Simple and efficient phosphine-free Pd(OAc)2 catalyzed urea accelerated Suzuki-Miyaura cross-coupling reactions in iPrOH-H2O at room temperature

Article abstract of DOI:10.1016/j.tetlet.2014.12.061

A simple, efficient, and less expensive protocol for the phosphine-free Suzuki-Miyaura cross-coupling reactions of aryl halides with different aryl boronic acids in ⁱPrOH-H₂O under aerobic conditions has been developed. The mixture of Pd(OAc)₂ and urea catalyzes the Suzuki-Miyaura cross-coupling of a variety of aryl halides with aryl boronic acids at room temperature, giving generally high yields even under low catalytic loads. The effect of solvent, base, and catalyst loading on the coupling reaction of aryl halide with arylboronic acid is also described.

Full text of DOI:10.1016/j.tetlet.2014.12.061

Accepted Manuscript
Simple and Efficient Phosphine-Free Pd(OAc)2 Catalyzed Urea Accelerated
i
Suzuki–Miyaura Cross-Coupling Reactions in PrOH-H2O at Room Temper-
ature
Bishwajit Saikia, Preeti Rekha Boruah, Abdul Aziz Ali, Diganta Sarma
PII:
S0040-4039(14)02127-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.061
TETL 45585
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 November 2014
4 December 2014
10 December 2014
Please cite this article as: Saikia, B., Boruah, P.R., Ali, A.A., Sarma, D., Simple and Efficient Phosphine-Free
i
Pd(OAc)2 Catalyzed Urea Accelerated Suzuki–Miyaura Cross-Coupling Reactions in
PrOH-H2O at Room
Temperature, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.12.061
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Simple and Efficient Phosphine-Free Pd(OAc)2
Catalyzed Urea Accelerated Suzuki–Miyaura
Cross-Coupling Reactions in iPrOH-H2O at
Room Temperature
Leave this area blank for abstract info.
Bishwajit Saikia*, Preeti Rekha Boruah, Abdul Aziz Ali and Diganta Sarma
Department of Chemistry, Dibrugarh University, Dibrugarh-786004, Assam, India
X
B(OH)2
Pd(OAc)2, Urea
+
K2CO3, rt, 10-30 min
iPrOH/H2O (1:1 v/v)
R1
R1
X = Cl, Br, I
R2
R2

