Carbon−Carbon Coupling Reactions Catalyzed by Heterogeneous ...

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138 Chemical Reviews, 2007, Vol. 107, No. 1 Yin and Liebscher 2.1.2. In the Absence of Phosphine Ligands Already in the early investigations of the application of Pd/C in Suzuki-Miyaura couplings, it was found that ligandfree methodology can be advantageous. 92 Good to excellent yields of coupling products were obtained when bromide, iodide, or triflate acted as leaving group (Table 3). Chloro substituents in the arylboronic acid were tolerated; that is, they do not react in the Suzuki coupling. The results gave evidence that the Pd/C-assisted coupling reactions might occur by heterogeneous catalysis under these conditions. Table 3. Ligand-Free Pd/C-Catalyzed Suzuki Coupling Ar, X Ar′ base t (h) yielda (%) 4-CHO-Ph, Br 4-CN-Ph, Br 3,5-(CF3)2-Ph, Br 4-n-Pr-Ph, Br 3-F-4-OH-Ph, Br 4-F-Ph 4-Cl-3-F-Ph 4-n-Pr-Ph 3,5-di-F-Ph 4-n-Pen-Ph Et3N Na2CO3 Na2CO3 2 M Na2CO3 Na2CO3 5 1 0.5 19 19 84 94 90 88 80b 4-Me2N-Ph, Br Ph, I 4-Cl-3-F-Ph 4-Cl-3-F-Ph 4-Cl-3-F-Ph Na2CO3 Na2CO3 Na2CO3 19 19 19 95 91 94 4-Et-Ph, Br 4-Cl-3-F-Ph 2 M Na2CO3 19 87 b 4-CN-Ph, OTf Ph Na2CO3 19 50 Ph Na2CO3 18 84 c a Isolated yields. b DME as solvent. c DMF as solvent. In 2001, LeBlond and co-workers 76 found an efficient methodology to couple weakly reactive aryl chlorides, which had been a problem in homogeneous Suzuki coupling for a long time. Pd/C in DMA/water was appropriate. The optimal volumetric ratio of DMA/water was found to be 20:1, enabling the cross-coupling to go to completion within 1.5 h without the formation of homocoupling products from the aryl chlorides. These conditions are generally applicable toward aryl chlorides with electron-withdrawing groups and gave 79-95% yields (Table 4). Moderate yields were obtained with neutral or electron-rich aryl chlorides, which could be improved by using greater amounts of catalyst (see entry 7). Table 4. Pd/C-Catalyzed Suzuki Coupling of Aryl Chlorides entry R R′ yield a (%) conv (%) 1 NO2 H 93 100 2 CF3 H 95 100 3 CN H 83 100 4 Ac H 79 100 5 H OMe 45 61 6 OMe H 32 37 7 Me H 36, b 54 c 65, b 76 c a Isolated yield. b 48 h. c 15 mol % of Pd/C. Detailed investigations by Köhler’s group on Suzuki reactions of aryl bromides and chlorides with phenylboronic acid gave important insights in the effect of the concentration of the Pd/C catalyst and other reaction conditions on the catalytic activity, the yield, and the selectivity. 81 Under optimized conditions, coupling products of bromoarenes and phenylboronic acid were obtained in excellent yields after short reaction times by using extremely low Pd concentrations of only 0.005-0.01 mol % (Table 5, entries 1-4). High TON, up to 20 000, were achieved. Also deactivated bromoarenes like p-bromoanisole could be converted up to 83% without dehalogenation within 60 min (Table 5, entry 5). The highest TOF was 16 600 h -1 , and 100% selectivity for the Suzuki coupling product (cross-coupling) was found nearly without exceptions. p-Chloroacetophenone could be converted quantitatively at Pd concentrations of 0.25 mol % within 4 h. Conversions up to 90% were achieved after 2 h using 0.005-0.10 mol % Pd. Table 5. Pd/C-Catalyzed Suzuki Coupling of Aryl Halides with Phenylboronic Acid