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e) Yoshida, J.-I.; Suga, S.; Nagaki, A. J. Synth. Org. Chem. Jpn.
005, 63, 511–522.
. Recent applications, see: (a) Pennemann, H.; Hessel, V.; Loewe, H.
Chem. Eng. Sci. 2004, 59, 4789–4794; (b) Jahnisch, K.; Hessel, V.;
Loewe, H.; Baerns, M. Angew. Chem., Int. Ed. 2004, 43, 406–446; (c)
Nagaki, A.; Togai, M.; Suga, S.; Aoki, N.; Mae, K.; Yoshida, J.-I. J.
Am. Chem. Soc. 2005, 127, 11666–11675; (d) Ratner, D. M.; Murphy,
E. R.; Jhunjhunwala, M.; Snyder, D. A.; Jensen, K. F.; Seeberger, P.
H. Chem. Commun. 2005, 578–580.
. (a) Fukase, K.; Takashina, M.; Hori, Y.; Tanaka, D.; Tanaka, K.;
Kusumoto, S. Synlett 2005, 2342–2346; (b) Tanaka, S.; Goi, T.;
Tanaka, K.; Fukase, K. J. Carbohydr. Chem. 2007, 26, 369–394; (c)
Tanaka, K.; Motomatsu, S.; Koyama, K.; Tanaka, S.; Fukase, K.
Org. Lett. 2007, 9, 299–302; (d) Tanaka, K.; Fukase, K. Synlett 2007,
enolate, in spite of the large differences in their pK
ꢀ20 for a-proton of carbonyls).
a
(ꢀ16 for H
2
O and
(
2
8. In order to compare the microfluidic and the batch conditions, the
same concentrations of the aldehydes (in acetone) and the aqueous
NaOH solution were used for the batch reaction: A 5.5 M solution of
the aldehyde (1.5 mol scale) in acetone was added to the premixed
biphasic solution of acetone and 2.5 M NaOH (2.7:1) at 8.5 °C over
1.5–3 h.
2
9. Typical procedure of microfluidic aldol condensation: Acetone and
2.5 M NaOH solution were injected to the first micromixer (Comet
X-01) at room temperature, by using syringe-pumps at a flow rate of
0.5 mL/min for acetone and 0.25 mL/min for NaOH solution. After
the mixture was allowed to flow for 45 s through a Teflon reactor tube
(£ = 1.0 mm, l = 0.9 m) at this temperature, the intermediary enolate
was mixed with a solution of isobutyraldehyde 2 (10 g, 139 mmol,
5.5 M) in acetone (25 mL) through the second micromixer (Comet
X-01) by another syringe-pump at a flow rate of 0.25 mL/min at room
temperature. After the reaction mixture was allowed to flow at the
same temperature for additional 15 s through a Teflon reactor tube
(£ = 1.0 mm, l = 0.3 m), the mixture was quenched by another flow
of 2.5 M HCl solution (0.25 mL/min) using the T-shaped mixer at
room temperature. It takes about 20 min to consume 10 g of substrate
2 under the above conditions. The mixture was extracted with ethyl
3
164–166.
4
. (a) Heathcock, C. H. In Comprehensive Carbanion Chemistry, Part B;
Buncel, E., Durst, T., Eds.; Elsevier: Amsterdam, 1984; Chapter 4; (b)
Heathcock, C. H. In Asymmetric Synthesis, Part B; Morrison, D. J.,
Ed.; Academic Press: New York, 1984; Vol. 3, p 2111; (c) Evans, D.
A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1; (d)
Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1; (e) Heathcock, C. H. In Modern Synthetic
Methods; Scheffold, R., Ed.; G. Thieme: Stuttgart, 1992; p 1; (f)
Braun, M.. In Houben Weyl; Helmchen, G., Hoffmann, R. W.,
Mulzer, J., Schaumann, E., Eds.; G. Thieme: Stuttgart, 1995; Vol.
E21b, p 1603.
. A micromixing device, ‘Comet X-01’ was used. Available from
Techno Applications Co., Ltd, 34-16-204, Hon, Denenchofu, Oota,
Tokyo 145-0072, Japan.
. Usutani, H.; Tomida, Y.; Nagaki, A.; Okamoto, H.; Nokami, T.;
Yoshida, J. J. Am. Chem. Soc. 2007, 129, 3046–3047.
2 4
acetate, washed with brine, dried over Na SO , filtered, and concen-
trated in vacuo to give the crude product. The residue was purified by
distillation under reduced pressure (50–70 °C/20 mm Hg) to afford 7
(17 g, 95%). The spectrum data were in good agreement to those
reported in Ref. 10. The conditions established herein can be readily
applicable to the scale-up synthesis simply by preparing the stock
solutions of substrate and reagents and pumping them continuously
into the micromixing system.
5
6
10. Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem.
2004, 69, 5906–5925.
11. Geranyl aldehyde 5 was obtained by manganese dioxide oxidation of
geraniol. Crude 5 was directly used for the aldol reaction with
acetone.
7
. The treatment of acetone with aqueous NaOH solution affords a
biphasic mixture at a high concentration of NaOH. Micromixing
should promote efficient transfer of NaOH from aqueous layer to
organic layer and consequently form sufficient amount of acetone