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Iodobenzene

Iodobenzene is an aromatic organoiodine compound with the chemical formula C6H5I.
It is a colorless liquid with a pungent odor, used as a precursor in organic synthesis and as a reagent in various chemical reactions.
Iodobenzene has a wide range of applications in medicinal chemistry, polymer science, and materials science.
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Most cited protocols related to «Iodobenzene»

Synthesis of Substituted 2-Phenyl-2H-indazoles

Cited 8 times

General procedure for the synthesis of 1-(2-nitrophenyl)-N-phenylmethanimines (2–6). 2-Nitrobenzaldehyde (5 g, 33.08 mmol) and aniline or the corresponding substituted aniline (33.08 mmol, 1 eq) were dissolved in ethanol (12–40 mL; the minimum quantity to dissolve the starting materials) and stirred at reflux temperature for 1–4 h to yield compounds 2–4, 6. Finally, the mixture was cooled to induce crystallization and the solid formed was separated using vacuum filtration and washed with cold ethanol. This same reaction was carried out at room temperature to yield compound 5.
General procedure for the synthesis of 2-phenyl-2H-indazole derivatives (7–11). 2-Phenyl-2H-indazole derivatives were synthesized employing a slight modification of the Cadogan method [24 (link)]. The corresponding imine 2–6 (20 mmol) was heated in triethyl phosphite (60 mmol) at 150 °C (0.5–2 h) until the starting material was totally consumed. Then, phosphite and phosphate were separated using vacuum distillation and the residue was purified using column chromatography with hexane–ethyl acetate (90:10) as a mobile phase to give the respective 2-phenyl-2H-indazole derivatives 7–9 and 11. A slightly more polar mobile phase was used for the purification of the compound 10, hexane-ethyl acetate (80:20).
4-(2H-indazol-2-yl) phenol (12). Compound 9 (4 mmol) was dissolved in dichloromethane (12 mL) and cooled to 0 °C under N₂ atmosphere. Then, boron tribromide (12 mL of 1 M solution in dichloromethane, 12 mmol) was added and the reaction mixture was warmed to room temperature and stirred overnight. After completion of the reaction, a saturated sodium bicarbonate solution was added and the solid formed was filtered under vacuum. The crude product was purified using a short column packed with silica gel and ethyl acetate-hexanes (6:4) as a mobile phase to give compound 12.
General procedure for the synthesis of derivatives13, 20, and25. The appropriate methyl ester derivative (10, 18, and 23, 1.2 mmol) was dissolved in methanol (7.5 mL) and an aqueous solution of NaOH (3.6 mmol in 3 mL of water) was added. The reaction mixture was heated under reflux for five hours. After completion of the reaction, the mixture was cooled on ice and acidified to pH 1 with HCl to induce precipitation. The solid was separated using vacuum filtration and dried.
2-(4-(Methylsulfinyl) phenyl)-2H-indazole (14). To a solution of compound 11 (0.8 mmol) in 28 mL of CH₃CN/CH₃COOH (1:1), NaIO₄ (0.8 mmol) dissolved in 2 mL of H₂O/AcOH (4:1) was added. The reaction mixture was stirred at room temperature for 24 h. Then, the reaction was neutralized with a saturated solution of sodium bicarbonate and the product was extracted with dichloromethane (3 × 50 mL). The organic phase was dried with anhydrous sodium sulfate and concentrated under vacuum. The evaporation residue was purified by column chromatography using dichloromethane/methanol (98:2) as a mobile phase to give compound 14.
General procedure for the synthesis of derivatives15, 21, and 26. NaIO₄ (5 mmol) dissolved in 5 mL of H₂O/AcOH (4:1) were added to a solution of the proper indazole derivative 11, 19, or 24 (2 mmol) in 28 mL of CH₃CN/CH₃COOH (1:1). The reaction mixture was stirred at reflux temperature for 12 h. Then, the mixture was neutralized with a saturated solution of sodium bicarbonate and brine solution was added until complete precipitation. The solid was separated using vacuum filtration and dried. The crude product was purified by column chromatography using dichloromethane as a mobile phase.
General procedure for the synthesis of 2,3-diphenyl-2H-indazole derivatives16–19 and 22–24. Compounds 16–19 and 22–24 were synthesized by a palladium catalyzed arylation as previously described by Ohnmacht et al. [27 (link)]. It is worth mentioning that the previously-reported methodology was scaled up to 0.5 g of starting 2-phenyl-2H-indazole. Whereas compounds 16–19, 22, and 23, were synthesized using the proper 2-phenyl-2H-indazole and the substituted 4-iodobenzene, only compound 24 was synthesized from 2-phenyl-2H-indazole and 4-bromothioanisole.
1-(2-Nitrophenyl)-N-phenylmethanimine (2). Yellow solid (93% yield); m.p.: 64.1–64.9 °C (lit [24 (link)]: 63–64 °C); ¹H-NMR (600 MHz, CDCl₃) δ 8.94 (s, 1H), 8.31 (dd, J = 7.8, 1.4 Hz, 1H), 8.07 (dd, J = 8.2, 1.1 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.64–7.60 (m, 1H), 7.45–7.40 (m, 2H), 7.31–7.27 (m, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 155.84, 151.07, 149.34, 133.58, 131.18, 131.12, 129.75, 129.28, 126.92, 124.54, 121.18.
N-(4-Chlorophenyl)-1-(2-nitrophenyl) methanimine (3). Dark yellow solid (91% yield); m.p.: 91.2–92.2 °C (lit [36 (link)]: 91–92 °C). ¹H-NMR (600 MHz, CDCl₃) δ 8.93 (s, 1H), 8.29 (dd, J = 7.8, 1.5 Hz, 1H), 8.08 (dd, J = 8.2, 1.2 Hz, 1H), 7.78–7.72 (m, 1H), 7.67–7.61 (m, 1H), 7.41–7.36 (m, 2H), 7.25–7.20 (m, 2H); ¹³C-NMR (151 MHz, CDCl₃) δ 156.24, 149.49, 149.32, 133.64, 132.58, 131.40, 130.87, 129.72, 129.40, 124.61, 122.54.
N-(4-Methoxyphenyl)-1-(2-nitrophenyl) methanimine (4). Yellow solid (92% yield); m.p.: 79.1–79.9 °C (lit [36 (link)]: 81–82 °C); ¹H-NMR (600 MHz, CDCl₃) δ 8.97 (s, 1H), 8.32 (dd, J = 7.8, 1.4 Hz, 1H), 8.06 (dd, J = 8.2, 1.1 Hz, 1H), 7.75–7.70 (m, 1H), 7.62–7.57 (m, 1H), 7.35–7.29 (m, 2H), 6.98–6.94 (m, 2H), 3.85 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 159.09, 153.31, 143.88, 133.48, 131.36, 130.81, 129.55, 124.53, 122.78, 114.50, 55.53.
Methyl 4-((2-nitrobenzylidene) amino)benzoate (5) Pale yellow solid (73% yield); m.p.: 122.7–124.4 °C; ¹H-NMR (600 MHz, CDCl₃) δ 8.93 (s, 1H), 8.30 (dd, J = 7.7, 1.0 Hz, 1H), 8.10 (d, J = 8.4 Hz, 3H), 7.76 (t, J = 7.6 Hz, 1H), 7.68–7.63 (m, 1H), 7.30–7.25 (m, 2H), 3.93 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 166.66, 157.50, 155.14, 149.39, 133.71, 131.66, 130.95, 130.70, 129.84, 128.26, 124.65, 120.93, 52.15; MS (HR-ESI) for C₁₅H₁₂N₂O₄ [M + H]⁺, calcd: m/z 285.0870, found: m/z 285.0861.
N-(4-(Methylthio)phenyl)-1-(2-nitrophenyl)methanimine (6). Burnt orange solid (92% yield); m.p.: 69.3–70.4 °C; ¹H-NMR (600 MHz, CDCl₃) δ 8.96 (s, 1H), 8.31 (dd, J = 7.8, 1.4 Hz, 1H), 8.07 (dd, J = 8.2, 1.1 Hz, 1H), 7.73 (t, J = 7.5 Hz, 1H), 7.63–7.58 (m, 1H), 7.33–7.22 (m, 4H), 2.52 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 154.86, 149.25, 148.06, 137.45, 133.51, 131.07, 129.63, 127.37, 124.53, 121.89, 16.06; MS (HR-ESI) for C₁₄H₁₂N₂O₂S [M + H]⁺, calcd: m/z 273.0692, found: m/z 273.0683.
2-Phenyl-2H-indazole (7). White solid (64% yield); m.p.: 81.2–81.6 °C (lit [24 (link)]: 81–82 °C); the spectroscopic data matched previously reported data [37 (link)]: ¹H-NMR (600 MHz, CDCl₃) δ 8.40 (d, J = 0.9 Hz, 1H), 7.91–7.88 (m, 2H), 7.79 (dd, J = 8.8, 0.9 Hz, 1H), 7.70 (dt, J = 8.5, 1.0 Hz, 1H), 7.54–7.50 (m, 2H), 7.41–7.37 (m, 1H), 7.32 (ddd, J = 8.8, 6.6, 1.0 Hz, 1H), 7.11 (ddd, J = 8.4, 6.6, 0.7 Hz, 1H); ¹³C-NMR (151 MHz, CDCl₃) δ (ppm): 149.78, 140.52, 129.54, 127.88, 126.81, 122.76, 122.44, 120.99, 120.39, 120.37, 117.94.
2-(4-Chlorophenyl)-2H-indazole (8). White solid (57% yield); m.p.: 143.0–145.5 °C (lit [38 (link)]: 138–140 °C); the spectroscopic data matched previously reported data [38 (link)]: ¹H-NMR (600 MHz, CDCl₃) δ 8.37 (d, J = 1.0 Hz, 1H), 7.87–7.82 (m, 2H), 7.77 (dq, J = 8.8, 0.9 Hz, 1H), 7.69 (dt, J = 8.5, 1.0 Hz, 1H), 7.51–7.47 (m, 2H), 7.33 (ddd, J = 8.8, 6.6, 1.1 Hz, 1H), 7.12 (ddd, J = 8.5, 6.6, 0.8 Hz, 1H); ¹³C-NMR (151 MHz, CDCl₃) δ 149.89, 139.02, 133.55, 129.67, 127.09, 122.87, 122.71, 122.00, 120.29, 117.90.
2-(4-Methoxyphenyl)-2H-indazole (9). Beige solid (56 % yield); m.p.: 133.2–135.8 °C (lit [39 ]: 130–131 °C); the spectroscopic data matched previously reported data [40 (link)]: ¹H-NMR (600 MHz, CDCl₃) δ 8.30 (d, J = 0.9 Hz, 1H), 7.82–7.76 (m, 3H), 7.69 (dt, J = 8.4, 1.0 Hz, 1H), 7.31 (ddd, J = 8.7, 6.6, 1.0 Hz, 1H), 7.10 (ddd, J = 8.4, 6.6, 0.8 Hz, 1H), 7.05–6.99 (m, 2H), 3.86 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 159.28, 149.58, 134.12, 126.53, 122.70, 122.41, 122.22, 120.30, 120.25, 117.77, 114.63, 55.60.
