Benzofuran → 5-Chloro-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran

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Reaction Steps

Schema 7 illustrates the synthesis of an amino substituted 2,3-dihydro-2-alkoxycarbonyl-2-alkylbenzofuran, for example, 7-amino-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran by the cyclization of 5-chloro-2-hydroxybenzaldehyde with an alkyl 2-chloropropionate, for example, ethyl 2-chloropropionate, under basic conditions in N,N-dimethylformamide at 60°-70° C., affording the corresponding 5-chloro-2-ethoxycarbonyl-2,3-dihydro-3-hydroxy-2-methylbenzofuran (XXVII). The so-prepared benzofuran is chlorinated with thionyl chloride in the presence of pyridine in methylene chloride at 0°-10° C., then dechlorinated by treatment with hydrogen in the presence of 10% palladium on carbon in ethanol, yielding the corresponding 3-unsubstituted intermediate 5-chloro-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran (XXX). The 3-unsubstituted benzofuran is in turn nitrated with 90% nitric acid and concentrated sulfuric acid at 10°-16° C., affording 5-chloro-2-ethoxycarbonyl-2,3-dihydro-2-methyl-7-nitrobenzofuran (XXXI), which is then hydrogenated in the presence of 10% palladium on carbon in ethanol, affording the free amine intermediate 7-amino-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran ((XXXII). The so-prepared intermediate is optionally halogenated with, for example, N-bromosuccinimide in N,N-dimethylformamide, affording the corresponding 7-amino-4-bromo-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran (XXXIII) intermediate.

Provenance & Evidence