Cross-coupling in flow using supported catalysts: Mild, clean, efficient and sustainable suzuki-miyaura coupling in a single pass

Article abstract of DOI:10.1002/adsc.201200678

A mild, clean, practical, sustainable and high yielding procedure for Suzuki-Miyaura cross-coupling in a single pass using a silica-supported palladium catalyst is described. The catalyst can be used in more than 30 reactions and for more than 8 h of continuous processing without a decrease in reactivity due to the low leaching observed. Different halides/pseudo-halides and organoboron compounds can be used without modifying the standard procedure.

Full text of DOI:10.1002/adsc.201200678

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DOI: 10.1002/adsc.201200678
Cross-Coupling in Flow using Supported Catalysts: Mild, Clean,
Efficient and Sustainable Suzuki–Miyaura Coupling in a Single
Pass
a
a,
b
b
Juan de M. MuÇoz, Jesffls Alcµzar, * Antonio de la Hoz, and Angel Díaz-Ortiz
a
Janssen Research and Development, Janssen-Cilag, S.A., C/Jarama 75, 45007 Toledo, Spain
Fax : (+34)-92-524-5771; phone: (+34)-92-524-5750; e-mail: jalcazar@its.jnj.com
Facultad de Ciencias Químicas, Universidad de Castilla – La Mancha, Avda. Camilo JosØ Cela, 10, 13071 Ciudad Real,
b
Spain
Received: July 31, 2012; Published online: November 28, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200678.
Abstract: A mild, clean, practical, sustainable and
high yielding procedure for Suzuki–Miyaura cross-
coupling in a single pass using a silica-supported
palladium catalyst is described. The catalyst can be
used in more than 30 reactions and for more than
lization is of significance for flow chemistry due to
[
3]
the simple recovery and reuse. In addition, typical
packed-bed reactors provide a high ratio of catalyst
vs. substrate during the course of the reaction, an ad-
vantage that significantly increases the rate of reac-
tion and simplifies the purification of the final prod-
ucts. However, leaching of Pd species, swelling of
polymer supports, deposition of products/by-products
and poor catalyst cartridge life cycles complicate their
8
h of continuous processing without a decrease in
reactivity due to the low leaching observed. Differ-
ent halides/pseudo-halides and organoboron com-
pounds can be used without modifying the standard
procedure.
[
4]
use in continuous flow systems.
[
5]
Metal-catalyzed cross-coupling chemistry has had
a great impact on the pharmaceutical and other indus-
tries, as well as on the synthesis of natural products
Keywords: CÀC bond formation; cross-coupling;
flow chemistry; solid-supported catalyst; Suzuki–
Miyaura reaction
[
6]
and other biologically active compounds.
The
Suzuki–Miyaura cross-coupling reaction (SMC) is one
of the most important methods for the construction of
[
7]
carbon-carbon bonds. Several studies have been fo-
cused on the development of flow methods to per-
[
8]
The ability to conduct complex and routine chemical form this reaction using either homogeneous or het-
transformations in a clean, sustainable and easily scal- erogeneous catalysts. Within the field of heterogene-
able way without recourse to costly reagents, catalysts, ous catalysts a broad range of solid supports has been
[
9]
lab equipment or purification processes is highly de- developed and these include monolithic supports,
[
10]
TM [11]
sirable. The design of efficient and practical proce- polymer beads and PdEnCat
.
However, swel-
[12]
dures is an important goal in chemistry and especially ling and degradation of the polymer supports, grad-
[
13]
in process chemistry. In recent years flow chemistry ual leaching of the catalytically active palladium,
has been developed to improve the performance of the need to perform several passes through the cata-
[
1]
[11]
chemical synthesis. Among other advantages, this lyst to achieve full conversion, the replacement of
technology allows very efficient heat transfer, good the cartridge after performing a limited number of re-
control of reaction temperature and enhanced mass actions and the need to synthesize the supported cata-
transfer, thus avoiding the problems associated with lyst in the cartridge limit their practical use in or-
highly exothermic reactions and dangerous or air- and ganic and medicinal chemistry and decrease the sus-
moisture-sensitive compounds. This approach permits tainability of the processes.
