Electrochemical Deoxygenative Functionalisation of Alcohols

醇在有机合成中是一种有用的官能团，因为它们的反应范围很广，而且它们普遍存在于天然产物和合成目标中。醇的脱氧和脱氧官能化是常用的合成步骤。醇脱氧的常规方法包括醇的初始衍生化以形成更不稳定的功能，随后在第二步中裂解。这种化学反应的经典例子包括甲磺酸盐的还原，巴顿-麦克康比脱氧和Markó-Lam脱氧。这些醇的还原方法通常使用危险或有毒的试剂，使用两步法本质上比一步法更浪费。Ohmori等人在1994年发表的一篇文章中披露了醇的一步电化学脱氧，但所探索的范围和官能团耐受性有限，而且这种转化的机制也没有确定。最著名的醇的氧取代方法包括Appel反应和Mitsunobu反应。然而，Appel反应仅限于卤化物亲核试剂，而在Mitsunobu反应中，需要危险试剂来激活醇。典型的醇的脱氧官能化需要化学计量量的氧化剂，这导致产生化学计量量的废物。继Ohmori等人披露的电化学脱氧之后，已经发表了一些电化学脱氧取代的例子，但是醇和取代亲核试剂的范围非常有限。提出的解决方案和方法用于后期功能化的新合成方法的发展解决了快速和可持续地递送复杂分子的迫切需求。与从头合成相比，晚期醇功能化的新方法可以在更短的时间和更少的化学步骤中快速获取相关化合物库。利用电合成技术从醇中生成合成有用的反应物质仍然不发达。在本项目中，将探索和发展醇的电化学脱氧和醇的电化学脱氧功能化方法。使用阳极氧化，可以避免使用有毒和/或有害的氧化剂，也可以避免从废氧化剂中产生化学计量废物。本项目旨在推断Ohmori等人开发的电化学脱氧机制，提高其范围和官能团耐受性，并将探索其在复杂分子的后期功能化应用。在确定反应机理后，将扩大与电化学脱氧方法相容的醇类和官能团的范围。具有更大的官能团耐受性和选择性，复杂分子的脱氧将证明该方法在后期功能化中的应用。随着对电化学脱氧机理和优化条件的了解，一般脱氧功能化反应将得到发展。根据反应机理，这可以通过烷基溴或烷氧膦中间体或烷基自由基中间体进行。理想情况下，所开发的化学将适用于广泛的醇底物，包括复杂分子，将包含一系列亲核试剂，并将表现出广泛的官能团耐受性。

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.