Thermal Rearrangement of Allyl Substituted Unsymmetric 4H-1,2,4-Triazoles to the Corresponding 1H-1,2,4-triazoles.

A series of neat 4-(2-alkenyl) substituted 5-methyl-3-phenyl-4H-1,2,4-triazoles were thermolyzed at 320 °C producing a rearrangement products, of which the regioisomeric 1- and 2-substituted triazoles were the main products. The group migrations were rationalized in terms of consecutive SN2-type reactions. This mechanism was supported by a study of the alkylations of the triazoles which gave similar product mixtures. 4-(2-alkenyl) substituted 3- phenyl-4H-1,2,4-triazoles, on the other hand, gave predominantly elimination products.


Introduction
The thermal rearrangement of 4-allyl substituted 3,5-diphenyl-4H-1,2,4-triazoles to the corresponding 1-allyl-substituted compounds has been reported earlier [1]. The mechanistic pathway for the group migration was rationalized in terms of successive S N 2 / S N 2' type reactivity, as has also been observed before for the 4-alkyl substituted triazoles [2]. Small amounts of substituted pyridines were also isolated, formation of which were believed to take place via an initial allyl shift reaction from the 4-N position to one of the ring carbon atoms forming a sp 3 hybridized carbon, thus facilitating a subsequent ring cleavage, Scheme 1. To further investigate the generality of such a mechanistic pathway substituent effects were studied. The rationale for this, was that as different substituent exhibit different migratory aptitudes, either of the substituents in the sp 3 -intermediate may migrate. Depending on the substitution this may therefore lead to different type of products and at the same time shed light onto the mechanisms involved. A series of new 4-allyl-and 4-benzyl-substituted 3-phenyl-4H-1,2,4-triazoles was therefore prepared, with either a proton or a methyl group as 5substituent, and their thermal behavior was investigated.
Thermolysis of 50 mg samples in evacuated, sealed glass tubes was carried out at 320 o C for exactly 20 min. This was accomplished by inserting the sample tubes into a closely fitting hole in a large metal block, functioning as a heat reservoir, placed in an oven kept at the desired temperature. In addition, a temperature probe was inserted in the hear reservoir. The compositions of the reaction mixtures were determined by GLC analyses and the identity of the products were determined by comparison to authentic samples or by their characteristic spectroscopic properties. Table 1. Products formed by thermolysis at 320 o C of the neat allyl substituted triazoles.
The 4-allyl-and 4-(2-butenyl)-substituted 3-phenyl-4H-1,2,4-triazoles, 15 and 23 exhibited a different reactivity under the standard reaction conditions. Thus, 15 did not yield the expected rearrangement product but gave as the main products the allyl isomerization products, cis-and trans-4-(1-propenyl)-4H-1,2,4-triazoles, 16 and 17, which were merely the results of double bond migrations in the allyl group. Only 6 % of the 1-substituted was formed and then also here as the corresponding vinylic products 19 and 20. No traces of the allylic rearrangement products 21 and 22 were detected. The corresponding 4-(2-butenyl)-substituted triazole 23 exhibited an unexpected behavior, and gave a rather complex product mixture with the elimination product 18 as a major product (25 %) together with minor amounts of S N 2-type products 24 and 24 (20 %) and the S N 2'-products 26 and 27 (9 %). In addition was isolated small amounts of a product 28 (5 %) which structure was not identified but appeared to be an isomer of the major product, 29 (28-37 %), which based on spectroscopic properties was assigned the structure 1,3-di(3-phenyl-1H-1,2,4-triazol-1-yl)butane.
That the 4-(2-butenyl)-substituted triazole, 23, so readily undergo an elimination reaction may be ascribed to reduced steric hindrance compared to triazole, 7, facilitating an elimination pathway which may be rationalized as shown in Scheme 2.

Scheme 2. Mechanism for the elimination of butadiene group upon thermolysis of triazole, 23
The build-up of high concentrations of 18 may also be a prerequisite for the formation of product 29, which may be formed by a simple addition of triazole 18 over the double bond in the unsaturated side chain of the rearranged triazole 24 (or 25) as indicated in Scheme 3.

