Synthesis of Cyclopropaneacetylene by a One Pot Process

Utility Precursor for the Preparation of HIV Reverse Transcriptase (Note I) 

A solution of bromine (31.5 mmol) dissolved in 20 ml acetonitrile was cooled to — 15°C and hexaethylphosphorous triamide (34.1 mmol) added at such a rate the temperature was kept below 10°C. When the addition was completed sodium azide (34.2 mmol) was added and the resulting suspension allowed to warm to ambient temperature over 2 hours. The mixture was re-cooled to — 15°C and dimethyl-2-oxopropyl phosphate (28.6 mmol) and DBU (0.65 mmol) added. The solids were filtered off after 45 minutes, washed with acetonitrile, cyclopropanecarboxaldehyde (24.5 mmol) dissolved in 200 ml methyl alcohol containing K2CO3 (57.8 mmol) added, and the mixture stirred at ambient temperature 16 hours. The mixture was cooled to 0°C, diluted with 250 ml ice-cold water, and the product extracted 3 times with 30 ml n-octane. The extracts were combined, dried, and the product isolated in 73% yield. 

The reverse HIV transcriptase inhibitor is (—)-6-chloro-4-cyclopropyl-enthynyl-4-trifluoromethyl-l,4-dihydro-2H-3,l-benzoxanzin-2-one. 

Two reaction intermediates were generated neither of which were isolated. The first, azi-dotris(diethylamino)phosphonium bromide, (Et2N)3P+N3Br , was formed by the reaction of hexaethyl phosphorous triamide, bromine and sodium azide. It has also been prepared starting with phosphorous trichloride (1). The second reaction intermediate, dimethyl /3-keto-o -diazo phosphate (I), is the base catalysis product of azidotris(diethylamino)-phosphonium bromide and dimethyl-2-oxopropyl phosphate. 

In a separate experiment, the author reports that when azidotris (diethylamino)phospho-nium bromide was isolated and purified before adding to dimethyl-2-oxopropyl phosphate, the yield of cyclopropaneacetylene was increased to 95%. 

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