Syntheses of partially hydrogenated [1,2,4]triazolo[4,5-a] pyrimidine-4-ones through cyclisation of 2-arylidenehydrazino-6-methyl-4-pyrimidones

3-Arylsubstituted derivatives of 2H,3H,4H,7H - and 1H,2H,3H,4H -[1,2,4]triazolo[4,5-a]pyrimidin-4-ones were synthesized from 2-arylidenehydrazino-6-methyl-4-pyrimidones by treatment with acetic anhydride. The structures of the starting compounds and of the isomeric di-N-acetylated reaction products were established by NMR.


Introduction
Guanylhydrazones (alkylenaminoguanidines, carboximideamidehydrazones, diaminomethylene hydrazones) are condensation products of oxo-compounds with aminoguanidines.This class of compounds has been known for a long time 1 and is of considerable interest due to a wide variety of different pharmacological activities found with many representatives. 2,3Further, guanylhydrazones are valuable synthetic building blocks for ring closure reactions leading to several nitrogen-containing heterocycles. 4,5n this context, we have published the transformation of (E)-aromatic aldehyde guanylhydrazones into 3-acylamino-5-aryl-1,2-diacetyl-4,5-dihydro-1,2,4-triazoles, 6 the cyclization of N 1 -glycopyranosylamino)guanidines to 3-acetylamino-N 1 -glycopyranosyl-5methyl-1,2,4-triazoles, 7 and the synthesis of N 1 -cycloalkenyl substituted 3-acylamino-5-methyl-1,2,4-triazoles. 8All of these cyclisations are based on the reaction of guanylhydrazones with acetic anhydride in excess and proceed via an interesting type of ring closure mechanism through an acyliminium intermediate. 5,6owever, some related educts with a guanylhydrazone structure (e.g.2,6dichlorobenzaldehyde guanylhydrazone, various isatin guanylhydrazones or guanylhydrazones derived from (hetero)aryl methylketones) show different behavior and afford the corresponding N,N'-diacetyl derivatives upon treatment with acetic anhydride . 6,9,10It should be mentioned also that the attempted ring closure reaction of 2-amino-4-aryl-1-arylideneaminoimidazoles with several acid anhydrides led only to products acylated at various positions. 11Egyptian authors 13 investigated the reaction of 2-hydrazino-6-methyl-4-oxo-pyrimidine (1), 12 a cyclic aminoguanidine derivative, with aldose monosaccharides that were supposed to react in their acyclic forms like simple aldehydes.The aldehydo-sugar(6-methyl-4-oxo-2pyrimidinyl)hydrazones obtained did not undergo cyclisation upon treatment with acetic anhydride. 13Others have studied cyclisation reactions of analogous N-heterocyclic hydrazones 14- 16 and have established that the ring closure can follow two different pathways to result in the formation of polyaza-heterocycles with either linearly or angularly annellated rings [14][15][16] (cf.Scheme 3 below).In view of the divergent results with regard to the structures of the products obtained from N-heterocyclic hydrazones under acylating conditions, we have investigated the reactions of 1 with simple aromatic aldehydes and subsequent transformations of the products upon treatment with acetic anhydride.

Results and Discussion
To study the ring closure, 2-arylidenehydrazino-6-methyl-4-oxo-pyrimidines (3) were prepared by the reaction of aromatic aldehydes 2 with 1. Compounds 3a-d were prepared in good yield with acetic acid catalysis in ethanol using a described procedure. 17Product 3a could be prepared also by the cyclisation of benzaldehyde-guanylhydrazone with ethyl acetoacetate catalyzed by acetic acid.The educts 3a-d were treated with acetic anhydride under reflux and two new products could be detected after a short reaction time; these were separated by column chromatography.

Arylidenehydrazones
First, we set out to establish the structures of the condensation products of 1 with the aromatic aldehydes 2a-d.Knowledge of these structures is necessary to rationalize the subsequent reactions upon treatment with acetic anhydride.Elemental analyses and routine 1 H-and 13 C NMR spectra indicated formation of the expected hydrazone structures in the above reactions.Products 3a-d may, however, occur in three different tautomeric forms, I, II or III, each containing two sp 2 and two sp 3 nitrogens.Full characterization of these forms was achieved by 2D NMR measurements as follows.

