Pd-Catalyzed Approach for Assembling 9-Arylacridines via a Cascade Tandem Reaction of 2-(Arylamino)benzonitrile with Arylboronic Acids in Water

Article abstract of DOI:10.1021/acs.joc.0c01654

A novel palladium-catalyzed protocol for the synthesis of 9-arylacridines via tandem reaction of 2-(arylamino)benzonitrile with arylboronic acids in water has been developed with good functional group tolerance. The present synthetic route could be readily scaled up to gram quantity without difficulty. This methodology was further extended to the synthesis of a 4′-OH derivative, which showed estrogenic biological activity. Preliminary mechanistic experiments showed that this transformation involves a nucleophilic addition of aryl palladium species to the nitrile to generate an aryl ketone intermediate followed by an intramolecular Friedel-Crafts acylation and dehydration to acridines.

Full text of DOI:10.1021/acs.joc.0c01654

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Article
Pd-Catalyzed approach for assembling 9-arylacridines via a cascade
tandem reaction of 2-(arylamino)benzonitrile with arylboronic acids in water
Xuanzeng Ye, Beihang Xu, Jiani Sun, Ling Dai, Yinlin Shao, Yetong Zhang, and Jiuxi Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01654 • Publication Date (Web): 22 Sep 2020
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Pd-Catalyzed approach for assembling 9-arylacridines via a cascade
tandem reaction of 2-(arylamino)benzonitrile with arylboronic acids
in water
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Xuanzeng Ye,a Beihang Xu,a Jiani Sun, a Ling Dai,a Yinlin Shao,a,b* Yetong Zhang,a
and Jiuxi Chen a,*
a. College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325035, China
b.
Institute of New Materials & Industrial Technology, Wenzhou University, Wenzhou 325035,
China
Ar
CN
Pd
Ar2
Ar1
Ar
+
B(OH)2
Ar1
Ar2
41 examples
up to 98% yield
N
H
N
ABSTRACT: A novel palladium-catalyzed protocol for the synthesis of
9-arylacridines via tandem reaction of 2-(arylamino)benzonitrile with arylboronic
acids in water has been developed with good functional group tolerance. The present
synthetic route could be readily scaled up to gram quantity without difficulty. This
methodology was further extended to the synthesis of a 4’-OH derivative which
showed estrogenic biological activity. Preliminary mechanistic experiments showed
that this transformation involves a nucleophilic addition of aryl pallidium species to
the nitrile to generate an aryl ketone intermediate followed by an intramolecular
Friedel-Crafts acylation and dehydration to acridines.
_______________________________________________________________________________
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INTRODUCTION
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Acridines are an important class of heteroaromatic compounds1 which exhibit
versatile biological properties,2 such as antimalarial,2b anticancer2c and
antileukaemia.2d Acridines analogues have also been used as effective organocatalyst
for photocatalytic oxygenation of anthracenes and olefins3a and hydroetherification of
alkenols.3b In addition, 9-methylacridines and other acridine-containing analogues
have been applied to new fluorescent probes and organic light-emitting diodes.4
Consequently, the development of methods for the preparation of acridines is of
importance to medicinal chemistry and represents a worthwhile goal of organic
synthesis.
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Many elegant general synthetic approaches have been developed. The earliest
acridine synthesis was achieved by Brenthsen in 1878 by heating a diaryl amine and a
carboxylic acid under ZnCl2 at elevated temperatures.5 Inspired by this work, many
modifications have been discovered. Azides were nicely applied as the sole nitrogen
source in building acridine skeleton. Ellman and co-workers developed a
Rh-catalyzed formal [3+3] annulation of aromatic azides and imines to provide
acridine derivatives in reasonable yields.6a Wang and Jiang reported a nitrogen–iodine
exchange protocol of diaryliodonium salts with sodium azide salt for general
construction of acridines.6b Transient directing group promoted C(sp2)–H
functionalization of benzaldehydes for the construction of acridines have also been
achieved. Park and Kim disclosed the transient directing group assisted
Rh(III)-catalyzed C−H functionalization cyclization between benzaldehydes and
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anthranils.7a Cheng demonstrated an efficient procedure to access acridine analogues
starting from aromatic aldehydes and aryl nitrosos enabled by in situ formation and
removal of an imino transient directing group.7b Catalytic dehydrogenation reaction of
partially saturated N-heterocycles to acridines is also realized in contemporary
science.8 The most well-developed general methods for the construction of acridines
were inter-and intramolecular cyclizations with various in situ-generated
diphenylamine derivatives as the substrates (Scheme 1a).9
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Transition-metal-catalyzed transformation of nitriles serves as a powerful strategy
to build carbon–carbon and carbon–heteroatom bonds for organic chemistry
research.10 To date, a number of catalytic protocols for the carbometallization of
nitriles with organoboron reagents to ketones and nitrogen-containing compounds
such as quinolone, isoquinoline, quinazoline and indole have been realized (Scheme
1b).11 Compared to the nucleophilic addition of organometallic reagents such as
organolithium or organomagnesium to nitriles, organoboron reagents are highly
regarded due to their advantages of stability to air and moisture as well as good
functional group tolerance.12 However, transition-metal-catalyzed carbometallization
of nitriles with organoboron to acridines have not been realized to date. Chen reported
efficient tandem reaction to construct acridines derivatives with readily available
2-aminobenzonitrile and diaryliodonium salts (Scheme 1c).13 From the viewpoint of
diverse synthesis concerns, development of environmentally friendly shortcuts for
accessing acridine from easily available nitriles remains a demanding goal.
Additionally, water as a reaction medium for green chemistry has recently attracted
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considerable attention in organic synthesis due to its environmental acceptability,
abundance, safety and low cost, and would thus be highly advantageous alternatives
to organic solvents from both economical and ecological standpoints.14 Inspired by
hereinbefore work, as a part of our research program aimed at palladium-catalyzed
synthesis of N-containing heterocycles with organoboron reagents and nitriles,15 we
envisioned that carbopalladation of 2-aminobenzonitrile derivatives would afford
2-aminoaryl ketones easily, which might further prompt an intramolecular tandem
arylation/Friedel-Crafts procedure with the aid of lewis acid and/or acid medium,
providing the desire acridines skeletons (Scheme 1d).
