Novel Synthesis Of Chromone Compounds Via PhIO-mediated Dehydrogenation

Chromones are an important class of oxygenated heterocyclic compounds that are ubiquitous in nature and are particularly widely distributed in plants.The chromone skeleton is an important structural unit of many natural products and biologically active substances,and is also widely used in the development of various drugs.Because of its important application value,it has been widely concerned by the majority of scientific researchers.It was found that chromone derivatives exhibit a wide range of pharmacological effects,including antibacterial,antifungal,anticancer,antioxidant,anti-HIV,antiulcer,immunostimulatory,anti-inflammatory,as well as biocidal.Due to the important potential medicinal value of chromone skeleton,the development of related synthetic method strategies has also received increasing attention.According to literature research the existing methods mainly include oxidative dehydrogenation reaction,organometallic catalyzed synthesis of chromones and radical cyclo-addition reaction.Although the methods have their respective merits in the preparation of the corresponding chromone derivatives,it is obvious that some of them still suffer from drawbacks such as long time,high temperature,traditional-metal-catalyzed and so on.Therefore,the development of alternative approaches providing an efficient synthesis of chromones under mild conditions are desirable.The organic chemistry of hypervalent iodine compounds has experienced an unprecedented,explosive development during the last decade of the 20th century.In the last five years a vast literature on this subject is available in the literature.The oxidizing properties,benign environmental character and commercial availability of hypervalent iodine regents have developed the interest in the investigation of hypervalent iodine compounds.Hypervalent iodine reagents have emerged as a class of efficient and environmentally benign nonmetal“green”oxidants.Iodosobenzene（Ph IO）as one of the hypervalent iodine regents has been widely used in many synthetic transformations.It was found that Ph IO is efficient in epoxidation of olefins,converting alkynes and alkenes to ketones,oxidizing alcohols to aldehydes,as well as in the directα-hydroxylation of ketones.Furthermore,it could also be used to supply oxidative C-C,C-N,and C-O bond formations.Herein,we decided to develop an oxidative dehydrogenation reaction of substituted chromanones via Ph IO-mediated.Through consulting the literature,various chromanone derivatives were prepared according to known easily synthetic routes.We used the ethyl 4-oxo-2-phenylchromane-3-carboxylate（146a）as the model substrate to start out our investigation.After the screening of the oxidants,solvents,temperature and additives,we decided the optimal conditions to treat the ethyl 4-oxo-2-phenylchromane-3-carboxylate（146a）in DMF in the presence of Ph IO at room temperature about 10 minutes to afford the chromone（147a）with high yields.So the synthesis of chromone compounds was carried out via oxidative dehydrogenation reaction.In order to verify the applicability of the method we prepared a series of chromone derivatives under optimal conditions.Twenty-seven functionalized chromone derivatives successfully synthesized.The structures of all the reaction substrates and the obtained products were confirmed by melting point,¹H-NMR,¹³C-NMR and high resolution mass spectrometry（HRMS）to determine the correctness of the structure.Control experiments were designed and conducted to elucidate the reaction mechanism of this transformation.The two radical-trapping reagents TEMPO and BHT were treated separately of the reaction mixture.It was found that the products obtained from both show a yield of about 50%.Through literature research,previous work,and the results of control experiments,we tentatively propose that this dehydrogenative oxidation reaction may undergo both radical and non-radical pathways.In conclusion,we have successfully designed and developed a novel method for the construction of chromones via Ph IO-mediated oxidative dehydrogenation reaction under metal-free and mild reaction conditions.Although this new method has some obvious features,we found that is not perfect and more suitable to synthesize the trisubstituted chromone skeletons carrying electron-withdrawing groups.Further studies on the applications of the method are undergoing in our laboratory.