Synthesis of the Triazole Ring

Most of the important general methods of forming IZf-triazole derivatives involve azides several reviews discuss aspects of the formation of triazoles in this way. a-Diketones are also important precursors of both H- and 2 f-triazoles. Triazoles unsubstituted on nitrogen can be prepared by the direct addition of hydrazoic acid or of azide ion, but it is often more convenient to obtain these compounds by removal of a substituent from a H- or 2if-substituted triazole (Section IV, E). 

The thermal cycloaddition of azides to acetylenes is the most versatile route to 1,2,3-triazoles, because of the wide range of substituents that can be incorporated into the acetylene and azide components. The accepted mechanism for the reaction is a concerted 1,3-dipolar cycloaddition. The rates of addition of phenyl azide to several acetylenes have been measured the rates of formation of the aromatic triazoles are not appreciably different from the rates of cycloaddition to the corresponding olefins, indicating that the transition-state energy is not lowered significantly by the incipient generation of an aromatic system. 

Few unsymmetrical acetylenes give exclusively one isomer. Ynamines are exceptional in that they are reported to give solely the isomer with 

Alonso, M. T. Garoia-L6pez, G. Garcia-Muhoz, R. Madronero, and M. Rico, J. Heterocyd. Chem. 7, 1269 (1970). 

A very bulky group, such as trimethylsilyl, tends to occupy the 4-position. Addition of phenyl azide to phenyltrimethylsilylacetylene gives almost exclusively the 4-trimethylsilyltriazole. This can be useful because of the ease of removal of trimethylsilyl substituents. Additions to diacetylenes and addition of p-diazidobenzene to 1,4-diethynylbenzene are also claimed to be regiospecific. 

---

Chloromethyl-l,2,4-triazoles can be valuable intermediates in the synthesis of more complex compounds containing a 1,2,4-triazole moiety, and they can be accessed using a number of established methods for the synthesis of the triazole ring system. However, these processes often give variable yields and require much work to construct the starting material. A more convenient procedure has been developed, by which a hydroxymethyl-1,2,4-triazole is converted to the chloromethyl derivative by reaction with thionyl chloride (Equation 20 and Table 6) <2006S156>. 

---