Synthesis of substituted 3,4-dihydropyrimidin-2(1H)-ones and pyrimidin-2(1H)-ones by the Biginelli reaction with 3,5-Di-tert-butyl-4-hydroxybenzaldehyde

Abstract

Three-component acid-catalyzed cyclocondensation of 3,5-di-tret-butyl-4-hydroxybenzaldehyde with urea and ethyl acetoacetate or α-nitroacetophenone (Biginelli reaction) under homogeneous conditions gave the corresponding 5-substituted 3,4-dihydropyrimidin-2(1H)-ones having in position 4 of the heteroring an aryl substituent with sterically shielded hydroxy group. The condensation catalyzed by inorganic salts (Fe 3+ , Co 2+ , Zn 2+ , Li + ) was successful only with ethyl acetoacetate as initial methylene-active component. Under analogous conditions, acetophenone and 4-fluoroacetophenone gave rise to 4,6-diarylpyrimidin-2(1H)-ones which are capable of undergoing phenol-quinonemethide tautomerism.3,4-Dihydropyrimidin-2(1H)-ones exhibit a broad spectrum of biological activity, but the most interesting is their ability to modulate calcium channels [1-3]. We found that 4-aryl-5-nitro-6-phenyl-3,4-dihydropyrimidin-2(1H)-ones are low-toxic compounds and that they exert an appreciable antiarrhythmic effect even at a very low dose [4]. A usual technique in the design of biologically active compounds with a broad spectrum of biological activity is incorporation into a biologically active molecule of one or several additional pharmacophoric groups with a different activity [5]. In this connection, introduction into a 3,4-dihydropyrimidin-2-one molecule of a phenol fragment having sterically shielded hydroxy group could give rise to new properties, e.g., antiradical and antioxidant activity. Heterocyclic compounds containing a 3,5-di-tert-butyl-4-hydroxyphenyl group have been reported to exhibit antioxidant activity in combination with other kinds of biological activity. Examples are calcium channel antagonists of the 1,4-dihydropyridine [6] and thiazolidinone series [7], antisclerotic agents of the oxadiazole series [8], and lipoprotein oxidation inhibitors of the dihydropyrazole series [9]. Compounds possessing antioxidant properties were found among 4-aryl-3,4-dihydropyrimidin-2-one derivatives substituted at the 5-position with an alkoxycarbonyl group having both simple and bulky alkyl radicals [10].In the present work we tried to synthesize new 4-aryl-3,4-dihydropyrimidin-2(1H)-ones with a sterically shielded hydroxy group in the aryl substituent. For this purpose, we examined three-component cyclocondensation of 3,5-di(tert-butyl)-4-hydroxybenzaldehyde (I) with urea (IIa) or N-methylurea (IIb) and various compounds having an activated methylene group. As the latter, we used both traditional ethyl acetoacetate and less reactive CH acids, α-nitroacetophenone (III), acetophenone (IV), and 4-fluoroacetophenone (V).The reaction of ethyl acetoacetate with aldehyde I and urea (IIa) under standard Biginelli conditions (heating in boiling ethanol in the presence of a catalytic amount of hydrochloric acid) gave ethyl 4-(3,5-ditert-butyl-4-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (VIa) in 48% yield (Scheme 1). The condensation in the presence of inorganic salts, such as FeCl 3 · 6 H 2 O, CoCl 2 · 6 ...

Synthesis, Redox Properties and Antibacterial Activity of Hindered Phenols Linked to Heterocycles

“…However, in our hands, the products were not obtained when all these conditions were employed. Previously, researchers from the Vorozhtsov Novosibirsk Institute of Organic Chemistry have synthesized compound 9a in the presence of FeCl 3 •6H 2 O as a catalyst [50]. These conditions (with some correction) turned out to be suitable for the synthesis of compounds 9a-c with yields 55-64%.…”