A simple and efficient copper(II) complex as a catalyst for N-arylation of imidazoles

Article abstract of DOI:10.1002/cjoc.201201121

Four inexpensive and air-/moisture-stable pyrrolecarbaldiminato-Cu complexes 1-4 were synthesized and evaluated to be a novel class of catalysts for the N-arylation of imidazoles with aryl halides. A variety of aryl iodides, bromides and activated aryl chlorides underwent the coupling with imidazoles, promoted by the catalyst 4, in moderate to good yields without the protection by an inert gas. Copyright

Full text of DOI:10.1002/cjoc.201201121

FULL PAPER
DOI: 10.1002/cjoc.201201121
A Simple and Efficient Copper(II) Complex as a Catalyst for
N-Arylation of Imidazoles
Yanli Jiao, Nannan Yan, Jianwei Xie,* Xiaowei Ma, Ping Liu, and Bin Dai*
School of Chemistry and Chemical Engineering, the Key Laboratory for Green Processing of Chemical Engineering
of Xinjiang Bingtuan, Shihezi University, North 4th Road, Shihezi, Xinjiang 832003, China
Four inexpensive and air-/moisture-stable pyrrolecarbaldiminato-Cu complexes 1－4 were synthesized and
evaluated to be a novel class of catalysts for the N-arylation of imidazoles with aryl halides. A variety of aryl io-
dides, bromides and activated aryl chlorides underwent the coupling with imidazoles, promoted by the catalyst 4, in
moderate to good yields without the protection by an inert gas.
Keywords pyrrolecarbaldiminato-Cu complexes, homogeneous catalyst, N-arylation, imidazoles, N-heterocycles
Introduction
relatively milder conditions are still in demand.
N-Aryl imidazoles are prevalent building blocks of
numerous drugs, natural products and energetic materi-
als,[1] and have been exploited as important precursors
in the area of N-heterocyclic carbine chemistry.[2]
Therefore, their preparations have attracted much atten-
tion. Traditionally, these compounds were synthesized
via SNAr substitution of imidazoles with activated aryl
halides or the classic Ullmann-type coupling reactions,[3]
which were often suffered from harsh reaction condi-
tions and stoichiometric amounts of copper reagents. In
recent years, the transition-metal (such as palladium,
copper, nickel and iron), especially palladium-catalyzed
N-arylation of imidazoles has achieved remarkable
achievements, and shows relative mild reaction condi-
tions, broad substrate scope and excellent functional-
group tolerance.[4] However, in comparison with the use
of costly palladium and toxic phosphane-containing
ligands, it is desirable to develop more effective copper
catalytic systems for N-arylation of imidazoles. The
breakthroughs in this area, which were achieved by two
research groups of Buchwald[5] and Taillefer,[6] respec-
tively, have been typically driven by the implementation
of new class of ligands and only catalytic amounts of
copper metal under mild conditions. Following these
pioneering works, several classes of mono- and biden-
tate chelators have thereby been developed to expedite
the reaction rates and lower substantially the reaction
temperature of Cu-based C－N coupling reaction.[7] In
spite of the significant progress made in the aforemen-
tioned transformation, more efficient, air or/and mois-
ture-stable and easy-synthesis ligands or metal-com-
plexes for facilitating these coupling reactions under
Scheme 1 Preparation of catalyst 1－4 according to the
reported method
R
N
N
Cu
N
Cu(OAc)2
H2O
+
RNH2
N
R
CHO
N
H
Catalyst 1 - 4
1: R = CH3, 57%; 2: R = t-Bu, 30%; 3: R = Ph, 47%; 4: R = Bn, 48%
Since the first report of 2-pyrrolecarbaldimines and
its Co and Cu chelates,[8] several pyrrolecarbaldiminato-
metal complexes have been synthesized and demon-
strated potential applications to various processes, such
as C－H activation,[9] ethylene polymerization,[10] neu-
tral luminescent,[11] copper metal CVD (chemical va-
pour deposition) or ALD (atomic layer deposition) pre-
cursors,[12] and so on. However, these series of Cu-
complexes, to our knowledge, have seldom been used as
the catalysts for the C－N coupling reaction. Moreover,
imines have been reported as ligands to improve the
reaction efficiency for copper-catalysed Ullmann cou-
pling reaction.[13] Therefore, we reasonably assumed
that pyrrolecarbaldiminato-Cu complexes might be a
class of effective copper-catalysts for C－N coupling
reaction. Herein, we wish to report our results of pyr-
rolecarbaldiminato-Cu complexes as catalysts for the
N-arylation of imdazoles. This methodology has several
advantages as follows: (1) the catalysts were easily
synthesized from cheap starting materials with satisfied
yield on a multi-gram scale, and are stable in air and
moisture; (2) the reaction condition was relatively
*
E-mail: cesxjw@gmail.com (Xie, J.); db_tea@shzu.edu.cn (Dai, B.); Tel.: 0086-0993-205-7213; Fax: 0086-0993-205-7270
Received November 14, 2012; accepted December 10, 2012; published online January 8, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201201121 or from the author.
