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Green Chemistry
evaporation. The crude product was adsorbed on silica gel (230-400, 500
mg) and purified by flash chromatography (hexane:EtOAc, 90:10) to
70 obtain analytically pure product (364 mg, 92%).
Acknowledgement
Financial support as SRF (DNK and RC) and RA (DK) received
from CSIR, New Delhi, India.
Typical procedure for the synthesis of 1,2-disubstituted
benzimidazole 6a by tandem reduction-condensation process of N-
benzyl-2-nitroaniline 3a with benzaldehyde 5a in the presence of
In/HCl in water at 100 °C: To the mixture of N-benzyl-2-nitroaniline 3a
75 (456 mg, 2 mmol) in water (4 mL) was added In ( 574 mg, 5 mmol, 2.5
equiv), HCl (5 mL 2 N aq HCl, 10 mmol, 5 equiv) and stirred
magnetically at 100 °C (oil-bath) for 0.5 h (TLC). Benzaldehyde 5a (212
mg, 2 mmol, 1 equiv) was added and the stirring was continued for
another 30 min. The reaction mixture was cooled to rt and treated with
80 NaHCO3 (140 mg) and extracted with EtOAc (2 × 5 mL). The combined
EtOAc extracts were washed with water (5 mL), dried (MgSO4), and
concentrated under rotary vacuum evaporation. The crude product was
adsorbed on silica gel (230-400, 500 mg) and purified by flash
chromatography (hexane-EtOAc, 85:15) to obtain analytically pure 6a as
Notes and references
5
aDepartment of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S.
Nagar 160 062, Punjab, India. E-mail: akchakraborti@niper.ac.in
† Electronic Supplementary Information (ESI) available: [Spectral data
and scanned NMR spectra]. See DOI: 10.1039/b000000x/
10 ‡ Experimental section: The glassware to be used in reactions was
thoroughly washed and dried in an oven and the experiments were carried
out with required precautions. Chemicals and all solvents were
commercially available and used without further purification. H and 13C
1
NMR spectra were recorded on a 400 MHz NMR spectrometer in CDCl3
15 with residual undeuterated solvent (CDCl3 : 7.26/77.0) using Me3SiCl as
an internal standard. Chemical shifts () are given in ppm and J values are
given in Hz. 13C NMR spectra were fully decoupled and were referenced
to the middle peak of the solvent CDCl3 at 77.00 ppm. Splitting pattern
were designated as s, singlet; bs, broad singlet; d, doublet; dd, doublet of
20 doublet; t, triplet; m, multiplet. Mass spectra were recorded under APCI
mode of ionisation. Accurate mass measurements were performed on a Q-
TOF instrument calibrated internall with sodium formate. Infra-red (IR)
spectra were recorded in the range 4000-600 cm-1 either as neat for liquid
or KBr pellets for solid samples. Purity compounds were checked on the
25 silica gel GF-254 under UV at 254 nm. Melting points were measured
using melting point apparatus and were uncorrected. Evaporation of
solvents was performed at reduced pressure, using a rotary vacuum
evaporator.
Typical procedure for the selective N-mono-benzylation. N-
30 Phenylmethyl-2-nitroaniline (3a) (Entry 1, Table 3): The mixture of o-
nitroaniline 1a (276 mg, 2 mmol) and benzyl bromide 2a (407 mg, 2.4
mmol, 1.2 equiv) in water (4 mL) was stirred magnetically at 100 °C (oil-
bath) for 1.5 h (TLC). The reaction mixture was cooled to rt and treated
with NaHCO3 (170 mg) and extracted with EtOAc (2 × 5 mL). The
35 combined EtOAc extracts were washed with water (5 mL), dried
(MgSO4) and concentrated under rotary vacuum evaporation. The crude
product was adsorbed on silica gel (230-400, 500 mg) and purified by
flash chromatography (hexane:EtOAc, 90:10) to obtain analytically pure
°
85 a white solid (528 mg, 93%). mp = 131-132 C; IR (Neat) ν: 3030, 2949,
1608, 1464, 1453, 1365, 1255, 1162 cm-1; 1H NMR (DMSO, 400 MHz) δ:
7.91-7.89 (m, 1H), 7.73-7.72 (m, 2H), 7.71-7.70 (m, 3H), 7.54-7.45 (m,
3H), 7.38-7.23 (m, 3H), 7.13 (d, J = 7.68 Hz, 2H), 5.49 (s, 2H); MS
(+pAPCI) m/z: 285.3 (MH+), identical with those of an authentic
90 compound. 15
Typical procedure for the synthesis of 1,2-disubstituted
benzimidazole 6a by tandem reduction-condensation of N-benzyl-2-
nitroaniline 3a and benzaldehyde 5a in presence of In/HCl in water at
rt: To the mixture of N-benzyl-2-nitroaniline 3a (456 mg, 2 mmol) in
95 water (4 mL) was added In ( 574 mg, 5 mmol, 2.5 equiv), HCl (5 mL 2 N
aq HCl, 10 mmol, 5 equiv) and stirred magnetically at rt for 3 h (TLC).
Benzaldehyde 5a (212 mg, 2 mmol, 1 equiv) was added and the stirring
was continued for another 1 h. The reaction mixture was treated with
NaHCO3 (140 mg) and extracted with EtOAc (2 × 5 mL). The combined
100 EtOAc extracts were washed with water (5 mL), dried (MgSO4), and
concentrated under rotary vacuum evaporation. The crude product was
adsorbed on silica gel (230-400, 500 mg) and purified by flash
chromatography (hexane-EtOAc, 85:15) to obtain analytically pure 6a as
white solid (522 mg, 92%).
