Reactivity Tuning for Radical–Radical Cross-Coupling via Selective Photocatalytic Energy Transfer: Access to Amine Building Blocks

Abstract

Reductive N−O bond cleavage has been widely explored for providing either N or O radical species for various coupling processes. Despite significant advances, this photoredox pathway is less appealing due to poor atom economy owing to the loss of one fragment during the transformation. In this regard, the homolytic N−O bond cleavage by an energy-transfer pathway to provide two key radicals would be highly desirable for overcoming the limitations of the use of one fragment. We report an exclusive energy-transfer approach for the development of a challenging radical−radical C(sp 3 )− N cross-coupling process by reactivity-tuning of the catalytic system. The homolytic N−O bond cleavage of oxime esters in the presence of an Ir complex produces acyloxy and iminyl radicals, which undergo decarboxylative cross-coupling to yield valuable imines (typically 0.25 mol % cat. and 1 h reaction time). Extensive photophysical and electrochemical measurements, as well as density functional theory studies, were carried out to probe the mechanism and the operation of a Dexter-type energy-transfer pathway was revealed. The choice of solvent (EtOAc) and reaction concentration were critical for achieving the selectivity and reactivity in this cross-coupling process. The synthetic utility of this method was explored by studying highly functionalized oxime esters, including derivatives of biologically active natural products and drug molecules. Furthermore, in situ transformations of the imine products into pharmaceutically important amines were also demonstrated, showcasing the utility of the imine products as valuable amine building blocks.

Photosensitized Intermolecular Carboimination of Alkenes through the Persistent Radical Effect

“…Subsequently,w ee xplored the carboxylic acid scope, including two large-scale demonstrations.Aplethora of carboxylic acids featuring primary,s econdary,a nd tertiary carbon centers were found to be effective substrates for the carboimination reaction. Simple halides (20 and 21), trifluoromethyl (22), ester (23), azide (24), or ether (25)c ontaining primary carboxylic acids were employed without any problem. Similarly,p rimary carboxylic acids comprising heterocycles such as pyridine (26)o r1 ,2,4-triazole (27)w ere tolerated under the optimized conditions.B oth aliphatic (28)a nd aromatic a-oxy acids (29)c ould be applied successfully to form g-amino ethers.Different cyclic (30 and 31)and heterocyclic secondary carboxylic acids (32, 33,a nd 34)w ith varying ring sizes could be easily accommodated.…”

“…Thee xcited oxime ester I would participate in ac oncerted decarboxylation/ fragmentation process to generate aC-centered alkyl radical and N-centered diphenyliminyl radical pair II. [21,23] Thel ong lifetime of the diphenyliminyl radical IV should allow the transient alkyl radical to escape the solvent cage and add to the terminal position of the alkene to generate as tabilized radical III.L astly,ahighly selective radical-radical crosscoupling between III and IV would be kinetically feasible based on the persistent radical effect (PRE). [24] However, such ar adical-radical cross-coupling approach possesses numerous challenges connected to potentially unproductive pathways outperforming the desired reaction.…”

Recent Advances in Photocatalytic C–N Bond Coupling Reactions

“…The homolytic cleavage of oxime esters in the presence of an Ir complex produces acyloxy and iminyl radicals, which undergo decarboxylative cross-coupling to give structurally diversified imines (Scheme 41). 45 DFT studies with photophysical and electrochemical measurements indicated the operation of a photocatalytic Dexter-type energy transfer pathway.…”

Energietransfervermittelte intermolekulare Carboiminylierung von Alkenen durch den “Persistent Radical Effect”

“…Anschließend wurde das Substratspektrum bezüglich der Carbonsäuren untersucht, inklusive zweier Reaktionen in großem Maßstab.Eine Vielzahl an primären, sekundären und tertiären Carbonsäuren konnten unter den Reaktionsbedingungen erfolgreich zum carboiminylierten Produkt umgesetzt werden. Einfache Halogenide (20 und 21), Tr ifluormethyl- (22), Ester- ( 23), Azid- (24)o der Ethergruppen (25)w urden unter den Reaktionsbedingungen toleriert. Ebenso konnten primäre Carbonsäuren, die im Rückgrat mit Heterocyclen wie Pyridin (26)o der 1,2,f unktionalisiert sind, erfoglreich umgesetzt werden.…”

“…Unter Berücksichtigung der Tr iplett-Energien der Oximester aliphatischer Carbonsäuren (E T = 45.4 kcal mol À1 , siehe Abschnitt 2.1 in den Hintergrundinformationen) postulierten wir, dass ein Triplett-Triplett-Energietransfer (TTEnT) vom Photokatalysator auf den Oximester thermodynamisch begünstigt sein sollte.Dieser angeregte Oximester würde im Anschluss in einem konzertierten Fragmentierungs-Decarboxylierungs-Prozesse in C-zentriertes Radikal sowie ein N-zentriertes Diphenyliminylradikal II generieren. [21,23] Bereits während unserer früheren Untersuchungen zur Decarboxylierung von Oximestern [21] legte die Beobachtung Hydrazon-artiger Nebenprodukte eine relativ hohe Lebensdauer des Diphenyliminylradikals nahe.D iese hohe Lebensdauer sollte es dem transienten Alkylradikal ermçglichen, den Lçsungsmittelkäfig zu verlassen und an die terminale Position eines Olefins zu addieren. Das dabei gebildete Radikal III sollte gemäßd em "Persistent Radical Effect" in einer selektiven Radikal-Radikal-Rekombinationm it Diphenyliminylradikal reagieren kçnnen.…”