Dimethyl Sulfoxide → (S)-7-bromo-3-(neopentyloxy)-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine

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Reaction Steps

A vial was charged with 2,2-dimethylpropan-1-ol (100 mg, 1.130 mmol) and DMSO (1130 μL) to give a clear solution. Sodium hydride (60% in mineral oil; 45.2 mg, 1.130 mmol) was added and the vial was placed in a 100° C. oil bath for 5 min, then was removed from the heat and cooled to RT. (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (Intermediate 1B, 86 mg, 0.226 mmol) was added to give an orange solution. The vial was sealed and heated in a 100° C. oil bath for 2 h. The mixture was cooled to room temperature, then diluted with water and EtOAc. Brine was added and the layers were separated. The aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (0-100% EtOAc/Hexane) to give (S)-7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a light-yellow solid. Step 2: A vial was charged with (S)-7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (74.0 mg, 0.171 mmol) 4,4-difluoropiperidine hydrochloride (31.1 mg, 0.257 mmol), and chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butylether adduct (12.02 mg, 0.017 mmol). The vial was flushed with Argon and sealed. Lithium bis(trimethylsilyl)amide (1M in THF) (599 μL, 0.599 mmol) was added in one portion. The resulting mixture was sonicated for 1 min, then stirred for 30 min at rt. The reaction mixture was diluted with saturated aq ammonium chloride solution and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (0-10% MeOH/DCM) to give (S)-7-(4,4-difluoropiperidin-1-yl)-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as an off-white solid. [M+H]+=473.2.

Provenance & Evidence