Cross-coupling of aryl/alkenyl ethers with aryl grignard reagents through nickel-catalyzed C-O activation

Article abstract of DOI:10.1002/chem.201003731

The formation of a C-C bond has been achieved through the cleavage of the sp² C-O bond of aryl/alkenyl ethers catalyzed by a nickel complex, and by using Grignard reagents as nucleophiles (see scheme). This method displays a broad substrate scope and leads to good to excellent yields of the aryl-aryl or alkenyl-aryl cross-coupling products.

Full text of DOI:10.1002/chem.201003731

DOI: 10.1002/chem.201003731
Cross-Coupling of Aryl/Alkenyl Ethers with Aryl Grignard Reagents through
À
Nickel-Catalyzed C O Activation
Lan-Gui Xie and Zhong-Xia Wang*[a]
Cross-coupling reactions catalyzed by transition metals
ficient couplings of aryl and alkenyl ethers with aryl
Grignard reagents catalyzed by nickel complexes.
À
are versatile and powerful tools to construct new C C
bonds.[1,2] In a cross-coupling reaction, the electrophile spe-
cies are predominantly organic halides and aryl/alkenyl
ACHTUNGTRENNUNGtriflates or sulfonates. The reactions that proceed through
À
C O activation of ethers and esters are very limited al-
though these electrophilic substrates have drawn the atten-
tion of chemists even at the early stage of cross-coupling re-
actions.[3,4] The pioneering work on cross-coupling reactions
with aryl/alkenyl methyl ethers as electrophiles was carried
out by Wenkert et al. in 1979.[4a] However, this important
discovery has been ignored for a long time. Recently, signifi-
cant advances have been made in the cross-couplings of
ethers, esters, carbamates, carbonates, and sulfamates cata-
lyzed by transition metals and with Grignard reagents, orga-
nozinc reagents, and organoboron reagents as nucleo-
philes.[3,5–8] For example, Dankwardt has reported a reaction
of aryl methyl ethers with aryl Grignard reagents using
[(Cy3P)2NiCl2] or [(PhPCy2)NiCl2] as a catalyst in 2004.[5c] In
2008, Shi and co-workers have reported the cross-coupling
of aromatic or benzylic ethers with MeMgBr catalyzed by
[(Cy3P)2NiCl2].[5d,e] Very recently, Shi and co-workers have
reported a Kumada-type coupling of magnesium naphtho-
lates as electrophiles.[9] Ackermann and Mulzer have also re-
Complexes I–III have been previously synthesized by our
research group.[11] In preliminary studies of their catalytic
properties, we investigated the reaction of 1-methoxynaph-
thalene with p-MeC6H4MgBr and found that complexes I
and II catalyzed the reaction efficiently in THF at room
temperature with 2.5 mol% of catalyst loading or in toluene
at 1208C (bath temperature) with 1 mol% of catalyst load-
ing (Table 1). At lower reaction temperature and in toluene
the reaction did not reach completion (Table 1, entries 2, 3,
and 8). The reaction catalyzed by complex III (2.5 mol%)
À
ported the C OH bond functionalization of phenols through
À
À
Table 1. Evaluation of the catalytic activity of complexes I–III in the re-
action of 1-methoxynaphthalene with p-MeC6H4MgBr.[a]
the activation of a C O and a C H bond catalyzed by
ruthenium.[10] Although significant progress has been ach-
ieved, the substrate scope for these reactions is still limited
and the development of more efficient catalytic systems is
also desirable. In addition, alkenyl ethers are only seldom
used as electrophiles. Some examples have been reported by
Wenkert and et al., who carried out nickel-catalyzed cross-
coupling between alkenyl ethers and Grignard reagents that
resulted in relatively low yields of the products.[4] Related
Cat. ([mol%])
Conditions
Yield [%][b]
À
work is the nickel- or iron-catalyzed C O bond cleavage of
alkenyl carboxylates through reaction with organomagnesi-
1
2
3
4
5
6
7
8
9
I (2.5)
I (2.5)
I (2.5)
I (2.5)
THF, 258C, 24 h
91
28
81
99
95
96
99
69
toluene, 258C, 24 h
toluene, 808C, 24 h
toluene, 1208C, 16 h
toluene, 1208C, 16 h
THF, 258C, 24 h
toluene, 1208C, 16 h
toluene, 808C, 24 h
toluene, 1208C, 16 h
THF, 258C, 24 h
um, -zinc, or -boron reagents.[5f,6b,7d] Herein we report the ef-
I (1.0)
II (2.5)
II (2.5)
II (1.0)
II (1.0)
III (2.5)
III (2.5)
[a] L.-G. Xie, Prof. Dr. Z.-X. Wang
CAS Key Laboratory of Soft Matter Chemistry
and Department of Chemistry
98
trace
91
University of Science and Technology of China
Hefei, Anhui 230026 (P.R. China)
Fax : (+86)551-3601592
10
11
toluene, 1208C, 16 h
E-mail: zxwang@ustc.edu.cn
[a] The reactions were carried out using 1-methoxynaphthalene
(0.5 mmol) and p-MeC6H4MgBr (0.75 mmol) in the presence of the cata-
lyst under a nitrogen atmosphere. [b] Yield of isolated products.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003731.
