Novel Synthesis Of Deuterated Isobenzofuran-1(3H)-Ones Mediated By Hypervalent Iodine Reagent

The history of heterocyclic chemistry began in 1880,with the development of organic chemistry.Heterocyclic chemistry is an essential part of organic chemistry that deals with the heterocyclic compounds which constitutes about 65%of organic chemistry literature.Heterocyclic compounds are widely distributed in nature which are essential for life.Both natural and synthetic heterocyclic compounds are biologically active compounds because of their broad range of pharmacological activities.These heterocyclic compounds are divided into alicyclic and aromatic heterocycles.While,Phthalides also known as 3H-isobenzofuran-1-ones belongs to a class of o-heterocyclic compounds which are characterized by a bicyclic nucleus derived from the fusion of aγlactone ring between two carbon atoms carbon 1 and carbon 3 enclosed with a benzene ring.Fortunately,these phthalides are widely exist in natural products,pharmaceutical agents,biomolecules,dietary supplements and building blocks for the synthesis of more complex molecules.Recent studies estimated that over 60%approved marketed drugs have their roots in natural products.Some naturally occurring drugs such as phthalide isoquinolines,bicuculline,（+）-hydrastine and narcotine all possess phthalide moiety in their chemical structure.These biologically active phthalides have been forward to display anti-bacterial,anti-inflammatory,anti-tumor and anti-microbial,anti-cancer and anti-HIV activities.Due to important potential medicinal value of phthlaide skeleton,the development of related synthetic method strategies has also received increasing attention.According to literature research,the existing methods have their advantages,but they also have certain limitations.Therefore,the development of new strategies for synthesizing the phthalide skeleton,especially a non-metallic mediated has great significance.Organic hypervalent iodine chemistry has experienced rapid development in the past few decades and has developed into an important research area of organic chemistry.The hypervalent iodine reagents are widely used in a variety of oxidation reactions as a class of low-toxic,easy to prepare,mild,high selectivity,environmental friendly,oxidizing reagents that meets the requirement of green chemistry.Hypervalent iodine reagents,a class of non-metallic oxidant,have been successfully applied to the construction of the variety of heterocyclic compounds via C-C,C-O,C-hetero,hetero-hetero bond formation.Based on the literature research,we selected 2-（1-phenylvinyl）benzoic acid as a model substrate,and hypervalent iodine as oxidants to test the reaction conditions.After reaction screening,we obtained the optimal reaction conditions.Using 1.5 equiv of Ph IO react with 8 equiv of CD₃OD and 1 equiv of 2-（1-phenylvinyl）benzoic acid（model substrate）in DCM at 45 ^oC,the yield was high.After reaction screening,we postulated that the effective oxidant might not be the original Ph IO,but in situ generated hypervalent iodine species.But this hypervalent iodine specie is unstable at room temperature and gradually decomposed.This might be the fact that 1.5 equiv of Ph IO was required to realize a full consumption of starting material.Under optimal conditions,we are preparing a series of 3-（（methoxy-d₃）methyl）-3-phenylisobenzofuran-1（3H）-one derivatives to verify the applicability of the method.We synthesized some functionalized phthalide derivatives.For all the reaction substrates and the obtained phthalides,we confirmed their structures by melting point,¹H-NMR,¹³C-NMR and X-ray crystallography to determine the correctness of the structure.Through literature research,previous work,and experimental research results,we have proposed a mechanism for the formation of phthalides mediated by Ph IO/CD₃OD system via intramolecular lactonization,aryl migration and deuterated methoxylation.In summary,we have discovered a novel synthetic method to construct the phthalide skeleton with the application of Ph IO/CD₃OD system via intramolecular lactonization of C-O bond formation.The major features of this method include the synthesis of the biologically interesting phthalide under metal free and mild conditions.Furthermore,the deuterated methoxy group has been successfully incorporated into the heterocyclic skeleton.