A convergent synthesis of 1, 3, 4-oxadiazoles from acyl hydrazides under semiaqueous conditions. Issue 4 (23rd February 2017)

• Record Type: Journal Article
• Authors: Tokumaru, Kazuyuki; Johnston, Jeffrey N.
• Is Part Of: Chemical science. Volume 8:Issue 4(2017)
• Page Start: 3187
• Page End: 3191
• Publication Date: 2017-02-23
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c7sc00195a
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : An innovative new synthesis approach to disubstituted 1, 3, 4-oxadiazoles is described, inspired by Umpolung Amide Synthesis (UmAS). 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.