Atherton–Todd reaction: mechanism, scope and applications

Abstract

SummaryInitially, the Atherton–Todd (AT) reaction was applied for the synthesis of phosphoramidates by reacting dialkyl phosphite with a primary amine in the presence of carbon tetrachloride. These reaction conditions were subsequently modified with the aim to optimize them and the reaction was extended to different nucleophiles. The mechanism of this reaction led to controversial reports over the past years and is adequately discussed. We also present the scope of the AT reaction. Finally, we investigate the AT reaction by means of exemplary applications, which mainly concern three topics. First, we discuss the activation of a phenol group as a phosphate which allows for subsequent transformations such as cross coupling and reduction. Next, we examine the AT reaction applied to produce fire retardant compounds. In the last section, we investigate the use of the AT reaction for the production of compounds employed for biological applications. The selected examples to illustrate the applications of the Atherton–Todd reaction mainly cover the past 15 years.

Synthesis of the Campylobacter jejuni 81‐176 Strain Capsular Polysaccharide Repeating Unit Reveals the Absolute Configuration of its O‐Methyl Phosphoramidate Motif

“…Under these conditions, an ew product was formed that, when subjected to the Atherton-Todd reaction, [15] furnished the desired Omethyl phosphoramidate in 65 %y ield. As in other examples using this approach, [13a] products corresponding to both diastereomers on phosphorus were formed (19 and 20).…”

Fe3O4@MgO nanoparticles as an efficient recyclable catalyst for the synthesis of phosphoroamidates via the Atherton–Todd reaction

“…8 The Atherton-Todd reaction, which involves the one-pot reaction of a dialkyl phosphite with a primary amine and carbon tetrachloride (CCl 4 ) in the presence of base, is a typical method for the synthesis of phosphoroamidates. 9, 10 The key step is the in-situ formation of a dialkyl chlorophosphate via the reaction of dialkylphosphites with CCl 4 . This is then followed by nucleophilic addition of an amine to the resulting dialkyl chlorophosphate 2 (Scheme 2).…”

Synthesis of lipid-based unsymmetrical O,O-dialkylphosphites

“…These lipid-based phosphites are interesting intermediates for the synthesis of amphiphilic compounds by using, for instance, the Atherton-Todd coupling. 6 These new lipid and functionalized lipid building blocks will be used to produce new amphiphilic compounds that will be specially designed for gene delivery.…”

“…From a synthetic point of view, these bio-inspired vectors are prepared by the AthertonTodd reaction, that is, by mixing an O,O-dialkylphosphite, an amine and CBrCl 3 in the presence of a base (DIPEA). 6 Following this strategy, a wide variety of lipophosphoramidates with symmetrical hydrophobic domains (two identical alkyl chains) were prepared. [7][8][9] In a continuous effort to develop more efficient gene delivery vehicles, we were interested in the synthesis of unsymmetrical lipophosphoramidates that were characterized by the presence of two different lipid chains.…”