.
Angewandte
Communications
DOI: 10.1002/anie.201303213
Continuous-Flow Microreactors
Odorless Isocyanide Chemistry: An Integrated Microfluidic System for
a Multistep Reaction Sequence**
Siddharth Sharma, Ram Awatar Maurya, Kyoung-Ik Min, Guan-Young Jeong, and Dong-
Pyo Kim*
Isocyanides have a long history in organic chemistry and have
been used in all areas, from academia to industry.[1] It is one of
the most versatile and extensively examined stable divalent
carbon nucleophiles, and has the interesting ability to form
multiple bonds on the terminal carbon. It has drawn enduring
attention because of its ubiquitous applications in organo-
metallics, where isocyanides are a well-studied family of
ligands,[2] and in combinatorial syntheses, where new desired
products can be found by isocyanide-based multi-component
processes, such as Passerini and Ugi reactions.[3] These
intrinsic qualities of isocyanides, in combination with the
avalanche of research on their use in the synthesis of drug-like
molecules, make them a privileged group for synthetic
chemists.[4]
Despite the huge potential of the isocyanide chemistry,
some lack of academic interest toward this field is yet evident.
This reluctance is undoubtedly related to the extremely
distressing odor of isocyanides, which has also led to their
proposed use as non-lethal weapons.[5] The foul odor makes
their purification especially difficult, as exposure to them,
even at very low levels, is extremely agonizing. It is believed
that this characteristic foul odor of volatile isocyanides is the
reason for the underdevelopment of isocyanide chemistry for
so many years, as the foul smell turned away many potential
workers in this field. Therefore, a system that removes the
odor problem should enable the expansion of the scope of
isocyanide chemistry to new, unexplored dimensions. In this
report, we present an automated continuous microfluidic
system that performs a serial synthesis, purification, and
in situ consumption of isocyanides into final products with
little exposure to the surroundings.
microfluidics has emerged as a welcome development in
organic synthesis. In addition to enhanced process safety, this
technology offers important advantages, such as increased
surface-to-volume ratio and rapid mass and heat transfer,
which results in highly accelerated reaction rates, as well as
a reduction in reaction time.[6] Nowadays, this technique is
considered as an important approach towards green and
sustainable chemistry because it minimizes exposure to
reagents and products under reaction conditions when using
toxic materials.[7] Over the last few years, many important
efforts have been made to avoid exposure to toxic and
hazardous material through the microfluidic approach.[8]
Nonetheless, efficient separation of initially produced toxic
compounds from the reaction mixtures for subsequent down-
stream utilization in a continuous reaction is still an enormous
challenge.[9]
One way of accomplishing the task is to purify the
generated reagent by selective removal of unwanted chem-
icals and then to separate the reagent stream. Droplet
microfluidics could be used for purification by liquid–liquid
extraction.[10] A convenient medium for the extraction is
water, because the water phase containing the unwanted
chemicals can be separated from the organic-solvent phase
containing the reagent with the aid of a suitable thin
membrane. These requirements dictate the selection of the
synthesis method for the reagent.
The first synthesis of isocyanide goes back to 1859, and
involved allyl iodide and silver cyanide.[11] For our purpose,
however, dehydration of N-substituted formamides was
selected as a model reaction for in situ generation of
isocyanides, not only because of its quantitative yield and
wide substrate compatibility,[12] but, more importantly,
because of the compatibility of the synthesis method with
the aforementioned requirements for self-purification and
separation. In situ generation of isocyanides could be carried
out in a capillary microreactor. The reaction mixture would
then be combined with water for subsequent extraction. The
resulting biphasic fluid should self-separate into a water phase
and an organic phase in the microseparator. The purified
isocyanide would then be consumed in the capillary micro-
reactor to deliver the desired products, as shown in the
Figure 1.
Establishing safe and efficient procedures for conducting
chemical reaction has been greatly aided by technological
advances. Among these, continuous-flow synthesis based on
[*] Dr. S. Sharma,[+] Dr. R. A. Maurya,[+] K.-I. Min, G.-Y. Jeong,
Prof. Dr. D.-P. Kim
Department of Chemical Engineering, Pohang University of Science
and Technology, POSTECH, Pohang, 790-784 (Korea)
E-mail: dpkim@postech.ac.kr
Dr. R. A. Maurya[+]
Current address: Division of Medicinal Chemistry and Pharmacol-
ogy, CSIR-Indian Institute of Chemical Technology, Hyderabad,
500007 (India)
For the in situ generation of isocyanide, a solution of
N-cyclohexylformamide
in
N,N-diisopropylethylamine
(DIPEA; 1.0m) and a solution of POCl3 in toluene (2.0m)
were introduced into the capillary microreactor with a
T-mixer using two separate syringe pumps. The flow rate of
the DIPEA solution was kept at twice the rate of POCl3, in
accordance with the stoichiometry of reagent and substrates.
[+] These authors contributed equally to this work.
[**] This work was supported by a National Research Foundation of
Korea (NRF) grant funded by the Korean government(MEST) (2008-
0061983).
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!