Suzuki-Miyaura cross-coupling coupling reactions with low catalyst loading: A green and sustainable protocol in pure water

Article abstract of DOI:10.1039/c0dt01637c

The Suzuki-Miyaura coupling reaction represents one of the most important synthetic transformations developed in the 20th century. However, the use of toxic organic solvents remains a scientific challenge and an aspect of economical and ecological relevance, and benign water as a reaction medium was found to be highly effective to overcome some of these issues. In the present manuscript, we described Suzuki-Miyaura coupling reactions in neat water, without using any phase transfer reagent. Notably, this protocol also works with ultra-low loading of catalyst with high turnover numbers and also able to couple challenging substrates like aryl chlorides.

Full text of DOI:10.1039/c0dt01637c

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Suzuki–Miyaura cross-coupling coupling reactions with low catalyst loading:
a green and sustainable protocol in pure water
Aziz Fihri,*a Denis Luart,b Christophe Len,b Abderrahim Solhy,c Carole Chevrinb and Vivek Polshettiwar*a
Received 25th November 2010, Accepted 31st January 2011
DOI: 10.1039/c0dt01637c
The Suzuki–Miyaura coupling reaction represents one of
the most important synthetic transformations developed in
the 20th century. However, the use of toxic organic solvents
remains a scientific challenge and an aspect of economical
and ecological relevance, and benign water as a reaction
medium was found to be highly effective to overcome some of
these issues. In the present manuscript, we described Suzuki–
Miyaura coupling reactions in neat water, without using any
phase transfer reagent. Notably, this protocol also works with
ultra-low loading of catalyst with high turnover numbers and
also able to couple challenging substrates like aryl chlorides.
in various natural processes taking place inside and around us and
is responsible for our sustainable life, this encouraged researchers
to use water as a reaction medium in various challenging chemical
processes.
In general, water has not been considered to be an appropriate
solvent for synthetic chemistry because of several issues such as
substrate molecules themselves reacting with water molecules.
Insolubility of most of the organic reactants in water, making
the reaction mixture heterogeneous, was another worry. Even
though reactants and/or reagents are not homogenized in aqueous
medium, water was still found to speed up the rate of several
reactions.7–8 The rationale behind this is that water molecules
avoid high energy polar-non-polar mixing with the reactant
molecules for which it has to go through structural organization
modification, which in turn will decreases the entropy of the reac-
tion mixture. Thus to avoid this thermodynamically unfavorable
system, water molecules direct the organic molecules towards
each other, resulting in an isolated organic phase (from the water
phase) where the actual reaction takes place.9–11 Also, the isolation
of products from aqueous media is another concern. For this,
evaporation of water from the reaction mixture may be an option,
but it is not an energy-efficient process.
During the past decade, numerous reactions that were con-
ventionally carried out in organic solvents have been now
developed using water as a solvent.12–13 Among the various
reactions studied, in our recent review on Suzuki–Miyaura
reaction in an aqueous medium,14 we observed that although
the Suzuki–Miyaura coupling protocol is an excellent example
of this development and this process was exponentially benefited
by aqueous chemistry, however, despite the impressive progress,
a number of challenges remain unresolved; importantly the
coupling of the readily available and low-cost aryl chlorides
continues to pose difficulties and the difference between their
activity in homogeneous and heterogeneous phases is very
high.15
Introduction
Reaction solvents are one of the most important constituents
in any chemical process including Suzuki–Miyaura coupling
reactions1–3 and play a key role in deciding its environmental
impact as well as its cost, safety, and health issues. The majority
of these solvents are volatile and highly inflammable organic
liquids, which is the main cause of ecological contamination.
However, it is quite difficult to avoid the use of solvents as they are
crucial in various stages from reactant mixing to product isolation.
