Abstract
In view of the high propensity of tertiary alkyl amines to be bioactive, the development of new methods for their synthesis is an important challenge. Transition-metal catalysis has the potential to greatly expand the scope of nucleophilic substitution reactions of alkyl electrophiles; unfortunately, in the case of alkyl amines as nucleophiles, only one success has been described so far: the selective mono-alkylation of primary amines to form secondary amines. Here, using photoinduced copper catalysis, we report the synthesis of tertiary alkyl amines from secondary amines and unactivated alkyl electrophiles, two readily available coupling partners. Utilizing an array of tools, we have analysed the mechanism of this process; specifically, we have structurally characterized the three principal copper-based intermediates that are detected during catalysis and provided support for the key steps of the proposed catalytic cycle, including the coupling of a copper(II)–amine intermediate with an alkyl radical to form a C–N bond.
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Data availability
The data that support the findings of this study are available within the Article and its Supplementary Information (experimental procedures and characterization data). Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2346103 (20), 2346099 (23), 2346098 (26), 2346097 (28), 2346096 (34), 2346086 (A, PCuI(OPh)), 2346089 (G, PCuI(MSA), 2346084 ([(MSA)CuII(OPh)]4), 2346093(H, [(MSA)(HR2N)CuII(μ-OPh)]2), 2346085 (E1, (MSA)CuII(OAr1)(NR2H)2), 2346102 ([(MSA)CuII(OAr1)]2), 2346100 ((MSA)2CuII(NR2H)), 2346094 ((MSA)2CuII(NR12H)) and 2346095 ((MSA)2CuII(NR12H)2). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/ (or from Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, United Kingdom; fax: +44-1223-336-033; email: [email protected]).
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Acknowledgements
Support has been provided by the National Institutes of Health (National Institute of General Medical Sciences: R35–GM145315, Fu group), the Korea Foundation for Advanced Studies (graduate research fellowship to H.C.), the Swiss National Science Foundation (grant P2SKP2_191321 to G.Z.), the Beckman Institute at Caltech, the Dow Next-Generation Educator Fund (grant to Caltech) and Takasago International Corporation. We thank J. C. Peters, R. G. Hadt, P. H. Oyala (EPR Facility), M. K. Takase (X-ray Crystallography Facility), D. VanderVelde (NMR Facility), S. C. Virgil (Center for Catalysis and Chemical Synthesis), J. R. Winkler (Laser Resource Center), W. W. Brennessel (Mass Spectrometry Resource Laboratory), C. Chen, F. Schneck, S. Alabugin, D. A. Cagan, P. Garrido Barros, V. Hubble, C. M. Johansen, A. N. Kim, L. N. V. Le and M. Li for technical assistance and helpful discussions.
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Contributions
H.C. discovered and optimized the reaction, investigated its scope and performed mechanistic studies. X.T. investigated the scope of the reaction and optimized the three-component coupling. G.Z. investigated the scope of the reaction. R.L.A. performed density functional theory (DFT) calculations. All authors actively participated in writing the manuscript and contributed to the analysis and interpretation of the results.
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Supplementary information
Supplementary Information
Supplementary Figs. 1–28 and Tables 1–9.
Supplementary Data 1
Cartesian coordinates of calculated structures.
Supplementary Data 2
Crystallographic data for compound 20; CCDC reference 2346103.
Supplementary Data 3
Crystallographic data for compound 23; CCDC reference 2346099.
Supplementary Data 4
Crystallographic data for compound 26; CCDC reference 2346098.
Supplementary Data 5
Crystallographic data for compound 28; CCDC reference 2346097.
Supplementary Data 6
Crystallographic data for compound 34; CCDC reference 2346096.
Supplementary Data 7
Crystallographic data for compound A, PCuI(OPh); CCDC reference 2346086.
Supplementary Data 8
Crystallographic data for compound G, PCuI(MSA); CCDC reference 2346089.
Supplementary Data 9
Crystallographic data for compound [(MSA)CuII(OPh)]4; CCDC reference 2346084.
Supplementary Data 10
Crystallographic data for compound H, [(MSA)(HR2N)CuII(μ-OPh)]2; CCDC reference 2346093.
Supplementary Data 11
Crystallographic data for compound E1, (MSA)CuII(OAr1)(NR2H)2; CCDC reference 2346085.
Supplementary Data 12
Crystallographic data for compound [(MSA)CuII(OAr1)]2; CCDC reference 2346102.
Supplementary Data 13
Crystallographic data for compound (MSA)2CuII(NR2H); CCDC reference 2346100.
Supplementary Data 14
A CIF file for compound (MSA)2CuII(NR12H); CCDC reference 2346094.
Supplementary Data 15
A CIF file for compound (MSA)2CuII(NR12H)2; CCDC reference 2346095.
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Cho, H., Tong, X., Zuccarello, G. et al. Synthesis of tertiary alkyl amines via photoinduced copper-catalysed nucleophilic substitution. Nat. Chem. 17, 271–278 (2025). https://doi.org/10.1038/s41557-024-01692-w
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DOI: https://doi.org/10.1038/s41557-024-01692-w
