Pyridylidene ligand facilitates gold-catalyzed oxidative C–H arylation of heterocycles

Summary Triaryl-2-pyridylidene effectively facilitates the gold-catalyzed oxidative C–H arylation of heteroarenes with arylsilanes as a unique electron-donating ligand on gold. The employment of the 2-pyridylidene ligand, which is one of the strongest electron-donating N-heterocyclic carbenes, resulted in the rate acceleration of the C–H arylation reaction of heterocycles over conventional ligands such as triphenylphosphine and a classical N-heterocyclic carbene. In situ observation and isolation of the 2-pyridylidene-gold(III) species, as well as a DFT study, indicated unusual stability of gold(III) species stabilized by strong electron donation from the 2-pyridylidene ligand. Thus, the gold(I)-to-gold(III) oxidation process is thought to be facilitated by the highly electron-donating 2-pyridylidene ligand.


Introduction
Over the past decade, gold salts and complexes have emerged as unique catalysts for the transformation of alkynes, alkenes and allenes . In most of the gold-catalyzed reactions, phosphines, N-heterocyclic carbenes, pyridines and salen ligands have been applied as ligands for controlling the stability of catalysts, and chemo-, regio-and enantioselectivities of the reactions [31][32][33][34][35][36]. Recent advances in the gold-catalyzed reactions are represented by oxidative coupling that is expected to proceed through a gold(I)/gold(III) catalytic cycle . In particular, the elegant works of Lloyd-Jones and Russell on gold-catalyzed oxidative C-H arylation of simple arenes with arylsilanes have led the way to novel gold-catalyzed reactions that could not be achieved with other transition metals [68,69]. In these reactions, the oxidation of gold(I) to gold(III) is thought to be a key step in the catalytic cycle consisting of transmetalation with arylsilane, C-H activation and reductive elimination [69]. While gold(I) complexes bearing various ligands are used as gold(III) precursors, it remains unclear whether ligands can still coordinate to the gold center or not under such oxidative reaction conditions. For example, tri- phenylphosphine is easily oxidized to triphenylphosphine oxide by a hypervalent iodine reagent that has been used as an oxidant for gold-catalyzed C-H arylation [69]. Appropriate ligands that are tolerant to the oxidative conditions would offer numerous benefits such as high activity and stability of gold catalyst, thereby achieving otherwise-difficult oxidative transformations [37][38][39][40].

Reaction progress analysis
To further unveil the ligand effect of PyC, time-production profiles of coupling product 3ba were investigated for the reaction of 1b and 2a with AuCl(PyC), AuCl(PPh 3 ) and AuCl(IPr). The yield of 3ba was determined by GC analysis, whereas the consumption of IBA (oxidant) was estimated by the production of methyl 2-iodobenzoate (5). The reaction plots with AuCl(PyC), AuCl(PPh 3 ) and AuCl(IPr) are depicted in Figure 2. Noteworthy observations are as follows: (i) the reaction with AuCl(PyC) was fastest among those with three catalysts (Figure 2a), (ii) the induction periods with regard to the formation of 3ba were found in the reactions using AuCl(PyC) and AuCl(PPh 3 ) (Figure 2a,b), and (iii) the oxidant consumption began at the reaction initiation for all catalysts (Figure 2c). In the reaction using AuCl(PyC), the coupling product 3ba was generated after a shorter induction period of about 3 h and reached 60% yield after 50 h (Figure 2a). On the other hand, the reaction using AuCl(PPh 3 ) began after a longer induction period (ca. 5 h), and the yield of 3ba did not exceed the yield with AuCl(PyC) even after 100 h (see Supporting Information File 1 for details). No coupling product was produced with AuCl(IPr) although the consumption of about 10% of IBA was observed.

Mechanistic considerations
Based on the above results and the literature [68][69][70][71][72][73][74][75], we propose the reaction mechanism of the gold-catalyzed C-H arylation of heteroarenes with arylsilanes as shown in Scheme 1. A gold(I) complex A is first oxidized to gold(III)

Oxidation process of gold
In all reaction progress experiments with the three gold catalysts (Figure 2), the consumption of IBA (production of 5) was observed to some extent even in the induction period. Taking the possible reaction mechanism into consideration, the oxidation of gold(I) to gold(III) by the oxidant may occur during the induction period. While it is unclear what is oxidized in these reactions, we hypothesize that the highly electrondonating PyC ligand facilitates the oxidation of gold(I) to gold(III). As triphenylphosphine is known to be easily oxidized to triphenylphosphine oxide under the current oxidative conditions, the ligand-free gold(III) species is thought to be an active species in the arylation reaction with AuCl(PPh 3 ) [69]. While the IPr-gold(I) complex is known to undergo oxidation to an IPr-gold(III) species [114], its inactiveness in the current reaction indicates that the electron-donating capability is not high enough to facilitate this process.

