1.2.4- Triazole - from amidrazones

E. Grigat and R. Putter, Angew. Chem., Int. Ed. Engl. 6, 206-218 (1967). Triazoles, synthesis from amidrazones ... 

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. 

Therefore, acylamidrazones are intermediates in all three reactions. For this reason, 1,2,4-triazoles can also be prepared from amidrazones and acylating agents such as acid esters or acid chlorides. 

Scheme 62 illustrates extensions of these methods proceeding from or through hydrazidines, amidrazones or acylamidrazones to syntheses of 1,2,4-triazoles with sub-... 

Many convenient triazole syntheses proceed through amidrazones derived from formic acid. TTius DMF, thionyl chloride and hydrazine react to give the bisamidrazone (162) which is then cyclized by transamination (75JCS(P1)12) (Scheme 73). 

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. 

A different synthetic strategy for the preparation of triazoles with a carboxylic acid or related functional sidechain starts from oxazolinones or thiazolinones, i.e. cyclic amides, to provide the carboxylic function. An ArNj or ArNHN= functional group is attached to the reactive position to obtain amidrazones with endocyclic amide and exocyclic hydrazide moieties. Note that in the examples, which are not intended to exhaust variations of this approach, 4-ones as well as 5-ones may be used. 

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). 

Substituted 1,2,4-triazoles may be prepared from the reactions of amidrazones with phosgene according to the following general scheme [1700a] ... 

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). 

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