A convenient and efficient palladium-catalyzed system for cross-coupling of aryl bromides with active methylene compounds

Article abstract of DOI:10.1055/s-2003-41429

A simply catalytic system containing palladium-phosphine complex, generated in situ from PdCl₂/tert-phosphino ligand in pyridine, has been systematically studied in the cross-coupling of bromobenzene with malononitrile or ethyl cyanoacetate anion. The effect of molar ratio of phosphine ligand to PdCl₂ on the activity of the coupling was also discussed. It is found that the catalytic system has highly catalytic activity to produce aryl malononitriles and cyanoacetates in considerable yields (67-90%) when the substituted aryl bromides were used as substrates.

Full text of DOI:10.1055/s-2003-41429

1716
LETTER
A Convenient and Efficient Palladium-Catalyzed System for Cross-Coupling
of Aryl Bromides with Active Methylene Compounds
Convenient and
E
h
fficient Pall
e
adium-Cata
n
lyze
d
Systemgwei Gao, Xiaochun Tao, Yanlong Qian, Jiling Huang*
Laboratory of Organometallic Chemistry, East China University of Science and Technology, Shanghai 200237, P. R. China
E-mail: qianling@online.sh.cn
Received 3 June 2003
CN
Y
CN
Y
PdCl2 / PR3, NaH
Abstract: A simply catalytic system containing palladium-phos-
phine complex, generated in situ from PdCl2/tert-phosphino ligand
in pyridine, has been systematically studied in the cross-coupling of
bromobenzene with malononitrile or ethyl cyanoacetate anion. The
effect of molar ratio of phosphine ligand to PdCl2 on the activity of
the coupling was also discussed. It is found that the catalytic system
has highly catalytic activity to produce aryl malononitriles and cy-
anoacetates in considerable yields (67–90%) when the substituted
aryl bromides were used as substrates.
Ar
Br
CH2
Ar
CH
Pyridine, 85 °C, 12h
2 a–g
3 a–g
2, Y = CN
3, Y = CO2Et
1
Scheme 1
Now we herein report the palladium-catalyzed C-C bond
coupling of aryl bromides with active methylene com-
pounds using a simple catalytic system13 of Pd(II) chlo-
ride and tertiary phosphine ligand in pyridine. Our initial
experiments were carried out starting from the coupling of
bromobenzene with malononitrile as a model14 by directly
using catalytic amounts of PdCl2 (1 mmol%) and triphe-
nylphosphine ligand (TPP, 3 mol%) (Scheme 1). Phenyl-
malononitrile, the reaction product, was obtained in
satisfactory yield in the presence of sodium hydride at 85
°C (Table 1, entries 5 and 6). Obviously, without the pres-
ence of PdCl2 and phosphine ligand, the target product
was not detected (Table 1, entries 1–3). In addition, when
the amount of PdCl2 was increased by two times, the yield
was not enhanced evidently (Table 1, entry 6, 89% yield).
But when its amount was cut down to 0.5 mol%, the yield
was sharply decreased to 45% (Table 1, entry 4). When
employing tetrahydrofuran instead of pyridine as solvent,
it only afforded 24% yield (Table 1, entry 7). Obviously,
pyridine as solvent possibly plays an important role in
promoting the formation of the catalytic species.
Key word: palladium catalysis, cross-coupling, arylmalononitrile,
arylcyanoacetate, aryl bromide
Transition metal-catalyzed cross coupling reaction is a
key tool of carbon-carbon bond formation in organic
synthesis.1 Since the 1980s’, metal-mediated synthesis of
a-arylmalononitriles and a-aryl-b-cyanoacetates has at-
tracted a lot of interests due to their use as important inter-
mediates in the preparation of organic compounds like
bioactive materials,2 heterocyclic compounds,3 and or-
ganic conducting materials.4 After Suzuki et al.5 reported
the cross-coupling of aryl iodides with malononitrile or
cyanoacetate anion by using copper(I) iodide as catalyst,
several successful preparations of arylmalononitriles and
arylcyanoacetates by the catalytic cross-coupling of aryl
halides using PdCl2(PPh3)2,6 Pd(PPh3)4,7 Cu(I) salts8 and
PdCl2(PPh3)2/dppe9 as catalysts have been reported in sat-
isfactory yield. Cristau et al. also reported the arylation of
aryl halides with malononitrile catalyzed by 10–20 mol%
of nickel(0) complexes in good yields.10 Generally, the
amounts of the metal catalysts used in the reactions are 4
mol% or more, and sometimes in order to smoothly per-
form the process, some special solvents, such as HMPA,
DMSO and DME are employed.
The effect of the molar ratio of phosphine ligand to metal
palladium (II) on activity of the coupling was also inves-
tigated. As seen in Table 1 (entries 8–13), with the in-
crease of the amounts of triphenylphosphine ligand from
1 mol% to 3 mol%, the yields of catalytic reactions as-
cended from 65% to 88% (entries 8–10). While the ratio
was up to 10 equivalent, the excess ligand led to the de-
crease in the yields of the coupling product to a certain ex-
tent (entry 13). Therefore, the best ratio of phosphine
ligand to PdCl2 is 3:1.
A noteworthy advance in the palladium-catalyzed aryl-
ation of cyanoesters and malonates was made by Hartwig
et al. by using sterically hindered trialkyl- and ferrocenyl-
dialkylphosphine ligands.11 Recently we have reported
that the N-heterocyclic carbene palladium complexes
could effectively promote the arylation of aryl halides
with malononitrile anion in excellent yields.12
To explore the effect of phosphine ligands on the activity,
a series of tertiary phosphine ligands including some
chelating ligands were used in the coupling. The experi-
mental results demonstrated that other tert-phosphine
ligands, like tri-2-methoxyphenyl phosphine (TMPP),
bis(diphenylphosphino) methane(dppm), bis(1,2-diphe-
nylphosphino) ethane (dppe), bis(1,3-diphenylphosphino)
propane (dppp), bis(1,4-diphenylphosphino) butane
(dppb) and bis(diphenylphosphino) ferrocene (dppf),
Synlett 2003, No. 11, Print: 02 09 2003. Web: 25 08 2003.
Art Id.1437-2096,E;2003,0,MM,1716,1718,ftx,en;U10403ST.pdf.
DOI: 10.1055/s-2003-41429
© Georg Thieme Verlag Stuttgart · New York

