2- Substituted 1,2,3-triazole 1-oxides protonation

Protons of 1,2,3-triazole rings can also be activated by A -oxides. The H(4) and H(5) protons in 3-substituted 1,2,3-triazole-1 -oxides (254) are more reactive but exchange with deuterium at a similar... 

Studies on the potential of the electrochemical approach to pyrazolotriazoles 117 showed that under the conditions of bicycle synthesis from 3-amino-4-hydrazonopyrazoles the N-l-unsubstituted triazole ring of 117 was further oxidized in a one-electron peak, followed by proton removal to yield the bis-(l,l )-2-phenylpyrazolo[3,4-i/][l,2,3]triazoles 118. This observation is significant, since in spite of pronounced pharmaceutical applications of pyrazoles, the redox characteristics of substituted pyrazoles have received limited attention (Scheme 13) <2001MI1022>. 

The 1,2,3-triazole 1-oxides 326 are usually stable, crystalline, semipo-lar, and colorless compounds. The lower 2-alkyl-substituted 1,2,3-triazole 1-oxides tend to be slightly hygroscopic. They act as very weak bases, protonation requiring acids like triflic acid and O-alkylation requiring tri-methyloxonium salts. No pKa values have been reported. 

Bromine at C5 of 2-substituted 1,2,3-triazole 1-oxides 361 is readily removed without touching the N-oxygen by treatment with aqueous-methanolic Na2S03 (2010UP2). Debromination has also been achieved by metallation followed by protonation as described in Section 4.1.6.4 (Scheme 109). 

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). 

The 3-alkyl- or aryl-substituted 1,2,3-triazole 1-oxides 448 are usually stable, crystalline, polar, and somewhat hygroscopic compounds. 3-Sub-stituted 1,2,3-triazole 1-oxides 448 are weak bases being subject to protonation at the negatively charged oxygen atom. 3-Hydroxy-l,2,3-triazole 1-oxide 456 (R=OH) acts both as a base and as an acid. No pKa values for 3-substituted 1,2,3-triazole 1-oxide have been reported. 

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. 

Protons at positions 4 and 5 of 3-substituted 1,2,3-triazole 1-oxides 456 are more acidic than corresponding protons in the parent 1,2,3-triazoles 478 and are replaced quantitatively with deuterium within 1 h in deuterium oxide solution containing catalytic amounts of potassium carbonate (1987ACSA(B)724). In contrast, abstraction of H5 in 1-phenyl-l,2,3-triazole 478 (R=Ph) requires treatment with bases like n-butyllithium and the anion formed undergoes ring cleavage (1971CJC1792). 

Substituted 1,2,3-triazole 1-oxides 448 are protonated at the oxygen atom. The site of the protonation is evident from1H and 13C NMR spectra, which are similar to those of the l-methoxy-l,2,3-triazolium tetrafluorob-orates 507 described in Section 4.2.7.10. The hydrochlorides are manipula-ble and separate from solutions in dry methanol upon addition of diethyl ether (1987ACSA(B)724). 

Alkyl radicals. Alkyl radicals produced by oxidative decarboxylation of carboxylic acids are nucleophilic and attack protonated azoles at the most electron-deficient sites. Thus, imidazole and 1-alkylimidazoles are alkylated exclusively at the 2-position. Scheme 72 shows the substitution of a protected histidine <2001BML1133>. Similarly, thiazoles are attacked in acidic media by methyl and propyl radicals to give 2-substituted derivatives in moderate yields, with smaller amounts of 5-substitution. A-Alkyl-1,2,-4-triazoles can be radical substituted at C(5) <2001TL7353>. 

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