Pd-EDTA as an efficient catalyst for Suzuki-Miyaura reactions in water

Article abstract of DOI:10.1016/j.tetlet.2005.06.085

PdCl₂-EDTA complex 1 is an efficient catalyst for the Suzuki-Miyaura reactions of aryl and heteroaryl halides with aryl(heteroaryl)boronic acids in water at 20-100°C. Aryl iodides and bromides undergo the cross-coupling with turnover numbers (T

Full text of DOI:10.1016/j.tetlet.2005.06.085

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5751–5754
Pd–EDTA as an efficient catalyst for Suzuki–Miyaura
reactions in water
Dmitrii N. Korolev and Nikolay A. Bumagin*
Lomonosov MSU, Department of Chemistry, GSP-2, 119992 Moscow, Leninskie Gori, Russian Federation
Received 29 March 2005; revised 31 May 2005; accepted 8 June 2005
Available online 1 July 2005
Abstract—PdCl –EDTA complex 1 is an efficient catalyst for the Suzuki–Miyaura reactions of aryl and heteroaryl halides with
2
aryl(heteroaryl)boronic acids in water at 20–100 ꢀC. Aryl iodides and bromides undergo the cross-coupling with turnover numbers
ꢀ
1
TON) up to 97,000 and turnover frequencies (TOF) up to 582,000 h .
(
ꢁ
2005 Elsevier Ltd. All rights reserved.
The palladium-catalyzed Suzuki–Miyaura reaction,
which involves the cross-coupling of aryl halides with
aryl boronic acids, has become one of the most powerful
and convenient synthetic tools for preparation of biaryl
very expensive. So simple, inexpensive, easily accessible,
1
and stable catalysts are desired for these reactions.
2
Earlier, we and other authors showed that the Suzuki–
Miyaura reaction proceeds most effectively in the pres-
ence of ÔligandlessÕ palladium catalysts in basic aqueous
1
compounds. The widely employed reaction protocol
1
3
utilizes aqueous organic solvents in the presence of an
inorganic base (carbonate, bicarbonate, or hydroxide),
a palladium catalyst precursor and a ligand that coordi-
nates to the palladium center to stabilize the catalyst.
The right choice of the ligand is a key factor determining
the rate of the catalytic reaction. In addition to the tra-
media. However, this catalytic system was not stable
enough.
We report herein, a new PdCl –EDTA (ethylenedi-
2
0
0
amine-N,N,N ,N -tetraacetic acid)-based catalytic sys-
tem for the Suzuki–Miyaura cross-coupling reaction
(Scheme 1).
2
ditional triphenylphosphine ligand, electron-rich bulky
3
4
phosphines, phosphine oxides, and phosphine-based
5
palladacycles have been suggested as efficient ligands
5
A solution of PdCl –EDTA complex 1 was prepared
2
from PdCl , 1 equiv of EDTA (disodium salt dihydrate),
2
or catalyst precursors. Recently, a number of catalytic
systems with phosphine-free ligands, such as C-based
and 2 equiv of Na CO in water at room temperature. It
2
3
6
7
heterocyclic carbenes, C,N-based 2-aryl-2-oxazolines,
9
is a yellow-red solution with pH ꢁ 8–9, which is stable
14
8
aryl(heteroaryl)oximes, arylimines, and N,N-based
1
at room temperature and can be stored in air. According
to earlier data, Pd(II) salts react with EDTA easily in
water to form square complexes containing one ligand
0
11
diazabutadienes have been reported. However, most
of these new ligands are not readily available and are
X
X
0
.1 mol% 1, K CO
2 3
Hal
+
Ar
B(OH)2
Ar
o
H O, 20-100 C, 0.2-3 h
2
Hal = I, Br
6
2-96%
X = COOH, CHO, NH etc.
2
2
Scheme 1. Cross-coupling reactions of aryl halides with arylboronic acids catalyzed by PdCl –EDTA.
Keywords: Suzuki–Miyaura reaction; Palladium; EDTA; Biaryls; Catalysis.
