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. 2024 Sep 25;146(40):27736–27744. doi: 10.1021/jacs.4c09516

Chiral Polymeric Diamine Ligands for Iridium-Catalyzed Asymmetric Transfer Hydrogenation

Yaodong Lin †, Guangqing Xu †,*, Wenjun Tang †,‡,*
PMCID: PMC11669096  PMID: 39319748

Abstract

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A series of polymeric chiral diamine ligands are developed by diboron-templated asymmetric reductive couplings, and their iridium complexes Ir–polydiamines are efficient and recyclable catalysts for asymmetric transfer hydrogenation (ATH) of functionalized ketones, affording a series of optically active secondary alcohols in excellent enantioselectivities (up to 99% ee) and unprecedentedly high total TONs (12,000, six cycles). Ir–polydiamine catalysts with longer chains offered higher reactivities, providing a plausible deactivation mechanism and practical solutions of ATH for vitamin B5 and phenylephrine.

Introduction

Asymmetric transfer hydrogenation (ATH) using formic acid or alcohols as the hydrogen source has become an indispensable method for making chiral alcohols and amines in synthetic organic chemistry due to its inherently safe chemistry and operational simplicity. Also, it does not require any special equipment in contrast to direct hydrogenation using hydrogen as the reducing source.1 In particular, the development of half-sandwich bifunctional η6-arene metal catalysts with substituted 1,2-diamines or amino alcohols as chiral ligands (Noyori–Ikariya catalysts) has offered excellent enantioselectivities on a wide range of carbonyls or imines, significantly expanding the utilities of ATH in both academia and industry (Figure 1a).2 Despite its tremendous progress in the last three decades, ATH has a relatively limited scope compared to asymmetric hydrogenation. More strikingly, ATH is far less efficient than asymmetric hydrogenation in terms of catalyst loadings or turnovers, and >10,000 TONs have rarely been achieved.

Figure 1.

Figure 1

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Design of chiral polymeric diamine-supported Noyori–Ikariya iridium catalysts

The ligand structure plays a vital role in achieving high enantioselectivities.3 The ability to vary the ligand structure both electronically and sterically is essential to achieve the best ee values for various substrates due to the lack of a general catalyst solution in ATH. Our recent development4 on chiral vicinal diamines by diboron-templated asymmetric reductive couplings provided the opportunity to finely tune the structures of Noyori–Ikariya catalysts. In particular, recent reports by Ogo,5 Fukuzumi,6 and Carreira7 on the ATH of functionalized ketones in an aqueous solution employed iridium(III) catalysts with unfunctionalized chiral vicinal diamine ligands. The availability of a number of chiral vicinal diamines could allow these reductions to proceed in a highly enantioselective fashion (Figure 1b).

In order to make ATH catalysts recyclable and more efficient, various Noyori–Ikariya catalysts supported on silicas,8 polymers,9 ionic liquids,10 or micelles11 were developed, showing appreciable reactivities, enantioselectivities, and recyclability. Generally, the supported catalysts provided high reactivities and enantioselectivities similar to the corresponding unsupported Noyori–Ikariya catalysts for 3–10 cycles. However, because of the much lower total TONs compared to hydrogenation with molecular hydrogen, supported ATH catalysts are yet to be applied widely in industry.

Aiming to achieve high TONs applicable to industrial settings, we wish to develop a new type of supported ATH catalysts that will be not only recyclable but also highly efficient in terms of low catalyst loadings. The biggest challenge is to develop a supported ATH catalyst that is more efficient than the unsupported ATH catalyst. To address this question, the supported ATH catalyst should in principle alleviate the deactivation issue of Noyori–Ikariya catalysts and have a better longevity than the corresponding unsupported one. While no reports on supported ATH catalysts are available to address this issue to our knowledge, we herein report the development of polymeric chiral diamine ligands for preparing highly efficient supported ATH catalysts (Figure 1c). Controllable syntheses of chiral polymeric diamines are accomplished for the first time based on chiral diboron-templated asymmetric reductive couplings. The unprecedented Noyori–Ikariya catalysts supported on chiral polymeric diamine chains are found to be highly efficient in the ATH of functionalized ketones, affording a series of optically active secondary alcohols with excellent enantioselectivities (up to 99% ee) and unprecedentedly high total TONs (12,000, six cycles).

