Hiyama-Denmark Coupling

The Hiyama-Denmark Coupling is a modification of the Hiyama Coupling, in which the palladium-catalyzed coupling of deprotonated silanols with vinyl and aryl halides leads to cross-coupled products. In the Hiyama-Denmark coupling, fluoride is not needed as activator, so the reaction is compatible with substrates bearing silyl-protecting groups and can be performed in large-scale reactors.

---

Mechanism of the Hiyama-Denmark Coupling

The mechanistic proposal for the Hiyama Coupling includes oxidative addition to give a palladium(II) species, transmetalation and reductive elimination to regenerate the palladium catalyst:

For the Hiyama-Denmark Coupling, most of these steps are similar.

For the transmetalation to occur in the Hiyama Coupling, fluoride activation and the formation of a pentavalent silicon is essential. As the Hiyama-Denmark Coupling occurs in the presence of a base and also strongly depends on the steric and electronic properties of the silicon center, it was convenient to assume a mechanism for the transmetalation, in which a pentavalent silicon species is formed. Thus, it was first suggested that the in situ-generated silanolate forms an organopalladium complex, which is activated by a second equivalent of the silanolate prior to transmetalation.

Later, it has been shown, that the reaction is first-order in silanolate, so the transmetalation proceeds directly from an organopalladium(II) silanolate complex.

The new reaction is especially suitable for the conversion of aryl- and alkenyldimethylsilanolates, although aryldimethylsilanolates react much more slowly than alkenyl derivatives. Thus a second proof was established by the isolation and X-ray characterization of a quite stable palladium silanolate complex of an aryldimethylsilanolate. Heating to 100°C provided the biaryl product in quantitative yield in the absence of an activator.

This argued against a requirement for a pentavalent silicon species. In addition, the importance of complexation (Si-O-Pd) for this new transmetalation pathway was shown.

Since then, many protocols have been developed that allow the conversion of ester, ketone, and silyl-protected substrates. Mild bases such as KOSiMe₃ allow the reversible deprotonation of alkenyl- or alkynyldimethylsilanols. Arylsilanolates need more forcing conditions, for example with Cs₂CO₃ in toluene at 90 °C. Here, the addition of water suppresses homocoupling of the halide. For electron-rich heterocycles, the irreversible deprotonation using NaH for the prior generation of silanolates proved to be a suitable alternative.

Some of the protocols can be found in the recent literature section. A more comprehensive review dealing with mechanistic details and scope of the reaction has been written by Denmark and Regens (Acc. Chem. Res., 2008, DOI: 10.1021/ar800037p).

Recent Literature

Cross-Coupling Reactions of Aromatic and Heteroaromatic Silanolates with Aromatic and Heteroaromatic Halides
S. E. Denmark, R. C. Smith, W.-T. T. Chang, J. M. Muhuhi, J. Am. Chem. Soc., 2009, 131, 3104-3118.

Stereospecific Palladium-Catalyzed Cross-Coupling of (E)- and (Z)-Alkenylsilanolates with Aryl Chlorides
S. E. Denmark, J. M. Kallemeyn, J. Am. Chem. Soc., 2006, 128, 15958-19959.

Vinylation of Aromatic Halides Using Inexpensive Organosilicon Reagents. Illustration of Design of Experiment Protocols
S. E. Denmark, C. R. Butler, J. Am. Chem. Soc., 2008, 130, 3690-3704.

Fluoride-Free Cross-Coupling of Organosilanols
S. E. Denmark, R. F. Sweis, J. Am. Chem. Soc., 2001, 123, 6439-6440.

Sequential Cross-Coupling of 1,4-Bissilylbutadienes: Synthesis of Unsymmetrical 1,4-Disubstituted 1,3-Butadienes
S. E. Denmark, S. A. Tymonko, J. Am. Chem. Soc., 2005, 127, 8004-8005.

Cross-Coupling of Alkynylsilanols with Aryl Halides Promoted by Potassium Trimethylsilanolate
S. E. Denmark, S. A. Tymonko, J. Org. Chem., 2003, 68, 9151-9154.

Palladium-Catalyzed Cross-Coupling Reactions of Substituted Aryl(dimethyl)silanols
S. E. Denmark, M. H. Ober, Adv. Synth. Catal., 2004, 346, 1703-1715.

Cross-Coupling of Aromatic Bromides with Allylic Silanolate Salts
S. E. Denmark, N. S. Werner, J. Am. Chem. Soc., 2008, 130, 16382-16393.