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Rapid functionalization of multiple C–H bonds in unprotected alicyclic amines

Abstract

The synthesis of valuable bioactive alicyclic amines containing variable substituents in multiple ring positions typically relies on multistep synthetic sequences that frequently require the introduction and subsequent removal of undesirable protecting groups. Although a vast number of studies have aimed to simplify access to such materials through the C–H bond functionalization of feedstock alicyclic amines, the simultaneous introduction of more than one substituent to unprotected amines has never been accomplished. Here we report an advance in C–H bond functionalization methodology that enables the introduction of up to three substituents in a single operation. Lithiated amines are first exposed to a ketone oxidant, generating transient imines that are subsequently converted to endocyclic 1-azaallyl anions, which can be processed further to furnish β-substituted, α,β-disubstituted, or α,β,α′-trisubstituted amines. This study highlights the unique utility of in situ-generated endocyclic 1-azaallyl anions, elusive intermediates in synthetic chemistry.

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Fig. 1: Selected methods for the β-C–H bond functionalization of alicyclic amines and a new strategy for the multifunctionalization of secondary alicyclic amines.

Data availability

The data that support the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for structures (±)-13a and (±)-13q have been deposited at the Cambridge Crystallographic Data Centre, under deposition nos. 1935815 ((±)-13a) and 1935816 ((±)-13q). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/

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Acknowledgements

Financial support from the NIH–NIGMS (grant no. R01GM101389) is gratefully acknowledged. We thank I. Ghiviriga (University of Florida) for assistance with NMR experiments. Mass spectrometry instrumentation was supported by a grant from the NIH (S10 OD021758-01A1). We further acknowledge the National Science Foundation (grant no. 1828064) and the University of Florida for funding the purchase of the X-ray equipment.

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Contributions

W.C. developed the amine β- and multifunctionalization and explored the scope. A.P. performed initial studies on the amine β-functionalization and α,β-difunctionalization. K.A.A. performed crystallographic analyses for compounds (±)-13a and (±)-13q. D.S. conceived and supervised the project. D.S. and W.C. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Daniel Seidel.

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Supplementary information

Supplementary Information

Materials and methods, evaluation of reaction conditions, characterization data, GCOSY and NOESY analyses, crystallographic summaries and NMR spectra.

Crystallographic data

Crystallographic data of compound (±)-13a. CCDC reference 1935815.

Crystallographic data

Crystallographic data of compound (±)-13q. CCDC reference 1935816.

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Chen, W., Paul, A., Abboud, K.A. et al. Rapid functionalization of multiple C–H bonds in unprotected alicyclic amines. Nat. Chem. 12, 545–550 (2020). https://doi.org/10.1038/s41557-020-0438-z

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