1,2-Aminohalogenation Of Arynes

Arynes are very active intermediates and 1,2-difunctionalization of arynes can introduce two substituents into the aromatic rings at the same time,which provides convenient methods for the construction of bioactive molecules containing complex aromatic compounds.However,1,2-aminohalogenation of arynes has been rarely reported because of the narrow scope of substrates,harsh reaction conditions,and low yields.Here,we use inexpensive and readily available organohalides as halogen electrophiles to capture zwitterionic intermediates produced by the addition reaction of nitrogen nucleophiles,such as imines,N-heteroarenes,and amines,and arynes.As a result,we have developed some novel 1,2-aminohalogenation reactions of arynes and simply synthesized various o-haloaniline derivatives.The core structure of o-haloaniline derivatives exists in many bioactive molecules,such as aripiprazole,clinafloxaxin,dichloromethotrexate,and pirprofen.This dissertation is divided into four chapters:Chapter 1:1,2-Difunctionalization of arynes and synthesis of o-haloanilinesWe briefly introduced the methodologies for aryne generation and the reactions of arynes,and then described 1,2-difunctionalization of arynes by vicinal carbon-carbon/carbon-carbon,carbon-carbon/carbon-heteroatom,and carbon-heteroatom/carbon-heteroatom bond-forming reactions of arynes.Among them,the products of 1,2-aminohalogenation of arynes are o-haloanilines,but narrow scope of substrates,harsh reaction conditions,and low yields present in these reactions.At the same time,other synthetic methods for o-haloanilines were also introduced:(1)direct electrophilic halogenations of anilines with the disadvantages of narrow scope of substrates,low yields,and poor chemoselectivity and regioselectivity;(2)transition-metal catalyzed ortho-C-H halogenation of arylamides with the disadvantages of using directing groups and transition metal.Chapter 2:1,2-Aminohalogenation of arynes based on imines or N-heteroarenes and organohalidesWe used imines or N-heteroarenes as nitrogen nucleophiles and organohalides as halogen electrophiles to achieve 1,2-aminohalogenation of arynes.When using CsF and MeCN as reaction conditions and 2-(trimethylsilyl)phenyl triflate as aryne precursors,a series of imines or N-heteroarenes can react with arynes and organohalides(CCl4,CCl3CN,CBr4,and BrCF2CO2Et)to generate o-haloanilines with medium to excellent yields.The reactions can occur well with different alkyl and aryl substrates of different electronic effects and steric hindrance.Chapter 3:1,2-Aminohalogenation of arynes based on amines and organohalidesWe have achieved the 1,2-aminohalogenation of arynes by using amines as nitrogen nucleophiles and organohalides as halogen electrophiles.When using KF,18-Crown-6-Ether and THF as reaction conditions,tertiary amines with cyano,nitro,hydroxyl,ester,ketone,alkenyl,and alkynyl functional groups can react with arynes and organohalides(CCl4,CCl3CCl3,NCS,CBr4,CBr3F,NBS,CI4,and NIS)to get o-haloanilines with medium to excellent yields.Moreover,secondary amines can also participate in the 1,2-aminohalogenation of arynes with good yields.Chapter 4:1,2-Aminohalogenation of arynes based on the rearrangement of tertiary aminesWe used allyl and benzyl tertiary amines as nitrogen nucleophiles and organohalides as halogen electrophiles to achieve 1,2-aminohalogenation of arynes by the[2,3]and[1,2]rearrangements.When using CsF and MeCN as reaction conditions,[2,3]rearrangements occurred among allyl tertiary amines with ester,ketone,amide,and cyano groups,arynes and organohalides(CCl4,CCl3CN,CBr4,CBr3F,and BrCF2CO2Et)with moderate to good yields.Under the same conditions,[1,2]rearrangements occurred among benzyl tertiary amines with electron-withdrawing groups,such as fluorine and bromine,and electron-donating groups,such as methyl and methoxy groups,benzyne and CCl4 with moderate yields.Both rearrangement products are o-haloanilines,and effectively avoid the production of anilines by[2,3]and[1,2]rearrangements of allyl or benzyl tertiary amines and arynes...