1.2.4- Triazoles ring synthesis

Triazole ring synthesis Carboxylic acid hydrazides f carboxylic acid esters... 

For the preparation of triazolopyrimidines three main types of synthesis are in use. The first of these proceeds from a pyrimidine derivative (especially the 4,5-diamino derivatives) and closes the triazole ring. The second method proceeds, on the contrary, from derivatives of u-triazole to close the pyrimidine ring. The third method finally is one which yields the derivatives through substitution or replacement of substituents in compounds prepared by one of the first-named procedures. 

A. Synthesis by Annulation of the 1,2,4-Triazole Ring ONTO A Pyrimidine Structure... 

Insertion of a triazole ring in place of an imidazole ring is consistent in some cases with retention of antifungal activity. The synthesis of one such agent, azoconazole (64), proceeds simply by displacement of halide with 1,2,4-triazole. The route to terconazole (65) is rather like that to ketoconazole (34). ... 

Attempts to synthesize l,2-diazacycl[3.2.2]azines (l,2,4-triazolo)[3,4,5-ti/]indolizines, for example, 337, have met with very limited success. To date the ring system is known only when fused on its ef-faces to a cycloheptatriene ring (see Section 12.16.6.4). It may be that the 1,2-diazacyclazine system is more strained than that of the parent cyclazines, since the N-N bond of the triazole ring is expected to be shorter than a C-C or C-N bond. Similarly, all attempts to form the N-N bond as the final step in a synthesis of the 1,2,4-triazacyclazine ring system, 359, have been unsuccessful <1987J(P1)1159>. 

Click chemistry refers to the reaction between an azido functional group and an alkyne to form a [3 + 2] cycloaddition product, a 5-membered triazole ring. This reaction has been used for many years in organic synthesis to form heterocyclic rings. Normally, the click reaction requires high temperatures, and this was the main reason that it was not used as a bioconjugation tool. However, it was discovered that in aqueous solutions and in the presence of Cu(I), the reaction kinetics are dramatically accelerated to provide high yields even at room temperature and ambient pressures (Rostovtsev et al., 2002 Tornoe et al., 2002 Sharpless et al., 2005). 

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>. 

Due to the important pharmacological applications of this system, in particular the antidepressant trazodone, numerous articles deal with either its synthesis, or its incorporation into more complex substances, as a pharmacophore (see Section 11.13.12). Synthetic methods have been reviewed <1996CHEC-II(8)367>, and most of them are still in use or have been modified. Recent literature essentially focuses on the formation of the triazole ring. 

Ring Synthesis of Triazoles Fused to the c-Site of Pyrimidine Ring 733... 

In one case, synthesis of an 1SN-Iabeled derivative has been described containing the nitrogen label in the triazole ring adjacent to the bridgehead nitrogen position <2001SC2351>. The synthesis is shown in Scheme 51. 

The synthesis of the 1,2,3-triazole ring has been the subject of many reviews, and is very well documented in CHEC-I. Developments since 1984 will be discussed using the same system as was employed in CHEC-I. For a general description and early work, see <84CHEC-i(5)705>. 

Studies on the potential of the electrochemical approach to pyrazolotriazoles 117 showed that under the conditions of bicycle synthesis from 3-amino-4-hydrazonopyrazoles the N-l-unsubstituted triazole ring of 117 was further oxidized in a one-electron peak, followed by proton removal to yield the bis-(l,l )-2-phenylpyrazolo[3,4-i/][l,2,3]triazoles 118. This observation is significant, since in spite of pronounced pharmaceutical applications of pyrazoles, the redox characteristics of substituted pyrazoles have received limited attention (Scheme 13) <2001MI1022>. 

The only ring synthesis in this category is formation of the triazolotetrazine 26 by oxidation of the 1-aminotriazolo-triazole 61 (Equation 5), and this was discussed in CHEC-II(1996) <1996CHEC-II(7)513>. 

The starting material for the synthesis of the 4-substituted derivatives 176 was the tautomeric 4(7)-nitrobenzo-triazole 173, which upon methylation with dimethyl sulfate in aq NaOH afforded the 4-nitro-2-methylbenzotriazole 174. The H NMR spectrum of the purified reaction mtKture after methylation showed the existence of all three triazole ring iV-methylated isomers in equal amounts. Compound 174 was isolated by virtue of its insolubility in cone HCl. Purity of products was confirmed by gas liquid chromatography (GLC). 

Condensation with Triazole Ring/s Coburn and Jackson studied in detail the synthesis of various picryl and picrylamino-substituted 1,2,4-triazoles and 3,3 -bi-... 

A number of compounds in which two triazole rings are condensed on a single benzene nucleus have also been found to undergo the Anil Synthesis.73-75 For example, 2-(/>-tolyl)-7-phenylbenzo[l,2-t/ 3,4-[Pg.228]

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