Copper-Catalyzed Electrophilic Amination of Arylboronic Acids with Anthranils: An Access to N-Aryl-2-aminophenones

Article abstract of DOI:10.1021/acs.joc.0c01109

An efficient copper-catalyzed electrophilic amination strategy has been established for the rapid synthesis of N-aryl-2-aminophenones from readily available arylboronic acids/esters and anthranils. This protocol features good functional group tolerance, broad substrate scope, and operational simplicity. Moreover, a tandem C-H borylation and C-N coupling protocol has also been developed to transform simple arenes to the valuable N-aryl-2-aminophenones in one pot. Additionally, the synthetic potential of this methodology is further demonstrated by the synthesis of various useful N-heterocycles and derivatives.

Full text of DOI:10.1021/acs.joc.0c01109

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Note
Copper-Catalyzed Electrophilic Amination of Arylboronic
acids with Anthranils: An Access to N-Aryl-2-aminophenones
Yang Gao, Simin Yang, Yibiao Li, Yanping Huo, Zongyi Huang, Zumin Chen, and Xiao-Qiang Hu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01109 • Publication Date (Web): 07 Jul 2020
Downloaded from pubs.acs.org on July 7, 2020
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Copper-Catalyzed Electrophilic Amination of Arylboronic acids with Anthranils: An Access
to N-Aryl-2-aminophenones
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Yang Gao,§* Simin Yang,§ Yibiao Li,¶ Yanping Huo,§* Zongyi Huang,§ Zumin Chen,§ and
Xiao-Qiang Hu†*
§
School of Chemical Engineering and Light Industry, Guangdong University of Technology,
Guangzhou, 510006, China.
¶ School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, Guangdong Province
529090, China.
† Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education & Hubei
Key Laboratory of Catalysis and Materials Science, School of Chemistry and Materials Science,
South-Central University for Nationalities, Wuhan 430074, China.
*E-mail for Y. G.: gaoyang@gdut.edu.cn; *E-mail for Y. H.: yphuo@gdut.edu.cn; *E-mail for
X.-Q. H.: huxiaoqiang@mail.scuec.edu.cn
O
R3
CuCl2 (10 mol%)
K2CO3 (50 mol%)
H
B(OR)2
N
N
R2
O
R1
+
R1
R2
DMSO, 100 o
Ligand free
C
R3
R3 = aryl, alkyl, H
32 examples
upto 85% yield
Redox neutral
aminating reagents
Abstract. An efficient copper-catalyzed electrophilic amination strategy has been established for
the rapid synthesis of N-aryl-2-aminophenones from the readily available arylboronic acids/esters
and anthranils. This protocol features good functional group tolerance, broad substrate scope and
operational simplicity. Moreover, a tandem C-H borylation and C-N coupling protocol has also
been developed to transform simple arenes to the valuable N-aryl-2-aminophenones in one-pot.
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Additionally, the synthetic potential of this methodology is further demonstrated by the synthesis
of various useful N-heterocycles and derivatives.
8
9
Due to the importance of nitrogen-containing compounds in natural products, drug discovery
and material science, the development of efficient methods to construct C-N bonds has received
extensive attention from chemists.1 N-Aryl-2-aminophenones are versatile precursors for the
synthesis of various high-value N-heterocyclics such as acrdines, acridones, isatins, indazoles and
benzimidazoles,2 which are useful skeletons possessing significant biological activity. More
importantly, N-aryl-2-aminophenones have also been applied to synthesize the thermally active
delayed fluorescent (TADF) materials for organic light emitting diodes (OLED).3 Typically,
N-aryl-2-aminophenones are synthesized from the corresponding 2-nitrophenones,2b-e which are
firstly reduced to 2-aminophenones by a stoichiometric reductant, and then undergo transition
metal-catalyzed C-N coupling with aryl halides or arylboronic acids (Scheme 1a).4 In 2018, Xu
and co-workers reported a copper-catalyzed Chan-Lam reaction for the synthesis of
N-aryl-2-aminophenones from 2-aminophenones and arylboronic acids/esters,5 however, the
desired products were obtained in generally low yields. Moreover, aryl boronic acids bearing
electron-withdrawing substituents are usually poor substrates in the Chan-Lam reaction.6
Anthranils are an important class of easily accessible and highly versatile synthons, which
have recently been widely used in transition metal-catalyzed C–N bond formation.7 In 1987,
Baum and co-workers firstly reported a nickel-catalyzed cross-coupling reaction of organometallic
reagents (RZnCl) and anthranils for the formation of N-aryl-2-aminophenones.8 Recently, this
reaction was further improved by Knochel and co-workers by using a more stable organozinc
pivalate (RZnOPiv) to replace RZnCl with CoCl2 as catalyst (Scheme 1b).9 Despite the advances,
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these organozinc reagents are still not easily available and need to be stored under argon
protection, which largely limited the widespread application of these methods.
Scheme 1. Methods for the synthesis of N-aryl-2-aminophenones.
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a) Typical method for the synthesis of N-aryl-2-aminophenones
O
R3
R3
X
R3
R1
H
N
O
O
R2
R2
R1
R2
reduction
C-N bond
formation
NO2
NH2
X = B(OH)2 or I, Br
b) Ni/Co-catalyzed electrophilic amination of organozinc with anthranils
O
R3
ZnX
N
H
[Ni]/[Co]
R2
O
N
R1
+
R1
R2
R3
X = Cl or OPiv
Not bench stable
Not commercially available
c) This work: Electrophilic amination of arylboronic acids with anthranils
O
R3
B(OR)2
N
H
[Cu]
R2
O
N
R1
+
R1
R2
Ligand free
R3
Redox neutral
stable & readily available
Arylboronic acids are more readily available, easy-to-handle, and functional group tolerant
alternatives to the above organometallics.10 However, because of their relatively lower reactivity
than those organozinc reagents, the reported catalytic systems8, 9 are ineffective for the similar
reaction of arylboronic acids and anthranils as indicated in our primary study.11 Inspired by the
copper-catalyzed electrophilic amination reactions of arylboronic acids12 and our continuing
interest in the anthranils chemistry,13 we proposed that the C-N coupling of arylboronic acids and
anthranils could be achieved by a copper catalyst (Scheme 1c). Herein, we disclosed an efficient
method for the rapid synthesis of N-aryl-2-aminophenones from the readily accessible arylboronic
acids and anthranils through a copper-catalyzed electrophilic amination protocol. In this reaction,
anthranils acted as electrophilic aminating reagents and could simultaneously deliver an amino
group and a formyl group in an atom economical fashion.
To explore the feasibility of our hypothesis, phenylboronic acid (1a) and anthranil (2a) was
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chosen as the model substrates (Table 1). The initial experiment was performed with 1a and 2a in
presence of CuBr (10 mol%), K2CO3 (1.0 equiv) at 100 °C in MeOH (1 mL) for 6 h (entry 1).
However, only a trace amount of the desired amination product 3aa was detected. After screening
the different solvents (entries 1-4), a significant increase in yield was observed with DMSO as
solvent (entry 3). The decomposition of 2a led to the formation of the main by-product 4a. Other
metal catalysts such as CuCl, CuCl2, CuBr2, Cu(OAc)2, CoCl2 and NiCl2 were tested. CuCl2 gave
the best result and 3aa was detected in 72% yield (entry 8). Switching of the additives to other
bases resulted in lower yields (entries 12-15). The yield of 3aa increased to 81% when the amount
of K2CO3 was reduced to 50 mol% (entry 16). Next, different ligands were investigated. No
desired product was detected with PPh3 as ligand (entry 17), and reduced yields were observed
with Py or 1,2-bipy as ligand (entries 18 and 19). Amino acid also had inferior influence on this
reaction (entry 20). This reaction proceeded smoothly under argon atmosphere, which indicated
that no external oxidant was needed in this transformation (entry 21). Control experiment revealed
that copper catalyst was essential for this reaction (entry 22). Thus, the best reaction conditions
were CuCl2 (10 mol%), K2CO3 (50 mol%) at 100 °C in DMSO (1 mL) for 6 h under air
atmosphere.
