Activating amides for carbon-carbon bond formation

Bonds between carbon and nitrogen exist throughout Nature predominantly in the form of amide bonds and are the key chemical connection of life. Due to the importance of amides, a vast array of methods for synthesising this chemical bond have been developed by both chemists and biologists, though they are yet to catch up with Nature itself. The amide as a functional group is comparatively stable but what if we could selectively react at this position over other more reactive sites in the same molecule? The Maulide group has developed a number of reactions based on the ability to do this, meaning that it is possible to change the order in which reactions are carried out which can help to simplify chemical synthesis. However, the current methods, though extremely powerful, can be restrictive because the reagent which selectively activates the amide can react with other parts of the molecule which is not desired. Here, our first challenge is to obviate this unwanted reactivity by harnessing the energy of light. By taking a very small amount of a catalyst that can absorb visible light from a household lightbulb, the energy of the lightbulb can be selectively transferred to our amide activating chemical, turning on its reactivity. This alternative pathway allows a milder activating agent to be used and so widens the range of chemistry that can be carried out and allows much more user friendly conditions to be used. We will then explore the vast potential that selective activation of amides provides to synthesise new bonds between carbon atoms. In the first instance, we will use amides with an aromatic group on the nitrogen to form a bond between two aromatic rings. Traditionally, this chemistry is carried out at high temperatures with an expensive metal catalyst but we will show that a much more energy efficient pathway exists using amide activation. The significance of these findings will be emphasised by the fact that the resulting structures are commonplace in chemicals that are found in nature as well as number of commercial pesticides. Secondly, we will use amide activation to generate high-energy species called keteniminiums. The Maulide group has published a number of different transformations using these species and here we will further extend the toolbox available to the synthetic chemist. By using cycloaddition chemistry where two components link together via two new bonds we will make a range of different cyclic ring structures. These structures are prevalent in Nature but current methods can be limited in what they can achieve. We will build upon all of the knowledge we acquire to provide novel, simple and flexible approaches for making these scaffolds.

A range of new synthetic methodologies were developed during the course of this project. These methods all rely on selective amide activation. This enables us to take amides, one of the most pervasive and stable functional groups that exist, and react it in the presence of 'more reactive' moieties. A novel strategy was developed for the synthesis of 1,4-dicarbonyl compounds via a polarity reversal strategy. This valuable class of compound (a precursor to many heterocycles) is often difficult to synthesise, particularly selectively, but the strategy developed here enables selective cross-coupling and avoids the use of transition metal catalysts. A method for the selective ,dehydrogenation of amides in the presence of other carbonyl moieties under mild conditions was also established. Synthetically versatile products are generated at room temperature in a selenium mediated transformation. Finally, a state-of-the-art fluorination methodology was discovered, again using a polarity reversal strategy which allowed nucleophilic fluorinating agents to be used for the -C-H-fluorination of amides. Reduction of these products enables facile access to -fluorinated amines and the value of this methodology is shown by the easy preparation of a number of fluorinated analogues of drugs and agrochemicals. A fluorinated analogue of citalopram, a marketed antidepressant drug, was synthesised and the biological activity after fluorination investigated in collaboration with a team of medicinal chemists.