Facile synthesis of acridines via Pd(0)-diphosphine complex-catalyzed tandem coupling/cyclization protocol

Article abstract of DOI:10.1039/c5ob00755k

A facile and efficient approach for the synthesis of a variety of acridines via the tandem coupling/cyclization of substituted 2-bromobenzaldehydes and anilines is described. The reaction can be accomplished with ease in the presence of a catalytic amount of Pd₂(dba)₃ and diphosphine ligand dppf, providing a broad range of substituted acridines in good to excellent yields (up to 99%). The Lewis acid, AlCl₃, is required to promote the cyclization for less electron-rich anilines.

Full text of DOI:10.1039/c5ob00755k

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Biomolecular Chemistry
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Facile synthesis of acridines via Pd(0)-diphosphine
complex-catalyzed tandem coupling/cyclization
protocol†
Cite this: DOI: 10.1039/c5ob00755k
Ting-Jun Wang,a,b Wen-Wen Chen,a Yi Lia and Ming-Hua Xu*a
A facile and efficient approach for the synthesis of a variety of acridines via the tandem coupling/cycliza-
tion of substituted 2-bromobenzaldehydes and anilines is described. The reaction can be accomplished
with ease in the presence of a catalytic amount of Pd2(dba)3 and diphosphine ligand dppf, providing a
broad range of substituted acridines in good to excellent yields (up to 99%). The Lewis acid, AlCl3, is
required to promote the cyclization for less electron-rich anilines.
Received 15th April 2015,
Accepted 30th April 2015
DOI: 10.1039/c5ob00755k
www.rsc.org/obc
Owing to their importance in human medicines and many
other applications, considerable effort has been devoted to
Introduction
Acridines are an important class of biologically active com- developing efficient synthetic methodologies for the construc-
pounds that have been widely used as antibacterial, antiproto- tion of acridines over the past decades.7–13 One of the earliest
zoal and antileukemic agents, as well as anticancer drugs, methods, the Bernthsen reaction between diphenylamine and
mainly owing to their inhibition of DNA-related enzymes, such carboxylic acids, needs a high temperature (200–270 °C) to
as topoisomerases, by intercalation.1 Among the bioactive acri- furnish acridine products.7 Other reported methodologies
dines, porflavine,2,3a euflavine,3 aminacrine,4a,b and ethacridi- have mainly focused on strategies such as C–H functionali-
ne4b–d are already approved as antibacterial drugs and have zation,8 reduction,9 dehydration,10 intermolecular annula-
been in use for many years, whereas m-AMSA5 and DACA6 are tion,11 and intramolecular cyclization.12 However, those
two representative anticancer agents that have been in clinical methods are often limited in scope and generally require
trials for the treatment of leukemia (Fig. 1).
harsh, functional group-intolerant conditions.13 Very recently,
an interesting Pd(II)-catalyzed one-pot reaction was reported
for constructing acridines from 2-formylphenyl triflates and
aniline substrates, but only three examples of electron-rich
anilines were presented and electron-poor anilines did not
undergo the reaction.11e Moreover, the triflate group was
essential and almost no reaction was found to occur with com-
mercially available 2-bromobenzaldehyde as the substrate. In
this regard, there is still a lack of efficient methods for the syn-
thesis of acridines; therefore, the development of a new practi-
cal approach with broad substrate scope is of great importance
and highly desirable. Herein, we describe our findings on the
tandem coupling/cyclization reaction of easily accessed substi-
tuted 2-bromobenzaldehyde and a wide range of anilines to
afford various acridines.
Fig. 1 Representative bioactive acridines.
aState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
E-mail: xumh@simm.ac.cn; Fax: +86 21 5080 7388; Tel: +86 21 5080 7388
Results and discussion
As part of our ongoing interest in intramolecular aza-Friedel–
Crafts reactions,14 we initially attempted to synthesize o-amino-
benzaldehyde 4a through the coupling reaction of 2-bromo-
benzaldehyde (1a) and 3,5-dimethoxyaniline (2a) under
bNano Science and Technology Institute, University of Science and Technology of
China, 166 Ren-Ai Road, Suzhou, Jiangsu 215123, China
†Electronic supplementary information (ESI) available: Copies of NMR spectra.
See DOI: 10.1039/c5ob00755k
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and 11). Changing the solvent from toluene to DMF or dioxane
decreased the yield (entries 12 and 13). Moreover, the most
suitable ratio of [Pd]/L was 1 : 1 (entries 5 vs. 14 and 15). There-
fore, the optimal conditions were determined to be 2.5 mol%
Pd2(dba)3, 5 mol% dppf, and 2 equiv. K2CO3 in toluene at
80 °C (entry 5).
