A convenient oxime-carbapalladacycle-catalyzed suzuki cross-coupling of aryl chlorides in water

Article abstract of DOI:10.1002/1521-3773(20020104)41:1<179::AID-ANIE179>3.0.CO;2-O

Refluxing water is a good solvent for the coupling reactions of aryl and heteroaryl chlorides with phenylboronic acid (seescheme; FG = functional group). The reactions use oxime-derived palladacycles 1 as thermally stable catalysts, potassium carbonate as base, and tetrabutylammoniumbromide (TBAB), and can be carried out in the presence of air.

Full text of DOI:10.1002/1521-3773(20020104)41:1<179::AID-ANIE179>3.0.CO;2-O

COMMUNICATIONS
base (2equiv), and tetrabutylammonium bromide (TBAB,
A Convenient Oxime-Carbapalladacycle-
Catalyzed Suzuki Cross-Coupling of Aryl
Chlorides in Water**
0
.5 equiv) in refluxing water (Method A). After 2h, it was
found that palladacycles 1 were very effective catalysts under
these conditions, and gave high turnover numbers (TON;
Luis Botella and Carmen N a¬ jera*
À1
up to 7700) and turnover frequencies (TOF; up to 3850h )
Table 1, entries 1 ± 3), whereas no reaction or very low
conversions were obtained with Li PdCl or Pd(OAc)2,
(
The importance of biaryl units[1] as components of many
kinds of compounds, mainly pharmaceuticals, herbicides, and
natural products, as well as in the field of engineering
materials, such as conducting polymers, molecular wires, and
liquid crystals, has attracted enormous interest from the
chemistry community. Palladium- and nickel-catalyzed Suzu-
ki ± Miyaura cross-coupling[ is the most important and
efficient strategy for the construction of unsymmetrical biaryl
compounds. This cross-coupling methodology allows the use
of organic solvents and inorganic bases, tolerates many
functional groups, is not affected by steric hindrance of the
substrates, and is suitable for industrial processes.[3] From the
industrial point of view, some important goals need to be
realized for the development of this process: the functional-
2
4
respectively (Table 1, entries 4 and 5). For room temperature
coupling reactions it was necessary to use methanol/water
(
3:1), higher catalyst loading (1 mol% of palladium), KOH
base (2equiv), and TBAB (1 equiv) (Method B). Under these
conditions after 18 h, up to 50% yield was observed with
2]
palladacycles 1, whereas Pd(OAc) gave less than 2% yield
2
(
Table 1, entries 6 ± 9).
Table 1. Reaction conditions and catalyst studies on the Suzuki coupling of p-
chloroacetophenone and phenylboronic acid.
PdII
3
CH CO
Cl
+
B(OH)2
3
CH CO
Method A or B
[
4]
ization of inexpensive and readily accessible aryl chlorides
Entry Method[a] Catalyst (mol% Pd) t (h) Yield (%)[b] TON TOF hÀ1
and the use of water[ as a safe and inexpensive solvent.
Furthermore, to avoid an inert atmosphere, air-stable, effi-
cient, and nontoxic catalysts are desired. The activation of
both electron-deficient and electron-rich aryl chlorides has
been achieved by palladium complexes in the presence of
5]
1
2
3
4
5
6
7
8
9
A
A
A
A
A
B
B
B
B
1a (0.01)
1b (0.01)
1c (0.01)
Li PdCl (0.01)
2 4
Pd(OAc)
1a (1)
1b (1)
1c (1)
Pd(OAc)
269
277
269
2±
25
18
18
6900
7700
6900
±
3450
3850
3450
±
2
43
50
2
(0.01)
500 50
43
50
2.4
2.8
[
6]
[7]
expensive and toxic phosphanes, phosphites, phosphane
[8]
[9]
oxides, palladium N-heterocyclic carbene complexes, and
.3
18 2 4242
18 1.5
palladium on carbon.[ However, palladacycles have only
10]
[11]
(1)
1.5
0.008
2
been used in the case of electron-deficient aryl chlorides.[
12]
[
a] Method A: p-chloroacetophenone (2mmol), PhB(OH)
2
(3 mmol), K CO
2 3
Cross-coupling reactions with organoboranes are carried out (4 mmol), TBAB (1 mmol), water (7 mL), 1008C; Method B: p-chloroacetophe-
(3 mmol), KOH (4 mmol), TBAB (2mmol), meth-
in a mixture of an organic solvent and an aqueous inorganic none (2mmol), PhB(OH)
2
anol/water (3:1, 8 mL), room temperature. [b] Determined by means of GC,
based on the aryl chloride.