entry X R Pd/C (mol %) NMP/ H2O base t (h) conv (%) yield (%) TON TOF 1 Br CN 0.01 10:4 Na2CO3 1.5 100 100 10000 6666 2 Br H 0.005 10:4 Na2CO3 2 100 100 20000 10000 3 Br OH 0.01 10:4 Na2CO3 2 100 100 10000 5000 4 Br OMe 0.005 10:4 Na2CO3 2 100 100 20000 10000 5 Br OMe 0.005 10:4 Na2CO3 1 83 83 16600 16600 6 Cl Ac 0.25 10:3 NaOH 4 100 98 400 100 7 Cl Ac 0.10 10:3 NaOH 2 90 88 900 450 8 Cl Ac 0.05 10:3 NaOH 2 80 78 1600 800 The addition of water to the organic solvent increased the activity. A crucial influence was found for the base. Na2- CO3 gave the best results for couplings of aryl bromides, whereas NaOH promoted the deborylation and dehalogenation resulting in a decreased selectivity. In contrast, NaOH is found to be the best choice for activated aryl chlorides under the conditions applied (120 °C, NMP/water). Again it has to be mentioned that the optimum reaction temperature (120 °C) is higher than in a typical homogeneously catalyzed Suzuki reaction (about 80 °C). On the other hand, room temperature was appropriate in Pd/C-catalyzed coupling of iodophenols 17 with arylboronic acids in water in the presence of K2CO3 (Table 6). 88 In the case of bromophenol, higher temperature was advantageous (entries 8 and 9). Table 6. Pd/C-Catalyzed Coupling of Halophenols with Arylboronic Acid in Aqueous Media entry halophenol arylboronic acid T (°C) yield (%) 1 2 3 4 5 6 7 8 9 2-iodophenol 3-iodophenol 4-iodophenol 4-iodophenol 4-iodophenol 4-iodophenol 4-iodophenol 4-bromophenol 4-bromophenol PhB(OH)2 PhB(OH)2 PhB(OH)2 4-FC6H4B(OH)2 4-MeOC6H4B(OH)2 4-MeC6H4B(OH)2 2-MeOC6H4B(OH)2 PhB(OH)2 PhB(OH)2 RT RT RT RT RT RT RT RT 50 70 97 >99 >99 >99 >99 98 35 76 It is noteworthy that the recovered Pd/C possesses enough catalytic activity for further coupling reactions. Application of recovered Pd/C to the coupling of 4-iodophenol and phenylboronic acid revealed that the catalytic activity gradu-
Heterogeneous Pd Catalyzed C−C Coupling Reactions Chemical Reviews, 2007, Vol. 107, No. 1 139 ally diminished, but the yield was still 89% after the fifth reuse (Table 7). Table 7. Reaction of 4-Iodophenol with Phenylboronic Acid Using Recovered Pd/C as Catalyst entry Pd/C catalyst yield (%) 1 fresh >99 2 first reuse 95 3 second reuse 94 4 third reuse 90 5 fourth reuse 89 6 fifth reuse 89 Recently, Sajiki et al. reported an efficient protocol 94 for the phosphine-free Suzuki reaction catalyzed by Pd/C at room temperature. Unlike in the procedure used by Köhler et al. 81 (Vide supra), a commercial catalyst was used, and the reaction could be carried out at room temperature omitting the need for sealed tubes but needing much higher quantities of catalyst (10 mol %). Bromoarenes with either electronwithdrawing substituents, such as NO2, CHO, COCH3, or CO2C2H5, or electron-donating substituents, such as OCH3, coupled readily with arylboronic acids in excellent yields (Table 8) using commercially available 10% Pd/C (3.5 mol %) in ethanol-H2O (1:1) and Na2CO3. Aryl bromides containing electron-withdrawing substituents reacted faster than those with electron-donating substituents (for example, entry 1 vs entries 2-4). Table 8. Pd/C-Catalyzed Suzuki Coupling of Aryl Bromides and Arylboronic Acids at RT entry R R′ t (h) yielda (%) 1 OMe H 6 95 2 Ac H 5 99 3 4 NO2 CHO H H 2 5 >99 >99 