Copper-catalyzed synthesis of N-aryl acridones from 2-amino benzophenones and aryl boronic acids via sequential double oxidative C–N coupling

Article abstract of DOI:10.1002/aoc.5316

Pot-economic synthesis of N-aryl acridones was performed with 2-aminobenzophenones and aryl boronic acids as starting materials. Cu-catalyzed chelation-assisted oxidative C–N cross-coupling reactions were well merged with the following intra-molecular oxidative dehydrogenative C–H amination reactions under an air atmosphere. The use of reagent capsules can further resolve the compatibility problem of reagents and simplify the operational process, providing a more straightforward access to the target products.

Full text of DOI:10.1002/aoc.5316

Received: 19 July 2019
DOI: 10.1002/aoc.5316
Revised: 1 October 2019
Accepted: 4 October 2019
F U L L P A P E R
Copper-catalyzed synthesis of N-aryl acridones from 2-
amino benzophenones and aryl boronic acids via sequential
double oxidative C–N coupling
Yang He1 | Liang Xu1 | Jinli Zhang1,2,3 | Yu Wei1
1School of Chemistry and Chemical
Pot-economic synthesis of N-aryl acridones was performed with
2-aminobenzophenones and aryl boronic acids as starting materials. Cu-
catalyzed chelation-assisted oxidative C–N cross-coupling reactions were well
merged with the following intra-molecular oxidative dehydrogenative C–H
amination reactions under an air atmosphere. The use of reagent capsules can
further resolve the compatibility problem of reagents and simplify the opera-
tional process, providing a more straightforward access to the target products.
Engineering/Key Laboratory for Green
Processing of Chemical Engineering of
Xinjiang Bingtuan, Shihezi University,
Shihezi, 832003, China
2Key Laboratory for Systems
Bioengineering MOE, Tianjin University,
Tianjin, 300072, China
3Collaborative Innovation Center of
Chemical Science and Chemical
Engineering (Tianjin), Tianjin, 300072,
China
K E Y W O R D S
acridone, amination, Chan–Evans–Lam reaction, copper, cross-coupling
Correspondence
Jinli Zhang and Yu Wei, School of
Chemistry and Chemical
Engineering/Key Laboratory for Green
Processing of Chemical Engineering of
Xinjiang Bingtuan, Shihezi University,
Shihezi 832003, China.
Email: zhangjinli@tju.edu.cn;
yuweichem@shzu.edu.cn
Funding information
Shihezi University, Grant/Award Number:
CXRC201602; National Natural Science
Foundation of China, Grant/Award
Number: 21602141
1 | INTRODUCTION
electronic and photophysical properties.[8,9] Therefore,
synthetic methodologies for constructing the acridone
The acridone skeleton is frequently encountered in het-
erocyclic natural products[1,2] and functional molecules.
For example, acridone derivatives and analogs have been
demonstrated to possess a range of biological and phar-
macological activities such as antibacterial, antimalarial,
antiviral, and antitumor.[3–7] This privileged structure is
the core of the marketed antiviral drug Neovir (acridone
acetic acid sodium salt). Furthermore, acridone-based
organic electronics, fluorescent materials, and light-
emitting diodes (organic light emitting diodes [OLEDs])
have garnered a significant attention due to their unusual
scaffold have been continuously refined in recent decades
to broaden the accessibility of diverse substituted
acridone compounds.[10]
As for N-aryl acridones, whose nitrogen atoms are
substituted by three aryl groups, their synthesis generally
starts from pre-fabricated N,N-diaryl or N,N,N-triaryl as
starting materials. For example, traditionally, the N-aryl
acridone moiety is mainly constructed via the acid-
promoted annulation of N,N-diaryl anthranilic acids
(Scheme 1, a). Copper-catalyzed Ullmann coupling reac-
tions between unsubstituted acridin-9(10H)-one and aryl
Appl Organometal Chem. 2019;e5316.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5316

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HE ET AL.
SCHEME 1 The existing strategies for the synthesis of N-aryl acridones
(pseudo)halides are also frequently used in its construc-
tion (Scheme 1, c).[11–15] More recently, Cu-catalyzed oxi-
dative intra-molecular ring-closing methodologies, based
on the oxidative (dehydrogenative) coupling of C–H
bonds, have been utilized in N-aryl acridone
synthesis.[16–18] Although such strategies bypass the pre-
functionalization steps of the relatively inert C–H bonds,
the synthesis of N,N-diaryl or N,N,N-triaryl amines is still
necessary (Scheme 1, d and e). In fact, to the best of our
knowledge, there are only two approaches that can build
up the N-aryl acridone skeleton with simultaneous for-
mation of two or more C–N bonds. They rely on the utili-
zation of double halogenated substrates (Scheme 1, b)[19]
or aryne precursors (Scheme 1, f).[20–22] Although some
of the mentioned strategies (Scheme 1, a–f) have been
widely practiced, the use of pre-functionalized or expen-
sive starting materials necessitates their further improve-
ment to obtain more straightforward and efficient
approaches. Herein, we present a one-pot method to syn-
thesize N-aryl acridone compounds under the catalysis of
copper/air via sequential oxidative Chan–Evans–Lam
(CEL) C–N cross-couplings and the following oxidative
cross-dehydrogenative coupling (CDC)[23] of C–N bonds.
