Catalytic Enantioselective Aryl Transfer to Aldehydes Using Chiral 2,2’-Bispyrrolidine-Based Salan Ligands

Chiral C2-symmetric diamines have emerged as versatile auxiliaries or ligands in numerous asymmetric transformations. Chiral 2,2’-bispyrrolidine-based salan ligands were prepared and applied to the asymmetric aryl transfer to aldehydes with arylboronic acids as the source of transferable aryl groups. The corresponding diarylmethanols were obtained in high yields with moderate to good enantioselectivitives of up to 83% ee.


Introduction
Chiral diarylmethanols are important intermediates and precursors for the synthesis of pharmacologically and biologically active compounds [1][2][3][4][5][6][7][8]. Therefore, the development of effective catalyst systems for the synthesis of these compounds is of significant importance for organic chemists. The scientifically important protocols for the synthesis of chiral diarylmethanols commonly OPEN ACCESS involve two strategies: (1) the asymmetric reduction of prochiral diaryl ketones [9][10][11][12][13], (2) the enantioselective aryl transfer to aromatic aldehydes [14][15][16]. The reduction method requires an ortho substituent on one of the aryls or electronic different aryl groups for optimum results. The second method seems easy to realize chiral induction due to the large steric and electronic differences between an aryl group and a hydrogen atom on the aldehyde substrates with diphenylzinc. As reported previously, many functionalized diarylzincs used as the transferring nucleophiles are unstable and difficult to synthesize, so the method of the aryl transfer to aldehyde is greatly limited. Recently, an elegant method that the arylzinc species prepared in situ by transmetalation between organoboron [17][18][19] or organoboronic derivatives [20][21][22][23][24][25][26] and diethylzinc has been proposed as an alternative for the synthesis of salt-free organozinc reagents. We have also successfully developed an efficient and practical method for the synthesis of diarylmethanols by transmetalation using the arylboronic acid in the presence of trimethylgallium [27]. These methods allow the exploitation of a broad range of substituted aryl transfer reagents since numerous arylboronic acids are commercially available, and a lot of excellent ligands were developed and applied to the asymmetric aryl transfer reaction with good results [28][29][30][31][32][33][34][35][36][37][38][39][40][41]. For the future, the introduction of the new, effective and more easily available catalysts is also a field of continuous interest for the catalytic aryl transfer reaction.

Results and Discussion
A preliminary study was performed to test the catalytic property of the ligands L1-L6 (Figure 1) in the asymmetric phenyl transfer reaction to 4-nitrobenzaldehyde at 0 °C. As is evident from Table 1, the resulting products could be obtained in moderate yield, but low enantioselectivity when (1R,2R)cyclohexane-1,2-diamine-based ligands L1-L4 were tested (Table 1, entries 1-4). Gratifyingly, we found that the ligands L5 and L6 were more effective in this reaction ( After having established the optimal protocol for the asymmetric phenyl transfer reaction, we further extended the reaction to a series of aldehyde substrates ( Table 2). The electronic properties of the aromatic rings of the aldehydes have a significant influence on the enantioselectivity in this reaction. The aldehydes with electron-withdrawing substituents provided better results than those with electron-donating substituents in terms of ee values. 4-Nitrobenzaldehyde gave the corresponding diarylmethanol with 83% ee, but 4-methoxybenzaldehyde only with 11% ee (Table 2, entries 1, 2 and 10). Similar results were obtained when 3-substituted-benzaldehydes (Table 2, entries 3 and 9) or 2substituted-benzaldehydes (Table 2, entries 5, 6 and 8) were tested. However, an exception was observed for 2-nitrobenzaldehyde ( Table 2, entry 4), presumably caused by the chelating effect of the NO 2 group with the lewis acids [62,63]. The enantioselectivity was also found to be influenced by the steric effect with the same exception of 2-nitrobenzaldehyde. ortho-Substituted (-Cl or -Me) benzaldehydes gave higher ee values (Table 2, entries 6 vs 2 or 8 vs 9). It should be noted that the reaction of 2-naphthaldehyde proceeded well, giving 70% ee and good yield ( Table 2, entry 11), and α,β-unsaturated cinnamaldehyde gave the corresponding product with only moderate enantioselectivity ( Table 2, entry 12).
We also further investigated the asymmetric aryl transfer to aromatic aldehydes with substituted phenylboronic acids. As shown in Table 3, when 4-chlorophenylboronic acid was chosen as the aryl source and 4-nitrobenzaldehyde as the substrate, 71% ee was obtained (Table 3, entry 1). And 54% ee was obtained when 4-methoxylphenylboronic acid was tested (Table 3, entry 3).

General
All reactions were carried out under an argon atmosphere using standard Schlenk techniques. Solvents were dried and distilled prior to use according to standard methods. Unless otherwise indicated, all materials were obtained from commercial sources and liquid aldehydes were freshly distilled before use. For thin-layer chromatography (TLC), compounds were visualized by irradiation with UV light on GF 254 silica gel plates. 1 H-NMR and 13 C-NMR spectra were recorded in CDCl 3 on a Bruker ARX-300 spectrometer with chemical shifts being referenced to SiMe 4 used as internal standard. The coupling constants J are given in Hz. HPLC analysis were performed on a chiral column (Daicel Chiralcel OB-H, OD-H or AD-H column) on a Chromatography Interface 600 Series Link instrument and Series 200 pump), with Series 200 UV/VIS detection at 254 nm. The solvent system used has hexane (A)-2-propanol (B) in the indicated proportions. Optical rotations were measured on Rudolph Research Analytical Autopol III Automatic Polarimeter equipped with a 100 mm cell. Mass spectra (EI-MS) were taken using a Shimadzu GCMS-QP2010 mass spectrometer. High Resolution Mass Spectra (HRMS) were taken using a LTQ Orbitrap XL ThermoFisher unit.

Typical Procedure for the Asymmetric Aryl Transfer Reaction
In a 20 mL flame-dried Schlenk reaction tube, diethylzinc (0.9 mmol, 6 equiv, 1.5 M in toluene solution) was added dropwise to a solution of phenylboronic acid (0.3 mmol, 2 equiv) in toluene (3 mL) under an argon atmosphere. After stirring for 12 h at 60 °C, a toluene solution of L6 (20 mol%) was introduced. The reaction was stirred for an additional 30 minutes and cooled to −25 °C followed by the addition of aldehydes (0.15 mmol). After completion of the reaction (monitored by TLC), the reaction solution was quenched with saturated aqueous NH 4 Cl (3 mL) and further extracted with ethyl acetate (3 × 5 mL). The combined organic layer was dried over Na 2 SO 4 . Evaporation of the solvent gave the crude product, which was further purified by preparative TLC to afford the corresponding chiral diarylmethanols.

Conclusions
In summary, we haved reported the asymmetric aryl transfer to aldehydes with arylboronic acids as aryl sources in the presence of the chiral 2,2'-bispyrrolidine-based ligand L6. The corresponding diarylmethanols could be obtained in high yields with moderate to good enantioselectivities. Further work on the asymmetric addition mechanism and the broad application of chiral 2,2'-bispyrrolidinebased ligands in other asymmetric catalytic reactions are now in progress in our laboratory.