Pyrrole, 2- synthesis Mannich reaction

Knoevenagel reaction Knorr pyrrole synthesis. Kolbe>Schmitt reaction Leuckart reaction Mannich reaction... 

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). 

An interesting pyrrole synthesis involved a retro-Mannich reaction of tropinone derivatives <04EIO1397>. 

Rather than using a metal-catalyzed synthesis of the requisite aminoalkyne substrate, Dixon and coworkers used a one-pot synthetic approach beginning with a base-catalyzed nitro-Mannich reaction for the assembly of this reactive intermediate (Scheme 15.101). Sequential addition of the AuClj catalyst for the pyrrole ring formation then afforded the N-protected 2,5-substituted products in good yields (typically 56-76% overall yield from the imine starting material) [328]. 

Scheme 15.101 A/.protected 2,5-substituted pyrrole synthesis via a one-pot nitro-Mannich reaction followed by hydroamination.

Notice that both substitutions 104 and 108 occurred next to nitrogen. Indoles on the other hand react very selectively at C-3 113 with electrophiles such as Vilsmeier and Mannich salts.15 This is probably because reaction at C-2 116 would disrupt the benzene ring as well as the pyrrole ring. As you have seen, substituents at C-2 are easy to put in during indole synthesis, so this is no great handicap. 

A domino Mannich/aza-Michael reaction was applied to the synthesis of 2,5-cis-configured polysubstituted pyrrolidines from y-malonate-substituted a,P-unsaturated esters with N-protected arylaldimines [117]. In this report, bifunctional thioureas were trialed with the Takemoto catalyst, being the most efficient with respect to yield as well as enantiomeric and diastereomeric excess. In a separate approach, the Garcia-Tellado group approached the pyrrole ring system 234, beginning with a tertiary skipped diyne 233 and a primary amine (Scheme 7.50). 

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... 

---