Nickel-catalyzed cross-coupling of aryltrimethylammonium iodides with organozinc reagents

Article abstract of DOI:10.1002/anie.201100683

Broad scope and good tolerance: An efficient cross-coupling of aryltrimethylammonium iodide salts with aryl-, methyl-, and benzylzinc chlorides catalyzed by [Ni(PCy₃)₂Cl₂] has been achieved (see scheme). The reaction involves cleavage of the C-N bond and displays broad substrate scope and good functional group tolerance. NMP=N-methylpyrrolidine. Copyright

Full text of DOI:10.1002/anie.201100683

DOI: 10.1002/anie.201100683
À
C N Activation
Nickel-Catalyzed Cross-Coupling of Aryltrimethylammonium Iodides
with Organozinc Reagents**
Lan-Gui Xie and Zhong-Xia Wang*
Transition-metal-catalyzed cross-coupling reactions such as
Kumada coupling, Negishi coupling, Suzuki coupling, and
Stille coupling are reliable and versatile methods to construct
carbon–carbon bonds.[1] Among these coupling reactions the
Negishi coupling is one of the most powerful owing to the
wide-spread availability and high functional-group tolerance
of organozinc reagents.[1,2] Electrophiles used in the reaction
are predominantly organic halides.[3] Triflates, mesylates/
tosylates,[4] and carboxylates[5] are also seen as the alternative
coupling partners. However arylamines, whose amino groups
can direct the introduction of other functional groups onto the
aromatic ring (through ortho lithiation and electrophilic
aromatic substitution, etc.), have not yet been employed in
this context.
Table 1: Screening of catalysts and cosolvents.[a]
Entry
Catalyst
Cosolvent
Yield [%][b]
1
2
3
4
[Ni(dppe)Cl2]
[Ni(PPh3)2Cl2]
[Ni(PEt3)2Cl2]
[Ni(PCy3)2Cl2]
[Ni(PCy3)2Cl2]
[Ni(PCy3)2Cl2]+2PCy3
[Ni(acac)2]
PdCl2 +2PPh3
PdCl2 +2PCy3
[Ni(PCy3)2Cl2]
[Ni(PCy3)2Cl2]
[Ni(PCy3)2Cl2]
[Ni(PCy3)2Cl2]
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
–
91
85
94
99
87
89
88
37
37
57
trace
trace
25
5[c]
6[c]
7
8
9
10
11
12
13
Recently, Kakiuchi and co-workers reported ruthenium-
À
toluene
DMA
dioxane
catalyzed Suzuki coupling through cleavage of the C N bond
of anilines with a carbonyl group at the ortho position to act as
the ligating group.[6] Wenkert et al. carried out the nickel-
catalyzed Kumada coupling of aryltrimethylammonium
iodide salts in 1988.[7] Very recently, Reeves et al. developed
the same coupling using aryltrimethylammonium triflates as
the electrophiles and palladium as the catalyst.[8] Blakey and
MacMillan reported the Suzuki coupling of aryltrimethylam-
monium triflates with [Ni(cod)2]/IMes as a catalyst in 2003.[9]
These successes stimulated us to explore the possibility using
arylammonium salts as the electrophilic partners in the
Negishi coupling. Herein, we report our initial studies on
the nickel-catalyzed coupling of aryltrimethylammonium
iodide salts with aryl- and alkylzinc reagents.
[a] The reactions were carried out on a 0.5 mmol scale according to the
conditions indicated by the above equation unless otherwise specified;
1.5 equivalents of p-Me2NC6H4ZnCl was employed. [b] A mixture of the
cross-coupling product and PhNMe2 (formed by hydrolysis of unreacted
p-Me2NC6H4ZnCl) was isolated by column chromatography and the yield
was calculated based on the integratal ratio of 1H NMR spectrum of the
mixture. [c] 1 mol% of catalyst was employed. acac=acetylacetonate,
Cy =cyclohexyl,
DMA=N,N-dimethylacetamide,
dppe=1,2-
bis(diphenylphosphanyl)ethane, NMP=N-methylpyrrolidine, THF=tet-
rahydrofuran.