4972
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Chem. Eur. J. 2011, 17, 4972 – 4975

COMMUNICATION
Table 2. Cross-coupling of aryl ethers with ArMgBr catalyzed by I or II.[a]
products, owing to steric hin-
drance. However, a higher reac-
tion temperature in toluene
could drive the reaction to com-
pletion (Table 2, entry 4). The
Aryl ether
Product
Conditions
Cat.
([mol%])
Yield
[%][b]
AHCTUNGTRENNUNG
1
2
3
THF, 258C, 24 h
THF, 258C, 24 h
THF, 258C, 24 h
II (2.5)
II (2.5)
II (2.5)
94
92
85
2-methACHTNUTRGNEoNUG xynaphthalene species
has displayed a similar reactivi-
ty compared to 1-methoxynaph-
thalene: when treated with p-
MeC6H4MgBr under catalysis
by either I or II, led to excel-
lent yields of the corresponding
products (Table 2, entries 5 and
6). The reaction of 2-methoxy-
4
toluene, 1208C, 16 h
II (2.5)
89
naphthalene
with
2,4,6-
Me3C6H2MgBr catalyzed by II
in toluene at 1208C also result-
ed in good yields of the corre-
sponding product (Table 2,
entry 7). Also, both I and II
have efficiently catalyzed the
reaction of 1,4-dimethoxynaph-
5
6
I (2.5)
II (2.5)
92
95
THF, 258C, 24 h
7
toluene, 1208C, 16 h
II (2.5)
II (5)
81
thalene
naphthalene
MeC6H4MgBr, thus giving 1,4-
or 2,7-di(p-tolyl)naphthalene in
or
2,7-di
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
with
8
9
84
91
THF, reflux, 24 h
AHCTUNGTRENNUNG
84–91% yields (Table 2, en-
tries 8–10). It is noteworthy that
the reaction of 1,4-dimethoxy-
naphthalene required reflux
THF condition, whereas the re-
action of 2,7-dimethoxynaph-
thalene proceeded at 258C in
THF. Attempts to substitute
one of the MeO groups on the
dimethoxynaphthalenes by de-
10
11
I (5)
II (5)
89
91
THF, 258C, 24 h
12
13
I (10)
II (10)
81
82
THF, reflux, 24 h
[a] The reactions were carried out using of aryl alkyl ethers (0.5 mmol) and the Grignard reagents (0.75 mmol)
in the presence of complex I or II under nitrogen atmosphere; OMOM=Methoxymethoxy. [b] Yield of isolat-
ed products.
creasing
the
amount
of
Grignard reagent were unsuc-
also proceeded well in toluene at 1208C. However, the reac-
tion in THF at room temperature formed the product only
in trace amount. It was also found that in the catalyzed sub-
stitution reaction of 1-alkoxynaphthalene, MeO was a better
leaving group compared with nBuO, iPrO, OMOM, and
OTMS (see Table S1 in the Supporting Information).
The electron-rich Grignard reagents p-MeOC6H4MgBr
and p-Me2NC6H4MgBr reacted efficiently with 1-methoxy-
naphthalene in the presence of II (2.5 mol%) in THF at
room temperature, thus giving the corresponding cross-cou-
pling products in excellent yields (Table 2, entries 1 and 2).
