Tris(1,1-dimethylethyl)phosphine → 1-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indol-5-amine

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Reaction Steps

Compound 84 (73 mg, 0.2287 mmol), tris(dibenzylideneacetone)dipalladium (0) (20.9 mg, 0.0229 mmol) and anhydrous tetrahydrofuran (10 mL) were charged to a dry argon purged flask fitted with magnetic stir bar and condenser. A solution of tri-tert-butylphosphine (10 wt % in hexane, 92.5 mg, 0.0457 mmol) is added followed by dropwise addition of a 1M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (0.686 ml, 0.686 mmol) and mixture refluxed for a period of 90 minutes. The mixture was cooled to room temperature then to 0° C., quenched with 1M HCl (10 mL) and stirred for 15 minutes. The solution was diluted with ethyl acetate and conc. NH4OH added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated to yield crude. The crude amine was combined with a second crude from an identical reaction and the residue purified via chromatography on silica gel (EtOAc:methanol:Et3N, 8:1:1) to yield a brown solid 85 (52 mg, 37.6%) as a 5:1 or 1:5 mixture of endo/exo stereoisomers. 1H NMR (major isomer-DMSO-d6) δ 1.53-1.70 (m, 4H), 2.00-2.09 (m, 2H), 2.18 (s, 3H), 3.17-3.32 (m, 2H), 4.54 (quintuplet, 1H, J=8.2 Hz), 6.11 (d, 1H, J=3.1 Hz), 6.49 (dd, 1H, J=8.6, 2.1 Hz), 6.65 (d, 1H, J=1.9 Hz), 7.05 (d, 1H, J=8.7 Hz), 7.26 (d, 1H, J=3.2 Hz); ESI-MS (m/z, %): 256 (MH+, 100%).

Provenance & Evidence