Scheme 1 Initial discovery of the formation of the acridine product.
With the optimal reaction conditions established, we began
to explore the substrate generality. Firstly, a variety of 2-bromo-
benzaldehydes bearing different substituents were examined.
The results are summarized in Table 2. To our delight,
2-bromobenzaldehydes containing either electron-donating or
electron-withdrawing groups could be successfully applied,
providing expected acridine products 3b–h in good to excellent
yields (85–99%). Notably, the analogous cyclization of electron-
deficient 2-formylphenyl triflates with 3,5-dimethoxyaniline
only gave low yields of 3b (32%) and 3d (59%) with a pro-
longed reaction time.11e In addition, 4, 5 or 6-fluoro-substi-
tuted 2-bromobenzaldehydes reacted smoothly to produce
acridines 3h, 3c and 3i in excellent yields (85–99%). For sub-
strate 1j, which contained a methoxy group ortho to the
bromine, a lower yield (3j, 59%) was obtained, probably
because of the increased steric hindrance during amination.
Next, we investigated the substrate scope of anilines. The
yields decreased significantly when 3,5-dimethoxyaniline 2a
palladium catalysis (Scheme 1). Surprisingly, acridine 3a was
isolated in 55% yield instead of desired amination product 4a.
This result indicates that the reaction undergoes a smooth
one-pot coupling/cyclization process. In contrast to the pre-
viously reported method that is limited to the use of triflates,
we expected that this transformation could provide a more
simple, economical and efficient approach for accessing
diversely substituted acridines.
To improve the reaction efficiency, we began our investi-
gation by optimizing the reaction conditions (Table 1). Lower-
ing the reaction temperature to 80 °C only led to a slight
decrease in the yield of 3a (entry 2), suggesting that the reac-
tion is relatively unaffected by temperature. We found that the
desired acridine product could be obtained in 81% yield when
KOH was used as the base (entry 3). Further screening of bases
indicated that K2CO3 was the best choice, affording target acri-
dine 3a in almost quantitative yield (entry 5). Different palla-
dium precursors and phosphine ligands did not give better
results (entries 6–11). It is worth noting that the bi-dentate
phosphine ligand is probably essential for the reaction
because almost no product was detected in the presence of
monophosphine ligands such as X-Phos and PPh3 (entries 10
Table 2 Reaction of 2-bromobenzaldehydes 1 with 3,5-dimethoxy-
aniline (2a)a,b
Table 1 Optimization of the reaction conditionsa
Entry
Pd cat.
Ligand
Base
Solvent
Yieldb (%)
1c
2
3
4
5
6
7
8
9
10
11
12
13
14d
15e
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
PdCl2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppb
BINAP
X-Phos
PPh3
dppf
dppf
dppf
dppf
NaOtBu
NaOtBu
KOH
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
55
49
81
47
99
23
41
22
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
81
Trace
Trace
72
89
93
Dioxane
Toluene
Toluene
87
a Reactions were performed with 0.24 mmol of aldehyde 1, 0.2 mmol a Reactions were performed with 0.2 mmol of 3,5-dimethoxyaniline 2a,
of aniline 2 in the presence of 5 mol% of Pd catalyst and 2 equiv. of 0.24 mmol of substituted 2-bromobenzaldehyde 1, 2.5 mol% of
base in 2 mL of dry toluene at 80 °C. b Isolated yield. c 120 °C. d [Pd]/L Pd2(dba)3, 5 mol% of dppf, and 2 equiv. K2CO3 in 2 mL of dry toluene
= 1/2. e [Pd]/L = 2/1.
at 80 °C. b Isolated yield.
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Table 3 Reaction of 2-bromobenzaldehyde with less electron-rich
anilinesa,b
Scheme 2 Reaction with less electron-rich anilines.
was changed to electron-neutral aniline 2k or electron-
deficient aniline 2l. Unsurprisingly, the C–N coupling product
(4k and 4l) was mainly obtained (Scheme 2). Considering the
Friedel–Crafts cyclization mechanism, we speculate that the
presence of a Lewis acid may activate the aldehyde carbonyl,
thus favoring electrophilic attack by a less electron-rich
aniline.
