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In methanol; 5,5-dimethyl-1,3-cyclohexadiene for 4.33333h; Reflux;
1.2 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester
To a solution of NaOMe (35 mL, 4.37M in MeOH) and 70 mL of MeOH cooled at -20 °C was added a solution of 6-chloro-pyridine-3-carbaldehyde (10.9 g, 77 mmol) and azido- acetic acid methyl ester (22 g, 192.5 mmol) in 40 mL of MeOH dropwise over 10 min with a mechanical overhead stirrer. The resulting solution was stirred at 0 °C for 5 h and the cloudymixture with light yellow solid was poured into 500 g of ice with stirring and the solid was collected by filtration, dried under vacuum to give 13 g of the intermediate. The intermediate was dissolved in 200 mL of xylene and added dropwise over 20 min into 100 mL of boiling xylene. The mixture was refluxed for additional 4 h and concentrated. The residue was swished from 50 mL of 1 : 1 EtOAc/hexane to give 2.6 g of the desired product. NMR shows ~30% regioismeric indole (6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester) present.
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 16h;
Step 1. To a solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (3.00 g, 14.2 mmol) and cyclopropylmethyl bromide (2.1 mL, 21 mmol) in DMF (50 mL) was added sodium hydride (0.444 g, 18.5 mmol). The mixture was stirred at rt for 16 h and was then quenched by addition of sat NaHCO3 soln. The mixture was diluted with water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were washed successively with sat NaHCO3 soln and brine, dried (Na2SO4), filtered, and concentrated to give crude methyl 6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, which was taken on without purification. ES/MS: m/z 265.2 [M+H]+.
With [2,2]bipyridinyl; copper (II) acetate; anhydrous sodium carbonate In 1,2-dichloro-ethane at 80℃; for 19h;
Step 1. To a mixture of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.510 g, 2.42 mmol), 2,2’-bipyridyl (0.408 g, 2.61 mmol, cupric acetate (0.460 g, 2.53 mmol) and sodium carbonate (0.555 g, 5.24 mmol) in DCE (13 mL) was added cyclopropylboronic acid (0.24 mL, 5.06 mmol). The mixture was stirred at 80 °C for 3 h, at which point 0.1 equiv, each, of all reagents were added. The mixture was stirred at 80 °C for 16 h and was then cooled to rt and diluted with water. The mixture was extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified via flash column chromatography on silica gel to yield methyl 6-chloro-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate. ES/MS: m/z 251.0 [M+H]+.
With [2,2]bipyridinyl; copper (II) acetate; anhydrous sodium carbonate In 1,2-dichloro-ethane at 80℃; for 19h;
Step 1. To a mixture of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.510 g, 2.42 mmol), 2,2’-bipyridyl (0.408 g, 2.61 mmol, cupric acetate (0.460 g, 2.53 mmol) and sodium carbonate (0.555 g, 5.24 mmol) in DCE (13 mL) was added cyclopropylboronic acid (0.24 mL, 5.06 mmol). The mixture was stirred at 80 °C for 3 h, at which point 0.1 equiv, each, of all reagents were added. The mixture was stirred at 80 °C for 16 h and was then cooled to rt and diluted with water. The mixture was extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified via flash column chromatography on silica gel to yield methyl 6-chloro-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate. ES/MS: m/z 251.0 [M+H]+.
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