Triazolopyridines . Part 29 . 1 Direct arylation reactions with [ 1 , 2 , 3 ] triazolo [ 1 , 5-a ] pyridines

1,2,3]Triazolo[1,5-a]pyridine reacts with aryl halides in presence of catalytic amounts of Pd(OAc)2 and PPh3 in DMF to give, in medium or low yield, direct arylations in C3 and pyridyl aryl ketones. Thiazole and benzothiazole have been directly arylated using 7-halotriazolopyridines. These behaviours are unprecedented in the chemistry of [1,2,3]triazolo[1,5-a]pyridines.


Introduction
Triazolo [1,5-a]pyridines 1 are simple fused heterocycles, readily accessible by mild oxidation of pyridyl-ketone or pyridyl-aldehyde hydrazones.2a Their chemistry has been studied by Jones and ourselves. 2This system is used as building blocks of pyridines 2,6-disubstituted not available by other synthetic methodology. 3Indolizines, 4 and bipyridines, 5 have also been synthesized using [1,2,3]triazolo [1,5-a]pyridines as synthons.Their coordination chemistry 6 as well as their application in the field of magnetic materials have been reported.6d,7 One very interesting property of this system is the fluorescence of triazolopyridines 3 or 7 substituted by aryl or heteroaryl groups. 8his property provides molecular chemosensors for metal ions, anions, and amino acids. 1,9luorescent aryltriazolopyridines were synthesized with a triazolopyridine halide and an aryl or heteroaryl boronic acid, 8 by cross-coupling reactions, 10 especially the Suzuki-Miyaura reaction. 11However, the 3-halotriazolopyridines used as starting materials were obtained in very low yield. 12he reaction involving a triazolopyridyl boronic acid and an aryl halide was not successful.It was possible to synthesize and characterize some 7-triazolopyridyl boronic acids and esters that are stable when stored, but in solution under the various Suzuki reaction conditions experimented, were not stable and underwent protodeboronation. 13On the other hand, it was impossible to prepare 3-triazolopyridyl boronic acid. 12he requisite of triazolpyridine preactivation, such as halide or boronic acid, involves several manipulations prior to the cross-coupling reaction.In recent years, direct arylation reactions catalysed by palladium in a single step, have emerged as a very attractive alternative via to traditional cross-coupling methods for the functionalisation of unactivated C-H bonds in heterocycles. 142d Thus, we decided to explore the possibility of direct arylation of triazolopyridines.

Results and Discussion
Electrophilic aromatic substitution was initially proposed by Miura as a possible mechanism for direct arylation reactions, 16a since then distinct mechanisms have been proposed: C-H activation, 16b,c cross-coupling, 16a and Heck-type arylation.14d For palladium catalysed arylation of electron-rich heterocycles, the mechanistic pathway proposed by Miura 16a has often been considered as the most probable mechanism for arylation of heterocycles, 14d and has been strongly supported by a combination of experimental and computational data. 17Nevertheless, the potential involvement of other aforementioned pathways or mixed mechanisms could not be completely ruled out.14d It is known that in [1,2,3]triazolo [1,5-a]pyridine 1a the most acid hydrogen is the one in the C3 position, and that 1a reacts with electrophiles in two contrasting ways.2a In cases of Vilsmeier formylation or nitration, 3-substituted triazolopyridines are obtained, and with other electrophiles (acids, acetic anhydride, SeO 2 , etc) products resulting from a triazolo ring opening reaction losing dinitrogen are given.Thus, we decided to explore the possibility of direct arylation of triazolopyridine in the C3 position using Miura conditions.16a We first examined the reaction between triazolopyridine 1a and 2 equivalents of 4iodoanisole 2 in DMF at 140 ºC, in the presence of 0.05 equivalents of Pd(OAc)2, 0.1 equivalents of triphenylphosphine as ligand, and 2 equivalents of caesium carbonate as base.The reaction was completed after 3 days, and three compounds were isolated in moderate to low yields (Table 1, entry 1): 3-substituted triazolopyridine 3 (33%), 2pyridyl 4-methoxyphenyl ketone 4 (23%) and 4,4'-dimethoxybiphenyl 5 (24%) (Scheme 1).

Scheme 1
Triazolopyridine 3 is the first example of a compound obtained by direct arylation of a triazolopyridine system.Compound 3 was obtained previously by some of us, by Suzuki reaction of 3-iodotriazolopyridine and 4-methoxyphenyl boronic acid, in a global yield of only 13.7%. 8An interesting feature is the attainment of ketone 4, it must be formed from 3 by a triazolo ring opening reaction with the loss of N2. 18 The formation of the biaryl derivative 5 can be explained by a homocouplig reaction of 2. 19 Several attempts to improve these results have been made modifying the reaction conditions.We modified the reaction time and temperature (Table 1, entry 2), the ligand and reaction time (entries 3 20 -5), the catalyst (entry 6), yet we always obtained mixtures of difficult handling and unfavourable results.As reported by Bellina et al., the addition of copper(I) iodide (CuI) dramatically improved reaction efficiency of some direct arylations, 16b,c,21c thus we investigated the activity of this transition element in our reaction.However no arylation product was found, (entry 7).Fagnou et al. developed a palladium-pivalic acid co-catalyst combination exhibiting unprecedented reactivity in direct arylation, 22a that provides highly variable outcomes depending on the choice of base and the presence /absence of pivalic acid.22b They also established broadly applicable reaction conditions associated with the use of substoichiometric quantities of pivalic acid (in situ generated potassium pivalate) to accelerate direct arylation.22c Using some of these conditions, we tried to achieve better results, yet without success (entry 8).When 3-bromopyridine 6 was used as co-reagent in cited Miura conditions, 16a triazolopyridine 7, (16%), ketone 8 (21%), and 3,3'-bipyridine 9 (32%) were obtained (Scheme 1, entry 9).These compounds are analogous to 3, 4, and 5.
Some experiments were also carried using microwave conditions at a frequency of 2.45 GHz, however no reaction was observed.
We assume that the mechanism of these direct arylation reactions could be an electrophilic attack of the arylhalopalladium(II) species, which is formed by oxidative addition of aryl halide to the palladium (0) generated in situ, onto the triazolopyridine 1a generating intermediate 10, that by deprotonation gives aryl(triazolopyridyl) palladium(II) intermediate 11.By reductive palladium elimination the new triazolopyridines 3 or 7 could be formed (Scheme 2).