Mechanism of the Stereoselective α-Alkylation of Aldehydes Driven by the Photochemical Activity of Enamines

Abstract

Herein we describe our efforts to elucidate the key mechanistic aspects of the previously reported enantioselective photochemical α-alkylation of aldehydes with electron-poor organic halides. The chemistry exploits the potential of chiral enamines, key organocatalytic intermediates in thermal asymmetric processes, to directly participate in the photoexcitation of substrates either by forming a photoactive electron donor–acceptor complex or by directly reaching an electronically excited state upon light absorption. These photochemical mechanisms generate radicals from closed-shell precursors under mild conditions. At the same time, the ground-state chiral enamines provide effective stereochemical control over the enantioselective radical-trapping process. We use a combination of conventional photophysical investigations, nuclear magnetic resonance spectroscopy, and kinetic studies to gain a better understanding of the factors governing these enantioselective photochemical catalytic processes. Measurements of the quantum yield reveal that a radical chain mechanism is operative, while reaction-profile analysis and rate-order assessment indicate the trapping of the carbon-centered radical by the enamine, to form the carbon–carbon bond, as rate-determining. Our kinetic studies unveil the existence of a delicate interplay between the light-triggered initiation step and the radical chain propagation manifold, both mediated by the chiral enamines.

Photokatalyse mit sichtbarem Licht: Welche Bedeutung hat sie für die organische Synthese?

“…[13,14] Darüber hinaus wurden verschiedene Kombinationen von sichtbares Licht absorbierenden Photokatalysatoren und Organokatalysatoren entwickelt. [17] Aufd iese Weise gelang die direkte enantioselektive Alkylierung von nicht-aromatischen Aldehyden 10 mit Brommalonaten 23 (Schema 7b). Sie fanden heraus,dass Enamine,die durch Kondensation eines chiralen Katalysators 18 und eines Aldehyds 10 gebildet werden, unter Bestrahlung mit sichtbarem Licht mit Benzylbromiden reagieren und insgesamt eine enantioselektive a-Alkylierung von Aldehyden ermçglichen (Schema 7a).…”

“…Enamine kçnnen auch selbst als Photoinitiatoren (Absorptionsmaxima > 400 nm) ohne EDA-Komplexbildung wirken. [17] Aufd iese Weise gelang die direkte enantioselektive Alkylierung von nicht-aromatischen Aldehyden 10 mit Brommalonaten 23 (Schema 7b). [18] Darüber hinaus ist ausgehend von a-substituierten Enalen 22 eine Alkylierung in der g-Position über ein Dienamin mçglich, wobei Addukte vom Ty p 26 in guter Ausbeute,j edoch mit geringer Enantioselektivitäte rhalten werden.…”

Functionalization of Carbonyl Compounds via Photoredox Organocatalysis

“…The same approach has been successfully applied to cyclic ketones by using catalytic amount of cinchona-based primary amine 17 as catalyst (Scheme 4). [27] Later, Melchiorre [28] studied the factors governing these enantioselective photochemical catalytic processes via experimental methods such as measurements of the quantum yield, nuclear magnetic resonance spectroscopy, and kinetic studies. Enamine formation and the different photochemical pathways available to enamines to initiate the chain process (EDA complex formation vs. direct photoexcitation) were revealed.…”

Electrophilic Activation of Iodonium Ylides by Halogen‐Bond‐Donor Catalysis for Cross‐Enolate Coupling

“…Compared with a-arylation and a-alkynylation, C(sp 3 )ÀC(sp 3 )b ondforming reactions [4] are less well developed, despite the utility of the resulting products. [6] Many approaches have been investigated for the synthesis of these important synthetic intermediates; [7][8][9][10] however,t he activation of the iodonium ylide seems to be the most challenging aspect of such ah ypothetical reaction. [6] Many approaches have been investigated for the synthesis of these important synthetic intermediates; [7][8][9][10] however,t he activation of the iodonium ylide seems to be the most challenging aspect of such ah ypothetical reaction.…”

“…[1][2][3] We envisioned that the crosscoupling of an iodonium(III) ylide [1,5] with carbonyl compounds would enable C(sp 3 ) À C(sp 3 )b ond formation and provide 1,4-dicarbonyl compounds (Scheme 1c), which are found in av ariety of important natural product scaffolds or used for their preparation. [6] Many approaches have been investigated for the synthesis of these important synthetic intermediates; [7][8][9][10] however,t he activation of the iodonium ylide seems to be the most challenging aspect of such ah ypothetical reaction. This is the result of their facile decomposition, insertion, and transylidation in the presence of hard Lewis acids, [5,11] even though such reactions generally occur via metal carbenoids in the presence of rhodium or copper catalysts (Scheme 1b).…”