Biphenyl derivatives of imidazo[1,2ꢀa]benzimidazole Russ. Chem. Bull., Int. Ed., Vol. 66, No. 10, October, 2017 1909
and 7.69 (both d, 1 H each, H(5), H(6), J = 9.5 Hz, J = 8.5 Hz,
respectively); 7.81 (d, 2 H, H(γ), J = 7.8 Hz); 7.96 (d, 2 H,
H(β), J = 8.2 Hz); 8.17 (d, 2 H, H(α), J = 8.2 Hz); 8.88 (br.s,
2 H, N+H2).
and are promising for extended pharmacological studies
of the antioxidant, PTP1Bꢀinhibitory, AMPKꢀactivating
and antiplatelet activities. However, the level of the effiꢀ
ciency observed requires further optimization of their
structures.
Synthesis of 2ꢀ(4ꢀbiphenylꢀ4ꢀyl)ꢀ9Rꢀ9Hꢀimidazo[1,2ꢀa]ꢀ
benzimidazole hydrochlorides (3) (general procedure). A mixture
of bromide 2 (10 mmol), finely powdered Na2CO3 (2 g), ethanol
(100 mL), and water (20 mL) was heated until the reaction
reached completion (15—20 h). Then, the solvent was evapoꢀ
rated. Water (30 mL) was added to the residue, a precipitate
was collected by filtration, washed with water, and dried in air.
The resulting base was purified by either recrystallization, or
chromatography. Then, it was converted to hydrochloride upon
treatment with concentrated HCl.
2ꢀ(Biphenylꢀ4ꢀyl)ꢀ9ꢀmethylꢀ9Hꢀimidazo[1,2ꢀa]benzimidꢀ
azole hydrochloride (3a). The yield was 95%, m.p. 244—245 °C
(from ethanol). IR, ν/cm–1: 1513, 1616 (C=C), 1663 (C=N).
Found (%): C, 73.31; H, 5.13; Cl, 9.83; N, 11.59.
C22H17N3•HCl. Calculated (%): C, 73.42; H, 5.04; Cl, 9.86;
N, 11.68. 1H NMR (DMSOꢀd6), δ: 4.02 (s, 3 H, Me);
7.34—7.60 (m, 5 H, H(δ), H(ε), H(6), H(7)); 7.75 (d, 2 H,
H(γ), J = 7.9 Hz); 7.79 (d, 1 H, H(8), J = 8.4 Hz); 7.84 (d, 2 H,
H(β), J = 8.4 Hz); 7.98 (d, 1 H, H(5), J = 8.1 Hz); 8.03 (d, 2 H,
H(α), J = 8.4 Hz); 8.66 (s, 1 H, N+H).
2ꢀ(Biphenylꢀ4ꢀyl)ꢀ9ꢀethylꢀ9Hꢀimidazo[1,2ꢀa]benzimidazole
hydrochloride (3b). The yield was 95%, m.p. 231 °C (from ethanol).
IR, ν/cm–1: 1512, 1614 (C=C), 1663 (C=N). Found (%):
C, 73.74; H, 5.48; Cl, 9.46; N, 11.15. C23H19N3•HCl. Calcuꢀ
lated (%): C, 73.83; H 5.39; Cl, 9.54; N, 11.24. 1H NMR
(DMSOꢀd6), δ: 1.33 (t, 3 H, CH2CH3, J = 7.1 Hz); 4.59 (q, 2 H,
CH2CH3, J = 7.2 Hz); 7.30, 7.37, 7.46 (all t, 1 H each, H(4),
H(7), H(ε), J = 7.6 Hz, J = 7.3 Hz, J = 7.2 Hz, respectively);
7.54 (t, 2 H, H(δ), J = 7.2 Hz); 7.64 and 7.69 (both d, 1 H each,
H(5), H(6), J = 9.5 Hz, J = 8.5 Hz, respectively); 7.81 (d, 2 H,
H(γ), J = 7.8 Hz); 7.96 (d, 2 H, H(β), J =8.2 Hz); 8.17 (d, 2 H,
H(α), J = 8.2 Hz); 8.88 (br.s, 2 H, N+H2).
