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RSC Advances
DOI: 10.1039/C5RA19286B
Journal Name
COMMUNICATION
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.
Ashikari, T. Morofuji, R. Hayashi, T. Nokami, and A. Nagaki,
Bull. Chem. Soc. Jpn., 2015, 88, 763; (c) A. Nagaki, M. Takumi,
Y. Tani, J. Yoshida, Tetrahedron, 2015, 71, 5973.
(a) D. Horii, T. Fuchigami, and M. Atobe, J. Am. Chem. Soc.,
2007, 129, 11692; (b) D. Horii, F. Amemiya, T. Fuchigami, and
M. Atobe, Chem. Euro. J., 2008, 14, 10382; (c) F. Amemiya, K.
Fuse, T. Fuchigami, and M. Atobe, Chem. Commun., 2010, 46
,
2730; (d) F. Amemiya, H. Matsumoto, K. Fuse, T. Kashiwagi,
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.
2011, 9, 4256; (e) F. Amemiya, T. Kashiwagi, T. Fuchigami,
and M. Atobe, Chem. Lett., 2011, 40, 606; (f) T. Kashiwagi, F.
Amemiya, T. Fuchigami, and M. Atobe, Chem. Commun.,
2012, 48, 2806; (g) T. Kashiwagi, F. Amemiya, T. Fuchigami,
Conclusions
and M. Atobe, J. Flow Chem., 2012, 3, 17; (h) T. Kashiwagi, T.
Fuchigami, T. Saito, S. Nishiyama, and M. Atobe, Chem. Lett.,
2014, 43, 799; (i) T. Arai, H. Tateno, K. Nakabayashi, T.
Kashiwagi, and M. Atobe, Chem. Commun., 2015, 51, 4891.
R. C. Hallcher, and M. M. Baizer, Liebigs Ann., 1977, 737.
T. Shono, S. Kashimura, and H. Nogusa, J. Org. Chem., 1984,
49, 2043.
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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