The ideal solution is to use a “green solvent” which does not
pollute the environment.4–6 Biphasic solvent systems such as the
combination of fluorous and ionic liquids along with aqueous
systems and supercritical carbon dioxide have created the central
drive of this movement. However, the cost and toxicity of these
systems are core issues in using them as a solvent. Thus, naturally
abundant water appears to be a superior choice as a ‘green solvent’
because of its non-toxic, non-corrosive and non-flammable nature.
It possesses several unique characteristic such as polarity, elevated
surface tension, and strong hydrogen bonding potential. Also,
water can be easily contained because of its comparatively high
vapor pressure with respect to organic solvents, rendering it as a
sustainable alternative. Importantly, ‘water’ is the primary solvent
Another difficulty is to design and prepare ligands that are
suitable for aqueous phase reactions. The development of greener
and sustainable pathways for organic transformations16–19 and
the necessity to provide catalytic systems minimizing the con-
sumption of expensive transition-metals can be fulfilled through
the synthesis of accessible, efficient and inexpensive ligands.
Ligand 1 reported herein was developed following these ob-
jectives and pertains to a family of highly efficient catalytic
auxiliaries.
aKAUST Catalysis Center (KCC), King Abdullah University of Science
and Technology, Thuwal, 23955, Kingdom of Saudi Arabia. E-mail: aziz.
fihri@kaust.edu.sa, vivek.pol@kaust.edu.sa; Fax: +966 28-08-03-02;
Tel: +966 28-08-45-70
bTransformations Inte´gre´es de la Matie`re Renouvelable ESCOM-UTC, 1-
Alle´e du Jean-Marie Buckmaster, 60200, Compie`gne, France
cInstitute of Nanomaterials & Nanotechnology (INANOTECH), MAScIR
Foundation, ENSET, Av. de l’Arme´ Royale, Madinat El Irfane, 10100,
Rabat, Morocco
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Table 1 Optimization of the reaction conditions
Entry
Solvent
Base
Yield (%)
1
2
3
4
5
6
H2O
H2O
H2O
H2O
H2O
H2O
KF
85
88
89
95
92
81a
K3PO4
NaOH
K2CO3
Cs2CO3
K2CO3
a 0.1 mol% of 2
but is soluble in refluxing water. Pd(II) complex 2 was purified
and stored under nitrogen. It was isolated with 85% yield and
characterized by 1H, 31P NMR and MS.
Results and discussion
Mannich-type reactions of various phosphines, formaldehyde
and amines were demonstrated to be a powerful method
of constructing aminomethylphosphines, which are promising
ligands for the design of homogeneous catalysts.20,21 Starting
We initially investigated the reaction of 4-bromoacetophenone
with phenylboronic acid to establish the feasibility of our strategy
and to optimize the reaction conditions (Table 1). First the
reaction was conducted without any base and no reaction (NR)
was observed. Then several bases were tested and a good to
excellent yield of the coupling product was observed in all cases.
Interestingly, under the same conditions catalyst 2 gave the product
in 81% yield. Considering the economical and environmental
advantages, we chose K2CO3 as the base.
To further define the scope of this protocol and following
our catalysis objective, the coupling of various aryl halides
by palladium complexes stabilized by 1 was investigated and
representative results are summarized in Table 2.
from the work of Markl et al.22,23 and Tzschach and co-
24,25
workers
a wide variety of chelate complexes of this type
has been obtained, including phosphines with cyclodextrin,26
dendrimer,27,28 amino acid and peptide29 moieties. Herein, we
report the synthesis and catalytic activity of 1,5-diphenyl-3,7-
dicyclohexyl-1,5-diaza-3,7-diphosphacyclooctane 1 which is ob-
tained from bis(hydroxymethyl)cyclohexylphosphine by addition
of aniline (Scheme 1). The palladium complex was synthesized by
treatment of 1 with palladium acetate at room temperature for
two hours, this ligands is not soluble in water at room temperature
Scheme 1 Synthesis of 1 and 2.
