DOI: 10.1002/cssc.201100373
Room-Temperature, Acid-Catalyzed [2+2] Cycloadditions: Suppression of
Side Reactions by using a Flow Microreactor System
[
a]
Kei Kurahashi, Yoshiji Takemoto, and Kiyosei Takasu*
Dedicated to the memory of Eiichi Fujita, Emeritus Professor, Kyoto University, who passed away on July 24, 2011.
Microreactors enable microscale reactions under continuous
flow conditions. During recent decades, many studies have
been devoted to the development of new and efficient pro-
[1–3]
cesses using flow microreactor systems in organic synthesis.
Compared to conventional batch methods, advantageous fea-
tures of microreactor protocols include high mixing efficien-
cies, rapid mass and heat transfer (precise temperature con-
[
4]
trol), and continuous operation and mixing. Recently, Yoshida
[5]
and co-workers proposed two key terms, “flash chemistry”
[
6]
and “space integration”, to describe flow microreactions.
Flash chemistry is defined as a field of chemical synthesis
where extremely fast reactions are conducted in a highly con-
trolled manner to produce compounds at high selectivities.
These are due to efficient mixing and rapid heat transfer.
Space integration refers to performing a series of reactions in
sequence, in different reactors by using a continuous flow
system. With these microreactor protocols, substrates, inter-
mediates, and products that are transient and/or unstable can
be used because the residence times can be reduced to the
order of seconds or milliseconds, while maintaining the flexibil-
ity of adding reaction components in a desired order. In con-
trast, running selective reactions in conventional batch reactors
is difficult because short-lived intermediates must be stored
until the dosing of reagents is finished and the next reaction
Scheme 1. [2+2] Cycloaddition of silyl enol ethers with a,b-unsaturated
esters and formable by-products in the reaction.
substituted cyclobutanes 3 in high yields with good diastereo-
selectivity, there exist some limitations on the reaction. The
first problem is that the oligomerization and polymerization of
a,b-unsaturated esters 2, especially acrylates, occur as side re-
actions in the presence of acid catalysts. To avoid these side re-
actions, the [2+2] cycloaddition must be performed at a low
temperature (e.g., À788C). Another problem is that unstable
silyl enol ether substrates 1 are unavailable for the [2+2] cyclo-
addition. Reaction of silyl enol ethers from the corresponding
aldehydes was unsuccessful, yielding only undesired products
formed by the self-aldol-type reaction of 1. A third problem is
decomposition of 3 by the retro-aldol-type ring opening. The
cleavage of the siliconÀoxygen bond of 3 easily induces an
opening of the cyclobutane ring to give d-ketoester, which for-
mally corresponds to the Mukaiyama Michael adduct. When cy-
cloadduct 3, especially bearing a trimethylsilyl group, was
treated with the catalyst at ambient temperature, it decom-
posed gradually into the d-ketoester. We envisaged that these
problems, which are caused by the poor stability of substrates,
intermediates, and products, can be solved by using micro-
reactor technology. Chemical reactions at ambient temperature
[
7]
step may be performed. Microreactor protocols offer many
advantages over traditional batch methods, such as increased
reaction rates and yields, suppressed side reactions, minimal
reaction and solvent wastes, decreased energy use, and high
reproducibility.
This Communication involves the cyclobutane ring, which
forms part of various natural and synthetic bioactive substan-
ces as well as synthetic intermediates. However, the number of
reports on the efficient and practical synthesis of this four-
[
8]
membered ring is limited. Recently, we reported a catalytic
[
2+2] cycloaddition of silyl enol ethers 1 with a,b-unsaturated
would be practical synthetic processes. We report the Tf NH-
2
[
9,10]
esters 2, giving siloxycyclobutanes 3 (Scheme 1).
nally reported that the cycloaddition is activated by EtAlCl2,
and then found that triflic imide (Tf NH) works as a highly
We origi-
catalyzed [2+2] cycloaddition of highly reactive substrates at
room temperature in a flow microreactor system.
[10a]
At the outset of our study, we examined the [2+2] cycload-
dition using a flow microreactor system consisting of standard
Y-shape mixers and poly(tetrafluoroethylene) (PTFE) microtube
reactors, as represented in Figure 1. Firstly, solutions of silyl
2
[
10c]
active catalyst.
Further study revealed that Tf NH is a pre-
2
catalyst but silyl triflic imide (SiNTf ), which forms in situ from
Tf NH and silyl enol ether substrates,
2
[
9,10c,11]
acts as a strong
2
Lewis acid. Although these catalysts give a variety of highly
enol ether 1 and Tf NH (a catalytic amount) were introduced
2
into a micromixer [M1, 500 mmꢀ100 mm (channel width)] by
using syringe pumps. The resulting mixture was passed
through a microtube reactor [R1, 500 mmꢀ34.5 cm (f, l)]. In
this space, a strong Lewis-acidic SiNTf2 must be generated
[
a] K. Kurahashi, Prof. Y. Takemoto, Prof. K. Takasu
Graduate School of Pharmaceutical Sciences
Kyoto University
Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan)
Fax: (+81)75-753-4604
from Tf NH and 1 within the residence time (t ). The resulting
2
1
E-mail: kay-t@pharm.kyoto-u.ac.jp
mixture was mixed with a solution of a,b-unsaturated ester 2
2
70
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2012, 5, 270 – 273