Chemistry
All solvents and reagents were purchased from Shanghai Titan Scientific Co., Ltd, and were analytical grade or chemically pure. The melting point of all compounds (4a-4x) was determined by the X-4B melting point apparatus ((Beijing Tech Instrument Co, Beijing. China). 1H NMR, 13C NMR and 19F NMR were obtained on Bruker Ascend-400 spectrometer (Bruker Optics, Germany) Tetramethylsilane (TMS) as internal standard and DMSO was used as solvent; Mass spectral studies were performed on a quadrupole electrostatic field orbitrap mass spectrograph (Thermo Scientific, USA). The synthetic route of pyrimidine-containing 4H-Chromen-4-one derivatives was shown in Scheme 1. Intermediates 1 were prepared according to the reported methods. [26, 41, 42]
General synthesis procedure for intermediate 1.
Based on the previous reported method [41, 42], the ethyl cyanoacetate (5 mmol), substituted aromatic aldehyde (5 mmol), thiourea (5 mmol) and anhydrous K2CO3 (7.5 mmol) were added in ethanol (50 mL) then refluxed for about 4–6 h, after the reaction was completed (monitoring the reaction by TLC), mixture was cooled to room temperature and diluted with ice water, a large amount of solids precipitated as the pH was adjusted with glacial acetic acid to weak acidity, solids were filtered and dried with suction, recrystallized with absolute ethanol to obtain Intermediate 1
General synthesis procedures for intermediate 2
Myricetin as raw material, iodomethane as the methylation reagent and anhydrous K2CO3, heated to reflux in DMF and then extracted with methylene chloride, deglycosylation with concentrated hydrochloric acid under reflux in ethanol to prepare 3-hydroxy-3',4',5',5,7- pentamethoxymyricetin (Intermediate 2).
General synthesis procedures for intermediate 3
Intermediate 2 (2 mmol) and K2CO3 (3 mmol) are dissolved in certain amount of N,N-dimethylformamide (DMF). After the solution had been stirred at room temperature for 0.5–1 h, the different dibromoalkane (2 mmol) was added and reaction system continued at room temperature for 10 h. Mixture was dispersed in 50 mL ice water when reaction was completed (reaction was monitored by TLC) so a white solid was precipitated, sample was passed through a suction filter to remove the liquid, solid was continuously stirred in a mixed solution of 30 mL petroleum ether and ethyl acetate for 3–4 hours, then filtered and dried under reduced pressure to obtain Intermediate 3.
General synthesis procedures for title compounds 4
A solution of intermediates 1 (3 mmol), intermediates 3 (3 mmol) and K2CO3 (4.5 mmol) in DMF (40 mL) was stirred under reflux for 4–5 h, after reaction was completed (reaction was monitored by TLC), the mixture was cooled to room temperature then poured into 80 mL ice water and extracted with ethyl acetate (3 × 30 mL), organic layer was washed with 5% hydrochloric acid solution, saturated NaHCO3 aqueous solution, saturated NaCl solution successively and dried with anhydrous Na2SO4, solvent was removed under vacuum and crude product was separated by column chromatography with petroleum ether/ethyl acetate (V:V = 1:1) to obtain the title compound 4a. Based on the similar method, the title compounds 4b-4x were prepared.
2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)propyl)thio)-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitrile (4a): white solid, m.p. 144.3-145.8 °C; yield: 41.3%; 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 7.3 Hz, 2H, Ph-H), 7.56 (d, J = 7.0 Hz, 1H, Ph-H), 7.50 (t, J = 7.2 Hz, 2H, Ph-H), 7.34 (s, 2H, Ph-H), 6.84 (s, 1H, Ph-H), 6.50 (s, 1H, Ph-H), 4.03 (s, 2H, -O-CH2CH2CH2-), 3.90 (s, 3H, Ph-OCH3), 3.85 (s, 3H, Ph-OCH3), 3.81 (s, 6H, 2 × Ph-OCH3), 3.72 (s, 3H, Ph-OCH3), 3.39 (s, 2H, -CH2CH2CH2-S-), 2.12 (d, J = 5.7 Hz, 2H, -CH2CH2CH2-); 13C NMR (101 MHz, DMSO-d6) δ 172.57, 164.27, 160.77, 158.65, 153.17, 152.21, 140.16, 139.89, 132.18, 129.08, 128.99, 125.94, 116.45, 108.88, 106.12, 96.41, 93.60, 93.39, 70.50, 60.63, 56.57, 56.49, 30.06, 27.80; HRMS calcd for C34H31N3O9S [M + H]+: 658.1854, found 658.1851.
