A versatile and efficient cu-catalyzed N-Arylation of aromatic cyclic secondary amines with aryl halides

Article abstract of DOI:10.2174/157017811795684974

A copper-catalyzed coupling reaction of aryl halides with various aromatic cyclic secondary amines in DMSO has been developed efficiently. The versatile and efficient copper catalyst system is of wide-spread and practical application in cross-coupling reactions.

Full text of DOI:10.2174/157017811795684974

Letters in Organic Chemistry, 2011, 8, 325-331
325
A Versatile and Efficient Cu-Catalyzed N-Arylation of Aromatic Cyclic
Secondary Amines with Aryl Halides
Haitao Yang, Zhiwei Miao* and Ruyu Chen*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, People’s Republic of China
Received August 28, 2010: Revised February 09, 2011: Accepted February 25, 2011
Abstract: A copper-catalyzed coupling reaction of aryl halides with various aromatic cyclic secondary amines in DMSO
has been developed efficiently. The versatile and efficient copper catalyst system is of wide-spread and practical
application in cross-coupling reactions.
Keywords: N-Arylation, Aromatic cyclic secondary amines, Copper catalyst, Cross-coupling.
Aryl-functionalized N-heterocyclic moieties play
important roles in organic synthesis, pharmaceutical, or
biological areas [1]. The most practical methods in
synthesizing arylated N-heterocycle compounds are classic
Ullmann-type coupling reactions [2]. Copper catalyzed
Ullmann coupling is recognized as one of the most common
synthetic protocols for their preparation [3]. However, these
methods suffer from the harsh reaction conditions such as
high temperatures (125-220ºC), the requirement of a
stoichiometric amount of copper catalyst, and the low to
moderate yields, which have limited their applications [4].
Thus, the development of a mild as well as highly efficient
method for constructing N-arylazole units has received
increasing interest.
We first focused on the N-arylation of imidazole without
ligand as the model substrates for optimization of the
reaction conditions, and the results are summarized in Table
1. CuSO4, Cu(AcO)2, Cu2O, and CuI were tested as copper
sources in the Ullmann condensation with DMSO as solvent
and K2CO3 as base at 80°C, and the results showed that CuI
was the best catalyst (entries 1-4, Table 1). A blank
experiment confirmed that in the absence of the metal
catalyst no arylated product was formed. We next examined
the effect of base on the coupling reaction. After screening a
variety of bases (i. e., K2CO3, K3PO4, KOH, NaOt-Bu,
Na2CO3, and Cs2CO3), we found that Cs2CO3 gave the best
result of 98% yield in DMSO (entries 4-9, Table 1).
Furthermore, we studied the effect of the amount of CuI on
the reaction efficiency, and found that the negative effect
was observed while the amount of CuI was reduced or
increased (entry 10-11, Table 1). Probing of the solvent
effect revealed that DMSO was superior to 1,2-
dichloroethane, dioxane or toluene (entries 12-14, Table 1).
Compared with You’s work [9h], DMSO was recognized as
another good choice for N-arylation of aromatic cyclic
secondary amines. Thus, the optimal reaction conditions for
this transformation were determined to be 1.0 mmol aryl
halides (1), 1.1 equivalents of azoles (2), 10 mol% of CuI
and 2.0 equivalents of Cs2CO3 in DMSO as solvent at 80 °C
under nitrogen atmosphere.
In the past few years, much attention has been paid to the
improvement of these type of transformations, and a number
of ligands have thereby been developed to facilitate various
copper catalyzed carbon-heteroatom coupling reactions [5].
An effective catalytic system was recently reported by Lv
and Bao, who used the ꢀ-ketoester ligand to perform the N-
arylation reaction at mild temperature [6]. Ma and co-
workers showed that amino acids were excellent bidentate
ligands for copper-catalyzed Ullmann-type reactions [5f, 7].
Recently, Chen also reported that 1,3-diketone combined
with CuI is an efficient catalytic system for the coupling of
aryl bromides with nitrogen heterocycles [8]. Despite these
advances, considerable attention has been focused on the
development of cheap, experimentally simple, ligand-free
catalytic systems [9]. For example, You and co-workers
developed a copper-catalyzed process for the N-arylation
reaction under very mild conditions in the absence of
additional ligand and the reaction temperature can be
reduced to below 40 °C [9h]. Herein, we wish to report our
preliminary findings on copper iodide catalyzed N-arylation
of a variety of aromatic cyclic secondary amines under very
mild conditions.
