Knorr Pyrrole Synthesis

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.