base, generally under an inert atmosphere. In neat water, only
sodium tetraphenylborate has been employed in the case of
[13]
aryl chlorides, with PdCl (3 mol%) as catalyst. Herein we
2
describe that oxime-derived palladacycles[ are air- and
14]
In both methods, the presence of TBAB[16, 17] was crucial to
enhance the rate of the coupling, presumably because of the
water-stable catalysts that are
suitable for cross-coupling dif-
ferent aryl and heteroaryl chlor-
ides with boronic acids in neat
water.
Different palladacycles and
À
‡ [18]
R1
formation of PhB(OH) Bu N .
3
4
The catalyst 1b was
deactivated after the third cycle, when the coupling in water
(Method A) was carried out in 1-h intervals (0.1 mol%
catalyst): 99%(first and second cycle), 75% (third cycle),
and 46% (fourth cycle).
The cross-coupling reactions with different aryl and heter-
oaromatic chlorides were studied with complex 1b as catalyst
N
OH
)2
R2
Pd
Cl
1
2
palladium salts were initially
tested as possible candidates to
study their catalytic activity on a
model coupling reaction be-
tween phenylboronic acid and
1
1
1
a; R = CH3, R = H
1
2
b; R = CH3, R = OH
1
2
c; R = p-HOC6H4, R = OH
(
2
Table 2, Method A). For the synthesis of 4'-methylbiphenyl-
-carbonitrile, an intermediate in the preparation of angio-
tensin II receptor antagonists such as DuP753 and other
antihypertensive drugs, 2-chlorobenzonitrile was coupled with
p-tolylboronic acid (Table 2, entry 3).
For less reactive aryl chlorides, the catalyst loading and the
amount of TBAB was increased to accelerate the reactions
p-chloroacetophenone (Table 1). New oxime palladacycles 1b
and 1c with hydroxy substituents on the aromatic ring were
prepared by palladation with lithium tetrachloropalladate, as
described for 1a.[ We have established the most efficient
reaction conditions: palladium catalyst (0.01 mol%), K CO
15]
2
3
(
Table 2, entries 4 ± 9, 12, and 13). Biaryl/acetic acids have
applications in the pharmaceutical industry as well as in
materials science[ and have been prepared recently by
means of a Suzuki reaction on a multigram scale by using Pd/C
21]
[
*] Prof. Dr. C. N a¬ jera, Dipl.-Chem. L. Botella
Departamento de QuÌmica Org a¬ nica, Universidad de Alicante
Apartado 99, 03080 Alicante (Spain)
Fax : (‡34)965-903-549
**] This work was supported by the DGES of the Spanish Ministerio de
Educaci o¬ n y Cultura (MEC) (PB97-0123). L.B. thanks the Generalitat
Valenciana for a predoctoral fellowship.
(
3 mol%) in refluxing isopropyl alcohol/water for four
[22]
days. Similar reaction conditions were employed for the
[
[23]
synthesis of p-aryl mandelic acids. We found that biphenyl-
acetic acid and p-phenylmandelic acid could be prepared for
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179

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Table 2. Suzuki coupling of aryl chlorides and aryl boronic acids in water with 1b as catalyst.
