1,3-Dipolar Cycloaddition Reactions of Substituted Benzyl Azides with Acetylenic Compounds

We review in this article some of our work which has been published over the last fifteen years in the area of 1,3-dipolar cycloaddition reactions of substituted benzyl azides with acetylenic compounds to form the corresponding 1,2-3-triazoles. Several triazole derivatives were transformed into triazolopyridazine and triazolo-1,3,4-oxadiazole derivatives upon their reactions with hydrazine.


Introduction
Azides are considered very important compounds due to both their industrial as well as biological applications [1]. Azide derivatives have been used in rubber vulcanization, polymer crosslinking, dyes, tire cored adhesives, foaming of plastics, pharmaceuticals, pesticides and herbicides [1]. Many azide compounds show mutagenic activities [2][3][4].
Over the last fifteen years we have contributed extensively to this field. Thus, in 1986 we reported the preparation of bis(azidomethyl)benzenes 1a-c and their reaction with acetylendicarboxaldehyde bisdiethylacetal to form the phenylenebis(methylene)bis(triazole-4,5-dicarboxaldehyde)tetrakis(ethyl acetals) 2a-c as shown in Scheme 1 [18].

Scheme 4
On the other hand, the reactions of azides 9a-r with phenylacetylene afforded, as expected and revealed by thin layer chromatography, a mixture of two isomeric products in over 85% overall yield. The isomeric triazoles 11a-r, 12a-r are shown in Scheme 4. The product mixtures were separated by preparative thin layer chromatography using silica gel and a toluene-ethyl acetate mixture as eluent. The relative ratios of the two isomeric products was found to be in the range of 10:90 to 40:60. Surprisingly, the isomers separated in each reaction gave identical IR and 1 H-NMR spectral data and melting points. This might be due to the similarity of the chemical environment of the protons in either position 4 or 5 in the triazole ring. The less hindered triazoles 11a-r are believed to be the major products on the basis of steric considerations. This assignment is quite compatible with the reported results of Tsypin and Mihelcic and their co-workers on the addition of heterocyclic and aliphatic azides to phenylacetylene [23][24]. Unlike the reactions with phenylacetylene, the reactions of azides 9a-r with ethyl propiolate were found to be completely regiospecific. Thin layer chromatography using different solvent systems confirmed the presence of a single product in each reaction. These products are believed to be triazoles 13a-r as depicted in Scheme 4.
In 1991, we reported the reactions of bis(azidomethyl) benzenes 1a-c with several substituted acetylenes that formed the corresponding bistriazoles [26]. Thus 1,2-, 1,3-and 1,4-bis (azidomethyl) benzenes (1a-c) underwent cycloaddition reactions with dimethyl-, diethyl-and di-tert-butyl acetylenedicarboxylate, respectively, in methanol or ethanol at reflux temperature to form the corresponding tetramethyl, tetraethyl and tetra-tert-butyl 1,1′-(phenylenedimethylene) bis-1H-1,2,3triazole-4, 5-dicarboxylates 16a-c, 17a-c and 18a-c  Likewise, bis-azides 1a-c reacted with phenylacetylene to give a mixture of two isomeric products as revealed by thin-layer chromatography, although three isomeric products are theoretically possible as shown in Scheme 7. 1a-c 1 H-NMR spectroscopy did not differentiate between the two isomeric bistriazoles. Thus, the four benzylic protons in the product mixture appeared as a sharp singlet in the range 5.52-5.70 ppm. This is quite consistent with our previously reported results on the reactions of monoazides with phenylacetylene [22]. Although the two products were not separated, it is believed that the major products are the less sterically hindered 1,1′-(phenylendimethylene) bis-[4-phenyl-1H-1,2,3-triazoles] 19a-c while the minor products should be the isomers 20a-c on the basis of steric and statistical considerations. The isomeric bistriazoles 21a-c are excluded on the same basis. This regiochemical assignment is compatible with the literature reports, one of the recent reports being published by Fouli and co-workers [27].
In great contrast with the latter reactions, the reactions of bis-azides 1a-c with ethyl propiolate, have displayed complete regiospecificity under similar conditions. Only one product was obtained in a high yield, again, this result is consistent with our previous findings [22]. In addition, on the basis of steric and electronic factors, the products are assigned structures 22a-c as shown in Scheme 8. The remarkable difference in the reactivities of the three bis-azides 1a-c is worthy of comment. The trend is quite clear. The 1,4-isomer 1c is the most reactive whereas the 1,2-isomer 1a is the least reactive. indeed, the decisive factor is the steric hindrance which is lowest in the 1,4-bis-azide 1c and highest in the 1,2-isomer 1a [26]. Scheme 8 a, ortho b, meta 22a-c c, para Moreover, we have studied the effect of solvent and reaction time on the products of the 1,3dipolar cycloaddition of substituted benzyl azides with di-tert-butyl acetylenedicarboxylate [28]. Substituted benzyl azides 9a-r underwent cycloaddition reactions with di-tert-butyl acetylenedicarboxylate, in refluxing methanol or ethanol for 3-20 hrs producing di-tert-butyl 1-(substituted benzyl)-1H-1,2,3-triazole-4,5-dicarboxylates 23a-r in 73-94% yield, as shown in Scheme 9.

Scheme 9
The reactions of azides 9a-r with di-tert-butyl acetylenedicarboxylate, however, was found to be sensitive to the nature of the solvent being used and the type of the substituents on the phenyl ring. Thus prolonged reflux (2-3 days) of azides 9e-r in protic solvents such as methanol or ethanol resulted in the formation of the triazole monoesters, methyl 1-(substituted benzyl)-1H-1,2,3-triazole-4-carboxylates 24e-r and ethyl 1-(substituted benzyl)-1H-1,2,3-triazole-4-carboxylates 25e-r, respectively. Unexpectedly, the reaction of azides 9a-d with di-tert-butyl acetylenedicarboxylate did not show the same trend under the same conditions since the triazole diesters 23a-d were the only products obtained [28].