Green Chemistry
Communication
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ment of the literature conditions (i.e. toluene as solvent) to program and Dr Boris Gorin for helpful discussions.
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use highly solubilizing CHCl /DMF or NMP/MeOH/H O.
R. J. S. thanks NSERC for a graduate scholarship (CGS-D).
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Using tributylamine as a base and toluene as solvent, 2-chloro-
acetylchloride and 2,6-dimethylaniline were mixed in a flow
reactor at 90 °C, followed by addition of diethylamine
and DBU to give a 66% isolated yield of lidocaine (Scheme 3).
At a 0.4 M concentration with a total residence time of
Notes and references
1 H. Porta, M. Benaglia and A. Puglisi, Org. Process Res. Dev.,
2016, 20, 2–25.
1
0.8 minutes this allowed production of 0.37 g of lidocaine per
hour in the 1.1 mL reactor coil, equivalent to a space time
2 (a) C. Wiles and P. Watts, Green Chem., 2012, 14, 38–54;
(b) S. V. Ley, Chem. Rec., 2012, 12, 378–390; (c) J.-i. Yoshida,
H. Kim and A. Nagaki, ChemSusChem, 2011, 4, 331–340;
yield of 0.34 kg h−
1
L .
−1
(
d) S. G. Newman and K. F. Jensen, Green Chem., 2013, 15,
Conclusions
1456–1472.
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4
C. Jiménez-González, P. Poechlauer, Q. B. Broxterman,
B.-S. Yang, D. am Ende, J. Baird, C. Bertsch, R. E. Hannah,
P. Dell’Orco, H. Noorman, S. Yee, R. Reintjens, A. Wells,
V. Massonneau and J. Manley, Org. Process Res. Dev., 2011,
Despite the many advantages of running reactions continu-
ously, the barriers associated with adapting batch procedures
to flow hinder the adoption of this technology. We believe that
the challenges associated with solid formation, particularly in
reactions that require an acid scavenging base, are some of the
most common and frustrating problems in flow chemistry.
Through the careful selection of bases that form ionic liquids
upon protonation, we have demonstrated that these solid-
handling issues can be easily alleviated. In particular,
N-methylimidazole, tributylamine, DBU, and N-butylimidazole
are demonstrated to enable precipitate-free reactions of acyl,
aryl, alkyl, and silyl halide electrophiles using N, O, and S
nucleophiles. These reactions give high yields with short reac-
tion times. Furthermore, concentrations ranging from 0.5 M to
neat are utilized, demonstrating that the use of flow chemistry
to enable more efficient chemical synthesis doesn’t come at
the consequence of requiring wasteful, dilute reaction con-
ditions. In the case where the base utilized is less accessible
than the more traditional alternative (i.e., N-butylimidazole), it
was also demonstrated that direct recovery from the reaction
mixture is easily achievable. Lastly, the ability to simplify
implementation of telescoped processes for multistep synth-
eses was demonstrated by the synthesis of lidocaine via
sequential acylation and alkylation reactions. We anticipate
that this strategy will reduce the barrier to implementing con-
tinuous flow reactions so that chemists can readily exploit the
green chemistry benefits accessible through flow chemistry.
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M. B. Plutschack, B. Pieber, K. Gilmore and
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Conflicts of interest
Chem., 2011, 54, 3451–3479.
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For example, Micahel additions of amine nucleophiles.
See: H. Löwe, V. Hessel, P. Löbe and S. Hubbard,
Org. Process Res. Dev., 2006, 10, 1144–1152.
There are no conflicts to declare.
(a) K. R. Seddon, Nat. Mater., 2003, 2, 363–365;
Acknowledgements
(
b) M. Maase and K. Massonne, in Ionic Liquids IIIB:
Financial support for this work was provided by the University
of Ottawa, the National Science and Engineering Research
Council of Canada (NSERC), and the Canada Research Chair
program. The Canadian Foundation for Innovation (CFI) and
the Ontario Ministry of Economic Development and
Innovation are thanked for essential infrastructure. We thank
Apotex Pharma Inc. for support via the NSERC Engage
Fundamentals, Progress, Challenges, and Opportunities, ed.
R. D. Rogers and K. R. Seddon, American Chemical Society,
Washington, 2005, ch. 10, 126–132.
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108, 206–237; (b) J. A. Dean, Lange’s Handbook of Chemistry,
McGraw-Hill, New York, 1999; (c) M. Maase and
O. Huttenloch, WO Pat, 2005061416A1, 2005.
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Green Chem.