Toluene → 6-(1-Cyclopropylmethyl-piperidin-4-yloxy)-pyridin-2-ylamine

Participants

Reaction Steps

Combine 2-chloro-6-(1-cyclopropylmethyl-piperidin-4-yloxy)-pyridine (preparation 56, 480 mg, 1.80 mmol), benzophenone imine (391 mg, 2.16 mmol), BINAP (67 mg, 0.11 mmol), pd2(dba)3 (33 mg, 0.036 mmol), sodium t-butoxide (242 mg, 2.52 mmol) and toluene (8 mL) and heat at 100° C. for 14 hr. Quench the reaction with saturated NaHCO3 solution, extract with ethyl acetate three times. Combine the organic layers, dry over Na2SO4, filter and concentrate under reduced pressure to give a residue. Dissolve the residue in THF (10 mL), add 5N HCl (1.0 mL) and stir for 30 min. Dilute the mixture with 0.1N HCl solution, extract twice with ethyl acetate-hexanes (1:2). Keep the aqueous layer and adjust pH>11 with 5N NaOH solution, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 7% 2M NH3-methanol in methylene dichloride provides 310 mg (70%) of the title compound as a white solid: mass spectrum (ion spray): m/z=248.1 (M+1); 1H NMR (CDCl3, ppm): 7.23 (t, 1H), 5.95 (pseudo-t, 2H), 4.81 (m, 1H), 4.14 (s, br, 2H), 2.76 (m, 2H), 2.26 (m, 2H), 2.18 (d, 2H), 1.92 (m, 2H), 1.71 (m, 2H), 0.80 (m, 1H), 0.44 (m, 2H), 0.00 (m, 2H).

Provenance & Evidence