Anodic C,C Cross-Coupling Reaction of Aromatic Compounds Using an Electrochemical Flow Microreactor

Monday, May 12, 2014: 15:00
Floridian Ballroom D, Lobby Level (Hilton Orlando Bonnet Creek)
T. Arai, T. Kashiwagi, and M. Atobe (Department of Environment and System Sciences, Yokohama National University)
The C,C cross-coupling reaction of aromatic compounds is important in various fields such as syntheses of ligands, polymers, and natural products contain nonsymmetrical biaryl structures. Therefore, a number of synthetic approaches have been developed1. Typical approaches (such as Negishi coupling and Suzuki-Miyaura coupling) were achieved by using transition metal catalysts and by incorporating leaving functionalities2. Thereby several synthetic steps are needed for the preparation of starting aromatic compounds with leaving functionalities. Reducing these synthetic steps is identical because it leads to reduce the amount of reagent waste. Hence C,H direct activation is cutting edge concept because it doesn't require any special leaving functionalities3. Especially anodic cross-coupling reaction serves as an efficient method that doesn't require transition metal catalysts, leaving functionalities, and also oxidants. Thus it is economically and environmentally attractive. However, when the oxidation potentials of two starting aromatic compounds are near each other, the selective oxidation is hard to conduct. Also, a desired biaryl product suffers from overoxidation because the oxidation potential of the biaryl products are generally lower than that of starting aromatic compounds. As a result, the yield should be decreased. To solve these problems, several approaches were recently developed. For example, Waldvogel and co-workers reported a selective phenol-arene anodic C,C cross-coupling reaction using boron-doped diamond electrodes4. On the other hand, Yoshida and co-workers reported C-H/C-H cross-coupling method using radical cation pools5. Thus, developing efficient anodic cross-coupling reactions is attractive and further investigation is still challenging target.

  To achieve selective anodic oxidation, we have developed an electrosynthetic system using a pararell laminar flow in a flow microreactor6. Since the channel of flow micrioreactor is narrow, it ensures that the flow is stable and laminar. As shown in Figure 1, when two solutions are introduced through the two inlets (named inlets 1 and 2 in Figure 1), a stable liquid-liquid pararell interface can be formed; mass transfer between input streams occurs only via diffusion. Hence, when a substrate solution is introduced through inlet 1 (anode side) and a nucleophile solution is introduced thorough inlet 2 (cathode side), the substrate is dominantly oxidized to generate a carbocation while oxidation of the nucleophile is avoided. Consequently the carbocation generated at anode rapidly diffuse to the bulk electrolytic solution and react with the nucleophile to afford a desired product. This approach would enable to achieve selective oxidation of aromatic substrates regardless of their oxidation potential. In addition, overoxidation would be avoided because the desired biaryl product would be immediately ejected from reaction field.  Thus, this system would overcome existing problems associated with the oxidation potential of substrates and the overoxidation.

  Figure 2 shows a schematic illustration of the typical 2-inlets flow microreactor for electrosynthetic reaction. The flow microreactor consisted of two plates, which were glued platinum (Pt) plates and glass plate together. A slit was provided on anode side for introducing substrate solutions into the reactor. A spacer was used to leave a rectangular channel exposed, and the two plates were simply sandwiched together. After connecting Teflon tubing to inlets and outlet, the reactor was sealed with epoxy resin. Bulk electrolysis was conducted with a constant current and solution flowing through the electrolysis cell. The flow rate was controlled by using syringe pump. Reaction mixture was collected and then analyzed by HPLC.

  Consequently, anodic cross-coupling reaction in the flow microreacter resulted in improvement of the current efficiency of 3up to 87 % (scheme 1), while it was 49 % in a batch type reactor. 

  In the presentation, detail of experimental conditions will be discussed.


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2          a) E. Negishi, Acc. Chem. Res. 1982, 15, 340-348 b) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483.

3          D. Alberico, et al., Chem. Rev. 2007 107, 174-238.

4          A. Kirste, et al., Org. Lett. 2011 13, 3127.

5          T. Morofuji, et al., Angew Chem. Int. Ed. 2012, 51, 1-5.