G. G. Danagulyan

Kost-Sagitullin Rearrangement and Other Isomerization Recyclizations of Pyrimidines. (Review)

Data on the isomerization recyclizations of pyrimidines, particularly the Kost-Sagitullin and other transformations accompanied by substitution of an endocyclic atom in pyrimidine by an extracyclic nitrogen or carbon atom (N-N, N-C, or C-C recyclizations), are summarized and analyzed. Data from research on the Kost-Sagitullin and certain other isomerization transformations of pyrimidines at the Institute of Organic Chemistry, National Academy of Sciences of the Republic of Armenia, in recent years are presented.

Recyclization of Condensed Carbethoxypyrimidines Accompanied by Substitution of a Carbon Atom into the Heterocycle

Condensation in ethanol of ethyl ethoxymethyleneacetoacetate with systems containing an amidine fragment (substituted 3-aminopyrazoles and 3-amino-1,2,4-triazole) gave 6-carbethoxy-7-methylpyrazolo[1,5-a]pyrimidines. Addition of base to solutions of the obtained bicyclic carbethoxy derivatives in the course of several minutes caused rearrangement to 6-acetyl-7-hydroxypyrazolo[1,5-a]pyrimidine and 6-acetyl-7-hydroxy-1,2,4-triazolo[1,5-a]pyrimidine respectively. A more prolonged refluxing in 15% aqueous alcohol solution of base caused 6-carbethoxy-7-methyl-2-phenylpyrazolo[1,5-a]pyrimidine and 6-acetyl-7-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidine to recyclize to 7-methylpyrazolo[1,5-a]pyrimidine.

RECYCLIZATION OF PYRIMIDINIUM SALTS INTO 1,2,4-TRIAZOLE DERIVATIVES

The interaction of the iodomethylates of pyrimidinyl-2-acetic acid derivatives with monosubstituted hydrazines, in addition to the products of a Kost-Sagitullin rearrangement, leads also to N-substituted triazoles. The structure of the triazoles was demonstrated by NOESY NMR experiments. The structure of the reaction products was determined on the basis of the response observed in the spectra between the methyl group protons of the triazole ring and the spatially close proton of the substituent in position 1 and a conclusion was drawn on the direction of the primary attack of nucleophile in the recyclization process of the pyrimidinium salts into a 1,2,4-triazole.

Intermediates in the transformation of 1,2-dialkylpyrimidinium iodides in the Kost-Sagitullin rearrangement

Intermediate recyclization products were obtained in a study of the Kost-Sagitullin rearrangement of a series of 1,2-dialkylpyrimidinium iodides. The initial attack of the nucleophile leads to the formation of products of the addition of the hydroxyl group, namely, the corresponding pseudo bases. Heating one of these intermediates in ethanol or in the presence of primary amines leads to rearrangement to give a pyridone derivative. Upon heating in chloroform, the pseudo bases readily lose a water molecule and are converted to anhydro bases, namely, derivatives of 1-alkyl-1,2-dihydro-2-methylidenepyrimidine.

EFFECT OF THE AMOUNT OF SODIUM ETHOXIDE ON THE DIRECTION OF CYCLIZATION IN REACTIONS OF AMIDINES WITH ETHOXYMETHYLENE ACETOACETATE

Recyclization of pyrimidines occurring with substitution of the endocyclic carbon atom C(4) by a nonring carbon atom of the 5-ethoxycarbonyl group was reported earlier in [1, 2]. Such a rearrangement was classified as C–C recyclization of pyrimidines, in contrast to N–N recyclization (the Dimroth rearrangement) [3] and N–C recyclization (the Kost–Sagitullin rearrangement) [4]. In studying the condensation of hydrochlorides of acetamidine (1a) and phenylacetamidine (1b) with ethoxymethylene acetoacetate in the presence of sodium ethoxide, we noted that the amount of sodium ethoxide has a considerable effect on the direction of heterocyclization. We found that for an equimolar ratio of the amidines, ethoxymethylene acetoacetate, and sodium ethoxide, we obtain 5-ethoxycarbonyl-2-methyl(2-benzyl)4-methyl-pyrimidines 2a,b in high yield; while for a two-fold excess of sodium ethoxide relative to the amounts of the reagents used, 5-acetyl-4-hydroxy-2-methyl(2-benzyl)pyrimidines 3a,b are formed. We hypothesize that in the case of an excess of sodium ethoxide, as for an equimolar ratio of the reagents, the reaction initially occurs with formation of compounds 2. However, during treatment, the base formed in the presence of water (for excess sodium ethoxide) leads to recyclization of compounds 2 to form pyrimidines 3.

Direction of the primary nucleophilic attack in the Kost-Sagitullin rearrangement

In work on the Kost–Sagitullin rearrangement [1], we proposed the possibility of the primary attack of the nucleophile at C(2) of the pyrimidine ring. Previously, the rearrangement of pyrimidines was thought possible only through attack at C(6) of the heterocycle [2, 3]. In the present communication, experimental results are given, which support our previous hypothesis. The action of an equivalent of potassium hydroxide in ethanol on 2-ethoxycarbonylmethyl-1,4,6trimethylpyrimidinium iodide (salt 1) in cold ethanol gave a yellow product, which is the adduct of the covalent addition of a hydroxyl group at C(2). The structure of this compound was supported by H NMR and IR spectroscopy. The H NMR spectrum of product 2 shows a broad signal for the hydroxyl group proton. The signals of all the groups attached to the pyrimidine ring are shifted upfield relative to the signals of the protons in the salt [4]. The greatest shift (2.49 ppm) is noted for 5-H, which is directly attached to the heterocycle. The H NMR spectrum holds indirect evidence for the formation of an intramolecular hydrogen bond between the hydroxyl group and carbonyl oxygen atom of the ester group, leading to a structure, in which the protons of the methylene side-group are no longer identical. The existence of such a hydrogen bond is indicated by the IR spectrum of the product, in which the stretching band of the ester carbonyl group is shifted by 90 cm relative to the position of this band in the spectrum of the starting salt (1640 vs. 1730 cm). The spectrum of the compound studied also shows a band for the hydroxyl group at 3300-3500 cm (no such band exists in the IR spectrum of the starting salt) and bands for conjugated double bonds at 1510, 1540, and 1600 cm. We should note that dilution of the solution of this compound in CCl4 does not lead to shift in the carbonyl group frequency. This unequivocally indicates the existence of an intramolecular rather than intermolecular hydrogen bond, which is possible only upon addition of the hydroxyl group at C(2). The mass spectrum of adduct 2 shows the molecular ion peak [M] at 208, which corresponds to the mass of a molecule formed upon the elimination of water from 2, i.e., the mass of the anhydro base 3. The mass spectrum of the starting salt itself did not reveal a peak corresponding to the anhydro base.