From the perspective of atom economy and green
chemistry, one-pot strategies, which incorporate tradi-
tional purification-dependent stepwise reactions into a
single vessel, represent a practical means to approach
highly efficient synthesis.[24] The one-pot assembly of
sophisticated targeted molecules can bypass isolation and
purification of intermediates, which will dramatically
reduce the use of solvent, time, labor, cost, and waste pro-
duction. Despite obvious advantages, the challenge in the
design and development of such sequential reactions can
be daunting. In general, elaborately screened reaction con-
ditions, including catalysts, reagents, additives, solvent,
and even concentration, are utilized to satisfy a specific
transformation, which may be invalid and even detrimen-
tal to the following reactions. As the number of individual
reactions in a pot increases, by-products and side products
accumulate and the associated selectivity and compatibil-
ity issues rise sharply. Therefore, careful harmonization
and balance of multiple reaction conditions should be nec-
essary to achieve an efficient reaction sequence.
In this context, the CEL reactions, which take advan-
tage of oxidative coupling between boronic species and
amines,[25–28] natively have the potential of collaborating
with aerobic Cu-catalyzed dehydrogenative cyclization
reactions to construct heterocycles.[29–32] However, lim-
ited success has been achieved in the application of this
strategy, relative to the wide application of Cu-catalyzed
Ullmann reaction-based sequential, cascade, or tandem
cyclization reactions.[33] In the disclosed methodologies,
only the synthesis of benzimidazole[34] and acridone deriv-
atives[35] (including an example of N-phenyl acridone) has
been systemically studied by catalyzed oxidative sequen-
tial C–N coupling reactions using O2 as oxidant
(Scheme 2, a, b). Very recently, based on our research on
the chelation-assisted CEL reactions,[36–38] we have dem-
onstrated the one-pot assembly of N,N0-diarylindazol-
3-ones[39] via Cu-catalyzed sequential CEL/CDC reactions
(Scheme 2, c). As the carbonyl group of ketones is also a
good chelation group for CEL reactions,[37] we became
SCHEME 2 Cu-catalyzed one-pot oxidative Chan–Evans–
Lam/dehydrogenative cyclization reactions. DMSO, dimethyl
sulfoxide

SYNTHESIS OF N-ARYL ACRIDONES VIA DOUBLE OXIDATIVE C−N COUPLING
3 of 9
interested in applying such chelation function and the
sequential CEL/CDC strategy in the one-pot inter-
molecular synthesis of heterocycles. Herein, we report the
synthesis of N-aryl acridones from readily available
2-aminobenzophenones and aryl boronic acids.
(3 × 5.0 mL). The combined organic layer was dried
over sodium sulfate and concentrated to afford residue,
which was purified by column chromatography on sil-
ica gel to give the target product.
2.2.2 | General procedure B
2 | EXPERIMENTAL SECTION
2.1 | Materials and instruments
The following were added into a 25-mL reaction tube
with a stirring bar: 1a (39.5 mg, 0.2 mmol, 1.0 equiva-
lent), Cu(OAc)2 (5.5 mg, 0.03 mmol, 15 mol%),
Cu(OAc)2 (3.7 mg, 0.02 mmol, 10 mol%) wrapped in par-
affin wax, CsF (15.2 mg, 0.1 mmol, 0.5 equivalent), aryl
boronic acid (0.3 mmol, 1.5 equivalent), and MeOH
(0.6 mL). The resulting mixture was stirred slowly at
ambient temperature for 12 hr. Then DMF (2.0 mL) was
added and the temperature was raised to 130 ꢀC. The
mixture was stirred for 24 hr. After cooling, the reaction
mixture was treated with EtOAc (5.0 mL) and water
(5.0 mL). The organic layer was separated, and the aque-
ous layer was extracted with EtOAc (3 × 5.0 mL). The
combined organic layer was dried over sodium sulfate,
and concentrated to afford residue, which was purified
by column chromatography on silica gel to give the tar-
get product.
