Continuous flow Sonogashira C-C coupling using a heterogeneous palladium-copper dual reactor

Article abstract of DOI:10.1021/ol303046e

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 C-C 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.

Full text of DOI:10.1021/ol303046e

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
kenlee@sp.edu.sg
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

residence time, and the nonleaching nature of the system
promoted green chemistry efforts.
catalytic amount of leached Pd for the Sonogashira reaction.
Indeed, the reaction with the PdÀCu flow reactor afforded
the desired product in quantitative conversions (Table 1,
entry 5). Notably, the Pd collected from the PdÀCu dual
reactor was much lower (51.7 ppb) than the single Pd reactor
(3785 ppb),11 probably due to the redeposition of Pd
particles on the Cu reactor.12 The deposition of the Pd
catalyst was also observed for the homogeneous system.
Pd is a precious metal of relatively low abundance, high
toxicity, and higher risk to sustainable sourcing.6 Many
cross-couplings are carried out with the use of Pd cata-
lysis.7 There is a great need to further reduce the amount of
Pd used for practical applications. In this paper, a dual
PdÀCu inline tubular reactor was reported. A Pd coated
tubular reactor was placed in line with a Cu tubing, pro-
viding facile access to a wide range of Sonogashira coupling
products from moderate to good yields under ambient
conditions, while utilizing only a minimal amount of Pd.
An in-line scavenger resin column easily removed the minute
amount of leached Pd and Cu.
Scheme 1. Outline of the Reaction Mechanism for Sonogashira
CÀC Coupling Reaction14
Our initial setup showed good conversions when a homo-
geneous Pd catalyst was used in a Cu reactor (Table 1,
entries 1À3).8 Notably, the efficiency was maintained at a
low catalyst loading (0.1 mol %). It has been widely re-
ported that a quasi-homogeneous mechanism takes place in
a heterogeneous Pd reaction where the leached Pd(II) from
solid supports catalyzes the reaction.9 To explore a new Pd-
source, we chose a Pd tubular reactor and carried out the
same reaction without any homogeneous Pd catalyst10
where 47% of the desired product was observed (Table 1,
entry 4). Leaching of 3785 ppb of Pd occurred from the Pd
reactor, and we assume this to be the standard catalytic
amount needed for this transformation. The amount of
Pd leached is equivalent to about 0.5 mol % of the homo-
geneous Pd system. We also noticed that a negligible
amount (∼6 ppb) of Pd is leached out when only solvent
is flowing through the Pd tube. Apparently, the Pd was
leached out during oxidative addition in Cycle A (Scheme 1).
The sequence and the presence of Cu from the PdÀCu
dual reactor are crucial to the overall efficiency. Low con-
versions were obtained when (i) the sequence was re-
versed (Table 1, entry 6) and (ii) Cu was absent (Table 1,
entries 4, 7, and 8).13 These investigations revealed that
the heterogeneous PdÀCu dual reactor follows the
Sonogashira mechanism, where the transmetalation in
Cycle B with Cu occurs after the oxidative addition in
Cycle A (Scheme 1).14 The close proximity of the Pd cata-
lyst with Cu during transmetalation probably aids the
redeposition of the Pd on the Cu tubing.
Table 1. Sonogashira Coupling Reactions between 1c and 2a
Showing the Efficiency of the PalladiumÀCopper Dual Reactor
yieldb
(%)
Pd collectedc
(ppb)
(6) (a) Price of Pd was US $690/oz on January 12, 2012. (b) Oral
exposure limit is 10 ppm based on Specific Limits for Residues of Metal
Catalysts, accessed May 13, 2012. (c) Supply risk index is 8.5, based on
“British Geological Survey: Risk List 2011”, accessed May 13, 2012.
(7) (a) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062–5085. (b) Magano,
J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177–2250.
(8) Refer to Supporting Information for more homogeneous Pd
catalysis in Cu reactor. In this study, we found out that the optimum
(where highest yield of the products were obtained) concentration of
reactants and flow rate are 0.05 M and 0.6 mL/min respectively. We
decided to use these conditions for the rest of our experiments.
(9) Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133–173 and refer-
ences cited therein.
(10) The Pd tubular reactor was purchased from Autochem Pte Ltd.,
and according to the vendor, the metal was coated onto Cu tubing using
conventional electroplating methods.
(11) Leached Pd(II) was collected at two different points: at the exits
of the Pd and the Cu reactors, measured using the inductively coupled
plasma optical emission spectrophotometer (ICP-OES).
(12) Zhao, F.; Bhanage, B. M.; Shirai, M.; Arai, M. Chem.;Eur. J.
2000, 6, 843–848.
entrya
reaction conditions
1
2
3
4
5
6
7
8
Pd(Cl2)(PPh3)2 (1 mol %)d
Pd(Cl2)(PPh3)2 (0.5 mol %)d
Pd(Cl2)(PPh3)2 (0.1 mol %)d
Pd reactor
quant
95
102.9 (7601)e
78.9 (3801)
65.7 (760.1)
3785 (NA)
51.7 (3785)
À (NA)
90
47
PdÀCu dual reactor
CuÀPd dual reactor
PdÀPFA dual reactor
PdÀSS dual reactor
quant
60
0
À (NA)
10
À (NA)
a 0.6 mL/min flow rate and residence times of 2 min (Cu reactor),
2.67 min (Pd reactor), 3.67 min (PFA reactor), and 6.83 min (stainless
steel reactor) where applicable. b Normalized GC yield. c Palladium
collected was analyzed using ICP-OES for entries 1À5 only. d Reaction
was carried out using homogeneous catalyst in a Cu reactor. e Amount of
Pd introduced into the reaction.
We then decided to place the Pd reactor in line with a
Cu reactor where the former may provide the required
(13) Pd-Perfluoroalkoxy (Pd-PFA) and Pd-Stainless steel (Pd-SS)
flow reactors.
66
Org. Lett., Vol. 15, No. 1, 2013