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Table 2 Suzuki–Miyaura coupling reactions of aryl bromides in neat water
Entry
1
R1
R2
H
Product
Yield (%)
90
OMe
2
3
4
5
6
7
8
9
CN
H
93
92
95
92
93
92
91
26
NO2
H
MeCO
OMe
CN
H
OMe
OMe
OMe
OMe
NO2
MeCO
10
83a
11
12
85
0
a 0.4 mole% of Pd(OAc)2 and 1
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Aryl bromides with various functional groups efficiently reacted
with boronic acids (entries 1–10), to yield Suzuki–Miyaura
products in good to excellent yields. 2-Bromopyridine underwent
smooth reaction with phenylboronic acid (entry 11), providing
a useful way for the synthesis of aryl-substituted nitrogen het-
erocycles; however no product was observed in the case of 2-
bromothiophene, which may be due to its instability in water.
These results indicate that with these a-substituted heteroaryl
bromides, a possible interaction between the hetero-element and
the palladium complex has a deactivation effect on the rate of the
reaction.
In order to test the feasibility of this protocol for challenging
substrates, we conducted two reactions with aryl chloride (Scheme
2) and observed good product yield. Importantly, no phase
transfer catalyst (which is generally used by most of the reports)
was used during these reactions.
We also studied the effect of catalyst amount on the reaction
rate and product yield (Scheme 3). Interestingly, these reactions
could also be conducted with ultra-low loading of catalyst as low
as 0.0001 mol%, with high turnover numbers.
For practical applications of any catalyst systems, the lifetime of
the catalyst and its level of reusability are very important factors.
Although recycling of homogeneous catalysts is difficult and
generally not preferred, since we were using water as the reaction
medium, we studied the possibility of recycling and reusing the
catalyst. We established a set of experiments using the recycled
catalyst for the Suzuki–Miyaura reaction of 4-bromoactephenone
and phenylboronic acid and the reactions were carried out under
similar conditions in water. After completion of the reaction, the
4-acetobiphenyl was extracted from the reaction mixture with n-
pentane and the catalyst was reused for another run by adding
fresh 4-bromoactephenone, phenylboronic acid and potassium
carbonate to the reaction media. The first reaction afforded the
corresponding coupling product in 95% yield, the product yield
for the 2nd cycle was nearly the same (85%), however in the 3rd
cycle it was reduced to 57%. Thus, this catalyst system could be
used for at least 3 times, which is fairly good for a homogenous
system.
Conclusions
In conclusion, we have developed efficient Suzuki–Miyaura
coupling reactions in neat water, which does not use any
phase transfer reagent and was also able to couple challenging
substrates like aryl chloride. Reactions also work with ultra-
low loading of catalyst with high turnover numbers. Our cur-
rent investigations are focused on the feasibility of electronic
modification around phosphine-palladium catalysts, through
phosphorus substituents, with the view to increasing their
activity.
Scheme 2 Suzuki–Miyaura coupling reactions using challenging substrates.
Scheme 3 Suzuki–Miyaura coupling reactions using ultra-low loading of catalyst.
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organic layers were combined, dried over MgSO4, filtered and
evaporated under reduced pressure. Purification of the crude
product by flash chromatography on silica gel afforded 1070 mg
Experimental
All reactions and workup procedures were performed under an
inert atmosphere of argon using conventional vacuum-line and
glasswork techniques. Solvents were dried and freshly distilled
under argon. All other materials were obtained from commercial
suppliers and used as received. Water (deionized) was degassed
by sparging with nitrogen. Chromatography was performed on
neutral silica gel. NMR spectra were recorded on a Bruker
instrument operating at 400.13 MHz for proton, 100.62 MHz for
carbon, and 161.96 MHz for phosphorus.
1
of 4-acetyl-4¢-methoxybiphenyl (91%) as white solid. H NMR
(400.13 MHz, CDCl3): d 7.95 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.8
Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.79
(s, 3H), 2.56 (s, 3H). 13C NMR (125 MHz, CDCl3): d 197.7, 159.9,
145.3, 135.3, 132.2, 128.9, 128.3, 126.6, 114.4, 55.4, 26.6.
