SolutionsHeterocycle synthesis: Paal-Knorr, Hantzsch and Fischer
Exercise 1
Propose Paal–Knorr syntheses of 1-benzyl-2,5-dimethylpyrrole and 2,5-diphenylfuran. Which 1,4-dicarbonyl compound do you need in each case?
1-Benzyl-2,5-dimethylpyrrole: hexane-2,5-dione and benzylamine, with a weak acid (acetic acid) and heat; the nitrogen of the primary amine becomes N1 of the pyrrole. 2,5-Diphenylfuran: 1,4-diphenylbutane-1,4-dione (dibenzoylethane) with an acid (H2SO4, TsOH or P2O5) that catalyses cyclization of the enol onto the other carbonyl and dehydration.
Exercise 2
Which indole is formed in the Fischer synthesis with phenylhydrazine and butan-2-one in strong acid? And with phenylhydrazine and pyruvic acid? Say which bond is formed in the [3,3] rearrangement.
With butan-2-one the more substituted ene-hydrazine (towards the CH2) predominates and 2,3-dimethylindole is formed; the other ene-hydrazine would give 2-ethylindole. With pyruvic acid indole-2-carboxylic acid is obtained, which gives indole on decarboxylation. In the [3,3] rearrangement the N–N bond breaks and a C–C bond forms between the α carbon of the ketone (which becomes C3 of the indole) and the ortho carbon of the aromatic ring.