At such a temperature, the coupling product 1-(4-methoxy-
cessful, because they led to the formation of a mixture of
mono- and di-substituted products. In addition, it was also
noted that II exhibited a higher catalytic activity than I in
the reaction of dimethoxynaphthalenes. An interesting ex-
ample is the reaction between 2,2’-bis(methoxymethoxy)-
1,1’-binaphthyl and p-MeC6H4MgBr catalyzed by either I or
II (Table 2, entries 12 and 13). Only one OMOM group was
substituted, even when an excess of Grignard reagent was
employed. The 2,2’-BisACTHNUGRTENUNG(methoxy)-1,1’-binaphthyl species
showed much lower reactivity compared with 2,2’-bis(meth-
oxymethoxy)-1,1’-binaphthyl; the former gave the product
in trace amount when treated with p-MeC6H4MgBr in the
presence of II.
Substituted phenyl methyl ethers exhibited a lower reac-
tivity than methoxynaphthalenes. Solvent optimization
showed toluene to be superior to THF, dioxane, nBu2O,
À
phenyl)naphthalene did not undergo further C O cleavage.
Reaction of o-MeC6H4MgBr with 1-methoxynaphthalene
under the same reaction conditions resulted in a slightly
lower yield of coupling product than that of p-MeC6H4MgBr
(Table 1, entry 6 and Table 2, entry 3). The reaction between
iPr2O, DME, and CH2ACTHNUGRTNE(NUG OEt)2 (see Table S2 in the Support-
2,4,6-Me3C6H2MgBr and 1-methoxy
lar reaction conditions resulted in a very low yield of the
naphthalene under simi-
ing Information). Experimental results have also shown that
for the substituted phenyl ethers, each of OTMS, OMOM,
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4973

Z.-X. Wang and L.-G. Xie
Table 3. Reaction of substituted phenyl ethers, 2-methoxypyridine, and 2,6-dimethoxypyridine with aryl
exhibited a high reactivity. It re-
Grignard reagents catalyzed by complex I or II.[a]
acted
MeC6H4MgBr in the presence
of I or II to form 2,6-di(p-tol-
with
excess
p-
Aryl
Product
Conditions
Cat.
([mol%])
Yield
[%][b]
ether
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
yl)pyridine in 93% and 95%
yields, respectively.
1
2
toluene, 1208C, 16 h
toluene, 1208C, 16 h
toluene, 1208C, 16 h
toluene, 1208C, 16 h
I (5)
67
72
Alkenyl alkyl ethers also re-
acted smoothly with aryl
Grignard reagents when I or II
were used as the catalyst
(Table 4). The bond cleavage of
I (5)
I (5)
3
4
72
74
II (5)
À
the C O bond in the alkenyl
was observed in each case. The
reaction was carried out in
THF at 508C or in toluene at
1208C. For example, the reac-
tion of PhCH=CHOMe with p-
Me2NC6H4MgBr catalyzed by I
formed the coupling product
with 93% yield in toluene at
1208C and with 91% yield in
THF at 508C (Table 4, entries 1
and 2). Complex II showed a
slightly higher catalytic activity
than I. However, the reaction
5
II (5)
68
6
7
I (5)
II (5)
71
70
toluene, 1208C, 16 h
8
9
I (5)
II (5)
70
75
toluene, 1208C, 16 h
toluene, 1208C, 16 h
THF, 258C, 24 h
10
11
I (5)
II (5)
83
83
12
13
II (5)
II (5)
91
97
of
p-MeOC6H4MgBr
with
PhCH=CHOMe catalyzed by II
gave a lower yield of the prod-
uct compared with that of p-
Me2NC6H4MgBr. This may be a
result of the coordination of the
MeO group to the metal ion
(e.g., Mg2+), which would de-
crease the nucleophility of p-
THF, 258C, 24 h
14
15
I (5)
II (5)
61
63
toluene, 908C, 16 h
THF, 258C, 24 h
16
17
I (10)
II (10)
93
95
À
MeOC6H4 . The sterically hin-
[a] The reactions were carried out using aryl alkyl ethers (0.5 mmol) and the Grignard reagents (0.75 mmol) in
the presence of complex I or II under nitrogen atmosphere; Py=pyridine, TMS=trimethylsilyl. [b] Yield of
isolated products.
dered
species
2,4,6-
Me3C6H2MgBr showed low re-
activity in the catalytic reaction.
