1.2.4- Triazoles halogenation

In azole chemistry the total effect of the several heteroatoms in one ring approximates the superposition of their separate effects. It is found that pyrazole, imidazole and isoxazole undergo nitration and sulfonation about as readily as nitrobenzene thiazole and isothiazole react less readily ica. equal to m-dinitrobenzene), and oxadiazoles, thiadiazoles, triazoles, etc. with great difficulty. In each case, halogenation is easier than the corresponding nitration or sulfonation. Strong electron-donor substituents help the reaction. 

In contrast, substituents in 1,2,4-triazoles are usually rather similar in reactivity to those in benzene although nucleophilic substitution of halogen is somewhat easier, forcing conditions are required. 

Halogen exchange followed by debenzylation of 1,2,4-triazole 55 was employed in the preparation of 3-bromo-5-fluoro-1/7-1,2,4-triazole 56 in 59% overall yield (Equation 17) <1998S1357>. 

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>. 

In the presence of sodium acetate in acetic acid, the arylhydrazones 54 (available from the reaction of tu-halogen-tu-(arylhydrazono)acetophenones with 3-amino[l,2,4]triazole) undergo cyclization to yield 3-aroyl-l-aryl-l//-[l,2,4]-tria-zolo[3,4-c][l,2,4]triazoles 55 (Equation 7) <1987CB965>. 

Several ring-closure reactions for [l,2,4]triazolo[3,4- ][l,3,4]thiadizines have been described, and all these procedures started from 3-mercapto-4-amino[l,2,4]triazole 135 (Scheme 26). A common structural feature of the reagents is the presence of the CH2X (X = halogen atom) moiety which allows the alkylation at the sulfur atom followed by a ring-closure reaction via an elimination step. Some typical ring closures are shown in Scheme 26. 

Synthesis was directed towards metabolic stability and this was found in the bis-triazole series of compounds. Metabolic stability is achieved by the relative resistance of the triazole moiety to oxidative attack, the presence of halogen functions on the phenyl grouping, another site of possible oxidative attack, and steric hindrance of the hydroxy function, a site for possible conjugation. 

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. 

A textured metallocene polyethylene foam sheet suitable for use in a floor covering is made using a highly coactivated azodicarbonamide package which blows the metallocene polyethylene effectively. The preferred coactivators are zinc oxide and urea. The textured surface of metallocene polyethylene foam is formed by a chemical embossing process which utilises a liquid triazole having an alkyl moiety as a foam-expansion inhibitor. The triazole is dissolved in a non-polar solvent to form the foam inhibitor. The preferred inhibitor is a hydrocarbon which may be halogenated. 

The C(5) position of 1-substituted 1,2,3-triazoles is activated towards nucleophilic attack by a pyridine-like nitrogen, and the equivalent C(4) and C(5) positions of 2-substituted 1,2,3-triazoles are weakly activated. However, a suitable leaving group, such as a halogen, is generally required for nucleophilic substitution <88BSB573>. 

The nucleophilic substitution of 1,2,3-triazole is also activated by A-oxidation. In 3-substituted 1,2,3-triazole 1-oxides, a halogen substituent at C(4) is more reactive than one at C(5) <87ACS(B)724>. Therefore, the C(4) chlorine of compound (221) (Equation (19)) is displaced by methoxide under much milder conditions than the corresponding C(5) chlorine of (222) (Scheme 39), and the only C(5) bromine is displaced in the case of 4,5-dibromotriazole 1-oxide <88BSB573>. 

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>. 

Halotriazoles can act as halogenating agents and A-acyltriazoles can act as acyl transfer reagents. Triazole can be used for the synthesis of peptide bonds and is superior to imidazole in that less racemization is observed. It can also be used to transfer the t-butyloxycarbonyl (t-Boc) protecting group to the nitrogen of amino acids. For details see Polya <84CHEC-I(5)733, p. 786). 

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]. 

Strongly activating substituents assist halogenation at the adjacent ring site. When 4-hydroxy-2-phenyl-1,2,3-triazole was treated with bromine, the product was mainly 5-bromo, but a small amount of 2-p-bromophenyl product was also observed. The corresponding 1-oxide gave only resins when similarly treated (88JOU599). 

As with the 1,2,3-isomers, 1,2,4-triazoles can also be halogenated on N-l to form reasonably stable products that are then subject to thermal... 

The benzodiazepines are widely used sedative-hypnotics. All of the structures shown in Figure 22-2 are 1,4-benzodiazepines, and most contain a carboxamide group in the 7-membered heterocyclic ring structure. A substituent in the 7 position, such as a halogen or a nitro group, is required for sedative-hypnotic activity. The structures of triazolam and alprazolam include the addition of a triazole ring at the 1,2-position. 

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