Study On Intramolecular [4+2] Reaction Of Photogenerated Ketene Methide Intermediate

Cycloaddition reactions have long played a significant role in synthetic organicchemistry, and are often utilized to form six-membered or other size rings.Photocycloaddition, which represents an important strategy for the synthesis ofthree-to eight-membered rings, is an important part of cycloaddtion for it can offertremendous scope for stereocontrol and enable the preparation of cyclic systems thatare difficult to access by alternative thermal methods. The Diels-Alder reaction, orso called [4+2] cycloaddition which has undergone in-depth studies, is the mostrepresentative synthesis method among the cycloaddition reactions, and has beenwidely utilized in the synthesis of some important intermediates. Regretfully, the[4+2] reaction involving ketene methide intermediate as unstable dienes was lessstudied, and the ketene methide only generated from benzocyclobutenones can betrapped by added dienophiles.In addition, ketene methide intermediate can be obtained from ortho-vinylbenz-aldehyde and its derivatives under photoirradiation. In this article, theseortho-vinylbenzaldehyde derivatives were synthesized, but the intermediate cannotbe trapped by added dienophiles as previously reported, which makes theintermolecular [4+2] reaction not come true. On basis of these unsuccessful facts,the reactants were redesigned after rational thinking and theoretical analysis.orth-formyl dienes were synthesized starting from phthalic acid and led to [4+2]adducts through ketene methide intermediate under UV-irradiating. This pioneeringsuccess makes it a great progress in ketene-methide-focused [4+2] reaction. Thisintramolecular [4+2] reaction exerts excellent regioselectivity, and two products ofthis reaction are proved to be diastereoisomers possessing benzocycloheptanone andbridge ring structures. Given the initial success, a more detailed study wasperformed, such as optimization of the reaction condition, studying the influence ofsubstituent group. Furthermore, the mechanism of this reaction was thoroughlystudied through deuterium-labeled experiments, trapping of ketene methide,rejection of radical generation and kinetic experiment. Meanwhile, this reaction wasamplified and its quantum yield was determined. Interestingly, the ketene methideintermediate, generated in situ under photoirradiation, is identified aselectron-deficient dienes according to our studies. But it totally goes against thepublished conclusion that the ketene methide intermediate is electron rich dienesystem. Benzobicycloheptanones, the products of this intramolecular [4+2]cycloaddition, are pivotal intermediates of certain bridged and fused type agonists of GPR40which are generally used in the treatment or prevention of type2diabetes.So, this reaction will play an important role in future application.