Sustainable Suzuki-Miyaura reaction catalyzed by Pd(OAc)2 immobilized on reversed-phase alumina

Article abstract of DOI:10.1055/s-2008-1032081

Employing Pd(OAc)₂ immobilized on amorphous N,N- diethylaminopropyl alumina, Suzuki-Miyaura coupling of aryl halide with arylboronic acid was realized in 50% aqueous ethanol at room temperature, which enabled repeated use up to four times in 96% average yield and achieved a turnover number of 15 000. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032081

LETTER
611
Sustainable Suzuki–Miyaura Reaction Catalyzed by Pd(OAc)2 Immobilized
on Reversed-Phase Alumina
S
ustainable Suzuk
i
i–Miya
s
ura Reacti
a
on Catalyzhed byPd(OA 2
i
c) ro Hagiwara,*a Keon Hyeok Ko,a Takashi Hoshi,b Toshio Suzukib
a
Graduate School of Science and Technology, Niigata University, 8050, 2-Nocho, Ikarashi, Nishi-ku, Niigata 950-2181, Japan
Fax +81(25)2627368; E-mail: hagiwara@gs.niigata-u.ac.jp
b
Faculty of Engineering, Niigata University, 8050, 2-Nocho, Ikarashi, Nishi-ku, Niigata 950-2181, Japan
Received 22 November 2007
X
Abstract: Employing Pd(OAc)2 immobilized on amorphous N,N-
diethylaminopropyl alumina, Suzuki–Miyaura coupling of aryl ha-
lide with arylboronic acid was realized in 50% aqueous ethanol at
room temperature, which enabled repeated use up to four times in
96% average yield and achieved a turnover number of 15 000.
R1
R2
1
NDEAP-Al2O3-Pd(OAc)2
+
R1
H2O–EtOH (1:1)
K2CO3 (2 equiv)
r.t.
3
Key words: arylations, boron, cross-coupling, heterogeneous ca-
R2
talysis, palladium, supported catalysis
(HO)2B
2
NEt2
Et2N
Suzuki–Miyaura reaction is one of the most versatile and
well-utilized cross-coupling reactions between arylboron-
ic acids and aryl halides, and is catalyzed by palladium to
afford biaryls.1 Its wide applicability to a variety of sub-
strates has enabled its application to the syntheses of var-
ious chemicals such as electrochemicals, pharmaceuticals
and polymers, in which a more mild, efficient and sustain-
able protocol has been desired,2 since palladium catalysts
easily deteriorate by forming clusters. One way to solve
this issue is to immobilize palladium catalyst on solid sup-
port. Shimizu et al.3a and subsequently Crudden et al.3b re-
Si
Si
OMe
O
O
O
O
NDEAP-Al2O3
alumina surface
Scheme 1 Suzuki–Miyaura reaction catalyzed by immobilized
Pd(OAc)2 on reversed-phase alumina
Table 1 Investigation of Optimum Reaction Conditions in the Re-
action of 4-Bromoanisole (1; R1 = 4-MeO, X = Br) and Phenylboronic
Acid (2; R2 = H)a
Entry
Support
Yield (%)b
ported
immobilization
of
palladium
on
mercaptopropylated mesoporous silica gel and its applica-
tion to Suzuki–Miyaura reaction. Recently, during the
course of our investigation, Onaka et al.4 reported the re-
action catalyzed by palladium-loaded alumina, which was
prepared by impregnation of Pd(OAc)2 followed by calci-
nation.
1
polyimino-SiO2
3
24
64
42
63
83
2
ethylenediamino-SiO2
N,N-diethylaminopropyl-SiO2
N,N-diethylaminopropyl-Al2O3
N,N-diethylaminopropyl-Al2O3
N,N-diethylaminopropyl-Al2O3
3
4c
5d
These investigations prompted us to report our indepen-
dent efforts on efficient and sustainable Suzuki–Miyaura
reaction in 50% aqueous ethanol catalyzed by Pd(OAc)2 6e
immobilized on N,N-diethylaminopropyl amorphous alu-
mina (Scheme 1).
a Reaction was carried out at r.t. for 3 h as described in ref. 7 employ-
ing a low-loading catalyst (Pd/silica = 0.025 mmol/g; 0.05 equiv) in
EtOH–H2O (1:1) unless otherwise specified.
b Yield of isolated pure product based on 4-bromoanisole.
c Dioxane–H2O (1:1) was used.
Immobilization of Pd(OAc)2 on amorphous silica gel or
alumina was carried out simply by stirring the suspension
of the inorganic solids in THF solution of Pd(OAc)2. Re-
versed-phase solid supports were prepared by post modi-
fication method.5 After observation of transfer of the color
of Pd(OAc)2 into the solid support, the solvent was evap-
orated to dryness to give an orange-colored silica or alu-
mina. For facile separation of immobilized catalyst after
Suzuki–Miyaura reaction, pellets of supports were em-
ployed. The amount of Pd(OAc)2 loading was adjusted to
d THF–H2O (1:1) was used.
e EtOH–H2O (1:1) was used.
0.1 mmol/g unless otherwise indicated. Pd(OAc)2 could
not be immobilized on normal-phase silica gel by our
method.
The optimized reaction condition was investigated by em-
ploying the reaction of 4-bromoanisole (1; R1 = 4-MeO,
X = Br) with phenylboronic acid (2; R2 = H) in the pres-
ence of 0.05 equivalent of low-loading catalyst (Pd/silica
or alumina = 0.025 mmol/g) in 50% aqueous ethanol, and
SYNLETT 2008, No. 4, pp 0611–0613
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1032081; Art ID: U11707ST
© Georg Thieme Verlag Stuttgart · New York

