Studies On Phosphorylation Of Carboxylic Acid And Alcohol

Organophosphorus compounds are widely used in the fields of pesticides,medicines,materials and etc.However,their synthetic methods are limited and highly dependent on the transformation of organohalides such as the Michael-Arbuzov reaction of phosphites with alkyl halides at a high temperature,the nucleophilic substitution of phosphoryl halides with Grignard reagent or lithium reagent,and cross coupling of organohalide compounds with P（O）-H compounds catalyzed by transition metal.Though these methods can efficiently synthesize organophosphorus compounds,but these reactions usually suffer from harsh conditions and low functional group tolerance.Therefore,it is very important to develop greener and more efficient synthetic methods of organophosphorus compounds.In this paper,cheap and available carboxylic acids and alcohols were used as the starting materials and allowed to react with P（O）-H compounds for greenly preparing organophosphorus compounds.Specific research contents are as follows:（1）Synthesis of bisphosphoryl compounds by bisphosphorylation of carboxylic acids with P（O）-H compounds:carboxylic acids are firstly activated by an anhydride electrophilically in situ to generate the mixing anhydrides,and then react with P（O）-H compounds to efficiently generate the corresponding bisphosphoryl compounds via bisphosphorylation.This reaction does not require the addition of transition metal catalyst and solvent,only a catalytic amount of base is used.Both aromatic and aliphatic carboxylic acids can effectively participate in this chemical reaction under the reaction conditions.All the three kinds of P（O）-H compounds（H-phosphonates,H-phosphinate,and secondary phosphine oxide）act well as the phosphorylating reagent.It is worth noting that this reaction can be scaled up in gram scale,and can be applied to the modification of many drug molecules such as adaparine（84%yield）,telmisartan（96%yield）,3-methylflavone-8-carboxylic acid（55%yield）,ibuprofen（83%yield）and so on.These results well demonstrate the potential value.These results well demonstrate the potential value of this reaction in organic synthesis.（2）Dehydrative coupling of alcohols and P（O）-H compounds to form alkyl phosphoryl compounds:the dehydration coupling of benzyl alcohols with P（O）-H compounds catalyzed by Fe（acac）₃ could efficiently produce the corresponding alkyl phosphoryl compounds.The reaction can proceed smoothly without the addition of ligand and shows a wide substrate scope.Various functional groups such as methoxy（91%yield）,alkyl（72%-82%yield）,halogen groups（68%-92%yield）,trifluoromethyl and so on can be well compatible in the reaction system.In addition,this reaction can also be applied to the phosphorylation of bioactive alcohols such as perillyl alcohol（85%yield）and nerolol（85%yield）.The reaction has simple conditions and wide substrate scope,showing well application prospect.