TBHP/TBAI-Mediated Synthesis Of Pyrrolin-4-one Derivatives

Pyrroline-4-one derivatives are an important class of heterocyclic compounds which possess diverse pharmacological properties including anti-HIV-1,antimalarial and antimicrobial activities.Several works have reported synthesizing this compound,however,all of them has their own drawbacks.Strategies towards pyrrolin-4-ones could be classified into the following four types:1)condensation of?-amino acid esters with aldehydes,vicinal tricarbonyl compounds with enamines or amidines with acetylenic esters;2)[2+3]cycloaddition reaction of cyclopropenones with imines and?-diazoimines with ketenes;3)transitionmetal-catalyzed intramolecular cyclization of?-aminoynones;4)dimerization of enamines or?-oxoamides followed by a 1,2 alkyl migration.1,2-Aryl migration,with its unique manner of reconstructing a molecular skeletal,has become one of the most fundamental strategies in organic synthesis.Generally speaking,1,2-aryl migration can be categorized into three types:?i?via a carbocation intermediate,either generated in an acidic environment?TfOH,H₂SO₄,BF₃·Et₂O?or in the presence of a transition metal catalyst?Rh,Sm?;?ii?via a carbanion intermediate,such as in the classic Zimmerman-Grovenstein rearrangement reaction;?iii?via a free radical intermediate,generated upon treatment with a metal catalyst?Cu,Pd,Ag,Ni?,a non-metal oxidant?TBPB,DTBP,TBHP,hypervalent iodine?,or photoirradiation.However,only a few examples involving 1,2-aryl migration via a radical intermediate have been reported for synthesis of heterocyclic compounds.We established a new strategy toward pyrrolin-4-ones using the 1,2-aryl migration strategy.Explore the new strategy starting with using TBHP/TBAI as oxidants,enamines as substrates and changing different reaction conditions including solvents,catalysts,temperature and dosage of oxidants to test the reaction conditions.We found that when using 3 equiv of TBHP and 0.2 equiv of TBAI with 1 mmol of enamines in HFIP?4 mL?at 40 ^oC,the yield is high.Then a variety of enamines with different kind of substitution were converted into pyrroline-4-ones under the optimal reaction conditions.The impact of different substituted groups on the outcome of the reaction yields was studied.To identify the reaction mechanism,TEMPO??2,2,6,6-Tetramethylpiperidin-1-yl?oxyl?was used to test the reaction.When adding 3 equiv of TEMPO to the reaction system,the yield was suppressed to only 20%.This result indicated the reaction was at least partially through a radical process.Based on the control experiment and results from previous literature,a reasonable mechanism was proposed.This metal-free oxidative cascade reaction consists of key steps of coupling two radical intermediates,intramolecular ring closure and an exclusive 1,2-aryl radical migration.One important application of the obtained pyrroline-4-ones was transformed them into 4-hydroxypyrroles upon treated them with base via a simple decarboxylation and enol tautomerization process.In summary,we have described a metal-free synthesis of pyrrolin-4-ones from enamine esters via a one-pot cascade reaction which consisted of dimerization,cyclization and 1,2-aryl migration processes via a radical mechanism.The obtained pyrrolin-4-ones,in good to excellent yield,could be further transformed into the biologically active compounds of 4-hydroxypyrroles.