Technical Library

The advent of the cross-coupling reaction introduced a new and highly useful methodology for the formation of carbon-carbon bonds.1,2 This general class of reactions involves two partners, with one typically being a suitable organometallic reagent (the nucleophile) and the other a suitable organic substrate, normally an unsaturated halide, tosylate, or similar (the electrophile).

Numerous examples of the coupling of aryl and vinyl halides with olefins in the Heck reaction,1a with organotin reagents in the Stille reaction,3,4 with boronic acids in the Suzuki-Miyaura coupling,5,6 and the coupling of aryl and vinyl halides with acetylenes in the Sonogashira reaction7,8 have been reviewed. The vinylation of aryl halides has been recently reviewed.9 An excellent perspective on the development and mechanistic understanding of the silicon-based cross- coupling methods has appeared.10 A review on the practical aspects of the silicon-based cross-coupling chemistry provides a useful view of the potential utility and advantages and disadvantages of the various protocols available.11

A general review of alkyl, alkenyl, and alkynyl cross-coupling reactions compares those of silicon with other available methods.12 A review emphasizing the mechanistic aspects of the activation of organosilanes in the silicon-based cross-coupling reactions has appeared.13 ln addition, the use of Pd-catalyzed cross-coupling reactions in total synthesis has been reviewed.14 Hiyama and coworkers have reviewed the use of internal activation of the organosilane in silicon-based cross-coupling reactions.15 All of these reactions have demonstrated the ability to generate biaryls, 1,3-dienes, and styrene derivatives in excellent yields principally from aryl or vinyl iodides and bromides, although the less expensive corresponding chlorides can also be used in certain circumstances. These reactions are in large part promoted by a palladium catalyst. Differences come in the choice of the palladium catalyst and, equally importantly, the choice of ligands to complex the palladium during the reaction.

The early work of Hiyama16-18 showed that arylsilanes and vinylsilanes with fluorine ligands are capable of undergoing cross-coupling reactions with aryl and vinyl iodides in a manner similar to the reactions of the organostannanes and boronic acids. This work has been greatly expanded upon by others, most notably Denmark, with significant input by DeShong, Najera, and Wolf, among others, in addition to the continuing excellent work of the Hiyama group. These authors have illustrated numerous methods of utilizing organosilanes in a variety of cross-coupling applications.

The table below summarizes a comparison of the various cross-coupling approaches.

A Comparison of Cross-Coupling Methods

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ReactionMetalCatalystAdvantagesDisadvantages
StilleTinPalladiumgood yieldstin toxicity
Bu3Sn is large
Suzuki MiyauraBoronPalladiumgood yields
varied syntheses of boronic acids
boronic acids commercially available
organoboranes are air-sensitive
cost of boronic acids
SonogashiraPalladium
Copper
Silicon
good yields
acetylenes available
HiyamaSiliconPalladium good yields
aqueous solvent possible
silanes are air-stable, easily handled, and readily synthesized
can require 1-3 equivalents of fluoride
few commercial sources of organsilanes
NegishiZincCopper
Nickel
Palladium
made from inexpensive zinc functional group
tolerant strong for sp3 cross-couplings
excellent selectivity
many commercially available
typically need organoiodides for both partners