Palladium-catalyzed Suzuki-Miyaura reaction using aminophosphine as ligand

Article abstract of DOI:10.1016/S0040-4039(03)01743-X

Suzuki-Miyaura cross-coupling reaction has been achieved under the catalysis of Pd(OAc)₂ in the presence of readily accessible and easily tunable aminophosphine ligands with high efficiency under mild reaction condition.

Full text of DOI:10.1016/S0040-4039(03)01743-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7095–7098
Palladium-catalyzed Suzuki–Miyaura reaction using
aminophosphine as ligand
Jiang Cheng,b Feng Wang,a Jian-Hua Xu,b Yi Panb and Zhaoguo Zhanga,*
aState Key laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
bDepartment of Chemistry, Nanjing University, 22 Hankou Road, Nanjing 210093, China
Received 16 May 2003; revised 17 June 2003; accepted 4 July 2003
Abstract—Suzuki–Miyaura cross-coupling reaction has been achieved under the catalysis of Pd(OAc)2 in the presence of readily
accessible and easily tunable aminophosphine ligands with high efficiency under mild reaction condition.
© 2003 Elsevier Ltd. All rights reserved.
Palladium-catalyzed cross-coupling reactions between
aryl (alkenyl) halides or triflates and organometallic
reagents (Mg, Sn, B, Zn, Li, Zr, etc.) have been devel-
oped as a versatile and efficient method for a variety of
synthetic transformations.1 Among these reactions, pal-
ladium-catalyzed cross-coupling reaction between aryl
halides and aryl boronic acids, known as Suzuki–
Miyaura reaction, is highly valuable for the synthesis of
symmetrical and unsymmetrical biaryls.2–4 There have
been a number of protocols to achieve an efficient
Suzuki–Miyaura reaction, however, the utilization of
expensive bases, solvents, scarce or difficult-handling
ligands made the reaction not practical. The growing
demand for a practical and efficient Suzuki–Miyaura
reaction has yielded many recent achievements in lig-
ands design and synthesis. For example, the bulky
electron-rich phosphine ligands,5 phosphites,6 and N-
heterocyclic carbenes7 were used in Suzuki–Miyaura
reaction.
There are three elementary reactions involved in
Suzuki–Miyaura reaction, i.e. oxidative addition,
transmetallation, and reductive elimination. Oxidative
addition is usually the rate-determining step in cross-
coupling reactions,10 thus, electron-rich phosphine lig-
ands are usually needed to make the transition metal
easily oxidized. Based on the above discoveries, we
studied monoaminophosphines and diaminophosphines
as electron rich ligands for cross-coupling reactions
(Scheme 1).
Ligand 1 and 2 could be easily made from the corre-
sponding commercially available amines and phenyl
chlorophosphines according to the literature (See sup-
porting information).11 We first used 1a as ligand to
test the cross-coupling reaction between 4-bromoanisole
(3a) and phenyl boronic acid (4a) and 5aa was isolated
in 84% yield after 24 h in refluxing THF (entry 1, Table
1).
Trivalent aminophosphines, which contained one or
more PꢀN bonds, have not been used so widely as
ligand in transition metal catalyzed cross-coupling reac-
tions.8 A few reports on the coordination chemistry of
aminophosphine compounds revealed that the function
of amino groups was more diversified than alkoxy
groups in phophites:9 In mono- and di-aminophosphi-
nes, alkyl and/or aryl amino groups served as strong
electron-donating groups, making the phosphines
stronger s-donor ligands.
The ligand showed good reactivity toward Suzuki–
Miyaura reaction. Since bromoanisole is electron-rich
* Corresponding author. Tel.: 86-21-64163300-3435; fax: 86-21-
64166128; e-mail: zhaoguo@mail.sioc.ac.cn
Scheme 1. Aminophosphine ligands.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01743-X

