Radical Reaction of Sodium Hypophosphite with Terminal Alkynes:  Synthesis of 1,1-Bis-H-phosphinates

Abstract

The room temperature radical addition of sodium hypophosphite to terminal alkynes produces the previously unknown 1-alkyl-1,1-bis-H-phosphinates in moderate yield. The reaction is initiated by R 3 B and air and proceeds under mild conditions in an open container. The bis-sodium salts precipitate spontaneously from the reaction mixtures, thus providing a simple purification procedure and the opportunity for multigram synthesis. The 1,1-bis-H-phosphinate products are novel precursors of the biologically important 1,1-bisphosphonates. We recently reported a novel and general approach towards H-phosphinate derivatives, based on the room temperature radical addition of hypophosphorous compounds to alkenes (Equation 1). 1 Since then, we have studied the reactions of alkynes with sodium hypophosphite under similar conditions and discovered the formation of a new class of compounds: 1-alkyl-1,1-bis-H-phosphinates. 2 We now report the results of this study. The thermal, peroxide-initiated radical reaction of hypophosphorous acid with alkynes has been studied by Nifant'ev and coworkers. 3 Several products were identified depending on the conditions employed (Equation 2). A mixture of trans-and cis-alkenyl-H-phosphinic acids were produced as the major components, along with minor amounts of disubstituted 1,2-bis-H-phosphinic acids. Nifant'ev had also investigated alkenes under the same conditions. 4 Previously, we found that our milder reaction conditions considerably expanded the scope of H-phosphinates which could be produced both in terms of functional group tolerance on the alkene, and hypophosphorous reagent employed. 1 These differences prompted the study of alkynes as substrates under our R 3 B/air and room temperature conditions. As a model study, the reaction of sodium hypophosphite with 1-hexyne was investigated using Et 3 B/air to promote radical formation. The results are summarized in Table 1. Methanol was initially selected as solvent, since sodium hypophosphite has no significant solubility in other common organic solvents at room temperature. Interestingly, the novel 1,1-bis-H-phosphinate was always obtained as the major product (the remaining filtrate contains some unreacted

Rapid and Efficient Synthesis of Unsymmetrical Phosphinic Acids R′P(O)OHR″

“…When starting from alkylphosphinates with ketal protection (products 3-6, method A), direct silylation was not possible irrespective of the conditions used, probably due to the greater stability of the ketal protection. Typical acidic deprotection, which quantitatively yielded the unprotected alkylphosphinic acids (11)(12)(13)(14), was used. [16] Persilylation of these pentavalent phosphorus acids led to highly reactive P III -silylated intermediates, which underwent the Arbuzov reaction with alkyl halides or Michael addition with methyl methacrylate.…”

“…New reactions are continuously being developed for the efficient synthesis of such compounds. [11,12] However, most of the methods reported for their preparation are not general and suffer from severe limitations: [7,13] A large excess of reagents, the direct formation of symmetrical dialkylphosphinate or the instability and handling difficulties of the starting materials. Thus, new methods using more general and milder conditions are required to allow the preparation of functionalized dialkylphosphinates.…”

Recent Developments in the Addition of Phosphinylidene‐Containing Compounds to Unactivated Unsaturated Hydrocarbons: Phosphorus–Carbon Bond Formation by Hydrophosphinylation and Related Processes

“…Reaction with sodium hypophosphite gives the novel 1,1-bis- H -phosphinates in good yield (Equation 3), and these products precipitate from the reaction mixture, allowing easy purification. [xxii] These compounds have great potential as bisphosphonate precursors, and other compounds such as 1,1-bisphosphinomethane derivatives. [xxiii] Interestingly, anilinium hypophosphite tends to give 1,2-disubstitution instead.…”

Recent advances in sulfur- and phosphorous-centered radical reactions for the formation of S–C and P–C bonds

“…In both cases, no significant amounts of dialkyl phosphonates were observed. Similar method has been used for the reactions of alkynes in the synthesis of 1,1-bis-H-phosphinate products 371 (Scheme 158) 258. Antczak and Montchamp reported AIBN-initiated reactions of phosphinates with alkenes and alkynes to form products 372 and 373, respectively (Scheme 159) 259.…”