Based on the above optimization efforts, the substrate
scope of this reaction was investigated. We applied this
process to a series of nitrogen heterocycles and aryl halide
derivatives. The results indicated that all the examined
substrates could furnish the desired products in good to
excellent yields. The electronic nature of the aryl iodide was
found to have some effect on the reaction yields. Both the
electron-donating and electron-withdrawing group on the
aryl halides underwent the reaction to afford high yields
ranging from 51 to 95%. Electron-withdrawing groups on
the aryl halides usually promoted the reactions (entries 4-9,
Table 2). Notably, we were able to exploit the difference in
reactivity of aryl halides (I > Br > Cl) in the present method
(entries 5-7, Table 2) [6, 10]. Furthermore, good to excellent
yields of N-arylimidazole were obtained when other kinds of
*Address correspondence to these authors at the State Key Laboratory of
Elemento-Organic Chemistry, Research Institute of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071, People’s Republic of China;
Tel: +86-22-23504783: Fax: +86-22-23502351;
E-mail: miaozhiwei@nankai.edu.cn
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

326 Letters in Organic Chemistry, 2011, Vol. 8, No. 5
Yang et al.
Table 1. The Screening of Reaction Conditions for the N-Arylation of Imidazoles with Iodobenzenea
N
N
[Cu] cat., base
solvent, 80 ꢁC
I
N
+
N
H
1a
2a
3a
Entry
Catalyst
Base
Solvent
Yieldb (%)
1
2
CuSO4
Cu(OAc)2
Cu2O
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
25
31
87
91
82
35
66
49
98
65
65
0
3
4
5
CuI
6
CuI
KOH
7
CuI
NaOt-Bu
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
8
CuI
9
CuI
10c
11d
12
13
14
CuI
CuI
CuI
ClCH2CH2Cl
1,4-dioxane
toluene
CuI
0
CuI
0
aReaction conditions: 1a (1.0 mmol), 2a (1.1 mmol), base (2.0 mmol) in the presence of [Cu] cat. (10 mol%) in 2.0 mL of solvent at 80 °C under N2 atmosphere for 24 h.
bIsolated yield.
c5 mol% of CuI was used.
d20 mol% of CuI was used.
Table 2. Copper-Catalyzed Cross-Coupling of Imidazole with Different Substituted Aryl Halidesa
N
CuI (10 mol%)
N
Ar-X
+
N
Ar
Cs2CO3, DMSO
80 ꢂC, 24 h
N
H
X = I, Br
1
2a
3
Yieldb (%)
Aryl halides
Product
Entry
N
N
1
I
98
51
1a
3a
I
N
N
2
3
3b
1b
I
N
H3CO
N
86
1c
3c
H3CO
O2N
Cl
I
N
O2N
4
5
N
95
87
1d
3d
I
N
Cl
N
3e
1e

A Versatile and Efficient Cu-Catalyzed N-Arylation
Letters in Organic Chemistry, 2011, Vol. 8, No. 5
327
(Table 2). Contd…..
Yieldb (%)
Aryl halides
Entry
Product
I
N
Br
N
6
7
80
62
1f
3f
Br
Cl
Cl
N
N
3g
I
1g
F3C
F3C
N
N
I
3h
8
89
1h
F3C
F3C
NO2
NO2
N
N
9
94
65
3i
N
Br
I
1i
N
1j
3j
10
OCH3
N
OCH3
11
12
N
N
66
98
1k
1l
I
3k
3a
Br
N
13
79
1m
N
3m
Br
N
N
Br
N
14
15
90
91
1n
3n
N
N
Br
3o
1o
aReaction conditions: 1 (1.0 mmol), 2a (1.1 mmol), Cs2CO3 (2.0 mmol) in the presence of CuI (10 mol%) in 2.0 mL of solvent at 80 °C under N2 atmosphere for 24 h.
bIsolated yield.
aryl halides such as bromoanthracene, bromonaphthalene
and 4-bromobiphenyl were used (entries 13-15, Table 2)
[11].
yields. A variety of aryl iodides bearing both electron-
donating and electron-withdraw groups underwent the
reaction to afford good yields ranging from 55-98% (entries
1-10, Table 3). 2-Bromopyridine was also found exclusively
react with imidazole and afforded corresponding coupling
product in 90% yield (entry 11, Table 3).