We first screened the catalysts and solvents using phenyl-
trimethylammonium iodide and p-Me2NC6H4ZnCl as the
substrates (Table 1). On the basis of studies by Wenkert and
MacMillan, nickel complexes can activate the aryl–ammoni-
um bond in both Kumada coupling and Suzuki coupling.[7,9]
Hence we examined a series of nickel complexes as catalyst
precursors. It was found that monodentate and bidentate
phosphine coordinated NiII complexes could drive the reac-
tion to proceed in a 1:1 mixture of THF and NMP (Table 1,
entries 1–5). Complex [Ni(PCy3)2Cl2] gave the best result
compared with the nickel complexes coordinated by PPh3,
PEt3, and dppe, and led to the desired cross-coupling product
in 99% yield of isolated product. Decreasing the [Ni-
(PCy3)2Cl2] loading to 1 mol% resulted in diminished yield
(Table 1, entry 5). The yield was not remarkably enhanced
when an additional 2 mol% of PCy3 was added to the reaction
mixture (Table 1, entry 6). Interestingly, in the absence of
phosphine ligands the [Ni(acac)2] complex also catalyzed the
coupling to give 88% yield (Table 1, entry 7). The same
reaction substrates were also tested with PdCl2/PPh3 and
PdCl2/PCy3 as catalyst precursors. However, these palladium
complexes were not as effective as the nickel analogues for
this transformation (Table 1, entries 8 and 9). Appropriate
cosolvents are also critical. The absence of a cosolvent or
using toluene, DMA, and dioxane as the cosolvents resulted
in much lower yields (Table 1, entries 10–13). The role of
NMP is presumably to stabilize the organometallic inter-
mediates formed during the reaction through its coordination
with the nickel center.[10] It is also possible that the combi-
nation of NMP and THF provides a medium which has the
[*] L.-G. Xie, Prof. Dr. Z.-X. Wang
CAS Key Laboratory of Soft Matter Chemistry
Joint laboratory of Green Synthetic Chemistry and Department of
Chemistry, University of Science and Technology of China
Hefei, Anhui 230026 (China)
Fax: (+86)551-360-1592
E-mail: zxwang@ustc.edu.cn
[**] This research was supported by the National Basic Research
Program of China (grant no. 2009CB825300) and the National
Natural Science Foundation of China (grant no. 20772119).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100683.
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Table 3: Nickel-catalyzed coupling of aryltrimethylammonium iodide
suitable polarity for the reaction of an ammonium salt with
salts with arylzinc reagents.[a]
the active catalyst in the catalytic cycle.[11]
The counterion effect was also investigated by reaction of
the same nucleophile as above with phenyltrimethylammo-
nium salts with BrÀ, ClÀ, BF4À, and OTfÀ, respectively, as a
counterion in a 1:1 mixture of NMP and THF at 908C
(Table 2). In the presence of 2 mol% of [Ni(PCy3)2Cl2] the
tetrafluoroborate salt exhibited the lowest reactivity (Table 2,
entry 1). The bromide and chloride salts showed higher
Entry ArNMe3+IÀ
Product
Yield [%][b]
91
1
1a
4
Table 2: Counterion screening with [Ni(PCy3)2Cl2].[a]
2
1a
88
5
5
3[c]
4
1a
1a
95
84
Entry
X
Amount of
Yield [%][b]
catalyst [mol%]
6
7
1
2
3
4
5
BF4 (1b)
Br (1c)
Cl (1d)
OTf (1e)
OTf (1e)
2
2
2
2
1
64
84
90
99
73
5
6
1a
83
83
[a] The reactions were carried out on a 0.5 mmol scale according to the
conditions indicated by the above equation; 1.5 equivalents of p-
Me2NC6H4ZnCl was employed. [b] Yield of isolated product. Tf=tri-
fluoromethanesulfonyl.
8
9
7
8
89
92
10
12
11
13
reactivity than the tetrafluoroborate (Table 2, entries 2 and
3). The triflate salt was the most reactive among the four
compounds. It led to 99% yield of cross-coupling product
(Table 2, entry 4), being identical with the corresponding
iodide salt. However, when catalyst loading was decreased to
1 mol%, the triflate salt gave a lower yield compared with the
iodide salt (Table 2, entry 5). More examples using arylam-
monium triflates as the electrophilic partners are summarized
in Table S1 in the Supporting Information.