2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)propyl)thio)-6-oxo-4-(m-tolyl)-1,6-dihydropyrimidine-5-carbonitrile (4b): white solid, m.p. 231.6-232.8 °C; yield: 67.2%; 1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 2H, Ph-H), 7.37 (d, J = 6.9 Hz, 2H, Ph-H), 7.34 (s, 2H, Ph-H), 6.85 (d, J = 2.2 Hz, 1H, Ph-H), 6.50 (d, J = 2.2 Hz, 1H, Ph-H), 4.02 (t, J = 5.8 Hz, 2H, -O-CH2CH2CH2-S-), 3.90 (s, 3H, Ph-OCH3), 3.85 (s, 3H, Ph-OCH3), 3.80 (s, 6H, 2 × Ph-OCH3), 3.72 (s, 3H, Ph-OCH3), 3.34 (s, 2H, O-CH2CH2CH2-S-), 2.31 (s, 3H, Ph-CH3), 2.15–2.04 (m, 2H, -CH2CH2CH2-); 13C NMR (101 MHz, DMSO-d6) δ 172.56, 167.64, 164.26, 160.75, 158.65, 153.16, 152.18, 140.20, 139.82, 138.29, 132.64, 129.49, 128.85, 126.31, 125.94, 108.85, 106.03, 96.41, 93.57, 70.55, 60.63, 56.53, 56.45, 30.17, 27.74, 21.32; HRMS calcd for C35H33N3O9S [M + H]+: 672.2010, found 672.1999.
2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)propyl)thio)-6-oxo-4-(p-tolyl)-1,6-dihydropyrimidine-5-carbonitrile ( 4c ): White solid, m.p. 201.8-203.6 °C; yield: 30.3%; 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 8.1 Hz, 2H, Ph-H), 7.35 (s, 2H, Ph-H), 7.27 (d, J = 8.1 Hz, 2H, Ph-H), 6.85 (d, J = 2.1 Hz, 1H, Ph-H), 6.51 (d, J = 2.1 Hz, 1H, Ph-H), 4.03 (t, J = 5.9 Hz, 2H, -O-CH2CH2CH2-S-), 3.91 (s, 3H, Ph-OCH3), 3.86 (s, 3H, Ph-OCH3), 3.82 (s, 6H, 2 × Ph-OCH3), 3.72 (s, 3H, Ph-OCH3), 3.36 (d, J = 6.5 Hz, 2H, -O-CH2CH2CH2-S-), 2.34 (s, 3H, Ph-CH3), 2.12 (dd, J = 12.8, 6.3 Hz, 2H, -O-CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.57, 166.16, 164.28, 160.78, 158.66, 153.18, 152.18, 142.51, 140.17, 139.90, 132.85, 129.56, 129.18, 125.94, 116.59, 108.90, 106.11, 96.42, 93.61, 92.75, 70.53, 60.61, 56.77, 56.39, 55.39, 30.13, 27.78, 21.51; HRMS calcd for C35H33N3O9S [M + H]+: 671.1932, found 671.1905.
2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)propyl)thio)-4-(4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile ( 4d ): white solid, m.p. 179.2-181.1 °C; yield: 32.5%; 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 8.8 Hz, 2H, Ph-H), 7.35 (s, 2H, Ph-H), 7.02 (d, J = 8.9 Hz, 2H, Ph-H), 6.84 (d, J = 2.2 Hz, 1H, Ph-H), 6.50 (d, J = 2.2 Hz, 1H, Ph-H), 4.04 (t, J = 5.9 Hz, 2H, -O-CH2CH2CH2-S-), 3.91 (s, 3H, Ph-OCH3), 3.86 (s, 3H, Ph-OCH3), 3.81 (s, 6H, 2 × Ph-OCH3), 3.80 (s, 3H, Ph-OCH3), 3.72 (s, 3H, Ph-OCH3), 3.39 (d, J = 6.9 Hz, 2H, -O-CH2CH2CH2-S-), 2.17–2.07 (m, 2H, -O-CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.57, 164.27, 162.66, 160.77, 158.65, 153.17, 152.14, 140.19, 139.90, 131.27, 125.93, 116.88, 114.42, 108.88, 106.09, 96.42, 93.60, 70.51, 60.62, 56.57, 56.52, 56.48, 55.88, 55.39, 30.16, 27.76; HRMS calcd for C35H33N3O10S [M + H]+: 688.1959, found 688.1952.