612
H. Hagiwara et al.
LETTER
Table 2 Reaction of Various Aryl Halides 1 with Various Phenyl-
boronic Acids 2a
Table 3 Recycle of the NDEAP-Al2O3-Pd(OAc)2 Catalyst in the
Reaction of 4-Bromoacetophenone (1; R1 = 4-Ac, X = Br) with
Phenylboronic Acid (2; R2 = H)a
Entrya
1
X
R1
R2
H
H
H
H
H
Time (h) Yield (%)b
Cycle
Time (min)
Yield (%)b
Br 4-HO2C
Br 4-HO
Br 2-Me
4
97
98
92
62
83
98
97
100
94
100
94
82
97
97
74
94
97
1
2
3
4
1
5
97
95
94
96
2
6
3
5
10
30
4c
Br 4-Me
4
5c
Br 4-MeO
3
a Reaction was carried out as described in ref. 7 employing low-load-
ing catalyst (Pd/silica = 0.025 mmol/g; 0.1 equiv).
6
Br 4-EtO2C H
4
b Yield of isolated pure product based on 4-bromoacetophenone (1).
7c
Br 4-Ac
Br 4-Ac
Br 4-Ac
Br 4-Ac
Br 4-Ac
Br 4-Ac
Br 4-O2N
Br 4-Cl
Br 4-H2N
H
1 min
2
8d
2-Me
2,2¢-Me2
4-Ac
Table 4 Performance of the Catalyst in the Reaction of 4-Bromoac-
etophenone and Phenylboronic Acida
9d
2
Entry Catalyst Time
(equiv)
Yield (%)b TON
TOF (h–1)
10
11
12d
13
14
15d
16
17
5 min
20 min
4-MeO
1
2
3
0.005
10 min 100
200
1,200
2,000
3,750
2-furylboronic acid 5
0.0005
1 h
100
75
2,000
15,000
H
H
H
H
H
1
0.00005 4 h
1.5
a Reaction was carried out as described in ref. 7.
b Yield of isolated pure product based on 4-bromoacetophenone (1).
5
I
I
4-Ac
10 min
15 min
The catalyst was reused up to four times in 96% average
yield after decantation of water followed by washing with
water and Et2O, although the catalytic activity gradually
decreased during recycles (Table 3). Leaching of Pd in
combined organic layer after four recycle experiments
was 0.5% by ICP analysis, which means leaching of Pd
during recycle experiments was minimum (vide supra).
This result suggests that the deterioration of the catalytic
activity might be attributable to the formation of Pd clus-
ter inside the immobilized catalyst.
4-MeO
a Reaction was carried out as described in ref. 7.
b Yield of isolated pure product based on aryl halide 1.
c A low loading catalyst (Pd/silica = 0.025 mmol/g, 0.05 equiv) was
used.
d Microwave irradiation (300 W, 80 °C) was employed.
the results are shown in Table 1. The color of the immobi-
lized catalysts turned black soon after the reaction, show-
ing the generation of Pd(0) species. Among various solid
supports investigated, pellets of N,N-diethylaminopropyl
(NDEAP) alumina gave the best result as shown in entry
6. Choice of the reaction medium was critical and 50%
aqueous ethanol was found to be a better solution than
aqueous dioxane or aqueous THF (entries 4–6).6 Leaching
of Pd was determined to be 0.3% by ICP analysis.
The amount of catalyst was successfully reduced to
0.00005 equivalent, which corresponds to a catalyst turn-
over number of 15,000 and turnover frequency of 3,750
(Table 4, entry 3). In entry 3, the reaction was carried out
in a new flask to avoid the possibility of Suzuki–Miyaura
reaction catalyzed by Pd contamination.8
In summary, we have demonstrated efficient, sustainable
and practical Suzuki–Miyaura coupling of aryl halides
with arylboronic acids in 50% aqueous ethanol employing
Pd(OAc)2 immobilized on NDEAP alumina pellets. Im-
mobilization was easily carried out without calcination.
The reaction proceeded without a phosphine ligand at
room temperature in a shorter period of time than in other
reaction conditions. The immobilized catalyst was reused
up to four times in 96% average yield. Although the turn-
over number of the catalyst was not high (TON = 15,000)
compared with the catalyst immobilized with the aid of
the ionic liquid [bmim]PF6 (Pd-SILC, TON = 2,000,000),
the present immobilized catalyst supplements substrate
compatibility of Pd-SILC especially for the syntheses of
sterically demanding biaryls (Table 2, entries 3, 8 and 9).6f
Based on the optimized reaction conditions (Table 1, en-
try 6), the present protocol was applied to a combination
of various aryl halides 1 and boronic acids 2. As shown in
Table 2, aryl halides 1 with not only electron-withdrawing
(entries 6–13) but also electron-donating characters pro-
vided the cross-coupling products 3 in good to excellent
yields. Especially noteworthy was the fact that the reac-
tion of 4-bromoacetophenone terminated instantaneously
(entry 7). Moreover, sterically demanding ortho-substitut-
ed biaryls 3 were obtained in entries 3, 8, and 9. Acidic
(entries 1 and 2) or basic (entry 15) substituents did not
hinder the reaction. Although the reactions of 2-furylbo-
ronic acid and aniline were sluggish, microwave heating
solved this issue as shown in entries 12 and 15.
Synlett 2008, No. 4, 611–613 © Thieme Stuttgart · New York

