(3) dehydration, and (4) hydrogenation, as shown in Scheme
1. Small quantities (50 mg) of the sample are readily prepared
as diene 4, under acidic conditions; hence the method is well-
suited for the present large-scale dehydration of 3. We have
recently applied a microfluidic system to other cation-
mediated reactions and improvements have been realized for
glycosylation reaction6 and the reductive opening of ben-
zylidene groups.7
Scheme 1. Synthesis of Pristane
We examined the microfluidic dehydration under the
following conditions (Figure 1): Allylic alcohol 3 (1.0 M
via this route; however, synthesis of the required 200 kg
annually at greater than 98% purity presents unique chal-
lenges. In particular, the preparation of 5 kg of pristane per
week is necessary to supply enough material to the market.
The challenging step in Scheme 1 is the acid-catalyzed
dehydration of allylic alcohol 3. When the reaction was
performed on a 100 mg scale with a catalytic amount of
p-TsOH in benzene at 80 °C, the corresponding diene 4 was
obtained in 55% yield as a mixture of (E)- and (Z)-
stereoisomers, which was transformed to pristane by hydro-
genation. However, when the scale was increased to 100 g,
various cation-mediated byproducts, such as cyclized prod-
ucts or alkyl group-migrated compounds, were produced. As
expected, these hydrocarbons were very difficult to separate
from the desired diene 4 (yield estimated to be less than
20%), even by repeated distillation or by silica gel chroma-
tography, although the latter is not realistic for kilogram-
scale purification. A more direct olefination with use of the
Wittig reaction with aldehyde 2 cannot be used either, since
the triphenylphosphine oxide generated is problematic for
such a large-scale synthesis. In this paper, we report the
successful application of a continuous microfluidic system
to the dehydration reaction, which led to the 5-kg-scale
synthesis of pristane performed only by one chemist within
a week.
Figure 1. Optimization of microfluidic dehydration.
in THF) was mixed with a solution of p-TsOH (various
concentrations of 0.2-1.0 M in THF:toluene 1:1)8 at 90 °C
by using an IMM micromixer9 at a flow rate of 0.3 mL/
min. After the reaction mixture was allowed to flow for an
additional 47 s through a reactor tube (Φ ) 1.0 mm, l ) 1.0
m) at 90 °C, the mixture was quenched with a saturated
NaHCO3 solution at room temperature. When a 0.2 M
solution of p-TsOH was used, only a trace amount of 4 was
obtained and the starting material 3 was largely recovered.
However, we found that the yield of the dehydrated
compound depends on the concentration of the acid; 4 was
finally obtained in 80% yield (overall, from farnesol 1) at
an acid concentration of 1.0 M. It is noted that under the
established microfluidic conditions, the formation of other
byproducts could not be detected by TLC analysis.10
To evaluate the efficiency of dehydration under the
microfluidic conditions, the reactivity of â-hydroxyketone
5 and alkanol 7 was also tested (Scheme 2). Gratifyingly,
both substrates provided the corresponding dehydrated
products in almost quantitative yields under the conditions
established in Scheme 2. Thus, â-hydroxyketone 5 gave (E)-
unsaturated ketone 611 quantitatively upon mixing with
A continuous flow microreactor, which is reported to
realize efficient mixing and fast heat transfer, is recognized
as an innovative technology in recent organic syntheses.4,5
The flow system also allows the reaction to be quenched
immediately after the formation of an unstable product, such
(4) Representative reviews, see: (a) Ehrfeld, W., Ed. Microreaction
Technology; Springer: Berlin, Germany, 1998. (b) Manz, A.; Becker, H.,
Eds. Mycrosystem Technology in Chemistry and Life Sciences; Springer:
Berlin, Germany, 1998. (c) Ehrfeld, W.; Hessel, V.; Lowe, H. Microreactors;
Wiley-VCH: Weinheim, Germany, 2000. (d) Hessel, V.; Hardt, S.; Lowe,
H. Chemical Micro Process Engineering; Wiley-VCH: Weinheim, Ger-
many, 2004. (e) Yoshida, J.-I.; Suga, S.; Nagaki, A. J. Synth. Org. Chem.
Jpn. 2005, 63, 511-522.
(5) 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.
(6) Fukase, K.; Takashina, M.; Hori, Y.; Tanaka, D.; Tanaka, K.;
Kusumoto, S. Synlett 2005, 2342-2346.
(7) Tanaka, K.; Fukase, K. Synlett. In press.
(8) p-Toluenesulfonic acid was not completely soluble in toluene. The
use of methanol as a cosolvent provided the methoxylated product.
(10) We also tested hydrochloric acid or sulfuric acid as more easily
used acids for a large-scale synthesis, but the starting material 3 was not
consumed completely under these conditions.
(11) Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem.
2004, 69, 5906-5925.
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Org. Lett., Vol. 9, No. 2, 2007
Tanaka, Katsunori
