All the regents and solvents used for chemical synthesis were purchased from (Spectrochem, Sigma Aldrich, and Alfa Aesar) commercial chemical suppliers and used without further purification. Reaction were monitored by thin-layer chromatography (TLC) with Merck Silica Gel 60 F254 and the spots were visualized using ultraviolet (UV) light with an excitation wavelength of 254 nm. The melting points were determined in open glass capillaries and are uncorrected. The identity of the compounds were confirmed by 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded in CDCl3 or DMSO-d6 solvents by using Bruker Avance II 400 spectrometer. The chemical shifts value (δ) are expressed in ppm (ppm) relative to the standard TMS as an internal reference. The chemical shifts (d) are expressed in parts per million (ppm). Multiplicity of the signals is shown as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and doublet of doublets (dd), and coupling constants (J) were given in Hz. The phenyl azides (1,2) were prepared according to the reported procedures in the literature. High resolution mass spectra General procedure for the synthesis (E)-3-(4-fluorophenyl)-1-(2-hydroxyphenyl)prop-2.en-1-one (2)
The synthesis (E)-3-(4-fluorophenyl)-1-(2-hydroxyphenyl)prop-2.en-1-one was prepared from using 2-Hydoxyacetophenones (0.01 mol) and 4-fluorobenzaldehyde (0.01 mol) were added to a solution of KOH (0.03 mol) in ethanol (15 mL) at 0–5 0C. The reaction mixture was stirred 2–3 h at room temperature. Then the reaction mixture was quenched with crushed ice and neutralized carefully with 2 N HCl, and the obtained solid precipitate was filtered, washed with water, and dried. The crude product was crystallized with chloroform-ethanol to afford desired compound.
(E)-3-(4-fluorophenyl)-1-(2-hydroxyphenyl) prop-2-en-1-one (2)
Yellow solid, m.p. 96–98 0C, yield: 68 %. IR (KBr, cm-1): 3218 (OH), 2915 (CH), 1604 (C=O), 1562 (C=C). 1H NMR (400 MHz, CDCl3, dH ppm): 6.95 (ddd, 1H, J = 1.1, 7.2, 8.2 Hz, ArH), 7.03 (dd, 1H, J = 0.7, 8.4 Hz, ArH), 7.13 (t, 2H, J = 8.6 Hz, ArH), 7.51 (ddd, 1H, J = 1.8, 7.5, 7.7 Hz, ArH), 7.58 (d, 1H, J = 15.4 Hz, olefinic proton), 7.66 (dd, 2H, J = 5.3, 8.6 Hz, ArH), 7.89 (d, 1H, J = 15.4 Hz, olefinic proton), 7.92 (d, 1H, J = 1.8 Hz, ArH), 12.81 (s, 1H, OH). 13C NMR (100 MHz, CDCl3, dC ppm): 116.1(CH), 116.3(CH), 118.6(CH), 118.8(CH), 119.7(C), 119.9(CH), 129.6(CH), 130.5(CH), 130.6(C), 130.8(CH), 136.4(CH), 144.1(CH), 163.6(C), 165.5(C), 193.5(C). LCMS Anal. For C15H11FO2 (M + H) +: Calculated 242.0743 Found: 243.1370
General procedure for the synthesis 2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-one (3)
To a mixture of (E)-3-(4-fluorophenyl)-1-(2-hydroxyphenyl)prop-2.en-1-one (0.010319 mol) sodium hydroxide (0.03095 mol) hydrogen peroxide (30%) in ethanol (10 mL) was stirred vigorously for 30 min and kept for 2-3 h ice cold condition. The progress of the reaction was monitored by TLC. After completion of reaction indicated by TLC, the reaction mixture was poured into ice cold water and acidified with 1 M HCl, and solid obtained was washed with water and crystallized from ethanol to afford pure product.
