Suzuki-Miyaura coupling reactions using phosphite ligands

Article abstract of DOI:10.1055/s-0029-1216822

A new catalytic system based on palladium phosphites for Suzuki coupling reactions of aryl bromides is described. An airstable catalytic system effectively promotes Suzuki couplings of aryl bromides with a range of boronic acids to afford diaryl products in high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216822

SPECIAL TOPIC
2073
Suzuki–Miyaura Coupling Reactions Using Phosphite Ligands
S
uzuki–Miyaura Coup
i
ling Re
h
actions
U
sin
e
g Phosphite
e
Ligands Jang,a Youngshin Jo,a Il-Kwon Oh,b Hyun Min Jung,c Sunwoo Lee*a
a
b
c
Department of Chemistry, Chonnam National University, 300 Yongbong-dong, Buk-gu, Gwangju 500-757, Republic of Korea
Fax +82(62)5303389; E-mail: sunwoo@chonnam.ac.kr
School of Mechanical Systems Engineering, Chonnam National University,
300 Yongbong-dong, Buk-gu, Gwangju 500-757, Republic of Korea
Advanced Materials Division, Korea Research Institute of Chemical Technology,
100 Jang-dong, Yuseong-gu, Daejeon 305-600, Republic of Korea
Received 31 March 2009
most of them should be prepared through multistep syn-
thesis in spite of their increased stability.
Abstract: A new catalytic system based on palladium phosphites
for Suzuki coupling reactions of aryl bromides is described. An air-
stable catalytic system effectively promotes Suzuki couplings of
aryl bromides with a range of boronic acids to afford diaryl products
in high yields.
In contrast to the phosphine ligands, much less attention
has been paid to phosphite ligands, although they are very
cheap and stable to air and moisture. Recently, we have
developed new catalytic systems based on phosphite
ligands and employed them in the palladium or nickel cat-
alyzed-transformations.11 All phosphites, which were em-
ployed in the transformations, have been widely used as
antioxidants.12 Phosphite compound 1 showed good activ-
ity in Hiyama reaction11a and the homocoupling of aryl
halides,11b and phosphite 3 (Figure 1) was found as the
best ligand in the dehalogenation11c and aminocarbonyla-
tion.11d
Key words: cross-coupling, palladium, phosphorus, Suzuki–
Miyaura coupling, phosphite
The synthesis of biaryls has received increasing attention
due to their important role in natural products, agrochem-
icals, pharmaceuticals, and new materials.1 The Suzuki re-
action of organoboron compounds with aryl halides
provides a most straightforward and powerful tool for
such synthetic strategies.2 Compared to other organome-
tallic nucleophiles such as orgnomagnesium, organozinc,
and organotin, the key advantages of organoboranes are
their stability to heat, oxygen, and water, in addition to the
ease of handling and separation process.3
t-Bu
t-Bu
O
O
O
O
Me
O
P
P
O
Me
t-Bu
t-Bu
t-Bu
t-Bu
To extend the Suzuki–Miyaura coupling reaction for fine
chemical applications, numerous studies have been re-
ported in the literature including the use of phase-transfer
complex,4 low palladium loading,5 reaction under micro-
wave irradiation,6 phosphine-free catalyst system,7 and
iron catalyst system.8 Despite these recent advances, there
still remains improvement for a general protocol that
could be employed as a practically useful process with
broadened scope of this transformation.
1
O
O
t-Bu
O
P
P
O
t-Bu
O
O
2
t-Bu
t-Bu
t-Bu
O
Usually, the Suzuki–Miyaura reaction is mediated by a
palladium–phosphine complex as catalyst. Most research
has focused on the development of efficient ligands to ob-
tain high catalytic activity. Recently sterically bulky and
electron-rich phosphine lgiands9 and carbene-type
ligands10 have been reported to display high activity in
Suzuki–Miyaura coupling of aryl halides. They showed
good reactivity to even aryl chlorides, which are the most
challenging substrates. However, most alkylphosphine
ligands including P(t-Bu)3, are sensitive to oxygen and
moisture. Therefore they require an inert environment for
carrying out the reaction. In case of carbene-type ligands,
P
O
t-Bu
O
t-Bu
t-Bu
3
Figure 1 Phosphite ligands 1–3
To the best of our knowledge, phosphite compounds have
never been employed as ligands in Suzuki cross-coupling
reaction, although a variety of new ligands have been de-
veloped and employed in this transformation.13 Therefore,
we report here the recent development of Suzuki cross-
coupling reaction using phosphite ligands as important
progress of practical utility.
SYNTHESIS 2009, No. 12, pp 2073–2075
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Advanced online publication: 14.05.2009
DOI: 10.1055/s-0029-1216822; Art ID: C01209SS
© Georg Thieme Verlag Stuttgart · New York

