Methodology Research On The N-alkylation Of Phosphonic/Phosphinic Amides

Phosphonic/phosphinic amides are nitrogen containing organic compounds with a unique O=P-N structure.They are found in some natural products and have a variety of pharmacological activities such as antibacteria,antivirus and antitumor.They are also applied as flame retardants,catalysts in asymmetric synthesis,and directing groups in C-H activation.Due to their wide range of uses in multiple fields,the research of synthesizing phosphonic/phosphinic amides is also of great significance.So far the synthetic methods are mainly traditional nucleophile substitution reactions,they suffer from disadvantages like harsh conditions and poor compatibility,which could hardly meet the fine requirements of modern organic synthesis.Moreover,currently reported synthetic methods are mainly based on construction of N-P bonds,the derivation of phosphonic/phosphinic amides,such as N-H functionization,remains rare.The research of N-H functionization of phosphonic/phosphinic amides could offer a new route to synthesizing them.Transision metal catalyzed oxidative cross coupling is a newly developing type of organic reactions.Comparing with the early cross coupling reactions,it avoids the pretreatment of reagents which means extra reaction steps,and exhibits great atom economy.In recent years lots of attention has been paid to the research of oxidative coupling and abundant achievement has been obtained.Various chemical bonds,including N-C,N-X,have been successfully constructed with this method.A variety of N-H functionization of many N-H-group-containing compounds,such as amines/anilines,amides,sulfonic amides,sulfoximines and nitrogen containing heterocycles,have all been accomplished via oxidative coupling.So it is prospective that this reaction could also help in N-H functionization of phosphonic/phosphinic amides.Therefore,research was carried out in this article and 3 effective methods of N-H functionization of phosphonic/phosphinic amides were found.(sp~3)C-N bonds were constructed,and saturated carbon chains were introduced to the nitrogen atom.Transision-metal-catalyzed oxidative cross coupling played a crucial role in these methods.This article mainly contains:1)A method to obtain N-alkyl phosphonic/phosphinic amides from phosphonic/phosphinic amides and alkanes was presented.The oxidative cross coupling took place with the participation of dicumyl peroxide(DCP)as the oxidant and cuprous iodide as the catalyst.Reaction condition was optimized from parameters like oxidants,catalysts,ligands,solvents and temperature.Various subtrates were explored and 19 target compounds were synthesized.Their structure was comfirmed via nuclear magnetic resonance(NMR),mass spectroscopy(MS)and infrared spectrum(IR).Difference in reactivities of different substrates was checked.A radical mechanism was proved for this reaction and a reliable assumpsion of the process was given.2)An N-methylation method was accidentally discovered while trying intramolecular N-allylation reaction of phosphonic/phosphinic amides.It could be achieved by simply changing the solvent of N-allylation reaction.Several phosphonic/phosphinic amides were tested in this method and 15 N-methylated products were obtained.The structure of all products was confirmed with NMR,MS and IR.Reactivity of the two reactions was compared.The mechanism of this reaction was observed and a possible process was assumed.3)An oxidative cross coupling between phosphonic/phosphinic amides and methyl arenes was demonstrated.The reaction went under the catalysis of cuprous iodide,leading to N-benzyl phosphonic/phosphinic amides.Reaction condition was optimized with parameters including oxidants,catalysts,additives,solvents and temperature.Different substrates were explored and 29 N-benzyl phosphonic/phosphinic amide products were acquired.Structure of all products was corfirmed by NMR,MS and IR.Reactivity of different substrates was compared.A plausible mechanism of this reaction was discussed.