Pd(OAc)2/2-aryl-2-oxazolines catalyzed Suzuki coupling reactions of aryl bromides and arylboronic acids

Article abstract of DOI:10.1016/S0040-4039(02)00955-3

A series of 2-aryl-2-oxazolines were prepared and examined as ligands for the Suzuki coupling reaction of aryl bromides and arylboronic acids. 2,2′-(1,3-Phenylene)bisoxazoline/Pd(OAc)₂ was found to be an efficient catalyst for a variety of substrates to afford the coupling products in good to excellent yields.

Full text of DOI:10.1016/S0040-4039(02)00955-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4955–4957
Pd(OAc) /2-aryl-2-oxazolines catalyzed Suzuki coupling
2
reactions of aryl bromides and arylboronic acids
Bin Tao and David W. Boykin*
Department of Chemistry, Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30303, USA
Received 29 April 2002; accepted 14 May 2002
Abstract—A series of 2-aryl-2-oxazolines were prepared and examined as ligands for the Suzuki coupling reaction of aryl bromides
and arylboronic acids. 2,2%-(1,3-Phenylene)bisoxazoline/Pd(OAc) was found to be an efficient catalyst for a variety of substrates
2
to afford the coupling products in good to excellent yields. © 2002 Elsevier Science Ltd. All rights reserved.
1
9
The palladium-catalyzed Suzuki coupling reaction of
aryl halides with arylboronic acids (or esters) has
become a general and convenient synthetic method in
the Heck reaction. Oxazoline ligands are expected to
have advantages over phosphine ligands due to their
ease of synthesis and air stability. We report here our
initial results for 2-aryl-2-oxazolines as ligands for the
Suzuki coupling reaction and the influence on the cou-
pling reaction of electronic properties of substituents on
the phenyl ring of the 2-aryl-2-oxazolines. The oxazoli-
nes in Table 1 (except for 4,4-dimethyl-2-phenyl-2-oxa-
zoline, which is commercially available) were prepared
from the corresponding aryl nitriles and 2-amino-2-
methylpropanol or aminoethanol at 120°C in ethylene
1
organic chemistry for biaryl compounds, which has
2
been applied to many areas, including natural product
3
syntheses. Triarylphosphine/Pd complexes are com-
1
a
monly used as catalysts for the reaction. In the past
few years, great advances have been made in developing
active and efficient catalysts by modifying traditional
ligands and discovering new ones. Sterically demand-
ing, electron-rich phosphines, such as tri-t-butylphos-
4
phine and its analogs,
di(t-butyl)aryl and
20
glycol in the presence of catalytic amounts of K CO ,
and characterized by H, C NMR spectra and elemen-
tal analysis.
2
3
5
dicyclohexylaryl phosphines have shown high coupling
activities for a variety of substrates. Trialkylphospho-
nium hydroboronofluorides have recently been reported
as replacements for trialkylphosphines while retaining
their high coupling activities and overcoming the air-
1
13
With these oxazolines in hand, they were examined as
ligands in the coupling reaction of 4-bromoanisole and
phenylboronic acid (1.5 equiv.) in the presence of 2
6
sensitive problem of phosphine-based catalysts. Other
phosphine ligands/complexes, such as phosphine
7
8,9
mol% of Pd(OAc)
2
, 2 mol% of oxazoline, and 2 equiv.
oxides,
phospha-palladacycles,
water-soluble
1
0
11
of Cs CO in dioxane at 80°C. We thought that oxazo-
2
3
phosphines and chelating phosphine compounds
have also been developed. In the meantime, new types
of non-phosphine ligands/complexes, such as hetero-
13
line palladacycles might be generated in situ from
Pd(OAc)2 and oxazolines under reaction conditions
which would simplify the reaction operations. Towards
this end, two different procedures of in situ generation
of the oxazoline palladacycles were examined. In the
1
2
cyclic carbenes, imine and amine palladacycles,
1
4
15
oxime palladacycles and diazabutadienes, have also
emerged for use in the Suzuki reaction.
first one, Pd(OAc) and 4,4-dimethyl-2-phenyl-2-oxazo-
2
line were heated in dioxane at 80°C for 30 min, fol-
lowed by the addition of the substrates to the yellow
cooled solution at room temperature, and the mixture
was then heated to 80°C. In the second one, all the
reaction reagents were added together at room temper-
ature and the mixture was heated. To our delight, the
two different procedures afforded the coupling product
in good and comparable yields. Subsequently, the sec-
ond procedure was adopted for the other coupling
2
-Aryl-2-oxazoline palladacycles can be prepared from
16
Pd(OAc) and oxazolines either in acetic acid at reflux
or ortho-lithiation of the oxazolines, followed by
quenching with a palladium salt. They have been
reported as catalysts for the Michael addition
2
1
7
17,18
and
*
Corresponding author. Fax: 404-651-1416; e-mail: dboykin@
gsu.edu
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00955-3