Methyl 4-(2H-indazol-2-yl) benzoate (10). White solid (52% yield); m.p.: 185.8–186.2 °C (lit [41 ]: 186–187 °C); the spectroscopic data matched previously reported data [40 (link)]: ¹H-NMR (600 MHz, CDCl₃) δ 8.47 (d, J = 0.7 Hz, 1H), 8.22–8.18 (m, 2H), 8.02–7.99 (m, 2H), 7.77 (dd, J = 8.8, 0.8 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.33 (ddd, J = 8.8, 6.6, 1.0 Hz, 1H), 7.14–7.10 (m, 1H), 3.95 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 166.19, 150.19, 143.64, 131.16, 129.27, 127.45, 123.01, 122.98, 120.47, 120.26, 118.06, 52.33.
2-(4-(Methylthio) phenyl)-2H-indazole (11). Pale yellow solid (61% yield); m.p.: 148.3–149.7 °C (lit [38 (link)]: 137–139 °C); the spectroscopic data matched previously reported data [38 (link)]: ¹H-NMR (600 MHz, CDCl₃) δ 8.35 (d, J = 0.8 Hz, 1H), 7.84–7.80 (m, 2H), 7.79–7.76 (m, 1H), 7.68 (dt, J = 8.5, 0.9 Hz, 1H), 7.39–7.35 (m, 2H), 7.31 (ddd, J = 8.7, 6.6, 1.0 Hz, 1H), 7.10 (ddd, J = 8.4, 6.6, 0.8 Hz, 1H), 2.53 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 149.72, 138.63, 137.78, 127.27, 126.82, 122.77, 122.46, 121.26, 120.30, 120.12, 117.84, 15.88.
4-(2H-Indazol-2-yl) phenol (12). Beige solid (64% yield); m.p.: 179–181 °C (lit [25 (link)]: 193–194 °C); the spectroscopic data matched previously reported data [42 ]: ¹H-NMR (600 MHz, DMSO-d₆) δ 9.85 (s, 1H), 8.91 (d, J = 0.9 Hz, 1H), 7.91–7.84 (m, 2H), 7.75 (dt, J = 8.4, 1.0 Hz, 1H), 7.69 (dq, J = 8.8, 0.9 Hz, 1H), 7.29 (ddd, J = 8.7, 6.6, 1.1 Hz, 1H), 7.08 (ddd, J = 8.3, 6.6, 0.8 Hz, 1H), 6.98–6.92 (m, 2H); ¹³C-NMR (151 MHz, DMSO-d₆) δ 157.09, 148.47, 132.11, 126.10, 122.24, 121.75, 121.57, 120.78, 120.58, 117.12, 115.81.
4-(2H-Indazol-2-yl) benzoic acid (13). White solid (96% yield); m.p.: 288.3–288.5 °C (lit [41 ]: 286–288 °C); ¹H-NMR (600 MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.29–8.23 (m, 2H), 8.18–8.12 (m, 2H), 7.79 (dt, J = 8.5, 1.0 Hz, 1H), 7.73 (dq, J = 8.8, 0.9 Hz, 2H), 7.35 (ddd, J = 8.8, 6.5, 1.1 Hz, 1H), 7.13 (ddd, J = 8.5, 6.6, 0.8 Hz, 1H); ¹³C-NMR (151 MHz, DMSO-d₆) δ 166.46, 149.22, 142.83, 130.82, 129.65, 127.28, 122.54, 122.43, 122.04, 120.99, 119.86, 117.48.
2-(4-(Methylsulfinyl) phenyl)-2H-indazole (14). White solid (92% yield); m.p.: 150.1–152.7 °C; ¹H-NMR (600 MHz, CDCl₃) δ 8.47 (d, J = 0.9 Hz, 1H), 8.13–8.07 (m, 2H), 7.83–7.75 (m, 3H), 7.70 (dt, J = 8.5, 1.0 Hz, 1H), 7.34 (ddd, J = 8.8, 6.6, 1.1 Hz, 1H), 7.13 (ddd, J = 8.5, 6.6, 0.8 Hz, 1H), 2.78 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 150.14, 145.05, 142.47, 127.45, 125.03, 123.01, 121.49, 120.46, 120.43, 118.01, 44.10; MS (HR-ESI) for C₁₄H₁₂N₂OS [M + Na]⁺, calcd: m/z 279.0562, found: m/z 279.0481.
2-(4-(Methylsulfonyl) phenyl)-2H-indazole (15). White solid (68% yield); m.p.: 200.6–201.5 °C; ¹H-NMR (600 MHz, CDCl₃) δ 8.50 (d, J = 0.8 Hz, 1H), 8.19–8.05 (m, 4H), 7.76 (m, 1H), 7.70 (m, 1H), 7.35 (ddd, J = 8.8, 6.6, 1.0 Hz, 1H), 7.14 (ddd, J = 8.5, 6.6, 0.7 Hz, 1H), 3.11 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 150.43, 144.23, 139.27, 129.18, 127.87, 123.36, 123.18, 120.99, 120.57, 120.54, 118.11, 44.62; MS (HR-ESI) for C₁₄H₁₂N₂O₂S [M + H]⁺, calcd: m/z 273.0692, found: m/z 273.0659.
2,3-Diphenyl-2H-indazole (16). White solid (77% yield); mp: 107.4–107.9 °C (lit [27 (link)]: 102–103 °C); ¹H-NMR (600 MHz, CDCl₃) δ 7.82–7.79 (m, 1H), 7.73–7.70 (m, 1H), 7.45–7.42 (m, 2H), 7.41–7.34 (m, 9H), 7.14 (ddd, J = 8.4, 6.6, 0.8 Hz, 1H); ¹³C-NMR (151 MHz, CDCl₃) δ 148.99, 140.24, 135.41, 129.91, 129.69, 128.97, 128.76, 128.30, 128.25, 126.98, 126.02, 122.50, 121.74, 120.52, 117.76.
2-(4-Chlorophenyl)-3-phenyl-2H-indazole (17). White solid (45% yield); m.p.: 124.4–125.0 °C (lit [43 (link)]: 126 °C); ¹H-NMR (600 MHz, CDCl₃) δ 7.78 (dt, J = 8.8, 0.9 Hz, 1H), 7.68–7.69 (dt, J = 8.5, 0.9 Hz, 1H), 7.45–7.32 (m, 10H), 7.14 (ddd, J = 8.4, 6.6, 0.8 Hz, 1H); ¹³C-NMR (151 MHz, CDCl₃) δ 149.12, 138.75, 135.47, 134.09, 129.67, 129.63, 129.18, 128.94, 128.55, 127.26, 127.10, 122.73, 121.86, 120.49, 117.72; MS (HR-ESI) for C₁₉H₁₃ClN₂ [M + H]⁺, calcd: m/z 305.0840, found: m/z 305.0736.
Methyl 4-(3-phenyl-2H-indazol-2-yl) benzoate (18). Pale yellow solid (40% yield); m.p.: 152.4–154.9 °C; ¹H-NMR (600 MHz, CDCl₃) δ 8.07–8.04 (m, 2H), 7.80 (dt, J = 8.8, 0.8 Hz, 1H), 7.69 (dt, J = 8.6, 1.0 Hz, 1H), 7.55–7.52 (m, 2H), 7.44–7.34 (m, 6H), 7.15 (ddd, J = 8.5, 6.6, 0.8 Hz, 1H), 3.93 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 166.21, 149.34, 143.76, 135.69, 130.42, 129.70, 129.62, 128.98, 128.66, 127.46, 125.69, 122.89, 122.08, 120.53, 117.81, 52.33; MS (HR-ESI) for C₂₁H₁₆N₂O₂ [M + H]⁺, calcd: m/z 329.1285, found: m/z 329.1103.
2-(4-(Methylthio) phenyl)-3-phenyl-2H-indazole (19). Pale yellow solid (71% yield) m.p.: 87.7–89.0 °C; ¹H-NMR (600 MHz, CDCl₃) δ 7.79 (dt, J = 8.9, 1.0 Hz, 1H), 7.70 (dt, J = 8.6, 1.0 Hz, 1H), 7.43–7.34 (m, 8H), 7.24–7.21 (m, 2H), 7.13 (ddd, J = 8.4, 6.6, 0.8 Hz, 1H), 2.49 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 148.97, 139.16, 137.23, 135.26, 129.88, 129.68, 128.83, 128.35, 127.00, 126.40, 126.19, 122.50, 121.78, 120.46, 117.68, 15.58; MS (HR-ESI) for C₂₀H₁₆N₂S [M + H]⁺, calcd: m/z 317.1107, found: m/z 317.1108.
4-(3-Phenyl-2H-indazol-2-yl) benzoic acid (20). White solid (70% yield); m.p.: 129.2–130.1 °C; ¹H-NMR (600 MHz, DMSO-d₆) δ 8.04–7.99 (m, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.59–7.55 (m, 2H), 7.51–7.37 (m, 6H), 7.18 (dd, J = 8.4, 6.6 Hz, 1H); ¹³C-NMR (151 MHz, DMSO-d₆) δ 166.41, 148.44, 143.00, 135.18, 130.45, 130.07, 129.44, 128.95, 128.87, 128.63, 127.18, 125.91, 122.73, 121.30, 120.32, 117.41; MS (HR-ESI) for C₂₀H₁₄N₂O₂ [M + H]⁺, calcd: m/z 315.1128, found: m/z 315.1142.
2-(4-(Methylsulfonyl) phenyl)-3-phenyl-2H-indazole (21). Pale yellow solid (77% yield), m.p.: 101.8–102.7 °C; ¹H-NMR (600 MHz, CDCl₃) δ 7.98–7.94 (m, 2H), 7.78 (dt, J = 8.9, 0.8 Hz, 1H), 7.70–7.66 (m, 3H), 7.48–7.42 (m, 3H), 7.39 (ddd, J = 8.8, 6.5, 1.0 Hz, 1H), 7.38–7.35 (m, 2H), 7.16 (ddd, J = 8.4, 6.5, 0.7 Hz, 1H), 3.08 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 149.58, 144.52, 139.70, 135.94, 129.70, 129.28, 129.23, 129.00, 128.41, 127.85, 126.45, 123.23, 122.29, 120.58, 117.81, 44.52; MS (HR-ESI) for C₂₀H₁₆N₂O₂S [M + H]⁺, calcd: m/z 349.1005, found: m/z 349.1005.
3-(4-Chlorophenyl)-2-phenyl-2H-indazole (22). White solid (67% yield); m.p.: 141.1–142.8 °C (lit [27 (link)]: 134–135 °C); the spectroscopic data matched previously reported data [27 (link),44 (link)]: ¹H-NMR (600 MHz, CDCl₃) δ 7.80 (dt, J = 8.8, 0.8 Hz, 1H), 7.67 (dt, J = 8.6, 1.0 Hz, 1H), 7.44–7.35 (m, 8H), 7.30–7.27 (m, 2H), 7.16 (ddd, J = 8.4, 6.5, 0.7 Hz, 1H); ¹³C-NMR (151 MHz, CDCl₃) δ 149.00, 139.98, 134.45, 134.08, 130.84, 129.14, 129.12, 128.48, 128.38, 127.08, 126.01, 122.86, 121.71, 120.11, 117.91.
Methyl 4-(2-phenyl-2H-indazol-3-yl) benzoate (23). Pale yellow solid (76% yield): m.p.: 164.5–166.3 °C; the spectroscopic data matched previously reported data [45 (link)]: ¹H-NMR (600 MHz, CDCl₃) δ 8.08–8.04 (m, 2H), 7.84–7.80 (m, 1H), 7.72 (dt, J = 8.5, 0.9 Hz, 1H), 7.45–7.37 (m, 8H), 7.19 (ddd, J = 8.5, 6.5, 0.6 Hz, 1H), 3.93 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 166.55, 149.08, 139.99, 134.37, 134.13, 129.97, 129.66, 129.49, 129.18, 128.59, 127.14, 126.04, 123.18, 121.90, 120.09, 118.02, 52.29.
3-(4-(Methylthio) phenyl)-2-phenyl-2H-indazole (24). White solid, (36% yield); m.p.: 119.3–121.4 °C; the spectroscopic data matched previously reported data [45 (link)]: ¹H-NMR (600 MHz, CDCl₃) δ 7.79 (dt, J = 8.8, 0.9 Hz, 1H), 7.70 (dt, J = 8.5, 1.0 Hz, 1H), 7.46–7.43 (m, 2H), 7.42–7.34 (m, 4H), 7.29–7.23 (m, 4H), 7.14 (ddd, J = 8.5, 6.6, 0.8 Hz, 1H), 2.50 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 149.01, 140.22, 139.32, 134.94, 129.90, 129.06, 128.29, 126.99, 126.27, 126.16, 126.02, 122.50, 121.66, 120.43, 117.80, 15.26.
4-(2-Phenyl-2H-indazol-3-yl) benzoic acid (25). White solid (87% yield); mp: 296.2–298.2 °C; ¹H-NMR (600 MHz, DMSO-d₆) δ 7.94–7.90 (m, 2H), 7.75 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.49–7.42 (m, 5H), 7.38 (ddd, J = 8.7, 6.6, 0.9 Hz, 1H), 7.30–7.26 (m, 2H), 7.16 (ddd, J = 8.4, 6.6, 0.6 Hz, 1H); ¹³C-NMR (151 MHz, DMSO-d₆) δ 169.13, 148.11, 140.15, 139.79, 135.10, 129.32, 129.17, 128.98, 128.37, 128.26, 126.77, 125.88, 122.34, 121.02, 120.38, 117.29; MS (HR-ESI) for C₂₀H₁₄N₂O₂ [M + H]⁺, calcd: m/z 315.1128, found: m/z 315.1139.
3-(4-(Methylsulfonyl) phenyl)-2-phenyl-2H-indazole (26). Pale yellow solid (60% yield), mp: 206.9–208.8 °C; ¹H-NMR (600 MHz, CDCl₃) δ 7.98–7.94 (m, 2H), 7.84 (dt, J = 8.7, 0.9 Hz, 1H), 7.71 (dt, J = 8.5, 1.0 Hz, 1H), 7.57–7.54 (m, 2H), 7.45–7.39 (m, 6H), 7.22 (ddd, J = 8.5, 6.6, 0.9 Hz, 1H), 3.11 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ 149.10, 139.83, 139.71, 135.46, 132.95, 130.24, 129.40, 128.90, 127.86, 127.27, 126.06, 123.70, 122.03, 119.64, 118.22, 44.42; MS (HR-ESI) for C₂₀H₁₆N₂O₂S [M + H]⁺, calcd: m/z 349.1005, found: m/z 349.1005.