2-(4-Fluorophenyl)-3-hydroxy-4H-chromen-4-one (3)
Yellow solid, m. p. 152–154 0C, yield: 74 %. IR (KBr, cm-1): 3297 (OH), 2925 (CH), 1618 (C=O), 1572 (C=C). 1 H NMR (400 MHz, CDCl3, dH ppm): 7.11 (brs, 1H, OH), 7.22 (t, 2H, J = 8.6 Hz, Ar-H), 7.42 (ddd, 1H, J = 1.1, 7.5, 7.6 Hz, Ar-H), 7.58 (d, 1H, J = 8.4 Hz, Ar-H), 7.71 (ddd, 1H, J = 1.7, 7.1, 8.5 Hz, Ar-H), 8.24 (d, 1H, J = 1.8 Hz, Ar-H), 8.27–8.30 (m, 2H, Ar-H). 13C NMR (100 MHz, CDCl3, d C ppm): 115.7(CH), 115.9(CH), 118.2(CH), 120.7(CH), 124.6(C), 125.5(C), 127.3(CH), 129.9(CH), 133.7(CH), 138.2(CH), 144.1(C), 155.3(C), 162.3(C), 164.8(C), 173.4(C). LCMS Anal. Calcd. For C15H9FO3 (M+H) +: Calculated 256.2286 Found: 257.1060
General procedure for the synthesis of compound 2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-one (4)
A mixture of substituted 2-(4-fluorophenyl)-3-hydroxy-4H-chromen-4-one (2) (0.00097568 mol, 0.25 gm) an propargyl bromide (3) (0.001365 mol, 0.1624 gm) (2) was dissolved in DMF (4 to 5 ml ) and to this solution K2CO3 (0.001951 mol, 0.269 gm ) was added. The reaction mixture was stirred at room temperature for 3-4 h. The progress of reaction was monitored by TLC. After completion of reaction the reaction mixture was poured on crushed ice and the precipitated solid was filtered, washed with water and crystallized from ethanol.
2-(4-Fluorophenyl)-3-(prop-2-ynyloxy)-4H-chromen-4-one (4)
Yellow solid, m. p. 106–108 ºC, yield: 74 %. IR (KBr, cm-1): 3238(C-CH), 3069 (=CH), 2952 (–CH), 2108 (C-C), 1628 (C=O), 1600 (C=C). 1H NMR (300 MHz, CDCl3, dH ppm): 2.32 (t, 1H, J = 2.4 Hz, alkyne proton), 5.00 (d, 2H, J = 2.4 Hz, OCH2), 7.16–7.26 (m, 2H, ArH), 7.42 (ddd, 1H, J = 1.2, 7.5, 7.6 Hz, ArH), 7.54 (dd, 1H, J = 1.2, 8.6 Hz, ArH), 7.70 (ddd, 1H, J = 1.8, 7.8, 7.8 Hz, ArH), 8.18 (dd, 2H, J = 5.4, 9.3 Hz, ArH), 8.26 (dd, 1H, J = 1.2, 8.0 Hz, ArH). 13C NMR (100 MHz, CDCl3, dC ppm): 59.2(CH2), 76.3(CH), 78.5(C), 115.5(CH), 115.7(CH), 118(CH), 124(CH), 124.9(C), 125.8(C), 127.1(CH), 131.3(CH), 133.7(CH), 138.4(CH), 155.2(C), 155.8(C), 162.8(C), 165.3(C), 174.8(C). HRMS Anal. For C18H11FO3 (M+Na)+: Calculated 294.0692. Found: 316.9881
General procedure for the synthesis of phenyl azide derivatives (5a-q):
Aniline (0.5 g, 5.4 mmol) was charged into a 50 ml round -bottomed flask which was then placed into an ice water bath (0° -5°C). conc. HCl was added up to the formation of ppt & then by adding ethanol at 0 clear solution was form and stirred for 1 min. followed by the dropwise addition of a solution of NaNO2 (3.87 mmol) in water (4.03 mL) over a period of 10 min with constant stirring. After stirring the reaction mixture for 1 h at 0 °C, a solution of NaN3 (3.87mmol) in water (4.03 mL) was added to this mixture and allowed to stir at room temperature for 3 h. The progress of the reaction was monitored by TLC using ethyl acetate: hexane (1:9) as a solvent system. After completion of the reaction, the mixture was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuo to give azide, which was used further without purification.[33]
General procedure for synthesis of compounds (6a–q)
The title compounds was synthesized using mixture 2-(4-fluorophenyl)-3-(prop-2-ynyloxy)-4H-chromen-4-one (4a) (0.0006802 mol 0.2 gm) and freshly prepared substituted phenyl azide (5a-q) (0.0006802 mol 0.08 gm) were stirred in presence of CuSO4.5H2O (20 mol%) and sodium ascorbate (20 mol%) was dissolved in PEG-400. The reaction mixture was stirred for 6h at room temperature. The progress of the reaction was monitored by TLC. After stirring for 6h, the reaction mass was poured on crushed ice. The product obtained was filtered, washed with water, and crystallized from ethanol.
