Bis([1,3,4]thiadiazolo)[1,3,5]triazinium halides 4: 1 syntheses of azole-substituted guanidines and bis(azolyl)alkanes

The reaction of bis([1,3,4]thiadiazolo)[1,3,5]triazinium bromides 3 with 1 H [1,2,4]triazole 6 , imidazole 7 , 1-methylimidazole 8 , and benzimidazole 9 in pyridine solution yielded product mixtures containing the highly substituted guanidines N -[[(1 H -azolyl)[1,3,4]thiadiazol-3(2 H )- yl]methylene][1,3,4]thiadiazol-2-amines 10 , 11 , 12 as main products, and varying amounts 2-[[1,3,4]thiadiazol-2-yl)imino][1,3,4]thiadiazol-3(2 H -yl][1,3,4]thiadiazol-2(3 H )-ones 13 , 14 , 15 , and bis[2,3-dihydro [ (5-methyl[1,3,4]thiadiazol-2-yl)imino][1,3,4]thiadiazol-3-yl]methanes 16 , 17 , 18 [ bis(azolyl)alkanes, “aminals”], which were easily separated by column chromatography. The formation of the products appears to be the result of a novel S N (ANRORC) reaction cascade which competes with an azole catalyzed reaction. The latter causes partially ring destruction of 3 .


Results and Discussion
The reactions of azoles 6-9 with the tricyclic cations 3a-c were performed in pyridine solution by varying both reaction time and temperature (Table 1).While reactions of primary or secondary aliphatic/alicyclic amines 4 yielded up to 85% of the highly substituted guanidines 5 7,8 as the result of novel examples for S N (ANRORC) reaction, 10 the analogous reactions of azoles 6-9 with 3 led to product mixtures.These mixtures contained variable amounts of the novel azolesubstituted guanidines 10-12.Furthermore, the novel aminals 13-15, and 16-18 (Table 1) were formed.Notably, compounds 16-18 (ca.12%) had been isolated previously 4 from the product mixture resulting from the initial cyclization reaction, which transforms 1a-c and 2 into 3.The formation of products 13-18 (Scheme 2) could be caused by the well-known acid-base properties (bifunctional catalysis) of azoles. 11In our case, these azole properties give rise to a catalytic hydrolysis reaction of cations 3 (caused by atmospheric moisture) which is followed by ring destruction and by the formation of both the components used for the synthesis of 3 and 1, i.e. the 2-aminothiadiazole 2 and the corresponding aldehydes (4-methylbenzaldehyde, 1naphthaldehyde, pentanal).The aldehydes as well as thiadiazole 2 have been qualitatively identified in the reaction mixtures (GC, DC, IR, formation of 2,4-dinitrophenylhydrazones).This hydrolysis competes with the formation of the main products (guanidines 10-12) and interferes with the above mentioned S N (ANRORC) reaction.
As expected, an excess of 2 reacts with cations 3 giving the adduct 19 (Scheme 3): The amine group of 2 reacting as the nucleophile attacks the electrophilic carbon atom 3a-C of 3.After another multi-step reaction sequence, which presumably includes several intra-and intermolecular proton migrations followed by a ring-opening reaction, the intermediate 20 is formed; 20 is then attacked either by water − resulting in the formation of 13-15 − or by an additional 2aminothiadiazole molecule 2 giving rise to the formation of 16-18 with concomitant elimination of NH 4 Br.

Scheme 3
The novel compounds 13-15 are representatives of a specific class of bis(azolyl)alkanes 12 ("aminals").Interestingly, only few derivatives have been reported with 3H [1,3,4]thiadiazol-2one moieties being part of an aminal structure. 13,14The structure assignments of the guanidines 10-12, of the novel aminals 13-15, and of 17 are based on NMR data, mass spectra (CI), IR spectra, and elemental analyses.The formation of the [1,2,4]triazolyl isomers, the guanidines 10a and 10b, 11a and 11b, 12a and 12b is not unexpected owing to the fact that [1,2,4]triazole 6 is an ambident nucleophilic species. 15oth the simple separation procedure for the isomeric products by column chromatography and the reliable structure determination by 1 H/ 13 C NMR correlation spectroscopy (HMQC, HMBC, DEPT) qualifies these compounds for future investigations.We believe that due to the biological significance of some azoles an increasing interest in the synthesis of such highly azole-substituted compounds can be expected. 16Especially, we are interested to use such compounds for modifying the biologically active sites of zinc complexes to study the chemistry of zinc by the modulation of its coordination environment. 17Azoles 6-9 are commercial products (Sigma-Aldrich Fine Chemicals) and were used as acquired.
General procedure for the reaction of azoles 6-9 with the 5/6/5-heterocycles 3 To a suspension of 3a−c (5 mmol) in pyridine (60 mL) was added the azole 6, 7, 9 (10.15 mmol) or 8 (5.10 mmol) (reaction temperature and time cf.Table 1).The suspension gradually changed to a clear solution.The solvent was evaporated in vacuo, and the residue was washed with ice water.The resulting crude product mixture was subjected to column chromatography (eluent: ethyl acetate).The separation of the products 10-18 was monitored by pre-coated plastic sheets for TLC (Polygram ® SIL G/UV 254 , 0.2 mm silica gel).

Table 1 .
Continue Determined by column chromatography.c Determined by 1 H NMR spectroscopy.
a Based on 3. b