A Telescoped Strategy for the Preparation of Five-Membered Hetero- and Carbocycles via Hydrogen Atom Transfer Photocatalysis in Flow.

Five-membered heterocycles such as pyrroles and thiophenes, along with cyclopentenones, are key scaffolds in pharmaceutical chemistry. However, the synthesis of these motifs via diversity oriented synthesis is hindered by the limited accessibility of unsymmetrical 1,4-diketones. Herein, a practical and sustainable flow protocol is presented for the telescoped synthesis of pyrroles, thiophenes, and cyclopentenones. The process begins with decatungstate-photocatalyzed hydrogen atom transfer from aldehydes to generate acyl radicals, which undergo regioselective addition to functionalized enones. The resulting diketones are then fed into a second reactor-tubular or packed-bed-to undergo Paal-Knorr or Hunsdiecker condensation reactions. This modular strategy enables rapid access to densely substituted, biorelevant hetero- and carbocycles with unconventional substitution patterns, as demonstrated by the synthesis of tri-, tetra-, and pentasubstituted pyrroles and thiophenes, and mono-, di-, and trisubstituted cyclopentenones.