7096
J. Cheng et al. / Tetrahedron Letters 44 (2003) 7095–7098
Table 1. Base effect in Suzuki–Miyaura reactiona
Table 2. Pd(OAc)2-Ph2PNPri2 catalyzed Suzuki–Miyaura
reactiona
Entry
Base
Reaction time (h)
Yield (%)b
1
2
3
4
5
6
7
8
KF
NaOAc
Et3N
K3PO4·3H2O
Na2CO3
K2CO3
NaOBut
No base
24
24
24
24
7
4
7
24
84c
31c
32c
73c
85d
97d
85d
24c
Entry
3
4
5
Yield (%)b
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3b
3b
3b
3c
3d
3e
3e
3f
4a
4b
4c
4d
4e
4a
4b
4c
4a
4a
4a
4b
4a
4a
5aa
5ab
5ac
5ad
5ae
5ba
5bb
5bc
5ca
5da
5ea
5eb
5fa
5ga
97
– (97)
89 (78)
80 (73)
95
94
86
– (99)
98 (79)
99
a Bromoanisole (1 mmol), phenyl boronic acid (1.5 mmol), base (3
mmol), Pd(OAc)2 (0.025 mmol), 1a (0.075 mmol), THF (3 mL),
reflux.
b Isolated yield.
c Bromoanisole was not completely consumed.
d Bromoanisole was consumed.
9
10
11
12
13
14
93
93c
and is usually difficult to be activated in cross-coupling
reactions, the ligand seems to be applicable to both
electron-rich and electron-deficient aryl bromides. The
choice of a base usually is important in achieving an
efficient cross-coupling reaction. We therefore screened
different bases and the results are summarized in Table
1. The widely used bases, such as KF, K3PO4·3H2O,
Na2CO3 and K2CO3 had remarkable effect in the cou-
pling reaction (entries 1, 4–6, Table 1), and K2CO3 was
the best among the bases. Stronger base was not neces-
sary in the reaction (entry 7, Table 1).
94
3g
99d
a Aryl bromide (1 mmol), aryl boronic acid (1.5 mmol), K2CO3 (3
mmol), Pd(OAc)2 (0.025 mmol), 1a (0.075 mmol), THF (3 mL),
reflux for 12 h.
b Isolated yield (isolated yield if the reaction was run at room
temperature for 24 h.
c Pd2(dba)3 was used.
d Reaction time, 48 h.
determining step. Changing the catalyst to Pd2(dba)3-
1a, we could obtain excellent yield from the reaction of
2,6-dimethyl phenyl bromide and 2-methylphenyl
boronic acid (entry 12, Table 2). The catalytic system
showed good reactivity and high efficiency and the
reactions proceeded smoothly even at room tempera-
ture, giving biaryls 5 in good to excellent yields (entries
2–4, 8, 9, Table 2). Using less reactive aryl bromide,
such as 4-bromanisole, a TON (turn over number) of
8,600 could be obtained after 24 h in refluxing THF.13
Screening of palladium precursors in the presence of 1a
showed that Pd(OAc)2-1a was superior to other combi-
nations (Table 2). Although other ligands also showed
good reactivity and gave high yields (for 1b, 86%; 1c,
87%) when Pd(OAc)2 was used as catalyst precursor,
they are not so air-stable as 1a (no significant change
occurred when 1a was exposed to air for 3 days).
As expected, both electron-rich and electron-deficient
aryl bromides were applicable for this reaction. Highly
electron-rich aryl bromide, such as 5-bromo-benzo-
[1,3]-dioxole (3d), could be used as a substrate to give
excellent yield (entry 10, Table 2); electron-deficient aryl
bromides, such as 4-bromobenzaldehyde, worked also
well (entry 13, Table 2). When 2,6-dimethyl phenyl
bromide and 2-methylphenyl boronic acid were
employed as substrates, the reaction could not be com-
pleted after 12 h. However, if phenyl boronic acid was
used, the coupling proceeded smoothly to give the
desired reaction product with excellent yield (entry 11,
Table 2). This implies that the activation of bulky aryl
bromides with the catalytic system was not problematic,
and the rate-limiting step occurred after the oxidative
addition, so that transmetallation might be the rate-
When aryl chloride 3h was employed, the reaction
underwent sluggishly under the catalysis of 2.5 mol%
Pd(OAc)2 and 1. The yield of biaryl 5ha did not exceed
40% after 12 h in refluxing THF (Scheme 2). This could
be ascribed to the retardation of the oxidative addition,
since the transmetallation rate for the species (ArPdCl)
with phenyl boronic acid is decreasing in the order of
Cl>Br>I12 while the reductive elimination should be
similar.
To improve the reactivity for the activation of aryl
chloride, one easy way is to increase the electron den-
sity of the phoshpine ligand to make the oxidative step
more favorable. As reported in the literature,8a,d
a
second amino group also serves as an electron donating

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Scheme 2. Suzuki–Miyaura reaction with activated aryl chlo-
ride.
functional group. The introduction of the second amino
group might therefore improve the electron density of
the phosphorus atom of the phosphine ligand. In light
of this argument, bis(dialkylamino)phenyl phosphine
2a–c were made to test the reactivity.
Unexpectedly, when 2a was used as the ligand to
perform the coupling reaction outlined in Scheme 2, the
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not complete after 12 h of refluxing in THF, and the
product was isolated in 23% yield with unreacted 4-
chlorobenzaldehyde. However, under the same reaction
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reactivity was greatly improved, giving the product 5ha
with yields of 67 and 88%, respectively.
In summary, we have developed a new type of easily-
prepared aminophosphine ligands in the Suzuki–
Miyaura
coupling
reaction.
The
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Acknowledgements
We thank the National Natural Science Foundation of
China, Chinese Academy of Sciences, and the Science
and Technology Commission of Shanghai Municipality
for financial support.
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reaction tube was charged successively with THF (3 mL),
K2CO3 (414 mg, 3 mmol), Pd(OAc)2 (5.6 mg, 0.025
mmol), 1a (21.4 mg, 0.075 mmol), aryl bromide (1 mmol)
and aryl boronic acid (1.5 mmol) under a nitrogen atmo-
sphere. The reaction mixture was refluxed for 12 h or
stirred at room temperature (20–24°C) for 24 h. After the
removal of the solvent, 20 mL of ether and 10 mL of
water were added, the organic layer was separated and
the water phase was extracted twice with ether (2×10 ml).
The combined organic extract was dried over anhydrous
sodium sulfate. After evaporation of the solvent, the
residue was purified by flash chromatography (hexane or
hexane–ethyl acetate) to afford the pure desired product.
13. A general procedure was as follows: A degassed Schlenk