Bromo-l,2,4-triazoles

The position of the (V-bromine is determined by the nature of the R1 and R2 substituents as with chlorination. Bromine enters the position close to an electron-donating and far from an electron-accepting substituent. 

5-Disubstituted triazoles are brominated to give unstable intermediates, said to have structure 48. Subsequent treatment leads to their decom- 

N-Iodo-1,2,4-triazoles cannot be obtained by treating the corresponding triazoles with iodine. 

The reported attempts to obtain iY-chloro-5-phenyltetrazole led to isolation of l,4-dichloro-l,4-diphenyl-2,3-diazabutadiene 51, probably through the formation of an intermediate V-chloro-5-phenyltetrazole with subsequent rearrangement to a C-chloroderivative and finally to the cleavage of the latter [79JCS(CC)419] (Fig. 3). 

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Ball et al. [14] developed a one-pot expedient microwave approach for the synthesis of novel [l,3]oxazolo[3,2,b][l,2,4]triazoles (ii) via a tandem alkylation/ cyclisation reaction of 3-bromo-l,2,4-triazoles and a-haloketone via an intermediate enolate. 

When the substituent in position 5 is absent, 1- and 4-substituted N-bromotriazolium bromides 45 and 47 are easily converted to 5-bromo-l,2,4-triazoles by heating in water (75BSF647) (Scheme 35). 

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). 

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>. 

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>. 

Alkylation of thiazolo[3,2-fi][l,2,4]triazoles takes place at N(l). Treatment of 180 with 2-bromo-l-arylethanones (acetone, heating) yields 181 [94JAP(K)06/184165, 94TL4587]. 

A novel ring-closure starting from 2-aryl-l-(12/-l,2,4-triazol-l-yl)alk-3-yn-2-ols has been reported <2006T8966>. Treatment of these alkynols with Bt2 at room temperature yielded 5-alkyl-7-aryl-6-bromo-7-hydroxy-7,8-dihydro-[l,2,4]triazolo[l,2- ]pyridazin-4-ium bromides which upon hydrolysis give 3-alkyl-5-arylpyridazines. 

Triazolo-fused dioxazepine 201 was obtained as a by-product in Suzuki coupling reactions of 5-bromo-l-(2-hydroxyethoxymethyl)-l,2,4-triazole-3-carboxamide the reaction, however, can be shifted towards 201 by using a strong base <2007TL2389>. 

The reaction of 5-bromo-3-nitro-l,2,4-triazole and 3,5-dinitro-l,2,4-triazole with a variety of oxiranes yielded the expected 1-substituted imidazoles, and also resulted in the formation of 5,6-dihydrooxazolo[3,2-6]-s-triazoles upon treatment with base (75CHE612). The proposed pathway involves proton abstraction from the imidazole and subsequent attack of the oxirane on the N-anion followed by cyclization in a concerted fashion (equation 56). 2,4(5)-Dinitroimidazole reacts analogously with oxiranes to give isomeric nitro-imidazo[2,1 -f>]oxazoles in good overall yield (8UMC601). 

The alkylation products of A -chloro-3-nitro-l,2,4-triazole [580], heterylation products of nitrotriazoles [612], glycosylation products of 3-bromo-5-nitro-l,2,... 

There are some literature reports on the reactions of 1,2,4-triazoles. 2-Amino-4-aryl-5-( I //-l, 2,4-triazol-1 -yl)thiazolc derivatives were synthesized from the reaction of a-bromo substituted acetophenone and thiourea <07SC199>. 5-Amino-l-methyl-l//-[l,2,4]triazole-3-carboxylic acid were employed as precursors in peptide synthesis <07SC1917>. 3-... 

A mixture of anti- and. vyw-diastereomers 4 with undetermined ratio is isolated by the cycloaddition of 4-phenyl-3//-l,2,4-triazole-3,5(4//)-dionc and 5-chlorocyclopentadiene59, but only the a/m -isomers 5 and 6 arc obtained from 5-bromo- and 5-iodocyclopentadiene59-60. 

In the same way, in 1-methyl-l,2,3-triazole (26) in CDCI3 H-4 and H-5 are not equivalent and the assignment was made by comparison with l-methyl-4-bromo-l,2,3-triazole (27) 67BSF2998). 

