Organic Letters
Letter
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obtain 5.4 g of the desired fluconazole 9 in 52% yield over two
steps.
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(5) (a) Kobrich, G. The Chemistry of Carbenoids and Other
In summary, we have developed a safe and scalable
procedure for the epoxidation of ketones, based on the
generation of (bromomethyl)lithium in a continuous flow
reactor. The reactive intermediate was generated in situ from
inexpensive CH2Br2 and readily available MeLi. This
chemistry, difficult to carry out in batch in a controllable
manner, has been performed in multigram scale under
continuous flow conditions. Compared to the classic Corey-
Chaykosky reaction, the present methodology has shown to be
superior for the epoxidation of α-chloroketones, which
typically fail using Me3SOI or Me3SI as reagents. This
advantage has been exploited to establish a novel route for
the preparation of the drug fluconazole, featuring the
epoxidation of a α-chloroketone as the key step. A robust
preparative method has been achieved by transferring the
continuous procedure to a readily scalable plate-based
platform.
Thermolabile Organolithium Compounds. Angew. Chem., Int. Ed.
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Engl. 1972, 11, 473−485. (b) Kobrich, G.; Akhtar, A.; Ansari, F.;
Breckoff, W. E.; Buttner, H.; Drischel, W.; Fischer, R. H.; Flory, K.;
̈
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Frohlich, H.; Goyert, W.; et al. Chemistry of Stable α-
Halogenoorganolithium Compounds and the Mechanism of Carbe-
noid Reactions. Angew. Chem., Int. Ed. Engl. 1967, 6, 41−52.
(6) Matteson, D. S. Bromomethyllithium. In Encyclopedia of Reagents
(7) (a) Michnick, T. J.; Matteson, D. S. (Bromometyhyl)lithium:
Efficient in Situ Reactions. Synlett 1991, 1991, 631−632. (b) Cainelli,
G.; Tangari, N.; Ronchi, A. U. Chemistry of α-Halometalcompounds.
Tetrahedron 1972, 28, 3009−3013. (c) Cainelli, G.; Ronchi, A. U.;
Bertini, F.; Grasselli, P.; Zubiani, G. Chemistry of α-Halometal
Compounds. Tetrahedron 1971, 27, 6109−6114.
(8) Hartwig, J.; Metternich, J. B.; Nikbin, N.; Kirschning, A.; Ley, S.
V. Continuous Flow Chemistry: A Discovery Tool for New Chemical
Reactivity Patterns. Org. Biomol. Chem. 2014, 12, 3611−3615.
(9) Degennaro, L.; Fanelli, F.; Giovine, A.; Luisi, R. External
Trapping of Halomethyllithium Enabled by Flow Microreactors. Adv.
Synth. Catal. 2015, 357, 21−27.
ASSOCIATED CONTENT
* Supporting Information
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S
(10) (a) Hafner, A.; Filipponi, P.; Piccioni, L.; Meisenbach, M.;
Schenkel, B.; Venturoni, F.; Sedelmeier, J. A Simple Scale-up Strategy
for Organolithium Chemistry in Flow Mode: From Feasibility to
Kilogram Quantities. Org. Process Res. Dev. 2016, 20, 1833−1837.
(b) Hafner, A.; Mancino, V.; Meisenbach, M.; Schenkel, B.;
Sedelmeier, J. Dichloromethyllithium: Synthesis and Application in
Continuous Flow Mode. Org. Lett. 2017, 19, 786−789.
The Supporting Information is available free of charge at
Experimental procedures, supplementary figures and
compound characterization data (PDF)
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(11) Khutorianskyi, V. V.; Klepetarova, B.; Beier, P. Vicarious
Nucleophilic Chloromethylation of Nitroaromatics. Org. Lett. 2019,
21, 5443−5446.
AUTHOR INFORMATION
Corresponding Authors
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(12) (a) Monticelli, S.; Colella, M.; Pillari, V.; Tota, A.; Langer, T.;
Holzer, W.; Degennaro, L.; Luisi, R.; Pace, V. Modular and
Chemoselective Strategy for the Direct Access to α-Fluoroepoxides
and Aziridines via the Addition of Fluoroiodomethyllithium to
Carbonyl-Like Compounds. Org. Lett. 2019, 21, 584−588. (b) Colella,
M.; Tota, A.; Großjohann, A.; Carlucci, C.; Sheikh, N. S.; Degennaro,
L.; Luisi, R. Straightforward chemo- and stereoselective fluorocyclo-
propanation of allylic alcohols: exploiting the electrophilic nature of
the not so elusive fluoroiodomethyllithium. Chem. Commun. 2019, 55,
8430−8433.
(13) For a recent review describing the stability of this type of
compounds, see: Gessner, V. H. Stability and reactivity control of
carbenoids: recent advances and perspectives. Chem. Commun. 2016,
52, 12011−12023.
(14) Pace, V.; Castoldi, L.; Holzer, W. Chemoselective Additions of
Chloromethyllithium Carbenoid to Cyclic Enones: A Direct Access to
Chloromethyl Allylic Alcohols. Adv. Synth. Catal. 2014, 356, 1761−
1766.
cessed November 2019).
(16) Szeto, J.; Vu, V.-A.; Malerich, J. P.; Collins, N. Multi-step
continuous flow synthesis of fluconazole. J. Flow Chem. 2019, 9, 35−
42.
(17) Yoshida, J. I.; Takahashi, Y.; Nagaki, A. Flash Chemistry: Flow
Chemistry That Cannot Be Done in Batch. Chem. Commun. 2013, 49,
9896−9904.
(18) Colella, M.; Nagaki, A.; Luisi, R. Flow Technology for the
Genesis and Use of (Highly) Reactive Organometallic Reagents.
(19) For an example involving CH2Br2 on pilot scale, see: Broom,
T.; Hughes, M.; Szczepankiewicz, B. G.; Ace, K.; Hagger, B.; Lacking,
G.; Chima, R.; Marchbank, G.; Alford, G.; Evans, P.; et al. The
Synthesis of Bromomethyltrifluoroborates through Continuous Flow
Chemistry. Org. Process Res. Dev. 2014, 18, 1354−1359.
ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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The CCFLOW Project (Austrian Research Promotion Agency
FFG Grant No. 862766) is funded through the Austrian
COMET Program by the Austrian Federal Ministry of
Transport, Innovation and Technology (BMVIT), the Austrian
Federal Ministry of Science, Research and Economy
(BMWFW), and the State of Styria (Styrian Funding Agency
SFG).
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