4-(3-chlorophenyl)-2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)propyl)thio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile ( 4e ): Brown solid, m.p. 119.6-121.9 °C; yield: 23.9%; 1H NMR (400 MHz, DMSO-d6) δ 7.94–7.84 (m, 2H, Ph-H), 7.62 (d, J = 8.0 Hz, 1H, Ph-H), 7.53 (t, J = 7.9 Hz, 1H, Ph-H), 7.33 (s, 2H, Ph-H), 6.83 (d, J = 1.6 Hz, 1H, Ph-H), 6.50 (s, 1H, Ph-H), 4.02 (t, J = 5.5 Hz, 2H, -O-CH2CH2CH2-S-), 3.90 (s, 3H, Ph-OCH3), 3.85 (s, 3H, Ph-OCH3), 3.81 (s, 6H, 2 × Ph-OCH3), 3.72 (s, 3H, Ph-OCH3), 3.35 (d, J = 6.3 Hz, 2H, -O-CH2CH2CH2-S-), 2.13–2.02 (m, 2H, -O-CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.58, 165.98, 164.24, 160.75, 158.64, 153.14, 152.19, 140.21, 139.85, 137.87, 133.66, 131.70, 130.91, 128.69, 127.77, 125.96, 108.87, 106.08, 96.39, 93.57, 70.49, 60.63, 56.56, 56.51, 56.47, 30.11, 27.76; HRMS calcd for C34H30ClN3O9S [M + H]+: 692.1464, found 692.1455.
4-(4-chlorophenyl)-2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)propyl)thio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile ( 4f ): White solid, m.p. 182.4-183.8 °C; yield: 41.7%; 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 8.5 Hz, 2H, Ph-H), 7.55 (d, J = 8.5 Hz, 2H, Ph-H), 7.36 (s, 2H, Ph-H), 6.84 (d, J = 2.0 Hz, 1H, Ph-H), 6.50 (d, J = 2.0 Hz, 1H, Ph-H), 4.03 (t, J = 6.0 Hz, 2H, -O-CH2CH2CH2-S-), 3.91 (s, 3H, Ph-OCH3), 3.87 (s, 3H, Ph-OCH3), 3.83 (s, 6H, 2 × Ph-OCH3), 3.73 (s, 3H, Ph-OCH3), 3.28 (d, J = 6.9 Hz, 2H, -O-CH2CH2CH2-S-), 2.14–2.06 (m, 2H, -O-CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.59, 166.22, 164.26, 160.76, 158.65, 153.18, 152.15, 140.18, 139.89, 136.55, 135.01, 130.89, 129.03, 125.95, 108.89, 106.09, 96.42, 93.61, 70.60, 60.62, 56.59, 56.50, 30.29, 27.55; HRMS calcd for C34H30ClN3O9S [M + H]+: 692.1640, found 692.1450.
4-(4-bromophenyl)-2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)propyl)thio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4 g): White solid, m.p. 183.2-185.1 °C; yield: 25.7%; 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.5 Hz, 2H, Ph-H), 7.70 (d, J = 8.5 Hz, 2H, Ph-H), 7.35 (s, 2H, Ph-H), 6.85 (d, J = 1.8 Hz, 1H, Ph-H), 6.51 (d, J = 1.7 Hz, 1H, Ph-H), 4.03 (s, 2H, -O-CH2CH2CH2-S-), 3.91 (s, 3H, Ph-OCH3), 3.87 (s, 3H, Ph-OCH3), 3.83 (s, 6H, 2 × Ph-OCH3), 3.73 (s, 3H, Ph-OCH3), 3.37 (s, 2H, -O-CH2CH2CH2-S-), 2.16–2.06 (m, 2H, -O-CH2CH2CH2-S-). 13C NMR (101 MHz, DMSO-d6) δ 172.59, 166.41, 164.28, 160.76, 158.65, 153.18, 152.17, 140.14, 139.89, 134.84, 132.08, 131.16, 125.96, 116.36, 108.88, 106.07, 96.43, 93.52, 70.48, 60.63, 56.63, 56.50, 30.16, 27.74; HRMS calcd for C34H30BrN3O9S [M + H]+: 736.0959, found 736.0927.
2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)propyl)thio)-4-(3-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4 h): Brown solid, m.p. 204.6-206.4 °C; yield: 57.0%; 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 7.8 Hz, 1H, Ph-H), 7.70 (d, J = 9.8 Hz, 1H, Ph-H), 7.55 (dd, J = 14.0, 8.0 Hz, 1H, Ph-H), 7.40 (td, J = 8.5, 2.3 Hz, 1H, Ph-H), 7.34 (s, 2H, Ph-H), 6.83 (d, J = 2.1 Hz, 1H, Ph-H), 6.49 (d, J = 2.1 Hz, 1H, Ph-H), 4.02 (t, J = 5.8 Hz, 2H, -O-CH2CH2CH2-S-), 3.90 (s, 3H, Ph-OCH3), 3.85 (s, 3H, Ph-OCH3), 3.81 (s, 6H, 2 × Ph-OCH3), 3.72 (s, 3H, Ph-OCH3), 3.34 (d, J = 6.8 Hz, 2H, -O-CH2CH2CH2-S-), 2.16–2.03 (m, 2H, -O-CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.59, 166.00, 164.24, 163.41, 160.98, 160.75, 158.64, 153.15, 152.19, 140.18, 139.85, 131.15, 131.07, 125.95, 125.28, 118.86, 118.66, 116.75, 115.94, 115.71, 108.87, 106.07, 96.39, 93.57, 70.52, 60.62, 56.55, 56.51, 56.46, 30.13, 27.72; 19F NMR (376 MHz, DMSO-d6) δ -112.23 (d, J = 6.1 Hz); HRMS calcd for C34H30FN3O9S [M + H]+: 676.1760, found 676.1755.
