β-Ketoimine as an efficient ligand for copper-catalyzed N-arylation of nitrogen-containing heterocycles with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2008.05.008

An efficient copper catalyst system, Cu₂O/β-ketoimine L₁, for the N-arylation of nitrogen-containing heterocycles with aryl iodides and bromides has been developed. The system works well with the electron-rich, -neutral, and -deficient aryl bromides to afford the products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2008.05.008

Tetrahedron Letters 49 (2008) 4386–4389
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Tetrahedron Letters
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b-Ketoimine as an efficient ligand for copper-catalyzed N-arylation
of nitrogen-containing heterocycles with aryl halides
*
*
Fei Xue, Chengyi Cai, Hongmei Sun , Qi Shen , Jiao Rui
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering Suzhou (Soochow) University,
Ren’ai Road, Suzhou Industrial Park, Suzhou 215123, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient copper catalyst system, Cu O/b-ketoimine L , for the N-arylation of nitrogen-containing
2
1
Received 25 January 2008
Revised 29 April 2008
Accepted 5 May 2008
Available online 9 May 2008
heterocycles with aryl iodides and bromides has been developed. The system works well with the
electron-rich, -neutral, and -deficient aryl bromides to afford the products in good to excellent yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
b-Ketoimine copper-catalyzed
Coupling
N-Arylation
Imidazole
Arylbromide
The Ullmann-type coupling reactions are one of the most pow-
erful approaches for the formations of N-Arylazoles (N-arylimidaz-
oles, N-arylpyrroles, N-arylindoles, etc.) which are the structural
motif found in many biologically active natural products and phar-
bromides or of hindered substrates or of functional substrates by
use of the new ligands explored, such as 4,7-dimethoxy-1,10-
6
7
0
phenanthrolines, (s) pyrrolidinylmethylmidazoles, N,N -dimeth-
8
9
ylethylenediamine, 2-aminopyrimidine-4,6-diol, and b-keto
1
10
maceutically interesting compounds. The traditional copper-cata-
esters. Therefore, the further discovery of new facile ligand
lyzed Ullmann coupling reactions were conducted under harsh
conditions, including high temperature, stoichiometric amount of
copper agent, and extended periods of time. Moreover, the method
has the drawback of low functional group tolerance and poor sub-
structures for the copper-catalyzed cross-coupling reactions of
imidazoles with aryl halides is still an area of considerable interest.
Here we report the efficient use of b-ketoimine for the copper
catalyzed N-arylation of imidazoles with aryl bromides bearing
electron-donating groups (see Scheme 1).
2
3
4
strate generality. Since Buchwald and Taillefer reported, respec-
tively, that copper-based coupling reaction of nitrogen-containing
heterocycles with aryl halides could be improved with an addition
of diamines and oxime/imine derivatives as additives, exhaustive
efforts have been paid to exploring efficient ligands. Indeed, vari-
ous compounds have been found to be efficient as ligands for these
coupling reactions, including amino acids, diamines, diimines,
aminoarenethiol, oxime-phosphine, 8-hydroxyquinoline, 1,10-
1 7
The ligands L –L were synthesized by known literature meth-
1
1
ods (Fig. 1) Reaction of iodobenzene with imidazole was con-
ducted with varied copper salt, ligand, base and solvent in order
to find the optimum conditions. The results are listed in Table
1
2
1. No desired coupling product was obtained without the pres-
ence of copper salt and ligand. It was notable that the reaction with
t
Cu
2
O catalyst and KO Bu as the base could afford the coupling
5
phenanthrolines, etc. However, the majority of the reactions are
product in 47% yield at 60 °C after 24 h without ligand (Table 1,
1
3
limited to the coupling of imidazoles with aryl iodides or of hetero-
arylamines possessing strongly electron-donating groups or aryl
halides with strongly electron-withdrawing groups or of unhin-
dered substrates.
Only very recently have significant advances been achieved for
the copper-catalyzed coupling reactions of imidazoles with aryl
entry 2). Upon addition of a ligand, however, the remarkable
Cu
2
O(5-10%), L
1
(10-20%)
Ar-X
+
Het-NH
Ar-N-Het
o
t-BuOK, DMF, 45-130 C
X=I,Br
Ar=Aryl
Het-NH=N-Heterocycle
*
Corresponding authors. Fax: +86 512 65880306.
E-mail addresses: sunhm@suda.edu.cn (H. Sun), qshen@suda.edu.cn (Q. Shen).
Scheme 1.
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.008