Pérez-Villanueva J., Yépez-Mulia L., González-Sánchez I., Palacios-Espinosa J.F., Soria-Arteche O., Sainz-Espuñes T.D., Cerbón M.A., Rodríguez-Villar K., Rodríguez-Vicente A.K., Cortés-Gines M., Custodio-Galván Z, & Estrada-Castro D.B. (2017). Synthesis and Biological Evaluation of 2H-Indazole Derivatives: Towards Antimicrobial and Anti-Inflammatory Dual Agents. Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry, 22(11), 1864.

Publication 2017

Palladium-Catalyzed Aryl Amidation Reaction

Cited 2 times

A 8-dram vial equipped with a magnetic stir-bar was charged with amide (0.5 mmol), 1-fluoro-4-iodobenzene (278 mg, 1.25 mmol), Pd(OAc)₂ (5.7 mg, 5 mol %), AgOCOCF₃ (133 mg, 1.2 equiv), NaOTf (86 mg, 1.0 equiv), and hexafluoroisopropanol (3.5 mL). The mixture was stirred at room temperature for 5 min, covered with aluminum foil, and then heated at 90 °C for 24 h. After completion, the reaction was cooled to room temperature and diluted with a CH₂ Cl₂/MeOH mixture (5 mL, 9:1). The suspension was filtered through a pad of Celite, and the solid phase was washed with dichloromethane (2 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel using an appropriate eluent. After purification, the product was dried under reduced pressure.

Le K.K., Nguyen H, & Daugulis O. (2019). 1-Aminopyridinium Ylides as Monodentate Directing Groups for sp3 C—H Bond Functionalization. Journal of the American Chemical Society, 141(37), 14728-14735.

Publication 2019

Aluminum Amides Celite Chromatography hexafluoroisopropanol iodobenzene Methylene Chloride Pressure Silica Gel

Tetrachloroethene Behavior in Porous Media

Cited 2 times

Tetrachloroethene was used as the model organic liquid for this study. To enhance image contrast, tetrachloroethene was doped with iodobenzene (8% by volume). Measurements conducted prior to the study indicated minimal impact of the dopant on tetrachloroethene-water interfacial tension and measured interfacial areas (11 ). All chemicals were reagent grade (Sigma-Aldrich Co.).
A total of ten porous media were used in the study: three soils, five natural, commercially available sands (Accusand and Granusil, Unimin Co.), and two glass-bead media. Relevant physical properties of the porous media are provided in Table 1. The median grain sizes (d₅₀) and the grain-size distributions, as characterized by the uniformity coefficient (U), vary considerably. The organic-carbon contents of the media also vary, from zero for the glass beads, to low values for the sands (~0.02%), to moderate values for the soils (0.08, 0.09, and 0.38% for Hayhook, Vinton, and Eustis, respectively). The porous media are considered to be completely to predominantly water-wetting.

Brusseau M.L., Narter M., Schnaar G, & Marble J. (2009). Measurement and Estimation of Organic-Liquid/Water Interfacial Areas for Several Natural Porous Media. Environmental science & technology, 43(10), 3619-3625.

Publication 2009

Carbon Cereals Interfacial Force iodobenzene Physical Processes Tetrachloroethylene

T4 lysozyme L99A Ligand Binding Analysis

Cited 2 times

A crystallographic structure of T4 lysozyme L99A bound to hexafluorobenzene was downloaded from the Protein Data Bank (PDB ID 3DMZ). Hydrogen atoms were added using pdb2pqr.^{27 (link)} The protein was prepared with AMBER^{28 (link)} ff14 parameters using AmberTools 14.
We prepared a total of 141 ligands whose activity has been measured, primarily by the Shoichet group.^{29 (link)–35 (link)} Of these, 70 are active and 71 inactive. With the exception of iodobenzene, which was determined to be active by isothermal titration calorimetry,^{36 (link)} molecules were considered active if they increase the thermal denaturation temperature of T4 lysozyme. Excluding ligands that appear in multiple references, the library includes 91 ligands from Morton et al.^{29 (link)}, 2 from Morton and Matthews^{30 (link)}, 6 from Su et al.^{31 (link)}, 6 from Wei et al.^{32 (link)}, 22 from Graves et al.^{33 (link)}, 4 from Mobley et al.^{34 (link)}, 9 from Graves et al.^{35 (link)}, and 1 from Liu et al.^{36 (link)}. For the names and SMILES strings³⁷ of all 141 ligands, see Table S1 in the SI. Ligand protonation states were assigned using OpenEye QUACPAC.³⁸ Three-dimensional models of the ligands were built using BALLOON.^{39 (link)} The models were parameterized with the generalized AMBER force field^{40 (link)} from AmberTools 14 using Bondi radii⁴¹ and AM1BCC partial charges^{42 ,43 (link)} using antechamber^{44 (link)} in UCSF Chimera.^{45 (link)}For our binding free energy calculations (both with multiple rigid structures and with a flexible protein) we defined the T4 lysozyme L99A binding site as a sphere that contains the ligand center of mass. The site was measured based on the following crystal structures, given by PDB ID (chain): 188I (A), 187I (A), 186I (A), 185I (A), 184I (A), 183I (A), 182I (A), 3HH6 (A), 3HH5 (A), 3DN6 (A), 3DN3 (A), 3DN2 (A), 3DN1 (A), 3DN0 (A), 2RB2 (X), 2RB1 (X), 2RB0 (X), 2RAZ (X), 2RAY (X), 2OTZ (X), 2OTY (X), 1NHB (A). Prody^{46 (link)} was used to align the structures to minimize the α-carbon root mean square deviation between each chain and the reference chain, 3DMZ (A). The center of mass was calculated for each ligand. The site center was defined as the mid-point of the range. The site radius, 5.0 Å, was determined by rounding the maximum distance from the site center to a ligand center of mass up to the nearest Ångstrom.

Xie B., Nguyen T.H, & Minh D.D. (2017). Absolute binding free energies between T4 lysozyme and 141 small molecules: calculations based on multiple rigid receptor configurations. Journal of chemical theory and computation, 13(6), 2930-2944.

