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DOI: 10.1055/s-0037-1611054
Dimethylisosorbide (DMI) as a Bio-Derived Solvent for Pd-Catalyzed Cross-Coupling Reactions
We thank the University of Strathclyde for a PhD studentship (KLW) and Merck KGaA, Darmstadt, Germany, for financial and material support.Publication History
Received: 09 August 2018
Accepted after revision: 04 September 2018
Publication Date:
28 September 2018 (online)
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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).
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1611054.
- Supporting Information
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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.