5 Ac 4-OMe 2 97 6 CHO 4-OMe 2 96 7 8 NO2 OMe 4-OMe 4-OMe 1 5 98 >99 9 Ac 3-OMe 3 >99 10 OMe 2-OMe 5 94 11 12 NO2 CHO 2-OMe 2-OMe 4 5 >99 98 13 Ac 2-OMe 4 >99 14 15 NO2 CO2Et 4-Ac H 19 3 >99 99 a Isolated yield. The catalyst could be recovered using a simple filtration and washing sequence. Reuse was possible without significant decrease in coupling yield even in the fourth run. Ligand-free Pd/C-catalyzed Suzuki-Miyaura coupling also tolerates acid groups in the haloarene and in the arylboronic acid. It was used in the synthesis of biarylacetic acids 21 (Scheme 3). 95 Scheme 3. Synthesis of Biarylacetic Acids by Pd/ C-Catalyzed Arylation The Pd/C-mediated synthesis of the diarylcarboxylic acid 24 was implemented on a large scale (2 × 6.3 kg batches) in a pilot plant (Scheme 4). 31 Similarly, a phenyldiboronate was coupled twice with 3-iodophthalate under ligand-free conditions in the presence of Cs2CO3. 96 Scheme 4. Multikilogram-Scale Synthesis of SB-251475 The integrity of the configuration was maintained in the Pd/C-catalyzed Suzuki coupling of optically active 4-bromomandelic acids in the presence of Na2CO3 providing enantiopure 4-arylmandelic acids 26 (Scheme 5). 97 Both, electron-donating and electron-withdrawing groups were tolerated in the arylboronic acid. Scheme 5. Coupling of Optically Active 4-Bromomandelic Acid with Arylboronic Acids Recently, it was shown that tetraarylborates can be used in ligand-free Pd/C-catalyzed Suzuki reaction of bromoarenes. 98 Various biaryl carboxylic acids and phenols were prepared in high yields (Table 9). Again, the catalyst could be reused several times. For example, coupling of 4-bromobenzoic acid with sodium tetraphenylborate catalyzed by recovered Pd/C provided 88%, 84%, 81%, and 76% yield in the first to the fourth reuse, respectively. Bromo- and iodoheteroarenes can also be used in ligandfree Pd/C-catalyzed Suzuki coupling. Thus the quinoline 30 was obtained with a very low level of residual Pd. Leached Pd was found in the reaction mixture, which diminished to less than 4 ppm after completion of the reaction; that is, the reaction runs by homogeneous catalysis (Scheme 6). 87 The Pd/C-catalyzed synthesis of pyrazolylphenylsulfonamides 32 was implemented in 100-mg scale using a Quest model 210 synthesizer (Scheme 7). 99 5-Aryl-2-furfurals 34 were synthesized by Pd/C catalyzed, ligand-free Suzuki coupling starting from the corresponding diethyl acetal 33 (Table 10). 100 A strong effect of the halide was found in Pd/C-catalyzed ligand-free Suzuki cross-coupling of 2-halocycloalkenones with arylboronic acids. 101 While 2-iodocycloalkenones 35 reacted under mild conditions at 25 °C under air in aqueous DME (Table 11), the corresponding 2-bromo-2-cyclohexen- 1-one completely failed to undergo Suzuki coupling under the same conditions. Only extensive decomposition of starting materials was observed. 101 The coupling of 2-iodo-2-cyclohexen-1-one with phenylboronic acid was also examined using recovered catalyst. It was found that the Pd/C catalyst could be reused at least five runs without affecting the yield (79-85%). The progressive decrease in the activity could be efficiently balanced by increasing the temperature of the reaction from 25 to 50 °C. 101
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