[
9]
the integration of several steps into one single stream-
Silica-supported catalysts offer better chemical and
lined process, thus shortening the time from research thermal stability as well as a rigid but porous struc-
[
2]
to development and production.
ture devoid of swelling properties, a characteristic
Coupling these methodologies with heterogeneous that makes them compatible with a wide range of sol-
catalysis produces a synergistic effect, since in most vents. The use of these catalysts for Suzuki–Miyaura
cases, they complement each other. Catalyst immobi- cross-coupling (SMC) has been described in two arti-
3456
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Adv. Synth. Catal. 2012, 354, 3456 – 3460

Cross-Coupling in Flow using Supported Catalysts
cles. The first paper concerned the combined use of Table 1. Optimization of the SMC reaction of bromoben-
zene 2a and (4-methoxyphenyl)boronic acid 1a.
electroosmotic flow with the microporous silicate
structure in palladium-catalyzed organic synthesis.
[
14]
This coupling reaction illustrated the use of the flow
injection microreactor but the reaction itself was not
optimized. The second article concerned silica-sup-
ported nanoparticles, which can be heated by magnet-
[15]
ic induction. However, due to leaching of palladi-
um, the catalyst could be reused only three times. Ad-
ditionally the use of a third silica-supported catalyst
[
15c]
has been described in an application note.
Even
though good conversions and acceptable catalyst ca-
[
a]
[b]
[b]
pacity are reported, measurements of palladium Entry Base
leaching and number of cycles that can be used with-
out a drop in activity are not provided. Moreover,
a relationship between metal leaching and the high
temperatures employed to complete the reaction
Temp.
[8C]
Time
[min]
Conv.
[%]
Sel.
[%]
1
2
3
4
5
6
7
8
9
KOH
KOH
KOH
KOH
KOH
60
60
60
80
60
60
10
5
1
1
2
5
5
5
5
100
100
56
59
72
94
70
85
76
100
100
100
100
100
100
98
(
from 1308C to 1508C) was found.
Recently, a new commercially available silica-sup-
ꢁ
[16]
ported catalyst (SiliaCat ) has been described. It is
claimed that this novel catalyst presents several ad-
vantages, such as high turnover number (TON) and
low leaching. The catalyst costs less than other com-
monly used palladium sources, such as palladium ace-
tate or Pearlmanꢂs catalyst. Herein, an efficient, clean
and high yielding procedure for Suzuki–Miyaura
cross-coupling using this silica-supported palladium
catalyst is reported.
K
CO
2
3
NaHCO3 60
[
[
c]
KOH
KOH
60
60
100
100
d]
[a]
1
-mmol scale, SiliaCat DPP-Pd as catalyst, 0.15M boron-
ic acid, 0.125M halide.
Conversions (based on halide consumption) and selectivi-
ties (product vs. hydrodeboronation or hydrodehalogena-
tion) were determined by GC/MS.
-mmol scale, SiliaCat DPP-Pd as catalyst, 0.3M boronic
acid, 0.25M halide.
SiliaCat S-Pd as catalyst.
[b]
[
[
c]
1
We started our investigation by examining the reac-
tion of bromobenzene 2a and (4-methoxyphenyl)bor-
d]
ꢁ
[16]
onic acid 1a using SiliaCat DPP-Pd as the support-
ed catalyst. A solution of the aryl halide in THF was
combined with a solution of the boronic acid and the time of 10 min (Table 1, entry 1). A clean crude prod-
[
17]
base in water using the Vapourtec R2+R4 system.
uct was obtained in this first experiment (Figure 2).
