Continuous in situ electrogenaration of a 2-pyrrolidone anion in a microreactor: application to highly efficient monoalkylation of methyl phenylacetate

Abstract

We have successfully demonstrated effective generation of an electrogenerated base (EGB) such as the 2-pyrrolidone anion and its rapid use for the following alkylation reaction in a flow microreactor system without the need for severe reaction conditions. The key feature of the method is effective and selective preparation of monoalkylated products.

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Generation and control of reactive species (including short-lived molecules) are one of the most important issues in organic reactions. Temperature, solvent, reaction time, additives, etc. have been commonly examined for this purpose. On the other hand, recent progress of organic synthesis in flow conditions has opened a new reaction system to control highly reactive species. The key feature of the system is the fast generation and consumption of the reactive species. Hence, the reactions using the reactive species can be operated even under mild conditions. Chemically generated reactive species have been employed for the several organic synthetic systems in flow conditions.¹ Although electrochemically generated species can be also employed for organic reactions in flow conditions,^2,3 the application of the species has been limited so far.

Anionic species generated cathodically act not only as nucleophiles but also as bases, which have interesting reactivities in organic synthesis. Baizer et al. demonstrated that cathodically generated anion radical of hindered azobenzene could be utilized as a useful base for various organic syntheses, and they named such base as “electrogenerated base” (EGB).⁴ The EGBs could be also 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 α-monoalkylation of α-(aryl)acetate esters, and α-monoalkylation of 1,3-diketones.^5,6 However, severe reaction conditions such as low temperature, inert gas are usually required for the use of EGBs.

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

Scheme 1 Monoalkylation of methyl phenylacetate.

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 formed by the reaction 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 Fig. 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.

Fig. 1 Schematic representation of flow microreactor.

Prior to using the flow microreactor, the model reaction was examined by a conventional method using a divided electrochemical cell (batch type cell) equipped with a glass filter diaphragm and platinum mesh anode (90 cm²) and cathode (40 cm²). Methyl phenylacetate 3 was added to catholyte of the cell at sufficiently low temperature (−70 °C) under an atmosphere of nitrogen after the electrochemical reduction of 1. Subsequently, methyl iodide was added as an alkyl iodide (R-I) to this solution and the reaction mixture was stirred for 15 min at −70 °C. In this case, the monomethylated product 5a was obtained in a good yield but the dimethylated product 6a was also slightly obtained (Table 1, entry 1). On the other hand, the total yield of both products 5a and 6a drastically decreased when 3 was added to catholyte of the cell at ambient temperature (Table 1, entry 2). This was ascribed to a low stability of the intermediate 4 at ambient temperature. In addition, the selectivity of monomethylated product 5a was quite low and main product was found to be the dimethylated product 6a.

Table 1 Methylation of methyl phenylacetate using batch cell and flow microreactor

Entry	Reactor type	Temperature	Conversion of 3^c (%)	Yield^d	Selectivity^c
				5a + 6a	5a : 6a
a Anode, Pt mesh (90 cm^2); cathode, Pt mesh (40 cm^2); current density, 5.0 mA cm^−2; solvent, N,N-dimethylformamide; substrate, 500 mM 2-pyrrolidone, and 125 mM methyl phenylacetate; supporting electrolyte, 750 mM Bu4NClO4; electrophile, 500 mM iodomethane.b Anode, Pt plate (1 × 3 cm^2); cathode, Pt plate (1 × 3 cm^2); current density, 1.5 mA cm^−2; electrode distance, 80 μm; flow rate, 0.1 mL min^−1; solvent, N,N-dimethylformamide; substrate, 500 mM 2-pyrrolidone and 50 mM methyl phenylacetate; supporting electrolyte, 100 mM Bu4NClO4; electrophile, 500 mM iodomethane.c Determined by RP-HPLC (CH3CN/H2O = 50/50, ethylbenzene as an internal standard).d Yield based on the amount of consumed starting material.
1	Batch type cell^a	−70 °C	76	91	94 : 6
2	Batch type cell^a	r.t.	35	46	<1 : >99
3	Flow microreactor^b	r.t.	52	85	100 : 0

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In sharp contrast, the use of a flow microreactor enabled the yield to improve drastically even at ambient temperature (Table 1, entry 3). Because the conversion yield based on the amount of consumed 3 was 85%, the intermediate 4 deprotonated from 3 could react with methyl iodide effectively before its decomposition. Moreover, the selectivity for 5a reached to 100% and the dimethylated product 6a was never obtained in this case.

