An efficient water-soluble surfactant-type palladium catalyst for Suzuki cross-coupling reactions in pure water at room temperature

Article abstract of DOI:10.1039/c6nj00377j

A palladium catalyst based on a bidentate phosphine-type zwitterionic surfactant as a ligand exhibited an excellent catalytic activity in the Suzuki-Miyaura cross coupling reactions. This novel method allowed the reaction of aryl halides with arylboronic acids to occur in pure water at room temperature, forming a variety of biaryls in good to high yields. Heterobiaryls were also efficiently assembled even in the presence of water-insoluble heteroaryl halides as substrates. In addition, such a coupling protocol was successfully used in the iterative diarylation of 2,5-dibromopyridine in one-pot.

Full text of DOI:10.1039/c6nj00377j

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Efficient water-soluble surfactant-type palladium catalyst for Suzuki
cross-coupling reactions in pure water at room temperature
Pei Qiu,a Jing Yang Zhao,a Xu Shia and Xin Hong Duanb,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Palladium catalyst based on bidentate phosphine-type development of new and efficient Pd catalytic systems for the
zwitterionic surfactant as ligand exhibited an excellent catalytic SM cross coupling reactions in water is still a highly desired
activity in the Suzuki-Miyaura cross couplings. This novel method and challenging goal.
allowed the reaction of aryl halides with arylboronic acids to occur
in pure water at room temperature, forming a variety of biaryls in
good to high yields. Heterobiaryls were also efficiently assembled
even in the presence of water-insoluble heteroaryl halides as
substrates. In addition, such coupling protocol was successfully
used to the iterative diarylation of 2,5-dibromopyridine in one-
pot.
Palladium-catalyzed Suzuki-Miyaura (SM) cross coupling is one
of the most powerful transformations for biaryl synthesis in
laboratories and industry, as well as in the synthesis of fine
chemicals and pharmaceuticals.1 Typically, such reaction of
aryl halides with arylboronic acids occurs in organic solvents
such as MeCN, EtOH, DMF and toluene, etc. However, with the
increasing demand for green chemistry, water as a nontoxic,
Scheme 1 Representative water-soluble monodentate ligands for the Pd-catalyzed SM
inexpensive and safe solvent for organic synthesis has been of
widespread interest in recent years.2 As such, strategies have
cross-couplings in aqueous media.
been investigated in order to carry out the SM cross coupling
reactions in aqueous media.3 Besides heterogeneous catalysis4
Zwitterionic surfactants (i.e., bearing both positive and
and the use of surfactants as additives,5 a number of water-
negative charge) display much lower critical micellization
concentrations and surface tensions as compared to the
soluble ligands developed from sulfonating or quaternizing the
conventional ionic surfactants (SDS or CTAB).7 In addition, Pd(II)
commonly-used monodentate phosphine ligands in the C-C
complexes with bidentate phosphine ligands have been shown
coupling reactions have been applied to the Pd-catalyzed SM
to be efficient catalysts for C-N coupling reactions.8 Motivated
reactions in water.6 They include, for example, TPPMS,6a
sulfonated biphenyl,6b fluorene6c or dibenzofuran,6d and t-Bu-
Amphos or t-Bu-Pip-Phos6e,f (Scheme 1). Although high
by the attractive features of zwitterionic surfactants and
bidentate phosphine ligands, we have recently started
exploring a simple and novel ligand by integrating a bidentate
activities were obtained in water, these Pd catalytic systems
phosphine ligand into a zwitterionic surfactant, and herein we
typically required organic co-solvents and/or heating
first report a new in situ-generated catalyst that consists of
temperatures. Moreover, many such ligands encountered a
PdCl2 and such ligand for the SM cross coupling in pure water
variety of synthetic challenges and expensive prices. Thus, the
at room temperature. The Pd complex carries two substantial
benefits. On the one hand, zwitterionic surfactant as ligand
leads to relatively high water-solubility of the complex, hence
increasing largely the efficiency of the Pd catalysis in pure
water. On the other hand, bidentate phosphine-type ligand
binds with Pd to form a six-membered ring structure of the
active catalytic site,9 thereby contributing to the high activity
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and stability of the catalyst. As such, the Pd complex not only forms micelles in addition to supporting the Pd catalyst.
is highly efficient catalyst to cross-couple aryl substrates, but Therefore, such catalytic system in combination with pure
also allows the SM reaction of various water-insoluble water as solvent is optimal for the reaction at room
heteroaryl halides and of 2,5-dibromopyridine by the regio- temperature. Also, bases were screened and found that the
selective diarylation in one pot, which have been no previous bases such as K3PO4, K2CO3, Na2CO3 and NaOH had almost no
report in pure water at room temperature.
influence on the catalytic activity (Table 1, entries 4, 6-8). In
addition, a much lower catalyst loading of 0.15 mol % turned
out to be sufficient for the reaction leading to a high yield of
93 % (Table 1, entry 10 versus entries 8 and 9). At this loading,
a 1:4 ratio of Pd:L gave a more active catalysis, while the
catalytic activity was significantly diminished at a lower 1:2
ratio (Table 1, entry 11).
