Angewandte
Chemie
DOI: 10.1002/anie.201410062
Microreactor Synthesis
Integrated One-Flow Synthesis of Heterocyclic Thioquinazolinones
through Serial Microreactions with Two Organolithium
Intermediates**
Heejin Kim, Hyune-Jea Lee, and Dong-Pyo Kim*
Abstract: The synthesis of pharmaceutical compounds via
short-lived intermediates in a microreactor is attractive,
because of the fast flow and high throughput. Additionally,
intermediates can be utilized sequentially to efficiently build up
a library in a short time. Here we present an integrated
microfluidic synthesis of biologically active thioquinazolinone
libraries. Generation of o-lithiophenyl isothiocyanate and
subsequent reaction with aryl isocyanate is optimized by
controlling the residence time in the microreactor to 16 ms at
Scheme 1. Comparison of integrated one-flow synthesis of thioquina-
zolinones using a microfluidic device compared with conventional
flask synthesis.
room temperature. Various S-benzylic thioquinazolinone
derivatives are synthesized within 10 s in high yields (75–
98%) at room temperature. These three-step reactions involve
two organolithium intermediates, an isothiocyanate-function-
alized aryllithium intermediate, and a subsequent lithium
thiolate intermediate. We also demonstrate the gram-scale
synthesis of a multifunctionalized thioquinazolinone in the
microfluidic device with a high yield (91%) and productivity
(1.25 g in 5 min).
a scale-up of the lab-scale reaction a re-optimization of the
reaction conditions is necessary. Therefore, it is desirable to
develop a synthetic route toward thioquinazolinones that
proceeds under mild conditions to facilitate the development
of pharmaceuticals. Furthermore, continuous and integrated
synthesis would allow for fast screening and scale-up pro-
duction.
D
ue to their ubiquitous structure as well as biological and
pharmacological activity, quinazolinone derivatives are
important heterocyclic compounds.[1] They are well-known
as a class of drugs with hypnotic and sedative function and
contain a 4-quinazolinone core such as afloqualone, cloro-
qualone, and diproqualone.[2] Moreover, several quinazoli-
none derivatives have anti-inflammatory[3] and antifungal[4]
properties. In addition, S-functionalized thioquinazolinones
have recently been reported as a new type of bioactive
chemical structure with antiplatelet activity that prohibits
platelet aggregation induced by AA (arachidonic acid) and
collagen.[5]
Flow microreactors based on microfluidics[7] have been
shown to be excellent devices for organic chemical synthesis.
They are effective in exploring undiscovered synthetic path-
ways, including in total synthesis, and have recently been
utilized for various applications in green chemistry.[8]
A
unique area, in which microfluidic devices are useful, are
syntheses involving short-lived, highly reactive intermediates
to produce chemical substances with high efficiency.[9]
In the conventional flask reactor, it is challenging to
utilize highly unstable intermediates for the synthesis of
chemicals, even at very low temperature. In contrast, the use
of a one-flow microreactor enables precise control of the
reaction time for vigorously reactive intermediates in the
order of milliseconds at room or modest temperatures,
resulting in high yields.[10] In particular, it has been reported
that short-lived organolithium intermediates such as alkoxy-
carbonyl-, nitro-, cyano-, or acyl-substituted aryllithium
compounds generated in a flow microreactor could be used
for reactions with electrophilic reagents.[11] To date, however,
there has been no attempt to utilize aryllithiums bearing
a strongly electrophilic isothiocyanate (NCS) group in flow
chemistry for synthetic chemistry, although the NCS group
with two heteroatoms has great potential for the construction
of biologically active heterocycles. Therefore, we envisage
that biologically active thioquinazolinone libraries can be
In general, S-functionalized thioquinazolinones are syn-
thesized from anthranilic acid and isothiocyanate under harsh
reaction conditions and low yield of around 50% are
obtained. Long reaction times of several hours are required
and the intermediate after the first step (Scheme 1) needs to
be separated for the subsequent reaction.[6] Moreover, for
[*] Dr. H. Kim, H.-J. Lee, Prof. Dr. D.-P. Kim
National Centre of Applied Microfluidic Chemistry
Department of Chemical Engineering
POSTECH (Pohang University of Science and Technology)
Pohang, 790-784 (South Korea)
E-mail: dpkim@postech.ac.kr
[**] This work was supported by a National Research Foundation of
Korea (NRF) grant funded by the Korean government (MSIP) (No.
2008-0061983).
formed by an intramolecular cyclic reaction of aryllithium-
1
À
bearing isothiocyanate (NCS) groups with isocyanates (R
NCO) from commercially available starting materials in
a continuous one-flow microreactor (Scheme 1).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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