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Scheme 1. Acridines synthesis strategies
a) Synthesis of acridines via in situ-generated diphenylamine derivatives
R
N
X
X
R
R
+
Y
NH2
X = O, NPh, NNHTs Y = Br, OTf, PhI
b) Transitional-metal-catalyzed addition of organoboron reagents to nitriles
N
H
O
s
i
s
y
l
o
r
d
[M]
Ar
y
t
h
R
Ar
N
[M]
R CN
+
ArB(OH)2
a
n
z
d
e
m
o
c
R
y
c
l
i
a
t
i
N-heterocycles
n
c) Synthesis of acridines via with 2-aminobenzonitrile and diaryliodonium salts
NHAr
CN
Cu(OTf)2
Ar
I
Ar
+
NH2
N
OTf
d) This work: Pd-Catalyzed tandem reaction of 2-(arylamino)benzonitrile with ArB(OH)2
Ar
CN
Pd
+
ArB(OH)2
N
H
N
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RESULTS AND DISCUSSION
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At the outset of our study, 2-(phenylamino)benzonitrile (1a) and phenylboronic acid
(2a)were chosen as the model reaction to optimize the reaction conditions. The
reaction in the presence of Pd(OAc)2 (10 mol%), 2,2'-bipyridine (L1) (20 mol%) and
D-camphorsulfonic acid (D-CSA) (5 equiv) was performed in toluene (2mL) at 100
oC for 24 h under air atmosphere, affording the target structure 9-phenylacridine (3a)
in 54% yield (Table 1, entry 1). A survey of the solvent effect revealed that water was
optimal to give a best 84% yield, and the use of toluene, N,N-Dimethylformamide
(DMF) and MeOH led to lower yields (Table 1, entries 1-4). Among the various acid
additives
we
screened,
methanesulfonic
acid
(CH3SO3H)
and
trifluoromethanesulfonic acid (CF3SO3H) were most effective, affording 3a in the
highest yield of 93% (Table 1, entries 5-8). A variety of Pd(II) salts are reactive, with
Pd(OAc)2 being the optimal choice (Table 1, entries 9-11). It was worth noting that
the reaction did not work when Pd(0) such as Pd(PPh3)4 was employed as catalyst
(Table 1, entry 12). Other bidentate nitrogen ligands, such as
5,5'-dimethyl-2,2'-bipyridine (L2) and 6,6'-dimethyl-2,2'-bipyridine (L3) and
4,4'-dimethyl-2,2'- bipyridine (L4) affected the tandem reaction adversely due to the
steric effect or electronic effect (Table 1, entries 13-15). The yield decreased to 61%
when the temperature was 80 oC. No significantly improvement of yield was achieved
o
by elevating reaction temperature to 120 C (Table 1, entries 16-17). Shorten the
reaction time to 12 h led to a lower yield of the desire product (Table 1, entry 18). To
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our delight, the isolated yield of 3a remained when catalyst loading was 5 mol%
(Table 1, entry 19). The transformation efficiency of acridines decreased to some
extent either lower the amount of phenylboronic acid (2a) or CH3SO3H (Table 1,
entry 20). The reactants remained unreacted when the Pd catalyst was absent (Table 1,
entry 21). Only trace amount of 3a was detected when the ligand was omitted from
the reaction medium (Table 1, entry 22). The reaction could not work well when the
methanesulfonic acid was absent (Table 1, entry 23). Therefore, the optimal reaction
conditions can be summarized as follows: 0.5 mmol 2-(phenylamino)benzonitrile and
0.75 mmol phenylboronic acid in water (2 mL) with Pd(OAc)2 catalyst (5 mol %),
CH3SO3H (5 equiv), 2,2'-bipyridine (10 mol%), at 100 °C for 24 h under air
atmosphere.
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Table 1. Optimization of reaction conditionsa
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CN
B(OH)2
Catalyst, Ligand
6
7
8
+
Solvent, Additive
N
H
N
9
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1a
2a
3a
N
N
N
N
N
N
N
N
L1
L2
L3
L4
Temp(oC)
Pd Source Ligand
Additive
Solvent
Time(h)
Entry
Yield(%)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
L1
L1
L1
-
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(acac)2
Pd(CF3CO2)2
PdCl2
toluene
DMF
MeOH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
12
24
24
24
24
24
54
64
76
84
13
82
93
93
81
75
75
trace
81
<10
73
61
92
85
D-CSA
D-CSA
2
3
D-CSA
4
D-CSA
5
CH3CO2H
CF3CO2H
CF3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
-
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
120
100
100
100
100
100
100
92b
(70)c
68d(76)e
NR
Pd(OAc)2
Pd(OAc)2
trace
trace
L1
a
1a
2a
(0.75 mmol), Pd Source (10 mol %), Ligand (20 mol %),
Conditions:
(0.5 mmol),
Solvent (2.0 mL), additive (5 equiv), 100 oC, 24 h, air, isolated yields, b Pd Source (5 mol %),
c
d
Ligand (10 mol %). Pd Source (3 mol %), Ligand (10 mol %). 3 equiv of CH3SO3H was
used. e 1.2 equiv of
2a
was used.
With these optimized conditions in hand, we subsequently explored the substrate
scope and limitations of this palladium-catalyzed addition/cyclization of organoboron
to 2-(phenylamino)benzonitrile derivatives for the construction of acridines. First, the
variation of the arylboronic acids was investigated (Table 2). The results showed that
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the steric effect of the substituent had an obvious impact on the reaction under the
standard conditions. For example, treatment of 1a with para- and meta-tolylboronic
acids provided 88% and 86% yields of 3b and 3c, respectively, while the
ortho-tolylboronic acid afforded the desired product 3d with a diminished yield of
51%. 3,5-Dimethyl phenylboronic acid afforded the desire 3e in comparable 84%
yield while bulky (2-isopropylphenyl)boronic acid only afforded the desired acridine
3f in 37% yield. 2,4,6-Trimethyl phenylboronic acid were unsuitable in this
transformation. The electronic properties of the substituents on the phenyl ring of the
arylboronic acids affected the reaction to some extent. In general, the substrates
bearing a moderate electron-withdrawing substituent provided a slightly higher yield
than those of substrates with electron-donating groups. For example,
(4-isopropylphenyl)boronic acid and (4-(tert-butyl)phenyl)boronic acid provided the
corresponding acridines 3h and 3i in 88 and 89% yield, while arylboronic acids
bearing methoxy substituents at 4-positions can only provide the corresponding
product 3j in 56% yield, with 1j recovered in 30% yield. To our delight, the method
tolerates the entire range of halogen substituents, affording the desired products 3k-3s
in 62-98% yield, which makes this method particularly appealing, enabling further
access to more complex compounds in combination with cross-coupling
transformations. However, arylboronic acids bearing strong electron-withdrawing
groups decreased the reactivity. For examples, (4-(trifluoromethyl)phenyl)boronic
acid was converted to 3t in 63% yield, accompanied by the formation of uncyclized
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ketone (2-(phenylamino)phenyl)(4-(trifluoromethyl)phenyl)methanone 3t-1 in 32%
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yield, and 4-nitrophenyl)boronic acid was inefficient substrate under current
conditions. Additionally, naphthalen-2-ylboronic acid was also successfully
transformed to target acridine 3v in 86% yield. However, when thiophen-3-ylboronic
acid was subjected to the reaction condition, the desired product 3w was obtained in
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only
29%
yield. Unfortunately,
(4-hydroxyphenyl)boronic
acid
and
(4-(methoxycarbonyl)phenyl)boronic acid did not undergo any detectable conversion
to afford the desired acridine products 3x and 3y, with 2-(phenylamino)benzonitrile
recovered. The acridine 3z was obtained in only 10% yield when the
(4-formylphenyl)boronic acid was used in the reaction. At last, other organo boronic
acids such as methylboronic acid and (E)-styrylboronic acid were also tried in this
reaction respectively, but the desired acridines 3za and 3zb were not obtained.
