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Water-Tuned Tautomer-Selective Tandem Synthesis of the 5,6-Dihydropyrimidin-4(3H)‑ones, Driven under the Umbrella of Sustainable Chemistry

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posted on 2018-08-22, 00:00 authored by Nenad Janković, Srđan Stefanović, Jelena Petronijević, Nenad Joksimović, Slađana B. Novaković, Goran A. Bogdanović, Jovana Muškinja, Milan Vraneš, Zoran Ratković, Zorica Bugarčić
The selective synthesis of 5,6-dihydropyrimidin-4­(3H)-one scaffold (precursor of dihydrouracil) was a very difficult synthetic challenge that, so far, has not been achieved. For the first time, in this paper, green, selective and high-yields approach to 40 novel 5,6-dihydropyrimidin-4­(3H)-ones (DHPMs) by one-pot reaction of aldehydes, Meldrum’s acid and isothioureas under solvent-free conditions, in the presence of water, since an additive is presented. In the majority of cases, introduced methodology gave an unprecedented tautomer-selective fashion toward targeted compounds with excellent tautomeric purity (>99.9%), which reached 100% in few cases. The molecular structure of the five compounds has been determined by X-ray crystallography. In each one of them, very short length for the corresponding N2–C1 bond was noticed, making them especially interesting from a structural standpoint. This experimental fact can imply a highly localized electron π density in this part of each heterocyclic ring. The obtained experimental results, which are determined from NMR and ESI-MS study, indicate that this Biginelli-type reaction smoothly proceeds in a one-pot mode, pointing to the three-step tandem process, proceeding via the Knoevenagel, aza-Michael, and retro-Diels–Alder reactions. The presented strategy also had the following advantages: reduction amount of waste, excellent values of green chemistry metrics (cEF, EcoScale and GCIS), and it is the first eco-friendly strategy toward the DHPMs scaffold.