Ethylene Oxide → 7-Benzyl-2-oxa-7-azaspiro[4.4]nonan-1-one

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Reaction Steps

A solution of diisopropylamine (6.6 ml, 0.047 mole) in dry ether (100 ml) at -65° C. under nitrogen was treated with 1.6 M n-butyllithium in hexane (26.2 ml, 0.042 mole) and the solution stirred for 15 min, before treating with N,N,N',N'-tetramethylethylenediamine (12.3 ml). After stirring for a further 10 min, the solution was treated dropwise over 10 min with a solution of (±) methyl 1-benzyl-4-pyrrolidylcarboxylate (D17, 7.50 g, 0.034 mole) in dry ether (20 ml) and stirring continued at -65° C. for 15 min. Ethylene oxide (3.1 g, 0.070 mole) was then bubbled into the solution over 20 min and the mixture was allowed to warm to room temperature over 2 h followed by 40 min at reflux. The reaction mixture was treated with saturated sodium hydrogen carbonate solution (50 ml) and extracted with ether (3×100 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave an orange oil. The unreacted starting material was removed by heating under reflux in 8 M hydrochloric acid (50 ml) for 2 h, followed by basifying to saturation with sodium hydrogen carbonate and extraction with ether. The organic extract was dried (Na2SO4) and concentrated in vacuo to leave an orange oil, which was distilled in a Kugelrohr apparatus (b.p. 190° C.-210° C./0.2-0.5 mmHg) followed by column chromatography on silica gel eluting with ether, to give the title compound (D18) as a pale yellow oil (2.50 g, 36%).

Provenance & Evidence