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

Article abstract of DOI:10.1039/c5ra19286b

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.

Full text of DOI:10.1039/c5ra19286b

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DOI: 10.1039/C5RA19286B
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Continuous In Situ Electrogenaration of 2-Pyrrolidone Anion in
Microreactor: Application to Highly Efficient Monoalkylation of
Methyl Phenylacetate
Received 00th January 20xx,
Accepted 00th January 20xx
Yoshimasa Matsumura, Yoshinobu Kakizaki, Hiroyuki Tateno, Tsuneo Kashiwagi, Yoshiyuki Yamaji,
and Mahito Atobe*
DOI: 10.1039/x0xx00000x
www.rsc.org/
We have successfully demonstrated an effective generation of
electrogenerated base (EGB) such as 2-pyrrolidone anion and its monoalkylation of 1,3-diketones.5,6 However, severe reaction
rapid use for the following alkylation reaction in flow conditions such as low temperature, inert gas are usually
microreactor system without need for severe reaction conditions. required for the use of EGBs.
α
monoalkylation of
α
(aryl)acetate esters, and
α-
a
The key feature of the method is an effective and selective
preparation of monoalkylated products.
In this paper, we wish to demonstrate that
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 in
this work, we chose alkylations of methyl phenylacetate
using electrogenerated (Scheme 1). It is well known that the
monoalkylated product can be converted into some
alkylphenylacetic acids, which possess high anti-
a flow
2
Generation and controlling of reactive species (including
short-lived molecules) are one of the most important issues in
organic reaction. Temperature, solvent, reaction time,
additives, etc. have been commonly examined for this
purpose. On the other hand, recent progress of organic
synthesis in flow condition opened a new reaction system
controlling highly reactive species. The key feature of the
system is that 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.
1
α
3
2
5
α
inflammatory and analgetic activities.
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
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
reaction between and , and the final alkylation reaction part
for the rapid use of the unstable intermediate for obtaining
the monoalkylated product formed by the reaction with alkyl
2, the deprotonation part for the
2
3
4
5
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
Department of Environment and System Sciences, Yokohama National University,
79-7 Tokiwadai, Hodogaya-ku, Yokohama, 2408501, Japan.
E-mail: atobe@ynu.ac.jp; Fax: +81 45 339 4214; Tel: +81 45 339 4214
Electronic Supplementary Information (ESI) available: Chemicals and experimental
details. See DOI: 10.1039/x0xx00000x
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
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means of diffusion. Therefore, the probase
1 introduced product 5a was quite low and main product was found to be
through cathodic side inlet (inlet 1) could be predominantly the dimethylated product 6a
reduced, and in addition the re-oxidation of electrogenerated In sharp contrast, the use of a flow microreactor enabled the
could be avoided by its rapid reaction with at a liquid-liquid yield to improve drastically even at ambient temperature
interface before reaching to the anode surface. Furthermore, (Table 1, entry 3). Because the conversion yield based on the
the reactive intermediate formed at the interface could be amount of consumed was 85%, the intermediate
used rapidly for the following alkylation reaction with alkyl deprotonated from could react with methyl iodide effectively
.
2
3
4
3
4
3
iodide at the downstream in the flow operation.
before its decomposition. Moreover, the selectivity for 5a
reached to 100% and the dimethylated product 6a was never
obtained in this case.
Table 2 Monoalkylation of methyl phenylacetate using various flow modes
in flow microreactor
Fig. 1 Schematic representation of flow microreactor.
Table 1 Methylation of methyl phenylacetate using batch cell and flow
microreactor
a
Anode, Pt mesh (90 cm2); cathode, Pt mesh (40 cm2); 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
b
iodomethane. Anode, Pt plate (1 x 3 cm2); cathode, Pt plate (1 x 3 cm2); 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
a Anode, Pt plate (1 x 3 cm2); cathode, Pt plate (1 x 3 cm2); current density, 1.5 mA cm-2