Publication 2017

Synthesis and Characterization of THC Derivatives

Cited 2 times

Supporting Information (see footnote on the first page of this article): copies of 1D and 2D NMR spectra and extensive NMR studies are provided in Supporting Information.
1. General information: NMR spectra were recorded on a Bruker Avance III 400 MHz or a Bruker 500 MHz spectrometer and the compounds were assigned using ¹H NMR, ¹³C NMR, ¹¹B NMR, ¹⁹F NMR, COSY, HSQCED and HMBC spectra. Chemical shifts were reported in parts per million (ppm.) relative to reference (CDCl₃: ¹H: 7.26 ppm. and ¹³C 77.16 ppm; CD₃OD: ¹H: 3.31 ppm. and ¹³C 49.00 ppm; (CD₃)₂SO: ¹H: 2.50 ppm. and ¹³C 39.52 ppm.) NMR data are presented in the following way: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, dd = doublet of doublets, ddd = doublet of doublet of doublets, dtd = doublet of triplet of doublets h = heptet, m = multiplet and/or multiple resonances) and coupling constants J in Hz. Reactions were monitored using TLC F₂₅₄ (Merck KGaA) using UV absorption detection (254 nm) and by spraying them with cerium ammonium molybdate stain (Hannesian's stain) followed by charring at ca 300 °C. Mass spectra were recorded on a JEOL AccuTOF CS JMS‐T100CS (ESI) mass spectrometer. Melting points (m.p.) were determined using a Büchi Melting Point B‐545. Automatic flash column chromatography was executed on a Biotage Isolera Spektra One using SNAP or Silicycle cartridges (Biotage, 30–100 μm, 60Å) 4–50 g. Reactions under protective atmosphere were performed under positive Ar./N₂ flow in flame‐dried flasks. Atom‐numbering of the THC compounds is derived from an earlier reported NMR assignment in literature.192. General proceduresGeneral procedure I for potassium trifluoroborate salt synthesis from boronic acid (22–25):21 Boronic acid (1 equiv.) was dissolved in acetonitrile (0.1M), KF (4 equiv.) in water (1M) was added at r.t. and the reaction was left stirring for 5 min. 2,3‐Dihydroxysuccinic acid (2.05 equiv.) dissolved in THF (0.3M) (heat was required) was added dropwise to the vigorously stirred biphasic mixture and a white precipitate formed immediately. The reaction was diluted with acetonitrile and filtered. The flask and filter were rinsed with acetonitrile and the filtrate was concentrated in vacuo. The residue was dried under high vacuum affording the trifluoroborate salt as pure product (22–25).
General procedure II for sp²‐sp² Suzuki Miyaura coupling (10a–c, 11a–c):10 Cs₂CO₃ (3 equiv.), PdCl₂(dppf) (5 mol‐%) and the trifluoroborate salt (1.6 equiv.) were added in a flask which was evacuated and backfilled thrice with Ar. Bromo‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (6)/(7) (1 equiv.) was added in dry MeOH (0.1M) and the reaction was stirred at 65 °C. After 16 h the mixture was cooled to r.t. and diluted with Et₂O. The mixture was filtered through Celite, dried with MgSO₄, concentrated in vacuo and purified through silica gel column chromatography or preparative HPLC to afford the product (10a–c, 11a–c).
General procedure III for sp²‐sp³ Suzuki Miyaura coupling (12a–12b, 13a–13b):20 Bromo‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (6)/(7) (1 equiv.) was dissolved in toluene (0.2M) and Pd(OAc)₂ (10 mol‐%), RuPhos (20 mol‐%), alkyl trifluoroborate salt (1.5 equiv.) and aqueous sodium hydroxide (3M, 3 equiv.) were added. The reaction mixture was stirred at 120 °C and followed with TLC until full conversion (± 64 h) after which it was diluted with aqueous hydrochloric acid (1M) and DCM. The mixture was extracted with DCM and the combined organic layers were filtered through Celite, dried with MgSO₄, concentrated in vacuo and purified through silica gel column chromatography or preparative HPLC to afford the product (12a, 12b, 13a, 13b).
3. Experimental details and analysis5‐Propylbenzene‐1,3‐diol (1c):23 1‐Bromo‐3,5‐dimethoxybenzene (400 mg, 1.84 mmol) was dissolved in dry toluene. n‐Propylboronic acid (21) (243 mg, 2.76 mmol), PdCl₂(dppf) (5 mol‐%) and potassium phosphate (1.17 g, 5.53 mmol) were added and the flask was evacuated and backfilled with argon thrice. The reaction was stirred at 110 °C for 16 h. The mixture was cooled to r.t. and diluted with Et₂O after which it was filtered through Celite, dried with MgSO₄ and concentrated in vacuo, the crude 1,3‐dimethoxy‐5‐propylbenzene was directly used in the next step. The product was dissolved in dry DCM (20 mL) and kept under protective atmosphere. The solution was cooled to 0 °C and boron tribromide (455 µL, 4.79 mmol) was carefully added dropwise. The reaction was left stirring for 16 h and warmed‐up to r.t. The reaction was cooled to 0 °C before saturated aqueous NaHCO₃ (15 mL) was added. After no more gas evolution was observed NaOH (3M, 5 mL) was added. The mixture was extracted with DCM (2 × 50 mL) and EtOAc (2 × 50 mL) and the resulting aqueous phase was acidified with HCl (1M) until pH 2. The aqueous layer was washed again with DCM (2 × 50 mL) and EtOAc (2 × 50 mL). The combined organic layers were dried with MgSO₄, concentrated in vacuo and purified by silica gel column chromatography (0→30 % EtOAc in n‐heptane) to afford 14 (168 mg, 60 % over two steps) as a green oil. TLC (EtOAc/n‐heptane, 3:7 v/v): R_f = 0.28. ¹H‐NMR (400 MHz, CDCl₃) δ 6.25 (d, J = 2.2 Hz, 2H), 6.18 (t, J = 2.3 Hz, 1H), 4.93 (s, 2H), 2.50–2.41 (m, 2H), 1.66–1.54 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 156.66, 146.06, 108.28, 100.34, 38.02, 24.26, 13.93. HRMS (m/z): [M + H]⁺ calcd. for C₉H₁₂O₂: 152.08373, found 152.08270.
4′‐Hydroxyl‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (3): Benzene‐1,3,5‐triol (1b, 9.94 g, 78.8 mmol) was dissolved in dry Et₂O (200 mL) and stirred vigorously. (S)‐cis‐verbenol (4.00 g, 26.3 mmol) was added and the reaction was stirred at r.t. Trifluoromethanesulfonic acid (581 µL, 6.60 mmol) was added dropwise at –10 °C and the reaction was left stirring for 4 h. To stop the reaction saturated aqueous NH₄Cl (100 mL) was added and the mixture was extracted with Et₂O (2 × 100 mL). The combined organic layers were dried with MgSO₄, concentrated in vacuo and purified by silica gel column chromatography (0→50 % EtOAc in n‐heptane) to give 3 (3.61 g, 53 %) as a yellow solidified oil. TLC (EtOAc/n‐heptane, 1:1 v/v): R_f = 0.60. ¹H NMR (400 MHz, CDCl₃) δ 5.94–5.93 (m, 1H), 5.86 (d, J = 2.4 Hz, 1H), 5.41 (d, J = 4.8 Hz, 1H), 5.17 (bs, 2H), 3.14 (dd, J = 15.3, 4.0 Hz, 1H), 2.64 (td, J = 10.9, 4.7 Hz, 1H), 2.18–2.09 (m, 1H), 1.86–1.74 (m, 3H), 1.69 (s, 3H), 1.36 (s, 3H), 1.09 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 156.04, 155.82, 154.98, 134.85, 119.41, 106.45, 97.30, 96.05, 77.36, 45.01, 36.33, 31.45, 27.98, 27.60, 23.62, 18.62. HRMS (m/z): [M + H]⁺ calcd. for C₁₆H₂₀O₃: 261.14907, found 261.14737.
4′‐Triflate‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (4): 4′‐Hydroxyl‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (3, 100 mg, 384 µmol) was dissolved in dry DCM (4 mL) and stirred at 0 °C before 2,6‐dimethylpyridine (36 µL, 311 µmol) was added. Trifluoromethanesulfonic anhydride (52 µL, 311 µmol) was added over a course of 10 min. After 14 h the reaction was diluted with DCM (10 mL) and washed with water (4 mL), HCl (1M, 4 mL), saturated aqueous NaHCO₃ (3 mL) and brine (3 mL). The organic layer was dried with MgSO₄, concentrated in vacuo and purified by silica gel column chromatography (0→25 % EtOAc in n‐heptane) to afford 4 (58.9 mg, 56 %, based on recovery of SM) as a yellow oil. TLC (EtOAc/n‐heptane, 1:1 v/v): R_f = 0.79. ¹H NMR (400 MHz, CDCl₃) δ 6.37 (d, J = 2.5 Hz, 1H), 6.23 (d, J = 2.5 Hz, 1H), 5.47–5.41 (m, 1H), 5.21 (s, 1H), 3.20–3.10 (m, 1H), 2.70 (td, J = 11.0, 4.8 Hz, 1H), 2.20–2.10 (m, 1H), 1.89–1.76 (m, 3H), 1.71 (s, 3H), 1.39 (s, 3H), 1.10 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 156.15, 155.84, 148.26, 134.54, 119.43, 113.81, 103.63, 100.81, 78.02, 44.64, 35.68, 31.67, 27.89, 27.49, 23.56, 18.64. ¹⁹F NMR (377 MHz, CDCl₃) δ –72.93. HRMS (m/z): [M + H]⁺ calcd. for C₁₇H₁₉F₃O₅S: 393.09835, found 393.10073.
5‐Bromobenzene‐1,3‐diol (5):24 1‐Bromo‐3,5‐dimethoxybenzene (5.00 g, 23.0 mmol) was dissolved in dry DCM (100 mL) and kept under protective atmosphere. The solution was cooled to 0 °C and boron tribromide (7.62 mL, 80.62 mmol) was added carefully dropwise. The reaction was left stirring for 16 h and warmed to r.t. The reaction was cooled to 0 °C before saturated aqueous NaHCO₃ (70 mL) was added. After no more gas evolution was observed NaOH (1M, 5 mL) was added. The mixture was extracted with DCM (2 × 100 mL) and EtOAc (2 × 100 mL) and the resulting aqueous phase was acidified with HCl (1M) until pH 2. The aqueous layer was extracted again with DCM (3 × 100 mL) and EtOAc (3 × 100 mL). The combined organic layers were dried with MgSO₄, concentrated in vacuo and purified through silica gel column chromatography (0→30 % EtOAc in n‐heptane) to afford 5 (4.35 g, 100 %) as a brown solid. TLC (EtOAc/n‐heptane, 3:7 v/v): R_f = 0.20. ¹H‐NMR (400 MHz, CDCl₃) δ 6.59 (d, J = 2.2 Hz, 2H), 6.28 (t, J = 2.2 Hz, 1H), 5.15 (s, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 157.76, 122.97, 111.56, 102.21. m.p. 86.9 °C.
