Monoalkylation of Methyl Phenylacetate Using in Situ Electrogenaration of 2-Pyrrolidone Anion in an Electrochemical Flow-Microreactor
Authors: Matsumura Yoshimasa , Kakizaki Yoshinobu , Tateno Hiroyuki , Atobe Mahito 
Published: February 2020

Anionic species are important reaction intermediate in the field of organic synthesis. Among them, electrogenerated base (EGB) generated cathodically act not only as nucleophiles but also as bases, which have interesting reactivities.1 The EGBs could be formed by cathodic reductive deprotonation of probases such as 2-pyrrolidone, hindered phenol like 2,6-tert-butyl-4-methylphenol, and triphenylmethane. In particular, EGB derived from 2-pyrrolidone is a versatile base and applicable to organic reactions such as Stevens rearrangement, selective a-monoalkylation of α-(aryl)acetate esters, and α-monoalkylation of 1,3-diketones.2,3 However, severe reaction conditions such as low temperature, inert gas are usually required for the use of EGBs in batch type reactors.

Recently, flow microreactors are reserved much attentions as an attractive reaction field. Namely, they enable the precise control of short-lived species and thereby facilitate highly selective reactions that are difficult to achieve in a conventional reactor.

In this sturdy, we wish to demonstrate that a flow microreactor is extremely useful in controlling reactions involving an EGB such as 2-pyrrolidone anion formed by the cathodic reduction of 2-pyrrolidone. As a model reaction, a-alkylation of methyl phenylacetate 3 using electrogenerated 2 was employed (Scheme 1). It is well known that the monoalkylated product 5 can be converted into some a-alkylphenylacetic acids, which possess high anti-inflammatory and analgetic activities.

The flow microreactor fabricated for the model reaction consists of three reaction parts such as the cathodic reaction part for the generation of 2, the deprotonation part for the reaction between 2 and 3, and the final alkylation reaction part for the rapid use of the unstable intermediate 4 for obtaining the monoalkylated product 5 formedby thereaction with alkyl iodide (R–I). To perform such a multi-step reaction in a single-flow operation, we conceived the use of parallel laminar flow in a flow microreactor. The channel of the reactor is sufficiently small to ensure stable and laminar flow solutions. As shown in Figure 1, when two solutions (DMF solutions of probase 1 and methyl phenylacetate 3 are introduced through respective inlets (inlet 1 and inlet 2) of the two inlets flow microreactor, a stable liquid-liquid interface can be formed, and mass transfer between the input streams occurs only by means of diffusion. Therefore, the probase 1 introduced through cathodic side inlet (inlet 1) could be predominantly reduced, and in addition the re-oxidation of electrogenerated 2 could be avoided by its rapid reaction with 3 at a liquid-liquid interface before reaching to the anode surface. Furthermore, the reactive intermediate 4 formed at the interface could be used rapidly for the following alkylation reaction with alkyl iodide at the downstream in the flow operation.

   Consequently, the monoalkylation in electrochemical flow-microreactor was proceeded very efficiency at ambient temperature. Namely, the monoalkylated product 5 was obtained in 85% yield without forming any by-products.

References

1          R. C. Hallcher, and M. M. Baizer, Liebigs Ann.,
1977, 737.

2          T. Shono, S. Kashimura, and H. Nogusa, J. Org. Chem.,
1984, 49, 2043.

3          T. Shono, S. Kashimura, M. Sawamura, and T. Soejima, J. Org. Chem.,
1988, 53, 907.

Figure 1