Pyrroles formaldehyde, reaction with

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. 

Pyrrole can be condensed under alkaline conditions with formaldehyde to give products of either N- or C-hydroxymethylation (Scheme 56). Benzo[ ]furan gives an isolable alcohol on reaction with glyoxylate using Y (OTf)3 as catalyst where attack has taken place at C(3) <2000JOC4732>. 

The reactions of ethyl 2,4-dimethylpyrrole-3-carboxylate with a number of primary amines and an excess of formaldehyde lead to the formation of 2,3-dihydro-l//-imidazo[l,5-a]pyrroles. The reaction of cyclohexylamine, which, as indicated in the foregoing section, would not be expected to yield a product involving two pyrrole nuclei, does result in the formation of the dihydroimidazopyrrole in 70% yield as shown in Scheme 6. ... 

From 2-methylpyrrole and formaldehyde, orange-coloured pyrrolyl(pyrrol-2-ylidene)methane is formed, which is unsubstituted in the 5-position. In acid-catalysed reactions with carbonyl compounds, pyrroles behave similarly to phenols, which give diphenylmethanes via hydroxymethyl compounds. 

Addition of Alkyl Groups. Katrizky reported that in the presence of bismuth(lll) chloride-metallic aluminum, alkyl (as well as allyl) halides react with A-(alkylamino)benzotriazoles at 20°C in THF-water to give the corresponding homoalkylated amines in high yields (Eq. 11.48). Competitive addition of CCI3 anions to N-alkyl-pyridinium salts was studied in a two-phase system of chloro-form/concentrated aqueous NaOH and in a homogeneous medium. Aminomethylation of 1-alkylpyrroles by aqueous formaldehyde and dimethylamine hydrochloride, followed by reaction with iodomethane, affords the l-alkyl-2,5- A[(trimethylammonio)methyl]pyrrole diiodide... 

A synthesis of 2,3-diarylpyrroles was based on the use of a difunctional phosphine imine which is capable of both Wittig and aza-Wittig condensation. <94J0C4551> The reagent is prepared from benzotriazole, formaldehyde, sodium azide and triphenylphosphine which gives the precursor 13. Reaction with methylidene-triphenylphosphorane and butyllithium generated 14 which reacted with benzil derivatives to give the pyrroles. 

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. 

Whereas 2,4-dialkyl-phenols react readily with HCHO, the 2,6-analogues show little or no reactivity, depending on the size of the alkyl groups. The kinetics and mechanism of the reaction between 4-t-butylphenol and formaldehyde in the presence of alkaline hydroxide catalysts have been studied the efficiencies of catalysts are in the order Careaction between 3,4-disubstituted pyrroles and HCHO, with acid catalysis, in good yields. 

All acid-catalyzed electrophilic substitution reactions are held by Treibs to occur by way of the distinct reactive species (23), thus the very greatly accelerated interaction of pyrrole and formaldehyde in acid solution involves attack of neutral formaldehyde on (23). Another example is the interaction of 2,3,4,6-tetramethylpyrrole with p-dimethylaminobenzaldehyde in acid solution, for which the following reaction (Scheme 2) is given,(23a) being presumably intended... 

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 " ... 

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 combined reaction of formaldehyde and Meldrum s acid with pyrroles and indoles provides a synthetic route to the corresponding heteroarylpropionic acid (e.g. 810PP39). 

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. 

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