Amidrazones 1.2.4- triazole ring

Synthesis starting from amidrazones (Scheme 59, c -d") is the most versatile preparation of the 1,2,4-triazole ring. Application to specific cases is governed by three considerations. One is the formation of the required amidrazone from a hydrazine with or without substituents and amide derivatives RC(=NH)X or RC(=NCOR )X where X = halide, OH, OAlk, SAlk, NH2, etc. With two reactive hydrazinic NH groups, isomeric amidrazones can be formed but the relative basicities usually predict the correct product. Unsymmetrical hydrazines YZNNH2 also form amidrazones but these cannot be cyclized unless Y or Z is reactive. 

Poly(bis-l,2,4-triazole)s are a class of polymers in which two triazole rings are immediately adjacent. These polymers can be obtained by the reaction of oxalic acid bis-amidrazone with aromatic dicarboxylic acid dihalides or with fumaroyl chloride and subsequent cyclodehydration of the poly(acyl oxamidrazone)s. The process is shown in Figure 9.3. 

Methods of this type are best considered as reactions of the fused ring-systems in question (see Chapter 4.15). The example illustrated in Scheme 91 is of potential interest in pharmacology (75T1363, cf. 74CPB1938). The conversion of the 1-aminoadenosine (192) into the imidazolyltriazole (193) amounts to triazole formation from an amidrazone intermediate and a formyl group derived from the pyrimidine moiety. 

The ring system to be destroyed may be constructed as a measure of synthetic strategy as illustrated (Scheme 92) by the preparation of a triazole (194) used to synthesize fused rings of pharmacological interest. The dihydroquinazoline (195) provides the amidrazone intermediate and the aromatic substituent required (75JHC717). 

Of about 300 publications dealing with the synthesis of mono-, di- and tri-alkyl- or aryl-triazoles, 76% establish the functions by method (i), 18% by (ii) and 6% by (iii) (i) is broken down further into 63% for amidrazone methods, 3% for 1,3-cycloadditions and 16% for other procedures, mainly the cleavage of fused ring systems. This rough analysis will be modified if extended to include current and future references but it may serve as a heuristic guide for those intending to devise triazole syntheses. 

The use of 6-membered ring systems as sources of amidrazones to be converted into triazoles is relatively rare the case of 1-aminoadenine (Scheme 91) has already been mentioned. Transformations of 4,6-dihydrazinopyrimidine, hydrazines formed from haloaminopyridazine (81 HC(37)l, p. 8) and 1,2,4-triazines (8lHC(37)i, pp.409,424,488) all involve amidrazone intermediates cyclized to triazoles with the acyl function derived from the original ring. For instructive examples of preparative links between tetrahydrotetrazine, formazans and 1,2,4-triazoles, see Scheme 120 (81KGS694). 

Of the ring systems under discussion in this chapter, only the pyrrolotriazoles (2) and (3) and the pyrrolothiadiazoles (7) have been prepared by more than one route. For example, pyrrolo[l,2-6][l,2,4]triazoles (2) have been prepared (i) by cyclization of substituted triazolium salts (Equation (1)), a [5 + 0] synthesis (ii) from cyclic amidrazone (73, Scheme 11), a [4 + 1] synthesis (iii) from thiosemicarbazides (90, Scheme 15), a synthesis involving simultaneous formation of both rings and (iv) from triazolo[4,3-6]pyridazines (94, Scheme 16) by photochemical addition of an alkene. However, as each of these routes yields different groups of products and no individual compound has been prepared by more than one of these routes, it is not possible to compare them in a meaningful manner. The same is true for ring systems (3) and (7). 

Hydrazine or its salts are known to form amidrazone salts (1) by nucleophilic attack on acetonitrile. Compound 2 (4-amino-3,5-dimethyl-1,2,4-triazole) appears to be formed through six-membered ring... 

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