I encountered a major problem in my research. Currently, we are trying to synthesize ethyl 3-(2-methylpropyl)oxirane-2-carboxylate from isovaleric aldehyde and ethyl chloroacetate using the Darzens reaction. Although the synthesis using sodium hydride in hexane seems to yield only the desired product, it is not convenient for a multigram scale due to the evolving gaseous hydrogen. Thus, through literature we came up with a methodology using solid NaOH with or without the addition of quaternary ammonium salts, with the reaction conducted in THF or acetonitrile. Yet, this route does not go to a single product, as the GC analysis shows a number of compounds in the reaction mixture, with one of the main being the hydrolyzed epoxy acid, and also some aldehyde condensation products. Purification of the epoxy ester via distillation also leads to mixtures, albeit with a much higher content of the desired epoxide. Therefore I have a question. Can anyone suggest me a route towards the desired epoxide which can be applied on a scale of several grams of substrate, which preferably can be conducted in THF, and which yields the epoxy ester with a minimal amount of contaminating byproducts, or perhaps someone knows how to improve the protocols using NaOH or KOH to avoid the hydrolysis of the epoxy ester and minimize condensation? Diastereoselectivity of the process is irrelevant. I know that there is a possibility of synthesis in diethyl ether using sodium ethoxylate, and this will be our next trial, but any alternatives will be helpful. The search for a review article on Darzens reaction protocols gave us the most recent one from the late 70s, and we find it impossible that no one worked with the process since then.

Any help will be appreciated. Thank You all in advance.