The poly(ethylene glycol) ester of bromo-, iodo-, and triflate-para-substituted benzoates are smoothly cross-coupled with aryl boronic acids (Suzuki reaction) under "ligandless" palladium acetate catalysis in water. The reaction proceeds without organic cosolvent under conventional thermal conditions (70 °C, 2 h) and under microwave irradiation (75 W, 2-4 min). The polymeric support remains stable under both reaction conditions. Whereas conventional thermal conditions induced ester cleavage (up to 45%), this side reaction is suppressed when microwave conditions are employed. Aryl nonaflates give fair yields under these conditions. Non-polymer-bound aryl halides form biaryls in good to excellent yields in water/poly(ethylene glycol) mixtures under microwave irradiation (4 min, 75 W).

The liquid phase synthesis of biaryls via Suzuki crosscoupling reaction on poly(ethylene glycol) supports (PEGs) is described. The reaction is exemplified by parallel coupling of polymer bound aryl halides with boronic acids. Four different PEGs were employed as soluble polymer supports for parallel synthesis. The generated libraries include both sterically hindered aryl halides (2b, 2d) and boronic acids. The reactions were run in the homogeneous phase and the synthetic sequences performed in parallel fashion. Quantitative conversion in the Suzuki couplings was verified by 1 H-NMR analysis (3a-r). The polymer bound products were isolated in good to excellent (52% to 98%) yields by either simple precipitation of the soluble support or column filtration.The availability of general reaction protocols for organic molecule libraries which lead to high yields of pure products is essential for the success of combinatorial chemistry. Solid-phase synthesis can be complicated by heterogeneous reaction conditions, the requirement for large quantities of solid support and the difficulty in monitoring reactions. 1 The use of soluble supports offers a method to overcome these difficulties while maintaining the ease of solid phase synthesis. 2 PEG is soluble in most common solvents 3 and has a strong propensity to crystallize. 4 Inclusions due to gelatinous precipitation are avoided. 5 The recent interest in PEG-supported synthesis 6 including liquid phase combinatorial strategies 7 prompted us to report our results.The biaryl subunit is an important pharmacophore in a variety of biologically active compounds. 8 We synthesized small libraries of biaryls via the Suzuki cross-coupling reaction 9 of aryl bromides or iodides on four different PEGs. The aryl halides were activated for the cross-coupling reaction by the electron withdrawing effect of the ester linkage to the polymer. 9 Commercially available monofunctional PEG 2000 monomethylether (MeO-PEG 2000), MeO-PEG 5000, difunctional PEG 4000 and PEG 6000 were chosen as polymer supports. Our target was to generate the libraries by using parallel synthesis and to find the most suitable polymer in terms of loading capacity and ease of workup.5-Bromothiophene-2-carboxylic acid was esterified with MeO-PEG 2000 employing a variation of the DCC/DMAP method. 10 The recovered yield of the product 2a was 73%. The conversion estimated by NMR was >95%. No starting material was found by MALDI-TOF MS. The iodo benzoic acids were esterified with the soluble polymers employing the same reaction conditions as above (Table 1). 10The cross-coupling reaction 9 was readily accomplished on the PEG esters 2a-f 11 utilizing a variation of standard Suzuki conditions. Aqueous DMF was used as a solvent in combination with the weak base Na 2 CO 3 . The aryl halides were converted quantitatively on the polymer at 110°C overnight. Compared to non-polymer supported liquid phase chemistry higher temperatures were necessary to assure quantitative conversion of 2 a-f into the Suzuki reaction products. Both st...

The parallel synthesis of 25 biaryl 1H-benzimidazoles, 1H-imidazo [4,5-b]pyridines and 1H-imidazo [4,5-c]pyridines on soluble polyethylene glycol support is described. Polymer-esterified biaryl aldehydes were prepared in parallel fashion by coupling polymer-bound aryl halides with o-, m-, or p-formyl benzene boronic acid in a first step. Subsequently the aldehydes were treated with o-arylenediamines to form the title compounds. Nitrobenzene was used as solvent and oxidant in this one-pot conversion. The polymer support remained stable under the drastic conditions (180°C, 3d) necessary for quantitative conversion as determined by MALDI-TOF-MS. The recovery of the polymer-bound products was good to excellent, but cleavage of the ester bond off the polymeric support (up to 33%) was observed as the main side reaction. Transesterification with sodium methanolate and subsequent purification by solid phase extraction with strongly acidic ion exchange resin and flash chromatography yielded the desired methyl ester.

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