Development of chiral ferrocenyl P,P,N,N,O-ligands for ruthenium-catalyzed asymmetric hydrogenation of ketones

Abstract

A new type of ferrocenyl P,P,N,N,O-ligand has been developed through a one-step transformation. This represents a rare example of a ligand containing both chiral bisphosphine and diamine groups suitable for ruthenium-catalyzed asymmetric hydrogenation. Its ruthenium complex can be directly prepared by stirring the ligand and [Ru(benzene)Cl₂]₂ at 90 °C in DMF for 4 hours. The catalyst showed high reactivity and enantioselectivity in the hydrogenation (AH) of simple ketones and α,β-unsaturated ketones, providing the corresponding chiral aryl alkyl alcohols and chiral allyl alcohols with up to 99% yield and 96% ee.

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In modern organic synthetic chemistry, chiral metal catalysts are of vital importance.^1–10 Among them, diphosphine–ruthenium–diamine complexes^11–14 (Noyori's second-generation catalysts) are landmark works (Fig. 1a). The use of chiral diphosphines such as BINAP, as well as certain chiral diamines, has led to the development of highly effective enantioselective catalysts.^15–17 A significant advantage of these catalysts, compared to Ru(diphosphine)X_n salts (Noyori's first-generation catalysts), is their ability to be used for the asymmetric hydrogenation of ketones.¹⁸ With the development of a large number of chiral diphosphine ligands such as BICP, PhanePhos and etc.,^1,19–24 many catalysts of this general type have been prepared. Although these catalysts have achieved great success, they still have significant drawbacks, including relatively poor stability.²⁵ In some cases, the products may exhibit lower enantioselectivity (ee) values due to catalyst decomposition.²⁵

Fig. 1 Metal-catalyzed asymmetric hydrogenation of ketones.

Ferrocene-based chiral ligands represent a class of ligands widely applied in asymmetric synthesis.²⁶ Since Hayashi developed the first example of such ligands (ppfa, N,N-dimethyl-1-[2-(diphenylphosphino) ferrocenyl]ethylamine, a asymmetric ligand for ruthenium) in 1974,²⁷ a large number of ferrocene ligands such as Josiphos, Walphos, Taniaphos have been developed. In 2007, a ferrocenyl phosphine-thioether ligand suitable for iridium-catalyzed asymmetric hydrogenation of ketones was developed by Peruzzini and coworkers.²⁸ Due to the chelating effect, multidentate ligands showed higher stability and selectivity compared with the traditional bidentate ligands.² In 2013, Chen developed a tridentate P,N,N-ligand, which showed moderate enantioselectivity in iridium-catalyzed asymmetric hydrogenation of acetophenone derivatives (60%–85% ee).²⁹ Our group has focused on the design and synthesis of efficient ligands for the asymmetric hydrogenation of ketones for over two decades.³⁰ Since 2016, we have developed a series of multidentate ligands such as f-amphox,³¹ f-amphol,³² f-ampha,³³ f-amphamide.³⁴ Recently, we developed the tetradendate ligand f-phamidol, for iridium-catalyzed asymmetric hydrogenation of ketones, whose iridium complex is used for the asymmetric hydrogenation of acetophenone with a TON of up to 13 million (Fig. 1b).³⁵

While there are many polydentate ligands suitable for iridium, there are few suitable for ruthenium.^36–38 Herein, we report the design and synthesis of an air-stable ferrocenyl P,P,N,N,O-ligand for ruthenium-catalyzed asymmetric hydrogenation of simple ketones with good yields and high enantioselectivities, which represents a rare example of a ligand containing both chiral bisphosphines and diamine groups suitable for ruthenium-catalyzed asymmetric hydrogenation reactions (Fig. 1c).

At the beginning of this study, we attempted to introduce a glycyl tert-leucinol moiety into (S_C,R_FC)-PPFOAc [(S_c,R_FC)-1] to synthesize the P,P,N,N,O-ligand (Scheme 1). A substitution reaction between (S_c,R_FC)-PPFOAc [(S_c,R_FC)-1] and (S)-glycyl tert-leucinol (2) proceeded smoothly to yield the target ligand (S_C,R_FC,S_C)-3 with retention of enantioselectivity. Ligand (S_C,R_FC,S_C)-3 is air-stable and it could be easily purified by column chromatography, accordingly, ligand (R_C,S_FC,S_C)-3 can be prepared using the same method. The ruthenium complex 4 can be easily prepared by stirring ligand (S_C,R_FC,S_C)-3 and [Ru(benzene)Cl₂]₂ at 90 °C in DMF for 4 hours, and complex 5 can be prepared using the same method.

Scheme 1 Synthetic ligand 3 and complexes 4, 5.