Table 2. The scope of arylboronic acids a
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Pd(OAc)2 (5 mol%)
Ar
CN
bpy (10 mol%)
B(OH)2
H2O, CH3SO3H (5 eq)
Ar
+
100oC, 24 h, air
N
H
7
N
3
8
9
1a
2
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N
N
N
N
N
3b
, 88%
3c
3d
3e
3f
, 37%
, 86%
, 51%
, 84%
OCH3
F
N
N
N
N
, 88%
3g
, ND
3h
3i
3j
3k
, 89%
, 56%
, 96%
F
Cl
Br
Cl
Br
N
N
N
N
N
b
b
b
b
3l
3m
3n
3o
3p
, 94%
, 76% (98%)
, 56% (90%)
, 37% (76%)
, 62%
Cl
Br
I
CF3
NO2
N
N
N
N
N
b
3q
3r
3s
3t
3u
, ND
, 92%
, 60% (94%)
, 92%
, 62%
OH
COOCH3
CHO
S
N
N
N
N
N
3v
3w
3x
3y
3z
, 10%
, 86%
, 29%
, 0%
, 0%
Ph
CH3
N
N
3za
, 0%
3zb
, 0%
a
1a
2
(0.5 mmol), (0.75 mmol), Pd(OAc)2 (5 mol%), bpy (10 mol%), H2O (2.0 mL), CH3SO3H
(5 equiv), 100 oC, 24 h, air, isolated yield. b CF3SO3H was used instead of CH3SO3H.
Reaction conditions:
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Encouraged by these results, we next set out to investigate the reaction of various
substituted 2-(phenylamino)benzonitriles with phenylboronic acid under our optimal
conditions (Table 3). The influence of substitutions on the aniline ring Ar1 was first
investigated. The electronic effect of the substituents affected the yields of this
transformation to some extent. For example, when substrates bearing an ortho-,
para-methyl, 2, 4-dimethyl, 4-tertiary butyl and 4-methoxyl on the Ar1 ring were
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examined,
3zc-3zg
were
obtained
in
90-94%
yield,
respectively.
Electron-withdrawing groups, such as fluoro, chloro, bromo on the Ar1 ring at the
para-position, were well tolerated in this transformation, affording the desired
9-phenylacridines 3zh-3zj in a lower yield, ranging from 81 to 86%.
Naphthyl-containing compound such as 1zk do not interfere with the
palladium-catalyzed addition/cyclization progress, afforded the acridine 3zk in 85%
yield. We next examined the influence of substitutions on the aryl nitriles ring Ar2.
Substrates bearing a methyl and chloro group attaching to the Ar2 ring were evaluated,
affording 3zl-3zo in 88-94% yield respectively. However, the yield was decreased
dramatically when 2-(phenylamino)nicotinonitrile (1zp) was used as the substrate.
Table 3. The scope of 2-(phenylamino)benzonitriles. a
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Pd(OAc)2 (5 mol%)
bpy (10 mol%)
H2O, CH3SO3H (5 eq)
CN
B(OH)2
Ar2
Ar1
+
100oC, 24 h, air
N
H
7
Ar2
Ar1
8
9
N
3
1
2a
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OMe
Ar1
Ar1
Ar1
Ar1
Ar1
N
N
N
N
N
3zc
3zd
3ze
3zf
3zg
, 93%
, 90%
, 90%
, 94%
, 92%
F
Cl
Br
Ar2
Ar1
Ar1
Ar1
Ar1
N
N
N
N
N
3zk
, 85%
3zh
3zi
3zj
3zl
, 93%
, 81%
, 84%
, 86%
Cl
Ar2
Ar2
Ar2
Ar2
N
N
Cl
N
N
N
3zm
, 88%
3zn
3zo
3zp
, 19%
, 94%
, 88%
a
1
2
Reaction conditions: (0.5 mmol), (0.75 mmol), Pd(OAc)2 (5 mol%), bpy (10 mol%), H2O (2.0 mL), CH3SO3H
(5 equiv), 100 oC, 24 h, air, isolated yield.
The efficiency of this catalytic system was further demonstrated by running the
transformation on a laboratory preparative scale. For example, the tandem reaction of
2-(naphthalen-2-ylamino)benzonitrile with (4-chlorophenyl)boronic acid was
performed on a gram scale (4.19 mmol), and 3zq was obtained in 84% isolated yield
(Scheme 2). Furthermore, the utility of this methodology was further applied to the
synthesis of 4-(benzo[b]acridin-12-yl)phenol (3zr), which showed estrogenic
biological activity.16
Scheme 2 Gram-scale synthesis of 3zq and subsequent hydroxylation
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Cl
OH
4
5
CN
standard
conditions
B(OH)2
ref. 16
+
6
7
8
9
N
H
83% yield
Cl
N
N
3zr
3zq
, 1.19 g
1.02 g
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Scheme 3 Control experiments
Ph
CN
Ph
standard conditions
without CH3SO3H
O
a)
b)
+
PhB(OH)2
N
Ph
N
H
H
1a
2a
3a-1
, 85%
Ph
Ph
CH3SO3H (5 eq)
O
Ph
100 oC, 24 h, air
N
H
N
3a
, 83%
3a-1
Pd(OAc)2 (5 mol%)
bpy (10 mol%)
CN
c)
d)
H2O, CH3SO3H (5 eq)
100oC, 24 h, air
N
H
N
1a
3zs
, 0%
Ph
Ph
N
R
CN
standard
conditions
+
R
PhB(OH)2
+
N
H
N
R
1zt
3zt
, R = CH3, 88%
3zt'
3zu
R = CH3,
1zu
, R = CH3, trace
, R = Cl, 17%
3zo
R = Cl,
, R = Cl, 70%
To gain some insight into the mechanism of this palladium-catalyzed
addition/cyclization process, a set of control experiments were conducted. First,
phenyl(2-(phenylamino)phenyl)methanone (3a-1) was obtained in 85% yield when
the model reaction was performed without methanesulfonic acid (Scheme 3a),
indicating that the ketone 3a-1 might be an intermediate in the current transformation.
Furthermore, the reaction of 3a-1 under methanesulfonic acid condition could afford
cyclized acridine 3a in 83% yield (Scheme 3b), indicating the reaction may involve a
Friedel-Crafts procedure. These results showed that the palladium catalyst is essential
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for the formation of intermediate 3a-1, and the acid is crucial for further
Friedel-Crafts cyclization. Furthermore, the 2-(phenylamino)benzonitrile 1a remained
unchanged under the standard conditions in the absence of phenyl boronic acid with
no simple acridine 3zs formed (Scheme 3c), indicating that the palladium-aryl species
which generated from the transmetalation process derived from the Pd(II) catalyst and
arylboronic acid is essential to the transformation. To further prove the reaction
mechanism may involve intramolecular Friedel-Crafts procedure, meta-substituted
starting materials (1zt and 1zu) were investigated (Scheme 3d). These two reactions
showed interesting regioselectivities and led to a mixture of products, i.e., 3zt and 3zt’
as well as 3zo and 3zu, in total yields of 88% and 87%, respectively. These results
show that cyclization favors the higher electron density carbon of the Ar1 ring for the
formation of acridines, which is consistent with the rules of Friedel-Crafts acylation.
On the basis of the above mentioned results and relevant reports in the literature, a
plausible mechanism for this palladium-catalyzed addition/cyclization reaction is
shown in Scheme 4. First, palladium-aryl species A is generated from the
transmetalation process derived from the Pd(II) catalyst and arylboronic acid.
