1,4-Addition of an aryllithium reagent to diethyl ketomalonate. Scalable synthesis of ethyl 1-(hydroxymethyl)-1,3-dihydroisobenzofuran-1-carboxylate |
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Authors: | Benjamin N Rocke Edward L ConnShane A Eisenbeis Roger B Ruggeri |
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Institution: | Pfizer Worldwide Research and Development, Eastern Point Rd., Groton, CT 06340, USA |
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Abstract: | While optimizing the synthesis of pharmaceutical building block 3 ethyl 1-(hydroxymethyl)-1,3-dihydroisobenzofuran-1-carboxylate], we encountered an unusual addition of an aryllithium reagent to the ketone oxygen atom of diethyl ketomalonate. Compound 3 was ultimately prepared on a large scale by a two-step sequence involving (1) annulation of a functionalized Grignard reagent with diethyl ketomalonate and (2) selective mono-reduction of a geminal diester using lithium tri-tert-butoxyaluminum hydride. |
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Keywords: | Directed ortho metalation 1 4-Addition Annulation Mono-reduction Diethyl ketomalonate |
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