2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)propyl)thio)-4-(4-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4i): White solid, m.p. 197.5-199.4 °C; yield: 31.7%; 1H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, J = 8.1, 5.6 Hz, 2H, Ph-H), 7.39–7.30 (m, 4H, Ph-H), 6.84 (d, J = 1.3 Hz, 1H, Ph-H), 6.50 (s, 1H, Ph-H), 4.02 (t, J = 5.9 Hz, 2H, -O-CH2CH2CH2-S-), 3.91 (s, 3H, Ph-OCH3), 3.86 (s, 3H, Ph-OCH3), 3.82 (s, 6H, 2 × Ph-OCH3), 3.73 (s, 3H, Ph-OCH3), 3.37 (d, J = 6.5 Hz, 2H, -O-CH2CH2CH2-S-), 2.18–2.06 (m, 2H, -O-CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.57, 166.40, 165.71, 164.25, 163.22, 160.72, 158.64, 153.16, 152.16, 140.13, 139.83, 131.99, 131.89, 125.92, 116.46, 116.25, 116.03, 108.85, 106.01, 96.40, 93.58, 93.21, 70.42, 60.61, 56.51, 56.46, 30.10, 27.72; 19F NMR (376 MHz, DMSO-d6) δ -107.84; HRMS calcd for C34H30FN3O9S [M + H]+: 676.1760, found 676.1755.
2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)propyl)thio)-6-oxo-4-(thiophen-2-yl)-1,6-dihydropyrimidine-5-carbonitrile (4j) : Gray solid, m.p. 145.4-147.8 °C; yield: 50.6%; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 3.8 Hz, 1H, thienyl-H), 7.94 (d, J = 5.0 Hz, 1H, thienyl-H), 7.36 (s, 2H, Ph-H), 7.31–7.27 (m, 1H, thienyl -H), 6.82 (d, J = 2.1 Hz, 1H, Ph-H), 6.49 (d, J = 2.1 Hz, 1H, Ph-H), 4.07 (t, J = 6.0 Hz, 2H, -O-CH2CH2CH2-S-), 3.90 (s, 3H, Ph-OCH3), 3.85 (s, 3H, Ph-OCH3), 3.84 (s, 6H, 2 × Ph-OCH3), 3.73 (s, 3H, Ph-OCH3), 3.30 (d, J = 7.0 Hz, 2H -O-CH2CH2CH2-S-), 2.17–2.09 (m, 2H -O-CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.60, 164.24, 160.75, 158.95, 158.64, 153.16, 152.23, 140.33, 140.17, 139.87, 134.86, 131.58, 129.84, 125.97, 117.16, 108.88, 106.16, 96.40, 93.57, 88.04, 70.60, 60.64, 56.57, 56.51, 30.09, 27.86; HRMS calcd for C33H28N4O3[M + H]+: 664.1418, found 664.1411.
2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)propyl)thio)-4-(furan-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4 k): Gray solid, m.p. 229.4-231.3 °C; yield: 60.3%; 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 0.8 Hz, 1H, furyl-H), 7.47 (d, J = 3.5 Hz, 1H, furyl-H), 7.36 (s, 2H, Ph-H), 6.83 (d, J = 2.2 Hz, 1H, furyl-H), 6.70 (dd, J = 3.5, 1.7 Hz, 1H, Ph-H), 6.49 (d, J = 2.2 Hz, 1H, Ph-H), 4.06 (t, J = 6.0 Hz, 2H, -O-CH2CH2CH2-S-), 3.91 (s, 3H, Ph-OCH3), 3.86 (s, 3H, Ph-OCH3), 3.84 (s, 6H, 2 × Ph-OCH3), 3.73 (s, 3H, Ph-OCH3), 3.35 (s, 2H, -O-CH2CH2CH2-S-), 2.15–2.06 (m, 2H, -O-CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.59, 164.25, 160.77, 158.64, 154.94, 153.17, 152.21, 149.92, 148.42, 140.17, 139.91, 125.94, 118.62, 115.85, 113.63, 108.90, 106.14, 96.41, 93.58, 88.01, 70.64, 60.63, 56.57, 56.51, 55.39, 30.06, 27.81; HRMS calcd for C32H29N3O10S [M + H]+: 648.1646, found 648.1638.
