Mild and General One-Pot Reduction and Cyclization of Aromatic and Heteroaromatic 2-Nitroamines to Bicyclic 2H-Imidazoles

Abstract

A one-pot procedure for the conversion of aromatic and heteroaromatic 2-nitroamines into bicyclic 2H-benzimidazoles is described. The procedure employs formic acid, iron powder, and an additive such as NH₄Cl to reduce the nitro group and effect the imidazole cyclization with high-yielding conversions generally within one to two hours. The compatibility with a wide range of functionality demonstrates the general utility of this procedure.

Key words

cyclization - heterocycles - imidazole - iron - reduction

References and Notes

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8

The role of the alcohol co-solvent in this reaction is to increase solubilization of the substrate and may be omitted for substrates with good solubility in neat formic acid (unpublished observation).

9

If the reaction is followed by LC-MS at shorter time intervals, the progression from starting material to bisaniline to N-formylated aniline to cyclized product can typically be observed.

10

Analytical Data for Compounds 2-19
1-Ethyl-1 H -benzo[ d ]imidazole ^¹6 (2) ESI-MS: m/z = 147.4 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 8.23 (s, 1 H), 7.62 (dd, J = 18.0, 7.9 Hz, 2 H), 7.22 (dt, J = 15.0, 7.2 Hz, 2 H), 4.28 (q, J = 7.3 Hz, 2 H), 1.41 (t, J = 7.3 Hz, 3 H).
1-Phenyl-1 H -benzo[ d ]imidazole ^¹7 (3)
ESI-MS: m/z = 195.4 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 8.56 (s, 1 H), 7.78 (dd, J = 6.5, 2.3 Hz, 1 H), 7.69 (dd, J = 8.4, 1.1 Hz, 2 H), 7.67-7.60 (m, 3 H), 7.51 (t, J = 7.2 Hz, 1 H), 7.38-7.28 (m, 2 H).
N , N -Dimethyl-1 H -benzo[ d ]imidazol-6-amine (4)
ESI-MS: m/z = 162.4 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 12.0 (br s, 1 H), 7.96 (s, 1 H), 7.40 (br s, 1 H), 6.78 (d, J = 7.9 Hz, 2 H), 2.88 (s, 6 H).
5-Ethoxy-1 H -benzo[ d ]imidazole ^¹8 (5) ESI-MS: m/z = 163.0 [M + H]⁺. ^¹H NMR (400 MHz, DMSO, reported as a mixture of tautomers): δ = 12.25 (br s, 0.4 H), 12.20 (br s, 0.6 H), 8.10 (br s, 0.4 H), 8.04 (br s, 0.6 H), 7.49 (br d, J = 8.8 Hz, 0.6 H), 7.38 (br d, J = 8.2 Hz, 0.4 H), 7.14 (br s, 0.4 H), 6.98 (br s, 0.6 H), 6.83-6.77 (m, 1 H), 4.03 (q, J = 6.9 Hz, 2 H), 1.34 (t, J = 6.9 Hz, 3 H).
1 H -Benzo[ d ]imidazole-5-carbonitrile ^¹9 (6)
ESI-MS: m/z = 144.4 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 12.96 (s, 1 H), 8.47 (s, 1 H), 8.16 (s, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.59 (d, J = 8.1 Hz, 1 H).
5-Chloro-1 H -benzo[ d ]imidazole ^²0 (7) ESI-MS: m/z = 152.9 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 12.60 (s, 1 H), 8.27 (s, 1 H), 7.62 (m, 2 H), 7.22 (d, J = 7.7 Hz, 1 H).
4-Chloro-1 H -benzo[ d ]imidazole ^²¹ (8)