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Table 1. Optimization of the reaction conditions.a
O
Ph
NH2
N
OH
OH
catalyst/additive
ligand/solvent
O
H
O
B
+
N
+
Cl
Ph
Ph
Cl
Cl
1a
2a
3aa
4a
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entry
catalyst
additive
ligandb
solvent
yieldc (%)
6
7
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9
3aa
trace
0
4a
1
2
CuBr
CuBr
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
MeOH
DMF
5
trace
10
12
45
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3
CuBr
DMSO
MeCN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
35
trace
50
24
38
72
56
0
4
CuBr
5
Cu(OAc)2
CuCl
6
7
CuI
36
25
37
0
8
CuCl2
CuBr2
CoCl2
NiCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
9
10
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12
13
14
15
16d
17
18
19
20
26
10
60
5
0
72
30
25
27
Na2CO3
tBuOK
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
6
81 (78) 17
PPh3
Py
0
0
66
48
10
21
50
22
1,2-biPy
N,N-Dimethylglycine
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21e
22
CuCl2
-
K2CO3
K2CO3
DMSO
DMSO
75
0
18
0
7
8
9
a Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), catalyst (10 mol%), base (1.0 equiv), solvent
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b
c
1
(1.0 mL) at 100 °C for 6 h. Ligands (10 mol%). Yields determined by H NMR spectroscopy
using dibromomethane as the internal standard. d K2CO3 (0.5 equiv). e Under argon.
The scope and limitation of this transformation was then investigated under the optimized
reaction conditions. As shown in Scheme 2, this protocol is widely applicable to various
arylboronic acids bearing a variety of functional groups such as fluorine (3ab) chlorine (3ac),
bromo (3ad), phenyl (3ae), methoxy (3af). The tolerant of halogens opens a gate for the further
transformation through the cross-coupling reactions. Importantly, substrates bearing the
electron-withdrawing substituents such as trifluoromethyl (3ah), and cyano (3ai), which are
usually poor substrates in the Chan-Lam reaction,6 reacted smoothly in this transformation.
Notably, 3aj was obtained in 65% yield without any protection step for the -OH group. The
sterically demanding (2,6-dimethylphenyl)boronic acid furnished the corresponding product 3am
in 70% yield. Pyrene derivate 3ap was synthesized in 58% yield through this electrophilic
amination protocol. Heterocycles such as quinolone and carbazole were also well tolerated,
providing the corresponding 3aq and 3ar in 50% and 74% yields, respectively. Additionally, 3as
bearing the triphenylamine structure, which was widely used in organic luminescent materials,
was synthesized in 77% yield. However, alkylboronic acids such as cyclopropylboronic acid and
methylboronic acid failed to give the desired products under the current reaction system. In
addition, other coupling reagents such as aryl iodide and aryl silanes are also not suitable in this
reaction.
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Scheme 2. Substrate scope of various arylboronic acids.a
5
6
7
8
9
O
O
Ph
Ph
OH
B
CuCl2 (10 mol%)
K2CO3 (50 mol%)
N
H
N
O
OH
+
R1
R1
DMSO, 100 o
C
Cl
Ph
Cl
2a
1
3
10
11
12
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O
Ph
O
Ph
H
H
H
N
N
N
O
HO
R
Cl
Cl
Cl
b
3aa
3ab
3ac
3ad
3ae
3ak
, 73%
, R = H, 78%, 72%
3aj
, 64%
O
, R = F, 70%
Ph
O
Ph
, R = Cl, 70%
Me
Me
H
N
H
N
, R = Br, 72%
, R = Ph, 78%
, R = OMe, 75%
3af
Cl
Me
Cl
3ag
3ah
, R = OPh, 74%
, R = CF3, 68%
, R = CN, 63%
3al
3am
, 76%
, 70%
O
3ai
O
Ph
Ph
O
Ph
H
H
N
H
N
EtO
Ph
N
Cl
Cl
Cl
3an
3ao
3ap
, 78%
O
, 72%
, 58%
O
O
Ph
Ph
H
Ph
N
N
H
H
N
N
Ph
Cl
N
Ph
N
Cl
Cl
Ph
3aq
3ar
3as
, 77%
, 50%
, 74%
a
Reaction conditions: 1 (0.45 mmol), 2a (0.3 mmol), CuCl2 (10 mol%), K2CO3 (50 mol%),
DMSO (1.0 mL) at 100 °C for 6 h. Isolated yields were given. b 5 mmol scale.
Next, the electrophilic amination with an array of anthranils were carried out. As shown in
Scheme 3, various substituents like CHO (3fa), F (3ga), Cl (3ha), Br (3ia), OMe (3ja), acetal (3ka)
and CF3 (3ma) were well tolerated. The 3-substituent (R3) of anthranils could be aryl and alkyl
and hydrogen, and a range of amino-ketones (3ba-3da) and amino-aldehydes (3ea-3na) were
obtained in moderate to good yields (68%-85%). The tolerance of alkenyl (3na) further showed
the good functional group compatibility of this reaction. Additionally, 5 mmol scale experiments
were conducted for the synthesis of 3aa and 3ea, and the desired products were obtained in
72% (1.1 g) and 80% (0.85 g), respectively, without significant reducing in yields.
Scheme 3. Substrate scope of various anthranils.a
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O
R3
H
N
CuCl2 (10 mol%)
K2CO3 (50 mol%)
OH
OH
N
R2
O
R
B
+
R2
DMSO, 100 o
C
R3
R
1
2
3
7
8
O
O
Ph
O
Ph
H
H
H
N
N
N
9
Me
Cl
Me
Me
10
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3ba
3ca
3da
3ha
, 74%
, 75%
O
, 80%
O
O
H
H
H
N
N
N
R
Me
F
Me
Cl
O
b
3ea
, R = Me, 85%, 80%
, R = CHO, 78%
O
3ga
, 75%
O
, 80%
O
3fa
H
H
H
N
N
N
Me
Me
Br
Me
OMe
O
3ia
3ja
3ka
, 75%
, 81%
, 79%
O
O
O
H
N
H
N
H
N
Me
Me
Me
O
CF3
Cl
3la
3ma
3na
, 80%
, 77%
, 68%
a Reaction conditions: 1 (0.45 mmol), 2 (0.3 mmol), CuCl2 (10 mol%), K2CO3 (50 mol%), DMSO
(1.0 mL) at 100 °C for 6 h. Isolated yields were given. b 5 mmol scale.
Fortunately, aryl boronic acid pinacol ester 1a' could also smoothly react with 2a, affording
the corresponding N-aryl-2-aminophenones in 81% yield (Scheme 4a). This result is important
because aryl boronic pinacol ester (ArBpin) can be readily obtained from simple arenes through
the well-developed C-H boronation.14 Accordingly, a tandem C-H borylation and C-N coupling
protocol was developed to transform simple arenes to the valuable N-aryl-2-aminophenones in
one-pot (Scheme 4b). Notably, although the Rh/Co-catalyzed Csp2-H amination with anthranils
have been extensively explored,15 directing groups are generally requested and difficult to be
removed. Therefore, this tandem reaction provides a straightforward strategy for the synthesis of
high-value N-aryl-2-aminophenones from simple arenes and anthranils without the assistant of
directing groups.
Scheme 4. Synthesis of N-aryl-2-aminophenones from simple arenes and anthranils.a
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(a)
(b)
CuCl2 (10 mol%)
K2CO3 (50 mol%)
B(OH)3 (2.0 equiv)
O
Ph
H
N
O
O
N
O
B
+
DMSO, 100 o
C
Cl
Cl
Ph
1a'
2a
3aa
, 81%
O
Ph
1) [Ir(COD)Cl]2
H
H
N
dtbpy, Bipn2, 80 o
C
FG
FG
2a,
2)
CuCl2, K2CO3, B(OH)3
DMSO, 100 o
10
11
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Cl
C
5
3
O
Ph
H
N
5a
3aa
, 56%
Cl
Ph
Me
O
Me
3at
, 55%
H
N
o/p/m = 0/1/2
ratio determined
by 1H NMR
5b
5c
o
p
m
Cl
O
Ph
Cl
Cl
Cl
H
N
3au
, 80%
Cl
Cl
a
Bipn2 = 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi(1,3,2-dioxaborolane). dtbpy = 4,4-Di-tert-butyl
bipyridine. Isolated yields were given.