Scheme 2 The ligand preparation. Reaction conditions: a) H2NC2H4SO3Na, EtOH/H2O,
Table 2 The SM cross couplings for biaryls.a
Et3N, reflux, 3h; b) BrC2H4SO3Na, EtOH/H2O, 50 oC, 24 h.
Entry
Aryl halide
Time (h)
Product (Yield b)
The ligand of bidentate phosphine-type zwitterionic
1
14
surfactant (L) was readily prepared by a two-step procedure.
1b (76 %)
As shown in Scheme 2, [Ph2P(CH2OH)2]Cl was treated
successively with sodium 2-aminoethanesulfonate and sodium
7 (X = Br)
14 (X = Cl)
2
3
2-bromoethanesulfonate to give L in a 75 % total yield.
1c (X = Br, 91 %; X = Cl, 21 %)
(X = Br, Cl)
Table 1 Optimization of the reaction conditions.a
6
6
1d (94 %)
4
5
Pd catalystb
Time
(h)
12
8
Yieldc
(%)
9 (24)d
52
Entry
Base
1e (90 %)
1f (92 %)
(mol %)
1
PdCl2 (2)
K3PO4
2
PdCl2 (2) + SDS (8)
PdCl2 (2) + CTAB (8)
PdCl2 (2) + L (8)
PdCl2 (2) + L (8)
PdCl2 (2) + L (8)
PdCl2 (2) + L (8)
PdCl2 (2) + L (8)
PdCl2 (0.5) + L (2.0)
PdCl2 (0.15) + L (0.6)
PdCl2 (0.15) + L (0.3)
K3PO4
10
10
3
8
K3PO4
60
4
5e
6
K3PO4
96
12
6
K3PO4
54
6
K2CO3
NaOH
Na2CO3
Na2CO3
Na2CO3
Na2CO3
95
6
7
6
97
8
6
96
1g (80 %)
1h (96 %)
9
8
95
10
11
8
93
7
8
6
9
12
59
a Conditions: 4-bromophenylethanone (1 mmol), phenylboronic acid (1.5 mmol),
b
base (2 mmol). The PdCl2/L catalyst was in-situ prepared as follows: 1) the
mixture of PdCl2 and L was heated in 3 mL water at 80 oC for 5 min, and until a
light brown solution was formed; 2) the resulting solution was cooled down to
c
d
e
room temperature. Yield of the isolated product. Yield in refluxing water.
MeCN/H2O (1:1, 3 mL) as solvent.
1h (91 %)
HOOC
H2N
To probe the catalytic activity of the in situ-generated Pd/
L
9
12
8
Br
complex and optimal conditions in the SM cross couplings, 4-
bromoacetophenone and phenylboronic acid were selected as
the model substrates10 (Table 1). At room temperature, in the
absence of ligand the reaction with PdCl2 as catalyst
proceeded rather sluggishly in pure water (Table 1, entry 1).
Upon using SDS (sodium dodecyl sulfate) or CTAB (hexadecyl
trimethyl ammonium bromide) as an additive, only a moderate
1i (78 %)
10
1j (87 %) (88 %)c
a Conditions: the halide (1 mmol), the boronic acid (1.5 mmol), PdCl2 (0.15 mol-
%)/L = 1:4, Na2CO3 (2 mmol). Yield of the isolated product. Reaction was
performed on 10-mmol scale: 2-bromoaniline (10 mmol), 4-chlorophenylboronic
acid (13 mmol), PdCl2 (0.15 mol-%)/L = 1:4, Na2CO3 (18 mmol), H2O (30 mL), 8 h.
b
c
yield was obtained (Table 1, entry 2 or 3). Interestingly, when
L
was used as ligand, a complete conversion was achieved
within 6 h (Table 1, entry 4). If the same reaction was carried
out in MeCN/H2O, however, the yield of 1a decreased
With the above optimized conditions in hand, we next
investigated the substrate scope of this catalytic system by
significantly (54 %, Table 1, entry 5). These indicate that
L
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using various aryl halides and arylboronic acids as coupling
COMMUNICATION
Table 3 The SM cross couplings for heterobiaryls.a
partners, and the results were shown in Table 2. As expected, Entry
phenols and benzoic acids were found to be high yielding
Heteroaryl halide
Time (h)
Product (Yieldb)
(Table 2, entries 4 and 5). More importantly, the substrates
1
8
without hydrophilic substituents could also be well coupled.
