Substitutions at pyrrole nitrogen

A palladium-catalyzed /V-alkylation (Buchwald-Hartwig amination) of pyrroles with cyclic p-chloroenals, was reported 07S1571 . 

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As with any metalloprotein, the chemical and physical properties of the metal ion in cytochromes are determined by the both the primary and secondary coordination spheres (58-60). The primary coordination sphere has two components, the heme macrocycle and the axial ligands, which directly affect the bound metal ion. The pyrrole nitrogen donors of the heme macrocycle that are influenced by the substitutents on the heme periphery establish the base heme properties. These properties are directly modulated by the number and type of axial ligands derived from the protein amino acids. Typical heme proteins utilize histidine, methionine, tyrosinate, and cysteinate ligands to affect five or six coordination at the metal center. 

Pyrroles, indoles, isoindoles and carbazoles having no substituent at the nitrogen atom are weakly acidic and, upon treatment with a strong base, form anions which are capable of subsequent reaction with electrophiles at the nitrogen atom and/or the 1-position of isoindoles, the 2-position of pyrroles and the 3-position of indoles. 1-Substituted pyrroles and indoles also react with butyllithium to give 1-substituted 2-pyrrolyl and 2-indolyl anions (see Section 3.05.1.2.9). 

Dioxacorroles are 18-7r-electron aromatic systems like corroles. They exhibit basicity intermediate between that of porphyrin and corrole, and require 1 h at 100 °C in TFA for complete deuteration of the meso positions. The furan protons are also substituted by deuterium under the same conditions after lOOh. Friedel-Crafts acylation occurs at C-5 while alkyl halides attack on the pyrrolic nitrogens to give a mixture of mono- and di-alkyl derivatives. 

Only a few investigations of electrophilic substitution reactions of pseudo-azulenes containing a pyrrole-type nitrogen have been reported. There are many examples of alkylations (see Table VI). An alkylation always takes place at the nitrogen of the five-membered ring. For 7H-pyrrolo[2,3-b]-pyridine 68 azocoupling and reaction with dithiolium salts have been reported.166... 

In the reaction with acetic anhydride in an inert solvent, pyrrole gives a mixture of 1- and 2-acetyl derivatives.139 The substitution at the 2-carbon seems to involve the neutral molecule of pyrrole, whereas that at nitrogen probably involves the dissociated anion. In fact, the C/N isomer ratio is decreased by adding sodium acetate (which favors ionization) and increased by adding acetic acid (which opposes it). 

The electron-dona ting power of thye indole and pyrrole nitrogens is never better demonstrated than in the use to which these Mannich bases (the products of the reaction) are put. You may remember that normal Mannich bases can be converted to other compounds by alkylation and substitution (see p. 758). No alkylation is needed here as the indole nitrogen can even expel the Me2N group when NaCN is around as a base and nucleophile. The reaction is slow and the yield not wonderful but it is amazing that it happens at all. The reaction is even easier with pyrrole derivatives. 

Arylpyrroles, substituted or unsubstituted at the nitrogen, undergo a much more drastic oxidation than alkyl derivatives by the action of hydrogen peroxide. In most cases opening of the heterocyclic ring occurs, both at the bond between the heteroatom and the a-carbon and between the a- and )8-carbon atoms. From 2,5-diphenylpyrrole in acetic medium benzoic acid and acetophenone are formed.51 From 2,3,5-triphenyl-pyrrole (58, R = H) the product is 59,61 while from 58 (R = benzyl) the compounds 60 (R = benzyl) and 61 are produced.62 Other pyrroles that were found to behave similarly are listed below. 

In order to accelerate the slow metalation, several methods have been proposed (1) use of substitution reaction of cadmium(II) or mercuty(II) porphyrin, (2) use of N-substituted porphyrins at the pyrrole nitrogen, (3) addition of aromatic heterocyclic bases such as pyridine and imidazole, (4) introduction of functional groups to bind metal ions in the vicini of the porphyrin nucleus (e. g. tetracarboxylic add "picket-fence" porphyrins) and (5) use of reducing agents such as hydroxylamine and ascorbic add in copperfll) incorporation. 

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