40▌ PRACTICAL SYNTHETIC PROCEDURES Apractical Practical synthetic procedures Protocol for the Hiyama Cross-Coupling Reaction Catalyzed by Palladium on Carbon YasunariHiyama Cross-CouplingMonguchi,* Catalyzed by Palladium on Carbon Takayoshi Yanase, Shigeki Mori, Hironao Sajiki* Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan Fax +81(58)2308109; E-mail: [email protected]; E-mail: [email protected] PSP Received: 11.09.2012; Accepted after revision: 20.09.2012 240 No Abstract: A method for the palladium on carbon (Pd/C) catalyzed cross-coupling reaction between aryl halides and trialkoxy(aryl)silanes in the presence of a small amount of water is established using tris(4-fluorophenyl)phosphine as the ligand. A range of biaryl compounds is prepared using this protocol. Key words: palladium, cross-coupling, heterogeneous, silicon, biaryls 10% Pd/C (0.5 mol%) (4-FC6H4)3P (1 mol%) X Si(OR3) 2 3 TBAF·3H2O (2 equiv) R R1 + R2 4.8% aq toluene R1 120 °C X = I, Br, Cl 1.5 equiv up to 90% yield R3 = Me, Et Scheme 1 Pd/C-catalyzed cross-coupling between aryl halides and trialkoxy(aryl)silanes in the presence of (4-F-C6H4)3P, TBAF·3H2O and a small amount of water in toluene The palladium-catalyzed cross-coupling reaction between water as an additive on the reaction progress, the use of organic halides and organosilanes, the Hiyama coupling, tris(4-fluorophenyl)phosphine [(4-FC6H4)3P] as the li- is of practical use due to the low toxicity of organosilanes gand, and broad substrate applicability were demonstrat- and the easy access it provides to biaryl skeletons, which ed.11 Furthermore, a ligand-free palladium on carbon are partial structures of various functional molecules, in- catalyzed Hiyama reaction was achieved by the addition cluding pharmaceuticals.1,2 The development of heteroge- of acetic acid.12 In this report, a detailed investigation neous palladium-catalyzed cross-coupling reactions has leading to optimized conditions in the presence of tris(4- attracted significant attention from both environmental fluorophenyl)phosphine as the ligand, and their applica- and economic points of view, as the catalysts can be read- bility to a range of substrates is discussed (Scheme 1). 3 ily recovered from the reaction mixture. Although the ap- While the cross-coupling reaction between 1-iodo-4-ni- plication of palladium nanoparticles on surfactants,4 5 6 trobenzene and triethoxy(phenyl)silane (1.5 equiv) in the polyethylene glycol, and a dendrimer have been report- presence of 1,1′-bis(diphenylphosphino)ferrocene (dppf) ed as heterogeneous catalysts for the Hiyama cross-cou- (10 mol%) and tetra-n-butylammonium fluoride trihy- pling, many of them require complicated procedures for drate (TBAF·3H2O) (2 equiv) at 120 °C (bath tempera- their preparation. We have been interested in the applica- ture) proceeded disappointingly in alcoholic, ethereal, and tion of palladium on carbon (Pd/C), a commercially avail- polar aprotic solvents (Table 1, entries 1–9), toluene was able conventional hydrogenation catalyst,7 for cross- 8,9 found to be a good solvent leading to the desired cross- coupling reactions. Although a report on the palladium This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 10 coupled product, 4-nitrobiphenyl, in 64% yield (Table 1, on carbon catalyzed Hiyama coupling was published entry 10). Although tetra-n-butylammonium fluoride tri- during the course of our preparation of a previous commu- 11 hydrate and tetra-n-butylammonium fluoride in tetrahy- nication, it focused on the variation in the catalyst activ- drofuran were both able to activate ity of palladium on carbon supplied by different vendors triethoxy(phenyl)silane to promote the cross-coupling toward several types of cross-coupling reactions, includ- (Table 1, entries 10 and 15), no reaction took place using ing the Hiyama reaction. However, the reaction condi- other inorganic fluoride salts, probably due to their poor tions and substrate scope were not investigated in detail. solubility in toluene (Table 1, entries 11–14). Therefore, In our above-mentioned communication, the effect of tetra-n-butylammonium fluoride trihydrate was chosen as the activator of choice for silane derivatives because of its SYNTHESIS 2013, 45, 0040–0044 better efficiency in the coupling reactions. Advanced online publication: 09.10.20120039-78811437-210X DOI: 10.1055/s-0032-1316801; Art ID: SS-2012-Z0714-PSP © Georg Thieme Verlag Stuttgart · New York PRACTICAL SYNTHETIC PROCEDURES Hiyama Cross-Coupling Catalyzed by Palladium on Carbon 41 Table 1 Evaluation