Cation flow method: A new approach to conventional and combinatorial organic syntheses using electrochemical microflow systems

Full text of DOI:10.1021/ja015823i

J. Am. Chem. Soc. 2001, 123, 7941-7942
“Cation Flow” Method: A New Approach to
7941
Conventional and Combinatorial Organic Syntheses
Using Electrochemical Microflow Systems
Seiji Suga, Masayuki Okajima, Kazuyuki Fujiwara, and
Jun-ichi Yoshida*
Department of Synthetic Chemistry and
Biological Chemistry, Graduate School of Engineering
Kyoto UniVersity Kyoto 606-8501, Japan
ReceiVed March 15, 2001
ReVised Manuscript ReceiVed June 28, 2001
Figure 1. Schematic diagram of “cation flow” system.
Microflow reactors1 have received significant interest in the
stream of downsizing of chemistry,2 and they are expected to make
an innovative and revolutionary change for chemical synthesis.3
In addition to the safety and environmental benefits of dealing
with smaller quantities of material, microflow reactors have
several advantages4 over conventional systems stemming from
the high surface-to-volume ratio; for example, precise temperature
control and high efficiency of heterogeneous mass transfer. Short
residence times in reactors may also be advantageous from a
viewpoint of the control of highly reactive intermediates. The
advantages of microflow reactors of easy modulation5 and the
possibility of combining reactors in parallel promising a quick
means for scale-up6 also warrant comment.
Recently we have developed a “cation pool” method that
involves generation and accumulation of highly reactive carbo-
cations by low-temperature electrolysis.7 This method enables the
manipulation of carbocation intermediates to achieve direct
oxidative C-C bond formation, but its applicability strongly
depends on the stability of the carbocation that is accumulated.
We envisioned that the application of microflow systems expands
the scope of this methodology because of high efficiency of the
temperature control and short residence time.
To prove the principle of the “cation flow” method, we chose
carbamates as precursors of cations because their chemistry is
well established in the “cation pool” method. We developed the
electrochemical microflow reactor composed of diflone and
stainless steel bodies by a mechanical manufacturing technique
(Figure 1). The two-compartment cell was divided by a diaphragm
of PTFE membrane. A typical reaction procedure is as follows.
A 0.05 M solution of methyl pyrrolidinecarboxylate (1) containing
supporting electrolyte (Bu4NBF4, 0.3 M) in dichloromethane was
introduced with cooling (-72 °C) by syringe pumping (flow rate
is 2.1 mL/h) to the anodic chamber equipped with a carbon felt
anode (7 mm × 7 mm × 5 mm) made of carbon fibers (φ 10
µm). A solution of the supporting electrolyte and trifluo-
romethanesulfonic acid (TfOH) as a proton source was introduced
to the cathodic chamber equipped with a platinum wire cathode.
The cationic intermediate generated by low-temperature elec-
trolysis (14 mA) of 1 was immediately transferred to a vessel in
which a nucleophilic reaction took place to give the final coupling
product.
It is important to construct a monitoring device for the flow
system. FTIR spectroscopy was applied for the online monitoring
of the cationic intermediate. The starting material 1 exhibited an
absorption at 1694 cm-1 due to the carbonyl stretching, while
the acyliminium cation generated by the “cation pool” method7a
from 1 exhibited an absorption at 1814 cm-1. The higher
wavenumber of the cation is consistent with the formation of a
positive charge at the nitrogen adjacent to the carbonyl carbon.
The shift to higher wavenumber is also supported by DFT (density
functional theory) calculations,10 which indicate that wavenumbers
for CdO vibration of model compounds (CH3)2N(CO2CH3) and
CH3N+(dCH2)CO2CH3 are 1734 and 1856 cm-1, respectively.
Thus, the “cation flow” system was monitored by the FTIR
spectrometer (ATR method) equipped with a low-temperature
flow cell attached to the outlet of the electrochemical microflow
reactor. The formation of the acyliminium cation was indicated
by the absorption at 1814 cm-1, which increased with the increase
of the electric current (Figure 2). The current of 14 mA was
applied in the following preparative reactions, because FTIR
monitoring indicated that it was sufficient for the generation of
the acyliminium cation.