Thereafter, functionalized nitrile 1a coordinated to Pd[Ar] to afford the intermediate
B, which undergoes an intramolecular insertion of the cyano group to yield the
corresponding ketimine palladium complex C. The ketone intermediate D will be
formed after the hydrolysis, accompanied by the regeneration of the Pd(II) species.
The ketone intermediate D undergoes Friedel-Crafts acylation to afford E, which is
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followed by intramolecular dehydration to yield the desired product 3.
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Scheme 4 Proposed mechanism.
6
CN
7
8
9
N
H
1a
Ar[Pd]
ArB(OH)2
A
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Ar
[Pd]
N
C
O
C
Ar
Ar
OH
Friedel-Crafts
acylation
N
H
[Pd]
C
N
H
B
N
H
E
D
[Pd]
Ar
N
C
- H2O
H3O+
Ar
N
NH
3
C
CONCLUSIONS
In summary, we have developed a new approach for the synthesis of 9-arylacridines
by the Pd-catalyzed tandem reaction of 2-(arylamino)benzonitrile with arylboronic
acids in water. This protocol provides an alternative synthetic pathway to access
arylacridines compared with classical condensation reaction of diphenylamine
derivatives. Moreover, this methodology was further extended to the synthesis of a
4’-OH derivative which shows estrogenic biological activity. Further efforts to extend
this catalytic system to the preparation of other useful heterocyclic compounds are
currently underway in our laboratories.
EXPERIMENTAL SECTION
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General Methods. Melting points are uncorrected. 1H NMR and 13C NMR spectra
were measured on a 500 MHz spectrometer (1H at 500 MHz, 13C at 125 MHz), using
CDCl3 and d6-DMSO as the solvent at room temperature. Chemical shifts are given δ
relative to TMS, and the coupling constants J are given in hertz. High-resolution mass
spectra were recorded on an ESI-Q-TOF mass spectrometer. 2-Aminobenzonitriles
derivatives were synthesized according to the literature.17a Column chromatography
was performed using EM silica gel 60 (300−400 mesh).
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General procedure for the synthesis of 9-arylacridines.
In a 25 mL Schlenk reaction tube, 2-aminobenzonitrile 1 (0.5 mmol), arylboronic
acid 2 (0.75 mmol, 1.5 equiv.), Pd (OAc)2 (0.025 mmol, 5 mol%), 2,2'-bipyridyl (0.05
mmol, 10 mol%) and methylsulphonic acid/ trifluoromethanesulfonic acid (2.5 mmol,
5.0 equiv) were dissolved in H2O (2.0 mL). The heterogeneous reaction mixture was
then heated at 100 °C (oil bath) with vigorous stirring for 24 hours. After the reaction
equilibrium, the mixture was poured into ethyl acetate, which was washed with
saturated NaHCO3 (2 × 10 mL) and then brine (1 × 10 mL). After the aqueous layer
was extracted with ethyl acetate, the combined organic layers were dried over
anhydrous Na2SO4 and evaporated under vacuum. The filtrate was concentrated in
vacuo and purified by a silica gel packed flash chromatography column with
hexane/ethyl acetate (20:1) as the eluent to afford the desired products 3.
2-((3,5-Dimethylphenyl)amino)benzonitrile (1ze): White solid (270.8 mg, 61%). MP:
100-101 °C. Column chromatography on silica gel (Eluent: hexane/ethyl acetate,
40/1). 1H NMR (500 MHz, CDCl3) δ 7.50-7.47 (m, 1H), 7.37-7.34 (m, 1H), 7.21-7.19
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(m, 1H), 6.84-6.80 (m, 3H), 6.78 (s, 1H), 6.24 (brs, 1H), 2.31 (s, 6H); 13C{1H}NMR
(125 MHz, CDCl3) 147.7, 139.9, 139.5, 134.0, 133.1, 126.2, 119.7, 119.1, 117.7,
7
8
9
+
114.5, 98.4, 21.5. HRMS calcd for C15H15N2 [M + H]+: 223.1230, found 223.1228.
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IR (cm−1) 3313, 2220, 1600, 1504, 1453 ,1320, 1288, 1176, 859, 818, 752, 571, 538,
509, 480.
2-((3-(tert-Butyl)phenyl)amino)benzonitrile (1zf): White solid (295.0 mg, 59%). MP:
119-120 °C. Column chromatography on silica gel (Eluent: hexane/ethyl acetate,
40/1). 1H NMR (500 MHz, CDCl3) δ 7.51-7.49 (m, 1H), 7.38-7.28 (m, 2H), 7.19-7.17
(m, 3H), 7.05-7.03 (m, 1H), 6.84-6.80 (m, 1H), 6.34 (brs, 1H), 1.33 (s, 9H);
13C{1H}NMR (125 MHz, CDCl3) 153.3, 147.8, 139.7, 134.0, 133.1, 129.3, 121.6,
119.1, 119.0, 118.9, 117.8, 114.1, 98.3, 34.9, 31.4. HRMS calcd for C17H19N2 + [M +
H]+: 251.1543, found 251.1546. IR (cm−1) 3315, 2959, 2227, 1603, 1574, 1454, 1296,
747, 704, 498, 491.
2-(Naphthalen-2-ylamino)benzonitrile (1zk): White solid (278.2 mg, 57%). MP:
117-118 °C. Column chromatography on silica gel (Eluent: hexane/ethyl acetate,
1
40/1). H NMR (500 MHz, CDCl3) δ 7.86-7.81 (m, 2H), 7.75-7.73 (m, 1H), 7.60 (s,
1H), 7.55-7.53 (m, 1H), 7.50-7.46 (m, 1H), 7.44-7.38 (m, 2H), 7.34-7.29 (m, 2H),
13
6.90-6.87 (m, 1H), 6.53 (brs, 1H); C{1H}NMR (125 MHz, CDCl3) 147.3, 137.6,
134.3, 134.1, 133.3, 130.8, 129.7, 127.9, 127.2, 126.9, 125.2, 122.0, 119.7, 117.7,
117.6, 114.6, 99.0. HRMS calcd for C17H13N2 + [M + H]+: 245.1073, found 245.1080.
IR (cm−1) 3312, 3050, 2220, 1600, 1503, 1453, 1288, 1048, 817, 752, 572, 480.
4-Methyl-2-(phenylamino)benzonitrile (1zl): White solid (212.2 mg, 51%). MP:
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122-123 °C. Column chromatography on silica gel (Eluent: hexane/ethyl acetate,
6
7
1
40/1). H NMR (500 MHz, CDCl3) δ 7.40-7.35 (m, 3H), 7.20-7.12 (m, 3H), 7.01 (s,
8
9
1H), 6.68-6.66 (m, 1H), 6.27 (brs,1H), 2.29 (s, 3H); 13C{1H}NMR (125 MHz, CDCl3)
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δ 147.4, 145.2, 140.2, 132.9, 129.7, 124.2, 121.9, 120.7, 118.0, 114.7, 96.0, 22.3.
+
HRMS calcd for C14H13N2 [M + H]+: 209.1073, found 209.1075. IR (cm−1) 3304,
2960, 2223, 1597, 1569, 1494, 1286, 804, 743, 693, 523, 480.
5-Methyl-2-(phenylamino)benzonitrile (1zm): White solid (237.1 mg, 57%). MP:
88-89 °C. Column chromatography on silica gel (Eluent: hexane/ethyl acetate, 40/1).
