O. P. Shkurko

Two Directions of the Reaction of 4-Bromobenzaldehyde with Substituted Acetophenones and Urea. Synthesis of Aryl-substituted Pyrimidin-2-one and Hexahydropyrimido[4,5-d]pyrimidin-2,7-dione

Condensation of 4-bromobenzaldehyde, urea, and 4-alkyl-substituted acetophenones gave substituted hexahydro-1H,8H-pyrimido[4,5-d]pyrimidin-2,7-diones or 1H-pyrimidin-2-ones, depending on the substituent on the acetophenone ring and the nature of the solvent (i-PrOH, BuOH, AcOH). The corresponding 5-bromopyrimidin-2-ones were formed on bromination of these compounds. The structures of these compounds were confirmed by IR, UV, and 1H NMR spectroscopy.

Synthesis of 5-nitro-3,4-dihydropyrimidin-2(1H)-ones catalyzed by metal salts. Retro-Henry reaction with formation of N,N′-disubstituted ureas

Three-component condensation of α-nitroacetophenone with aromatic aldehydes and urea in the presence of iron(III), cobalt(II), nickel(II), and copper(II) salts as catalyst led to the formation of 4,6-diaryl-5-nitro-3,4-dihydropyrimidin-2(1H)-ones and N-benzoyl-N′-(1-aryl-2-nitroethyl)ureas. The latter were formed as a result of retro-nitroaldol (retro-Henry) reaction of intermediate 4,6-diaryl-6-hydroxy-5-nitro-3,4,5,6-tetra-hydropyrimidin-2(1H)-ones.

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

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 (Fe3+, Co2+, Zn2+, 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.

Synthesis and intramolecular conversion of substituted 2-methyl-11-nitro-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5] oxadiazocin-4(3H)-ones in different solvents

A Biginelli reaction of 5-R-salicylic aldehydes (R = H, Me, Br) with nitroacetone and urea in each case leads to a predominant formation of 2R*,6S*,11S* diastereomers of 8-R-2-methyl-11-nitro-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one. In solutions in DMF and DMSO, these diastereomers undergo the oxadiazocine ring opening with setting a three-component equilibrium between predominant 4-(2-hydroxy-5-R-phenyl)-6-methyl5-nitro-3,4-dihydropyrimidin-2(1H)-ones and 2R*,6S*,11S* and 2R*,6S*,11R* diastereomers of methanobenzoxadiazocine as two minor components.

Synthesis and Antiarrhythmic Effect of 4-Aryl-5-nitro-6-phenyl-3,4-dihydro-(1H)-pyrimidin-2-ones

As is known [1, 2], 1,4-dihydropyridine derivatives act as calcium channel blockers. Some compounds of this group (nifedipine, nicardipine, amlodipine, etc.) are used as antihypertensive and antianginal agents [2, 3]. In addition, these compound possess antiarrhythmic activity, which has drawn the interest of clinical chemotherapists [4, 5]. 3,4-Dihydro-(1H)-pyrimidin-2-ones, which are close analogs of 1,4-dihydropyridines, possess the same spectrum of pharmacological activity [3]. The hypotensive and spasmolytic properties of dihydropyrimidin-2-ones were originally demonstrated for 5-alkoxycarbonyl-4-phenyl derivatives [6]. Most of the aforementioned dihydropyridine and dihydropyrimidinone derivatives contain ester groups in position 5 of the heterocycle [7, 8]. It was demonstrated that substitution of NO2 for COOR in the dihydropyridine molecule changes the character of biological action and leads to compounds exhibiting higher toxicity [9, 10]. In the search for new effective cardiovascular drugs among dihydropyrimidines, we have synthesized a series of 4-aryl-5nitro-6-phenyl-3,4-dihydro-(1H)-pyrimidin-2-ones (I – VII) and studied their pharmacological properties. The interest in these derivatives is due to the generally lower toxicity of pyrimidines as compared to that of pyridines [11, 12]. Below we present data on the antiarrhythmic activity of the synthesized compounds. The new compounds (II – VII) were obtained via interaction of -nitroacetophenone, aromatic aldehydes, and urea, by analogy with the synthesis of well-known compound I [13]. The reaction includes the following sequential transformations: (i) acid-catalyzed condensation of aldehyde and urea with the formation of active N-acylimmonium cations, (ii) reaction of these N-acylimmonium cations with nitroacetophenone with the formation of ureido derivatives, and (iii) cyclization of these derivatives into dihydropyrimidinones. R = H (I), p-HO (II), p-CH3O (III), m-F (IV), m-Cl (V), m-NO2 (VI), and o-NO2 (VII).

Crystal Structure of 6-Chloro-4-nitro-2-phenylpyrimidine

The crystal structures of 6-chloro-4-nitro-2-phenylpyrimidine and 6-chloro-2-phenylpyrimidine have been determined using X-ray diffraction. The effect of the nitro group and the endocyclic nitrogen atoms on the geometric parameters of the 2- and 4-nitropyrimidine molecules, and also related α-nitroazines are compared.

Manganese dioxide oxidation of hydroxyamino-sym-triazines

The hydroxyamino group in sym-triazines is readily oxidized by the action of manganese dioxide. The stability of the nitrosotriazines formed in this oxidation depends on the electron donor properties of the other substituents in the molecule.

Reaction of 3-(R-methylidene)-2-ethoxylindolenines with N,N'-binucleophiles

Reactions of 3-isopropylidene- and 3-cyclohexylidene-2-ethoxyindolenine tetrafluoroborates with guanidine afford dihydropyrimido[4,5-b]indole derivatives containing a hydroxy group, unlike analogous reactions of 3-arylmethylidene and 3-(dimethylamino)methylidene tetrafluoroborates.

Formation of the fused system 5H,7H-pyrido[2,3-b:6,5-b′]diindole from 3-arylidene-2-ethoxyindolenines and hydrazine hydrate

Three 12-aryl-5H,7H-pyrido[2,3-b:6,5-b′]diindoles (Ar = Ph, 4-BrC6H4, and 4-MeOC6H4) were obtained from appropriate 3-arylidene-2-ethoxyindolenines and hydrazine hydrate.

Selective acylation of 5-nitro- and 5-ethoxycarbonyl-4,6-diaryl-3,4-dihydropyrimidin-2(1H)-ones

The acetylation and chloroacetylation of 5-nitro- and 5-ethoxycarbonyl-substituted 4,6-diaryl-3,4-dihydropyrimidin-2(1H)-ones proceeds regioselectively at the N3 atom of the heterocycle whereas the acetylation of the 5-aryloxy-substituted analog results in a mixture of N1- and N3-acetylated regioisomers.