The biphasic solvent system was used to ensure com- The residence time can be shortened to 5 min without
plete dissolution of any solid, thus avoiding any subse- a reduction in conversion (Table 1, entry 2), but the
quent clogging. The mixture was then passed through conversion falls dramatically when the residence time
a 6.6 mm (i.d.) Omnifit column containing 1 g of sup- was decreased below 2 min, even on increasing the
ported catalyst (Figure 1). The residence time was cal- temperature (Table 1, entries 3–5). The use of K CO3
2
culated based on flow and confirmed using violet as base also provided excellent conversion and this
crystal as tracer (see the Supporting Information). represents an interesting alternative to KOH. Howev-
The outcome was collected and analyzed. On using er, the use of NaHCO resulted in incomplete conver-
3
KOH as a base, bromobenzene 2a successfully cou- sion (Table 1, entries 6 and 7). The concentration of
pled with boronic acid 1a at 608C with a residence reagents is important as the use of higher concentra-
tions did not lead to full conversion (Table 1, entry 8).
Finally, a different silica-supported catalyst was tested
under the best conditions found, but this catalyst
proved to be less efficient (Table 1, entry 9).
The mild flow conditions shown in Table 1 entry 2
were chosen to explore the scope of the SMC reaction
to different halides/pseudo-halides with boronic acid
1
a (Table 2, entries 1–4). Bromobenzene 2a, iodoben-
zene 2b, chlorobenzene 2c and phenyl triflate 2d pro-
vided excellent yields on using the same reaction con-
ditions. Despite the fact that chloro- and bromoben-
zene gave similar results, it is possible to couple selec-
tively the bromo substituent in the chloro-bromo de-
Figure 1. Experimental set-up of the flow system.
Adv. Synth. Catal. 2012, 354, 3456 – 3460
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3457

Juan de M. MuÇoz et al.
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Figure 2. GC-mass spectra of the crude reaction mixture of bromobenzene 2a and (4-methoxyphenyl)boronic acid 1a.
[a]
Table 2. Scope of the reaction with different aryl bromides
Table 3. Use of different organoboron derivatives (1b–g).
(
2) and 1a.
Entry
R-BR2
R-X
Comp.
[b]
[a]
[b]
Entry
R-X
Compound [%]
[
%]
1
2
3
4
5
6
7
8
9
C H -Br (2a)
3a (98)
3a (99)
3a (98)
3a (93)
3b (90)
3c (96)
3d (90)
3e (95)
3f (88)
3g (50)
3h (72)
3i (81)
3i (77)
3j (86)
6
5
1
2
3
4
5
6
4-CF -C H -B(OH) (1b)
2a
2a
2a
2a
2d
2a
3k (97)
3l (87)
3m (87)
3n(99)
3o (89)
3a (96)
3
6
4
2
C H -I (2b)
6
5
4-NO -C H -B(OH) (1c)
2
6
4
2
C H -Cl (2c)
6
5
2-furyl-B(OH) (1d)
2
C H -OTf (2d)
6
5
3,5-diMeO-C H bpin (1e)
6
3
4-Cl-C H -Br (2e)
6
4
3-pyridine-B(Et) (1f)
2
4-NO -C H -Br (2f)
2
6
4
4-MeO-C H -B ACHTUNGTRENN(UNG O-i-Pr) Li (1g)
6
4
3
4-Cl- C H CHO (2g)
6
4
[a]
o-MeC H -Br (2h)
1-mmol scale, SiliaCat DPP-Pd as catalyst, 0.15M boron-
ic acid, 0.125M halide.
Isolated yield in brackets.
6
4
o-MeOC H -Br (2i)
6
4
[b]
10
11
12
13
14
2,4-diMeOC H -Br (2j)
6
3
3-Br-pyridine (2k)
2-Br-pyridine (2l)
2-Cl-pyridine (2m)
4-Br-C H CO Me (4n)
In order to explore further the scope of the reac-
6
4
2
tion, other boronic acids and organoboranes were
tested with bromobenzene 2a or phenyl triflate 2d
(Table 3). Boronic acids 1b and 1c were selected due
to their low solubility in water (entries 1 and 2). Al-
though cloudy solutions in water were observed for
both compounds, they coupled in good yields using
[
a]
1
-mmol scale, SiliaCat DPP-Pd as catalyst, 0.15M boron-
ic acid, 0.125M halide.