Results and Discussion

ATH of Functionalized Ketones

Asymmetric hydrogenation of α-keto acids/esters by employing chiral rhodium,12 iridium,13 and ruthenium14 catalysts has become an important method for the preparation of chiral α-hydroxy acids with a few successful examples. In contrast, the ATH of α-keto acids/esters has rarely been reported.15 Carreira reported a simple ATH system in an aqueous solution employing a chiral iridium diamine catalyst, affording excellent reactivities and enantioselectivities in the ATH of α-cyano or α-nitro aryl ketones.16 We wonder whether chiral iridium catalysts based on substituted N,N’-dimethyl-1,2-diphenylethane-1,2-diamine ligands would be applicable to the ATH of α-keto acid 4a. Thus, a series of chiral N,N′-dimethyl-1,2-diphenylethane-1,2-diamine ligands 2a–j were prepared by chiral diboron-templated asymmetric reductive coupling.4 Their air-stable iridium complexes were prepared by mixing them with iridium hydrate [Cp*Ir(H2O)3]SO4 in an aqueous solution at room temperature (rt). The ATH of 2-oxo-2-(o-tolyl)acetic acid (4a) proceeded smoothly to completion in water/MeOH (1/1) at 70 °C for 12 h in the presence of chiral iridium catalysts (0.5 mol %). As shown in Figure 2, Ir complex 3a provided product 5a with 73% ee. Ortho-chloro-substituted complex 3b offered a higher ee (83% ee). When the chloro substituents were installed at meta positions, a better ee (88%) was realized with catalyst 3c. Employment of trifluoromethyl substituents (3d) led to 92% ee. Catalysts (3e and 3f) with electron-withdrawing substituents at para positions were inferior to the reaction. Catalysts (3h–j) with electron-withdrawing substituents at 3,5 positions proved to be superior. In particular, 3j with trifluoromethyl groups at 3,5 positions provided product 5a with 99% ee.

Figure 2.

Figure 2

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ATH of 2-oxo-2-(o-tolyl)acetic acid (4a) catalyzed by chiral iridium(III) complexes. The reactions were carried out at 70 °C using 0.5 mmol of ketone in 2.5 mL of a 1:1 mixture of water/methanol with 0.5 mol % catalysts; quantitative yield and ee values were determined by conversion to its corresponding methyl ester using TMSCHN2 through chiral high-performance liquid chromatography (HPLC) on a Chiralcel OJ-H column.

By employing 3j as the optimal catalyst, a series of functionalized ketones were reduced in MeOH–H2O (1/1 v/v) at 70 °C with formic acid as the reducing reagent, providing a variety of chiral alcohols in excellent yields and good to excellent ee values (Figure 3). It is noteworthy that a series of ortho-substituted α-phenyl-α-hydroxy carboxylic acids 5a–g were formed with excellent enantioselectivities (92 → 99% ee) and yields. Mandelic acid 5h was afforded with 95% ee. 1-Naphthyl-substituted carboxylic acid 5i was obtained with 93% ee. The enantioselectivities of α-hydroxy carboxylic acids 5j–r with meta or para substituents were slightly inferior, ranging within 80–90% ee values. Encouragingly, iridium catalyst 3j was applicable to the ATH of the corresponding α-aryl-α-keto esters, which were not suitable substrates by direct hydrogenation with Zhou’s iridium catalyst.13b Three ortho-substituted α-phenyl-α-hydroxy carboxylic acid esters 5s–u were all formed with excellent ee values (92–99%). Consistent with Carreira’s work,163j was also efficient for the ATH of substituted 2-cyanoacetophenones and 2-nitroacetophenones, providing β-hydroxynitriles 5v–x and β-nitro alcohol 5y with excellent ee values. 1-Acetylnaphthalene was also applicable, affording chiral alcohol 5z with 93% ee. Iridium catalyst 3j was also applicable to the ATH of trifluoromethyl aryl ketones, leading to the corresponding α-trifluoromethyl-substituted alcohols in 78–96% ee values. Excitingly, α-ketolactone was also applicable to the ATH reaction, providing d-pantolactone (5ba), the precursor for the synthesis of d-vitamin B5, with 95% ee and 96% isolated yield. With 3j as the catalyst, N-methylisatins were transformed to corresponding chiral alcohols 5bb and 5bc with 83–88% ee values.

