Copper-catalyzed dehydrogenative γ-C(sp3)-H amination of saturated ketones for synthesis of polysubstituted anilines

Abstract

Metal-catalyzed β -C-H functionalization of saturated carbonyls via dehydrogenative desaturation proved to be a powerful tool for simplifying synthesis of valuable β -substituted carbonyls. Here, we report a copper-catalyzed dehydrogenative γ -C(sp 3 )-H amination of saturated ketones that initiates the three-component coupling of saturated ketones, amines and N -substituted maleimides to construct polysubstituted anilines. The protocol presented herein enables both linear and α -branched butanones to couple a wide spectrum of amines and various N -substituted maleimides to produce diverse tetra- or penta-substituted anilines in fair-to-excellent yields with good functional group tolerance. The mechanism studies support that this ketone dehydrogenative γ -C(sp 3 )-H amination was triggered by the ketone α,β -dehydrogenation desaturation that activates the adjacent γ -C(sp 3 )-H bond towards functionalization. This α,β -dehydrogenation desaturation-triggered cascade sequence opens up a new avenue to the remote C(sp 3 )-H functionalization of saturated ketones and has the potential to enable the rapid syntheses of complex compounds from simple starting materials.

1,2‐Aryl Migration Induced by Amide C−N Bond‐Formation: Reaction of Alkyl Aryl Ketones with Primary Amines Towards α,α‐Diaryl β,γ‐Unsaturated γ‐Lactams

“…This result indicates that a Cu catalyst may not be responsible for 1,2‐aryl migration event, which is supported by the fact that a chiral pyridine oxazoline ligand gave no diastereoselectivity in the reaction of 2‐(3‐bromophenyl)‐1‐(4‐(tert‐butyl)phenyl)butan‐1‐one with chiral ( S )‐1‐cylohexylethan‐1‐amine, similar to the reaction outcome with nonchiral bipyridine ligand. Our previous work confirmed that γ‐keto enal resulted from oxygenation of γ‐C−H of enone [10] . These experiments shed light on the possible intermediate products in the cascade reaction of α‐aryl‐substituted alkyl aryl ketone with primary amine.…”

“…In light of such a potential reaction diversity, these dehydrogenative desaturation‐triggered cascade reactions promisingly complement the regular metal‐catalyzed direct C(sp 3 )‐H functionalization reactions [9] by generating the formal C−H functionalization products that are not easy to access by way of other approaches. To date, the vast majority of the established dehydrogenative desaturation‐triggered cascade reactions of carbonyl compounds have focused on the β‐functionalization reactions, and the examples of the dehydrogenative desaturation‐triggered cascade towards the remote C−H functionalization of carbonyl compounds have been extremely scarce [7c, 10] . Our recent investigations on the metal‐catalyzed dehydrogenative desaturation‐triggered cascade reactions of ketones have uncovered that α,β‐desaturation of ketone leads to the activation of γ‐Csp 3 −H bond [11] .…”

“…(1)]. Interestingly, our previous work demonstrated that the dehydrogenation‐triggered cascade reaction of α‐aryl‐substituted alkyl aryl ketones with secondary amines produced 2‐amino furan, [10] reflecting the dependence of chemoselectivity on the substrate identity [Scheme 1 c, Eq. (2)].…”

“…Our previous work confirmed that g-keto enal resulted from oxygenation of g-C À H of enone. [10] These experiments shed light on the possible intermediate products in the cascade reaction of a-arylsubstituted alkyl aryl ketone with primary amine. In light of these results, a plausible reaction pathway is proposed for this cascade reaction (Scheme 4 d).…”

Copper‐Catalyzed Cross‐Dehydrogenative Coupling Reactions

“…The mechanism involves Chan-Lam arylation between arylboronic acid 302 and ester (Z)-3-aminoacrylates 123 under Hu et al established the dehydrogenative coupling of saturated ketones through γÀ C(sp 3 )À H amination using copper as the catalyst for the synthesis of polysubstituted anilines (343). [75] Amines (341), saturated ketones (340), and N-substituted maleimides (342) were reacted in the presence of 10 mol% Cu(OAc) 2 and 10 mol% 2, 2'-bipyridine(bpy) as a catalyst, 3 equiv. 2, 2, 6, 6-tetramethylpiperidine-N-oxide (TEMPO) as oxidant, p-TsOH as additive, and PhCH 3 as solvent at 120°C for 48 h under N 2 atmosphere (Scheme 103).…”