With the ligand and catalyst in hand, we evaluated their efficacy in asymmetric hydrogenation with acetophenone (6a) as a model substrate and ruthenium complex 4 as the catalyst, and the results were depicted in Table 1. Using 0.1 mol% of 4 as the catalyst, t-BuOK as the base and i-PrOH as the solvent, 7a was obtained with 99% yield and 83% ee (entry 1). When i-PrOH was replaced with other solvents such as MeOH, THF and 1,4-dioxane, no target product was detected (entries 2–4). Subsequently, we examined the effect of the base on the reaction. With t-BuONa as the base, 99% yield, and 86% ee were achieved (entry 5). However, when K₂CO₃ or Cs₂CO₃ was used as the base, the target product could not be detected at all (entries 6 and 7). To our delight, when 5 was used as the catalyst, the ee value of the target alcohol was increased to −94% with 99% yield (entry 8). The reaction could not proceed in the absence of base, catalyst or hydrogen (entries 9–11).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Solvent	Base	Yield^b (%)	ee
a Reaction condition: acetophenone 6a (240 mg, 2.0 mmol), solvent (2.0 mL), catalyst (1.8 mg, 0.002 mmol, 0.001 equiv.), t-BuONa (0.02 mmol, 0.01 equiv.), H2 (10 atm), 10 h. b Isolated yields.
1	4	i-PrOH	t-BuOK	99	83
2	4	MeOH	t-BuOK	0	—
3	4	THF	t-BuOK	0	—
4	4	Dioxane	t-BuOK	0	—
5	4	i-PrOH	t-BuONa	99	86
6	4	i-PrOH	K2CO3	0	—
7	4	i-PrOH	Cs2CO3	0	—
8	5	i-PrOH	t-BuONa	99	−94
9	—	i-PrOH	t-BuONa	0	—
10	5	i-PrOH	—	0	—
11	5	i-PrOH	t-BuONa	0	—

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Following the optimal reaction conditions, we then examined the scope of the ruthenium-catalyzed asymmetric hydrogenation (Table 2). For different acetophenone-derived substrates with various substituents on the aromatic ring, the conversion of all substrates was good, with ee values ranging from 83% to 96%. This catalytic system could also tolerate various substituents at the para or meta position of aromatic rings with different electronic properties. Substituted acetophenones bearing electron-donating groups, such as alkyl (7b–7e), dimethylamino (7g), and methylthio (7h), as well as electron-withdrawing groups like fluorine (7j, 7k), chlorine (7l, 7m), and bromine (7n, 7o), were well tolerated. Notably, acetophenone with two substituents (7f), 2-naphthalene ethyl ketone (7i), various derivatives of phenylacetone (7p–7r), 2-methyl-1-phenylpropan-1-one (7s) and cyclohexyl(phenyl)methanone (7t) were also compatible with this reaction. Generally, substrates with electron-donating substituents on aromatic rings or large alkyl substituents resulted in higher enantioselectivities of the products.

Table 2 Scope of ketones^a

a Reaction condition: ketone (2.0 mmol), i-PrOH (2.0 mL), 5 (1.8 mg, 0.002 mmol, 0.001 equiv.), t-BuONa (1.9 mg, 0.02 mmol, 0.01 equiv.), H₂ (10 atm), 10 h, isolated yields.

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To further test the applicability of the catalyst, a range of substituted–unsaturated aryl ketones were evaluated, and the results were depicted in Table 3 (for the detailed optimization of the reaction conditions, see Table S1†). The conversion of all substrates was good, with ee values ranging from 67% to 82% (9a–9g). The introduction of substituents on the aromatic rings had a significant effect on the ee value of the product. Products with methyl (9b) or fluorine (9d) substituents at the para position of the aromatic ring, or chlorine (9e) at the meta position, were generally produced with increased ee. In contrast, the ee values of products with methoxy (9c) or chlorine (9f) substituents at the para position were significantly reduced. The reaction could also tolerate the 2-naphthalene substrate, producing 9g with 93% yield and 82% ee.

Table 3 Scope of α,β-unsaturated ketones^a

a Reaction condition: α,β-unsaturated ketones (0.1 mmol), o-xylene (0.4 mL), 5 (1.8 mg, 0.002 mmol, 0.02 equiv.), DABCO (0.1 mmol, 1.0 equiv.), TMG (0.1 mmol, 1.0 equiv.), H₂ (50 atm) stir for 10 hours, isolated yields. DABCO = triethylenediamine; TMG = tetramethylguanidine.

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In summary, an air-stable chiral ferrocenyl P,P,N,N,O-ligand (R_C,S_FC,S_C)-3 suitable for ruthenium-catalyzed asymmetric hydrogenation has been developed. This ligand combines a chiral bisphosphine ligand and a chiral diamine. Its ruthenium complexes can be prepared by a straightforward one-step method, which is suitable for the asymmetric hydrogenation of simple ketones and α,β-unsaturated aryl ketones, and provides the target chiral alcohols with high yield and moderate to high enantioselectivity.

Author contributions

L. Xu, G.-Q. Chen and X. Zhang devised the project. L. Xu and G.-Q. Chen designed and discussed the experiments; L. Xu performed the experiments, compound characterization and data analysis. L. Xu and G.-Q. Chen prepared the manuscript.

Data availability

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

Conflicts of interest

There are no conflicts of interest to declare.

Acknowledgements

X. Zhang is indebted to the financial support from the National Key R&D Program of China (2021YFA1500200), National Natural Science Foundation of China (No. 21991113), Chemistry and Chemical Engineering Guangdong Laboratory (Grant No. 2011006 and 2132013) and Innovative Team of Universities in Guangdong Province (No. 2020KCXTD016). G.-Q. Chen gratefully acknowledges the National Natural Science Foundation of China (No. 22171129), Shenzhen Science and Technology Innovation Committee (JCYJ20210324104202007) and the Guangdong Basic and Applied Basic Research Foundation (2022B1515020055) for financial support. The authors acknowledge the assistance of SUSTech Core Research Facilities.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4ob01679c

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