2′‐Bromo‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (6): 5‐Bromobenzene‐1,3‐diol (5, 1.35 g, 7.14 mmol) was dissolved in dry DCM (100 mL) and stirred vigorously. (S)‐cis‐verbenol (1.09 g, 7.14 mmol) was added and the reaction was stirred at r.t. Trifluoromethanesulfonic acid (284 µL, 3.21 mmol) was added dropwise at 0 °C and the reaction was left stirring for 20 h. To stop the reaction saturated aqueous NaHCO₃ (50 mL) was added and the mixture was extracted with DCM (2 × 100 mL). The combined organic layers were dried with MgSO₄, concentrated in vacuo and purified through silica gel column chromatography (0→4 % EtOAc in n‐heptane) to afford 6 (1.32 g, 57 %) as a yellow oil and 7 as a minor product (199 mg, 9 %). TLC (EtOAc/n‐heptane, 1:9 v/v): R_f = 0.23. ¹H NMR (400 MHz, CDCl₃) δ 6.68 (d, J = 2.6 Hz, 1H), 6.28 (d, J = 2.6 Hz, 1H), 5.46–5.41 (m, 1H), 5.05 (s, 1H), 3.41 (dd, J = 16.4, 3.4 Hz, 1H), 2.64 (td, J = 10.5, 4.3 Hz, 1H), 2.18–2.11 (m, 1H), 1.86 (m, 3H), 1.71 (s, 3H), 1.37 (s, 3H), 1.07 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 155.81, 155.01, 134.84, 123.71, 119.64, 118.78, 113.64, 104.40, 77.51, 46.55, 36.80, 35.15, 28.41, 27.41, 23.56, 18.29. HRMS (m/z): [M + H]⁺ calcd. for C₁₆H₁₉BrO₂: 323.06467, found 323.06511. 4′‐Bromo‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (7): TLC (EtOAc/n‐heptane, 1:9 v/v): R_f = 0.35. ¹H NMR (400 MHz, CDCl₃) δ 6.61 (d, J = 1.9 Hz, 1H), 6.43 (d, J = 1.9 Hz, 1H), 5.46–5.40 (m, 1H), 5.24 (s, 1H), 3.16 (dd, J = 15.7, 4.4 Hz, 1H), 2.66 (td, J = 11.1, 4.8 Hz, 1H), 2.19–2.09 (m, 1H), 1.84–1.74 (m, 3H), 1.70 (s, 3H), 1.38 (s, 3H), 1.09 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 155.94, 155.79, 134.67, 119.77, 119.43, 113.82, 112.74, 110.84, 77.62, 44.81, 35.81, 31.70, 27.93, 27.53, 23.58, 18.58. HRMS (m/z): [M + H]⁺ calcd. for C₁₆H₁₉BrO₂: 323.06467, found 323.06620.
5‐Chlorobenzene1,3‐diol (8): 1‐Chloro‐3,5‐dimethoxybenzene (1.01 g, 5.85 mmol) was dissolved in ACN (12 mL) and kept under protective atmosphere. Iodotrimethylsilane (4.78 mL, 35.11 mmol) was added and the solution was heated to 70 °C. The reaction was left stirring overnight at reflux. The mixture was cooled to r.t. and concentrated in vacuo. The residue was dissolved in 1M aqueous HCl (10 mL) and DCM (15 mL), after which the aqueous layer was extracted with DCM (2 × 15 mL). The combined organic layers were dried with Na₂SO₄, concentrated in vacuo and purified using silica gel column chromatography (0→20 % EtOAc in n‐heptane) to afford 8 (222 mg, 26 %) as a yellow solidified oil. TLC (EtOAc/n‐heptane, 1:4 v/v): R_f = 0.20 ¹H‐NMR (500 MHz, CDCl₃) δ 6.44 (d, J = 2.2 Hz, 2H), 6.24 (s, 1H), 5.01 (s, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 157.51, 135.23, 108.46, 101.52. m.p. 58.8 °C.
5‐Iodobenzene‐1,3‐diol (9): 3,5‐Dimethoxyiodobenzene (15, 0.867 g, 3.28 mmol) was dissolved in ACN (7 mL) and kept under protective atmosphere. Iodotrimethylsilane (2.80 mL, 19.7 mmol) was added and the solution was heated to 70 °C. The reaction was left stirring overnight at reflux. After cooling to r.t. the reaction mixture was concentrated in vacuo and the residue was dissolved in 1 M aqueous HCl (10 mL) and DCM (15 mL). The aqueous layer was extracted with DCM (2 × 15 mL), the combined organic layers were dried with Na₂SO₄, concentrated in vacuo and purified with silica gel column chromatography (0→20 % EtOAc in n‐heptane) to afford 9 (198 mg, 26 %, based on recovery of SM) as a brown solid. TLC (EtOAc/n‐heptane, 1:1 v/v): R_f = 0.50; ¹H NMR (400 MHz, CDCl₃) δ 6.79 (d, J = 2.2 Hz, 2H), 6.31 (t, J = 2.2 Hz, 1H), 5.22 (s, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 157.42, 117.59, 103.01, 93.80. m.p. 74.1 °C.
2′‐Styrene(–)‐trans‐Δ⁸‐Tetrahydrocannabinol (10a): Synthesized according to general procedure II from 2′‐bromo‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (6, 88.3 mg, 258 µmol) and potassium (E)‐styryl trifluoroborate (86.6 mg, 412 µmol) which afforded (10a, 69.2 mg, 78 %) as a colorless oil. TLC (EtOAc/n‐heptane, 1:9 v/v): R_f = 0.11. ¹H NMR (500 MHz, CDCl₃) δ 7.51–7.47 (m, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.29–7.26 (m, 1H), 7.19 (d, J = 16.0 Hz, 1H), 6.93 (d, J = 16.0 Hz, 1H), 6.66 (d, J = 2.6 Hz, 1H), 6.28 (d, J = 2.6 Hz, 1H), 5.45 (m, 1H), 4.79 (bs, 1H), 2.83 (td, J = 10.8, 4.5 Hz, 1H), 2.71–2.64 (m, 1H), 2.23–2.15 (m, 1H), 1.89–1.80 (m, 2H), 1.62 (s, 3H), 1.40 (s, 3H), 1.14 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 155.14, 154.84, 138.54, 137.62, 134.88, 128.97, 128.90, 128.24, 127.77, 126.65, 119.99, 117.32, 106.33, 103.98, 76.73, 46.01, 39.69, 33.10, 28.42, 27.59, 23.74, 18.38. HRMS (m/z): [M + H]⁺ calcd. for C₂₄H₂₆O₂: 347.20110, found 347.20075.
2′‐Naphthalene(–)‐trans‐Δ⁸‐tetrahydrocannabinol (10b‐S_a and 10b‐R_a): Synthesized according to general procedure II from 2′‐bromo‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (6) (150 mg, 464 µmol) and potassium (1‐naphthalene) trifluoroborate (24, 174 mg, 743 µmol) and purified using preparative HPLC to afford (10b, 28.5 mg, 17 %) as a colorless oil. The product was obtained as an inseparable mixture of two atropisomers 10b‐R_a and 10b‐S_a in ratios of 0.64:1.00, respectively. TLC (EtOAc/n‐heptane, 1:9 v/v): R_f = 0.15. 10b‐R_a:¹H NMR (500 MHz, [D₆]DMSO) δ 7.94 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.56 (dd, i = 6.8, 1.6 Hz, 1H), 7.56–7.52 (m, 1H), 7.45–7.43 (m, 1H), 7.41–7.39 (m, 1H), 7.32 (dd, J = 7.1, 1.2 Hz, 1H), 6.23 (d, J = 2.6 Hz, 1H), 6.16 (d, J = 2.6 Hz, 1H), 5.18 (d, J = 2.7 Hz, 1H), 2.69 (dt, J = 11.2, 5.6 Hz, 1H), 2.04 (m, 1H), 1.77–1.67 (m, 1H), 1.58 (dd, J = 11.6, 4.4 Hz, 1H), 1.33 (s, 3H), 1.19 (s, 3H), 1.17 (s, 1H), 0.93 (d, J = 12.6 Hz, 1H), 0.92–0.86 (bs, 3H). ¹³C NMR (126 MHz, [D₆]DMSO) δ 156.09, 155.36, 140.94, 140.22, 133.93, 133.30, 132.06, 128.49, 127.63, 126.62, 126.36, 126.29, 125.92, 125.85, 119.94, 115.78, 111.97, 103.51, 76.41, 45.15, 36.65, 32.61, 27.75, 27.56, 23.14, 18.86. 10b‐S_a: ¹H NMR (500 MHz, [D₆]DMSO) δ 8.00–7.98 (m, 2H), 7.60 (dd, J = 8.3, 7.0 Hz, 1H), 7.51 (d, J = 1.5 Hz, 1H), 7.45 (m, 2H), 7.41–7.39 (m, 1H), 6.27 (d, J = 2.6 Hz, 1H), 6.25 (d, J = 2.6 Hz, 1H), 5.08 (d, J = 4.3 Hz, 1H), 2.16 (td, J = 10.7, 4.9 Hz, 1H), 1.97–1.93 (m, 1H), 1.55–1.53 (m, 2H), 1.32 (s, 3H), 1.31–1.29 (m, 1H), 1.18 (s, 3H), 1.06 (s, 3H), 0.97–0.90 (m, 1H). ¹³C NMR (126 MHz, [D₆]DMSO) δ 156.85, 154.69, 141.46, 141.14, 133.30, 133.26, 130.55, 128.83, 127.89, 126.93, 126.67, 126.45, 126.09, 125.41, 119.68, 115.84, 111.66, 103.65, 76.35, 45.01, 37.58, 33.44, 27.75, 27.56, 23.31, 18.90. HRMS (m/z): [M + H]⁺ calcd. for C₂₆H₂₆O₂: 371.20110, found 371.20214.
2′‐(4‐Methoxybenzene)‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (10c): Synthesized according to general procedure I from 2′‐bromo‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (6, 98.0 mg, 68 µmol) and potassium (4‐methoxyphenyl) trifluoroborate (25, 104 mg, 485 µmol) to afford 10c (24.0 mg, 23 %) as a colorless oil. TLC (EtOAc/n‐heptane, 1:9 v/v): R_f = 0.07. ¹H NMR (400 MHz, CDCl₃) δ 7.25 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.29 (d, J = 0.6 Hz), 5.28 (m, 1H), 4.72 (s, 1H), 3.85 (s, 3H), 2.86 (td, J = 10.9, 4.8 Hz, 1H), 2.13–2.06 (m, 1H), 1.76–1.69 (m, 2H), 1.58–1.52 (m, 1H), 1.45–1.40 (m, 1H), 1.38 (s, 3H), 1.35–1.33 (m, 3H), 1.22 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 158.70, 155.14, 154.35, 143.56, 135.50, 134.66, 129.10, 118.93, 116.34, 113.89, 110.62, 102.94, 76.41, 55.37, 45.11, 36.70, 32.68, 27.99, 27.50, 23.29, 18.34. HRMS (m/z): [M + H]⁺ calcd. for C₂₃H₂₆O₃: 351.19602, found 351.19571.
4′‐Styrene‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (11a): Synthesized according to general procedure II from 4′‐bromo‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (7, 20.0 mg, 62 µmol) and potassium (E)‐styryl trifluoroborate (21.0 mg, 99 µmol) to afford 11a (4.8 mg, 27 %) as a colorless oil. TLC (EtOAc/n‐heptane, 1:9 v/v): R_f = 0.27. ¹H NMR (500 MHz, CDCl₃) δ 7.49–7.45 (m, 2H), 7.34 (t, J = 7.7 Hz, 2H), 7.24 (m 1H), 7.02 (d, J = 16.3 Hz, 1H), 6.92 (d, J = 16.3 Hz, 1H), 6.62 (d, J = 1.6 Hz, 1H), 6.44 (d, J = 1.7 Hz, 1H3′), 5.45–5.43 (m, 1H), 4.81 (s, 1H), 3.21 (dd, J = 15.9, 4.5 Hz, 1H), 2.74 (td, J = 10.8, 4.7 Hz, 1H), 2.20–2.12 (m, 1H), 1.92–1.78 (m, 3H), 1.72 (s, 3H), 1.40 (s, 3H), 1.13 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 155.48, 155.31, 137.44, 137.04, 134.81, 128.80, 128.77, 128.21, 127.71, 126.64, 119.51, 113.30, 108.77, 105.63, 77.06, 44.99, 36.08, 31.98, 28.03, 27.71, 23.65, 18.68. HRMS (m/z): [M + H]⁺ calcd. for C₂₄H₂₆O₂: 347.20110, found 347.20105.