LETTER
Convenient and Efficient Palladium-Catalyzed System for Cross-Coupling
1717
Table 2 The Reaction of Aryl Bromide with Malononitrile and
Table 1 Effect of Molar Ratio of Ligand TPP to PdCl2 and tert-
Phosphino Ligands on Cross-Coupling of Bromobenzene with Mal-
ononitrile Aniona
Ethyl Cyanoacetate Aniona
Entry
Ar
Product
Yieldb (%)
Entry
1
Ligand (mol%)
None (0)
None (0)
TPP (3)
PdCl2 (mol%)
Yieldb (%)
1
2
C6H5
C6H5
2a (Y = CN)
3a (Y = CO2Et)
88
84
1
0
0
0.5
1
2
1
1
1
1
1
1
1
1
1
1
1
1
1
0
3
4
2-CH3C6H4
2-CH3C6H4
2b (Y = CN)
3b (Y = CO2Et)
73
77
2
0
3
0
5
6
4-CH3C6H4
4-CH3C6H4
2c (Y = CN)
3c (Y = CO2Et)
80
85
4
TPP (1.5)
TPP (3)
45
88
89
24
65
80
88
86
80
70
87
85
87
88
90
86
7
8
2- CH3OC6H4
2- CH3OC6H4
2d (Y = CN)
3d (Y = CO2Et)
75
73
5
6
TPP (6)
9
10
4-CH3OC6H4
4-CH3OC6H4
2e (Y = CN)
3e (Y = CO2Et)
72
75
7c
8
TPP (3)
TPP (1)
11
12
4-F-C6H4
4-F-C6H4
2f (Y = CN)
3f (Y = CO2Et)
73
85
9
TPP (2)
13
14
1-Napthelyl
1-Napthelyl
2g (Y = CN)
3g (Y = CO2Et)
82
67
10
11
12
13
14
15
16
17
18
19
TPP (3)
a Reaction conditions: ArBr:CH2(CN)Y:NaH:PdCl2:PPh3 =
2:2.5:5.4:2%:6%; Pyridine (6 mL), 85 °C for 10–12 hours;
b Isolated yields were based on ArBr after separation of preparative
TLC using silica gel.
TPP (4)
TPP (6)
TPP (10)
TMPP (3)
dppm (3)
dppe (3)
dppp (3)
dppb (3)
dppf (3)
Briefly, we herein provide a convenient and effective pro-
cedure of preparing a-aryl-malononitriles and a-aryl-b-
cyanoacetates by the arylation of aryl bromides with a a-
difunctionalized anion using a convenient and efficient
catalytic system of PdCl2–PAr3. The reaction, simple and
inexpensive, works effectively with low moles of metal
palladium(II) and mild reaction conditions in good yields.
In addition, there is no need to prepare the palladium com-
plex prior to use.
a All reactions were performed in pyridine at 85 °C for 10–12 h;
PhBr:CH2(CN)2:NaH = 1:1.25:2.7.
b Isolated yields were based on ArBr after separation of preparative
TLC using silica gel.
References
c Reacted in THF.
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have similar excellent activity to that of triphenylphos-
phine (TPP) for the coupling under the mentioned reaction
conditions (Table 1, entries 14–19). It indicates that a
broad spectrum of tert-phosphino-ligands could be ap-
plied to this kind of catalytic coupling.
On the basis of the above results, we have tried to extend
the application field of the PdCl2–PPh3 catalysis system to
the preparation of substituted arylmalononitriles and aryl-
cyanoacetates. As seen from Table 2, a series of substitut-
ed aryl bromides could smoothly proceed the catalytic
coupling with a malononitrile anion or an ethyl cyanoace-
tate anion in high efficiency, and the corresponding cou-
pling products of aryl substituted malononitriles or ethyl
cyanoacetates were obtained in good yields of 67–88%
(Table 2, entries 1–14).
Synlett 2003, No. 11, 1716–1718 ISSN 1234-567-89 © Thieme Stuttgart · New York