Figure 3.

Figure 3

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ATH of various functionalized ketones catalyzed by chiral iridium(III) complex 3j The reactions were carried out at 70 °C for 12 h with ketone 4 (0.5 mmol) and formic acid (2.5 mmol) in water/methanol (1/1 v/v, 2.5 mL) in the presence of 3j (0.5 mol %); isolated yields and ee values were determined by chiral HPLC analysis.

Although it was not possible to get the X-ray structure of 3j, its corresponding Ir chloride complex 3j′ was successfully prepared from 3j with a saturated sodium chloride aqueous solution, and its structure was confirmed by X-ray crystallography.17 Complex 3j′ could also be applied to the ATH of 4a, albeit with a low ee value (86%, 5a).

Ir–Polydiamine Complex for ATH

Despite excellent enantioselectivities achieved with iridium catalyst 3j, the catalyst loading (0.5 mol %) employed in ATH was too high to be applicable in industrial settings. Due to the high cost of iridium, the ATH would be economically viable only if a low catalyst loading (<0.1 mol %) or a high TON (>1000) could be reached. The challenge was how to design an ATH catalyst capable of high TONs. Previous studies18 on ATH showed that major deactivation pathways of ATH with the iridium metal could be ligand dissociation of chiral diamine from the iridium metal, association with other ligands, or aggregation resulting in inactive iridium species. We envisioned that such deactivation pathways would be significantly inhibited or eliminated if a number of chiral diamine ligands were orderly arranged, allowing a dissociated iridium species to be able to find another diamine ligand to resume activity while disallowing extra diamine ligands to inhibit its reactivity by further coordinating active iridium. Thus, a polymeric chiral diamine ligand could serve the purpose of providing a highly active ATH catalyst. In addition, the iridium catalyst supported on a polymeric diamine ligand could be recyclable and reusable, providing even higher total TONs after several cycles. Thus, the development of polymeric chiral diamine ligands was pursued.

We have developed a single-step, highly diastereoselective, and enantioselective method of forming chiral vicinal diamines by chiral diboron-templated asymmetric reductive coupling of imines.4 We believed this method would be applicable to the reductive coupling of bisimines, providing chiral diamine polymers in a highly diastereoselective and enantioselective fashion. Thus, a series of polymeric N,N′-dimethyl chiral vicinal diamines (PDA-1 to PDA-6) were synthesized for the first time, as shown in Figure 4. The polymerizations proceeded at rt in tetrahydrofuran (THF) with bisaldimine DI (1 mmol) and chiral diboron CDB (1 mmol) in THF (4 mL) for 24 h. The Mn’s of these polymeric chiral diamines ranged from 5000 (PDA-1) to 14,000 (PDA-6), which were likely to be controlled by their solubility in THF, while their PDIs were in the range of 1.02–1.91. Interestingly, the molecular weight of these polymeric diamines could be easily controlled simply by variation in the reaction time. For instance, during the preparation of PDA-6, the reaction was stopped at 1, 3, 9, and 24 h, and the Mns of the polymers increased gradually from 1974, 3496, and 9300 to 13301, indicating the controllable synthesis of polymeric chiral diamines. It should be noted that polymers PDA-1 to PDA-6 all exhibited marked CD properties, indicating the high stereoselectivities (both diastereoselectivities and enantioselectivities) of the polymerization.

Figure 4.

Figure 4

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Controllable preparation of polymeric chiral diamine ligands The reactions were carried out at 25 °C with dialdimine DI (1 mmol) and chiral diboron CDB (1 mmol) in THF (4 mL) for 24 h.

