Suzuki reaction solid-phase coupling

To date a number of reactions have been carried out in ionic liquids [for examples, see Dell Anna et al. J Chem Soc, Chem Commun 434 2002 Nara, Harjani and Salunkhe Tetrahedron Lett 43 1127 2002 Semeril et al. J Chem Soc Chem Commun 146 2002 Buijsman, van Vuuren and Sterrenburg Org Lett 3 3785 2007]. These include Diels-Alder reactions, transition-metal mediated catalysis, e.g. Heck and Suzuki coupling reactions, and olefin metathesis reactions. An example of ionic liquid acceleration of reactions carried out on solid phase is given by Revell and Ganesan [Org Lett 4 3071 2002]. 

There are many other examples in the literature where sealed-vessel microwave conditions have been employed to heat water as a reaction solvent well above its boiling point. Examples include transition metal catalyzed transformations such as Suzuki [43], Heck [44], Sonogashira [45], and Stille [46] cross-coupling reactions, in addition to cyanation reactions [47], phenylations [48], heterocycle formation [49], and even solid-phase organic syntheses [50] (see Chapters 6 and 7 for details). In many of these studies, reaction temperatures lower than those normally considered near-critical (Table 4.2) have been employed (100-150 °C). This is due in part to the fact that with single-mode microwave reactors (see Section 3.5) 200-220 °C is the current limit to which water can be safely heated under pressure since these instruments generally have a 20 bar pressure limit. For generating truly near-critical conditions around 280 °C, special microwave reactors able to withstand pressures of up to 80 bar have to be utilized (see Section 3.4.4). 

A divergent protocol for a solid-phase synthesis of 3-substituted 2,5-biarylfurans was reported. Thus, reaction of furan zincate A with polymer bound aryl bromide or iodide provides resin intermediates 61. Subsequent bromination-Suzuki coupling reaction followed by further transformations gives rise to structurally diverse 2,3,5-trisubstituted furans 68 in good overall yields and chemical purities <00TL5447>. 

Another Suzuki coupling reaction was described by Zhang et al., to produce arylindoles 116a and b, using solid-phase synthesis [76]. The synthesis was achieved by palladium-mediated coupling/intramolecular indole cycli-zation of resin-bound 2-trimethylsilylindole 117, Scheme 29. 

A solid-phase Suzuki reaction has been described by Kurth et al. in their syntheses of novel isoxazolinoisoquinoline heterocycles via a traceless strategy (Scheme 43).93 The Suzuki coupling was used as an efficient means to introduce extra diversity into the pharmacophore, and a Reissert-based... 

Fluorous phase modifications of the Stille reaction were shown by Curran et al. to be accelerated by microwave irradiation.10 Similarly, Hallberg et al. demonstrated that such irradiation gives remarkably fast solid-phase Suzuki reactions, in the generation of biaryl units.9 Their reaction involved the coupling of a tethered (Rink amide TentaGel) aryl iodide or bromide with several boronic acids under 45 W of irradiation at 2450 MHz in sealed... 

Ruhland, B. Bombrun, A. Gallop, M. A. Solid-Phase Synthesis of 4-Ary-lazetidin-2-ones via Suzuki and Heck Cross-Coupling Reactions, J. Org. Chem. 1997, 62, 7820-7826. 

Piettre, S. R. Baltzer, S. A New Approach to the Solid-Phase Suzuki Coupling Reaction, Tetrahedron Lett. 1997, 38, 1197-1200. 

Polystyrene-bound trialkylboranes, which can be prepared by hydroboration of support-bound alkenes with 9-BBN, undergo palladium-mediated coupling with alkyl, vinyl, and aryl iodides (Suzuki coupling Entries 1 and 2, Table 5.3 for vinylations, see Section 5.2.4). Because boranes are compatible with many functional groups and do not react with water, these coupling reactions could become a powerful tool for solid-phase synthesis. To date, however, few examples have been reported. 

