SHORT COMMUNICATION. Study of CuI catalyzed coupling reactions of aryl bromides with imidazole and aliphatic amines under microwave dielectric heating

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1 Chemical Papers 62 (3) (2008) DI: /s z SHT CMMUICTI Study of CuI catalyzed coupling reactions of aryl bromides with imidazole and aliphatic amines under microwave dielectric heating Eva Veverková*, Štefan Toma Department of rganic Chemistry, Faculty of atural Sciences, Comenius University, SK ratislava eceived 1 ugust 2007; evised 8 ovember 2007; ccepted 30 ovember 2007 mination of a variety of functionalized aryl bromides with imidazole and primary and secondary amines was accomplished using a CuI/amino acid catalyst system under microwave heating. pplication of microwave irradiation shortened the reaction time from 2 40 h to 6 20 min. Good to very good yields of the corresponding coupling products were obtained when imidazole and secondary amines were used as starting materials. In case of primary amines, the outcome of the reaction was dependent on the character of the substituent on aryl bromide. c 2008 Institute of Chemistry, Slovak cademy of Sciences Keywords: arylamines, coupling reactions, microwave irradiation, CuI/amino acid catalysis -ryl compounds are common objectives for pharmaceutical synthesis, and for synthesis of other biologically active molecules. Improving methods for their synthesis are therefore important. Traditional method for the preparation of these compounds is the Ullmann-type coupling reaction of an aryl halide and an amine. These reactions usually proceed at high temperatures; and consequently, their usefulness is limited (Lindley, 1984). During the past decade, milder coupling conditions using either palladium catalyst (Wolfe et al., 1998) or copper catalyst systems have been developed (Ley &Thomas, 2003; Kunz et al. 2003; ntilla et al., 2002; van llen & Venkataraman, 2003; Han et al., 2004). Ma and co-workers (2003) have recently developed an improved CuI catalytic system using readily available and cheap amino acids as promotors (Cai et al., 200; Zhang et al., 200; Ma et al., 2003). wide range of substrates including primary and secondary aliphatic amines, primary aryl amines, electron rich and electron deficient aryl bromides and aryl iodides are compatible with Ma s protocol. However, one drawback of this reaction is its long reaction time. In recent years, microwave heating has become a popular method of improving the efficiency of many organic reactions (Kappe, 2004). dvantages of the microwave method over the conventional techniques include a much shorter reaction time and, in some cases, higher purity of the final products (Perreux & Loupy, 2001; Lindström et al., 2001). This technology has been explored for use in the Ullmann ether synthesis (Li et al., 200, 2003; D ngelo et al., 2006) and in copper catalyzed coupling of (S)-1-(3-bromophenyl)- ethylamine with a variety of H heteroarenes (Wu et al., 2003). Several reports of microwave-assisted Pd catalyzed aminations have appeared in last years, e.g. Jensen et al. (2004) and references therein. However, to our knowledge, the use of microwave methodology in CuI catalyzed amination of aryl halides has not been reported. ll materials were of commercial quality and were used as received. Most of the microwave experiments were carried out in a SYTHEWVE 402,P- L reactor at constant microwave power of 120 W or at constant temperature of 170 C, power fluctuation from W to 30 W. Microwave experiments at high pressure were carried out in an Initiator ITGE reactor at constant temperature (10 C, power range from W to 30 W, pressure 2 bar). M spectra were measured on a Varian Gemini 2000 spectrometer in CDCl 3 with TMS as an internal standard. The typical procedure employed for the microwave *Corresponding author, veverkova@fns.uniba.sk Download Date 11/24/1 3:06 M

