New Transition Metal Catalysed Methods for Alkyl C-N Bond Formation

Forming bonds between carbon and nitrogen (C-N bonds) is an important process in organic chemistry but in many instances this represents a very difficult task. The goal of this research proposal is to provide new methods, which involve metal catalysts, for particularly challenging types of C-N bond formation:

Part 1. The first area will look at is forming C-N bonds in an intramolecular fashion. We will investigate cases where the carbon atom is bonded to three other atoms, of which at least one is another carbon atom. Here, we will develop a method which forms this type of C-N bond from a simple alkene precursor. In this area we will also look at the possibility of controlling which mirror image of the C-N bond we form. This particular aspect is of relevance in cases where the carbon atom of the C-N bond is attached to three other different groups.

Part 2. The second area we will look at is forming C-N bonds in an intermolecular manner. These processes will be much more challenging to develop and we will use the knowledge we gain from Part 1 to aid this aspect.

To facilitate these new methods we will examine the chemistry of a specific nitrogenous organic functionality that allows redox neutral C-N bond forming processes; this, in combination with a metal catalyst, will act as the source of nitrogen. The new C-N bond forming reactions will initially be developed in systems where this functionality is part of the same molecule as the alkene with which it reacts. When the new C-N bond forms a ring structure will therefore be generated. As our understanding of the reactions improves, we will see if the organic functionality and alkene can be part of different molecules. This type of C-N bond formation is anticipated to be much more challenging.

This research area has been chosen because C-N bonds are vital components in living structures (e.g. amino acids) and drug compounds. By developing these new reactions we will be providing methods which allow chemists to make biologically important molecules in a quicker and more efficient manner. Indeed, these new reactions may even allow people to make molecules which are presently inaccessible. In the long term, this research can benefit wider society by enabling the development of drugs for the treatment of illnesses or by providing molecular probes for understanding biological processes. Additionally, there is an inherent need for new C-N bond forming processes as many current methods are subject to patent protection (e.g. the Buchwald-Hartwig amination) which can limit their deployment in industrial settings.

Aspects of this research programme have previously been submitted as part of a successful EPSRC CAF application which was not taken up by the PI as a Royal Society URF was accepted instead.

Academia: The processes proposed herein will be of fundamental utility and interest to synthetic chemists in academia. This new chemistry will provide enabling methods for the construction of alkaloid natural products and nitrogen containing medicinal agents. The more mechanistic aspects of the research deal with transition metal catalysis and this aspect is likely to be of fundamental interest to both organometallic and mechanistic chemists. New catalyst systems will be developed which may be of use outside of this specific research programme.

Industry - pharmaceutical, agrochemical and fine chemical sectors: Outside of academia, the primary impact of this research will be in the pharmaceutical, agrochemical and fine chemical sectors. The fundamentally new reactivity modes for the synthesis of carbon-nitrogen bonds proposed here should enable the more efficient and greener production of nitrogen containing organic molecules. Such compounds are vital for the development of new drugs and molecular probes for biological systems. As such, eventual impact upon the health and wellbeing of society is envisaged. Applicability to those involved in the development of agrochemicals is also likely. The chemistry here may facilitate the development of more efficient pesticides and herbicides, which, in turn, may help to increase the efficiency of global food production. Researchers involved in many other disciplines will also find this research useful; for example applicability in the development of new organic materials and dyes is anticipated.

Research team capability: Another important aspect of this funding proposal relates to the PI's development as an independent academic. The fulfillment of the PI's initial career goals will provide other high impact research avenues outside of the ideas outlined here. Additionally, it is Dr Bower's ambition to provide a rigorous education for co-workers through excellence in scientific research. This EPSRC funding application will allow Dr Bower to commence developing an array of important research projects and will also enable him to benefit the chemical industry by facilitating the transformation of new PhD students into highly trained scientists. This specific research project will provide excellent training for a PhD student in the areas of organometallic, mechanistic and N-heterocyclic chemistry. As such, important economic impact is anticipated beyond just the scientific results of the research described here.

The synthetic requirements of the pharmaceutical industry will be addressed through close consultation with that sector. This will enable the tailoring of the chemistry to areas which are considered to be of primary importance within the industry and will also take the chemistry directly to an important end user. Publication of results in high quality journals of international standing will further aid dissemination into both industry and academia. Additionally, resources are already available (through the PI's Royal Society URF) to enable attendance at international and national conferences, with a primary aim being to publicise results. Opportunities should also arise to present the research in full lectures at both the national and international level. A proactive approach will be taken, and major international conferences with a significant industrial presence, such as the Heterocyclic GRC, will be targeted. Commercially valuable results will be exploited through the University of Bristol's Research and Enterprise Development department. The PI has extensive experience in the identification and development of expansive research programmes in the areas of organic synthesis and catalysis. Additionally, the PI has been heavily involved in the preparation of manuscripts for publication in the primary literature and as book chapters.