Scheme 3. Formation of product 29
Support for this mechanism was established by a control experiment, where thermolysis under the standard conditions of a mixture of the authentic triazoles 18 and 24 gave rise to formation of the same product 29.
Thermolysis of the 4-benzyl substituted triazoles was straightforward as well, yielding exclusively the corresponding 1-and 2-benzyl substituted products (Table 1). Contrary to what was observed for 3,5-diphenyl triazoles, formation of substituted pyridines was never observed. Triazoles 1, 7 and 12 showed a preference for group migration to the triazole N1-atom. In the context of the proposed S N 2-type mechanism, this was in reasonable agreement with the selectivities observed for alkylation of triazoles 6 and 18 (Table 4). Uda et al. [4] in a study showed that the selectivity in the N-alkylation of 1,2,4-triazoles was mainly controlled by steric factors. In our study thermolysis of the benzyl substituted triazole 12 gave a 58 : 42 mixture of the 1-and 2-benzyl triazoles. The 3-phenyl group may stabilize a developing negative charge on the N-1 atom, in agreement with reports by Gautun et al.
[2] that electronic effects may control the regioselectivity. The regioselectivity in the rearrangement was further compared to the selectivity observed for the alkylation reactions with the anion of triazoles 6 and 18 in DMF. Conveniently, this study also supplied necessary reference compounds.
Allylations of 6 and 18 were carried out in DMF with the appropriate bromo-alkenes in the presence of sodium hydride. The reactions with 6 readily gave the desired products in good yields. However, alkylations of 18 were less successful, as all products were isolated in low yields only, 3-10 % after preparative chromatography. An important competing reaction appeared to be decomposition of 18 under the reaction conditions. The nature of this decomposition is so far not clear. and 14 in a 90:10 ratio. The regioisomers were all isolated by preparative TLC or flash chromatography. The identities of the regioisomers were established by NMR and NOE-measurements. E.g., the assignment of structure 13 was based on the increased of intensity of the CH 3 -NMR signal upon irradiation of the benzylic CH 2 -signal. In addition, the 1 H-NMR spectra of all the N-1-alkylation products, the orto-protons of the 3-phenyl group were shifted 0.4-0.5 ppm downfield to approx. 8.0 ppm, relative to triazole substituted at the N-2 nitrogen. The regioselectivities were then determined by GLC analysis. The results are summarized in Table 4. The tendency in regioselectivity was the same for thermolysis at 320 o C as for alkylation at room temperature. Ratios were in better agreement for the less hindered 5-hydrogen-substituted systems than for the more hindered 5-methyl substituted triazoles. These results therefore constitute an additional support for the proposed nucleophilic displacement mechanism.
Other groups have studied thermal rearrangement reactions with triazoles. Thus Gilchrist and coworkers [13] showed that 3,4,5-triphenyl-triazoles undergo a 1,5-shift reaction under vacuum flash conditions. Similar observations were done by Habraken et al. [8] for 1-nitro-1,2,4-triazoles. In light of these results, it may be surprising that in our study, no sign of products were isolated or could be detected, that corresponded to migration of the allyl moiety from 4-to the 3-or 5-positions of the triazoles. The possibility of intramolecular [2,3]-allyl shifts taking place was therefore ruled out.

Conclusions
The type of substituent in the 5-ring position of the triazole clearly had a major effect of the outcome of the thermolyses. Changing the substituent from a hydrogen-into a methyl-or phenyl group made rearrangements via a nucleophilic substitution mechanism to be dominant. Thus, 4-allyl-3phenyl-5-methyl-4H-1,2,4-triazole yielded only rearrangement products that can be derived from S N 2 and S N 2'-type mechanisms. The corresponding 4-allyl-3-phenyl-4H-1,2,4-triazole in addition formed large amounts of elimination products. The reason for this difference in behavior is not clear, but can best be rationalized by differences in stereoelectronic properties. chromatograph equipped with a CP-Sil 5 CB capillary column (25 m). GLC analyses were performed on a Perkin-Elmer Autosystem gas chromatograph equipped with a CP-Sil 5 CB capillary column (25 m).

Base catalyzed isomerization of allylic substituted triazoles. General procedure.
To solutions containing the appropriate triazole (0.15-0.20 g) in dry THF (5 mL) was added catalytic amounts of potassium tert-butoxide (0.02 g). The reaction mixtures were stirred at room temperature for 6 days, then quenched by addition of water and the solvent evaporated under reduced pressure. The residues were dissolved in dichloromethane (20 mL) and the solutions dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The pure products were obtained after flash chromatography or recrystallization.

Alkylation of 1,2,4-triazoles. General procedure.
To a solution of the appropriate triazole (6 or 18) in DMF (20 mL/g of triazole) under a nitrogen atmosphere was added sodium hydride (1-2.5 eq). The mixture was stirred for 1 h at room temperature and then added the alkenyl bromide (1.5 eq). The resulting reaction mixture was stirred overnight, and then added water. The solution was concentrated under reduced pressure and dissolved in dichloromethane. The solution was washed with 1 M HCl, 1M NaOH, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Reaction mixtures from the alkylation of 18 were dissolved in ethanol and filtered before the solvent was evaporated under reduced pressure. The products were separated by preparative TLC (silica / multi elution with chloroform). -5-methyl-3-phenyl-1H-1,2,4-triazole (4) and 1-allyl-3-methyl-5-phenyl-1H-1,2,4-triazole (5).