Knorr Pyrrole Synthesis – a heterocycle formation reaction

In 1886, L. Knorr heated a mixture of alpha-nitroso ethyl acetoacetate and ethyl acetoacetate together in glacial acetic acid in the presence of zinc dust, forming a tetra-substituted pyrrole. Since then, the condensation of an alpha-amino ketone or alpha-amino-beta ketoester with an active methylene compound has been known as the Knorr pyrrole synthesis.

The Neber rearrangement can be used to prepare the precursor alpha-aminoketones from the corresponding oxime by reaction with tosyl chloride.

α-aminoketones are often quite labile and can undergo self-condensation, forming a pyrazine; so, they are often prepared by first nitrosating the ketone, and then reducing it in situ.

An anti-inflammatory analgesic compound, 4,5,8,9-tetrahydro-8-methyl-9-oxothieno[3’3’:5,6]cyclohepta[1,2-b]-pyrrole-7-acetic acid, was synthesized by H.E. Rosenberg and R.W. Ward utilizing the Knorr pyrrole synthesis.

Mechanism of the Knorr pyrrole synthesis

Review available Thermo Scientific products for the Knorr pyrrole synthesis: