Copper-catalyzed aerobic oxidative intramolecular C-H amination leading to imidazobenzimidazole derivatives

Article abstract of DOI:10.1021/ol202884z

A highly efficient copper-catalyzed aerobic oxidative intramolecular C-H amination has been developed using substituted 2-(1H-imidazol-1-yl)-N- alkylbenzenamines as the starting materials, and the corresponding imidazobenzimidazole derivatives were obtain

Full text of DOI:10.1021/ol202884z

ORGANIC
LETTERS
2012
Vol. 14, No. 2
452–455
Copper-Catalyzed Aerobic Oxidative
Intramolecular CÀH Amination Leading to
Imidazobenzimidazole Derivatives
Xiaoqiang Wang,† Yunhe Jin,† Yufen Zhao,†,‡ Lin Zhu,§ and Hua Fu*,†
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of
Education), Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China,
Key Laboratory for Chemical Biology of Fujian Province, Department of Chemistry, College
of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China,
and Department of Chemical Engineering, Tsinghua University, Beijing 100084, P. R. China
fuhua@mail.tsinghua.edu.cn
Received October 25, 2011
ABSTRACT
A highly efficient copper-catalyzed aerobic oxidative intramolecular CÀH amination has been developed using substituted 2-(1H-imidazol-1-yl)-
N-alkylbenzenamines as the starting materials, and the corresponding imidazobenzimidazole derivatives were obtained in excellent yields. This is
an economical and practical method for the construction of N-heterocycles.
Compounds containing nitrogen widely occur in natural
products and synthetic drugs. In fact, the synthetic drugs
generally contain more nitrogen than the natural products
because nitrogen can carry a positive charge, and act as a
hydrogen bond donor and/or acceptor that strongly influ-
ences the interaction between the medicinal agent and its
target.1 In addition, the pKa values of amines are often in
the range of physiological pH, a physical property essential
for improving the bioavailability of drugs.2 Therefore, the
development of novel CÀN bond forming methodologies
is of the utmost importance. For over a century, N-arylation
of amines has attracted wide attention, and the copper-
catalyzed Ullmann/Goldberg-type N-arylations3À5 and
palladium-catalyzed BuchwaldÀHartwig couplings6 are
popular methods thus far. However, the methods need
previously functionalized substrates (such as aryl halides
and tosylates). Obviously, the direct catalytic transformation
of carbonÀhydrogen bonds to carbonÀnitrogen bonds is
more economical and environmentally friendly because such
† Department of Chemistry, Tsinghua University.
‡ Xiamen University.
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Soc. 2002, 124, 7421. (c) Antilla, J. C.; Klapars, A.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 11684. (d) Okano, K.; Tokuyama, H.;
Fukuyama, T. Org. Lett. 2003, 5, 4987. (e) Gujadhur, R. K.; Bates,
C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315. (f) Gajare, A. S.;
Toyota, K.; Yoshifuji, M.; Yoshifuji, F. Chem. Commun. 2004, 1994.
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Cheng, L.; Zhang, Y.; Xie, R.; You, J. J. Org. Chem. 2007, 72, 2737.
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Angew. Chem., Int. Ed. 1998, 37, 2046. (b) Wolfe, J. P.; Wagaw, S.;
Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (c) Muci,
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§ Department of Chemical Engineering, Tsinghua University.
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r
10.1021/ol202884z
Published on Web 12/29/2011
2011 American Chemical Society

reactions do not require the presence of functional groups in
the substrates.7 Over the past decade, there has been great
progress in the direct functionalization of CÀH bonds,8 and
some N-heterocycles, such as benzimidazoles,9 indazoles,10
indolines,11 carbazoles,12 and N-methoxylactams,13 have
been made through a CÀH activation/CÀN bond-forming
strategy, but expensive palladium-, rhodium-, and ruthenium-
based catalysts are usually required. Recently, some in-
expensive copper-catalyzed sp2 CÀH aminations/
amidations have been developed,2,14 and the heterocycles
have been constructed via a copper-catalyzed sp2 CÀH
activation strategy15 using dioxygen as the oxidant.16 The
synthesizedimidazobenzimidazolederivatives exhibitvari-
ous biological and pharmacological activity. For example,
they are used as inhibitors of p5317a and β-lactamases,17b
Table 1. Copper-Catalyzed Intramolecular CÀH Amination of
N-(2-(1H-Imidazol-1-yl)phenyl)benzenamine (1a) Leading to
9-Phenylimidazo[1,2-a]benzimidazole (2a) under Oxygen:
Optimization of Conditionsa
yield
entry
cat.
ligand
base
solvent
(%)b
1
Cu(OAc)2
CuBr2
À
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
Na2CO3
K2CO3
Cs2CO3
K3PO4
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
DMSO
52
5
2
À
3
CuO
À
15
6
4
CuI
À
(7) (a) Bergman, R. G. Nature 2007, 446, 391. (b) Chen, M. S.; White,
M. C. Science 2007, 318, 783. (c) Dick, A. R.; Sanford, M. S. Tetrahedron
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Y. M.;Dinescu, A.;Dai, X.;Palomino, R. M.;Heinemann, F. W.;Cundari,
T. R.; Warren, T. H. Angew. Chem., Int. Ed. 2008, 47, 9961.
5
CuBr
À
8
6
CuCl
À
49
trace
trace
76
72
48
5
7
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(EH)2
À
8
À
DMF
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9
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
phen
DMEDA
proline
phen
phen
phen
À
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
o-xylene
p-xylene
m-xylene
m-xylene
10
11
12
13
14
15
16
17
18
19
20
21
37
35
93
65
51
86
88
65c
46d
NaHCO3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
a Reaction conditions: N-(2-(1H-imidazol-1-yl)phenyl)benzenamine
(1a) (0.3 mmol), catalyst (0.06 mmol), ligand (0.12 mmol), base (1.2 mmol),
solvent (1 mL), reaction temperature (155 °C), reaction time (24 h) in a
Schlenk tube under oxygen balloon (1 atm). b Isolated yield. c Under air.
d EH = 2-ethylhexanoate.
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Org. Lett., Vol. 14, No. 2, 2012
453

