Ammonia → 4,4-difluoro-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4'',6'-diamine

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Reaction Steps

6′-Bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 27, 116 mg, 0.30 mmol), trans-4-hydroxy-L-proline (40 mg, 0.30 mmol), copper(I) iodide (29 mg, 0.15 mmol) and K2CO3 (126 mg, 0.91 mmol) were mixed in dry dimethylsulfoxide (3 mL) in a microwave vial. The mixture was stirred under argon at r.t. for 30 min. Ammonia (30-33% in H2O) (0.285 mL, 4.55 mmol) was added, the vial was sealed and heated at 110° C. for 3 h in a microwave synthesizer. Additional copper(I) iodide (29 mg, 0.15 mmol) and trans-4-hydroxy-L-proline (40 mg, 0.30 mmol) were added and the mixture was then heated to 110° C. for 4 h. The mixture was diluted with EtOAc (10 mL) and washed with brine (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined and concentrated in vacuo. The residue was applied on a short column of silica (4 g SiO2) and eluted with 0-100% (7 M NH3 in MeOH and DCM 1:9) in DCM to give the title compound (46 mg, 48% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (t, 1 H), 1.48 (br. s., 2 H), 1.64-1.96 (m, 5 H), 2.11-2.17 (m, 3 H), 2.83 (d, 1 H), 2.90 (d, 1 H), 4.75 (s, 2 H), 5.83 (d, 1 H), 6.37 (dd, 1 H), 6.50 (s, 2 H), 6.90 (d, 1 H); MS (ES+) m/z 319.1 [M+H]+.

Provenance & Evidence