Chemicals were obtained commercially and used as
received, including 2-amino benzophenones and aryl
boronic acids (see supporting information). All reac-
tions were carried out under an air atmosphere. Ana-
lytical thin-layer chromatography was performed on
glass plates coated with silica gel containing a fluores-
cent indicator and visualized by a UV lamp. All prod-
ucts were purified by column chromatography using
silica gel (200–300 mesh). For solid products, melting
points were measured. Nuclear magnetic resonance
(NMR) spectra were measured on a Bruker Ascend
400 spectrometer. Chemical shifts (δ) were reported in
parts per million (ppm). 1H NMR spectra were
recorded at 400 MHz and 13C NMR spectra were
recorded at 101 MHz (for copies of NMR spectra, see
supporting information). Infrared (IR) spectra were col-
lected on a Thermo Fisher Nicolet 6700 Fourier-
transform IR spectrometer using the attenuated total
reflectance method. Absorption maxima (ν max) are
reported in wavenumbers (cm−1). High-resolution mass
spectra (HRMS) were acquired on a Thermo Scientific
LTQ Orbitrap XL with an electrospray ionization (ESI)
source.
2.3 | Characterization data for isolated
products
2.3.1 | 10-Phenylacridin-9(10H)-
one (3a)[17]
1
ꢀ
Yellow solid. Melting point (m.p.) 287–289 C. H NMR
(400 MHz, CDCl3) δ 8.59 (dd, J = 8.0, 1.6 Hz, 2H),
7.74–7.63 (m, 3H), 7.53–7.47 (m, 2H), 7.42–7.35 (m, 2H),
7.31–7.25 (m, 2H), 6.76 (d, J = 8.8 Hz, 2H). 13C NMR
(101 MHz, CDCl3) δ 178.17, 143.14, 138.97, 133.27,
131.10, 130.06, 129.60, 127.29, 121.81, 121.53, 116.80.
HRMS (ESI) m/z calcd for C19H14NO+ (M + H)+
272.1070, found 272.1069.
2.2 | Typical experimental procedures
2.2.1 | General procedure A
The following were added into a 25-mL reaction tube
with a stirring bar: 1a (39.5 mg, 0.2 mmol, 1.0 equiva-
lent), Cu(OAc)2 (5.5 mg, 0.03 mmol, 15 mol%), CsF
(15.2 mg, 0.1 mmol, 0.5 equivalent), arylboronic acid
(0.3 mmol, 1.5 equivalent), and MeOH (0.6 mL). The
resulting mixture was stirred at ambient temperature
for 12 hr. Then, Cu(OAc)2 (3.7 mg, 0.02 mmol,
10 mol%) and dimethylformamide (DMF; (2.0 mL) were
added and the temperature was raised to 130 ꢀC. The
mixture was stirred for 24 hr. After cooling, the reac-
tion mixture was treated with EtOAc (5.0 mL) and
water (5.0 mL). The organic layer was separated, and
the aqueous layer was extracted with EtOAc
2.3.2 | 10-4-Bromophenyl)acridin-9(10H)-
one (3b)[17]
Yellow-green solid. m.p. 259–261 ꢀC. 1H NMR (400 MHz,
CDCl3) δ 8.57 (dd, J = 8.0, 1.6 Hz, 2H), 7.90–7.80 (m,
2H), 7.55–7.48 (m, 2H), 7.37–7.22 (m, 4H), 6.75 (d,
J = 8.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 178.05,
142.87, 137.99, 134.50, 133.43, 131.91, 127.45, 123.76,
121.87, 121.77, 116.50. HRMS (ESI) m/z calcd for
C19H13BrNO+ (M + H)+ 350.0175, found 350.0176.

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HE ET AL.
2.3.3 | 10-(4-Chlorophenyl)acridin-9(10H)-
one (3c)[17]
116.24. HRMS (ESI) m/z calcd for C19H12Cl2NO+
(M + H)+ 340.0290, found 340.0295.
1
ꢀ
Light green solid. m.p. 232–234 C. H NMR (400 MHz,
CDCl3) δ 8.59 (dd, J = 8.0, 1.2 Hz, 2H), 7.74–7.66 (m,
2H), 7.55–7.49 (m, 2H), 7.36–7.27 (m, 4H), 6.75 (d,
J = 8.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 178.07,
142.94, 137.45, 135.71, 133.43, 131.58, 131.48, 127.45,
121.87, 121.76, 116.50. HRMS (ESI) m/z calcd for
C19H13ClNO+ (M + H)+ 306.0680, found 306.0682.