The synthetic utilities of this method were further investigated. The condensation of
N-aryl-2-aminophenones in TFA provided the corresponding acridine derivatives (6a, 6b and 6c)
in good yields (Scheme 5a). These condensed N-heterocycles may have potential applications in
OLED.16 A drug-like molecular 2-(p-tolylamino)benzoic acid 7 was obtained in 85% yield
through the oxidation of 3ea (Scheme 5b).17 Additionally, the intermolecular condensation of 3ea
with malononitrile produced 8 in 86% yield (Scheme 5c).3
Scheme 5. Synthetic applications.
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R3
(a)
O
R3
H
N
TFA, 80 o
C
R1
R2
R1
R2
N
6
3
7
8
9
Cl
N
Cl
Cl
N
N
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N
N
6a
6b
6c
, 90%
, 95%
, 80%
(b)
O
CO2H
H
N
H
N
FeCl3.6H2O
DCE, air, 100 o
C
Me
Me
3ea
7
, 85%
CN
CN
(c)
O
H
N
CN
CN
H
N
piperidine 10 mol%
EtOH, rt
+
Me
Me
3ea
8
, 86%
Control experiments were conducted to understand the reaction mechanism (Scheme 6).
Firstly, 2-aminobenzophenone 4a was employed as a substrate under the standard reaction
conditions, however the desired product 3aa was detected in only 9% yield (Scheme 6a).
Therefore, a stepwise process, which firstly generates 4a and then coupling with arylboronic acids,
is unlikely to be the main pathway for this transformation. In addition, the reaction of
pre-synthesized [PhCu] and 2a afforded the desired product 3aa in 36% yield (Scheme 6b).18 This
result indicated that the arylcopper species may be an active intermediate in this transformation.
Scheme 6. Mechanistic study.
O
Ph
Ph
(a)
H
N
NH2
O
B(OH)2
standard conditions
24 h
+
Cl
Cl
Cl
Ph
1a
4a
3aa
, 9%
O
(b)
[PhCu]
H
N
N
O
DMSO, 100 o
C
+
Cl
Ph
9
2a
3aa
, 36%
According to the above results and the previous works,12, 18 a plausible mechanism involving
a Cu(I)/Cu(III) catalytic cycle was proposed in Scheme 7. Firstly, the phenylcopper species A is
formed through the transmetalation of phenylboronic acid and the copper (I) catalyst in-situ
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generated from the reduction of Cu(II) by arylboronic acid and base.19 Then, the phenylcopper
intermediate A undergoes oxidative insertion into the N−O bond of anthranils, affording a copper
nitrene species C that is a resonance of B.12c Subsequently, intermediate D is formed through the
1,1-migratory insertion of the phenyl group. Finally, the amination product 3aa is obtained after
protonolysis of D with the regeneration of the active copper catalyst. It is worth to mention that
the main scope limitation of the Chan–Lam reaction was proposed to relate to the difficulty in
accessing the key CuIII intermediate.6 In this transformation, the CuIII intermediate could be readily
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12c
obtained through the oxidization of arylcopper species by the N-O bond of anthranils.7,
Therefore, the current method may have wider application in the synthesis of high-value
N-aryl-2-aminobenzophenones and derivatives.
Scheme 7. Plausible mechanistic pathway.
CuCl2
CuX
3aa
PhB(OH)2
H+
K2CO3
X-B(OH)2
Ph
N
Ph
Cu
Cu
O
A
PhCu
C
N
N
O
Ph
Ph
D
2a
Ph
Cu
O
Ph
B
In conclusion, an efficient copper-catalyzed electrophilic amination reaction of arylboronic
acids and anthranils was developed. A wide range of arylboronic acids and anthranils reacted
smoothly to give the N-aryl-2-aminobenzophenone and N-aryl-2-aminobenzaldehyde derivatives
in good yields. This protocol further provided quick accesses to various condensed N-heterocycles,
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which might have application in organic luminescent material. The properties and applications of
these compounds are under investigated in our lab.
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EXPERIMENTAL SECTION
General Information. All reactions were performed in oven-dried glassware containing a
Teflon-coated stirring bar. Commercial substrates were used as received unless otherwise stated.
Solvents were purchased (puriss p.A.) from commercial suppliers. 1H NMR spectra were recorded
in CDCl3 at 400 MHz. Chemical shifts (δ) are reported in ppm from the resonance of tetramethyl
silane as the internal standard (TMS: 0.00 ppm). Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants
(Hz) and integration. 13C NMR spectra were recorded on 100 MHz with complete proton
decoupling spectrophotometers. GC–MS was obtained using electron ionization. HRMS was
carried out on a MAT 95XP (Thermo). TLC was performed using commercially prepared 100-400
mesh silica gel plates (GF254), and visualization was effected at 254 nm.
General Procedure for the Synthesis of Compound 3. An oven-dried 20 mL vial equipped with
a Teflon-coated stirring bar was charged with CuCl2 (10 mol%), K2CO3 (50 mol%) and
arylboronic acid (0.45 mmol) and closed with a septum cap. Then DMSO (1.0 mL) and anthranil
(0.3 mmol) were added via syringe. The resulting mixture was stirred at 100 °C (heating mantle)
for 6 h. After completion of the reaction, the resulting mixture was diluted with saturated NaCl
aqueous solution (15 mL). Following phase separation, the aqueous layer was extracted 3 times
with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous MgSO4 and
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the organic phase was evaporated under reduced pressure (rotary evaporator). The residue was
purified by column chromatography (SiO2, ethyl acetate/petroleum ether gradient).
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Procedure for the synthesis of N-aryl-2-aminophenones from simple arenes and anthranils.
An oven-dried 20 mL vial equipped with a Teflon-coated stirring bar was charged with
[Ir(COD)Cl]2 (1.5 mol%), dtbpy (3.0 mol%), Bipn2 (0.3 mmol), arene (3.0 mmol) and closed with
a septum cap (in glove box). The resulting mixture was stirred at 80 °C (heating mantle) for 16 h.
After cooling to room temperature, CuCl2 (10 mol%), K2CO3 (50 mol%), anthranil (0.3 mmol),
B(OH)2 (0.6 mmol) and DMSO (1.0 mL) were added, and the mixture was stirred at 100 °C
(heating mantle) for 6 h. After completion of the reaction, the resulting mixture was diluted with
saturated NaCl aqueous solution (15 mL). Following phase separation, the aqueous layer was
extracted 3 times with ethyl acetate (10 mL). The combined organic phases were dried over
anhydrous MgSO4 and the organic phase was evaporated under reduced pressure (rotary
evaporator). The residue was purified by column chromatography (SiO2, ethyl acetate/petroleum
ether gradient).
5 mmol scale experiments for the synthesis of 3aa and 3ea. A round-bottomed flask 25 mL
equipped with a Teflon-coated stirring bar was charged with CuCl2 (10 mol%), K2CO3 (50 mol%),
5-chloro-3-phenylbenzo[c]isoxazole (5.0 mmol) and phenylboronic acid (7.5 mmol). Then DMSO
(10 mL) were added. The resulting mixture was stirred at 100 °C (oil bath) for 6 h. After
completion of the reaction, the resulting mixture was diluted with saturated NaCl aqueous solution
(30 mL). Following phase separation, the aqueous layer was extracted 3 times with ethyl acetate
(15 mL). The combined organic phases were dried over anhydrous MgSO4 and the organic phase
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was evaporated under reduced pressure (rotary evaporator). The residue was purified on silica gel
(PE/EA = 50:1, v/v), affording 3aa (1.1 g, 72%) as a yellow oil.
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Following the similar procedure, 3ea (0.85 g, 80%) was synthesized from benzo[c]isoxazole (5.0
mmol, added via syringe) and p-tolylboronic acid (7.5 mmol).
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Procedure for the synthesis of acridine derivatives 6. An oven-dried 20 mL vial equipped with
a Teflon-coated stirring bar was charged with N-aryl-2-aminophenones 3 (0.10 mmol) and closed
with a septum cap. Then TFA (1.0 mL) was added via syringe. The resulting mixture was stirred
at 80 °C (heating mantle) for 12 h. After completion of the reaction, the resulting mixture was
neutralized with saturated NaHCO3 aqueous solution. Following phase separation, the aqueous
layer was extracted 3 times with ethyl acetate (10 mL). The combined organic phases were dried
over anhydrous MgSO4 and the organic phase was evaporated under reduced pressure (rotary
evaporator). The residue was purified by column chromatography (SiO2, ethyl acetate/petroleum
ether gradient).
