Rowett Albert C, Heard David M, Koria Priya, Dean Alice C, Sweeting Stephen G, Lennox Alastair J J
School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, United Kingdom.
Chemistry. 2024 Dec 18;30(71):e202403045. doi: 10.1002/chem.202403045. Epub 2024 Nov 7.
Discovered in 1822, the haloform reaction is one of the oldest synthetic organic reactions. The haloform reaction enables the synthesis of carboxylic acids, esters or amides from methyl ketones. The reaction proceeds via exhaustive α-halogenation and then substitution by a nucleophile to liberate a haloform. The methyl group therefore behaves as a masked leaving group. The reaction methodology has undergone several important developments in the last 200 years, transitioning from a diagnostic test of methyl ketones to a synthetically useful tool for accessing complex esters and amides. The success of the general approach has been exhibited through the use of the reaction in the synthesis of many different complex molecules in fields ranging from natural product synthesis, pharmaceuticals, agrochemicals, fragrants and flavourings. The reaction has not been extensively reviewed since 1934. Therefore, herein we provide details of the history and mechanism of the haloform reaction, as well as an overview of the developments in the methodology and a survey of examples, particularly in natural product synthesis, in which the haloform reaction has been used.
卤仿反应于1822年被发现，是最古老的有机合成反应之一。卤仿反应能使甲基酮合成羧酸、酯或酰胺。该反应通过彻底的α-卤化，然后被亲核试剂取代以释放出卤仿来进行。因此，甲基起到了掩蔽离去基团的作用。在过去的200年里，该反应方法经历了几次重要的发展，从甲基酮的诊断测试转变为用于合成复杂酯和酰胺的合成有用工具。通过在天然产物合成、制药、农用化学品、香料和调味剂等领域的许多不同复杂分子的合成中使用该反应，展示了这种通用方法的成功。自1934年以来，该反应尚未得到广泛综述。因此，在此我们提供卤仿反应的历史和机理细节，以及该方法的发展概述和实例调查，特别是在天然产物合成中使用卤仿反应的实例。
