Pyrrole diazo coupling

Diazo coupling occurs very readily between pyrroles and indoles and benzenediazonium salts. Reaction is much more rapid in alkaline solution when the species undergoing reaction... 

Pyrazoles and imidazoles exist partly as anions (e.g. 108 and 109) in neutral and basic solution. Under these conditions they react with electrophilic reagents almost as readily as phenol, undergoing diazo coupling, nitrosation and Mannich reactions (note the increased reactivity of pyrrole anions over the neutral pyrrole species). 

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. 

Diazo-coupling products of 1-substituted l//-pyrrol-3(2//)-ones have been shown by X-ray crystallography to adopt the hydrazone structure 115 [91JCS(P1)701]. 

The same authors <2000J(P1)3584> studied the reactivity of 2 toward benzenediazonium (chloride or tetrafluoro-borate) salts. No diazo coupling took place under neutral or slightly acidic conditions. However, under basic conditions (NaOH in H20/MeOH), a mixture of 62 and 63 was obtained. This result clearly indicates that the diazo coupling takes place through the anion of 62 which arises from the base-catalyzed methanolysis of amide 2 in which the pyrrole ring is obviously not nucleophilic enough. 

The reaction of an azepinium ion (3), generated in situ, with a number of aromatic substrates (benzene, anisole, phenol, furan and thiophene) usually gave aryl-2//-azepines [e.g. (4) from benzene] as the major products.7 In the case of reaction with pyrrole, however, a ring-opened compound (5) was the major product. Some condensed thiophenes have been shown8 to give products of substitution at C(l). For example, (6a) gave (6b) on diazo coupling. 

There have been some studies of the diazo coupling and carbonyl reactions with imi-dazo[2,1 -b ]thiazol-3 (2//)-ones (67CHE706), 2,3 -dihydrothiazolo[4,3-c ]-s-triazol-5-ones (76ZN(B)853) and 2,3-dihydroimidazo[2,l-6]thiazol-3(2//)-ones (81ZN(B)50l). Oxidation of 2,3-dihydrothieno[3,2-fc]pyrrole with chloranil to thieno[3,2-fc]pyrrole has been reported (72CHE1428). 

Diazo coupling occurs readily between pyrroles and indoles and benzenediazonium salts. Reaction is much more rapid in alkaline solution when the species undergoing reaction is the N-deprotonated heterocycle. Depending on the conditions, pyrrole yields either 2-azo or 2,5-bis(azo) derivatives, e.g., 140 or 141, and indole gives a 3-substituted... 

Diazetine, see Diazete, dihydro-Diazirines, calculations, 56, 373 Diazirine, 3-chloro-3-trifluoromethyl-, reaction with pyrrole, 59, 10 3//-Diazirine, 3-fluoro-3-methoxy-, 59, 3 Diazo coupling... 

Pyrrole, by some sort of association with the anion (derived from the catalysing acid) was supposed to be activated towards electrophilic attack. The final expressions above represent the particular case of salt formation, the site of protonation depending on the substituents present in the ring. The reactive entities in electrophilic substitution are (69) and (70). In the case of, say, diazo coupling, reactivity in acid solution is attributed to these Pyrro-lensalz-Ionen . In neutral media, substitution is referred to the classical polarized form of pyrrole, and in alkaline media the enhanced reactivity is due to the presence of pyrrole anions. 

Although attempts to make pyrrole diazonium salts couple inter-molecularly have been unsuccessful, 3-diazo-2,4,5-triphenylpyrrole (21) on prolonged heating in dilute sulfuric acid undergoes internal coupling (21- -41).21 That coupling occurred with the phenyl group in the 4-position rather than the 2-position is shown by the formation of the diketone (42) on oxidation with nitric acid. 

---