Solid-Phase-Supported Stille Coupling

One of the first cross-coupling reactions performed on solid supports was the Stille reaction [250] which is a paUadium-catalyzed reaction of a trialkylaryl or trialkylalkenyl stannane with an aromatic iodide, bromide or triflate. In contrast to the process in liquid-phase, the organotin reagent is easily removed from the solid-phase because of the subsequent washing processes. Immobilized aryl halides have been frequently coupled with aryl and alkenylstannanes, whereas stan-nanes attached to the solid support have been used less frequently for the StiUe reaction. An example is the synthesis of a benzodiazepine library by EUman et al. Recently, a Stille cross-couphng reaction has been employed in the synthesis of al-kenyldiarylmethanes (ADAM) series of non-nucleoside HlV-1 Reverse Transcriptase Inhibitors (Scheme 3.14) [251]. 

Biaryls have also been prepared by coupling support-bound aryl halides with aryl-zinc compounds (Figure 5.20) or with aryl(fluoro)silanes [203]. As with Suzuki or Stille couplings, these reactions also require transition metal catalysis. An additional strategy for coupling arenes on solid phase is the oxidative dimerization of phenols (Figure 5.20). 

Thiophenes have been prepared on insoluble supports mainly by arylation or viny-lation of halothiophenes and thienylstannanes (Table 15.10). Heck, Suzuki, and Stille couplings with thiophenes usually proceed as smoothly as those with substituted benzenes, and arylations or vinylations of thiophenes have often been used as examples to illustrate new conditions for the realization of these coupling reactions on solid phase. 

However, even the pre-synthesized tetrazolides were still too reactive to be routinely used in the automated solid phase synthesis. The major advance that solved the problem was made in 1981, when Beaucage and Caruthers, who were experimenting with the nucleoside 3 -phosphoramidite derivatives [83] following some previous Russian work on the phosphorus(III)-amino compounds [84], discovered that these otherwise pretty stable compounds can be rapidly and very efficiently coupled to a solid-supported nucleoside in the presence of a mildly acidic nucleophilic catalyst, tetrazole [85]. This discovery combined with the already existing solid-phase assembly layout [68, 69, 82] paved the way for the very rapid expansion of the polymer-supported oligonucleotide synthesis, which has been summarized in the timely book edited by Gait [12a]. 

Franzen, R. (2000) The Suzuki, the Heck, the Stille reactions three versatile methods for introduction of C-C bond on solid support. Can. J. Chem. 78 957-962. Ruhland, B., Bombrun, A. iand Gallop, M.A. (1997) Solid-phase synthesis of 4-arylazetidin-2-ones via Suzuki and Heck cross-coupling reactions. J. Org. Chem. 62 7820-7826. 

To complete this short treatment on solid-phase synthesis, let us be mention the efforts made by several groups to obtain methods that allow a cyclorelease (also called cyclative cleavage) of the macrocycle, in other words, the cyclization reaction and the release from the polymer support occur simultaneously. The methods developed so far involve the metathesis reaction (Fig. 15a) the Stille coupling (Fig. ISb) and sulfur ylides (Fig. 16a). 

Many solid-phase syntheses that involve the extension of ir-conjugated systems are known in the literature. Heck, Stille, Suzuki, Homer-Emmons, Wittig, and other metal-induced coupling reactions were all demonstrated to work on solid supports, some at relatively high yields [154—156]. Table 7.2 summarizes some of these reactions with respect to conditions and yields many other examples may be found in the literature. 

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