4′‐Naphthalene‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (11b): Synthesized according to general procedure II from 4′‐bromo‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (7, 25.0 mg, 77 µmol) and potassium (1‐naphthalene) trifluoroborate (24, 29.0 mg, 120 µmol) to afford 11b (17.1 mg, 60 %) as a colorless oil. TLC (EtOAc/n‐heptane, 1:9 v/v): R_f = 0.27. ¹H NMR (500 MHz, CDCl₃) δ 8.04 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.51–7.44 (m, 2H), 7.44–7.39 (m, 2H), 6.59 (d, J = 1.7 Hz, 1H), 6.41 (d, J = 1.7 Hz, 1H), 5.49–5.47 (m, 1H), 4.98 (s, 1H), 3.30 (dd, J = 17.2, 4.7 Hz, 1H), 2.83 (td, J = 10.8, 4.8 Hz, 1H), 2.24–2.16 (m, 1H), 2.01–1.84 (m, 3H), 1.74 (s, 3H), 1.42 (s, 3H), 1.19 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 155.15, 154.85, 140.27, 139.85, 134.92, 133.90, 131.60, 128.29, 127.65, 126.69, 126.42, 126.01, 125.83, 125.44, 119.52, 112.43, 112.33, 109.44, 77.08, 45.10, 36.13, 31.95, 28.10, 27.75, 23.67, 18.76. HRMS (m/z): [M + H]⁺ calcd. for C₂₆H₂₆O₂: 371.20110, found 371.20176.
4′‐(4‐Methoxybenzene)‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (11c): Synthesized according to general procedure II from 4′‐bromo‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (7, 100 mg, 309 µmol) and potassium (4‐methoxyphenyl) trifluoroborate (25, 106 mg, 495 µmol) to afford 11c (31.0 mg, 29 %) as a colorless oil. TLC (EtOAc/n‐heptane, 1:9 v/v): R_f = 0.17. ¹H NMR (500 MHz, CDCl₃) 7.47 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 1.7 Hz, 1H), 6.48 (d, J = 1.8 Hz, 1H), 5.45 (d, J = 5.4 Hz, 1H), 4.87 (s, 1H), 3.83 (s, 3H), 3.23 (dd, J = 16.4, 4.5 Hz, 1H), 2.76 (td, J = 10.8, 4.6 Hz, 1H), 2.21–2.09 (m, 1H), 1.89–1.80 (m, 3H), 1.72 (s, 3H), 1.41 (s, 3H), 1.14 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 158.89, 155.55, 155.39, 143.91, 135.73, 134.85, 127.91, 119.51, 114.20, 112.61, 108.76, 105.89, 77.06, 55.46, 45.03, 36.12, 31.81, 28.05, 27.73, 23.65, 18.72. HRMS (m/z): [M + H]⁺ calcd. for C₂₃H₂₆O₃: 351.19602, found 351.19740.
Ortho‐n‐pentyl‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (12a): Synthesized according to general procedure III from 2′‐bromo‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (6, 77.9 mg, 241 µmol) and potassium n‐pentylboron trifluoride (23, 64.4 mg, 362 µmol). Silica gel column chromatography (0→8 % EtOAc/n‐heptane) afforded 12a (38.8 mg, 51 %) as an inseparable mixture with 6. TLC (EtOAc/n‐heptane, 1:9 v/v): R_f = 0.23. ¹H NMR (500 MHz, CDCl₃) δ 6.29 (d, J = 2.7 Hz, 1H), 6.16 (d, J = 2.6 Hz, 1H), 5.47–5.44 (m, 1H), 4.88 (s, 1H), 2.71–2.62 (m, 1H), 2.60–2.55 (m, 3H), 2.21–2.10 (m, 1H), 1.87–1.81 (m, 3H), 1.70 (s, 3H), 1.67–1.57 (m, 2H), 1.36 (s, 3H), 1.35–1.23 (m, 4H), 1.06 (s, 3H), 0.94–0.86 (m, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 154.94, 154.55, 143.99, 134.64, 120.13, 117.21, 109.24, 102.19, 76.35, 46.63, 38.86, 33.53, 33.47, 32.07, 31.07, 28.49, 27.59, 23.61, 22.67, 18.25, 14.22. HRMS (m/z): [M + H]⁺ calcd. for C₂₁H₃₀O₂: 315.23240, found 315.23200.
2′‐Ortho‐n‐propyl‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (12b): Synthesized according to general procedure III from 2′‐bromo‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (6, 130 mg, 402 µmol) and potassium n‐propylboron trifluoride (22, 90.5 mg, 603 µmol). Silica gel column chromatography (0→8 % EtOAc/n‐heptane) afforded 12b (63.9 mg, 56 %) as an inseparable mixture with 6. TLC (Toluene): R_f = 0.05. ¹H NMR (500 MHz, CDCl₃) δ 6.29 (d, J = 2.8Hz, 1H), 6.16 (d, J = 2.7 Hz, 1H), 5.48–5.43 (m, 1H), 4.97–4.89 (m, 1H), 2.71–2.62 (m, 1H), 2.60 (m, 1H), 2.56 (t, J = 7.9 Hz, 2H), 2.18–2.10 (m, 1H), 1.88–1.79 (m, 3H), 1.70 (s, 3H), 1.65–1.59 (m, 2H), 1.36 (s, 3H), 1.06 (s, 3H), 0.96 (t, J = 7.3 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 154.94, 154.56, 143.78, 134.65, 120.15, 117.28, 109.22, 102.24, 76.35, 46.65, 38.88, 35.62, 33.48, 28.50, 27.59, 24.54, 23.64, 18.25, 14.29. HRMS (m/z): [M + H]⁺ calcd. for C₁₉H₂₆O₂: 287.20110, found 287.20130.
(–)‐trans‐Δ⁸‐tetrahydrocannabinol (13a):9 5‐Pentylbenzene‐1,3‐diol (1a, 1.18 g, 6.60 mmol) and (S)‐cis‐verbenol (1.00 g, 6.60 mmol) were stirred at r.t. in dry DCM (70 mL). Trifluoromethanesulfonic acid (145 µL, 1.64 mmol) was added dropwise at 0 °C and the reaction was left stirring for 2 h. To stop the reaction saturated aqueous NaHCO₃ (70 mL) was added and the mixture was extracted with DCM (2 × 70 mL). The combined organic layers were dried with MgSO₄, concentrated in vacuo and purified through silica gel column chromatography (0→4 % EtOAc/n‐heptane) to afford 1 (691 mg, 33 %) as a yellow oil. TLC (EtOAc/n‐heptane, 1:9 v/v): R_f = 0.38. ¹H NMR (400 MHz, CDCl₃) δ 6.29 (d, J = 1.5 Hz, 1H), 6.11 (d, J = 1.5 Hz, 1H), 5.44 (d, J = 4.8 Hz, 1H), 4.93 (s, 1H) 3.22 (dd, J = 15.8, 4.2 Hz, 1H), 2.71 (td, J = 10.8, 4.6 Hz, 1H), 2.44 (td, J = 7.4, 2.0 Hz, 2H), 2.20–2.11 (m, 1H), 1.91–1.76 (m, 3H), 1.71 (s, 3H), 1.62–1.53 (m, 2H), 1.39 (s, 3H), 1.34–1.26 (m, 4H), 1.12 (s, 3H), 0.91–0.87 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.93, 154.92, 142.83, 134.89, 119.45, 110.70, 110.20, 107.83, 76.86, 45.05, 36.17, 35.59, 31.74, 31.72, 30.74, 28.04, 27.70, 23.63, 22.69, 18.63, 14.16. HRMS (m/z): [M + H]⁺ calcd. for C₂₁H₃₀O₂: 315.23240, found 315.23343.
(–)‐trans‐Δ⁸‐tetrahydrocannabinol (13a): Synthesized according to general procedure III from 4′‐bromo‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (7, 52.1 mg, 161 µmol) and potassium n‐pentylboron trifluoride (23, 43.0 mg, 242 µmol) to afford 13a (17.4 mg, 34 %) as a yellow oil. Spectral data were in agreement with previously synthesized 1 and hence no further purification was executed.
4′‐Propyl‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (13b): 5‐Propylbenzene‐1,3‐diol (1c, 150 mg, 986 µmol) and (S)‐cis‐verbenol (150 g, 986 µmol) were stirred at r.t. in dry DCM (20 mL). Trifluoromethanesulfonic acid (26.2 µL, 296 µmol) was added dropwise at 0 °C and the reaction was left stirring for 3 h. To stop the reaction saturated aqueous NaHCO₃ (20 mL) was added and the mixture was extracted with DCM (2 × 40 mL). The combined organic layers were dried with MgSO₄, concentrated in vacuo and purified through silica gel column chromatography (0→4 % EtOAc/n‐heptane) to afford 2 (55.9 mg, 20 %) as a yellow oil. TLC (EtOAc/n‐heptane, 1:9 v/v): R_f = 0.29. ¹H NMR (400 MHz, CDCl₃) δ 6.28 (d, J = 1.7 Hz, 1H), 6.10 (d, J = 1.6 Hz, 1H), 5.45–5.41 (m, 1H), 4.82 (s, 1H), 3.25–3.15 (m, 1H), 2.71 (td, J = 10.8, 4.6 Hz, 1H), 2.42 (td, J = 7.4, 2.4 Hz, 2H), 2.19–2.10 (m, 1H), 1.91–1.77 (m, 3H), 1.71 (s, 3H), 1.59 (t, J = 7.4 Hz, 2H), 1.38 (s, 3H), 1.11 (s, 3H), 0.92 (t, J = 7.3 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.94, 154.89, 142.58, 134.89, 119.46, 110.72, 110.31, 107.85, 76.83, 45.04, 37.71, 36.17, 31.73, 28.04, 27.71, 24.12, 23.63, 18.64, 14.07. HRMS (m/z): [M + H]⁺ calcd. for C₁₉H₂₆O₂: 287.20110, found 287.20004.
Propyl‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (13b): Synthesized according to general procedure III from 4′‐bromo‐(–)‐trans‐Δ⁸‐tetrahydrocannabinol (7, 38.2 mg, 118 µmol) and potassium n‐propylboron trifluoride (22, 26.6 mg, 177 µmol) to afford 13b (11.3 mg, 33 %) as a yellow oil. Spectral data were in agreement with previously synthesized 2 and hence no further purification was executed.
3,5‐Dimethoxyiodobenzene (15): 1‐Bromo‐3,5‐dimethoxybenzene (1.09 g, 5.00 mmol) was dissolved in THF (2.5 mL) and kept under protective atmosphere. Magnesium turnings (133 mg, 5.50 mmol) were added and the mixture was stirred vigorously. One drop of 1,2‐dibromoethane (±45 mg, 250 µmol) was added, and a reflux condenser was placed on top of the flask. The reaction was then heated to reflux temperature and allowed to stir for 2 h. After this time, the reaction mixture was cooled on ice, and iodine (845 mg, 3.33 mmol) in THF (2.5 mL) was added. The reaction was allowed to stir for 2 h at 0 °C. After this time, 1M aqueous HCl (10 mL) was added slowly and the mixture was extracted with Et₂O (3 × 10 mL). The combined organic layers were washed with 1M aqueous Na₂S₂O₃ (3 × 10 mL), concentrated in vacuo and purified through silica gel column chromatography (0→10 % EtOAc in n‐heptane) to afford 15 (1.00 g, 76 %) as a brown solidified oil. TLC (EtOAc/n‐heptane, 1:9 v/v): R_f = 0.45. ¹H‐NMR (500 MHz, CDCl₃) δ 6.86 (d, J = 2.2 Hz, 2H), 6.40 (t, J = 2.2 Hz, 1H), 3.76 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 161.07, 115.81, 100.67, 94.05, 55.49. m.p. 72.4 °C.