2.3.7 | 10-(4-[Trifluoromethyl]phenyl)
acridin-9(10H)-one (3g)[17]
Yellow solid. m.p. 328–330 ꢀC. 1H NMR (400 MHz,
CDCl3) δ 8.60 (dd, J = 8.0, 1.2 Hz, 2H), 8.01 (d,
J = 8.0 Hz, 2H), 7.58–7.50 (m, 4H), 7.34–7.29 (m, 2H),
6.68 (d, J = 8.6 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ
178.01, 142.70, 142.32 (q, J = 1), 133.54, 131.97 (q,
J = 33), 131.04, 128.40 (q, J = 4), 127.54, 123.62 (q,
J = 274), 121.93, 121.87, 116.33. 19F NMR (376 MHz,
2.3.4 | 10-(4-Fluorophenyl)acridin-9(10H)-
one (3d)[17]
CDCl3)
δ
−62.60. HRMS (ESI) m/z calcd for
Yellow solid. m.p. 279–281 ꢀC. 1H NMR (400 MHz,
CDCl3) δ 8.58 (dd, J = 8.0, 1.2 Hz, 2H), 7.55–7.49 (m,
2H), 7.44–7.34 (m, 4H), 7.32–7.27 (m, 2H), 6.75 (d,
J = 8.8 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 178.06,
162.85(d, J = 251 Hz), 143.15, 134.84 (d, J = 3 Hz),
133.39, 132.97 (d, J = 9 Hz), 127.37, 121.84, 121.68, 118.22
(d, J = 23 Hz), 116.55. 19F NMR (376 MHz, CDCl3) δ
−110.52. HRMS (ESI) m/z calcd for C19H13FNO+
(M + H)+ 290.0976, found 290.0975.
C20H13F3NO+ (M + H)+ 340.0944, found 340.0943.
2.3.8 | 10-(p-Tolyl)acridin-9(10H)-
one (3h)[17]
Yellow solid. m.p. 290–291 ꢀC. 1H NMR (400 MHz,
CDCl3) δ 8.58 (dd, J = 8.0, 1.6 Hz, 2H), 7.52–7.47 (m,
4H), 7.29–7.22 (m, 4H), 6.80 (d, J = 8.8 Hz, 2H), 2.54 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 178.19, 143.27,
139.69, 136.24, 133.20, 131.69, 129.68, 127.24, 121.82,
121.44, 116.90, 21.37. HRMS (ESI) m/z calcd for
C20H16NO+ (M + H)+ 286.1226, found 286.1231.
2.3.5 | 10-(3-Fluorophenyl)acridin-9(10H)-
one (3e)
Light yellow solid. m.p. 309–310 ꢀC. IR: 3080, 2900, 1599,
1
1488, 1419, 1228, 746. H NMR (400 MHz, CDCl3) δ 8.57
2.3.9 | 10-(m-Tolyl)acridin-9(10H)-
one (3i)[17]
(d, J = 76 Hz, 2H), 7.70 (q, J = 8.0 Hz, 1H), 7.52 (t,
J = 7.2 Hz, 2H), 7.41–7.35 (m, 1H), 7.32–7.24 (m, 2H),
7.21 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.76 (d,
J = 8.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 178.06,
164.13 (d, J = 252 Hz), 142.81, 140.38 (d, J = 9 Hz),
133.46, 132.42 (d, J = 9 Hz), 127.42, 126.05 (d, J = 3 Hz),
121.83, 121.80, 117.74 (d, J = 22 Hz), 117.04 (d,
J = 21 Hz), 116.49. 19F NMR (376 MHz, CDCl3) δ
−108.49. HRMS (ESI) m/z calcd for C19H13FNO+
(M + H)+ 290.0976, found 290.0979.
1
ꢀ
Cream color solid. m.p. 201–203 C. H NMR (400 MHz,
CDCl3) δ 8.59 (dd, J = 8.0, 1.2 Hz, 2H), 7.61–7.56 (m,
1H), 7.53–7.48 (m, 2H), 7.45 (d, J = 7.6 Hz, 1H),
7.31–7.25 (m, 2H), 7.18 (s, 2H), 6.79 (d, J = 8.4 Hz, 2H),
2.48 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 178.18,
143.15, 141.41, 138.87, 133.21, 130.80, 130.41, 130.32,
127.25, 126.89, 121.79, 121.46, 116.92, 21.38. HRMS (ESI)
m/z calcd for C20H16NO+ (M + H)+ 286.1226, found
286.1226.
2.3.6 | 10-(3,5-Dichlorophenyl)acridin-
9(10H)-one (3f)
2.3.10 | 10-(3,5-Dimethylphenyl)acridin-
9(10H)-one (3j)
Cream color solid. m.p. 304–306 ꢀC. IR: 3095, 2900,
1599, 1485, 1451, 1305, 799, 750. H NMR (400 MHz,
CDCl3) δ 8.57 (dd, J = 8.0, 1.6 Hz, 2H), 7.68 (t,
J = 2.0 Hz, 1H), 7.58–7.53 (m, 2H), 7.35 (d, J = 2.0 Hz,
2H), 7.33–7.29 (m, 2H), 6.75 (d, J = 8.8 Hz, 2H). 13C
NMR (101 MHz, CDCl3) δ 177.92, 142.49, 140.85,
137.41, 133.66, 130.28, 129.14, 127.60, 122.09, 121.85,
1
ꢀ
Tan solid. m.p. 254–256 C. IR: 3095, 1599, 1455, 1316,
1
939, 751, 700. H NMR (400 MHz, CDCl3) δ 8.58 (dd,
J = 8.0, 1.2 Hz, 2H), 7.53–7.47 (m, 2H), 7.29–7.24 (m,
3H), 6.98 (s, 2H), 6.82 (d, J = 8.4 Hz, 2H), 2.44 (s, 6H).