2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)propyl)thio)-6-oxo-4-(pyridin-4-yl)-1,6-dihydropyrimidine-5-carbonitrile (4 l): Brown solid, m.p. 147.8-149.8 °C; yield: 50.2%; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 5.8 Hz, 2H, Piperidinyl-H), 7.85 (dd, J = 4.5, 1.5 Hz, 2H, Piperidinyl-H), 7.34 (s, 2H, Ph-H), 6.84 (d, J = 2.1 Hz, 1H, Ph-H), 6.50 (d, J = 2.1 Hz, 1H, Ph-H), 4.03 (t, J = 6.0 Hz, 2H, -O-CH2CH2CH2-S-), 3.91 (s, 3H, Ph-OCH3), 3.86 (s, 3H, Ph-OCH3), 3.82 (s, 6H, 2 × Ph-OCH3), 3.73 (s, 3H, Ph-OCH3), 3.36 (t, J = 7.0 Hz, 2H, -O-CH2CH2CH2-S-), 2.15–2.07 (m, 2H, -O-CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.58, 167.58, 165.46, 164.28, 160.77, 158.65, 153.18, 152.20, 150.65, 142.98, 140.14, 139.92, 125.93, 122.83, 115.85, 108.89, 106.13, 96.42, 94.67, 93.62, 70.46, 60.65, 56.58, 56.52, 30.01, 27.84; HRMS calcd for C33H30N4O9S [M + H]+: 659.1806, found 659.1811.
2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)butyl)thio)-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitrile (4 m): Yellow solidd, m.p. 227.0-228.5 °C; yield: 42.9%; 1H NMR (400 MHz, DMSO-d6) δ 7.93–7.87 (m, 2H, Ph-H), 7.56–7.46 (m, 3H Ph-H), 7.33 (m, 2H, Ph-H), 6.83 (d, J = 2.1 Hz, 1H, Ph-H), 6.49 (d, J = 2.0 Hz, 1H, Ph-H), 3.95 (t, J = 5.8 Hz, 2H, -O-CH2CH2CH2CH2-S-), 3.90 (s, 3H, Ph-OCH3), 3.84 (s, 3H, Ph-OCH3), 3.83 (d, J = 5.0 Hz, 6H, 2 × Ph-OCH3), 3.74 (s, 3H, Ph-OCH3), 3.27 (t, J = 6.7 Hz, 2H, -O-CH2CH2CH2CH2-S-), 1.81 (dd, J = 14.0, 6.5 Hz, 4H, -O-CH2CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.63, 166.53, 164.23, 160.74, 158.62, 153.13, 152.05, 140.27, 139.86, 132.10, 129.03, 128.95, 125.99, 116.44, 108.90, 106.13, 96.38, 93.56, 71.38, 60.65 1, 56.56, 56.51, 30.44, 29.00, 26.05; HRMS calcd for C35H33N3O9S [M + H]+: 672.2010, found 672.2007.
2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)butyl)thio)-6-oxo-4-(m-tolyl)-1,6-dihydropyrimidine-5-carbonitrile (4n): Yellow solidd, m.p. 207.6-209.5 °C; yield: 45.8%;1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 8.8 Hz, 2H, Ph-H), 7.41–7.35 (m, 2H, Ph-H), 7.34 (s, 2H, Ph-H), 6.82 (d, J = 2.2 Hz, 1H, Ph-H), 6.49 (d, J = 2.3 Hz, 1H, Ph-H), 3.96 (t, J = 5.7 Hz, 2H, -O-CH2CH2CH2CH2-S-), 3.90 (s, 3H, Ph-OCH3), 3.84 (s, 3H, Ph-OCH3), 3.83 (s, 6H, 2 × Ph-OCH3), 3.26 (t, J = 6.8 Hz, 2H, -O-CH2CH2CH2CH2-S-), 2.32 (s, 3H, Ph-OCH3), 1.88–1.72 (m, 4H, -O-CH2CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.60, 164.22, 160.74, 158.61, 153.12, 152.03, 140.26, 139.87, 138.30, 132.71, 129.47, 128.84, 126.26, 125.98, 116.41, 108.90, 106.14, 96.36, 93.55, 71.36, 60.64, 56.50, 30.42, 29.01, 26.14, 21.33; HRMS calcd for C36H35N3O9S [M + H]+: 686.2167, found 686.2161.
