Pyrrole-2-carbaldehyde, formation

Reductive ring closure of l-(2-nitrobenzyl)-2-pyrrole carbaldehyde 200 results in pyrrolo[2,l-c][l,4]benzodiazepine 201 (Scheme 42 (1999BMCL1737)). On the other hand, oxo derivative 203 can be synthesized starting from aldehyde 200 through a nitrile formation/cyclizations multistep sequence. The alternate synthetic strategy included reduction of the intermediate acid (R = H) or ester (R = Et) 205 followed by CDI or thermal cyclization (1992JHC1005). 

Methylpyrrole is one of the four pyrroles isolated in the pyrolysis of trigonelline by Viani and Horman (1974). It was also formed by heating D-xylose with methylamine (Kato, 1966), from a cysteine/ cystine ribose browning system (Mulders, 1973c). Kato and Fujimaki (1968) observed the formation of A -substituted pyrrole-2-carbaldehydes when D-xylose reacted thermally with various amines or amino acids (glycine, alanine, 3-alanine, leucine). The intermediate 3,4-dideoxypentosulos-3-ene would either give 2-furaldehyde (mainly with a-amino acids) or substituted pyrrole-2-carbaldehydes and melanoidins (with 3-alanine or other amines). 

Alkylation of pyrroles proves to be problematic because the usual Lewis acid catalysts initiate polymerization. The Vilsmeier-Haack formylation, however, leads to the formation of pyrrole-2-carbaldehyde in good yield. The Houben-Hoesch acylation (reaction with nitriles in the presence of hydrogen chloride) provides 2-acylpyrroles ... 

Organometallic intermediates continue to be important in the synthetic methodology for substitution of pyrroles and indoles. Numerous lithiation techniques have been reported and provide a range of useful reaction conditions. The pyrrolyl dimer (120) (really a dimeric equivalent of pyrrole-2-carbaldehyde) can be lithiated at the 5- and 5 -positions. Electrophilic substitution then yields 5-substituted pyrrole-2-carbaldehydes (121) (Scheme 34) <88TL777>. The related monomeric ald-iminium salts (122) yield similar products after anion formation, bromination, lithiation, and electrophilic attack (Scheme 35) <88HCA2053>. In a similar process, the dimer (120) can be brominated at C-4 and converted into 4-substituted pyrrole-2-carbaldehydes <88TL3215>. 

Figure 4.90 Formation of polyhydroxyalkyl substituted pyrrole-2-carbaldehyde and pyrazine derivatives (R = H).

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