We were excited to find that the use of AlCl3 as a Lewis acid
dramatically promoted the formation of acridine. For example,
desired acridine 3k could be obtained in very good yield (96%)
by treatment of the crude amination product 4k with 2 equiv.
of AlCl3 in toluene at 80 °C for 12 h. Interestingly, the cycliza-
tion also proceeded when AlCl3 (2 equiv.) was added to the
reaction mixture after the amination step; however, a generally
lower yield (90% for 3k) was obtained, probably because of the
effect of the palladium species. With the optimized reaction
sequence (Pd-catalyzed coupling conditions followed by AlCl3/
toluene), a series of less electron-rich anilines substituted with
substituents, including chloro (2l, 2n, 2s), ester (2o), methoxy
(2m, 2p), and methyl (2q) groups, were tested (Table 3). In all
cases, good to excellent yields were attained. Notably, acridine
3o, the crucial intermediate for the synthesis of antileukemic
agent DACA,6 could be readily accessed in high yield (82%),15
whereas previous syntheses required three to four steps, some-
times under harsh conditions.6a–c Furthermore, 1-naphthyl-
amine with higher steric hindrance can be used for this
transformation, giving otherwise difficult-to-access 3r in excel-
lent yield (98%). Meanwhile, aniline with meta-substitution
was also compatible, although it produced regioisomers of
acridines 3s and 3s′ with a ratio of 1.64 : 1 in favor of 3s.
To extend the substrate scope of this method further, the
reaction between two electron-poor components of aldehyde
1b and aniline 2l was examined (Scheme 3a). Symmetrical
dichloro-substituted acridine 3t was obtained in excellent yield
(97%). The two halogen substituents on the benzene ring
could be useful functionalities for further elaboration through
coupling reactions. We also tested the reaction of 2-bromo-
cyclohexene-1-carbaldehyde (5) with aniline 2k (Scheme 3b).
Under the same conditions, we found that the core structure
of cholinesterase inhibitor tacrine,16 1,2,3,4-tetrahydroacridine
6, could be easily constructed in 73% yield.
a See Experimental section for details. b Isolated yield.
Scheme 3 Extension of the substrate scope.
reaction between bromobenzene (7) and aniline 2a hardly pro-
ceeded, and mainly 2a was recovered (Scheme 4). This result
suggests that the ortho-formyl group might be involved in sta-
bilizing the assumed palladacycle intermediate.
Based on these results and previous reports,12d,17,18 a plaus-
ible mechanism for this tandem reaction is shown in Fig. 2.
Initially, substituted 2-bromobenzaldehyde 1 undergoes oxi-
dative addition to the Pd(0) species to form complex A, which
is converted to intermediate C through transition state B. The
following reductive elimination yields amination product 4,
completing the palladium catalysis cycle. Subsequently, the
formyl carbonyl is attacked by the aromatic ring in the pres-
ence/absence of a Lewis acid, promoting the formation of cycli-
zation intermediate E from D. Finally, acridine product 3 is
obtained after Lewis acid dissociation and dehydration.
In the preliminary investigation of the reaction mechanism,
we found that the aldehyde functionality played a vital role in
the amination step. Under standard conditions, the coupling
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(300 MHz for 1H, and 125 MHz for 13C). Chemical shifts are
reported in δ ppm referenced to an internal SiMe4 standard for
1H NMR and chloroform-d (δ 77.36) for 13C NMR. MS and
HRMS were measured in ESI mode, and a Q-TOF mass analy-
zer was used for HRMS.
Scheme 4 Amination with simple bromobenzene 7.
General procedure for the tandem coupling/cyclization
reaction of substituted o-bromobenzaldehyde with
3,5-dimethoxyaniline
Under an N2 atmosphere, a reaction vessel was charged
sequentially with 3,5-dimethoxyaniline 2a (0.2 mmol),
Pd2(dba)3 (0.005 mmol), dppf (0.01 mmol), K2CO3 (0.4 mmol)
and freshly distilled toluene (1.0 mL). The mixture was stirred
for 5 min at room temperature then a solution of substituted
2-bromobenzaldehyde
1 (0.24 mmol) in freshly distilled
toluene (1.0 mL) was added. The reaction mixture was heated
at 80 °C for 12 h before being cooled to room temperature and
quenched with water (5 mL). The aqueous phase was extracted
with ethyl acetate (10 mL × 3) and the combined organic phase
was washed with brine then dried over Na2SO4. The residue
obtained after filtration and concentration was purified by
flash column chromatography (eluent: petroleum ether/
acetone = 10/1 to 1/1) to afford desired acridine product 3.