1H NMR (500 MHz, CDCl3) δ 7.36-7.31 (m, 3H), 7.21-7.14 (m, 4H), 7.10-7.07 (m,
13
1H), 6.21 (brs, 1H), 2.27 (s, 3H); C{1H}NMR (125 MHz, CDCl3) δ 145.0, 140.8,
135.0, 132.9, 129.7, 129.4, 123.7, 121.0, 117.8, 115.2, 99.2, 20.3. HRMS calcd for
+
C14H13N2 [M + H]+: 209.1073, found 209.1075. IR (cm−1) 3342, 2924, 2213, 1597,
1575, 1482, 1312, 815, 745, 696, 492, 488.
4-Chloro-2-(phenylamino)benzonitrile (1zn): White solid (264.5 mg, 58%). MP:
114-115 °C. Column chromatography on silica gel (Eluent: hexane/ethyl acetate,
40/1). 1H NMR (500 MHz, CDCl3) δ 7.43-7.39 (m, 3H), 7.22-7.20 (m, 3H), 7.11-7.10
(m, 1H), 6.80 (dd, J = 8.3 Hz, J = 1.9 Hz, 1H), 6.40 (brs, 1H); 13C{1H}NMR (125
MHz, CDCl3): 148.8, 140.8, 139.0, 134.0, 130.0, 125.5, 123.0, 119.5, 117.0, 113.8,
+
96.6. HRMS calcd for C13H10ClN2 [M + H]+: 229.0527, found 229.0529. IR (cm−1)
3315, 3031, 2228, 1870, 1491, 1425, 1178, 1074, 930, 852, 798, 736, 518, 502, 471,
424.
2-(m-Tolylamino)benzonitrile (1zt): White solid (253.8 mg, 61%). MP: 88-89 °C.
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Column chromatography on silica gel (Eluent: hexane/ethyl acetate, 40/1). H NMR
(500 MHz, CDCl3) δ 7.51-7.49 (m, 1H), 7.39-7.35 (m, 1H), 7.28-7.20 (m, 1H),
7.22-7.20 (m, 1H), 7.02-7.01 (m, 2H), 6.97-6.95 (m, 1H), 6.86-6.82 (m, 1H), 6.33
(brs, 1H), 2.36 (s, 3H); 13C{1H}NMR (125 MHz, CDCl3) δ 147.6, 140.0, 139.8, 134.0,
133.1, 129.5, 125.2, 122.6, 119.2, 119.0, 117.7, 114.4, 98.6, 21.8. HRMS calcd for
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C14H13N2 [M + H]+: 209.1073, found 209.1075. IR (cm−1) 3381, 2216, 1586, 1472,
+
1318, 1295, 1162, 787, 755, 691, 563, 407.
2-((3-Chlorophenyl)amino)benzonitrile (1zv): White solid (264.5 mg, 58%). MP:
114-115 °C. Column chromatography on silica gel (Eluent: hexane/ethyl acetate,
1
40/1). H NMR (500 MHz, CDCl3) δ 7.55-7.52 (m, 1H ), 7.45-7.41 (m, 1H),
7.30-7.24 (m, 2H), 7.20-7.19 (m, 1H), 7.09-7.04 (m, 2H), 6.94-6.89 (m, 1H), 6.31
(brs, 1H); 13C{1H}NMR (125 MHz, CDCl3) δ 146.4, 141.7, 135.4, 134.1, 133.3,
+
130.8, 124.1, 121.0, 120.5, 119.2, 117.4, 115.3, 99.9. HRMS calcd for C13H10ClN2
[M + H]+: 229.0527, found 229.0529. IR (cm−1) 3325, 2221, 1590, 1571, 1416, 1323,
1184, 1093, 921, 879, 751, 699, 491.
9-Phenylacridine (3a): Yellow solid (118.6 mg, 93%). Column chromatography on
silica gel (Eluent: hexane/ethyl acetate, 20/1). 1H NMR (500 MHz, CDCl3) δ 8.30 (d,
J =8.8 Hz, 2H), 7.80-7.76 (m, 2H), 7.72-7.70 (m, 2H), 7.61-7.58 (m, 3H), 7.46-7.41
(m, 4H); 13C{1H}NMR (125 MHz, CDCl3) δ 148.9, 147.2, 136.0, 130.5, 129.9, 129.7,
128.5, 128.4, 126.9, 125.6, 125.2. Spectroscopic data for the title compound were
consistent with those reported in the literature.17
Phenyl(2-(phenylamino)phenyl)methanone (3a-1): Yellow oil (116.0 mg, 85%).
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Column chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR
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(500 MHz, CDCl3) δ 10.14 (brs, 1H), 7.73-7.71 (m, 2H), 7.58-7.55 (m, 2H), 7.51-7.47
8
9
13
(m, 2H), 7.40-7.30 (m, 6H) 7.13-7.09 ( m, 1H) ,6.74-6.70 (m, 1H) ; C{1H}NMR
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(125 MHz, CDCl3) δ 199.3, 148.2, 140.7, 140.0, 135.1, 134.4, 131.5, 129.6, 129.5,
+
128.3, 123.7, 122.4, 119.9, 116.7, 114.8. HRMS calcd for C19H16NO [M + H]+:
274.1227, found 274.1229. Spectroscopic data for the title compound were consistent
with those reported in the literature.17
9-(p-Tolyl)acridine (3b): Yellow solid (118.4 mg, 88%). Column chromatography on
silica gel (Eluent: hexane/ethyl acetate, 20/1). 1H NMR (500 MHz, CDCl3) δ 8.29（d,
J = 8.7 Hz, 2H）, 7.79-7.74 (m, 4H), 7.44-7.32 (m, 4H), 7.34-7.32 (m, 2H), 2.53 (s,
3H); 13C{1H}NMR (125 MHz, CDCl3) 148.8, 147.9, 138.4, 133.0, 130.5, 130.2,
129.6, 129.3, 127.1, 125.7, 125.5, 21.5. Spectroscopic data for the title compound
were consistent with those reported in the literature.17
9-(m-Tolyl)acridine (3c): Yellow solid (115.7 mg, 86%). Column chromatography on
silica gel (Eluent: hexane/ethyl acetate, 20/1). 1H NMR (500 MHz, CDCl3) δ 8.30 (d,
J = 8.8 Hz, 2H), 7.80-7.72 (m, 4H), 7.51-7.48 (m, 1H), 7.45-7.38 (m, 3H), 7.25-7.23
(m, 2H), 2.48 (s, 3H); 13C{1H}NMR (125 MHz, CDCl3) δ 148.7, 148.0, 138.3,
136.0, 131.2, 130.3, 129.5, 129.3, 128.5, 127.7, 127.2, 125.7 ,125.4, 21.6.
