Green and scalable procedure for extremely fast ligandless Suzuki-Miyaura cross-coupling reactions in aqueous IPA using solid-supported Pd in continuous flow

Article abstract of DOI:10.1016/j.tetlet.2014.05.010

An environmentally friendly continuous-flow protocol for the Suzuki coupling of boronic acids and aryl halides under ligand-free conditions using solid-supported Pd is presented. The process described herein uses very simple reaction conditions and equipment setup and can be readily scaled up to provide multigram quantities of products containing low levels of residual Pd.

Full text of DOI:10.1016/j.tetlet.2014.05.010

Accepted Manuscript
Green and scalable procedure for extremely fast ligandless Suzuki-Miyaura
cross-coupling reactions in aqueous IPA using solid-supported Pd in continuous
flow
Carlos Mateos, Juan A. Rincón, Beatriz Martín-Hidalgo, José Villanueva
PII:
S0040-4039(14)00786-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.010
TETL 44600
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 April 2014
1 May 2014
5 May 2014
Please cite this article as: Mateos, C., Rincón, J.A., Martín-Hidalgo, B., Villanueva, J., Green and scalable procedure
for extremely fast ligandless Suzuki-Miyaura cross-coupling reactions in aqueous IPA using solid-supported Pd in
continuous flow, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
An environment friendly continuous-flow protocol
for the Suzuki coupling of boronic acids and aryl
halides under ligand-free conditions using solid-
supported Pd is presented. The process described
herein uses very simple reaction conditions and
equipment setup and can be readily scaled up to
provide multigram quantities of products containing
low levels of residual Pd.
Green and scalable procedure for extremely fast
ligandless Suzuki-Miyaura cross-coupling reactions
in aqueous IPA using solid-supported Pd in
continuous flow
Carlos Mateos,* Juan A. Rincón, Beatriz Martín-Hidalgo and
José Villanueva
150ºC
or
Pd/C Pd/Al
2
O3
3 mL/min
20 seconds residence time
IPA/H2O
X= Br, I

Tetrahedron Letters
journal homepage: www.els evier.com
Green and scalable procedure for extremely fast ligandless Suzuki-Miyaura
cross-coupling reactions in aqueous IPA using solid-supported Pd in
continuous flow
Carlos Mateos,* Juan A. Rincón, Beatriz Martín-Hidalgo and José Villanueva
Centro de Investigación Lilly S.A., Avda. de la Industria, 30, Alcobendas-Madrid 28108, Spain
ARTICLE INFO
ABSTRACT
Article history:
Received
An environment friendly continuous-flow protocol for the Suzuki coupling of boronic acids and
aryl halides under ligand-free conditions using solid-supported Pd is presented. The process
described herein uses very simple reaction conditions and equipment setup and can be readily
scaled up to provide multigram quantities of products containing low levels of residual Pd.
Received in revised form
Accepted
Available online
Keywords:
.
Suzuki-Miyaura
Cross-coupling
2014 Elsevier Ltd. All rights reserved.
Ligand free catalysis
Supported palladium
Flow chemistry
Scalable process
Continuous process
∗ Corresponding author. Tel.: +34-91-6233394; fax: +34-91-6633411; e-mail: c.mateos@lilly.com