In an endeavour to expand the scope of the methodology,
this new catalytic system was applied to a variety of N-
heterocycles derivatives, and the results are shown in Table
3. Under similar conditions, the coupling reactions of
benzimidazole, indole, benzotriazole, and pyrrole were found
to afford the corresponding N-arylated products in good
The possible mechanism for this coupling reaction is
shown in Scheme 1 that is based on the previously proposed
mechanism [3b, 4b, 4c, 5b, 12]. The rapid coordination and

328 Letters in Organic Chemistry, 2011, Vol. 8, No. 5
Table 3. Copper Catalyzed N-Arylation of Azoles with Iodobenzene and Bromobenzenea
CuI (10 mol%)
Yang et al.
X
+
Het-NH
N-Het
Cs2CO3, DMSO
80 ꢃC, 24 h
R
R
Y
Y
X = I, Br
Y = CH, N
1
2
3
Yieldb (%)
Het-NH
ArX
Product
Entry
N
N
N
I
1
96
N
H
3p
1a
2b
2b
N
I
N
N
2
55
N
H
3q
1b
I
N
OCH3
N
N
3
80
N
H
1c
3r
2b
OCH3
I
N
N
N
NO2
4
5
6
82
93
55
1d
N
H
3s
2b
2b
2b
NO2
I
N
N
N
Cl
1e
N
H
3t
Cl
I
N
N
N
N
H
1g
3u
O2N
NO2
N
N
N
Br
7
98
N
H
2b
3v
1l
N
I
8
98
N
H
3w
1a
2c

A Versatile and Efficient Cu-Catalyzed N-Arylation
Letters in Organic Chemistry, 2011, Vol. 8, No. 5
329
(Table 3). Contd…..
Yieldb (%)
Het-NH
Entry
ArX
Product
I
I
N
Cl
9
94
2d
N
Cl
Br
H
3x
1e
H
N
N
Br
N
N
N
10
11
77
90
N
3y
1f
2e
N
N
Br
N
2a
N
N
N
H
1p
3z
aReaction conditions: 1 (1.0 mmol), 2 (1.1 mmol), Cs2CO3 (2.0 mmol) in the presence of CuI (10 mol%) in 2.0 mL of solvent at 80 °C under N2 atmosphere for 24 h.
bIsolated yield.
Ar
N
S
N
O
O
S
Cu
S
reductive
elimination
N
I
O
X
Cu
N
H
O
S
N
N
Ar
TS III
S
oxidative
addition
O
Cu
O
S
S
N
I
ArX
O
N
H
Cu
S
O
TS I
B
N
N
TS II
B HI
Scheme 1.
dissolution of copper (I) iodide by heterocycles, such as
imidazole, in DMSO to form a transition state I (TS I)
involves a four-coordination copper complex. In the
presence of base, TS I released one molecular of HI to afford
TS II. The next step involves the oxidative addition of the
aryl halides to form a five-coordination copper complex (TS
III). The TS III complex can undergo reductive elimination
to give the C-N cross coupled products and regenerate the
active Cu (I) species.
In conclusion, we have developed a versatile and
efficient CuI-catalyzed N-arylation of aromatic cyclic
secondary amines with a variety of aryl iodides and
bromides in the absence of additional ligand in which
DMSO actually acted as both a ligand and a solvent. The
present protocol is applicable to a variety of nitrogen
heterocycles and aryl halides containing electron donating
and electron withdrawing substrates in good to excellent
product yields. The further study on broadening the scope of

330 Letters in Organic Chemistry, 2011, Vol. 8, No. 5
Yang et al.
