Catalytic Synthesis Of Organophosphorus Compounds Containing P-C And P-Z Bonds

Organophosphorus compounds are valuable intermediates in organic synthesis and also find numerous practical applications. Some optically active phosphonates and organophosphorus acid derivatives are valuable compounds, which show biological activities related to antitumor, HIV transcriptase inhibition and immunomodulation. Due to their special functional group, they also are used as materials with special optical properties, fire-retardant materials important and chiral auxiliaries for asymmetric catalysis and asymmetric synthesis. Traditional methods for the synthesis of these compounds are mainly using the P(O)-Cl compounds as the phosphorylation agents to react with alcohols and phe nols, or treating the three valent under the Michaelis–Arbuzov reaction conditions to prepare the corresponding organophosphorus compounds. However, both of the reactions are using the air-sensitive compounds as the starting materials, and suffered the har sh reaction conditions, low selectivity and functionalities. It is well known that P-chirogenic organophosphorus compounds can hardly be found in the natural product and the synthesis of such compounds in enantiomeric pure forms is usually a hard job. In recent years, there has been a growing interest in these kinds of phosphorus compounds. Thus, developing an efficient and stereospecific synthesis of these compounds is of particular importance and highly desired, and would have wide applications in organophosphorus chemistry.Among the environmentally friendly phosphorylation agents, the 4-coordinate forms of P(O)-H componds is known as a series of acitve nucleophiles, which would undergoes the intramolecular tautomerization to give out the corresponding P(III)-coordinate forms, then coordinated with transition-metals to react with other nucleophiles to construct the functionalized organophosphorus compounds. In addition, although the 4-coordinate forms of P(O)-OH componds could not proceed the tautomerization itself, which is a series of weaker nucleophiles, and can hardly to coordinate with metals or to react with other nucleophiles, but their weak P=O bond can coordinate with metals to realize them activation. Thus, developing an efficient and convenient method for the activation of P(O)-H compounds and P(O)-OH compounds would have significant influences in organophosphorus chemistry.In the present study, based on the special electronic properties of P(O)-H compounds, we have successfully developed an efficient and highly stereospecific method for the preparation of C-/O-phosphoryl substituted hydroquinones through the reaction of P(O)-H compounds selective 1,4-, 1,6- and 1,4-dual addition to p-quinones, respectively. Under the Atherton-Todd reaction conditions, the optically active P(O)-H compounds can react with nucleophles(.e.g., N-H, S-H, and O-H) stereospecifically to afford the corresponding optica lly active phosphinates. Moreover, with the assistance of copper salts, small-molecules and base, we have further realized the activation of P(O)-OH compounds. The results are summarized as follows:1. Highly selective 1,4- and 1,6-addition of P(O)-H compounds to p-quinones: The reaction of P(O)-H compounds with p-quinones could proceed either via 1,4- or 1,6-addition pathway(single electron transfer path) by employing different additives to selectively give the corresponding C- and O- phosphoryl hydroquinone derivatives in good yields. Meanwhile, oxidative double 1,4-addition of P(O)-H compounds to p-quinones was achieved by tuning the solvent, affording a facile synthesis of bis-substituted hydroquinones with phosphorus functionality. The findings lead to the establishment of a divergent method for the synthesis of C- and O- phosphoryl hydroquinone derivatives from easily available P(O)-H compounds.2. Under the Atherton-Todd reaction conditions, the stereochemistry on the reaction of optically active H-phosphinates with different nucleophiles(e.g., amines, alcohols, phenols, thiophenols) was investigated. Determined by the X-Ray analysis for the corresponding coupling compounds, a ll reactions took place stereospecifically with inversion of configurations at the phosphorus centers. The reaction might proceed via a phosphoryl chloride intermediate with reten tion of configuration at phosphorus, followed by the attack of nucleophiles from the backside of Cl to give the substitution products.3. Stereoselective synthesis of(Rp)-/(Sp)-phosphoryl-substituted phenols: Copper-catalyzed C-X activation-phosphorylation of aryls bearing different groups has been achieved using P(O)-H compounds as efficient phosphorylation reagents without the assistance of any ligand. Optically active H-phosphinates can also act as good substrates in the reaction, giving the( Sp)-phosphoryl substituted phenolic compounds stereospecifically with retention of configuration at the phosphorus center. Furthermore, it is shown that the migration of phosphorus on O-aryl phosphonates from oxygen to carbon also proceeds stereospecifically to prod uce the corresponding optically active(Rp)-phosphoryl substituted phenolic compounds with retention of configuration at phosphorus via the treatment of LDA(lithium diisopropyl amide).4. A novel base-promoted O-deprotonation/alkylation reaction of P(O)-OH compounds with alkyl halides in acetonitrile has been developed. The protocol is practical, representing a simple way to produce a broad spectrum of functionalized phosphinates, phosphonates, and phosphates from basic starting materials with good to excellent yields.5. Direct aerobic oxidative esterification and arylation of P(O)-OH compounds with alcohols and diaryliodonium triflates: Copper-catalyzed aerobic oxidative esterification of P(O)-OH compounds is achieved using alcohols as efficient esterification reagents, giving the expected products with good to moderate yields. The addition of oxygen is esstienal for the reaction. Furthermore, it is shown that the arylation of P(O)-OH compounds also proceeds efficiently to produce the corresponding products via the treatment of diaryliodonium triflates under mild reaction conditions. It is a simple way to produce a broad spectrum of functionalized phosphinates, phosphonates, and phosphates from basic starting materials with good to excellent yields. The protocol is convenient for practical application.6. A novel copper-catalyzed esterification reaction of P(O)-OH compounds with phenols has been developed. The protocol is facile and convenient, leading a simple way to afford a broad spectrum of functional ized phosphinates, phosphonates, and phosphates from basic starting materials with moderate to good yields. The three valent copper intermediate of P-O-Cu(III)-Ar may be generated in the reaction, and the final C-O bond formation via the reductive eliminat ion completes the catalytic cycle by regenerating Cu(I) as a catalytically active species.7. A 1000 t/year production of 2,5-dihydroxyphenyl phenyl(phenyl) phosphinate has been designed, and the reactions of material balance, energy balance and equipment selection were also for further analysis and computation.