Isolated yield in brackets.
[
b]
rivative 2e (entry 5). The reaction conditions also al- the injection loops provided in the R2+R4 instru-
lowed the presence of other functional groups, includ- ment. The reaction mixture clarified after passing
ing an aromatic ring bearing several electron-donor through the catalyst and this avoided clogging at the
groups (2j), although the yield decreased to 50% back pressure regulator. It is worth noting that the re-
(
entry 10). Chloro- and bromopyridines also provided action allows the use of different boron derivatives,
good yields without further optimization (entries 11– boronic esters 1e, boranes 1f and borates 1g, freshly
1
3). Ester functions were also tolerated despite the prepared from the corresponding bromo derivative by
[
8a,b]
use of the strong base (entry 14).
metalation
(entries 4–6). The excellent yields ob-
3458
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 3456 – 3460

Cross-Coupling in Flow using Supported Catalysts
In summary, a clean, mild, reproducible, scalable
and high yielding continuous flow process for Suzuki–
Miyaura cross-coupling using a silica-supported cata-
lyst has been developed. A wide scope of different
functional groups, that is, halides/pseudo-halides and
organoboron compounds, can be used with excellent
results. The low leaching of palladium, the consistent
outcome and the high yields of the reaction after 8 h
of continuous processing, the stability of the catalyst
after more than 30 reactions and the robustness of the
protocol, all of which can be reproduced in a custom
made instrument, are worth noting. This low leaching
Figure 3. SMC between (4-methoxyphenyl)boronic acid 1a together with the clean crude products, which are
and 1-bromo-2-methylbenzene 2h for 8 h.
devoid of ligand residues, as well as the affordable
price of the supported catalyst make this procedure
an efficient and practical alternative to perform
tained in all the cases increase the versatility of the Suzuki–Miyaura cross-couplings. Further applications
process. of this methodology to the preparation of compounds
The procedure is highly robust and reproducible with pharmaceutical interest will be the topic of
and similar results were obtained using an empty future publications.
Xterra column (4.6”50 mm) refilled with 400 mg of
catalyst, heated with a column heater (Lab Alliance),
both of which are generally used for HPLC purifica- Experimental Section
tions, and pumping the reagents with a dual syringe
pump (Harvard Apparatus). In consequence, an ex- General Flow Procedure
pensive commercial flow system is not a requirement
and the reaction can be performed with standard lab-
oratory equipment. Furthermore, purification of prod-
ucts was a matter of separation and evaporation of
the organic phase. Crude products are clean and free containing the catalyst supported (1 g), giving a residence
Two solution, boronic acid (1.2 equiv., 0.15M) and KOH
(
2 equiv., 0.25M) in water and halide (1 equiv., 0.125M) in
À1
THF were pumped at 0.2 mLmin (each one) using the
R2+R4 system. The mixed solution was driven to a column
of phosphine ligand, thus avoiding the need for chro- time of 5 min. The outlet solution was diluted with water
matographic purification.
and extracted with ethyl acetate. The organic layer was sep-
arated, dried (MgSO ), filtered and the solvents evaporated
Finally, we studied the stability of the supported
catalyst. It was found that the same cartridge could be
employed for more than 30 consecutive reactions
without a decrease in activity. The calculated TON
was higher than 100. In order to check the behaviour
of the catalyst, a long run (8 h) of the SMC between
4
under vacuum.