Direct observation and isolation of PyCgold(III) complex
To verify our hypothesis that PyC accelerates the gold(I)-togold(III) oxidation, we attempted the direct observation and the isolation of the PyC-gold(III) complex. First of all, the gold(III) complex AuCl 3 (PyC) was newly synthesized by treating AuCl(PyC) with PhICl 2 (see Experimental section and Supporting Information File 1 for details) [114]. The X-ray crystallographic analysis was successfully accomplished with a colorless single crystal of AuCl 3 (PyC), which was recrystallized from nitrobenzene and pentane (Figure 3) [115]. The X-ray crystal structure shows that the four gold bonds are in a planar surface, and the pyridylidene face and the added two chlorine atoms are in vertical positions. The ligand arrangement is quite similar to a series of reported NHC-AuCl 3 complexes [114]. With the authentic AuCl 3 (PyC) in hand, we next carried out the direct observation of PyC-gold(III) species under the catalytic conditions. The treatment of AuCl(PyC) with 5-fluoroiodosobenzoic acid (5F-IBA) and CSA in CDCl 3 /CD 3 OD at 65 °C resulted in the full consumption of 5F-IBA within 30 min (monitored by 19 F NMR). While the resulting mixture seemed to contain several PyC-gold(III) complexes, the formation of various gold(III) species bearing hydroxy, methoxy, sulfoxy and chloro groups made the analysis and isolation difficult. However, the subsequent addition of excess LiCl enabled us to detect the gold(III) species as AuCl 3 (PyC) by 1 H and 13 C NMR analyses. The 1 H NMR analysis revealed that about 90% of AuCl(PyC) was consumed and AuCl 3 (PyC) was produced in 50% NMR yield. Fortunately, the isolation from the messy crude mixtures was accomplished to give AuCl 3 (PyC) in 24% isolated yield. We also conducted the same experiment with the AuCl(IPr) complex. From the 19 F and 1 H NMR analyses, approximately half of AuCl(IPr) and oxidant 5F-IBA remained unreacted after heating for 30 min, and AuCl 3 (IPr) was observed only in 34% 1 H NMR yield [114] (Scheme 2).
These observations on gold(III) species support our hypothesis that the highly electron-donating PyC ligand strongly coordinates to a gold center and promotes the gold(I)-to-gold(III) oxidation by stabilizing a gold(III) species without dissociation. An IPr-gold(III) complex is known to be stable, but the lower electron-donation ability of IPr than that of PyC seems to result in the inefficient oxidation of AuCl(IPr). DFT calculations on the oxidation process of the AuCl(ligand) to AuCl 3 (ligand) also clarified the advantage of the PyC ligand over IPr by 3.6 kcal mol -1 (see Supporting Information File 1 for details). While it still remains unclear how the PyC ligand affects the transmetalation, C-H metalation and reductive elimination steps, we believe that the strongly electron-donating PyC not only facilitates gold(I)-to-gold(III) oxidation in catalysis but also prolongs the catalyst lifetime by preventing the ligand dissociation and formation of inactive gold nanoparticles.

Conclusion
In summary, we have developed the oxidative C-H arylation of heteroarenes with arylsilanes catalyzed by PyC-gold complex and revealed the advantageous features of using the PyC ligand. From the reaction progress, experiments and stoichiometric oxidation of gold(I) complexes, we conclude that the highly electron-donating PyC ligand promotes the gold(I)-to-gold(III) oxidation and stabilizes the gold(III) species, thereby facilitating the oxidative coupling reactions. The tube was sealed with a cap equipped with a Teflon ® -coated silicon rubber septum, and the mixture was stirred at 65 °C for 18-48 h. The reaction was quenched by addition of excess saturated aqueous NaHCO 3 , the aqueous layer was extracted with CH 2 Cl 2 , and the combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to afford the coupling product 3 ( Table 2). In situ observation and isolation of AuCl 3 (PyC): AuCl(PyC) (12.8 mg, 0.020 mmol), 5-fluoroiodosobenzoic acid (5F-IBA, 5.6 mg, 0.020 mmol) and CSA (4.6 mg, 0.020 mmol) were placed in an NMR tube, and CDCl 3 /CD 3 OD (10:1, 0.60 mL) was added under N 2 atmosphere. The tube was sealed with a cap equipped with a Teflon ® -coated silicon rubber septum and heated at 65 °C for 30 min. After cooling to room temperature, LiCl (8.4 mg, 0.20 mmol) was added. 1,1,2,2-Tetrachloroethane was added as an internal standard and an NMR yield of AuCl 3 (PyC) was estimated by 1 H NMR spectroscopy. The solvent was removed in vacuum, and the residue was dissolved in EtOAc. The organic layer was washed with saturated aqueous NaHCO 3 and brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuum to afford the crude mixture. The crude mixture was further washed with Et 2 O to give pure AuCl 3 (PyC) as a white powder (3.4 mg, 24%, Scheme 2).

Supporting Information
Supporting Information File 1 Experimental procedures, spectra of new compounds, CIF data, and details of the computational study.