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

Abstract

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.

Keywords: Hunsdiecker condensation; Paal–Knorr synthesis; flow chemistry; photocatalyzed hydrogen atom transfer; tetrabutylammonium decatungstate.

Scheme 1

Context and background: A) Five‐membered heterocycles and carbocycles are appealing scaffolds for the pharmaceutical industry. B) The hydroacylation of enones provides smooth access to nonsymmetrical 1,4‐diketones, an important value‐added scaffold for medicinal chemists. C) Our work: a telescoped platform for the modular synthesis of five‐membered heterocycles and carbocycles. Prices calculated as of May 6, 2025.^{[ 49 ]}

Scheme 2

Scope for the telescoped on‐demand synthesis of pyrroles (top) and thiophenes (bottom) in flow. All yields refer to the isolated heterocycle after two steps on a 0.1 mmol scale. Pyrroles were prepared according to GP1; thiophenes were prepared according to GP2 (see Sections 6.1 and 6.2 in the Supporting Information). [a] τ_R1  = 10 min, fr₁= 0.25 mL min⁻¹, fr₂ = 0.1 mL min⁻¹, τ_R2 = 43 min; [enone] = 0.12 M, [amine] = 1.25 M, and [PTSA] 0.25 M in CH₃CN. [b] [enone] = 0.12 M, fr₁ = 0.25 mL min⁻¹, τ_R1 = 10 min, τ_R2 = 3.6 min.

Scheme 3

Scope of the modular synthesis of cyclopentenones in flow. All reactions were performed on a 0.5 mmol scale. All yields refer to the isolated carbocycle after two steps. [a] Photocatalytic hydroacylation step performed at 0 °C.