Direct arylation of heteroaromatic compounds by Pd(OAc) 2 /tetrakis( N - benzimidazoliummethyl)benzene salt system

Six novel tetrakis( N -benzimidazoliummethyl)benzene salts were synthesized using 1,2,4,5-tetrakis-(bromomethyl)benzene with 1-alkylbenzimidazole. The structures of all isolated compounds were elucidated based on spectroscopic methods ( 1 H and 13 C NMR, and FT-IR spectroscopy) and were investigated for their catalytic activities in the direct arylation of 2-n-propylthiazole, 2-n-buthyltiophene, 2-n-butylfuran, and 4,5-dimethylthiazole. All synthesized salts showed high catalytic activity for direct arylation of heteroaromatic compounds.


Introduction
The discovery of N-heterocyclic carbenes (NHCs) as a unique ligand for transition metals is one of the most important advances for both organometallic chemistry and catalysis. 1,2,3The strong σ-donor and weak πacceptor binding properties of these ligands allow them to form more stable compounds with metals compared to their phosphine analogs.In addition, NHC ligands have less tendency to leave the metal center than phosphines, which interrupts the cocatalyst deactivation/decomposition pathways.In the 1960s, earlier studies by Wanzlick 4 and Ofele, 5 and then, synthesis of the first stable carbene by Arduengo 6 in 1991 led to an increase of experimental studies of novel NHCs.The intensive interest in NHCs has led to the parallel development of poly-NHCs [7][8][9][10][11][12][13] bearing bis-, tris-, tetra, and hexa ligands as well as mono-NHCs. 14,15][18][19] The investigation of poly-NHCs leads not only to the preparation of their metal complexes but also applications in catalysis (cross coupling reactions, 20,21 C-H activation and functionalization, 22 hydrogenation, 23 allylation 24 e.g.), medicinal chemistry, 25,26 and photophysics. 27,28The first example regarding poly-NHC catalyzed reaction had been published by Hermann's group in 1995. 29From then on, many studies were reported about poly-NHCs and their catalytic activities in cross-coupling reactions, 20,21 C-H activation, 22 or direct arylation reactions. 30he cross coupling reactions such as Suzuki-Miyaura, Mizoroki-Heck, Sonogashira, Hiyama, and Kumada-Tamao-Corriu have been generally used for the formation of carbon-carbon bonds.The use of organometallic partners and the formation of by-products in these reactions has resulted in palladiumcatalyzed direct C-H bond arylation during the past decades.Particularly, direct arylation of heteroaromatics attracted the researcher's attention due to their biological and physical properties. 31,32In 1990 it was reported that Otha's group achieved good yields by direct arylation (C2-or C5-) of heteroaromatics with aryl bromides to yield the corresponding aromatic heterocycles using Pd catalyst.][41][42][43][44] In the current work, we prepared six novel tetrakis(N-benzimidazoliummethyl)benzene salts (1a-1f) using 1,2,4,5-tetrakis(bromomethyl)benzene with 1-alkylbenzimidazole.After that, we investigated the in situ generated catalytic system using Pd(OAc) 2 as the palladium source and the tetrakis(Nbenzimidazoliummethyl)benzene salts (1a-1f) as a carbene precursor for direct C2-and C5-arylation of heteroaromatics.The catalytic activities of these salts in the direct arylation of 2-n-propylthiazole, 2-nbutylthiophene, 2-n-butylfuran, and 4,5-dimethylthiazole were tested and the synthesized salts showed high catalytic activity.

