Copper-catalyzed oxidative cyclisation of alkynyl oxetanes

Copper-catalyzed oxidative cyclisation of alkynyl oxetanes

To a dry flask under argon atmosphere were added AlCl3 (1.2 equiv) and dichloromethane (0.75 M compared to arene). The mixture was cooled to 0 °C. Then the acyl chloride (1.1 equiv) was added followed by addition of the arene. The reaction was stirred 30 minutes at 0 °C. The ice bath was removed and the reaction stirred for a total of 16 hours. After cooling to 0 °C, the reaction was slowly quenched with water. The mixture was poured into a separatory funnel containing water and dichloromethane. The phases were separated and the aqueous extracted twice with dichloromethane. The combined organic phases were washed with water and sat. NaHCO3 (aq.), then dried over Magnesium sulfate. The solvent was removed in vacuo and the crude purified by flash chromatography (Diethyl ether in petroleum ether) yielding the ketone. To a dry flask under argon atmosphere were added THF (0.4 M compared to ketone) and TMS- acetylene (1.5 equiv) and the mixture cooled to -78 °C. Then nBuLi (2.5 M in hexanes, 1.5 equiv) was added and the reaction stirred for 30 minutes. To this mixture was slowly added the ketone and the reaction left stirring for 2 hours at -78 °C. The reaction was quenched with sat. NH4Cl (aq.), then allowed to heat to room temperature before it was transferred to a separatory funnel containing water and Diethyl ether. The phases were separated and the aqueous extracted twice with Diethyl ether. The combined organic phases were washed with water and brine, then dried over Magnesium sulfate. The solvents were removed in vacuo and the crude product carried forward without further purification.

A flask containing the alcohol and THF (0.2 M compared to alcohol) was cooled to 0 °C. Then TBAF (1 M in THF, 1.3 equiv) was added and the reaction stirred 1 hour at 0 °C. The reaction mixture was poured into a separatory funnel containing water and Diethyl ether. The phases were separated and the aqueous extracted twice with Diethyl ether. The combined organic phases were washed with To a dry flask were added KH (30% weight dispersion in mineral oil, 2.0 equiv.) and THF (0.1 M compared to alcohol) and the mixture cooled to 0 °C. Then the alcohol was slowly added. The reaction was stirred 10 minutes at 0 °C, then allowed to heat to room temperature. The reaction was stirred for a total of 2 hours after which TLC showed full conversion of the alcohol. The reaction mixture was transferred to a separatory funnel containing water and Diethyl ether. The phases were separated and the aqueous extracted twice with Diethyl ether. The combined organic phases were washed with sat. NaHCO3 (aq.), water, and brine, then dried over Magnesium sulfate. The solvents were removed in vacuo and the crude purified by flash chromatography (Diethyl ether in petroleum ether) yielding the oxetane.

To a dry flask was added the oxetane (0.2 mmol), acetonitrile (0.2 M compared to the oxetane) and 3-bromopyridine oxide (0.4 mmol). Cu(MeCN)4NTf2 (0.004 mmol) was then added and the reaction mixture was heated to reflux (82 °C). The reaction was followed by TLC until no starting material remained. The reaction mixture was then filtered through a silica gel pad which was rinced with ethyl acetate (final volume 10 mL). Solvent was removed in vacuo. NMR analysis of the crude mixture gave the ratio of oxidised product. 4,5-dihydrofuran-2-carbaldehyde was purified by flash chromatography using petroleum ether:ethyl acetate (90:10) as eluent. To a dry flask was added the oxetane (0.2 mmol), acetonitrile (0.2 M compared to the oxetane) and 4-methoxypyridine oxide (0.4 mmol). Cu(MeCN)4NTf2 (0.004 mmol) was then added and the reaction mixture was heated to reflux (82 °C). The reaction was followed by TLC until no starting material remained. The reaction mixture was then filtered through a silica gel pad which was rinced with ethyl acetate (final volume 10 mL). Solvent was removed in vacuo. NMR analysis of the crude mixture gave the ratio of oxidised product. 4,5-dihydrofuran-2-carbaldehyde was purified by flash chromatography using ethyl acetate : petroleum ether (10 : 90) as eluent.