2-Chloro-4-(trifluoromethyl)pyridine → (1S,4S)-tert-butyl 5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Participants

Reaction Conditions

Reaction Steps

A 2.0-5.0 mL microwave vial was charged with (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (200 mg, 1.01 mmol), rac-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (62.8 mg, 0.10 mmol), Sodium tert-butoxide (116 mg, 1.21 mmol), 2-Chloro-4-(trifluoromethyl)pyridine (0.156 mL, 1.21 mmol) and a mixture of toluene (2.5 mL) and DMF (.5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (46.2 mg, 0.05 mmol) was added. The reaction mixture was stirred at 105°C in an oil bath 12h. The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was loaded on a 24g silica gel column and purified on a Teledyne Isco instrument, eluting with 10% to 40% ethyl acetate in heptane to provide (1S,4S)-tert-butyl 5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (254 mg, 73.3 %) as a solid. 1H NMR (400MHz ,CHLOROFORM-d) d 8.26 (d, J = 5.5 Hz, 1 H), 6.75 (d, J = 5.1 Hz, 1 H), 6.48 (s, 1 H), 4.99 - 4.83 (m, 1 H), 4.76 - 4.52 (m, 1 H), 3.56 (t, J = 8.4 Hz, 1 H), 3.49 - 3.32 (m, 3 H), 2.04 - 1.91 (m, 2 H), 1.45 (d, J = 18.0 Hz, 9 H); MS m/z 344.2 [M+H]+ (ESI).

Provenance & Evidence