Am. Chem. Soc. 2002, 124, 11684-11688. (c) Antilla, J. C.; Baskin,
J. M.; Barder, T. E.; Buchwald, S. L. Copper-diamine-catalyzed N-
arylation of pyrroles, pyrazoles, indazoles, imidazoles, and
triazoles. J. Org. Chem. 2004, 69, 5578-5587. (d) Altman, R. A.;
Buchwald, S. L. 4, 7-Dimethoxy-1,10-phenanthroline: an excellent
ligand for the Cu-catalyzed N-arylation of imidazoles. Org. Lett.
2006, 8, 2779-2782. (e) Altman, R. A.; Koval, E. D.; Buchwald, S.
L. Copper-catalyzed N-arylation of imidazoles and benzimidazoles.
J. Org. Chem. 2007, 72, 6190-6199. (f) Strieter, E. R.; Bhayana, B.;
Buchwald, S. L. Mechanistic studies on the copper-catalyzed N-
arylation of amides. J. Am. Chem. Soc. 2009, 131, 78-88. (g) Liang,
L.; Li, Z. K.; Zhou, X. G. Pyridine N-oxides as ligands in Cu-
catalyzed N-arylation of imidazoles in water. Org. Lett. 2009, 11,
3294-3297.
this catalytic system to catalyze C-C and C-O cross-coupling
reaction and to understand the mechanism is currently on
going.
ACKNOWLEDGEMENTS
We thank the National Natural Science Foundation of
China (21072102), Project 973 of the Ministry of Science
and Technology of China (2007CB914800) and State Key
Laboratory of Elemento-Organic Chemistry in Nankai
University for financial support.
[3]
[4]
(a) Ullmann, F. Ueber eine neue bildungsweise von
diphenylaminderivaten. Ber. Dtsch. Chem. Ges. 1903, 36, 2382-
2384. (b) Lindley, J. Tetrahedron report number 163: copper
assisted nucleophilic substitution of aryl halogen. Tetrahedron
1984, 40, 1433-1456.
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers
Web site along with the published article.
For reviews of copper-catalyzed reactions, see: (a) Kunz, K.;
Scholz, U.; Ganzer, D. Renaissance of Ullmann and Goldberg
reactions-progress in copper catalyzed C-N-, C-O- and C-S-
coupling. Synlett. 2003, 2428-2439. (b) Beletskaya, I. P.;
Cheprakov, A. V. Copper in cross-coupling reactions: the post-
Ullmann chemistry. Coord. Chem. Rev. 2004, 248, 2337-2364. (c)
Ley, S. V.; Thomas, A. W. Modern synthetic methods for copper-
mediated C(aryl)O, C(aryl)N, and C(aryl)S bond formation.
Angew. Chem. Int. Ed. 2003, 42, 5400-5449. (d) Evano, G.;
Blanchard, N.; Toumi, M. Copper-mediated coupling reactions and
their applications in natural products and designed biomolecules
synthesis. Chem. Rev. 2008, 108, 3054-3131. (e) Monnier, F.;
Taillefer, M. Catalytic C-C, C-N, and C-O Ullmann-Type Coupling
Reactions. Angew. Chem. Int. Ed. 2009, 48, 6954-6971.
REFERENCES
[1]
(a) Barchechath, S. D.; Tawatao, R. I.; Corr, M.; Carson, D. A.;
Cottam, H. B. Inhibitors of apoptosis in lymphocytes: synthesis and
biological evaluation of compounds related to pifithrin-ꢀ. J. Med.
Chem. 2005, 48, 6409-6422. (b) Zhong, C.; He, J.; Xue, C.; Li, Y.
A QSAR study on inhibitory activities of 1-phenylbenzimidazoles
against the platelet-derived growth factor receptor. Bioorg. Med.
Chem. 2004, 12, 4009-4015. (c) Theil, F. Synthesis of diaryl ethers:
a long-standing problem has been solved. Angew. Chem. Int. Ed.
1999, 38, 2345-2347. (d) Quan, M. L.; Lam, P. Y. S.; Han, Q. D.;
Pinto, J. P.; He, M.; Li, Y. R.; Ellis, C. D.; Clark, C. G.; Teleha, C.
A.; Sun, J. H.; Alexander, R. S.; Bai, S.; Luettgen, J. M.; Knabb, R.
[5]
For papers on copper-catalyzed N-arylations of imidazoles with
aryl halides, see: (a) Liu, Y. H.; Chen, C.; Yang, L. M.
