N-Heterocyclic carbene–palladium catalysts for the direct arylation of pyrrole derivatives with aryl chlorides

Summary New Pd–NHC complexes have been synthesized and employed for palladium-catalyzed direct arylation of pyrrole derivatives by using electron-deficient aryl chlorides as coupling partners. The desired coupling products were obtained in moderate to good yields by using 1 mol % of these air-stable palladium complexes. This is an advantage compared to the procedures employing air-sensitive phosphines, which have been previously shown to promote the coupling of aryl chlorides with heteroarenes.

The introduction of aryl groups at C2 or C5 positions of pyrroles is an important research area in organic synthesis as such motives are known to be present in several bioactive molecules, such as Atorvastatin, which is used for lowering blood cholesterol, Fendosal, which is an anti-inflammatory agent, or Tanaproget, which is a progesterone-receptor agonist ( Figure 1).
The influence of mono-or diphosphines as ligands for the palladium-catalyzed coupling of heteroarenes with aryl halides through a C-H bond activation has been largely explored. On the other hand, the influence of carbene ligands for such couplings remains largely unexplored [40][41][42][43][44][45][46][47]. Quite congested N-heterocyclic carbene-palladium catalysts have been employed by Fagnou and co-workers to promote intramolecular direct arylations of arenes [40]. A few examples of couplings of aryl bromides and iodides employing Pd-NHC complexes have also been reported [41][42][43][44][45]. For example, Sames and co-workers described the use of imidazolylidene carbene ligands for the Pd-catalyzed direct arylation of pyrroles or indoles using bromobenzene and aryl iodides [42]. They observed that an important steric demand on the carbene ligand led to better results. Recently, the use of palladium(II) acetate complexes bearing both a phosphine and a carbene ligand, was reported by Lee and co-workers for the direct arylation of imidazoles with some aryl chlorides [46]. However, to our knowledge, N-heterocyclic carbene ligands have not yet been employed for the palladium-catalyzed direct arylation of pyrroles with aryl chlorides. As carbene ligands have proved to be very useful for several palladium-catalyzed reactions involving aryl chlorides, we decided to explore their potential for the direct 2-or 5-arylation of pyrrole derivatives.

Results and Discussion
First, a range or Pd-NHC complexes employing a variety of carbene ligands was prepared (Scheme 1). The deviations from the accustomed structures of palladium-NHC complexes can be attributed to steric rather than to electronic factors [48]. The use of quite congested carbene ligands has been found to be required for the palladium-catalyzed direct arylation of pyrroles, indoles, benzothiophene [42,45] or arenes [40]. Therefore, we employed carbenes bearing relatively bulky N-substituents. The reaction of Pd(OAc) 2 with the corresponding benzimidazolium halides in DMSO at 60-110 °C gave 1-9 in 53-87% yields (Scheme 1). The geometry of these complexes was not defined, as no crystals suitable for X-ray analysis could be obtained.
Three aryl chlorides have also been coupled with 1-methylpyrrole (27 , Table 4). A large excess of 1-methylpyrrole (27) was employed (4 equiv) in order to avoid the formation of 2,5-diarylated pyrroles. From 2-and 4-chlorobenzonitrile, 28 and 29 were obtained in high yields in the presence of complexes 8 and 9. On the other hand, the formation of several side-products was observed during the coupling of 4-(trifluoromethyl)chlorobenzene (13) with this pyrrole derivative, and 30 was obtained in low yields (Table 4, entries 11-15).

Conclusion
In summary, we have demonstrated that the regioselective C2 or C5 direct arylation of a range of pyrrole derivatives using electron-deficient aryl chlorides can be promoted by N-heterocyclic carbene ligands associated to palladium. So far, the reason for the influence of the nature of the carbene ligand on such  couplings remains unclear. However, the presence of bulky N-substituents on the benzimidazole ring, such as 3,5-di-tertbutylbenzyl (1-4) or benzhydryl (8), appears to be favorable; whereas, 2-(2-ethoxy)phenoxyethyl substituent (5-7) generally led to lower yields. The presence of a 2-(2-ethyl)-1,3-dioxalane as N-substituent (9) was also found to be profitable. To our knowledge, these are the first examples of direct arylations of pyrroles by using aryl chlorides as the coupling partners and Pd-N-heterocyclic carbene complexes as the catalyst. Finally, as the major by-products are AcOK associated to HBr instead of metallic salts, this procedure is environmentally more attractive than the classical coupling procedures.

Experimental
The reaction of benzimidazolium halide (2 equiv) with Pd(OAc) 2 in DMSO according to Scheme 1 led to the forma-tion of the desired complexes of Pd(II) in 53-87% yield. The crude product was recrystallized from a dichloromethane/ diethyl ether mixture 1:3 at room temperature, which afforded the corresponding crystals. The new complexes were characterized by 1 H NMR, 13 C NMR, IR and elemental analysis techniques, which support the proposed structures.
The formation of the Pd-NHC complexes was confirmed by the absence of the 1 H NMR resonance signal of the acidic benzimidazolium C2-H. The 13 C NMR spectra of Pd-NHC complexes exhibit a resonance signal in the 181.2-183.6 ppm range ascribed to the carbenic carbon atom, which is consistent with the reported values for Pd-NHC complexes [43]. NMR data showed that complexes 2 and 4-7 were cis/trans mixtures.
General procedure for the preparation of the palladium-NHC complexes As described in [50], to a solution of benzimidazolium salts (10 mmol) in DMSO (5 mL) was added palladium(II) diacetate (5 mmol) under argon, and the resulting mixture was stirred at room temperature for 2 h, then at 60 °C for 4 h, at 80 °C for 2 h and finally at 110 °C for 2 h. Volatiles were removed in vacuo, and the residue was washed twice with THF (5 mL). The complex was crystallized from dichloromethane/diethyl ether 1:3 at room temperature.       General Procedure for direct arylations As described in [47], in a typical experiment, the aryl chloride (1 mmol), heteroaryl derivative (2 or 4 mmol) (see Table 1 -5) and KOAc (2 mmol) were introduced in a Schlenk tube, equipped with a magnetic stirring bar. The Pd complex (0.01 mmol, see Table 1-5) and DMAc (3 mL) were added, and the Schlenk tube was purged several times with argon. The Schlenk tube was placed in a preheated oil bath at 150 °C, and the reaction mixture was stirred for 20 h. Then, the reaction mixture was analysed by gas chromatography to determine the conversion of the aryl chloride. The solvent was removed by heating of the reaction vessel under vacuum and the residue was charged directly onto a silica-gel column. The products were eluted by using an appropriate ratio of diethyl ether and pentane.