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.…”

An Expanded EDA Complex Profile: Construction of Aza-arenes and Their Synthetic Application as Fluorescence Probes

“…Moreover, upon addition of stoichiometric radical scavengers, diphenyl diselenide (PhSeSePh), and 1,1-diphenylethylene as well as BHT (butylated hydroxytoluene) under standard conditions, negligible effects on the transformation were detected (Figure c). This observation implied that this transformation proceeds through the aza-6π electrocyclization pathway rather than a photoredox process . Furthermore, we prepared compound 4 via reduction of 3-methylquinoline by LiAlH 4 to obtain more details about aromatization.…”

Access to a Diverse Array of Bridged Benzo[1,5]oxazocine and Benzo[1,4]diazepine Structures

“…Many of these methods are not general and typically require significant prefunctionalization of starting materials or complex multistep syntheses. Recently, several more general approaches have been reported to generate bridged oxazocine and (di)­azepine structures, such as dearomatization, , [4 + 3] cycloaddition, Michael-addition/cyclization methodologies, and cascade reactions, , enabling the design of natural-product-resembling molecules in underexplored chemical space. Despite the increasing wealth of synthetic methods for the generation of complex three-dimensional molecular scaffolds, there remains a necessity for straightforward and broadly tolerant methods to generate ring systems that can be diversified and readily functionalized for structure–activity relationship exploration in drug discovery programmes.…”