2ꢀ(Biphenylꢀ4ꢀyl)ꢀ9ꢀbutylꢀ9Hꢀimidazo[1,2ꢀa]benzimidazole
hydrochloride (3c). The yield was 93%, m.p. 211—213 °C (from
ethanol). IR, ν/cm–1: 1512, 1614 (C=C), 1663 (C=N). Found (%):
C, 74.62; H, 6.10; Cl, 8.75, N, 10.34. C25H23N3•HCl. Calcuꢀ
lated (%): C, 74.70; H, 6.02; Cl, 8.83, N, 10.45. 1H NMR
(DMSOꢀd6), δ: 0.93 (t, 3 H, Me, J = 7.4 Hz); 1.31—1.50 (m, 2 H,
MeCH2); 1.89 (q, 2 H, NCH2CH2, J = 7.5 Hz); 3.50 (br.s, 1 H,
N+H, overlaps with the signal of H2O); 4.48 (t, 2 H, NCH2,
J = 7.0 Hz); 7.34—7.58 (m, 5 H, H(6), H(7), H(δ), H(ε)); 7.76
(d, 2 H, H(γ), J = 8.3 Hz); 7.80—7.89 and 7.95—8.06 (both m,
3 H each, H(α), H(β), H(5), H(8)); 8.64 (s, 1 H, H(3)).
2ꢀ(Biphenylꢀ4ꢀyl)ꢀ9ꢀ[2ꢀ(diethylamino)ethyl]ꢀ9Hꢀimidazoꢀ
[1,2ꢀa]benzimidazole hydrochloride (3d). The yield was 94%,
m.p. 203—204 °C (from ethanol). IR, ν/cm–1: 1512, 1614
(C=C), 1663 (C=N). Found (%): C, 72.78; H, 6.65; Cl, 7.88;
N, 12.56. C27H28N4•HCl. Calculated (%): C, 72.87; H, 6.57;
Cl, 7.97; N, 12.59. 1H NMR (DMSOꢀd6), δ: 1.27 (t, 6 H, 2 Me,
J = 7.0 Hz); 3.34 (d, 4 H, CCH2, J = 6.0 Hz); 3.69 (br.t, 2 H,
Et2NCH2); 4.97 (t, 2 H, NHetCH2, J = 6.0 Hz); 7.35—7.57 (m,
5 H, H(5), H(6), H(7), H(8), H(ε)); 7.75 (d, 2 H, H(γ), J = 7.8 Hz);
7.82 (d, 2 H, H(β), J = 7.9 Hz); 7.97 (t, 2 H, H(δ), J = 7.1 Hz);
8.06 (d, 2 H, H(α), J = 8.1 Hz); 8.62 (s, 1 H, H(3)); 10.71
(br.s, 1 H, N+H).
Experimental
IR spectra (ν/cm–1) of compounds obtained were recorded
on a Varian Excalibur 3100 FTꢀIR spectrophotometer (Varian,
USA) using the method of attenuated total reflection in powꢀ
der; 1H NMR spectra were recorded on Varian Unityꢀ300 (Varian,
USA) and Bruker Avance 600 N (USA) spectrometers. Chemical
shifts for 1H are given relative the signals of residual protons of
a deuterated solvent (DMSOꢀd6 and CDCl3, δ 2.49 and 7.24,
respectively). Melting points were measured on a FisherꢀJohns
Melting Point Apparatus (Fisher Scientific, USA). Elemental
analysis was carried out using a classical method.19 Reaction
progress and purity of synthesized compounds were monitored
by TLC (plates with Al2O3 III degree of activity, eluent CHCl3,
visualization with iodine vapors in a moist chamber).
