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. 2020 Jun 23;5(26):15936–15941. doi: 10.1021/acsomega.0c01124

Enantioselective C,P-Palladacycle-Catalyzed Arylation of Imines

Yinhua Huang †,*, Lijun Wang †, Junbao Li †, Huayu Qiu †,*, Pak-Hing Leung ‡,*
PMCID: PMC7345393  PMID: 32656414

Abstract

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Chiral diarylmethylamines are of great interest because of their prevalence in biological and pharmaceutical sciences. Herein, we report a C,P-palladacycle-catalyzed enantioselective synthesis of chiral diarylmethylamines via asymmetric arylation of N-protected imines with arylboronic acids. The C,P-palladacycle showed high reactivity (up to 99% yield) and enantioselectivity (up to 99% ee) toward this arylation, enabling the tolerance of a wide range of functionalities, providing a convenient and efficient access to enantiomerically enriched diarylmethylamines. The absolute configuration of the product was well rationalized by the proposed stereochemical pathway and the catalytical cycle.

Introduction

Chiral diarylmethylamines have attracted great interest because of their high utility in biological and pharmaceutical sciences as well as in organic chemistry.1 They are important intermediates or building blocks for the construction of biologically active molecules and pharmaceutically relevant products. Prominent examples include commercial drugs such as cetirizine (treatment of hayfever),2 meclozine (treatment of vertigo),3 solifenacin (treatment of overactive bladder),4 tianeptine (treatment of depressant),5 and biologically active compounds SNC80,6 (+)-BW373U86,6 HIV integrase inhibtor.7 (Figure 1).

Figure 1.

Figure 1

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Selective examples of commercial drugs and bioactive molecules containing diarylmethylamine motifs.

Given the widespread utility of chiral diarylmethylamines, several synthetic methods have been developed in the last few years.8 Catalytic enantioselective synthesis of chiral diarylmethylamines has been achieved by rhodium catalysts with chiral ligands.9 In contrast to rhodium, other transition metals have received relatively less attention. Recently, palladium-catalyzed addition of arylboronic acids to imines has become a subject of keen interest because of the high efficacy and robustness of palladium catalysts. In this scenario, N-heterocyclic carbene,10 bipyridine,11 and C,N-palladacycle12 have been reported in the asymmetric arylation of acyclic imines; pyridine–oxazoline13 and phosphinooxazoline14 as well as C,N-palladacycle12 have been reported for the asymmetric arylation of cyclic imines. Bisoxazoline15 has been reported for a three-component synthesis of α-arylamines.

Despite the valuable progress made in this area, developing practical, economical, and highly enantioselective synthesis of structurally diverse diarylmethylamines under mild conditions from readily available starting materials still remains desirable.

On the other hand, developments on chiral palladacycles have led to an exciting new research area of asymmetric reactions.16 During the past decade, we have developed the chiral dimeric C,P-palladacycle (S)-L2-Pd17 and its cationic derivative (S)-L1-Pd18 and applied them in asymmetric transformations.18,19 The cationic complex (S)-L1-Pd is one of the most efficient catalysts for asymmetric hydrophosphination of α,β-unsaturated ketones. We have continued our efforts on the development of chiral palladacycles and their new applications in asymmetric transformations. Herein, we report our new discovery that the C,P-palladacycle can efficiently catalyze the arylation of N-protected imines with arylboronic acids giving chiral diarylmethylamines (Scheme 1).

Scheme 1. Arylation of Imines Catalyzed by a C,P-Palladacycle.