4
956
B. Tao, D. W. Boykin / Tetrahedron Letters 43 (2002) 4955–4957
reactions. Using this procedure, all the reactions pro-
ceeded to completion in 4 h as monitored by TLC.
the electron-donating groups gave rise to more debrom-
ination by-product as indicated by TLC. The low yield
of these coupling reactions is a result of the diminished
aryl bromides due to the competitive debromination
reaction of the aryl bromide enhanced by the electron-
rich nature on the palladium center, which resulted
from the electron-donating groups on the phenyl ring
of the oxazolines. It is also worth noting that these
results are likely a reflection of electronic effects of the
different substituents, without steric contributions.
Such effect could be very useful in investigations of the
mechanisms of the coupling reactions.
Electronic effects of the substituents on the phenyl ring
of the oxazolines play a significant role on the coupling
reaction as indicated in Table 1. Compared to 4,4-
dimethyl-2-phenyl-2-oxazoline (entry 1), the oxazolines
with electron-donating groups on the phenyl ring gave
the product in low yields, while those with electron-
withdrawing groups afforded 4-methoxybiphenyl in
slightly higher yields. For instance, 2-aryl-2-oxazolines
with methyl and N,N-dimethylamino groups dimin-
ished the yield to 56 and 61% from 80%, respectively
Among the 2-aryl-2-oxazolines examined, bisoxazoline
(
entries 2 and 4); oxazolines with a cyano or nitro
7
was found to be the best ligand, giving the desired
group afforded the product in 83 and 88% (entries 5
product in almost quantitative yield. This great
improvement in the reaction yield is likely a result of
and 6). These observations, at first glance, seem to be in
1
5
contrast to those for other systems. Actually, we
observed that the reactions with the oxazolines bearing
1
1,15
chelating effects as observed for other ligands.
However, its 4,4-dimethyl counterpart 6 gave lower
yields. This result is probably due to the steric effects of
the four methyl groups present which hinder the two
nitrogen atoms of the two oxazoline rings from effec-
tively binding to the palladium atom.
Table 1. Effect of different ligands/Pd(OAc) on the
2
Suzuki coupling reaction of 4-bromoanisole with phenyl-
boronic acid
OMe
OMe
B(OH)2
The scope of the Suzuki coupling reactions using bisox-
azoline 7 as the ligand was investigated. The reaction is
general for a variety of substrates as illustrated in Table
2. The coupling reaction is very tolerant of functional
groups for both aryl bromides and arylboronic acids,
and the reactions with both electron-withdrawing and
electron-donating substituents gave the desired biaryl
products in good to excellent yields.
2
% Pd(OAc)2 / 2% Ligand
+
Cs2CO3 (2 eq), dioxane
o
8
0 C
Br
_
__________________________________________
a,b
Entry
_
Ligand
Yield (%)
__________________________________________
O
N
N
1
2
80
56
In summary, we have demonstrated a general and
O
efficient catalytic system based on Pd(OAc) /bisoxazo-
2
(
1)
2)
line 7 for the Suzuki coupling reaction of aryl bromides
Me
O
O
O
N
N
N
Table 2. Suzuki coupling reaction of aryl bromides and
arylboronic acids catalyzed by 7/Pd(OAc)2
(
66
3
4
5
MeO
R1
Br
B(OH)2
(
3)
4)
61
83
2% Pd(OAc)2 / 2% 7
Me2N
NC
+
R1
R2
Cs CO (2 eq), dioxane
2
3
(
o
8
0 C
R2
O
O
N
N
(
5)
6)
88
82
Entry
R1
R2
Yield (%)a,b
6
7
O2N
1
2
3
4
5
6
7
8
4-Cl
H
H
H
H
H
H
4-NO2
4-OMe
2-Me
81
76
96
77
89
75
93
82
77
95
3-NO2
4-NO2
4-Me
(
N
O
3-Me
c
O
N
3-NO2
4-Me
4-Me
2-CN
8
(7)
96
9
10
N
O
3,4-Methylenedioxo
_
_________________________________________
a
Reaction conditions: aryl bromide (1.0 mmol), boronic acid (1.5
a
Reaction conditions: 4-bromoanisole (1.0 mmol), phenylboronic acid
mmol), Pd(OAc)2 (2.0 mol%), ligand 7 (2.0 mol%), Cs CO3 (2.0
2
(
1.5 mmol), Pd(OAc)2 (2.0 mol%), ligand (2.0 mol%), Cs CO (2.0
mmol), dioxane (4 mL), 80°C, 4 h.
Isolated yield of average of two runs.
The substrate is 6-bromo-2-naphthol.
2
3
b
c
mmol), dioxane (4 mL), 80°C, 4 h.
Isolated yield of average of two runs.
b

B. Tao, D. W. Boykin / Tetrahedron Letters 43 (2002) 4955–4957
4957
and arylboronic acids. Different substituents on the
phenyl ring of 2-aryl-2-oxazoline have a dramatic influ-
ence on the coupling reaction. Investigations are under-
way to determine the influence of electronic effects and
chelating effects on the reaction.
6. Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
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Acknowledgements
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