Entry
ArCl
mol% Pd
TBAB(equiv)
t
Product
Yield (%)[a]
100 (98)
1
0.1
0.5
1 h
CH3CO
Cl
Cl
3
CH CO
2
3
0.01
0.1
0.5
0.5
2.5 h
91
69
CH3CO
3
CH CO
Cl ‰bŠ
2d
2
CN
CN
Cl
4
5
1
1
1
h
27
57
CHO
CHO
Cl
1[c]
32
h
CHO
CHO
4
0
6
7
1
1
1
1
6 h
CH3O
H2N
Cl
CH3O
H2N
6 h
83
Cl
Cl
Cl
8
9
1
1
1
1
2.5 h
2.5 h
50
HO2C
CO2H
HO
OH
42[d]
HO2C
2
CO H
Cl
Cl
1
0
1
1
0.5
0.5
3 h
3 h
92
60
N
N
N
1
0.1
N
MeO
O2N
MeO
1
1
2
3
1
1
1
4 h
1 h
76 (43)
Cl
O2N
Ph
N
N
N
Cl
Cl
Ph
‰eŠ
0.1
100 (92)
O
O
N
N
N
Me
Me
[
[
a] Determined by means of GC, based on the aryl chloride; yields in parenthesis are those of purified products. [b] p-Methylphenylboronic acid was used.
1
c] Method B was used. [d] Determined by means of H NMR spectroscopy. [e] PhB(OH)
2
(2equiv) was used.
the first time from the corresponding chlorides instead of
from the bromides in only 2.5 h in refluxing water (Table 2,
entries 8 and 9). Heteroaryl chorides, such as chloropyridines
CH3CO
Cl
1b (10 mol% Pd)
+
CH3CO
CH3
(1)
(
Table 2, entries 10 ± 12) and 2-methyl-4,5-dichloro-3(2H)pyr-
K CO , TBAB,
H2O, ∆, 4 h
2
3
CH3
B
[24]
(81%)
idazinone (Table 2, entry 13) were transformed efficiently
into the corresponding biaryl compounds. These reaction
conditions for the large-scale synthesis of pyridazinones,
which exhibit agrochemical and pharmaceutical activities, are
more convenient than the previously described syntheses,
which use Pd(PPh ) (3 mol%) in refluxing toluene under a
N atmosphere.
The cyclic anhydride trimethylboroxine (TMB) has been
used recently for the Pd(PPh ) -catalyzed (10 mol%) meth-
O
O
B
B
H3C
O
CH3
3
4
The Suzuki Pd(PPh ) -catalyzed method has also been
3 4
[24]
2
extended to the coupling of benzyl bromides and iodides with
aryl boronic acids in refluxing EtOH/dimethoxyethane/water
for 18 h under argon.[ Oxime-derived palladacycle 1b was
an effective catalyst for the coupling of benzylic chlorides with
phenylboronic acid. Benzyl chloride and 3-methoxybenzyl
chloride reacted with phenylboronic acid at room temper-
ature with low loading of catalyst (0.1 mol% Pd) to give
diarylated methanes in 66 and 75% yield, respectively
26]
3
4
ylation of electron-deficient aryl chlorides in refluxing
[25]
aqueous dioxane (10%) under nitrogen. The use of TMB
for the cross-coupling of 4-chloroacetophenone in refluxing
water and with complex 1b as catalyst (Method A) afforded
4
-methylacetophenone in 81% yield after 4 h [Eq. (1)].
180
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1433-7851/02/4101-0180 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 1

COMMUNICATIONS
[
Eq. (2)]. The best conditions for this reaction were similar to
Tetrahedron Lett. 1999, 40, 3855 ± 3858; g) X. Bei, H. W. Turner,
W. H. Weinberg, A. S. Guram, J. L. Petersen, J. Org. Chem. 1999, 64,
those for Method B: KOH as base and acetone/water (3:2) as
solvent. When the reaction was carried out in refluxing water,
considerable amounts of alcohols were formed.
6
797 ± 6803; h) F. Firooznia, C. Gude, K. Chan, Y. Satoh, Tetrahedron
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[
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Cl
1
b (0.1 mol% Pd)
+
B(OH)2
(2)
KOH, TBAB, RT
acetone/H2O (3:2)
[9] a) A. F¸rstner, A. Leitner, Synlett, 2001, 290 ± 292; b) C. Zhang, M. L.
