Ir/XuPhos-catalyzed direct asymmetric reductive amination of ketones with secondary amines

Abstract

A diverse array of bidentate P-containing ligands has been developed for Ir-catalyzed asymmetric hydrogenation, but chiral monodentate phosphine ligands have remained comparatively underexplored. We herein report a novel iridium catalyst with XuPhos as a chiral monodentate phosphine ligand for the direct asymmetric reductive amination of ketones with secondary amines. This catalytic system tolerates a wide range of substrates, providing a series of chiral tertiary amines efficiently with high enantioselectivities. The high catalytic activity is attributed to the presence of the aliphatic cyclohexyl group on the P-atom and the relative configuration of the ligand, which is crucial for XuPhos to act as a monodentate P-ligand for iridium.

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Introduction

Asymmetric hydrogenation catalyzed by chiral transition metal complexes contributes significantly to the synthesis of chiral compounds because of its perfect atom economy, high efficiency, and operational simplicity.¹ Over the past several decades, an abundance of chiral ligands has been developed, owing to their essential functions in asymmetric hydrogenations.² While there have been enormous efforts focused on the development of chiral P-containing bidentate and tridentate ligands, only a few chiral monodentate phosphorus ligands have been developed for asymmetric hydrogenation.² Nonetheless, chiral monophosphorus ligands were the first ligands used for asymmetric hydrogenation. In 1972, Knowles reported the monophosphine ligand CAMP, which promoted Rh-catalyzed asymmetric hydrogenation, achieving up to 88% ee.³ Around 2000, BINOL-derived monophosphorus ligands were developed and immediately became a privileged class of chiral ligands (Scheme 1a).⁴ Different biphenolic skeletons and the Y groups have been introduced into these types of chiral ligands to promote different asymmetric reactions, including hydrogenation reactions.⁵ However, the development of CAMP-type monophosphine ligands for asymmetric hydrogenation has encountered considerable challenges, possibly due to the difficulty in the preparation of P-stereogenic compounds.⁶

Scheme 1 Sadphos ligands for Ir-catalyzed asymmetric hydrogenation.

On the other hand, the asymmetric hydrogenation of ketimines (including ketiminiums) is one of the most widely used methods for the preparation of chiral amines, owing to its high efficiency and good atom-economy.⁷ Among the methods for the asymmetric hydrogenation of ketimines, direct asymmetric reductive amination (DARA) is a step economical method that is highly attractive to academia and industry because it allows for one-pot synthesis that eliminates the need for ketimine isolation. Many protocols have been reported for the DARA reaction using ammonium salts or primary amines as the coupling partner,⁸ but the use of secondary amines that could give valuable chiral tertiary amines has been relatively sparse. It should be noted that a successful study has been reported by the Chang group, wherein a phosphoramidite ligand/Ir catalytic system was employed to realize the DARA reaction using secondary amines to afford chiral tertiary amines with good yields and enantioselectivites.^9,10

Recently, we have developed the Sadphos family ligands, which feature a good chiral environment, ready accessibility, ease of modification, and relatively good stability.¹¹ It has been revealed that Sadphos ligands can act as monodentate or bidentate P-ligands to promote a wide range of metal-catalyzed asymmetric catalyses.¹² Following this success, we were also interested in the application of such ligands in asymmetric hydrogenations. As shown in Scheme 1b, upon the coordination of MingPhos (a Sadphos-derived ligand) with the iridium salt, P,N/Ir complexes could be generated selectively, catalyzing the asymmetric hydrogenation of α,β-unsaturated carbonyl compounds with excellent results.¹³ We noticed that one of the sub-classes of Sadphos, XuPhos, bears a part of the skeleton of CAMP (Scheme 1a). Therefore, we wondered whether XuPhos can be utilized as a monodentate phosphine ligand to promote asymmetric hydrogenations. Herein, we report for the first time that Sadphos can function as a monodentate phosphine ligand to coordinate with iridium. The resultant complex could catalyze the DARA reaction of secondary amines to give α-chiral tertiary amines with good yields and enantioselectivities (Scheme 1c).