Procedure for the synthesis of compound 7. An oven-dried 20 mL vial equipped with a
Teflon-coated stirring bar was charged with 3ea (0.10 mmol), FeCl3.6H2O (0.02 mmol). Then
DCE (2.0 mL) was added via syringe. The resulting mixture was stirred at 100 °C (heating mantle)
for 12 h. After completion of the reaction, the resulting mixture was evaporated under reduced
pressure (rotary evaporator). The residue was purified by column chromatography (SiO2, ethyl
acetate/petroleum ether/menthol gradient).
Procedure for the synthesis of compound 8. An oven-dried 20 mL vial equipped with a
Teflon-coated stirring bar was charged with 3ea (0.10 mmol), malononitrile (0.10 mmol) and
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piperidine (10 mol%), and closed with a septum cap. Then ethanol (1.0 mL) was added via syringe.
The resulting mixture was stirred at room temperature for 12 h. After completion of the reaction,
the resulting mixture was evaporated under reduced pressure (rotary evaporator). The residue was
purified by column chromatography (SiO2, ethyl acetate/petroleum ether gradient).
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(5-Chloro-2-(phenylamino)phenyl)(phenyl)methanone
(3aa).9
Purification
by
column
chromatography on silica gel (PE/EA = 50:1, v/v) afforded 3aa as a yellow oil (71.8 mg, 78%). 1H
NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.70 (dd, J = 5.2, 3.2 Hz, 2H), 7.60 – 7.55 (m, 1H), 7.50
(m, 3H), 7.39 – 7.33 (m, 2H), 7.30 – 7.24 (m, 4H), 7.14 – 7.09 (m, 1H) ppm. 13C{1H} NMR (100
MHz, CDCl3) δ 198.0, 146.7, 140.1, 139.0, 134.0, 133.6, 131.8, 129.5, 129.4, 128.4, 124.0, 122.3,
121.4, 120.6, 116.3 ppm. HRMS (ESI) m/z calcd. For C19H14ClNO [M+H]+ 308.0837, found
308.0836.
(5-Chloro-2-((4-fluorophenyl)amino)phenyl)(phenyl)methanone (3ab). Purification by column
chromatography on silica gel (PE/EA = 50:1, v/v) afforded 3ab as a yellow oil (68.2 mg, 70%). 1H
NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 7.59 (d, J = 1.5 Hz, 2H), 7.47 – 7.52 (m, 1H), 7.44 – 7.39
(m, 3H), 7.18 – 7.11 (m, 3H), 7.03 – 6.95 (m, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.1,
159.6 (d, J = 243.9 Hz,), 147.8, 139.2, 135.9 (d, J = 2.9 Hz,), 134.2, 133.7, 131.8, 129.3, 128.3,
125.0 (d, J = 8.2 Hz,), 120.8, 112.0, 116.3 (d, J = 22.6 Hz,), 115.6 ppm. 19F NMR (300 MHz,
CDCl3) δ -117.9 ppm. HRMS (ESI) m/z calcd. for C19H13ClFNO [M+H]+ 326.0742, found
326.0740.
(5-Chloro-2-((4-chlorophenyl)amino)phenyl)(phenyl)methanone (3ac). Purification by column
chromatography on silica gel (PE/EA = 50:1, v/v) afforded 3ac as a yellow oil (71.8 mg, 70%). 1H
NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 7.60 (dd, J = 5.2, 3.3 Hz, 2H), 7.52 – 7.46 (m, 1H), 7.45
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– 7.37 (m, 3H), 7.23 – 7.13 (m, 4H), 7.12 – 7.05 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3)
δ 198.0, 146.2, 138.8, 134.1, 133.7, 132.0, 129.6, 129.4, 128.8, 128.4, 123.4. 121.6, 121.0, 116.3
ppm. HRMS (ESI) m/z calcd. for C19H13Cl2NO [M+H]+ 342.0447, found 342.0441.
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(2-((4-Bromophenyl)amino)-5-chlorophenyl)(phenyl)methanone (3ad). Purification by column
chromatography on silica gel (PE/EA = 50:1, v/v) afforded 3ad as a yellow oil (83.7 mg, 72%). 1H
NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 7.65 (m, 2H), 7.57 – 7.51 (m, 1H), 7.48 – 7.43 (m, 3H), 7.42 –
7.38 (m, 2H), 7.25 – 7.19 (m, 2H), 7.10 – 7.06 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ
197.9, 145.9, 139.4, 138.8, 134.1, 133.7, 132.5, 132.0, 129.4, 128.4, 123.5, 121.7, 121.1, 116.3,
116.2 ppm. HRMS (ESI) m/z calcd. for C19H13BrClNO [M+H]+ 385.9942, found 385.9945.
(2-([1,1'-Biphenyl]-4-ylamino)-5-chlorophenyl)(phenyl)methanone (3ae). Purification by column
chromatography on silica gel (PE/EA = 50:1, v/v) afforded 3ae as a yellow solid (89.6 mg, 78%),
1
m.p: 136 – 137 °C. H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 7.61 (dd, J = 5.2, 3.3 Hz, 2H),
7.49 (dd, J = 8.7, 6.3 Hz, 5H), 7.41 (dd, J = 9.6, 4.9 Hz, 3H), 7.35 (dd, J = 10.5, 4.8 Hz, 2H), 7.29
13
(d, J = 9.1 Hz, 1H), 7.26 – 7.20 (m, 4H) ppm. C{1H} NMR (100 MHz, CDCl3) δ 197.9, 146.3,
140.4, 139.4, 138.9, 136.6, 134.0, 133.6, 131.8, 129.4, 128.8, 128.3, 128.1, 127.0, 126.7, 122.2,
121.2, 120.8, 116.5 ppm. HRMS (ESI) m/z calcd. for C25H18ClNO [M+H]+ 384.1150, found
384.1144.
(5-Chloro-2-((4-methoxyphenyl)amino)phenyl)(phenyl)methanone (3af).9 Purification by column
chromatography on silica gel (PE/EA = 30:1, v/v) afforded 3af as a yellow solid (75.8 mg, 75%),
1
m.p: 106 – 107 °C. H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 7.68 (dd, J = 5.2, 3.2 Hz, 2H),
7.60 – 7.55 (m, 1H), 7.52 – 7.48 (m, 3H), 7.21 (dd, J = 11.8, 5.1 Hz, 3H), 7.04 (d, J = 9.1 Hz, 1H),
6.95 – 6.92 (m, 2H), 3.83 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 157.0, 148.5,
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139.3, 134.3, 133.7, 132.6, 131.5, 129.2, 128.3, 125.7, 120.0, 119.1, 115.1, 114.8, 55.5 ppm.
HRMS (ESI) m/z calcd. for C20H16ClNO2 [M+H]+ 338.0942, found 338.0938.
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(5-Chloro-2-((4-phenoxyphenyl)amino)phenyl)(phenyl)methanone (3ag). Purification by column
chromatography on silica gel (PE/EA = 30:1, v/v) afforded 3ag as a yellow oil (88.6 mg, 74%). 1H
NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 7.68 (d, J = 7.3 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.49 (t,
J = 7.4 Hz, 3H), 7.33 (t, J = 7.9 Hz, 2H), 7.27 – 7.20 (m, 3H), 7.16 (d, J = 9.1 Hz, 1H), 7.09 (t, J =
7.4 Hz, 1H), 7.06 – 6.95 (m, 4H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 157.4, 153.8,
147.5, 139.1, 135.3, 134.2, 133.7, 131.7, 129.7, 129.3, 128.3, 124.8, 123.2, 120.6, 120.0, 119.8,
118.6, 115.8 ppm. HRMS (ESI) m/z calcd. for C25H18ClNO2 [M+H]+ 400.1099, found 400.1095.