Trudell, Tetrahedron Lett. 2000, 41, 595 ± 598; c) V. P. W. Bˆhm,
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Chem. 1998, 557, 93 ± 96.
R
R
R = H, 66% (3 d)
R = CH3O, 75% (19 h)
In summary, we have found that different types of Suzuki ±
Miyaura couplings can be carried out in water in the presence
of TBAB with activated and deactivated aryl or heteroaro-
matic chlorides as well as benzylic chlorides by means of
stable and easily available oxime-derived palladacycles.
Degassing of the solvent or inert atmosphere were unneces-
sary and other factors, such as the cost and stability of the
catalyst and the water medium make this green methodology
more useful than others recently described. All these features
are very appropriate for industrial environmentally friendly
processes. The accessibility and structural versatility of these
palladacycles render very promising catalysts and further
studies in the applicability of these systems in other organic
transformations are currently under investigation.
[
10] C. R. LeBlond, A. T. Andrews, Y. Sun, J. R. Sowa, Jr., Org. Lett. 2001,
3
, 1555 ± 1557.
[
11] For a recent review, see: J. Dupont, M. Pfeffer, J. Spencer, Eur. J.
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14] Oxime-derived palladacycles have been used as efficient catalysts in
Heck, Suzuki, Stille, Sonogashira, and homocoupling reactions of aryl
iodides and bromides: D. A. Alonso, C. N a¬ jera, M. C. Pacheco, Org.
Lett. 2000, 2, 1823 ± 1826.
[
[
[
15] H. Onoue, K. Minami, K. Nakagawa, Bull. Chem. Soc. Jpn. 1970, 43,
3
480 ± 3485.
[16] Palladium-catalyzed cross-coupling reactions can be performed in
water in the presence of tetralkylammonium salts: T. Jeffery,
Tetrahedron Lett. 1994, 35, 3051 ± 3054.
Experimental Procedure
[
17] Tetrabutylammonium bromide has been used in the cross-coupling of
aryl bromides[ and b-chloroacroleins with boronic acids in water
18]
[19]
A solution of aryl chloride (2mmol), PhB(OH)
(
compound 1b (0.01 to 1 mol% Pd, see Tables 1 and 2) in water (7 mL) was
heated at reflux. To measure the conversion of the reaction, a sample was
2 2 3
(0.37 g, 3 mmol), K CO
0.55 g, 4 mmol), tetrabutylammonium bromide (0.64 g, 2mmol), and
as well as of electron-deficient aryl chlorides by means of Pd(OAc)
2
in
DMF.[
20]
[
18] D. Badone, M. Baroni, R. Cardamone, A. Ielmini, U. Guzzi, J. Org.
Chem. 1997, 62, 7170 ± 7173.
19] S. Hesse, G. Kirsch, Synthesis, 2001, 755 ± 758.
2
taken from the cooled mixture and washed with H O and EtOAc.
[
[
Subsequently the cooled reaction mixture was extracted with EtOAc, the
organic phase was dried and evaporated under vacuum, and the crude
product was purified by recrystallization or by chromatography on
silica gel.
20] D. Zim, A. L. Monteiro, J. Dupont, Tetrahedron Lett. 2000, 41, 8199 ±
8
202.
[
21] a) 4-Biphenylacetic acid (felbinac) and 2-ethyl-4-biphenylacetic acid
with dimethylaminoethanol (namoxyrate) are anti-inflammatory and
analgesic drugs, respectively: USP Dictionary of USAN and Interna-
tional Drugs Names 98, U.S. Pharmacopeia, Rockville, 1997; b) 4-
biphenylacetamides have been used as mesogenic arms in porphyrin
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M. Bernitz, A. Natt, R. Newmann, J. Am. Chem. Soc. 1992, 114, 3612±
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[23] U. C. Dyer, P. D. Shapland, P. D. Tiffin, Tetrahedron Lett. 2001, 42,
1765 ± 1767.
Received: August 28, 2001 [Z17804]
[
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9
5, 2457 ± 2483.
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Angew. Chem. Int. Ed. 2002, 41, No. 1
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4101-0181 $ 17.50+.50/0
181