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

Emily J. Hanan; Bryan K. Chan; Anthony A. Estrada; Daniel G. Shore; Joseph P. Lyssikatos

doi:10.1055/s-0030-1259007

LETTER

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

Emily J. Hanan*, Bryan K. Chan, Anthony A. Estrada, Daniel G. Shore, Joseph P. Lyssikatos
Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
Fax: +1(650)7424943; e-Mail: hanan.emily@gene.com;

Abstract

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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

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References and Notes

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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to increase solubilization of the substrate and may be omitted for substrates with good solubility in neat formic acid (unpublished observation).

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.

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).

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