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Simple and Efficient Phosphine-Free Pd(OAc)2 Catalyzed Urea Accelerated Suzuki–
Miyaura Cross-Coupling Reactions in iPrOH-H2O at Room Temperature
Bishwajit Saikia*, Preeti Rekha Boruah, Abdul Aziz Ali and Diganta Sarma
Department of Chemistry, Dibrugarh University, Dibrugarh-786004, Assam, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A simple, efficient and less expensive protocol for the phosphine-free Suzuki–Miyaura cross–
coupling reactions of aryl halides with different aryl boronic acids in PrOH-H2O under aerobic
i
Received in revised form
Accepted
Available online
conditions has been developed. The mixture of Pd(OAc)2 and urea catalyzes the Suzuki–
Miyaura cross-coupling of a variety of aryl halides with aryl boronic acids at room temperature,
giving generally high yields even under low catalytic loads. The effect of solvent, base and
catalyst loading on the coupling reaction of aryl halide with arylboronic acid is also described.
Keywords:
Suzuki–Miyaura
Boronic acid
Palladium Acetate
Urea
2009 Elsevier Ltd. All rights reserved.
Ligand
The discovery of the Suzuki–Miyaura cross-coupling
reaction has brought revolutionary progress to synthetic organic
-eloped new eco-friendly catalytic systems for Suzuki–Miyaura
cross-coupling reactions as well as inexpensive inorganic base
and solvents are used in green Suzuki–Miyaura catalytic
systems.20 Specifically, cost effective catalyst systems that allow
for unconventional couplings to take place smoothly are of great
value.
chemistry by providing
a widely applicable method of
constructing sp2 C–C bonds via the coupling of aryl halides and
boranes.1 The characteristics of organoboron reagents (i.e. high
selectivity in cross-coupling reactions, stability, nontoxic nature
and tolerance towards functional groups) often give Suzuki-
Miyaura (SM) coupling a practical advantage over other cross-
coupling processes. It is one of the most powerful tools for the
preparation of unsymmetrical biaryl derivatives that are structural
elements of numerous natural products, agrochemicals,
pharmaceuticals, and polymers.2-3 In general, Pd-phosphine
complexes have been the most commonly employed catalysts for
the SM reaction. However, the major drawback of these catalyst
systems is that the phosphine ligands are comparatively difficult
to make or are rather more expensive, poor thermal and air
stability. These factors contribute to the growing interest in N,O-
coordinating ligands for catalysts in SM cross-coupling
reactions.4 A number of phosphine-free ligands for the Suzuki–
Miyaura reaction had been reported in numerous literature such
as N-heterocylic carbenes,5,6 diimines,7,8 diaminos,9,10 and N,O-
ligands.11–13. Most of the classical Suzuki–Miyaura reaction was
often carried out in organic media14-19, which was conflicting to
the idea of green chemistry. The majority of reported catalysts
are based on the preparation of Pd-ligand complexes by using
highly expensive and laborious methods. Similarly, the use of
strong bases, organic solvents and refluxed conditions are
required to maximize the catalytic performance.
Our group has been investigating the use of easily available
urea as a highly effective ligand with Pd(OAc)2, with particular
focus on optimizing new catalytic systems for eco-friendly
Suzuki–Miyaura cross-coupling reactions. Urea is a colorless,
odorless solid, highly soluble in water and practically non-toxic
substance, consequently its use as a ligand in Suzuki coupling
reaction is considered as environment friendly. On the other
hand, it is very cheap and easily available material. Therefore, the
chemistry of urea based ligands has been developed rapidly in
recent years because of interest in their geometrical structures
and complexing ability.21
Initially, we optimized the reaction conditions such as the
solvent, base and reaction temperature for Suzuki–Miyaura cross-
coupling reactions. Possible solvent mixtures for this cross-
coupling reaction are assessed in order to get excellent yield of
the desired cross-coupling products. We avoided all the
halogenated solvents such as methylene chloride, chloroform,
perchloroethylene and carbon tetrachloride as they have long
been identified as suspected human carcinogens.22 Similarly, the
roles of different bases were screened for Suzuki–Miyaura
reaction and it was found that bases had a significant influence on
the coupling efficiency. To find the efficiency of the Pd(OAc)2-
urea catalyst system, we performed the Suzuki–Miyaura cross-
coupling reaction with 4-nitrobromobenzene and phenylboronic
acid in presence of different bases and solvent systems at room
temperature and the results are summarized in Table 1.
From these standpoints, the development of efficient,
stable, economical, and environmentally friendly catalytic system
remains a challenging task. More recently, researchers have dev-
*Corresponding author. Tel.: +91 9954314676.
E-mail address: bishwajitsaikia@gmail.com (B. Saikia).