2 E. Veverková & Š. Toma/Chemical Papers 62 (3) (2008) 33 Table 1. CuI/amino acid catalyzed coupling reaction of 4-bromotoluene with imidazole; reaction conditions: CuI/,-dimethylglycine, K 2 C 3,solvent r + H Entry Solvent thod a Time/min t final / C Yield d /% 1 DMS b 2 DMS DMS c 4 toluene toluene/[emim] + [F 4 ] PEG PEG PEG PEG PEG PEG a) microwave exposure: (120 W), (30 20 W, constant t); b) ligand = l-proline; c) control experiment performed at conventional heating; d) isolated yield. Table 2. CuI/amino acid catalyzed coupling reaction of aryl bromides with imidazole; reaction conditions: CuI/ligand, K 2 C 3, DMS, microwave exposure (120 W) r + H Entry ryl bromide Ligand a t final / C Time/min Yield b /% 1 2 r r =HC r r r a) : L-proline, :,-dimethylglycine; b) isolated yield. assisted coupling reaction consisted of preparation of an equimolar solution of amine (0.00 mol) and aryl bromide (0.00 mol) in 3 ml of a solvent containing K 2 C 3 (0.001 mol). To this mixture, mol of CuI and mol of amino acid were added. The mixture was irradiated in the microwave reactor at constant temperature or constant input power for the time given in Tables 1 4. fter cooling to room temperature, the reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined extract was washed with brine, dried over a 2 S 4, concentrated in vacuo and purified by column chromatography on silica gel (isohexane/ethyl acetate, ϕ r =6:1). When the reactions were carried out in PEGs (Table 1, entries 6 11), the reaction mixture was extracted into CHCl 3 (3 20 ml). rganic phase was washed with water, dried over a 2 S 4, filtered, and concentrated. The product was isolated from the oily residue, which contained product as well as some PEG, by its trituration into hot hexane (0 ml). fter the removal of the solvent, very pure product was obtained. For example, 1-[4-(1,3-dioxolan-2- yl)phenyl]-1h-imidazole (entry, Table 2) was obtained as a white solid; m.p C; 1 H M (300 MHz, CDCl 3 ), δ: (m, 4H),.8 (s, 1H), 7.21 (s, 1H), 7.29 (s, 1H), 7.42 (d, J = 6.3 Hz, 2H), 7.69 (d, J = 6.3 Hz, 2H), 7.86 (s, 1H); 13 C M (7 MHz, CDCl 3 ), δ: 66.31, , , , , , 13.67, 137.3, Composition of Download Date 11/24/1 3:06 M

3 336 E. Veverková & Š. Toma/Chemical Papers 62 (3) (2008) Table 3. CuI/proline catalyzed coupling reaction of aryl bromides with secondary amines; reaction conditions.: CuI/L-proline, K 2 C 3, DMS, microwave exposure (120 W) 1 min r + H Entry ryl bromide mine t final / C Yield c /% 1 r H a /66/78 b 2 r H 11 16/49 b 3 r 4 r H /88 b H 12 22/42 b =HC r H /72 b 6 =HC r H 16 36/69 b 7 r H 170 7/84 b a),-dimethylglycine used as a ligand; b) experiment carried out in an Initiator-iotage reactor at constant temperature of 10 C and pressure 0. 1 MPa; c) isolated yields. C 12 H w i /mass % calculated: C 66.6, H.9, 12.96; found: C 66.21, H.68, Coupling of 4-bromotoluene and imidazole catalyzed by 10 mol % of CuI and 20 mol % of a ligand (according to Ma s protocol) was used as a model to explore the optimum reaction conditions. Initially, DMS, a typical dipolar aprotic organic solvent with a high dielectric constant, was chosen as a suitable solvent for the reaction under microwave irradiation. f the two ligands tested,,-dimethylglycine proved to be better than l-proline in terms of yield (Table 1, entry 1 vs. 2). ptimal microwave conditions were: input power of 120 W and reaction time of 20 min. To check if some specific microwave acceleration occurred in this reaction, a control experiment with thermal heating was performed. Comparison of the results (Table 1, entry 2 vs. 3) indicated that a mild microwave effect was observed. To explore the solvent scope, toluene was also tested, but no product was observed after 20 min of irradiation. The reaction was also tried with ionic liquids, because similar reactions were described as successful in these solvents (Lv et al., 2006). Using [emim] + [F 4 ] as the ionic liquid, no positive results were obtained as very high temperature (above 20 C) was reached within a short reaction time and polymerization of the product took place. To prevent this rapid increase of temperature, a mixture of toluene and a small amount of ionic liquid was used, but no conversion of 4-bromotoluene was observed (Table 1, entry 4). In recent years, polyethylene glycols (PEGs) have been used as a support (Vasudevan et al., 2001; Sauvagnat et al., 2000) or a solvent (Kamal et al., 2006) for various transformations. To investigate the possibility of using these polymers as solvents in the microwave reaction was therefore decided. Three polyethylene glycols (M r values of 400, 600, and 1000) were screened. To compare PEGs with other tested solvents, the experiments were first carried out at the temperature of 17 C and reaction time of 20 min, but the yields were not satisfactory (entries 6 8). Therefore it was decided to use input power of 120 W, without any pre-selection of the final temperature. Under these conditions, the temperature rose quickly to 220 C. fter a short time at this temperature, the appearance of dark brown color in the reaction mixture indicated the product degradation. It was best to stop the reaction after min of irradiation, although the isolated yields of the product at constant input power and final temperature of 220 C were higher in comparison to the longer experiments at lower temperatures (entries 9 11 vs. 6 8). This observation demonstrated that high temperature can cause the observed acceleration of the present reaction. The best yields (6 % and 79 %, respectively) were obtained with PEG 600 as the solvent. The yields obtained using DMS as the solvent were similar. s it is simpler to isolate the product from DMS, using an aqueous workup procedure, DMS as the solvent was used in our further investigations. Scope of the above described -arylation reaction was extended to other substituted aryl bromides. Table 2 shows that, while the character of a substituent had no significant effect on the yield of the coupling product, electron-withdrawing groups significantly re- Download Date 11/24/1 3:06 M

