Mannich reaction of pyrroles

In addition to the protected pyrroles mentioned above, the 1-azafulvene dimer formed by Mannich reaction of pyrrole-2-carboxaldehyde with di-methylamine has also been successfully lithiated adjacent to both pyrrole nitrogens (Scheme 10). Reaction with electrophiles and subsequent hydrolysis leads to 5-substituted pyrrole-2-carboxaldehydes in good yield [88TL777 92JOM(423)173]. 

The imine and iminium functional groupings are, of course, the nitrogen equivalents of carbonyl and O-protonated carbonyl groups, and their reactivity is analogous. The Mannich reaction of pyrrole produces dialkylaminomethyl derivatives, the iminium electrophile being generated in situ from formaldehyde, dialkylamine and acetic acid. There are only a few examples of the reactions of imines themselves with pyrroles the condensation of 1-pyrroline with pyrrole as reactant and solvent is one such example. N-Tosyl-imines react with pyrrole with Cu(OTf>2 as catalyst. ... 

Pyrroles are exceptionally nucleophilic heterocycles and undergo electrophilic substitution reactions with very weak electrophiles. The reactivity of pyrrole may be compared with that of N,(V-dimethyl-aniline or phenol all three compounds couple with the benzenediazonium ion. It is no surprise, therefore, that Mannich reactions of pyrrole and substituted pyrroles have been studied in considerable detail. We will concentrate our attention on recent studies. 

Oxyiminium cations formed from iV,0-diaIkyhydroxylamines and formaldehyde are sufficiently reactive for Mannich reactions with activated arenes. Mannich reactions of oxyiminium cations with indoles (e.g. 74, equation 48) " as well as pyrroles and furans but not phenol and thiophene have been reported. 

Quaternary anilinium salts (240), obtained from reaction of (pyrrol-l-yl)methanol and the appropriate aniline with trioctylphosphine, react in polar solvents via the azonia-fulvene ion (241) with enamines through a Mannich-type reaction followed by cyclization to give pyrrolizidines 242 and 243124. The ratio between the pyrrolizidines formed varies considerably with ring size of the enamine employed (equation 50). Pyrrolizines have also been obtained by reaction of pyrrole with two equivalents of enamine125 or condensation of some ketones with L-sodium or L-ethyl prolinate126. 

Thiophene itself undergoes Mannich reactions more sluggishly than furan or pyrrole. The Mannich reaction of 3-alkoxythiophenes and 3,4-dialkoxythiophenes has been investigated in detail <2001J(P1)2595>. The reaction of 3-methoxythiophene with secondary amines and formaldehyde in acetic acid at room temperature led to the... 

Reactions involving primary amines have been successfully carried out via Schiff s bases derived from a number of aldehydes. Thus, the reaction of pyrrole with the protonated enamine (1), which results in the formation of the pyrrole trimer (2 equation 1), constitutes a good example of a Mannich reaction involving an aldehyde other than formaldehyde. ... 

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

Mannich condensations of pyrroles and indoles are especially useful examples of alkylation by stabilized carbocations, in this case iminium ions. The traditional conditions involve reaction between the heterocycle, formaldehyde and a dialkylamine in acidic solution, as in the preparation of gramine (Equation (75)) <37CB567>. 

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. 

The retro-Mannich reaction of tropinones under the influence of certain catalysts, such as TMS-Br affords pyrroles (eq 50). In these reactions the nitrogen atom of the substrates typically is protected as a carbamate or as a sulfonamide. A basic amine is not conducive to this reaction with this t) e of reagent. The TMS-Br is used catalytically in amounts usually around 10%. The tropinone ketone may be a-substituted with various alkyl groups to give ultimately homologous ketone products. 

A number of instances have already been mentioned of reactions in which both N- and G-substitution occur. These are reactions of pyrroles with acid anhydrides (p. 64), alkylation and alkenylation of metallic derivatives of pyrroles (p. 66) and ethoxycarbonylation of metallic derivatives (p. 66 see also below). Most of the reactions of pyrrole Grignard reagents result in G-substitution, but occasionally N-substitution is also observed (p. 106). The Mannich reaction does not cause N-substitution (p. 70). Deuteration proceeds most easily at the nitrogen atom (p. 75), and reactions with metals (p. 61) cause displacement of hydrogen from nitrogen. 

