Halogen-substituted 1,2,3-triazoles

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>. 

Halogenation proceeds through N- halotriazoles or triazolium derivatives that have been discussed under Section 4.12.3.2.4. Also the bromination of AT-substituted triazoles by A-bromosuccinimide in chloroform (75BSF64 ) is thought to involve AT-bromotriazolium intermediates. If so, the same applies to halogenations with N- halotriazoles (69ZC32s). 

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. 

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 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]. 

The anions generated by proton-metal or halogen-metal exchange (Section 4.1.6.3-4) reacted readily with electrophiles like MeOD, Mel, I2, and A/-formyI morphol i ne (NFM) to give the 5-substituted 1,2,3-triazole 1-oxides 372 (2010UP2) (Scheme 112). 

Palladium activates halogen at the 5-position of 2-substituted 1,2,3-triazole 1-oxides and brings 361 and 370 to react as acceptors in crosscoupling reactions as described in Section 4.1.6.7. 

Substituted 1,2,3-triazole 1-oxides 448 have been reported to undergo electrophilic and nucleophilic aromatic substitution and are subject to debromination, proton-metal exchange, and halogen-metal exchange followed by electrophilic addition. Transmetallation and cross-coupling have not been described. 3-Substituted 1,2,3-triazole 1-oxides 448 can be proton-ated or alkylated at the O-atom and they can be deoxygenated and deal-kylated. The individual reactions are described in Section 4.2.7.1-4.2.7.14. 

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 activation of halogen in 4- and 5-halogeno-substituted 1,2,3-triazole 1-oxides is in keeping with the prediction discussed in Section 1.4.2. 

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 (approximately equal to -dinitrobenzene), and oxadiazoles, thiadiazoles, triazoles, etc. with great difficulty. In each case, halogenation is easier than nitration or sulfonation. Strong electron-donor substituents assist the substitution. 

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