4 E. Veverková & Š. Toma/Chemical Papers 62 (3) (2008) 337 Table 4. CuI/proline catalyzed reaction of aryl bromides with primary amines; reaction conditions: CuI/l-proline, K 3 P 4,DMS, microwave exposure (120 W) 1 min r-r + H 2 r-h- + r C 1 1 = H, CH 3 Entry ryl bromide mine t final / C Yield of a /% Yield of a /% 1 r H 2 H r nh =HC r H 2 H =HC r nh r CH= H 2 H r CH= nh r H 2 H r nh a) determined by GC-MS. duced the reaction time (entries 1 3 vs. 4, ). In all cases, the reaction efficiency was higher when,dimethylglycine was used as the ligand. Table 3 shows the results of some functionalized aryl bromides reactions with cyclic aliphatic secondary amines. The reaction time of 1 min was enough to complete these coupling reactions under microwave irradiation. It was found that L-proline is a better ligand compared to,-dimethylglycine (entry 1). Pyrrolidine gave a higher yield of the coupling products compared to morpholine, which is in good agreement with the results reported by Zhang et al. (200). s the low boiling points of pyrrolidine (86 88 C) and morpholine (129 C) probably accounted for the relatively low yields of the products, these reactions were repeated in a closed system at high pressure using the iotage-initiator reactor. The yields increased significantly in both cases. Finally, the coupling of some aryl bromides with primary amines was studied. The results summarized in Table 4 show that the reactions of 4-bromotoluene with benzylamine and 2-hydroxyethylamine resulted only in the product of the coupling reaction. However, aryl bromides bearing a carbonyl group provided products resulting from the condensation reaction of the carbonyl group (), and no (or only small amounts) of the coupling products (). This outcome is in contradiction with Ma s results, where only the coupling products were obtained in high yields under thermal heating (Zhang et al., 200). Two competitive reactions are supposed to proceed: reaction of primary amines with 4-bromobenzaldehyde or 4- bromoacetophenone by nucleophilic aromatic substitution, and imine-forming condensation. The second reaction (condensation) was favored in the microwave experiment as water strongly absorbed microwave energy and evaporated under the reaction conditions. The equilibrium of the condensation reaction was pushed towards imine formation. o such effect can be observed under classical heating. In conclusion, a useful and rapid method for CuI/amino acids catalyzed amination reactions of aryl bromides with various types of amine nucleophiles was found. It was found that the polar solvent media DMS and PEG-600 are suitable for use in microwave conditions. The present protocol represents an operationally simple substitute for the conventional heating method, where various functionalized aryl bromides are coupled with imidazole and secondary amines. limitation of microwave heating when primary amines are used as the nucleophiles was also revealed. cknowledgements. Financial support of the Ministry of Education of the Slovak epublic (CSTD 032/0010) is kindly acknowledged. Download Date 11/24/1 3:06 M

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