3-Methyl-7- triazolo pyridine

There are virtually no reports of homolytic reactions on the triazolo-pyridines. Unsuccessful attempts have been made to treat triazolopyridine (1) with methyl radicals,25 and a free radical mechanism is suggested as a possibility in the replacement of the methylthio group by chlorine (Section IV,C).208... 

HOAt, 7-aza-l-hydroxybenzotriazole HATU (CAS Registry No. 148893-10-1), A-[(dimethylamino) (3//-1,2,3-triazolo(4,5- )pyridin-3-yloxy)methylene]-A-methyl-methanaminium hexafluorophosphate, previously known as G-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate. [Note Assignment of structure to HATU as a guanidinium species rather than as a uronium species, i.e., attachment of the (Mc2NC=NMe2) unit to N3 of 7-azabenzotriazole 1-A-oxide instead of to the O, is based on X-ray analysis (ref. 33b)]. 

Cycloadditions are in general an effective way of constructing cyclobutane rings. A wide variety of heterocyclic systems dimerize in this way. 1,3-Diacetylindole, for example, affords the head-to-tail dimer 242 on irradiation in ethanol.185 Ethyl 2-ethoxy-l,2-dihydroquinoline-l-carboxy-late is similarly converted in diethyl ether into the trans head-to-head dimer.186 Notable among many analogous photodimerizations are those reported in 1,4-dihydropyridines,187 in furo[3,2-b]pyridin-2(4//)-ones,188 in 8-methyl-s-triazolo[4,3-a]pyridine,189 and in 2H-2-benzazepine-1,3-diones.190 The [ 2 + 2] dimerization of amidopyrine is the first reported example of a photocycloaddition in a 4-pyrazolin-3-one.191... 

As depicted in Scheme 11, ylides 39 derived from 4-methyl-[l,2,3]triazolo[l,5- ]pyridine react with Michael acceptors, which, upon nucleophilic attack at C3 and ring opening, lead to nucleophilic displacement of nitrogen. The intermediate diradical led to a mixture of compounds, including alkenes and a cyclobutane derivative when methyl acrylate was used, and the indolizine 40 with methyl propiolate as the electrophile <1998T9785>. Heating 4-methyl triazolopyridine with benzenesulfonyl chloride in acetone also confirmed decomposition via a radical pathway. 

Alkyne dipolarophiles such as methyl propiolate or DMAD reacted with ylides derived from [l,2,3]triazolo[l,5-tf]-pyridines, but the mechanism proposed involved a Michael addition and subsequent nucleophilic attack rather than a concerted [4+2] cycloaddition <1996T10519> (see Section 11.13.8). 

Zinc chloride-doped natural phosphate was shown to have catalytic behavior in the 1,3-dipolar cycloadditions of nucleoside acetylenes with azides to form triazolonucleosides <99SC1057>. A soluble polymer-supported 1,3-dipolar cycloaddition of carbohydrate-derived 1,2,3-triazoles has been reported <99H(51)1807>. 2-Styrylchromones and sodium azide were employed in the synthesis of 4(5)-aryl-5(4)-(2-chromonyl)-1,2,3-triazoles <99H(51)481>. Lead(IV) acetate oxidation of mixed bis-aroyl hydrazones of biacetyl led to l-(a-aroyloxyarylideneamino)-3,5-dimethyl-l,2,3-triazoles <99H(51)599>. Reaction of 1-amino-3-methylbenzimidazolium chloride with lead(fV) acetate afforded l-methyl-l/f-benzotriazole <99BML961>. Hydrogenation reactions of some [l,2,3]triazolo[l,5-a]pyridines, [l,2,3]triazolo[l,5-a]quinolines, and [l,2,3]triazolo[l,5-a]isoquinolines were studied <99T12881>. 

For compound 4 there is no recorded spectrum, but compound 5 is reported204 to absorb at 258 nm (e = 4300) in methanol solution. Jain and Anand have reported spectra for the four Af-methyl derivatives 111-114 in acid, neutral, and basic media149 of the two compounds 113 and 114 the spectrum of compound 5 most resembles the former, leading to a 1H-tautomer as the predominant structure. A more recent report205- of the spectrum of compound 111 differs considerably from that given by Jain and Anand. Because of the similarity of systems 4 and 5 to purine (nucleosides from both have been prepared), there has been much interest in the spectra of the amino derivatives and of the triazolopyridinones. For the [1,2,4]triazolo-[4,5-6]pyridines, spectra are reported for the 5-amino derivatives 115,187 116,194 117,153 and 118166 for the 3-amino derivatives 119 and 120181 and for... 

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... 

Reaction of the sulfoxide (174) with phenyl azide gave 3a,8b-dihydro-5-methyl-1 -phenyl-1H-1,2,3-triazolo[4,5 4,5]thieno[2,3-c]pyridine 4-dioxide (64) which, on aerial oxidation, gave 5-methyl-l-phenyl-l/M,2,3-triazolo[4,5 4,5]thieno[2,3-c]pyridine 4-dioxide (175) <80HCA1719>. 

In contrast to the ease of N-functionalization, shown in Scheme 1, the triazolopyridine nucleus is resistant to direct nuclear oxidation or electrophilic additions. Electrophilic additions will occur on aryl substituents for example, nitration of l-phenyltriazolo[4,5-c]pyridine (26) and sulfonation of 2-phenyl-2i/-triazolo[4,5-6]pyridine (28) occur exclusively in the para position of the phenyl ring <34LA(514)279, 38MI 710-01). Nuclear functionalization was observed when l-( -butyl)-5-methyl-tri-azolo[4,5-c]pyridinium iodide (30) was treated with potassium ferricyanide to afford triazolopyridin-4-one (31), as shown in Scheme 2. Similarly, the iodide (30) is converted by either phosphorus oxychloride-phosphorus pentachloride, or bromine or nitric acid to 7-substituted triazolopyridin-4-ones (32) <37LA(529)288>. 

In an approach to direct C-functionalization of triazolo[4,5-c]pyridines, shown in Scheme 3, 1-methyl (or phenyl)[l,2,3]triazolo[4,5-c]pyridines (26,33) are alkylated exclusively at C-4 by radicals generated by decarboxylation of carboxylic acids (ammonium persulfate-sulfuric acid-silver nitrate) <90ZOB683>. However, with /-butanol various products are obtained depending on the catalyst employed. For example, with ammonium persulfate-sulfuric acid-silver nitrate, exclusive C(4)-methylation (34) was observed, while ammonium persulfate-sulfuric acid gave exclusively C(4)-/ -hydroxy-/ ,/ -dimethylethylation (cf. (36)). The /-butyl analogue (35) was obtained by decarboxylation of pivalic acid. 

Examples of either the dihydro or tetrahydro analogues of the heterocycles in this chapter are rare. A synthesis of 3-aryl-4-methyl-4,5,6,7-tetrahydro-3/7-l,2,3-triazolo[4,5-6]pyridines was reported (see Section 7.10.9.1.1), but its chemistry was not discussed <86CB359i>. 

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