Transition-Metal-Free Easy Access to 2-(2-Oxo-2-arylethyl)-4H-chromen-4-ones from 2-Hydroxyacetophenone

Abstract

A stepwise synthetic strategy has been devised to access 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones from 2-hydroxyacetophenone, offering a structurally oxidized analogue of 2-(2-phenylethyl)chromones (PECs). The key substrate, 2-(methylthio)-4H-chromen-4-one, is readily synthesized in two steps from a protected 2-hydroxyacetophenone. Under mild reaction conditions (25 °C) in DMSO/KOH, 2-(methylthio)-4H-chromen-4-one undergoes nucleophilic substitution with various arylmethyl ketones to furnish 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones in moderate to good yields. The transformation exhibits broad substrate scope and excellent functional group tolerance. Notably, the resulting 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones can serve as valuable intermediates for the development of medicinally and materially relevant functionalized molecules, highlighting the synthetic and applicative significance of this methodology.

Key words

Ketene dithioacetal - chromones - arylmethyl ketones - nucleophilic substitution

Publication History

Received: 28 February 2025

Accepted after revision: 07 April 2025

Accepted Manuscript online:
07 April 2025

Article published online:
20 May 2025

• References and Notes

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• 15 1-[2-(Benzyloxy)phenyl]-3,3-bis(methylthio)prop-2-ene-1-one (3); General Procedure To a stirred solution containing NaH (20 mmol) in THF (20 ml) placed in ice cold water was added dropwise a solution of protected 2-hydroxy acetophenone (5 mmol). The addition continued for 15 min, and then the reaction mixture was stirred for another 15 min. Subsequently, a solution of carbon disulfide (6.5 mmol) in 5.0 mL of THF was added dropwise over 15 min at a constant temperature of less than 5 °C, and the reaction mixture was again kept stirred for 15 min. A solution containing methyl iodide (11 mmol) in 5.0 mL of THF was added to the reaction mixture in 15 min. The temperature of the resultant reaction mixture was maintained at 0–5 °C, and stirring was continued for 18 h at room temperature. Completion of the reaction was monitored by TLC. After completion, THF was removed under vacuum, followed by the addition of ice-cold water and stirred well. The formed solid was filtered and washed with water (2 × 25 mL). The compound was recrystallized for purification using hexane and ethyl acetate as solvent. 2-(Methylthio)-4H-chromen-4-one (4) To a 10 mL Schlenk tube, 0.5 mmol of 3, 2 mL of DCE (0.25 mmol), and iodine were added, and the reaction was closed well and stirred for 3 h at 80 °C. After completion, the reaction was quenched with 3% Na₂S₂O₃ (5 mL), diluted with brine (10 mL), and extracted with DCM (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, and crude product was purified through silica gel column chromatography using 10% EtOAc/hexane to afford the desired chromone. 