Chloro(–)‐trans‐Δ⁸‐tetrahydrocannabinol (16 and 17): 5‐Chlorobenzene1,3‐diol (8, 107 mg, 740 µmol) was dissolved in dry DCM (5 mL) and stirred vigorously. (S)‐cis‐verbenol (113 mg, 740 µmol) was added and the reaction was stirred at r.t. Trifluoromethanesulfonic acid (29 µL, 333 µmol) was added dropwise at 0 °C and the reaction was left stirring for 20 h. To stop the reaction saturated aqueous NaHCO₃ (50 mL) was added and the mixture was extracted with DCM (2 × 100 mL). The combined organic layers were dried with MgSO₄, concentrated in vacuo and purified through silica gel column chromatography (0→4 % EtOAc/n‐heptane) to afford 16 (53.3 mg, 26 %) as a yellow oil and 17 as a minor product (13.7 mg, 7 %). 2′‐Chloro(–)‐trans‐Δ⁸‐tetrahydrocannabinol (16): TLC (EtOAc/n‐heptane, 1:5 v/v): R_f = 0.40 ¹H NMR (500 MHz, CDCl₃) δ 6.40 (d, J = 2.6 Hz, 1H), 6.17 (d, J = 2.6 Hz, 1H), 5.39 (s, 1H), 5.36 (d, J = 4.1 Hz, 1H), 3.22 (dd, J = 16.4, 4.4 Hz, 1H), 2.61 (td, J = 10.8, 4.5 Hz, 1H), 2.12–2.02 (m, 1H), 1.77–1.73 (m, 2H), 1.71–1.66 (m, 1H), 1.63 (s, 3H), 1.30 (s, 3H), 0.99 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 155.73, 154.79, 134.68, 134.59, 119.43, 116.99, 110.19, 103.59, 77.39, 45.97, 36.32, 33.57, 28.15, 27.33, 23.44, 18.24; HRMS (m/z): [M + H]⁺ calcd. for C₁₆H₁₉ClO₂: 279.11518, found 279.11664. 4′‐Chloro(–)‐trans‐Δ⁸‐tetrahydrocannabinol (17): TLC (EtOAc/n‐heptane, 1:5 v/v): R_f = 0.47. ¹H NMR (500 MHz, CDCl₃) δ 6.45 (d, J = 2.1 Hz, 1H), 6.29 (d, J = 2.0 Hz, 1H), 5.43 (d, J = 3.7 Hz, 1H), 5.03 (s, 1H), 3.15 (dd, J = 15.7, 4.8 Hz, 1H), 2.67 (td, J = 11.0, 4.8 Hz, 1H), 2.16–2.10 (m, 1H), 1.85–1.76 (m, 3H), 1.70 (s, 3H), 1.37 (s, 3H), 1.09 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 155.72, 155.47, 134.53, 132.14, 119.31, 112.02, 110.79, 107.80, 77.35, 44.68, 35.77, 31.50, 27.80, 27.42, 23.45, 18.45; HRMS (m/z): [M + Na]⁺ calcd. for C₁₆H₁₉O₂Cl: 278.10736, found 278.10653.
Iodo(–)‐trans‐Δ⁸‐tetrahydrocannabinol (18 and 19): 5‐Iodobenzene‐1,3‐diol (9, 110 mg, 466 µmol) was dissolved in dry DCM (5 mL) and stirred vigorously. (S)‐cis‐verbenol (71.0 mg, 466 µmol) was added and the reaction was stirred at r.t. Trifluoromethanesulfonic acid (18.6 µL, 210 µmol) was added dropwise at 0 °C and the reaction was left stirring for 20 h. To stop the reaction saturated aqueous NaHCO₃ (50 mL) was added and the mixture was extracted with DCM (2 × 100 mL). The combined organic layers were dried with MgSO₄, concentrated in vacuo and purified through silica gel column chromatography (0→4 % EtOAc/n‐heptane) to afford 18 (43.7 mg, 25 %) as a yellow oil and 19 as a minor product (11.1 mg, 6 %). 2′‐Iodo(–)‐trans‐Δ⁸‐tetrahydrocannabinol (18): TLC (EtOAc/n‐heptane, 1:1 v/v): R_f = 0.35. ¹H NMR (500 MHz, CDCl₃) δ 7.00 (d, J = 2.6 Hz, 1H), 6.31 (d, J = 2.6 Hz, 1H), 5.44 (d, J = 3.7 Hz, 1H), 5.25 (s, 1H), 3.48 (dd, J = 17.2, 3.6 Hz, 1H), 2.52 (td, J = 10.7, 4.3 Hz, 1H), 2.19–2.13 (m, 1H), 1.93–1.82 (m, 2H), 1.72 (s, 3H), 1.69–1.66 (m, 1H), 1.36 (s, 3H), 1.05 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 155.09, 154.57, 134.64, 121.41, 120.46, 119.70, 105.30, 96.81, 77.28, 46.96, 37.45, 37.19, 28.40, 27.22, 23.41, 18.09. HRMS (m/z): [M + H]⁺ calcd. for C₁₆H₁₉IO₂: 371.05080, found 371.05235. 4′‐Iodo(–)‐trans‐Δ⁸‐tetrahydrocannabinol (19): TLC (EtOAc/n‐heptane, 1:1 v/v): R_f = 0.44. ¹H NMR (500 MHz, CDCl₃) δ 6.80 (d, J = 1.7 Hz, 1H), 6.62 (d, J = 1.7 Hz, 1H), 5.42 (d, J = 4.0 Hz, 1H), 4.93 (s, 1H), 3.15 (dd, J = 15.3, 4.4 Hz, 1H), 2.66 (td, J = 11.0, 4.7 Hz, 1H), 2.16–2.10 (m, 1H), 1.83–1.73 (m, 3H), 1.69 (s, 3H), 1.36 (s, 3H), 1.08 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 155.80, 155.53, 134.53, 119.80, 119.30, 116.35, 113.37, 90.32, 77.31, 44.65, 35.66, 31.61, 27.80, 27.43, 23.45, 18.47; HRMS (m/z): [M + Na]⁺ calcd. for C₁₆H₁₉O₂I: 370.04297, found 370.04265.
n‐Propylboronic acid (20): 1‐Bromopropane (2.15 mL, 23.6 mmol) and dry THF (12 mL) were combined and cooled to 0 °C. Magnesium turnings (631 mg, 25.9 mmol) and one drop of 1,2‐dibromoethane were added. After 15 min the cooling bath was removed and the reaction was refluxed for 2 h at 75 °C after which it was cooled to r.t. Trimethylborate (2.89 mL, 25.9 mmol) was dissolved in Et₂O (100 mL), stirred vigorously and cooled to –78 °C. Freshly prepared propylmagnesium bromide was added dropwise to the mixture. The reaction was left stirring for 2 h at –78 °C after it was warmed up to r.t. 10 % aqueous HCl (80 mL) was added slowly and the biphasic reaction mixture was left stirring for 15 min. The layers were separated and the aqueous layer was washed with Et₂O (2 × 80 mL). The combined organic layers were dried with MgSO₄, concentrated in vacuo and the crude product was recrystallized by dissolving in hot water (20 mL) and cooling to 0 °C. The product was isolated by filtration and the flask and filter were rinsed with n‐heptane (4 mL). The filtered solid was dried under high vacuum to afford 20 (539 mg, 26 % over two steps) as white crystals. ¹H NMR (400 MHz, (CD₃)₂SO) δ 7.33 (s, 2H), 1.39–1.28 (m, 3H), 0.85 (t, J = 7.3 Hz, 2H), 0.57 (t, J = 7.7 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 17.54, 17.09 (CH₂ next to B not visible; quadrupolar relaxation). ¹¹B NMR (128 MHz, CDCl₃) δ 32.18 (s). m.p. 101.1 °C.
n‐Pentylboronic acid (21): Trimethylborate (1.1 mL, 10.0 mmol) was dissolved in Et₂O (60 mL), stirred vigorously and cooled to –78 °C. Pentylmagnesium bromide (7.69 mL, 10.0 mmol, 1.3M in THF) was added dropwise. The reaction was left stirring for 2 h at –78 °C after it was warmed up to r.t. 10 % aqueous HCl (40 mL) was added slowly and the biphasic reaction mixture was left stirring for 15 min. The layers were separated and the aqueous layer was washed with Et₂O (2 × 40 mL). The combined organic layers were dried with MgSO₄, concentrated in vacuo and the crude product was recrystallized by dissolving in hot water (10 mL) and cooling to 0 °C. The product was isolated by filtration and the flask and filter were rinsed with n‐heptane (2 mL). The filtered solid was dried under high vacuum to afford 21 (774 mg, 67 %) as white crystals. ¹H NMR (400 MHz, CDCl₃) δ 1.49–1.36 (m, 2H), 1.34–1.27 (m, 4H), 0.95–0.84 (m, 4H), 0.84–0.75 (m, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 34.68, 28.20, 23.47, 22.65, 14.15. ¹¹B NMR (128 MHz, CDCl₃) δ 33.32 (s). m.p. 88.2 °C.
Potassium n‐propylboron trifluoride (22): Synthesized according to general procedure I from n‐propylboronic acid (20, 200 mg, 2.28 mmol), potassium fluoride (529 mg, 9.10 mmol) and 2,3‐dihydroxysuccinic acid (700 mg, 4.66 mmol) to afford 22 (257 mg, 75 %) as white crystals. ¹H NMR (400 MHz, (CD₃)₂SO) δ 1.22–1.06 (m, 2H), 0.83–0.76 (m, 3H), –0.01 to –0.10 (m, 2H). ¹³C NMR (100 MHz, (CD₃)₂SO) δ 18.74, 18.23 (CH₂ next to B not visible; quadrupolar relaxation). ¹¹B NMR (128 MHz, (CD₃)₂SO) δ 4.76 (d, J = 64.8 Hz). ¹⁹F NMR (377 MHz (CD₃)₂SO) δ –136.49 to –136.98 (m). m.p. 378.9 °C.
Potassium n‐pentylboron trifluoride (23): Synthesized according to general procedure I from n‐pentylboronic acid (21, 600 mg, 5.17 mmol), potassium fluoride (1.20 g, 20.7 mmol) and 2,3‐dihydroxysuccinic acid (1.59 g, 10.6 mmol) to afford 23 (872 mg, 95 %) as white crystals. ¹H NMR (400 MHz, (CD₃)₂SO) δ 1.26–1.07 (m, 6H), 0.82 (t, J = 7.1 Hz, 3H), –0.03 to –0.14 (m, 2H). ¹³C NMR (100 MHz, (CD₃)₂SO) δ 35.54, 25.30, 22.44, 14.18 (CH₃) (CH₂ next to B not visible; quadrupolar relaxation). ¹¹B NMR (128 MHz, (CD₃)₂SO) δ 4.83 (d, J = 65.6 Hz). ¹⁹F NMR (377 MHz (CD₃)₂SO) δ –136.86 (d, J = 74.4 Hz). m.p. 392.2 °C.
Potassium (1‐naphthalene) trifluoroborate (24): Synthesized according to general procedure I from naphthalene‐1‐ylboronic acid (400 mg, 2.33 mmol), potassium fluoride (540 mg, 9.30 mmol) and 2,3‐dihydroxysuccinic acid (716 mg, 4.77 mmol) to afford 24 (525 mg, 97 %) as white crystals. ¹H NMR (400 MHz, (CD₃)₂SO) δ 8.39 (d, J = 8.8 Hz, 1H), 7.74–7.69 (m, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.55–7.52 (m, 1H), 7.34–7.23 (m, 3H). ¹³C NMR (100 MHz, (CD₃)₂SO) δ 136.63, 132.99, 130.29, 128.55, 127.38, 125.20, 124.93, 123.90, 123.38 (C next to B not visible; quadrupolar relaxation). ¹¹B NMR (128 MHz, (CD₃)₂SO) δ 3.51 (d, J = 56.0 Hz). ¹⁹F NMR (377 MHz (CD₃)₂SO) δ –135.27 (d, J = 65.0 Hz). m.p. 117.9 °C.
Potassium (4‐methoxyphenyl) trifluoroborate (25): Synthesized according to general procedure I from (4‐methoxyphenyl)boronic acid (400 mg, 2.63 mmol), potassium fluoride (612 mg, 10.5 mmol) and 2,3‐dihydroxysuccinic acid (810 mg, 5.40 mmol) to afford 25 (548 mg, 97 %) as white crystals. ¹H NMR (400 MHz, (CD₃)₂SO) δ 7.21 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 7.7 Hz, 2H), 3.66 (s, 3H, CH₃). ¹³C NMR (100 MHz, (CD₃)₂SO) δ 157.20, 132.25, 111.87, 54.55 (C next to B not visible; quadrupolar relaxation). ¹¹B NMR (128 MHz, (CD₃)₂SO) δ 3.44 (m). ¹⁹F NMR (377 MHz (CD₃)₂SO) δ –138.19 (m). m.p. 256.9 °C.