For example, aldehydes, ketones and esters all proceeded
smoothly without competitive side reactions (Table 2, entries
2a (91 %)
2, 3,
7 and 8). With respect to the substrate 4-
2
3
9
6
chlorobenzaldehyde, the catalyst was less effective and only a
21 % yield was reached after 14 h (Table 2, entry 2). Notably,
the transformation was insensitive to steric hindrance: as
ortho substitution on either the aryl halide or the arylboronic
acid was well tolerated (Table 2, entries 4, 5, 7, 8 and 10). In
particular, the sterically more hindered 2,4,6-trimethylphenyl
bromide also proved to be an efficient substrate (Table 2,
entry 6). Moreover, the reaction outcomes were almost not
affected by the electronic factors and, for example, the yield of
1h reached 91 % even in the presence of the electron-rich aryl
bromide and electron-deficient arylboronic acid as coupling
partners (Table 2, entry 7 versus 8). Since the free -NH2 group
was demonstrated to be compatible with this catalytic system
2b (90 %)
2c (93 %)
2d (86 %)
4
5
10
6
2e (79 %)
2f (89 %)
2g (81 %)
(Table 2, entry 9), 4'-chlorobiphenyl-2-amine
(1j), an
intermediate in the synthesis of the fungicide Boscalid,11 was
formed by the direct cross coupling of 2-bromoaniline with 4-
chlorophenylboronic acid without the need for a nitro-
reduction step12 (Table 2, entry 10). To further verify the
potential of this catalytic system, the intermediate was
prepared on a 10-mmol scale and indeed, the reaction worked
as well as on a 1-mmol scale. So, this methodology represents
an attractive cross-coupling method for larger-scale
application.
6
7
8
10
8
9
6
Excitingly, the above method was also successfully applied
in the synthesis of heterobiaryls, an architectural motif that is
ubiquitous in biologically active molecules. However, to date
only very few examples of the SM cross couplings of water-
soluble heteroaryl halides in water have been published at
room temperature.3f,6b,13 Obviously when the water-insoluble
heteroaryl halides are employed as substrates, the reactions
should be much more challenging. In this context, the Pd
2h (92 %)
2i (87 %)
10
10
10
catalyst based on L showed an excellent catalytic activity in the
SM cross couplings of water-insoluble heteroaryl halides in
pure water at room temperature. As showed in Table 3, the
benzofuran, chromene and thiophene derivatives could be mmol), Pd (0.15 mol-%)/L = 1:4. b Yield of the isolated product.
2j (88 %)
a
Conditions: the halide (1.0 mmol), the boronic acid (1.5 mmol), Na2CO3 (2
efficiently cross-coupled to form the desired products in high
This catalytic system exhibited high regio-selectivity in the
SM cross coupling reaction, as shown by the arylation of 2,5-
dibromopyridine at the C2 position (Table 3, entry 5). Given
that its diarylation in a one-pot procedure has remained poorly
documented,12,16 especially uncovered in water at room
temperature, we preferred to iteratively diarylate this
compound in one pot. As shown in Scheme 3, after the first SM
cross coupling was complete, such diarylation was achieved
directly by the second SM reaction in a one-pot manner, which
led to isolation of the desired double-coupled product of 3a in
a 61 % overall yield. Although two different arylboronic acids
were used as substrates, only small amounts of homo-coupling
yields (Table 3, entries 1-3). Although N-heteroaryl halides
have proven to be difficult substrates in the Pd-catalyzed C-C
couplings,14 our method worked very well for a variety of such
substrates including the pyridine, benzothiazole, quinoline and
indole (with a free NH bond) derivatives (Table 3, entries 4-10).
Also, it is interesting to note that 2-amino-5-bromopyridine,
which is one of the most intractable among these substrates
due to its competitive binding with Pd center,14a,15 reacted in
good yield with phenylboronic acid (Table 3, entry 6). Thus,
this Pd catalytic system using
L as ligand provides a highly
stable and efficient catalyst for the SM reactions of heteroaryl
substrates.
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3
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Scheme 3 The diarylation of 2, 5-dibromopyridine in one-pot.
In summary, we have demonstrated that the novel Pd
catalyst based on the bidentate phosphine-type zwitterionic
surfactant as ligand is an efficient catalytic system for the SM
cross couplings in pure water at room temperature. The scope
of this method is broad with respect to both coupling partners,
and includes the much more challenging water-insoluble
heteroaryl halides as substrates. Furthermore, the potential of
this catalytic system to perform the SM cross couplings on a
preparative scale has been demonstrated by the gram-scale
assembly of the fungicide intermediate. In addition, the
method has successfully be used in one pot to the iterative
diarylation of 2,5-dibromopyridine with high regio-selectivity.
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The general procedure for the cross-coupled biaryls is as
follows: PdCl2 (0.27 mg, 1.5 μmol, 0.15 mol %),
L (4.6 mg, 6
μmol) and 3 mL H2O were mixed and heated at 80 oC for 5 min.
After cooling to room temperature, the bromine/iodine (1.0
mmol), the boronic acid (1.5 mmol) and Na2CO3 (212 mg, 2
mmol) were added. The reaction mixture was stirred at room
temperature until the coupling reaction reached. After
extracted with EtOAc, dried over Na2SO4, and concentrated in
vacuo, the product was obtained by purification with silica gel
flash chromatography.
7
8
Acknowledgements
This research is supported by grants from the Fundamental
Research Funds for the Central Universities (2015ZCQ-LY-03)
and the Beijing Forestry University Student Innovative Program
(X201510022133).
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Graphic Abstract
In situ-generated Pd catalyst with bidentate phosphine-type zwitterionic surfactant
as ligand showed high catalytic activity in the Suzuki reactions.