Diazabutadiene: a simple and efficient ligand for copper-catalyzed
N-arylation of aromatic amines. Tetrahedron Lett. 2006, 47, 9275-
9278. (b) Xie, Y. X.; Pi, S. F.; Wang, J.; Yin, D. L.; Li, J. H. 2-
Aminopyrimidine-4,6-diol as an efficient ligand for solvent-free
copper-catalyzed N-arylations of imidazoles with aryl and
heteroaryl halides. J. Org. Chem. 2006, 71, 8324-8327. (c) Kuil,
M.; Bekedam, E. K.; Visser, G. M.; van den Hoogenband, A.;
Terpstra, J. W.; Kamer, P. C. J.; Van Leeuwen, P. W. N. M.; van
Strijdonck, G. P. F. Mild copper-catalyzed N-arylation of
azaheterocycles with aryl halides. Tetrahedron Lett. 2005, 46,
2405-2409. (d) Alcalde, E.; Dinarès, I.; Rodríyguez, S.; Garcia de
Miguel, C. Synthetic approaches to sterically hindered N-
arylimidazoles through copper-catalyzed coupling reactions. Eur. J.
Org. Chem. 2005, 1637-1643. (e) Jerphagnon, T.; van Klink, G. P.
M.; de Vries, J. G.; van Koten, G. Aminoarenethiolate-copper (I)-
catalyzed amination of aryl bromides. Org. Lett. 2005, 7, 5241-
5244. (f) Zhang, H.; Cai, Q.; Ma, D. Amino acid promoted CuI-
catalyzed C-N bond formation between aryl halides and amines or
N-containing heterocycles. J. Org. Chem. 2005, 70, 5164-5173. (g)
Liu, L.; Frohn, M.; Xi, N.; Dominguez, C.; Hungate, R.; Reider, P.
J. A soluble base for the copper-catalyzed imidazole N-arylations
with aryl halides. J. Org. Chem. 2005, 70, 10135-10138. (h) Rao,
H.; Fu, H.; Jiang, Y.; Zhao, Y. Kumada coupling of aryl and vinyl
tosylates under mild conditions. J. Org. Chem. 2005, 70, 8107-
8109. (i) Zhang, Z.; Mao, J.; Zhu, D.; Wu, F.; Chen, H.; Wan, B.
Highly efficient and practical phosphoramidite-copper catalysts for
amination of aryl iodides and heteroaryl bromides with alkylamines
and N(H)-heterocycles. Tetrahedron 2006, 62, 4435-4443. (j)
Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Venkanna, G. T.;
Sreedhar, B. Design and evolution of copper apatite catalysts for N-
arylation of heterocycles with chloro-and fluoroarenes. J. Am.
Chem. Soc. 2005, 127, 9948-9949. (k) Son, S. U.; Park, I. K.; Park,
J.; Hyeon, T. Synthesis of Cu2O coated Cu nanoparticles and their
successful applications to Ullmann-type amination coupling
reactions of aryl chlorides. Chem. Commun. 2004, 778-779.
M.; Wong, P. C.; Wexler, R. R. Discovery of 1-(3ꢀ-
Aminobenzisoxazol-5ꢀ-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2ꢀ-
dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-
carboxyamide hydrochloride (razaxaban),
a highly potent,
selective, and orally bioavailable factor Xa inhibitor. J. Med.
Chem. 2005, 48, 1729-1744. (e) Dyck, B.; Goodfellow, V. S.;
Phillips, T.; Grey, J.; Haddach, M.; Rowbottom, M.; Naeve,;G. S.;
Brown, B.; Saunders, J. Potent imidazole and triazole CB1 receptor
antagonists related to SR141716. Bioorg. Med. Chem. Lett. 2004,
14, 1151-1154. (f) Smallheer, J. M.; Alexader, R. S.; Wang, J.;
Wang, S.; Nakajima, S.; Rossi, K. A.; Smallwood, A.; Barbera, F.;
Burdick, D.; Luettgen, J. M.; Knabb, R. M.; Wexler, R. R.; Jadhav,
P. K. SAR and factor IXa crystal structure of a dual inhibitor of
factors IXa and Xa. Bioorg. Med. Chem. Lett. 2004, 14, 5263-5267.
