Development of heterogeneous catalyst systems for the continuous synthesis of chiral amines via asymmetric hydrogenation

Abstract

Continuous-flow synthesis of fine chemicals has several advantages over batch synthesis in terms of environmental compatibility, efficiency and safety. Nevertheless, most preparative methods still rely on conventional batch systems. For instance, chiral amines are ubiquitous functionalities in pharmaceutical compounds, but methods for their continuous synthesis with broad substrate generality remain very challenging. Here we show the development of heterogeneous iridium complexes combined with chiral phosphoric acids for the asymmetric hydrogenation of imines towards the continuous synthesis of chiral amines. Direct asymmetric reductive amination of ketones under a hydrogen atmosphere also proceeded smoothly using the same catalyst systems. Various chiral aromatic and aliphatic amines including pharmaceutical intermediates could be prepared in high yields with high enantioselectivities. It was found that continuous-flow reactions that use columns packed with the heterogeneous iridium complexes afforded chiral amines continuously for more than two days even at pressures lower than those in the corresponding batch reactions.

Main

Chiral amines are observed in the molecular skeleton of many pharmaceuticals and agrochemicals1; thus, the development of efficient synthetic methods that can be used to access such moieties with broad substrate generality is required. Compared with traditional batch systems, which are most commonly used for fine chemical synthesis2, continuous-flow synthesis has advantages for large-scale production in terms of environmental compatibility, safety and automation. A few examples of continuous-flow syntheses of chiral amines by asymmetric hydrogenation of enamines have been reported; however, applicable substrates were limited to aromatics and dehydro α-amino acids3,4,5,6,7. More general synthetic approaches are therefore required for continuous-flow syntheses of chiral amines.

Although asymmetric hydrogenation of imines can produce chiral amines without waste, direct asymmetric reductive amination (DARA) of ketones under a hydrogen atmosphere is also attractive because no previous preparation of the imine is needed. Even though many catalyst systems have been reported8,9,10 for the preparation of chiral aromatic amines with high enantioselectivity, selectivity decreases considerably for chiral aliphatic amines in most cases11,12,13,14,15,16; even in successful cases, high pressure (0.5–5 MPa) is required17,18,19,20,21,22,23,24. Moreover, examples of asymmetric reductions of imines in continuous-flow systems were limited to those that required homogenous catalysts with reducing reagents other than hydrogen25,26,27. Whereas the development of homogeneous catalysts in the field of asymmetric catalysis is relatively advanced, heterogeneous catalysts have been hugely limited28,29, presumably because recovery and reuse of catalysts is less important from environmental and economic standpoints than high turnover numbers (TONs) and turnover frequencies (TOFs). However, we have recently been interested in heterogeneous catalysts because—in addition to ease of recovery and reuse—they can be used for continuous-flow processes2,3. A solution of substrates is thus flowed into a column packed with a heterogeneous catalyst, whereupon the product is obtained continuously and at the same time the product and the catalyst are separated as part of the process.

Herein we describe the use of heterogeneous iridium complexes that are combined with chiral phosphoric acids to catalyse asymmetric hydrogenation of imines and DARA of ketones under a hydrogen atmosphere. Various chiral aromatic and aliphatic amines could be prepared in high yields with high enantioselectivities, and the heterogeneous catalyst systems were successfully applied to continuous-flow reactions at pressures lower than those required for the corresponding batch reactions.

Results

Catalyst preparation and evaluation

Polystyrene-immobilized achiral diamine–iridium complexes were prepared on the basis of Xiao’s report18. Initially, diamine monomer L1—prepared from 4-vinylbenzenesulfonyl chloride—was copolymerized with styrene and divinylbenzene to form a polystyrene (PS)-supported ligand, followed by complexation with [Cp*IrCl2]2 to afford a heterogeneous iridium catalyst (PS–Ir A). The activity of the obtained catalyst was tested in the asymmetric hydrogenation of p-methoxyphenyl (PMP)-protected aromatic imine 1a. It was found that the desired reduction proceeded in the presence of a chiral phosphoric acid, 3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diylhydrogenphosphates (TRIP)17,18,19,30 under a hydrogen atmosphere of 2 MPa (Table 1, entry 1); however, both the yield and the enantioselectivity were lower than those obtained from the corresponding homogeneous catalyst (Supplementary Fig. 3). We then attempted to change the position at which the polymeric backbone was introduced, examining diamine monomer L2, in which the styryl group was attached to the amine group and a bulkier aryl group was attached to the sulfonamide group. PS–Ir B—prepared from L2—gave an excellent yield when the reaction time was 24 h; however, the enantioselectivity was still not satisfactory (entry 2). We assumed that the structure of an enantiodetermining transition state might be distorted by the polymer support, resulting in a decrease in the enantioselectivities. PS–Ir C was prepared to overcome this issue, bearing a diamine structure derived from monomer L3 in which a spacer was introduced to L2. Excellent yield and high enantioselectivity were achieved with this catalyst (entry 3). Finally, a slight improvement in the enantioselectivity was observed (entry 4) when styrene unit M1 in PS–Ir C was changed to 4-tert-butylstyrene unit M2; this catalyst (PS–Ir D) was determined to the optimal catalyst. We conducted scanning transmission electron microscopy analysis and energy dispersive X-ray spectrometry mapping of the catalyst to confirm that the iridium and sulfur atoms derived from the ligand moiety were well distributed over the polymer matrix (Supplementary Figs. 9 and 10).

