A Novel Consecutive Three-Component Coupling-Addition-S_NAr (CASNAR) Synthesis of 4H-Thiochromen-4-ones

Abstract

4H-Thiochromen-4-ones and 4H-thiopyrano[2,3-b]pyridin-4-ones are readily synthesized in good yields by a consecutive one-pot, three-component coupling-addition-S _N Ar (CASNAR) sequence starting from aroyl chlorides, alkynes, and sodium sulfide nonahydrate.

Key words

alkynes - catalysis - CC coupling - heterocycles - multicomponent reactions

References and Notes

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19

Representative Procedure - Synthesis of 2-Phenyl-4 H -thiochromen-4-one (1c; Table 2, Entry 3)
In a 10 mL microwave tube PdCl_{2 (}PPh₃)₂ (15 mg, 0.02 mmol) and CuI (8 mg, 0.04 mmol) were dissolved in degassed THF (4 mL). Then, to this orange soln acid chloride 3c (1.25 mmol), alkyne 4c (1.00 mmol), and Et₃N (1.05 mmol) were added. The reaction mixture was stirred at r.t. for 1 h. Finally, Na₂S˙9H₂O (5) followed by EtOH (1 mL) were added to this suspension, and the reaction mixture was heated at 90 ˚C in the microwave cavity for 90 min. After cooling to r.t., the solvent was removed under reduced pressure, and the crude products were purified by SiO₂ flash column chromatography (hexane-EtOAc) to afford the analytically pure 4H-thiochromen-4-one 1c in 174 mg (73%) yield as a yellow solid, mp 122 ˚C.
^¹H NMR (500 MHz, CDCl₃): δ = 7.06 (s, 1 H), 7.48-7.58 (m, 4 H), 7.62-7.71 (m, 4 H), 8.54-8.57 (m, 1 H) ppm. ^¹³C NMR (125 MHz, CDCl₃): δ = 123.4 (CH), 126.5 (CH), 127.0 (2 CH), 127.8 (CH), 128.6 (CH), 129.3 (2 CH), 130.8 (CH), 130.9 (C_quat), 131.6 (CH), 136.6 (C_quat), 137.7 (C_quat), 153.1 (C_quat), 180.8 (C_quat) ppm. MS (EI, 70 eV): m/z (%) = 239 (18), 238 (100) [M]⁺ , 211 (14), 210 (83), 165 (14), 136 (59), 108 (45), 105 (12), 92 (11), 82 (12), 69 (17). Anal. Calcd for C₂₀H₁₈O₃S (338.4): C, 75.60; H, 4.23. Found: C, 75.51; H, 4.41.
2-(3,4-Dimethoxyphenyl)-4 H -thiochromen-4-one (1f) ^¹H NMR (500 MHz, CDCl₃): δ = 3.94 (s, 3 H), 3.96 (s, 3 H), 6.96 (d, ^³ J = 8.4 Hz, 1 H), 7.19 (d, ⁴ J = 2.2 Hz, 1 H), 7.22 (s, 1 H), 7.31 (dd, ^³ J = 8.4 Hz, ⁴ J = 2.2 Hz, 1 H), 7.54 (ddd, ^³ J = 8.2 Hz, ^³ J = 6.8 Hz, ⁴ J = 1.3 Hz, 1 H), 7.61 (ddd, ^³ J = 8.2 Hz, ^³ J = 6.8 Hz, ⁴ J = 1.3 Hz, 1 H), 7.63-7.67 (m, 1 H), 8.53 (dd, ^³ J = 8.0 Hz, ⁴ J = 1.2 Hz, 1 H) ppm. ^¹³C NMR (125 MHz, CDCl₃): δ = 56.05 (CH₃), 56.06 (CH₃), 109.6 (CH), 111.3 (CH), 120.0 (CH), 122.3 (CH), 126.4 (CH), 127.7 (CH), 128.5 (CH), 129.1 (C_quat), 130.9 (C_quat), 131.5 (CH), 137.6 (C_quat), 149.5 (C_quat), 151.4 (C_quat), 152.9 (C_quat), 180.9 (C_quat) ppm. Anal. Calcd for C₁₇H₁₄O₃S (298.4): C, 68.44; H, 4.73. Found: C, 68.46; H, 4.57.

2-Ferrocenyl-4 H -thiochromen-4-one (1h) ^¹H NMR (500 MHz, CDCl₃): δ = 4.19 (s, 5 H), 4.52 (t, ^³ J = 1.9 Hz, 2 H), 4.81 (t, ^³ J = 1.9 Hz, 2 H), 7.12 (s, 1 H), 7.49-7.53 (m, 1 H), 7.58-7.60 (m, 2 H), 8.50 (dd, ^³ J = 8.0 Hz, 1 H) ppm. ^¹³C NMR (125 MHz, CDCl₃): δ = 67.4 (2 CH), 70.8 (5 CH), 71.1 (2 CH), 80.0 (C_quat), 119.8 (CH), 126.1 (CH), 127.4 (CH), 128.5 (CH), 131.2 (C_quat), 131.3 (CH), 137.4 (C_quat), 154.8 (C_quat), 180.2 (C_quat) ppm. Anal. Calcd for C₁₉H₁₄FeOS (346.2): C, 65.91; H, 4.08. Found: C, 65.64; H, 4.04.
2-Cyclopropyl-4 H -thiopyrano[2,3- b ]pyridin-4-one (8a)1Η ΝΜΡ (500 ΜΗζ, ΧΔΧλ3): δ = 1.06−1.09 (µ, 2 Η), 1.17∠1.21 (µ, 2 Η), 1.98∠2.03 (µ, 1 Η), 6.78 (σ, 1 Η), 7.43 (δδ, 3ϑ = 8.1 Ηζ, 4ϑ = 4.5 Ηζ, 1 Η), 8.68 (δδ, 3ϑ = 8.1 Ηζ, 4ϑ = 1.9 Ηζ, 1 Η), 8.73 (δδ, 3ϑ = 4.5 Ηζ, 4ϑ = 1.9 Ηζ, 1 Η). 13Χ ΝΜΡ (125 ΜΗζ, ΧΔΧλ3): δ = 10.6 (2 ΧΗ2), 18.0 (ΧΗ), 121.0 (ΧΗ), 122.6 (ΧΗ), 128.3 (Χθυατ), 136.6 (ΧΗ), 152.4 (ΧΗ), 158.6 (Χθυατ), 160.9 (Χθυατ), 180.8 (Χθυατ). Αναλ. Χαλχδ. ϕορ Χ11Η9ΝΟΣ (203.26): Χ, 65.00; Η, 4.46; Ν, 6.89. Φουνδ: Χ, 64.72; Η, 4.46; Ν, 6.73.