9
96
96
14
15
10
16
16
17
17
11[d]
12
85
92
With the optimized conditions in hand, we next tested the
scope of the cross-coupling reaction (Table 3). Besides p-
Me2NC6H4ZnCl, each of p-MeC6H4ZnCl, o-MeC6H4ZnCl, p-
MeOC6H4ZnCl, and 2-C4H3OZnCl (C4H3O = furyl) coupled
16
18
efficiently with PhNMe3 IÀ (Table 3, entries 1–5). The hin-
+
13
14
15
16
17
87
99
34
87
81
drance of o-MeC6H4ZnCl seems not to affect the coupling
very much. However, increasing the catalyst loading did
significantly enhance the yield (Table 3, entry 3). Bulkier zinc
reagent such as 2,6-(MeO)2C6H3ZnCl did not efficiently
couple with arylammonium salts. Its reaction with
19
21
23
20
22
24
26
27
PhNMe3 IÀ generated only a trace quantity of product.
+
Reaction of o-MeC6H4NMe3+IÀ with p-MeOC6H4ZnCl gave
+
similar yield to PhNMe3 IÀ (Table 3, entry 6). However,
bulkier ammonium salt led to unusual result. A reaction
between 2,4,6-Me3C6H2NMe3 OTfÀ (the corresponding
+
iodide cannot be obtained) and p-MeOC6H4ZnCl under the
same conditions generated 2,4,6-Me3C6H2NMe2 in low yield.
Arylammonium iodide salts with electron-donating substitu-
ents were highly reactive in the coupling. Both p-
25
25
+
+
MeOC6H4NMe3 IÀ and m-MeOC6H4NMe3 IÀ reacted effi-
ciently with p-MeC6H4ZnCl, and afforded the coupling
products in excellent yields (Table 3, entries 8 and 9). These
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Table 3: (Continued)
F3CC6H4ZnCl with an activated ammonium such as p-
EtO2CC6H4NMe3 IÀ afforded the product in excellent yield,
+
Entry ArNMe3+IÀ
Product
Yield [%][b]
37
but
with
a
deactivated
ammonium
salt,
m-
MeOC6H4NMe3 IÀ, led to low product yield (Table 3,
entries 21 and 22). In addition, the reaction can be carried
+
18[e]
21
28
28
28
out on
a bigger scale. Treatment of 5 mmol of p-
19[c,e] 21
58
trace
EtO2CC6H4NMe3 IÀ or m-MeOC6H4NMe3 IÀ with p-
MeC6H4ZnCl resulted in cross-coupling products in 92%
and 93% yields, respectively (Table 3, entries 23 and 24).
We also examined the reactivity of aryltrimethylammo-
nium iodide salts with primary alkylzinc reagents catalyzed by
[Ni(PCy3)2Cl2] (Table 4). Reaction of methylzinc chloride
+
+
20[f]
16
21
16
90
29
22
14
25
30
17
15
23[g]
24[g]
16
14
92
93
Table 4: Nickel-catalyzed coupling of aryltrimethylammonium iodide
salts with alkylzinc reagents.[a]
[a] The reactions were carried out on a 0.5 mmol scale according to the
conditions indicated by the above equation unless otherwise specified;
1.5 equivalents of arylzinc reagent was employed. [b] Yield of isolated
product. [c] 5 mol% of catalyst was employed. [d] Reaction was per-
formed at room temperature. [e] p-EtO2CC6H4ZnI was employed. [f] p-
NCC6H4ZnBr was employed. [g] The reaction was carried out on a
5 mmol scale.
Entry
1
ArNMe3+IÀ
Product
Yield [%][b]
96
16
19
31
32
results are consistent with those reported in arylammonium
Suzuki reaction.[9] The arylammonium salts with an electron-
withdrawing group such as COOEt, PhC(O), and CN each
showed superior reactivity (Table 3, entries 10–14). Reaction
2
3
92
68
of p-EtO2CC6H4NMe3 IÀ with p-MeC6H4ZnCl could even be
+
10
10
33
33
carried out at room temperature although the yield was lower
than that at 908C (Table 3, entries 10 and 11). We and the
Knochel research group previously observed that nitriles are
less active as substrates in the coupling with an arylzinc
4[c]
5
78
89
16
reagent.[3f–h] However, the reaction of p-NCC6H4NMe3 IÀ
+
34
proceeded in a normal fashion when using the present
6
19
19
76
82
catalyst system (Table 3, entry 14), however, p-
FC6H4NMe3 IÀ was an exception. Its reaction with p-
+
35
35
7[c]
MeC6H4ZnCl gave only 34% yield of the cross-coupling
product (Table 3, entry 15), along with 1,4-di(p-tolyl)benzene
(18%) as a side product. This outcome is attributed to the
[a] The reactions were carried out on a 0.5 mmol scale according to the
conditions indicated by the above equation unless otherwise specified;
1.5 equivalents of alkylzinc reagent was employed. [b] Yield of isolated
product. [c] 5mol% of catalyst was employed.
