| Phthalazines are an important N-heterocyclic compound.Many phthalazine derivatives have unique biological activities,including anticonvulsant,antiinflammatory,and antitumor effects etc.,thus their high–yield synthetic approaches are of great value in the regard of application.Organic phosphonic acids and esters have broad application in organic synthesis,pharmaceutical research,material synthesis and modification etc.,and ?-aminophosphonates possess multiple biological activities as amino acid analogues,thus their synthetic methods also draw wide attention.In this thesis,phthalazine was designed to react with organic halides to afford phthalazinium salts to modify its 2-position and greatly increase the electrophilicity of the 1-position.The phthalazinium salts as starting materials then went through nucleophilic addition with dialkyl phosphonates in alkaline conditions to give phthalazinyl ?-aminophosphonates.The optimal condition of the reaction was determined after extensive screening: conducting the reaction with Li2CO3 as base in N,N-dimethylformamide at room temperature for 12 hours.The applicability was then studied using different phthalazinium salts and phosphonates,18 phthalazinyl ?-aminophosphonates were synthesized,and the reaction proved to have a good substrate scope.Thus,a new synthetic method of phthalazine derivatives and ?-aminophosphonates was developed,which features advantages of no need of metals,mild conditions,facile operation and good applicability.The nucleophilic addition nature of this reaction was further confirmed with isotopic labelling experiments.The asymmetric version of this reaction was explored with chiral bases.During screening of conditions and structural modification of asymmetric bases,11 chiral bases were screened,and an ee of 31% was achieved when conducting the reaction with 1 equiv.of quinine as base in toluene at-40 ?,providing new ideas for the synthesis of chiral phthalazine derivatives and chiral ?-amino-phosphonates. |
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