1.2.3- Triazole bromination

Triazoles are brominated at the 4- or 5-positions, but only if there is no Af-substituent <74AHC(16)33). This also applies to 1,2,4-triazoles. Af-Halogeno derivatives are frequently isolated as intermediates (81HC(37)289). 

Thiazolo[3,2-/>][l,2,4]triazoles are often sufficiently reactive to be brominated in the thiazole nucleus (see also B,5). Thus, although the unsubstituted substrate and the 2-phenyl and 2-methyl derivatives would not react with NBS in refluxing chloroform, the 5-methyl, 2,5-dimethyl, and 5-methyl-2-phenyl compounds gave 6-bromo products (71JAP71/26498 74JHC459). 

Both rings were brominated when [l,2,3]triazolo[l,2-6][l,2,3]triazoles were treated with bromine in acetic acid (63CB1827) (see also B,5,6). The dibenzo derivatives brominated preferentially para to the nonfused nitrogens (67JA2626). 

In [l,2,4]triazolo[4,3-a]pyrazine (174) bromination took place at the 5-position rather than in the triazole ring (77JOC4197). It was not possible to convert the 3-hydroxy derivative into the 3-chloro analogue (68JHC485). The isomeric [1,5-a] compound (175) was also brominated at C-5 (74TL4539), whereas its 7-oxide gave the 8-chloro derivative under Meisenheimer conditions [80JCS(P1)506]. 

Scheme 203 provides a methodology for the conversion of aryl bromides onto 4-aryl-l,2,3-triazoles. In the given example, palladium-copper catalyzed substitution of the bromine atom in indole 1226 by trimethylsilylacetylene provides intermediate 1227. Hydrolysis of the trimethylsilyl protecting group releases terminal alkyne 1228, isolated... 

As may be expected, the bromine substituent in 3-bromo-5-fluoro-17/-l,2,4-triazoles 57a-c can be displaced using a variety of nucleophiles. In particular, treatment of compound 57c with cesium fluoride gave the corresponding difluoro derivative 58 (Equation 18) <1998S1357>. 

Synthesis of the amino-triazole derivative (43) was performed in the authors laboratory by Pati et al. [52] (Scheme 7). Substituted benzyl bromide was reacted with triphenylphosphine to produce the phosphonium bromide starting material, 44. The Wittig reagent, obtained by treatment with sodium hydride, was reacted with 3,4,5-trimethoxybenzaldehyde 18 to generate the nitro-stilbene 45 in good yields. The alkyne 46 was obtained by bromination of the stilbene, followed by didehydrobromination. Compound 46 was then reacted under thermal conditions with benzyl azides... 

Bromination of 2-aryl-thiazolo[3,2-A [l,2,4]triazoles 164 gives the corresponding 5-substituted 6-bromo thia-zolo[3,2-/ ][1,2,4]triazoles 165 (Equation 5) <2000FAR71>. 

The reaction of differently substituted 5-arylidenehydrazono-4-ethoxycarbonyl-3-methyl-(l/7)pyrazoles 194 (X = 2-NC>2, 4-NC>2, 2-Cl, 4-Me, 4-NMe2, 2-OMe) with bromine in acetic acid in the presence of sodium acetate leads mainly to 3-aryl-7-ethoxycarbonyl-6-methyl-(li/)pyrazolo[5,l-c][l,2,4]triazoles 195 (Scheme 7) <1977J(P1)2047>. 

Treatment of 3-rncthyl A-cthoxycarbonyl-5-aryIidcnchydrazono-l//-pyrazolcs 194 with bromine, in the presence of sodium acetate, in acetic acid gives substituted ethyl 3-aryl-7-cthoxycarbonyI-6-rncthyl-1 //-pyrazolo[5,1 -/ -[l,2,4]triazoles 55 (Equation 35) <2002ARK133>. Analogously, the reaction of compounds 194 with lead tetracetate [Pb(OAc)4] in acetic acid also gives l//-pyrazolo[5,l-c][l,2,4]triazoles 55 (unreported yield) (Equation 35) <2002ARK133>. 

Fused heterocyclic systems derived from 3-mercapto-l,2,4-triazole can be obtained by heterocyclization of 4-allyl-l,2,4-triazole-3-thione derivatives by treatment with halogens or mineral acids <1996T791>. Compounds 342 react with bromine yielding thiazolium halides 28 in good yield (Equation 64) <2000RJOC1033>. 

Heating to reflux a pyridine solution of 3-substituted-5-(l-aroyl-l-bromo)methylthio-4-phenylamino-4//-[l,2,4]tria-zoles 81 (available from the corresponding 1,2,4-triazoles with phenacyl bromides and subsequent ultraviolet (UV) light-induced bromination) affords 3-substituted-6-aroyl-5,6-dihydro-5-phenyl[l,2,4]triazolo[3,4-6][l,3,4]thiadiazoles 82 (Equation 19) <1993IJH135>. 

Halogenation of w-triazole and several monomethyl and dimethyl derivatives has been studied.Bromination of v-triazole gives the 4,5-dibromo derivative with an excess of sodium hypobromite, a 1,4,5-tribromo derivative can also be isolated. Attempted chlorination gave the hydrochloride salt instead, although 1-methyltriazole gives a 4-chloro derivative. A 1-iodo derivative, which rearranges on heating to the 4-isomer, is obtained with iodine. 

Arylthiazole-5-carboxylic acids on treatment with base and bromine yield the corresponding 5-bromothiazole (76AP128). The same behavior is observed for thiazolo[3,2-b][l,2,4]triazoles (91AP49 94MI2). 

Compound 185 can also be obtained by direct bromination of the corresponding thiazolo[3,2-ft][l,2,4]triazole (Bt2, acetie acid) (91AP49). Bromination at C-5 can also be affected by bromine/NBS in chloroform (72YZ935). Thiocyanation, which was possible in the imidazo[2,l-b]thia-zole and -[l,3,4]thiadiazole series (see Sections VI,B,l,a and VII,B,l) failed (72YZ935). 

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