Acknowledgements
(
4-methoxyphenyl)boronic acid 1a and 1-bromo-2-
The authors acknowledge Dr. L. Iturrino, Dr. L. M. Font and
methylbenzene 2h was performed, using the opti- Dr. F. Bꢀland for their collaboration in the preparation of
mized conditions with 1 g of new catalyst. The results this manuscript. Dr. C. J. Sꢁnchez is thanked for leaching
are represented in Figure 3 and it can be seen that the measurements. Financial support from the Spanish Ministerio
de Ciencia e Innovaciꢂn (project CTQ2011-22410) and the
Junta de Comunidades de Castilla-La Mancha (projects
HITO 2010-54 and PII2I09-0100).
outcome of the reaction did not change with time,
thus proving the efficiency of the catalyst for long
runs. The use of this flow procedure allowed up to
1.71 mmol/h of product to be produced without a de-
crease in the activity of the catalyst. Moreover, this
system could be used later for other reactions. Leach- References
ing of palladium was determined for the coupling re-
[
1] a) P. T. Anastas, J. C. Warner, Green Chemistry: Theory
action both in the organic and aqueous layers. In the
organic phase less than 10 ppb of Pd were deter-
mined. In the aqueous phase only 20 ppb were detect-
ed. These results demonstrate the low level of leach-
ing of metal catalyst from the support, compared with
other reported silica-supported catalyst where leach-
and Practice. Oxford University Press, Oxford, 2000;
b) Beilstein J. Org. Chem. 2011, 7, thematic issue on
flow chemistry; c) C. Wiles, P. Watts, Green Chem.
2
012, 14, 38–54; d) J. Yoshida, H. Kim, A. Nagaki,
ChemSusChem 2011, 4, 331–340.
[
2] a) Microreactors: New Technology for Modern Chemis-
try, (Eds.: W. Ehrfield, V. Hessel, H. Lçwe), Wiley-
VCH, Weinheim, 2000; b) C. Wiles, P. Watts, Eur. J.
[
15]
ing in the ppm range is described.
Adv. Synth. Catal. 2012, 354, 3456 – 3460
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3459

Juan de M. MuÇoz et al.
COMMUNICATIONS
Org. Chem. 2008, 1655–1671; c) T. Illg, P. Lçb, V.
Hessel, Bioorg. Med. Chem. 2010, 18, 3707–3719; d) P.
Watts, S. J. Haswell, Drug Disc. Today, 2003, 8, 586–
65, 1450–1454; c) R. C. Jones, A. J. Canty, J. A. Dever-
ell, M. G. Gardiner, R. M. Guijt, T. Rodemann, J. A.
Smith, V.-A. Tolhurst, Tetrahedron 2009, 65, 7474–7481;
d) K. Mennecke, A. Kirschning, Synthesis 2008, 3267–
3272; e) K. Mennecke, W. Sodolenko, A. Kirschning,
Synthesis 2008, 1589–1599; f) K. F. Bolton, A. J. Canty,
J. A. Deverell, R. M. Guijt, E. F. Hilder, T. Rodemann,
J. A. Smith, Tetrahedron Lett. 2006, 47, 9321–9324;
g) W. Sodolenko, K. Mennecke, C. Vogt, S. Gruhl, A.
Kirschning, Synthesis 2006, 1873–1881; h) U. Kunz, H.
Schçnfeld, W. Sodolenko, G. Jas, A. Kirschning, Ind.
Eng. Chem. Res. 2005, 44, 8458–8467; i) W. Sodolenko,
H. Wen, S. Leue, F. Stuhlmann, G. Sourkouni-Argirusi,
G. Jas, H. Schçnfeld, U. Kunz, A. Kirschning, Eur. J.
Org. Chem. 2004, 3601–3610.
5
93; e) Microreactors in Organic Synthesis and Cataly-
sis, (Ed.: T. Wirth), Wiley-VCH, Weinheim, 2008;
f) B. P. Mason, K. E. Price, J. L. Steinbacher, A. R.
Bogdan, D. T. McQuade, Chem. Rev. 2007, 107, 2300–
2
318; g) H. R. Sahoo, J. G. Kralj, K. F. Jensen, Angew.
Chem. 2007, 119, 5806–5810; Angew. Chem. Int. Ed.
007, 46, 5704–5708; h) R. L. Hartman, J. P. McMullen,
2
K. F. Jensen, Angew. Chem. 2011, 123, 7642–7661;
Angew. Chem. Int. Ed. 2011, 50, 7502–7519.
