A Direct Synthesis of Isocytosine Analogues by Carbonylative Coupling of α‐Chloro Ketones and Guanidines

Abstract

A valuable and direct method for the synthesis of 2‐aminopyrimidin‐4‐one derivatives is described. The strategy relies on the Pd‐catalysed carbonylation of α‐chloro ketones in the presence of mono‐ and disubstituted guanidines. Although the strategy also gave 2‐aminoimidazole derivatives as minor products, good chemoselectivity in favour of the six‐membered ring was achieved in all experiments. The in‐situ formation of a (β‐oxoacyl)palladium species has been invoked as the key step for the multicomponent process. Moreover, the method described could be of interest from a biological point of view, because it constitutes a straightforward strategy for the synthesis of structural analogues of the unnatural nucleobase isocytosine.

Towards Green Reductions in Bio‐Derived Solvents

“…Based on their research on Pd‐catalyzed reactions and sustainable synthetic processes in DESs, [34–43] Messa et al., very recently, described a safe, scalable and sustainable HY reaction of a variety of functional groups. The reactions, enabled by in situ generation of hydrogen from Al powder and small amount of basic water, were catalyzed by the cheap Pd/C catalyst.…”

Heterocycle Synthesis through Pd‐Catalyzed Carbonylative Coupling

“…Simply by replacing the 1,3‐bis nucleophile of the catalytic carbonylative coupling, i.e. using guanidine derivatives instead of the substituted urea, a different six‐membered carbonyl‐containing N ‐heterocycles was synthesized …”

“…using guanidine derivatives instead of the substituted urea, a different six-membered carbonylcontaining N-heterocycles was synthesized. [15] Indeed, the multicomponent carbonylation of α-chloroketones was also employed as a useful strategy for the one-pot synthesis of di-and trisubstituted 2-aminopyrimidin-4-ones, important structural analogues of nucleobases. [15] 2-Aminopyrimidin-4-one core represents a derivative of isocytosine, an unnatural nucleobase, structural isomer of the natural nucleobase cytosine ( Figure 1).…”

“…[15] Indeed, the multicomponent carbonylation of α-chloroketones was also employed as a useful strategy for the one-pot synthesis of di-and trisubstituted 2-aminopyrimidin-4-ones, important structural analogues of nucleobases. [15] 2-Aminopyrimidin-4-one core represents a derivative of isocytosine, an unnatural nucleobase, structural isomer of the natural nucleobase cytosine ( Figure 1). These analogues present relevant biological properties as, for example, they could act as probes or modifiers of the base pairing in nucleic acids.…”

Pd-Catalyzed Ring-Opening/Arylation/Cyclization of 2-Aminothiazole Derivatives Provides Modular Access to Isocytosine Analogues

“…However, if one wishes to subsequently functionalize one of the N-atoms, typically achieved using alkylation chemistry, regioselectivity issues are often observed . One strategy to alleviate this problem was reported by Troisi et al, who developed a method for the carbonylative coupling of substituted guanidines 8 and α-chloroketones 9 . While symmetrical di-substituted guanidines 8a delivered the corresponding cyclization products 10a in 56–76% yield, the arguably more valuable mono-functionalized products 10b , derived from mono-substituted guanidines 8b , were obtained in significantly lower yields (18 and 34%).…”