(5-Chloro-2-((4-(trifluoromethyl)phenyl)amino)phenyl)(phenyl)methanone (3ah). Purification by
column chromatography on silica gel (PE/EA = 50:1, v/v) afforded 3ah as a yellow oil (77.0 mg,
68%). 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.75 – 7.71 (m, 2H), 7.59 (dd, J = 10.1, 8.2 Hz,
3H), 7.52 (dd, J = 10.1, 4.9 Hz, 3H), 7.45 (d, J = 9.0 Hz, 1H), 7.36 (dd, J = 9.0, 2.5 Hz, 1H), 7.30
(d, J = 8.5 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 197.8, 144.2, 143.9, 138.4, 133.9,
133.6, 132.4, 129.6, 128.5, 126.7 (q, J = 3.8 Hz), 124.5 (q, J = 32.8 Hz), 123.1, 122.9, 122.8,
119.8, 117.5 ppm. 19F NMR (300 MHz, CDCl3) δ -61.9 ppm. HRMS (ESI) m/z calcd. for
C20H13ClF3NO [M+H]+ 376.0711, found 376.0707
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4-((2-Benzoyl-4-chlorophenyl)amino)benzonitrile (3ai). Purification by column chromatography
on silica gel (PE/EA = 15:1, v/v) afforded 3ai as a yellow solid (62.7 mg, 63%), m.p: 124 – 126
°C. 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 7.76 – 7.72 (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.57
(d, J = 8.6 Hz, 2H), 7.54 – 7.48 (m, 4H), 7.40 (dd, J = 8.9, 2.4 Hz, 1H), 7.23 (d, J = 8.6 Hz, 2H)
13
ppm. C{1H} NMR (100 MHz, CDCl3) δ 197.6, 145.1, 142.6, 138.0, 133.7, 133.6, 133.4, 132.7,
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129.7, 128.5, 124.4, 124.2, 119.2, 118.7, 118.6, 104.5 ppm. HRMS (ESI) m/z calcd. for
C20H13ClN2O [M+H]+ 333.0789, found 333.0785.
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(5-Chloro-2-((4-(hydroxymethyl)phenyl)amino)phenyl)(phenyl)methanone (3aj). Purification by
column chromatography on silica gel (PE/EA = 8:1, v/v) afforded 3aj as a yellow oil (64.5 mg,
64%). 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.69 – 7.64 (m, 2H), 7.57 – 7.52 (m, 1H), 7.50
– 7.43 (m, 3H), 7.32 (d, J = 8.3 Hz, 2H), 7.25 – 7.19 (m, 4H), 4.63 (s, 2H) ppm. 13C{1H} NMR
(100 MHz, CDCl3) δ 198.0, 146.5, 139.6, 138.9, 136.5, 134.1, 133.6, 131.9, 129.4, 128.4, 128.4,
122.3, 121.1, 120.6, 116.3, 64.9 ppm. HRMS (ESI) m/z calcd. for C20H16ClNO2 [M+H]+ 338.0942,
found 338.0938.
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4-((2-Benzoyl-4-chlorophenyl)amino)benzaldehyde (3ak). Purification by column chromatography
1
on silica gel (PE/EA = 30:1, v/v) afforded 3ak as a yellow oil (73.4 mg, 73%). H NMR (400
MHz, CDCl3) δ 9.87 (s, 1H), 7.82 (d, J = 8.5 Hz, 2H), 7.79 – 7.72 (m, 2H), 7.62 (t, J = 7.4 Hz,
1H), 7.53 (dt, J = 14.7, 8.1 Hz, 4H), 7.41 (dd, J = 8.9, 2.5 Hz, 1H), 7.30 – 7.26 (m, 2H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ 197.6, 190.4, 146.8, 142.7, 138.0, 133.6, 133.4, 132.6, 131.7,
130.6, 129.8, 128.5, 124.3, 124.2, 118.9, 118.2 ppm. HRMS (ESI) m/z calcd. for C20H14ClNO2
[M+H]+ 336.0786, found 336.0780.
(5-Chloro-2-(o-tolylamino)phenyl)(phenyl)methanone
(3al).
Purification
by
column
chromatography on silica gel (PE/EA = 50:1, v/v) afforded 3al as a yellow oil (73.2 mg, 76%). 1H
NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 7.78 – 7.74 (m, 2H), 7.66 – 7.61 (m, 1H), 7.54 – 7.58 (m,
3H), 7.40 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.32 – 7.26 (m, 2H), 7.14 – 7.18 (m, 1H),
7.06 (d, J = 9.1 Hz, 1H), 2.38 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 147.5,
139.2, 138.4, 134.2, 133.7, 132.4, 131.7, 131.2, 129.3, 128.3, 126.7, 124.9, 123.3, 120.4, 119.8,
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116.0, 18.0 ppm. HRMS (ESI) m/z calcd. for C20H16ClNO [M+H]+ 322.0993, found 322.0989.
(5-Chloro-2-((2,6-dimethylphenyl)amino)phenyl)(phenyl)methanone (3am). Purification by
column chromatography on silica gel (PE/EA = 50:1, v/v) afforded 3am as a yellow solid (69.0
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mg, 70%), m. p 103 – 105 °C. H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 7.75 – 7.71 (m, 2H),
7.62 – 7.57 (m, 1H), 7.56 – 7.50 (m, 3H), 7.21 – 7.16 (m, 4H), 6.29 (d, J = 9.0 Hz, 1H), 2.25 (s,
6H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.4, 149.0, 139.5, 136.5, 136.4, 134.6, 133.8,
131.4, 129.2, 128.6, 128.3, 126.8, 119.4, 118.1, 114.7, 18.3 ppm. HRMS (ESI) m/z calcd. for
C21H18ClNO [M+H]+ 336.1150, found 336.1146.
(2-([1,1'-Biphenyl]-3-ylamino)-5-chlorophenyl)(phenyl)methanone (3an). Purification by column
chromatography on silica gel (PE/EA = 50:1, v/v) afforded 3an as a yellow oil (89.6 mg, 78%). 1H
NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 7.60 (d, J = 7.9 Hz, 2H), 7.47 (t, J = 7.7 Hz, 3H), 7.42 –
7.36 (m, 4H), 7.32 (dd, J = 15.2, 7.5 Hz, 3H), 7.25 (dd, J = 13.0, 6.7 Hz, 3H), 7.19 – 7.11 (m, 2H)
ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 197.9, 146.5, 142.6, 140.6, 140.5, 138.9, 134.0, 133.6,
131.8, 129.8, 129.4, 128.8, 128.3, 127.5, 127.0, 122.7, 121.2, 120.9, 120.8, 120.7, 116.4 ppm.
HRMS (ESI) m/z calcd. for C25H18ClNO [M+H]+ 384.1150, found 384.1145.
(5-Chloro-2-((7-ethoxynaphthalen-2-yl)amino)phenyl)(phenyl)methanone (3ao). Purification by
column chromatography on silica gel (PE/EA = 30:1, v/v) afforded 3ao as a yellow solid (87.2 mg,
72%), m.p: 128 – 130 °C. 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 7.73 – 7.69 (m, 3H), 7.66
– 7.55 (m, 3H), 7.52 – 7.47 (m, 3H), 7.35 (dd, J = 8.7, 2.1 Hz, 1H), 7.29 – 7.24 (m, 2H), 7.16 –
7.11 (m, 2H), 4.13 (t, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3) δ 198.0, 156.5, 147.3, 139.1, 135.5, 134.2, 133.7, 131.9, 131.7, 129.5, 129.3, 128.5, 128.3,
128.1, 123.5, 120.8, 120.2, 119.6, 119.4, 116.2, 106.7, 63.5, 14.8 ppm. HRMS (ESI) m/z calcd.
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for C25H20ClNO2 [M+H]+ 402.1255, found 402.1252.
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(5-Chloro-2-(pyren-1-ylamino)phenyl)(phenyl)methanone (3ap). Purification by column
chromatography on silica gel (PE/EA = 50:1, v/v) afforded 3ap as a yellow oil (75.0 mg, 58%). 1H
NMR (400 MHz, CDCl3) δ 10.64 (s, 1H), 8.21 (d, J = 9.2 Hz, 1H), 8.09 (dd, J = 7.8, 3.1 Hz, 3H),
8.01 (d, J = 9.2 Hz, 1H), 7.98 – 7.90 (m, 4H), 7.75 – 7.70 (m, 2H), 7.52 (dd, J = 4.2, 2.0 Hz, 2H),
7.47 (t, J = 7.3 Hz, 2H), 7.12 (dd, J = 9.1, 2.5 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H) ppm. 13C{1H}
NMR (100 MHz, CDCl3) δ 198.4, 148.4, 139.2, 134.4, 133.8, 133.5, 131.8, 131.4, 131.2, 129.4,
129.0, 128.4, 128.0, 127.2, 126.8, 126.3, 125.9, 125.8, 125.3, 125.2, 125.0, 124.8, 122.3, 121.8,
120.9, 119.9, 116.2 ppm. HRMS (ESI) m/z calcd. for C29H18ClNO [M+H]+ 432.1150, found
432.1146.
