Formic Acid → 2-Methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline

Participants

Reaction Conditions

Reaction Steps

Formic acid (9.4 mL, 250 mmol) was added dropwise to Ac2O (19 mL, 202 mmol) at 0° C. The solution was stirred at 50° C. for 45 min, then cooled to −18° C., diluted with THF (100 mL) and a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline [(a) Tercel, M.; et al., J. Med. Chem. 1996, 39, 1084-1094; (b) Zhu, Z., et al., J. Med. Chem. 2003, 46, 831-837] (251) (13.8 g, 5.0 mmol) in THF (100 mL) was added and stirred at −15 to −18° C. for 30 min. The solution was warmed to 20° C., the solvent evaporated and the residue partitioned between saturated aqueous NaHCO3 solution (250 mL) and EtOAc (250 mL). The aqueous fraction was extracted with EtOAc (3×250 mL), dried and the solvent evaporated. The residue was dissolved in THF (200 mL), cooled to 10° C. and BH3-DMS solution (10 M, 19.4 mL, 194 mmol) was added. The solution was stirred at 20° C. for 1 h, diluted with MeOH (30 mL) and acidified with HCl solution (1 M, 45 mL). The solution was stirred at 40° C. for 15 min, the solvent evaporated and the residue partitioned between saturated aqueous NaHCO3 solution (250 mL) and EtOAc (250 mL). The aqueous fraction was extracted with EtOAc (3×250 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give isoquinoline 252 (12.6 g, 85%) as an orange solid: 1H NMR δ 8.09 (dd, J=8.4, 2.3 Hz, 1H, H-6), 7.95 (d, J=2.3 Hz, 1H, H-8), 7.37 (d, J=8.4 Hz, 1H, H-5), 4.27 (d, J=16.1 Hz, 1H, H-1), 3.94 (d, J=16.1 Hz, 1H, H-1), 3.23-3.34 (m, 2H, CH2), 2.99-3.18 (m, 2H, CH2), 2.17 (s, 3H, NCH3); MS (APCI) m/z 193 (MH+, 100%).

Provenance & Evidence