13C NMR (101 MHz, CDCl3) δ 178.19, 143.14, 141.03,
138.76, 133.15, 131.12, 127.31, 127.21, 121.77, 121.39,

SYNTHESIS OF N-ARYL ACRIDONES VIA DOUBLE OXIDATIVE C−N COUPLING
5 of 9
117.03, 21.30. HRMS (ESI) m/z calcd for C21H18NO+
(M + H)+ 300.1383, found 300.1385.
143.18, 142.45, 135.11, 133.63, 131.68, 127.65, 122.10,
121.88, 117.64, 116.09, 114.00. HRMS (ESI) m/z calcd for
C20H13N2O+ (M + H)+ 297.1022, found 297.1024.
2.3.11 | 10-(4-[tert-butyl]phenyl)acridin-
9(10H)-one (3k)
2.3.15 | 10-(4-Methoxyphenyl)acridin-
9(10H)-one (3o)[16]
Yellow solid. m.p. 316–317 ꢀC. IR: 3078, 2961, 1634,
1
1597, 1481, 1302, 1101, 753. H NMR (400 MHz, CDCl3)
Yellow solid. m.p. 216–218 ꢀC. 1H NMR (400 MHz,
CDCl3) δ 8.59 (d, J = 8.0 Hz, 2H), 7.54–7.47 (m, 2H),
7.31–7.24 (m, 4H), 7.22–7.17 (m, 2H), 6.82 (d, J = 8.4 Hz,
2H), 3.95 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 178.20,
160.14, 143.51, 133.23, 131.37, 131.00, 127.26, 121.88,
121.46, 116.90, 116.17, 55.69. HRMS (ESI) m/z calcd for
C20H16NO2+ (M + H)+ 302.1176, found 302.1176.
δ 8.59 (dd, J = 8.0, 1.6 Hz, 2H), 7.72–7.68 (m, 2H),
7.53–7.47 (m, 2H), 7.30–7.24 (m, 4H), 6.79 (d,
J = 8.8 Hz, 2H), 1.46 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ 178.18, 152.83, 143.29, 136.14, 133.18, 129.36,
127.95, 127.22, 121.82, 121.43, 116.94, 35.00, 31.42.
HRMS (ESI) m/z calcd for C23H22NO+ (M + H)+
328.1696, found 328.1698.
2.3.16 | 10-(3-Methoxyphenyl)acridin-
9(10H)-one (3p)
2.3.12 | 10-(4-[Methylthio]phenyl)acridin-
9(10H)-one (3l)
Cream color solid. m.p. 213–215 ꢀC. IR: 3091, 1497, 1445,
1228, 1098, 834, 752. 1H NMR (400 MHz, CDCl3) δ
8.62–8.56 (m, 2H), 7.60 (td, J = 8.0, 2.0 Hz, 1H), 7.54–7.48
(m, 2H), 7.32–7.23 (m, 2H), 7.21–7.15 (m, 1H), 6.83 (d,
J = 7.6 Hz, 1H), 6.89 (t, J = 2.0 Hz, 1H), 6.83 (d,
J = 8.8 Hz, 2H), 3.86 (s, 3H). 13C NMR (101 MHz, CDCl3)
δ 178.15, 161.82, 142.99, 139.99, 133.28, 131.74, 127.25,
121.92, 121.77, 121.53, 116.86, 115.55, 115.13, 55.60.
Tan solid. m.p. 263–266 ꢀC. IR: 3084, 2920, 1636,
1598, 1457, 1301, 819, 726. H NMR (400 MHz, CDCl3)
1
δ 8.58 (dd, J = 8.0, 1.6 Hz, 2H), 7.55–7.48 (m,
4H), 7.31–7.24 (m, 4H), 6.81 (d, J = 8.4 Hz, 2H),
2.61 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 178.12,
143.18, 141.03, 135.44, 133.29, 130.33, 128.08,
127.32, 121.85, 121.57, 116.77, 15.42. HRMS (ESI) m/z
calcd for C20H16NOS+ (M + H)+ 318.0947, found
318.0950.
HRMS (ESI) m/z calcd for C20H16NO2 (M + H)+
+
302.1176, found 302.1179.