Spectroscopic data for the title compound were consistent with those reported in the
literature.17
9-(o-Tolyl)acridine (3d): Yellow solid (68.6 mg, 51%). Column chromatography on
silica gel (Eluent: hexane/ethyl acetate, 20/1). 1H NMR (500 MHz, CDCl3) δ 8.30 (d,
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J = 8.8 Hz, 2H), 7.80-7.76 (m, 2H), 7.55-7.53 (m, 2H), 7.49-7.38 (m, 5H), 7.25-7.23
(m, 1H), 1.88 (s, 3H); 13C{1H}NMR (125 MHz, CDCl3) δ 149.0, 147.3, 137.1, 135.7,
130.4, 130.4, 130.2, 129.8, 128.8, 126.7, 126.0, 125.9, 125.3, 19.9. Spectroscopic data
for the title compound were consistent with those reported in the literature.17
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9-(3,5-Dimethylphenyl)acridine (3e): Yellow solid (118.9 mg, 84%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
MHz, CDCl3) δ 8.27 (d, J =8.6 Hz, 2H), 7.77-7.74 (m, 4H), 7.43-7.40 (m, 2H), 7.20
(s, 1H), 7.05 (s, 2H), 2.43 (s, 6H); 13C{1H}NMR (125 MHz, CDCl3) δ 148.9, 148.0,
138.1, 136.0, 130.1, 130.0, 129.7, 128.3, 127.2, 125.6, 125.4, 21.5. Spectroscopic data
for the title compound were consistent with those reported in the literature.17
9-(2-Isopropylphenyl)acridine (3f): Yellow solid (54.9 mg, 37%). MP: 185-186°C.
1
Column chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR
(500 MHz, CDCl3) δ 8.35-8.34 (m, 2H), 7.81-7.78 (m, 2H), 7.59-7.56 (m, 4H),
7.44-7.37 (m, 3H), 7.18-7.16 (m, 1H), 2.30-2.25 (m, 1H), 0.99-0.98 (m, 6H);
13C{1H}NMR (125 MHz, CDCl3) δ 148.0, 135.2, 134.8, 134.2, 130.9, 130.6, 130.3,
129.3, 129.2, 127.1, 126.0, 125.9, 125.9, 30.8, 24.2. HRMS calcd for C22H20N + [M +
H]+: 298.1590, found 298.1592. IR (cm−1) 3060, 2963, 1929, 1668, 1629, 1557, 1541,
1345, 1010, 957, 767, 751, 652, 619, 421.
9-(4-(tert-Butyl)phenyl)acridine (3h): Yellow solid (136.8 mg, 88%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
MHz, CDCl3) δ 8.30-8.28 (m, 2H), 7.79-7.76 (m, 4H), 7.62-7.60 (m, 2H), 7.44-7.41
13
(m, 2H), 7.39-7.37 (m, 2H), 1.43 (s, 9H); C{1H}NMR (125 MHz, CDCl3) δ 151.5,
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148.9, 147.8, 133.0, 130.4, 130.1, 129.7, 127.2, 125.6, 125.5, 125.4, 35.0, 31.6.
Spectroscopic data for the title compound were consistent with those reported in the
literature.17
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9-(4-Isopropylphenyl)acridine (3i): Yellow solid (132.2 mg, 89%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
MHz, CDCl3) δ 8.28 (d, J = 8.3 Hz, 2H), 7.79-7.75 (m, 4H), 7.47-7.40 (m, 4H),
13
7.37-7.35 (m, 2H), 3.10-3.07 (m, 1H), 1.40 (d, J = 6.9 Hz, 6H); C{1H}NMR (125
MHz, CDCl3) δ 149.2, 148.9, 147.8, 133.3, 130.6, 130.1, 129.7, 127.2, 126.6, 125.6,
125.5, 34.2, 24.2. Spectroscopic data for the title compound were consistent with
those reported in the literature.17
9-(4-Methoxyphenyl)acridine (3j): Yellow solid (79.8 mg, 56%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
MHz, CDCl3) δ 8.27 (d, J = 8.9 Hz, 2H), 7.77-7.76 (m, 4H), 7.43-7.40 (m, 2H),
7.37-7.36 (m, 2H), 7.13 (d, J = 8.3 Hz, 2H ), 3.94 (s, 3H); 13C{1H}NMR (125 MHz,
CDCl3) δ 159.9, 149.1, 147.3, 131.9, 130.0, 129.8, 128.2, 127.1, 125.7, 125.6, 114.1,
55.6. Spectroscopic data for the title compound were consistent with those reported in
the literature.17
9-(3-Fluorophenyl)acridine (3k): Yellow solid (131.0 mg, 96%). MP: 160-161 °C.
1
Column chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR
(500 MHz, CDCl3) δ 8.32 ( d, J = 8.8 Hz, 2H), 7.82-7.78 (m, 2H), 7.69 (d, J = 8.5 Hz,
2H),7.61-7.56 (m, 1H), 7.48-7.44 (m, 2H), 7.32-7.29 (m, 1H), 7.24-7.23 (m, 1H),
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1
7.20-7.17 (m, 1H); C{1H}NMR (125 MHz, CDCl3) 163.0 (C-F, JC-F=248 Hz),
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148.6, 138.2, 130.5, 130.4 (C-F, 3JC-F = 8.3 Hz), 130.3, 126.6, 126.3 (C-F, 4JC-F = 3.06
6
7
8
9
2
2
Hz), 126.4, 125.1, 117.8 (C-F, JC-F =21.9 Hz), 115.7 (C-F, JC-F = 20.8 Hz). HRMS
calcd for C19H12FNNa + [M + Na]+: 296.0852, found 296.0822. IR (cm−1) 3038, 1610,
1494, 1432, 1359, 1228, 1151, 978, 865, 783, 748, 707, 595, 531, 443.
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9-(3-Chlorophenyl)acridine (3l): Yellow solid (141.6 mg, 98%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
MHz, CDCl3) δ 8.30 (d, J = 8.8 Hz, 2H),7.81-7.77 (m, 2H), 7.67 (d, J = 8.7 Hz, 2H ),
7.59-7.55 (m, 2H),7.53-7.44 (m, 3H), 7.35-7.33 (m, 1H); C{1H}NMR (125 MHz,
13
CDCl3) δ 148.8, 138.0, 134.8, 130.6, 130.3, 130.0, 129.8, 128.8, 128.8, 126.6, 126.2,
125.1. Spectroscopic data for the title compound were consistent with those reported
in the literature.17
9-(3-Bromophenyl)acridine (3m): Yellow solid (149.9 mg, 90%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
MHz, CDCl3) δ 8.30 (d, J = 8.8 Hz, 2H), 7.81-7.77 (m, 2H), 7.74-7.72 (m, 1H),
7.68-7.66 (d, J = 8.4 Hz, 2H), 7.62-7.61 (m, 1H), 7.51-7.42 (m, 3H), 7.40-7.38 (m,
1H); 13C{1H}NMR (125 MHz, CDCl3) δ 148.7, 145.5, 138.3, 133.4, 131.7, 130.3,
130.2, 129.8, 129.3, 126.6, 125.1, 122.9. Spectroscopic data for the title compound
were consistent with those reported in the literature.17
9-(2-Chlorophenyl)acridine (3n): Yellow solid (109.8 mg, 76%). MP: 233-234 °C.
1
Column chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR
(500 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 2H), 7.81-7.77 (m, 2H), 7.61-7.65 (m, 1H),
7.56-7.43 (m, 6H), 7.36-7.34 (m, 1H); C{1H}NMR (125 MHz, CDCl3) δ 148.9,
13
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144.3, 135.1, 134.3, 132.2, 130.2, 130.2, 130.1, 130.0, 127.0, 126.4, 126.2, 125.1.
