Room-Temperature Alternative to the Arbuzov Reaction: The Reductive Deoxygenation of Acyl Phosphonates

Abstract

The reductive deoxygenation of acyl phosphonates using a Wolff-Kishner-like sequence is described. This transformation allows direct access to alkyl phosphonates from acyl phosphonates at room temperature. The method can be combined with acyl phosphonate synthesis into a one pot, four-step procedure for the conversion of carboxylic acids into alkyl phosphonates. The methodology works well for a variety of aliphatic acids, and shows a functional group tolerance similar to that of other hydrazone-forming reactions.Phosphonates are a key functional group in both organic synthesis and biological chemistry. 1 In synthesis, they are a direct precursor of olefins through the Horner-WadsworthEmmons reaction.2 In biological chemistry, their unique structure and charge distribution give them an important role in pharmaceuticals3 and phosphoester mimicry.4 Phosphonates have traditionally been accessed through the Arbuzov reaction:5 , 6 a double S N 2 process between an alkyl halide and a trialkylphosphite (Scheme 1), and this remains the most commonly employed route today. Notable exceptions include aryl/vinyl phosphonates,7 whose corresponding halides cannot readily participate in S N 2 reactions, and α-hydroxyl/α-amino phosphonates,8 whose corresponding halides are unstable.Despite its prevalence, the Arbuzov reaction has two key drawbacks. First, the elevated temperatures typically required limit the scope of substrates suitable for the reaction. Second, the reaction generates one equivalent of alkyl halide, which can react with the phosphite under the reaction conditions to reduce yield and reaction efficiency. A modification using dialkylphosphite salts instead of trialkylphosphites eliminates the problem of new alkyl halide generation, but the yields are typically poorer, and this strategy is much less used.9 A number of other strategies for alkyl phosphonate synthesis have been developed,10 , 11 most notably the transition metal-mediated hydrophosphonylation of olefins with cyclic five-membered hydrogen phosphonates.12 Yet even this reaction is limited by the phosphite component scope and prolonged heating. Here we present a roomtemperature alternative to the Arbuzov reaction that allows for the synthesis of phosphonates from carboxylic acids.We began with the observation that the Arbuzov reaction of acyl halides is strikingly mild in comparison to the alkyl variant, often going to completion in several minutes at room dadougherty@caltech.edu .

Copper‐Catalyzed Synthesis of Alkylphosphonates from H‐Phosphonates and N‐Tosylhydrazones

“…The Michaelis–Becker reaction sometimes requires a strong base and long reaction times, and these drawbacks can limit the range of substrates and the yield of products. The demand for functionalized organic phosphonates has stimulated extensive studies on phosphorylation8 and PC( sp 3 ) bond‐forming reactions involving arylmethyl halides/alcohols/carboxylic acids catalyzed by Pd,9a,b Lewis acids,9c,d Cu9e and N 2 H 4 9f…”

Fragmentation-Related Phosphonylation of Nucleophiles Utilizing P-Alkyl 2,3-oxaphosphabicyclo[2.2.2]octene 3-oxide Precursors

“…The dialkyl phosphonates (28-36) were obtained in 94-98% yields after flash column chromatography. Compounds 28-36 known from the literature [20][21][22][23][24][25][26] were identified on the basis of 31 P NMR and HRMS. Two species (34 and 36) lacking 31 P NMR chemical shifts were analyzed also by 1 H and 13 C NMR spectral data.…”

Pd-catalyzed carbonylative access to aroyl phosphonates from (hetero)aryl bromides

“…In comparison with the observed 86% NMR yield, slight decomposition of 3a had occurred during purification possibly via hydrolysis to 4-methoxylbenzoic acid. 16 The 80 methoxy-group in the meta-position also provided the product in a good isolated yield of 3b. Other electron donating substituents such as methyl, tert-butyl and dimethylamino were also tolerated under the optimised reaction conditions, thus providing products a 1 H-NMR yield using internal standard (1,3,5-trimethoxybenzene).…”