Results and discussion

In the beginning, we tested different Sadphos ligands via in situ coordination with an Ir salt using 1a and 2a as the substrates (Scheme 2). Ti(OEt)₄ was used to promote the in situ condensation between the amine and ketone and the additive I₂ was used based on the proposed oxidation of Ir(I) by I₂ to generate an active Ir(III) complex.^9,14 Firstly, we tested ligands with different substituents on the P-atom (entries 1–3). The results revealed that the P–Cy group is important for the enantio-inducing ability and catalytic activity of the NMe-XuPhos ligand (NMe-Xu1) in this reaction, since the ligand NMe-XiangPhos with a P-adamantyl group showed almost no enantioselectivity and NMe-MingPhos showed no activity. Next, we tested NMe-XuPhos ligands bearing different substituents on the carbon stereocenter. However, no improvement of the ee was observed (as shown by the results using NMe-Xu2). The opposite configuration of the stereogenic carbon in NMe-Xu3 with respect to NMe-Xu1 led to a lower ee (entry 5). In our previous work, the side arm ortho to PR₂ on the benzene ring plays an important role in the improvement of the ee in Pd-catalyzed cyclizations.^15,16 Therefore, we next tested the effect of the side arm of NMe-XuPhos on this DARA reaction. An obvious influence on the chiral-inducing ability of the ligand based on the bulkiness of the side arm ortho to the PCy₂ of NMe-XuPhos was realized (entries 6, 9 and 10). Moreover, the size of the aryl substituent on the stereogenic carbon also had a significant impact on the enantioselectivity (entries 6–8). NMe-Xu6 bearing the OiPr and DTBM groups gave the best collective impact and exhibited the best ee (94%). Finally, the N–Me group was essential for the catalytic activity of these ligands since the NH-XuPhos ligand did not catalyze the reaction at all (entries 11 and 12). The Me group might prevent the formation of the sulfinamidate–iridium complex.

Scheme 2 Screening of Sadphos family ligands.

Other conditions besides ligands were also screened (Table 1). Different solvents were tested using the in situ formed complex of the NMe-Xu6 ligand with [Ir(COD)Cl]₂ (entries 1–7) at 60 °C. Hydrogenation in THF, EtOAc, and DCE could give 3a with full conversion and similar ee values (entries 1–3). However, aromatic solvents such as toluene and PhCF₃ led to much lower enantioselectivities (entries 4 and 5). The reaction in methanol could also proceed smoothly, but no enantioselectivity was detected (entry 6). When the strong coordinating solvent MeCN was used, the reaction could also provide product 3a in a high yield with 51% ee (entry 7). The screening of different reaction temperatures (entries 1 & 8–10) revealed that 0 °C was the best temperature for this reaction (entry 9). There was no improvement of the ee when the reaction temperature was reduced further to −10 °C, but a lower conversion was observed (entry 10). Then we tested the reaction at 0 °C with 12 h reaction time, which generated the product with a lower conversion (entry 11). When NaBArF was added as an additive, it did not have any effect on this asymmetric hydrogenation.

Table 1 Optimization of reaction conditions^a,b

Entry	Solvent	T (°C)	t (h)	Conv.	ee
a Unless otherwise noted, all reactions were carried out with 1a (0.20 mmol), 2a (0.22 mmol), [Ir(COD)Cl]2 (1.0 mol%), NMe-Xu6 (2.2 mol%), I2 (2 mol%), and Ti(OEt)4 (0.4 mmol) in solvent (2 mL) under H2 (50 bar). b The conversion was determined by ^1H NMR and the ee was determined by HPLC using a chiral column. c NaBArF (2.4 mol%) was added as an additive.
1^c	THF	60	24	>99%	64
2	EtOAc	60	24	>99%	60
3	DCE	60	24	>99%	61
4	Toluene	60	24	>99%	30
5	PhCF3	60	24	>99%	27
6	MeOH	60	24	>99%	∼0
7	MeCN	60	24	>99%	51
8	THF	rt	24	>99%	85
9	THF	0	24	>99%	94
10	THF	−10	24	78%	94
11	THF	0	12	66%	94
12^c	THF	0	24	>99%	94