2
Tetrahedron Letters
17
EtOH/H2O
DMF/H2O (1:1 v/v)
CH3CN/H2O (1:1 v/v)
1,4-dioxane/H2O
(1:1 v/v)
Ethylene Glycol
Ethylene Glycol/H2O
(1:1 v/v)
K2CO3
K2CO3
K2CO3
K2CO3
60
60
60
60
30
20
12
25
In the beginning we investigated the SM reaction of 4-
18
19
20
nitrobromobenzene and phenylboronic acid, catalyzed by
Pd(OAc)2–urea in neat PrOH at room temperature under aerobic
conditions. We found that the coupled product was obtained in
only 25% isolated yield after 60 minutes (Table 1, Entry 3). The
yields of 4-nitrobiphenyl were 55%, 30%, 20%, 12%, 25% and
i
21
22
K2CO3
K2CO3
60
60
30
42
42%
when
tert-butanol, ethanol, dimethylformamide,
a
Reaction conditions: 4-nitrobromobenzene (1 mmol), phenylboronic acid
acetonitrile, 1,4-dioxane and ethylene glycol were used as
solvents respectively, with water as co-solvent in presence of
base K2CO3 (Table 1, after 60 min, Entries 13, 17-20 and 22).
Meanwhile, the yield reached up to 60% when the reaction
mixture was at room temperature for 60 min in H2O (Table 1,
Entry 1). The yields of 4-nitrobiphenyl were 20%, 10%, and 30%
when tert-butanol, ethanol, and ethylene glycol were used as
solvents respectively, in presence of base K2CO3 (Table 1,
Entries 4, 16 and 21). However, no significant improvement was
observed for these cases when the reaction time was enhanced.
(1.2 mmol), Pd(OAc)2 (1 mol%), Urea (0.01 mmol), base (3 mmol) in solvent
(4 mL) at room temperature.
b Isolated yields
After optimizing the reaction conditions, different aryl
bromides and iodides with electron-donating and electron-
withdrawing groups were investigated to check the feasibility of
this protocol whose results are tabulated in Table 2. The
arylboronic acids bearing methyl, methoxy, chloro, and
trifluoromethyl groups were rapidly converted to the
corresponding products at high yield for less than 1 h at room
temperature under the standard conditions as shown in Table 2
(Entries 3, 4, 7, 8, 16, 17 and 19). It is worth to note that the
electronic effects of either coupling partner produced no
significant impact on the reaction yields. These results suggest
that Pd(OAc)2/urea was a very effective catalyst for this cross-
coupling reaction. ortho-Substituted aryl bromides/iodides and
arylboronic acids were coupled smoothly (Table 2, Entries 6, 7
and 15), indicating that the steric hindrance of coupling partners
had less influence on this coupling reaction. Under slightly
extended reaction time, our catalyst can also allow for synthesis
of highly sterically hindered di–ortho as well as tri–ortho
substituted biphenyls (Table 2, Entries 7-8), under mild and
aerobic conditions in reasonably good yields. In order to show
the effect of urea in this reaction, we performed a reaction of 4-
nitrobromobenzene and phenylboronic acid in the absence of
urea at room temperature. The results of this study showed that in
the absence of the urea the reaction was sluggish and only 57%
GC yield was obtained. These results are quite significant as the
desired biaryls could be efficiently achieved at room temperature
using water as a co-solvent and with relatively lower palladium
loading (1 mol %) in the presence of easily available compound
urea. From these studies we can predict that this catalyst can be
applied to a wide range of aryl iodides and bromides. By
applying this protocol, we also investigated the reaction of un-
reactive arylchlorides with arylboronic acids. Unlike aryl
bromides, unfortunately, the coupling of aryl chlorides with
phenylboronic acid did not proceed at room temperature. As the
reaction temperature increased up to 100° C, however, the
reaction yields increased significantly (Table 2, Entries 18-20).24
i
Surprisingly in PrOH-H2O (1:1 v/v) solvent system, an excellent
yield (99%) of the desired product was observed after 10 min
(Table 1, Entry 5). We observed that the addition of appropriate
i
t
amounts of polar organic solvents such as PrOH, BuOH, EtOH
and Ethylene Glycol into water led to an increase in the activity,
and better yield was obtained. We are quite satisfied to see that
our reaction completed at room temperature (Scheme 1) and the
formation of undesired homo-coupling product was very
negligible. We further examined the effect of other bases such as
Na2CO3, NaOH, KOH, Na3PO4.12H2O, Na2HPO4, K3PO4, Et3N
etc (Table 1). to study if the rate of reaction could get enhanced,
but these turned out to be poorer bases as compared to K2CO3.
From the results in Table 1, it could be seen clearly that in
i
presence of K2CO3, the mixture of PrOH–H2O (1:1 v/v) was the
best media for this catalyst system, 10 min as the reaction time,
and room temperature. The important aspect of this system is
i
that, PrOH evaporates quickly compared to alternative organic
solvents. Generally, presence of water increases solubility of the
bases, which is responsible for the activation of boronic acid
resulting in enhancing the rate of the reaction in aqueous
medium.23 Finally, the synthetic route in Scheme 1 has several
advantages, including simple procedures, short reaction times,
excellent yields, mild conditions and commercially cheaper
reagents.
Table 1. Screening the solvent and base efficiency of the
Pd(OAc)2 and urea catalytic system at room temperature for the
Suzuki–Miyaura cross-coupling reactiona
Br
B(OH)2
Pd(OAc)2, Urea
+
O2N
Base, Solvent, rt
O2N
Urea has three coordination sites; the carbonyl oxygen and
the two nitrogen atoms and acts as a monodentate ligand. Our
protocol is completely free from those common disadvantages
involved during SM reaction such as the requirement of large
amount of catalysts, generation of homo–coupling by–products,
preparation of the Pd-ligand complex, inert reaction condition,
elevated reaction temperature, longer reaction times and use of
organic or biphasic reaction media etc.
Entry
Solvent
Base
Time
(min)
30
30
60
60
10
30
30
60
60
60
60
Yieldb
(%)
1
2
3
4
5
6
7
8
9
H2O
H2O
K2CO3
NaOH
60
30
25
20
99
70
46
38
35
iPrOH
tBuOH
K2CO3
K2CO3
K2CO3
Na2CO3
NaOH
iPrOH/H2O (1:1 v/v)
iPrOH/H2O (1:1 v/v)
iPrOH/H2O (1:1 v/v)
iPrOH/H2O (1:1 v/v)
iPrOH/H2O (1:1 v/v)
iPrOH/H2O (1:1 v/v)
iPrOH/H2O (1:1 v/v)
iPrOH/H2O (1:1 v/v)
Na3PO4.12H2O
Na2HPO4
K3PO4
10
11
12
35
Et3N
-
<20
No
reaction
55
55
30
60
13
14
15
16
tBuOH/H2O (1:1 v/v)
tBuOH/H2O (1:1 v/v)
tBuOH/H2O (1:1 v/v)
EtOH
K2CO3
Na2CO3
KOH
30
60
60
60
K2CO3
10