LETTER
Sustainable Suzuki–Miyaura Reaction Catalyzed by Pd(OAc)2
(5) For our representative efforts in this area, see:
613
Acknowledgment
(a) Hagiwara, H.; Inotsume, S.; Fukushima, M.; Hoshi, T.;
Suzuki, T. Chem. Lett. 2006, 35, 926. (b) Hagiwara, H.;
Isobe, K.; Numamae, A.; Hoshi, T.; Suzuki, T. Synlett 2006,
1601. (c) Hagiwara, H.; Numamae, A.; Isobe, K.; Hoshi, T.;
Suzuki, T. Heterocycles 2006, 68, 889; and earlier
references cited therein.
This work was partially supported by a Grant-in-Aid for Scientific
Research on Priority Areas (17073007 for H.H. and T.H.) from The
Ministry of Education, Culture, Sports, Science and Technology
(MEXT), Japan.
(6) For some selected Suzuki–Miyaura reactions in aqueous
alcohol, see: (a) Marck, G.; Villiger, A.; Buchecker, R.
Tetrahedron Lett. 1994, 35, 3277. (b) Liu, L.; Zhang, Y.;
Xin, B. J. Org. Chem. 2006, 71, 3994. (c) Zhang, G.
Synthesis 2005, 537. (d) Arvela, R. K.; Leadbeater, N. E.;
Collins, M. J. Jr. Tetrahedron 2005, 61, 9349.
References and Notes
(1) (a) Recent reviews: Miyaura, N.; Suzuki, A. Chem. Rev.
1995, 95, 2457. (b) Hassan, J.; Sévignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.
(c) Miyaura, N. Top. Curr. Chem. 2002, 219, 11. (d) Kotha,
S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633.
(e) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41,
4176.
(e) Chanthavong, F.; Leadbeater, N. E. Tetrahedron Lett.
2006, 47, 1909. (f) Hagiwara, H.; Ko, K. H.; Hoshi, T.;
Suzuki, T. Chem. Commun. 2007, 2838.
(7) Typical Experimental Procedure: To a stirred solution of
4-bromoacetophenone (96 mg, 0.48 mmol), 4-acetylphen-
ylboronic acid (110 mg, 0.67 mmol), and K2CO3 (141 mg, 1
mmol) in EtOH (1 mL) and H2O (1 mL) was added NDEAP-
Al2O3-Pd(OAc)2 (256 mg, Pd loading: 0.1 mmol/g alumina,
0.026 mmol). After stirring for 5 min, the product was
triturated with EtOAc several times. The combined organic
layer was evaporated to dryness and the residue was purified
by column chromatography (CH2Cl2–n-hexane, 3:10) to
provide a biaryl product (121 mg, 100%).
(2) Rouhi, A. M. Chem. Eng. News 2004, 82 (36), 49.
(3) (a) Shimizu, K.-I.; Koizumi, S.; Hatamachi, T.; Yoshida, H.;
Komai, S.; Kodama, T.; Kitayama, Y. J. Catal. 2004, 228,
141. (b) Crudden, C. M.; Sateesh, M.; Lewis, R. J. Am.
Chem. Soc. 2005, 127, 10045.
(4) Kudo, D.; Masui, Y.; Onaka, M. Chem. Lett. 2007, 36, 918.
(8) Arvela, R. K.; Leadbeater, N. E.; Sangi, M. S.; Williams, V.
A.; Granados, P.; Singer, R. D. J. Org. Chem. 2005, 70, 161.
Synlett 2008, No. 4, 611–613 © Thieme Stuttgart · New York

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