Palladium-Catalyzed Enantioselective C(sp³)–H/C(sp³)–H Umpolung Coupling of N-Allylimine and α-Aryl Ketones

Abstract

Asymmetric functionalization of the C­(sp3)–H bond is an attractive yet challenging strategy to achieve versatile bond-forming events, enabling the precise assembly of molecular complexity with minimal manipulation of functional groups. Here, we report an asymmetric C­(sp3)–H/C­(sp3)–H umpolung coupling of N-allylimine and coordinating α-aryl carbonyls by using chiral phosphoramidite-palladium catalysis. A wide variety of α-heteroaryl ketones and 2-acylimidazoles are nicely tolerated to open a convenient and tunable avenue for efficient synthesis of enantioenriched β-amino-γ,δ-unsaturated carbonyl derivatives with high levels of regio- and stereoselectivities, capable of providing a key intermediate for asymmetric synthesis of Focalin. This protocol showcases an umpolung reactivity of the N-allylimines through a concerted proton and two-electron transfer process to cleave the allylic C–H bond, effectively complementing established methodology for allylic C–H functionalization. An inner-sphere allylation pathway for both α-heteroaryl carbonyls and 2-acylimidazoles to attack the π-allylpalladium species is suggested by computational studies and experimental facts, wherein the nitrogen coordination to the palladium center enables the preference of branched regioselectivity.

Binaphthyl Scaffold: A Class of Versatile Structure in Asymmetric C–H Functionalization

“…Shortly after, a C3-branched selectivity was achieved via the asymmetric allylic C–H alkylation of terminal alkenes with 2-acylimidazoles 33 using a similar palladium/chiral BINOL-derived phosphoramidite L15 catalytic system (Scheme b) . In 2021, Gong and co-workers achieved the palladium-catalyzed enantioselective intermolecular allylic C–H allylation of N -allylimine 38 with α-aryl ketones using chiral BINOL-derived phosphoramidite L14 as ligand (Scheme c) . Notably, this reaction was proposed to proceed through a concerted proton and two-electron transfer step in the cleavage of allylic C–H bonds.…”

Photochemical Allylation of Alkanes Enabled by Nickel Catalysis

“…Transition-metal-catalyzed allylic alkylation represents one of the most prominent methods for C­(sp 3 )–C­(sp 3 ) bond formation and has had a historical impact on organic synthetic chemistry . To date, a broad spectrum of “soft” nucleophiles is known to participate in allylic substitutions, leading to a tremendous number of protocols for scalable preparation of synthetically significant substances (Scheme A) . “Hard” nucleophiles (p K a > 25), which coordinate to or undergo transmetalation with metal catalysts prior to the reductive elimination to generate coupling products, have been continuously investigated since Swierczewski reported the allylic alkylation between allylic alcohols and Grignard reagents .…”

Pd-Catalyzed Regioselective Intramolecular Allylic C–H Amination of 1,1-Disubstituted Alkenyl Amines

“…Since pioneered by Trost , and Beak, , the White group made a considerable contribution to catalytic allylic C–H functionalization of unactivated alkenes . Despite significant advances in this field, the allylic C–H amination of allyl ethers/amines is still a formidable challenge due to the above-mentioned side reactions, and very few successes have been reported (Scheme c) . Broggini and Poli employed N -Ts-tethered N -allyl amides as substrates that underwent either Pd-catalyzed allylic C–H amination (path c) or aza-Wacker-type cyclization (path a) depending on the reaction conditions.…”

“…Given the positive effect of Brønsted bases in the formation of π-allylpalladium species, − , various inorganic bases were examined, with NaHCO 3 preferentially increasing the yield of 2a . The effect of external ligands has been also examined using a wide range of N- and P-based ligands .…”

“…Interestingly, the inclusion of 5 mol % AgOTf, which is an effective Lewis acid for promoting the related reactions, ,, afforded only 2a′ (84% yield; entry 3). Consistent with the negative effect of external ligands, the addition of DMSO (entry 4) and the replacement of Pd­(OAc) 2 and CuCl 2 with White catalyst (entry 5) and benzoquinone (BQ) or another oxidants, respectively, significantly hampered the reaction, which is dissimilar to other related allylic C–H functionalization processes generally achieved by using a Pd­(II)-bis-sulfoxide catalytic system and a BQ-based oxidant. ,,, The outcomes of control experiments indicate that both Pd­(OAc) 2 and CuCl 2 are essential for the reaction to occur, while the reaction still proceeded in the absence of NaHCO 3 (albeit with a lower yield) (entries 6–8).…”