[
[
[
3] C. G. Frost, L. Mutton, Green Chem. 2010, 12, 1687–
1
703.
4] T. Nol, S. L. Buchwald, Chem. Soc. Rev. 2011, 40,
010–5029.
5
[10] N. T. S. Phan, J. Khan, P. Styring, Tetrahedron 2005, 61,
12065–12073.
5] a) F. Diederich, A. de Meijere, Metal-Catalyzed Cross-
Coupling Reactions, Wiley-VCH, New York, New
York, 2004; b) N. Miyaura, Top. Curr. Chem. 2002, 219,
[11] a) C. K. Y. Lee, A. B. Holmes, S. V. Ley, I. F. McCon-
vey, B. Al-Duri, G. A. Leeke, R. C. D. Santos, J. P. K.
Seville, Chem. Commun. 2005, 2175–2177; b) G. A.
Leeke, R. C. D. Santos, B. Al-Duri, J. P. K. Seville, C. J.
Smith, C. K. Y. Lee, A. B. Holmes, I. F. McConvey,
Org. Proces. Res. Dev., 2007, 11, 144–148.
1
–241.
[
6] K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem.
2
4
005, 117, 4516–4563; Angew. Chem. Int. Ed. 2005, 44,
442–4489.
[
7] a) N. Miyaura, A. Suzuki, J. Chem. Soc. Chem.
Commun. 1979, 866–867; b) R. Martin, S. L. Buchwald,
Acc. Chem. Res. 2008, 41, 1461–1473; c) F. Bellina, A.
Carpita, R. Rossi, Synthesis 2004, 2419–2440; d) N.
Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–2483.
8] For recent examples in the use of homogeneous cata-
lysts: a) W. Shu, L. Pellegatti, M. A. Oberli, S. L. Buch-
wald, Angew. Chem. 2011, 123, 10853–10857; Angew.
Chem. Int. Ed. 2011, 50, 10665–10669; b) T. Nçel, S.
Kuhn, A. J. Musacchio, K. F. Jensen, S. L. Buchwald,
Angew. Chem. 2011, 123, 6065–6068; Angew. Chem.
Int. Ed. 2011, 50, 5943–5946; c) T. Nçel, A. J. Musac-
chio, Org. Lett. 2011, 13, 5180–5183.
[12] I. R. Baxendale, C. M. Griffiths-Jones, S. V. Ley, G. K.
Tranmer, Chem. Eur. J. 2006, 12, 4407–4416.
[13] S. J. Broadwater, D. T. McQuade, J. Org. Chem. 2006,
71, 2131–2134.
[14] G. M. Greenway, S. J. Haswell, D. O. Morgan, V. Skel-
ton, P. Styring, Sens. Actuators B 2000, 63, 153–158.
[15] a) S. Ceylan, C. Friese, C. Lammel, K. Mazac, A.
Kirschning, Angew. Chem. 2008, 120, 9083–9086;
Angew. Chem. Int. Ed. 2008, 47, 8950–8953; b) S.
Ceylan, L. Coutable, J. Wegner, A. Kirschning, Chem.
Eur. J. 2011, 17, 1884–1893; c) http://www.vapourtec.-
co.uk/applications/appnotes.
[16] a) V. Pandarus, G. Gingras, F. BØland, R. Ciriminna, M.
Pagliaro, Org. Proces. Res. Dev., 2012, 16, 117–122;
b) M. Lemay, V. Pandarus, M. Simard, O. Marion, L.
Tremblay, F. BØland, Top. Catal., 2010, 53, 1059–1062.
[17] http://www.vapourtec.co.uk (last check 2012-07-27).
[
[
9] a) K. Mennecke, A. Kirschning, Beilstein J. Org. Chem.
2
009, 5, DOI: 10.3762/bjoc.5.21; b) A. Gçmann, J. A.
Deverell, K. F. Munting, R. C. Jones, T. Rodemann,
A. J. Canty, J. A. Smith, R. M. Guijt, Tetrahedron 2009,
3460
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 3456 – 3460