F. Xue et al. / Tetrahedron Letters 49 (2008) 4386–4389
4387
Table 1
F
R
R
Effect of ligand, base, solvent,and copper salt on the coupling of imidazole with
a
iodobenzene
N
O
N
N
Entry
L
x
Copper salt
—
Base
Solvent
Yieldb (%)
L1
R=F (L ), Cl(L )
NRc
47
63
7
2
3
1
2
3
4
5
6
7
8
9
—
—
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
TOL
2
Cu O
F
F
F
F
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
L
1
1
1
1
1
1
1
1
1
1
1
2
3
4
5
6
7
1
1
CuBr
CuCl
CuI
N
N
N
N
N
N
75
90
65
58
45
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
CsCO
3
L4
L5
K
K
3
PO
CO
4
iPr
Pri
2
3
c
10
Na
2
CO
3
NR
N
N
11
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
70
NR
c
1
1
2
3
iPr
iPr
3
CH CN
<5
80
76
67
53
78
L6
L7
14
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
15
Figure 1. Ligands for copper-catalyzed N-arylation of imidazoles.
16
17
18
19
20
21
60
increase in reactivity was observed (Table 1, entries 6 and 14–19).
Among the ligands L –L tested, L is the most efficient, while steric
hindered b-diketiimine L and b-diketiimine with strong electron-
withdrawing groups L are less efficient. For example, the reaction
with L afforded the coupling product in 90% yield using 5 mol %
Cu O at 60 °C after 24 h while only 53% and 60% yields were ob-
tained for the same reaction with L and L , respectively (Table 1,
entries 6, 17, and 19). The catalytic activity of cuprous salts was
d
100
1
7
1
e
84
7
a
Reaction conditions: iodobenzene (1 mmol), imidazole (1.2 mmol), Cu
2
O
5
(
0.05 mmol), ligand (0.1mmol),base (2 mmol) and DMF (1 ml) under Ar atmosphere
1
at 60 °C for 24 h.
2
b
Isolated yields.
No reaction.
At 80 °C.
c
5
7
d
e
2 1
Cu O (0.1 mmol), L (0.2 mmol) at 45 °C.
2
compared and Cu O was found to be the most efficient. The de-
Table 2
Catalytic N-arylation of diazoles with aryl halides by Cu
2
Oa
Entry
Aryl halide
Diazole
Product
Temperature (°C)
Yieldb (%)
90
N
110
1
Br
N
NH
N
N
2
N
NH
N
130
92
Br
N
3
4
5
Br
N
N
N
NH
NH
NH
N
130
130
130
99
92
91
N
OMe
OMe
Br
OMe
OMe
N
N
Br
N
N
MeO
Br
OMe
N
6
N
NH
130
73
N
7
8
9
OH
NH2
N
Br
N
N
N
NH
NH
NH
HO
N
130
130
130
95
85
N
Br
H N
2
N
N
Br
N
N
98
(continued on next page)

4
388
F. Xue et al. / Tetrahedron Letters 49 (2008) 4386–4389
Table 2 (continued)
Entry
Aryl halide
Diazole
Product
Temperature (°C)
Yieldb (%)
95
10
11
12
13
N
130
N
N
NH
NH
Cl
Cl
Br
N
N
53/70d
57/73d
92
O N
2
Br
O N
2
N
130
130
130
N
N
N
NH
NH
H COC
3
H COC
Br
3
N
Br
N
N
N
H
N
1
4
5
I
80
96c
82
H
N
1
Br
N
110
1
6
7
I
110
130
95c
45
N
N
N
H
1
Br
N
H
a
t
1 2
Reaction conditions: aryl halide (1.0 mmol), Het-NH (1.2 mmol), KO Bu (2.0 mmol) in the presence of L (20 mmol %) and Cu O (10 mmol %) in 1.0 ml of DMF under Ar
atmosphere for 24 h.
b
Isolated yields.
c
Cu
2
O (0.05 mmol), L
1
(0.1 mmol).
t
d
Cs
2
3
CO (2 mmol) instead of KO Bu.
crease in the order Cu
entries 3–6). Base influenced the progress of the reaction greatly.
The highest yield was obtained when KO Bu was used (Table 1,
entries 6–10). Of the solvents investigated, DMF was found to be
2
O > CuI > CuBr > CuCl was observed (Table 1,
Arylation of other N-containing heterocycles with aryl halides
was then examined (Table 2). The present catalyst system was
found to be efficient for the arylation of pyrrole with iodobenzene
at 80 °C to afford the product in 96% yield after 24 h, even the
t
the most effective, whereas CH
Table 1, entries 12 and 13). It was notable that the reaction could
be conducted at temperatures as low as 45 °C with 10 mol % Cu
3
CN and toluene were ineffective
2
amount of Cu O decreased to 5 mol % ( Table 2, entry 14). Further-
more, the catalyst system could also be applied in the reaction of
indole with iodobenzene. The corresponding product in high yield
(
2
O
t
and KO Bu in DMF to give the product in 84% yield (Table 1, entry
1).
The arylation of imidazole with various aryl bromides and of N-
2
(95%) was obtained at 110 °C with the same amount of Cu O (Table
2
2, entry 16). It was expected that the same two reactions with bro-
mobenzene were relatively difficult. To obtain the coupling product
in good yield (82%) for the reaction of pyrrole with bromobenzene,
containing heterocycles with aryl halides was further examined
under the optimum conditions to evaluate the scope and the
2
the amount of Cu O needs to increase to 10 mol % and the reaction
generality of Cu
2
O/L
1
system.
temperature should raise to 110 °C related to that with iodobenz-
ene (Table 2, entry 15). The arylation of indole with bromobenzene
afforded the product in moderate yield, even the reaction tempera-
ture increased to 130 °C (Table 2, entry 17).
In summary, b-ketoimine was found to be an efficient, inexpen-
2
sive, and facile ligand for the Cu O-catalyzed N-arylation of imida-
The reaction of imidazole with electron-rich, -neutral, and -defi-
cient aryl bromides was first tested, since substrates which contain
certain functional groups have proven to be problematic in the aryl-
ation of imidazoles. The results are collected in Table 2. As shown
in Table 2, the reactions with these aryl bromides proceeded
smoothly with 10 mol % Cu
2
O to provide the corresponding cou-
zoles with aryl iodides and bromides. Particularly, the system
works well with the electron-rich, -neutral, and -deficient aryl bro-
mides. The further study on design and application of new ligands
in copper based Ullmann-type coupling reaction is currently
ongoing.
pling products in good to excellent yields. Notably, the present
catalyst system could facilitate the arylation of imidazole with
ortho-substituted aryl bromides. For example, the reaction of
imidazole with 2-methyl bromobenzene and 2-methoxybromo-
benzene afforded the corresponding coupling products in 92%
and 73% yields at 130 °C (Table 2, entries 2 and 6). Generally, the
Ullmann-type condensations are sensitive to steric hindrance near
the halogen atom, and only a few examples concerning with the
Cu-catalyzed arylation of imidazole with hindered aryl halides
Acknowledgment
The authors are grateful to the National Natural Science Foun-
dation of China for the financial support.
were found in the literatures.6 The reaction with 4-NO
and 4-CH COC Br afforded the corresponding product in moder-
ate yields, 53% and 57%. The yields can be improved to 70% and
2 6 4
C H Br
3
6 4
H
References and notes
t
7
3%, respectively, when CsCO
3
was used, instead of KO Bu as the
1.
(a) Cozzi, P.; Carganico, G.; Fusar, D.; Grossoni, M.; Menichincheri, M.; Pinciroli,
base (Table 2, entries 11 and 12).
V.; Tonani, R.; Vaghi, F.; Salvati, P. J. Med. Chem. 1993, 36, 2964; (b) Craig, P. N.

