Highly Efficient Suzuki Coupling of Aryl Chlorides in a Continuous Flow ­Capillary Microreactor

Abstract

The Suzuki reactions of aryl chlorides containing both electron-donating and electron-withdrawing groups with aryl boronic acid, catalyzed by a simple non-phosphine ligand catalyst system, Pd(OAc)₂/DABCO, were performed in a continuous capillary microreactor at 50 ˚C. In the microreactor, the coupling product was obtained mostly in near quantitative yield within a four hour residence time. In contrast, the conversions were only 12-69% in batch reactions.

Suzuki - coupling - aryl chlorides - capillary - microreactor

References and Notes

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Microreactor Reaction; Typical Procedure. A stock solution of the aryl chloride (0.1 mmol), Pd(OAc)₂ (3 mol%), DABCO (6 mol%) and TBAB (0.1 equiv), in DMF (1 mL) was prepared and taken up in a SGE gas-tight syringe. A second stock solution containing K₃PO₄˙3H₂O (3 equiv), and phenylboronic acid (1.5 equiv) in H₂O (1 mL), containing DMF (50 µL) as an added to dissolve phenylboronic acid, was also prepared and taken up in a second SGE gas-tight syringe. The syringes were placed on a TS2-60 syringe pump that was set to deliver 0.9 µL/min and the oil bath was set at 50 ˚C. The output from the reactor was quenched with Et₂O immediately. The resulting mixture was extracted with Et₂O (3 × 5 mL) and the combined organic phase was washed with brine, and dried with anhydrous Na₂SO₄, then concentrated and the desired product was submitted for NMR analysis. In optimization experiments, the ^¹H NMR spectrum of the product mixture was recorded and the product conversion was determined by integration of the peaks arising from CH₃ or OCH₃ groups of both the aryl chloride and the product. The conversion was calculated using the formula: [Int.(prod)/Int.(prod + aryl chloride)] × 100.

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Batch Reaction; Typical Procedure. A mixture of aryl chloride (0.5 mmol), phenylboronic acid (1.5 equiv), Pd(OAc)₂ (3 mol%), DABCO (6 mol%), TBAB (0.1 equiv), K₃PO₄˙3H₂O (3 equiv), H₂O (5 mL) and DMF (5 mL), was added to a 25 mL round-bottomed flask, and stirred at 50 ˚C or 80 ˚C for either 4 h or 24 h. After the reaction, the solution was cooled to room temperature and extracted with Et₂O (3 × 15 mL). The combined organic phase was washed with brine, and dried with anhydrous Na₂SO₄, then concentrated and the product was analyzed by ^¹H NMR in order to judge the conversion of aryl chloride. All of the final compounds in this study were isolated by silica gel chromatography (petroleum ether) for the purpose of spectroscopic identification.

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