Green and scalable procedure for extremely fast ligandless Suzuki-
Miyaura cross-coupling reactions in aqueous IPA using solid-
supported Pd in continuous flow
Carlos Mateos,* Juan A. Rincón, Beatriz Martín-Hidalgoa and José Villanuevab
Centro de Investigación Lilly S.A., Avda. de la Industria, 30, Alcobendas-Madrid 28108, Spain
Undoubtedly, for the pharmaceutical and fine chemical industry, the Suzuki-Miyaura cross-coupling reaction1 represents
probably the most widely used carbon-carbon bond forming process, with application mainly in the construction of
(hetero)biaryls that are common scaffolds in natural products and bioactive compounds.2 Such reactions are usually catalyzed
by Pd(II) /Pd(0) complexes in the presence of phosphines or other ligands. However, these additives are expensive and often
require difficult purification steps to remove ligand and Pd from the desired product. Moreover, in many cases, ligands are air
and moisture sensitive, which makes reaction setup too complex for straightforward scale-up and makes ligand-free palladium
applications the alternative of choice from a green chemistry perspective.3
Among the supported catalytic systems available,4 palladium on carbon (Pd/C) is probably the most frequently used agent
for industrial processes due to its low price, high catalytic activity and easy removal after completion of the reaction. Moreover,
the possible use of aqueous media in combination with this catalyst, with concomitant reduction in use of organic solvents,
makes this approach highly desirable in terms of environmental protection.5 Some recent studies suggest, however, that the
active species in the cross-coupling process is homogeneous, resulting from a leaching process from the support matrix, and is,
after the reductive elimination, adsorbed again, giving rise to low free Pd levels in the crude reaction mixtures.6 Palladium on
charcoal is a highly pyrophoric material and when used in batch on large scale the filtration operations are especially hazardous,
where ignition can occur if not cautiously performed. Because of this, operations are typically carried out under inert
atmospheres, thus adding further complexity.7
To overcome many of these issues, we envisioned a continuous flow procedure using a packed bed reactor with a ligand-free
Palladium source for the Suzuki-Miyaura cross-coupling reaction of arylorganoboron species and aryl halides.8 It is well known
that flow chemistry offers advantages over batch processes in two main areas, improvement of mass transfer and heat transfer,
and that such features can make scale-up campaigns both higher yielding and more reproducible, having a desired impact on
sustainability.9 In this case, the combined use of a packed bed reactor, reported to increase interfacial contact between organic
and aqueous layers10 and the use of high temperatures to create a new processing window11 both enhance the efficiency of the
process, dramatically reducing the reaction time to seconds.
Our flow chemistry setup consisted of a ThalesNano H-Cube MIDI ®, a commercial packed bed flow hydrogenator, in our
case used only to work at high pressures and temperatures, without H2 generation. The reactants were injected using integrated
HPLC-type pump, and flowed into a MIDI Cart catalyst packed bed reactor at the desired temperature, controlled accurately by
the system.12 (Figures 1 and 2). We used that system for convenience but any setup consisting in a pump, the cartridge
(commercially available) a way to heat the cartridge (e.g. oven, oil bath etc) and back pressure regulator could be used as well.
3

Heat
H-Cube Midi
Pd supported cartridge
pump
X= Br, I
Figure 1
Continuous-Flow setup for Suzuki cross-coupling
Figure 2
H-Cube Midi modified setup for cross-coupling reactions.
As the starting point for our continuous flow investigation we used 3-bromophenol (1 equiv) or 3-iodophenol (1 equiv) and
phenylboronic acid (1 equiv) as model reagents for the Suzuki-Miyaura cross-coupling, a 10% Pd/C packed-bed cartridge as the
flow reactor,13 and screened several bases described for the transformation (Na3PO4, K3PO4, Li2CO3, Na2CO3, K2CO3; 3 equiv)
in aqueous media. As our initial aim was to have the greenest possible protocol, we used water as solvent in the first place,5
nevertheless, upon mixing these reagents, a slurry was formed, precluding a continuous flow process. In order to have a clear
solution we added small portions of methanol while applying ultrasonic irradiation until a complete solution was formed,
choosing finally K2CO3 (due to solubility and cost efficiency) in a 3:2 mixture of H2O/MeOH as the best option. With this
result in hand, we determined that the maximum viable concentration to maintain solubility was 0.15M for the aryl halide, so
we used this value from in all subsequent experiments. Subsequently, we performed the reaction by pumping the reactant
mixture through the cartridge at the minimum flow rate available (3 ml/min),14 heated at different T controlled by the H-Cube
MIDI system with no H2 gas generation. The results of this optimization showed that conversion to the desired product
increased with T, reaching a plateau at around 140ºC-150ºC with the iodide derivative much more reactive, having a conversion
4