2.3.13 | 10-(4-[Trimethylsilyl] phenyl)
acridin-9(10H)-one (3m)
2.3.17 | 2-Chloro-10-phenylacridin-9(10H)-
one (3q)[17]
Yellow solid. m.p. 206–208 ꢀC. IR: 3096, 3017, 1599,
1301, 1100, 826, 751. H NMR (400 MHz, CDCl3) δ 8.59
Yellow solid. m.p. 235–237 ꢀC. 1H NMR (400 MHz,
CDCl3) δ 8.54 (dd, J = 8.0, 1.6 Hz, 1H), 8.51 (d,
J = 2.8 Hz, 1H), 7.76–7.64 (m, 3H), 7.53–7.48 (m, 1H),
7.41 (dd, J = 9.2, 2.4 Hz, 1H), 7.39–7.34 (m, 2H),
7.30–7.25 (m, 1H), 6.75 (d, J = 8.8 Hz, 1H), 6.71
(d, J = 9.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 177.07,
143.00, 141.52, 138.65, 133.59, 133.40, 131.25, 129.90,
129.86, 127.53, 127.32, 126.40, 122.57, 121.91, 121.66,
118.62, 116.90. HRMS (ESI) m/z calcd for C19H13ClNO+
(M + H)+ 306.0680, found 306.0681.
1
(d, J = 7.2 Hz, 2H), 7.83 (d, J = 7.6 Hz, 2H), 7.52–7.47
(m, 2H), 7.34 (d, J = 7.6 Hz, 2H), 7.30–7.25 (m, 2H),
6.77 (d, J = 8.4 Hz, 2H), 0.40 (s, 9H). 13C NMR
(101 MHz, CDCl3) δ 179.22, 144.18, 143.90, 140.36,
137.04, 134.28, 130.19, 128.32, 122.86, 122.55, 117.95.
HRMS (ESI) m/z calcd for C22H22NOSi+ (M + H)+
344.1465, found 344.1468.
2.3.14 | 4-(9-oxoacridin-10[9H]-yl)
benzonitrile (3n)[17]
2.3.18 | 2-Chloro-10-(4-chlorophenyl)
acridin-9(10H)-one (3r)
Yellow solid. m.p. 332–335 ꢀC. 1H NMR (400 MHz, CDCl3)
δ 8.57 (dd, J = 8.0, 1.2 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H),
7.61–7.49 (m, 4H), 7.30 (t, J = 7.6 Hz, 2H), 6.64 (d,
J = 8.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 177.90,
Yellow solid. m.p. 309–312 ꢀC. IR: 3096, 2900, 1634, 1595,
1
1300, 1092, 748. H NMR (400 MHz, CDCl3) δ 8.51 (dd,
J = 8.0, 1.6 Hz, 1H), 8.48 (d, J = 2.8 Hz, 1H), 7.75–7.66

6 of 9
HE ET AL.
(m, 2H), 7.55–7.50 (m, 1H), 7.42 (dd, J = 8.8, 2.4 Hz, 1H),
7.38–7.32 (m, 2H), 7.30–7.25 (m, 1H), 6.74 (d, J = 8.8 Hz,
1H), 6.71 (d, J = 9.2 Hz, 1H). 13C NMR (101 MHz, CDCl3)
δ 176.93, 142.79, 141.30, 137.10, 136.00, 133.74, 133.54,
131.63, 131.42, 127.76, 127.43, 126.53, 122.60, 122.12,
121.68, 118.31, 116.60. HRMS (ESI) m/z calcd for
C19H12Cl2NO+ (M + H)+ 340.0290, found 340.0294.
138.40, 133.55, 131.34, 129.97, 129.87, 129.07, 127.27,
122.27, 122.05, 121.94, 120.21, 116.93, 116.29. HRMS
(ESI) m/z calcd for C19H13ClNO+ (M + H)+ 306.0680,
found 306.0681.
2.3.20 | 3-Chloro-10-(4-chlorophenyl)
acridin-9(10H)-one (3t)
2.3.19 | 3-Chloro-10-phenylacridin-9(10H)-
one (3s)[17]
Yellow solid. m.p. 284–287 ꢀC. IR: 3096, 2900, 1636, 1591,
1087, 839, 749. H NMR (400 MHz, CDCl3) δ 8.56–8.44
1
(m, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.55–7.49 (m, 1H),
7.38–7.25 (m, 3H), 7.21 (dd, J = 8.4, 1.6 Hz, 1H),
6.77–6.66 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 177.30,
143.53, 142.96, 139.92, 136.85, 136.10, 133.70, 131.73,
131.39, 129.19, 127.41, 122.49, 122.27, 121.98, 120.25,
116.64, 116.01. HRMS (ESI) m/z calcd for C19H12Cl2NO+
(M + H)+ 340.0290, found 340.0297.
