| 70% |
Stage #1: 2-methyl-1H-pyrrole With trichlorophosphate In N,N-dimethyl-formamide at 0 - 20℃; for 3h;
Stage #2: potassium formate In water; N,N-dimethyl-formamide at 0 - 105℃; for 3h; Inert atmosphere; |
5.11.8 General procedure H for the synthesis of compounds 35b-35x
General procedure: A mixture of 30 (4.06g, 50mmol) in anhydrous DMF (60mL) was stirred at 0°C, the solution was added dropwise POCl3 (9.32mL, 100mmol). The mixture was stirred at ambient temperature for 3h. Then the mixture was added dropwise 5M KOAc (24.54g, 250mmol) solution at 0°C, and the solution was stirred at 105°C under nitrogen for 3h. After cooling, the mixture was poured into water and was extracted with ethyl acetate (100mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (10-30% EtOAc/petroleum ether) to yield 31 (yield, 70%) as a brown solid. (0145) A mixture of AlCl3 (12g, 90mmol) in anhydrous dichloromethane (60mL) was stirred at 0°C, the solution was added dropwise acetyl chloride (3.2mL, 45mmol). Then the mixture was added compound 31 (3.27g, 30mmol) in four batches at 0°C, and the solution was stirred at ambient temperature for another 4h. The reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with saturated NH4Cl (100mL) and was extracted with dichloromethane (100mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (10-20% EtOAc/petroleum ether) to yield 32 (yield, 71%) as a white solid. (0146) A mixture of compound 32 (3.02g, 20mmol) in tetrahydrofuran (30mL) was stirred at 0°C, the solution was added NBS (4.27g, 24mmol). The mixture was stirred at ambient temperature for 5h. Then the reaction was partitioned between water and ethyl acetate, the aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed, eluting with a gradient of 5-20% EtOAc/petroleum ether to afford compound 33 (2.1g, yield, 46%) as a brown solid. (0147) A mixture of 34f, 34i - 34s, 34u - 35x (20mmol), pentane-2,4-dione (23.6mmol), NaOAc (120mmol) in EtOH (20mL) and H2O (20mL) was degassed under a stream of nitrogen. The resulting brown solution was heated at 85°C for about 3h. After cooling, the mixture was poured into water and was extracted with ethyl acetate (150mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (10-30% EtOAc/petroleum ether) to yield 3f, 3i - 3s, 3u - 3x (yield, 68-90%) as a brown solid. (0148) A mixture of 3f, 3i - 3s, 3u - 3x (10mmol) in anhydrous DMF (20mL) was stirred at 0°C, the solution was added dropwise POCl3 (20mmol). The mixture was stirred at ambient temperature for about 3h. Then the mixture was added dropwise 5M KOAc (50mmol) solution at 0°C, and the solution was stirred at 105°C under nitrogen for about 3h. After cooling, the mixture was poured into water and was extracted with ethyl acetate (100mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (10-30% EtOAc/petroleum ether) to yield 5f, 5i - 5s, 5u - 5x (yield, 51-78%) as a brown solid. (0149) A flask was charged with compound 33 (0.28g, 1.2mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.3g, 1.44mmol) or N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.36g, 1.44mmol), PdCl2(dppf) (0.09g, 0.12mmol), K2CO3 (0.83g, 6mmol) and sparged with nitrogen. Degassed dioxane (9mL) and water (3mL) was added and the mixture was heated at 100°C for 4h. The reaction mixture was partitioned between water and ethyl acetate, the aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (gradient elution, 10-30% EtOAc/petroleum ether) to yield 5h and 5t (yield, 77%, 77%) as a brown solid. (0150) A mixture of 5b - 5x (1.2mmol), Na2S2O5 (0.023g, 0.12mmol), 4-(4-methylpiperazin-1-yl)benzene-1,2-diamine (0.25g, 1.2mmol) or 4-morpholinobenzene-1,2-diamine (0.23g, 1.2mmol) in DMF (10mL) was degassed under a stream of nitrogen. The resulting brown solution was heated at 140°C overnight. The cooled reaction was purified by silica gel column chromatography (gradient elution, 2-5% MeOH/dichloromethane) to afford 35b - 35x (yield, 57-71%) as a white solid. (0151) 5-Methyl-1H-pyrrole-2-carbaldehyde (31). Compound 31 was prepared according to general procedure H on a 50mmol scale. Purification by column chromatography (10-30% EtOAc/petroleum ether) afforded the title compound (3.8g, 34.82mmol, 70% yield). [M+ H]+: 110.1. 1H NMR (400MHz, DMSO-d6) δ 11.87 (s, 1H), 9.30 (s, 1H), 7.01-6.72 (m, 1H), 6.10-5.91 (m, 1H), 2.24 (s, 3H). |
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