Next, the iridium complexes of these polymeric diamine ligands were prepared. [Cp*Ir(H2O)3]SO4 was treated with polymeric chiral diamines PDA-1–6 at an iridium/diamine ratio of 1/20, forming a series of Ir–polydiamine complex Ir-PDA-1–6 in excellent yields. The TEM and STEM images of Ir-PDA-6d solid were collected, and EDS elemental mapping analysis revealed the composition of all elements including carbon, oxygen, nitrogen, fluorine, and iridium, whose contents were in accordance with the ICP analyses (see the Supporting Information for more details). It should be noted that all of these iridium complexes were soluble in methanol, allowing homogeneous ATH in aqueous solution. Pleasingly, all catalysts Ir-PDA-1–6 were applicable to the ATH of 4h (Figure 5). The enantioselectivities were strongly dependent on the substituents on the aryl groups. The trifluoromethyl substituents were beneficial to enantioselectivities. In particular, catalyst Ir-PDA-6d provided 5h with 92% ee, equally effective as 3j in terms of enantioselectivity. Excitingly, the asymmetric hydrogenations with Ir–polydiamine complexes as catalysts showed much increased reactivities, and the reactions proceeded to completion at an iridium loading of 0.05 mol %, only 1/10 of that with 3j. Such low catalyst loadings offered potential for practical applications of ATH in industry. Thus, a series of functionalized ketones were reduced with Ir-PDA-6d as the catalyst at 0.05 mol % iridium loading to form chiral α-hydroxy carboxylic acids, α-trifluoromethyl alcohols, and α-hydroxy amides with excellent enantioselectivities and yields (Figure 6a).

Figure 5.

Figure 5

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ATH of 2-oxo-2-phenylacetic acid catalyzed by chiral iridium–polydiamine complexes. The reactions were carried out at 60 °C with ketone 4h (2 mmol) and formic acid (10 mmol) in water/methanol (1:1 v/v, 10 mL) in the presence of Ir-PDA (0.05 mol %); ee values were determined by chiral HPLC analysis.

Figure 6.

Figure 6

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ATH of various ketones catalyzed by chiral iridium–polydiamine Ir-PDA-6d.

To further demonstrate the synthetic utility of Ir–polydiamine catalysts, a gram-scale synthesis of l-phenylephrine, an oral or nasal decongestant, was studied.19 Nitro ketone 4y was prepared from 3-methoxyphenyl carboxylic acid by treatment with CDI, followed by nitromethane in THF in an 89% overall yield. Compound 4y was treated with formic acid in MeOH–H2O by employing Ir-PDA-6d as the catalyst at 0.05 mol % iridium loading, forming corresponding nitro alcohol 5y with 95% ee and 92% isolated yield at the multigram scale (3.2 g). Hydrogenative reduction of the nitro group followed by carbamate formation, LAH reduction, and demethylation with BBr3 provided l-phenylephrine hydrochloride (Figure 6b). The gram-scale asymmetric reduction of ketone 4aa was studied. By employing Ir-PDA-6d as the catalyst, product 5aa was obtained in 95% yield and 93% ee with 10,000 total TONs after five catalyst cycles (Figure 6c). d-pantolactone (7i) was the major chiral building block for d-vitamin B5 and pantothenamide in medicinal chemistry.20 Its synthesis from reduction of α-keto lacton 4ba remained very attractive, and there was a lack of an efficient ATH method at the commercial scale to our knowledge. α-Ketolactone 4ba was thus treated with formic acid as the reducing reagent in MeOH–H2O by employing Ir-PDA-6d as the catalyst, forming d-pantolactone (5ba) with 92% ee and 95% yield. Pleasingly, catalyst Ir-PDA-6d can be reused and applied for six cycles, and only a slight loss of ee was observed by the end of six cycles (Figure 6d). Importantly, no significant iridium leaching was observed during each catalytic run. The total TON reached 12,000, providing a practical solution to the synthesis of d-pantolactone for the first time with a TON of >1000 via ATH. Treatment of 5ba with β-alanine calcium in methanol under reflux yielded d-vitamin B5 in 78% yield.