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(5-Chloro-2-(quinolin-8-ylamino)phenyl)(phenyl)methanone (3aq). Purification by column
chromatography on silica gel (PE/EA = 10:1, v/v) afforded 3aq as a yellow solid (53.7 mg, 50%).
1H NMR (400 MHz, CDCl3) δ 11.08 (s, 1H), 8.99 – 8.93 (m, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.83
(dd, J = 13.8, 8.2 Hz, 3H), 7.70 (d, J = 7.5 Hz, 1H), 7.57 (dd, J = 12.5, 4.9 Hz, 2H), 7.51 – 7.41 (m,
5H), 7.36 (d, J = 8.0 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 196.9, 148.6, 143.2, 140.0,
138.5, 138.2, 136.1, 133.2, 133.2, 132.3, 129.9, 129.0, 128.3, 126.6, 125.2, 123.1, 121.8, 119.4,
118.7, 111.4 ppm. HRMS (ESI) m/z calcd. for C22H15ClN2O [M+H]+ 359.0946, found 359.0941.
(5-chloro-2-((9-phenyl-9H-carbazol-3-yl)amino)phenyl)(phenyl)methanone (3ar). Purification by
column chromatography on silica gel (PE/EA = 40:1, v/v) afforded 3ar as a yellow solid (104.7
mg, 74%), m.p: 132 – 134 °C. 1H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 8.12 (dd, J = 19.5, 4.6
Hz, 1H), 7.77 (d, J = 7.1 Hz, 2H), 7.68 – 7.61 (m, 5H), 7.59 – 7.51 (m, 4H), 7.49 – 7.45 (m, 3H),
7.38 – 7.31 (m, 2H), 7.27 (dd, J = 9.3, 2.4 Hz, 1H), 7.18 (d, J = 9.1 Hz, 1H) ppm. 13C{1H} NMR
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(100 MHz, CDCl3) δ 198.1, 149.1, 141.4, 139.4, 138.6, 137.5, 134.3, 133.7, 132.2, 131.5, 129.9,
129.2, 128.3, 127.5, 127.0, 126.3, 124.2, 123.6, 122.9, 120.4, 120.0, 119.8, 118.9, 116.4, 115.6,
110.6, 110.0 ppm. HRMS (ESI) m/z calcd. for C22H15ClN2O [M+H]+ 359.0946, found 359.0941.
(5-Chloro-2-((4-(diphenylamino)phenyl)amino)phenyl)(phenyl)methanone (3as). Purification by
column chromatography on silica gel (PE/EA = 50:1, v/v) afforded 3as as a yellow solid (109.4
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mg, 77%), m.p: 145 – 146 °C. H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 7.64 – 7.55 (m, 2H),
7.51 – 7.36 (m, 4H), 7.20 – 7.13 (m, 6H), 7.10 – 6.96 (m, 8H), 6.91 (t, J = 7.3 Hz, 2H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ 198.0, 147.7, 147.2, 144.2, 139.1, 134.8, 134.1, 133.7, 131.7,
129.3, 129.2, 128.3, 125.4, 123.8, 123.8, 122.6, 120.6, 120.0, 116.1 ppm. HRMS (ESI) m/z calcd.
for C31H21ClN2O [M+H]+ 473.1415, found 473.1414.
(5-Chloro-2-(p-tolylamino)phenyl)(phenyl)methanone
(3ba).
Purification
by
column
chromatography on silica gel (PE/EA = 50:1, v/v) afforded 3ba as a yellow solid (71.2 mg, 74%),
m.p: 103 – 105 °C. 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.62 – 7.58 (m, 2H), 7.50 – 7.45
(m, 1H), 7.43 – 7.38 (m, 3H), 7.14 (dd, J = 8.9, 2.5 Hz, 1H), 7.08 (dt, J = 8.3, 6.5 Hz, 5H), 2.26 (s,
3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 198.0, 147.4, 139.2, 137.3, 134.1, 134.0, 133.6,
131.6, 130.0, 129.3, 128.3, 123.0, 120.4, 119.8, 115.9, 20.9 ppm. HRMS (ESI) m/z calcd. for
C20H16ClNO [M+H]+ 322.0993, found 322.0990.
Phenyl(2-(p-tolylamino)phenyl)methanone (3ca). Purification by column chromatography on
silica gel (PE/EA = 50:1, v/v) afforded 3ca as a yellow solid (64.5 mg, 75%), m. p. 101 – 102 °C.
1H NMR (400 MHz, CDCl3) δ 7.73 – 7.69 (m, 2H), 7.56 (dd, J = 10.5, 4.2 Hz, 2H), 7.49 (t, J = 7.3
Hz, 2H), 7.35 – 7.27 (m, 2H), 7.24 – 7.17 (m, 4H), 6.67 (ddd, J = 8.1, 6.6, 1.6 Hz, 1H), 2.37 (s,
3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 199.1, 148.8, 140.0, 137.7, 135.0, 134.3, 133.5,
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131.2, 129.9, 129.3, 128.1, 122.9, 119.0, 116.0, 114.2, 20.9 ppm. HRMS (ESI) m/z calcd. for
C20H17NO [M+H]+ 288.1383, found 288.1381.
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1-(2-(p-Tolylamino)phenyl)ethan-1-one (3da). Purification by column chromatography on silica
gel (PE/EA = 50:1, v/v) afforded 3da as a yellow oil (54.0 mg, 80%). 1H NMR (400 MHz, CDCl3)
δ 7.81 (dd, J = 8.1, 1.5 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.20 – 7.14 (m, 5H), 6.73 – 6.69 (m, 1H),
2.65 (s, 3H), 2.36 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 201.0, 148.5, 137.5, 134.5,
133.8, 132.4, 129.9, 123.7, 118.5, 116.0, 113.9, 28.0, 20.9 ppm. HRMS (ESI) m/z calcd. for
C15H15NO [M+H]+ 226.1226, found 226.1222.
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2-(p-Tolylamino)benzaldehyde (3ea). Purification by column chromatography on silica gel
(PE/EA = 50:1, v/v) afforded 3ea as a yellow oil (53.8 mg, 85%). 1H NMR (400 MHz, CDCl3) δ
9.90 (s, 1H), 7.55 (dd, J = 7.7, 1.4 Hz, 1H), 7.36 – 7.31 (m, 1H), 7.21 – 7.12 (m, 5H), 6.80 (t, J =
7.4 Hz, 1H), 2.36 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 194.1, 148.4, 136.8, 136.5,
135.5, 134.3, 130.0, 123.6, 119.1, 116.7, 112.7, 20.9 ppm. HRMS (ESI) m/z calcd. for C14H13NO
[M+H]+ 212.1070, found 212.1069.
2-((4-Formylphenyl)amino)benzaldehyde (3fa). Purification by column chromatography on silica
gel (PE/EA = 40:1, v/v) afforded 3fa as a yellow solid (51.9 mg, 78%), m.p: 80 – 82 °C. 1H NMR
(400 MHz, CDCl3) δ 10.27 (s, 1H), 9.91 (d, J = 10.1 Hz, 2H), 7.87 – 7.82 (m, 2H), 7.65 (dd, J =
7.7, 1.0 Hz, 1H), 7.51 – 7.46 (m, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.01 (m, 1H) ppm. 13C{1H} NMR
(100 MHz, CDCl3) δ 194.5, 190.5, 146.1, 144.8, 136.8, 135.5, 131.5, 131.2, 121.0, 119.7, 119.5,
114.5 ppm. HRMS (ESI) m/z calcd. for C14H11NO [M+H]+ 226.0863, found 226.0860.