2-(2-Oxo-2-arylethyl)-4H-chromen-4-ones 5a–r; General Procedure A solution containing 0.5 mmol of 4, 0.75 mmol of arylmethyl ketone, 0.5 mmol of KOH in DMSO (2 mL) was stirred at 25 °C for 3 h. After the completion of reaction, which was indicated by TLC, the reaction mixture was poured onto ice-cold water and then neutralized by using 10% HCl solution. The resultant solution was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and purified through silica gel column chromatography using 15–30% EtOAc/hexane as eluent. 2-(2-Oxo-2-phenylethyl)-4H-chromen-4-one (5a) Yield 75% (100 mg); R_f = 0.25 (30% ethyl acetate–hexane); white solid; mp 145 °C. IR (KBr): 1714, 1681.9, 1593.2 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.29 (s, 2 H), 6.31 (s,1 H), 7.36–7.41 (m, 2 H), 7.51 (t, 2 H), 7.63 (t, 2 H), 8.01 (d, 2 H), 8.18 (d, 2 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.19, 112.91, 117.85, 123.65, 125.18, 125.70, 128.37, 128.92, 133.64, 134.03, 135.85, 156.62, 162.19, 177.92, 192.86. HRMS (ESI): m/z calcd for C₁₇H₁₃O₃: 265.0859 [M + H]⁺; found: 265.0859. 2-[2-Oxo-2-(p-tolyl)ethyl]-4H-chromen-4-one (5b) Yield 93% (130 mg); R_f = 0.25 (30% ethyl acetate–hexane); white solid; mp 70 °C. IR (KBr): 1639.4, 1681.9 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 2.42 (s, 3 H), 4.25 (s, 2 H), 6.29 (s,1 H), 7.29 (d, 2 H), 7.35–7.40 (m, 2 H), 7.62 (t, 1 H), 7.90 (d, 2 H), 8.16 (dd, 1 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 21.68, 44.08, 112.80, 117.93, 123.57, 125.11, 125.60, 128.55, 129.57, 133.25, 133.60, 145.06, 156.48, 162.61, 177.95, 192.50. HRMS (ESI): m/z calcd for C₁₈H₁₅O₃: 279.1016 [M + H]⁺; found: 279.1021. 2-(1-Oxo-1-phenylpropan-2-yl)-4H-chromen-4-one (5c) Yield 93% (130 mg); R_f = 0.25 (20% ethyl acetate–hexane); yellow liquid. IR (KBr) 1638, 1680.9 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 1.64 (d, J = 7.0 Hz, 3 H), 4.69 (q, J = 7.1 Hz, 1 H), 6.34 (s, 1 H), 7.40–7.36 (m, 2 H), 7.47 (t, J = 7.6 Hz, 2 H), 7.64–7.56 (m, 2 H), 8.01 (d, J = 7.3 Hz, 2 H), 8.15 (d, J = 7.8 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 15.37, 46.73, 110.53, 117.93, 123.65, 125.25, 125.68, 128.41, 128.61, 128.89, 130.11, 133.71, 133.75, 135.57, 156.27, 167.48, 178.09, 196.14 cm^–1. HRMS (ESI): m/z calcd for C₁₈H₁₅O₃: 279.1016 [M + H]⁺; found: 279.1019. 2-[2-(1,1′-Biphenyl)-4-yl]-2-oxoethyl)-4H-chromen-4-one (5d) Yield 47% (80 mg); R_f = 0.25 (30% ethyl acetate–hexane); yellow solid; mp 181 °C. IR (KBr): 1602.8, 1654.9 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.32 (s, 2 H), 6.34 (s, 1 H), 7.36–7.40 (m, 3 H), 7.84 (t, 2 H), 7.63 (d, 3 H), 7.72 (d, 2 H), 8.09 (d, 2 H),8.17–8.20 (d, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.17, 112.85, 117.92, 123.57, 125.16, 125.62, 127.22, 127.45, 128.46, 129.04, 133.64, 134.35, 139.37, 146.63, 156.48, 162.44, 178.16, 192.29. HRMS (ESI): m/z calcd for C₂₃H₁₇O₃: 341.1172 [M + H]⁺; found: 341.1180. 