Synthesis of New Chiral Benzimidazolylidene–rh Complexes and Their Application in Asymmetric Addition Reactions of Organoboronic Acids to Aldehydes

A series of novel chiral N-heterocyclic carbene rhodium complexes (NHC–Rh) based on benzimidazole have been prepared, and all of the NHC–Rh complexes were fully characterized by NMR and mass spectrometry. These complexes could be used as catalysts for the asymmetric 1,2-addition of organoboronic acids to aldehydes, affording chiral diarylmethanols with high yields and moderate enantioselectivities.


Introduction
Since N-heterocycliccarbenes (NHCs) are excellent σ-donors, and their metal complexes show higher air and thermal stability than phosphane ligands.NHCs are now well established as efficient alternatives to phosphane ligands [1][2][3][4][5][6][7][8][9][10].Much work has been devoted to the design and development of carbene compounds with new structures to tune their steric and electronic properties, and also to their application in organometallic catalysis.As excellent ligands for transition metals, NHCs have found multiple applications in some of the most important catalytic transformations in the chemical industry.As a logical extension of this development, chiral NHC ligands and their application in asymmetric catalysis are receiving increasing attention [11][12][13][14][15][16].Despite considerable efforts devoted to this field, the design and synthesis of novel chiral NHCs to enhance their enantioselectivity is still a challenge.
Enantioenriched diarylmethanols are the structural core unit in a considerable number of bioactive compounds and pharmaceuticals [17][18][19][20].The Rh-catalyzed enantioselective arylation of aromatic aldehydes with organoboronic acids has emerged as a direct and economical route for the synthesis of enantiomerically-enriched diarylmethanols [21].In 1998, Miyaura and co-workers initially reported the enantioselective Rh-catalyzed addition of phenylboronic acid to naphthaldehyde by using the (S)-MeO-MOP ligand, giving naphthyphenylmethanol in 78% yield and 41% ee [22].Since then, considerable efforts have been made in this type of reaction [23][24][25][26][27][28][29][30].However, examples of using chiral N-heterocycliccarbenes in the ligand-catalyzed asymmetric arylation of aldehydes are rare [31][32][33][34][35]. Therefore, developing new chiral N-heterocycliccarbene ligands for the asymmetric 1,2-addition of arylation of aldehydes are rare [31][32][33][34][35]. Therefore, developing new chiral N-heterocycliccarbene ligands for the asymmetric 1,2-addition of organoboronic acid to aldehydes is an important synthetic goal.The above-mentioned findings, and our interests in NHCs and C-C forming reactions triggered our efforts to develop new NHC ligands for application in homogeneous catalysis.After our recent report of the synthesis of several chiral benzimidazolium salts for the in situ Rh-catalyzed asymmetric arylation of aldehydes [36], we herein report the synthesis of a series of new NHC-Rh complexes based on benzimidazole and their application in the asymmetric 1,2-addition of arylboronic acids to aldehydes.

Results
The synthetic route to the new NHC-Rh complexes based on the benzimidazole skeleton is shown in Schemes 1 and 2. The NHC complexes were synthesized from enantiomerically-pure benzimidazolium salts (1a-g), which in turn can be prepared by following our previous articles [36,37].Among the NHC precursors prepared, compounds 1c and 1d were new and are reported for the first time in this paper.In the next step, the mild transmetalation developed by Wang and Lin was adopted to prepare rhodium(I) complexes of 1a-g.According to this strategy, the benzimidazolium salts 1 were treated with Ag2O in anhydrous CH2Cl2 at room temperature in the darkness.Then direct addition of [Rh(COD)Cl]2 to the freshly prepared solution of silver complexes yielded the corresponding chiral complexes 2a-g upon workup, which could be purified by chromatography on silica gel (Scheme 2).The complexes were characterized by 1 H NMR, 13 C NMR, and high-resolution mass spectrometry (HRMS), and the absence of an N-CNHC-N resonance in the 1 H NMR spectra confirmed the formation of the carbene complexes.With the chiral NHC-Rh complexes in hand, we examined their application in the asymmetric addition of organoboronic acids to aldehydes.Firstly, all of the NHC-Rh complexes were tested in enantioselective phenylation of 2-naphthaldehyde (3a) with PhB(OH) 2 .The reaction was performed with 3.0 mol % of NHC-Rh complex in DME/H 2 O (5:1) at 80 • C for 12 h.As shown in Table 1, diarylmethanol 4a was obtained in high yield with each of the NHC-Rh complexes, and compound 2g gave the best result (18% ee).With the chiral NHC-Rh complexes in hand, we examined their application in the asymmetric addition of organoboronic acids to aldehydes.Firstly, all of the NHC-Rh complexes were tested in enantioselective phenylation of 2-naphthaldehyde (3a) with PhB(OH)2.The reaction was performed with 3.0 mol % of NHC-Rh complex in DME/H2O (5:1) at 80 °C for 12 h.As shown in Table 1, diarylmethanol 4a was obtained in high yield with each of the NHC-Rh complexes, and compound 2g gave the best result (18% ee).
We then optimized the experimental conditions using 2g as catalyst.By screening bases in DME/H2O (5:1), we found that the addition of excess KF (6.0 equiv.)significantly improved the enantioselectivity as well as yield (Table 2, entry 6).Next, variation of the solvent indicated that the 5:1 mixture of EtOH/DME was the best choice of solvent (Table 2, entry 16).Further screening of reaction temperature showed that lower temperature afforded the product with similar enantioselectivities but inferior yields (Table 3, entries [20][21][22].With the chiral NHC-Rh complexes in hand, we examined their application in the asymmetric addition of organoboronic acids to aldehydes.Firstly, all of the NHC-Rh complexes were tested in enantioselective phenylation of 2-naphthaldehyde (3a) with PhB(OH)2.The reaction was performed with 3.0 mol % of NHC-Rh complex in DME/H2O (5:1) at 80 °C for 12 h.As shown in Table 1, diarylmethanol 4a was obtained in high yield with each of the NHC-Rh complexes, and compound 2g gave the best result (18% ee).
We then optimized the experimental conditions using 2g as catalyst.By screening bases in DME/H2O (5:1), we found that the addition of excess KF (6.0 equiv.)significantly improved the enantioselectivity as well as yield (Table 2, entry 6).Next, variation of the solvent indicated that the 5:1 mixture of EtOH/DME was the best choice of solvent (Table 2, entry 16).Further screening of reaction temperature showed that lower temperature afforded the product with similar enantioselectivities but inferior yields (Table 3, entries [20][21][22].We then optimized the experimental conditions using 2g as catalyst.By screening bases in DME/H 2 O (5:1), we found that the addition of excess KF (6.0 equiv.)significantly improved the enantioselectivity as well as yield (Table 2, entry 6).Next, variation of the solvent indicated that the 5:1 mixture of EtOH/DME was the best choice of solvent (Table 2, entry 16).Further screening of reaction temperature showed that lower temperature afforded the product with similar enantioselectivities but inferior yields (Table 3, entries 20-22).Having optimized reaction conditions, we examined the reactions with various aldehydes, and the results are summarized in Table 3.The arylations with either electron-rich or electron-deficient benzaldehydes proceeded smoothly to afford the corresponding diarylmethanols in excellent yields and moderate enantioselectivities.The best enantioselectivity was obtained starting from o-anisaldehyde (46% ee, entry 3).

