The cross-coupling of organosilanols has emerged as a viable alternative to the classical methods of Suzuki (boronic acids), Stille (stannanes) and Negishi (organozincs).² The major developments over the past years have been the significant expansion of the scope of the organosilanol (or silanol precursor) and the introduction of non-fluoride activation of the silanols. Both advances will be summarized here.

Over the past ten years, a wide range of organosilanols have been prepared³ and shown to be competent partners in the fluoride-activated cross coupling with aromatic and olefinic halides (including bromides⁴) and triflates.⁵ Most notable has been the extension to pyranylsilanols,⁶ cyclic siloxanes generated by intramolecular hydrosilylation,⁷ intramolecular silylformylation,⁸ and ring-closing metathesis⁹ (Figure 1). The latter tandem process (RCM-cross-coupling) was featured in a total synthesis of (+)-brasilenyne (Figure 2).¹⁰ In addition, silylcarbocyclization-formylation¹¹ allowed for the construction of the pyrrolidine core of isodomoic acids G and H (Figure 3).¹² The final cross-coupling step involved a fluoride mediated process that employed a buffered form of TBAF (octahydrate).

By far the most important advance in the past five years has been the discovery of a preparatively useful and mechanistically distinct¹³ pathway for cross-coupling of organosilanols that employs various Brønsted bases as activators.^2d This discovery has allowed for a wider range of coupling partners to be incorporated and also for milder reaction conditions to be employed. For example is it now possible to effect the cross-coupling of simple alkenylsilanols and alkynylsilanols (with KOTMS),¹⁴ arylsilanols (with Cs₂CO₃),¹⁵ and 2-indolylsilanols (with KOt-Bu),¹⁶ and isoxazolinylsilanols (with KOt-Bu)¹⁷ (Figure 4).

The ability to couple silanols under fluoride-free conditions has allowed the introduction of the preformed silanolate salts as viable coupling partners. The salts can be easily prepared by deprotonation with NaH or KH and are, in general, stable, free flowing powders. The silanolates couple directly without the need for added bases or activators. Accordingly, heterarylsilanolates derived from indoles, thiophenes, furans¹⁸ as well as a wide range of aromatic silanolates¹⁹ have been successfully employed. Finally, alkenylsilanolates also undergo high yielding and highly stereospecific cross-coupling with aryl chlorides²⁰ (Figure 5).

The demonstration of both fluoride and non-fluoride activation for silicon-based cross-coupling has led to the development of a conjunctive reagent that allows for sequential coupling at separate ends of a 1,4-butadiene unit.²¹ This application was featured in the total synthesis of RK-397 (Figure 6).²²

The construction of the key aryl glycosidic bond en route to papulacandin D highlights the synthetic utility of the Brønsted base activation method (Figure 7).²³ The glycal silanol would not withstand activation by fluoride and the resorcinol coupling partner is highly deactivated. Nevertheless, the desired coupling could be achieved by the action of sodium tert-butoxide at 50 °C in the presence of Pd₂(dba)₃•CHCl₃. The coupled product contains the entire carbon framework of the sugar fragment of papulacandin D.