General procedure for reaction of substituted
2-bromobenzaldehyde with less electron-rich anilines
Under an N2 atmosphere, a reaction vessel was charged with
Fig. 2 Proposed reaction mechanism.
aniline
2 (0.24 mmol), Pd2(dba)3 (0.005 mmol), dppf
(0.01 mmol), K2CO3 (0.4 mmol) and freshly distilled toluene
(1.0 mL). The solution was stirred for 5 min at room tempera-
ture, and then a solution of substituted 2-bromobenzaldehyde
1 (0.2 mmol) in freshly distilled toluene (1.0 mL) was added.
The reaction mixture was heated at 80 °C for 12 h, and then
cooled to room temperature and filtered through Celite. The
filtrate was concentrated under reduced pressure and AlCl3
(0.4 mmol) followed by freshly distilled toluene (2.0 mL) was
added to the residue. The mixture was heated at 80 °C for
another 12 h before being cooled to room temperature and
quenched with water (5 mL). The aqueous phase was extracted
with ethyl acetate (10 mL × 3) and the combined organic phase
was washed with brine and dried over Na2SO4. The residue was
filtered and concentrated under reduced pressure and was
purified by flash column chromatography (eluent: petroleum
ether/ethyl acetate = 20/1 to 10/1) to give acridine product 3.
1,2,3,4-Tetrahydroacridine 6 was synthesized with the same
procedure.
Conclusions
In summary, we have demonstrated an efficient tandem coup-
ling/cyclization approach for facile synthesis of diversely sub-
stituted acridines. The reaction could be accomplished with
ease under Pd(0)-catalysis by using readily available 2-bromo-
benzaldehydes and anilines as starting materials. The Lewis
acid AlCl3 is required to promote the sequential cyclization for
less electron-rich anilines. The method allows the construction
of a broad range of symmetrical and unsymmetrical acridines
bearing multifunctional substituents, as well as the unusual
1,2,3,4-tetrahydroacridine in good to excellent yields (up to
99%). Moreover, antileukemic agent DACA can be easily
accessed in just two simple linear steps using our method. We
believe that this work provides further opportunities for exten-
sive future applications of acridines in medicinal chemistry,
organic synthesis and material science.
1,3-Dimethoxyacridine (3a).11e Yellow solid (47.6 mg, 99%);
1H NMR (300 MHz, CDCl3) δ 9.00 (s, 1H), 8.11 (d, J = 8.7 Hz,
1H), 7.95 (d, J = 8.4 Hz, 1H), 7.74 (ddd, J1 = 8.0 Hz, J2 = 7.7 Hz,
J2 = 1.5 Hz, 1H), 7.45 (ddd, J1 = 7.5 Hz, J2 = 7.5 Hz, J2 = 1.2 Hz,
1H), 7.06 (d, J = 1.5 Hz, 1H), 6.42 (d, J = 2.1 Hz, 1H), 4.02 (s,
3H), 3.98 (s, 3H).
Experimental
General methods
7-Chloro-1,3-dimethoxyacridine
(3b).11e Yellow
solid
1
All reactions were carried out in dry glassware with magnetic (54.3 mg, 99%); H NMR (300 MHz, CDCl3) δ 8.89 (s, 1H), 8.03
stirring. Solvents were dried and distilled by standard pro- (d, J = 9.3 Hz, 1H), 7.92 (s, 1H), 7.65 (dd, J1 = 9.3 Hz, J2 = 2.1
cedures. NMR spectra were recorded on a spectrometer Hz, 1H), 7.03 (s, 1H), 6.45 (s, 1H), 4.03 (s, 3H), 3.98 (s, 3H).
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7-Fluoro-1,3-dimethoxyacridine (3c). Yellow solid (48.9 mg,
1,3,5-Trimethoxyacridine (3j).11e Yellow solid (31.4 mg,
1
95%); H NMR (300 MHz, CDCl3) δ 8.94 (s, 1H), 8.11 (dd, J1 = 59%); 1H NMR (300 MHz, CDCl3) δ 8.98 (s, 1H), 7.54 (d, J = 8.4
10.2 Hz, J2 = 5.4 Hz, 1H), 7.58–7.51 (m, 2H), 7.04 (d, J = 1.8 Hz, Hz, 1H), 7.36 (dd, J1 = 7.8 Hz, J2 = 7.8 Hz, 1H), 7.26–7.25 (m,
1H), 6.45 (d, J = 1.8 Hz, 1H), 4.03 (s, 3H), 3.98 (s, 3H); 13C NMR 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.45 (d, J = 1.8 Hz, 1H), 4.13 (s,
(125 MHz, CDCl3) δ 162.5, 159.4 (d, JC–F = 245.6 Hz), 156.1, 3H), 4.02 (s, 3H), 3.97 (s, 3H).