*
Corresponding author. Tel.: +7 095 939 1383; fax: +7 095 939 0126; e-mail: bumagin@org.chem.msu.su
0
040-4039/$ - see front matter ꢁ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.085

5752
D. N. Korolev, N. A. Bumagin / Tetrahedron Letters 46 (2005) 5751–5754
a
Table 1. Cross-coupling reactions of aryl iodides
0
b
Yield (%)
Entry
Ar-I
Ar -B(OH)
2-Furyl-B(OH)
3-Thienyl-B(OH)
2-FC B(OH)
2-MeC B(OH)
2,4,6-Me
2
T (ꢀC)
Time (h)
1
2
3
4
4-IC
3-IC
2-IC
2-IC
3-IC
6
6
6
6
6
H
4
H
4
H
4
H
4
H
4
CO
CO
CO
CO
CO
2
H
2
H
2
H
2
H
2
H
2
20
20
10 min
1
83
90
71
91
76
2
6
H
4
2
100
100
20
2
6
H
4
2
3
c
5
3
C
6
H
2
B(OH)
2
15 min
I
d
6
e
94
PhB(OH)
2
100
1
N
CH(Me)OEt
N
I
I
d
e
7
3-HO
3-HO
2
CC
6
H
4
B(OH)
2
100
100
15 min
76
N
N
CH(Me)OEt
CH(Me)OEt
N
N
d,f
8
e
89
2
CC
6
H
4
B(OH)
2
1
d,g
h
9
2-IC
4-IC
6
H
4
NH
NH
2
2-Furyl-B(OH)
2-Thienyl-B(OH)
2
20
20
2
2
88
d,g
0
h
83
1
6
H
4
2
2
a
b
c
0
1
mmol of Ar-I, 2 mL of water, 2 mmol of K
Isolated yield.
mmol of KOH as base.
2
CO , 1.05 mmol of Ar -B(OH)
3
2
2
, 0.1 mol % of PdCl –EDTA, Ar.
3
d
e
4
In the presence of 1 mol % of n-Bu NBr.
After protecting group removal.
50 mmol scale, 0.001 mol % of 1.
f
g
h
MeOH–water (2:1).
As hydrochloride.
residue per Pd atom. EDTA is used as bidentate ligand
which coordinates with two nitrogen atoms.
A high temperature was also required for the coupling
reactions of some particular water-insoluble aryl iodides
in water without an organic co-solvent. For example,
the reactions of 1-(1-ethoxyethyl)-4-iodo-1H-pyrazole
and arylboronic acids took place in water at 100 ꢀC in
the presence of 0.1 mol % of complex 1 and 1 mol %
To evaluate the scope and limitations of this protocol,
we carried out a number of reactions of aryl- and hetero-
arylboronic acids with water-soluble and water-insolu-
ble aryl iodides (Table 1).
of Bu NBr in 0.4–1 h to give the cross-coupled products
4
in good yields (entries 6 and 7). To provide a sense for
the turnover numbers that are achievable with the new
catalyst, we have examined the reactions of 1-(1-ethoxy-
ethyl)-4-iodo-1H-pyrazole and 3-carboxyphenyl-boro-
nic acid with low catalyst loadings (entry 8). The
cross-coupling proceeded in 89% yield at 100 ꢀC in 1 h
with a 0.001% loading of palladium, corresponding to
89,000 turnover numbers (TON).
For initial studies, we performed the Suzuki–Miyaura
coupling of 4-iodobenzoic acid and 2-furylboronic acid
(
entry 1). In the presence of 0.1 mol % of complex 1,
the reaction proceeded in water without organic co-
solvent at room temperature (2 equiv of K CO ) in less
2
3
than 10 min, clearly indicating the high activity of the
new catalyst. The product was isolated in 83% yield.
Even sterically hindered mesityleneboronic acid reacted
with 3-iodobenzoic acid at room temperature in 15
min, yielding 76% of pure 3-mesitylbenzoic acid (entry
Then, we tested the catalytic activity of the new catalyst
in cross-coupling reactions of aryl bromides (Table 2).
