Direct C-H amidations of N-heterocycles

Abstract

N-Heterocycles are well-studied structures in synthetic organic chemistry and their prevalence in the pharmaceutical industry, for example, has led to this great interest. Therefore, the ability to directly C-H functionalisation N-heterocycles would be of great interest to the synthetic organic chemistry community, allowing access to valuable targets without the need for non-productive chemical steps (such as protection/deprotection, functional group interconversions (FGI) or oxidation manipulation chemistry). This thesis will describe the development of two complementary C-H amidations of N-heterocycles (one thermally mediated and one light-mediated) which will allow for the C-H amidation of phenanthrolines, purines and 1,3-azoles. The term “amidation” is predominately used in this thesis to refer to carbamoylation. Please note that the more specialist term “carbamoylation” was initially used in Chapters 1 and 2 (and the publications contained within them). Recently, however, the more general and well-known term “amidation” tended to be the preferred terminology to refer to carbamoylation, and this change in notation is reflected in the publications contained within Chapters 3 and 4.* Strictly speaking, there are two possible types of amidation: carboxyamidation (bond-forming at the C of the amide) and N-amidation.) Amidation in this thesis refers to carboxyamidation throughout, unless otherwise stated. Chapter 1 will provide an introduction to the work discussed within this thesis. More specifically, chapter 1 will introduce the Minisci reaction, a powerful method for C-H functionalisation of electron-deficient N-heterocycles. Chapter 2 presents a metal- and light-free C-H diamidation of 1,10-phenanthrolines. This is the first C-H diamidation of 1,10-phenanthrolines which is capable of directly installing primary, secondary and tertiary amides. This method is cheap, operationally simple and scalable. Moreover, the facile 2-step (vs. previous 11-step) synthesis of a diamidated 1,10- phenanthroline target is demonstrated. Chapter 3 showcases the development of a direct C-H amidation of purines. As well as being able to install primary, secondary and tertiary amides, this method is the first to demonstrate a direct C-H amidation on a wide range of purines (e.g. xanthines, guanines, adenines, including guanosine- and adenosine-type nucleosides). This procedure is not only cheap, operationally simple and scalable as before, but is also applicable to the late-stage functionalisation of many biologically important molecules. Chapter 4 communicates the development of two complementary methods (one thermally-mediated and one light-mediated) for the direct C-H amidation of 1,3-azoles. This work is applicable to the four most important 1,3-azoles in medicinal chemistry: benzothiazoles, thiazoles, benzimidazoles and for the first time, imidazoles. As with the previous chapters, the methods developed are cheap, operationally simple and scalable but also allow for the first late-stage C-H functionalisations of 1,3-azoles. The light-mediated method presented is the first photosensitiser-free direct Minisci-type amidation which proceeds via an EDA. Furthermore, this newly developed photosensitiser-free Minisci-type amidation is not only limited to azoles but can be applied to other N-heterocycles. Chapter 5 will draw an overall conclusion of the work presented within this thesis and discuss the possible future work.

* Since this thesis is in part by publication, it was decided to keep the terminology used within the respective publications included in this thesis.