Copper-catalyzed intramolecular direct amination of sp2 C-H bonds for the synthesis of N-aryl acridones

Article abstract of DOI:10.1039/c2cc35425j

A copper-catalyzed approach for the synthesis of N-aryl acridones via sp² C-H bond amination using air as oxidant under neutral conditions is disclosed. This reaction not only provides a complementary method for synthesizing medicinally important acridones, but also offers a new strategy for sp² C-H bond amination.

Full text of DOI:10.1039/c2cc35425j

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COMMUNICATION
Copper-catalyzed intramolecular direct amination of sp2 C–H bonds for
the synthesis of N-aryl acridonesw
Wang Zhou,*a Yong Liu,b Youqing Yanga and Guo-Jun Deng*b
Received 27th July 2012, Accepted 1st September 2012
DOI: 10.1039/c2cc35425j
A copper-catalyzed approach for the synthesis of N-aryl acridones
via sp2 C–H bond amination using air as oxidant under neutral
conditions is disclosed. This reaction not only provides a comple-
mentary method for synthesizing medicinally important acridones,
but also offers a new strategy for sp2 C–H bond amination.
There are a limited number of methods employing cheaper
copper salts along with dioxygen as the terminal oxidant
in direct intramolecular C–H amination. In 2008, Brasche
and Buchwald5a reported a copper-catalyzed intramolecular
C–H functionalization for the synthesis of benzimidazoles
(Scheme 1). Later, Zhu et al.5b reported a copper(II)/iron(III)
co-catalyzed intramolecular amination. In addition, these
intramolecular C–H amination methods mostly delivered five-
membered ring products. Yet, the homologous intramolecular
amination remains a research topic of great value. Moreover,
acridones were prepared by the acid-induced ring closure
of N-phenyl anthranilic acids, nucleophilic substitution of
Transition-metal-catalyzed C–N bond formation is of great
importance due to the ubiquity of amino groups in pharma-
ceuticals, agrochemicals, dyes, and bioactive compounds.1
Compared with the traditional transition-metal-catalyzed
strategies to construct C–N bonds,2 direct amination of C–H
bonds has many incomparable advantages, including atom-
and step-efficiency and environmental benignity of the trans-
formation.3 The reported methods for direct amination of
C–H bonds are commonly catalyzed by Pd4 or Cu5 catalysts.
Terminal oxidants, such as hypervalent iodine(III),4h,5c
copper(II),4g silver(I),4e,j and fluorine(I),4d,i are indispensable
for these methods generally. Among these oxidant candidates,
oxygen is obviously considered as an ideal choice due to its
inexhaustible, inexpensive, and environmentally benign features.6
Table 1 Screening of reaction conditionsa
Entry
Cat. (mol%)
Solvent
Yieldb (%)
1c
2
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
None
DMSO
DMSO
DMSO
PhCl/DMSO
DMA
DMF
NMP
PhCl
Dioxane
Anisole
PivOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
75
78
14
77
62
37
62
5
Trace
Trace
Trace
0
Trace
67
Trace
42
42
64
54
3d
4
5
6
7
8
9
10
11
12e
13
14f
15
16
17
18
19
20
21
22
CuI (20)
CuI (5)
CuI (10)
Cu(OAc)2 (20)
CuBr (20)
CuCl (20)
CuBr2 (20)
CuCl2 (20)
Pd(OAc)2 (20)
Scheme 1 Intramolecular C–H amination using the copper–O2 cata-
9
15
Trace
lytic system.
a
a College of Chemical Engineering, Xiangtan University,
Xiangtan 411105, China. E-mail: wzhou@xtu.edu.cn
b College of Chemistry, Xiangtan University, Xiangtan 411105, China.
E-mail: gjdeng@xtu.edu.cn
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc35425j
Reaction conditions: 1a (0.3 mmol), catalyst, and solvent (1.6 mL)
b
c
were stirred at 120 1C under air (1 atm) for 48 h. Isolated yield. The
reaction was carried out at 140 1C. The reaction was carried out at
100 1C. The reaction was carried out under N2. The reaction was
carried out under O2.
d
e
f
c
10678 Chem. Commun., 2012, 48, 10678–10680
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electron-withdrawing groups substituted arenes or the coupling of
