Palladium-Catalyzed Cross-Coupling Reaction via C–H Activation of Furanyl and Thiofuranyl Substrates

: The present study explores the potential of four NHC-palladium(II) complexes derived from ( Z )- or ( E )-styryl- N -alkylbenzimidazolium salts, namely trans -dichloro-[( Z )-1-styryl- 3-benzyl-benzimidazol-2-yliden]pyridine palladium(II) ( 6 ), trans -dichloro-[( E )-1-styryl-3-benzyl- benzimid-azol-2-yliden]pyridine palladium(II) ( 7 ), trans -dichloro-[( Z )-1-styryl-3-(3-fluorobenzyl)- benzimid-azol-2-yliden]pyridine palladium(II) ( 8 ) and trans -dichloro-[( E )-1-styryl-3- (3-fluorobenzyl)-ben- zimidazol-2-yliden]pyridine palladium(II) ( 9 ), to be use as pre-catalysts for the cross-coupling reactions between furanyl or thiofuranyl derivatives and arylbromides via the C–H activation of the heterocycles. The structures of the four Pd(II) complexes have been elucidated through the use of multinuclear NMR, FT-IR and mass spectroscopy. Furthermore, the cis or trans conformation of the styryl substituents and the geometry of two different compounds was substantiated by single-crystal X-ray diffraction, which was carried out on organometallic species 6 , 8 and 9 . After the optimization of catalytic conditions, which was carried out with 1 mol% of pre-catalyst with KOAc as a base in dimethylacetamide at 120 °C for 3 h, complex 6 proved to be the most effective pre-catalyst agent, with full or quasi full conversions being observed in the cross-coupling of 4-bromoacetophe-none with 2-butylfuran, 1-(2-furanyl)-ethanone, furfuryl acetate, furfural, 1-(2-thienyl)-ethanone, thenaldehyde and 2-methylthiophene.


Introduction
C-H bond activation has become an inescapable methodology for the formation of carbon-carbon bonds.Its success is mainly due to the fact that it is no longer necessary to use organic boron or metal reagents as in conventional cross-coupling reactions, which makes this reaction more economical and environmentally friendly [1][2][3][4].
The direct arylation of benzothiophene was achieved, for example, with 4-bromotoluene or 4-bromoanisole with conversions of 89 and 70%, respectively, with a catalyst loading of only 0.1 mol%, using the [Pd(SIPr)(cinnamyl)Cl] complex (C; Figure 1) as a pre-catalyst with K 2 CO 3 and PivOH over 16 h at 140 • C in DMAc [15].Dimeric complex D (Figure 1), consisting of two abnormal N-heterocyclic carbenes, is an effective coupling promoter for the cross-reaction between benzothiophene and the more challenging 4-chlorobenzonitrile (conversion of 41%).The group of Mandal carried out the catalytic test in DMAc using a catalyst loading of 0.5 mol% at 150 • C over 8 h [16].
The direct arylation of benzothiophene was achieved, for example, with 4-bromotoluene or 4-bromoanisole with conversions of 89 and 70%, respectively, with a catalyst loading of only 0.1 mol%, using the [Pd(SIPr)(cinnamyl)Cl] complex (C; Figure 1) as a pre-catalyst with K2CO3 and PivOH over 16 h at 140 °C in DMAc [15].Dimeric complex D (Figure 1), consisting of two abnormal N-heterocyclic carbenes, is an effective coupling promoter for the cross-reaction between benzothiophene and the more challenging 4-chlorobenzonitrile (conversion of 41%).The group of Mandal carried out the catalytic test in DMAc using a catalyst loading of 0.5 mol% at 150 °C over 8 h [16].

Synthesis of Palladium(II) Complexes
The synthesis of the four targeted Pd(II) complexes 6-9 required the preparation of adequate benzimidazolium salts 3-5.These salts were obtained by the alkylation of (E)or (Z)-styryl-benzimidazole 1 and 2, respectively, with benzyl chloride or 3-fluorobenzyl chloride in DMF at 80 °C for 24 h (Scheme 1).After precipitated by the addition of Et2O, the three salts were isolated in 59-73% yields and fully characterized by FT-IR, 1 H, 13 C and 19 F NMR spectroscopy and an elemental analysis (see the Experimental Procedure Section and Supplementary Materials).The 1 H NMR spectra of these compounds show a significant downfield of the NCHN proton, which appeared in the range from 10.12 to 11.49 ppm.It is interesting to note that the presence of a fluorine atom in position 3 of the aromatic cycle (salt 4) has no influence on the σ-donor properties.Indeed, the careful study of the 1 H spectra of salts 3 (without a F atom) and 4 (with a F atom) revealed no difference between the two 1 JHC constants (222.3Hz).These values are close to that measured for the well-known 1,3-di(2,6-diisopropylphenyl)-imidazolium chloride (IPr.HCl) salt [44].

