Studies On The Synthesis Of Small Molecular Organophosphorus Compounds Through Sp~3C–P Bond Formation

Organophosphorous compounds is a kind of important functional molecules,which is widely used in organic synthesis,calalysis,medicine and materials.Traditional synthesis of organophosphorus compounds depends on the reaction of alkyl halides with alkyl phosphite at high temperature(Arbuzov reaction)and the nucleophilic substitution of organometallic reagents with phosphoryl halides.These reactions usually proceed under harsh reaction conditions with low functional-group tolerance.Therefore,development of more simple,green,and efficient methods for their preparation is highly desirable.Over the past decades,chemists have developed many methods to construct C–P bonds,i.e.the transition metal-catalyzed cross coupling of P(O)–H compounds with aryl halides(Hirao coupling)and the transition metal-catalyzed dehydrogenative coupling with P(O)–H compounds.However,these reactions mainly studied the construction of sp C–P,sp~2C–P and special benzylic sp~3C–P bonds,only limited examples are reported for general sp~3C–P bonds formation.This paper utilizes P(O)–H compounds to react with alkyl nitriles,terminal alkynes,cinnamonitriles and allyl chlorides to build sp~3C–P bonds.Detailed research contents come as follows:1.Nickel-catalyzed cleavage of sp~3C–CN bonds for constructing sp~3C–P bonds:direct phosphorylation of alkylnitriles.A nickel-catalyzed direct phosphorylation of unstrained sp~3C–CN bonds is disclosed.Under the optimal reaction conditions,benzylic nitriles,3-aryl propanenitriles,4-phenyl butanenitrile,and even 6-phenyl hexanenitrile could readily couple with H-phosphine oxides to produce the corresponding organophosphorus compounds in moderate to high yields.The gram-scale(10 mmol)experiment and application in the synthesis of anticancer drugs Combretastatin-A4 as a key step demonstrating well the potential synthetic value of this new reaction in organic synthesis.2.t-BuOK-mediated reductive addition of P(O)–H compounds to terminal alkynes forming?-arylphosphine oxides.A novel and efficient t-BuOK-mediated reductive addition of P(O)–H compounds to terminal alkynes is developed.A variety of?-arylphosphine oxides including the valuable?-heteroarylphosphine oxides were produced in moderate to high yields under a mild reaction condition.This reaction may proceed via a tandem process involving regio-selective double addition and subsequent transfer hydrogenative dephosphorylzation(benzylic C–P cleavage).3.t-BuOK-mediated reductive coupling of P(O)–H compounds with cinnamonitriles forming?-arylphosphine oxides.A t-BuOK-mediated reductive coupling between cinnamonitriles and P(O)-H compounds has been disclosed.Under the reaction conditions,cinnamonitriles including those bearing functional groups coupled with P(O)–H compounds,producing the corresponding?-arylphosphine oxides in high yields.Preliminary mechanistic studies showed that this reaction proceeded through sequential cleavage of sp~3C–CN and sp~3C–P(O)bonds:a P(O)–H compound added to a cinnamonitrile,followed by denitrilation,generating an alkenyl phosphoryl compound,which further undergoes hydrophosphorylation with another P(O)–H compound to produce a1,2-diphosphoryl compounds.The resulting diphosphoryl compound is transfer-hydrogenatively dephosphorylated with i-PrOH by the aid of a base to yield the expected product.4.Base-mediated reactions of P(O)–H compounds with allyl chlorides:synthesis of allyl phosphoryl compounds,alkenyl phosphoryl compounds and 1,2-diphosphoryl compounds.Allyl phosphoryl compounds are generally prepared by classic Arbuzov reaction at a high reaction temperature.However,under the reaction conditions,the double bond would shift to generate a by-product alkenyl phosphoryl compound(>15%),leading to difficulty in isolation and purification of products.By extensive studies,we find a weak base can promote the nucleophilic substitution of allyl chlorides with P(O)–H compounds under mild reaction conditions(-15–60 ~oC),high selectively producing the corresponding allyl phosphoryl compounds(>97%).This reaction can proceed at 100 mmol scale without any decrease of reaction efficiency.By simple filtration,the analytically pure products are obtained,showing potential application in industrial.At room temperature,the reaction of allyl chloride with P(O)–H compounds promoted by a strong base NaOH can selectively produce the alkenyl phosphoryl compounds with double bond migration.While elevating the reaction temperature to 100-130 ~oC,the 1,2-diphosphoryl compounds can be selectively generated from the reaction of allyl chloride and P(O)–H compounds under similar reaction conditions.