Journal of the American Chemical Society
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formation. Nat. Commun. 2016, 7, 13491. (b) Seo, H.; Katcher M. H.;
Tsuchihashi, Y.; Yoshida, J. Alkyllithiums Bearing Electrophilic
Jamison, T. F. Photoredox activation of carbon dioxide for amino
acid synthesis in continuous flow. Nat. Chem. 2017, 9, 453. (c)
Parisi, G.; Colella, M.; Monticelli, S.; Romanazzi, G.; Holzer, W.;
Langer, T.; Degennaro, L.; Pace, V.; Luisi, R. Exploiting a “Beast” in
Carbenoid Chemistry: Development of a Straightforward Direct
Nucleophilic Fluoromethylation Strategy. J. Am. Chem. Soc. 2017,
139, 13648. (d) Inuki, S.; Sato, K.; Fukuyama, T.; Ryu, I.; Fujimoto, Y.
Formal Total Synthesis of l-Ossamine via Decarboxylative
Functionalization Using Visible-Light-Mediated Photoredox
Catalysis in a Flow System. J. Org. Chem. 2017, 82, 1248. (e) Islam,
M.; Kariuki, B. M.; Shafiq, Z.; Wirth, T.; Ahmed, N. Efficient
Electrosynthesis of Thiazolidin-2-imines via Oxysulfurization of
Thiourea-Tethered Terminal Alkenes Using the Flow Microreactor.
Eur. J. Org. Chem. 2019, 1371. (f) Miyamura, H.; Tobita, F.; Suzuki,
A.; Kobayashi, S. Direct Synthesis of Hydroquinones from Quinones
through Sequential and Continuous-Flow Hydrogenation-
Derivatization Using Heterogeneous Au-Pt Nanoparticles as
Catalysts. Angew. Chem., Int. Ed. 2019, 58, 9220. (g) Masui, S.;
Manabe, Y.; Hirao, K.; Shimoyama, A.; Fukuyama, T.; Ryu, I.; Fukase,
K. Kinetically Controlled Fischer Glycosidation under Flow
Conditions: A New Method for Preparing Furanosides. Synlett
2019, 30, 397. (h) Elsherbini, M.; Winterson, B.; Alharbi, H.;
Folgueiras-Amador, A. A.; Génot, C.; Wirth, T. Continuous-Flow
Electrochemical Generator of Hypervalent Iodine Reagents:
Synthetic Applications. Angew. Chem., Int. Ed. 2019, 58, 9811. (i)
Cambié, D.; Dobbelaar, J.; Riente, P.; Vanderspikken, J.; Shen, C.;
Seeberger, P. H.; Gilmore, K.; Debije, M. G.; Noël, T. Energy-Efficient
Solar Photochemistry with Luminescent Solar Concentrator Based
Photomicroreactors. Angew. Chem., Int. Ed. 2019, 58, 14374. (j)
Ahn, G.-N.; Yu, T.; Lee, H.-J. Gyak, K.-W.; Kang, J.-H.; You, D.; Kim, D.-
P. A numbering-up metal microreactor for the high-throughput
production of a commercial drug by copper catalysis. Lab Chip,
2019, 19, 3535. (k) Picard, B.; Pérez, K.; Lebleu, T.; Vuluga, D.;
Burel, F.; Harrowven, D. C.; Chataigner, I.; Maddaluno, J.; Legros, J.
Bromine–lithium exchange on gem-dibromoalkenes part 1: batch
vs microflow conditions. J. Flow. Chem. 2020, 10, 139.
(11) Selected our recent reports: (a) Nagaki, A.; Takahashi Y.;
Yoshida, J. Generation and Reaction of Carbamoyl Anions in Flow:
Applications in the Three-Component Synthesis of Functionalized
-Ketoamides. Angew. Chem. Int. Ed. 2016, 55, 5327. (b) Kim, H.;
Min, K.-I.; Inoue, K.; Im, D. J.; Kim, D.-P.; Yoshida, J. Submillisecond
organic synthesis: Outpacing Fries rearrangement through
microfluidic rapid mixing. Science 2016, 352, 691. (c) Ashikari, Y.;
Saito, K.; Nokami, T.; Yoshida, J.; Nagaki, A. Oxo-Thiolation of
Cationically Polymerizable Alkenes Using Flow Microreactors.
Chem. Eur. J. 2019, 25, 15239. (d) Baralle, A.; Inukai, T.; Yanagi, T.;
Nogi, K.; Osuka, A.; Nagaki, A.; Yoshida, J.; Yorimitsu, H. Tf2O-
mediated Reaction of Alkenyl Sulfoxides with Unprotected Anilines
in Flow Microreactors. Chem. Lett. 2020, 49, 160. (e) Colella, M.;
Tota, A.; Takahashi, Y.; Higuma, R.; Ishikawa, S.; Degennaro, L.;
Luisi, R.; Nagaki, A. Fluoro-Substituted Methyllithium Chemistry:
External Quenching Method Using Flow Microreactors. Angew.
Chem. Int. Ed. 2020, 59, 11924.
Functional Groups: A Flash Chemistry Approach. Angew. Chem. Int.
Ed. 2019, 58, 4027. (g) Nagaki, A. Recent Topics of Functionalized
Organolithiums using Flow Microreactor Chemistry. Tetrahedron
Lett. 2019, 60, 150923. (h) Nagaki, A.; Yamashita, H.; Hirose, K.;
Tsuchihashi, Y.; Takumi, M.; Yoshida, J. Generation and Reaction of
Functional Alkyllithiums Using Microreactors and Their
Application to Heterotelechelic Polymer Synthesis. Chem. Eur. J.
