New possibilities of the functionalization of 6-hydrazino-1,3-dimethyluracils: one-pot synthesis of 5,7-dimethylpyrazolopyrimidine-4,6-dione and 1,3-dimethyl-5-arylidenebarbituric acid derivatives

3-aryl-5,7-dimethylpyrazolopyrimidine-4,6-diones and 5-benzylidene-1,3-dimethylpyrimidine-2,4,6-triones were obtained by heating hydrazones of 1,3-dimethyl-6 -hydrazinouraciles in trifluoroacetic acid (TFA). The same compounds were also obtained by heating the hydrazones of 1,3-dimethyl-6-hydrazinouraciles in aqueous ethanol in the presence of hydrochloric acid.


Introduction
Derivatives of pyrimidine (uracil, cytosine, thymine) are part of nucleic acids, which are carriers of hereditary traits in living organisms and are involved in the synthesis of proteins. The pyrimidine core is a component of bicyclic systems such as purine and pteridine. It is known that pyrazolopyrimidine derivatives have a wide spectrum of biological activity, including antimicrobial [1,2,3], antiviral [4,5], anti-inflammatory and etc. [6,7,8].
Analysis of the literature showed that pyrimidopyrazoles were obtained in the presence of an easily leaving group in the hydrazinouracil molecule, which undergoes ipso-substitution followed by annulation of the pyrazole ring.
In this work, we have studied the transformations of 6-hydrazino-1,3-dimethyluracil to find ways to synthesize new potentially biologically active compounds, as well as to improve the methods for preparing known compounds.

Experimental
Unless otherwise indicated, all common reagents and solvents were used from commercial suppliers without further purification.
The reaction progress and purity of the obtained compounds were controlled by TLC method on Sorbfil UV-254 plates, using visualization under UV light. Melting points were determined on a Stuart SMP10 melting point apparatus. 1  1,3-Dimethyl-6-hydrazinopyrimidine-2,4-dione 1 was obtained according to the method described in [13].
The general method for the synthesis of hydrazones 2а-c 1.0 mmol of hydrazine 1 was dissolved in a mixture of 3 ml of water and 3 ml of alcohol, 1.0 mmol of aldehyde dissolved in 5 ml of alcohol was added to the resulting solution, and the mixture was heated for 1-2 minutes. The formed precipitate was filtered off, washed with 1 ml of alcohol.
6-(2-benzylidenehydrazinyl)-1,3dimethylpyrimidine-2,4(1H,3H)-dione 2а. Yield  Reactions of hydrazones 2a-c with TFA 0.5 mmol of hydrazone 2 was heated in 1.5 ml of TFA in a closed vessel at 110 ° C for 85-90 hours. The solvent was removed in vacuo. The solid residue was treated with 3 ml of ethanol. The resulting precipitate of product 4 was filtered off. The alcoholic mother liquor was treated with 1-2 ml of water, the precipitate that formed was filtered off to obtain product 3. -4,6(5H,7H)  0.02 Mmol of the corresponding compound 2 in 3 ml of ethanol and the presence of 0.25 ml of concentrated hydrochloric acid was kept at reflux for 2.5-3 hours. The reaction mixture was cooled, precipitate 4 was filtered off.
Reaction of 1,3-dimethylbarbituric acid with aldehydes. 0.05 mmol of barbituric acid 5 was heated in 5.0 ml of ethanol with 0.05 mmol of the corresponding aldehyde in the presence of 0.25 ml of HCl for 25-30 minutes. The reaction mixture was cooled, the precipitate of the corresponding product 4 was filtered off.
The melting points and spectral characteristics of the obtained compounds 4a-c were similar to those obtained earlier.

Results and Discussion
We used hydrazones 2a-c, as objects of study, obtained by short-term heating of 1,3-dimethyl-6-hydrazinouracil 1 in aqueous-alcoholic solutions with the corresponding aldehydes in the presence of HCl (Scheme 1).
We found that heating hydrazones 2а-c in TFA gave 5,7-dimethylpyrazolopyrimidine-4,6-diones 3а-c and 5benzylidene-1,3-dimethylpyrimidine-2,4,6-trione deriva-tives 4а-c. Considering the literature data, it can be assumed that the formation of pyrazolopyrimidines 3a-c occurs through the 5-trifluoroacyl intermediate A. The formation of intermediate A occurs as a result of acylation of the starting hydrazones 2a-c of TFA. During this process, water is released and the process of cleavage of hydrazones with the formation of compounds 4a-c is started.
To confirm the proposed reaction mechanism, we investigated the transformations of hydrazones 2 upon heating in aqueous ethanol in the presence of hydrochloric acid. As a result of the reactions, derivatives of barbituric acid 4a-c were obtained (Scheme 2).
The formation of arylidene derivatives apparently occurred as a result of the transfer of the aldehyde group from the hydrazine fragment to the 5-position of the pyrimidine nucleus with the formation of intermediate A.
Then, acid hydrolysis of the hydrazino group of intermediate A took place, giving derivatives of barbituric acid 4.
Products 4a-c were also obtained by heating 1,3dimethylbarbituric acid 6 with the corresponding aldehydes.