Preparation of pyrimidine derivatives through three-component reactions of dialkyl (2-oxo-3,3,3-trifluoropropyl)phosphonates

Abstract

Progress in the chemistry of multicomponent reactions and an increasing interest when compared with traditional, multistage syntheses is evidence for the high synthetic potential of this route which is both a simple and rapid method for preparing different classes of compounds [1].Multicomponent reactions leading to formation of nitrogen-containing heterocyclic systems such as pyridine and pyrimidine [2, 3] have recently been studied. Derived compounds show a broad spectrum of biological activity [4, 5] hence preparation of novel representatives of this class of compounds is an urgent challenge in the chemistry of heterocycles [6]. Amongst a significant number of synthesized, functionally substituted pyrimidines finding use in pharmaceutical chemistry [7,8], pyrimidines containing phosphorus substituents remain little studied due to the limited number of methods of preparing them.One of the most widely used methods currently in use for preparing pyrimidines is the three-component Biginelli reaction. The use of traditional methodology in this reaction for the cyclocondensation of dialkyl 2-oxopropylphosphonates, aryl aldehydes, and urea is inefficient, the 4-aryl-5-(O,O-dialkylphosphoryl)-3,4-dihydropyrimidin-2-ones being obtained only under catalysis with the use of Yb(OTf) 3 [9]. A further reported method for preparing hexahydropyrimidine-5-phosphonates is the reaction of N-(1-tosylprop-1-yl)thiourea with 2-oxopropylphosphonate enolates [10].We have found that diethyl (3,3,3-trifluoropropyl-2-oxo)phosphonate (1a) reacts with aryl aldehydes and urea under Biginelli conditions to give the diethyl (6-aryl-4-hydroxy-2-oxo-4-trifluoromethylhexahydropyrimidin-5-yl)phosphonates 2a-c.

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

“…The trimethylchlorosilane-mediated one-pot reaction of diethyl (3,3,3-trifluoropropyl-2-oxo)phosphonate ( 8 ) with aryl aldehydes 9 and urea under Biginelli conditions has been presented by Timoshenko et al ( Scheme 3 ) [ 27 ]. The resulting 4-hydroxytetrahydropyrimidin-2-ones 10 were unstable and underwent dephosphorylation to give dihydropyrimidin-2-ones 11 after one week at room temperature.…”

2-Oxo-2-polyfluoroalkylethane-1-sulfones and -sulfamides in the three-component reactions leading to pyrimidine derivatives

“…Previously 24 we have shown that β-polyfluoroalkyl-β-ketophosphonates undergo threecomponent cyclocondensation reaction with trialkyl orthoformate and urea giving phosphonylcontaining 3,4-dihydropyrimidin-2(1H)-ones. The advantage of the elaborated one-pot procedure was its simplicity, avoiding isolation of intermediates and use of additional reagents to accomplish cyclization step to heterocyclic core.…”

Synthesis of Phosphorus(V)-Substituted Six-Membered N-Heterocycles: Recent Progress and Challenges

“…In addition, it may be noted that, recently, three-component acidic condensation of β-keto phosphonates with aldehydes and urea (Biginelli reaction) was shown to be efficient for synthesis of 1,4-dihydro-2-oxopyrimidine-5-phosphonates [ 122 , 123 , 124 ]. In this regard, it can be assumed that, in the future, a similar approach using amidines can also be implemented to obtain pentavalent phosphorus-substituted pyrimidines.…”