The present “cation flow” system can be applied to the direct
oxidative C-C bond formation with various carbon nucleo-
philes.11,12 Thus, the stream of the cation generated from 1 was
allowed to react with various carbon nucleophiles such as
allylsilanes and enol ethers to obtain the corresponding C-C bond
In this paper we report direct electrooxidative C-C bond
formation using a low-temperature electrochemical microflow
system.8 This system generates carbocation continuously as
“cation flow”. The “cation flow” method is expected to enable
the manipulation of unstable carbocations and opens a new aspect
of chemical synthesis using carbocation intermediates.9
(1) (a) Ehrfeld, W., Ed. Microreaction Technology; Springer: Berlin, 1998.
(b) Ehrfeld, W.; Hessel, V.; Lo¨we, H. Microreactors; Wiley-VCH: Weinheim,
2000. (c) Manz, A.; Becker, H., Eds. Microsystem Technology in Chemistry
and Life Sciences; Springer: Berlin, 1999. (d) Zech, T.; Ho¨nicke, D. Erdoel
Erdgas Kohle, 1998, 114, 578. (e) Schubert, K. Chem. Technol. (Heidelberg)
1998, 27, 124.
(2) (a) Harrison, D. J.; Fluri, K.; Seiler, K.; Fan, Z.; Effenhauser, C. S.;
Manz, A. Science 1993, 261, 895. (b) Kitamori, T.; Fujinami, M.; Odake, T.;
Yokeshi, M.; Sawada, T. Proc. µTAS 1998, 295. (c) Freemantle, M. Chem.
Eng. News 1999, 78(February 22), 27. (d) Fletcher, P.; Haswell, S. Chem.
Brit. 1999 (November), 38. (e) Hsing, I. M.; Srinivasan, R.; Harold, M. P.;
Jensen, K. F.; Schmidt, M. A. Chem. Eng. Sci. 2000, 55, 3.
(3) (a) Salimi-Moosavi, H.; Tang, T.; Harrison, D. J. J. Am. Chem. Soc.
1997, 119, 8716. (b) Chambers, R. D.; Spink, R. C. H. Chem. Commun. 1999,
883. (c) Kenis, P. J. A.; Ismagilov, R. F.; Takayama, S.; Whitesides, G. M.;
Li, S.; White, H. S. Acc. Chem. Res. 2000, 33, 841. (d) Greenway, G. M.;
Haswell, S. J.; Morgan, D. O.; Skelton, V.; Styring, P. Sens. Actuators, B
2000, 63, 153.
(4) Reviews on the applications of microreactors in organic synthesis: For
example, (a) DeWitt, S. H. Curr. Opin. Chem. Biol. 1999, 3, 350. (b) Okamoto,
H. J. Synth. Org. Chem., Jpn. 1999, 57, 805. (c) Sugawara, T. Pharmacia
2000, 36, 34.
(5) Bard, A. J. Patent WO 9,526,796, 1995.
(6) Chopey, N. P.; Ondrey, G.; Parkinson, G. Chem. Eng. 1997 (March),
30.
(7) (a) Yoshida, J.; Suga, S.; Suzuki, S.; Kinomura, N.; Yamamoto, A.;
Fujiwara, K. J. Am. Chem. Soc. 1999, 121, 9546. (b) Suga, S.; Suzuki, S.;
Yamamoto, A.; Yoshida, J. J. Am. Chem. Soc. 2000, 122, 10244. (c) Suga,
S.; Okajima, M.; Yoshida, J. Tetrahedron Lett. 2001, 42, 2173.
(8) Electrochemical microreactors, see: Lo¨we, H.; Ehrfeld, W. Electrochim.
Acta 1999, 44, 3679. Electrochemical flow reactors: For example, Karakus,
C.; Zuman, P. J. Electrochem. Soc. 1995, 142, 4018.
(9) For example, Prakash, G. K. S.; Schleyer, P. v. R, Eds. Stable
Carbocation Chemistry; Wiley: New York, 1997.
