84 Pyrroles
nucleophilic addition to generate the N-1-C-2 bond are involved, though the exact order of events is not certain – prob-
ably the N-C bond is formed fi rst, giving an enamine. Note: -Amino-ketones are unstable in that they self-condense
to form dihydropyrazines (cf. page 60). Two strategies are available to avoid this problem. The amino-ketone can be
provided in N-protected form, as a protonic salt for example, the amine being liberated by base in the presence of the
other synthesis component. Alternatively, the amino-ketone can be formed in the presence of the other component, for
example by reduction of a precursor -keto-oxime. The synthesis of the ethyl 2,4-dimethylpyrrole-3-carboxylate shown
involves pyruvaldehyde oxime and ethyl acetoacetate. The amino-ketone is produced by reduction of the oxime in situ.
A useful route to N-protected -amino-ketones is the reaction between the ‘Weinreb amide’ [RCON(OMe)Me] of an
N-Cbz-protected -amino acid and an alkyl- or aryllithium or Grignard reagent, to give the ketone. In this situation,
the-amino-ketone is released by hydrogenolysis of the Cbz protecting group, in the presence of the other ring syn-
thesis component, as illustrated for a reaction with ethyl acetoacetate.
The Knorr synthesis often produces pyrrole esters and it is relevant to recall (page 82) their hydrolysis and easy decar-
boxylation, if the ester is not required.
Synthesis of pyrroles using isocyanides (2,3- and 4,5-bonds made)
An important disconnection for pyrrole ring synthesis leads back to a two-carbon fragment and a C-N-C fragment – it
is this latter unit which includes an isocyanide – tosylmethyl isocyanide (TolSO 2 CH 2 NC, TosMIC) has been the most
frequently used – the van Leusen synthesis. The anion of TosMIC, easily generated, is reacted with an alkene conjugated
with an ester or ketone; we represent the sequence (again a one-pot process in which several mechanistic steps occur)
as starting with a Michael-type addition. The next step, perhaps strange looking at fi rst sight, is intramolecular nucle-
ophilic addition of the enolate -carbon to the carbon of the isocyanide, formally negative in the resonance form shown
(the other contributor is RN=C:). Proton transfers and fi nally loss of p-toluenesulfi nate (Note: the sulfur has changed
oxidation level from sulfonate to sulfi nate) gives a species requiring only tautomerism to arrive at the aromatic pyrrole.