Pyrrolidine → N-Boc-7-Fluorospiro[chromene-2,4'-piperidin]-4(3H)-one

Participants

Reaction Conditions

Reaction Steps

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (7.5 g, 37.8 mmol) in pyrrolidine (4.5 mL, 54.1 mmol) and anhydrous methanol (10.2 mL) was added 1-(4-fluoro-2-hydroxy-phenyl)ethanone (5.8 g, 37.6 mmol). The reaction mixture was stirred at 80° C. for 2.5 hours. The methanol was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate (150 mL), washed with 1 N HCl (1×150 mL) and brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. The oil was diluted with hexanes (400 mL) and was heated at 60° C. until in solution. Once dissolved, the solution was allowed to cool to 25° C. The crystals were collected via vacuum filtration, rinsing with hexanes to remove tert-butyl 4-oxo-7-pyrrolidin-1-yl-spiro[chromane-2,4′-piperidine]-1′-carboxylate (8.6 g), which was collected as light yellow solid; ESI-MS m/z calc. 386.2, found 387.2 (M+1)+; Retention time: 2.59 minutes (3 min run). The filtrate was concentrated and the residue was subjected to column chromatography (0-100% ethyl acetate/hexanes) to give tert-butyl 7-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (2.7 g, 21%) as a light yellow solid; ESI-MS m/z calc. 335.2, found 336.2 (M+1)+; Retention time: 2.49 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J=8.6, 6.7 Hz, 1H), 6.80-6.62 (m, 2H), 3.88 (d, J=12.1 Hz, 2H), 3.21 (t, J=12.0 Hz, 2H), 2.71 (s, 2H), 2.02 (d, J=12.8 Hz, 2H), 1.62 (td, J=14.1, 4.8 Hz, 2H), 1.46 (s, 9H).

Provenance & Evidence