Table 2. Sonogashira CÀC Coupling Using the PdÀCu
Flow Reactor
Figure 1. Performance of the PdÀCu dual reactor during a con-
tinuous run of 10 cycles of the Sonogashira CÀC coupling reaction.
amounts of Pd and Cu were effectively trapped with less
than 20 ppb of these metals detected using ICP-OES.
Most of the continuous flow reactors with prepacked
catalysts usually require postloading after extended usage.
For our PdÀCu dual reactor, the performance was main-
tained even after a continuous run of 10 cycles (Figure 1).
Since only a minute amount of Pd is used in each cycle, the
Pd tube provides a quasi-unlimited source of Pd catalyst.
In conclusion, we have established the first continuous
flow Sonogashira CÀC coupling reaction on a heteroge-
neous PdÀCu dual reactor, through a quasi-homogeneous
type mechanism. The Pd reactor can serve as a Pd source,
and the catalytic amount can be reduced significantly with
no loss of reaction efficiency. The following advantages
strongly increase the appeal of this method: (i) ease of
setting up and carrying out the reactions; (ii) promoters
such as phosphines are not needed; (iii) only the required
amount of Pd is leached out from the Pd tubing through
oxidative addition; (iv) traces of leached Pd can be re-
moved effectively with the Cu reactor and, subsequently,
the metal scavenging resins at the backend of the flow
setup; (v) the performance can be maintained after several
catalytic cycles. Subsequent applications of this method on
the large-scale synthesis of chemicals will be reported in
due course.
a Flow rates for selected entries were set at 0.6 mL/min to give a
residence time of 2.83 min in the Pd reactor and 2 min in the Cu reactor,
with reagent concentrations at 0.05 M. b Normalized GC yield. c Flow
rates were set at 0.1 mL/min with a lower reagent concentration (0.025 M).
Having developed the optimal conditions for this PdÀ
Cu dual reactor, we then extended this methodology to a
range of commercially available substituted iodobenzenes.
The range of substitution patterns and functionalities that
were tested using this setup is shown in Table 2. From the
results shown, substrates with both electron-withdrawing
and -donating substituting groups afforded the diarylal-
kynes through coupling with the terminal alkyne and the con-
versions range from 40% to 98%. Generally, substrates
with electron-withdrawing groups afforded a higher con-
version due to the ease of oxidative addition. The unsatis-
factory conversion for 4-iodoaniline (Table 2, entry 6) could
be attributed to the coordination of the amino group to the
Pd particles to form a Pd complex, thereby deactivating the
catalytic system in the Pd reactor.15 Although the Cu reactor
has shown to be an effective scavenger by facilitating the
redeposition of Pd particles, the backend of the continuous
flow was fitted with a chromatographic column, packed
with metal scavenging resin (QuadraPure TU). Trace
Acknowledgment. We would like to thank Singapore
Polytechnic for financial support on our continuous flow
projects (votes R736, R758, 45-3406, and 45-2201). The
NMR facilities at Singapore Polytechnic are funded by
36-R107.
Supporting Information Available. Experimental pro-
cedures and full characterization (1H and 13C NMR data
and spectra, and GCMS) for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46–49.
(15) (a) Li, Y.; El-Sayed, M. A. J. Phys. Chem. B 2001, 105, 8938–
8943. (b) Crooks, R. M.; Zhao, M.-Q.; Sun, L.; Chechik, V.; Yeung,
L. K. Acc. Chem. Res. 2001, 34, 181–190.
The authors declare no competing financial interest.
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