Temperature switchable Brønsted acid-promoted selective syntheses of spiro-indolenines and quinolines

Abstract

A high-yielding, temperature switchable divergent approach towards the synthesis of either spiro-indolenines or quinolines is described, starting from easily available indolyl ynones. The application of TFA at rt promotes the dearomatization of the indole, resulting in the formation of the spiro-indolenine, while at higher temperature, rearrangement results in the formation of the quinoline.

Synthetic and Mechanistic Studies into the Rearrangement of Spirocyclic Indolenines into Quinolines

“…19 F NMR (376 MHz, CDCl 3 ): δ = –114.5 ppm. Spectroscopic data matched those reported in the literature …”

“…R f = 0.48 (hexane/EtOAc, 1:1); 1 H NMR (400 MHz, CDCl 3 ): δ = 8.11 (d, J = 8.5 Hz, 1H), 7.77 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.67 (ddd, J = 8.5, 1.5, 0.5 Hz, 1H), 7.39 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.33–7.25 (m, 3H), 7.13–7.09 (m, 2H), 4.98 (dd, J = 7.5, 2.5 Hz, 1H), 3.38 (dd, J = 19.0, 7.5 Hz, 1H), 3.06 (s, 3H), 2.75 ppm (dd, J = 19.0, 2.5 Hz, 1H). Spectroscopic data matched those reported in the literature …”

“…Then, the addition of AlCl 3 · 6H 2 O directly to this reaction mixture and heating to 100 °C in a microwave was found to promote a hitherto unprecedented rearrangement into quinoline 2a ; the rearrangement was tentatively proposed to proceed via an enolisation ( 3a → 4a ), cyclopropanation ( 4a → 5a ), ring expansion ( 5a → 6a ) and tautomerisation ( 6a → 2a ) cascade sequence, as shown in Scheme b, although it should be stressed that no evidence was obtained in support of this mechanism. Later, Van der Eycken and co‐workers went on to develop a transition metal‐free variant of this transformation,, using trifluoroacetic acid (TFA) to promote the same overall transformation, enabling a broad range of quinolines to be prepared using a simple, single step protocol that also benefitted from reduced reaction times ( 7 → 8 , Scheme c). The authors proposed broadly the same mechanism as that shown in Scheme b for this metal‐free variant, although again, no evidence was obtained in its support.…”

“…should be stressed that no evidence was obtained in support of this mechanism. Later, Van der Eycken and co-workers went on to develop a transition metal-free variant of this transformation, [12,13] using trifluoroacetic acid (TFA) to promote the same overall transformation, enabling a broad range of quinolines to be prepared using a simple, single step protocol that also benefitted from reduced reaction times (7 → 8, Scheme 1c). The authors proposed broadly the same mechanism as that shown in Scheme 1b for this metal-free variant, although again, Scheme 1.…”

Organocatalyzed Synthesis of Functionalized Quinolines

“…Fedoseev et al . reported a selective synthesis of 3,4‐cyclopentan‐quinoline‐3‐ones from indolyl‐ynone intramolecular cyclization under the influence of microwave (100W) with Brønsted acid (trifluoro acetic acid in chloroform).…”