1.2.4- Triazolo pyridazines synthesis

Another interesting scavenger is polymer-supported anthracene, developed by Porco for the scavenging of dienophiles [109]. An example of its application to the synthesis of a complex 5,8-dihydro-(l,2,4)triazolo[l,2-a]pyridazine-l,3-diones via hetero-Diels-Alder reaction followed by removal of the excess of triazole-3,5-dione under microwave irradiation is depicted in Scheme 24. For this particular example, moving from thermal heating (toluene, 100 °C) to a microwave-assisted protocol (DCE, 150 °C) reduced scavenging time from 3 h to just 15 min. 

Two types of addition to pyrimidine bases appear to exist. The first, the formation of pyrimidine photohydrates, has been the subject of a detailed review.251 Results suggest that two reactive species may be involved in the photohydration of 1,3-dimethyluracil.252 A recent example of this type of addition is to be found in 6-azacytosine (308) which forms a photohydration product (309) analogous to that found in cytosine.253 The second type of addition proceeds via radical intermediates and is illustrated by the addition of propan-2-ol to the trimethylcytosine 310 to give the alcohol 311 and the dihydro derivative 312.254 The same adduct is formed by a di-tert-butyl peroxide-initiated free radical reaction. Numerous other photoreactions involving the formation by hydrogen abstraction of hydroxyalkyl radicals and their subsequent addition to heterocycles have been reported. Systems studied include 3-aminopyrido[4,3-c]us-triazine,255 02,2 -anhydrouri-dine,256 and sym-triazolo[4,3-fe]pyridazine.257 The photoaddition of alcohols to purines is also a well-documented transformation. The stereospecific addition of methanol to the purine 313, for example, is an important step in the synthesis of coformycin.258 These reactions are frequently more... 

Several interesting 1,2,4-triazole fused-ring systems have been reported. A facile synthesis of 3,5-dihydro-677-imidazo[l,2-fc]-l,2,4-triazol-6-ones 162 was obtained by an iminophosphorane-mediated annulation <06EJ04170>. 8-Trifluoromethyl-l,2,4-triazolo[4,3- >]pyridazines 163 has been prepared from 4-trifluoromethyl-4,5-dihydropyridazin-3-one... 

A rapid synthesis of trisubstituted l,2,4-triazolo[4,3-b]pyridazines has been devised to give selective variation of the three substituents through combinations of silicon-directed anion formation, palladium-catalyzed couplings and SnAt displacements <00TL781>. The synthesis of new l,2,4-triazolo[l,5-a]pyrimidines <00M1435>, 1,2,3-triazolo[4,5-(f]... 

With the synthesis of novel [l,2,4]triazolo[4,3-A]pyridazine derivatives 385 from the pyridazylhydrazone 384, Doring et al. followed a well-established route (cf. Table 12, entry 11) <2005T5942>. The specificity of this study is, however, the use of cupric chloride as an oxidizing agent (which has not been used before). 

Matsuda et al. <1995H(41)2777> described an efficient synthesis of mesoionic [l,2,4]triazolo[4,3-A]pyridazines 390 and 391. The starting compound for the synthesis is the A-aminotriazole 389, which can be treated either with ethyl 2-chloro-3-ethoxyacrylate to yield 390 or with ketene dithioacetals to afford 391. The reactions proceed in good to high yield. 

The synthesis of fused 1,2,3-triazoles is nearly always achieved by treating 1,2-diamines attached to diazines with nitrous acid (e.g., [l,2,3]triazolo[4,5-f]pyridazine (Section 10.13.9.2.1(iii)) and [l,2,3]triazolo[4,5-rf pyrimidine (Section 10.13.9.2.1(iv)), <1996CHEC-II(7)489>). When a heterocyclic system containing a diazole fused onto 1,2,4-triazine is required, annulation of the five-membered heterocycle is nearly always the most facile route (e.g., imidazo[4,5-r ][l,2,4]triazine (Section 10.13.9.2.l(i)) and pyrazolo[4,3-r ][l,2,4]triazine (Section 10.13.9.2.1(ii))). In support of the latter, the synthesis of the fused six-membered ring of pyrazolo[3,4-r ][l,2,4]triazine from the pyrazo-ledione was reported as low yielding <1996CHEC-II(7)489>. 

The only other synthesis of a benzo fused derivative involves the pyridazino[4,3-c]isoquinoline series, the isoquinoline derivative (377) reacting with hydrazine to give (378) (74YZ607), although an s-triazolo-fused pyrido[2,3-with hydrazine and formic acid (56GEP951993). 

Under this heading, the synthesis of l,2,4-triazolo[4,3-fe]pyridazines (255) as well as the closely related and medicinally very important 1,2,4-triazolo[3,4-a]phthalazines (256), in addition to l,2,4-triazolo[4,3-( ]-cinnolines (257), will be discussed. 

The most attractive application of the 3//-indazole route is the synthesis of the first cyclo-propapyridine In contrast, the biradicals formed upon irradiation of 9,9-dimethyl-9//-l,2,4-triazolo[h]pyrazolo[4,3-<7]pyridazines 5 did not cyclize to a cyclopropa[<7]pyridazine-type Structure. ... 

Although this route has not been used extensively there are several examples. The synthesis of 3-aryl-7-bromo-6-chloro[l,2,4]triazolo[4,3- ]pyridazines (39) from 3-aryl-6-chloro-... 

Isomeric N-methyltriazolopyridazines. During the synthesis of a pair of isomeric W-methyl-[l,2,3]triazolo[4,5J]-pyridazines, Csampai and co-workers utilized long-range correlation data to determine the position of the N-methyl group on... 

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). 

Intramolecular cyclisation of nitrile imine ylides occurs when 2-pyridyl- (22 X= CH) or 3-pyridazinylhydrazones (22 X= N) are treated with chloramine-T to yield 1,2,4-triazolo[4,3-a] pyridines (23 X= CH) and l,2,4-triazolo[4,3-l>]pyridazines (23 X= N) in a simple one-pot synthesis [93SC319S]. 

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