Table 1 Activity evaluation of PS–Ir

Substrate scope

With the optimized catalyst (PS–Ir D) in hand, substrate generality was surveyed (Fig. 1). Regardless of the substituents, various PMP-protected aromatic imines were reduced to the corresponding chiral amines in high yields and enantioselectivities (2ag). The catalyst could be reused for three runs without any loss of either activity or enantioselectivity in the reaction with imine 1a.

Fig. 1: The substrate scope for asymmetric hydrogenation of aromatic imines.
figure1

The substrate generality was confirmed and reusability of the heterogeneous catalyst was examined in the reaction with imine 1a. The reported values correspond to the isolated yield. The e.e. values were determined by HPLC analysis. aSecond run with the recovered catalyst. bThird run with the recovered catalyst. c2 mol% catalyst.

We then attempted to synthesize chiral aliphatic amines by DARA of the corresponding aliphatic ketones as aliphatic imines are relatively unstable and their preparation requires tedious procedures (Fig. 2). Preliminary examinations revealed that the enantioselectivity was improved by changing the nitrogen-protecting group from a PMP to an o-methoxyphenyl (OMP) group (Supplementary Fig. 1). The reaction of 4-methylpentan-2-one (3h) with o-anisidine (4a) proceeded smoothly to afford the OMP-protected amine 2h in high yield with high enantioselectivity under the heterogeneous iridium catalyst system. PS–Ir D-catalysed DARA was applicable to the synthesis of other linear alkyl chain-substituted amines (2i and 2j) and the double-bond-containing amine 2k in high yields with high enantioselectivities. Methyl tert-butyl ketone, however, as a sterically bulky substrate, did not react at all (Supplementary Fig. 2).

Fig. 2: The substrate scope for DARA.
figure2

The substrate generality was confirmed and the effect of protecting groups was further examined (2m versus 2n). The reported values correspond to the isolated yield. The e.e. values were determined by HPLC analysis. aAt 10 °C.

The synthesis of a selection of drug molecule precursors was performed to demonstrate the utility of the heterogeneous catalyst system; OMP-protected chiral amine 2l (which is a potential precursor of chiral dobutamine, an adrenoceptor agonist31,32) could be obtained in high yield with high enantioselectivity using this method. We could also synthesize OMP-protected chiral amine 2m, which could be converted into a substructure of tamsulosin (an α1-adrenoceptor antagonist)33,34,35. The enantioselectivity was further improved for the synthesis of the potential precursor of tamsulosin when 2,5-dimethoxyaniline was used for DARA in the PS–Ir D/TRIP catalyst system. The dimethoxyphenyl group on chiral amine 2n that was obtained from this reaction was deprotected with H5IO6 (ref. 36) to afford chiral primary amine 5 (Fig. 3). This amine can be further converted into tamsulosin according to published procedures33,34,35.

Fig. 3: The formal synthesis of tamsulosin.
figure3

The deprotection of the Ar2 group on 2n is demonstrated. The corresponding amine 5 (which according to the literature can lead to tamsulosin) was obtained in good yield without considerable loss of enantiopurity. The e.e. of 5 was determined by HPLC analysis of the corresponding benzyl-protected amine.

We were intrigued by the high efficiency of DARA, so a comparison with asymmetric hydrogenation of imines of aliphatic substrates was performed to gain insights into the reaction mechanism (Supplementary Fig. 4). The reaction profile in asymmetric hydrogenation of imine 1h showed that lower enantioselectivity was observed at the initial stage (after 1 h) of the reaction and the enantiomeric excess (e.e.) gradually increased as the reaction proceeded, whereas the E/Z ratio of the remaining 1h stayed almost constant (Supplementary Table 7). However, no change of the enantioselectivity at any stage was observed in DARA to form 2h and no imine intermediate 1h was detected. As a result, the enantioselectivity in the asymmetric hydrogenation of imine 1h was much lower than that in DARA of the corresponding ketone. Furthermore, a faster reaction rate of DARA than that of the hydrogenation of 1h was observed. A similar tendency was also observed in the reaction to access amine 2m (Supplementary Table 8). DARA of an aromatic ketone to form 2a hardly proceeded and no imine 1a was observed (Supplementary Fig. 5), although asymmetric hydrogenation of the aromatic imine 1a worked well. We also performed DARA on propiophenone and neither the desired product nor imine intermediate were observed (Supplementary Fig. 5). Considering that the preparation of aliphatic ketimines requires harsher conditions than that of aromatic ketimines, smooth formation of aliphatic imines was unlikely to occur under the reaction conditions of DARA. We therefore assumed that there were different mechanisms between asymmetric hydrogenation of imines and DARA of ketones. We further conducted DARA on deuterated aliphatic ketones, of which all of the hydrogens at the α-positions of the carbonyl were deuterated (Supplementary Fig. 6). As a result, hydrogen atoms were incorporated into both positions. These results indicated that the mechanism involving direct formation of an imine followed by its direct hydrogenation without isomerization was not active in DARA20.