2019, 25, 13719. (i) Pérez, K.; Picard, B.; Vuluga, D.; Burel, F.; Hreiz,
R.; Falk, L.; Commenge, J.-M.; Nagaki, A.; Yoshida, J.; Chataigner, I.;
Maddaluno, J.; Legros, J. Bromine–Lithium Exchange on a gem-
Dibromoalkene, Part 2: Comparative Performance of Flow
Micromixers. Org. Process Res. Dev. 2020, 24, 787.
(13) Ichinari, D.; Ashikari, Y.; Mandai, K.; Aizawa, Y.; Yoshida, J.;
Nagaki, A. A Novel Approach to Functionalization of Aryl Azides via
Generation and Reactions of Organolithiums Bearing Masked
Azides Using Flow Microreactors. Angew. Chem. Int. Ed. 2020, 59,
1567.
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(14) In
a few research papers, lithiation of arylboron-ate
complexes was reported, although they need harsh conditions,
long reaction time, and lowly accessible starting materials: (a)
Molander G. A.; Ellis, N. M. Linchpin Synthons:ꢀ Metalation of Aryl
Bromides Bearing a Potassium Trifluoroborate Moiety. J. Org.
Chem. 2006, 71, 7491. (b) Jiang, Q.; Ryan, M.; Zhichkin, P. Use of in
Situ Isopropoxide Protection in the Metal−Halogen Exchange of
Arylboronates. J. Org. Chem. 2007, 72, 6618.
(15) (a) Usutani, H.; Tomida, Y.; Nagaki, A.; Okamoto, H.; Nokami T.;
Yoshida, J. Generation and Reactions of o-Bromophenyllithium
without Benzyne Formation Using a Microreactor. J. Am. Chem. Soc.
2007, 129, 3046. (b) Nagaki, A.; Tomida, Y.; Usutani, H.; Kim, H.;
Takabayashi, N.; Nokami, T.; Okamoto, H.; Yoshida, J. Integrated
Micro Flow Synthesis Based on Sequential Br-Li Exchange
Reactions of p-, m-, and o-Dibromobenzenes. Chem. Asian J. 2007,
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(16) 11B NMR (160 MHz) analysis was carried out using CD3OD as
a solvent in a quartz NMR tube. The solution of BF3∙OEt2 in CDCl3
was used as an external standard (0 ppm).
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characterization of phenylacetylene tripodal compounds
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Aquino, M.; Guerrero, M. D.; Bruno, I.; Terencio, M. C.; Paya, M.;
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microsomal prostaglandin E synthase 1 expression bearing the -
hydroxybutenolide scaffold. Bioorg. Med. Chem. 2008, 16, 9056. (c)
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(18) We have reported a bi-functionalization of dibromopyridines
using butyllithiums in a flow microreactor. See; Nagaki, A.; Yamada,
D.; Yamada, S.; Doi, M.; Ichinari, D.; Tomida, Y.; Takabayashi, N.;
Yoshida, J. Generation and Reactions of Pyridyllithiums via Br/Li
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(19) (a) Nagaki, A.; Takabayashi, N.; Tomida, Y.; Yoshida, J. Selective
Monolithiation of Dibromobiaryls Using Microflow Systems. Org.
Lett. 2008, 10, 3937. (b) Nagaki, A.; Jiang, Y.; Yamashita, H.;
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bithiophene Using Flow Microreactors. Mechanistic Implications
and Synthetic Applications. Chem. Eng. Technol. 2019, 42, 2113.
(20) (a) Nagaki, A.; Moriwaki, Y.; Yoshida, J. Flow Synthesis of
Arylboronic Esters Bearing Electrophilic Functional Groups and
Space Integration with Suzuki–Miyaura Coupling without
Intentionally Added Base. Chem. Commun. 2012, 48, 11211. (b)
Nagaki, A.; Hirose, K.; Moriwaki, Y.; Mitamura, K.; Matsukawa, K.;
Ishizuka, N.; Yoshida, J. Integration of Borylation of Aryllithiums
and Suzuki-Miyaura Coupling Using Monolithic Pd Catalyst. Catal.
Sci. Technol. 2016, 6, 4690. (c) Nagaki, A.; Hirose, K.; Tonomura, O.;
Taga, T.; Taniguchi, S.; Hasebe, S.; Ishizuka N.; Yoshida, J. Design of
a Numbering-up System of Monolithic Microreactors and Its
(12) (a) Nagaki, A.; Kim H.; Yoshida, J. Aryllithium Compounds
Bearing Alkoxycarbonyl Groups: Generation and Reactions Using a
Microflow System. Angew. Chem. Int. Ed. 2008, 47, 7833. (b)
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Thermodynamic Control. Angew. Chem. Int. Ed. 2009, 48, 8063. (c)
Nagaki, A.; Kim, H.; Usutani, H.; Matsuo, C.; Yoshida, J. Generation
and Reaction of Cyano-substituted Aryllithium Compounds Using
Microreactors. Org. Biomol. Chem. 2010, 8, 1212. (d) Nagaki, A.;
Kim, H.; Moriwaki, Y.; Matsuo, C.; Yoshida, J. A Flow Microreactor
System Enables Organolithium Reactions without Protecting
Alkoxycarbonyl Groups. Chem. Eur. J. 2010, 16, 11167. (e) Kim, H.;
Nagaki, A.; Yoshida, J. A Flow Microreactor Approach to Protecting-
group-free Synthesis Using Organolithium Compounds. Nat.
Commun. 2011, 2, 264. (f) Nagaki, A.; Yamashita, H.; Hirose, K.;
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