Bromo-substituted 1,2,3-triazole

The direct lithiation of a 2-substituted 1,2,3-triazole has not been reported. Halogen-metal exchange of 4,5-dibromotriazole with n-butyllithium at — 80 °C occurs smoothly and the subsequent reaction of the lithium intermediate (244) with various electrophiles except aldehydes gives the 4-bromo-5-substituted triazoles (245) (Scheme 46). The corresponding 1-substituted 4,5-dibromo-1,2,3-triazole undergoes a similar reaction at the 5-position . 

Halogenation usually proceeds through the A-halotriazoles, as described in Section 4.02.5.3. The bromination of N-substituted triazoles by NBS in CHCI3 is also believed to involve A-bromo-triazolium intermediates <75BSF647>. 

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-... 

The synthesis of a gas-generating composition starts with the synthesis of a poly(vinyltriazole). A substituted triazole salt is added to a free radical brominating reagent, such as A-bromo succinimide, and to a radical initiator to form a brominated triazole. The brominated triazole is then added to triphenylphosphine to form a Wittig salt. Formaldehyde in alkaline medium effects the formation of a vinyltriazole salt, which can be polymerized with AIBN and a catalytic amount of a cationic initiator or a Ziegler-Natta catalyst. The reaction sequence is shown in Figure 9.10. 

In the course of work leading to substituted triazoles, dehydro-L-ascorbic acid 3-oxime 2-phenylhydrazone was converted to its 5-0-aoetyl-6-bromo-6-deoxy-derivative (22). 

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>. 

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>. 

Predictably, 1,2,4-triazole is alkylated preferentially at the 1-position [36, 38,39]. Specific alkylation at the 4-position can be achieved by the initial reaction with dibromomethane to form the bis-triazol-l-ylmethane (see below), followed by quat-emization of the triazole system at the 4-position and subsequent C-N cleavage of the 1,1 -methylenebistriazolium salts [40]. 1,2,3-Benztriazole yields a mixture of the isomeric 1- and 2-alkylated derivatives [41]. The 1-isomer predominates, but the ratio depends on whether the reactions are conducted in the presence, or absence, of a nonpolar organic solvent (Table 5.33). Higher ratios of the 1-isomer are obtained under solidrliquid two-phase conditions. Thus, alkylation of 1,2,3-benztriazole with benzyl chloride produces an overall yield of 95% with the l- 2-isomer ratio of ca. 5.7 1 similar reactions with diphenylmethyl and triphenylmethyl chlorides gives overall yields of 95% (9 1 ratio) and 70% (100% 1-isomer), respectively [38], 6-Substituted purines are alkylated at the N9-atom and reaction with 1-bromo-3-chloropropane yields exclusively the 9-chloropropyl derivative (cf. reaction wi phenols) [42]. 

The 5-unsubstituted-l,2,3-triazol-4-ones (176, R = H) participate in electrophilic substitution reactions. Bromination in chloroform of anhydro-4-hydroxy-l,3-dimethyl-1,2,3-triazolium hydroxide (180) gave its 5-bromo derivative (182). The meso-ionic 3-aryl-1,2,3-triazol-4-ones (176, R = Me, R = Ar, R = H) gave 5-bromo derivatives (176, R = Me, R = Ar, R = Br) with bromine in acetic acid. Their reaction with sulphur monochloride gave the sulfide (189, X = S), and with thionyl chloride they gave the sulfoxide (189, X = SO). ... 

The oxide group mildly activates 3-substituted 1,2,3-triazole 1-oxides to electrophilic attack. Thus, 3-benzyl-1,2,3-triazole 1-oxide reacted much more rapidly than the unoxidized compound in giving the 5-bromo derivative, and there have been a number of other examples of 5-bromination and 5-chlorination of triazole oxides, including that of the 3-phenyl-l-oxide, which was not para-halogenated [87ACS(B)724]. 

While 5-chloro-l,2,3-triazole 1-oxide 467 reacted with sodium methox-ide with replacement of the chlorine (see Section 4.1.6.8), the corresponding bromo compound 468 under similar conditions afforded the cme-substitution product 483 as the main product (1987ACSA(B)724). A mechanism involving halogen dance and supported by control experiments is sketched in Scheme 142. The bromine in 468 is located at the less activated position with respect to nucleophilic displacement. On the other... 

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). 

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-... 

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. ... 

On bromination of 4-substituted 1,2,4-triazoles, l-bromo-4-substituted triazolium bromides 45 are formed as intermediates. Heating in water causes their rearrangement to 4-substituted 5-bromotriazoles 46 (75BSF647) (Scheme 18). 

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). 

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