Homocoupling of aryl halides using catalytic system of palladium and phosphite

Article abstract of DOI:10.1246/cl.2007.1432

The palladium-catalyzed homocoupling of aryl halides was carried out using phosphite ligands. The optimized reaction conditions were Pd2(dba)3, phosphite 1, and NaOt-Bu in diglyme, and the desired homocoupling products were afforded in moderate to good yields. Copyright

Full text of DOI:10.1246/cl.2007.1432

1432
Chemistry Letters Vol.36, No.12 (2007)
Homocoupling of Aryl Halides Using Catalytic System of Palladium and Phosphite
Jeongju Moon, Hyungoog Nam, Jinhun Ju, Miso Jeong, and Sunwoo LeeÃ
Department of Chemistry, Chonnam National University, 300 Yongbong-dong, Buk-gu, Gwangju, 500-757, Korea
(Received August 21, 2007; CL-070888; E-mail: sunwoo@chonnam.ac.kr)
The palladium-catalyzed homocoupling of aryl halides was
system. Table 1 summarizes our results from screening a variety
of palladium sources, ligands, bases and solvents. Among the
ligands tested, phosphite 1 showed the best activity (Entry 1).
The reactions using phosphite 2 and 3 resulted in poor yields
of 47 and 40%, respectively (Entries 2 and 3). However, the
single phosphadioxa cycle type lignad13 was employed as ligand,
it gave only 35% yield. Small phosphites such as P(OEt)3 afford-
ed a low yield of homocoupling product (Entry 4), while PPh3
afforded a low yield of 35% (Entry 5). In the absence of phos-
phite 1, no homocoupling products were formed and no other
reactions occurred with aryl bromides under the conditions
shown in Table 1 (Entry 6). Among the catalysts tested,
{Pd2(dba)3, Pd(OAc)2, Pd(CH3CN)2Cl2, {Pd(allyl)Cl}2,
Pd(acac)2}, Pd2(dba)3 proved to be the most efficient, which af-
forded 72% yield (Entries 1, 7, 8, 9, and 10). Palladium(0) source
carried out using phosphite ligands. The optimized reaction con-
ditions were Pd2(dba)3, phosphite 1, and NaOt-Bu in diglyme,
and the desired homocoupling products were afforded in moder-
ate to good yields.
The synthesis of symmetrical biaryls has been receiving
increasing research attention due to their important roles in the
natural products, functional polymers, and ligands of catalyst
systems.1 These compounds are conventionally prepared by
the Ullmann reaction, which involves reductive aryl halide ho-
mocoupling in the presence of stoichiometric amounts of copper
reagents at high temperature (>200 ꢀC).2 This relatively harsh
condition prevents its application in the synthesis of functional-
ized biaryls. Recently, various aryl metals such as aryl boronic
acids,3 arylstannanes,4 and arylzinc5 have been used for the syn-
thesis of symmetric biaryls. However, they suffer the major
drawback of requiring more than one equimolar amount of orga-
nometallic reagents. To address these problems, the transition-
metal-catalyzed, the Ullmann-type, reductive coupling of aryl
halides has been used as an alternative synthetic method. The
palladium-catalyzed method has been most commonly used for
the homocoupling of aryl halides. This reaction method is usual-
ly conducted in the presence of the reducing agents such as
amines,6 alcohols,7 zinc,8 and hydroquione.9 As a ligand, the
arylphosphines9 or arylarsines10 are usually employed. To our
knowledge, phosphites have never been used as ligands in the
palladium-catalyzed homocoupling reactions, despite their low
cost and stability to air and moisture. We recently reported the
Hiyama cross coupling reactions by using phosphite ligands
(Figure 1).11 In the search for the optimized condition, homocou-
pled aryl halide has occasionally been found as a minor constit-
uent. Therefore, we decided to find a suitable and viable reaction
method to produce a homocoupling product as the major out-
come. The DeShong research group has reported a similar result
in the use of tetrabutylammonium fluoride with palladium cata-
lyst.12 In the present study, we report an efficient homocoupling
reaction involving various aryl bromides catalyzed by the palla-
dium/phosphite system.