F. Xue et al. / Tetrahedron Letters 49 (2008) 4386–4389
4389
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1
characterization data for L . A mixture of acetylacetone (25.75 ml, 0.25 mol),
4-fluoroaniline (24.0 ml, 0.25 mol), and (5 mmol) toluene-4-sulfonic acid was
refluxed for 4 h in toluene, and the water was removed. The reaction mixture
was filtered through a plug of silica gel and concentrated to dry in vacuo. The
residue was dissolved in refluxing hexane and then cooled for crystallization.
2
.
.
Ligand L
(300 MHz, CDCl
1
was obtained as colorless crystals. (33.8 g, 70% yield). 1H NMR
3
): d 1.91 (s, 3H), 2.08 (s, 3H), 5.18 (s, 1H), 7.00–706 (m, 4H),
13
3
12.33 (s, 1H) ppm. C NMR: d 19.6, 29.1, 97.4, 115.7, 116.0, 126.7, 126.8, 134.6,
135.0, 158.9, 160.4, 162.1, 196.2 ppm. HRMS m/z: 193.0910 (193.0903 calcd.
(
1
b) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
23, 7727; (c) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org.
for C11H12NOF ). Mp: 45.9–47.2C. °C.
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(a) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M. Eur. J. Org. Chem. 2004,
12. A typical procedure for the arylation is as follows: To a solution of imidazole
(1.2 mmol) and iodobenzene (1 mmol) in DMF (1 ml) under an argon
4
.
.
6
1
2
95; (b) Taillefer, M.; Cristau, H. J.; Cellier, P. P.; Spindler, J. F. FR 2001, 01,
6547; (c) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M. Chem. Eur. J.
004, 10, 5607.
atmosphere were added Cu O (7.2 mg, 5 mol %), L (19.3 mg, 10 mol %), and
2
1
t
KO Bu (2 mmol, 224 mg)in turn under Ar atmosphere. The reaction mixture
was stirred for 20 min at room temperature, and then heated to 60 °C for 24 h.
The reaction mixture was then cooled to ambient temperature, diluted with
2–3 ml of ethyl acetate, filtered through a plug of silica gel, and washed with
ethyl acetate (3 ꢀ 20 ml). The filtrate was concentrated and the resulting
residue was purified by column chromatography on silica gel to provide the
5
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desired product (138 mg, 90% yield).
1
1-Phenyl-1H-imidazole (Table 1). H NMR (300 MHz, CDCl
3
): d 7.22 (s, 1H), 7.30
13
(s, 1H), 7.36–7.41 (m, 3H), 7.47–7.51 (m, 2H), 7.87 (s, 1H) ppm. C NMR: d
118.1, 121.3, 127.4, 129.8, 130.3, 135.4, 137.2 ppm. HRMS m/z: 144.0685
6
7
8
9
.
.
.
.
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9 8 2
(144.0687 calcd. for C H N ).
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