Palladium-catalyzed Directing Group-controlled Cross-coupling Reactions Of Alkynes With Alkenes

Transition metal-catalyzed cross-coupling reactions have occupied a significant area in organic synthesis meanwhile transition metal plays a key role in those reactions. Among the transition metals, chemists have made a lot of detailed research on palladium-catalyzed cross-coupling reactions. Basing on these results to form C-C bond and C-hetero bond, palladium-catalyzed cross-coupling reactionsof alkynes and alkenes have received considerable attentions and have developed to a high level. In 2010, the palladium catalyzed Heck-type reaction, recognized with Nobel Prized, has also lead to development of oxidative Heck reaction. At present, palladium-catalyzed crossing reactions have been extensively applied in the syntheses of medicinal intermediates and total syntheses of natural products. During the process of mechanism, palladium-catalyzed cross-coupling reactions of alkynes and alkenes contain forming of the C-Pd bond, insertion of alkenes and cleavage of C-Pd bond. β-H elimination, β-heteroatom elimination, reductive elimination and protonolysis are main cleavage ways of C-Pd bond. Furthermore, β-H elimination has been regarded as the most important step in the transition metal-catalyzed reactions and Heck reactions. The directing-groups in our reactions can change the direction of β-H elimination or suppress β-H elimination to achieve new approaches which are totally different from former reactions to synthetize highly atom economic,regio- and stereoselective products to fulfill the demanding of Green Chemistry. In this context, we have studied:(1) directing group-controlled selective β-H elimination to form β-indole ketones;(2) directing group-controlled ways to suppress the β-H elimination to achieve the functionalization of alkenes.We have systematically studied palladium-catalyzed cross-coupling reactions of alkenes and alkynes in this context, and developed a series of efficient, convenient and environmental-friendly methods. The details are summarized as following:(1) Palladium-catalyzed cross-coupling reaction of 2-alkynyl anilines and allylic alcohols: owe to the direction of β-H elimination, alkyl-Pd intermediates can generate mixture products. In our reactions, the hydroxyl group can assisted alkyl-Pd intermediates to solve this problem. Basing on these encouraging results, a simple and efficient palladium-catalyzed oxidative coupling is described by using cheap and green dioxygen as the oxidant. These cross-couplings have a large functional group tolerance and are of higher reactivity toward electron nonbaised allylic alcohols meanwhile to form C(sp2)-N bond and C(sp2)- C(sp3) bond. The resultant β-indole ketones are readily converted to pharmaceutically significant β-indole alcohol/amine and pyrrolo[2,1-a]isoquinolines.(2) Palladium-catalyzed cross-coupling reaction of alkynamides and alkenes: This paper describes two efficient strategies to suppress β-H elimination. Remote donor groups with the terminal olefins, such as toluenesulfonamide, phosphate, sulfone, etc., cooperate with the amide of alkynamides and chelate the palladium active center, to promote C(sp3)-O bond formation by suppressing the β-H elimination. Furthermore, the highly functionalized a-methylene-glactone is an important moiety existing in numerous natural products with biological activities. Another strategy uses the rigid structure of norbornene to make an intermediate without a syn-β-hydrogen to achieve reductive elimination of the C-Cl bond.(3) Pd-catalyzed carboetherification of alkenes with alkynamides:Highly regio- and stereoselective nucleopalladation of alkynes initiates the cross-coupling between alkynamides and alkenes to give the olefin oxyalkenylation products in good to excellent yields. The hydroxyl group in the olefins cooperates with the amide in alkynamides to promote the cyclization by suppressing β-H elimination. A mechanism involved trans-halopalladation of alkynes, following by insertion of alkenes and reductive elimination of C-O bond. A convenient and efficient approach to construct functionalized oxygen heterocycles, i.e., tetrahydrofurans, tetrahydropyrans, and γ-lactones, has been reported.