Under moderate conditions, e.g. reacting potassium triazolate at 0 °C, bromine affords iV-bromotriazoles. If the triazole is 3,5-substituted, iV-bromotriazole may be obtained without special care otherwise C-bromination occurs (67CB22so), presumably through iV-bromo intermediates since 1,3-dichlorotriazole and 1,3,5-tribromo-l,2,4-triazoles may be used for the halogenation of other triazoles (eezcszs). Bromination of the 1,2,4-triazole-... 

The nitrosamine (121) and especially diazonium salts (122) prepared from it, as well as their alkyl and aryl derivatives, are important synthetic intermediates (b-76MI4i200, p. 325). For conditions that decide between nitrosamine function or diazotization see (73jcS(P1)13S7). At room temperature or in concentrated hydrochloric acid nitrosamines derived from triazoles are unstable, and their decomposition products include chlorotriazoles (63LA(665)144) 5-nitrosamino-3-phenyl-l,2,4-triazole affords the 5-bromo compound with hydrobromic acid at 0 °C and reacts violently with hydroiodic acid (05lA(343)i). Thermal arylation with triazole nitrosamines is possible (73jcs(pi)i357). 

Bromination of the parent system (32) resulted in the 5-bromo derivative which with a variety of nucleophiles at elevated temperatures could be converted into other 5-substituted [l,2,4]triazolo[l,5-a]pyrazines (245). At room temperature, tele substitution occurred and the C-8 products (247) were obtained (74TL4539). Base-catalyzed deuterium exchange occurs at C-5 of (32) and treatment with hot, 50% aqueous sodium hydroxide formed 3-aminomethyl-l,2,4-triazole (246) and glycolic acid as a result of base attack at C-5. 

Another situation in which the chemically robust nature of the 4-methyI-l, 2,4-triazole-3,5-dione adducts has been exploited is in the synthesis of bicyclobutane derivatives.Addition of 4-methyl-l,2,4-triazole-3,5-dione to bicyclo[1.1.0]butane gave the urazole 20, which was converted to 2,3-diazabicyclo[2.1.1]hex-2-ene and by thermolysis or photolysis back to bi-cyclo[1.1.0]butane. While this is not in itself a useful synthetic sequence, the urazole intermediates in such a sequence can be chemically modified in ways that would be impossible for the bicyclobutanes themselves. Hence for the adduct 21 of dimethyl bicyclo[1.1.0]butane-l,3-dicarboxylate, the ester groups can be modified into ethyl, vinyl, substituted vinyl, hydroxymethyl, bromo and other substituents and this was used to prepare, for example, 1,3-divinylbicyclo[1.1.0]butane (22) and l-ethyl-3-vinylbicyclo[1.1.0]butane. ... 

The Suzuki cross-coupling reactions could also be extended to fused pyridazines bearing a halogen atom on the 1,2-diazine nucleus. For example, 7-bromo-3-(2-fluorophenyl)-6-[(1 -methyl-1/7-1,2,4-triazol-5-yl)methoxy] [ 1,2,4]triazolo[4,3-Z ]pyridazine (84) was successfully coupled with phenylboronic acid to yield 3-(2-fluorophenyl)-6-[(l-methyl-l//-l,2,4-triazol-5-yl)methoxy]-7-phenyl[l,2,4]triazolo[4,3-Z ]pyridazine (85) in 51% yield [35]. Compounds like 85 might give access to new anxiolytic drugs since trisubstituted... 

The applicability of cyanation has been successfully demonstrated in several instances. Thus, a 2 -phosphonylated 3 -trifluoromethylsulfonyhiucleoside reacts smoothly with w-Bi Nf N in MeCN to give the cyanation product in 45% yield (Scheme 6.36). With halo derivatives, assistance is needed, and 3-bromo-3-(l-trityl-l,2,4-triazol-3-yl)propylphosphonate reacts with NaCN and 15-crown-5 in DMF at room temperature,2 295 whereas diethyl 4-(bromomethyl)benzylphosphonate reacts with KCN and Nal in AcjO/HgO.- The preparation of (3-cyanaziridiii-2-yl)methylphospho-nates by addition of McjSiCN to (2H-azirin-2-yl)metliylphosphonates has also been reported. ... 

In contrast to other azoles whose stability decreases from A-iodo to A-bromo and further to A-chloro derivatives, l-chloro-3-nitro-l,2,4-triazoles are more stable that their 1-bromo and 1-iodo analogs. In this series the stability order is reversed (96UP1). Rearrangement of A-halo-1,2,4-triazoles is described in Section IV,B,2. 

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