A new tandem coupling approach to synthesize 2-alkynyl indoles and benzofurans is described. This reaction utilizes easily accessible gem-dibromovinyl substrates and terminal alkynes and proceeds via Pd/C- and CuI-catalyzed tandem Ullman/Sonogashira couplings.
To a flask containing a solution of 2-nitrobenzaldehyde (1.51g, 10 mmol) and CBr4 (4.97 g, 15 mmol) in DCM (50 mL) at 0 °C was added dropwise a solution of PPh3 (7.86 g, 30 mmol) in DCM (15 mL). Then the mixture was stirred for another 0.5 h, warmed to room temperature, and stirred for an additional 0.5 h. Next, diethyl ether (50 mL) was added to the reaction mixture, which was then filtered through a short plug of Celite and washed with diethyl ether (10 mL). The filtrates were concentrated under vacuum, and EtOH (50 mL) and SnCl2 (13.3 g, 70 mmol) were added to the crude product. The suspension was then placed into a preheated oil bath with stirring at 100 °C for 1 h. Upon completion of the reaction as monitored by TLC, the reaction flask was allowed to cool to room temperature. After most of the ethanol was removed under vacuum, H2O (30 mL) and EtOAc (30 mL) were added to the residue. Solid K2CO3 was carefully added to the resulting mixture until pH was above 10. The EtOAc layer was separated from the heterogeneous mixture, and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and then dried over anhydrous Na2SO4. The solvent was evaporated under vacuum, and the crude product was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (5:1) as the eluent to give 2-(2,2-dibromovinyl)-aniline (III) (2.3 g, 83% over two steps) as a white solid (mp 41−42°C).
To a tube equipped with a magnetic stir bar were added 2-(2,2-dibromovinyl)aniline (III) (277 mg, 1 mmol), Pd(OAc)2 (11.2 mg,0.05 mmol), P(t-Bu)3·HBF4 (17.4 mg, 0.06 mmol), and K2CO3 (276 mg, 2 mmol). The tube was flushed with nitrogen three times, after which toluene (3 mL) was added and the tube was sealed. The mixture in the tube was stirred at room temperature for 5 min, and then the tube was placed into a preheated oil bath at 100 °C. After 14 h of stirring, the reaction tube was allowed to cool to room temperature. Then the reaction was quenched with H2O, and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and then dried over anhydrous Na2SO4. The solvent was evaporated under vacuum, and the crude product was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (5:1) as the eluent to give 2-bromoindole (IX) (166 mg, 85%) as a white solid。
Org. Lett. 2007, 9, 15, 2955–2958