Photoinduced, Copper-Catalyzed Decarboxylative C–N Coupling to Generate Protected Amines: An Alternative to the Curtius Rearrangement

Abstract

The Curtius rearrangement is a classic, powerful method for converting carboxylic acids into protected amines, but its widespread use is impeded by safety issues (the need to handle azides). We have developed an alternative to the Curtius rearrangement that employs a copper catalyst in combination with blue-LED irradiation to achieve the decarboxylative coupling of aliphatic carboxylic acid derivatives (specifically, readily available N-hydroxyphthalimide esters) to afford protected amines under mild conditions. This C–N bond-forming process is compatible with a wide array of functional groups, including an alcohol, aldehyde, epoxide, indole, nitroalkane, and sulfide. Control reactions and mechanistic studies are consistent with the hypothesis that copper species are engaged in both the photochemistry and the key bond-forming step, which occurs through out-of-cage coupling of an alkyl radical.

Decarboxylative C(sp3)–N cross-coupling via synergetic photoredox and copper catalysis

“…Extension to a decarboxylative carbon-heteroatom, particularly C-B bond formation has also been reported 19,[25][26][27][28][29] . The key attributes of alkyl carboxylic acids 30,31 are their unparalleled availability, stability and non-toxic nature, which are in stark contrast with alkyl halides, ketones and aldehydes.…”

“…A notable exception is the light-induced, copper-catalysed C-N coupling of alkyl halides recently developed [16][17][18] . Nevertheless, the scope of amine nucleophiles is limited to carbazoles 16,18 and amides 17,19 . Alternative, formal C-N coupling of alkyl electrophiles via the addition of alkyl radicals to nitroarenes has been reported 20,21 .…”

“…The key attributes of alkyl carboxylic acids 30,31 are their unparalleled availability, stability and non-toxic nature, which are in stark contrast with alkyl halides, ketones and aldehydes. While several precedents of decarboxylative imidation 32 and amination 19,33 are known, they are limited to a narrow scope of very special substrates or intramolecular reactions. A general metal-catalysed decarboxylative C-N coupling of redox-active esters with anilines will provide valuable methodology for the synthesis of alkylated anilines (Fig.…”

Visible‐Light‐Driven, Copper‐Catalyzed Decarboxylative C(sp3)−H Alkylation of Glycine and Peptides

“…[3] In 2016, the group of Baran pioneered ag eneral alkyl-alkyl cross-coupling using alkyl NHP esters,w hich provided new opportunities for choosing alkyl electrophiles in C(sp 3 )ÀC(sp 3 )b ond formations (Figure 1a). [6] Thed irect alkylation of C(sp 3 )ÀHp rovides ac onvenient alternative for C(sp 3 )ÀC(sp 3 )c ross-coupling.V ery recently, the photoinduced alkylation of C(sp 3 )ÀHw as developed by the groups of MacMillan [7] and Yu, [8] using either alkyl bromides or benzyl chlorides as electrophiles.MacMillan and co-workers also reported its applications in alkylated modification of peptides and pharmaceutical compounds. [6] Thed irect alkylation of C(sp 3 )ÀHp rovides ac onvenient alternative for C(sp 3 )ÀC(sp 3 )c ross-coupling.V ery recently, the photoinduced alkylation of C(sp 3 )ÀHw as developed by the groups of MacMillan [7] and Yu, [8] using either alkyl bromides or benzyl chlorides as electrophiles.MacMillan and co-workers also reported its applications in alkylated modification of peptides and pharmaceutical compounds.…”

“…[7] In the reactions,t he precious transition-metal photocatalysts,f or example,I ro rP d, were used to mediate the single-electron transfer. [6] Despite this achievement, the visible-light-induced Cu-catalyzed intermolecular decarboxylative C(sp 3 )ÀC(sp 3 )c ross-coupling,e specially the C(sp 3 )ÀHa lkylation, has still not been realized. [9] In 2017, Fu and coworkers reported the first visible-light-induced Cu-catalyzed intramolecular C(sp 3 ) À Nc oupling by the decarboxylation of an alkyl NHP ester (Figure 1b).…”