Radical-Based Strategies for C-N Bond Formation

Abstract

C-N bonds are ubiquitous in natural products and pharmaceuticals. Chemists engaged in the preparation of pharmaceuticals spend a large share of their time forging C-N bonds in their quest for new therapeutics. Methods which allow accessing new nitrogen-containing building blocks more efficiently therefore attract major attention from synthetic chemists. The exploration of synthetic methods using radicals is currently experiencing a renaissance and offers great potential for simplifying the preparation of nitrogen-containing organic molecules. In this thesis, the development of three different methodologies for C-N bond formation is discussed, combining elements of radical and polar chemistry. Syntheses for three specific compound classes of pharmaceutical interest were developed: alkyl amines (vicinal diamines), cyclic amides (oxindoles) and aromatic nitrogen heterocycles (indoles). The synthesis of differentially substituted diamines requires many steps and their modular preparation from complex olefins is essentially unknown. Using electrophilic nitrogen radicals, olefins were converted to ambiphilic beta-chloroamines in an atom-transfer radical addition (ATRA) chain reaction and further to highly reactive, tetra-substituted aziridinium ions which undergo ring-opening with amine nucleophiles. Both reactions are completely regioselective and the development of this approach now allows introducing two different, substituted alkyl amines across the alkene double bond in a controllable manner. Many routes to prepare oxindoles exist, but all require aromatic aniline or indole starting materials. By converting gamma-keto-esters to 2-amino-phenylacetic acid derivatives through radical dehydrogenation of enamine condensation products, a number of oxindoles can now be prepared from non-aromatic cyclic ketones. Finally, a new approach for indole synthesis was developed using radical azo coupling. Azo precursors function as stable hydrazone surrogates in the Fischer indole synthesis and can be prepared from alkyl iodides and diazonium salts using halogen-atom transfer (XAT) chemistry by reduction with an iron(II) salt. The C-N bond forming event of the indole synthesis occurs without acids or bases, and circumvents the need to prepare toxic and unstable hydrazines and hydrazones. The combination of these factors has led to the development of an indole synthesis with excellent functional group compatibility, which can be used to prepare indoles with uncommon substitution patterns of potential interest in medicinal chemistry.

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Jordi Bures (Supervisor) & Daniele Leonori (Supervisor)