Synthesis of Palladium(II) Complexes
The synthesis of the four targeted Pd(II) complexes 6-9 required the preparation of adequate benzimidazolium salts 3-5.These salts were obtained by the alkylation of (E)or (Z)-styryl-benzimidazole 1 and 2, respectively, with benzyl chloride or 3-fluorobenzyl chloride in DMF at 80 • C for 24 h (Scheme 1).After precipitated by the addition of Et 2 O, the three salts were isolated in 59-73% yields and fully characterized by FT-IR, 1 H, 13 C and 19 F NMR spectroscopy and an elemental analysis (see the Experimental Procedure Section and Supplementary Materials).The 1 H NMR spectra of these compounds show a significant downfield of the NCHN proton, which appeared in the range from 10.12 to 11.49 ppm.It is interesting to note that the presence of a fluorine atom in position 3 of the aromatic cycle (salt 4) has no influence on the σ-donor properties.Indeed, the careful study of the 1 H spectra of salts 3 (without a F atom) and 4 (with a F atom) revealed no difference between the two 1 J HC constants (222.3Hz).These values are close to that measured for the well-known 1,3-di(2,6-diisopropylphenyl)-imidazolium chloride (IPr.HCl) salt [44].
The two NHC-complexes bearing the benzyl substituents 6 and 7 were obtained from (Z)-1-styryl-3-benzyl-benzimidazolium chloride (3) through the reaction with [PdCl 2 ] in the presence of K 2 CO 3 in pyridine (Scheme 2).It is important to mention that the temperature of the reaction determines the configuration of the double bond of the styryl substituent.When the reaction was carried out at 80 • C, the cis geometry of the double bond was maintained with coupling constants of 3 J HH = 8.5 Hz for the two NCH=CHPh signals (complex 6).Conversely, a reaction temperature of 120 • C resulted in the isomerization of the double bond, and the trans complex 7 was isolated in a 61% yield ( 3 J HH = 14.5 Hz for the NCH=CHPh signals).The two NHC-complexes bearing the benzyl substituents 6 and 7 were obtained from (Z)-1-styryl-3-benzyl-benzimidazolium chloride (3) through the reaction with [PdCl2] in the presence of K2CO3 in pyridine (Scheme 2).It is important to mention that the temperature of the reaction determines the configuration of the double bond of the styryl substituent.When the reaction was carried out at 80 °C, the cis geometry of the double bond was maintained with coupling constants of 3 JHH = 8.5 Hz for the two NCH=CHPh signals (complex 6).Conversely, a reaction temperature of 120 °C resulted in the isomerization of the double bond, and the trans complex 7 was isolated in a 61% yield ( 3 JHH = 14.5 Hz for the NCH=CHPh signals).Taking this observation into account, fluorinated Pd(II) complexes 8 and 9 were prepared from salts 4 and 5, respectively, with stoichiometric amounts of [PdCl2] and K2CO3 in pyridine at 80 °C (Scheme 3).Both complexes were isolated in 65-67% yields and, according to their 1 H NMR spectra, no isomerization of the double bond was observed.The two NHC-complexes bearing the benzyl substituents 6 and 7 were obtained from (Z)-1-styryl-3-benzyl-benzimidazolium chloride (3) through the reaction with [PdCl2] in the presence of K2CO3 in pyridine (Scheme 2).It is important to mention that the temperature of the reaction determines the configuration of the double bond of the styryl substituent.When the reaction was carried out at 80 °C, the cis geometry of the double bond was maintained with coupling constants of 3 JHH = 8.5 Hz for the two NCH=CHPh signals (complex 6).Conversely, a reaction temperature of 120 °C resulted in the isomerization of the double bond, and the trans complex 7 was isolated in a 61% yield ( 3 JHH = 14.5 Hz for the NCH=CHPh signals).Taking this observation into account, fluorinated Pd(II) complexes 8 and 9 were prepared from salts 4 and 5, respectively, with stoichiometric amounts of [PdCl2] and K2CO3 in pyridine at 80 °C (Scheme 3).Both complexes were isolated in 65-67% yields and, according to their 1 H NMR spectra, no isomerization of the double bond was observed.Taking this observation into account, fluorinated Pd(II) complexes 8 and 9 were prepared from salts 4 and 5, respectively, with stoichiometric amounts of [PdCl 2 ] and K 2 CO 3 in pyridine at 80 • C (Scheme 3).Both complexes were isolated in 65-67% yields and, according to their 1 H NMR spectra, no isomerization of the double bond was observed.The two NHC-complexes bearing the benzyl substituents 6 and 7 were obtained from (Z)-1-styryl-3-benzyl-benzimidazolium chloride (3) through the reaction with [PdCl2] in the presence of K2CO3 in pyridine (Scheme 2).It is important to mention that the temperature of the reaction determines the configuration of the double bond of the styryl substituent.When the reaction was carried out at 80 °C, the cis geometry of the double bond was maintained with coupling constants of 3 JHH = 8.5 Hz for the two NCH=CHPh signals (complex 6).Conversely, a reaction temperature of 120 °C resulted in the isomerization of the double bond, and the trans complex 7 was isolated in a 61% yield ( 3 JHH = 14.5 Hz for the NCH=CHPh signals).Taking this observation into account, fluorinated Pd(II) complexes 8 and 9 were prepared from salts 4 and 5, respectively, with stoichiometric amounts of [PdCl2] and K2CO3 in pyridine at 80 °C (Scheme 3).Both complexes were isolated in 65-67% yields and, according to their 1 H NMR spectra, no isomerization of the double bond was observed.The four Pd(II) complexes were fully characterized by FT-IR, 1 H, 13 C and 19 F NMR spectroscopy, an elemental analysis and mass spectroscopy (see the Experimental Procedure Section and Supplementary Materials).The 1 H spectra showed the presence of the pyridine ligand coordinated to the metal center and the disappearance of the NCHN protons of the benzimidazole moieties.Moreover, the 13 C spectra displayed a downfield of the corresponding carbon atoms from 141.00 to 143.73 ppm in benzimidazolium salts 3-4 to 165.15-165.87ppm in complexes 6-9, which are characteristic of the formation of Pd-NHC bonds [28,32].Finally, a mass spectra analysis revealed the presence of peaks corresponding to either [M − Cl] + or [M + H] + cations with the expected isotopic profiles.

