Study On Regioselective Cyclization Of Bifunctional Synthons Containing Amide-tethered Alkynes

The carbon-carbon triple bond(alkyne bond)is one of the most basic and important functional groups in organic chemistry.As a multifunctional chemical synthon,alkyne bonds can be used to efficiently construct a variety of compounds with practical value.For example,nitrogen-containing heterocyclic compounds or oxygen-containing heterocyclic compounds can be selectively constructed through the selection of reaction conditions by using bifunctional synthons containing amide and alkyne bonds.However,we know that regioselectivity control remains a major challenge for alkyne chemistry.For example,in the above-mentioned regioselective cyclization reactions of bifunctional synths containing amide and alkyne bonds,there has been few studies on regioselective N-cyclization reactions of alkyne bonds attacked by amide nitrogen atoms.Therefore,in this paper,the regioselectivity cyclization of the alkyne bond attacked by the amide nitrogen atom is studied through the design of different reaction mechanisms based on the bifunctional synthon containing amide and alkyne bonds,which contain 6-endo-dig aza-cyclization,6-endo-dig aza-cyclization in an oxygen atmosphere,5-exo-dig aza-cyclization,and oxidative 5-exo-dig aza-cyclization.And differently substituted skeleton compounds such as isoquinolin-1-one,3-hydroxyisoquinolin-1,4-dione,isoindole-1-one and 3-hydroxyisoindole-1-one were constructed.The main contents are as follows:1.Copper-catalyzed 6-endo-dig aza-cyclization of alkynes initiated by amide nitrogen radicals to synthesize isoquinolin-1-oneA copper-catalyzed N-attack 6-endo-dig cyclization of 2-alkynylbenzamide initiated by an amide nitrogen radical was developed.In the reaction,a series of isoquinolin-1-one compounds were efficiently and rapidly constructed with 20 mol% copper chloride as a catalyst in a nitrogen atmosphere under mild conditions.The mechanism study showed that the single electron transfer(SET)of copper chloride with N-methoxyamide produced 2-alkynylamide nitrogen radical A and monovalent copper.Monovalent copper can be detected by XRD.The generated amide nitrogen radical undergoes intramolecular alkyne bond radical 6-endo-dig aza-cyclization reaction to obtain isoquinolin-1-one radical intermediate B,which is then reacted with the raw material 2-alkynylbenzamide In the N-H bond,hydrogen abstraction takes place to obtain the final product isoquinolin-1-one,and a new 2-alkynylbenzamide nitrogen radical is regenerated.2.Synthesis of 3-hydroxyisoquinoline-1,4-dione by 6-endo-dig aza-cyclization of alkynes initiated by amide nitrogen radicals catalyzed by copper under oxygen atmosphereInterestingly,the amide nitrogen radical starts,and the isoquinolin-1-one radical intermediate B obtained through the radical 6-endo-dig aza-cyclization can be captured by oxygen to form isoquinolin-1-one-4-Peroxy radical C.The peroxy radical is liable to undergo 4-endo-trig cyclization reaction,oxygen-oxygen bond cleavage and hydrogen extraction,and 3-hydroxyisoquinoline-1,4-dione can be obtained.Furthermore,it was found that reducing the amount of copper chloride used can greatly inhibit the hydrogen abstraction by-products of the isoquinolin-1-one radical intermediate B.3.Synthesis of 3-hydroxyisoquinoline-1,4-dione by generating hypervalent iodine reagent strategy in situAn N-attack 6-endo-dig cyclization reaction of a bifunctional synthons containing an amide and alkyne bond was developed.The catalytic amount of iodobenzene was oxidized by m-chloroperoxybenzoic acid(m-CPBA).A hypervalent iodine reagent was generated in situ in a mixed solvent of water and acetonitrile,and a series of 3-hydroxyisoquinoline-1,4-dione derivatives were synthesized simply and efficiently using boron trifluoride ether as a Lewis acid additive.Compared with the direct use of stoichiometric hypervalent iodine reagents,this method avoids the waste of stoichiometric iodobenzene by-products,and is a more gentle and economical method for constructing 3-hydroxyisoquinoline-1,4-dione.4.Synthesis of 3-hydroxyisoindolin-1-one by 5-exo-dig aza-cyclization promoted by cyclic ethers in the aqueous phaseA new method for constructing 3-hydroxyisoindole-1-ones in aqueous phase was promoted by 1,4-dioxane promoted oxidative 5-exo-dig aza-cyclization.In the reaction,tetrabutylammonium bromide(TBAB)was used as an additive,and oxone was used as an oxidant.The reaction was highly efficient and the substrate was widely applicable.The mechanism study shows that the reaction may first involve the regioselective nitrogen radical 5-exo-dig bromine cyclization to obtain a key intermediate,3-bromomethylene isoindole-1-one.Then,this key intermediate undergoes a bromine hydration reaction and a hydrolysis reaction of a dibromo compound to obtain 3-hydroxyisoindolin-1-one.5.TBAB-catalyzed regioselective cyclization of 2-alkynylbenzamide to isoindole-1-oneA N-5-exo-dig cyclization reaction catalyzed by TBAB was developed using alkynes linked with N-methoxyamide as raw materials and used to construct a series of isoindoles-1-one compound.Studies have shown that the N-methoxy protecting group is the key to the success of the reaction.During the reaction,the N-methoxy group is prone to undergo 1,2-migration of the hydrogen atom,and an intra-salt intermediate containing a nitrogen anion and an oxygen positive ion is obtained.Then,it undergoes N-5-exo-dig nucleophilicity.The addition gave an isoindole-1-one compound.The reaction uses water as a solvent,does not require transition metals,oxidants and alkalis,has high atom utilization,economical steps,and meets the requirements of "green chemistry".