Chin. J. Chem. 2013, 31, 267—270
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
267

Jiao et al.
FULL PAPER
milder and did not require protection by an inert atmos-
phere; (3) the catalysts worked well for aryl iodides,
bromides and electronic-withdrawing aryl chlorides
with moderate to good yield.
Table 1 Screening reaction conditions for N-arylation of imi-
dazole with 4-iodotoluenea
I
N
Catalyst
N
N
+
Solvent, base
120 oC, 24 h
N
H3C
H
H3C
Results and Discussion
Entry
Catalyst
Solvent
Base
Yieldb/%
77
Considering that the electronic effects and steric ef-
fects of pyrrolate-imine moieties could play an impor-
tant role in the catalytic activities, we selectively pre-
pared four typical pyrrolecarbaldiminato-Cu complexes
(R＝CH3, t-Bu, Ph, and Bn) by reacting the pyrrole-2-
carboxaldehyde, corresponding amines, with Cu(OAc)2
in situ according to the reported procedures,[12a,14] and
the four copper-complexes were characterized by ele-
mental analysis. The synthetic route was shown in
Scheme 1. Subsequently, the catalytic activity of the
four catalysts was evaluated by using the C－N cou-
pling of 4-iodotoluene with imidazole as a model reac-
tion in the presence of K3PO4•3H2O at 120 ℃ for 24 h
in DMSO. As expected, the four Cu-complexes all ex-
hibited high catalytic activity for this process, and cata-
lyst 4 was the best, which gave the desired product in
87% isolated yield (Table 1, Entries 1－4). Control ex-
periment conducted in the absence of Cu-complex from
the reaction mixture resulted in no product (Table 1,
Entry 5).
1
2
1
2
3
4
－
4
4
4
4
4
4
4
4
4
4
4
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
K3PO4•3H2O
K3PO4•3H2O
K3PO4•3H2O
K3PO4•3H2O
K3PO4•3H2O
K3PO4•3H2O
73
3
66
4
87
5
0
6
80
7
Dioxane K3PO4•3H2O
Toluene K3PO4•3H2O
38
8
70
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
K3PO4
77
10
11
12
13
14
15
16
NaOH
86
KOH
85
K2CO3
81
CsCO3
88
K3PO4•3H2O
K3PO4•3H2O
K3PO4•3H2O
71c
76d
67e
a
Unless otherwise noted, the reaction was carried out with
With the appropriate catalyst in hand, it was reason-
able for us to further optimize the other reaction condi-
tions, including solvents, bases, catalyst loading, tem-
perature and reaction times, and the results are listed in
Table 1. It was found that DMSO performed as the
prime solvent; DMF and toluene were fairish, but were
not as good as DMSO; meanwhile, dioxane was not
suitable as a solvent (Table 1, Entries 6－8). Investiga-
tion into the bases with different basicities revealed that
the Cs2CO3 demonstrated the best improvement among
those screened (NaOH, KOH, K2CO3, Cs2CO3, and
K3PO4) to give the corresponding product in 88% yield
(Table 1, Entries 9－13). However, K3PO4•3H2O was
the recommended base as it was less expensive and
weaker basicity than Cs2CO3. It must be pointed out that
the hydrate of K3PO4 can dramatically accelerate the
arylation of imidazole (Table 1, Entry 4 vs. Entry 9).
