Poly(ethylene glycol) Supported Liquid Phase Synthesis of Biaryls

Abstract

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...

Recent applications of the Suzuki–Miyaura cross-coupling reaction in organic synthesis

“…Schotten and co-workers 106 recently reported the poly-(ethyleneglycol) (PEG)-supported liquid-phase synthesis of biaryls by the SM cross-coupling reaction (Scheme 46). Compared to the non-polymer-supported liquid-phase reaction, a higher temperature is necessary to assure the quantitative conversion of the polymer-bound aryl halide into the SM coupling products, but the polymer-bound products were isolated in good yields by either simple precipitation of the soluble support or column filtration.…”

Bis(triphenylphosphine)palladium(II)succinimide as a precatalyst for Suzuki cross-coupling—subtle effects exerted by the succinimide ligand

“…The following compounds were characterized by 1 H, 13 C NMR spectroscopy and mass spectrometry and compared to the known literature data: biphenyl 5a, 27 4-methylbiphenyl 5b, 27 4 0 -formylbiphenyl 5c, 28 4-chlorobiphenyl 5d, 28 4-acetylbiphenyl 5e, 29 4-acetyl-4 0 -methylbiphenyl 5f, 30 4-acetyl-4 0 -formylbiphenyl 5g, 31 4-acetyl-4 0 -chlorobiphenyl 5h, 32 4-nitrobiphenyl 5i, 33 4-nitro-4 0 -methylbiphenyl 5j, 34 4 0 -nitro-biphenyl-4-carbaldehyde 5k, 35 4-nitro-4 0 -chlorobiphenyl 5l, 36 2-methoxybiphenyl 5m, 37 2-methoxycarbonylbiphenyl 5n, 38 2-methoxycarbonyl-4 0 -formylbiphenyl 5o, 39 2-methoxycarbonyl-4 0 -chlorobiphenyl 5p, 36 2-methoxycarbonyl-4 0 -methylbiphenyl 5q, 40 4-methoxycarbonylbiphenyl 5r, 38 2-methoxycarbonyl-4 0 -formylbiphenyl 5s, 39 2,6-dimethylbiphenyl 5t, 41 2.1.2. Synthesis of (Ph 3 P) 2 Pd(N-Succ) 2 (2).…”

Exploiting Poly(ethylene glycol) as a Matrix for Liquid-Phase Organic Synthesis

“…MeO-PEG 5000 was initially esterified with either para-or ortho-iodobenzoic acid using DCC and DMAP to give para-and ortho-polymer-supported iodides, 15a-b respectively, with polymer recoveries being > 95% [46]. The conversion was quantitative based upon 1 H NMR spectroscopic analysis of 15ab.…”

“…A number of efficient reaction conditions for solution-phase Stille couplings have been developed [39,40,47,48] and initially we utilized a number of these for the reaction between PEG-iodide 15a and tributyl phenyltin (16) to explore the viability of PEG as a soluble polymer support for this reaction and then to identify the optimal conditions necessary for the PEG-supported Stille variant (Scheme 3 and Table 4). Previous work has revealed conflicting evidence regarding the potential for coordination of the PEG polyether backbone to transition metals [49][50][51]. Initially therefore, we had serious concerns that the PEG-backbone may serve to either retard or completely inhibit the Stille reaction via complexation of either the palladium catalyst, the alkali metal halide or the organostannane reagent.…”