;
electrode distance, 80 µm; flow rate, 0.1 mL min-1; solvent, N,N-dimethylformamide;
c
iodomethane. Determined by RP-HPLC (CH3CN/H2O = 50/50, ethylbenzene as an
internal standard). d Yield based on the amount of consumed starting material.
substrate, 500 mM 2-pyrrolidone and 50 mM methyl phenylacetate; supporting
b
electrolyte, 100 mM Bu4NClO4; electrophile, 500 mM iodomethane. Determined by
c
RP-HPLC (CH3CN/H2O = 50/50, ethylbenzene as an internal standard). Yield based on
Prior to using the flow microreactor, the model reaction was
the amount of consumed starting material.
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
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
cathode (40 cm2). Methyl phenylacetate
3 was added to
catholyte of the cell at sufficiently low temperature (–70 ºC)
under an atmosphere of nitrogen after the electrochemical
reduction of 1. Subsequently, methyl iodide was added as an
of
1 and 3 were not separated by the laminar flow at the
alkyl iodide (R–I) to this solution and the reaction mixture was
stirred for 15 min at –70 ºC. 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
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
drastically decreased when
cell at ambient temperature (Table 1, entry 2). This was
ascribed to a low stability of the intermediate at ambient
3 was added to catholyte of the
EGB
2
was suppressed in this case. On the other hand, in the
, the substrate , and methyl iodide
flow mode C, the probase
1
2
4
were mixed in the same electrolytic solution and then the
solution was flowed through the microreactor. However, we
temperature. In addition, the selectivity of monomethylated
2 | J. Name., 2012, 00, 1-3
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could not confirm conversion of the substrate
3
and formation
Acknowledgement
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.
This work was financially supported by The Grant-in-Aid for
Scientific Research on Innovative Areas (No. 2707: Middle
Molecular Strategy).
Notes and references
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
1
Some selected recent examples: (a) T. Kawaguchi, H. Miyata,
K. Ataka, K. Mae, and J. Yoshida, Angew. Chem. Int. Ed.,
2005, 44, 2413; (b) A. Nagaki, K. Imai, S. Ishiuchi, and J.
Yoshida, Angew. Chem. Int. Ed., 2015, 54, 1914; (c) A. Nagaki,
phenylacetate was decreased in the order of 5a
> 5b > 5c.
S. Tokuoka, and J. Yoshida, Chem. Commun., 2014, 50
,
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
15079; (d) A. Nagaki, D. Ichinari, and J. Yoshida, J. Am. Chem.
Soc., 2014, 136, 12245; (e) J. Yoshida, Y. Takahashi, and A.
Nagaki, Chem. Commun., 2013, 49, 9896; (f) A. Nagaki, D.
Ichinari, and J. Yoshida, Chem. Commun., 2013, 49, 3242; (g)
A. Nagaki, D. Yamada, S. Yamada, M. Doi, D. Ichinari, Y.
Tomida, N. Takabayashi, and J. Yoshida, Aust. J. Chem., 2013,
66, 199; (h) H. Usutani, Y. Tomida, A. Nagaki, H. Okamoto, T.
Nokami, and J. Yoshida, J. Am. Chem. Soc., 2007, 129, 3046;
(i) W. Shu, and S. L. Buchwald, Angew. Chem. Int. Ed., 2012,
51, 5355; (j) A. Nagaki, Y. Moriwaki, and J. Yoshida, Chem.
Commun., 2012, 48, 11211; (k) A. S. Kleinke, and T. F.
Jamison, Org. Lett., 2013, 15, 710.
SN2 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.
2
3
(a) S. Suga, M. Okajima, K. Fujiwara, and J. Yoshida, J. Am.
Chem. Soc., 2001, 123, 7941; (b) J. Yoshida, A. Shimizu, Y.
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,
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C. Kuroda, T. Fuchigami, and M. Atobe, Org. Biomol. Chem.,
a Determined by RP-HPLC (CH3CN/H2O = 50/50, ethylbenzene Std). b Yield based on the
amount of consumed starting material.
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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 monoalkyration 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.
4
5
6
T. Shono, S. Kashimura, M. Sawamura, and T. Soejima, J. Org.
Chem., 1988, 53, 907.
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Graphical abstract
We have successfully demonstrated an effective generation of electrogenerated base (EGB) such as 2-pyrrolidone anion
and its rapid use for the following alkylation reaction in a flow microreactor system without need for severe reaction
conditions. The key feature of the method is an effective and selective preparation of monoalkylated products.