4ꢀAcetylbiphenyl used in the work was purchased from Alfa
Aesar (United Kingdom). The starting 1ꢀalkylꢀ and 1ꢀdialkylꢀ
aminoalkylꢀ2ꢀaminobenzimidazoles 1 were synthesized by
Nꢀalkylation of 2ꢀaminobenzimidazole with the corresponding
alkyl halides or 2ꢀdialkylaminoalkyl chlorides in the system
acetone—KOH.20 2ꢀAminobenzimidazole was obtained by alꢀ
kaline hydrolysis of methyl Nꢀ(benzimidazoleꢀ2ꢀyl)carbamate
(technical grade).21 4ꢀ(Bromoacetyl)biphenyl was synthesized
by bromination of 4ꢀacetylbiphenyl with bromine in a mixture
of diethyl ether—dioxane according to a modified procedure.14
Synthesis of 2ꢀaminoꢀ3ꢀ[(2ꢀbiphenylꢀ4ꢀyl)ꢀ2ꢀoxoethyl)]ꢀ1ꢀ
Rꢀ1Hꢀbenzimidazolium bromides
2 (general procedure).
4ꢀ(Bromoacetyl)biphenyl (5 mmol) was added to a refluxing
solution of the corresponding amine 1 (5 mmol) in acetone or
acetonitrile at room temperature. The reaction mixture was
allowed to stand at this temperature for 3—4 h. A precipitate of
hydrobromide was collected by filtration and thoroughly washed
with acetone. The resulting chromatographically pure salt was
dried in air and used in the next step without additional purifiꢀ
cation. The structure of salts 2a,b was confirmed by their conꢀ
version to imidazo[1,2ꢀa]benzimidazoles, as well as by the data
of spectroscopic studies.
2ꢀAminoꢀ3ꢀ[2ꢀ(biphenylꢀ4ꢀyl)ꢀ2ꢀoxoethyl]ꢀ1ꢀmethylꢀ1Hꢀ
benzimidazolium bromide (2a). The yield was 94%, m.p.
253—253.5 °C. IR, ν/cm–1: 3207, 3240 (NH2), 1687 (C=O).
1H NMR (DMSOꢀd6), δ: 3.74 (s, 3 H, Me); 5.99 (s, 2 H,
CH2CO); 7.30, 7.37, 7.46 (all t, 1 H each, H(4), H(7) and
H(ε), J = 7.6 Hz, J = 7.3 Hz, J = 7.2 Hz, respectively); 7.54
(t, 2 H, H(δ), J = 7.2 Hz); 7.64 and 7.69 (both d, 1 H each, H(5),
H(6), J = 9.5 Hz, J = 8.5 Hz, respectively); 7.81 (d, 2 H, H(γ),
J = 7.8 Hz); 7.96 (d, 2 H, H(β), J = 8.2 Hz); 8.17 (d, 2 H, H(α),
J = 8.2 Hz); 8.88 (br.s, 2 H, N+H2).
2ꢀAminoꢀ3ꢀ[2ꢀ(biphenylꢀ4ꢀyl)ꢀ2ꢀoxoethyl]ꢀ1ꢀethylꢀ1Hꢀbenzꢀ
imidazolium bromide (2b). The yield was 92%, m.p. 227—228 °C.
IR, ν/cm–1: 3158, 3205 (NH2), 1688 (C=O). 1H NMR
(DMSOꢀd6), δ: 1.33 (t, 3 H, CH2CH3, J = 7.1 Hz); 4.2 (q, 2 H,
CH2CH3, J = 7.2 Hz); 6.01 (s, 2 H, CH2CO); 7.30, 7.37, 7.46
(all t, 1 H each, H(4), H(7), H(ε), J = 7.6 Hz, J = 7.3 Hz,
J = 7.2 Hz, respectively); 7.54 (t, 2 H, H(δ), J = 7.2 Hz); 7.64
2ꢀ(Biphenylꢀ4ꢀyl)ꢀ9ꢀ[2ꢀ(morpholino)ethyl]ꢀ9Hꢀimidazoꢀ
[1,2ꢀa]benzimidazole hydrochloride (3e). The yield was 92%,