Table 1. Optimization of conditions for homocoupling of 1-
bromo-4-tert-butylbenzenea
5% Pd/L
t-Bu
Br
t-Bu
t-Bu
Base, Solvent
Yield
/%b
Entry
Pd
Ligand
Base
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(CH3CN)2Cl2
[PdCl(allyl)]2
Pd(acac)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
1
2
3
NaOtBu Diglyme 72
NaOtBu Diglyme 47
NaOtBu Diglyme 40
P(OEt)3 NaOtBu Diglyme 37
PPh3
—
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
NaOtBu Diglyme 35
NaOtBu Diglyme NRc
NaOtBu Diglyme 63
NaOtBu Diglyme 65
NaOtBu Diglyme 57
NaOtBu Diglyme 50
NaOMe Diglyme 33
NaOH
Diglyme
5
KOtBu Diglyme NDd
KOMe Diglyme NDd
NaHMDS Diglyme
n-BuLi Diglyme
5
9
Cs2CO3 Diglyme NRc
K2CO3 Diglyme NRc
First, we chose 4-tert-butylbromobenzene as the substrate to
search for the optimized condition with the palladium/phosphite
K3PO4
NaOtBu
NaOtBu
Diglyme NRc
DMF
NMP
17
11
5
tBu
tBu
tBu
tBu
O
O
O
O
Me
O
P
P
O
Me
tBu
1
NaOtBu p-Xylene
tBu
tBu
tBu
O
O
1
tBu
aReaction conditions: 1-bromo-4-tert-butylbenzene (1.0 mmol),
solvent (3.0 mL), 5 mol % palladium, 10 mol % ligand, base
(2.0 mmol), 12 h, 130 ꢀC. bYield was determined by GC by com-
parison to an internal standard (naphthalene). cNo Reaction: only
P
O
tBu
tBu
tBu
O
P
O
tBu
O
P O
tBu
O
O
2
3
d
starting materials appeared in GC. The desired homocoupling
product was not detected in GC.
Figure 1. Phosphite ligands.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.12 (2007)
1433
Table 2. Homocoupling reaction of different aryl halidesa
bromides afforded a low yield of the homocoupling products
(Entries 12–14). We attempted to expand this reaction method
to apply to aryl chlorides, which are more challengeable sub-
strates. However, this catalytic system afforded less than 30%
yield of the desired product.
The 31P NMR spectrum of the complexation of Pd2(dba)3
and ligand 1 showed only one peak.16 However, it showed
several peaks at 0 ꢀC.17 In case of phosphite 2 and 3, they showed
several peaks.16 Even though their exact coordination manners
are not identified, their different manners might give the
different reactivities. Further studies of coordination manners
are in progress in our laboratory.
Yield
/%b
Yield
/%b
Entry
ArX
Entry
9
ArX
Br
I
1
2
80
61
45
62
Me
OMe
Br
I
10
Me
I
OMe
Br
Br
3
4
5
65
75
75
11
12
13
60
48
30
MeO
MeO
Br
Br
N
In summary, we presented the first homocoupling of
aryl halides using the palladium/phosphite catalytic system. Dif-
ferent aryl halides were reacted in the presence of Pd2(dba)3,
phosphite 1 to give symmetric biaryl compounds.
Me
tBu
N
S
Br
Br
6
7
72
21
14
15
33
27
Br
Cl
Br
Ph
Br
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD, Basic
Research Promotion Fund) (KRF-2006-003-C00178).
Me
Cl
8
10
16
14
Me
Me
Me
References and Notes
1
aReaction conditions: aryl halide (3.0 mmol), 2.5 mol %
Pd2(dba)3, 10 mol % phosphite 1, NaOt-Bu (6.0 mmol), diglyme
(0.3 M), 130 ꢀC, 12 h. bIsolated yields of compounds are the
average of at least two runs. All compounds were characterized
by comparison of 1H and 13C NMR spectra with authentic sam-
ples or literature data.
K. C. Nicolaou, C. N. Boddy, S. Brase, N. Winssinger,
¨
Angew. Chem., Int. Ed. 1999, 38, 2096.
2
a) G. Bringmann, R. Walter, R. Weirich, Angew. Chem., Int.
Ed. Engl. 1990, 29, 977. b) J. Hassan, M. Sevignon, C.
Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359.
a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457. b) T.
Ishiyama, S. Abe, N. Miyaura, A. Suzuki, Chem. Lett. 1992,
691. c) Y. Yamamoto, Synlett 2007, 1913.
3
showed a better result than palladium(II) source. As for the base,
sodium t-butoxide proved to be highly effective. In the presence
of other kinds of base, the reaction yield was insufficient or zero.
NaOMe and NaOH afforded very low yields of 33 and 5%, re-
spectively (Entries 11 and 12). Using potassium bases such as
KOMe and KOt-Bu, the desired product was not detected in
GC data (Entries 13 and 14). When inorganic weak bases such
as Cs2CO3, K2CO3, and K3PO4 were used, no reactions were ob-
served (Entries 17, 18, and 19). The screening of several solvents
indicated that the reaction in diglyme afforded a homocoupling
product in good yield. Amide-type solvents such as DMF and
NMP showed less than 20% yield (Entries 20 and 21). p-Xylene,
which was a suitable solvent for the palladium/phosphite system
in the Hiyama coupling,11 afforded only trace amounts of the
desired product (Entry 22).
4
5
6
V. Farina, Pure Appl. Chem. 1996, 68, 73.
E. Negishi, Acc. Chem. Res. 1982, 15, 340.
J. Hassan, C. Hathroubi, C. Gozzi, M. Lemair, Tetrahedron
2001, 57, 7845.
7
8
9
J. Hassan, V. Penalva, L. Lavenot, C. Gozzi, M. Lemaire,
Tetrahedron 1998, 54, 13793.
a) S. Venkatraman, C.-J. Li, Org. Lett. 1999, 1, 1133. b) J.-H.
Li, Y.-X. Xie, D. L. Yin, J. Org. Chem. 2003, 68, 9867.
D. D. Hennings, T. Iwama, V. H. Rawal, Org. Lett. 1999, 1,
1205.
10 H. S. He, C. Zhang, C. K.-W. Ng, P. H. Toy, Tetrahedron
2005, 61, 12053.
11 J. Ju, H. Nam, H. M. Jung, S. Lee, Tetrahedron Lett. 2006,
47, 8673.
12 W. M. Seganish, M. E. Mowery, S. Riggleman, P. DeShong,
Tetrahedron 2005, 61, 2117.
To demonstrate the scope of this palladium–phosphite
catalytic system, a variety of representative aryl halides were
examined (Table 2).
As could be expected in the homocoupling of aryl halides,
iodides afforded better results than the corresponding bromides
or chlorides: 4-Iodotoluene afforded 80% yield, 4-bromotoluene
75% yield and 4-chlorotoluene only 14% yield (Entries 1, 5, and
16, respectively). The homocoupling product yield decreased
with increasing steric hindrance of the substrate. 2-Iodotoluene
showed 61% yield. Similar trends have been reported by Li et
al.14 and Wu et al.15 However, in the present study ortho-disub-
stituted aryl bromides such as 2-bromobiphenyl and mesityl
bromide afforded a very low yield of homocoupling product
(Entries 7 and 8). Bromoanisole derivatives afforded the desired
coupling products in moderate yields (Entries 9–11). Heteroaryl
13 [O(CH2CMe2CH2)O]PO(2,4-tBu-4-MeC6H2).
14 S. Venkatraman, T. Huang, C.-J. Li, Adv. Synth. Catal. 2002,
344, 399.
15 N. Ma, Z. Duan, Y. Wu, J. Organomet. Chem. 2006, 691,
5697.
16 The palladium complexes of phosphites (Pd/L mol ratio =
1/2) were check by 31P NMR at 25 ꢀC. Complex of 1: ꢀ
À9:44, (141.5, 136.2, À9:44, À10:37 at 0 ꢀC); Complex of
2: ꢀ 138.1 (br), 132.7 (br), 130.1(br), À12:26; Complex of
3: ꢀ 120.43, 85.42, À18:42.
17 Supporting Information is available electronically on the
CSJ-Journal Web site; http://www.csj.jp/journals/chem-lett/.
Published on the web (Advance View) November 3, 2007; doi:10.1246/cl.2007.1432