Pyrrole Mannich bases

Fig. 141. Synihesis of porphirines involving pyrrole Mannich bases.

Pyrrole Mannich bases are intermediates in the synthesis of porphirines 360 (Fig. 

Pyrrole Mannich bases have been transformed into the tertiary ammonium salt as a good leaving group. Therefore, treatment of the quaternary ammonium salt with sodium sulfinate to give the corresponding sulfonyl pyrrole, which in turn, could undergo another Mannich reaction to synthesize sulfonyl pyrrole Mannich bases as germicides. ... 

Pyrrole Mannich bases have been prepared as potential antipsychotic agents that do not have the extrapyramidal side effects (EPS). In one case, A -methylpyrrole was amidomethylated with l-(hydroxymethyl)azepan-2-one, which was assembled by condensation between the seven-membered lactam and formaldehyde. The amidomethylated 7V-methylpyrrole then underwent the Mannich reaction with arylpiperazine and formaldehyde in the presence of trifluoroacetic acid (TEA). The pyrrole Mannich bases synthesized in this manner exhibited a high affinity for the serotonin 5-HT-lA and 5-HT-lB binding sites. Although these arylpiperazines interact weakly with dopamine D-1 and D-2 receptors, they were reasonably potent in an in vivo model in the rat CAR (conditioned avoidance responding), an indication of potent antipsychotic activity. 

Outside the CNS (central nervous system), pyrrole Mannich bases have found utility in other therapeutic areas as well. The Mannich reaction between iminoibitol and 9-deazahypoxanthine took place at the C3 position to provide an A-pyrrolylmethyl substituted iminoribitol as an inhibitor of a purine-specific nucleoside hydrolase. In terms of regiochemistry, this particular Mannich reaction of 9-deazahypoxanthine behaved similarly to indole rather than to pyrrole. The resulting Mannich bases are potential treatment for parasitic infections. 

C-10 pyrrole Mannich bases of artemisinin have been aceessed as potential anti-malarial agents. Treatment of dihydroartemisinin with N-methylpyrrole in the presence of a Lewis acid gave rise to the C-10 pyrrole analogue. The subsequent Mannich reaction used preformed Eschenmoser s salt to afford the dimethylaminopyrrole, which was an anti-malarial with enhanced water solubility. 

Leonard and Burk44 found that Mannich bases of the pyrrole series are convenient starting compounds for the syntheses of pyrrolizidine... 

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. 

The dialkylamino group of a 2-dialkylaminomethyl pyrrole can also be displaced by various nucleophiles. In a typical example, displacement of trimethylamine from the quaternary salt derived from the Mannich base of a 1-arylpyrrole gives an azide which can be reduced to give the aminomethylpyrrole (Scheme 129). 

Heterocyclic substrates, such as pyrrole and imidazole derivatives 68, may undergo selective Mannich reactions. C-Aminomethylation is favored by acidic conditions, whereas N-Mannich bases are produced when free amine and formaldehyde, or N,0-acetals in anhydrous solvents, are employed. Heterocyclic N-Mannich bases, however, are not particularly stable and may therefore behave as aminomethylation agents (see,... 

In addition to the ketonic and phenolic bases, Mannich bases of ferrocene and pyrrole provide further notable examples of ring-forming synthesis. Ferrocenes (Fig. 

Porphyrin synthesis and functionalization based on the chemistry of Mannich bases, briefly mentioned in previous chapters, are recalled here. As far as porphyrin synthesis is concerned, studies of biomimetic models of photochemically active reaction centers are worth noting. The synthetic procedure involves amino group replacement of the pyrrole bis-Mannich base with formation of the tetrapyrrole ring of porphyrin (see 360, Chap. 11). 

Although formaldehyde has been most common, other aldehydes have also been used successfully for the formation of iminium ion. The Mannich reaction also proceeds with the other activated hydrogen compounds such as indole, furan, pyrrole and phenols. When primary amine is used, the Mannich base formed is a secondary amine and may undergo further condensation to yield tertiary amine. The Mannich base may eliminate an amine... 

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. ... 

For the systematic synthesis of naturally occurring bile pigments, the most versatile method is still the stepwise coupling of pyrrole—or partially reduced analogs— to form dipyrrolic units, cf. which can be coupled together. C-labeled bilirubin IXa (40), for example, has now been synthesized by condensation of an a-unsubstituted oxopyrromethene (38) with an oxopyrromethene Mannich base (39) the label was incorporated in the dimethylaminomethyl res-... 

Pyrrole was discovered in 1834 by Friedlieb Ferdinand Runge in coal tar, where it is present in a concentration of less than 0.01%. Production from coal tar is, therefore, not economical. Pyrrole is synthesized by the reaction of furan with ammonia. Pyrrole is used in the production of polypyrrole and pharmaceuticals, such as the anti-inflammatory drug tolmetin. In tolmetin synthesis, the acidity of pyrrole is made use of. It is transformed into the potassium salt, which reacts with methyl chloride to form 1-methylpyrrole. The reaction of methylpyrrole with formaldehyde and dimethylamine produces the Mannich base, which is then quatemized... 

We have synthesized such a precursor polymer by using the Stetter reaction (scheme 2). Poly-1,4-phenylene-1, 4 -butanedione 9 was formed in the reaction of terephthalic-dicarboxaldehyde 10 and the bis-Mannich base of 1,4-diaeetylbenzene 11 in a yield of 81%. The conversion of 9 into the alternating copolymers of p -phenylene-2,5-pyrrole 12 and p-phenylene-2,5-thiophene 13 is performed with liquid NH3 and Lawesson s reagent, respectively (scheme 3). Upon doping with either Ig or AsFg both polymers 12 and 13 become electrically conducting with specific conductivities up to 0.1 S/cm. 

Albertson, N.F., 1948. Alkylation with non-ketonic Mannich bases. Aminothiazoles and pyrrole. J. Am. Chem. Soc. 70, 669—670. 

Whatever the detailed mechanism of the reaction between formaldehyde, secondary or primary amines and a suitably reactive aromatic compound, it is clear that essentially the Mannich aminomethylation is an electrophilic substitution. It is therefore not surprising that pyrrole reacts very readily with formaldehyde and secondary amines to give Mannich bases . If an excess of pyrrole is not maintained during the reaction, more highly substituted products result" 4, 1-Methylpyrrole reacts, if anything, more readily... 

An interesting substitution which gives a product (13) related to the Mannich bases, by means of a modified Vilsmeier reaction, occurs between pyrrole, pyrrolidone and phosphoryl chloride . Other examples are known27i, 3i3 ... 

Pyrrole-based PNP and PNNP pincer diphosphines were synthesized starting from pyrrole and dipyrrolyl-diphenylmethane utilizing a double Mannich reaction and then the reaction of the Mannich bases with two equivalents of Ph2PH at 110-150 °C. It is noteworthy that there was no need to use Ph2PLi in the substitution reaction. The bisphosphines were converted to the oxides and sulfides (Scheme 10). ... 

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