of 88% to the desired heteroaryl coupling product (Error! Reference source not found.). The pinacol boronic ester derivative
was also tested, producing this time a slightly lower conversion of 62% to the desired product. Finally, the influence of the
alcohol solvent was studied, whereupon isopropanol was identified as the most efficient in terms of desired product generation.
1 equiv
2
K CO
2
H O/solvent
3 mL/min
3
10% Pd/C cartridge
Temperature
1 equiv
Table 1
Optimization of the reaction conditions for the Pd/C catalyzed Suzuki cross-coupling in flow
Entry
X
Br
Br
I
R
T (C) Solvent Conversiona
1
2
OH
OH
OH
OH
OH
OH
OH
OH
OH
80°C
MeOH
0%b
3%b
110°C MeOH
80 °C MeOH
100 °C MeOH
120 °C MeOH
140°C MeOH
150°C MeOH
3
50%c
55%c
60%c
70%c
73%c
80%c
88%c
70% c
4
I
5
I
6
I
7
I
8
I
150°C
EtOH
9
I
150°C iPrOH
10
I
-pinacol- 150°C iPrOH
aHPLC peak integration.
bMixtures of SM, aryl halide homocoupling and dehalogenated species were formed.
cNon-product HPLC peaks corresponded to unreacted SM and aryl halide homo-coupling.
5

With this set of variables optimized, we turned our attention to the influence of the residence time in the conversion values
observed. Thus, we designed a new equipment setup with control over smaller flow rates so residence times could be
increased.15 The results showed that residence time had little influence over the Suzuki cross-coupling reactivity, using the
same reaction partners and catalyst, with similar values across the range. (Figure 3).
Figure 3 Influence of flow rate over conversion.
A further important parameter that was investigated was the palladium support.12 As shown in figure 4, the use of Pd/C 10%
or Pd over alumina 5% provided highest conversion, being largely comparable. When using Pd/C Powder type16 or Pd black,
conversion figures were more modest. For the case of Pd on silica, inconsistent results were obtained, along with some
overpressure issues and so this support was disregarded. Interestingly, when a Pd black cartridge was employed the impurity
profile of the crude samples changed dramatically, showing only unreacted SM and product with no detected aryl halide
homocoupling byproducts.
1 equiv
2
K CO
3
"Pd" cartridge
150ºC
2
H O/IPA
3 mL/min
1 equiv
Figure 4
Influence of the palladium support upon conversion for the reaction between 3-iodophenol and phenylboronic acid.
6

With these optimization results in hand, we designed a more extensive study of the scope of this transformation based on the
electronic nature of both aryl halide and boronic acid (Table 2). Thus, various ortho-, metha- and para- substituted aryl iodides
and bromides were cross-coupled with boronic acids. As demonstrated previously, bromide derivatives proved less efficient
than the corresponding iodide derivatives (compare entries 5 and 6, and entries 10 and 12). Interestingly, the reactivity of
simple iodobenzene (entry 1) was moderate compared with more substituted aromatics, regardless of electronic factors.
Notably, the transformation was successful with electron-donating (entries 2, 3, 4) and electron-withdrawing substituents
(entries 5-15) as well as heteroaromatic substitution (entry 16). With regard to the boronic acid, the methoxyphenyl derivative
gave excellent results compared with phenyl boronic acid (entries 2-3, 7-9 and 10-14) whereas (E)-styryl boronic acid provided
only moderate conversion to the desired cross-coupling product (entry 13).
The reusability of the supported catalyst17 is a very important factor for the reproducibility of scale-up preparations under a
continuous flow regime, and is also desirable for economic and environmental reasons.18 With the aim of assessing the stability
of the supported catalyst over time and also to verify the data obtained by HPLC peak integration, we performed several
experiments at multigram scale, isolating the final compounds. To our delight, we found that catalyst activity was not
diminished over time19 and we were able to scale-up some examples up to 10 g (entries 7-8) and 100 g (entries 10-11),
obtaining excellent yields after isolation.20
The residual palladium content was also investigated for some selected examples, to evaluate the extent of metal leaching
from the solid support. The results showed Pd levels in the crude reaction solutions to be in the low double-digit ppm range
using either Pd/C or Pd/Al2O3 (entries 7-8 and 10-11). Interestingly, the experiments run at larger scale (entries 7-8, and 10-11)
gave a similar outcome, showing the robustness and reliability of the procedure.
Table 2 Suzuki cross-coupling reactions with supported Pd catalysis under continuous flow conditions
Pd
Entry
Aryl Halide
Boronic acid
Product (scale) a
Cartridge Purityb(%) content
(ppm)c
e
1
Pd/C 10%
Pd/C 10%
51
70
-
e
-
2
3
4
PhB(OH)2
e
-
Pd/C 10%
Pd/C 10%
68
88
PhB(OH)2
40
(1 g)
7