ESI-MS: m/z = 153.4 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 8.31 (s, 1 H), 7.55 (d, J = 7.9 Hz, 1 H), 7.30-7.05 (m, 2 H).
5-Iodo-1 H -benzo[ d ]imidazole ^²² (9)
ESI-MS: m/z = 244.9 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 12.52 (br s, 1 H), 8.19 (s, 1 H), 7.95 (s, 1 H), 7.47 (dd, J = 8.4, 1.4 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 1 H).
Methyl 1 H -Benzo[ d ]imidazole-7-carboxylate ^²³ (10)
ESI-MS: m/z = 177.3 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 12.56 (s, 1 H), 8.31 (s, 1 H), 7.97 (d, J = 8.0 Hz, 1 H), 7.86 (d, J = 7.6 Hz, 1 H), 7.32 (t, J = 7.8 Hz, 1 H), 3.95 (s, 3 H).
1 H -Benzo[ d ]imidazol-5-ol ^²4 (11)
ESI-MS: m/z = 135.4 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 12.21 (br s, 1 H), 9.08 (s, 1 H), 8.03 (s, 1 H), 7.37 (d, J = 8.6 Hz, 1 H), 6.87 (s, 1 H), 6.68 (d, J = 8.5 Hz, 1 H).
5-(Allyloxy)-1 H -benzo[ d ]imidazole (12)
ESI-MS: m/z = 175.4 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 12.25 (s, 1 H), 8.08 (s, 1 H), 7.45 (s, 1 H), 7.08 (s, 1 H), 6.83 (dd, J = 8.7, 2.0 Hz, 1 H), 6.07 (ddt, J = 17.2, 10.5, 5.2 Hz, 1 H), 5.41 (ddd, J = 17.3, 3.4, 1.6 Hz, 1 H), 5.26 (dd, J = 10.5, 1.5 Hz, 1 H), 4.61-4.54 (m, 2 H).
5-(Triisopropylsilyloxy)-1 H -benzo[ d ]imidazole (13)
ESI-MS: m/z = 291.4 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 12.17 (s, 1 H), 8.09 (s, 1 H), 7.43 (s, 1 H), 6.99 (s, 1 H), 6.76 (d, J = 8.9 Hz, 1 H), 1.25 (dd, J = 14.9, 7.2 Hz, 3 H), 1.07 (d, J = 7.4 Hz, 18 H).
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -benzo[ d ]imidazole (14)
ESI-MS: m/z = 245.4 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 12.48 (s, 1 H), 8.24 (s, 1 H), 7.90 (s, 1 H), 7.57 (s, 1 H), 7.50 (d, 1 H), 1.31 (s, 12 H).
3 H -Imidazo[4,5- f ]quinoline ^²5 (15)
ESI-MS: m/z = 169.9 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 13.51 (br s, 0.5 H), 12.94 (br s, 0.5 H), 8.86-8.85 (m, 1 H), 8.78 (br s, 1 H), 8.38 (br s, 1 H), 7.97 (br d, J = 7.8 Hz, 1 H), 7.81 (d, J = 8.9 Hz, 1 H), 7.61 (dd, J = 8.3, 4.3 Hz, 1 H).
3-{1 H -Benzo[ d ]imidazol-5-yl}-3 H -imidazo[4,5- b ]pyridine (16)
ESI-MS: m/z = 250.2 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 12.72 (s, 1 H), 8.83 (s, 1 H), 8.36 (s, 1 H), 8.28 (s, 1 H), 8.13 (s, 1 H), 8.02 (s, 1 H), 7.85-7.60 (m, 2 H), 2.46 (s, 3 H).
6-Bromo-7-methyl-3 H -imidazo[4,5- b ]pyridine ^²6 (17)
ESI-MS: m/z = 211.9 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 8.42 (s, 1 H), 8.40 (s, 1 H), 2.60 (s, 3 H).
6-Phenyl-1 H -imidazo[4,5- c ]pyridine (18)
ESI-MS: m/z = 196.3 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 9.00 (s, 1 H), 8.40 (s, 1 H), 8.16-8.06 (m, 3 H), 7.53-7.43 (m, 2 H), 7.43-7.34 (m, 1 H).
6-Chloro-1 H -imidazo[4,5- c ]pyridine ^²7 (19)
ESI-MS: m/z = 153.8 [M + H]⁺. ^¹H NMR (400 MHz, DMSO): δ = 8.74 (s, 1 H), 8.45 (s, 1 H), 7.67 (s, 1 H).