Scheme 2. Possible tautomers of arylidenehydrazones.
The NH-protons undergo fast exchange on the NMR time scale so they are not suitable for structural characterization. 15N-HMBC connectivities were, on the other hand, instrumental in determining the prevailing tautomeric form in each of the above cases.Inspection of formulas I-III reveals that the 15 N chemical shifts of N1 and N3 in the pyrimidine ring are of diagnostic value for this purpose.Assignments of these nitrogens are straightforward from the 15 N-HMBC spectra; while H-5 can, in principle, be coupled to both N1 and N3, only N1 can give a cross peak to the CH 3 -6 protons.In fact, H-5 shows a HMBC correlation to a nitrogen with δ N ∼145 ppm in all hydrazones 3a-d, whereas the protons of CH 3 -6 are coupled to an aromatic N (δ N ∼186 ppm) in 3a, 3b and 3c and to an sp 3 -N (δ N =119.2ppm) in 3d.These chemical shifts clearly indicate the prevalence of tautomeric forms I for the former three derivatives and II for the fourth.Furthermore, occurrence of tautomer III can be safely excluded in all cases investigated.The 15 N chemical shift values of the hydrazone nitrogens in Table 1 are in full agreement 18 with these structures.In addition to tautomerism, the E/Z isomerism also is of interest in describing the structure of the hydrazones.The configuration about the CH=N -bond was found to be E in all four derivatives 3a-d from the fact that the 1 J CH -values were less than ∼170 Hz (Experimental); these values are expected to be significantly larger for the Zconfiguration. 20oducts obtained by acetylation 13 C-HMBC spectra of the acetylation products (4, 5) provide clear evidence of cyclisation reactions occurring during treatment of 3a-d with acetic anhydride.Specifically, the CH-proton at around 7 ppm in the 1 H NMR spectra displays long-range couplings to C-2 and C-4 pyrimidine carbons in each of the reaction products containing two acetyl groups.The 13 C chemical shifts of these CHs, on the other hand, are much less (∼73 ppm) than that expected for a CH=N carbon (around 150 ppm) in each of the products.Therefore, the acylhydrazone structure (Scheme 3) can be safely discounted from further considerations.Furthermore, these observations eliminate structures originating from angular type ring closure (Scheme 3).
The CH-proton of the triazole ring (H-3) displays long-range coupling to one of the acetyl carbonyl carbons in both products 4 and 5 (Scheme 4).H-3 is, in addition, weakly coupled ( 13 C-HMBC) to the other C=O carbon in 4a but not in 5a.This suggests structures for 4 and 5 as shown in Scheme 4. This hypothesis was then fully confirmed by determining the 15 N chemical shifts through 15 N-HMBC measurements.Specifically, N-7 is clearly an sp 2 , aromatic type N in 4a-d whereas 15 N chemical shifts indicate an sp 3 amide type N-7 in 5a-d (Table 2).Key 1 H/ 15 N HMBC correlations allowing unequivocal 15  A possible mechanism for the ring closure reactions is set out in Scheme 3. Acyliminium ion A, depicted in two mesomeric forms A-1 and A-2, is supposed to form, 5,6 as a first step, from tautomeric forms II of arylidenehydrazones 3a-d, via direct nucleophilic attack upon Ac 2 O. Form I may tautomerize into II under the reaction conditions.Ring closure can be effected by intramolecular nucleophilic attack either from ring N-3 or N-1 onto the formal carbocationic center in A-2, followed by deprotonation, leading to products B and C (route [1]) or D and E (route [2]).The single NH group in these intermediates is acetylated in situ in the presence of excess acetic anhydride.Since we could isolate N-acetylated derivatives (4 and 5) of [1,2,4]triazolo [4,5-a]pyrimidine tautomers (B and C) only and no products from the alternative structures D and E, route [1] appears to be favored over route [2] under the conditions employed.Inspection of Table 2 and 1 H chemical shifts (see, Experimental) reveals that the chemical shifts of H-5, C-5 and C-6 are of diagnostic value in determining the positions of the N-acetyl groups and, therefore, discriminating between 4a-d vs. 5a-d.Namely, H-5, C-5 and C-6 are all shifted upfield significantly in the 5a-d isomers (typical values being ∼5, ~96 and ~152 ppm for H-5, C-5 and C-6, respectively) with respect to those in their 4a-d counterparts (typical values at ~6, ~108 and ~164 ppm, respectively, for H-5, C-5 and C-6).These chemical shift changes reflect the presence vs. absence of the acetyl group at N-7 through substituent effects on the respective carbons and the neighbour anisotropy of the acetyl carbonyl on the H-5 chemical shift, respectively.These characteristic differences have, on the other hand, a welcome practical consequence in that they make it easy to identify the isomeric structures by simply relying on 1D 1 H-and 13 C-NMR spectra.
In summary, we have determined the tautomeric forms and the configuration of the CH=N bond in pyrimidine hydrazones 3 by NMR.It has been established that cyclisation of hydrazones 3 with acetic anhydride results in the exclusive formation of the linear type of heterobicycles featuring different acetylation patterns (4, 5).