Since it was the first report to our knowledge in which a supported catalyst (Ir–polydiamine) was 10 times more active than the corresponding nonpolymeric iridium diamine catalyst in ATH, it was important to understand why the polymeric diamine ligand provided higher reactivities and more effectively inhibited the deactivation processes. We proposed a plausible catalytic cycle of ATH, as depicted in Figure 7a. Ligand exchange of Ir-PDA-6 with a formic acid anion leads to the formation of Ir-PDA-6I, which after elimination of CO2 gives rise to Ir hydride Ir-PDA-6II. Then, Ir-PDA-6II reacts with ketone and formic acid to form an alcohol product and regenerate Ir-PDA-6I. Several possible deactivation pathways of the catalytic cycle could be as follows (Figure 7b): (1) Dissociation of the diamine ligand to form inactive [Cp*Ir(H2O)3]SO4. This deactivation pathway should be effectively inhibited with the employment of polymeric diamine ligands, since there are plenty of diamine sites on the polymer chain to pick up free [Cp*Ir(H2O)3]SO4 to resume activity. (2) Association of a spectator ligand with Ir-PDA-6 or Ir-PDA-6I to form inactive Ir-PDA-6III. Despite the presence of many diamine sites on the polymeric ligand, they were orderly arranged on a rigid polymer to avoid the deactivation of the active iridium species. (3) The rigid polymeric diamine ligand could effectively reduce the dimerization or aggregation of iridium species. (4) Since the ATH proceeds under acidic conditions without adding any base, the formation of inactive Ir-OH species17 is less likely to be a major issue. By analyzing these deactivation pathways, we predicted that a polymeric diamine ligand with a larger molecular weight would have fewer opportunities to be deactivated with a reduced probability of ligand association and metal aggregation issue than that with a smaller one, therefore providing higher TONs. To verify this, four PDA-6 polymers PDA-6a–d (0.5 mol % monomer) with different Mns together with monomer 2j (0.5 mol %) were subjected to the ATH of 4c at an iridium loading of 0.025 mol % (Figure 6c). All ATH reactions were stopped after 8 h. While ATH with 2j as the ligand showed <5% conversion, ligands PDA-6a, PDA-6b, PDA-6c, and PDA-6d provided, respectively, 16, 42, 63, and >99% conversions. In particular, a TON of 4000 was obtained with PDA-6d as the ligand, clearly demonstrating the advantages of polymeric diamine ligands on reactivity in ATH.

Figure 7.

Figure 7

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Mechanistic rationale.

Conclusions

We have developed a series of unprecedented polymeric chiral diamine ligands via the chiral diboron-templated asymmetric reductive coupling of bisaldimines. Their iridium complexes iridium–polydiamines are efficient and recyclable asymmetric hydrogenation catalysts of various functionalized ketones, affording a series of optically active secondary alcohols with excellent enantioselectivities (up to 99% ee) and exceptionally high total TONs (12,000, six cycles). Mechanistic studies showed that Ir–polydiamine catalysts with longer chains and large molecular weights showed higher reactivities, offering a plausible deactivation mechanism of ATH. The high efficiency of these recyclable iridium catalysts in terms of both reactivity and enantioselectivity, simple operational procedures, and use of an aqueous system have offered great potential of ATH for practical applications, as demonstrated in the synthesis of phenylephrine and vitamin B5. While ATH in the past was often considered less practical than asymmetric hydrogenation due to lower turnover numbers, this work by developing polymeric diamine ligands has opened the discussion that ATH could be a viable, safe, and convenient alternative to asymmetric hydrogenation in industrial settings.

Acknowledgments

The work is supported by the National Key R&D Program of China (2022YFA1503702 and 2021YFF0701601), NSFC (82188101 and 22071261), and Youth Innovation Promotion Association, CAS.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c09516.

  • General information; experimental procedures; characterization data; X-ray structure of product 3j’; NMR spectra; and HPLC traces; X-ray crystallographic data for 3j′ (PDF)

The authors declare no competing financial interest.

Supplementary Material

ja4c09516_si_001.pdf (21MB, pdf)

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