Improved reaction conditions for Suzuki-Miyaura couplings with pyridylboronate esters

Two recent publications^1,2 from the Merck Medicinal Chemistry Laboratories describe improved methodology for carrying out Suzuki-Miyaura coupling reactions with pyridyl boronates.

Pyridyl boronates and boronic acids have traditionally been difficult to make and relatively unstable often readily undergoing proto-deboronation and so often give low yields in Suzuki-Miyaura coupling reactions.  Workers at Pfizer^3,4 found that diethanolamine and N-phenyldiethanolamine esters of pyridineboronic esters were stable but these new papers use readily available pinacol esters of pyridylboronic acids.

In the first paper 1 equivalent of a copper (I) salt leads to significant improvements in coupling yields whilst in the second paper it is the use of palladium phosphine oxide and phosphine chloride catalysts of the type shown that is beneficial.  The use of copper chloride as an additive has precedence in Stille coupling reactions.  It is thought that under “normal” reaction conditions transmetallation from boron to palladium is slow allowing proto-deboronation to compete leading to low yields of coupling products.  In the presence of copper (I) a fast transmetallation from boron to copper takes place giving a stable intermediate which can subsequently transmetallate to palladium.

1 J.Z. Dheng et al (Merck), Org. Lett., 2009, 11, 345.
2 D.X. Yang et al (Merck), Org. Lett., 2009, 11, 381.
3 S. Caron et al (Pfizer), J. Org. Chem., 1998, 63, 2054.
4 P. Hodgson et al (Pfizer), Tet. Letts., 2004, 45, 685.