Organic Letters
Letter
Angew. Chem., Int. Ed. 2012, 51, 10190. (c) Rodrigues, T.; Schneider,
P.; Schneider, G. Angew. Chem., Int. Ed. 2014, 53, 5750. (d) Shu, W.;
6.5 min at 120 °C was enough to catalyze the reaction to obtain
triazole (9). The Cu supported catalyst (III) was continuously
fed into the system via a pump for recirculation. The reaction
time was 10 h with 8.26 g of product (productivity = 2.64 mmol
h−1) collected in 88% overall yield. The integrated microfluidic
system took only 6.5 min with comparable yields to the
conventional batch process without any detectable metal
leaching.
In summary, we have developed a microfluidic loop system
for continuous recirculation of a polymer supported metal
catalyst for novel cross-coupling reactions under thermomor-
phic multicomponent system conditions. This approach takes
full advantage of a homogeneous catalyst system while retaining
the advantage a heterogeneous catalyst system offers for easy
separation and recirculation of the catalyst. This automated
microreactor system successfully demonstrated a novel method
for the chemical library synthesis of quinazolinone derivatives
as well as an important intermediate of Merck’s LTD4
antagonist “Singulair”.
Buchwald, S. L. Angew. Chem., Int. Ed. 2012, 51, 5355. (e) Lev
F.; Seeberger, P. H. Angew. Chem., Int. Ed. 2012, 51, 1706. (f) Noel, T.;
Buchwald, S. L. Chem. Soc. Rev. 2011, 40, 5010. (g) Wegner, J.; Ceylan,
S.; Kirschning, A. Chem. Commun. 2011, 47, 4583. (h) Wiles, C.;
Watts, P. Chem. Commun. 2011, 47, 6512. (i) Hessel, V.; Kralisch, D.;
́
esque,
̈
Kockmann, N.; Noel, T.; Wang, Q. ChemSusChem 2013, 6, 746.
̈
(j) Mastronardi, F.; Gutmann, B.; Kappe, C. O. Org. Lett. 2013, 15,
5590. (k) Wirth, T. ChemSusChem 2012, 5, 215. (l) Opalka, S. M.;
Park, J. K.; Longstreet, A. R.; McQuade, D. T. Org. Lett. 2013, 15, 996.
(8) (a) Theberge, A. B.; Whyte, G.; Frenzel, M.; Fidalgo, L. M.;
Wootton, R. C. R.; Huck, W. T. S. Chem. Commun. 2009, 6225.
(b) Liu, S.; Fukuyama, T.; Sato, M.; Ryu, I. Org. Process Res. Dev. 2004,
8, 477. (c) Solodenko, W.; Mennecke, K.; Vogt, C.; Gruhl, S.;
Kirschning, A. Synthesis 2006, 1873. (d) Mennecke, K.; Solodenko,
W.; Kirschning, A. Synthesis 2008, 1589. (e) Li, P.; Moore, J. S.;
Jensen, K. F. ChemCatChem 2013, 5, 1729. (f) Fukuyama, T.; Rahman,
M. T.; Sumino, Y.; Ryu, I. Synlett 2012, 23, 227. (g) Fukuyama, T.;
Rahman, M. T.; Kamata, N.; Tokizane, M.; Fukuda, Y.; Ryu, I. J. Flow
Chem. 2013, 3, 4.
(9) (a) Schafer, E.; Brunsch, Y.; Sadowski, G.; Behr, A. Ind. Eng.
Chem. Res. 2012, 51, 10296. (b) Marchetti, A.; Preti, C.; Tagliazucchi,
M. J. Chem. Eng. Data 1991, 36, 360.
(10) Bergbreiter, D. E.; Hughes, R.; Besinaiz, J.; Li, C.; Osburn, P. L.
J. Am. Chem. Soc. 2003, 125, 8244.
(11) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290−1309.
(12) (a) Vlaar, T.; Ruijter, E.; Maes, B. U. W.; Orru, R. V. A. Angew.
Chem., Int. Ed. 2013, 52, 7084. (b) Vlaar, T.; Cioc, R. C.; Mampuys, P.;
Maes, B. U. W.; Orru, R. V. A.; Ruijter, E. Angew. Chem., Int. Ed. 2012,
51, 13058.
ASSOCIATED CONTENT
* Supporting Information
Complete experimental procedures and characterization of new
products. This material is available free of charge via the
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S
AUTHOR INFORMATION
Corresponding Author
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(13) DeRuiter, J.; Brubaker, A. N.; Millen, J.; Riley, T. N. J. Med.
