The direct approach: Tandem cyclization of 1‐aryl‐4‐aza‐2‐bromo‐1‐alken‐6‐ynes with catalytic Pd(OAc)2 and cesium carbonate in EtOH led to direct construction of tri‐ or tetracyclic heterocycles, through intramolecular carbopalladation and aromatic CH bond functionalization (see scheme). This route in which two CC bonds are formed enables the construction of complex heterocyclic skeletons directly from readily prepared enynes.

Direct construction of fused aromatic ring systems by "zipper-mode" double C-H bond activation is described. Treatment of (Z)-3-bromo-N-(2-bromo-3-phenylprop-2-enyl)aniline derivatives with a catalytic amount of Pd(OAc)2 and PCy3.HBF4 in the presence of Cs2CO3 in dioxane affords 4,5-naphtho[3,2,1-cd]indole derivatives in good yields. Introduction of heterocycles such as benzofuran, benzothiophene, or indole moieties into the substrates leads to the efficient construction of highly fused heterocyclic aromatic ring systems via C-H bond activation of the heteroaromatic rings.

Cascade cyclization of bromoenynes bearing an aryl group with catalytic amounts of palladium(II) acetate and cesium carbonate led to the direct construction of tri-or tetracyclic heterocycles. Direct arylation of a pyrrole, furan or thiophene ring in the cascade reaction affords the corresponding fused heteroarenes in moderate to good yields.The development of cascade reactions that realize stepeconomical syntheses of complex compounds by multiple bond formation represents one of the most attractive subjects in modern organic chemistry. 1 A challenge in this area is to improve atom economy by minimizing waste product formation. 2 C-H bond activation (including direct arylation), which avoids pre-activation of the substrate and thus minimizes the production of waste, is an important strategy for this purpose. 3 As a result, considerable attention has been paid recently to catalytic cascade reactions involving a C-H bond activation step. 4Palladium catalysts are known to promote a variety of transformations, including C-H bond activation. Several palladium-catalyzed cascade reactions have been reported recently, including carbopalladation onto a carbon-carbon multiple bond, followed by C-H bond activation to form cyclic products. 4,5 Reactions involving carbopalladation onto a carbon-carbon triple bond are especially useful for the direct construction of fused aromatic ring systems 6,7 such as oxindoles, 6a,b fluorenes, 6c indoles, 6d phenanthrenes, 6e biarylidenes, 7a,b acenaphthylenes, 7c and fused fulvenes. 7d We recently found that palladium-catalyzed cascade cyclization of bromoenynes 1 provides direct access to benzoisoindole derivatives 2 (Scheme 1). 8 This reaction proceeds through oxidative addition of a bromoenyne 1 to palladium(0), carbopalladation, and aromatic C-H bond activation. Herein, our detailed studies on this cascade cyclization, which includes aromatic C-H bond activation, for the synthesis of various tri-and tetracyclic heterocycles, are reported. A reaction involving direct arylation with heteroarenes is also described. Scheme 1 Synthesis of isoindoles by palladium-catalyzed cascade reaction through C-H bond activation.The cinnamylamine-type bromoenynes 11 required for the cascade reaction were prepared according to the general route shown in Scheme 2. Carreira asymmetric alkynylation 9 of aldehydes 5 with alkynes 6 gave propargylic alcohols 7, which were converted into the corresponding protected propargylic amines 8 by Mitsunobu reaction with Boc-amides followed by acid treatment. In some cases, racemic propargylamines, which were readily prepared by reaction of lithium acetylide with aldehydes followed by amination, were used. A second Mitsunobu condensation with 2-bromocinnamyl alcohols 10, which were obtained by Wittig reaction of aldehydes 9 followed by reduction with diisobutylaluminum hydride (DIBAL-H), afforded the desired bromoenynes 11 in good yields.