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We wanted to gain insights into the key aspects that made the catalytic behaviour of NMe-XuPhos much different from that of NMe-MingPhos in this DARA reaction. Therefore, NMe-Xu1 and NMe-Xu3 were used to prepare the Ir-complex by mixing the ligand with [Ir(COD)Cl]₂ in THF. Single crystal X-ray structure analysis of the NMe-Xu1/Ir complex indicated that NMe-Xu1 behaved as a chiral monodentate phosphine ligand (Scheme 3a and Fig. 1). Even in the presence of NaBArF, this complex was stable and no counterion exchange occurred. This is consistent with the experimental evidence that NaBArF had no effect on the catalytic activity and enantioselectivity of NMe-Xu1 (Table 1, entry 9 vs. 12). Interestingly, NMe-Xu3 with the opposite configuration of the stereogenic carbon formed a chiral P,O/Ir complex in the presence of NaBArF under similar conditions, where NMe-Xu3 acted as a bidentate ligand (Scheme 3b and Fig. 1). In contrast, our previous study showed that the NMe-MingPhos ligand coordinated with [Ir(COD)Cl]₂ in the presence of NaBArF to generate the P,N/Ir complex by eliminating the ^tBuSO group (Scheme 3c).¹³ When these types of N-stereogenic P,N/Ir complexes (Ir-cat3 and Ir-cat4) were used in the DARA reaction (Scheme 3d), no desired tertiary amine product was formed, even at 60 °C, indicating that the P,N-coordination is substantially detrimental to the DARA reaction. On the other hand, the NMe-Xu1-Ir complex catalyzed the reaction smoothly (Scheme 3d), and the results were the same as those of the in situ formed complex (Scheme 2, entry 3). The NMe-Xu3-Ir-BArF complex was also tested for this reaction, giving the desired product with full conversion and −10% ee, which was different from the result obtained using the in situ formed complex without NaBArF (Scheme 2, entry 5, 20% ee). These results suggest that the three different coordination (P,N- vs. P,O- vs. monophosphine) behaviors of these two types of ligands (NMe-XuPhos and NMe-MingPhos) with iridium lead to very different catalytic activities for different reactions. The P–Cy group may prevent the formation of the P,N-complex by exerting specific electronic and steric effects. Together with the effect of the side arm (OiPr) vicinal to PCy₂ and the aryl substituent (DTBM) on the carbon stereocenter, the NMe-Xu6 ligand provides a good chiral environment for this reaction.

Scheme 3 Different coordination and catalytic behaviours of Sadphos ligands with Ir.

Fig. 1 Single crystal X-ray diffraction structures of Ir-complexes.

With the optimized conditions in hand, we examined the substrate scope using NMe-Xu6 as the chiral ligand and I₂ and Ti(OEt)₄ as the additives, and running the reaction in THF at 0 °C for 24 h under 50 bar of H₂ (Scheme 4). All the tested ketones and secondary amines underwent condensation and hydrogenation under our catalytic system, and most of the products were obtained with more than 90% ee. Electron-donating or electron-withdrawing groups on the benzene ring of the ketone substrates only had a slight impact on the enantioselectivity, while different positions of the substituent (3b–3q) only resulted in slight changes in the ee values. Notably, the ortho substituents did not show an obvious steric effect when compared with the results of the para or meta-substituted substrates (3n–3qvs.3b–3m). However, the dialkyl ketone 1r was not compatible with the chiral environment of the catalyst, giving 3r with low enantioselectivity. Next, different secondary amines were investigated. Cyclic and acyclic secondary amines were suitable coupling partners for this reaction, and the desired tertiary amines were prepared with excellent yields and good ee values (3s–3w).

Scheme 4 Substrate scope.

A gram-scale reaction was also carried out using the standard amine 1a and ketone 2a (Scheme 5a). Product 3a was prepared with good results, demonstrating the practical applicability of our method. To further establish the utility of this protocol, two transformations of the DARA products were carried out (Scheme 5b and c). The DARA reaction of substrate 1h with amine 2f smoothly gave the tertiary amine 3x, which was directly used for the next deprotection step to yield the chiral secondary amine 4 with good results. Rivastigmine 5, a drug used for the treatment of dementia associated with Alzheimer's and Parkinson's diseases and Lewy body dementia, was synthesized using 1t as the starting material. It reacted with dimethylamine under our conditions to yield 3y, which was directly used without purification for the next step. Thereafter, rivastigmine 5 was obtained in 85% yield with 90% ee over two steps.

Scheme 5 Synthetic applications of chiral tertiary amine products.

Conclusions

In summary, we have developed a new asymmetric iridium catalytic system with the chiral monodentate phosphine ligand NMe-XuPhos for the direct asymmetric reductive amination of ketones with secondary amines, yielding chiral tertiary amines in excellent yields with good ee values. The side arm (OiPr) and substituent (DTBM) on the carbon stereocenter enabled the NMe-Xu6 ligand to provide a good chiral environment for this reaction.

Data availability

The data supporting this article have been included as part of the ESI.†

Crystallographic data for NMe-Xu3-Ir-BArF and NMe-Xu1-Ir have been deposited at the CCDC under 2328618 (NMe-Xu3-Ir-BArF) and 2371593 (NMe-Xu1-Ir)† and can be obtained from https://www.ccdc.cam.ac.uk/deposit.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We gratefully acknowledge the funding support from the National Key R&D Program of China (2021YFF0701600), the NSFC (22031004, 21871088, and 22371073), and the Shanghai Municipal Education Commission (20212308).

References

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2328618 and 2371593. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01495b

‡ These authors contributed equally to this work.

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