Synthesis of 10-methylacridin-9(10H)-ones through Cu-Catalyzed Intramolecular Oxidative C(sp2)-H Amination of 2-(Methylamino) benzophenones

Article abstract of DOI:10.1002/ejoc.201201748

An efficient synthesis of a diverse set of 10-methylacridin-9(10H)-ones from 2-(methylamino)benzophenones has been developed. The reaction proceeds though Cu-catalyzed intramolecular aromatic C-H amination by using O₂ as the sole oxidant to provide the desired products in moderate to good yields. In addition, 2-allylamino- and 2-(benzylamino)benzophenones as well as unprotected substrates can also undergo the C-H amination reaction to deliver the corresponding cyclization products smoothly. Preliminary mechanistic studies suggest that C-H activation is involved in a rate-limiting step. An efficient synthesis of a diverse set of 10-methylacridin-9(10H)-ones from 2-(methylamino)benzophenones has been developed. The reaction proceeds through Cu-catalyzed intramolecular aromatic C-H amination by using O₂ as the oxidant. Mechanistic studies suggest that a rate-limiting C-H activation step is involved in the C-N bond-formation process.

Full text of DOI:10.1002/ejoc.201201748

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201748
Synthesis of 10-Methylacridin-9(10H)-ones through Cu-Catalyzed
2
Intramolecular Oxidative C(sp )–H Amination of
2
-(Methylamino)benzophenones
[a]
[b]
[b]
[a]
Jinbo Huang, Congqing Wan, Ming-Fang Xu,* and Qiang Zhu*
Keywords: Nitrogen heterocycles / Fused-ring systems / Amination / Copper / C–H activation
An efficient synthesis of a diverse set of 10-methylacridin-
(10H)-ones from 2-(methylamino)benzophenones has been
developed. The reaction proceeds though Cu-catalyzed in-
tramolecular aromatic C–H amination by using O as the sole
oxidant to provide the desired products in moderate to good
yields. In addition, 2-allylamino- and 2-(benzylamino)benzo-
phenones as well as unprotected substrates can also undergo
the C–H amination reaction to deliver the corresponding
cyclization products smoothly. Preliminary mechanistic stud-
ies suggest that C–H activation is involved in a rate-limiting
step.
9
2
Introduction
In recent years, much cheaper and less toxic copper salts
along with oxygen, an ideal terminal oxidant, have been
Nitrogen-containing heterocycles (azaheterocycles) are
omnipresent in natural products, drugs, and other biolo-
gically active molecules.[1] As a consequence, a substantial
amount of synthetic methods have been established to con-
struct azaheterocycles. Among those, transition-metal-cata-
lyzed intramolecular C–N bond-formation reactions start-
ing from aryl or vinyl (pseudo)halides has been recognized
as a powerful method for the preparation of azahetero-
[8]
used in direct C–H/C–N oxidative coupling processes. In
[9]
the pioneering work of Buchwald’s group, they disclosed
a novel Cu(OAc) /O catalytic system for the synthesis of
2
2
benzimidazoles through intramolecular C–H imidation of
[10]
N-arylamidines. Our group
also developed an efficient
synthesis of pyrido[1,2-a]benzimidazoles through direct
aromatic C–H amination of N-aryl-2-aminopyridines under
an atmosphere of oxygen. Recently, Chiba and co-
[
2,3]
cycles.
Over the past decade, the direct transformation
[11]
workers
reported an approach for the synthesis of bi-
of C–H bonds into C–N bonds catalyzed by transition
metals has emerged as an efficient and environmentally be-
and tricyclic amidines through copper-catalyzed aerobic
C–H imidation of N-alkenylamidines.
nign alternative to traditional C–N bond-forming methods
Despite the significant advances of Cu/O catalytic sys-
in the synthesis of azaheterocycles.[4] Notable progress has
2
[
12]
tem in C–H amination reactions,
the type of azahetero-
[
5]
been made predominantly by using ruthenium-, rhodi-
cycles constructed by applying this strategy is still limited.
Herein, we report a copper-catalyzed intramolecular C–H
amination reaction for the synthesis of a diverse set of 10-
methylacridin-9(10H)-ones starting from 2-(methylamino)-
benzophenones under balloon pressure of O2.
[
6]
[7]
um-, and palladium-based systems. In most of these
cases, stoichiometric or excess amounts of oxidants, such as
+
Cu(OAc) , AgOAc, BQ, CeSO , and/or F , are inevitable to
2
4
achieve catalytic turnover.[
5–7]
The disadvantages associated
with these methods include not only the use of expensive
transition-metal catalysts, but also the use of a large
amount of heavy metal based oxidants, which may limit ap-
plications in the synthesis of drugs.
Acridone is a ubiquitous structural motif that exists in a
[
13]
wide range of biologically active compounds.
Methods
leading to the construction of this scaffold are mainly based
on the acid-promoted annulation of N-phenylanthranilic
acids or the intramolecular nucleophilic substitution of 2-
[
a] State Key Laboratory of Respiratory Disease, Guangzhou
Institutes of Biomedicine and Health, Chinese Academy of
Sciences,
[
14]
amino-2Ј-halobenzophenones (Scheme 1, path a).
Re-
[15a]
[15b]
cently, Larock
and Shi
described novel approaches
1
90 Kaiyuan Avenue, Guangzhou 510530 China
to acridones through tandem reactions involving intermo-
lecular coupling of benzoates or benzamides with arynes
generated from silylaryl triflate precursors in the presence
of CsF (Scheme 1, path b). However, the methods devel-
oped thus far suffer from tedious workup procedures and
have a limited substrate scope and/or unsatisfactory yields.
Inspired by the recent advances in Cu-catalyzed C–H func-
Fax: +86-20-3201-5299
E-mail: zhu_qiang@gibh.ac.cn
http://www.gibh.cas.cn
[
b] Department of Biotechnology, Jinan University,
Huangpu Road West 601, Guangzhou 510632 China
E-mail: txmfxmf2006@126.com
Homepage: http://www.jnu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201748.
1876
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1876–1880