Continuous-flow reactions

Finally, PS–Ir D was applied to a continuous-flow system (Fig. 4). A solution of a substrate and TRIP was flowed into a column packed with PS–Ir D and molecular sieves 4Å (4Å MS), and the column was connected to a back pressure controller to keep the pressure in the range 0.50–0.55 MPaG. Additional 4Å MS was packed at both ends of the column to prevent clogging due to polymer swelling. The product was obtained in high yield with excellent enantioselectivity from 5 h after starting the system and the system could be run for over 50 h without considerable loss of activity. A TON of ~200 was achieved to produce 3.3 g of the product and the highest TOF was 4 h–1. A high level of performance was achieved even at a low pressure of hydrogen. We examined the effect of pressure in the corresponding batch system (Supplementary Table 9). The yield was 76% even at 1 MPa after 24 h, and the TON and TOF were 76 and 3.2 h−1, respectively, which were lower than those in the continuous-flow system. Furthermore, the enantioselectivity in the continuous-flow system (94–95% e.e.) was slightly higher than that in the batch system (91–92% e.e.). DARA of a ketone under a continuous-flow system was also examined to produce drug precursor 2n (Fig. 5). We initially conducted the reaction without a back pressure controller. Even in this case, a moderate yield (35% yield) and a high enantioselectivity (92% e.e.) were obtained. When the pressure was increased to 0.2 MPaG, a high yield (81–95%) could be maintained over the following 30 h with high enantioselectivity (91–92% e.e.). A TON of ~100 was achieved to produce 2.3 g of the product and the highest TOF was 3.2 h−1. The corresponding batch system afforded the product in 63% yield even at 0.5 MPa (Supplementary Table 10). These results clearly demonstrated the advantage of the continuous-flow system and showed that the reaction could be efficiently carried out even under milder pressures.

Fig. 4: Asymmetric hydrogenation of an imine with a continuous-flow system.
figure4

Asymmetric hydrogenation of imine 1a was performed in a continuous-flow system. Hydrogen gas and a toluene solution of 1a and TRIP were flowed into a column packed with molecular sieves and PS–Ir D to afford the corresponding amine 2a in high yield and enantioselectivity continuously over 50 h. Φ represents the diameter (mm) of the column.

Fig. 5: Direct asymmetric reductive amination of a ketone with a continuous-flow system.
figure5

DARA was performed in a continuous-flow system to afford amine 2n, a precursor of tamsulosin. A toluene solution of reactants and TRIP and hydrogen gas were flowed into a column packed with molecular sieves and PS–Ir D to afford the corresponding amine 2n in high yield and enantioselectivity continuously over 30 h.

In a practical sense, because the chiral source is also valuable, we attempted to recover and reuse TRIP (Supplementary Fig. 7). The liquid phase of the crude mixture was treated with Amberlite IR 900 (a basic resin to trap TRIP) and pure TRIP could be easily recovered with good efficiency from this resin after acidification. The recovered TRIP could be used for the asymmetric hydrogenation of an imine without loss of either activity or selectivity. A similar recovery protocol could be achieved for the continuous-flow system by connecting a column packed with the same basic resin to a column packed with PS–Ir D (Supplementary Fig. 8).

Conclusions

We have developed PS-immobilized diamine–iridium complexes that are combined with chiral phosphoric acids to catalyse the asymmetric hydrogenation of imines. High yields and enantioselectivities were achieved for several aromatic substrates when the spacer moiety was introduced into the monomer of the diamine ligand. The catalyst system was also applicable for DARA of ketones to synthesize various chiral aliphatic amines, including the precursors of pharmaceuticals. Moreover, the heterogeneous iridium complexes could be utilized for the asymmetric hydrogenation of an imine under continuous-flow conditions and the product was obtained continuously for more than 2 d in high yield and enantioselectivity. The continuous-flow reaction was carried out at lower H2 pressure (0.5 MPaG) than the corresponding batch reactions, achieving better yield and enantioselectivity37. The continuous-flow reaction of DARA of a ketone showed similar superiority. This is the example that used a heterogeneous catalyst system for the asymmetric hydrogenation of imines and DARA of ketones, and the achieved contentious synthesis of valuable chiral amines, including aliphatic ones3,4,38. This work demonstrates the potential of continuous-flow reactions using columns packed with heterogeneous catalysts and provides a more efficient approach to asymmetric synthesis.

