Flow Photo-Nazarov Reactions of 2-Furyl Vinyl Ketones: Cyclizing a Class of Traditionally Unreactive Heteroaromatic Enones

Abstract

Nazarov reactions of 2-furyl vinyl ketones and related heteroaromatic enones, to produce furan-fused cyclopentanones using a flow photochemical approach, are described. Compounds possessing this connectivity between heterocycle and ketone (2-furyl, 2-benzofuryl, 2-thiophene-yl, and 2-benzothiophene-yl) have traditionally proven difficult or impossible to cyclize with typical Brønsted and Lewis acid mediated methods. Using mild flow photochemistry conditions and acetic acid (AcOH) or hexafluoroisopropanol (HFIP) as solvent, these compounds were found to cyclize in 45-97% yields, with typical UV exposure times of 3.4-6.8 min. In all cases, 2-furyl and 2-thiophene-yl enones cyclized, whereas 2-benzofuryl and 2-benzothiophene-yl enones exhibited divergent properties with reactivity patterns tied to the identity of the vinyl group. This report discloses the first photo-Nazarov reactions of tetrahydropyridine-substituted 2-furyl ketones, providing a direct approach to the corresponding fused heterocyclic motifs built around a central cyclopentanone. These motifs constitute the core structures of biologically active natural products, including the marine alkaloid nakadomarin A.

Synthesis of Heteroarene‐Fused Cyclopentadienes and Related Compounds Suitable for Metallocene Preparation

“…[92] Promising results were obtained very recently by Coombs et al, who performed the photocyclization of 2-and 3-furyl vinyl ketones to form cyclopentenones 88-92 in AcOH using a flow reactor (Scheme 12C). [103] A moderate yield of 5,6-dihydro-4H-cyclopenta[b]furan-4-one 86 was obtained from the Rh-catalyzed cyclization of 1-(furan-3-yl)-3-(trimethylsilyl)prop-2-yn-1-ol (Scheme 12D). [104] The use of 10 mol% catalyst devalues this approach.…”

Light on the Horizon: Current Research and Future Perspectives in Flow Photochemistry

“…Coombs and co-workers have developed a method to generate furan-fused cyclopentanones using a flow photochemical approach. 64 In particular, a photo-Nazarov reaction was employed as a key strategic step to access the corresponding heterocyclic motif, which is present in the core structures of different alkaloid or flavonoid natural products with important biological activities. 65 Starting with the 2-furyl or 2-thiophenyl enones and using an FEP tubing reactor, photocycloaddition was conducted using acetic acid (AcOH) or hexafluoroisopropanol (HFIP) as solvent, giving cyclic products in 45−97% yields with exposure times of 3.4− 6.8 min (Scheme 11).…”

“…By chiral auxiliary removal and subsequent reductions, (+)-epigalcatin was achieved with an overall yield of 5% (Scheme 10). Total synthesis of (+)-epigalcatin employing photocyclization as a key strategic step.Coombs and co-worker have developed a method to generate furan-fused cyclopentanones using a flow photochemical approach 64. Particularly, a photo-Nazarov reaction was employed as a key strategic step to access the corresponding heterocyclic motif which is present in the core structures of different alkaloid or flavonoid natural products with important biological activity 65.…”

Scaling Up UV-Mediated Intramolecular Photodehydro-Diels–Alder Reactions Using a Homemade High-Performance Annular Continuous-Flow Reactor

“…Conducting a photochemical reaction in batch is generally hampered by the attenuation effect of photons, as can be expressed by the Bouguer–Lambert–Beer law. , As the light intensity decreases logarithmically with increasing optical path length with respect to the excitation source, this results in longer irradiation times and therefore in rapid overirradiation of photosensitive products. One prominent option to tackle this particular problem during photoexitation is to use continuous-flow reactor technology. , Several technical realizations have been made by others resulting in a broad range of multifunctional targets including pharmaceutically relevant products − (e.g., active pharmaceutical ingredients) and polymeric materials. − The ongoing interest in continuous-flow methodology can also be observed in the growing commercial availability of flow reactors from leading companies. − …”