Cu-Catalyzed Intramolecular Oxidative Amination
tionalization processes,[12] we envisaged[16] that the acridone Table 1. Optimization of the reaction conditions.[a]
nucleus could also be constructed by direct intramolecular
C–H amination reactions of readily available 2-(meth-
ylamino)benzophenones[ (Scheme 1, path c).
17]
Entry Cat.
Solvent Ligand Additive Yield [%][b]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
CuBr
CuI
CuTc
CuTc
CuI
CuTc
Cu(OAc)
Cu(OTf)
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
DMF
DMF
DMF
DMA
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO phen
DMSO bipy
DMSO TMEDA –
DMSO PPh
DMSO PPh
DMSO PPh
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
20[c]
30
35
Ͻ10
55
[
c]
63
[
[
c]
c]
2
49
40
2
PivOH
TFA
79
0
1
2
3
4
5
6
7
8
trace
KOAc[
d]
36
[c]
K
–
–
2
CO
3
Ͻ5
[
c]
52
70
Scheme 1. Major approaches to acridone derivatives.
[c]
73
[
c]
3
3
3
–
70
84 (74)
[
e]
PivOH
PivOH
[
f]
0
Results and Discussion
[
a] The reactions were carried out at 130 °C in O
2
(1 atm) with 1a
0.2 mmol), catalyst (0.04 mmol), ligand (0.04 mmol), and additive
0.02 mmol) in solvent (2 mL) for 23 h. CuTc = copper(I) thio-
To test the idea, we began our investigation with 2-
(
(
(methylamino)benzophenone (1a) as a substrate, and the re-
sults are summarized in Table 1. The reaction afforded de- phene-2-carboxylate, DMA = dimethylacetamide, 1,10-phen =
1
,10-phenanthroline, bipy = 2,2-bipyridine, TMEDA = tetra-
sired annulation product 2a in 20% yield, as determined by
NMR spectroscopy, when CuBr (20 mol-%) was used as the
catalyst in DMF at 130 °C under balloon pressure of oxy-
methylethylenediamine, PivOH = trimethylacetic acid, TFA = tri-
fluoroacetic acid. [b] Isolated yield. [c] Determined by NMR spec-
troscopy by using 4-iodoanisole as an internal standard.
gen (Table 1, entry 1). Screening of various copper salts re- [d] 1.0 equiv. of KOAc was used. [e] 10 mol-% of CuTc was used.
vealed that the yield of 2a could be improved to 35% by [f] The reaction was carried out under an Ar atmosphere, 73% of
1a was recovered.
using CuTc (Table 1, entries 2 and 3). Switching the solvent
from DMF to DMA and DMSO identified DMSO as the
optimum solvent. Copper(II) sources such as Cu(OAc) and
With the optimal reaction conditions in hand, the scope
2
Cu(OTf) were also effective in this transformation (Table 1, of the substrates (Table 2) was investigated as illustrated in
2
entries 7 and 8), although the products were obtained in Scheme 1. The amination reaction displayed good func-
lower yields. To our delight, the yield of 2a was improved tional group tolerance and proved to be a quite general ap-
to 79% (Table 1, entry 9) when pivalic acid (10 mol-%) was proach to a diverse set of acridones. Substrates bearing elec-
used as an additive. However, alteration of the amount of tron-donating (Me, MeO, Et) or electron-withdrawing (Cl,
pivalic acid (from 10 to 50 mol-%) did not improve the yield Br, CF ) groups in the para position of the non-aniline aryl
3
of 2a further (Table S1, Supporting Information). When pi- ring of 2-(methylamino)benzophenones 1 cyclized ef-
valic acid was replaced by trifluoroacetic acid, only a trace ficiently in good yields (i.e., 2b–g), with a slight preference
amount of 2a was detected (Table 1, entry 10). On the con- for electron-rich substrates. Unlike Cheng’s catalytic sys-
[
16a]
trary, basic additives including KOAc and K CO gave poor tem,
no regioisomeric byproducts were observed. No-
2
3
results (Table 1, entries 11 and 12). Next, several ligands tably, meta-methoxy-substituted substrate 1j reacted re-
such as 1,10-phenanthroline, 2,2-bipyridine, TMEDA, and gioselectively at the less sterically hindered C–H bond to
PPh were screened (Table 1, entries 13–16). It was found furnish 2j exclusively in 79% yield. However, substituents
3
that the ligands alone (without pivalic acid) did not en- in the ortho position hampered the reaction for steric hin-
hance the reaction efficiency; in these cases, 2a was afforded drance reasons (i.e., for 2h and 2i). Substituent effects of
in 52–73% yield. Lowering the catalyst loading (10 mol-%) the aniline ring were also examined. The reaction proceeded
led to a less efficient formation of 2a (74%). A synergistic more efficiently for substrates in which the aniline ring con-
2
effect was observed by combining PPh and PivOH in the tained an electron-withdrawing group (R = F, Cl, I) than
3
catalytic system (84%; Table 1, entry 17). Notably, when the for substrates in which the aniline ring contained an elec-
2
reaction was performed under an atmosphere of argon, no tron-donating group (R = OMe, Me) in the same position.
reaction was observed and 1a was recovered in 73%, which To access products such as 2b, 2c, and 2j, higher yields were
suggests that O plays a vital role in the catalytic cycle obtained by placing the electron-donating group in the non-
2
(Table 1, entry 18).
aniline moiety. Notably, the aryl iodide in 1n and 1s was
Eur. J. Org. Chem. 2013, 1876–1880
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1877

