Applying the conformational bias of amides to the synthesis of triarylmethanes, difluoromethyl arenes and medium-sized rings

Chapter 1 — Triarylmethanes by the Truce–Smiles rearrangement of benzanilidesThe triarylmethane (TRAM) motif can be found embedded within the structures of compounds with applications across diverse fields, rendering methods to construct TRAMs of significant value. In Chapter 1, we present a new approach to TRAM synthesis, employing the intramolecular nucleophilic aromatic substitution, or Truce–Smiles rearrangement, of readily accessible 2-benzylbenzanilide precursors. In contrast to classical rearrangements of this kind, the reaction succeeds without electronic activation of the arene that serves as electrophile, with rate acceleration instead provided by the conformational preference of an amide tether within the substrate. Access to TRAM products of varied structure was achieved, with the methodology allowing for independent modification of each of the three aromatic rings. It was demonstrated that the amide function of the reaction products can be removed or used as a functional handle in further transformations. Mechanistic investigation by in situ infrared spectroscopy, a deuterium exchange study and Hammett analysis suggest the reaction proceeds through a partially concerted aryl migration. In addition, a ring-expanding version of the rearrangement provided access to novel TRAM-containing medium ring lactams. On account of the broad tolerance of steric and electronic parameters tolerated for each of the three (hetero)aromatic rings, this methodology is expected to be an attractive approach to TRAM derivatives that are important within various areas of science.Chapter 2 — Difluoromethyl arenes by the monodefluorination of trifluoromethyl arenesAs a consequence of being an unusual hydrogen bond donor, and a potential bioisostere for a range of functionalities, the difluoromethyl group has attracted much interest amongst designers of pharmaceutical and crop protection agents. In addition, it has emerged as an appealing substitute for the trifluoromethyl group, whose inclusion in industrial products is thought to be having unforeseen negative impacts on the environment. Hence, the defluorination of trifluoromethylated precursors to valuable difluoromethylated products is an intriguing prospect. In Chapter 2, we describe the realisation of this transformation by designing a four-step protocol that employs an amide-based auxiliary to selectively delete one fluorine atom from the CF3 group of widely available trifluoromethylated benzaldehydes. Diversely substituted CF2H-containing products could be obtained, including building blocks relevant to medicinal and agrochemical discovery, which highlights the utility and practicality of the method for industrial application. The defluorination of other polyfluoroalkyl groups could also be effected by the method. By probing the defluorination reaction using in situ infrared spectroscopy, and deuterium studies that allowed for measurement of a primary kinetic isotope effect, a viable mechanism was proposed, which includes loss of fluoride by a rate-limiting elimination reaction. We anticipate this is a timely discovery of a highly applicable entry into CF2H-functionalised arenes that allows for direct replacement of trifluoromethylated intermediates within industrial settings.Chapter 3 — Medium-sized rings by the migratory ring expansion of alkenesOwing to their characteristic conformational properties, medium-sized rings are favourable scaffolds for exploration within drug and agrochemical discovery. However, these conformational properties are often a double-edged sword, precluding medium ring formation by the cyclisation of an acyclic precursor. This remains a considerable barrier to the inclusion of medium-sized rings in screening libraries or novel compound designs. The strategy of ring expansion has recently been fruitful for unlocking methods that access medium ring products. In Chapter 3, we describe investigations into employing a ring expansion strategy towards the synthesis of medium-sized rings by the conformationally-enhanced migration of alkenes. This is both an enticing and ambitious endeavour, which could offer a route to enlarged cyclic frameworks with diverse structure. An amide linkage between a 1-phenylethyl anion-stabilising group and a migrating alkene provided the conformational bias to promote vinyl transfer, generating sterically congested olefin products. Although reactivity was unfortunately limited to this specific system, some degree of structural variation was attainable through a carbolithiation–vinyl migration cascade of a related amide-containing substrate. Significantly, the availability of common-sized heterocycles could be leveraged to rapidly access ring expansion precursors from pyridine. Furthermore, progress has been made towards elucidating the mechanism of unactivated vinyl migration processes by identification of a candidate system for a kinetic isotope effect study.</div

Selective Defluorination of Trifluoromethyl Substituents by Conformationally Induced Remote Substitution

The selective reduction of an aromatictrifluoromethyl substituent to a difluoromethyl substitu-ent may be achieved by base-promoted elimination toform a difluoro-p-quinomethide which is trapped by anintramolecular nucleophile. High yields are obtainedwhen the nucleophilic trap entails the conformationallyfavoured cyclisation of an aminoisobutyric acid (Aib)derivative. The resulting cyclised difluoromethyl-substi-tuted arylimidazolidinone products are readily con-verted to versatile difluoromethyl-substituted aldehydesby reduction and hydrolysis. Defluorination is successfulon a range of benzenoid (both para and ortho CF3-substituted) and heterocyclic substrates. Double de-fluorination may likewise be achieved sequentially, or ina single step, from an Aib dipeptide derivative