2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)butyl)thio)-6-oxo-4-(p-tolyl)-1,6-dihydropyrimidine-5-carbonitrile (4o): White solid, m.p. 229.8-231.2 °C; yield: 59.1%; 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 8.2 Hz, 2H, Ph-H), 7.35 (s, 2H, Ph-H), 7.27 (d, J = 8.1 Hz, 2H, Ph-H), 6.83 (d, J = 2.2 Hz, 1H, Ph-H), 6.49 (d, J = 2.2 Hz, 1H, Ph-H), 3.97 (t, J = 5.8 Hz, 2H, -O-CH2CH2CH2CH2-S-), 3.90 (s, 3H, Ph-OCH3), 3.84 (s, 9H,3 × Ph-OCH3), 3.27 (t, J = 6.7 Hz, 2H, -O-CH2CH2CH2CH2-S-), 2.32 (s, 3H, Ph-OCH3), 1.81 (dd, J = 11.6, 6.6 Hz, 4H, -O-CH2CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.62, 167.36, 166.21, 164.23, 160.75, 158.6, 153.12, 151.97, 142.47, 140.26, 139.87, 132.85, 129.51, 129.10, 125.98, 116.57, 108.89, 106.11, 96.37, 93.56, 92.76, 71.33, 60.64, 56.54, 56.51, 30.38, 28.96, 26.12, 21.45; HRMS calcd for C36H35N3O9S [M + H]+: 686.2167, found 686.2191.
2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)butyl)thio)-4-(4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4p): Yellow solidd, m.p. 236.4-237.8 °C; yield: 51.9%; 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 8.9 Hz, 2H, Ph-H), 7.35 (s, 2H, Ph-H), 7.04 (d, J = 9.0 Hz, 2H, Ph-H), 6.82 (d, J = 2.2 Hz, 1H, Ph-H), 6.48 (d, J = 2.2 Hz, 1H, Ph-H), 3.97 (t, J = 5.6 Hz, 2H, -O-CH2CH2CH2CH2-S-), 3.90 (s, 3H, Ph-OCH3), 3.84 (s, 9H, 3 × Ph-OCH3), 3.80 (s, 3H, Ph-OCH3), 3.74 (s, 3H, Ph-OCH3), 3.28 (t, J = 6.6 Hz, 2H, -O-CH2CH2CH2CH2-S-), 1.88–1.76 (m, 4H, -O-CH2CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.64, 164.2, 162.63, 160.74, 158.59, 153.12, 151.95, 140.28, 139.88, 131.16, 125.98, 116.90, 114.39, 108.87, 106.11, 96.36, 93.55, 71.35, 60.64, 56.51, 55.87, 30.38, 28.99, 26.12; HRMS calcd for C36H35N3O10S [M]+: 701.2038, found 701.2026.
4-(3-chlorophenyl)-2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)butyl)thio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4q): Yellow solidd, m.p. 137.2-139.2 °C; yield: 41.8%; 1H NMR (400 MHz, DMSO-d6) δ 7.81 (dd, J = 7.2, 1.3 Hz, 2H Ph-H), 7.59–7.48 (m, 2H, Ph-H), 7.35 (s, 2H, Ph-H), 6.82 (d, J = 2.2 Hz, 1H, Ph-H), 6.49 (d, J = 2.2 Hz, 1H, Ph-H), 3.95 (s, 2H, -O-CH2CH2CH2CH2-S-), 3.90 (s, 3H, Ph-OCH3), 3.84 (s, 9H, 3 × Ph-OCH3), 3.74 (s, 3H, Ph-OCH3), 3.16 (s, 2H, -O-CH2CH2CH2CH2-S-), 1.79 (s, 4H, -O-CH2CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.63, 165.88, 164.21, 160.75, 158.61, 153.12, 152.03, 140.30, 139.86, 133.53, 131.09, 130.76, 128.51, 127.53, 126.01, 108.91, 106.14, 96.36, 93.55, 71.47, 60.64, 56.52, 56.50, 30.24, 29.10, 26.25; HRMS calcd for C35H32ClN3O9S [M + H]+: 706.1621, found706.1605.
4-(4-chlorophenyl)-2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)butyl)thio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4r): Yellow solidd, m.p. 129.5-131.8 °C; yield: 61.5%; 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 8.6 Hz, 2H, Ph-H), 7.70 (d, J = 8.6 Hz, 2H, Ph-H), 7.35 (s, 2H, Ph-H), 6.83 (d, J = 2.2 Hz, 1H, Ph-H), 6.49 (d, J = 2.2 Hz, 1H, Ph-H), 3.96 (t, J = 5.8 Hz, 2H, -O-CH2CH2CH2CH2-S-), 3.91 (s, 3H, Ph-OCH3), 3.85 (s, 3H, Ph-OCH3), 3.84 (s, 6H, 2 × Ph-OCH3), 3.74 (s, 3H, Ph-OCH3), 3.27 (t, J = 6.8 Hz, 2H, -O-CH2CH2CH2CH2-S-), 1.81 (dd, J = 14.8, 6.6 Hz, 4H, -O-CH2CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.65, 166.79, 166.44, 164.24, 160.75, 158.60, 153.13, 151.96, 140.28, 139.90, 134.84, 132.05, 131.06, 125.97, 116.27, 108.88, 106.13, 96.41, 93.59, 71.36, 60.65, 56.57, 56.53, 30.42, 28.93, 26.08; HRMS calcd for C35H32ClN3O9S [M + H]+: 706.1621, found 706.1592.
