Published: March 21, 2011 r2011 American Chemical Society 2433 dx.doi.org/10.1021/jo1018188 | J. Org. Chem. 2011, 76, 2433–2438 ARTICLE pubs.acs.org/joc Chelation-Mediated Palladium(II)-Catalyzed Domino HeckMizoroki/ SuzukiMiyaura Reactions Using Arylboronic Acids: Increasing Scope and Mechanistic Understanding Samir Yahiaoui, Ashkan Fardost, Alejandro Trejos, and Mats Larhed* Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden b S Supporting Information ABSTRACT: A palladium(II)-catalyzed HeckMizoroki/SuzukiMiyaura domino reaction involving metal coordinating dimethylaminoethyl vinyl ethers and a number of electron-rich and electron-deficient arylboronic acids has been developed. Through variation of the temperature and the concentration of the p-benzoquinone (p-Bq) ligand/reoxidant, conditions for the robust and convenient one- pot generation of diarylated-saturated ethers were identified. With the aid of coordination of the dimethylamino group to the arylpalladium intermediate, the otherwise predominant formation of the β-arylated olefin could be reversed. A reaction route involving a chelation-controlled carbopalladation, providing a p-Bq stabilized six-membered palladacycle, followed by transmetala- tion and reductive elimination is suggested to explain the selective formation of saturated diarylated ether products. ’ INTRODUCTION Palladium-catalyzed coupling reactions continue to be one of the most important tools for the construction of CC bonds in organic synthesis, with the HeckMizoroki reaction playing a prominent role for the arylation and vinylation of olefins. 1 The first palladium(0)-catalyzed arylations of an alkene with an organic halide were reported independently by Mizoroki 2 and Heck 3 in the early 1970s. This was followed by Heck’s discovery in 1975 of an analogous palladium(II)-mediated vinylation of an olefin using a vinylboronic acid and stoichiometric amounts of palladium acetate. 4 Despite the fact that reoxidizing agents had been reported to enable palladium(II) catalysis in the 1960s, 5 the field of palladium(II)-catalyzed Heck reactions would not emerge until in 2001. 6 This was a result of an innovation in terms of preparative viability by Mori and co-workers utilizing Cu(OAc) 2 as the reoxidant to regenerate Pd(II) from Pd(0). 6 In addition, Jung reported in 2003 that molecular oxygen could serve as a capable reoxidant of palladium in a vinylic substitution reaction with arylboronic acids, 7 a transformation that gradually became known as the oxidative Heck reaction. 8,9 Today, palladium(II)-catalyzed oxidative HeckMizoroki ar- ylation reactions have been developed into smooth and high- yielding synthetic methods. 10,11 Arylboronic acids 6,1216 are com- monly employed arylpalladium precursors in the oxidative Heck reaction, but other arylating agents have also been reported, e.g., arylstannanes, 17 arylsilanes, 18,19 arylmercury, 20 arylphosphonic acids, 21 arylbismuth, 22 and arylantimony 23 compounds. In the endeavor toward more preparatively feasible and environmentally benign methods for the synthesis of organic compounds, there is an emerging interest to incorporate dif- ferent palladium-catalyzed reactions into one-pot domino reactions. 24,25 Palladium(0)-catalyzed domino processes have received special attention for the mild, selective, and modular construction of highly functionalized molecules. 26,27 Although these advancements have facilitated the preparative procedures immensely, they are still limited to substrates (or substrate combinations) with both a palladium(0)-activated leaving group and a palladium(II) reactive functionality. 28 With these consid- erations in mind, there is a timely need to expand the scope of palladium-catalyzed domino reactions to utilize the oxidative palladium(II)-catalyzed pathway using arylboronic acids as ar- ylating agents. Sequential one-pot transformations initiated by a palladium- (II)-catalyzed transmetalation and a subsequent Heck Mizoroki carbopalladation involve a reactive σ-alkyl palladium- (II) intermediate. Depending on the substrate and the catalytic conditions, it is often possible to react the transient σ-alkyl palladium(II) species in situ through various cross-coupling reactions, yielding difunctionalized target structures. 29,30 The ability of intramolecular factors to overcome the reluctance of substituted alkenes to participate in the Heck insertion process, Received: December 28, 2009