Acknowledgements
The authors acknowledge Ayoub Hassine for experimental work
during his Master’s training and the Re´gion Picardie for their
financial support.
Synthesis of 1,5-diphenyl-3,7-dicyclohexyl-1,5-diaza-3,7-
diphosphacyclooctane 1
A Schlenk flask was charged with cyclohexylphosphine (10% in
hexane, 14.6 mL, 8.3 mmol) and degassed aqueous formaldehyde
(37%, 1.92 mL, 25.8 mmol) in degassed CH3CN (20 mL). After
stirring for 30 min at room temperature, the solvent was removed
under vacuum and the resulting oil was combined with aniline
(773 mg, 8.3 mmol) in degassed EtOH (20 mL) and the solution
was refluxed overnight. The solution was allowed to cool down
to room temperature. A white precipitate was filtered and washed
with EtOH and dried under vacuum to give a white powder (3.28 g,
Notes and references
1 N. Miyaura, T. Yanagi and A. Suzuki, Synth. Commun., 1981, 11, 513.
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New York, 2002.
4 J. H. Clark, Green Chem., 2006, 8, 17–21.
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Chem. Rev., 2010, 110, 6302.
1
7.1 mmol, 85%). 31P{ H} NMR (CDCl3, 161.96 MHz, d in ppm):
1
- 40.9 ppm (s). H NMR (CDCl3, 400.13 MHz): 7.18–7.27 (m,
10H, NC6H5), 4.47 (d, 2H, 2JHH = 12.8 Hz, NCH2P), 4.50 (d, 2H,
8 D. L. Severance and W. L. Jorgensen, J. Am. Chem. Soc., 1992, 114,
10966.
9 R. Breslow, Science, 1982, 218, 532.
10 A. J. Kirby, Angew. Chem., Int. Ed. Engl., 1996, 35, 706.
11 A. Heine, G. Desantis, J. G. Luz, M. Mitchell, C.-H. Wong and I. A.
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12 Aqueous Microwave Assisted Chemistry: Synthesis and Catalysis”, ed.
V. Polshettiwar and R. S. Varma, 2010, Royal Society of Chemistry
(Green Chemistry Series), Cambridge, UK.
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(b) D. Dallinger and C. O. Kappe, Chem. Rev., 2007, 107, 2563; (c) C. J.
Li and T. H. Chan, Organic Reactions in Aqueous Media, John Wiley &
Sons, New York, 1997; (d) C.-J. Li, T.-H. Chan, Comprehensive organic
reactions in aqueous Media, Wiley and sons, New York,2007.
14 V. Polshettiwar, A. Decottignies, C. Len and A. Fihri, Chem. Sus.
Chem., 2010, 3, 502.
2
2JHH = 12.8 Hz, NCH2P), 4.83 (d, 2H, JHH = 12.8 Hz, NCH2P),
2
4.86 (d, 2H, JHH = 12.8 Hz, NCH2P), 1.82–0.88 (m) (22H total,
1
C6H11). 31C{ H} NMR (CDCl3, 100.62 MHz): 15.21 (d, 4JCP = 1.2
2
1
Hz, CCy), 25.41 (d, JCP = 10.7 Hz, CCy), 28.07 (d, JCP = 14.5
Hz, CCy), 29.66 (d, 3JCP = 9.4 Hz, CCy),45.4 (d, 1JCP = 19.8 Hz,
NCP), 115.8 (s, C6H5), 118.8 (s, C6H5), 128.3 (s, C6H5), 149.6 (s,
C6H5).