This could be attributed to that the hydrate of K3PO4
increased the rate of the arylation reaction by solubiliz-
ing the base in DMSO, and thus facilitating deprotona-
tion of imidazole, which is in good agreement with the
reported results.[15] Furthermore, decreasing the loading
of catalyst 4 from 10 mol% to 5 mol% led to a decrease
of the yield. In addition, reaction time and reaction
temperature were also proved to have effects on the re-
action, shorter reaction time than 24 h or lower tem-
perature than 120 ℃ can both decelerate the reaction
rate and led to lower yields (Table 1, Entries 15, 16). As
mentioned above, the combination of Cu-catalyst 4 (10
mol %), K3PO4•3H2O (2 equiv.) at 120 ℃ for 24 h in
DMSO was chosen as the optimal conditions for
4-iodotoluene (0.5 mmol), imidazole (0.75 mmol), catalyst (10
mol%), base (1.0 mmol), and solvent (1 mL) at 120 ℃ for 24 h.
b
c
d
Isolated yield. Catalyst (5 mol%). Reaction time: 12 h.
e Temperature: 100 ℃.
N-arylation of imidazole with 4-iodotoluene.
After the best reaction condition was set, the reaction
scope and limitations of the catalytic system were then
investigated. As shown in Table 2, the good to excellent
yields were obtained for the N-arylation of imidazole
with aryl iodides. To our delight, arylation of other ni-
trogen-containing heterocycles such as benzimidazole
and indole are also efficient with good yield under the
standard conditions (Table 2, Entries 1－5). In general,
although aryl bromides were less reactive than aryl io-
dides, satisfactory yields were still obtained for the aryl
bromide only with prolonging the reaction time to 36 h.
As we can see, the coupling of imidazole with most of
electron-rich, electron-neutral, and electron-poor aryl
bromides afforded the corresponding products with
good to excellent yields. In the case of p-bromoanisole,
which contains a strongly electron-donating substituent,
it is a good substrate, while the 1-bromo-4-(trifluoro-
methyl) benzene reacts relative slowly (Table 2, Entries
8, 9). Notably, a high level of selectivity was also ob-
served in the amination of aryl bromide bearing another
amino or hydroxyl group without formation of diaryl
ether or diarylamine products (Table 2, Entries 14, 15).
Interestingly, heteroaryl bromides were also coupled
with imidazole to afford the desired product in impres-
sive yields (Table 2, Entries 16, 17). In addition, the
268
www.cjc.wiley-vch.de
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 267—270

A Simple and Efficient Copper(II) Complex as a Catalyst for N-Arylation of Imidazoles
Table 2 N-Arylation of imidazoles with aryl iodides, bromides
Continued
Yieldb/%
and chlorides catalyazed by catalyzed 4a
Entry
ArX
Het-NH
Product
X
Catalyst 4
+
Het
R
NH
N
Br
N
N
.
DMSO, K3PO4 3H2O
10
80
65
120 oC
N
H
X = Cl, Br, I
O2N
O2N
7
Bn
N
N
Cu
N
N-Het
N
N
R
Br
N
N
11
12
13
14
15
Bn
N
H
Cl
5 - 18
Cl
Catalyst 4
12
Entry
1
ArX
Het-NH
Product
Yieldb/%
87
N
N
Br
N
70
82
79
56
N
I
N
N
N
H
H3COC
H3COC
N
H
13
H3C
H3C
5
N
N
Br
N
N
N
I
N
N
H
2
3
85
80
Ph
N
H
Ph
H2N
HO
14
6
N
I
I
I
N
N
Br
N
N
N
N
H
N
H
O2N
H3C
H3C
H2N
O2N
7
15
N
N
N
N
Br
N
N
4
88
N
H
N
H
HO
H3C
8
16
H
N
N
N
N
N
Br
Br
N
5
6
7
73
70
72
16
17
18
19
80
46
N
H
N
N
H3C
9
17
N
N
N
Br
N
N
N
H
N
H
S
S
18
6
N
N
N
Br
N
N
Br
N
N
N
N
50
N
H
N
H
H3C
O2N
H3C
O2N
5
7
N
N
Cl
N
N
Br
Br
trace
N
H
8
9
81
62
N
H
O
6
O
10
a
Reaction conditions: ArX (0.5 mmol), imidazoles (0.75 mmol),
catalyst 4 (10 mol%), K3PO4•3H2O (1.0 mmol), and DMSO (1
mL), 120 ℃, 24 h (X＝I) or 36 h (X＝Br and Cl). Isolated
b
N
N
yield.
