Suzuki solid-phase synthesis

Combs and coworkers have presented a study on the solid-phase synthesis of oxa-zolidinone antimicrobials by microwave-mediated Suzuki coupling [38], A valuable oxazolidinone scaffold was coupled to Bal resin (PS-PEG resin with a 4-formyl-3,5-dimethoxyphenoxy linker) to afford the corresponding resin-bound secondary amine (Scheme 7.18). After subsequent acylation, the resulting intermediate was transformed to the corresponding biaryl compound by microwave-assisted Suzuki coupling. Cleavage with trifluoroacetic acid/dichloromethane yielded the desired target structures. 

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. 

Raju and Kogan demonstrated the synthesis of simple, diverse sulfonamides using a new carbamate linker.44 They also showed that the Suzuki reaction could be used for convenient introduction of diversity in their solid-phase synthesis. The three-step sequence is shown in Scheme 48. The purities of the cleaved compounds are good, but the sequence yields are low (32-33%). 

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. 

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). 

Nicolaou KC, Mitchell HJ, Flyaktakidou KC, Suzuki H, Rodriguez RM, 1,2-Seleno migrations in carbohydrate chemistry Solution and solid-phase synthesis of 2-deoxy glycosides, orthoesters, and allyl orthoesters, Angew. Chem. Int. Ed., 39 1089-1093, 2000. 

Numerous linkers have been developed with the aim of immobilizing substrates on a solid support. Commercially available (+)-a-lipoic acid has been employed as a novel, chemically stable linker for the immobilization of ketones. The utility of this thioacetal-based linker in solid-phase synthesis has been demonstrated by the synthesis of several 4-acetylbiphenyls by means of the Suzuki reaction. The products were readily cleaved from the solid support by treatment with [bis(trifluoroacetoxy)iodo]benzene [PhI(OCOCF3)2] [107]. 

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],... 

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. 

A solid-phase synthesis of the lamellarin alkaloids Q and O featured the preparation of scaffold 79 and subsequent Suzuki coupling [24]. Dibromopyrrole 78 was synthesized as shown earlier for 14. 

Another germanium-based hnker has been developed for solid-phase synthesis of a pyrazole hbrary [79]. A new iterative synthesis of regioregular oligothiophenes has been developed in which double-couphng after each iteration minimizes deletion sequences. The method exploits the susceptibility of a-silyl- but not a-ger-myl-substituted thiophene derivatives towards nucleophilic ipso protodemetalation and features an unusual base-free Suzuki-type coupling product. The strategy... 

The Suzuki-Miyaura reaction has proven useful for synthetic chemists in the formation of aryl-aiyl bonds. Benefits include generally mild reaction conditions, compatibility with most functional groups, and the use of readily available boronic acids known for their stability. In the reaction shown below, Meldal and co-workers reported a palladium-catalyzed Suzuki cross-coupling reaction of a bromothiophene using a solid-phase synthesis protocol. ... 

The same kind of resin was used for the solid phase synthesis of 2-furylarenes, which were further elaborated in a Suzuki coupling (Table 9, entry 46). 

Due to the substantial amount of literature, even when excluding supported catalysts, only selected articles on the solid phase Suzuki reaction are mentioned here, concentrating on the more recent publications. Apart from the general palladium reviews cited in Sect. 5, some examples of solid phase synthesis can be found in a review of apphcations of the Suzuki-Miyaura cross-coupling reactions in organic synthesis by Kotha in 2002 [114]. 

Another example is the synthesis of functionaUzed biaryl a-ketophospho-nic acids, a class of compound with a wide range of biological activity [116]. Initial solution phase Suzuki reactions showed that the a-ketophosphonic acid moiety was unaffected by the reaction conditions, which were then transferred to the solid phase synthesis. This involved the synthesis of several polymer-supported amide-arylboronic acids and their coupling to three different bromobenzyl a-ketophosphonates (Scheme 40). Microwave heating was utilized to produce functionalized biaryl a-ketophosphonic acids 58 in good yield. 

Vaultier has developed a solid-phase synthesis of macroqfdic systems by intramolecular Suzuki-Miyaura aryl-aryl macrocydization of polymer ionically bound borates 87 obtained by trapping of the respective aryl boronic adds by an ammonium hydroxide form Dowex ion exchanger resin (D-OH), leading to macro-cydes of type 88 in 16-22% yield (Scheme 3.38) [57]. 

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