ORGANIC
LETTERS
2013
Vol. 15, No. 1
65–67
Continuous Flow Sonogashira CÀC
Coupling Using a Heterogeneous
PalladiumÀCopper Dual Reactor
Li-Min Tan,‡ Zhi-Yu Sem,‡ Wei-Yuan Chong,‡ Xiaoqian Liu,† Hendra,§ Wei Lek Kwan,
and Chi-Lik Ken Lee*,†
Center for Biomedical and Life Sciences, Singapore Polytechnic, 500 Dover Road,
Singapore 139651, Singapore, School of Chemical and Life Sciences, Singapore
Polytechnic, 500 Dover Road, Singapore 139651, Singapore, School of Mechanical and
Aeronautical Engineering, Singapore Polytechnic, 500 Dover Road, Singapore 139651,
Singapore, and Engineering Product Development, Singapore University of Technology
and Design, 20 Dover Road, Singapore 138682, Singapore
Received November 16, 2012
ABSTRACT
We report the development of a heterogeneous catalyst system on continuous flow chemistry. A palladium (Pd) coated tubular reactor was placed
in line with copper (Cu) tubing using a continuous flow platform, and a Sonogashira CÀC coupling reaction was used to evaluate the performance.
The reactions were favorably carried out in the Cu reactor, catalyzed by the traces of leached Pd from the Pd reactor. The leached Pd and Cu were
trapped with a metal scavaging resin at the back-end of the continuous flow system, affording a genuine approach toward green chemistry.
Microreactor and tubular reactor technologies in con-
tinuous flow are particularly advantageous as they im-
prove heat transfer and atom economy through better
reaction control.1 Recent trends have shown an increase
in the use of metal tubular reactors as a catalytic source to
promote green chemistry.2 The Cu tubular reactor has
been shown to be effective in catalyzing the click reactions
from simple starting materials using the one-pot method-
ology, employing conventional heating and ultrasound as
additional sources of energy.3 Commercially available Cu
tube flow reactor has also been used to carry out several
synthetic transformations in good yields.4 Kawanami et al.
developed a PdÀCu alloy on the inner surface of the tubular
reactor and investigated Sonogashira CÀC coupling under
elevated temperature and pressure.5 Despite the tedious Pd
coating, the use of water as a reaction solvent, the short
‡ School of Chemical and Life Sciences, Singapore Polytechnic.
† Center for Biomedical and Life Sciences, Singapore Polytechnic.
§ School of Mechanical and Aeronautical Engineering, Singapore
Polytechnic.
Singapore University of Technology and Design.
(1) For a few selected reviews and examples of continuous flow
chemistry, see: (a) Kirschning, A.; Jas, G. In Applications of Immobilized
Catalysts in Continuous Flow Processes; Topics in Current Chemistry, Vol.
242; Springer-Verlag: Berlin Heidelberg, 2004; p 209. (b) Watts, P.;
Wiles, C. J. Chem. Res. 2012, 36, 181–193. (c) van den Broek, S. A. M.
W.; Leliveld, J. R.; Becker, R.; Delville, M. M. E.; Nieuwland, P. J.;
Koch, K.; Rutjes, F. P. J. T. Org. Process Res. Dev. 2012, 16, 934–938.
(d) Calabrese, G. S.; Pissavini, S. AIChE J. 2011, 5, 828–834. For a few
examples on using microreactors and tubular reactors in continuous
flow chemistry, see: (e) Razzaq, T.; Kappe, O. C. Chem.;Asian J. 2010,
5, 1274. (f) Hartman, R.; McMullen, J.; Jensen, K. Angew. Chem., Int.
Ed. 2011, 50, 7502–7519. (g) Yoshida, J. I.; Kim, H.; Nagaki, A.
ChemSusChem 2011, 4, 331–340.
(3) For some selected examples using Cu tubular reactor, see:
(a) Bogdan, A. R.; Sach, N. W. Adv. Synth. Catal. 2009, 351, 849–854.
(b) Bogdan, A. R.; James, K. Chem.;Eur. J. 2010, 16, 14506–14512.
(c) Bogdan, A. R.; James, K. Org. Lett. 2011, 13, 4060–4063. (d) Tu,
N. P.; Hochlowski, J. E.; Djuric, S. W. Mol. Diversity 2012, 16, 53–58.
(4) Zhang, Y.; Jamison, T. F.; Patel, S.; Mainolfi, N. Org. Lett. 2011,
13, 280–283.
(5) (a) Javaid, R.; Kawanami, H.; Chatterjee, M.; Ishizaka, T.;
Suzuki, A.; Suzuki, T. M. Chem. Eng. J. 2011, 167, 431–435 and
references cited therein. (b) Kawanami, H.; Matsushima, K.; Sato, M.;
Ikushima, Y. Angew. Chem., Int. Ed. 2007, 46, 5129–5132.
(2) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.;
McQuade, D. T. Chem. Rev. 2007, 107, 2300–2318.
r
10.1021/ol303046e
2012 American Chemical Society
Published on Web 12/18/2012