Yellow solid. m.p. 268–270 ꢀC. 1H NMR (400 MHz,
CDCl3) δ 8.55 (dd, J = 8.0, 1.6 Hz, 1H), 8.50 (d,
J = 8.6 Hz, 1H), 7.76–7.65 (m, 3H), 7.52–7.47 (m, 1H),
7.40–7.35 (m, 2H), 7.31–7.26 (m, 1H), 7.21 (dd,
J = 8.8, 1.6 Hz, 1H), 6.77–6.69 (m, 2H). 13C NMR
(101 MHz, CDCl3) δ 177.43, 143.74, 143.18, 139.71,
TABLE 1 The optimization of reaction conditionsa
Entry
Base
NEt3
Catalyst A/Catalyst B
Cu(OAc)2/—
Solvent A/Solvent B
MeOH/DMSO
MeOH/DMSO
MeOH/DMSO
MeOH/DMSO
MeOH/DMSO
MeOH/DMSO
EtOH/DMSO
MeOH/NMP
MeOH/DMF
MeOH/DMF
MeOH/DMF
MeOH/DMF
MeOH/DMF
MeCN/DMF
Yields (%)b
18%
1
2
NEt3
Cu(OAc)2/Cu(OAc)2
Cu(OAc)2/CuO2
25%
3
NEt3
18%
4
NEt3
Cu(OAc)2/CuCl
20%
5
Cs2CO3
LiOMe
Cs2CO3
Cs2CO3
CsF
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
CuCl/CuCl
62%
6
22%
7
31%
8
18%
9
68%
16%
10
11
12
13
14
15
CsF
CsF
Cu(OTf)2/Cu(OTf)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
33%
KOtBu
K3PO4
CsF
61%
60%
20%
CsF
DCM/DMF
9%
aGeneral reaction conditions: 0.2 mmol 1a (1.0 equivalent), 0.3 mmol 2a (1.5 equivalent), 0.03 mmol copper catalyst A (15 mol%), 0.1 mmol base (0.5
equivalent), solvent A (0.6 mL), room temperature, 12 hr. Then 0.02 mmol catalyst B (10 mol%), solvent B (2.0 mL), 130 ꢀC, 24 hr.
bIsolated yields.
Abbreviation: rt, room temperature.

SYNTHESIS OF N-ARYL ACRIDONES VIA DOUBLE OXIDATIVE C−N COUPLING
7 of 9
2.3.21 | 10-(4-Chlorophenyl)-3-fluoroacridin-
9(10H)-one (3u)
NMR (376 MHz, CDCl3) δ −102.73. HRMS (ESI) m/z calcd
for C19H12ClFNO+ (M + H)+ 324.0586, found 324.0589.
Yellow solid. m.p. 250–251 ꢀC. IR: 3095, 2900, 1639, 1591,
1
1304, 1090, 750. H NMR (400 MHz, CDCl3) δ 8.61–8.51
2.3.22 | 10-(4-Phenoxyphenyl)acridin-
(m, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.55–7.49 (m, 1H),
7.37–7.25 (m, 3H), 7.02–6.94 (m, 1H), 6.73 (d, J = 8.6 Hz,
1H), 6.38 (dd, J = 11.2, 2.0 Hz, 1H). 13C NMR (101 MHz,
CDCl3) δ 177.13, 165.91 (d, J = 251 Hz), 144.6 (d,
J = 12 Hz), 143.14, 137.04, 136.08, 133.53, 131.70, 131.36,
130.66 (d, J = 11 Hz), 127.45, 122.22, 121.94, 118.70,
116.52, 110.58 (d, J = 23 Hz), 102.50 (d, J = 27 Hz). 19F
9(10H)-one (3v)
Yellow solid. m.p. 226–227 ꢀC. IR: 3095, 2900, 1634, 1595,
1
1455, 1228, 750. H NMR (400 MHz, CDCl3) δ 8.59 (dd,
J = 8.0, 1.2 Hz, 2H), 7.56–7.51 (m, 2H), 7.48–7.42 (m, 2H),
7.32–7.18 (m, 9H), 6.84 (d, J = 8.8 Hz, 2H). 13C NMR
(101 MHz, CDCl3) δ 177.90, 143.18, 142.45, 135.11, 133.63,
SCHEME 3 Substrate scope of Cu-
catalyzed one-pot synthesis of N-aryl acridones.
DMF, dimethylformamide; rt, room
temperature

8 of 9
HE ET AL.
131.68, 127.65, 122.10, 121.88, 117.64, 116.09, 114.00.
derivatives, in comparison with the halogen-substituted
ones. For example, when (methoxyphenyl)boronic acids
were used as the starting materials, about 50% yields of
target products could be obtained (3o and 3p).
HRMS (ESI) m/z calcd for C25H18NO2 (M + H)+
+
364.1332, found 364.1335.
In addition, aryl boronic acid pinacol esters, which
were usually considered to be reluctant to go through
CEL reactions,[40,41] could also participate in such a one-
pot reaction process, affording products in medium yields
(63% for 3d, 54% for 3f, and 42% for 3h). Then, variation
of the 2-aminobenzophenone component was tested.
Starting materials, which contained substituents on
either of their two phenyl rings, also went through such
stepwise transformations well, affording products in
61%–76% yields (3q–3u).
