Ir-catalyzed reductive amination and transfer hydrogenation of diketones: access to β- and γ-amino alcohols

Abstract

β- and γ-Amino alcohols are among the most significant structural motifs in pharmacologically active molecules and pharmaceuticals. Herein, a protocol for the construction of β- and γ-amino alcohols via reductive amination and transfer hydrogenation of diketones with aromatic amines is described. This reaction is performed by utilizing iridium complexes as catalysts and HCO₂H as a hydrogen donor to deliver a library of β- and γ-amino alcohols under mild and operationally simple conditions. Successful scale-up performance was also conducted under standard conditions.

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β- and γ-Amino alcohol backbones are extensively found in pharmacologically active molecules and pharmaceutical compounds. Amino alcohols also serve as key intermediates of various pharmacophores in medicine, cosmetics, materials science, organic synthesis and medicinal chemistry.¹ For instance, metaraminol is frequently employed as a rescue drug in patients with shock, chloramphenicol shows potent antibacterial activity against Gram-negative bacteria, and indinavir and adrenaline are used to treat HIV-1 infections in adults and children (Scheme 1).² Amino alcohols also serve as ligands in the field of catalytic organic synthesis.³ Therefore, it is of great significance to develop a new universal, atomic and step-economical strategy for the synthesis of amino alcohols in the rapid development of innovative drugs.⁴

Scheme 1 β- and γ-Amino alcohol motifs existing in biologically active molecules.

Ring-opening aminolysis of epoxides represents one of the classical strategies for constructing β-amino alcohols. Scandium,⁵ niobium,⁶ gadolinium,⁷ chromium,⁸ and organic molecules⁹ are employed as catalysts for the construction of β-amino alcohols. In addition, the Ru-catalyzed hydrogenation of α-amino ketones constitute an alternative effective strategy for β-amino alcohol synthesis.¹⁰ In 2019, Zhong's group reported a highly efficient Rh-catalyzed hydroxylation of alkenes to access β-amino alcohol compounds.¹¹ In addition, the radical domino reaction¹² and N-alkylation of amines with alcohols¹³ were employed for β-amino alcohol synthesis.

The hydrogenation of β-amino ketones¹⁴ could also be employed for γ-amino alcohol synthesis.¹⁵ In 2015, Zhang's group successfully reported the ruthenium complex-catalyzed hydrogenation of β-amino ketones to produce γ-amino alcohols.¹⁶ Furthermore, the hydroamination of allyl ketones¹⁷ and alcohols,¹⁸ ring-opening of epoxides with amines,² oxidative amination of alkenes,¹⁹ addition or reduction of amino aldehydes or ketones,²⁰ addition of an amino-carbon anion to a carbonyl compound,²¹ and the amine-allylation of alcohols²² were utilized as effective strategies for the formation of γ-amino alcohols. Although many encouraging achievements have been made in the synthesis of chiral β- and γ-amino alcohols, there are still some deficiencies in the substrate scope. Therefore, employing the easily accessible materials as substrates is still highly desirable for the production of β- and γ-amino alcohols.

In recent years, we have studied transfer hydrogenation reactions using N,N-iridium complexes as catalysts.²³ Recently, Kuwata et al. developed an efficient asymmetric reductive amination of α-keto acids to access α-amino acids catalyzed by Cp*Ir catalysts bearing a chiral N-(2-picolyl)sulfonamidato ligand.²⁴ Very recently, we also reported the protocol for N-aryl-substituted pyrrolidine synthesis via Ir-catalyzed successive reductive amination of diketones (Scheme 2a).²⁵ Based on the successful formation of five-membered pyrrolidines with 2,5-diketones as substrates, the construction of four-membered or even the three-membered heterocyclic ring was also designed using 2,4-diketones or 2,3-diketones as substrates. However, this only produced β- and γ-amino alcohols, and no desired cyclic products were formed under standard conditions. Herein, we report on an Ir-catalyzed reductive amination and transfer hydrogenation of 2,4-diketones or 2,3-diketones to access β- and γ-amino alcohols (Scheme 2b). Various 2,4-diketones or 2,3-diketones and aromatic amines could be employed as substrates in this catalytic system, delivering the desired amino alcohols in moderate to excellent yields. This Ir-catalyzed reductive amination and transfer hydrogenation process offers an alternative protocol for β-and γ-amino alcohol synthesis.

