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A convergent synthesis of 1,3,4-oxadiazoles from acyl hydrazides under semiaqueous conditions.

ABSTRACT: The 1,3,4-oxadiazole is an aromatic heterocycle valued for its low-lipophilicity in drug development. Substituents at the 2- and/or 5-positions can modulate the heterocycle's electronic and hydrogen bond-accepting capability, while exploiting its use as a carbonyl bioisostere. A new approach to 1,3,4-oxadiazoles is described wherein ?-bromo nitroalkanes are coupled to acyl hydrazides to deliver the 2,5-disubstituted oxadiazole directly, avoiding a 1,2-diacyl hydrazide intermediate. Access to new building blocks of oxadiazole-substituted secondary amines is improved by leveraging chiral ?-bromo nitroalkane or amino acid hydrazide substrates. The non-dehydrative conditions for oxadiazole synthesis are particularly notable, in contrast to alternatives reliant on highly oxophilic reagents to effect cyclization of unsymmetrical 1,2-diacyl hydrazides. The mild conditions are punctuated by the straightforward removal of co-products by a standard aqueous wash.

SUBMITTER: Tokumaru K

PROVIDER: S-EPMC5414388 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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A convergent synthesis of 1,3,4-oxadiazoles from acyl hydrazides under semiaqueous conditions.

Tokumaru Kazuyuki K Johnston Jeffrey N JN

Chemical science 20170223 4

The 1,3,4-oxadiazole is an aromatic heterocycle valued for its low-lipophilicity in drug development. Substituents at the 2- and/or 5-positions can modulate the heterocycle's electronic and hydrogen bond-accepting capability, while exploiting its use as a carbonyl bioisostere. A new approach to 1,3,4-oxadiazoles is described wherein α-bromo nitroalkanes are coupled to acyl hydrazides to deliver the 2,5-disubstituted oxadiazole directly, avoiding a 1,2-diacyl hydrazide intermediate. Access to new ...[more]

PMID: 28507694

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