Its reaction with PhCH=
and OCF3, was a better leaving group than OMe (Table 3,
entries 1–9). The reaction of PhOCF3 with p-
Me2NC6H4MgBr catalyzed by either I or II in toluene at
1208C generated the cross-coupling products in 83% yields
(Table 3, entries 10 and 11). This result is quite different
from that reported by Dankwardt, in which OCF3 was indi-
cated to be a poor leaving group.[5c] Reactions of other sub-
stituted phenyl ethers with p-MeC6H4MgBr under the same
reaction conditions led to yields of 67–75% of the corre-
sponding products (Table 3, entries 1-9). 2-Methoxypyridine
resulted to be a very reactive species in cross-coupling reac-
tions: its reaction with p-Me2NC6H4MgBr or p-
MeC6H4MgBr in the presence of II produced corresponding
coupling product in excellent yields. However, the reaction
of 2-methoxypyridine with 2,4,6-Me3C6H2MgBr was much
more difficult. It required higher reaction temperature and
gave coupling products in 61–63% yields with both I or II
as the catalyst. On the other hand, 2,6-dimethoxypyridine
CHOMe catalyzed by II in THF at 508C led to only 41%
yield (Table 4, entry 6). This result was improved by using
more extreme reaction conditions. The same reactants in
toluene at 1208C afforded a 91% yield of the coupling prod-
uct (Table 4, entry 7). Ph2C=CHOMe also reacted efficiently
with p-MeC6H4MgBr in THF in the presence of I or II, thus
giving the corresponding coupling products in 91% and
95% yields, respectively. MeCH=CHOEt showed good reac-
tivity in the catalytic cross-coupling. Its reaction with p-
MeC6H4MgBr or p-Me2NC6H4MgBr in THF in the presence
of I or II resulted in the formation of MeCH=CHAr (Ar=
p-MeC6H4 or p-Me2NC6H4) in excellent yields. We noted
that the analogue reaction with p-MeOC6H4MgBr as nucleo-
phile gave a lower yield compared with other nucleophiles.
In addition, the reaction of PhCH=CHOMe resulted in the
E-PhCH=CHAr product, while the reaction of MeCH=
CHOEt always formed a mixture of the Z- and E-MeCH=
CHAr products.
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Nickel-Catalyzed Cross-Coupling Reactions
COMMUNICATION
Table 4. Reaction of alkenyl methyl ethers with aryl Grignard reagents
Acknowledgements
catalyzed by complex I or II.[a]
We thank the National Basic Research Program of China
(2009CB825300) and the National Natural Science Foundation of China
(20772119) for financial support. We also thank Professor Lutz Acker-
mann for the constructive comments.
Alkenyl
ether
Product
Conditions
Cat.
Yield
AHCTUNGTRENNUNG
([mol%]) [%][b]
toluene,
1208C, 12 h
THF, 508C,
12 h
THF, 508C,
12 h
1
2
3
I (5)
I (5)
II (5)
93
91
94
À
Keywords: C O activation
· cross-coupling · Grignard
reagents · homogeneous catalysis · nickel
THF, 508C,
12 h
4
5
II (5)
II (5)
92
80
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12 h
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10
11
THF, 508C,
12 h
I (5)
II (5)
87
90
THF, 508C,
12 h
12
13
II (5)
II (5)
98[c]
77
THF, 508C,
12 h
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and the Grignard reagents (0.75 mmol) in the presence of complex I or II
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isolated by column chromatography and the yield was calculated based
1
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À
In summary, we have shown the formation of a C C bond
through the cleavage of a sp2 C O bond in aryl/alkenyl
À
ethers catalyzed by nickel and using aryl Grignard reagents
as nucleophiles. In most cases, the nickel complex
[(iPr2PR)NiCl2] (II) displays a higher catalytic activity than
[(Cy2PR)NiCl2] (I) and both of them are much more active
than [(Ph2PR)NiCl2] (III). The reaction has a wide substrate
scope and leads to the formation of the products in good to
À
excellent yields. Further studies to activate the C O bonds
in substituted phenyl ethers more efficiently are under way.
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Experimental Section
Representative procedure: A Schlenk tube was charged with a nickel
complex (the amount needed), THF (2.0 mL), and aryl/alkenyl alkyl
Received: December 27, 2010
Published online: March 1, 2011
ethers (0.5 mmol).
A solution of ArMgBr (0.75 mL, 1m in THF,
0.75 mmol) was added dropwise at 258C under stirring. After stirring at
this temperature for 24 h, the reaction mixture was quenched with water
and extracted with diethyl ether (5 mLꢁ3). The combined organic phases
were dried over MgSO4, concentrated by rotary evaporation and purified
by column chromatography on silica gel.
Chem. Eur. J. 2011, 17, 4972 – 4975
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4975