5-Fluoro-2-(p-tolylamino)benzaldehyde (3ga). Purification by column chromatography on silica
gel (PE/EA = 50:1, v/v) afforded 3ga as a yellow oil (51.6 mg, 75%). 1H NMR (400 MHz, CDCl3)
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δ 9.83 (s, 1H), 9.75 (s, 1H), 7.23 (dd, J = 7.9, 2.0 Hz, 1H), 7.19 – 7.17 (m, 2H), 7.15 – 7.12 (m, 2H),
7.11 – 7.07 (m, 2H), 2.36 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 192.8 (d, J = 2.3 Hz),
154.2 (d, J = 236.9 Hz), 145.1 (d, J = 0.6 Hz), 136.9, 134.4, 130.1, 123.6, 123.5 (d, J = 23.3 Hz),
120.2 (d, J = 21.4 Hz), 118.6 (d, J = 5.2 Hz), 114.6 (d, J = 6.6 Hz), 20.9 ppm. 19F NMR (300 MHz,
CDCl3) δ -127.99 (s, 1H) ppm. HRMS (ESI) m/z calcd. for C14H12FNO [M+H]+ 230.0976, found
230.0974.
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5-Chloro-2-(p-tolylamino)benzaldehyde (3ha). Purification by column chromatography on silica
gel (PE/EA = 50:1, v/v) afforded 3ha as a yellow oil (58.8 mg, 80%). 1H NMR (400 MHz, CDCl3)
δ 10.01 (s, 1H), 9.84 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 8.3 Hz,
2H), 7.06 (s, 4H), 6.74 (dd, J = 8.3, 1.8 Hz, 1H), 2.37 (s, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3) δ 193.1, 149.3, 142.4, 137.7, 136.0, 135.2, 130.2, 124.2, 117.5, 117.2, 112.4, 21.0 ppm.
HRMS (ESI) m/z calcd. for C14H12ClNO [M+H]+ 246.0680, found 246.0678.
5-Bromo-2-(p-tolylamino)benzaldehyde (3ia). Purification by column chromatography on silica
gel (PE/EA = 50:1, v/v) afforded 3ia as a yellow oil (76.2 mg, 81%). 1H NMR (400 MHz, CDCl3)
δ 9.86 (d, J = 18.2 Hz, 1H), 9.81 (s, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 9.1, 2.4 Hz, 1H),
7.19 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 9.1 Hz, 1H), 2.36 (s, 3H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ 192.8, 147.4, 138.1, 136.3, 134.9, 130.1, 123.8, 120.2, 114.9,
107.5, 20.9 ppm. HRMS (ESI) m/z calcd. for C14H12BrNO [M+H]+ 290.1075, found 290.1072.
5-Methoxy-2-(p-tolylamino)benzaldehyde (3ja). Purification by column chromatography on silica
gel (PE/EA = 40:1, v/v) afforded 3ja as a yellow oil (57.1 mg, 79%). 1H NMR (400 MHz, CDCl3)
δ 9.87 (s, 1H), 9.65 (s, 1H), 7.18 – 7.12 (m, 5H), 7.03 – 6.98 (m, 2H), 3.82 (s, 3H), 2.34 (s, 3H)
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ppm. C{1H} NMR (100 MHz, CDCl3) δ 193.5, 151.0, 143.0, 137.6, 133.5, 129.9, 124.4, 122.7,
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119.0, 117.7, 114.8, 55.9, 20.8 ppm. HRMS (ESI) m/z calcd. for C15H15NO2 [M+H]+ 242.1176,
found 242.1173.
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6-(p-Tolylamino)benzo[d][1,3]dioxole-5-carbaldehyde
(3ka).
Purification
by
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chromatography on silica gel (PE/EA = 30:1, v/v) afforded 3ka as a yellow oil (57.3 mg, 75%). 1H
NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 9.61 (s, 1H), 7.15 (dd, J = 19.4, 8.3 Hz, 4H), 6.86 (s,
1H), 6.62 (s, 1H), 5.91 (s, 2H), 2.35 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 190.6,
154.7, 147.8, 139.3, 136.9, 134.4, 130.0, 123.7, 112.2, 112.2, 101.5, 93.2, 20.9 ppm. HRMS (ESI)
m/z calcd. for C15H13NO3 [M+H]+ 256.0968, found 256.0967.
4-Chloro-2-(p-tolylamino)benzaldehyde (3la). Purification by column chromatography on silica
gel (PE/EA = 50:1, v/v) afforded 3la as a yellow oil (56.6 mg, 77%). 1H NMR (400 MHz, CDCl3)
δ 10.01 (s, 1H), 9.84 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 8.3 Hz,
2H), 7.06 (s, 1H), 6.74 (dd, J = 8.3, 1.8 Hz, 1H), 2.37 (s, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3) δ 193.1, 149.3, 142.4, 137.7, 136.0, 135.2, 130.2, 124.2, 117.5, 117.2, 112.4, 21.0 ppm.
HRMS (ESI) m/z calcd. for C14H12ClNO [M+H]+ 246.0680, found 246.0678.
2-(p-Tolylamino)-4-(trifluoromethyl)benzaldehyde (3ma). Purification by column chromatography
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on silica gel (PE/EA = 50:1, v/v) afforded 3ma as a yellow oil (56.9 mg, 68%). H NMR (400
MHz, CDCl3) δ 10.04 (s, 1H), 9.97 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H), 7.23 (d, J = 8.2
Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 6.99 (d, J = 8.1 Hz, 1H), 2.38 (s, 3H) ppm. 13C{1H} NMR (100
MHz, CDCl3) δ 193.8, 148.4, 137.1, 136.5 (q, J = 34.1 Hz), 135.8, 135.4, 130.3, 124.0, 123.4 (q, J
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= 271.8 Hz), 120.4, 112.6 (q, J = 3.6 Hz), 109.9 (q, J = 4.0 Hz), 21.0 ppm. F NMR (300 MHz,
CDCl3) δ -63.9 ppm. HRMS (ESI) m/z calcd. for C15H12F3NO [M+H]+ 280.0944, found 280.0941.
5-(Allyloxy)-2-(p-tolylamino)benzaldehyde (3na). Purification by column chromatography on
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silica gel (PE/EA = 40:1, v/v) afforded 3na as a yellow oil (64.0 mg, 80%). H NMR (400 MHz,
CDCl3) δ 9.85 (s, 1H), 9.66 (s, 1H), 7.18 – 7.13 (m, 5H), 7.07 – 7.03 (m, 2H), 6.06 (ddt, J = 17.2,
10.5, 5.3 Hz, 1H), 5.43 (ddd, J = 17.3, 3.1, 1.6 Hz, 1H), 5.31 (ddd, J = 10.5, 2.7, 1.3 Hz, 1H), 4.53
(dt, J = 5.3, 1.5 Hz, 2H), 2.35 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 193.4, 149.8,
143.1, 137.5, 133.6, 133.2, 129.9, 125.2, 122.8, 119.3, 119.0, 117.7, 114.7, 69.8, 20.8 ppm.
HRMS (ESI) m/z calcd. for C17H17NO2 [M+H]+ 280.0944, found 280.0941.
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Mixture
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(5-chloro-2-(m-tolylamino)phenyl)(phenyl)methanone
(3at). Purification by
and
(5-chloro-2-(p-tolylamino)phenyl)(phenyl)methanone
column
chromatography on silica gel (PE/EA = 50:1, v/v) afforded 3at as a yellow oil (53.1 mg, 55%). 1H
NMR (400 MHz, CDCl3) δ 9.89 (d, J = 8.1 Hz, 1H), 7.64 – 7.59 (m, 2H), 7.53 – 7.47 (m, 1H),
7.45 – 7.39 (m, 3H), 7.24 – 7.12 (m, 3H), 7.10 – 7.06 (m, 1H), 6.99 – 6.86 (m, 2 H), 2.28 (s, 3H)
ppm. C{1H} NMR (100 MHz, CDCl3) δ 198.0, 198.0, 147.5, 146.8, 140.0, 139.5, 139.2, 139.1,
13
137.8, 134.2, 134.1, 133.6, 133.6, 131.8, 131.7, 130.1, 129.4, 129.3, 129.3, 128.3, 124.8, 123.1,
120.8, 120.4, 119.8, 119.7, 116.4, 115.9, 21.4, 20.9 ppm. HRMS (ESI) m/z calcd. for C20H16ClNO
[M+H]+ 322.0993, found 322.0991.