3
Table 2. Pd(OAc)2 and urea catalysed Suzuki–Miyaura cross-coupling reaction of aryl halides with aryl boronic acids at room
temperature
X
B(OH)2
Pd(OAc)2, Urea
+
K2CO3, iPrOH/H2O (1:1 v/v)
rt, 10-30 min
R2
R1
R1
X = Cl, Br, I
R2
Scheme 1: Suzuki–Miyaura cross-coupling between different aryl halides and arylboronic acids
Entry
1
ArX
ArB(OH)2
Time (min)
Yieldb (%)
99
B(OH)2
Br
O2N
10
Br
B(OH)2
2
10
98
O2N
Br
B(OH)2
B(OH)2
MeO
NC
MeO
3
4
5
10
15
15
99
96
96
Br
Br
F3C
B(OH)2
B(OH)2
OHC
Br
CHO
6
15
20
94
94
7
8
B(OH)2
B(OH)2
Br
Br
30
15
90
95
O
Br
B(OH)2
B(OH)2
9
Br
HOH2C
HOOC
10
11
12
20
20
15
97
92
90
B(OH)2
B(OH)2
Br
Br
B(OH)2
B(OH)2
I
MeO
O2N
13
14
15
10
10
10
99
99
98
I
I
B(OH)2
OMe
I
HO
F
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
Cl
16
17
18
19
20
15
15
95
94
I
MeO
300
68c
Cl
O2N
80c
70c
Cl
MeO
240
Cl
240
MeO
a Reaction conditions: arylhalide (1 mmol), arylboronic acid (1.2 mmol), Pd(OAc)2 (1 mol%), urea (0.01 mmol), K2CO3 (3 mmol) in

4
Tetrahedron
iPrOH/H2O (1:1, v/v, 4 mL) at room temperature.
b Isolated yields.
C Temperature 100° C
22. Anastas, P. T.; Warner, J. C. In: Green Chemistry: Theory and
Practice; Oxford University Press: Oxford, 1998.
In summary, we have successfully developed a palladium
23. Cornils, B.; Herrmann, W. A.; Horvth, I. T.; Leitner, W.;
Mecking, S.; Olivier-Bourbigou, H.; Vogt, D. Multiphase
Homogeneous Catalysis; Wiley-VCH:Weinheim, 2008; pp 2–23.
24. Typical experimental procedure: In a 50 mL round bottomed
flask, a mixture of aryl halide (1 mmol), arylboronic acid (1.2
mmol), Pd(OAc)2 (1 mol%), urea (0.01 mmol) and K2CO3 (3
catalyzed Suzuki–Miyaura reaction using urea as a ligand in
iPrOH-H2O media under aerobic conditions. This facile, mild,
and low-cost ligand protocol represents, to a certain extent, a new
advance in Suzuki–Miyaura cross-coupling reactions.
i
mmol) in PrOH/H2O (1:1, v/v, 4 mL) and the mixture was stirred
References and notes:
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chromatography over silica gel using hexane/ethyl acetate (9:1
v/v) to get the desired coupling product. The products were
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