Study On Arene Trifunctionalization Via 1,2-Benzdiyne

Aryne has been developed for nearly 100 years since it was first speculated.However,due to the harsh generation conditions and poor functional group compatibility in early era,arynes have yet been emphasized for a long period of time by synthetic chemists.Along with the discovery of mild aryne generating conditions,in the past two decades,new chemical transformations involving aryne intermediates gained rapid development.Meanwhile,the advantage of aryne chemistry on versatily introducing two vicinal functional groups attracked much attention from broad fields of synthetic organic chemistry,medicinal chemistry,and functional organic materials.By overviewing the achievements on aryne chemistry,it was noticed that traditional single aryne intermediate could only afford vicinal difunctionalization of arenes;whereas,it remains unachievable to introduce three or even more substituents on a single aryne in one operation.In contrast,natural products or drug molecules containing three or more substituents on the aromatic ring are prevail.Therefore,the application of aryne intermediates in one-step synthesis of multi-substituted aromatic compounds will greatly expand the scope of aryne chemistry in organic synthesis.In order to solve the limitation of traditional single aryne reaction,chemists put forward the concept of polyaryne,in which two or even three acetylene bonds are present on the same aromatic ring.Such as benzdiynes,and benztriynes.Although the chemistry of polyaryne has gained some achievements in the past three decades,several disadvantages remain,such as harsh generation conditions,poor selectivity,and multistep prepration.To overcome the above-mentioned problems of aryne chemistry,we designed and synthesized a new 1,2-benzdiyne equivalent,namely 2-（trimethylsilyl）-1,3-phenylene bis（trifluoromethanesulfonate）,in which TPBT can be used as its brief name.This aryne precursor owns the following charactors:once activated,two aryne intermediates can be generated in a consequtive sequence,just like pulling down a line of dominos.Therefore,this TPBT reagent can also be named as domino aryne precursor.When thioamides is used as substrates,upon activation of TPBT to form1,2-aryne intermediate,sulfur acts as the first nucleophilic reagent to attack it,producing 2,3-aryne intermediate with concomitant departure of OTf group.This2,3-aryne is attacked intramolecularly by N-nucleophile of the thioamide and afforded 1,2,3-trisubstituted aromatic compounds in one step after carbonyl group migration.The carbonyl group in the product can be further converted to cyanyl,amides,and carboxylic acids,the structure of which have shown antitumor activity.The third chapter of this dissertation introduces a new way upon selective formation of 2,3-aryne through Grob fragmentation of a benzocyclobutenes,which was formed via[2+2]cycloaddition of 3-LG substituted aryne with olefins.In this work,we first screened the leaving group and found that when OTf is the leaving group,the reaction efficiency is the highest.Next,the regioselectivity of the2,3-aryne reaction was optimized,which is the best whenever gem-dimethyl or gem-dimethoxy groups replace the two hydrogens on CH₂ of the four-membered ring.We also tried to use a variety of arynophiles to react with 2,3-aryne.At last,two medicines,Fenoprofen and Carprofen,and an anticancer drug Niraparib for ovarian cancer were synthesized by this method.In summery,with 3-OTf aryne as 1,2-benzdiyne precursor,a series of compounds with 1,2,3-trisubstituted aromatic ring were synthesized through two synthetic strategies:（1）3-OTf aryne reacted with thioamide to afford2,4-disubstituted benzothiazole;（2）selective ring-opening of the[2+2]cycloadduct of 3-OTf aryne to give a series of 1,2,3-trisubstituted arenes.Both research works break the limitation that single aryne can only carry on ortho-difunctionalization.Further expansion of these two methods could synthesize fenoprofen,carprofen and niraparib,showing their potential in the field of drug synthesis.