N
H
F3C
F3C
11
reaction of electron-deficient aryl chloride such as
Chin. J. Chem. 2013, 31, 267—270
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
269

Jiao et al.
FULL PAPER
Chem., Int. Ed. 2009, 48, 6954; (b) Wang, Y.; Zeng, J.; Cui, X. Chin.
J. Org. Chem. 2010, 30, 181 (in Chinese); (c) Surry, D. S.; Buch-
wald, S. L. Chem. Sci. 2011, 2, 27; (d) Maiti, D.; Fors, B. P.; Hen-
derson, J. L.; Nakamura, Y.; Buchwald, S. L. Chem. Sci. 2011, 2, 57.
[5] (a) Buchwald, S. L.; Klapars, A.; Antilla, J. C.; Job, G. E.; Wolter, M.;
Kwong, F. Y.; Nordmann, G.; Hennessy, E. J. WO 02/085838 (Prior-
ity number US 0286286, 2001); (b) Klapars, A.; Antilla, J. C.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727.
1-chloro-4-nitrobenzene with imidazole was also suc-
cessful and provided the desired product in moderate
yield (Table 2, Entry 18). However, only trace
N-arylation product was observed under the experimen-
tal condition, when chlorobenzene was used as the sub-
strate (Table 2, Entry 19).
[6] Taillefer, M.; Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Ouali, A.
Fr 2833947-WO 0353225 (Priority number Fr 16547, 2001).
[7] For some selected examples, see: (a) Klapars, A.; Huang, X.; Buch-
wald, S. L. J. Am. Chem. Soc. 2002, 124, 7421; (b) Lu, Z.; Twieg, R.
Tetrahedron Lett. 2005, 46, 2997; (c) Rao, H.; Fu, H.; Jiang, Y.;
Zhao, Y. J. Org. Chem. 2005, 70, 8107; (d) Zhang, H.; Cai, Q.; Ma,
D. J. Org. Chem. 2005, 70, 5164; (e) Chen, Y.; Chen, H. Org. Lett.
2006, 8, 5609; (f) Yang, M.; Liu, F. J. Org. Chem. 2007, 72, 8969; (g)
Suresh, P.; Pitchuman, K. J. Org. Chem. 2008, 73, 9121; (h) Wang,
D.; Ding, K. Chem. Commun. 2009, 1891; (i) Zhao, H.; Fu, H.; Qiao,
R. J. Org. Chem. 2010, 75, 3311; (j) Hu, Z.; Ye, W.; Zou, H.; Yu, Y.
Synth. Commun. 2010, 40, 222; (k) Thakur, K. G.; Srinivas, K. S.;
Chiranjeevi, K.; Sekar, G. Green Chem. 2011, 13, 2326; (l) Xie, R.;
Fu, H.; Ling, Y. Chem. Commun. 2011, 47, 8976; (m) Wang, D.;
Zhang, F.; Kuang, D.; Yu, J.; Li, J. Green Chem. 2012, 14, 1268; (n)
Zhang, J. X.; Yin, H. Q; Han, S. Q. Chin. J. Org. Chem. 2012, 32,
1429 (in Chinese); (o) Yang, X.; Xing, H.; Zhang, Y.; Lai, Y.; Zhang,
Y.; Jiang, Y.; Ma, D. Chin. J. Chem. 2012, 30, 875.