2-[2-(4-Methoxyphenyl)-2-oxoethyl]-4H-chromen-4-one (5e) Yield 68% (100 mg); R_f = 0.24 (40% ethyl acetate–hexane); yellow solid; mp 119 °C. IR (KBr): 1643, 1681 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 3.87 (s, 3 H), 4.23 (s, 2 H), 6.29 (s, 1 H), 6.95 (d, 2 H), 7.34–7.39 ( m, 2 H), 7.61 (t, 1 H), 7.98 (d, 2 H), 8.16 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 43.89, 55.52, 112.71, 114.02, 117.92, 123.42, 125.10, 125.57, 128.72, 130.60, 133.59, 156.47, 162.81, 164.12, 177.98, 191.35. HRMS (ESI): m/z calcd for C₁₈H₁₅O₄: 295.0965 [M + H]⁺; found: 295.0973. 2-[2-Oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (5f) Yield 65% (115 mg); R_f = 0.25 (50% ethyl acetate–hexane); white solid; mp 157 °C. IR (KBr): 1126.4, 1647.2 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = ¹H NMR (400 MHz, CDCl₃): δ = 3.93 (s, 10 H), 4.27 (s, 2 H), 6.32 (s, 1 H), 7.26 (s, 3 H), 7.39 (s, 2 H), 7.64 (s, 1 H), 8.18 (d, J = 8.0 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 43.80, 56.04, 61.10, 106.06, 112.58, 117.87, 123.59, 125.26, 125.68, 130.79, 133.73, 143.44, 153.07, 156.50,162.61, 177.98, 191.60. HRMS (ESI): m/z calcd for C₂₀H₁₉O₆: 355.1176 [M + H]⁺; found: 355.1170. 2-[2-(4-Fluorophenyl)-2-oxoethyl)-4H-chromen-4-one (5g) Yield 75% (105 mg); R_f = 0.25 (22% ethyl acetate–hexane); white solid; mp 114 °C. IR (KBr): 1681, 1593 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.26 (s, 2 H), 6.29 (s, 1 H), 7.17 (t, 2 H), 7.37 (d, 2 H), 7.63 (t, 1 H), 8.04 (dd, 2 H), 8.16 (d, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.32, 112.88, 115.92, 116.22, 117.89, 123.59, 125.20, 125.65, 128.79, 131.12, 131.21, 132.22, 133.67, 156.55, 162.07, 164.84, 167.46, 177.84, 191.29. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃F: 283.0765 [M + H]⁺; found: 283.0772. 2-[2-(4-Chlorophenyl)-2-oxoethyl)-4H-chromen-4-one (5h) Yield 70% (100 mg); R_f = 0.28 (15% ethyl acetate–hexane); white solid; mp 109 °C. IR (KBr): 1688.2, 1590 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.26 (s, 2 H), 6.30 (s, 1 H), 7.38 (m, 2 H), 7.48 (d, 2 H), 7.63 (t, 1 H), 7.95 (d, 2 H), 8.17 (d, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.39, 112.93, 117.91, 123.60, 125.26, 125.70, 129.27, 129.83, 133.72, 134.07, 140.63, 156.63, 161.86, 177.70, 191.71. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃Cl: 299.0469 [M + H]⁺; found: 299.0475. 2-[2-(2,4-Dichlorophenyl)-2-oxoethyl]-4H-chromen-4-one (5i) Yield 96% (160 mg); R_f = 0.29 (40% ethyl acetate–hexane); yellow solid; mp 161 °C. IR (KBr): 1317.3, 1614 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.31 (s, 2 H), 6.29 (s, 1 H), 7.34–7.40 (m, 3 H), 7.47 (d, 1 H), 7.57 (d, 1 H), 7.64 (dt, 1 H), 8.17 (d, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 47.74, 112.97, 117.88, 123.57, 125.29, 125.71, 127.68, 130.76, 132.47, 133.99, 135.60, 138.55, 156.42, 161.15, 177.73, 194.21. HRMS (ESI): m/z calcd for C₁₇H₁₁O₃Cl₂: 333.0080 [M + H]⁺; found: 333.0086. 