Sulfonation of azoles

Sulfonation conditions are given in Table 4. The orientation is as expected. Azolinones react as readily as the corresponding azoles sulfonation of (117) occurs at the positions indicated (H2SO4/SO3 at 100 °C). Imidazoles are readily chlorosulfonated at C-4. 

Amination at an azole ring nitrogen is known for Af-unsubstituted azoles. Thus 4,5-diphenyl-1,2,3-triazole with hydroxylamine-O-sulfonic acid gives approximately equal amounts of the 1- (104) and 2-amino derivatives (105) (74AHC(16)33). Pyrazole affords (106) and indazole gives comparable amounts of the 1- and 2-amino derivatives. 

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. 

The general discussion (Section 4.02.1.4.1) on reactivity and orientation in azoles should be consulted as some of the conclusions reported therein are germane to this discussion. Pyrazole is less reactive towards electrophiles than pyrrole. As a neutral molecule it reacts as readily as benzene and, as an anion, as readily as phenol (diazo coupling, nitrosation, etc.). Pyrazole cations, formed in strong acidic media, show a pronounced deactivation (nitration, sulfonation, Friedel-Crafts reactions, etc.). For the same reasons quaternary pyrazolium salts normally do not react with electrophiles. 

It is important to note that SNAr displacement reactions of heteroatom functional groups other than halides have been demonstrated on purine substrates, including mesitylenesulfonates <20000L927>, sulfones (see Section 10.11.7.5), nitro substituents <2006S2993>, and T-azoles (see Section 10.11.7.3.2). Halopurines have been reduced using sodium naphthalenide <1997T6295>. 

Oxidation of sulfur-containing azoles quite often leads to the formation of sulfones and sulfoxides. Thus, 3-alkyl-1,2-benzisothiazoles 142 with MCPBA give the oxaziridines 143, and the use of a chiral 3-alkyl substituent leads to pure diastereomers. Reaction of 1,2,3-benzothiadiazole with 30% hydrogen peroxide in a mixture of acetic acid and methanol for 45 days affords 144 in 60% yield. 

Hasiotis, C. et al.. Development and characterization of acid-doped polybenzimid-azole/sulfonated polysulfone blend polymer electrolytes for fuel cells, J. Electrochem. Soc., 148, A513, 2001. 

Sulfur is a useful link for heterocycles because its use as a leaving group (or better, after conversion to sulfoxide or sulfone) can bring about cleavage from the support combined with addition of a nucleophile. This method has been nsed for both azoles and azines, as shown below. 

Saleh et al. (2012) have developed a novel and efficient three-component condensation reaction of an aldehyde, amino azoles, and p-keto sulfone for the synthesis of pyrimido[l,2-a]benzimidazoles (143) and pyrazolo[3,4-b]pyridines (146) under ultrasonic irradiation via utilization of P-keto sulfone as an important synthon (Schemes 8.47 and 8.48). 

Other nitrogen nucleophiles can react efficiently with triflyl chloride. Below —30°C, 1,1-dimethylhydrazine was sulfonated to afford the corresponding trifluoromethanesulfonic hydrazide. In the azole series, the side chain of some 1,2,3-triazoles was functionalized with a trifluoromethanesulfonyl group (eq 10). When pentafluoroethanesulfonyl chloride was used in this transformation, a mixture of mono- and di-sulfonylated derivatives was... 

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