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7
+
HRMS calcd for C19H13ClN [M + H]+: 290.0731, found 290.0737. Spectroscopic
8
9
data for the title compound were consistent with those reported in the literature.17
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9-(2-Bromophenyl)acridine (3o): Yellow solid (100.0 mg, 62%). MP: 234-235 °C.
1
Column chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR
(500 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 7.2 Hz, 1H), 7.81-7.77 (m,
2H), 7.55-7.51 (m, 3H), 7.47-7.43 (m, 3H), 7.34 (dd, J = 1.6 Hz, J = 7.5 Hz, 1H);
13C{1H}NMR (125 MHz, CDCl3) 148.9, 145.8, 137.3, 133.2, 132.1, 130.3, 130.2,
+
129.9, 127.6, 126.4, 126.2, 124.9, 124.2. HRMS calcd for C19H13BrN [M + H]+:
334.0226, found 334.0330. Spectroscopic data for the title compound were consistent
with those reported in the literature.17
9-(4-Fluorophenyl)acridine (3p): Yellow solid (128.3 mg, 94%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
MHz, CDCl3) δ 8.28 (d, J = 8.7 Hz, 2H), 7.80-7.77 (m, 2H), 7.68 (d, J = 8.6 Hz, 2H),
7.46-7.41 (m, 4H), 7.33-7.30 (m, 2H); 13C{1H}NMR (125 MHz, CDCl3) δ 163.0
(C-F, 1JC-F = 247.9 Hz), 149.0, 146.1, 132.3 (C-F, 3JC-F = 8.1 Hz), 132.0 (C-F, 4JC-F
=
2
3.4 Hz), 131.1, 129.9, 126.7, 126.0, 125.4, 115.8 (C-F, JC-F = 21.5 Hz).
Spectroscopic data for the title compound were consistent with those reported in the
literature.17
9-(4-Chlorophenyl)acridine (3q): Yellow solid (132.9 mg, 92%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
MHz, CDCl3) δ 8.29 (d, J = 8.7 Hz, 2H), 7.80-7.76 (m, 2H), 7.67 (d, J = 8.4 Hz, 2H),
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7.61-7.58 (m, 2H), 7.47-7.42 (m, 2H), 7.40-7.37 (m, 2H); C{1H}NMR (125 MHz,
CDCl3) δ 148.9, 145.8, 134.8, 134.6, 132.0, 130.1, 129.9, 129.0, 126.6, 126.0, 125.1.
Spectroscopic data for the title compound were consistent with those reported in the
literature.17
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9-(4-Bromophenyl)acridine (3r): Yellow solid (156.5 mg, 94%). MP: 244-245 °C.
1
Column chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR
(500 MHz, CDCl3) δ 8.29 (d, J = 8.8 Hz, 2H), 7.80-7.74 (m, 4H), 7.67 (d, J = 8.7 Hz,
2H), 7.46-7.42 (m, 2H), 7.32 (d, J = 8.2 Hz, 2H); 13C{1H}NMR (125 MHz, CDCl3) δ
148.8, 145.9, 135.0, 132.3, 131.9, 130.3, 129.8, 126.6, 126.1, 125.1, 123.0.
Spectroscopic data for the title compound were consistent with those reported in the
literature.17
9-(4-Iodophenyl)acridine (3s): Yellow solid (175.3 mg, 92%). MP: 238-239 °C.
1
Column chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR
(500 MHz, CDCl3) δ 8.34 (d, J= 8.8 Hz, 2H), 7.98-7.97 (m, 2H), 7.82-7.79 (m, 2H),
13
7.70-7.69 (m, 2H), 7.49-7.46 (m, 2H), 7.19-7.18 (m, 2H); C{1H}NMR (125 MHz,
CDCl3) δ 137.9, 135.2, 132.3, 131.2, 131.1, 128.7, 126.7, 126.4, 125.0, 95.0. HRMS
calcd for C19H13IN [M + H]+: 382.0087, found 382.0088. IR (cm−1) 2928, 2250,
+
1722, 1551, 1263, 1054, 1027, 1006, 752, 705, 490.
9-(4-(Trifluoromethyl)phenyl)acridine (3t): Yellow solid (100.1 mg, 62%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H), 7.82-7.78 (m, 2H),
7.62-7.58 (m, 4H), 7.48-7.44 (m, 2H); 13C{1H}NMR (125 MHz, CDCl3) 148.8, 145.5,
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140.1, 131.1 (C-F, JC-F = 32.2 Hz), 131.9, 130.3, 129.9, 126.3 (C-F, 4JC-F = 3.6 Hz),
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7
8
9
3
1
125.7 (C-F, JC-F = 5.4 Hz), 125.0, 124.3 (C-F, JC-F = 272.3 Hz), 121.0.
Spectroscopic data for the title compound were consistent with those reported in the
literature.17
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(2-(Phenylamino)phenyl)(4-(trifluoromethyl)phenyl)methanone (3t-1): Yellow oli
(54.6 mg, 32%). Column chromatography on silica gel (Eluent: hexane/ethyl acetate,
1
20/1). H NMR (500 MHz, CDCl3) δ 10.24 (brs, 1H), 7.80-7.74 (m, 4H), 7.46-7.44
(m, 1H), 7.41-7.36 (m, 4H), 7.32-7.30 (m, 2H), 7.16-7.12 (m, 1H), 6.72-6.68 (m, 1H);
13C{1H}NMR (125 MHz, CDCl3) 198.0, 148.9, 143.3, 140.2, 135.1, 135.0, 132.9
2
3
(C-F, JC-F = 32.8 Hz), 129.6, 129.5, 125.4 (C-F, JC-F = 3.7 Hz), 124.2, 123.9 (C-F,
1JC-F = 272.7 Hz), 122.9, 118.8, 116.7, 114.8. HRMS calcd for C20H15F3NO + [M +
H]+: 342.1100, found 342.1108.
9-(Naphthalen-2-yl)acridine (3v): Yellow solid (131.2 mg, 86%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
MHz, CDCl3) δ 8.33 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 8.3 Hz, 1H), 8.03-8.01 (m, 1H),
7.95-7.91 (m, 2H), 7.81-7.73 (m, 4H), 7.64-7.61 (m, 2H), 7.56 (d, J = 8.4 Hz, 1H),
7.43-7.40 (m, 2H); C{1H}NMR (125 MHz, CDCl3) δ 148.9, 147.4, 133.6, 133.3,
13
133.2, 130.2, 129.9, 129.8, 128.4, 128.3, 128.3, 128.1, 127.1, 127.0, 126.9, 125.9,
125.5. Spectroscopic data for the title compound were consistent with those reported
in the literature.17
9-(thiophen-3-yl)acridine (3w): Yellow solid (37.8 mg, 29%). MP: 182-183°C.
1
Column chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR
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(500 MHz, CDCl3) δ 8.28 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H), 7.80-7.76 (m,
2H), 7.63-7.61 (m, 1H), 7.48-7.44 (m, 3H), 7.27 (dd, J = 4.9 Hz, J = 1.1 Hz, 1H);
13C{1H}NMR (125 MHz, CDCl3) δ 148.9, 142.8, 135.9, 130.3, 130.2, 129.8, 126.8,
126.2, 126.0, 125.9, 125.8. HRMS calcd for C17H12NS + [M + H]+: 262.0685, found
262.0688. IR (cm−1) 3037, 2928, 1723, 1600, 1551, 1514, 1459, 1422, 1273,
1181,1030, 762, 751, 704, 491, 477, 438.