Synthesis of 1,5-diphenyl-3,7-dicyclohexyl-1,5-diaza-3,7-
diphosphacyclooctane palladium complex 2
To a 20 mL dichloromethane solution of 0.1 g (0.22 mmol) of 1,5-
diphenyl-3,7-dicyclohexyl-1,5-diaza-3,7-diphosphacyclooctane
was dropwise added a solution of 0.05 g (0.22 mmol) of Pd(OAc)2
in 10 mL of the same solvent. After stirring 2 h at room
temperature, the solvent was removed under vacuum to give a
solid that was washed with cold pentane and dried under vacuum
15 For a discussion, see: (a) V. V. Grushin and H. Alper, in Activation of
Unreactive Bonds and Organic Synthesis, ed. S. Murai, Springer, Berlin,
1999, p. 193; (b) V. V. Grushin and H. Alper, Chem. Rev., 1994, 94,
1047.
16 (a) V. Polshettiwar and R. S. Varma, J. Org. Chem., 2008, 73, 7417;
(b) V. Polshettiwar and R. S. Varma, J. Org. Chem., 2007, 72, 7420;
(c) V. Polshettiwar and R. S. Varma, Tetrahedron Lett., 2008, 49, 397;
(d) V. Polshettiwar and R. S. Varma, Tetrahedron Lett., 2007, 48, 8735;
(e) V. Polshettiwar and R. S. Varma, Tetrahedron Lett., 2007, 48, 5649;
(f) V. Polshettiwar and R. S. Varma, Tetrahedron Lett., 2007, 48, 7343;
(g) Y. Ju and R. S. Varma, J. Org. Chem., 2006, 71, 135.
17 (a) V. Polshettiwar and R. S. Varma, Tetrahedron Lett., 2008, 49, 7165;
(b) V. Polshettiwar and R. S. Varma, Tetrahedron, 2008, 64, 4637; (c) V.
Polshettiwar and R. S. Varma, Tetrahedron Lett., 2008, 49, 879; (d) V.
Polshettiwar and R. S. Varma, Tetrahedron Lett., 2008, 49, 2661.
18 (a) V. Polshettiwar, M. N. Nadagouda and R. S. Varma, Chem.
Commun., 2008, 6318; (b) V. Polshettiwar, B. B. Baruwati and R. S.
Varma, ACS Nano, 2009, 3, 728.
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(b) V. Polshettiwar and R. S. Varma, Org. Biomol. Chem., 2009, 7, 37;
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1
to yield complex 2 as a brown solid (129 mg, 85%). 31P{ H} NMR
(CDCl3, 161.96 MHz, d in ppm): 31.9 ppm (s).1H NMR (CDCl3,
400.13 MHz): 1.5 (s, 6H, CH3), 2.1–0.9 (22 H total, C6H11), 4.13
(d, 2JHH = 13.2 Hz, PCH2N), 4.42 (dd, 2JHH = 14.2 Hz, 2JPH = 5.7
Hz, PCH2N), 4.18 (d, 2JHH = 12.8 Hz, PCH2N), MS (ES): m/z (%):
707.37 (100) [M - NH4]+.
A general procedure for the cross-coupling reaction is as
follows: to a solution of 4-methoxyphenylboronic acid (1.14 g,
7.5 mmol), 4¢-bromoacetophenone (995.25 mg, 5 mmol), K2CO3
(1.38 g, 10 mmol), 1,5-diphenyl-3,7-dicyclohexyl-1,5-diaza-3,7-
diphosphacyclooctane (2.34 mg, 5 10-3 mmol, 0.1 mol%) and
Pd(OAc)2 (1.2 mg, 5 10-3 mmol, 0.1 mol%) in 5 mL water was
flushed with nitrogen and capped. The reaction mixture was heated
and stirred in the oil bath at reflux for 2 h and the reaction mixture
was extracted with dichloromethane (3 ¥ 5 mL). The combined
dichloromethane phase was dried with anhydrous MgSO4. The
20 K. Kellner and A. Tzschach, Z. Chem., 1984, 24, 365.
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60.
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