Next, we investigated the utility of the parallel laminar flow mode illustrated in Fig. 1 for the effective production of 5a in this model reaction. In this demonstration, the methylation was carried out in different types of flow modes (flow modes B and C illustrated in Table 2). In the flow mode B, two solutions of 1 and 3 were not separated by the laminar flow at the electrolysis part and the solution of methyl iodide was introduced at the downstream of the reactor. By this operation (entry 2), however, the conversion and yield were remarkably decreased in comparison with those obtained by the flow mode A (entry 1). Probably the effective generation of EGB 2 was suppressed in this case. On the other hand, in the flow mode C, the probase 1, the substrate 2, and methyl iodide were mixed in the same electrolytic solution and then the solution was flowed through the microreactor. However, we could not confirm conversion of the substrate 3 and formation of the product 5a by the operation of the flow mode C. In this case, the reduction of methyl iodide might be occurred dominantly due to its low reduction potential. From these facts, it can be stated that the liquid–liquid parallel laminar flow mode illustrated in Fig. 1 (flow mode A in Table 2) is necessary for the efficient flow reaction.

Table 2 Monoalkylation of methyl phenylacetate using various flow modes in flow microreactor

Entry	Flow mode^a	Conversion of 3^b (%)	Yield of 5a^c (%)
a Anode, Pt plate (1 × 3 cm^2); cathode, Pt plate (1 × 3 cm^2); current density, 1.5 mA cm^−2; electrode distance, 80 μm; flow rate, 0.1 mL min^−1; solvent, N,N-dimethylformamide; substrate, 500 mM 2-pyrrolidone and 50 mM methyl phenylacetate; supporting electrolyte, 100 mM Bu4NClO4; electrophile, 500 mM iodomethane.b Determined by RP-HPLC (CH3CN/H2O = 50/50, ethylbenzene as an internal standard).c Yield based on the amount of consumed starting material.
1	A	52	85
2	B	35	16
3	C	n.d.	n.d.

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Furthermore, we investigated general versatility of alkyl iodide agents such as methyl-, iso-propyl-, and tert-butyl-iodides for the model alkylation using the optimized flow reactor system (Table 3). The yields of alkylated methyl phenylacetate was decreased in the order of 5a > 5b > 5c. Notably, product 5c having tertiary alkyl group was not obtained by the reaction of phenylacetate with tert-butyliodide. This result based apparently on low reactivity of S_N2 nucleophilic substitution reaction of the intermediate 4 with a bulky halide like tert-butyliodide. Hence, the flow reactor system might be usable for reactions with various alkyl halides other than tert-butylhalides.

Table 3 Monoalkylation of methyl phenylacetate with various alkyl iodides in flow microreactor system

Entry	Alkyl iodide (R-I)	Product	Conversion^a (%)	Yield^b (%)
a Determined by RP-HPLC (CH3CN/H2O = 50/50, ethylbenzene Std).b Yield based on the amount of consumed starting material.
1	Me-I	5a	52	85
2	^iPr-I	5b	56	54
3	^tBu-I	5c	60	0

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Conclusions

We successfully demonstrated efficient alkylation of methyl phenylacetate using liquid–liquid parallel flow mode in the two-inlet flow microreactor. By using the flow microreactor, the monoalkylation of methyl phenylacetate proceeded selectively without the need for the low temperature condition. Although the conversion of substrate was moderate, the conversion yield of the product was enough high. The selectivity and yield of the products for the model reaction would be influenced by the electrode size, applied voltage, length of the microchannel, flow rate, reaction temperature, and so on. A systematic study on the effect of these parameters on the model reaction is in progress. In addition, on the bases of the advantage of flow systems, the alkylation of various methyl arylacetates and investigation of the other reaction processes with EBG are also in progress.

Acknowledgements

This work was financially supported by The Grant-in-Aid for Scientific Research on Innovative Areas (No. 2707: Middle Molecular Strategy).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Chemicals and experimental details. See DOI: 10.1039/c5ra19286b

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