Synthesis of Substituted Pyrroles from 2-Azetidinone Allenols

Significance

Reported is the formation of highly substituted pyrrole systems by reaction of β-lactams with sodium methoxide. The required β-lactams were formed through an indium-mediated Barbier-type allenylation reaction previously developed by the authors. Reaction of these allenyl β-lactams with sodium methoxide opens the lactam ring to a secondary amine, which then undergoes reaction with the allene to form the desired pyrrole ring upon workup. Two examples of the intermediate amine (structures A above) were isolated and cyclized to pyrroles using catalytic silver nitrate. All other analogues examined spontaneously formed pyrroles under the sodium methoxide reaction conditions.

Comment

Highly substituted pyrrole ring systems are of interest to many areas of chemistry, particularly within the pharmaceutical industry, either as building blocks for biologically active compounds, or as the drugs themselves (e.g. roseophilin: A. Fürstner Angew. Chem. Int. Ed. 2003, 42, 3582). The method for their formation outlined above provides either fully substituted pyrroles, or less substituted pyrroles with a chiral tether and should prove useful as it complements classical (Paal-Knorr, Knorr, Hantzsch) pyrrole synthetic methods, which rely on the formation of 1,4-diketones, β-keto esters and α-halo ketones or α-amino ketones. The substrate range has been moderately explored and the concept of β-lactam ring fragmentation-recyclization to an allene has been successfully demonstrated in two different ways.