À
cleavage of the aryl F bond under the current reaction
+
conditions. If p-ClC6H4NMe3 IÀ is employed as an electo-
philic partner, no simple cross-coupling product can be
isolated. Instead,
a
disubstituted product of p-
ClC6H4NMe3 IÀ was obtained (Table S2 in the Supporting
Information). Pyridyltrimenthylammonium iodide is also a
good electrophile for the coupling reaction. Its reaction with
p- MeC6H4ZnCl and p-Me2NC6H4ZnCl proceeded in 87%
and 81% yield, respectively (Table 3, entries 16 and 17).
Arylzinc reagents with an electron-withdrawing group
showed lower reactivity. Reaction of p-EtO2CC6H4ZnI with
with aryltrimethylammonium iodide salts that incorporate
electron-withdrawing substituents proceeded smoothly in the
presence of 2 mol% of [Ni(PCy3)2Cl2] and gave the coupling
products in excellent yields (Table 4, entries 1 and 2).
+
+
Reaction of p-(p-MeC6H4)C6H4NMe3 IÀ under the same
conditions resulted in lower yield (Table 4, entry 3). This
outcome is ascribed to an electronic effect exerted by the
substituent on the phenyl ring. Increasing the catalyst loading
improved the yield of the product (Table 4, entry 4). Benzyl-
zinc chloride also reacted smoothly with the activated
either PhNMe3 IÀ or p-MeOC6H4NMe3 IÀ using 2 mol% of
+
+
[Ni(PCy3)2Cl2] as a catalyst gave only a trace amount of
products, and with p-NCC6H4NMe3 IÀ only 37% of cross-
+
+
coupling product was formed (Table 3, entry 18). Increasing
catalyst loading to 5 mol% resulted in 58% yield of the
product (Table 3, entry 19). Reaction of p-NCC6H4ZnBr with
arylammonium iodide salts such as p-EtO2CC6H4NMe3 IÀ
+
and p-PhC(O)C6H4NMe3 IÀ (Table 4, entries 5–7). However,
the yields are lower than those corresponding with MeZnCl.
p-EtO2CC6H4NMe3 IÀ was also unsuccessful. Reaction of p-
In addition, reaction of p-PhC(O)C6H4NMe3 IÀ with either
+
+
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nBuZnCl or EtZnCl resulted in a mixture of the cross-
coupling product and benzophenone. A similar result was
obtained in the nickel-catalyzed cross-coupling reaction of p-
nBuC6H4NMe3 IÀ with iPrMgBr.[7]
+
In summary, a highly efficient process for the nickel-
catalyzed cross-coupling of aryltrimethylammonium iodide
salts with arylzinc or alkylzinc reagents has been developed.
The coupling reaction using arylzinc reagents as nucleophiles
displays a broad substrate scope and good functional group
tolerance. Meanwhile methyl and benzylzinc reagents were
applicable to the coupling with arylammonium iodide salts
containing electron-withdrawing substituents.
Experimental Section
A
representative procedure (Table 2): Aryltrimethylammonium
iodide (0.5 mmol), [Ni(PCy3)2Cl2] (0.0069 g, 0.01 mmol), and NMP
(1.5 mL) were added to a Schlenk tube. To the stirring mixture was
added ArZnCl solution (1.5 mL, 0.5m solution in THF, 0.75 mmol) by
syringe. The reaction mixture was stirred at 908C (bath temperature)
for 8 h and then cooled to room temperature. Water (10 mL) and
several drops of acetic acid were successively added. The resulting
mixture was extracted with Et2O (3 ꢀ 10 mL) and the extract was
dried over Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography on sillca gel (eluent: petroleum
ether or petroleum ether/ethyl acetate 60:1).
Received: January 27, 2011
Revised: March 23, 2011
Published online: April 26, 2011
À
Keywords: C N activation · cross-coupling ·
homogeneous catalysis · nickel · organozinc reagents
.
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