1.2.4- Triazolo pyridine, synthesis from

In a different strategy (Scheme 46), albeit specialized, the tandem cycloaddition-aldol synthesis of triazolo[l,5-a]pyridines (249) from the azidotriazoles (247) proceeds with the intermediacy of the... 

The synthesis of the triazolo-pyridine-fused 1,3-diazocine 20a was achieved starting from 56a, which by de-O-benzoylation followed by reaction with NaN3 in DMF afforded the triazolo-pyridine 57. The latter by treatment with a mixture of acetone and 2,2-dimethoxypropane in the presence of acid afforded the O-isopropylidene derivative 60. The Mitsunobu reaction led to the diazocine 19a, which, as mentioned in Section 14.05.2.5 (Scheme 2), afforded 20a in 19% overall yield (Scheme 11) <2005JME6454>. 

B. Synthesis of [1,2,4]Triazolo[1,5-<7]Pyridines 1. Syntheses from Pyridines... 

As previously mentioned, the methyl group of 2-(p-tolyl)-s-triazolo-[l,5-a]pyridine is inert under the conditions of the Anil Synthesis. However, introduction of a chlorine atom in ortho position to this methyl group enables reaction to be carried out at 20°-30°C (Section II,E,3). Thus, for example, from 2-(3-chloro-4-methylphenyl)-j-triazolo[l,5-a]pyridine (19) and Schiff s base 171, the stilbene 172 is formed. In the case of 2-phenyl-7-methyl-j-triazolo[l,5-a]pyridine (173), however, reaction with 171 gives the styryl derivative 174, without additional activation of the methyl group.19... 

In addition to those 6- and 8-substituted [4,3-n] systems mentioned previously in the Dimroth rearrangement discussion, a variety of 5-substituted derivatives has been described (78JHC439) from ring closure of 6-chloro-2-hydrazinopyridine (see synthesis section). A useful material obtained from this investigation was 5-chloro-[l,2,4]triazolo[4,3-n]pyridine (102) which was susceptible to nucleophilic substitution by strong nucleophiles (sodium... 

The 3-amino-[l,2,4]triazolo[4,3-a]pyridines (95) have been prepared by the reaction of (279) with cyanogen bromide (66JOC251). It was necessary to neutralize the product from this reaction with sodium acetate in order to obtain the free base. This synthesis proceeds via an intermediate cyanohydrazine. Cyanogen chloride has been used in preparing 3-amino-[l,2,4]triazolo[4,3-c]pyrimidines or 2-amino-[l,2,4]triazolo[l,5-c]pyrimidines (vide infra), depending on the reaction conditions (63JCS5642). 

The standard activation method on the Pioneer is with AI-[(dimethylannino)(3-oxido-l//-l,2,3-triazolo[4,5-b]pyridin-l-yl)methylene]-A-methylmethananunium hexafluorophosphate (HATU). The concentration of activated amino add depends on the scale of synthesis, ranging from 0.06 M (0.02-mmol scale) to 0.13 M (0.1-mmol scale) to 0.25 M (>0.2-mmol scale). The recommended resin for the Pioneer is PEG-PS. The volume of the column depends on the void volume of the solid support (the void volume for PEG-PS is ca.4.4mL-g" ). 

An interesting synthesis of these C-nucleosides utilized the easily accessible 5-(j3-D-ribofuranosyl)tetrazoles 235 as masked C-glycosyl-diazometh-ane. Reacting 235 with 2-chloro-3-nitropyridine gave a mixture of 1,2,4-triazolo[4,3-fl]pyridin-3-yl (236) and l,2,4-triazolo[l,5-a]pyridin-2-yl (237) C-nucleosides. The latter (237) resulted from thermally induced Dimroth-like rearrangement of the former (236) (86MI9) (Scheme 70). Compounds 236 and 237 possess considerable cytotoxic effect (86MI9). 

The most commonly used synthesis of [l,2,3]triazolo[l,5-fl]pyridines remains that from the hydrazones of 2-p) idyl-carboxaldehydes or -ketones by oxidation. Some hydrazones give triazolop) dines when boiled in methanol in the presence of air, but all other reported cases require an added oxidant. The use of the most common oxidants illustrates the versatility of the synthesis. Nickel peroxide, potassium ferrocyanide and bicarbonate, air and a copper-II salt, manganese dioxide or (diacetoxyiodo)benzene have been used (02AHC1). An alternative route from tosylhydrazones of 2-pyridyl-carboxaldehydes or ketones by treatment with base, usually morpholine, has been used for high yields of sensitive materials (02AHC1). 

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