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Synlett 2013; 24(18): 2411-2418
DOI: 10.1055/s-0033-1339870
letter
© Georg Thieme Verlag Stuttgart · New York

Arylation of Pyridines via Suzuki–Miyaura Cross-Coupling and Pyridine-­Directed C–H Activation Using a Continuous-Flow Approach

Maria Christakakou
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, 1060 Vienna, Austria   Fax: +43(1)588019163616   eMail: michael.schnuerch@tuwien.ac.at
,
Michael Schön
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, 1060 Vienna, Austria   Fax: +43(1)588019163616   eMail: michael.schnuerch@tuwien.ac.at
,
Michael Schnürch*
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, 1060 Vienna, Austria   Fax: +43(1)588019163616   eMail: michael.schnuerch@tuwien.ac.at
,
Marko D. Mihovilovic
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, 1060 Vienna, Austria   Fax: +43(1)588019163616   eMail: michael.schnuerch@tuwien.ac.at
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Publikationsverlauf

Received: 31. Juli 2013

Accepted after revision: 05. September 2013

Publikationsdatum:
01. Oktober 2013 (online)

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Dedicated to Professor Manfred Schlosser who is missing in the Swiss alps he loved so much

Abstract

Suzuki–Miyaura cross-coupling reactions between heteroaryl bromides and arylboronic acids were performed employing a continuous-flow approach using a simple flow reactor designed in-house. Pd(PPh3)4 was used as catalyst, and arylboronic acids containing both electron-withdrawing and electron-donating groups were applied. The coupling process required 23 minutes of residence time to be completed and generally good yields were obtained. Subsequent arylation of 2-phenyl pyridine was carried out via a C–H activation strategy using substituted bromobenzene compounds and a ruthenium(II) catalyst. To the best of our knowledge in this work we present for the first time the possibility of performing intermolecular C–H activation in a continuous-flow system.

Key words

heterocycles - cross coupling - flow chemistry - C–H activation - catalysis

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • References and Notes

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  • 17 Preparation of 2-Aryl- and 3-Aryl Derivatives 3a–f and 5a–f To a round-bottomed flask was added the appropriate amount of 2-bromo- or 3-bromopyridine (1 or 4, 1 equiv, 1 mmol), boronic acid 2a–f (1.2 equiv, 1.2 mmol), K2CO3 (2 equiv, 276 mg, 2 mmol), Pd(PPh3)4 (2.1 mol%, 24 mg, 0.021 mmol), and a dioxane–H2O mixture as solvent (1:1, 20 mL). The mixture was stirred for 5 min at r.t. and was then filtered through filter paper, before being transferred to the syringe pump. The residence time was 23 min, and the temperature of the heating plate was set to 90 °C. The inner diameter of the capillary was 1 mm. The flow rate was 0.695 mL/min, and the volume of the reactor was 16 mL. Reference NMR Spectra for 2-(4-methoxyphenyl)-pyridine (3d) 1H (200 MHz CDCl3): δ = 3.86 (s, 3 H), 6.95–7.05 (m, 2 H), 7.13–7.23 (m, 1 H), 7.62–7.79 (m, 2 H), 7.90–8.01 (m, 2 H), 8.60–8.71 (m, 1 H). 13C (50 MHz, CDCl3): δ = 55.5 (q), 114.3 (d), 120.0 (d), 121.6 (d), 128.3 (d), 132.1 (s), 136.9 (d), 149.6 (d), 157.2 (s), 160.6 (s). Preparation of ortho-Arylated 2-Phenylpyridine Derivatives 7a–e, 8a–f To a round-bottomed flask was added the appropriate amount of 2-arylpyridine derivative 7a or 7b (1 equiv, 0.25 mmol), the appropriate bromobenzene derivative 6a–e (3 equiv, 0.75 mmol), DBU (4 equiv, 152 mg, 1 mmol), Ph3P (10 mol%, 6.5 mg, 0.025 mmol), dichloro(p-cymene)ruthenium(II) dimer [5 mol%, 7.6 mg, 0.0125 mmol; with the exception of the synthesis of 8f, in which 7.5 mol% of dichloro(p-cymene)ruthenium(II) dimer were used (7.5 mol%, 11.5 mg, 0.01875 mmol) and NMP as solvent (1 mL)]. The mixture was stirred at r.t. until complete dissolution of all reagents. Then this solution was transferred to the syringe pump system. The flow rate was set to 0.533 mL/min which corresponded to a residence time of 30 min, and the temperature of the heating plate was set to 160 °C. After pumping through the reaction mixture, 20 mL pure solvent was pumped through as well. The inner diameter of the capillary was 1 mm. The volume of the reactor was 16 mL. Reference NMR spectra for 2-[4′-methoxy-(1,1′-biphenyl)-2-yl]pyridine (7b) 1H (200MHz, CDCl3): δ = 3.78 (s, 3 H), 6.72–6.82 (m, 2 H), 6.90 (dt, J = 7.8, 1.0 Hz, 1 H), 7.01–7.15 (m, 3 H), 7.33–7.50 (m, 4 H), 7.61–7.73 (m, 1 H). 13C (50 MHz, CDCl3): δ = 55.3 (q), 113.7 (d), 121.4 (d), 125.6 (d), 127.4 (d), 128.6 (d), 130.6 (d), 130.6 (d), 130.9 (d), 133.8 (s), 135.4 (d), 139.5 (s), 140.3 (s), 149.6 (d), 158.6 (s), 159.6 (s).