While reactions of aryl iodides proceeded at room
temperature in most cases, aryl bromides required an
elevated temperature. In the presence of 0.1 mol %
of complex 1, water-soluble aryl bromides (3-bromo-
benzoic, 5-bromofuroic, 5-bromothiophene-2-carboxy-
lic, and 5-bromosalicylic acids) afforded the coupled
products in high yields at 100 ꢀC in 0.5–2 h (entries 2–
9). Even the electron-rich aryl bromide as 4-bromo-
phenol reacted in 0.5 h (entry 10). Only 2-bromobenzoic
acid was found to be inactive under the conditions
tried (entry 1). Both aryl- and heteroarylboronic acids
reacted smoothly to give cross-coupled products in high
yields.
5
). The reactions of electron-rich water-insoluble 2-
and 4-iodoanilines also proceeded at room temperature
in aqueous methanol, giving cross-coupling products
with high yields in 2 h (entries 9 and 10).
While 3- and 4-iodobenzoic acid reacted with boronic
acids in water at room temperature, 2-iodobenzoic acid
required an elevated temperature. As shown in Table 1
(
entries 3 and 4), the reactions of 2-iodobenzoic acid
with 2-methylphenyl- and 2-fluorophenylboronic acids
gave the coupling products in high yields at 90–100 ꢀC
in 2–3 h.

D. N. Korolev, N. A. Bumagin / Tetrahedron Letters 46 (2005) 5751–5754
5753
a
Table 2. Cross-coupling reactions of aryl bromides
0
b
Yield (%)
Entry
Ar-Br
Ar -B(OH)
2
T (ꢀC)
Time (h)
1
2
3
2-BrC
3-BrC
3-BrC
4-BrC
4-BrC
6
H
6
H
6
H
6
H
6
H
4
CO
4
CO
4
CO
4
CO
4
CO
2
2
2
2
2
H
H
H
H
H
2-MeC
2-MeC
6
H
H
4
B(OH)
B(OH)
2
100
100
100
100
100
6
0.5
0
84
86
97
92
6
4
2
3-Thienyl-B(OH)
2
1
c
4
c
4-ClC
4-CF
6
H
4
B(OH)
2
10 min
15 min
5
3
C
6
H
4 2
B(OH)
6
7
8
4-MeOC
6
H
4
B(OH)
2
100
100
100
1
96
81
84
Br
Br
Br
CO H
2
O
O
S
3-Benzothienyl-B(OH)
2
0.5
2
CO H
2
2-MeOC
6
H
H
4
B(OH)
2
2
CO H
2
OH
9
4-MeOC
6
4
B(OH)
100
0.5
78
Br
CO H
2
10
11
12
13
4-BrC
4-BrC
3-BrC
3-BrC
6
H
6
H
6
H
6
H
4
4
4
4
OH
3-HO
2
CC
6
H
4
B(OH)
2
100
100
65
0.5
1
66
88
79
74
d
CHO
3-Thienyl-B(OH)
2
d,e
d,e
CHO
3-MeOC
2-ClC
6
H
4
B(OH)
2
0.5
2
COCH
3
6
H
4
B(OH)
2
65
d
1
1
4
5
3-HO
2
CC
6
6
H
4
4
B(OH)
2
2
50
50
10 min
10 min
86
92
Br
CHO
CHO
S
O
d
3-HO
2
CC
H
B(OH)
Br
Br
d
1
6
3-HO
2
2
CC
6
6
H
4
4
B(OH)
2
2
100
8
82
62
N
OMe
d
1
1
1
2
7
8
9
0
2-BrC
3-BrC
4-BrC
4-BrC
6
6
6
6
H
H
H
H
4
4
4
4
NH
NH
NH
NH
2
2
2
2
3-HO
CC
H
B(OH)
100
100
100
100
0.5
1
d
f
4-MeOC
4-FC
3-F,4-ClC
6
H
4
B(OH)
2
95
d,g
d,g
f
6
H
4
B(OH)
2
0.5
1
91
85
6
H
3
B(OH)
2
a
b
c
d
e
f
0
1
mmol of Ar-Br, 2 mL of water, 2 mmol of K
Isolated yield.
0 mmol scale, 0.001 mol % of 1.
2
CO , 1.05 mmol of Ar -B(OH)
3
2
2
, 0.1 mol % of PdCl –EDTA, Ar.
5
In the presence of 1 mol % of n-Bu
In methanol–water (2:1) mixture.
As hydrochloride.