of Solvents and Fluoride Sources on the 10% tylphosphino)biphenyl (JohnPhos), did not promote the Pd/C-Catalyzed Cross-Coupling between 1-Iodo-4-nitrobenzene and coupling as efficiently (Table 2, entries 15 and 16). Triethoxy(phenyl)silane 10% Pd/C (5 mol%) DPPF (10 mol%) Table 2 Evaluation of Ligands for the 10% Pd/C-Catalyzed Cross- I Ph F– source (2 equiv) Coupling between 1-Iodo-4-nitrobenzene and Triethoxy(phenyl)si- + PhSi(OEt)3 lane 120 °C O N O N 2 1.5 equiv 2 10% Pd/C (5 mol%) I ligand Ph Entry Solvent F– source Time (h) Yield (%)a TBAF·3H2O (2 equiv) + PhSi(OEt)3 O N toluene O N 2 1.5 equiv 120 °C 2 1 MeOH TBAF·3H2O240 a b 2 THF TBAF·3H2O8 7 Entry Ligand mol% Time (h) Yield (%) 3 1,4-dioxane TBAF·3H2O5 7 1c ––2452 4 MeCN TBAF·3H2O 1 trace 2 dppf 10 14 64 5 DMPU TBAF·3H2O3 0 3 dppe 10 24 50 b 6 NMP TBAF·3H2O3 8 4 dppp 10 24 39 7 DMF TBAF·3H2O1 16 5 dppb 10 24 46 c b 8DMA TBAF·3H2O3 17 6 PPh3 20 20 63 b 9 DMSO TBAF·3H2O3 24 7(4-ClC6H4)3P20669 10 toluene TBAF·3H2O1464 8(4-FC6H4)3P20683 11 toluene NaF 9 0 9(C6F5)3P20656 12 toluene KF 14 0 10 (2-MeC6H4)3P202453 13 toluene CsF 14 0 11 (3-MeC6H4)3P202062 14 toluene CuF2 90 12 (4-MeC6H4)3P202066 15 toluene TBAF in THF 5 52 13 (4-MeOC6H4)3P202450 a 1 Determined by H NMR spectroscopy with 1,4-dioxane as the inter- 14 [2,6-(MeO) C H ] P20 20 39 nal standard. 2 6 3 3 b Yield of isolated product. 15 Cy3P201258 c DMA = N,N-dimethylacetamide. 16 JohnPhos 20 24 45 Interestingly, this cross-coupling was found to proceed a The total amount of phosphine atoms in each entry are equal. b 1 under ligand-free conditions to afford 4-nitrobiphenyl in Determined by H NMR spectroscopy with 1,4-dioxane as the inter- 12 nal standard. 52% yield (Table 2, entry 1). No other bidentate ligands, c PhSi(OEt) (2 equiv) were used. apart from 1,1′-bis(diphenylphosphino)ferrocene, in- 3 creased the efficiency of the reaction (Table 2, entries 2– 5). When triphenylphosphine derivatives were employed When dried tetra-n-butylammonium fluoride13 was used as monodentate ligands, the reaction efficiency was af- for the cross-coupling reactions, the efficiency decreased fected strongly by the electron density of the aromatic nu- significantly in comparison to those using tetra-n-butyl- clei (Table 2, entries 7–14); triphenylphosphine ammonium fluoride trihydrate (Table 3, entries 1 vs. 2 and This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. derivatives bearing electron-withdrawing chlorine or flu- 6 vs. 7), suggesting that the presence of water promotes orine atoms on each aromatic ring were found to be good the coupling. The yield was improved significantly by ligands (Table 2, entries 7 and 8). However, no improve- adding a small amount of water (4.8 v/v% aqueous tolu- ment in the yield was observed when using perfluorinated ene) (Table 3, entries 3 and 8). Increasing the amount of triphenylphosphine as the ligand (Table 2, entry 9). On the added water (9.1, 17 or 31 v/v%) did not improve the re- other hand, ligands with one or two electron-donating sults further (Table 3, entries 4, 5, 9 and 10). These results substituents on the aromatic rings proved to be less effec- indicate that addition of a small amount of water acceler- tive in this coupling reaction (Table 2, entries 10–14). ates the present cross-coupling reaction. Therefore, tris(4- Furthermore, monodentate phosphine ligands with bulky fluorophenyl)phosphine and 4.8 v/v% aqueous toluene and non-aromatic substituents on the phosphine atom, were chosen as the optimum ligand and solvent, respec- such as tricyclohexylphosphine (Cy3P) and 2-(di-tert-bu- tively.14–17 © Georg Thieme Verlag Stuttgart · New York Synthesis 2013, 45, 40–44 42 Y. Monguchi et al. PRACTICAL SYNTHETIC PROCEDURES Table 3 Effect of Water on the 10% Pd/C-Catalyzed Cross-Coupling Table 4 Optimization of the Amount of Catalyst and Ligand between 1-Iodo-4-nitrobenzene and Triethoxy(phenyl)silane 10% Pd/C 10% Pd/C (5 mol%) I (4-FC6H4)3P Ph I ligand (20 mol%) Ph TBAF·3H2O (2 equiv) + PhSi(OEt)3 TBAF·3H2O (2 equiv) + PhSi(OEt)3 4.8% aq toluene O2N 1.5 equiv O2N O N aq toluene O N 2 1.5 equiv 120 °C 2 Entry Catalyst Ligand Temp Time Yield a b (mol%) (mol%) (°C)a (h) (%)b Entry Ligand H2O (v/v%) Time (h) Yield (%) c 1 5 20 120 6 83 1 (4-ClC6H4)3P– 2464 2 5 15 120 9 83 2(4-ClC6H4)3P– 6 69 3 5 10 120 9 87 3(4-ClC6H4)3P4.8 6 80 45 5 120976 4(4-ClC6H4)3P9.1 1380 50.51 120690 5(4-ClC6H4)3P33 2424 c 6 0.3 0.6 120 6 81 6 (4-FC6H4)3P– 1770 70.51 802466 7(4-FC6H4)3P– 6 83 8 0.5 1 100 24 89 8(4-FC6H4)3P4.84 83 90.51 140689 9(4-FC6H4)3P9.14 80 a Bath temperature.