Transition‐Metal‐Catalyzed Alkylations of Amines with Alkyl Halides: Photoinduced, Copper‐Catalyzed Couplings of Carbazoles

Bissember, Alex C.; Lundgren, Rylan J.; Creutz, Sidney E.; Peters, Jonas C.; Fu, Gregory C.

doi:10.1002/anie.201301202

Cited by 213 publications

(105 citation statements)

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“…Indeed, in the field of asymmetric synthesis as a whole, highly stereoselective reactions of tertiary electrophiles are relatively uncommon, despite the fact that fully substituted carbons are a common motif in organic molecules (19). We anticipated that the radical mechanism that we have postulated for C–X bond cleavage in the presence of copper and light (vide infra) (13,14) might enable us to surmount this challenge, because a single, comparatively stable tertiary radical could be formed from a racemic mixture of electrophiles (Fig. 1B).…”

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“…Indeed, the previously described methods for photoinduced, copper-catalyzed N-alkylation had employed CuI as a pre-catalyst with no added ligand (13,14). …”

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“…2A, entry 1). In contrast to our earlier studies of photoinduced, copper-catalyzed N-alkylations, this process operates under visible light from a blue LED (rather than an ultraviolet source) and at relatively low catalyst loading (1.0 mol% rather than 10 mol%); a catalyst loading of 0.25 mol% led to only a modest loss in yield and no erosion in ee (entry 2: ~300 turnovers; previously, the highest turnover number for a photoinduced, copper-catalyzed N-alkylation was ~9) (13,14). …”

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Asymmetric copper-catalyzed C-N cross-couplings induced by visible light

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Bartoszewicz

et al. 2016

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Despite a well-developed and growing body of work in copper catalysis, the potential of copper to serve as a photocatalyst remains underexplored. Herein, we describe a photoinduced, copper-catalyzed method for coupling readily available racemic tertiary alkyl chloride electrophiles with amines to generate fully substituted stereocenters with high enantioselectivity. The reaction proceeds at –40 °C under excitation by a blue light-emitting diode and benefits from the use of a single, Earth-abundant transition metal acting as both the photocatalyst and the source of asymmetric induction. An enantioconvergent mechanism transforms the racemic starting material into a single product enantiomer.

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“…Indeed, the previously described methods for photoinduced, copper-catalyzed N-alkylation had employed CuI as a pre-catalyst with no added ligand (13,14). …”

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confidence: 99%

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Asymmetric copper-catalyzed C-N cross-couplings induced by visible light

Kainz

Matier

Bartoszewicz

et al. 2016

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“…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 .…”

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“…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 .…”

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

et al. 2018

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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...

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