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Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines

Nature volume 618, pages 294–300 (2023)Cite this article

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Abstract

Chiral amines are commonly used in the pharmaceutical and agrochemical industries1. The strong demand for unnatural chiral amines has driven the development of catalytic asymmetric methods1,2. Although the N-alkylation of aliphatic amines with alkyl halides has been widely adopted for over 100 years, catalyst poisoning and unfettered reactivity have been preventing the development of a catalyst-controlled enantioselective version3,4,5. Here we report the use of chiral tridentate anionic ligands to enable the copper-catalysed chemoselective and enantioconvergent N-alkylation of aliphatic amines with α-carbonyl alkyl chlorides. This method can directly convert feedstock chemicals, including ammonia and pharmaceutically relevant amines, into unnatural chiral α-amino amides under mild and robust conditions. Excellent enantioselectivity and functional-group tolerance were observed. The power of the method is demonstrated in a number of complex settings, including late-stage functionalization and in the expedited synthesis of diverse amine drug molecules. The current method indicates that multidentate anionic ligands are a general solution for overcoming transition-metal-catalyst poisoning.

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Fig. 1: Challenges and development of enantioconvergent N-alkylation of aliphatic amines and ammonia for the synthesis of α-chiral aliphatic amines.
Fig. 2: Substrate scope of amines.
Fig. 3: Substrate scope of α-carbonyl alkyl chlorides.
Fig. 4: Synthetic applications and proposed mechanism.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information (experimental procedures and characterization data) and from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/structures; crystallographic data are available free of charge under CCDC reference numbers CCDC 2190243–2190245, 2204330, 2204331 and 2238358).

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Acknowledgements

Financial support from the National Key R&D Program of China (nos. 2021YFF0701604 and 2021YFF0701704), the National Natural Science Foundation of China (nos. 22025103, 92256301 and 21831002), Guangdong Innovative Program (no. 2019BT02Y335), Guangdong Innovative and Entrepreneurial Research Team Program (no. 2021ZT09C278), Guangdong Provincial Key Laboratory of Catalysis (no. 2020B121201002) and Shenzhen Science and Technology Program (nos. KQTD20210811090112004 and JCYJ20200109141001789) is acknowledged. We appreciate the assistance of SUSTech Core Research Facilities.

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  1. These authors contributed equally: Ji-Jun Chen, Jia-Heng Fang, Xuan-Yi Du

Authors and Affiliations

  1. Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, China

    Ji-Jun Chen, Jia-Heng Fang, Xuan-Yi Du, Jia-Yong Zhang, Jun-Qian Bian, Fu-Li Wang, Wei-Long Liu, Ji-Ren Liu, Xiao-Yang Dong, Zhe Dong & Xin-Yuan Liu

  2. Academy for Advanced Interdisciplinary Studies and Department of Chemistry, Southern University of Science and Technology, Shenzhen, China

    Cheng Luan, Zhong-Liang Li & Qiang-Shuai Gu

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Contributions

J.-J.C., J.-H.F. and X.-Y.D. designed the experiments and analysed the data. J.-J.C., J.-H.F., X.-Y.D., J.-Y.Z., J.-Q.B., F.-L.W., C.L., W.-L.L., X.-Y.D. and Z.-L.L. performed the experiments. J.-R.L. performed the theoretical calculations. Q.-S.G., Z.D. and X.-Y.L. wrote the paper. X.-Y.L. conceived and supervised the project.

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Correspondence to Xin-Yuan Liu.

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Extended data figures and tables

Extended Data Fig. 1 Continued scope of amines.

Standard reaction conditions: amine (0.20 mmol), racemic alkyl chloride E1 (1.5 equiv.), CuI (10 mol%), L*4 (15 mol%) and Cs2CO3 (3.0 equiv.) in 1,4-dioxane (4.0 ml) under argon at 45 °C. The yields are isolated. The e.e. values are based on chiral high-performance liquid chromatography analysis. The d.r. value is based on crude 1H NMR analysis. aAmine hydrochloride (0.20 mmol) and Cs2CO3 (4.0 equiv.). bL*5 (15 mol%) in N-methyl-2-pyrrolidone/ethyl acetate (2.8 ml/1.2 ml) at r.t. cL*5 (15 mol%) in N-methyl-2-pyrrolidone/ethyl acetate (2.4 ml/1.6 ml) at r.t. dL*2 (15 mol%). eL*4 (15 mol%). fCuBH4(PPh3)2 (10 mol%), L*5 (15 mol%) in N,N-dimethylformamide/cyclohexane (3.2 ml/0.80 ml) at r.t. gAmine dihydrochloride (0.20 mmol) and Cs2CO3 (5.0 equiv.).

Extended Data Fig. 2 Continued scope of α-carbonyl alkyl chlorides.

