Studies On The One-pot Synthesis Of Quinazolinone Under Metal-free Conditions By Using Arylmethyl Mercaptan Or Benzyl Alcohol As Substrate

Quinazolinones,an important nitrogen-containing heterocycle,which are widely found in natural products and have good biological and pharmaceutical activities.For example,some quinazolinones have significant antitumor,antihistamine,anti-inflammatory,analgesic activities and are also used as central nervous stimulants,analgesics,sedatives and anxiolytics.Therefore,the synthetic method for quinazolinone has been a research hotspot in the field of organic chemistry and medicinal chemistry.The straightforward functionalization of inert C(sp3)-H bond under metal-free conditions is still a challenge in organic synthesis,especially for the one-pot convenient synthesis of quinazolinone with commercially available raw materials.In this paper,the new menthods for the synthesis of 2-arylquinazolin-4(3H)-one were established by using commercial available anthranilamide and arylmethyl mercaptan(ArCH2SH)as the starting materials to construct new multi-C-N bonds via one-pot C(sp3)-H oxidative desulfurization,dehydrogenative/cyclization,and dehydroaromatization under metal-free and external oxidant-free conditions.The main research contents are as follows:(1)Initially,the reaction between anthranilamide and benzyl mercaptan was choosed as the model reaction to optimize the reaction conditions including solvent,alkali,reaction temperature and substrate ratio etc.A new method for the synthesis of 2-arylquinazolin-4(3H)-one derivatives was successfully developed via the oxidative cyclization of thiol with inert C(sp3)-H bond.(2)With the optimal reaction conditions in hand,the scope and limitation of substrates was investigated.Overall,various anthranilamide and benzyl mercaptan derivatives could be amenable to this reaction.A wide range of functional groups on the aromatic ring were well tolerated,providing a convenient way to 2-arylquinazolin-4(3H)-one.And the electronic effect and steric hindrance effect of substituents on the aromatic ring in both substrates has little effect on the reaction yields.Four series of 43 kinds of 2-aryl(heteroaryl)quinazolin-4(3H)-ones were obtained in 25～98%isolated yields under metal-free conditions.The Structure ofobtained products was confirmed by 1H NMR,13C NMR;4new compounds were further confimed by HRMS(Scheme 1).(3)The control experiments,radical trapping reagents(for example TEMPO and BHT),1H NMR and MS tracking experiments were conducted to gain some insight into the reaction mechanism.The results revealed that the thiobenzaldehyde,generated in situ from thiol,underwent the nucleophilic addition with anthranilamide to start the one-pot cyclization.And the thiol substrate could promot the yield of dehydroaromatization of 2-phenyl-2,3-dihydroquinazolin-4-(3H)-one.A plausible mechanism was proposed based on control experimental results and literatures.(4)Under the optimal conditions,the reaction of benzyl alcohol and anthranilamide was slao examined.The structure of the 17 kinds of products was confirmed by 1H NMR,13C NMR.The electronic effect and steric hindrance effect of substituents on the aromatic ring iof substrates has no significent effect on the reaction yields.