General
MS spectra were measured on a Finnigan LCQDECA XP instrument (ThermoFinnigan Co., California, CA, USA) and an Agilent Q-TOF 1290LC/6224 MS system (Aglient Technologies Inc., California, CA, USA); 1 H and 13 C NMR spectra were obtained on Bruker AVANCE III 500 MHz and 600 MHz spectrometers (Bruker Co., Faellanden, Switzerland) with TMS as the internal standard; silica gel GF254 and H (10-40 mm, Qingdao Marine Chemical Factory, Qingdao, China) were used for  Having optimized reaction conditions, we examined the reactions with various aldehydes, and the results are summarized in Table 3.The arylations with either electron-rich or electron-deficient benzaldehydes proceeded smoothly to afford the corresponding diarylmethanols in excellent yields and moderate enantioselectivities.The best enantioselectivity was obtained starting from o-anisaldehyde (46% ee, entry 3).

General
MS spectra were measured on a Finnigan LCQDECA XP instrument (ThermoFinnigan Co., California, CA, USA) and an Agilent Q-TOF 1290LC/6224 MS system (Aglient Technologies Inc., California, CA, USA); 1 H and 13 C NMR spectra were obtained on Bruker AVANCE III 500 MHz and 600 MHz spectrometers (Bruker Co., Faellanden, Switzerland) with TMS as the internal standard; silica gel GF 254 and H (10-40 mm, Qingdao Marine Chemical Factory, Qingdao, China) were used for TLC and CC.Unless otherwise noted, all reactions were carried out under an atmosphere of argon or nitrogen.

Preparation of NHC-Rh Complexes 2a-g
To a solution of imidazolinium salt 1a (364.0 mg, 1.00 mmol) in CH 2 Cl 2 (25 mL) was added silver(I) oxide (115.9 mg, 0.50 mmol) in one portion.The suspension was stirred for 3 h in the darkness, during which the black color gradually diminished.The reaction mixture was filtered through a small pad of Celite, [Rh(COD)Cl] 2 (246.5 mg, 0.50 mmol) was added in one portion, and the reaction mixture was stirred for an additional 16 h.The solvent was evaporated, and the residue was purified by flash chromatography on silica gel with CH 2 Cl 2 as eluent.After evaporation of volatiles, the residue was purified by column chromatography (CH 2 Cl 2 ) to give 2a (515.0 mg, 88% yield). 1   Analogous compounds 2b-g were prepared according to the similar procedure for 2a.HR-ESIMS, 1 H and 13 C NMR data see Supplementary Materials.2b: 97% yield; 1

Conclusions
In conclusion, seven NHC-Rh complexes (2a-f) have been prepared.Their applicability in the asymmetric arylation of aromatic aldehydes has been demonstrated, and the corresponding diarylmethanols were obtained with high yields and moderate enantiomeric excesses (up to 46%).Further work is in progress to utilize these complexes in asymmetric 1,2-addition reactions of arylboronic acids with ketones, as well as their applications in fields of nanoscience [39,40].

Table 2 .
Optimization of the reaction conditions.

Table 2 .
Optimization of the reaction conditions.

Table 3 .
Scope of methodology.

Table 3 .
Scope of methodology.

a Ar1 Yield (%) b ee (%) c
b Isolated yields; c Determined by chiral HPLC (CHIRALCEL OD or AD Column) analysis.