2074
M. Jang et al.
SPECIAL TOPIC
As a starting point for the development of the methodolo-
gy, we chose the coupling between 4-bromotoluene and
phenylboronic acid in the presence of palladium catalyst
with a variety of phosphite ligands as a model reaction.
The results are summarized in Table 1. As the findings in
our previous study,11a a Pd-to-ligand ratio of 1:1 gave the
best result. Among the phosphite ligands screened, phos-
phite 1 showed the highest yield as expected from the re-
sults in Hiyama reaction (entry 1). Thus, we investigated
the effect of various reaction parameters (palladium cata-
lyst, base, solvent, catalyst loading, and temperature) over
the yields of the coupling reactions. Pd(acac)2 was found
to be superior to other palladium source such as
Pd(OAc)2, Pd(MeCN)2Cl2, and Pd2(dba)3 (entries 1, 4–6).
K3PO4, which is commonly employed with dialkylbi-
arylphosphine ligands9a to accelerate the Suzuki–Miyaura
reaction gave very low yield (entry 7). K2CO3, Cs2CO3,
KF, and CsF showed moderate efficiency, giving the
product in 70, 73, 60, and 63% yield, respectively (entries
8–11). Na2CO3 was found to be the best base for this
transformation. The reaction proceeded well in polar sol-
vents, such as NMP (N-methyl-2-pyrrolidinone) and
DMA (dimethylacetamide) in 89 and 75% yield, respec-
tively (entries 1 and 15). The yield decreased in less polar
solvents such as toluene (entry 12). It was found that the
presence of water was critical in obtaining high yields of
the desired product. Thus, the optimized reaction condi-
tions were found to consist of 1,4-dioxane–H2O (10:1) as
solvent, Na2CO3 as base, phosphite 1 as ligand, and
Pd(acac)2 as catalyst (entry 16).
Table 1 Reaction Conditions for Optimized Suzuki–Miyaura Reac-
tion Using Phosphite Ligandsa
Pd/ligand
base, solvent
Br
(HO)2B
Me
+
90 °C
Me
Entry Pd/L
Base
Solvent
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
toluene
diglyme
THF
Yield (%)b
1
2
Pd(acac)2/1
Pd(acac)2/2
Pd(acac)2/3
Pd(OAc)2 /1
Na2CO3
Na2CO3
Na2CO3
Na2CO3
89
38
5
3
4
25
56
52
5
5
Pd(MeCN)2Cl2/1 Na2CO3
6
Pd2(dba)3/1
Pd(acac)2/1
Pd(acac)2/1
Pd(acac)2/1
Pd(acac)2/1
Pd(acac)2/1
Pd(acac)2/1
Pd(acac)2/1
Pd(acac)2/1
Pd(acac)2/1
Pd(acac)2/1
Na2CO3
K3PO4
K2CO3
Cs2CO3
KF
7
8
70
73
60
63
5
9
10
11
12
13
14
15
16
CsF
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
31
38
75
DMA
dioxane–H2O 94
In an effort to explore the scope of this method, we have
screened the coupling of representative aryl bromides
with arylboronic acids. The reaction system is generally
applicable for a variety of substrates as illustrated in
Table 2. The coupling reaction is very tolerant of func-
tional groups for aryl bromides, and the reactions with
both electron-withdrawing and electron-donating substit-
uents gave the desired biaryl products in good to excellent
yields. In case of bromoanisole derivatives, all substrates
showed good yields (entries 3–5).
a Reaction conditions: 4-bromotoluene (1.0 mmol), PhB(OH)2 (1.1
mmol), Pd (2 mol%), ligand (2 mol%), and solvent (3.0 mL).
b The yield was determined by GC by comparison with an internal
standard (naphthalene).
strates. However, only activated aryl chlorides afforded
the desired product in 25% yield. Substrates bearing elec-
tron-donating and electron-neutral groups showed very
low yields. Longer reaction time and high catalyst loading
did not significantly improve the yield of the product in ei-
ther case.
1-Bromonaphthalene gave higher yield than 2-bro-
monaphthalene (entries 6 and 7). Heteroaryl bromides
such as 2-bromothiophene and 3-bromopyridine afforded
the desired coupling product in high yields, however, 2-
bromopyridine showed somewhat low yield (entries 8–
10). Activated aryl bromides afforded coupled products in
excellent yields, especially, ortho-substituted phenyl bro-
In summary, we have shown that sterically bulky phos-
phite 1 exhibits good activity as a ligand in the palladium-
catalyzed Suzuki–Miyaura coupling reactions. This cata-
lytic system was not sensitive to oxygen or moisture; no
change in their efficiencies was observed even if the cou-
mides such as 2-nitrophenyl bromide and 2-bromobiphe- pling reactions were carried out under aerobic conditions.
nyl showed very high yields (entries 11 and 16). Sterically In addition, considering the cost and the stability of phos-
hindered aryl bromides such as bromomesitylene were phite as ligand, this method provides a convenient route to
coupled with phenylboronic acid and 2-tolylboronic acid synthesize the biaryl compounds.
to give the desired biaryl products in 85 and 74% yield, re-
spectively (entries 17 and 18). Aryl bromides bearing
electron-donating group (entries 19–22) and electron-
withdrawing group (entries 23 and 24) were coupled with
a variety of arylboronic acids to give the products in good
to excellent yields. We attempted to extend this catalytic
system to aryl chlorides, which are more challenging sub-
Synthesis 2009, No. 12, 2073–2075 © Thieme Stuttgart · New York