Scheme 2 Ir-catalyzed difunctionalization of diketones.

We initiated our attempts at this Ir-catalyzed reductive amination and transfer hydrogenation of 2,3-butanedione (1a) with aniline (2a) as model substrates (Table 1). Preliminary reaction condition screens with TC-1–TC-6 as catalysts and 20.0 equivalent of HCO₂H as the hydrogen donor in the presence of toluene afforded the β-amino alcohol 3aa in low yields (Table 1, entries 1–6). Based on our previous work^21,22 showing that the reaction media would enhance the solubility of iridium complexes, we then investigated the influence of solvents (Table 1, entries 7–12). As anticipated, an increased yield of 80% was attained in the presence of H₂O (Table 1, entry 12). To afford the optimal conditions, different quantities of HCO₂H and other reaction times were further explored (Table 1, entries 13–19). Indeed, increasing the loading of HCO₂H and prolonging the reaction time furnished the best yield of 93% (Table 1, entry 19). Decreasing the reaction temperature showed reduced performance (Table 1, entries 20–22). Control studies confirmed the necessity of the iridium complex and HCO₂H for this reductive amination and transfer hydrogenation transformation (Table 1, entries 23 and 24).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Solvent	T (°C)	HCO2H (equiv.)	Time (h)	Yield^b (%)
a Reaction conditions: a mixture of 1a (0.5 mmol, 1.0 equiv.), 2a (0.6 mmol, 1.1 equiv.), TC catalyst (1.0 mol%), HCO2H, and solvent (2.0 mL) was sealed in a 25.0 mL Schlenk tube under air.b Yield was determined by NMR with dimethyl terephthalate as internal standard.c Parenthesis is isolated yield based on 1a.
1	TC-1	Toluene	80	20	6	10
2	TC-2	Toluene	80	20	6	11
3	TC-3	Toluene	80	20	6	3
4	TC-4	Toluene	80	20	6	15
5	TC-5	Toluene	80	20	6	14
6	TC-6	Toluene	80	20	6	4
7	TC-4	DMF	80	20	6	27
8	TC-4	1,4-Dioxane	80	20	6	n.d.
9	TC-4	THF	80	20	6	n.d
10	TC-4	MeOH	80	20	6	54
11	TC-4	Acetone	80	20	6	n.d
12	TC-4	H2O	80	20	6	80
13	TC-4	H2O	80	5	6	45
14	TC-4	H2O	80	10	6	54
15	TC-4	H2O	80	15	6	72
16	TC-4	H2O	80	25	6	83
17	TC-4	H2O	80	30	6	83
18	TC-4	H2O	80	25	9	90
19	TC-4	H2O	80	25	12	99 (93%)^c
20	TC-4	H2O	rt	25	12	87
21	TC-4	H2O	60	25	12	97
22	TC-4	H2O	100	25	12	99
23	—	H2O	80	25	12	—
24	TC-4	H2O	80	—	12	—

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With the optimized reaction conditions in hand, we next probed the generality of the substrate scope. As showed in Table 2, 2,3-butanedione (1a) was capable of reductive amination with electron-withdrawing and electron-donating para-substituted aromatic amines (2b–2f) and transfer hydrogenation under standard conditions, furnishing the β-amino alcohol products 3ba–3fa in moderate yields and stereoselectivities. Meta-, ortho-, and di-substituted aromatic amines (2g–2i) also participated, producing the corresponding β-amino alcohols 3ga–3ia in similar moderate yields and stereoselectivities. Large block amines such as naphthylamine (2j), 4-cyclohexyl aniline (2k), and 5,6,7,8-tetrahydronaphthalen-2-amine (2l) were also tolerated in this catalytic system, providing the desirable reductive amination and transfer hydrogenation products of 3ja–3la. On the other hand, the more steric hindrance of 2,3-hexanedione (1b) gave same moderate yield and stereoselectivity of the corresponding product (3ab). Interestingly, aromatic diketone of 1-phenylpropane-1,2-dione (1c) was also a successful substrate, and showed improved stereoselectivity (anti/syn > 99 : 1) and excellent regioselectivity.

