1,2-Dimethoxyethane → tert-butyl 4-(8-carbamoyl-6-(1-methyl-1H-indazol-5-yl)-9H-carbazol-2-yl)piperazine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

A 20 ml microwave vial was loaded with tert-butyl 4-(6-bromo-8-carbamoyl-9H-carbazol-2-yl)piperazine-1-carboxylate (0.49 g, 0.518 mmol), 1-methyl-1H-indazol-5-ylboronic acid (0.255 g, 1.377 mmol), DME (15 mL), PdCl2(dppf)-CH2Cl2 adduct (40 mg, 0.049 mmol) and Na2CO3 (2M) (1.55 mL, 3.10 mmol). The vial was sealed, flushed with nitrogen for 15 minutes, then heated to 100° C. for 2 hours. LCMS showed partial conversion of bromide starting material. 1-Methyl-1H-indazol-5-ylboronic acid (0.115 g, 0.621 mmol), PdCl2(dppf)-CH2Cl2 adduct (30 mg, 0.037 mmol) and Na2CO3 (2M) (1.0 mL, 2.0 mmol) were added and heating continued for 4 hours at 100° C. The reaction mixture was poured into a separating funnel that is loaded with 100 ml water+25 ml sat. aq. NH4Cl solution and extracted with EtOAc (2×). The organic layers were washed once with dilute NaHCO3 solution, then brine, then dried over MgSO4+3 g SILICYCLE® thiol resin [to capture Pd and ferrocene] overnight. Filtration and evaporation to dryness gave the crude product, which was purified by chromatography on silica. (Gradient from 100% dichloromethane to 50% DCM+50% EtOAc (85 fractions a 12 ml, fractions A), then gradient from 50% DCM+50% EtOAc to 40% DCM+40% EtOAc+20% MeOH (85 fractions a 12 ml, fractions B). Product containing fractions (B20-B27) were combined and evaporated to dryness to give 168 mg tert-butyl 4-(8-carbamoyl-6-(1-methyl-1H-indazol-5-yl)-9H-carbazol-2-yl)piperazine-1-carboxylate. Estimated purity ˜50% (contains significant amount of 1-methyl-1H-indazol-5-ylboronic acid). MS (ESI) m/e+=525.

Provenance & Evidence