Dimethylisosorbide (DMI) as a Bio-Derived Solvent for Pd-Catalyzed Cross-Coupling Reactions

Abstract

Palladium-catalyzed bond-forming reactions, such as the ­Suzuki–Miyaura and Mizoroki–Heck reactions, are some of the most broadly utilized reactions within the chemical industry. These reactions frequently employ hazardous solvents; however, to adhere to increasing sustainability pressures and restrictions regarding the use of such solvents, alternatives are highly sought after. Here we demonstrate the utility of dimethyl isosorbide (DMI) as a bio-derived solvent in several benchmark Pd-catalyzed reactions: Suzuki–Miyaura (13 examples, 62–100% yield), Mizoroki–Heck (13 examples, 47–91% yield), and Sonogashira (12 examples, 65–98% yield).

Key words

cross-coupling - green chemistry - palladium - solvents

• References and Notes

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• 54 General Procedure for Suzuki–Miyaura Coupling in DMI To an oven-dried 5 mL microwave vessel was added Pd(dppf)Cl₂·CH₂Cl₂ (4 mol%), aryl halide/pseudohalide (1 equiv.), organoboron (1 equiv.), and K₃PO₄ (3 equiv.). The vessel was then capped and purged with N₂ before addition of DMI (1 mL, 0.25 M) and H₂O (5 equiv.). The reaction mixture was heated to 60 °C and maintained at this temperature with stirring for 1 h before the vessel was vented and decapped. The solution was then diluted with EtOAc (10 mL) and washed with water (2 × 20 mL) and brine (2 × 20 mL). The organics were then passed through a hydrophobic frit and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (silica gel) to afford the product. 4-Phenyltoluene (3a) Prepared according to the General Procedure using Pd(dppf)Cl₂·CH₂Cl₂ (8.2 mg, 0.01 mmol, 4 mol%), bromotoluene (1a, 43 mg, 0.25 mmol, 1 equiv.), phenylboronic acid (2a, 30.5 mg, 0.25 mmol, 1 equiv.), K₃PO₄ (159 mg, 0.75 mmol, 3 equiv.), DMI (1 mL, 0.25 M), and H₂O (23 μL, 1.25 mmol, 5 equiv.). After 1 h, the reaction mixture was subjected to the purification method outlined in the General Procedure (silica gel, 0–5% EtOAc in petroleum ether) to afford the title compound as a white solid (42.9 mg, quant.). ¹H NMR (400 MHz, CDCl₃): δ = 7.62 (dd, J = 8.3, 1.2 Hz, 2 H), 7.53 (d, J = 8.1 Hz, 2 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.38–7.33 (m, 1 H), 7.29 (d, J = 7.9 Hz, 2 H), 2.43 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 141.3, 138.5, 137.2, 129.6, 128.9, 127.1, 21.2.
• 55 General Procedure for Mizoroki–Heck Coupling in DMI To an oven-dried 5 mL microwave vessel was added Pd(dppf)Cl₂·CH₂Cl₂ (5 mol%) and aryl halide (1 equiv.). The vessel was capped and purged with N₂ before addition of DMI (1 mL, 0.25 M), alkene coupling partner (2 equiv.), and Et₃N (3 equiv.). The reaction mixture was heated to either 80 °C (X = I) or 115 °C (X = Br) and maintained at this temperature with stirring for 1 h (X = I) or 24 h (X = Br) before the vessel was vented and decapped. The solution was then diluted with EtOAc (10 mL) and washed with water (2 × 20 mL) and brine (2 × 20 mL). The organics were then passed through a hydrophobic frit and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (silica gel) to afford the product. Methyl Cinnamate (6a) Prepared according to the General Procedure using Pd(dppf)Cl₂·CH₂Cl₂ (10.2 mg, 0.013 mmol, 5 mol%), iodobenzene (4a, 28 μL, 0.25 mmol, 1 equiv.), methyl acrylate (5a, 45 μL, 0.5 mmol, 2 equiv.), Et₃N (105 μL, 0.75 mmol, 3 equiv.), DMI (1 mL, 0.25 M). After 1 h, the reaction mixture was subjected to the purification method outlined in the General Procedure (silica gel, 0–5% EtOAc in petroleum ether) to afford the title compound as a white solid (40 mg, 99%). ¹H NMR (500 MHz, CDCl₃): δ = 7.70 (d, J = 16.0 Hz, 1 H), 7.53 (dd, J = 6.6, 2.8 Hz, 2 H), 7.41–7.37 (m, 3 H), 6.45 (d, J = 16.0 Hz, 1 H), 3.81 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 167.6, 145.0, 134.6, 130.4, 129.0, 128.2, 117.9, 51.8.
• 56 General Procedure for Sonogashira Coupling in DMI To an oven-dried 5 mL microwave vessel was added Pd(PPh₃)₂Cl₂ (2 mol%), aryl halide (1 equiv.), and alkyne coupling partner (1.05 equiv.). The vessel was capped and purged with N₂ before addition of DMI (0.5 mL, 0.5 M), and Et₃N (1.1 equiv.). The reaction mixture was maintained at room temperature (25 °C) with stirring for 1 h before the vessel was vented and decapped. The solution was then diluted with EtOAc (10 mL) and washed with water (2 × 20 mL) and brine (2 × 20 mL). The organics were then passed through a hydrophobic frit and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (silica gel) to afford the product. 1-Fluoro-4-(phenylethynyl)benzene (9a) Prepared according to the General Procedure using Pd(PPh₃)₂Cl₂ (3.5 mg, 0.005 mmol, 2 mol%), 4-fluoroiodobenzene (7a, 29 μL, 0.25 mmol, 1 equiv.), phenylacetylene (8a, 29 μL, 0.26 mmol, 1.05 equiv.), Et₃N (38 μL, 0.28 mmol, 1.1 equiv.), DMI (0.5 mL, 0.5 M). After 1 h, the reaction mixture was subjected to the purification method outlined in the General Procedure (silica gel, 0–5% EtOAc in petroleum ether) to afford the title compound as a white solid (45 mg, 92%). ¹H NMR (500 MHz, CDCl₃): δ = 7.55–7.50 (m, 4 H), 7.38–7.33 (m, 3 H), 7.05 (t, J = 8.7 Hz, 2 H). ¹³C NMR (126 MHz, CDCl₃): δ = 162.7 (d, ¹ J = 249.6 Hz), 133.6 (d, ³ J = 8.2 Hz), 131.7, 128.5, 128.5, 123.3, 119.5 (d, ⁴ J = 3.4 Hz), 115.8 (d, ² J = 22.4 Hz), 89.2, 88.4. ¹⁹F NMR (471 MHz, CDCl₃): δ = –110.98.