In the Suzuki reaction, an aryl iodide or synthetic equivalent thereof is coupled with an arylboronic acid or a borane, again using palladium(O) as the catalyst. This reaction is usually used to prepare biaryls, and few examples have been reported of the solid-phase synthesis of alkenes by means of a Suzuki coupling (Table 5.8). 

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. 

The time consuming chromatographical purification of heterocycles 28 and 29 slowed down the rate of library production. A phase separation using fluorous chemistry was employed by Zhang and Lu to address the workup and purification of fused 3-aminoimidazo[ l,2-a]pyridines (such as 30) [54]. Thus, attachment of a perfluorooctanesulfonyl tag to aldehydes and subsequent Ugi three-component microwave-assisted condensations with 2-aminopyridines and isocyanides furnished the desired heterocycles 30, which were conveniently isolated by fluorous solid-phase extraction. The fluorous tag could be subsequently used as an activating group in the post-condensation modifications, such as Suzuki-Miyaura cross-coupling reactions. 

Workers at Sphinx [24] have published a synthetic route to a series ofhighly functionalized biphenyl compounds. The key reactions in this sequence are the biaiyl Stille and/or Suzuki couplings to form the biphenyl nucleus and the use of Mitsunobu chemistry to attach the variable side chains (Fig. 2). The illustrated route utilizes a solution-based diaryl coupling followed by on-resin Mitsunobu reactions. Although the diaiyl coupling proceeds on solid phase, this group s desire to maximize resin loading prompted them to implement the former route. 

A traceless solid-phase synthetic strategy has been developed. For example, a solid-phase Suzuki coupling of the Reissert intermediate 30 to 31 has been reported. The process consists of three steps (a) Solid-phase Reissert formation by the reaction of polymer-supported benzoic acid chloride resin with an isoquinoline, followed by reaction with TMSCN to afford the aryl bromide of Reissert 30, (b) Suzuki coupling of the solid-phase Reissert 30 with phenylboronic acid to provide the coupling product, and (c) subsequent treatment of the coupling product with aqueous KOH to produce 31 (86 % overall yield based on the starting bromide) (Eq. (62)) [99]. 

A 9-phenylfluoren-9-yl polystyrene-based resin has been described for the attachment of nitrogen and oxygen nucleophiles. Greater acid stability compared to the standard trityl resins that are widely used in solid-phase peptide synthesis make this solid support an interesting alternative in solid-phase organic synthesis. This resin can be used in Suzuki coupling reactions to furnish biaryls in good yields [100]. 

Recently, the Suzuki reaction has been extensively developed for solid-phase organic chemistry as a method allowing the parallel synthesis of potential medicinal compounds [108]. Chan et al. reported a versatile polymer-supported 4-[4-methylphenyl(chloro)methyl]-phenoxy linker for the solid-phase synthesis of pseudopeptides based on the Suzuki coupling (Eq. (67)) [109],... 

Solid-phase synthesized polymer-bound 3-iodoindole 845 subjected to the Sonogashira and Suzuki coupling reactions afforded the corresponding coupling products 846 and 847 in 91% and 80% yields, respectively, as determined by transesterification and isolation of the corresponding methyl esters (Scheme 161) <2005JC0809>. 

Ellman utilized the Suzuki coupling twice between a support-bound vinyl bromide and an alkyl 9-BBN derivative in a solid-phase synthesis of E- and F-series prostaglandins. The Suzuki reaction was performed in situ, with the hydroboration of a terminal olefin being followed by the palladium-mediated step. This sequence is attractive in library synthesis because of the wide range of suitable commercially available alkenes. The inspiration behind this chemistry was the solution-phase work of Johnson and Braun, where the couplings of 35 with 2-iodo-4-(silyloxy)cyclopent-2-enone 36 went well at room temperature with PdCljCdppO-AsPhj as catalyst (Scheme 41). The modular chemistry demonstrated in this paper was clearly amenable to adaptation to a solid-phase strategy. 

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