(g) Venkatesan, A. M.; Gu, Y.; Santos, O. D.; Abe, T.; Agarwal,
A.; Yang, Y.; Petersen, P. J.; Weiss, W. J.; Mansour, T. S.;
Nukaga, M.; Hujer, A. M.; Bonomo, R. A.; Knox, J. R. Structure-
activity relationship of 6-methylidene penems bearing tricyclic
heterocycles
as
broad-spectrum
ꢄ-lactamase
inhibitors:
crystallographic structures show unexpected binding of 1,4-
thiazepine intermediates. J. Med. Chem. 2004, 47, 6556-6568. (h)
Lange, J. H. M.; van Stuivenberg, H. H.; Coolen, H. K. A. C.;
Adolfs, T. J. P.; McCreary, A. C.; Keizer, H. G.; Wals, H. C.;
Veerman, W.; Borst, A. J. M.; de Looff, W.; Verveer, P. C.; Kruse,
C. G. Synthesis, biological properties, and molecular modeling
investigations of thiazoles, triazoles, and imidazoles as potent and
selective CB1 cannabinoid receptor antagonists. J. Med. Chem.
2005, 48, 1823-1838. (i) Campeau, L.C.; Fagnou, K. Direct
transition metal-catalyzed functionalization of heteroaromatic
compounds. Chem. Soc. Rev. 2007, 36, 1173-1193. (j) Wiglenda,
T.; Gust, R. Structure-activity relationship study to understand the
estrogen receptor-dependent gene activation of aryl- and alkyl-
substituted 1H-imidazoles. J. Med. Chem. 2007, 50, 1475-1484. (k)
Kison, C.; Opatz, T. Modular synthesis of tetrasubstituted
imidazoles and trisubstituted oxazoles by aldimine cross-coupling.
Chem. Eur. J. 2009, 15, 843-845.
[6]
[7]
Lv, X.; Bao, W. A ꢄ-keto ester as a novel, efficient, and versatile
ligand for copper(I)-catalyzed C-N, C-O, and C-S cupling ractions.
J. Org. Chem. 2007, 72, 3863-3867.
(a) Ma, D.; Cai, Q. L-Proline promoted Ullmann-type coupling
reactions of aryl iodides with indoles, pyrroles, imidazoles or
pyrazoles. Synlett 2004, 128-130. (b) Cai, Q.; Zhu, W.; Zhang, H.;
Zhang, Y.; Ma, D. Preparation of N-aryl compounds by amino
[2]
(a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. A
general and efficient copper catalyst for the amidation of aryl
halides and the N-arylation of nitrogen heterocycles. J. Am. Chem.
Soc. 2001, 123, 7727-7729. (b) Antilla, J. C.; Klapars, A.;
Buchwald, S. L. The copper-catalyzed N-arylation of indoles. J.

A Versatile and Efficient Cu-Catalyzed N-Arylation
Letters in Organic Chemistry, 2011, Vol. 8, No. 5
331
acid-promoted Ullmann-type coupling reactions. Synthesis, 2005,
496-499.
Xi, Z.; Liu, F.; Zhou, Y.; Chen, W. CuI/L (L=pyridine-
functionalized 1,3-diketones) catalyzed C–N coupling reactions of
aryl halides with NH-containing heterocycles. Tetrahedron 2008,
64, 4254-4259.
catalyzed amination of aryl halides in water. Eur. J. Org. Chem.
2009, 635-642. (c) Rao, H. H.; Jin, Y.; Fu, H.; Jiang, Y. Y.; Zhao,
Y. F. A versatile and efficient ligand for copper-catalyzed
[8]
[9]
formation of C-N, C-O, and P-C Bonds: pyrrolidine-2-phosphonic
acid phenyl monoester. Chem. Eur. J. 2006, 12, 3636-3646.
