SYNTHESIS AND N-ALKYLATION OF DIETHYL 4 , 7-DIHYDROAZOLO [ 1 , 5-a ] PYRIMIDIN-5 , 6-DICARBOXYLATES

It has been shown that the ternary condensation of oxaloacetic ester (diethyl 2-oxosuccinate), aromatic aldehydes and 3-amino-1,2,4-triazole or 5-aminotetrazole in dimethylformamide results in formation of the corresponding diethyl 7-aryl-4,7-dihydroazolo[1,5-a]pyrimidin-5,6-dicarboxylates. By 1H NMR spectroscopy (according to the data of the chemical shifts of C(2)H-protons for the corresponding N(4)Hand N(4)-methylderivatives of 7-phenyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-5,6-dicarboxylate) it has been found that alkylation of 4,7-dihydro[1,2,4]azolo[1,5-a]pyrimidin-5,6-dicarboxylates in the acetonitrile–saturated water alkali system leads selectively to formation of N(4)-alkyl derivatives. Both the starting compounds obtained and their N(4)-methylsubstituted analogues together with relative diethyl 4-aryl-3,4-dihydropyrimidin-2(1H)-on-5,6-dicarboxylates, 6-unsubstituted 4-aryl-3,4-dihydropyrimidin-2(1H)-on-5-dicarboxylates and the derivatives of 6-COR-7-aryl-4,7-dihydro[1,2,4] triazolo[1,5-a]pyrimidines are the promising objects for studying benzyl C(7)-functionalization of 4,7-dihydroazolo [1,5-a]pyrimidines, as well as of reactions associated with the presence of double C=C-bonds activated by two electron withdrawing groups. Obtaining of the key N(4)Hand N(4)Ме-derivatives of 7-phenyl-4,7-dihydro[1,2,4] triazoloand tetrazolo[1,5-a]pyrimidin-5,6-dicarboxylates also opens the way to the research of biological properties of the compounds of this class. It is noteworthy that being a three-component one the reaction studied, without any doubts, are appropriate for the synthesis of the derivatives of 7-aryl-4,7-dihydro[1,2,4]triazoloand tetrazolo[1,5-a]pyrimidines containing two electron withdrawing substituents in positions 5 and 6.

However, the compounds of type 4b should not have these disadvantages: a) the allyl (benzyl) position is the only one in the structure; b) alkylation of such compounds should be selective due to additional activation with 6-ethoxycarbonyl group; c) the benzyl position is also activated by withdrawing a substituent in position 6; d) there is no hydrogen atom being able to be metallated in the heterocycle (for tetrazole derivatives).
Thus, the aim of the study was the synthesis of the compounds of type 4a (Ar = Ph) and the study of their methylation.
Alkylation of the compounds 5 obtained was studied in DMF/NaH and MeCN/KOH-H 2 O systems.The second variant seemed to be the most convenient, and it allowed to isolate N-alkylderivatives with a good yield (Scheme 2).
It is interesting that unlike the above-mentioned alkylation of 6-acetyl-5-methyl-7-phenyl-4,5-dihydro [1,2,4]triazolopyrimidine [8] the process in this case occurred selectively (which was favoured by 1 H NMR-spectra of the products obtained).In contrast to the 1 H NMR spectrum of the initial compounds 5, the signal of NH-protons is absent in a low field, but the signal of NCH 3 -group is present.
In our opinion, the only products of the reaction are exactly N(4)-methylderivatives (but not the possible N(3)-isomers).As evidence we give the following suggestion.For instance, the chemical shift of the signal of C(2) proton for compound 3c is 7.63 ppm, for N(3)-methylderivative 3e -8.31 ppm (Fig. 2) [8].The fact of such a considerable shift of the signal of the given proton, in our opinion, may be explained by the presence of the resonance form of type 3.1e.Such a mesomer can not be for structure 3d, so the chemical shifts for C(2) protons for compounds 3c and 3d do not differ fundamentally.
As it is seen in Fig. 2, the difference in the chemical shifts of C(2) protons for compounds 5a and 6a is only 0.07 ppm.This gives reason to believe that the alkylated product has exactly the structure of compound 6a.
At the same time, IR-spectra of compounds 5 and 6 differ considerably: the broad bands corresponding to stretching vibrations of NH-bonds in the region of 2800-3300 Cm -1 are characteristic for com-pounds 5.However, the similar signals are absent in IR-spectra of N-methylsubstituted 6a,b.Furthermore, the change in the melting points of the compounds obtained is the evidence of disappearance (or decrease) of intermolecular H-bonds: 202-4°С (5a) → 103-5°С (6a) and 174-6ºС(5b) → 113-5°С (6b).
It is noteworthy that the benzyl proton in the product 1d obtained is additionally activated by the nitrogroup.

Experimental Part
1 H NMR spectra were recorded at 200 MHz using a Varian Mercury VX-200 spectrometer with Si(CH 3 ) 4 as an internal standard, chemical shifts are given in ppm, coupling constants are given in Hz.IR spectra were recorded in KBr pellets using a Specord IR-75 spectrometer.Elemental analyses were carried out using an EuroEA-3000 element analyzer.The purity of the compounds was checked by TLC (Merck ALU-GRAM Xtra SIL G/UV 254 plates) with EtOAc-hexane and EtOAc-CH 2 Cl 2 mixtures as eluents developing by UV-light and iodine vapours.Melting points were determined using a Köfler hot-stage apparatus.OAE was obtained, as pointed in the source [15], ethyl 3,3-diethoxyproponoate was synthesized by the method [8].DMF was distilled under reduced pressure and stored under molecular sieves, HOAc was freezed for water deleting [16].
All the other reagents and solvents were commercially available and were purchased from SPE "Ukrorgsynthez".

1 H
NMR-spectra of the compounds obtained contain the signals of N(4)-protons in low fields, the signals of aromatic protons, the singlet of C(7)H-proton and the signals of two EtO-groups.Besides, for compound 5a the signal of C(2)-proton at 7.70 ppm (separately from aromatic protons signals) is observed.

Fig. 1 .
Fig.1.The known compounds and the objects of research.

Fig. 2 .
Scheme 1.The synthesis of the starting compounds.