X-ray Crystal Structure Analysis of Palladium(II) Complexes
Single crystals of Pd(II) complexes 6, 8 and 9, which were suitable for X-ray analysis, unambiguously confirmed the formation of the attempt complexes.
pyridine ligand coordinated to the metal center and the disappearance of the NCHN protons of the benzimidazole moieties.Moreover, the 13 C spectra displayed a downfield of the corresponding carbon atoms from 141.00 to 143.73 ppm in benzimidazolium salts 3-4 to 165.15-165.87ppm in complexes 6-9, which are characteristic of the formation of Pd-NHC bonds [28,32].Finally, a mass spectra analysis revealed the presence of peaks corresponding to either [M − Cl] + or [M + H] + cations with the expected isotopic profiles.

X-ray Crystal Structure Analysis of Palladium(II) Complexes
Single crystals of Pd(II) complexes 6, 8 and 9, which were suitable for X-ray analysis, unambiguously confirmed the formation of the attempt complexes.
Complexes 6 (Figure 3) and 8 (Figure 4), due to the cis configuration of the styryl substituent blocking free rotation around the N-C bond, crystallized in the orthorhombic chiral Sohncke group P212121 [45] with Flack parameters of 0.07(4) and −0.04(4), respectively [46].In both solid-state structures, four molecules of complexes were present in the unit cell, and each Pd(II) atom adopted a square planar geometry with C1-Pd1-N3 angles of 176.5(3) and 176.7(2)° and Cl1-Pd1-Cl2 angles of 176.80 (7) and 177.83(8)° in complexes 6 and 8, respectively.The bond lengths of Pd-C1 were found to be 1.966 (7) and 1.938( 6) Å in complexes 6 and 8, respectively, which are distances in agreement for Pd-NHC bonds [47].The benzimidazole aromatic rings were almost planar with the pyridine moieties, with dihedral angles of 8.49 and 6.79°, in complexes 6 and 8, respectively, and inclined relative to the phenyl of the styryl substituents with dihedral angles of 57.14 and 60.34° in complexes 6 and 8, respectively.Complex 9 (Figure 5) crystallized in the monoclinic form with the C2/c space group.Eight molecules of complexes were present in the unit cell.The fluorine atom was disordered over two positions with a ratio of 0.6/0.4.As previously mentioned, the Pd(II) atom adopted a square planar geometry with C1-Pd1-N3 and Cl1-Pd1-Cl2 angles of 179.82(17) and 177.78 (6), respectively.The bond lengths of Pd-C1 and Pd-N3 were found to be 1.959(5) and 2.076(4) Å, respectively.In the present complex, the phenyl of the styryl substituent was slightly inclined to the benzimidazole and to the pyridine rings with dihedral angles of 14.76 and 10.91°, respectively.Complex 9 (Figure 5) crystallized in the monoclinic form with the C2/c space group.Eight molecules of complexes were present in the unit cell.The fluorine atom was disordered over two positions with a ratio of 0.6/0.4.As previously mentioned, the Pd(II) atom adopted a square planar geometry with C1-Pd1-N3 and Cl1-Pd1-Cl2 angles of 179.82(17) and 177.78 (6), respectively.The bond lengths of Pd-C1 and Pd-N3 were found to be 1.959(5) and 2.076(4) Å, respectively.In the present complex, the phenyl of the styryl substituent was slightly inclined to the benzimidazole and to the pyridine rings with dihedral angles of 14.76 and 10.91 • , respectively.

Palladium-Catalyzed C-H Activation
We tested the four PEPPSI-type Pd(II) complexes 6-9 in the C-H activation of furanyl and thiofuranyl substrates.In the initial phase, the optimal catalytic conditions were determined.For this, the cross-coupling reaction between 2-butylfuran (10a) and the 4-bromoacetophenone (11a) was tested with complex 6 as the pre-catalyst (Table 1).
In the second series of runs, the solvent was evaluated.Changing DMAc with toluene or dimethylsulfoxide (DMSO) drastically decreased the conversions (Table 1, entries 7 and 8).A modest conversion of 54% was obtained when N,N-dimethylformamide (DMF) was employed (Table 1, entry 9).
In the second series of runs, the solvent was evaluated.Changing DMAc with toluene or dimethylsulfoxide (DMSO) drastically decreased the conversions (Table 1, entries 7 and 8).A modest conversion of 54% was obtained when N,N-dimethylformamide (DMF) was employed (Table 1, entry 9).
Finally, the four Pd(II) complexes were ranked.It has been shown that complexes with an F atom (complexes 8 and 9) are less efficient than their non-fluorinated counterparts (complexes 6 and 7) (Table 1, entries 6 and 10-12).We can note that the most active complex has the trans configuration of the styryl substituent (complex 7: 79%).It is quite conceivable that during the test realized at 120 °C, an isomerization of the cis double bond of the styryl substituent, complex 6, was performed, ultimately generating the same active species formed starting from complex 7.The slightly superior efficiency of the (E)-complex 7 compared to the (Z)-complex 6 can be explained by this additional activation step, the isomerization of cis-styryl into trans-styryl, in the case of (Z)-complex 6.Finally, the four Pd(II) complexes were ranked.It has been shown that complexes with an F atom (complexes 8 and 9) are less efficient than their non-fluorinated counterparts (complexes 6 and 7) (Table 1, entries 6 and 10-12).We can note that the most active complex has the trans configuration of the styryl substituent (complex 7: 79%).It is quite conceivable that during the test realized at 120 • C, an isomerization of the cis double bond of the styryl substituent, complex 6, was performed, ultimately generating the same active species formed starting from complex 7.The slightly superior efficiency of the (E)-complex 7 compared to the (Z)-complex 6 can be explained by this additional activation step, the isomerization of cis-styryl into trans-styryl, in the case of (Z)-complex 6.

