Visible Light‐Mediated Cyclisation Reaction for the Synthesis of Highly‐Substituted Tetrahydroquinolines and Quinolines

Abstract

Condensation of 2-vinylanilines and conjugated aldehydes followed by an efficient light-mediated cyclisation selectively yields either substituted tetrahydroquinolines with typically high dr, or in the presence of an iridium photocatalyst the synthesis of quinoline derivatives is demonstrated. These atom economical processes require mild conditions, with the substrate scope demonstrating excellent site selectivity and functional group tolerance, including azaarene-bearing substrates. A thorough experimental mechanistic investigation explores multiple pathways and the key role that imine and iminium intermediates play in the absorption of visible light to generate reactive excited states. The synthetic utility of the reactions is demonstrated on gram scale quantities in both batch and flow, alongside further manipulation of the medicinally relevant products.

Divergent Synthesis of Highly Substituted Tetrahydroquinolines and Cyclopentenes via Lewis Base Catalyzed Switchable [4 + 2] and [3 + 2] Annulations of MBH-Carbonates with Activated Olefins

“…13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 162. 8,162.7 (d,J = 247.7 Hz),153.7,147.7,140.8,138.0,137.0,131.5,130.5,130.1,130.04,129.98,129.4,127.7,127.4,124.6,124.2,116.1 (d,J = 21.7 Hz),113.4,80.2,78.0,56.0,52.4,49.9,28.4,21.9 ppm. HRMS (ESI) m/z: [M + H] + calcd for C 32 H 32 FN 2 O 6 S 591.1960FN 2 O 6 S 591. , found 591.1954 5e.…”

“…13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 166. 8, 165.6, 152.9, 137.9, 137.6, 136.0, 134.6, 130.1, 130.0, 129.1, 129.0, 128.6, 126.9, 126.5, 125.5, 117.0, 82.0, 63.9, 59.7, 58.0, 52.4, 46.7, 28.0, 21.2, 13 8,165.5,162.5 (d,J = 245.4 Hz),152.8,137.4,135.0 (d,J = 3.0 Hz),134.4,130.3,129.9,129.1,129.0,128.9,128.6,126.5,125.6,116.7,115.4 (d,J = 23.4 Hz),82.3,64.1,59.2,57.8,52.5,46.7,28.0,13.7 6d. Purification by flash chromatography (PE/EA = 5:1) gave a white solid (42.4 mg, 81% yield); >20:1 dr, determined by 1 H NMR (400 MHz, CDCl 3 ) analysis; 1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J = 8.0 Hz, 1H), 7.48−7.44 (m, 1H), 7.29−7.20 (m, 6H), 6.47 (s, 1H), 5.68 (s, 1H), 5.45 (s, 1H), 4.78 (s, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 1.33−1.30 (m, 12H) ppm.…”

“…Owing to the importance of the THQ rings, it was not surprising that more researchers were being attracted to developing effective and advanced methods for the construction of THQ frameworks. 8 Despite these advances, new strategies for the construction of THQ scaffolds are still highly desired.…”

2‐Vinylaniline in the synthesis of heterocycles: Recent advances

“…This readily available synthon is considered as an alternative synthetic reagent in modern organic syntheses. A wide range of functionalized N ‐heterocyclic scaffolds, including quinolines [4], tetrahydroquinolines [5], 2‐quinolinones [6], quinolone‐2‐thiones [7], indoles [8], indazoles [9], oxindoles [10], benzoxazines, benzoazepines [11], quinazolines [12], and cinnolines [13] have been provided via cascade C‐H activation/annulation of 2‐vinylanilines. These reactions can be carried out in the presence of transition metal catalysts, or under metal‐free conditions.…”