2-(4-fluorophenyl)-3-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)-4H-chromen-4-one (6a)
Green Soild, m.p. 166 – 168 yield: 85 %
IR (ATR µ max cm-1) 1558.48 cm-1 (N=N), 1465.90 cm-1 (C=C), 2912.42cm-1 C-H).
1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H, triazoyl-H), 8.12 (dd, J = 8.6, 5.4 Hz, 3H, Ar-H), 7.79 – 7.63 (m, 3H, Ar-H), 7.62 – 7.50 (m, 3H, Ar-H), 7.46 (t, J = 7.5 Hz, 2H, Ar-H), 7.18 (t, J = 8.6 Hz, 2H, Ar-H), 5.41 (s, 2H OCH2). 13C NMR (101 MHz, CDCl3) δ 175.05 (s, C=O), 165.25 (s, C), 155.28 (s, C), 133.69 (s, C), 131.09 (s, CH), 129.75 (s, CH), 128.81 (s, CH), 125.80 (s, CH), 124.94 (s, CH), 120.54 (s, CH), 118.05 (s, CH), 115.54 (s, CH), 65.08 (S, CH2).
HRMS (ESI)+ Calculated for C24H16FN3O3 [M+H] +: Calculated 413.1176 and found 414.1234
2-(4-fluorophenyl)-3-((1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-4H-chromen-4-one (6b)
Green Soild, m.p. 158 – 160 yield: 82 %
1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H, triazoyl-H), 8.12 (dd, J = 20.4, 14.2 Hz, 3H, Ar-H), 7.71 (t, J = 8.5 Hz, 2H, Ar-H), 7.53 (d, J = 8.3 Hz, 1H, Ar-H), 7.42 (dd, J = 15.3, 7.6 Hz, 2H, Ar-H), 7.11 (dt, J = 14.7, 8.1 Hz, 4H, Ar-H), 5.46 (s, 2H, OCH2), 3.77 (s, J = 38.0 Hz, 3H, OCH3).
13C NMR (101 MHz, CDCl3) δ 175.10 (s, C=O), 165.17 (s, C), 162.66 (s, C), 155.55 (s, C), 150.94 (s, C), 133.59 (s, C), 130.06 (s, CH), 127.21 (s, CH), 125.78 (s, CH), 124.83 (s, CH), 121.15 (s, CH), 118.01 (s, CH), 115.40 (s, CH), 112.19 (s, CH), 77.39 (s, CH), 64.91 (s, CH2), 55.83 (s, OCH3).
HRMS (ESI)+ Calculated for C25H18FN3O4[M+] +: 443.1281 and found 444.1360
2-(4-fluorophenyl)-3-((1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-4H-chromen-4-one (6c)
Green Soild, m.p. 124 – 126 yield: 84 %
1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H, triazoyl-H), 8.18 – 8.07 (m, 3H, Ar-H), 7.73 (t, J = 7.7 Hz, 1H, Ar-H), 7.64 – 7.34 (m, 2H, Ar-H), 7.25 – 7.09 (m, 4H, Ar-H), 6.99 (d, J = 8.4 Hz, 1H, Ar-H), 5.40 (s, 2H, OCH2), 3.85 (s, J = 42.8, Hz, 3H, OCH3). 13C NMR (101 MHz, CDCl3) δ 175.05 (s, C=O), 165.25 (s, C), 162.74 (s, C), 155.55 (s, C), 133.69 (s, C), 131.09 (d, CH), 130.50 (s, CH), 125.79 (s, CH), 124.94 (s, CH), 118.04 (s, CH), 115.76 (s, CH), 112.40 (s, CH), 106.25 (s, CH), 65.04 (s, CH2), 55.63 (s, OCH3).
HRMS (ESI)+ Calculated for C25H18FN3O4[M+] +: 443.1281 and found 444.1360
2-(4-fluorophenyl)-3-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-4H-chromen-4-one (6d).
Yellow Soild, m.p. 190 – 192 yield: 80 %
1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H, triazoyl-H), 8.11 (s, 2H, Ar-H), 7.72 (s, 1H, Ar-H), 7.61 – 7.37 (m, 4H, Ar-H), 7.23 (d, J = 45.2 Hz, 2H, Ar-H), 7.00 (d, 2H, Ar-H), 5.38 (s, 2H, OCH2), 3.82 (s, 3H, OCH3).