General procedure for C-N coupling reaction of aryl halide and
heterocycle: A flame-dried Schlenk test tube with a magnetic
stirring bar was charged with CuI (19.2 mg, 0.1 mmol), Cs2CO3
(650 mg, 2.0 mmol), nitrogen-containing heterocycle (1.1 mmol),
aryl halide (1.0 mmol), and DMSO (2 mL) under nitrogen
atmosphere. A rubber septum was replaced with a glass stopper,
and the system was then evacuated twice and back filled with
nitrogen. After being stirred at 80 °C for 24 h, the reaction mixture
was diluted with 5 mL of ethyl acetate, filtered through a plug of
silica gel, and washed with 10-20 mL of ethyl acetate. The filtrate
was concentrated and the resulting residue was purified by column
chromatography on silica gel (ethyl acetate-petroleum ether) to
provide the desired product.
(a) Cohen, T.; Wood, J.; Jr. Dietz, A. G. Organocopper
intermediates in the exchange reaction of aryl halides with salts of
copper(I). The possible role of copper(III). Tetrahedron Lett. 1974,
15, 3555-3558. (b) Paine, A. J. Mechanisms and models for copper
mediated nucleophilic aromatic substitution. 2. Single catalytic
species from three different oxidation states of copper in an
Ullmann synthesis of triarylamines. J. Am. Chem. Soc. 1987, 109,
1496-1502. (c) Aalten, H. L.; van Koten, G.; Grove, D. M.;
Kuilman, T.; Piekstra, O. G.; Hulshof, L. A.; Sheldon, R. A. The
copper catalysed reaction of sodium methoxide with aryl bromides.
A mechanistic study leading to a facile synthesis of anisole
derivatives. Tetrahedron 1989, 45, 5565-5578. (d) Zhang, S.;
Zhang, D.; Liebeskind, L. S. Ambient temperature, Ullmann-like
reductive coupling of aryl, heteroaryl, and alkenyl halides. J. Org.
Chem. 1997, 62, 2312-2313.
[11]
Selected examples in the absence of additional ligand: (a) Correa,
A.; Bolm, C. Ligand-free copper-catalyzed N-arylation of nitrogen
nucleophiles. Adv. Synth. Catal. 2007, 349, 2673-2676. (b)
Taillefer, M.; Xia, N.; Oualli, A. Efficient iron/copper Co-catalyzed
arylation of nitrogen nucleophiles. Angew. Chem. Int. Ed. 2007, 46,
934-936. (c) Zhao, Y.; Wang, Y.; Sun, H.; Li, L.; Zhang, H.
Ullmann reaction in tetraethyl orthosilicate: a novel synthesis of
triarylamines and diaryl ethers. Chem. Commun. 2007, 3186-3188.
(d) Rout, L.; Sen, T. K.; Punniyamurthy, T. Efficient CuO-
nanoparticle-catalyzed C-S cross-coupling of thiols with
iodobenzene. Angew. Chem. Int. Ed. 2007, 46, 5583-5586. (e)
Sperotto, E. G.; van Klink, P. M.; de Vries, J. G.; van Koten, G.
Ligand-free copper-catalyzed CꢀS coupling of aryl iodides and
thiols. J. Org. Chem. 2008, 73, 5625-5628. (f) Zhu, R.; Xing, L.;
Wang, X.; Cheng, C.; Su, D.; Hu, Y. Highly practical “ligand-free-
like” copper-catalyzed N-arylation of azoles in lower nitrile
solvents. Adv. Synth. Catal. 2008, 350, 1253-1257. (g) Kelkar, A.
A.; Patil, N. M.; Chaudhari, R. V. Copper-catalyzed amination of
aryl halides: single-step synthesis of triarylamines. Tetrahedron
Lett. 2002, 43, 7143-7146. (h) Zhu, L. B.; Li, G. C.; Luo, L.; Guo,
P.; Lan, J. B.; You, J. S. Highly functional group tolerance in
copper-catalyzed N-arylation of nitrogen-containing heterocycles
under mild conditions. J. Org. Chem. 2009, 74, 2200-2202.
[12]
[10]
(a) Huang, H.; Yan, X. H.; Zhu, W. L.; Liu, H.; Jiang, H. L.; Chen,
K. X. Efficient copper-promoted N-arylations of aryl halides with
amines. J. Comb. Chem. 2008, 10, 617-619. (b) Zhu, X. H.; Su, L.;
Huang, L. Y.; Chen, G.; Wang, J. L.; Song, H. C.; Wan, Y. Q. A
facile and efficient oxalyldihydrazide/ketone-promoted copper-