(5-Chloro-2-((2,5-dichlorophenyl)amino)phenyl)(phenyl)methanone (3au). Purification by column
chromatography on silica gel (PE/EA = 50:1, v/v) afforded 3au as a yellow oil (90.2 mg, 80%). 1H
NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.64 – 7.60 (m, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.40 (d, J =
2.2 Hz, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 2.3 Hz, 1H), 7.29 – 7.22 (m, 2H), 7.18 (d, J =
8.5 Hz, 1H), 6.77 (dd, J = 8.5, 2.3 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 197.1, 143.0,
138.9, 138.0, 133.6, 133.3, 132.8, 132.4, 130.8, 129.7, 128.4, 123.8, 123.7, 123.2, 122.7, 118.6,
117.9 ppm. HRMS (ESI) m/z calcd. for C19H13Cl3NO [M+H]+ 376.0057, found 376.0059.
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2-Chloro-9-phenylacridine (6a).9 Compound 6a was prepared from 3aa (30.7 mg, 0.1 mmol).
Purification by column chromatography on silica gel (PE/EA = 30:1, v/v) afforded 6a as a yellow
solid (27.4 mg, 95%), m.p: 200 – 202 °C. 1H NMR (400 MHz, CDCl3) δ 8.28 (dd, J = 13.6, 9.0 Hz,
2H), 7.82 – 7.77 (m, 1H), 7.71 – 7.67 (m, 3H), 7.65 – 7.59 (m, 3H), 7.48 – 7.40 (m, 3H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ 148.4, 146.9, 146.6, 135.2, 131.6, 131.4, 131.0, 130.5, 130.3,
129.3, 128.7, 128.7, 126.8, 126.3, 125.4, 125.4, 125.1 ppm. HRMS (ESI) m/z calcd. for
C19H12ClN [M+H]+ 290.0731, found 290.0728.
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7-Chloro-N,N,9-triphenylacridin-2-amine (6b). Compound 6b was prepared from 3as (47.4 mg,
0.1 mmol). Purification by column chromatography on silica gel (PE/EA = 20:1, v/v) afforded 6b
as a yellow solid (36.5 mg, 80%), m.p: 215 – 216 °C. 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J =
30.4, 9.0 Hz, 2H), 7.66 – 7.59 (m, 3H), 7.43 – 7.39 (m, 3H), 7.25 – 7.21 (m, 6H), 7.06 (dd, J =
11.6, 7.6 Hz, 6H), 6.99 (d, J = 2.5 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 146.4, 145.9,
134.5, 132.1, 131.0, 130.1, 129.7, 129.4, 128.7, 128.4, 126.6, 125.7, 125.1, 124.7, 124.3, 113.9
ppm. HRMS (ESI) m/z calcd. for C31H21ClN2 [M+H]+ 457.1466, found 457.1463.
2-Chloro-11,13-diphenyl-11H-indolo[2,3-b]acridine (6c). Compound 6c was prepared from 3ar
(47.2 mg, 0.1 mmol). Purification by column chromatography on silica gel (PE/EA = 20:1, v/v)
afforded 6c as a yellow solid (40.8 mg, 90%), m.p: 242 – 244 °C. 1H NMR (400 MHz, CDCl3) δ
8.07 (dd, J = 26.5, 9.2 Hz, 2H), 7.76 (d, J = 2.2 Hz, 1H), 7.66 (d, J = 9.3 Hz, 1H), 7.56 – 7.49 (m,
8H), 7.47 – 7.39 (m, 3H), 7.17 – 7.13 (m, 1H), 7.07 – 7.01 (m, 1H), 6.58 (ddd, J = 8.2, 7.0, 1.1 Hz,
1H), 5.75 (d, J = 8.5 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 148.0, 144.0, 141.9, 139.8,
139.2, 139.2, 136.5, 132.1, 131.6, 131.0, 130.0, 129.9, 129.4, 129.2, 128.8, 128.6, 128.3, 126.2,
124.9, 124.1, 124.0, 123.8, 123.2, 120.0, 118.1, 113.4, 109.8 ppm. HRMS (ESI) m/z calcd. for
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C31H19ClN2 [M+H]+ 455.1310, found 455.1305.
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2-(p-Tolylamino)benzoic acid (7). Compound 7 was prepared from 3ea (42.2 mg, 0.2 mmol).
Purification by column chromatography on silica gel (PE/EA/MeOH = 50:10:1, v/v/v) afforded 7
as a yellow oil (38.6 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.27 (dd, J = 31.4, 7.9
Hz, 2H), 7.99 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 14.0 Hz, 2H), 7.65 (d, J = 8.2 Hz, 1H), 7.55 (d, J =
6.6 Hz, 1H), 2.58 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 147.4, 136.1, 135.9, 134.0,
130.5, 128.4, 128.2, 128.0, 126.6, 126.2, 125.8, 21.8 ppm. HRMS (ESI) m/z calcd. for C14H14NO2
[M+H]+ 228.1019, found 228.1013.
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2-(2-(p-Tolylamino)benzylidene)malononitrile (8). Compound 8 was prepared from 3ea (42.2 mg,
0.2 mmol) and malononitrile (13.2 mg, 0.2 mmol), piperidine (10 mol%) and ethanol (1.0 mL).
Purification by column chromatography on silica gel (PE/EA = 10:1, v/v) afforded 7 as a yellow
solid (44.5 mg, 86%), m.p: 125 – 126 °C. 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.44 (dd, J
= 13.1, 7.9 Hz, 3H), 7.29 (dd, J = 11.6, 4.3 Hz, 1H), 7.13 (d, J = 8.2 Hz, 2H), 7.06 (t, J = 7.4 Hz,
1H), 6.38 (d, J = 8.5 Hz, 1H), 2.48 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 153.8, 144.3,
142.9, 140.0, 133.6, 133.2, 132.0, 129.4, 128.9, 121.8, 118.2, 115.8, 115.3, 108.1, 21.3 ppm.
HRMS (ESI) m/z calcd. for C17H14N3 [M+H]+ 260.1182, found 260.1181.
Control experiment (Scheme 6a). An oven-dried 20 mL vial equipped with a Teflon-coated
stirring bar was charged with CuCl2 (4 mg, 10 mol%), K2CO3 (20.7 mg, 50 mol%), 4a (0.3 mmol)
and 1a (0.45 mmol), and closed with a septum cap. Then DMSO (1.0 mL) was added via syringe.
The resulting mixture was stirred at 100 °C (heating mantle) for 24 h. Then, the resulting mixture
was added n-tetradecane (0.3 mmol) as internal standard and diluted with ethyl acetate (15 mL).
The resulting solution was washed with saturated NaCl aqueous solution. After drying over
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anhydrous MgSO4, the solution was analyzed with GC. 3aa was detected only in 9% yield even
extended the reaction time to 24 h. This result indicated that 4a is not an intermediate for this
reaction.
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Control experiment (Scheme 6b). [PhCu] was prepared from PhMgBr and CuI following the
reported procedure.18 Then the in situ generated [PhCu] was added a solution of 2a (0.3 mmol) in
DMSO (1.0 mmol) via syringe. The resulting mixture was stirred at 100 °C (heating mantle) for 6
h. Then the resulting solution was added n-tetradecane (0.3 mmol) as internal standard and diluted
with ethyl acetate (15 mL). The resulting solution was washed with saturated NaCl aqueous
solution. After drying over anhydrous MgSO4, the solution was analyzed with GC. The desired
product 3aa was detected in 36% yield. Thus, this result indicated that the [PhCu] species might
be an intermediate for this transformation.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
1H and 13C NMR spectra for all compounds
AUTHOR INFORMATION
ORCID
Yang Gao: 0000-0001-9513-6899
Xiao-Qian Hu: 0000-0001-9094-2357
Notes
The authors declare no competing financial interest.
Acknowledgements
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The authors thank the National Natural Science Foundation of China (21901045, 21901258,
21975055, and 21975053), the Technology Plan of Guangdong Province
(2018A030310570, 2019A050510042) and the Guangdong Basic and Applied Basic
Research Foundation (2019B1515120023, 2019B1515120035) for financial support.
References
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