Scheme 1

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Results and Discussion

To achieve high yield and enantioselectivity of the arylation of acyclic imines, the problems from syn-anti equilibration20 and hydrolysis of the acyclic imines, which has been reported under palladium catalysis conditions, must first be overcome.12b Accordingly, we examined a series of organometallic complexes (palladacycles) as catalysts for this bond formation reaction. The cationic complex, (S)-L1-Pd, which has been previously used as one of the most efficient catalysts for hydrophosphination, was examined first for the reaction of acyclic N-tosylarylimine 1a and phenylboronic acid 2a. Unfortunately, it did not give any desired product, instead, the starting material 1a was decomposed under the conditions (entry 1, Table 1). Next, we examined the neutral chloro-bridged dimeric complex (S)-L2-Pd as a catalyst for this reaction, to our surprise, it catalyzed the reaction very efficiently giving the addition product in almost a quantitative yield with 95% ee (entry 2) at room temperature (25 °C). The absolute configuration of 3aa was determined to be (S) by X-ray analysis.21 Importantly, the decomposition of the starting material 1a was inhibited completely. Use of the analogue C,N-palladacycle (S)-L3-Pd as a catalyst under otherwise the same conditions gave a lower yield (81%) of 3aa with higher enantioselectivity (99% ee). In contrast, the C,N-platinacycle (S)-L3-Pt was inactive for this reaction under otherwise the same conditions with starting material 1a recovered. (S)-L4-Pd10 and (R,S,S)-L5-Pd11 were reported for the same reaction with a little bit lower enantioselectivity (entries 5 and 6). A C,N-palladacycle (imidazoline complex)12 was also reported for the asymmetric arylation of acyclic imines with high enantioselectivity. Screening of the reaction solvents revealed that toluene is the best solvent for this reaction. Lower yields and/or enantioselectivity of 3aa were obtained when THF, dioxane, DCM, DCE, and acetonitrile were used as the solvents (entries 7–11). The presence of a base is found to be essential with KOH being the best choice for this reaction (entries 12–14). Employment of Et3N, K3PO4, and K2CO3 resulted in lower yields.

Table 1. Optimization of Catalytic Conditionsa.

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entry catalyst base solvent yieldb (%) eec (%)
1d (S)-L1-Pd KOH toluene 0  
2 (S)-L2-Pd KOH toluene 99 95
3 (S)-L3-Pd KOH toluene 81 99
4e (S)-L3-Pt KOH toluene 0  
5f (R)-L4-Pd K3PO4 THF 99 92
6g (R,S,S)-L5-Pd   TFE 95 91
7 (S)-L2-Pd KOH THF 40 93
8 (S)-L2-Pd KOH dioxane 99 93
9 (S)-L2-Pd KOH DCE 99 93
10 (S)-L2-Pd KOH DCM 91 92
11d (S)-L2-Pd KOH NCMe 20 93
12 (S)-L2-Pd Et3N toluene 79 95
13 (S)-L2-Pd K3PO4 toluene 68 94
14 (S)-L2-Pd K2CO3 toluene 10  
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a

Unless otherwise noted, the reactions were carried out using imine 1a (0.12 mmol), PhB(OH)2 (0.24 mmol), and cat (5 mol % Pd) in a solvent (1.0 mL) at 25 °C for 3 h.

b

The yields indicated in the table are isolated yields.

c

Determined by HPLC analysis with a chiral stationary phase. The absolute configurations of 3aa were determined to be (S) by X-ray analysis, for more details see Supporting Information.

d

Starting material 1a was decomposed.

e

Starting material 1a was recovered.

f

Reported results (4 °C, 12–36 h), see ref (10).

g

Reported results (0 °C, 24 h), see ref (11); DCE = 1,2-dichloroethane; DCM = dichloromethane; TFE = trifluoroethanol.

The highly reactive C,P-palladacycle (S)-L2-Pd catalyst was widely applicable in the asymmetric addition of arylboronic acids to the o-methoxy-substituted aldimine 1a (Table 2). The addition of phenylboronic acids with a substituent (methyl, methoxy, halides, CF3, and CO2Me) at the para, meta, or ortho position gave the corresponding arylation products in high enantioselectivities (92–99% ee) and yields (60–99%), thus exhibiting good functional group compatibility. Use of 2-naphthaleneboronic acid gave 99% yield with 94% ee while use of 1-naphthaleneboronic acid gave lower yield (60%) with higher enantioselectivity (97% ee).

Table 2. Substrate Scope of Arylboronic Acidsa.

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a

Reaction conditions: 1a (0.12 mmol), Ar2B(OH)22 (0.24 mmol), and (S)-L2-Pd (5 mol % Pd) in toluene (1 mL) at 25 °C for 3 h. The yields are isolated yields. ee % was determined by HPLC analysis with a chiral stationary phase. The absolute configurations are proposed by similarity of the stereochemical pathway to that giving (S)-3aa.

