Potassium Carbonate → tert-butyl 2-[(1R)-5-pyrimidin-2-yl-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate

Participants

Reaction Conditions

Reaction Steps

To an oven-dried round-bottomed flask was added tert-butyl 2-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (3-1a, 267 mg, 0.63 mmol), anhydrous dioxane (9 mL), bis(pinacolato)diboron (177 mg, 0.69 mmol) and potassium acetate (249 mg, 2.53 mmol). The resulting mixture was purged with nitrogen for 15 minutes. Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added and the reaction mixture was purged with nitrogen for an additional 15 minutes. The reaction was heated under nitrogen at 110° C. for 5 hours. After consumption of the starting material (as monitored by TLC), the reaction was cooled to room temperature and 2-chloro-pyrimidine (71.0 mg, 0.63 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol) and aqueous K2CO3 solution (2M, 2.25 mL, de-oxygenated with nitrogen for 15 minutes prior to addition) were added. The reaction was purged with nitrogen (3×) and heated under nitrogen for 20 hours at 110° C. The reaction was cooled to room temperature and was filtered through a short plug of silica gel, eluting with methanol. The solvents were removed in vacuo and the residue was partitioned between 50 mL of ethyl acetate and 50 mL of 1N NaOH solution. The layers were separated and the organic layer was washed with 50 mL of brine. The organic layer was dried (Na2SO4) and concentrated to give the crude product as a black semi-solid. The crude product was purified by column chromatography using a Combiflash ISCO purification system (Teledyne Isco Inc., Lincoln, Nebr.) system, eluting with 0-10% MeOH in CH2Cl2 to give the title compound as a black gum (208 mg, 78%). MS (ES+) 421.2 (M+H)+. 1H NMR (CDCl3) δ 1.39 (s, 9H), 1.59-1.69 (m, 4H), 1.75-1.94 (m, 1H), 2.12 (dq, 1H), 2.76-2.92 (m, 1H), 2.95-3.18 (m, 5H), 3.19-3.36 (m, 4H), 3.92 (dd, 1H), 7.09 (t, 1H), 7.33 (d, 1H), 8.18-8.26 (m, 2H), 8.71 (d, 2H).

Provenance & Evidence