SPECIAL TOPIC
Suzuki–Miyaura Coupling Reactions Using Phosphite Ligands
2075
All reagents were obtained from commercial suppliers and used
without further purification.
Table 2 Suzuki–Miyaura Reaction of Aryl Halides with Arylboron-
ic Acidsa
Pd(acac)2/phosphite 1
Ar1X+ Ar2B(OH)2
Ar1 Ar2
Suzuki–Miyaura Coupling Reaction Using Phosphite Ligand 1;
General Procedure
Na2CO3, dioxane–H2O
90 °C
Pd(acac)2 (0.06 mmol), phosphite 1 (0.06 mmol), aryl halide (3.0
mmol), and aryl boronic acid (3.3 mmol) were combined with
Na2CO3 (3.6 mmol) in a round-bottomed flask. 1.4-Dioxane (10.0
mL) and H2O (1.0 mL) were added, and the flask was sealed with a
septum. The resulting mixture was placed in an oil bath at 90 °C un-
til the starting material was consumed, as determined by GC and
TLC. The reaction was poured into aq sat. NH4Cl (20 mL) and ex-
tracted with Et2O (3 × 20 mL). The combined Et2O extracts were
washed with brine (60 mL), dried (MgSO4), and filtered. The sol-
vent was removed under vacuum, and the resulting crude product
was purified by flash choromatography on silica gel. The product
was eluted with 5% EtOAc in hexane (Table 2).
Entry Ar1X
Ar2B(OH)2
Yield (%)b
98
1
2
PhBr
PhB(OH)2
4-MeC6H4Br
PhB(OH)2
94
3
2-MeOC6H4Br
3-MeOC6H4Br
4-MeOC6H4Br
1-bromonaphthalene
2-bromonaphthalene
2-bromothiophene
2-bromopyridine
3-bromopyridine
2-O2NC6H4Br
4-O2NC6H4Br
4-MeCOC6H4Br
4-MeOCOC6H4Br
4-HOC6H4Br
PhB(OH)2
76
4
PhB(OH)2
84
5
PhB(OH)2
85
6
PhB(OH)2
98
Acknowledgment
7
PhB(OH)2
76
This work was supported by the Korea Science and Engineering
Foundation (KOSEF) NRL Program grant funded by the Korean
government (MEST) (No. R0A-2008-000-20012-0).
8
PhB(OH)2
88
9
PhB(OH)2
45
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
PhB(OH)2
85
Reference
PhB(OH)2
98
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PhB(OH)2
94
PhB(OH)2
95
PhB(OH)2
91
PhB(OH)2
88
2-PhC6H4Br
PhB(OH)2
99
mesityl bromide
mesityl bromide
2-MeOC6H4Br
4-MeC6H4Br
PhB(OH)2
85
2-MeC6H4B(OH)2
2-MeC6H4B(OH)2
4-MeOC6H4B(OH)2
74
70
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72
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(13) Orthopalladated phospihte complexes have been employed
in the Suzuki reaction, see: Bedford, R. B.; Hazelwood, S.
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4-MeC6H4Br
4-MeCOC6H4B(OH)2 81
4-MeC6H4Br
4-MeC6H4B(OH)2
2-MeC6H4B(OH)2
4-MeC6H4B(OH)2
PhB(OH)2
73
98
98
4-MeCOC6H4Br
4-MeCOC6H4Br
PhCl
5 (8)c
4-MeCOC6H4Cl
4-MeOC6H4Cl
PhB(OH)2
25 (27)c
5 (5)c
PhB(OH)2
a Reaction conditions: Ar1X (1.0 equiv), Ar2B(OH)2 (1.1 equiv),
Pd(acac)2 (2 mol%), phsophite 1 (2 mol%), Na2CO3 (1.2 equiv), 1,4-
dioxane–H2O (10:1, 0.3 M), 12 h at 90 °C under aerobic conditions
(time is not optimized).
b The isolated yields of compounds are an average of at least two runs.
All compounds are characterized by comparison of 1H NMR spectra
with literature data.
c Amount of Pd(acac)2 and phosphite 1 used: 5 mol% each.
Synthesis 2009, No. 12, 2073–2075 © Thieme Stuttgart · New York