A variety of N-tosylarylimines were further examined with several arylboronic acids in the presence of (S)-L2-Pd as the catalyst to give the corresponding enantiomerically enriched diaryl methylamines. The results are summarized in Table 3. The reactions of N-tosylaldimines bearing F, Cl, Br, and OMe led to products 3ba–3if in 51–99% yields with 87–99% ee. Significantly, the protocol can be extended to heteroaryl N-tosylaldmines containing thiophene or furan, which provided 3ja (57%, 99% ee) and 3ka (51%, 99% ee). Notably, the cyclic aldimine 3l is also a good substrate for the reaction with arylboronic acids, giving the corresponding addition products 3la, 3li, and 3lk in good yields (80–99%) and enantioselectivity (87–89% ee). Cyclic ketimine 3m is not reactive enough for this reaction under the same conditions. It is anticipated that the use of a 4-nitrobenzenesulfonyl (Ns) group in place of a tosyl group makes the deprotection much easier.19 Thus, N-4-nitrobenzenesulfonylimine 3n and 3o were reacted with PhB(OH)2 under the standard conditions. The results revealed that the target addition products 3na (83%, 96% ee) and 3oa (83%, 93% ee) were formed in slightly lower yields but with higher enantioselectivity compared with the N-Ts protected partners. N-benzenesulfonylimine 3p and 3q were also examined giving the target product 3pa (82%, 95% ee) and 3qa (57%, 91% ee) in similar yields and enantioselectivity.

Table 3. Substrate Scope of Iminesa.

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a

Reaction conditions: 1a (0.12 mmol), Ar2B(OH)22 (0.24 mmol), and (S)-L2-Pd (5 mol % Pd) in toluene 1 mL at 25 °C for 3 h. The yields are isolated yields. ee % was determined by HPLC analysis with a chiral stationary phase. The absolute configurations are proposed by similarity of the stereochemical pathway to that giving (S)-3aa.

A possible catalytic cycle is postulated, as illustrated in Scheme 2, for the palladacycle-catalyzed arylation of 1a with phenylboronic acid 2a. The dimeric palladacycle equilibrated with the monomeric form A in a solvent, followed by the formation of the hydroxo-palladium species B. A phenyl–palladium bond is formed in C by transmetalation between B and phenylboronic acid. Syn-addition of the phenyl-palladium to C=N bond forms an aminopalladium species F, which undergoes the transmetalation with PhB(OH)2 to regenerate the phenyl-palladium species C and to produce the phenylated intermediate, which undergoes hydrolysis after workup to give the product 3aa.

Scheme 2. Proposed Catalytic Cycle for the Arylation of 1a with PhB(OH)2 Catalyzed by (S)-L2-Pd.

Scheme 2

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The S configuration of the arylation product 3aa obtained with the (S)-complex is confirmed by X-ray analysis21 and rationalized by the coordination of imine 1a to the palladium with its si-face,13b followed by phenylpalladation giving (S)-3aa (Figure 2).22 The (S)-L2-Pd constructs an effective chiral environment because of the asymmetric skew conformation of the five-membered organometallic ring.23 Furthermore, the complex (S)-L2-Pd provides two dramatically different coordination sites resulting from the trans-effects24 originated from the P and aromatic-C donor atoms, accommodating an electrophile and a nucleophile simultaneously to trigger subsequent intramolecular asymmetric bond formation. During the course of the bond formation reaction in the catalytic cycle, the C=N double bond coordinates to the palladium trans to naphthyl carbon in a manner avoiding the steric repulsions between the phenyl group on phosphorus and the sulphonyl moiety of the imine. The coordination with the other face is sterically much less favorable. It is worthy to note that this intramolecular stereochemical pathway model was proposed for the palladacycle catalysis for the first time with the support of experimental observations and X-ray analysis, and it may be generally used for the prediction of the absolute configurations of the addition products produced by this family of palladacycle catalysts.

Figure 2.

Figure 2

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Proposed stereochemical pathway for the arylation of 1a with PhB(OH)2 catalyzed by (S)-L2-Pd.

