Prof. Lionel Delaude, University of Liege in Belgium Cross-Coupling 1 Coupling Reactions
Organometallic chemistry has provided important new methods to carry out
carbon-carbon or carbon-heteroatom bond formation. Such processes, termed
coupling reactions, now have a central place in organic synthesis. The most
important ones are summarized below. They often bear the name of their
discoverer (organic tradition). Stille coupling:
R-R' + XSnRR-X + R'-SnR33
vinyl halide Negishi coupling:
R-R' + XZnRR-X + R'-ZnR
vinyl halide Suzuki coupling:
R-R' + XB(OH)R-X + R'-B(OH)22
vinyl halide Heck reaction:
R-X ++ HX
vinyl halide Sonogashira coupling:
+ HXRR'R-X +R'
Prof. Lionel Delaude, University of Liege in Belgium Cross-Coupling 2
Cross-Coupling of Organometallics and Halides
R-R' + MXR-X + R'-M
M = MgX, ZrCpCl, ZnX, SnR, B(OR), AlMe, SiR, Cu,… 23223
The mechanism involves oxidative addition of the halide or triflate to the initial Pd(0) phosphine complex to form a Pd(II) species. The key slow step is a transmetallation, so called because the nucleophile (R') is transferred
from the metal in the organometallic reagent to the palladium and the counterion (X = halide or triflate) moves in the opposite direction. The new Pd(II) complex with two organic ligands undergoes reductive elimination to give the coupled product and the Pd(0) catalyst ready for another cycle.
The halide partner (R–X) must be chosen with care, as ；-hydride elimination
would decompose the first intermediate during the slow transmetallation step. The choice for R is restricted to substituents without ；-hydrogen atoms: vinyl,
allyl, benzyl, and polyfluoroalkyl halides, triflates, and phosphates have all been coupled successfully.
Prof. Lionel Delaude, University of Liege in Belgium Cross-Coupling 3
The organometallic reagent (R'–M) can be based on Mg, Zn, Cu, Sn, Si, Zr, Al, or B and the organic fragment can have a wide variety of structures as
coupling is faster than ；-hydride elimination.
Formation of the active species may conveniently be carried out in situ by
reduction of a Pd(II) precursor, for example, PdCl, Pd(OAc), or NaPdCl. 2224
The reduction of Pd(II) to Pd(0) can be achieved with amines, phosphines,
alkenes, and organometallics such as DIBAL-H, butyl lithium, or
Reduction with EtN: 3
Reduction with PPh: 3
ligandreductivePhPPPh33exchangeeliminationPdOAcOPdPd(OAc)Pd-PPh23PPhPOAc3AcOPh3+ AcO2OAcOPO+ Ph3
Reduction with ethylene:
Reduction with an organometallic:
PdLX+ R-RPdL+ 2 MXPdL2222R
Usually, a stoichiometric excess of an amine such as EtN is part of the 3
reaction mixture, serving both as a base to trap the HX formed and as a reducing agent for Pd.
Prof. Lionel Delaude, University of Liege in Belgium Cross-Coupling 4
The Stille coupling uses organotin compounds (called stannanes) as organometallic components. Since its first reported use in the late 1970's, the reaction has been widely used for the coupling of both aromatic and vinylic systems. The Stille coupling represents over half of all current cross-coupling reactions, however, due to their high toxicity, stannanes tend to be replaced more and more with organozinc and organoboron compounds.
The reaction may be carried out intramolecularly and with alkynyl stannanes instead of the more usual aryl or vinyl stannanes to form medium-sized rings. For example, the reaction below forms a 10-membered ring containing two alkynes.