J. Huang, C. Wan, M.-F. Xu, Q. Zhu
SHORT COMMUNICATION
compatible with the reaction conditions, and this provides were inaccessible by connecting the C–N bond on the other
the opportunity to elaborate the scaffold further. Although side, which enabled the synthesis of 4-substituted acidones
the presence of substituents ortho to the N-methylamino 2p and 2q by applying this strategy. In addition, substrates
group retarded the cyclization, the corresponding products 2r–u containing fused-rings or polysubstituted groups were
also suitable for the oxidative annulation reaction.
2
NH-free acridone 4a can also be prepared in lower yield
by applying the same protocol starting from unprotected 2-
aminobenzophenone (3a, Scheme 2). 2-Allylamino- (3b)
and 2-(benzylamino)benzophenones (3c) gave correspond-
ing products 4b and 4c, respectively, in good yields. Never-
theless, electron-withdrawing groups such as Ac, Ts, and
Boc on the nitrogen atom failed to afford the corresponding
products.
Table 2. Scope of CuTc-catalyzed intramolecular C(sp )–H amina-
tion.
[
a]
Scheme 2. Preparation of acridones with substituents on the nitro-
gen atom.
To gain insight into the reaction mechanism, radical-
trapping experiments were carried out by using 2,2,6,6-
tetramethylpiperidine N-oxide (TEMPO) or 1,1-diphenyl-
ethylene (1 equiv.), which are known as radical scavengers.
The reactions were not greatly suppressed under otherwise
identical conditions (Table S2, Supporting Information),
and this suggests that radical intermediates are likely not
involved in the catalytic cycle, whereas a radical-involved
[
16a]
mechanism was proposed by Cheng.
In addition, the
kinetic isotope effect (KIE) was measured by parallel reac-
tions with using 1a and deuterated analogue 1a-d5
(
Scheme 3). The KIE (2.2) indicates that C–H activation is
[
18]
a rate-limiting step.
Scheme 3. KIE study.
On the basis of the mechanistic studies and literature re-
[
19]
ports,
we propose the reaction mechanism in Scheme 4.
II
Initially, coordination of the substrate with the Cu species
generated from Cu by oxidation of O delivers intermediate
I
2
A, followed by ligand-assisted rate-limiting C–H bond acti-
vation. The presence of catalytic amounts of PivOH has
[
19c,20]
been reported to promote C–H activation.
The re-
II
sulting aryl–Cu intermediate could be further oxidized to
Cu by disproportionation of another Cu species before
III
II
reductive elimination via B. Direct reductive elimination
from the aryl–Cu intermediate cannot be ruled out at the
current stage.
[
(
(
a] Reaction conditions: 1 (0.2 mmol), CuTc (0.04 mmol), PivOH
II
0.02 mmol), PPh
3 2
(0.04 mmol), DMSO (2 mL), 130 °C, O
1 atm), 23 h, isolated yields. [b] 26 h. [c] 29 h. [d] 45 h. [e] 48 h.
1878
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Eur. J. Org. Chem. 2013, 1876–1880

