Batch and continuous flow C-H functionalisation of azoles

Abstract

This thesis describes the development of novel heterobenzylic, organometallic mediated C-H functionalisation methodologies of alkylazoles under batch and continuous flow conditions. Chapter 2 outlines the study of lithiation-substitution of unprotected alkyltetrazoles. Although the double lithiation of unprotected alkyltetrazoles was found to be impractical for use in synthesis, unprotected benzyltetrazoles underwent effective double lithiation to give functionalised products in high yields after electrophilic trapping. Chapter 3 details the development of lithiation-substitution protocols for N-cumyl protected alkyltetrazoles. Two complementary sets of optimised conditions were identified in batch as well as continuous flow conditions (identified through the use of thermal imaging), which can be carried out at room temperature with high productivity. Enantioselective lithiationsubstitutions of N-cumyl protected alkyltetrazoles were also investigated. Chapter 4 describes the development of metalation-substitution protocols for alkyl-1,3,4- oxadiazoles. Optimal lithiation-substitution conditions were found to be at –30 °C in batch. The unstable lithiated oxadiazole intermediate could also be trapped efficiently at room temperature by adopting the flash chemistry approach under continuous flow conditions. The structure of lithiated oxadiazoles in solution was also studied via VT in situ NMR to gain insights into the reason behind the lack enantioselectivity when chiral lithium complexes were employed for the lithiation-substitution.