2-[2-(4-Bromophenyl)-2-oxoethyl-4H-chromen-4-one (5j) Yield 82% (140 mg); R_f = 0.26 (20% ethyl acetate–hexane); white solid; mp 148 °C. IR (KBr): 1651, 1687.7 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.25 (s, 2 H), 6.30(s, 1 H), 7.37–7.40 (m, 2 H), 7.61–7.66 (m, 3 H), 7.88 (d, 2 H), 8.17 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.11, 112.94, 117.90, 123.59, 125.26, 125.70, 129.41, 129.89, 132.28, 133.73, 134.44, 156.48, 161.91, 177.87, 191.93. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃Br: 342.9964 [M + H]⁺; found: 342.9969. 2-[2-(2-Bromophenyl)-2-oxoethyl]-4H-chromen-4-one (5k) Yield 59% (100 mg); R_f = 0.12 (30% ethyl acetate–hexane); pale yellow solid; mp 107 °C. IR (KBr): 1666, 1698 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.22 (s, 2 H), 6.25 (s, 1 H), 7.33–7.24 (m, 4 H), 7.44 (dd, J = 7.6, 1.8 Hz, 1 H), 7.58–7.55 (m, 2 H), 8.08 (dd, J = 7.9, 1.5 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 47.20, 112.74, 117.80, 118.78, 123.36, 125.07, 125.40, 127.52, 128.80, 132.36, 133.60, 133.81, 139.68, 156.24, 161.32, 177.39, 196.34. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃Br: 342.9964 [M + H]⁺; found: 342.9966. 2-[2-(3-Bromophenyl)-2-oxoethyl]-4H-chromen-4-one (5l) Yield 76% (130 mg); R_f = 0.26 (30% ethyl acetate–hexane); pale yellow solid; mp 115 °C. IR (KBr): 1645, 1695 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.26 (s, 2 H), 6.29 (s, 1 H), 7.36–7.41 (m, 3 H), 7.63 (dt, 1 H), 7.74 (d, 1 H), 7.92 (d, 1 H), 8.13 (t, 1 H), 8.16 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.14, 112.96, 117.74, 123.23, 123.54, 125.24, 125.65, 126.91, 130.47, 131.43, 133.73, 136.83, 137.36, 156.45, 161.75, 177.86, 191.61. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃Br: 342.9964 [M + H]⁺; found: 342.9979. 2-[2-Napthalen-1-yl)-2-oxoethyl]-4H-chromen-4-one (5m) Yield 76% (120 mg); R_f = 0.12 (20% ethyl acetate–hexane); bright yellow; mp 118 °C. IR (KBr): 1670, 1643 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.37 (s, 2 H), 6.34 (s, 1 H), 7.30–7.46 (2 H), 7.62–7.50 (m, 4 H), 7.87 (d, J = 7.7 Hz, 1 H), 8.02 (t, J = 8.2 Hz, 2 H), 8.17 (dd, J = 8.0, 1.5 Hz, 1 H), 8.74 (d, J = 8.7 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 46.94, 76.68, 77.00, 77.32, 112.81, 117.87, 123.51, 124.19, 125.11, 125.56, 126.72, 128.52, 128.79, 130.20, 133.61, 133.92, 134.02, 156.41, 162.50, 177.92, 196.07. HRMS (ESI): m/z calcd for C₂₁H₁₅O₃: 315.1016 [M + H]⁺; found: 315.1023. 