Electrochemical Deoxygenative Functionalisation of Alcohols

Alcohols are a useful functionality in organic synthesis due to the wide range of reactions to and from them, and due to their prevalence in natural products and synthetic targets. The deoxygenation and deoxygenative functionalisation of alcohols are often-employed synthetic steps. Conventional methods for the deoxygenation of alcohols involve an initial derivatisation of the alcohol to form a more labile functionality, which is subsequently cleaved in a second step. Classic examples of this chemistry include the reduction of tosylates, the Barton-McCombie deoxygenation and the Markó-Lam deoxygenation. These methods for the reduction of alcohols often use hazardous or toxic reagents, and the use of a two-step process is inherently more wasteful than a one-step reduction. In a 1994 publication, Ohmori et al. disclosed a one-step electrochemical deoxygenation of alcohols, but the scope and functional group tolerance explored was limited, and the mechanism of this transformation was not determined.The most notable protocols for the deoxygenative substitution of alcohols include the Appel reaction and the Mitsunobu reaction. However, the Appel reaction is limited to halide nucleophiles, and in the Mitsunobu reaction hazardous reagents are required to activate the alcohol. Typical deoxygenative functionalisations of alcohols require stoichiometric quantities of oxidant, which result in the production of stoichiometric waste. Following the electrochemical deoxygenation disclosed by Ohmori et al., a few examples of electrochemical deoxygenative substitutions have been published, however the scope of alcohols and substituting nucleophiles is extremely limited.Proposed solution and methodologyThe development of new synthetic methods for late-stage functionalisation addresses the pressing need for delivering complex molecules swiftly and sustainably. New methodologies for functionalisation of alcohols at the late stage permit rapid access to libraries of related compounds, in less time and fewer chemical steps than de novo syntheses. The generation of synthetically useful reactive species from alcohols using electrosynthetic techniques remains underdeveloped. In this project, methods for the electrochemical deoxygenation of alcohols and for the electrochemical deoxygenative functionalisation of alcohols will be explored and developed. Using anodic oxidation, the use of toxic and/or hazardous oxidising agents is avoided, as is the generation of stoichiometric waste from spent oxidant.This project aims to deduce the mechanism of the electrochemical deoxygenation developed by Ohmori et al., improve its scope and functional group tolerance, and will explore its applications to complex molecules for late-stage functionalisation. Following determination of the reaction mechanism, the scope of alcohols and functional groups compatible with the electrochemical deoxygenation methodology will be expanded. With greater functional group tolerance and selectivity, the deoxygenation of complex molecules will demonstrate the applications of this methodology in late-stage functionalisation.With mechanistic understanding of the electrochemical deoxygenation and optimised conditions, general deoxygenative functionalisation reactions will be developed. Depending on the reaction mechanism this could be via alkyl bromide or alkoxyphosphonium intermediates or via alkyl radical intermediates. Ideally, the chemistry developed will be applicable to a wide scope of alcohol substrates including complex molecules, will incorporate a range of nucleophiles, and will exhibit broad functional group tolerance.

Alcohols are a useful functionality in organic synthesis due to the wide range of reactions to and from them, and due to their prevalence in natural products and synthetic targets. The deoxygenation and deoxygenative functionalisation of alcohols are often-employed synthetic steps. Conventional methods for the deoxygenation of alcohols involve an initial derivatisation of the alcohol to form a more labile functionality, which is subsequently cleaved in a second step. Classic examples of this chemistry include the reduction of tosylates, the Barton-McCombie deoxygenation and the Markó-Lam deoxygenation. These methods for the reduction of alcohols often use hazardous or toxic reagents, and the use of a two-step process is inherently more wasteful than a one-step reduction. In a 1994 publication, Ohmori et al. disclosed a one-step electrochemical deoxygenation of alcohols, but the scope and functional group tolerance explored was limited, and the mechanism of this transformation was not determined.The most notable protocols for the deoxygenative substitution of alcohols include the Appel reaction and the Mitsunobu reaction. However, the Appel reaction is limited to halide nucleophiles, and in the Mitsunobu reaction hazardous reagents are required to activate the alcohol. Typical deoxygenative functionalisations of alcohols require stoichiometric quantities of oxidant, which result in the production of stoichiometric waste. Following the electrochemical deoxygenation disclosed by Ohmori et al., a few examples of electrochemical deoxygenative substitutions have been published, however the scope of alcohols and substituting nucleophiles is extremely limited.Proposed solution and methodologyThe development of new synthetic methods for late-stage functionalisation addresses the pressing need for delivering complex molecules swiftly and sustainably. New methodologies for functionalisation of alcohols at the late stage permit rapid access to libraries of related compounds, in less time and fewer chemical steps than de novo syntheses. The generation of synthetically useful reactive species from alcohols using electrosynthetic techniques remains underdeveloped. In this project, methods for the electrochemical deoxygenation of alcohols and for the electrochemical deoxygenative functionalisation of alcohols will be explored and developed. Using anodic oxidation, the use of toxic and/or hazardous oxidising agents is avoided, as is the generation of stoichiometric waste from spent oxidant.This project aims to deduce the mechanism of the electrochemical deoxygenation developed by Ohmori et al., improve its scope and functional group tolerance, and will explore its applications to complex molecules for late-stage functionalisation. Following determination of the reaction mechanism, the scope of alcohols and functional groups compatible with the electrochemical deoxygenation methodology will be expanded. With greater functional group tolerance and selectivity, the deoxygenation of complex molecules will demonstrate the applications of this methodology in late-stage functionalisation.With mechanistic understanding of the electrochemical deoxygenation and optimised conditions, general deoxygenative functionalisation reactions will be developed. Depending on the reaction mechanism this could be via alkyl bromide or alkoxyphosphonium intermediates or via alkyl radical intermediates. Ideally, the chemistry developed will be applicable to a wide scope of alcohol substrates including complex molecules, will incorporate a range of nucleophiles, and will exhibit broad functional group tolerance.