4
NBr.
g
0.01 mol % of 1.
For preparative scale synthesis, the catalyst amount can
be reduced to a 0.001 mol % level without a noticeable
decrease in activity. For instance, 4-bromobenzoic acid
reacted with 4-trifluoromethylphenyl- and 4-chloro-
phenylboronic acids (entries 4 and 5) in 10–15 min with
turnover numbers (TON) up to 97,000 and turnover
groups gave the coupled products in high yields (entries
12–15) at 50–65 ꢀC in 10–30 min. Reactions of aryl-
boronic acids, which are unstable to protodeboration
were carried out in aqueous methanol (entries 12 and
13).
ꢀ
1
frequencies (TOF) up to 582,000 h
.
Reactions of electron-rich bromoanilines proceeded at
high temperature (entries 19 and 20). These reactions
may also be carried out at lower catalyst loading.
4-Bromoaniline reacted at 100 ꢀC in 85–91% yields in
0.5–1 h at a 0.01% loading of complex 1, corresponding
to 8500–9100 TON.
Reactions of water-insoluble aryl bromides also pro-
ceeded in water without an organic co-solvent in the
presence of 0.1 mol % of complex 1 and 1 mol % of
Bu NBr. Aryl bromides with electron-withdrawing
4

5754
D. N. Korolev, N. A. Bumagin / Tetrahedron Letters 46 (2005) 5751–5754
This catalytic system is highly tolerant to a broad range
of functional groups. The cross-couplings proceeded
smoothly to give the products in good yields even in
the presence of very sensitive groups, such as CHO,
2. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun.
981, 11, 513–519.
. (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998,
7, 3387–3388; (b) Shae, B. L.; Perera, S. D. Chem.
1
3
3
Commun. 1998, 1863–1864; (c) Wolfe, J. P.; Buchwald, S.
L. Angew. Chem., Int. Ed. 1999, 38, 2413–2416; (d) Littke,
A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
MeCO, COOH, NH , and OH without any protection.
2
In addition to substituted aryl iodides and bromides,
the coupling reactions with heterocyclic halides also
led to the formation of the desired products in high
yields (Table 2, entries 6–8, 14–16). It is also noteworthy
that these reactions can be performed in a short reaction
time with low catalyst loadings. As a result, this new cat-
alytic system provides an easy, quick, and convenient
protocol for Suzuki–Miyaura reactions.
4
020–4028; (e) Feuerstein, M.; Laurenti, D.; Bougeant, C.;
Doucet, H.; Santelli, M. Chem. Commun. 2001, 325–326;
(f) Shaughnessy, K. H.; Booth, R. S. Org. Lett. 2001, 3,
2757–2759; (g) Yin, J.; Rainka, M. P.; Zhang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1162–
1163; (h) Nishimura, M.; Ueda, M.; Miyaura, N. Tetra-
hedron 2002, 58, 5779–5787.
4
. (a) Li, G. Angew. Chem., Int. Ed. 2001, 40, 1513–1516; (b)
Li, G. J. Org. Chem. 2002, 67, 3643–3650; (c) Bedford, R.
B.; Hazelwood, S. L.; Limmert, M. E.; Albisson, D. A.;
Draper, S. M.; Scully, P. N.; Coles, S. J.; Hursthouse, M.
B. Chem. Eur. J. 2003, 9, 3216–3227.
In summary, PdCl –EDTA was found to be an effective
2
catalyst for the Suzuki–Miyaura cross-coupling. It is
inexpensive, air-stable, and easy to prepare. A new cat-
alytic system (K CO or KOH in water or in H O–
2
3
2
5. Beller, M.; Fischer, H.; Herrmann, W. A.; Ofele, K.;
Krobmer, C. Angew. Chem., Int. Ed. 1995, 34, 1848–
1849.
6. (a) Weskamp, T.; Bohm, V. P. W.; Herrmann, W. J.
Organomet. Chem. 1999, 585, 348–352; (b) Zhang, C.;
Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem.
MeOH) provided good conditions for the coupling of
aryl and heteroaryl halides in high yields, and demon-
strated excellent tolerance to a wide range of sensitive
functional groups on both substrates.
1
999, 64, 3804–3805; (c) Bohm, V. P. W.; Gstottmayr, C.
