Continuous Paal—Knorr pyrrole synthesis

Scheme 8 Continuous Paal—Knorr pyrrole synthesis.

As will be discussed later, the novel pentacyclic antitumor alkaloid roseophilin continues to attract much synthetic effort and several approaches relied on the venerable Paal-Knorr condensation for construction of the pyrrole moiety. For instance, Trost utilized this reaction upon diketone 1 to afford the tricyclic core 2 of roseophilin in a strategy featuring an enyne metathesis as a key step <00JA3801>, while another formal synthesis of this alkaloid utilized a radical macrocyclization to produce the ketopyrrole core <00JCS(P1)3389>. 

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

Schwalbe and co-workers reported on the Paal-Knorr synthesis under continuous flow (Scheme 6.26). Rutjes et al. more recently demonstrated the reaction of acetony-lacetone 47 and 2-aminoethanol 48 in a microreactor, subsequently scaling the reaction to four meso reactors capable of producing 2-(2,5-dimethyl-177-pyrrol-l-yl)ethanol 49 at a throughput of 55 g h ... 

---