4-(3-bromophenyl)-2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)butyl)thio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4 s): Yellow solidd, m.p. 119.5-121.4 °C; yield: 30.5%; 1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 1.7 Hz, 1H, Ph-H), 7.90 (d, J = 7.8 Hz, 1H, Ph-H), 7.73 (d, J = 7.9 Hz, 1H, Ph-H), 7.46 (t, J = 7.9 Hz, 1H, Ph-H), 7.35 (d, J = 9.9 Hz, 2H, Ph-H), 6.82 (d, J = 2.1 Hz, 1H, Ph-H, Ph-H), 6.49 (d, J = 1.9 Hz, 1H, Ph-H), 3.96 (s, 2H, -O-CH2CH2CH2CH2-S-), 3.90 (s, 3H, Ph-OCH3), 3.84 (d, J = 3.1 Hz, 12H, 4 × Ph-OCH3), 3.73 (d, J = 1.8 Hz, 3H, Ph-OCH3), 3.26 (t, J = 6.5 Hz, 2H, -O-CH2CH2CH2CH2-S-), 1.80 (s, 4H, -O-CH2CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.62, 165.89, 164.21, 160.73, 158.60, 153.11, 152.03, 140.26, 139.83, 137.89, 134.64, 131.56, 131.12, 128.06, 125.98, 122.05, 116.14, 108.89, 106.11, 96.36, 93.54, 71.37, 60.64, 56.50, 30.44, 28.97, 26.10; HRMS calcd for C35H32BrN3O9S [M + H]+: 750.1115, found 750.1126.
4-(4-bromophenyl)-2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)butyl)thio)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4t): White solid, m.p. 153.6-155.4 °C; yield: 46.1%; 1H NMR (400 MHz, DMSO-d6) δ 7.86–7.81 (m, 2H, Ph-H), 7.73–7.66 (m, 2H, Ph-H), 7.35 (s, 2H, Ph-H), 6.83 (d, J = 2.2 Hz, 1H, Ph-H), 6.49 (d, J = 2.2 Hz, 1H, Ph-H), 3.96 (t, J = 5.8 Hz, 2H, -O-CH2CH2CH2CH2-S-), 3.91 (s, 3H, Ph-OCH3), 3.85 (s, 3H, Ph-OCH3), 3.84 (s, 6H, 2 × Ph-OCH3), 3.74 (s, 3H, Ph-OCH3), 3.27 (t, J = 6.8 Hz, 2H, -O-CH2CH2CH2CH2-S-), 1.81 (dd, J = 14.8, 6.6 Hz, 4H, -O-CH2CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.65, 166.79, 166.44, 164.24, 160.75, 158.60, 153.13, 151.96, 140.28, 139.90, 134.84, 132.05, 131.06, 125.97, 116.27, 108.88, 106.13, 96.41, 93.59, 71.36, 60.65, 56.57, 56.53, 30.42, 28.93, 26.08; HRMS calcd for C35H32BrN3O9S [M + H]+: 750.1115, found 750.1108.
2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)butyl)thio)-4-(3-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4u): White solid, m.p. 119.8-121.64 °C; yield: 70.8%; 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 7.9 Hz, 1H, Ph-H), 7.65 (dd, J = 9.8, 2.0 Hz, 1H, Ph-H), 7.55 (td, J = 8.0, 6.1 Hz, 1H, Ph-H), 7.41–7.36 (m, 1H, Ph-H), 7.35 (d, J = 3.9 Hz, 2H, Ph-H), 6.83 (d, J = 2.2 Hz, 1H, Ph-H), 6.48 (d, J = 2.2 Hz, 1H, Ph-H), 3.95 (t, J = 5.5 Hz, 2H, -O-CH2CH2CH2CH2-S-), 3.90 (s, 3H, Ph-OCH3), 3.84 (s, 9H, 3 × Ph-OCH3), 3.73 (s, 3H, Ph-OCH3), 3.24 (t, J = 6.4 Hz, 2H, -O-CH2CH2CH2CH2-S-), 1.80 (d, J = 3.2 Hz, 4H, -O-CH2CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.63, 164.21, 160.94, 160.73, 158.60, 153.12, 152.02, 140.27, 139.84, 131.09, 125.99, 125.22, 115.87, 115.64, 108.88, 106.10, 96.35, 93.53, 71.38, 60.64, 56.51, 30.41, 28.98, 26.04; 19F NMR (376 MHz, DMSO-d6) δ -112.28; HRMS calcd for C35H32FN3O9S [M + H]+: 690.1916, found 690.1915.
