ALPHA-FLUORINATION OF NITROBENZENES AND NITROPYRIDINES VIA VICARIOUS NUCLEOPHILIC SUBSTITUTION OF HYDROGEN

Abstract

A vicarious nucleophilic substitution reaction involves the nucleophilic substitution of hydrogen on to an electron deficient aromatic ring. This type of C-H activation requires that a β-elimination of the hydrogen and the leaving group attached to the nucleophile occurs in order for the activation to be achieved. The kinetics of these reactions show that the rate of the nucleophilic addition on to either a site containing a hydrogen or a halogen are not influenced by addition of excess base. The β-elimination in the case of the VNS pathway is influenced by excess of base. If the base concentration is high enough, the H-X elimination will be faster than the reversal of the adduct to starting material leading to the exclusive formation of VNS products. VNS reactions have been extensively reported on for the past 40 years. However, utilizing nucleophilic intermediates of this type of reaction have so far been limited to alkylations and arylations in literature. Reacting electrophilic heteroatoms on to these intermediates presented itself as an unexplored area of research, which could prove to be potentially impactful with the right choice of heteroatom. α-fluorination of nitrobenzenes and nitropyridines via a VNS-electrophilic fluorination coupled reaction have been achieved rapidly under mild conditions with the use of selectfluor as the electrophilic fluorinating agent. A wide range of fluorinated aromatic compounds were generated using this protocol, potentially this protocol could be incorporated into the synthesis of pharmaceutically relevant compounds as a means of introducing late stage fluorination which would provide added complexity to these compounds.

Date of Award	1 Aug 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Michael Greaney (Supervisor) & Igor Larrosa (Supervisor)