Pyrrole Mannich reaction

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

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). 

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. 

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. 

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]. 

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... 

Pyrrole is aminomethylated to give products of type (106). The intermediate immonium ion generated from formaldehyde, dimethylamine and acetic acid is not sufficiently reactive to aminomethylate furan, but it will form substitution products with alkylfurans. The Mannich reaction appears to be still more limited in its application to thiophene chemistry, although 2-aminomethyl-thiophene has been prepared by reaction of thiophene with formaldehyde and ammonium chloride. The... 

The Mannich reaction on the thieno[3,2-6]pyrrole (47) gave the 6-substituted dialkyl-aminomethyl derivative (50 Scheme 10). The dialkylamino function in (50) was replaced by CN following standard procedures (64JOC2160). 

We still have to make the pyrrole with the alkyl side chain for this acylation reaction. Friedel-Crafts alkylation is not an option but pyrroles are reactive enough to do the Mannich reaction. Formaldehyde and an amine combine to give another iminium salt 107 that reacts with A-methyl pyrrole to give, after rearomatisation 109 the substituted pyrrole 110. 

Under certain circumstances, the conjugate addition and cycloaddition reaction pathways overlap for a,P-unsaturated electrophiles. For example, when the 2,5-dimethylpyrrole complex 22 is combined with 1 equiv of MVK in acetonitrile, a 1 1 ratio of the p-alkylated 3//-pyrrole complex 96 and the a-alkylated 2Z/-pyrrole complex 98 is isolated (Figure 18). When the reaction is monitored by H NMR in CD3CN, an intermediate 7-azabicyclo[2.2.1]heptene complex (97) is observed at early reaction times, and eventually converts (tm 1 h) to compound 98 via a retro-Mannich reaction followed by proton transfer. 

Thiophene, alkyl-substituted furans, and especially pyrrole, undergo Mannich reactions. 

Like pyrrole, indole readily undergoes the Mannich reaction affording the aminomethyl derivative 7.26. A variety of nucleophiles can displace the amine via an elimination followed by a 1,4-addition reaction, as in the preparation of acetate 7.27. 

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