Synthesis of 3,4-Dihydropyrimidin-2(1H)-one-phosphonates by the Microwave-Assisted Biginelli Reaction

Abstract

The synthesis of novel 3,4-dihydropyrimidin-2(1H)-one-phosphonates was elaborated by the microwave (MW)-assisted three-component Biginelli reaction of β-ketophosphonates, aromatic or aliphatic aldehydes and urea derivatives. The condensation was optimized on a selected model reaction in respect of the reaction parameters, such as the heating method, the type of the catalyst and solvent, the temperature, the reaction time and the molar ratio of the starting materials. The fast and solvent-free MW-assisted procedure was then extended for the preparation of further new 3,4-dihydropyrimidin-2(1H)-one-phosphonate derivatives starting from different aromatic aldehydes, β-ketophosphonates and urea derivatives to prove the wide scope of the process. As a novel by-product of the Biginelli-type synthesis of 3,4-dihydropyrimidin-2(1H)-one-phosphonates, the 5-diethoxyphosphoryl-4-phenyl-6-styryl-3,4-dihydropyrimidin-2(1H)-one was also isolated and characterized. Our MW-assisted method made also possible the condensation of aliphatic aldehydes, diethyl (2-oxopropyl)phosphonate and urea, which reaction was previously reported to be impossible in the literature.

Multicomponent Synthesis of Potentially Biologically Active Heterocycles Containing a Phosphonate or a Phosphine Oxide Moiety

“…The Biginelli reaction of diethyl (2-oxopropyl)phosphonate, benzaldehyde and urea was studied by us. 77 The conditions (heating mode, temperature, reaction time, molar ratio of the starting materials, catalyst and solvent) were changed to maximize the conversion. Based on our results, a new solvent-free MW-assisted method was developed for the synthesis of (dihydropyrimidinone) phosphonates 53-57 by the Zn(OTf) 2 -catalyzed Biginelli reaction.…”

Synthesis of 3,4-Dihydropyrimidin(thio)one Containing Scaffold: Biginelli-like Reactions

“…When PdCl 2 as a metal catalyst and trifluoroacetic acid as a Brønsted acid were combined in this reaction, the corresponding Biginelli reaction took place in excellent yields and complete diastereoselectivities, to afford a variety of spirofuran-hydropyrimidinone compounds 135 (Scheme 58); this is one of the few reports that deal with the synthesis of spirocyclic DHMP-derivatives. Bálint et al described the synthesis of DHPM-containing phosphonates at the 5 position by using beta-ketophosphonates 136 as the keto ester component [134]. The MCR reaction took place under solvent-free microwave irradiation to render the corresponding Biginelli adducts 137 in good yields, even with aliphatic aldehydes (Scheme 59).…”

“…The use of ketophosphonates in the Biginelli reaction was also reported with Zn(OTf)2 in refluxing toluene [135], or using acetic acid [136,137] or p-toluene sulfonic acid [138] as catalysts. Bálint et al described the synthesis of DHPM-containing phosphonates at the 5 position by using beta-ketophosphonates 136 as the keto ester component [134]. The MCR reaction took place under solvent-free microwave irradiation to render the corresponding Biginelli adducts 137 in good yields, even with aliphatic aldehydes (Scheme 59).…”

Thiolated 2-Methyl-β-Cyclodextrin as a Mucoadhesive Excipient for Poorly Soluble Drugs: Synthesis and Characterization

“…A CD selectively methylated in the C 2 position was used to optimize the microwave assisted synthesis process, in the complete absence of organic solvents. Indeed, microwave assisted synthesis was demonstrated to be more efficient, more selective and provides, in most cases, a higher yield than conventional reactions at high temperatures [ 15 ]. The product was deeply characterized through NMR investigation as well as in terms of mucoadhesion, cytotoxicity, complexing capability toward dexamethasone (Dex), and as for the formation of self-assembled nanoaggregates in aqueous solutions.…”