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Issue 4, 2017
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A convergent synthesis of 1,3,4-oxadiazoles from acyl hydrazides under semiaqueous conditions

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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 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 building blocks of oxadiazole-substituted secondary amines is improved by leveraging chiral α-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.

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

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Publication details

The article was received on 13 Jan 2017, accepted on 16 Feb 2017 and first published on 23 Feb 2017


Article type: Edge Article
DOI: 10.1039/C7SC00195A
Citation: Chem. Sci., 2017,8, 3187-3191
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    A convergent synthesis of 1,3,4-oxadiazoles from acyl hydrazides under semiaqueous conditions

    K. Tokumaru and J. N. Johnston, Chem. Sci., 2017, 8, 3187
    DOI: 10.1039/C7SC00195A

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