AgNO₃ Catalyzed C_SP²-H Keys Directly Phosphonic Acylation Using Free Radical Reaction

Objective:New Csp2-P bond construction method was investigated via AgNO3-catalyzed reaction of nitrostyrolenes and a, β-unsaturated carbonyl with sub phosphate ester. It has been applied to the direct phosphonation of natural compounds such as coumarin and quinolinone and achieved a high efficiency of direct phosphonation through Csp2-H bond.This method provide solid foundation for the development of phosphoruscontaining drugs.Methods:1. The phosphonationwas carried out by reacting trans-β-Nitrostyrene or a, β-unsaturated carbonyl with coumarinunder the catalysis of AgNO3 respectively. Wattecs parallel reaction apparatus was employed to evaluatecatalyst types and quantity, type and amount of additives, solvents, reaction time, temperature, molar ratio of raw material and other factors’effect on the phosphonation, and the optimized condition was screened out.The structure of the reaction substrate was also investigated, and their effects on the yield of the reaction were summarized.2. The structures of the final products were confirmed with IR, NMR and MS.3. A possible mechanism was proposed based on 31P NMR spectrum analysis and previous reports.Results:1. When nitrostyrolenes and sub phosphate ester react in acetonitrile under AgNO3(15 mol%)and 90℃, a total of twenty-three vinylphosphonates compounds were synthesized and five of them had never been reported.2. With a, β-unsaturated carbonyls as reaction substrate, AgNO3(10 mol%) as catalyst, Mg(NO3)2·6H2O (0.5 equiv) as additives, THF as solvent, AgNO3 (10mol%) as catalyst, microwave assisteddirect regioselectivephosphonation of a,β-unsaturated carbonyls successfully synthesized twenty-two compounds and twenty-one of them had never been reported before. The configurations of these compounds have been confirmed with chemical shift value and the coupling constant of NMR.3. When use AgNO3 (5 mol%) as catalyst, Mg(NO3)26H2O (0.5 equiv) as additives, acetonitrile as solvent, temperature set at 90℃, the reaction of coumarin and quinoline ketone with sub phosphate ester produced 21 coumarin-3-phosphate and 8quinoline-3-phosphate, and 18 of them had not been reported before.4. The reaction mechanism was peculatedto be AgNO3 catalyzed free radical reactionbased on thecontrol study, radical blockingand 31P NMR Real time tracking techniques..Conclusion:The phosphonation of nitrostyrene,a, β-unsaturated carbonyl, coumarine and quinolinonewere successfully achieved through direct phosphonation of Csp2-H bond with the catalysis of AgNO3.74 phosphate ester detectives were synthesized and 44 of them were new compounds, their structures had been confirmed with IR,1H NMR,13C NMR,31P NMR and ESI-MS. An Ag-catalyzed radical reaction mechanism was proposed based on control study, radical blocking and 31P tracking, and the intermediate was captured using 31P tracking technique. This method is applicable to vast range of substrates with mild condition and good stereo selectivity. It provided an effective way for the construction of Csp2-P bonds.