W. K.; Weskamp, T.; Herrmann, W. J. Organomet. Chem.
000, 595, 186–190; (d) Zhang, C.; Trudell, M. L.
Procedure for catalyst preparation. To a 5 mL, 0.1 M
solution of PdCl (0.5 mmol) in distilled water, 0.186 g
2
2
(
and 0.106 g (1 mmol, 2 equiv) of Na CO were added
0.5 mmol, 1 equiv) of EDTA (disodium salt dihydrate)
Tetrahedron Lett. 2000, 41, 595–598; (e) Gstottmayr, C.
W. K.; Bohm, V. P. W.; Herdtweck, E.; Grosche, M.;
Herrmann, W. Angew. Chem., Int. Ed. 2002, 41, 1363–
1365.
2
3
and the mixture stirred to give a yellow-red solution.
The resulting solution can be kept in air for months
without activity reduction.
7. Tao, B.; Boykin, D. W. Tetrahedron Lett. 2002, 43, 4955–
4
957.
. (a) Alonso, D. A.; Najera, C.; Pacheco, M. C. Org. Lett.
000, 2, 1823–1826; (b) Botella, L.; Najera, C. Angew.
Chem., Int. Ed. 2002, 41, 179–181; (c) Solodenko, W.;
Sch o¨ n, U.; Messinger, J.; Glinschert, A.; Kirschning, A.
Synlett 2004, 1699–1702.
8
Typical procedure for cross-coupling reactions. To a
Schlenk vessel, 1 mmol of aryl halide, 2 mL of water,
2
2
arylboronic acid and 0.1 mL (0.01 M) solution of
mmol (0.276 g) of K CO , 1.05 mmol (5% excess) of
2 3
ꢀ
3
PdCl –EDTA (1 · 10 mmol, 0.1 mol %) were added,
2
9
. (a) Weissman, H.; Milstein, D. Chem. Commun. 1999,
1
in that order, under argon. In the case of water-insoluble
aryl halides, 0.0032 g (1 · 10 mmol, 1 mol %) of n-
Bu NBr was also added to the reaction mixture. The
901–1902; (b) Bedford, B.; Cazin, C. S. Chem. Commun.
001, 1540–1541.
ꢀ2
2
4
10. Grasa, G. A.; Hillier, A. C.; Nolan, S. P. Org. Lett. 2001,
3, 1077–1080.
11. Last review on catalyst systems for Suzuki–Miyaura
reaction: Bellina, F.; Carpita, A.; Rossi, R. Synthesis
mixture was stirred for the time and under conditions re-
quired (Tables 1 and 2). After the reaction was com-
plete, the mixture was acidified. Analytically pure
substances were isolated by filtration through a glass fil-
ter with drying for solids or by extraction with ether fol-
lowed by solvent evaporation for liquids.
2
004, 2419–2440.
1
2. The Pd complexes of simple amines have been reported as
catalysts for Suzuki–Miyaura reactions: Tao, B.; Boykin,
D. W. J. Org. Chem. 2004, 69, 4330–4335, and references
cited therein.
1
3. (a) Bumagin, N. A.; Bykov, V. V.; Beletskaya, I. P. Bull.
Acad. Sci. USSR, Div. Chem. Sci. 1989, 38, 2206; (b)
Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59, 5034–
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
5
037; (c) Campi, E. M.; Jackson, W. R.; Marcuccio, S. M.;
Naesland, C. G. M. Chem. Commun. 1994, 2395; (d)
Moreno-Manas, M.; Pajuelo, F.; Pleixats, R. J. Org.
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V. Tetrahedron 1997, 53, 14437–14450; (f) Badone, D.;
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Chem. 1997, 62, 7170–7173; (g) Bumagin, N. A.; Korolev,
D. N. Tetrahedron Lett. 1999, 40, 3057–3060, For
recent applications of ligandless Pd catalysts see also
Ref. 11.
2
005.06.085.
References and notes
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1
1
1
1
995, 95, 2457–2483; (b) Stanforth, S. P. Tetrahedron
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Neorgan. Khim. 1965, 10, 2657–2663.
D. Tetrahedron 2002, 58, 9633–9695.