RKCL4625 NICKEL-PROMOTED LIGAND-FREE PALLADIUM-CATALYZED SUZUKI COUPLING REACTION

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1 Jointly published by React.Kinet.Catal.Lett. Akadémiai Kiadó, Budapest Vol. 85, No. 2, and Springer, Dordrecht (2005) RKCL4625 NICKEL-PROMOTED LIGAND-FREE PALLADIUM-CATALYZED SUZUKI COUPLING REACTION Wei Wang, Rongliang Wang, Fan Wu and Boshun Wan* Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian , P. R. China, and Graduate School of the Chinese Academy of Sciences, P. R. China Received July 21, 2004 In revised form November 24, 2004 Accepted November 29, 2004 Abstract A Ni-promoted ligand-free palladium catalyst system for Suzuki coupling of aryl bromides has been developed in high efficiency under mild reaction conditions. It was obtained in situ by introducing NiCl 2 to PdCl 2 /PVP using a parallel highthroughput screening technique. A wide range of aryl bromides bearing a variety of functional groups was evaluated. Keywords: Ni-promoted Pd-catalyst, Suzuki coupling, ligand-free, aryl bromides INTRODUCTION Carbon-carbon bond-forming reactions are important fundamental transformations in synthetic chemistry. The palladium-catalyzed Suzuki coupling of aryl halides with arylboronic acids, first disclosed by Miyaura and Suzuki, is one of the most powerful and versatile methods for the formation of C-C bonds, in particular for the preparation of biaryl compounds [1-4]. Today, the Suzuki coupling is routinely applied in organic syntheses, such as drug discovery via high-throughput screening and the syntheses of natural products and conducting polymers. Although several transition-metal complexes have been used as catalysts, palladium complexes undoubtedly predominated in this reaction. In a typical Pd-catalyzed Suzuki coupling cycle, the oxidative addition * Corresponding author. Tel/Fax: ; bswan@dicp.ac.cn /2005/US$ Akadémiai Kiadó, Budapest. All rights reserved.

2 278 WEI WANG et al.: Ni-PROMOTED Pd-CATALYST step, where aryl halides add to Pd(0) to form Pd(II), is usually the ratedetermining step, while, after the transmetallation step, Pd(II) returns Pd(0) in the reductive elimination step and Pd(0) can easily form palladium black [1-4]. In order to improve the catalytic properties of the palladium and prevent the formation of palladium black, chemists have designed and developed many ligands, mainly phosphorus ones, and successfully employed them in these highly effective Suzuki coupling [1-9]. However, these phosphorus ligands usually require tedious multistep syntheses and are often expensive or sensitive to moisture and air, except for a limited number of comparatively air-stable catalysts [10-16]. Recently, progress has been achieved in developing ligandfree palladium-mediated, catalytic Suzuki coupling, using for example simple palladium salts [17-18], microwave-irradiated palladium salts [19-20], Pd/C and Pd/Al 2 O 3 [21-22], palladium hollow spheres [23], nanoparticle Pd catalyst [24-26], or mixed Cu/Pd nanocluster alloy catalyst [27]. We are also interested in developing a highly efficient and ligand-free Pd-mediated catalyst for Suzuki coupling under mild conditions. Therefore, if we can find a readily available and highly effective co-catalyst instead of ligand in the reaction, we can conveniently use palladium salts to perform the Suzuki coupling. In this paper, we report a Ni-promoted PdCl 2 /PVP poly(n-vinyl-2-pyrrolidone)-catalyzed Suzuki coupling in high efficiency under mild conditions. EXPERIMENTAL The aryl bromides and boronic acids were purchased from Aldrich. The other reagents were of commercial reagent grade. Melting points were measured on a Yazawa micro melting point apparatus (uncorrected). 1 H NMR spectra were recorded on a Bruker DRX-400 spectrometer (400 MHz). Column chromatography was performed on silica gel. Commercially available parallel synthesis apparatus was Chemspeed ASW 500 with 80 reaction vessels. General procedure for HTS experiments Each reaction vessel of parallel synthesis apparatus was charged with 1.5 mmol base, 1.5 ml ethanol, 0.2 ml M ( mmol, mol%) of the second transition metal salt in ethanol, 0.5 ml M ( mmol, mol%) PdCl 2 /PVP (PdCl 2 :PVP = 1:15) in ethanol. Then 0.5 ml 1.0 M (0.5 mmol) of 4-bromotoluene in ethanol and 0.75 ml 1.0 M (0.75 mmol) of phenylboronic acid in ethanol were added. The total solvent volume was 3.45 ml. The reaction vessels were heated to 80 C and oscillated for 15 h. After cooling to room temperature, 0.4 ml ( g/ml) hexadecane in