3-((1-(2-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(4-fluorophenyl)-4H-chromen-4-one (6e)
Yellow Soild, m.p. 144 – 146 yield: 83 %
1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H, triazoyl-H), 8.15 (d, J = 5.8 Hz, 2H), 8.08 (s, 1H, Ar-H), 7.70 (t, J = 7.3 Hz, 1H, Ar-H), 7.54 (d, J = 6.7 Hz, 3H, Ar-H), 7.44 (d, J = 5.5 Hz, 3H, Ar-H), 7.17 (t, J = 8.1 Hz, 2H, Ar-H), 5.48 (s, 2H, OCH2).
3-((1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(4-fluorophenyl)-4H-chromen-4-one (6f)
Yellow Soild, m.p. 134 – 136 yield: 77 %
HRMS (ESI)+ Calculated for C24H15ClFN3O3[M+H] +: 447.0786 and found 448.0868
1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H, triazoyl-H), 8.12 (dd, J = 9.6 Hz, 3H, Ar-H), 7.78 – 7.70 (m, 2H, Ar-H), 7.58 (dd, J = 13.0 Hz, 2H, Ar-H), 7.52 – 7.40 (m, 3H, Ar-H), 7.29 (s, 1H, Ar-H), 7.23 – 7.12 (m, 2H, Ar-H), 5.41 (s, 2H, OCH2).
3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(4-fluorophenyl)-4H-chromen-4-one (6g)
Green Soild, m.p. 208 – 210 yield: 72 %
1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H, triazoyl-H), 8.13 (s, 3H, Ar-H), 7.73 (s, 1H, Ar-H), 7.65 (d, J = 6.3 Hz, 2H Ar-H), 7.52 (t, J = 21.4 Hz, 4H Ar-H), 7.19 (s, 2H, Ar-H), 5.39 (s, 2H, OCH2).
3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(4-fluorophenyl)-4H-chromen-4-one (6h)
Green Soild, m.p. 152 – 154 yield: 89 %
1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H, triazoyl-H), 8.12 (d, 3H, Ar-H), 7.89 (s, 1H, Ar-H), 7.71 (s, 1H, Ar-H), 7.58 – 7.49 (m, 1H, Ar-H), 7.47 – 7.24 (m, 4H, Ar-H), 7.15 (s, 2H, Ar-H), 5.43 (s, 2H, OCH2).
HRMS (ESI)+ Calculated for C25H15F2N3O3 [M+H] +: 431.1099 and found 432.1154
2-(4-fluorophenyl)-3-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-4H-chromen-4-one (6i)
Green Soild, m.p. 186 – 188 yield: 83 %
1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H, triazoyl-H), 8.11 (s, 2H, Ar-H), 7.62 (d, J = 35.9 Hz, 3H, Ar-H), 7.45 (s, 2H, Ar-H), 7.22 (s, 4H, Ar-H), 5.38 (s, 2H, OCH2).
3-((1-(4-ethylphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(4-fluorophenyl)-4H-chromen-4-one
(6j)
Green Soild, m.p. 128 – 130 yield: 81 %
2-(4-fluorophenyl)-3-((1-(o-tolyl)-1H-1,2,3-triazol-4-yl)methoxy)-4H-chromen-4-one (6k)
Green Soild, m.p. 138 – 140 yield: 78 %
1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H, triazoyl-H), 8.17 (s, 2H, Ar-H), 7.90 (s, 1H, Ar-H), 7.71 (s, 1H, Ar-H), 7.55 (s, 1H, Ar-H), 7.42 (d, J = 7.6 Hz, 2H, Ar-H), 7.34 (s, 2H, Ar-H), 7.21 (d, J = 24.7 Hz, 3H, Ar-H), 5.44 (s, 2H,OCH2), 2.11 (s, 3H, OCH3).