Conclusions
In summary, we have developed a general, mild and
experimental method for the arylation of imidazoles
with aryl iodides, bromides and electron-withdrawing
aryl chlorides, promoted by inexpensive, air- and mois-
ture-stable pyrrolecarbaldiminato-Cu complexes with-
out the protection of an inert gas. Further application of
these copper(II) complexes catalyzed organic reactions
is currently ongoing in our laboratory.
Acknowledgement
We acknowledge the National Basic Research Pro-
gram of China (973 Program) (No. 2012CB722603) and
Start-Up Foundation for Young Scientists of Shihezi
University (Nos. RCZX201012, RCZX201014,
RCZX201015) for their financial support.
[8] Emmert, B.; Diehl, K.; Gollwitzer, F. Ber. Dtsch. Chem. Ges. 1926,
62B, 1733.
[9] Iverson, C. N.; Carter, C. A. G.; Baker, R. T.; Scollard, J. D.; Labin-
ger, J. A.; Bercaw, J. E. J. Am. Chem. Soc. 2003, 125, 12674.
[10] (a) Yoshida, Y.; Matsui, S.; Takagi, Y.; Mitani, M.; Nakano, T.; Ta-
naka, H.; Kashiwa, N.; Fujita, T. Organometallics 2001, 20, 4793; (b)
Matsui, S.; Spaniol, T. P.; Takagi, Y.; Yoshida, Y.; Okuda, J. J. Chem.
Soc., Dalton Trans. 2002, 4529.
References
[1] For selected reviews and examples, see: (a) Jacobs, C.; Frotscher, M.;
Dannhardt, G.; Hartmann, R. W. J. Med. Chem. 2000, 43, 1841; (b)
Zhong, J. Nat. Prod. Rep. 2005, 22, 196; (c) Kison, C.; Opatz, T.
Chem. Eur. J. 2009, 15, 843; (d) Gao, H.; Shreeve, J. M. Chem. Rev.
2011, 111, 7377; (e) Fujishima, S.; Yasui, R.; Miki, T.; Ojida, A.;
Hamachi, I. J. Am. Chem. Soc. 2012, 134, 3961.
[2] (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,
5606; (b) Benhamou, L.; Chardon, E.; Lavigne, G.; Bellemin-
Laponnaz, S.; César, V. Chem. Rev. 2011, 111, 2705.
[3] (a) Ohmori, J.; Shimizu-Sasamata, M.; Okada, M.; Sakamoto, S. J.
Med. Chem. 1996, 39, 3971; (b) Antonini, I.; Cristalli, G.; Franchetti,
P.; Grifantini, M.; Martelli, S. Synthesis 1983, 47; (c) Lo, Y. S.;
Nolan, J. C.; Maren, T. H.; Welstead, W. J. Jr.; Gripshover, D. F.;
Shamblee, D. A. J. Med. Chem. 1992, 35, 4790; (d) Kiyomori, A.;
Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657.
[4] For some selected reviews, see: (a) Monnier, F.; Taillefer, M. Angew.
[11] Crestani, M. G.; Manbeck, G. F.; Brennessel, W. W.; McCormick, T.
M.; Eisenberg, R. Inorg. Chem. 2011, 50, 7172.
[12] (a) Grushin, V. V.; Marshall, W. J. Adv. Synth. Catal. 2004, 346,
1457; (b) Vidjayacoumar, B.; Emslie, D. J. H.; Blackwell, J. M.;
Clendenning, S. B.; Britten, J. F. Chem. Mater. 2010, 22, 4854.
[13] (a) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.
Eur. J. 2004, 10, 5607; (b) Liu, Y.-H.; Chen, C.; Yang, L.-M. Tetra-
hedron Lett. 2006, 47, 9275; (c) Wang, Y.; Wu, Z. Q.; Wang, L. X.;
Li, Z. K.; Zhou, X. G. Chem. Eur. J. 2009, 15, 8971.
[14] Wansapura, C. M.; Juyoung, C.; Simpson, J. L.; Szymanski, D.;
Eaton, G. R.; Eaton, S. S.; Fox, S. J. Coord. Chem. 2003, 56, 975.
[15] Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421.
(Pan, B.; Fan, Y.)
270
www.cjc.wiley-vch.de
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 267—270