Supplementary Materialsmolecules-21-01366-s001. than apoptosis induction in the membrane alteration assay. with

Supplementary Materialsmolecules-21-01366-s001. than apoptosis induction in the membrane alteration assay. with 3-Fluoroaniline The presence of a halogen atom (F, Cl, and Br) within the 3-position of the aniline ring was previously found to enhance the potency of the 4-anilinoquinazolines as non-competitive antagonists of metabotropic glutamate receptor 5 (mGlu5) compared to unsubstituted aniline derivatives [19]. Based on this literature precedent, we decided to incorporate a 3-fluoroaniline moiety within the 4-position of the 2-aryl-6-bromo-4-chloro-8-iodoquinazoline platform to serve as a template for the design of unsymmetrical polycarbo-substituted 4-anilinoquinazolines. Even though C-4 position of 4-chloroquinazoline moiety is known to be probably the most electronegative due to -nitrogen effect [17], efforts to an effective amination of the known 2-aryl-6-bromo-4-chloro-8-iodoquinazolines 1aCd [20] with 3-fluoroaniline in various solvents (e.g., DMSO, DMF, and THF-DCM) at RT or under reflux led to the recovery of the starting material. However, the traces of the desired product, 4-anilinoquinazoline, were recognized in tetrahydrofuran-isopropyl alcohol (THF-iPrOH) combination under reflux. Since the quinazoline ring undergoes protonation at (2a). Yellow solid (1.07 g, 92%), mp. 199C200 C; maximum (ATR) 445, 551, 701, 770, 957, 1128, 1306, 1397, 1448, 1541, 1590, 1616, 3424 cm?1; H (500 MHz, DMSO-= 2.5 and 8.0 Hz, 1H), 7.50 (q, = 8.0 Hz, 1H), 7.55C7.58 (m, 3H), 7.75 (d, = 8.5 Hz, 1H), 7.95 (dt, = 2.0 and 11.5 Hz, 1H), 8.48C8.49 (m, 2H), 8.57 (d, = 1.5 Hz, 1H), 8.89 (d, = 1.5 Hz, 1H), 10.13 (s, 1H); C (125 MHz, DMSO-520 (100, MH+); HRMS (Sera): MH+, found out 519.9230. C20H13BrFIN3+ requires 519.9243. 3.3. Standard Procedure for the One-Pot Two-Step Sequential Amination and SuzukiCMiyaura Cross-Coupling of (3a). A stirred mixture of 1a (0.50 g, 1.12 mmol), 3-fluoroaniline (0.14 g, 1.23 mmol) and concentrated HCl (0.01 g, 0.27 mmol) in 3:1 THF-isopropanol (= 2.0 and 8.5 Hz, 1H), LY317615 inhibition 7.10 (d, = 8.5 Hz, 2H), 7.50 (m, 4H), 7.77 (d, = 8.5 Hz, 2H), 7.79 (d, = 8.5 Hz, 1H), 7.97 (d, = 2.5 Hz, 1H), 8.00 (dt, = 2.0 and 8.5 Hz, 1H), 8.30C8.32 (m, 2H), 8.82 (d, = 2.0 Hz, 1H), 10.04 (s, 1H); C (125 MHz, DMSO-500 (100, MH+); HRMS (Sera): MH+, found out 500.0780. C27H20BrFN3O+ requires 500.0774. 3.4. Standard Procedure for the One-Pot Two-Step Sequential Amination and Sonogashira Cross-Coupling LY317615 inhibition of = 6.5 Hz, 3H), 4.76 (d, = 6.0 Hz, 1H), 5.60 (d, = 6.0 Hz, 1H), 7.00 (td, = 2.5 and 8.0 Hz, 1H), 7.51 (q, = 8.0 Hz, 1H), 7.52C7.59 (m, 3H), 7.74 (d, = 8.0 Hz, 1H), 7.95 (dt, = 2.0 and 11.5 Hz, 1H), 8.05 (d, = 2.0 Hz, 1H), 8.46C8.49 (m, 2H), 8.83 (d, = 2.0 Hz, 1H), 10.06 (s, 1H); C (125 MHz, DMSO-462 (100, MH+); HRMS (Sera): MH+, found out 462.0620. C24H18BrFN3O+ requires 462.0617. 3.5. Standard Procedure for the One-Pot Three-Step Sequential Amination and Bis-Suzuki-Miyaura Cross-Coupling of (5a). A stirred LY317615 inhibition mixture of 1a (0.50 LY317615 inhibition g, 1.12 mmol), 3-fluoroaniline (0.14 g, 1.23 mmol) and concentrated HCl (0.01 g, 0.27 mmol) in 3:1 THF-isopropanol (= 2.5 and 8.5 Hz, 1H), 7.12 (d, = 9.0 Hz, 2H), 7.41 (t, = 8.5 Hz, 2H), 7.48C7.54 (m, 4H), 7.80 (dd, = 2.0 and 8.5 Hz, 1H), 7.86 (d, = 8.5 Hz, 2H), 8.00C8.04 (m, 3H), 8.15 (d, = 2.0 Hz, 1H), 8.35 (d, = 8.0 Hz, 2H), 8.78 (d, = 2.0 Hz, 1H), 10.11 (s, 1H); c (125 MHz, DMSO-516 (100, MH+); HRMS (Sera): MH+, found out 516.1895. C33H24F2N3O+ requires 516.1887. 3.6. Standard Procedure for the One-Pot Three-Step Sequential Amination and Subsequent Sonogashira and Stille Cross-Coupling of (6a). A stirred mixture of 1a (0.30 g, 0.67 mmol), 3-fluoroaniline (0.082 g, 0.74 mmol) and concentrated HCl (0.01 g, 0.27 mmol) in 3:1 THF-isopropanol (= 2.0 and 3.5 Hz, 1H), 7.01 (td, = 2.5 and 8.5 Hz, 1H), 7.26 (d, = 3.5 Hz, 1H), 7.47C7.59 (m, 7H), 7.70 (dd, = 2.0 and LY317615 inhibition 8.0 Hz, 2H), 7.79 (d, = 8.0 Hz, 1H), 7.91 (d, = 2.0 Hz, 1H), 7.96 CLU (dt, = 2.5 and 11.5 Hz, 1H), 8.44 (d, = 2.0 Hz, 1H), 8.51 (dd, = 2.0 and 8.5 Hz, 2H), 8.86 (d, = 2.0 Hz, 1H), 10.23 (s, 1H); c (125 MHz, DMSO-482 (100, MH+); HRMS.