Regioselectivity in the Thermal Rearrangement of Unsymmetrical 4-Methyl-4H-1,2,4-triazoles to 1-Methyl-1H-1,2,4-triazoles

The rearrangement of 4-methyl-3,5-diaryl-4H-1,2,4-triazoles to the corresponding 1-methyl-3,5-diaryl-1H-1,2,4-triazoles showed regioselectivity comparable to that observed for the alkylation of 3,5-diaryl-1H-1,2,4-triazoles. This lends support to a proposed mechanism for the rearrangement that involves consecutive nucleophilic displacements steps.


Introduction
Previous studies of the thermal rearrangement reactions of 4-alkyl substituted 4H-1,2,4-triazoles to the corresponding 1-alkyl-1H-1,2,4-triazoles provided evidence supporting the existence of intermolecular nucleophilic displacement reaction pathways, proceeding through the formation of dialkyltriazolium triazolate ion-pair intermediates or neutral molecules in a chain reaction [1]. The nucleophilic nature of these rearrangements therefore suggests that electronic effects may play a role in their outcome. Alkylation of 3,5-disubstituted-1H-1,2,4-triazoles has also been reported to take place exclusively at the ring 1-position [2]. On alkylation of unsymmetrical substituted triazoles Uda et al. [3] found that the 1-2 selectivity was affected by the nature of the substituents, and that alkylation takes place preferentially at the nitrogen next to the ring-carbon with the most electron donating group [3]. The selectivity was assumed to be a result of stereoelectronic control. The nucleophilic nature we have proposed for the rearrangement of 4-alkyl-3,5-diphenyl-4H-1,2,4-triazoles to the corresponding 1-alkyl-3,5-diphenyl-1H-1,2,4-triazoles should therefore also exhibit sensitivity to electronic effects. In this paper we report a study of the regioselectivity for the rearrangement of a series of unsymmetrically substituted triazoles.

Results and Discussion
A series of triazoles of the general structures 1 and 2 were required for this study. They were readily prepared by a modification of a procedure using unsymmetric bis(α-alkylaminobenzylidene)-hydrazines, 5, which has been described earlier [4] and is outlined in Scheme 1. Compounds 5 were formed from the corresponding N,N'-diarylhydrazides, 6, which in turn were obtained by reacting aroyl chlorides 7 with monohydrazide 8. In the synthesis of compound 2 a 40% aqueous methylamine solution was used. For the synthesis of triazole 1 saturated NH 3 in 2-propanol was used, which was found to be superior to a procedure described previously by Stollè et al. [5].

Scheme 1
The synthetic results are summarized in Table 1. The yields are those of the pure products obtained after recrystallization or sublimation.  A series of neat unsymmetrical substituted 4-methyl-3,5-diaryl-4H-1,2,4-triazoles, 2, were next thermolyzed at 330 o C for 30 min to investigate the regioselectivity as a function of the electronic conditions induced by the para-substituents in one of the phenyl rings. These results were also compared with those obtained for the selectivity upon alkylation of the corresponding unsymmetrical 3,5-diaryl-1H-1,2,4-triazoles, 1, with methyl iodide. The general reactions are shown in Scheme 2.

Scheme 2
The thermolyses were carried out with samples of the appropriate triazoles in sealed glass tubes under nitrogen at ca. 330 o C for 30 minutes. The unsymmetrically substituted triazoles rearrange, as expected, to yield mixtures of the two possible regioisomers, i.e., the methyl group migrated to the a-and b-ring positions respectively, as indicated in Scheme 2, thus forming compounds 3 and 4. The product distributions are compiled in Table 2. The results of alkylation of triazole 1 with methyl iodide in DMF using sodium hydride as base are also shown.  The regioisomer ratios were determined by 400 MHz proton NMR spectroscopy of the crude reaction mixtures by measuring the intensities of characteristic signals. The assignment of the regioisomers was based on comparison of the NMR spectra to those of authentic samples of triazoles 3 [8], which were prepared by independent syntheses. Triazoles 4 were not prepared independently. The experiments were repeated and results were found to be reproducible within 1-2% of the values reported in the Table. Authentic samples of the methyl substituted triazoles 3 were prepared using a modification of a method developed by Huisgen and coworkers [6], by reacting 2-methyl-5-phenyl-1H-1,2,3,4-tetrazole [7] with the appropriate 4-substituted benzonitriles, 4-X-Ph-CN, which in general gave better yields than were reported before.
The results reported in Table 2 provide support for the proposed mechanism for the rearrangement reactions. The data from the thermolysis series and the alkylation series, respectively, exhibited the very same trend with respect to regioselectivity. This supports the feasibility of a nucleophilic type mechanism in the rearrangements. The ratios were not identical. However, first of all, the reaction conditions were very different, as were the systems that were reacted. At high temperatures, selectivity will usually diminish. In the two systems, i.e., triazole 1 and 2, the electronic effects of the substituents may also be transmitted to a different extent to the reaction sites. Thus, it was shown by X-ray crystallography, that due to steric interactions with the methyl group, the phenyl ring in 2 are twisted approx. 44 -48 degrees out of the triazole ring plane, thereby diminishing the overlap of the π-electron systems [8]. Triazole 1, on the other hand is nearly planar, with the phenyl ring only 8-9 degrees out of plane [9]. Therefore, the trends are similar, but the transmission of electronic effects is diminished for triazoles 2. Electron donating substituents in the aryl group resulted in an increased electron density and therefore increased nucleophilicity at the a-position (Scheme 2). As a result of this, products 3 were slightly predominant for aryl groups para-substituted with methoxy-and methyl groups respectively. The opposite effect, as expected, was clearly observed for the electron withdrawing substituents (Cl-, CF 3 -).

Scheme 3
1 H-and 13 C-NMR spectra were recorded on a JEOL JNM-EX400 FT NMR spectrometer, using CDCl 3 as the solvent (unless otherwise indicated) and tetramethylsilane (TMS) as the internal standard. IR and GC-IR spectra were obtained on a Nicolet 20-SXC FT-IR (GC Carlo Erba 5160, 25 m, CP-Sil-5 CB). Mass spectra were recorded on a AEI MS-902 spectrometer at 70 eV (IP). GC measurements were performed on a Varian 3700 capillary gas chromatograph.

3-(4-Trifluoromethylhenyl)-4-methyl-5-phenyl-
The appropriate substituted di(α-chlorobenzylidene)hydrazine, 5, (2 mmol) was dissolved in 2-propanol (100 mL) saturated with NH 3 , and the resulting mixture was stirred at room temperature overnight and finally refluxed for 30 h. Evaporation of the solvent under reduced pressure gave the crude product, which was further purified by crystallization or sublimation. The spectroscopic properties were all in agreement with those reported in the literature [15].