2-[2-(Napthalen-2-yl)-2-oxoethyl]-4H-chromen-4-one (5n) Yield 80% (125 mg); R_f = 0.20 (40% ethyl acetate–hexane); white solid; mp 110 °C. IR (KBr): 1681.9, 1645.2 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.42 (s, 2 H), 6.36 (s, 1 H), 7.35–7.41 (m, 2 H), 7.56–7.65 (m, 3 H), 7.88–7.94 (m, 2 H), 7.98 (d, 1 H), 8.05 (dd, 1 H), 8.18 (dd, 1 H), 8.53 (s, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.19, 112.91,117.92, 123.64, 125.16, 125.64, 127.11, 127.82, 129.87, 129.05, 129.62, 130.52, 132.34, 133.64, 135.85, 156.51, 162.47, 177.96, 192.83. HRMS (ESI): m/z calcd for C₂₁H₁₅O₃: 315.1016 [M + H]⁺; found: 315.1019. 2-(2-Oxo-1,2,3,4-tetrahydronapthalen-1-yl)-4H-chromen-4-one (5o) Yield 36% (50 mg); R_f = 0.25 (30% ethyl acetate–hexane); orange solid; mp 138 °C. IR (KBr): 1618, 1722.2 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.68–2.76 (m, 1 H), 2.81–2.88 (m, 1 H), 3.08–3.15 (m, 1 H), 3.26–3.34 (m, 1 H), 4.67 (s, 1 H), 6.16 (s, 1 H), 7.15 (d, 1 H), 7.24–7.28 (m, 1 H), 7.31 (s, 1 H), 7.32 (s,1 H), 7.38 (t, 2 H), 7.63 (t, 1 H), 8.15 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 27.82, 37.78, 58.57, 112.53, 118.09, 123.51, 125.32, 125.65, 127.53, 128.30, 128.47, 128.90, 132.24, 133.80, 136.51, 156.22, 164.57, 178.23, 205.22. HRMS (ESI): m/z calcd for C₁₉H₁₅O₃: 291.1016 [M + H]⁺; found: 291.1019. 2-(1-Oxo-1,2,3,4-tetrahydronapthalen-2-yl)-4H-chromen-4-one (5p) Yield 96% (140 mg); R_f = 0.25 (36% ethyl acetate–hexane); yellow solid; mp 131 °C. IR (KBr): 1617.3, 1722 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 2.49 (td, J = 8.9, 4.4 Hz, 1 H), 2.67–2.57 (m, 1 H), 3.17–3.12 (m, 2 H), 3.79 (dd, J = 11.8, 4.5 Hz, 1 H), 6.26 (s, 1 H), 7.30 (d, J = 7.8 Hz, 1 H), 7.40–7.34 (m, 3 H), 7.56–7.52 (m, 1 H), 7.65–7.61 (m, 1 H), 8.08 (d, J = 7.0 Hz, 1 H), 8.18 (d, J = 9.0 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 27.61, 28.49, 53.20, 111.74, 117.84, 123.81, 125.00, 125.66, 127.09, 127.89, 128.87, 131.82, 133.57, 134.12, 143.49, 156.52, 166.05, 177.95, 193.73. HRMS (ESI): m/z calcd for C₁₉H₁₅O₃: 291.1016 [M + H]⁺; found: 291.1025. 2-[2-(Furan-2-yl)-2-oxoethyl]-4H-chromen-4-one (5q) Yield 94% (120 mg); R_f = 0.20 (30% ethyl acetate–hexane); white solid; 99 °C. IR (KBr): 1433, 1637, 1678 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.14 (s, 2 H), 6.32 (s, 1 H), 6.59 (dd, 1 H), 7.32–7.41 (m, 2 H), 7.61 (dd,1 H), 7.63 (m, 1 H), 8.16 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 43.97, 112.90, 117.96, 118.55, 123.59, 125.18, 125.63, 133.68, 147.24, 151.74, 156.47, 161.67, 177.62, 181.73. HRMS (ESI): m/z calcd for C₁₅H₁₁O₄: 255.0652 [M + H]⁺; found: 255.0659. 2-[2-Oxo-2-(thiophen-2-yl)]-4H-chromen-4-one (5r) Yield 74% (100 mg); R_f = 0.22 (28% ethyl acetate–hexane); brown solid; mp137 °C. IR (KBr): 1631, 1660.7 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.20 (s, 2 H), 6.32 (s, 1 H), 7.17 (t, 1 H), 7.34–7.40 (m, 2 H), 7.62 (t, 1 H), 7.72 (dd, 1 H), 7.82 (dd, 1 H), 8.15 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 45.03, 112.76, 117.92, 123.53, 125.18, 125.70, 128.44, 132.98, 133.68, 135.25, 142.78, 156.26, 161.97, 177.87, 185.44. HRMS (ESI): m/z calcd for C₁₅H₁₁O₃S: 271.0423 [M + H]⁺; found: 271.0433.