Table 2. Copper-Catalyzed Aerobic Oxidative Intramolecular CÀH Amination Leading to Imidazobenzimidazole Derivativesa
a Reaction conditions: 1 (0.3 mmol), Cu(OAc)2 (0.06 mmol), 1,10-phen (0.12 mmol), NaOAc (1.2 mmol), m-xylene (1 mL), reaction temperature (155 °C),
reaction time (24 or 55 h) in a Schlenk tube using an oxygen balloon (1 atm). b Isolated yield.
2-aminobenzimidazoles with 1-bromoalkan-2-ones are com-
mon methods,17 but the prefunctionalization approaches are
not economical. Herein, we report a novel copper-catalyzed
aerobic oxidative intramolecular CÀH amination leading to
imidazobenzimidazole derivatives under oxygen.
Here, N-(2-(1H-imidazol-1-yl)phenyl)benzenamine (1a)
was used as the model substrate to optimize reaction
conditions including catalysts, ligands, bases, and solvents
under oxygen (1 atm). As shown in Table 1, six copper salts
(0.2 equiv) were screened in the presence of 4 equiv of
454
Org. Lett., Vol. 14, No. 2, 2012

NaOAc (relative to amount of 1a) in m-xylene at 155 °C
(entries 1À6), and Cu(OAc)2 afforded the highest yield
(entry 1). Only a trace amount of product was observed
when DMSO and DMF were used as the solvents (entries 7
and 8). The yields obviously increased when PPh3 was
applied as the ligand (entry 9). Various bases were deter-
mined (entries 10À14), and NaOAc showed the highest
efficiency (entry 9). Other ligands were also investigated
(entries 15À17), and 1,10-phenanthroline (phen) provided
the highest yield (93%) (entry 15). We attempted o-xylene
and p-xylene as the solvents. Surprisingly, they were
inferior to m-xylene (compare entries 15, 18, and 19).
The reaction under air gave a 65% yield (entry 20). When
copper(2-ethylhexanoate)2 was used as the catalyst in the
presence of ligand, the target product was obtained in 46%
yield (entry 21).
As shown in Table 2, the scope of copper-catalyzed
aerobic oxidative intramolecular CÀH amination of 1
leading to imidazobenzimidazole derivatives (2) was in-
vestigated under the optimized conditions (using 20 mol %
of Cu(OAc)2 as the catalyst, 40 mol % phen as the ligand,
4 equiv of NaOAc as the base (relative to amount of 1), and
m-xylene as the solvent). The reactions provided the
corresponding target products in excellent yields. The
copper-catalyzed intramolecular CÀH amination showed
tolerance of some functional groups in the substrates
including ether (entry 5), CÀCl bond (entries 6, 13, 18
and 23), nitro (entry 24) and N-heterocyles.
Figure 1. Crystal structure of compound 2m.
Scheme 1. Possible Mechanism for Copper-Catalyzed Aerobic
Oxidative Intramolecular CÀH Amination Leading to Imidazo-
benzimidazole Derivatives (2)
In order to ascertain structures of the newly synthesized
imidazobenzimidazole derivatives (2), a single crystal of
2m was prepared, and its structure was unambiguously
confirmed by X-ray diffraction analysis (Figure 1) (see
Supporting Information for details).
A possible mechanism for copper-catalyzed aerobic oxi-
dative synthesis of imidazobenzimidazole derivatives (2) is
suggested in Scheme 1. Coordination of 1,10-phenanthroline
(phen) with Cu(OAc)2 first forms complex LnCu(OAc)2.
Treatment of substrate (1) with LnCu(OAc)2 provides
intermediate I in the presence of base (NaOAc), and
reductive elimination of I affords the target product (2)
leaving the Cu(II)Ln catalyst under oxygen.14d,e
In summary, we have developed a highly efficient cop-
per-catalyzed aerobic oxidative intramolecular sp2 CÀH
amination leading to imidazobenzimidazole derivatives.
The protocol uses inexpensive Cu(OAc)2 as the catalyst,
1,10-phenanthroline as the ligand, NaOAc as the base, and
economical and environment friendly oxygen as the oxi-
dant, and the corresponding N-heterocycles were obtained
in excellent yields. This method should provide a new and
useful strategy for the construction of N-heterocycles.
Acknowledgment. The authors wish to thank the Na-
tional Natural Science Foundation of China (Grant Nos.
20972083, 21172128) and the Ministry of Science and
Technology of China (2012CB722600) for financial
support.
Supporting Information Available. Synthetic proce-
dures, characterization data, and 1H, 13C NMR spectra
of these synthesized compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.
org.
Org. Lett., Vol. 14, No. 2, 2012
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