Metal‐Catalyzed Cross‐Couplings of Aryl Halides to Form C–C Bonds in Aqueous Media

Abstract

Metal-catalyzed cross-coupling reactions have developed into a standard component of the synthetic chemist’s toolbox [1–4]. These reactions date to thework ofUllmann and Goldberg in the early 1900s on copper-promoted C–C and C–heteroatom bond formations. Copper remained the catalyst of choice for these reactions until the pioneeringwork ofHeck, Suzuki, Stille, Negishi, and others on palladium-catalyzed cross-coupling reactions. Palladium-catalyzed reactions, which can be generally carried out under milder conditions and with a wider range of substrates than reactions catalyzed by copper or other metals, have become standard methods for formation of carbon–carbon and carbon–heteroatom bonds. Cross-coupling reactions are characterized by the metal-catalyzed coupling of an organic electrophile, typically an organic halide, with an organic nucleophile (Scheme 1.1). The organic halide can be an sp-, sp2-, or sp3-hybridized carbon with any halogen or pseudohalogen leaving group. The majority of research has focused on sp2 carbon–halogen bonds. A variety of name reactions have been developed using organometallic carbon nucleophiles. Examples with nearly every metal in the periodic table have been demonstrated, but the most common organometallic species used include organotin (Stille), organoboron (Suzuki), Grignard reagents (Kumada), organosilicon (Hiyama), organozinc (Negishi), and in situ generated acetylide anions (Sonogashira). Key steps in these cross-coupling reactions include oxidative addition of the organic halide, transmetalation of the nucleophilic carbon, and reductive elimination to form the product. The Heck coupling of aryl halides and alkenes also falls into this class of reactions, although it involves a migratory insertion/β-hydride elimination sequence in the key bond-forming step rather than reductive elimination. Organic synthetic methodology has largely developed using organic solvents. Homogeneous-metal-catalyzed reactions have similarly largely relied on the use of traditional organic solvents. Organic solvents have a number of advantages: they are good solvents for organic compounds, there are a range of properties (polarity, protic/aprotic, boiling point, viscosity) that can be chosen, and certain