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4-(acridin-9-yl)benzaldehyde (3z): Yellow solid (14.2 mg, 10%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
MHz, CDCl3) δ 10.21 (brs, 1H), 8.30 (d, J = 8.9 Hz, 2H), 8.14 (d, J = 8.0 Hz, 2H),
7.81-7.77 (m, 1H), 7.65-7.59 (m, 4H), 7.47-7.43 (m, 2H); 13C{1H}NMR (125 MHz,
CDCl3) δ 191.9, 148.8, 145.5, 142.7, 136.4, 131.4, 130.3, 130.0, 129.9, 126.3, 124.7,
121.2. Spectroscopic data for the title compound were consistent with those reported
in the literature.17
4-Methyl-9-phenylacridine (3zc): Yellow solid (125.1 mg, 93%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
MHz, CDCl3) δ 8.33 (d, J = 8.8 Hz, 1H), 7.77-7.73 (m, 1H), 7.69-7.66 (m, 1H),
7.62-7.54 (m, 5H), 7.45-7.41 (m, 3H), 7.33-7.29 (m, 1H), 3.01 (s, 3H); 13C{1H}NMR
(125 MHz, CDCl3) δ 148.5, 148.2, 147.0, 137.5, 136.7, 130.6, 130.4, 129.5, 129.3,
128.5, 128.3, 126.8, 125.6, 125.5, 125.2, 125.1, 125.0, 18.8. Spectroscopic data for
the title compound were consistent with those reported in the literature.17
2-Methyl-9-phenylacridine (3zd): Yellow solid (121.0 mg, 90%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
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MHz, CDCl3) δ 8.26 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.74-7.70 (m,
1H),7.67-7.64 (d, J = 8.7 Hz, 1H), 7.61-7.56 (m, 4H), 7.43-7.36 (m, 4H), 2.43 (s, 3H);
13C{1H}NMR (125 MHz, CDCl3) δ 148.4, 147.9, 146.1, 136.3, 135.5, 132.9, 130.6,
129.7, 129.5, 128.5, 128.3, 126.8, 125.6, 125.4, 125.2, 124.8, 22.1. Spectroscopic data
for the title compound were consistent with those reported in the literature.17
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1,3-Dimethyl-9-phenylacridine (3ze): Yellow solid (127.3 mg, 90%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
MHz, CDCl3) δ 8.20 (d, J = 8.7 Hz, 1H), 7.94 (s, 1H), 7.72-7.68 (m, 1H), 7.53-7.51
(m, 3H), 7.43-7.41 (m, 1H), 7.37-7.32 (m, 3H), 7.08 (s, 1H), 2.52 (s, 3H), 1.99 (s,
13
3H); C{1H}NMR (125 MHz, CDCl3) δ 150.5, 147.9, 147.0, 140.0, 139.9, 135.8,
132.0, 130.3, 129.7, 129.1, 128.1, 128.0, 127.5, 127.2, 126.3, 125.1, 123.1, 24.8, 21.8.
Spectroscopic data for the title compound were consistent with those reported in the
literature.17
3-(tert-Butyl)-9-phenylacridine (3zf): Yellow solid (146.2 mg, 94%). MP:
150-151 °C. Column chromatography on silica gel (Eluent: hexane/ethyl acetate,
1
20/1). H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 8.7 Hz, 1H), 8.22-8.21 (m, 1H),
7.77-7.73 (m, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.59-7.56 (m,
3H), 7.54-7.51 (m, 1H), 7.44-7.37 (m, 3H), 1.46 (s, 9H); 13C{1H}NMR (125 MHz,
CDCl3) δ 153.3, 149.3, 149.0, 146.8, 136.2, 130.6, 129.9, 129.5, 128.5, 128.4, 126.9,
126.5, 125.4, 125.3, 125.1, 124.2, 123.6, 35.4, 31.0. HRMS calcd for C23H22N + [M +
H]+: 312.1747, found 312.1760. IR (cm−1) 3051, 2966, 1612, 1542, 1416, 1351, 1264,
1071, 1013, 957, 821, 737, 736, 640, 612, 564, 491, 433, 407.
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2-Methoxy-9-phenylacridine (3zg): Yellow solid (131.1 mg, 92%). MP: 153-154 °C.
6
7
1
Column chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR
8
9
(500 MHz, CDCl3) δ 8.23 (d, J = 8.7 Hz, 1H), 8.16 (d, J = 9.4 Hz, 1H), 7.69-7.65 (m,
1H), 7.62-7.53 (m, 4H), 7.45-7.34 (m, 4H), 6.80-6.79 (m,1H), 3.69 (s, 3H);
13C{1H}NMR (125 MHz, CDCl3) δ 157.0, 147.3, 146.1, 144.7, 136.4, 131.3, 130.4,
129.7, 128.8, 128.7, 128.3, 126.4, 126.0, 125.8, 125.5, 125.0, 102.1, 55.3. HRMS
calcd for C20H16NO + [M + H]+: 286.1227, found 286.1228. Spectroscopic data for the
title compound were consistent with those reported in the literature.17
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2-Fluoro-9-phenylacridine (3zh): Yellow solid (110.6 mg, 81%). MP: 192-193°C.
1
Column chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR
(500 MHz, CDCl3) δ 7.96-7.91 (m, 2H), 7.44-7.40 (m, 1H), 7.35 (d, J = 8.7 Hz, 1H ),
7.29-7.21 (m, 4H), 7.12-7.08 (m, 3H), 6.96-6.93 (m, 1H), 13C{1H}NMR (125 MHz,
CDCl3) δ 159.8 (C-F, 1JC-F = 248.9 Hz), 148.5 (C-F, 4JC-F = 2.1 Hz), 146.6 (C-F, 3JC-F
= 7.8 Hz), 146.4, 135.8, 132.6 (C-F, 3JC-F = 9.1 Hz), 130.4, 129.9, 128.8, 128.7, 126.5
(C-F, 2JC-F = 32.8 Hz, 125.5 (C-F, 3JC-F = 9.5 Hz), 125.4, 121.8 (C-F, 3JC-F = 9.5 Hz),
108.9, 108.7. HRMS calcd for C19H12FNNa + [M + Na]+: 296.0852, found 296.0822.
IR (cm−1) 3062, 2923, 1635, 1451, 1156, 999, 861, 753, 600, 580, 490.
2-Chloro-9-phenylacridine (3zi): Yellow solid (121.4 mg, 84%). Column
1
chromatography on silica gel (Eluent: hexane/ethyl acetate, 20/1). H NMR (500
MHz, CDCl3) δ 8.25 (dd, J = 8.8 Hz, J = 18.5 Hz, 2H), 7.80-7.76 (m, 1H), 7.69-7.66
(m, 3H), 7.64-7.54 (m, 3H), 7.46-7.41 (m, 3H); 13C{1H}NMR (125 MHz, CDCl3) δ
148.8, 147.0, 146.0, 146.8, 135.4, 131.7, 131.4, 131.3, 130.5, 129.7, 128.8, 128.8,
29
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