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

Abstract

A mines are one of the most important structural motifs in pharmaceuticals, agrochemicals and organic materials 1,2 . Alkylation and reductive amination reactions are still commonly used to prepare and modify amines, and new methods derived from reductive amination, such as the borrowing hydrogen 3 strategy, have been reported [4][5][6][7] . Nevertheless, the most significant development in amine synthesis has been transition-metal-catalysed C-N coupling of aryl electrophiles (halides and pseudo halides) with amine nucleophiles [8][9][10][11] (Fig. 1a). The C-N coupling of alkyl electrophiles, however, is largely under-developed (Fig. 1a). A perceived difficulty is β -hydrogen elimination from a metal alkyl intermediate originated from oxidative addition of the alkyl electrophile, which has posed considerable challenges in analogous C-C crosscoupling of alkyl electrophiles [12][13][14] . Moreover, the product-yielding C(sp 3 )-N reductive elimination step is rarely demonstrated 15 . 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 group of Baran has recently trailblazed the use of redox-active esters derived from alkyl carboxylic acids as superior surrogates of alkyl halides in decarboxylative C-C cross-coupling reactions [22][23][24] . 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. 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. 1b), which requires alkyl halides and carbonyl compounds 6 as starting reagents using the currently standard methods of alkylation and reductive amination, respectively. Further foreseen advantages of such a decarboxylative amination include applicability to bulky primary and secondary alkyl groups and immunity to over-alkylation, both of which are major limitations of direct alkylation (Fig. 1b). Despite its conceptual simplicity and resemblance to decarboxylative C-C coupling, the intermolecular decarboxylative C-N coupling of redoxactive esters poses significant hurdles. The activation principle of redox-active esters originates from amide-bond synthesis; thus, amide formation can compete when amine nucleophiles are used. Moreover, decarboxylative C-C coupling reactions of redox-active esters were, until now, all init...

Direct Catalytic Decarboxylative Amination of Aryl Acetic Acids

“…We selected piperidine as at arget amine nucleophile for catalytic oxidative benzylation because of the inability of established photoredox methods to engage this class of substrate. [12,13] Thec arboxylate 1 underwent direct decarboxylative amination promoted by CuI/MnO 2 mixtures under operationally simple conditions to give the benzylic amine product 2 in 92 %y ield ( Figure 3A). Thef ree acid could be used instead of the potassium carboxylate by adding K 2 CO 3 , with no change in efficiency( 94 %y ield).…”

“…[18c] Under the optimized reaction conditions,ah ost of alkyl amine nucleophiles and electron-poor aryl acetic acids can be decarboxylatively cross-coupled ( Figure 4). Both cyclic and acyclics econdary amines,i na ddition to primary amines, undergo benzylation in moderate to excellent yields (2,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”

“…To investigate the possibility of decarboxylation by CÀ CO 2 homolysis to generate ar adical intermediate, [24] the alkene functionalized substrate 59 was subjected to the standard Cu-catalyzed conditions.O nly direct amination (60,6 4% yield) and protodecarboxylation (61,2 7%)w ere observed. In contrast to photoredox-mediated pathways involving alkyl radical intermediates, [12,13] no cyclized products were obtained ( Figure 6A).…”

“…Included are examples of amines featuring unprotected alcohol groups (11,21,24), various potentially reactive amide or aniline groups (12)(13)(14)16), and electrophilic or potentially oxidizable groups (15,18). When primary amine substrates were used, bis-alkylation was not observed, enabling facile isolation of the alkylated products (22)(23)(24)(25).…”

“…[10] Existing methods for intermolecular decarboxylative cross-coupling of carboxylic acids and NH nucleophiles to generate C(sp 3 )ÀNb onds require stoichiometric activation of the acid. These approaches include Curtius-type rearrangements [11] and photoredox-mediated coupling of Nhydroxyphthalimide esters [12] and iodonium carboxylates [13] ( Figure 1B). Thei socyanate intermediates generated in Curtius-type rearrangements [11a] may be incompatible with nucleophilic functional groups,a nd photoredox-mediated processes are limited to weakly nucleophilic substrates like imides, [12a] anilines, [12b,13a] sulfonamides, [13] and select N-heterocycles.…”