2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)butyl)thio)-4-(4-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4v): White solid, m.p. 223.0-224.8 °C; yield: 25.3%; 1H NMR (400 MHz, DMSO-d6) δ 7.99 (dd, J = 8.9, 5.5 Hz, 2H, Ph-H), 7.38–7.32 (m, 4H, Ph-H), 6.84 (d, J = 2.2 Hz, 1H, Ph-H), 6.50 (d, J = 2.2 Hz, 1H, Ph-H), 3.96 (t, J = 5.8 Hz, 2H, -O-CH2CH2CH2CH2-S-), 3.90 (s, 3H, Ph-OCH3), 3.84 (d, J = 2.0 Hz, 9H, 3 × Ph-OCH3), 3.74 (s, 3H, Ph-OCH3), 3.27 (t, J = 6.7 Hz, 2H, -O-CH2CH2CH2CH2-S-), 1.81 (dd, J = 9.6, 4.5 Hz, 4H, -O-CH2CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.67, 164.24, 160.72, 158.61, 153.12, 152.00, 140.27, 139.82, 131.81, 125.98, 116.54, 116.21, 115.99, 108.86, 106.07, 96.40, 93.56, 71.39, 60.64, 56.51, 30.39, 28.97, 26.07; 19F NMR (376 MHz, DMSO) δ -105.82; HRMS calcd for C35H32FN3O9S [M + H]+: 690.1916, found 690.1894 .
2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)butyl)thio)-4-(furan-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4w): Black solid, m.p. 236.8-238.7 °C; yield: 73.2%; 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H, Ph-H), 7.45 (d, J = 3.4 Hz, 1H, Ph-H), 7.36 (d, J = 4.2 Hz, 2H, Ph-H), 6.82 (d, J = 2.2 Hz, 1H, Ph-H), 6.71 (dd, J = 3.5, 1.7 Hz, 1H, Ph-H), 6.49 (d, J = 2.1 Hz, 1H, Ph-H), 4.00 (d, J = 5.2 Hz, 2H, -O-CH2CH2CH2CH2-S-), 3.90 (s, 3H, Ph-OCH3), 3.85 (s, 6H, 2 × Ph-OCH3), 3.84 (s, 3H, Ph-OCH3), 3.76–3.72 (m, 3H, Ph-OCH3), 3.29 (s, 2H, -O-CH2CH2CH2CH2-S-), 1.81 (d, J = 2.9 Hz, 4H, -O-CH2CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.67, 164.22, 160.71, 158.59, 154.86, 153.11, 151.97, 149.77, 148.57, 140.29, 139.80, 125.99, 118.73, 115.71, 113.67, 108.85, 106.03, 96.38, 93.53, 71.34, 60.65, 56.50, 30.29, 28.91, 26.04; HRMS calcd for C33H31N3O10S [M + H]+: 662.1803, found 662.1790.
2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)butyl)thio)-6-oxo-4-(pyridin-4-yl)-1,6-dihydropyrimidine-5-carbonitrile (4x): Yellow solidd, m.p. 213.8-215.8 °C; yield:56.6%; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 5.8 Hz, 2H, Ph-H), 7.81 (dd, J = 4.5, 1.6 Hz, 2H, Ph-H), 7.34 (s, 2H, Ph-H), 6.83 (d, J = 2.2 Hz, 1H, Ph-H), 6.49 (d, J = 2.2 Hz, 1H, Ph-H), 3.95 (t, J = 5.8 Hz, 2H, -O-CH2CH2CH2CH2-S-), 3.90 (s, 3H, Ph-OCH3), 3.84 (s, 3H, Ph-OCH3), 3.83 (s, 6H, 2 × Ph-OCH3), 3.73 (s, 3H, Ph-OCH3), 3.28 (t, J = 6.7 Hz, 2H, -O-CH2CH2CH2CH2-S-), 1.85–1.75 (m, 4H, -O-CH2CH2CH2CH2-S-); 13C NMR (101 MHz, DMSO-d6) δ 172.64, 167.52, 165.49, 164.23, 161.16, 160.72, 158.60, 153.12, 152.01, 150.62, 142.98, 140.27, 139.82, 125.97, 122.79, 115.76, 108.86, 106.07, 96.38, 94.82, 93.56, 71.35, 60.65, 56.55, 56.50, 30.52, 28.97, 25.97, 21.24; HRMS calcd for C34H32N4O9S [M + H]+: 673.1963, found 673.1943.