arynes and benzoates or benzamides traditionally.7 However,
inaccessible substrates and an excess amount of acidic catalysts
or reagents are generally required. Herein, we disclose a copper-
catalyzed intramolecular direct amination of sp2 C–H bonds for
the synthesis of N-aryl acridones using air as oxidant under
neutral conditions.
CuBr2, and Cu(OAc)2, led to a decreased yield of products
(entries 17–21). Moreover, Pd(OAc)2 could not catalyze the
transformation efficiently (entry 22).
With the optimized reaction conditions in hand, the scope of this
direct amination was explored (Table 2). Several functional groups,
such as methyl (entries 2–4), phenyl (entry 5), chloro (entry 8),
fluoro (entry 9), ethoxycarbonyl (entry 10), cyano (entry 11)
and trifluoromethyl (entry 12), on the N-aryl moiety were well-
tolerated, delivering the corresponding products in moderate to
good yields. In general, electron-rich substrates were more
reactive than electron-deficient ones in terms of yields. To our
delight, iodo and bromo substituents were also found to be
compatible with the reaction, affording the acridones which
could be readily subjected to further transformation (entries 6
and 7). Substrates 1m–1t worked well to provide the corre-
sponding acridones in 30–85% yields (entries 13–20).
Our study was initiated using phenyl-(2-phenylaminophenyl)-
methanone 1a as the substrate to determine the optimized
conditions (Table 1). Substrate 1a could be smoothly converted
to the cyclized product N-phenyl acridone 2a in 75% yield upon
the treatment with CuI (20 mol%) and air (1 atm) in DMSO at
140 1C (entry 1). An acceptable yield was obtained at 120 1C
(78%, entry 2), but a significantly decreased yield was observed
at a lower temperature (entry 3). Except for the mixed solvent
DMSO–PhCl (entry 4), other solvent systems failed to provide
more favorable outcomes (entries 5–11). The concurrence of CuI
and air is crucial for this C–H amination (entries 12 and 13). A
comparable yield was observed when the reaction was carried out
under O2 (entry 14). Other copper catalysts, such as CuBr, CuCl,
It is worth noting that N-(2-benzylphenyl)benzenamine 3
was completely consumed and successfully converted to N-phenyl
acridone 2a in 47% yield under the optimized conditions
(Scheme 2). Interestingly, chalcone 4 was aminated to give
10H-acridin-9-one 5 under the same conditions. We could
detect 10-phenyl-9,10-dihydroacridine by GC-MS analysis
during the reaction, so the ketone group may not be necessary
for the reactivity.
Table 2 The direct amination of sp2 C–H bondsa
Three separate reactions were conducted by stoichiometric
addition of an electron-transfer scavenger (1,4-dinitrobenzene), a
radical clock (diallyl ether) or a radical inhibitor (hydroquinone).8
The reaction still proceeded smoothly to afford the desired
product (Scheme 2). These observed results suggest that the
radical process is not involved in this transformation.
On the basis of these preliminary results, a catalytic cycle of
this transformation was hypothesized as shown in Fig. 1.
Initially, a reactive Cu(III) intermediate A is formed by the
reaction of Cu(I) and substrate 1 with the aid of O2 in situ6 via
an electrophilic metallation or a C–H bond activation.5b,9,10
Reductive elimination delivers the product 2 with concurrent
formation of Cu(I).
Yieldb
(%)
Substrate
R1
Entry
Product
1
2
3
4
5
6
7
8
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a 78
2b 73
2c 53
2d 93
2e 73
2f 80
2g 81
2h 85
2i 71
2j 58
2k 30
2l 42
2-Me
3-Me
4-Me
4-Ph
4-I
4-Br
4-Cl
4-F
9
10
11
12
4-COOEt 1j
4-CN
4-CF3
R2
1k
1l
13
14
15
16
17
18
Me
tBu
OMe
OCF3
Cl
1m
1n
1o
1p
1q
1r
2m 67
2n 70
2o 30
2p 46
2q 76
2r 33
F
19
1s
1t
2r 83
20
2s 85
a
Reaction conditions: 1 (0.3 mmol), CuI (20 mol%) in DMSO (1.6 mL)
b
were stirred at 120 1C under air (1 atm) for 48 h. Isolated yield.
Scheme 2 Mechanism probing experiments.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 10678–10680 10679