In the aforementioned stepwise process, the addition
of the second portion of Cu(OAc)2 was necessary to
achieve satisfactory yields. This stimulated us to further
simplify the operational procedure. Recently, paraffin
wax capsules, which were originally developed to mini-
mize the inconvenience from storage and utilization of
air- or moisture-sensitive compounds, have been
exploited to solve the compatibility problem in mul-
ticomponent reactions.[42–46] The release of specific
reagents could be controlled via the change of reaction
temperature. In view of the change of temperature in our
aforesaid procedure, the feasibility of reagent capsules
was tested. Paraffin wax capsules containing 10 mol%
Cu(OAc)2 were prepared and added in the first step. A
controlled release was then achieved in the second step.
Without changing other reaction parameters, about 10%
higher yield could be obtained than the previous proce-
dure (3b, 3j, and 3l), demonstrating the feasibility and
advantage of the utilization of reagent capsules.
3 | RESULTS AND DISCUSSION
Initially, 2-aminobenzophenone 1a and phenylboronic
acid 2a were chosen as model reactants to examine the
feasibility of our assumptions. Similar reaction condi-
tions for the synthesis of N,N0-diarylindazol-3-ones were
tested at first. Under such conditions, only dimethyl sulf-
oxide was added in the second step. As anticipated, the
product 10-phenylacridin-9(10H)-one 3a was obtained
after the CEL/CDC sequence reaction using air as the
oxidant, albeit in 18% yield (Table 1, Entry 1). Further
optimization was then performed by adding extra copper
salts in the second step. However, the variation of the
catalyst sources in the second step resulted in no better
results (Entries 2–4). Then, the change of NEt3 to an
inorganic base (Cs2CO3) gave a much better yield (62%,
Entry 5). The use of CsF could further improve the over-
all yield to 68% under the condition that MeOH/DMF
was used (Entry 9). Other inorganic bases, such as
LiOMe, KOtBu, and K3PO4 (Entries 6, 12, and 13), and
other combinations of solvents (Entries 7, 8, 14, and 15),
resulted in inferior yields. When CuCl or Cu(OTf)2 was
used in place of Cu(OAc)2, only 16% and 33% yield of
the final product was obtained after the reaction
sequence (Entries 10 and 11), demonstrating the essen-
tial role of the copper sources. Finally, the optimal reac-
tion conditions were found to be as follows: under an air
atmosphere, 1a, 1.5 equivalents of 2a, 15 mol%
Cu(OAc)2, and 50 mol% CsF in MeOH were stirred at
room temperature for 12 hr. Then, additional 10 mol%
Cu(OAc)2 and DMF were added, and the mixture was
4 | CONCLUSION
ꢀ
heated at 130 C for 24 hr.
With these optimal conditions in hand, we subse-
quently investigated their applicability. As shown in
Scheme 3, when the substitution groups of the boronic
acids changed, the final N-aryl acridones could be
obtained in 49%–79% yields after one-pot stepwise trans-
formations. The boronic acids with halogen atoms on the
aryl rings, such as Br (3b), Cl (3c), F (3d and 3e), well tol-
erated the reaction conditions, affording target products
in 71%–79% yields. In addition to halogens, a variety of
other substituents at the meta or para position were also
compatible with the reaction process, such as
trifluoromethyl (3g), methyl (3h–3j), tert-butyl (3k), met-
hylthio (3l), trimethylsilyl (3m), cyano (3n), methoxyl
(3o and 3p), and phenoxyl (3v). In general, aryl boronic
acids with electron-donating groups (3h–3m, 3o, 3p, 3v)
rendered less yields of the corresponding acridone
In
synthetic method has been established to access N-aryl
acridone derivatives from readily available
summary,
a
Cu-catalyzed
pot-economical
2-aminobenzophenones and aryl boronic acids. This
one-pot protocol takes advantage of sequential double
oxidative C–N coupling reactions using air as oxidant,
namely, CEL couplings and oxidative CDCs. The utili-
zation of reagent capsules can further simplify the
operational procedure. The application of such a strat-
egy to construct other types of heterocycles is under-
way in our laboratory.
ACKNOWLEDGMENTS
We are thankful for financial support from the National
Natural Science Foundation of China (21602141) and
Shihezi University (CXRC201602).

SYNTHESIS OF N-ARYL ACRIDONES VIA DOUBLE OXIDATIVE C−N COUPLING
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ORCID
Yu Wei https://orcid.org/0000-0002-4432-7190
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How to cite this article: He Y, Xu L, Zhang J,
Wei Y. Copper-catalyzed synthesis of N-aryl
acridones from 2-amino benzophenones and aryl
boronic acids via sequential double oxidative C–N
coupling. Appl Organometal Chem. 2019;e5316.
https://doi.org/10.1002/aoc.5316