C–H functionalization to form C–C bonds
Catalytic asymmetric C–H functionalization reactions result in the replacement of an unactivated carbon–hydrogen bond with a functional group in an asymmetric manner, most typically through the action of a chiral transition metal catalyst and a Lewis basic directing group in the substrate. Complexes of palladium, rhodium, and iridium are most often employed in these reactions. C–H functionalization reactions that establish carbon–carbon bonds represent a valuable alternative to traditional methods that rely on pre-functionalized organic nucleophiles and electrophiles. Catalytic C–H functionalizations can avoid the generation of stoichiometric quantities of potentially toxic organometallic reagents and can shorten synthetic sequences. Enantioselective C–H functionalization reactions fall into one of three categories: selective reaction of one of a pair of enantiotopic C–H bonds, face-selective migratory insertion of a prochiral alkene into a metal–hydrogen bond, or kinetic resolution of a racemic mixture containing enantiomorphic C–H bonds. Most commonly, a transition metal coordinated to a chiral ligand reacts selectively with one of two enantiotopic C–H bonds in the stereodetermining step.
Mechanisms of transition metal catalyzed C–H functionalization reactions vary substantially. Mechanisms can be divided into inner-sphere and outer-sphere varieties depending on whether the reactive C–H bond engages directly with the metal center or not. The C–H activation step may involve oxidative addition to the metal complex, concerted metalation-deprotonation (CMD) by the metal complex and either an external or internal (ligated) Brønsted base, sigma-bond metathesis, or deprotonation following coordination of an attached pi system to the metal center as in electrophilic aromatic substitution (SEAr). Carbon–carbon bond formation typically involves reductive elimination; this step may follow transmetalation, oxidative addition of an organic electrophile, or insertion of an alkene into a metal–hydrogen bond. In some cases, stoichiometric quantities of an oxidant are required to turn over the catalytic cycle.