Improvements, Variations and Biomedical Applications of the Michaelis–Arbuzov Reaction

Abstract

Compounds bearing the phosphorus–carbon (P–C) bond have important pharmacological, biochemical, and toxicological properties. Historically, the most notable reaction for the formation of the P–C bond is the Michaelis–Arbuzov reaction, first described in 1898. The classical Michaelis–Arbuzov reaction entails a reaction between an alkyl halide and a trialkyl phosphite to yield a dialkylalkylphosphonate. Nonetheless, deviations from the classical mechanisms and new modifications have appeared that allowed the expansion of the library of reactants and consequently the chemical space of the yielded products. These involve the use of Lewis acid catalysts, green methods, ultrasound, microwave, photochemically-assisted reactions, aryne-based reactions, etc. Here, a detailed presentation of the Michaelis–Arbuzov reaction and its developments and applications in the synthesis of biomedically important agents is provided. Certain examples of such applications include the development of alkylphosphonofluoridates as serine hydrolase inhibitors and activity-based probes, and the P–C containing antiviral and anticancer agents.

Synthesis of Hydroxylated Stilbenes in a Batch and Flow Reactor: An Overview

“…Phosphonates can be synthesized by a two-step Michaelis-Arbuzov reaction of halides and phosphites in two S N 2 reactions. [64] This type of intermediates for hydroxylated stilbene synthesis was prepared in the paper of Li et al [43] in the presence of tetra-n-butylammonium iodide (n-Bu) 4 NI at 100-120 °C, which gave hydroxylated trans-stilbene derivatives after the subsequent Wittig olefination reaction and demethoxylation.…”

“…Besides the aforementioned phosphonium salts coupled with aldehydes in a Wittig reaction to obtain hydroxylated stilbenes, phosphonates are also a possible intermediate in hydroxylated stilbene synthesis. Phosphonates can be synthesized by a two‐step Michaelis‐Arbuzov reaction of halides and phosphites in two S N 2 reactions [64] . This type of intermediates for hydroxylated stilbene synthesis was prepared in the paper of Li et al [43] .…”

Zn-Catalyzed Dehydroxylative Phosphorylation of Allylic Alcohols with P(III)-Nucleophiles

“…The use of P­(III) reagents as the starting materials to synthesize allyl-functionalized phosphonates/phosphinates/phosphine oxides represents an important alternative approach to the use of P­(V)–H substrates as the phosphorylation reagents. This approach serves as an extension and advancement of the Michaelis–Arbuzov rearrangement reaction . Given our group’s longstanding interest in the synthesis of organophosphorus compounds, we present here a highly efficient method for the synthesis of diarylallyl-functionalized phosphonates/phosphinates/phosphine oxides through the zinc-catalyzed dehydroxylative phosphorylation of allylic alcohols with P­(III)-nucleophiles via the Michaelis–Arbuzov-type rearrangement (Scheme B).…”

Water-Promoted Mild and General Michaelis–Arbuzov Reaction of Triaryl Phosphites and Aryl Iodides by Palladium Catalysis

“…The classic Michaelis–Arbuzov reaction has emerged as a premier synthetic tool for the preparation of organophosphonates from phosphites and halides. − The reaction mainly involves two sequential S N 2 processes, in which a phosphonium intermediate was first generated and then rearranged to the phosphonate products. However, limitations of this reaction are also obvious, which mainly include: (a) a high reaction temperature (>150 °C) is usually required; (b) the reaction suffers from poor functional group tolerance; (c) the generated halide byproduct may compete with the substrate halide to give undesired phosphonate byproducts; and (d) the reaction is essentially restricted to aliphatic phosphites for the preparation of aliphatic phosphonates due to the low nucleophilicity of triaryl phosphites (Scheme B).…”