Wilkinson, Christopher Trevor (2014) Hard to make space: improving access to privileged pharmacophores. Masters thesis, University of Huddersfield.

Limited examples of the successful ring expansion of aziridines with sulfonium ylides to generate azetidines are known, but typically result in functional groups on azetidine that are not broadly useful for downstream chemistry. Described here is an investigation into the scope of this reaction including the discovery that N-activated 2-methoxy ester functionalised aziridines are not compatible with this protocol. Advances have also been made in understanding the reactivity of azirines with rhodium carbenoids to generate azetines from successful ring expansion, or N-vinylimine from ring opening.

An alternative route to azetidines from the 1,3-cleavage of azabicyclo[1.1.0]butanes is described, along with a proposed route to highly functionalised azetidines with control over the absolute configuration at each step. Early success reacting a range of reagents with an azabicyclo[1.1.0]butane of moderate steric bulk has been shown, as well as early steps towards a novel azetidine 3-sulfonamide synthesis.

Difluorocyclopropanation of alkenes using fluorinated acetate salts is often a slow, inefficient and energy-intensive process. Reported here is a modified protocol enabling the preparation of 1,1-difluorocyclopropanes in less than five minutes, using microwave irradiation. The new procedure is considerably faster than previously reported methods, employs easily removed, low-boiling point solvents and avoids the use of highly toxic or ozone-depleting substances. The method has been exemplified in a high-yielding synthesis of a difluoro analogue of a clinically used drug substance, and has also shown some utility in preparing 1,1-difluorocyclopropenes and as a novel procedure for the synthesis of halogenated alkyl ether esters from cyclic ethers.

Other investigations into the generation and reactivity of difluorocarbene reported here include successful proof of concept experiments showing the sensitivity of allyl functionalised difluoromethylene containing compounds to palladium species to generate difluorocarbene, as well as exploratory reactions to build on methods to generate 2,2-difluoroaziridines by addition of difluorocarbene to imines.

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