(10) DFT calculations were carried out at B3LYP/6-31(d) level with full
geometry optimization using G98W program (the scale factor ) 0.9613),
see: Wong, M. W. Chem. Phys. Lett. 1996, 256, 391.
(11) Synthetic applications of electrochemical oxidation: Moeller, K. D.
Tetrahedron 2000, 56, 9527.
10.1021/ja015823i CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/24/2001

7942 J. Am. Chem. Soc., Vol. 123, No. 32, 2001
Communications to the Editor
Scheme 1. Continuous Sequential Combinatorial Synthesis
Using “Cation Flow” System
Figure 2. FTIR spectra of the “cation flow”.
Table 1. Direct Electrooxidative C-C Bond Formation of
Carbamates Using “Cation Flow” Systema
Another outstanding feature of the “cation flow” system is that
continuous sequential combinatorial synthesis13 can be ac-
complished by simple flow switching. The results of preliminary
experiments are shown in Scheme 1. In the first step, the “cation
flow” generated from 1 was allowed to react with nucleophile
A. Then, the “cation flow” was allowed to react with nucleophile
B. In the third step, the “cation flow” was allowed to react with
nucleophile C. Then, the precursor of the cation was switched to
2, and the “cation flow” generated from 2 was allowed to react
with nucleophiles A, B, and C sequentially. Then the precursor
of the cation was switched to 3, and the “cation flow” generated
from 3 was allowed to react with nucleophiles A, B, and C
sequentially. Although parallel syntheses enjoy versatile applica-
tions in combinatorial chemistry, the present continuous sequential
method opens a new intriguing aspect of combinatorial synthesis.
Further downsizing of the reactor together with the development
of related techniques will hopefully lead to a new dimension of
combinatorial synthesis.
The results shown here demonstrate that electrochemical
microflow systems open a new aspect of the chemistry using
carbocations. Further work aimed at establishing the scope of the
“cation flow” system and its applications to conventional and
combinatorial organic syntheses are currently in progress.
a The nucleophilic reactions were usually carried out with a car-
bamate (0.4 mmol) and a carbon nucleophile (0.8 mmol) at -72 °C.
b Yield based on consumed starting material. c The nucleophilic reac-
tions were caried out at -28 °C. d 2.3 mmol of the enol silyl ether was
used.
Acknowledgment. This work is partially supported by Grant-in-Aid
for Scientific Research and Special Coordination Funds for Promoting
Science and Technology from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan. We thank Hokuto Denko for manufac-
turing of the electrochemical microflow reactors, and ST Japan Inc. for
the use of TravelIR systems. We also thank Mr. N. Kinomura, Mr. R.
Fukuda, and Dr. N. Kise for their contribution to the very early stage of
this work.
formation products (Table 1). The “cation flow” method can also
be applicable to other carbamates (2-4) as cation precursors.
Supporting Information Available: Experimental procedures and
analytical and spectroscopic data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) Two-step procedures for the electrooxidative C-C bond formation,
see: (a) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981,
103, 1172. (b) Shono, T. Tetrahedron 1984, 40, 811. (c) Malmberg, M.;
Nyberg, K. Acta Chem. Scand., Ser. B 1979, 33, 69. (d) Mori, M.; Kagechika,
K.; Sasai, H.; Shibasaki, M. Tetrahedron 1991, 47, 531. (e) Li, W.; Moeller,
K. D. J. Am. Chem. Soc. 1996, 118, 10106. (f) Danielmeier, K.; Schierle, K.;
Steckhan, E. Tetrahedron 1996, 52, 9743. (g) Matsumura, Y.; Kanda, Y.;
Shirai, K.; Onomura, O.; Maki, T. Org. Lett. 1999, 1, 175.
JA015823I
(13) Combinatorial chemistry using microreactors: For example, (a)
Senkan, S. M.; Ozturk, S. Angew. Chem., Int. Ed. 1999, 38, 791. (b) Senkan,
S. Angew. Chem., Int. Ed. 2001, 40, 312.