Pyrano[4,3-b]quinolines Library Generation via Iodocyclization and Palladium-Catalyzed Coupling Reactions

Abstract

Synthesis of a 80-member library of novel pyrano[4,3-b]quinolines in solution-phase is reported. The key intermediate, 4-iodopyrano[4,3-b]quinolines were synthesized by the electrophilic iodocyclization of corresponding ortho-alkynyl aldehydes in good to excellent yields under mild reaction conditions. Subsequently a diverse set of libraries was generated by employing palladium-catalyzed Suzuki-Miyaura, Heck, and Sonogashira coupling reactions on 4-iodopyrano[4,3-b]quinolines. In this way, a series of structurally different and biologically interesting molecules were obtained. Some of the selected compounds were screened against 3D7 strains of Plasmodium falciparum for antimalarial activity. Suzuki coupling products 6{3} and 6{21} and Heck coupling product 8{12} exhibit promising antimalarial activity.

Iodine-mediated synthesis of heterocycles via electrophilic cyclization of alkynes

“…These 4-iodopyranoquinolines 46 were further diversified by palladium-catalyzed cross coupling reactions to obtain a vast library of substituted pyranoquinolines 29 The synthesis of substituted dihalogenated dihydrobenzo [b] oxepines 55 from aryl propargylic alcohols 54 under mild reaction conditions has been developed by Liang and co-workers in 2011 (Scheme 18). These 4-iodopyranoquinolines 46 were further diversified by palladium-catalyzed cross coupling reactions to obtain a vast library of substituted pyranoquinolines 29 The synthesis of substituted dihalogenated dihydrobenzo [b] oxepines 55 from aryl propargylic alcohols 54 under mild reaction conditions has been developed by Liang and co-workers in 2011 (Scheme 18).…”

Tandem Synthesis of Pyrroloacridones via [3 + 2] Alkyne Annulation/Ring-Opening with Concomitant Intramolecular Aldol Condensation

“…The substrates 4-iodopyranoquinolines 2a – i , required for the designed approach, were prepared in good yields by the electrophilic iodocyclization of 2-(alkynyl)quinoline-3-carbaldehydes 1a – i using standard procedures developed in our laboratory (Scheme ) …”

2‐(1‐Benzotriazolyl)pyridine: A Robust Bidentate Ligand for the Palladium‐Catalyzed CC (Suzuki, Heck, Fujiwara–Moritani, Sonogashira), CN and CS Coupling Reactions

“…4‐(4‐Ethylphenyl)‐1‐methoxy‐3‐phenyl‐1 H ‐pyrano[4,3‐ b ]quinoline (3j): 43 The product was obtained as orange needles (DCM/ether); yield: 310.0 mg (79%); mp 92–94 °C; 1 H NMR (300 MHz, CDCl 3 ): δ =8.05 (s, 1 H), 7.97 (d, J =8.4 Hz, 1 H), 7.77 (d, J =8.1 Hz, 1 H), 7.60 (td, J =6.9 and 1.2 Hz, 1 H), 7.42 (t, J =8.1 Hz, 1 H), 7.35–7.31 (m, 4 H), 7.23–7.13 (m, 5 H), 6.29 (s, 1 H), 3.74 (s, 3 H), 2.67 (q, J =7.5 Hz, 2 H), 1.26 (t, J =7.8 Hz, 3 H); 13 C NMR (75 MHz, CDCl 3 ): δ =153.2, 150.0, 148.8, 143.7, 135.5, 132.7, 132.3, 132.2, 129.9, 129.5, 128.7, 128.4, 128.0, 127.6, 127.3, 126.8, 126.4, 125.7, 122.6, 117.5, 100.0, 56.1, 28.6, 15.4; HR‐MS (ESI): m/z =393.1729, calcd. for C 27 H 23 NO 2 (M+H + ): 393.1729.…”

“…( E )‐Methyl3‐(1‐methoxy‐3‐( p ‐tolyl)‐1 H ‐pyrano[4,3‐ b ]quinolin‐4‐yl)acrylate (5d): 43 The product was obtained as a pale yellow needles (DCM/ether); yield: 298.0 mg (77%); mp 149–150 °C; 1 H NMR (300 MHz, CDCl 3 ): δ =8.24 (d, J =8.8 Hz, 1 H), 8.19 (s, 1 H), 7.82–7.79 (m, 3 H), 7.73 (t, J =5.8 Hz, 1 H), 7.54–7.51 (m, 3 H), 7.28 (d, J =8.08 Hz, 2 H), 6.21 (s, 1 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 2.41 (s, 3 H); 13 C NMR (75 MHz, CDCl 3 ): δ =169.0, 162.6, 148.9, 148.2, 141.1, 139.5, 132.9, 13o.8, 130.5, 130.2, 129.4, 129.2, 127.6, 126.5, 126.3, 122.7, 119.2, 110.9, 100.7, 56.7, 51.3, 21.5; HR‐MS (ESI): m/z =387.1471, calcd. for C 24 H 21 NO 4 (M+H + ): 387.1471.…”