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

Chemical Science
Kazuyuki Tokumaru, Jeffrey N Johnston

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.

References

Oct 3, 2008·Chemical Communications : Chem Comm·Gonzalo BlayJosé R Pedro
Jun 26, 2010·Nature·Bo ShenJeffrey N Johnston
Dec 3, 2010·Angewandte Chemie·Tsuyoshi TaniguchiHiroyuki Ishibashi
Dec 21, 2011·Proceedings of the National Academy of Sciences of the United States of America·Jessica P ShacklefordJeffrey N Johnston
Dec 22, 2011·Journal of Medicinal Chemistry·Jonas BoströmAlleyn T Plowright
Sep 13, 2012·Journal of the American Chemical Society·Matthew W LeightyJeffrey N Johnston
Jul 8, 2010·ACS Medicinal Chemistry Letters·Yves DucharmeRichard W Friesen
Apr 4, 2015·Chemical Science·Kenneth E Schwieter, Jeffrey N Johnston
Nov 23, 2016·Nature Chemistry·John R FrostAndrei K Yudin
Jan 1, 2016·Organic Syntheses; an Annual Publication of Satisfactory Methods for the Preparation of Organic Chemicals·Victoria T LimJeffrey N Johnston

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Methods Mentioned

BETA
amidation

Software Mentioned

UmAS

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