Reaction Steps
Nitrogen was slowly bubbled for 5 min through a suspension of 8-bromo-5H-chromeno[3,4-e]pyridine (26 mg, 0.1 mmol), (R)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (116 mg, 0.47 mmol, 4.7 equiv), 5-(di-tert-butylphosphino)-1′,3′,5′-triphenyl-1′H-1,4′-bipyrazole (30 mg, 0.06 mmol, 0.6 equiv), Cs2CO3 (49 mg, 0.15 mmol, 1.5 equiv) and Pd(OAc)2 (7 mg, 0.03 mmol, 0.3 equiv) in toluene (0.5 mL) in a thick glass vial. The vial was capped and then heated at 80° C. for 19 h. The reaction mixture was cooled to ambient temperature and filtered through celite, washing with dichloromethane. The combined filtrate was concentrated under reduced pressure and the residue obtained was purified via silica gel chromatography with EtOAc:DCM (1:4) as the eluant. Fractions containing the desired product (with impurities) were concentrated under reduced pressure to give (R)-2-(1-(5H-chromeno[3,4-c]pyridin-8-yloxy)-4-methylpentan-2-yl)isoindoline-1,3-dione: 1H NMR (500 MHz, CDCl3) δ 8.54 (d, J=5.2 Hz, 1H), 8.37 (s, 1H), 7.89-7.82 (m, 2H), 7.77-7.70 (m, 2H), 7.59 (d, J=8.9 Hz, 1H), 7.41 (d, J=5.5 Hz, 1H), 6.60 (dd, J=8.7, 2.6 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 5.12 (s, 2H), 4.85-4.75 (m, 1H), 4.57 (t, J=9.5 Hz, 1H), 4.18 (dd, J=9.5, 4.9 Hz, 1H), 2.27-2.17 (m, 1H), 1.63-1.54 (m, 2H), 1.00 (d, J=5.8 Hz, 3H), 0.97 (d, J=6.1 Hz, 3H). By proton NMR the mixture was determined to be desired product, reagent and the phosphine oxide derived from the catalyst in an approximately 10:10:3 ratio respectively. Without further purification this mixture was taken to the next step of deprotection of phthalimido group as follows: A solution of (R)-2-(1-(5H-chromeno[3,4-c]pyridin-8-yloxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (44 mg, 0.102 mmol) in ethanol (2 mL) was combined with hydrazine (0.022 mL, 714 mmol) and the solution was stirred at 45° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with diethylether (10 mL) then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Method A). (R)-1-(5H-chromeno[3,4-c]pyridin-8-yloxy)-4-methylpentan-2-amine (23 mg, 0.077 mmol, 43% yield for two steps) was obtained as a pale yellow oil. 1H NMR (500 MHz, CD3OD) δ 8.71-8.57 (m, 2H), 8.24 (d, J=6.4 Hz, 1H), 8.08 (m, 1H), 6.95 (dd, J=8.9, 2.4 Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 5.37 (s, 2H), 4.36 (m, 1H), 4.19 (dd, J=10.5, 6.4 Hz, 1H), 3.78-3.66 (m, 1H), 1.88-1.76 (m, 1H), 1.75-1.60 (m, 2H), 1.09-0.98 (m, 6H); LCMS (Method A) (ESI) m/e 299.2 [(M+H)+, calcd for C18H22N2O2 299.2]; optical rotation: [α]20D (MeOH)=−5.9°.