2-(4-fluorophenyl)-3-((1-(m-tolyl)-1H-1,2,3-triazol-4-yl)methoxy)-4H-chromen-4-one (6l)
Green Soild, m.p. 126 – 128 yield: 80 %
1H NMR (400 MHz, CDCl3) δ 8.31 (d, 1H, triazoyl-H), 8.10 (s, 3H), 7.72 (s, 1H), 7.51 (dd, J = 31.2, 12.6 Hz, 4H), 7.22 (d, J = 39.3 Hz, 3H), 5.40 (s, 2H), 2.34(s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 175.06 (s, C=O), 165.24 (s, C), 162.72 (s, C), 155.27 (s, C), 139.34 (s, C), 136.82 (s, C), 133.69 (s, C), 131.10 (d, J = 8.7 Hz, CH), 125.78 (s, CH), 124.93 (s, CH), 121.18 (s, CH), 118.04 (s, CH), 115.74 (s, CH), 65.08 (s, CH2), 21.38 (s, CH3).
2-(4-fluorophenyl)-3-((1-(p-tolyl)-1H-1,2,3-triazol-4-yl)methoxy)-4H-chromen-4-one (6m)
Brown Soild, m.p. 182 – 184 yield: 86 %
1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H, triazoyl-H), 8.10 (dd, J = 14.9, 9.2 Hz, 3H, Ar-H), 7.55 (d, J = 8.1 Hz, 3H, Ar-H), 7.45 (dd, J = 7.3 Hz, 2H, Ar-H), 7.29 (s, 2H, Ar-H), 7.17 (s, J = 8.3 Hz, 2H, Ar-H), 5.39 (s, 2H, OCH2), 2.44 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 175.05 (s, C=O), 165.23 (s, C), 162.72 (s, C), 155.26 (s, C), 138.94 (s, C), 134.63 (s, C), 131.09 (d, J = 8.7 Hz, CH), 130.22 (s, CH), 125.78 (s, CH), 124.92 (s, CH), 120.43 (s, CH), 118.04 (s, CH), 115.74 (s, CH), 65.09 (s, CH2), 21.09 (s, CH3).
HRMS (ESI)+ Calculated for: C25H18FN3O3 [M+] +: 427.1326 and found 428.1358
3-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(4-fluorophenyl)-4H-chromen-4-one (6n)
Brown Soild, m.p. 198 – 200 yield: 82 %
1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H, triazoyl-H), 8.12 (dd, J = 8.2, 5.4 Hz, 3H, Ar-H), 7.78 – 7.63 (m, 3H, Ar-H), 7.21 (d, J = 20.0 Hz, 2H, Ar-H), 5.38 (s, 2H, OCH2). 13C NMR (101 MHz, CDCl3) δ 175.03 (s, C=O), 155.28 (s, C), 135.87 (s, C), 132.91 (s, C), 131.08 (d, J = 8.8 Hz, CH), 125.78 (s, CH), 124.97 (s, CH), 122.19 (d, J = 60.9 Hz, CH), 118.06 (s, CH), 115.79 (s, CH), 65.05 (s, CH2).
HRMS (ESI)+ Calculated for C24H15BrFN3O3 [M+H] +: 491.0281 and found 493.0494
2-(4-fluorophenyl)-3-((1-(2-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-4H-chromen-4-one (6o)
Green Soild, m.p. 126 – 128 yield: 83 %
1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H, triazoyl-H), 8.15 (dd, J = 8.4, 5.5 Hz, 2H, Ar-H), 8.06 (d, J = 8.0 Hz, 1H, Ar-H), 7.79 (t, J = 7.4 Hz, 1H, Ar-H), 7.71 (dd, J = 12.5, 7.1 Hz, 2H, Ar-H), 7.59 – 7.52 (m, 2H, Ar-H), 7.43 (t, J = 7.4 Hz, 1H, Ar-H), 7.19 (t, J = 8.5 Hz, 2H, Ar-H), 5.44 (s, 2H, OCH2).
2-(4-fluorophenyl)-3-((1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-4H-chromen-4-one (6p)
Green Soild, m.p. 182 – 184 yield: 79 %
1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H, triazoyl-H), 8.43 – 8.25 (m, 3H, Ar-H), 8.17 – 8.10 (m, 2H, Ar-H), 7.83 – 7.67 (m, 2H, Ar-H), 7.56 (d, J = 8.3 Hz, 1H, Ar-H), 7.46 (t, J = 7.1 Hz, 1H, Ar-H), 7.30 – 7.11 (m, 2H, Ar-H), 5.40 (s, 2H, OCH2).
3-((1-(2,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(4-fluorophenyl)-4H-chromen-4-one (6q)
Green Soild, m.p. 140 – 142 yield: 84 %
(HRMS) were recorded on a Bruker Micro TOF-QII spectrometer