Abstract
In this paper, a simple and clean process for the alkylation and arylation of nitrogen-containing heterocycles is reported. The reactions were conducted using the Q-tube® as a non-conventional technology, in water as a green solvent, at overboiling temperature. The developed strategy was used to improve two steps in the total synthesis of caffeine, as reported by Narayan, and then extended to the preparation of N-decorated xanthines. Finally, piperidine, methyl piperazine, and isatine were proven to be suitable substrates for the protocol proposed herein.
Highlights
The reaction conditions were optimized for the conversion of theophylline (8) into caffeine 1, exploring the effect of microwave irradiation (Method A) or using Q-tube®(Method B)
Carrying out the reaction in the Q-tube®, the NMR conversion was almost quantitative; considering that, with respect to the MW reactor, it is a simpler and cheaper apparatus [30], we evaluated the scope of explorations using the conditions reported in Table 1, entry 6
We developed a ileged scaffolds for medicinal chemistry purposes
Summary
Chemistry 2021, Xanthines [3,9 dihydro-1H-purine-2,6-dione] are alkaloids discovered in the 19th century by the German chemist Emil Fisher, who synthesized all the naturally occurring ones together with some other structurally related compounds [1]. The most thoroughly studied xanthine derivative, caffeine (1,3,7-trimetyxanthine, compound 1a, Scheme 1), is abundant in coffee, tea, kola nuts, mate leaves, guarana paste, cocoa beans, and other natural matrixes [2]. It is a known neuro-stimulatory and a neuro-protective compound able to alleviate drowsiness and promote mental alertness. Due to its presence in many energy drinks, caffeine is the most consumed psychoactive compound worldwide [3]. A comprehensive review article focusing on its beneficial effects on human health has been published [6]
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