Cu-Catalyzed Intramolecular Oxidative Amination
5
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the preparation of acridones through intramolecular
2
C(sp )–H amination by using molecular oxygen as an oxi-
dant. A variety of functional groups are compatible with
the catalytic system and a diverse set of acridones were ob-
tained in moderate to good yields. A reaction mechanism
involving rate-limiting C–H activation was proposed. The [6] For recent examples of rhodium-catalyzed C–H amination/am-
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Experimental Section
General Procedure for the Synthesis of N-Methyl Acridones 2: To a
solution of 2-(methylamino)benzophenone 1 (0.2 mmol) in DMSO
5
134; Angew. Chem. Int. Ed. 2008, 47, 5056; j) H. Lebel, K.
(
2 mL) was added CuTc (0.04 mmol), PivOH (0.02 mmol), and
PPh (0.04 mmol). The reaction mixture was then stirred at 130 °C
under an O atmosphere until the starting material was consumed
23–48 h). After cooling to ambient temperature, the reaction mix-
ture was quenched with a concentrated solution of ammonia
5 mL) and extracted with EtOAc (3ϫ5 mL). The combined or-
ganic extracts were washed with brine (3ϫ5 mL), dried with
Na SO , and concentrated under vacuum. The residue was purified
by column chromatography on silica gel to give cyclized products
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NMR spectra of all new compounds.
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1879

J. Huang, C. Wan, M.-F. Xu, Q. Zhu
SHORT COMMUNICATION
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Received: December 27, 2012
Published Online: February 25, 2013
1880
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