105 Typical procedure for the synthesis of 1,2-disubstituted
benzimidazole 6a by tandem reduction-condensation of N-benzyl-2-
nitroaniline 3a and benzaldehyde 4a in the presence of In/HOAc at
100 °C: The mixture of N-benzyl-2-nitroaniline 3a (456 mg, 2 mmol) and
In (574 mg, 5 mmol, 2.5 equiv), HOAc (0.6 mL, 10 mmol, 5 equiv) was
110 stirred magnetically at 100 °C (oil-bath) for 0.5 h (TLC). Benzaldehyde
5a (212 mg, 2 mmol, 1 equiv) was added and the stirring was continued
for another 30 min. The reaction mixture was cooled to rt and treated with
NaHCO3 (140 mg) and extracted with EtOAc (2 × 5 mL). The combined
EtOAc extracts were washed with water (5 mL), dried (MgSO4), and
115 concentrated under rotary vacuum evaporation. The crude product was
adsorbed on silica gel (230-400, 500 mg) and purified by flash
chromatography (hexane-EtOAc, 85:15) to obtain analytically pure 6a as
white solid (85 mg, 15%).
Typical procedure for tandem N-alkylation-reduction-condensation
120 process for the synthesis of 1,2-disubstituted benzimidazole (1-
Benzyl-2-phenyl-1H-benzimidazole (6a); Entry 1, Table 5): The
mixture of o-nitroaniline 1a (276 mg, 2 mmol) and benzyl bromide 2a
(407 mg, 2.4 mmol, 1.2 equiv) in water (4 mL) was stirred magnetically
at 100 °C (oil-bath) for 1.5 h (TLC) followed by addition of In ( 574 mg,
125 5 mmol, 2.5 equiv), HCl (5 mL 2N aq HCl, 10 mmol, 5 equiv) and
continued stirring for further 30 min. Benzaldehyde 5a (212 mg, 2 mmol,
1 equiv) was added and the stirring was continued for another 30 min.
The reaction mixture was cooled to room temperature and treated with
NaHCO3 (140 mg) and extracted with EtOAc (2 × 5 mL). The combined
130 EtOAc extracts were washed with water (5 mL), dried (MgSO4), and
concentrated under rotary vacuum evaporation. The crude product was
adsorbed on silica gel (230-400, 500 mg) and purified by flash
chromatography (hexane-EtOAc, 85:15) to obtain analytically pure 6a as
white solid (511 mg, 90%).
°
3a (437 mg, 96%); Red solid; mp = 74-76 C; IR (Neat) ν: 3435, 2940,
40 1618, 1573, 1510, 1350, 1262, 1152 cm-1; 1H NMR (CDCl3, 400 MHz) δ:
8.42 (brs, 1H), 8.19-8.17 (m, 1H), 7.54-7.16 (m, 6H), 6.80 (d, J = 8.60
Hz, 1H), 6.67-6.63 (m, 1H), 4.53 (d, J = 5.64 Hz, 2H); 13C NMR (CDCl3,
100 MHz) δ: 145.3, 137.4, 136.3, 132.2, 128.9, 127.7, 127.1, 126.9,
115.7, 114.2, 47.1; MS (+pAPCI) m/z: 229.5 (MH+), identical with those
45 of an authentic compound.14
Typical procedure for the synthesis of N1-benzylbenzene-1,2-diamine
(4a) at 100 °C: To the mixture of N-benzyl-2-nitroaniline 3a (456 mg, 2
mmol) in water (4 mL) was added In ( 574 mg, 5 mmol, 2.5 equiv), HCl
(5 mL 2N aq HCl, 10 mmol, 5 equiv) and stirred magnetically at 100 °C
50 (oil-bath) for 0.5 h (TLC). The reaction mixture was cooled to room
temperature, treated with NaHCO3 (170 mg), and extracted with EtOAc
(2 × 5 mL). The combined EtOAc extracts were washed with water (5
mL), dried (MgSO4) and concentrated under rotary vacuum evaporation.
The crude product was adsorbed on silica gel (230-400, 500 mg) and
55 purified by flash chromatography (hexane:EtOAc, 90:10) to obtain
analytically pure 4a (376 mg, 95%); Low melting solid; 1H NMR (400
MHz, 25 °C, CDCl3): δ = 7.21-7.45 (m, 5 H; Ar-H), 6.79 (t, J = 7.2 Hz,
1H; Ar-H), 6.65-6.72 (m, 3 H; Ar-H), 4.29 (s, 2 H; CH2), 3.39 (bd, s, 3 H,
NH); MS (+pAPCI) m/z: 199.4 (MH+), identical with those of an
60 authentic compound.13
Typical procedure for the synthesis of N1-benzylbenzene-1,2-diamine
at rt: To the mixture of N-benzyl-2-nitroaniline 3a (456 mg, 2 mmol) in
water (4 mL) was added In ( 574 mg, 5 mmol, 2.5 equiv), HCl (5 mL 2 N
aq HCl, 10 mmol, 5 equiv) and stirred magnetically at rt for 3 h (TLC).
65 The reaction mixture was treated with NaHCO3 (170 mg) and extracted
with EtOAc (2 × 5 mL). The combined EtOAc extracts were washed with
water (5 mL), dried (MgSO4), and concentrated under rotary vacuum
135
1
Angiotensin II receptor antagonist: Y. Kohara, K. Kubo, E.
Imamiya, T. Wada, Y. Inada and T. Naka, J. Med. Chem. 1996, 39,
5228; Neuropeptide Y Y1 receptor antagonist: H. Zarrinmayeh, A.
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