Solid Suzuki 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]. 

The first example of microwave-promoted solid-phase methodology in heterocyclic chemistry was the arylation of thiophene and indole via Suzuki couplings on TentaGel S RAM resin, as demonstrated by Hallberg and coworkers in 1996, before temperature- and pressure-controlled microwave instruments were even available [189]. Three years later Schotten and coworkers presented analogous but aqueous Suzuki couplings of 5-bromo-thiophene anchored to PEG soluble support via a carboxylic function at its C-2 position [116]. Unfortunately, this work was performed in a do-... 

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. 

In closely related work, similar solid-phase chemistry was employed by the same research group to prepare biaryl urea compound libraries by microwave-assisted Suzuki couplings followed by cleavage from the resin with amines (Scheme 7.47) [18]. The above described procedure enabled the generation of large biaryl urea compound libraries employing a simple domestic microwave oven. 

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. 

Scheme 3.12 Solid supported boronic acids (144) as reagents for Suzuki couplings [107],...

Spear et al. chose the Heck reaction to elaborate 4-iodophenylsulfonyl chloride attached to Rink amide resin, that is, sulfonamide 18.43 The reaction (Scheme 16) was reported to be quantitative, as was a simple Stille coupling on the same molecule. Raju and Kogan used a Suzuki coupling on solid support (see below)44 to illustrate use of a new carbamate linker for the generation of more diverse sulfonamides than those above. 

Veber et al.88 used Suzuki couplings on a solid support to generate simple biphenyls (Scheme 38), in the presence of a silyl linker, which was cleaved to release these structures without trace of the linkage position. 

Ellman used silyl chemistry for the direct linkage of aromatics onto the solid support by converting an aryl bromide to aryl lithium and reacting this with a silyl resin.90 It is the production of the silyl resin that is of interest in the context of this review, since an in situ Suzuki coupling was used to link the allyl silane to bromomethyl polystyrene resin (Scheme 40). 9-BBN is used to carry out the regioselective hydroboration, and this is linked to the resin with palladium catalysis in the usual way. After brief exposure of this... 

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... 

Sarkar et al.94 constructed the relatively complicated structure 40 (Scheme 45) on a solid support by using a Suzuki coupling. The objective of this work was to demonstrate the efficacy of spin echo MAS H NMR spectroscopy for gauging reactions on solid supports. The coupling was performed successfully under standard conditions, and a KCN in DMSO wash was used to remove adsorbed palladium after the reaction. 

Larhed, M. Lindeberg, G. Hallberg, A. Rapid Microwave-Assisted Suzuki Coupling on Solid Phase, Tetrahedron Lett. 1996, 37, 8219-8222. 

Frenette, R. Friesen, R. W. Biaryl Synthesis via Suzuki Coupling on a Solid Support, Tetrahedron Lett. 1994, 35, 9177-9180. 

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). 

Larhed, M., Lindeberg, G. and Hallberg, A., Rapid microwave-assisted Suzuki coupling on solid-phase,... 

The Suzuki coupling of arylboronic acids to the solid-supported arylha-lide 4 was initially performed by conventional heating methods, DMF at 85° in an oil bath for 16 h, to provide the desired products 6 after TFA cleavage. Due to the extended heating times necessary for the Suzuki reaction, full optimization of the reaction conditions were not investigated prior to compound library synthesis. Reaction conditions sufficient for the library synthesis were determined within a couple of weeks affording moderate yields of the desired oxazolidinones. Libraries of hundreds of... 

Microwave-Assisted Solid-Phase Suzuki Coupling... 

Suzuki Coupling to Displace the Remaining Chloro Atom on C2 with Aryl Groups (Fig. 10).15 To a 10-ml flame-dried Schlenk flask containing the solid supported intermediate 61 (0.10 mmol, 1.0 equiv.) are added an arylboronic acid (0.50 mmol, 5.0 equiv.), Pd2(dba)3 (0.007 mmol, 0.07 equiv.), l,3-bis(2,6-diisopropylphenyl)-lH-imidazol-3-ium chloride (carbine ligand, 0.014 mmol, 0.14 equiv.), and Cs2C03 (0.60 mmol,... 

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