For comparison of the catalytic reactivity between the C,P-palladacycle and the well-established rhodium catalyst in the arylation of imines, competition experiments were carried out (Scheme 3).25 The rhodium dimer [RhCl((R,R)-Ph-bod*)]2 has been reported as an excellent catalyst for this transformation giving (S)-3aa in high yields and enantioselectivity.9a Thus, we employed the [RhCl((S,S)-Ph-bod*)]2 as a catalyst for the reaction of 1a and 2a under the reported conditions (conditions 2), and (R)-3aa was obtained in 98% yield with 99% ee (eq 2). Next, we loaded both (S)-L2-Pd and [RhCl((S,S)-Ph-bod*)]2 with the same amount (5 mol % Rh and Pd) as two catalysts for the competition reaction under conditions 2 (eq 3) and conditions 1 (eq 4). To our surprise, (S)-3aa was obtained (95%, 65% ee, conditions 2; 91%, 66% ee, conditions 1) indicating that the C,P-palladacycle showed higher catalytic reactivity under these conditions. Furthermore, 2c and 2e were employed instead of 2a for the competition reaction under conditions 1 (eq 4). As a result, (S)-3ac (89%, 45% ee) and (R)-3ae (90%, 71% ee) were obtained, indicating that under ambient reaction conditions (conditions 1), the C,P-palladacycle has higher catalytic reactivity with electron-rich arylboronic acids while the [RhCl((S,S)-Ph-bod*)]2 catalyst has higher catalytic reactivity with electron-deficient arylboronic acids toward the addition to 1a.

Scheme 3. Competition Experiments.

Scheme 3

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Conclusions

In summary, the C,P-palladacycle has showed its high catalytic reactivity and enantioselectivity toward the arylation of imines with arylboronic acids under mild conditions. This protocol provides the access to enantiomerically enriched diarylmethylamines in high yields with high optical purity. A possible catalytic cycle has been proposed for the present catalysis, and the resulting absolute configuration of the arylation product was rationalized by a proposed stereochemical pathway.

Experimental Section

General Information

All air-sensitive manipulations were carried out with standard Schlenk techniques under nitrogen or argon. Solvents were degassed prior to use when necessary. 1H NMR signals were reported in chemical shifts downfield from SiMe4 using the respective residual solvent peak as the internal standard (chloroform = 7.26 ppm) and listed as follows: chemical shifts (δ, ppm), multiplicity, coupling constant(s) in Hz, and integration. 13C NMR signals were reported in chemical shifts downfield from SiMe4, using the respective residual solvent peak as the internal standard. (CDCl3 = 77.16 ppm). Optical rotations were measured on an Anton Paar MCP 200 polarimeter. HRMS (ESI) was recorded on a time-of-flight (TOF) LC/MS instrument. Flash column chromatography was performed with Silica gel 60 (Merck) or Al2O3 (activated 200) (Merck). Enantiomeric excesses (ee) were determined by HPLC analysis on Shimadzu HPLC with Daicel chiral columns.

General Procedure for Catalytic Asymmetric Arylation of Imines with Arylboronic Acids

N-protected arylimine 1 (0.120 mmol), ArB(OH)22 (0.240 mmol), (S)-L2-Pd (3.0 mg, 0.003 mmol, 5 mol % Pd), and KOH (3.4 mg, 0.06 mmol) were placed in a Schlenk tube under nitrogen. Toluene (1.0 mL) was added, and the mixture was stirred at 25 °C for 3 h. Filtration through a short pad of silica, followed by concentration under reduced pressure and purification by silica-gel chromatography (EtOAc/petroleum), afforded 3 as a white solid.

Acknowledgments

We gratefully acknowledge the Natural Science Foundation of Zhejiang Province (ZJNSF) (LY19B020005) and the Pandeng Plan Foundation of Hangzhou Normal University for financial support. We are also grateful to Prof. T. Hayashi for his insightful discussions which contributed to this work.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c01124.

  • Experimental details, characterization data including 1H NMR and 13C NMR spectra, HPLC charts, and X-ray data (PDF)

  • Crystallographic data of CCDC-1973471 (CIF)

The authors declare no competing financial interest.

Supplementary Material

ao0c01124_si_001.pdf (4.6MB, pdf)
ao0c01124_si_002.cif (445.3KB, cif)

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ao0c01124_si_001.pdf (4.6MB, pdf)
ao0c01124_si_002.cif (445.3KB, cif)

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