), 7.11-7.71 (m, 6H, Ar), 7.30 (s,
2H, NH2), 12.37 (s, 1H, benzimidazole)
3.29-3.36 (dd, 1H, C4-HA), 3.83-3.93 (dd, 1H, C4- HB),
5.46-5.51 (dd, 1H, C5-HX), 8.90 (s, 1H, CHO),
3.263.34(dd, 1H, CHA), 3.063.95(dd, 1H, C4-HB),
5.435.49(dd, 1H, C5HX), 8.93 (s, 1H, CHO),
3.26-3.34 (dd, 1H, C4-HA), 3.85-3.95 (dd, 1H, C4-HB),
5.44-5.49 (dd, 1H, C5-HX), 8.84 (s, 1H, CHO)
3.30-3.38 (dd, 1H, C4-HA), 3.88- 3.98 (dd, 1H, C4-HB),
5.39-5.45 (dd, 1H, C5-Hx), 8.80 (s, 1H, CHO)
Compd
5c
5d
4a
4c
4e
4f
H NMR (CDCl3, δ ppm)
368M+(80), 369M+1(100),
261(50)
372M+(85), 373M+1(100),
261(20)
322M+1(90), 321(60)
382M+1(60), 381M+(60),
289(40)
412M+1(90), 411M+ (45),
378(40)
291M+1 (100), 290M+
(79) 237(25)
351M+1(100), 350M+(70),
297(25)
326M+1(100), 325M+(80),
237(25)
334M+1(100), 333M+ (60)
992
INDIAN J. CHEM., SEC B, JULY 2010
General Procedure
MWI Process
Synthesis of 1-phenyl-3-benzimidazolyl-5-aryl-2pyrazolines, 3a-f
Compound (2a-f; 0.01mole) and phenyl hydrazine
(0.012 mole) were mixed thoroughly to form an
intimate mixture. It was then subjected to microwave
irradiation at 300 watt power for 4-6 min. After
completion of reaction as indicated by TLC, the
reaction-mixture was cooled to RT and extracted with
ethanol. The solid separated on standing was filtered
and crystallized from benzene, petroleum ether to get
analytical sample of 3a-f.
Synthesis of 3-benzimidazolyl-5-aryl-2-pyrazolinyl-1-carboxaldehydes, 4a-f
An intimate mixture of compound (2a-f; 0.01
mole) hydrazine hydrate (0.015 mole) and formic acid
(15 mL) was subjected to MWI for 4-6 min at 240
watt power. After completion of reaction the
separated solid was washed thoroughly with water,
dried and crystallized from benzene-ethyl acetate to
get analytical sample of 4a-f.
Synthesis of-1-thiocarbamido-3-benzimidazolyl-5aryl-pyrazolines, 5a-f
An intimate mixture of compound (2a-f; 0.01
mole), thiosemicarbazides (0.015 mole) and anhydrous K2CO3 (4 g) was subjected to MWI at 300 watt
for 3-5 min. After completion of reaction the reactionmixture after cooling at RT, was extracted with water
and filtered. The residue obtained was washed again
with water and dried. It was crystallized from ethanol
to get analytical sample of 5a-f.
Table III ― Biological screening results of compounds 3 and 4
(Zone of inhibition in mm)
Compd
K. pneumonae E. coli P. aeruginosa B. subtilis
12
14
10
12
3a
10
12
11
11
3b
14
13
12
10
3c
12
11
10
3d
08
10
10
08
3e
12
16
14
3f
16
18
12
12
4a
13
16
10
11
4b
15
17
14
12
4c
14
19
12
09
4d
11
17
14
09
4e
20
23
12
24
Ciproflaxange
std.drug
Synthesis of 3-benzymidazolyl-5-aryl-2-pyrazolinyl-1-carboxaldehyde, 4a-f
Compound (2a-f; 0.01 mole) was taken in formic
acid (50 mL). To it, hydrazine hydrate (0.015 mole)
was added. The reaction-mixture was refluxed for
about 6 hr and then left overnight at RT. The
separated solid was filtered, washed with water and
crystallized to get analyzed sample of 4a-f.
Synthesis of 1-thiocarbamido-3-benzimidazolyl-5aryl-2-pyrazolines, 5a-f
Compound (2a-f; 0.01mole) was dissolved in dry
benzene (50 mL). To it, thiosemicarbazide (0.015
mole) and anhydrous. K2CO3 (4 g) was added. The
reaction-mixture was refluxed for about 7-8 hr. It was
then left at RT. The solid separated was filtered,
washed with little benzene, dried and crystallized to
get analytical sample of 5a-f.
Conventional Process
Antibacterial activity
Synthesis of 1-phenyl-3-benimidazolyl-5-aryl-2pyrazoline, 3a-f
The newly prepared pyrazoline derivatives were
screened for their antibacterial activity using paper
disc method in vitro against E. coli, K. pneumonae B.
subtilis and P. aeruginosa at a maximum
concentration 250 ppm. The results were compared
with standard drug ciproflaxange. All the compounds
were found to possess moderate to good
activity against gram +ve and gram –ve strains.
(Table III)
Compound (2a-f; 0.01 mole) and phenyl hydrazine
(0.012 mole) were dissolved in absolute alcohol and
reaction-mixture was refluxed for 6-8 hr on water
bath. After cooling at RT the solid separated out was
filtered, dried and crystallized to get analytical sample
3a-f.
NOTES
Acknowledgement
Authors are grateful to Dr. B. L. Verma (Retd.
Prof, M L S University, Udaipur) for guidance,
encouragement and useful discussions.
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