e
5
6
PhB(OH)2
PhB(OH)2
Pd/C 10%
75
42
-
e
-
Pd/C 10%
7
8
9
PhB(OH)2
Pd/C 10%
90d
92d
95
44
31
43
(10 g)
Pd/Al2O3
10%
(10 g)
Pd/C 10%
10
11
12
PhB(OH)2
Pd/C 10%
98d
96d
50
26
35
(100 g)
Pd/Al2O3
10%
(100 g)
e
-
PhB(OH)2
Pd/C 10%
8

e
-
13
Pd/C 10%
60
14
15
16
Pd/C 10%
Pd/C 10%
Pd/C 10%
98
97
70
39
e
-
PhB(OH)2
PhB(OH)2
e
-
aProduct obtained using a 0.15M solution of aryl halide and boronic acid, 150ºC, 3 mL/min, 0.5 g scale unless otherwise noted.
bHPLC peak integration at 214 nm.
cPd content values obtained by Inductively Coupled Plasma Mass Spectrocopy (ICP-MS).
dIsolated yield.
eNot determined
In conclusion, we have developed an easy and scalable procedure for the Suzuki-Miyaura cross-coupling reaction of aryl
halides and arylboronic acids using supported Pd catalysis in continuous flow. The packed-bed reactors used are commercially
available and, with the reaction conditions described herein, provided great stability over time and reproducible results. The
methodology was demonstrated to be viable for large-scale preparations of organic compounds presenting low levels of residual
Pd in the crude reaction products. Moreover, the use of benign isopropanol/water solution mixtures, very short residence times
and reduced catalyst amounts without the need of expensive ligands offers a sustainable, safe and cost-effective synthetic
approach to the synthesis of biaryls. Additionally, the simple nature of the flow chemistry method potentially allows for
multistep automation. Work is being undertaken in our laboratories in this regard and will be reported in due course.
Acknowledgments
We thank Dr Graham Robert Cumming and Lorena López for their assistance during the preparation of the manuscript. B.
M-H and J. V. thank the Fundación Universidad-Empresa (FUE) for financial support.
References and notes
Centro de Investigación Lilly S.A., Avda. de la Industria, 30, Alcobendas-Madrid 28108, Spain
9

