Xanthine Scaffold: Available Synthesis Routes to Deliver Diversity by Derivatization

Abstract

: The functionalization of the skeletal systems of heterocycles represents a significant goal for new compounds development. The heterocyclic molecule xanthine (3,7-dihydro-1H-purine-2,6-dione) is a purine base with a bicyclic ring skeleton and four different nitrogen atoms, three of them are -NH groups. The principal derivatives are the well known natural methylxanthines (e.g. caffeine, theophylline and theobromine) that have prominent physiological effects at very low dose. The natural methylated xanthines, theophylline, theobromine and caffeine, are present in different plants such as the tea, cocoa and coffee species. For this reason natural xanthines can be considered as bio-based and renewable starting materials; their use in organic synthesis is strongly recommended in order to carry out sustainable chemistry. Essentially, the xanthine scaffold led to the preparation of numerous compounds very attractive in the pharmaceutical field, and these drugs are commercialized for a wide range of biological activities. The scope of this Mini Review is to consider the use of natural xanthines as starting material in chemical transformations carried out in organic solvents, without the intent to be exhaustive of all the synthetically chemical applications. More information on the chemical and electrochemical reactivity of this structural core in organic solvent can be useful for the scientific community. The effectiveness of natural xanthines can be improved by modifying the structures of these already biologically active compounds.

Electrochemical Transformations of Methylxanthines in Non‐Aqueous Medium

“…Caffeinium salts have been used in organic synthesis as precursors of NHC in metal complexes, some of which are biologically active [4,5c–d,18] . Nevertheless, free NHC derivatives have never been evidenced.…”

“…Furthermore, their potentialities as antioxidants have been recently focused on, [2] the question remaining under discussion, however [3] . In addition, the versatility of the xanthine scaffold makes these natural compounds very appealing as bio‐based and renewable starting materials for organic synthesis, and useful precursors for molecules attractive in the pharmaceutical fields [4] . In particular, the structural core of caffeine was evaluated in the sustainable synthesis of drugs mainly addressed to contrast damages from oxidative stress [5] .…”

Luminescent Platinum(II) Complexes with a Tridentate Caffeine‐Based NHC‐Pincer Ligand: Synthesis, Electrochemistry and Photophysics

“…[51][52] Xanthines, on the other hand, are naturally occurring alkaloids, which allow for a more sustained and eco-friendlier NHC synthesis via straightforward derivatization. [53] According to the statistics of the worldwide coffee market, ca. 166.63 Mio bags, each with 60 kg of coffee beans, were sold in 2020/21.…”

“Greening” Ruthenium–Arene Catalyst Precursors with N-Heterocyclic Carbene Ligands Derived from Caffeine and Theophylline

“…Furthermore, extracting caffeine and theophylline from vegetable sources requires only supercritical carbon dioxide as a solvent, and their separation can be achieved through ion-exchange columns using water of variable pH as the eluent . Hence, the whole supply chain involved in bringing methylxanthines “from earth to the chemical flask” is a sustainable process, which makes these nitrogen-based heterocyclic compounds ideal building blocks for green organic synthesis and organometallic chemistry …”

“…10 Furthermore, extracting caffeine and theophylline from vegetable sources requires only supercritical carbon dioxide as a solvent, and their separation can be achieved through ion-exchange columns using water of variable pH as the eluent. 11 Hence, the whole supply chain involved in bringing methylxanthines "from earth to the chemical flask" is a sustainable process, which makes these nitrogen-based heterocyclic compounds ideal building blocks for green organic synthesis 12 and organometallic chemistry. 13 Herein, we report on the synthesis and characterization of two ruthenium−arene complexes bearing NHC ligands derived from caffeine and theophylline and we assess their catalytic potentials in three miscellaneous reactions, namely, the transfer hydrogenation of ketones with isopropanol, the oxidation of alkenes with sodium periodate, and the synthesis of vinyl esters from benzoic acid and 1-hexyne.…”