1718
C. Gao et al.
LETTER
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(13) Preparation of the catalyst in pyridine:
Triphenylphosphine (0.06 mmol) and palladium chloride
(0.02 mmol) were mixed in a predried Schlenk tube under
dry argon. Then 1 mL of dry pyridine was added and the
mixture was stirred at 60 °C for 15 min.
(14) General procedure for the cross-coupling of aryl
bromides with active methylene compounds: Under an Ar
atmosphere to a predried Schlenk tube with 5 mL of dry
pyridine was added a mixture of NaH (5.4 mmol) and
malononitrile or ethyl cyanoacetate (2.5 mmol),
respectively. Following the catalyst (PdCl2/Ligand)13
prepared as described above was injected, and the mixture
was stirred at ambient temperature for 5min. After addition
of an aryl bromide (2 mmol), the mixture was heated at
85 °C for an appropriate time (10–12 h). The progress of the
reaction was monitored by TLC. After removal of the
solvent by distillation in vacuum, the residue was neutralized
with diluted hydrochloric acid (10 mL), and the product was
extracted with 15 mL × 3 diethylether, washed with 2 × 10
mL of brine, dried over Na2SO4, filtered and concentrated.
The residue from the ether extract was purified by TLC
(silica gel GF254, 20 × 20 cm) using a developing solution
of petroleum ether (60–90 °C)/ethyl acetate (6:1 for
arylmolononitriles or 10:1 for aryl ethyl cyanoacetates), and
the fractions containing the products were collected and
extracted with CH2Cl2. The products were obtained after
evaporation of the extract. The arylmolononitriles were
further purified by recrystallization [petroleum ether
(60–90 °C)/CH2Cl2, 6:1]. The products of coupling were
identified by means of 1H NMR and mp, which are in
agreement with literature data.5–11
Synlett 2003, No. 11, 1716–1718 ISSN 1234-567-89 © Thieme Stuttgart · New York