Suzuki-Miyaura Cross-Coupling Reaction

Carbon-Carbon cross-coupling reactions represent one of the biggest revolutions in organic chemistry and are currently some of the most common reactions in synthetic organic chemistry. Their invention won Akira Suzuki, Ei-Ichi Neghishi and Richard Heck the Nobel Prize for Chemistry in 2010.

Among the various type of cross-coupling, the Suzuki-Miyaura – usually simply called “Suzuki coupling” - is arguably the one with the broadest utility and applicability. The Suzuki chemistry is based on the Pd(0) catalysed coupling of an aryl or vinyl halide with an aryl or vinyl boronic acid.

Its advantages over similar reactions reside in the mild reaction conditions, common availability of the starting materials and their general low toxicity. Boronic acids are easily prepared, widely available on the market and reasonably cheap. As a matter of fact, they present lower environmental impact and safety hazards than organozinc or organostannane compounds. The inorganic bi-products are easily removed from the mixture. It is also often possible to run the reaction in water with obvious benefits to its green profile, while opening its scope to a wide variety of water-soluble substrates.

Since its invention in 1979, significant progresses have been made and the use of boronic acids, esters and trifluoroborates salts, is widely reported, while despite a lower reactivity, even alkyl boronic acids can be considered (with the use of late generation catalysts).

The scope of the other coupling partner has also expanded over time to include pseudo-halides, such as triflates or aryl diazonium salts, and alkyl halides. The relative reactivity of the halide/pseudo-halide coupling partner is:

R-I > R-Br > R-OTf >> R-Cl

Aryl > Vinyl >> Alkyl

Recent generation homogeneous Pd catalysts have reduced the catalyst loading by orders of magnitude, contributing to the economy of the reaction, now utilised in numerous commercial processes. It is possible – in fact beneficial – to screen many different catalysts, from relatively simple Pd(0) complexes, such as Pd acetate and Pd tetrakis, or various forms of Pd precatalysts + phosphine ligand and fully formed (pre)catalysts, often as air-stable complexes for an easier handling by the bench chemist.

Heterogeneous Pd catalysts can also be used for some simple coupling, although their reactivity is much lower than homogeneous catalysts for highly hindered substrates, or low reactivity electrophiles (e.g. Ar-Cl). The use of aryl diazonium salts, often called “super-electrophiles”, as coupling partners make heterogeneous catalysts quite an attractive option.