Development of new multicomponent reactions for 1,3,4-oxadiazole synthesis

Thesis

Chapter 1 introduces the chemistry of 1,3,4-oxadiazoles with a specific focus on currently available strategies, and methodologies for their synthesis. Five distinct synthetic approaches – 1) dehydration of 1,2-diacylhydrazines; 2) oxidative cyclizations of N-acyl hydrazones; 3) C-H functionalization of 2-substituted 1,3,4-oxadiazoles; 4) rearrangements of N-H tetrazoles; 5) reactions using (N-isocyanoimino)triphenylphosphorane (NIITP) as a three atom CNN source – are discussed in detail and their limitations evaluated.

Chapter 2 focuses on a novel three-component reaction for the reductive synthesis of α-amino 1,3,4-oxadiazoles (or heterodiazoles), from tertiary amides and lactams, feedstock carboxylic acids (or appropriate C-, S-, N-Brønsted acids), and NIITP. Taking advantage of the mild and chemoselective reductive activation of tertiary amides provided by the combination of Vaska’s complex and 1,1,3,3-tetramethyldisiloxane (TMDS) the reaction was applied to the late-stage functionalization of ten drug-like amides and carboxylic acids and culminated in the synthesis of three heterodiazole-fused drug-drug conjugates.

Chapter 3 demonstrates that N-carbamoyl imines, with carboxylic acid (or N-acyl sulfonamide) coupling partners and NIITP, can efficiently generate N-carbamoyl α-amino 1,3,4-oxadiazole (or 1,2,4-triazole) structures in a three-component reaction – expanding the existing scope of C=N electrophiles used with NIITP. A successful scale-up of this methodology allowed the gram-scale synthesis of a primary α-amino 1,3,4-oxadiazole, and a subsequent investigation into its derivatization.

Chapter 4 presents the merger of two modern approaches for 1,3,4-oxadiazole synthesis – 2-substituted 1,3,4-oxadiazole construction using NIITP and the C-H functionalization of 2-substituted 1,3,4-oxadiazoles – into a one-pot and multicomponent protocol for synthesis of 2,5-disubstituted, or 2-amino-5-substituted, 1,3,4-oxadiazoles. A preliminary investigation into the use of nucleophilic secondary amine coupling partners for synthesis of 2-amino-5-substituted 1,3,4-oxadiazoles is additionally discussed.

Authors: Matheau-Raven, D

• DOI: 10.5287/ora-ppgnqmpnm
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: 3; organic chemistry; 4-oxadiazole; 1; multicomponent reactions
• Subjects: Organic Chemistry