Angewandte
Chemie
DOI: 10.1002/anie.201410717
Microreactors
Reactions of Difunctional Electrophiles with Functionalized
Aryllithium Compounds: Remarkable Chemoselectivity by Flash
Chemistry**
Aiichiro Nagaki, Keita Imai, Satoshi Ishiuchi, and Jun-ichi Yoshida*
Abstract: Flash chemistry using flow microreactors enables
highly chemoselective reactions of difunctional electrophiles
with functionalized aryllithium compounds by virtue of
extremely fast micromixing. The approach serves as a powerful
method for protecting-group-free synthesis using organo-
lithium compounds and opens a new possibility in the synthesis
of polyfunctional organic molecules.
Scheme 1. Reactions of functionalized aryllithium compounds with
aromatic compounds bearing two electrophilic functional groups.
F
low chemistry[1–3] has attracted significant attention by
researchers from both academia and industries. Various
benefits over conventional batch processes include increased
controllability, safety, and selectivity because of improved
heat and mass transfer and shorter residence times. In
particular, flash chemistry[4,5] using flow microreactors ena-
bles synthetic transformations that are very difficult or
impossible to achieve by conventional batch reactions.
Herein we report a proof-of-principle study that shows how
remarkable chemoselectivity that is difficult to attain by
conventional batch processes, can be achieved by flash
chemistry.
To achieve the transformation, we must solve the follow-
ing three problems:
1. A lithiating agent (RLi) should undergo halogen–lithium
exchange to generate a functionalized aryllithium without
affecting FG3.[9]
2. The functionalized aryllithium should react selectively
with difunctional electrophiles at FG1 without affecting
FG2.[10,11]
3. The functionalized aryllithium should not attack FG3.
Chemoselectivity is defined as “the preferential reaction
of a chemical reagent or reactive species with one of two or
more different functional groups”, and is one of the central
issues in organic synthesis. The development of new methods
or principles for controlling chemoselectivity is still a big
challenge in current synthetic chemistry.[6] Chemoselectivity is
particularly important for reactions of highly reactive species,
such as organolithium compounds.[7] Herein we focused on
the following transformation, that is, the reactions with
difunctional electrophiles, such as the reactions of aromatic
compounds bearing two different electrophilic functional
groups (FG1 and FG2) with aryllithium compounds also
bearing an electrophilic functional group (FG3; Scheme 1).
The transformation should serve as a useful method for
protecting-group-free synthesis[8] of a variety of polyfunc-
tional organic molecules.
We have already solved the first problem by high-
resolution control of the reaction time by space in flow
microreactors, but the second problem seems to be more
challenging because controlling the reaction time is not
effective. We envisaged extremely fast micromixing[12] to be
effective in solving the second problem, because mixing is
crucial for the product selectivity of fast competitive parallel
and serial reactions.[13]
One may think that chemoselective nucleophilic reactions
of difunctional electrophiles are easy if the reactivity of FG1
is higher than that of FG2. However, this is not true if the
reaction is very fast. In fact, the reaction of 4-benzoylbenzal-
dehyde (1) with one equivalent of phenyllithium (Scheme 2)
[*] Dr. A. Nagaki, K. Imai, S. Ishiuchi, Prof. J.-i. Yoshida
Department of Synthetic and Biologycal Chemistry
Graduate School of Engineering, Kyoto University
Nishikyo-ku, Kyoto, 615-8510 (Japan)
Scheme 2. Reaction of 4-benzoylbenzaldehyde (1) with one equivalent
of PhLi in a batch macro reactor.
E-mail: yoshida@sbchem.kyoto-u.ac.jp
e.html
in a batch reactor (50 mL round-bottom glass flask with
a magnetic stirrer) leads to the formation of a mixture of three
products, that is, 2, 3, and 4, although aldehyde carbonyl
groups are generally more reactive than ketone carbonyl
groups.
[**] This work was partially supported by the Grant-in-Aid for Scientific
Research (S) (no. 26220804) and Scientific Research (B) (no.
26288049)
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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