Materials and Methods
All reactions involving organometallic derivatives were carried out under an inert atmosphere of argon with dried solvents.Routine 1 H and 13 C{ 1 H} spectra were recorded with a 500 MHz Bruker Avance III spectrometer (Billerica, MA, USA).Chemical shifts and coupling constants are reported in ppm and Hz, respectively.The spectra were calibrated according to the residual protonated solvent (in CDCl 3 δ = 7.26 and 77.16 ppm for 1 H and 13 C{ 1 H}, respectively, or in DMSO-d 6 δ = 2.50 and 39.52 ppm for 1 H and 13 C{ 1 H}, respectively). 19F NMR spectroscopic data are given relative to external CCl 3 F. Mass spectra were recorded on a Bruker MicroTOF spectrometer (ESI-TOF).The catalytic solutions were analyzed by using a Varian 3900 GC equipped with a WCOT fused-silica column (25 m × 0.25 mm).Infrared spectra were recorded on a Bruker FT-IR Alpha-P spectrometer.Elemental analyses were carried out by the Service de Microanalyse, Institut de Chimie, Université de Strasbourg.(Z)-1-Styryl-benzimidazole (1) [48] and (E)-1-styrylbenzimidazole (2) [49] were prepared according to the procedures in the literature.

The General Procedure for the Synthesis of Palladium(II) Complexes
Benzimidazole salt (0.5 mmol) and [PdCl 2 ] (88 mg, 0.5 mmol) were added to a stirred suspension of K 2 CO 3 (345 mg, 2.5 mmol) in pyridine (5 mL).The resulting reaction mixture was stirred at 80 • C for 4 h, except for the synthesis of complex 7, for which the reaction mixture was heated to 120 • C.After cooling to room temperature, the pyridine was removed under a vacuum.The solid residue was dissolved in CH 2 Cl 2 (10 mL), and the mixture was filtered through Celite.After the evaporation of the solvent, the crude solid was purified by flash chromatography (CH 2 Cl 2 as eluent) to afford the yellow palladium(II) complex.

The General Procedure for the Palladium-Catalyzed C-H Activation
A 5 mL vial under an argon atmosphere was filled with KOAc (32 mg, 0.32 mmol), aryl bromide (0.25 mmol), furan or thiofurane derivative (0.30 mmol), decane (0.025 mL, internal reference) and a solution of palladium complex (2.5 µmol, 1 mol%) in DMAc (1 mL).Then, the reaction mixture was heated at 120 • C for 3 h.After cooling to room temperature, the crude reaction was passed through a Millipore filter and analyzed by GC.All products were unambiguously identified by NMR after their isolation.

X-ray Crystal Structure Analysis
The slow diffusion of Et 2 O into a CH 2 Cl 2 solution of palladium complexes 6, 8 and 9 led to the formation of single crystals suitable for an X-ray analysis.The analysis was carried out on a Bruker APEX II DUO Kappa-CCD diffractometer for complexes 6 and 8 or a Bruker Photon III CPAD diffractometer for complex 9 using Mo-Kα radiation (λ = 0.71073 Å).The structures were solved using the SHELXT-2018 program [50].The refinement and all further calculations were carried out using SHELXL-2019 [51].The H-atoms were included in the calculated positions and treated as riding atoms using SHELXL default parameters.The non-H atoms were refined anisotropically using weighted full-matrix least-squares on F 2 .The data collection and structure refinement details are given in Table 3.

Conclusions
In this article, we reported the synthesis of four NHC-Pd(II) complexes derived from (Z)-or (E)-styryl-N-alkylbenzimidazolium salts.During the formation of the latter organometallic compounds, the cis or trans configuration of the double bond of the styryl substituent depends on the temperature of the reaction.In fact, a temperature of 120 • C resulted in the isomerization of the cis double-bond of the benzimidazolium salt into the trans configuration in the resulting Pd(II) complex.These Pd(II) complexes were fully characterized using spectroscopic methods, and for three of them, a single-crystal X-ray diffraction study was carried out.The catalytic abilities of these Pd(II) pre-catalysts to form carbon-carbon bonds via the C-H activation of the furanyl and thiofuranyl derivatives were investigated.After the optimization of the catalytic conditions using DMAc and KOAc as bases for 3 h at 120 • C, full or quasi-full conversions were observed in the arylation of seven heteroaryls with 4-bromoacetophenone or when bromobenzene and 1-bromonaphthalene were reacted with 2-butylfuran, 1-(2-furanyl)-ethanone or 1-(2-thiephyl)-ethanone.
Future works will aim to exploit this thermal modification, the isomerization of a double bond from cis to trans configuration, of the coordination sphere of the catalytic center in cross-coupling reactions.

Table 3 .
Crystal data and structure refinement parameters for palladium(II) complexes 6