Table 2 Substrate scope of the Ir-catalyzed reductive amination and transfer hydrogenation of 2,3-diketones with aromatic amines^a,b,c

a Reaction conditions: a mixture of 1 (0.5 mmol, 1.0 equiv.), 2 (0.6 mmol, 1.1 equiv.), TC-4 (1.0 mol%), HCO₂H (12.5 mmol, 25.0 equiv.), and H₂O (2.0 mL) were sealed in a 25.0 mL Schlenk tube under air at 80 °C for 12 h.b Isolated yield based on 1.c The value of the anti/syn ratio.

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We next investigated the substrate scope with respect to the 1,3-diketones with aromatic amines (Table 3). The γ-amino alcohol of 4-(phenylamino)pentan-2-ol could also be prepared through this method (75% yield) using pentane-2,4-dione (4a) as the substrate. Moreover, para-substituted aromatic amines (2b–2f) could also be used in the reaction. However, products of 5da–5fa were formed in lower yields (32–42%) when the para-substituted aromatic amines bearing electron-withdrawing groups were used (2d–2f). A low yield was also observed for a meta-benzyl substituted aniline (2m). Pleasingly, 62% yield and moderate stereoselectivity of reductive amination and transfer hydrogenation product 5na were provided when 2,3-dihydro-1H-inden-5-amine (2n) was used in this reaction. Other aromatic and sterically more hindered diketones were also tolerated to produce 5ab and 5ac in moderate yields and excellent stereoselectivity (>99 : 1).

Table 3 Substrate scope of Ir-catalyzed reductive amination and transfer hydrogenation of 2,4-diketones with aromatic amines^a,b,c

a Reaction conditions: a mixture of 4 (0.5 mmol, 1.0 equiv.), 2 (0.6 mmol, 1.1 equiv.), TC-4 (1.0 mol%), HCO₂H (12.5 mmol, 25.0 equiv.), and H₂O (2.0 mL) were sealed in a 25.0 mL Schlenk tube under air at 80 °C for 12 h.b Isolated yield based on 4.c The value of the anti/syn ratio.

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The robustness of this Ir-catalyzed reductive amination and transfer hydrogenation transformation was documented by performing the model reaction on a larger scale. As showcased in Scheme 3, 1.37 g of the product 3aa was afforded in 83% yield when 2,3-butanedione (1a) was loaded at a 10.0 mmol scale under standard conditions. With this successful large-scale performance, the follow-up asymmetric studies using chiral iridium complexes are underway and will be reported soon. In addition, the asymmetric Ir-catalyzed reduction amination of ketones with the model reaction was investigated under the optimized conditions (Scheme S1, ESI†). The desired reductive product 3aa was obtained using the chiral iridium complexes C1–C6 as catalysts, while a low enantioselectivity of the product was observed. The design and synthesis of more chiral iridium complexes are underway, and will be further applied in the asymmetric synthesis.

Scheme 3 Large-scale synthesis of 3aa.

The proposed catalytic cycle of this Ir-catalyzed reductive amination and transfer hydrogenation is showcased in Scheme 4. On the one hand, the active Ir–H intermediate of Int-II was formed under the conditions of the iridium complex and HCO₂H. On the other hand, the intermediate of imidone 6 was generated, which was subsequently reduced by Int-II to form the amino ketone 7. A more similar reduction of carbonyl by the active Ir–H was performed to furnish the desired product 5 and finish the catalytic cycle. Of note, it is possible that the transfer hydrogenation of the carbonyl group took place first, followed by the reductive amination process.

Scheme 4 Proposed mechanism.

Conclusions

In summary, we report the reductive amination and transfer hydrogenation of diketones enabled by iridium complexes, facilitating access to diverse β- and γ-amino alcohols in moderate yields and stereoselectivities. The 2,3-diketones, 2,4-diketones and various substituted aromatic amines could be successfully employed in this system. The synthetic potential of this protocol was solidified by the large-scale performance.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Fundamental Research Funds for Gannan Medical University (QD202019, QD202106, TD202310), and the Ganzhou Bureau of Science and Technology (2022-YB1402).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4ra07386j

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