Four-Component Synthesis of Indazole through Ugi-Azide Coupling

Abstract

ortho-Nitrobenzaldehyde and trimethylsilyl azide were used in a Ugi-Cadogan cascade towards tetrazolyl indazoles. After the Ugi step, the intermediate tetrazoles were not purified but directly heated with triethyl phosphite to form the final indazoles.

Ugi - tetrazole - phosphite - cadogan - indazole

References and Notes

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General Procedure for the Synthesis of Indazoles: To a 3 M solution of o-nitrobenzaldehyde (1 mmol) in MeOH were added successively amine (1.0 equiv), isocyanide (1.0 equiv) and trimethylsilyl azide (1.0 equiv). The resulting mixture was stirred at r.t. overnight. After removal of the excess MeOH, the crude tetrazole product was used as such for the next step. A 2 M solution of tetrazole (1 mmol) and triethyl phosphite (5.0 equiv) in DMF was heated at 140 ˚C for 10 h. After completion of the reaction, the solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography on silica gel.
3-(1-Cyclohexyl-1 H -tetrazol-5-yl)-2-propyl-2 H -indazole (2a): Prepared on a 1-mmol scale according to the general procedure, 2a was isolated as a yellow solid in 62% yield; mp 110-111 ˚C; R _f 0.3 (petroleum ether-Et₂O, 20:80). ^¹H NMR (400 MHz, CDCl₃): δ = 7.85 (d, J = 8.6 Hz, 1 H), 7.39 (t, J = 7.8 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.23 (t, J = 7.8 Hz, 1 H), 4.48 (t, J = 7.3 Hz, 2 H), 4.19-4.29 (m, 1 H), 2.05-2.18 (m, 2 H), 1.82-2.03 (m, 6 H), 1.63-1.72 (m, 1 H), 1.15-1.33 (m, 3 H), 0.88 (t, J = 7.3 Hz, 3 H). ^¹³C NMR (100.6 MHz, CDCl₃): δ = 148.1, 145.5, 126.5, 124.4, 122.1, 118.7, 117.5, 117.4, 58.7, 53.7, 33.4, 25.1, 24.5, 24.1, 11.0. IR (thin film): 2937, 2857, 1574, 1500, 1454, 1411, 1354, 1095, 1005 cm^-¹. HRMS: m/z calcd for C₁₇H₂₂N₆: 310.1906; found: 310.1901.

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See ref. 8d.