Bloemendal V.R., Sondag D., Elferink H., Boltje T.J., van Hest J.C, & Rutjes F.P. (2019). A Revised Modular Approach to (–)‐trans‐Δ8‐THC and Derivatives Through Late‐Stage Suzuki–Miyaura Cross‐Coupling Reactions. European Journal of Organic Chemistry, 2019(12), 2289-2296.

Publication 2019

Most recents protocols related to «Iodobenzene»

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Novel Indole-Sulfonamide Synthesis

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Synthesis of Iodoalkyne Precursor

The precursor for iodoalkyne (1)
was prepared from 1-bromo-2-iodobenzene by sequential coupling reactions.
Thus, palladium-catalyzed coupling of 1-bromo-2-iodobenzene with 3-ethynylpyridine
yielded 3-[(2-bromophenyl)ethynyl]pyridine that was then coupled with
TMS acetylene, followed by base hydrolysis to yield 3-[(2-ethynylphenyl)ethynyl]pyridine
with spectral data identical to that previously reported.^{26 (link)}A solution of 3-[(2-ethynylphenyl)ethynyl]pyridine
(0.160 g, 0.79 mmol) in acetone (5 mL) under argon was treated with N-iodosuccinimide (0.249 g, 1.11 mmol) and silver(I) nitrate
(0.034 g, 0.20 mmol). The reaction was sealed and stirred for 24 h.
The reaction crude was extracted with ethyl acetate, and the extract
was washed with water and brine and dried over sodium sulfate. After
evaporation of the solvent, the product was purified by flash chromatography
to yield the product as colorless crystals (0.227 g, 85%). ¹H NMR (400 MHz, CDCl₃): δ 8.82 (br d, J = 2.0 Hz, 1H), 8.56 (dd, J = 1.6, 7.8 Hz, 1H),
7.85 (td, J = 2.0, 7.6 Hz, 1H), 7.54–7.52
(m, 1H), 7.49–7.47 (m, 1H), 7.34–7.29 (m, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 152.5, 148.7,
138.6, 132.5, 131.5, 128.6, 128.4, 126.2, 123.1, 120.3, 92.7, 91.1,
90.2, 11.5.

Bosch E., Speetzen E, & Bowling N.P. (2024). Halogen-Bonded Supramolecular Parallelograms: From Self-Complementary Iodoalkyne Halogen-Bonded Dimers to 1:1 and 2:2 Iodoalkyne Halogen-Bonded Cocrystals. Crystal Growth & Design, 24(4), 1674-1681.

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Palladium-Catalyzed Vinylation of Iodobenzene

In an NMR tube,
0.033 mL of iodobenzene (0.30 mmol, 1.0 equiv), 0.097 mL of tributylvinyltin
(0.33 mmol, 1.1 equiv), 5 mol % [Pd] catalyst, and 0.05 g of (0.03
mmol, 0.1 equiv) 1,3,5-trimethoxybenzene were dissolved in 1 mL dry,
degassed THF-d₈. The reactions were carried
out in the dark and monitored every 2 h by ¹H, ³¹P{¹H}, and, when applicable, ¹⁹F NMR spectroscopy.
The reaction yields are an average of two replicates.

Sherstiuk A., Lledós A., Lönnecke P., Hernando J., Sebastián R.M, & Hey-Hawkins E. (2024). Dithienylethene-Based Photoswitchable Phosphines for the Palladium-Catalyzed Stille Coupling Reaction. Inorganic Chemistry, 63(17), 7652-7664.

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Top products related to «Iodobenzene»

Iodobenzene by Merck Group

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Iodobenzene is a chemical compound with the formula C6H5I. It is a clear, colorless liquid that is commonly used as a laboratory reagent and a precursor in organic synthesis.

Phenylboronic acid by Merck Group

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Phenylboronic acid is a chemical compound used as a laboratory reagent. It is a crystalline solid with the chemical formula C6H7BO2. The compound can be used in various organic synthesis reactions and as a building block for other chemical compounds.

Sodium hydroxide (naoh) by Merck Group

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Chlorobenzene by Merck Group

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Chlorobenzene is a colorless, volatile liquid used as an intermediate in the production of various chemicals. It serves as a precursor for the synthesis of other organic compounds.

Potassium carbonate by Merck Group

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Potassium carbonate is a chemical compound with the formula K2CO3. It is a white, crystalline salt that is soluble in water. Potassium carbonate is commonly used in various laboratory applications as a reagent or a source of potassium ions.

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O-phenylendiamine is a chemical compound that is commonly used as a reagent in analytical and diagnostic laboratory applications. It serves as a precursor for the synthesis of various dyes and pharmaceuticals. O-phenylendiamine has a core function as a chemical building block for diverse laboratory and industrial purposes.

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What are the common uses and applications of Iodobenzene?

Iodobenzene is a versatile aromatic organoiodine compound with a wide range of applications in various fields. It is commonly used as a precursor in organic synthesis, where it serves as a building block for the preparation of more complex molecules. Iodobenzene also finds use as a reagent in various chemical reactions, such as cross-coupling reactions, electrophilic aromatic substitution, and halogenation reactions. Additionally, Iodobenzene has applications in medicinal chemistry, polymer science, and materials science, where it is utilized in the synthesis of pharmaceuticals, polymers, and functional materials.

What are some common challenges faced when working with Iodobenzene?

One of the main challenges in working with Iodobenzene is its relatively high reactivity and sensitivity to certain conditions. Iodobenzene can undergo unwanted side reactions, such as halogen-metal exchange or decomposition, if not handled properly. Additionally, the pungent odor of Iodobenzene can be a nuisance, and proper ventilation and personal protective equipment are necessary when working with this compound. Researchers must also consider the potential toxicity and environmental impact of Iodobenzene and take appropriate safety precautions.

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PubCompare.ai is an AI-driven platform that can greatly assist researchers in optimizing their Iodobenzene experiments. The platform allows you to efficiently screen protocol literature and leverage AI to pinpoint critical insights. By using PubCompare.ai, you can identify the most effective protocols related to Iodobenzene for your specific research goals. The platform's AI-driven analysis can highlight key differences in protocol effectiveness, enabling you to choose the best option for reproducibility and accuracy, and unlocking the full potential of your Iodobenzene research.

Are there different types or variations of Iodobenzene, and how do they differ in their properties and applications?

While Iodobenzene is the most common form, there are some variations and derivatives of this compound that can have slightly different properties and applications. For example, substituted Iodobenzenes, where the hydrogen atoms on the aromatic ring are replaced by other functional groups, can exhibit unique reactivity and be used in more specialized applications. Additionally, Iodobenzene can be found in different isomeric forms, such as ortho-, meta-, and para-Iodobenzene, which can have slight differences in their physical and chemical characteristics. Researchers should carefully consider these variations when selecting the appropriate form of Iodobenzene for their specific experiments and applications.

More about "Iodobenzene"

Phenyl iodide, Organoiodine, Organic synthesis, Chemical reactions, Medicinal chemistry, Polymer science, Materials science, Suzuki coupling, Diazotization, Polymer synthesis, Sodium hydroxide, Potassium carbonate, Acetonitrile, Dimethylformamide, Agilent GC System, Chromatography