Three-Step Synthesis of 3-Phosphonopyrroles via Hydroamination

Significance

Reported are extensive studies concerning the synthesis of phosphonylated pyrroles via zinc-catalyzed hydroamination and further attempts to derivatize the pyrrole products. The synthesis of the pyrrole precursors proceeds by transforming readily available β-keto phosphonates into imines, followed by deprotonation with a strong base and alkylation using propargylic bromide. While imination proceeded uneventfully, the alkylation afforded poor yields of products because of formation of bis-propargylated products and subsequent difficulties in purification. The cyclization to pyrroles was effected using different metal salts of which AgNO ₃ was found to be superior, affording faster reaction rates compared to ZnCl₂ which, however, was chosen for economic reasons. The authors attempted to further derivatize the resulting pyrroles via metalation strategies or cross-coupling techniques. Further metalation and cross-coupling reactions (Sonagashira: failure; Stille and Suzuki: poor scope) did not provide synthetically useful results.

Comment

Phosphonylated pyrroles are of interest because of their presence in bioactive molecules (e.g., analgesic properties are ascribed to 2-phosphonopyrroles: G. Dondio, S. Ronzoni, P. Gatti, D. Graziani PCT Int. Appl. WO97/25331, 1997). Although hydroamination chemistry has been frequently used to prepare polysubstituted pyrroles, only a few cases are reported to give 3-phosphonopyrroles (see Review below). The value of the paper is that it presents an alternate route to 3-phosphonopyrroles, and the presentation of failed reactions is refreshing, as opposed to the currently prevalent ‘99% conversion on 8 mg scale’ reports.

Review

S. Van der Jeugh, C. V. Stevens Chem. Rev. 2009, 109, 2672–2702.