Methods

A general procedure for the asymmetric hydrogenation of imines

Imine 1 (0.30 mmol), PS–Ir D (50.0 mg, 1 mol%) and 4Å MS (30 mg) were added to a reaction tube, followed by TRIP solution (2.3 mg, 1 mol%) in dry toluene (1.4 ml). After the tube was placed in an autoclave, H2 (2 MPa) was charged three times and the mixture was stirred at 30 °C for 24 h. After carefully releasing the hydrogen gas, the reaction solution was filtered before concentration. The residue was purified by preparative thin-layer chromatography to afford the corresponding chiral amine 2. The e.e. of 2 was determined by HPLC analysis.

A general procedure for DARA of ketones

PS–Ir D (50.0 mg, 1 mol%) and 4Å MS (150 mg) were added to a reaction tube, followed by TRIP solution (4.6 mg, 2 mol%) in dry toluene (1.4 ml). Ketone 3 (1.2 equiv.) and amine 4 (0.30 mmol, 1.0 equiv.) were added before the reaction tube was placed in an autoclave; H2 (2 MPa) was charged into the autoclave three times and the mixture was stirred at 20 °C for 24 h. After carefully releasing the H2 gas, the reaction solution was filtered before concentration. The residue was purified by preparative thin-layer chromatography to afford the corresponding chiral amine 2. The e.e. of 2 was determined by HPLC analysis.

Asymmetric hydrogenation of imine 1a under a continuous-flow system

PS–Ir D (1.20 g, Ir: 0.072 mmol) and 4Å MS (2.5 g) were mixed well and a column (Φ10 × 100 mm) was packed with 4Å MS (0.5 g), the above mixture and 4Å MS (0.5 g) in that order. A toluene solution of imine 1a (0.05 M) and TRIP (1 mol%) was flowed into the column using a peristaltic pump without prewetting the catalyst. At the same time, H2 gas (0.7 MPa, 5.0 ml min–1) was flowed into the column using a mass flow controller. The column was set vertically and the continuous-flow reactions were performed with downwards flow. A back pressure controller was used to maintain the pressurized conditions in the column. One fraction was collected for several hours or overnight and the solvent was evaporated. The residue was purified by preparative thin-layer chromatography and the e.e. was determined by HPLC analysis.

Direct asymmetric reductive amination of ketone under a continuous-flow system

PS–Ir D (1.20 g, Ir: 0.072 mmol) and 4 A MS (2.5 g) were mixed well and a column (Φ10 × 100 mm) was packed with 4Å MS (0.5 g), the above mixture and 4Å MS (0.5 g) in that order. A toluene solution of 4-methoxyphenylacetone (0.06 M), 2,5-dimethoxyaniline (0.05 M) and TRIP (2 mol%) was flowed into the column using a peristaltic pump without prewetting the catalyst. At the same time, H2 gas (0.5 MPa, 5.0 ml min–1) was flowed into the column using a mass flow controller. The column was set vertically and the continuous-flow reactions were performed with downwards flow. At the initial stage a back pressure was not performed, and after 470 min a back pressure controller was turned on to keep pressurized conditions in the column. One fraction was collected for several hours or overnight, and the solvent was evaporated. The residue was purified by preparative thin-layer chromatography and the e.e. was determined by HPLC analysis.

Data availability

Other reaction procedures and characterization data of compounds are available in the Supplementary Information. All data is available from the authors on reasonable request.

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Acknowledgements

This work was supported in part by a Grant-in-Aid for Scientific Research from JSPS, the University of Tokyo, MEXT (Japan), AMED and JST. We thank T. Maki (The University of Tokyo) for scanning transmission electron microscopy and energy dispersive X-ray spectrometry analyses.

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T.Y. and R.M. designed and performed the experiments. T.Y. conceived and designed the study. S.K. conceived, designed and directed the investigations and wrote the manuscript with revisions provided by T.Y and R.M.

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Correspondence to Shū Kobayashi.

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Supplementary Figs. 1–11, Tables 1–11, methods and references.

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Yasukawa, T., Masuda, R. & Kobayashi, S. Development of heterogeneous catalyst systems for the continuous synthesis of chiral amines via asymmetric hydrogenation. Nat Catal 2, 1088–1092 (2019). https://doi.org/10.1038/s41929-019-0371-y

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