Pyrroles aminoalkylation

Phenols, secondary and tertiary aromatic amines, pyrroles, and indoles can be aminomethylated by treatment with formaldehyde and a secondary amine. Other aldehydes have sometimes been employed. Aminoalkylation is a special case of the Mannich reaction (16-15). When phenols and other activated aromatic compounds are treated withA-hydroxymethylchloroacetamide, amidomethylation takes place " ... 

Secondary and tertiary aminoalkylbenzotriazoles (108) react with pyrrole, indole, and their N-methyl analogues under mild conditions in the presence of a Lewis acid to afford selectively the corresponding secondary or tertiary aminoalkyl derivatives (Scheme 22) (92T4971). A,A-Bis(alk-oxymethyl)amines can also be used to give secondary alkylamines, which operate via reactive iminium salts formed by treatment with trimethylsilyl chloride (90TL4229). 

N-Aminoalkylation of l//-pyrrole was achieved with 2-chloroethylamine under phase-transfer conditions (TEAS, NaOH, MeCN) <2004JOC8668>. Synthesis of N-alkylated indoles 121 (e.g., RO 60-0175, R = 5-F-6-Cl), that are selective 5HT2C agonists with potential therapeutic utility in the treatment of obsessive compulsive disorder... 

First, 2-pyrrol-1-yl-benzaldchyde 159 (Fig. 55), which combines in the same molecule the functions of both substrate and aldehyde, gives aminoalkylation in position 2 of the pyrrole ring by reaction with the secondary amine, thus yielding an interesting precursor (160) of polycyclic derivatives with fused nuclei. ... 

Pyrrole reacts with aqueous formaldehyde and secondary amines in the presence of acetic acid to afford, in some cases, mixtures of products derived from attack at the 2- and 2,5-positions. The disubstitution products can be obtained in very high yields at about room temperature for example, a 92% yield of 2,5-bis(piperidylmethyl)pyrrole is obtained using this method. The same procedure apparently does not yield a Mannich base with l-methylpyrrole, but the use of aqueous formaldehyde and dimethylamine hydrochloride at 60 °C results in the formation of the 2-substitution product in 73% yield. Even highly substituted pyrroles react. Thus, ethyl 4,5-dimethylpyrrole-2-carboxylate and ethyl 2,5-dimethylpyrrole-3-carboxylate both undergo C-aminoalkylation at the unsubstituted position in 45 and 68% yields, respectively, with dimethylamine and formaldehyde in ethanolic solution. A number of tri- and tetra-substituted 2-methylpyrroles have been investigated with the exception of Knorr s pyrrole all gave side-chain substituted products with formaldehyde and a secondary amine in acetic acid. ... 

The reaction of l-(2-isocyanoaryl)pyrroles with Eschenmoser s salt 147 also goes smoothly with the formation of dimethyl(pyrrolo[l,2-tz]quinoxalin-4-ylmethyl)ammonium iodides 148 (Scheme 3.44), which after treatment with an aqueous solution of NaHCOs readily give quantitative yields of the free bases. In the case of the reactions of l-(2-isocyanophenyl)pyrroles 137a, b with other salts of the iminium type 149 and 151, obtained from secondary amines and aldehydes in the presence of MesSiCl/Nal/EtsN, it was shown that such a synthesis of 4-(l-dialk yl-aminoalkyl)pyrrolo[l,2-ti]quinoxalines 150, 152, and 153 is universal (Kobayashi et al. 2001b). 

When working with enzymes on conducting surface, for example, during characterization of amperometric biosensors, overlap of different feedback mechanisms must be expected as exemplified in the work by Kranz et al. who used A-(a)-aminoalkyl)pyrrole to form derivatized PPy that provides amino groups for binding periodate-oxidized GOx to the outer polymer surface [11]. 

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