Results and Discussion
Synthesis of 2,3,5,6-tetrakis(N-benzimidazoliummethyl) salts 2,3,5,6-tetrakis(N-benzimidazoliummethyl) salts were synthesized according to the literature. 24The reaction of 2,3,5,6-tetrakis(bromomethyl)benzene with 1-alkylbenzimidazole in DMF at 80 o C for 12 h gave the corresponding salts (1a-1f) as shown in Scheme 1.The new tetraazolium salts (1a-f) were obtained with higher yields (79-93%).The N-heterocyclic carbene precursors stable to air and moisture are soluble in polar solvents such as ethanol, dichloromethane, and dimethylformamide.The structure of these salts was elucidated with 1 H and 13 C NMR, and FT-IR spectroscopies.The 1 H NMR spectroscopy shows that the NCHN proton of the benzimidazolium salts appeared between 9.43-10.28ppm.Additionally, the 13 C NMR reveals that the values for C(2) carbon are between 159.9-163.0ppm.All data for these salts are compatible with the literature. 24heme 1.The procedure for the synthesis of tetraazolium salts.

Direct arylation of heteroaromatics
In the current work, we researched the activity of in-situ generated Pd(OAc) 2 /1(a-f) catalyst systems for direct C2-and C5-arylation of heteroaromatics.For this purpose, we investigated the binding of aryl bromides (4bromoasetofenone and 4-bromobenzene) to the C5-position of 2-n-buthyltiophene, 2-n-propylthiazole, 2-nbutylfuran, and C2-position of 4,5-dimethylthiazole. Based on previous studies on Pd-catalyzed direct arylation, for this study, DMAc (N,N-dimethylacetamide) and KOAc (potassium acetate) were selected as the solvent and base, respectively.The experiments were performed at 120 o C for 1 h.As shown in Table 1 and Table 2, the high GC yields were obtained using low Pd(OAc) 2 /NHC precursor loadings at the end of the reaction.
In this study, under optimal conditions, C2-and C5-arylated products were obtained with the reaction of heteroaromatics with 4-bromoacetofenone and 4-bromobenzene at high yields.Particularly, 4bromoacetophenone was found to be more active than 4-bromobenzene due to its electron-attracting group (Table 1).When 2-n-butylfuran was used as heteroaromatic derivative in direct arylation reactions, the C5arylated product was obtained with higher yields (Table 1 and 2).This is due to the ability of the oxygen atom in the ring to activate the C5-carbon in heteroaromatics. 45In addition, arylated products were obtained with good yields in the direct arylation reactions where the other heteroaromatic compounds were used.
Eventually, we researched tetrazolium salts which we used as NHC precursor for the Pd(OAc) 2 /NHC catalyst system in the direct arylation reactions of heteroaromatics with aryl bromides.All of the tetrazolium salts are active compounds for this reaction.There are no significant differences between the catalytic activities of tetraazolium salts used in the catalytic system with Pd(OAc) 2 .However, It was found that the most effective catalyst is 1a containing 4-methoxybenzyl group in the direct C2-and C5-arylation of heteroaromatics.On the contrary, the tetraazoluim salt 1e showed lower activity in all direct arylation reactions.The steric and electronic properties of the alkyl group bearing to the compound may be the reason for this difference.

Conclusions
In summary, the novel six tetraazolium salts (1a-f) which are stable to air and moisture were synthesized from 2,3,5,6-tetrakis(bromomethyl)benzene according to the literature 12 .The characterization of the synthesized compounds was determined using 1 H NMR, 13 C NMR, and FT-IR spectroscopies.Also, the catalytic activities of tetraazolium salts/Pd(AOc) 2 systems were investigated in the direct C5-arylation of 2-n-butylthiophene, 2-npropylthiazole and 2-n-butylfuran and C2-arylation of 4,5-dimethylthiazole with 4-bromobenzene /4bromoacetophenone.It was found that prepared tetrazolium salts/Pd(AOc) 2 systems were efficient catalysts for the arylation of heteroaromatic compounds.Particularly, these in situ generated system showed very high activity especially in the direct arylation of 2-n-butylfuran.According to the obtained results, salt 1a showed the highest activity for all reactions when compared to other salts.Finally, the desired products were obtained in high yields for direct arylation of heteroaromatics with different aryl bromides in the presence of low catalyst loading.This study is more environmentally benign and economical than other classic coupling reactions due to low catalyst loading and short reaction time.