Multicomponent Synthesis of Uracil Analogues Promoted by Pd-Catalyzed Carbonylation of α-Chloroketones in the Presence of Isocyanates and Amines

Abstract

A short and efficient one-pot synthesis of uracil derivatives with a high structural variability is described. The process is a multicomponent reaction based on a palladium-catalyzed carbonylation of α-chloroketones in the presence of primary amines and isocyanates. In most cases, when the formation of unsymmetrical N,N'-disubstituted uracil derivatives can occur, the methodology demonstrates to be highly regioselective. A mechanistic hypothesis involving β-dicarbonyl palladium intermediates and urea derivatives, generated in situ, has been discussed.

Heterocycle Synthesis through Pd‐Catalyzed Carbonylative Coupling

“…Indeed, uracil derivatives 3 , 4 with high structure variability were successfully prepared through a Pd‐catalyzed multicomponent reaction, starting from easily available starting materials. Simply by combining four components (isocyanate, primary amine, α ‐chloroketone under an atmosphere of CO), and in a one‐pot process, uracil derivatives were obtained with moderate to good yields (Scheme ) …”

“…The hypothesized mechanism involves the acylpalladium intermediate 2 , derived from a palladium‐catalyzed carbonylation step of the α ‐chloroketone, and the in situ‐generated di‐substituted urea. The reactive 1,3‐bis electrophilic palladium complex 2 should promote the acylation of the 1,3‐bidentate nucleophilic urea providing, after a condensation reaction, the uracil analogue (Scheme ) …”

“…Simply by combining four components (isocyanate, primary amine, α-chloroketone under an atmosphere of CO), and in a one-pot process, uracil derivatives were obtained with moderate to good yields (Scheme 2). [14] Scheme 2. Palladium-catalyzed multicomponent synthesis of uracil analogues.…”

“…Moreover, when the carbonylative coupling of α-chloroketones was performed in the presence of aromatic isocyanates and aliphatic primary amines or complementarily, aliphatic isocyanates and aromatic primary amines, the methodology showed a complete regioselectivity leading to a only one unsymmetrical N,N′-disubstituted uracil isomer. [14] Regioselectivity was shown to be strongly dependent on the N-nucleophilicity in the urea generated in situ from amines and isocyanates. The hypothesized mechanism involves the acylpalladium intermediate 2, derived from a palladium-catalyzed carbonylation step of the α-chloroketone, and the in situ-generated di-substituted urea.…”

α‐Oxo‐Ketenimines from Isocyanides and α‐Haloketones: Synthesis and Divergent Reactivity

“…The palladium-catalyzed carbonylation of a-haloketones is known and, till now,t he scope of this synthetically useful transformationw as appliedm ainly to haloketones lacking the b-hydrogen [26] because intermediates relatedt oB are known to undergo rapid b-hydride elimination to enone 21 even under the carefully optimized conditions. [27] The fact that this supposedly facile process, am ain concern at the outset of our reactiond esign, did not take place under our conditions is remarkable.…”