3 WEI WANG et al.: Ni-PROMOTED Pd-CATALYST 279 cyclohexane was added as internal standard. The mixture was analyzed by GC after a centrifugation. General procedure for Suzuki coupling A 100 ml two-necked flask with a reflux condenser and a thermometer, was charged with 12.5 ml ethanol, 1.05 g (7.6 mmol) K 2 CO 3, 1.0 ml M ( mmol, mol%) of NiCl 2 in ethanol and 2.5 ml M ( mmol, mol%) PdCl 2 /PVP in ethanol. Then 2.5 mmol aryl bromide and 3.75 mmol arylboronic acid were added. Under magnetic stirring the mixture was heated to reflux. After the reaction, the mixture was cooled to room temperature, K 2 CO 3 was filtered off and the wet cake was washed with ethanol. The solvent was removed under reduced pressure. The residue was purified by column chromatography to afford the product. RESULTS AND DISCUSSION We started our investigation with a standard Pd-catalyzed Suzuki coupling between 4-bromotoluene and phenylboronic acid with a catalyst loading of mol% Pd. The reaction was carried out in the presence of K 2 CO 3 in refluxing ethanol. As can be seen from Table 1, when only PdCl 2 was used as catalyst, the yield was 59% after 15 h. It is not surprising that PdCl 2 /PVP can give a higher yield of 77% because PVP can disperse Pd(0) and effectively prevent the formation of palladium black [24]. Although the true mechanism of Pd-catalyzed Suzuki coupling in situ remains unclear [28], phosphorus or other ligands can usually be employed in the Suzuki reaction. In this case we wondered whether adding an alternative transition metal salt could effectively improve the palladium-mediated reaction without using ligands. For tuning a variety of transition metal salts and bases, the methods of combinatorial chemistry such as high-throughput screening (HTS) are increasingly being employed for the discovery and optimization of homogeneous transition-metal catalysts [29]. Accordingly, we used parallel HTS experimentation to screen the reaction with various transition metal salts, such as, Cu, Cr, Zn, Mn, Fe, Ni ion salt as the promoters in the presence of various bases. Surprisingly, it can be seen from Table 1 that adding Cr(NO 3 ) 3, Zn(OAc) 2 with K 2 CO 3 as base, and Zn(OAc) 2 with Na 3 PO 4 as base can improve the PdCl 2 /PVP-catalyzed Suzuki coupling, giving 92%, 94% and 91% yield, respectively. Furthermore, among the tested transition metal salts, Ni(II) salts can strongly promote the reaction. In particular, using NiCl 2 and NiSO 4 as the additives, the reaction gave near quantitative yield of the product. No reaction

4 280 WEI WANG et al.: Ni-PROMOTED Pd-CATALYST was observed when only Ni(II)/PVP was added under these reaction conditions, although in the presence of some ligands Ni(II) can catalyze the Suzuki coupling [30, 31]. The synergistic effect of Pd/Ni is obvious. Moreover, compared to K 2 CO 3, several other bases including Na 2 CO 3, Na 3 PO 4, KF all gave inferior results and Et 3 N was almost ineffective. Therefore, it is found that using K 2 CO 3 as a base, NiCl 2 or NiSO 4 can greatly promote the PdCl 2 /PVPcatalyzed Suzuki coupling of 4-bromotoluene in refluxing ethanol. Table 1 The Pd-catalyzed Suzuki coupling of 4-bromotoluene with phenylboronic acid a, b Catalyst H 3 C Br + PhB(OH) 2 CH Base 3 Catalyst K 2 CO 3 Na 2 CO 3 Na 3 PO 4 KF Et 3 N PdCl PdCl 2 /PVP PdCl 2 /PVP+CuSO Traces PdCl 2 /PVP+CuCl Traces PdCl 2 /PVP+Cr(NO 3 ) Traces PdCl 2 /PVP+Zn(OAc) Traces PdCl 2 /PVP+MnCl Traces PdCl 2 /PVP+FeCl Traces PdCl 2 /PVP+Ni(OAc) Traces PdCl 2 /PVP+NiCl Traces PdCl 2 /PVP+NiSO Traces M/PVP c a Reaction conditions: 0.50 mmol 4-bromotoluene, 0.75 mmol PhB(OH) 2, 1.5 mmol base, mol% Pd, transition metal salt 1 equiv of Pd, 3.45 ml EtOH, air, 15 h, reflux. Total solvent 3.45 ml. b GC average yield of two runs based on 4-bromotoluene (hexadecane internal standard). c M/PVP represents each screened transition metal salt in the presence of PVP. With the above results in hand, the protocol using PdCl 2 /PVP+NiCl 2 catalyst system is applicable to other representative aryl bromide substrates bearing different functional groups with good yields obtained in the reaction with phenylboronic acid (Table 2, entries 1-8). A wide range of functional groups is tolerated in the reaction. Sterically hindered 2-bromotoluene can also be coupled with phenylboronic acid to afford the product in high yield (entry 6). Other representative boronic acids also gave good yields of the reaction (entries 9, 10). Although aryl chlorides cannot be effectively coupled by this method (entries 11, 12), in the presence of p-toluenesulfonyl chloride, ligandless palladium chloride catalyzes the homo-coupling of arylboronic acids in water to afford symmetrical biaryls [32], using the present catalyst system. In aqueous

5 WEI WANG et al.: Ni-PROMOTED Pd-CATALYST 281 media the Suzuki coupling of 4-bromotoluene with phenylboronic acid can effectively be carried out in high yield (entry 13). The reaction of other representative aryl bromides with phenylboronic acid also gave good yields (entries 14, 15). In conclusion, we have developed a Ni-promoted palladium catalyst system, discovered in situ by introducing NiCl 2 to PdCl 2 /PVP using a parallel highthroughput screening technique, for the Suzuki coupling of aryl bromides with

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