Chem. 1986, 29, 627.
(14) (a) Glorius, F. N-Heterocyclic Carbenes in Transition Metal
Catalysis Series: Topics in Organometallic Chemistry; Springer: Berlin,
2007; pp 22−30. (b) Uozumi, Y.; Nakai, Y. Org. Lett. 2002, 4, 2997.
(15) (a) Karimi, B.; Enders, D. Org. Lett. 2006, 8, 1237. (b) Valente,
C.; Çalimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.; Organ, M. G.
Angew. Chem., Int. Ed. 2012, 51, 3314.
Author Contributions
§S.S. and K.C.B. contributed equally to this work.
Notes
The authors declare no competing financial interest.
(16) Sharma, S.; Maurya, R. A.; Min, K.-I.; Jeong, G.-Y.; Kim, D.-P.
Angew. Chem., Int. Ed. 2013, 52, 7564.
(17) Hajduk, P. J. Nature 2011, 470, 42.
ACKNOWLEDGMENTS
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This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government
(MSIP) (No. 2008-0061983)
(18) (a) Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008, 41, 1440.
(b) Selvakumar, K.; Zapf, A.; Beller, M. Org. Lett. 2002, 4, 3031.
(c) Cyr, P.; Deng, S. T.; Hawkins, J. M.; Price, K. E. Org. Lett. 2013,
15, 4342.
(19) (a) King, A. O.; Corley, E. G.; Anderson, R. K.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1993, 58, 3731.
(20) (a) Yamada, Y. M. A.; Sarkar, S. M.; Uozumi, Y. J. Am. Chem.
Soc. 2012, 134, 6243. (b) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem.
Soc. 2008, 130, 833. (c) Gao, Y.; Wang, G.; Chen, L.; Xu, P.; Zhao, Y.;
Zhou, Y.; Han, L.-B. J. Am. Chem. Soc. 2009, 131, 7956.
REFERENCES
■
(1) (a) Clark, J. H. Nat. Chem. 2009, 1, 12. (b) Elvira, K. S.; Solvas,
X. C.; Wootton, R. C. R.; deMello, A. J. Nat. Chem. 2013, 5, 905.
(2) (a) Fan, Q.-H.; Li, Y.-M.; Chan, A. S. C. Chem. Rev. 2002, 102,
3385. (b) Cole-Hamilton, D. J. Science 2003, 299, 1702. (c) Molnar
Chem. Rev. 2011, 111, 2251.
(3) (a) Gates, B. C. Catalytic Chemistry; Wiley-Interscience: New
York, 1991; Chapter 6. (b) Duran, P. L.; Rothenberg, G. Appl.
Organometal. Chem. 2008, 22, 288.
́
́
, A.
́
(4) (a) Bergbreiter, D. E. Chem. Rev. 2002, 102, 3345. (b) Behr, A.;
Henze, G.; Johnen, L.; Awungacha, C. J. Mol. Catal. A: Chem. 2008,
285, 20. (c) Behr, A.; Henze, G.; Obst, D.; Turkowski, B. Green Chem.
2005, 7, 645.
(5) (a) Bergbreiter, D. E.; Liu, Y.-S.; Osburn, P. L. J. Am. Chem. Soc.
1998, 120, 4250. (b) Bergbreiter, D. E.; Osburn, P. L.; Wilson, A.;
Sink, E. M. J. Am. Chem. Soc. 2000, 122, 9058. (c) Bergbreiter, D. E.;
Osburn, P. L.; Smith, T.; Li, C.; Frels, J. D. J. Am. Chem. Soc. 2003,
125, 6254. (d) Bergbreiter, D. E.; Hamilton, P. N.; Koshti, N. M. J.
Am. Chem. Soc. 2007, 129, 10666. (e) Brunsch, Y.; Behr, A. Angew.
Chem., Int. Ed. 2013, 52, 1586.
(6) Bergbreiter, D. E.; Weatherford, D. A. J. Org. Chem. 1989, 54,
2726.
(7) Selected readings on microreactors: (a) Whitesides, G. Nature
2006, 442, 368. (b) Cantillo, D.; Baghbanzadeh, M.; Kappe, C. O.
3977
dx.doi.org/10.1021/ol501802w | Org. Lett. 2014, 16, 3974−3977