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. 2020 May 11;59(20):7921-7927.
doi: 10.1002/anie.201916710. Epub 2020 Mar 17.

Visible-Light-Enabled Direct Decarboxylative N-Alkylation

Vu T Nguyen  1 , Viet D Nguyen  1 , Graham C Haug  1 , Ngan T H Vuong  1 , Hang T Dang  1 , Hadi D Arman  1 , Oleg V Larionov  1
Affiliations

Visible-Light-Enabled Direct Decarboxylative N-Alkylation

Vu T Nguyen et al. Angew Chem Int Ed Engl. .

Abstract

The development of efficient and selective C-N bond-forming reactions from abundant feedstock chemicals remains a central theme in organic chemistry owing to the key roles of amines in synthesis, drug discovery, and materials science. Herein, we present a dual catalytic system for the N-alkylation of diverse aromatic carbocyclic and heterocyclic amines directly with carboxylic acids, by-passing their preactivation as redox-active esters. The reaction, which is enabled by visible-light-driven, acridine-catalyzed decarboxylation, provides access to N-alkylated secondary and tertiary anilines and N-heterocycles. Additional examples, including double alkylation, the installation of metabolically robust deuterated methyl groups, and tandem ring formation, further demonstrate the potential of the direct decarboxylative alkylation (DDA) reaction.

Keywords: amination; carboxylic acids; copper catalysis; photocatalysis; visible light.

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Figures

Figure 1.
Figure 1.
Decarboxylative N-alkylation of anilines.
Figure 2.
Figure 2.
Mechanistic studies of the DDA reaction.
Scheme 1.
Scheme 1.
Scope of the direct decarboxylative N-alkylation. Method A: aniline (0.3 mmol), carboxylic acid (0.75 mmol), A1 (10 mol%), Cu(hfac)2 (10 mol%), DTBP (0.6 mmol), EtOAc (4.5 mL), LED (400 nm). Method A was used unless otherwise specified. [a] Carboxylic acid (1.5 mmol). [b] DCP (0.45 mmol). [c] Method B: aniline (0.75 mmol), carboxylic acid (0.3 mmol), A1 (10 mol%), Cu(hfac)2 (10 mol%), DTBP (0.6 mmol), EtOAc (4.5 mL), LED (400 nm). [d] PhCF3 (4.5 mL). [e] A2 (10 mol%). [f] A1 (15 mol%).
Scheme 2.
Scheme 2.
N-Alkylation of heteroaromatic amines.
Scheme 3.
Scheme 3.
N-Alkylation of natural products and drugs.
Scheme 4.
Scheme 4.
N-Trideuteromethylation by DDA with AcOH-d4.
Scheme 5.
Scheme 5.
One-step access to N-arylpyrrolidine by DDA with acid 99.
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