Standard reaction conditions: amine (0.20 mmol), racemic alkyl chloride (1.5 equiv.), CuI (10 mol%), L*4 (15 mol%) and Cs2CO3 (3.0 equiv.) in 1,4-dioxane (4.0 ml) under argon at 45 °C. The yields are isolated. The e.e. values are based on chiral high-performance liquid chromatography analysis. The d.r. value is based on crude 1H NMR analysis. aCuBH4(PPh3)2 (10 mol%) and L*5 (15 mol%) in N,N-dimethylformamide/cyclohexane (3.2 ml/0.80 ml) at r.t. bL*7 (15 mol%) in benzene (4.0 ml) at 50 °C. cRacemic alkyl chloride (1.0 equiv.). dAmine hydrochloride (0.20 mmol) and Cs2CO3 (4.0 equiv.). eL*5 (15 mol%). fRacemic alkyl chloride (2.0 equiv.) and L*10 (15 mol%). gL*10 (15 mol%). hCuSCN (10 mol%) and L*8 (15 mol%) in tetrahydrofuran (4.0 ml) at r.t.

Extended Data Fig. 3 Continued Synthetic applications in the late-stage functionalization and the preparation of complex molecules.

a, Modular construction of hybrid chiral amine-containing drug molecules. b, Synthesis of chiral unnatural α-amino carboxamides via late-stage C(sp3)–H functionalization of bioactive carboxylic acid molecules. c, Reduction of 115 to amine 188. d, Conversion of carboxamide 141 to alcohol 188. aRacemic alkyl chloride (1.0 equiv.). bYield of α-chloro amide.

Extended Data Fig. 4 Summary table for rapid identification of the desired chiral ligand and reaction conditions for enantioconvergent copper-catalyzed N-alkylation of aliphatic amines.

This copper-catalyzed N-alkylation reaction has excellent scopes for both the alkyl halide and the amine parts; however different types of ligands were still required to achieve high enantioselectivity and reactivity. Generally speaking, alkyl halides predominantly determined the ligand choice; by contrast, amines had limited impact on the ligand choice. Specifically, small secondary alkyl chlorides such as 2-chloropropanamide required sterically congested ligand L*4 or L*5 for good enantioselectivity. For bulkier secondary alkyl chlorides with large α-alkyl or -aryl substituents, sterically less congested tridentate ligand L*7 or L*10 or bidentate ligand L*8 performed the best. Regarding the bulkiest tertiary alkyl chlorides, planar tridentate ligand L*9 with a likely more opened catalyst pocket was necessary for maintaining good reaction efficiency and enantioselectivity. Within the same series of alkyl chlorides, minor ligand changes such as from L*4 or L*7 to L*5 or L*10, respectively, might deliver slightly boosted enantioselectivity.

Extended Data Fig. 5 Mechanistic experiments.

a, Synthesis of copper(II) complex C1 from L*7 and its X-ray structure. b, Complex C1 exhibited comparable catalytic activity with that in situ generated from CuI and L*7. c, EPR and HRMS experimental results indicated the formation of 190 from DMPO and the corresponding alkyl radical. d, In addition to the N-alkylation product 191, the radical clock substrate E46 also delivered 192-d1, likely via radical cyclopropane ring opening and subsequent deuterium atom abstraction from THF-d8. e, In the absence of amine nucleophiles, E1 was still completely consumed to afford the β-elimination product 1′ in high yield. f, By contrast, E40 bearing no β-hydrogen atoms gave rise to 193-d1, likely via the formation of the corresponding alkyl radical and its subsequent deuterium atom abstraction from THF-d8. g, A12 underwent highly chemoselective amine N-alkylation and sulfoximine C–N cross-coupling under the current and previously reported conditions, respectively, indicating strikingly different reaction mechanisms. DCM, dichloromethane. EPR, electron paramagnetic resonance. Calc., calculated. ESI, electrospray ionization. HRMS, high-resolution mass spectroscopy. DMPO, 5,5-dimethyl-1-pyrroline N-oxide. THF-d8, tetrahydrofuran. Tol, p-toluenyl. HFacac, hexafluoroacetylacetonate.

Supplementary information

Supplementary Information

Additional condition optimization results, experimental and theoretical mechanistic results, detailed experimental procedures, compound characterization, nuclear magnetic resonance spectra, and chiral high-performance liquid chromatography analysis.

Supplementary Data 1

CIF file of compound 1 (CCDC no. 2190245).

Supplementary Data 2

CIF file of compound 98 (CCDC no. 2190244).

Supplementary Data 3

CIF file of compound 121 (CCDC no. 2238358).

Supplementary Data 4

CIF file of compound C1 (CCDC no. 2190243).

Supplementary Data 5

CIF file of compound L4·TfOH (CCDC no. 2204330).

Supplementary Data 6

CIF file of compound L7 (CCDC no. 2204331).

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Chen, JJ., Fang, JH., Du, XY. et al. Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines. Nature 618, 294–300 (2023). https://doi.org/10.1038/s41586-023-05950-8

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