Benzophenone imine → 4-(6-Amino-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester

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Reaction Steps

Combine 4-(6-chloro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (preparation 57, 2.256 g, 7.2 mmol), benzophenone imine (1.568 g, 8.6 mmol), BINAP (269 mg, 0.43 mmol), Pd2(dba)3 (132 mg, 0.144 mmol), sodium t-butoxide (969 mg, 10.08 mmol) and toluene (50 mL) and heat at 95° C. for 12 hr. Quench the reaction with saturated NaHCO3 solution, extract with ethyl acetate three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Dissolve the residue in methanol (70 mL), add sodium acetate (1.42 g, 17.3 mmol) and hydroxylamine hydrochloride (900 mg, 13 mmol), stir at room temperature for 30 min. Partition between 1N NaOH and CH2Cl2, extract the aqueous layer twice with CH2Cl2. Combine the organic layers and wash with saturated NaCl solution, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel, eluting with 12-25% ethyl acetate in hexanes) provides 2.06 g (98%) of the title compound as a yellow solid: mass spectrum (ion spray): 294.1 (M+1); 1H NMR (CDCl3, ppm): 7.35 (t, 1H), 6.08 (d, 1H), 6.06 (d, 1H), 5.09 (m, 1H), 4.32 (s, br, 2H), 3.75 (m, 2H), 3.29 (m, 2H), 1.94 (m, 2H), 1.73 (m, 2H), 1.49 (s, 9H).

Provenance & Evidence