Reactions of aromatic and heteroaromatic rings are usually only found with highly reactive compounds containing strongly electron donating substituents or hetero atoms (e.g. phenols, anilines, pyrroles, indoles). Such molecules can be substituted by weak electrophiles, and the reagent of choice in nature as well as in the laboratory is usually a Mannich reagent or... 

Frontier orbital theory predicts that electrophilic substitution of pyrroles with soft electrophiles will be frontier controlled and occur at the 2-position, whereas electrophilic substitution with hard electrophiles will be charge controlled and occur at the 3-position. These predictions may be illustrated by the substitution behaviour of 1-benzenesulfonylpyr-role. Nitration and Friedel-Crafts acylation of this substrate occurs at the 3-position, whereas the softer electrophiles generated in the Mannich reaction (R2N=CH2), in formylation under Vilsmeier conditions (R2N=CHC1) or in formylation with dichloromethyl methyl ether and aluminum chloride (MeO=CHCl) effect substitution mainly in the 2-position (81TL4899, 81TL4901). Formylation of 2-methoxycarbonyl-l-methylpyrrole with... 

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 two C—C bond-forming reactions in the trimerization of pyrrole are thus seen to be Mannich-type condensations and find many simple analogies, the most relevant one being that used to prepare 2-2 -pyrrolidinylpyrrole (19)."... 

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 " ... 

The wide latitude of structural variation consistent with bioactivity in this series is illustrated by the observation that antiinflammatory activity is maintained even when the second aromatic group is attached directly to the pyrrole nitrogen rather than to the heterocyclic ring via a carbonyl group as in the previous case. Condensation of p-chloroaniline with hexane-2,5-dione (or its dimethoxy-tetrahydrofuran equivalent) affords pyrrole 7. The acetic acid side chain is then elaborated as above. Thus, Mannich reaction leads to the dimethylaminomethyl derivative 8, which is in turn methylated (9) the quaternary nitrogen replaced by cyanide to afford 10. Hydrolysis of the nitrile then gives clopirac (11). 

A novel intramolecular photocycloaddition involving vinylogous amides and allenes led to an interesting type lb entry to functionalized pyrroles <060L4031>. For example, photolysis of allene 11 provided fused pyrrole 12 via a [2+2] cycloaddition and retro-Mannich reaction. 

Reaction of phenyl-5H,llH-pyrrolo[2,l-c][l,4]benzothiazepine 297 (R = Ph) with paraformaldehyde and 1-methylpiperazine dihydrochloride in methanol occurs on the 2-pyrrole position and affords Mannich product 372 (Equation (41) (1999JMC3334)). 

Pyrrole-containing thiourea derivatives 52 and 53 were developed and optimized for hydrogen-bonding activation of N-acyliminium ions [76] in the acyl-Pictet-Spengler [202, 205] (Schemes 6.50 and 52) and acyl-Mannich reaction [204] (Scheme 6.51). List et al. extended the applicability of this thiourea type to... 

Mannich reaction Pyrrole and alkyl substituted furan undergo the Man-nich reaction. Thiophene also undergoes this reaction, but, instead of acetic acid, hydrochloric acid is used. 

Shkurko and Mamaev50,408 have studied the l//-benzothieno[3,2-6]-pyrrole system 391 extensively. Electrophilic substitution (e.g., Mannich reaction, acetylation, diazonium coupling) takes place at C-2, as predicted by MO calculations.4080 If position 2 is occupied, substitution occurs at C-3.44 The Vilsmeier reaction on the 2-aryl derivative gave the expected product, but bromination of the parent system 391 failed. A 3-bromo derivative was successfully obtained from the N-methyl compound 392 with bromine in chloroform.44... 

Snyder51 has studied the 5-carbethoxy derivative of thieno[3,2-Z>]-pyrrole (460, R = H) and shown that the Mannich reaction gives 6-substituted products and acetylation takes place at C-2. Bromination gave a 2,6-dibromo-compound, and the N-benzyl-derivative (460, R = CH2Ph) yielded a 2-lithium-compound with butyllithium which was converted to a 2-carbomethoxy derivative.5,b... 

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