e-mail: c.mateos@lilly.com
aCurrent address: Envirohemp, Logroño, Spain
bCurrent address: ILS-Integrated Lab Solutions GmbH, Berlin, Germany
1 Seminal paper: Miyaura, N.; Yamada, K.; Suzuki A. Tetrahedron Lett. 1979, 36, 3437-3440.
2 Kozlowski, M. C.; Morgana B. J.; Lintona E. C. Chem. Soc. Rev. 2009, 38, 3193-3207.
3Dmitrii N. K., Nikolay A. B. Tetrahedron Lett. 2006, 47, 4225-4229. (b) Lu G, Franzén R., Zhang Q., Xu Y. Tetrahedron
Lett. 2005, 46, 4255-4259.
4 Blaser, H-U.; Indolese, A.; Schnyder, A.; Steiner, H.; Studer, M. J. Mol. Cat. A: Chemical 2001, 173, 3–18.
5 Recent Suzuki-Miyaura reactions in aqueous media: (a) Liua, H.; Liua, B. H.; Lia, R.; Chena H. Tetrahedron Lett. 2014, 55,
415-418. (b) Edwards, G. A.; Trafford, M. A.; Hamilton, A. E.; Buxton, A. M.; Bardeaux, M. C.; Chalker, J. M. J. Org. Chem.,
2014, 79, 2094-2104. (c) Liu, C.; Rao, X.; Zhang, Y.; Li, X.; Qiu, J.; Jin Z. Eur. J. Org. Chem. 2013, 20, 4345–4350. (d) For a
recent review see: Polshettiwar, V.; Decottignies, A.; Len, C.; Fihri, A. ChemSusChem. 2010, 3, 502-522.
6
(a) Kitamura, Y.; Sako, S.; Tsutsui, A.; Monguchi, Y.; Maegawa, T.; Kitade, Y.; Sajikia, H. Adv. Synth. Catal. 2010, 352,
718–730. (b) Rothenberg, G.; Gaikwad, A. V.; Holuigue, A.; Thathagar, M. B.; ten Elshof J.E. Chem. Eur. J. 2007, 13, 6908–
6913 (c) Khinast, J. G. et al, Applied Catalysis A: General 2007, 325, 76–86.
7 Crowl, A.; Louvar, J. F. Chemical Process Safety: Fundamentals with Applications; Prentice Hall, 2011.
8 For recent examples of Suzuki cross-couplings in continuous flow using a supported Pd-ligand complex see: Muñoz, J. de M.;
Alcazar, J.; de la Hoz, A.; Diaz-Ortiz, A. Adv. Synth. Catal. 2012, 354, 3456–3460. For a review see: Nöel, T.; Buchwald, S. L.
Chem. Soc. Rev. 2011, 40, 5010-5029.
9 (a) Newman, S. G.; Jensen, K. F. Green Chemistry 2013, 15, 1456-1472. (b) Vadula, B. R.; Gonzalez, M. A. Chemistry
Today 2013, 31, 16-20.
10 Shang, M.; Noël, T.; Wang, Q.; Hessel, V. Chem. Eng. & Tech. 2013, 36, 1001-1009.
11
(a) Boodhoo, K.; Harvey, A. Process Intensification Technologies for Green Chemistry: Engineering Solutions for
Sustainable Chemical Processing; Wiley-Blackwell, 2013. (b) Damm, M.; Glasnov, T. N.; Kappe, C. O. Org. Process Res.
Develop. 2010, 14, 215-224. (c) Kumar, V.; Nigam, K. D. P. Green Processing and Synthesis 2012, 1, 79. (c) Hessel, V. Chem.
Eng. & Tech. 2009, 32, 1655-1681.
12
ThalesNano Nanotechnology Inc., Graphisoft Park, H-1031 Budapest, Zahony u.7., Hungary. http://www.ThalesNano.com.
Palladium packed bed cartridges are available on various supports: none (Pd black), charcoal (standard and powder type),
alumina and silica.
13 The void volume for an H-Cube MIDI cartridge is around 1-1.2 mL (measured experimentally).
14 Estimated residence time is 20 seconds based on calculated cartridge void volume.
15 The equipment setup consisted of a new external syringe pump that injected the reactant solution into the cartridge, placed in
the H-Cube MIDI for temperature control. The output of the cartridge was connected to a 100 psi back pressure regulator (to
prevent gas bubble formation and ensure accurate residence times).
16 The difference between the powder type and the 10% Pd/C are in the particle size; the powder type is sieved to be higher than
32 micron, and so has a larger active surface area compared to the 10% Pd/C, which is of 20-40 mesh.
17 For recyclable Pd catalysts in cross-coupling reactions see: Nasir Baig, R. B.; Varma, R. S. Chem. Commun. 2013, 49, 752.
18 Koenig S. G. Scalable Green Chemistry, Pam Standford Publishing, 2013.
19 The same catalyst cartridge was under continuous operation for 18 h.
20
Representative large-scale continuous-flow procedure: A solution of 2-iodo-benzonitrile (100 g, 1,00 equiv; 436,64
mmoles) and phenylboronic acid (1 equiv , 436,64 mmoles; 53,24 g) in 2-propanol (1800 mL) was combined with a solution of
10

potassium carbonate (3 equiv, 1,31 moles; 181,04 g in water (1200 mL). The resulting mixture was sonicated until a clear
biphasic solution was obtained. The solution was added to a round bottomed flask and was pumped, while stirring, through a
Pd/C 10% H-Cube midi cartridge at 150ºC at a rate of 3 ml/min (approx. 20 seconds residence time) and without H2 generation,
using an H-Cube MIDI apparatus. After all the solution had passed through the cartridge, it was washed with 2-propanol/water
(3:2 ratio. 200 mL) and the product solution was combined with the wash run. 2-Propanol was removed on the rotavap and the
aqueous residue was extracted with ethyl acetate (2x100 ml). The combined organic phases were washed with brine (50 mL),
dried over sodium sulfate and concentrated to afford a crude product (tan solid) that was purified via SiO2 pad filtration
1
(MTBE/hexane mixtures as eluent) to afford 2-phenylbenzonitrile (76.5 g, 98% yield). H-NMR data was consistent with
reported values.
11

Highlights
•
Large-Scale Suzuki-Miyaura cross-coupling in continuous flow.
Simple and sustainable flow chemistry procedure.
•
•
Commercially available, cost-effective reusable catalyst.