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For examples of intramolecular Pd-catalyzed sp2 C–H amination
reactions, see: (f) W. C. P. Tsang, N. Zheng and S. L. Buchwald,
J. Am. Chem. Soc., 2005, 127, 14560; (g) M. Wasa and J.-Q. Yu, J. Am.
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Johansson, M. Gulias, E. M. Beck and M. Gaunt, J. Am. Chem.
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Chem. Soc., 2009, 131, 10806; (j) J. Neumann, S. Rakshit, T. Droge
¨
and F. Glorius, Angew. Chem., Int. Ed., 2009, 48, 6892; (k) Y. Tan and
J. F. Hartwig, J. Am. Chem. Soc., 2010, 132, 3676.
5 For recent examples of Cu-catalyzed intramolecular sp2 C–H
amination reactions, see: (a) G. Brasche and S. L. Buchwald,
Angew. Chem., Int. Ed., 2008, 47, 1932; (b) H. Wang, Y. Wang,
C. Peng, J. Zhang and Q. Zhu, J. Am. Chem. Soc., 2010,
132, 13217; (c) S. H. Cho, J. Yoon and S. Chang, J. Am. Chem.
Soc., 2011, 133, 5996. For recent examples of Cu-catalyzed inter-
molecular sp2 C–H amination reactions, see: (d) D. Monguchi,
T. Fujiwara, H. Furukawa and A. Mori, Org. Lett., 2009, 11, 1607;
(e) Q. Wang and S. L. Schreiber, Org. Lett., 2009, 11, 5178;
(f) T. Kawano, K. Hirano, T. Satoh and M. Miura, J. Am. Chem.
Soc., 2010, 132, 6900; (g) H. Zhao, M. Wang, W. Su and M. Hong,
Adv. Synth. Catal., 2010, 352, 1301; (h) M. Miyasaka, K. Hirano,
T. Satoh, R. Kowalczyk, C. Bolm and M. Miura, Org. Lett., 2011,
13, 359; (i) N. Matsuda, K. Hirano, T. Satoh and M. Miura, Org.
Lett., 2011, 13, 2860.
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see: (a) A. E. Wendlandt, A. M. Suess and S. S. Stahl, Angew.
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Fig. 1 A possible catalytic cycle for C–H bond amination.
In conclusion, we have demonstrated a copper-catalyzed
approach for the synthesis of N-aryl acridones via sp2 C–H
bond amination using air as oxidant under neutral conditions.
This reaction not only provides a complementary method for
constructing medicinally important acridones, but also offers a
new strategy for sp2 C–H bond amination. Further studies on
the reaction scope and the detailed mechanism are under
investigation in our group.
Financial support from National Science Foundation of
China (No. 21102123), Hunan Province Department of Education
(No. 11C1208) and Xiangtan University (No. KZ08018 and
KZ03011) is greatly appreciated.
Notes and references
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10 Control experiments showed that CuI and Cu(OAc)2 could
catalyze the transformation under air, but, under N2, almost
no product was detected (see Table S2 in ESIw for details).
These results suggest that Cu(III) species may be involved in this
transformation.
c
10680 Chem. Commun., 2012, 48, 10678–10680
This journal is The Royal Society of Chemistry 2012