Cyrene as a Bio-Based Solvent for the Suzuki–Miyaura Cross-Coupling

Abstract

The Suzuki–Miyaura (SM) cross-coupling is the most broadly utilized Pd-catalyzed C–C bond-forming reaction in the chemical industry. A large proportion of SM couplings employ dipolar aprotic solvents; however, current sustainability initiatives and increasingly stringent regulations advocate the use of alternatives that exhibit more desirable properties. Here we describe the scope and utility of the bio-derived solvent Cyrene™ in SM cross-couplings and evaluate its suitability as a reaction medium for this benchmark transformation from discovery to gram scale.

Key words

boron - cross-coupling - green chemistry - palladium - solvents

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• 64 General Procedure for Suzuki–Miyaura Coupling in Cyrene To an oven dried 5 mL microwave vessel was added Pd(dppf)Cl₂·CH₂Cl₂ (4 mol%), halide/pseudohalide (1 equiv), boron coupling partner (1 equiv), and Cs₂CO₃ (3 equiv). The vessel was then capped and purged with N₂ before addition of Cyrene (1 mL, 0.25 M) and H₂O (1.8 mL). The reaction mixture was heated to 50 °C and maintained at this temperature with stirring for 5 h before the vessel was vented and decapped. The solution was then diluted with Et₂O (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 title compound. 4-Phenyltoluene (4a) Prepared according to the General Procedure using Pd(dppf)Cl₂·CH₂Cl₂ (8.2 mg, 0.01 mmol, 4 mol%), bromotoluene 2a (42.8 mg, 0.25 mmol, 1 equiv), phenylboronic acid (3a, 30.5 mg, 0.25 mmol, 1 equiv), Cs₂CO₃ (244.5 mg, 0.75 mmol, 3 equiv), Cyrene (1 mL, 0.25 M), and H₂O (1.8 mL, 400 equiv). After 5 h, the reaction mixture was subjected to the purification method outlined in the General Procedure (silica gel, 0–5% Et₂O in PE) to afford the title compound as a white solid (42.9 mg, quant). ¹H NMR (CDCl₃, 400 MHz): 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 (CDCl₃, 101 MHz): δ = 141.2, 138.4, 136.9, 129.5, 128.7, 126.9, 21.1.