Knorr pyrrole synthesis
| Knorr pyrrole synthesis | |
|---|---|
| Named after | Ludwig Knorr |
| Reaction type | Ring forming reaction |
| Identifiers | |
| RSC ontology ID | RXNO:0000497 |
The Knorr pyrrole synthesis is a widely used chemical reaction that synthesizes substituted pyrroles (3). The method involves the reaction of an α-amino-ketone (1) and a compound containing an electron-withdrawing group (e.g. an ester as shown) α to a carbonyl group (2).
The mechanism requires zinc and acetic acid as catalysts. It will proceed at room temperature. Because α-amino-ketones self-condense very easily, they must be prepared in situ. The usual way of doing this is from the relevant oxime.
The original Knorr synthesis employed two equivalents of ethyl acetoacetate, one of which was converted to ethyl 2-oximinoacetoacetate by dissolving it in glacial acetic acid, and slowly adding one equivalent of saturated aqueous sodium nitrite, under external cooling. Zinc dust was then stirred in, reducing the oxime group to the amine. This reduction consumes two equivalents of zinc and four equivalents of acetic acid.
Modern practice is to add the oxime solution resulting from the nitrosation and the zinc dust gradually to a well-stirred solution of ethyl acetoacetate in glacial acetic acid. The reaction is exothermic, and the mixture can reach the boiling point, if external cooling is not applied. The resulting product, diethyl 3,5-dimethylpyrrole-2,4-dicarboxylate, has been called Knorr's Pyrrole ever since. In the Scheme above, R2 = COOEt, and R1 = R3 = Me represent this original reaction.
Knorr's pyrrole can be derivatized in a number of useful manners. One equivalent of sodium hydroxide will saponify the 2-ester selectively. Dissolving Knorr's pyrrole in concentrated sulfuric acid, and then pouring the resulting solution into water will hydrolyze the 4-ester group selectively. The 5-methyl group can be variously oxidized to chloromethyl, aldehyde, or carboxylic acid functionality by the use of stoichiometric sulfuryl chloride in glacial acetic acid. Alternatively, the nitrogen atom can be alkylated. The two ester positions can be more smoothly differentiated by incorporating benzyl or tertiary-butyl groups via the corresponding acetoacetate esters. Benzyl groups can be removed by catalytic hydrogenolysis over palladium on carbon, and tertiary-butyl groups can be removed by treatment with trifluoroacetic acid, or boiling aqueous acetic acid. R1 and R3 (as well as R2 and "Et") can be varied by the application of appropriate beta-ketoesters readily made by a synthesis emanating from acid chlorides, Meldrum's acid, and the alcohol of one's choice. Ethyl and benzyl esters are easily made thereby, and the reaction is noteworthy in that even the highly hindered tertiary-butyl alcohol gives very high yields in this synthesis.
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