Knorr synthesis of pyrroles

The preparation of 2 4-dimethyl-3 5-dicarbethoxypyrrole (II) is an example of the Knorr synthesis of pyrrole derivatives, involving the reaction of an -aminoketone (or a derivative thereof) with a reactive methylene ketone (or a derivative thereof). The stages In the present synthesis from ethyl acetoacetate (I) may be represented as follows ... 

Some advances have been made in the Paal-Knorr synthesis of pyrroles by the condensation of primary amines with 1,4-dicarbonyl species. For instance, a new synthetic route to monosubstituted succinaldehydes allows for the facile preparation of 3-substituted pyrroles <96TL4099>. Additionally, a general method for the synthesis of 1-aminopyiroles has been devised by the condensation of commercially available 2,2,2-trichloroethyl- or 2-(tri-methylsilyl)ethylhydrazine with 1,4-dicarbonyl compounds <96JOCl 180>. A related route to such compounds involves the reaction of a-halohydrazones with p-dicarbonyl compounds <96H(43)1447>. Finally, hexamethyldisilazane (HMDS) can be utilized as the amine component in the Paal-Knorr synthesis in the presence of alumina, and this modification has been employed in the synthesis of tm azaprostacyclin analog <96S1336>. 

Ferreira developed a novel method for the preparation of masked 1,4-dicarbonyl derivatives for utilization in the Paal-Knorr synthesis of pyrroles <00SC3215>. In this process, the reaction between diazocompound 3 and n-butyl vinyl ether using dirhodium tetraacetate as catalyst provides dihydrofurans 4 which are easily converted into substituted... 

The time-proven approaches for the synthesis of pyrroles and more elaborate systems have been thoroughly reviewed in the literature. Our focus is drawn to the Knorr synthesis of pyrroles as the [3 + 2] component condensation-type approach which serves as the foundation for the methodology discussed in this chapter.3 The classic reaction entails the reaction of an a-aminoketone with a P-dicarbonyl compound (Eq. 1). The likely intermediate is a P-aminoenone, which undergoes an acid-catalyzed internal cyclization reaction leading to the pyrrole ring. A variation of this process involves the condensation of a-aminoesters and... 

Scheme 6.1 Paal-Knorr synthesis of pyrrole 3 conducted under continuous flow in the absence of a solvent.

An attempt to employ the Paal-Knorr synthesis of pyrrole to prepare 3-benzazepines failed. For example, 40 (R = CHO) treated with n-propylamine gave the benzofulvene 104."... 

This is an example of a Paal-Knorr synthesis of pyrrole. It consists in a double condensation of a primmy amine with a 1,4-diketone, giving a cyclic bis-enmnine, which happens to be an m omatic pyrrole ring. The Ti(IV) tetra-isopropoxide acts as a Lewis acid in catalytic quantities... 

Looking at the first step of the reaction, you should recognize a Michael addition of cyclohexanone to an unsaturated ketone. (You can review this reaction in Section 18-11). The transformation in the second step looks similar to the Paal-Knorr synthesis of pyrroles... 

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