150.8, 146.9, 131.2 (d, JC–F = 8.9 Hz), 130.9 (d, JC–F = 6.6 Hz),
1
Acridine (3k).10 Light yellow solid (34.2 mg, 96%); H NMR
125.1 (d, JC–F = 9.9 Hz), 122.1 (d, JC–F = 27.0 Hz), 118.0, 110.8 (300 MHz, CDCl3) δ 8.78 (s, 1H), 8.25 (d, J = 9.0 Hz, 2H), 8.01
(d, JC–F = 21.3 Hz), 98.4, 98.2, 56.2, 56.1; ESI-MS (m/z, %) 258 (d, J = 8.4 Hz, 2H), 7.79 (dd, J1 = 7.5 Hz, J2 = 7.5 Hz, 2H), 7.54
[M + H]+; ESI-HRMS calcd for C15H13O2NF [M + H]+ 258.0925, (dd, J1 = 7.5 Hz, J2 = 7.5 Hz, 2H).
found 258.0932.
2-Chloroacridine (3l).11a Light yellow solid (39.3 mg, 92%);
1,3-Dimethoxy-7-nitroacridine (3d).11e Yellow solid (57.1 mg, 1H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.20 (dd, J1 = 12 Hz,
1
99%); H NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 8.85 (d, J = 2.4 J2 = 9.6 Hz, 1H), 8.00–7.97 (m, 2H), 7.82–7.77 (m, 1H), 7.69
Hz, 1H), 8.40 (dd, J1 = 9.3 Hz, J2 = 2.4 Hz, 1H), 8.08 (d, J = 9.6 (dd, J1 = 9.3 Hz, J2 = 2.4 Hz, 1H), 7.59–7.54 (m, 1H).
Hz, 1H), 7.01 (d, J = 1.8 Hz, 1H), 6.45 (d, J = 1.8 Hz, 1H), 4.04 (s,
1
2-Methoxyacridine (3m).12e Yellow solid (33.4 mg, 80%); H
3H), 4.00 (s, 3H).
NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.20 (dd, J1 = 8.7 Hz, J2 =
1,3,7-Trimethoxyacridine (3e).11e Yellow solid (47.6 mg, 0.6 Hz, 1H), 8.13 (d, J = 9.6 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H),
88%); 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.06 (d, J = 9.3 7.74–7.69 (m, 1H), 7.54–7.45 (m, 2H), 7.15 (d, J = 2.7 Hz, 1H),
Hz, 1H), 7.45 (dd, J1 = 9.3 Hz, J2 = 2.7 Hz, 1H), 7.18 (d, J = 2.4 3.97 (s, 3H).
Hz, 1H), 7.08 (s, 1H), 6.45 (s, 1H), 4.03 (s, 3H), 3.98 (s, 3H),
3.95 (s, 3H).
4-Chloroacridine (3n).12b Light yellow solid (33.9 mg, 80%);
1H NMR (300 MHz, CDCl3) δ 8.78 (s, 1H), 8.38 (dd, J1 = 8.7 Hz,
7,9-Dimethoxy-[1,3]dioxolo[4,5-b]acridine (3f). Yellow solid J2 = 0.6 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.94–7.93 (m, 1H),
1
(54.5 mg, 96%); H NMR (300 MHz, CDCl3) δ 8.68 (s, 1H), 7.31 7.91 (s, 1H), 7.82 (ddd, J1 = 8.0 Hz, J2 = 7.6 Hz, J2 = 1.5 Hz, 1H),
(s, 1H), 7.08 (s, 1H), 6.96 (s, 1H), 6.37 (s, 1H), 6.06 (s, 2H), 3.97 7.57 (ddd, J1 = 7.6 Hz, J2 = 7.4 Hz, J2 = 0.9 Hz, 1H), 7.43 (dd,
(s, 3H), 3.94 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 161.7, 156.2, J1 = 7.8 Hz, J2 = 7.8 Hz, 1H).
152.5, 149.7, 148.7, 147.2, 129.7, 122.4, 116.1, 104.0, 102.7,
Methyl acridine-4-carboxylate (3o).6b Brown oil (38.9 mg,
102.0, 98.1, 97.3, 56.1, 55.9; ESI-MS (m/z, %) 284 [M + H]+; 82%); 1H NMR (300 MHz, CDCl3) δ 8.80 (s, 1H), 8.30 (d, J = 9.0
ESI-HRMS calcd for C16H14O4N [M + H]+ 284.0917, found Hz, 1H), 8.13 (d, J = 7.8 Hz, 2H), 8.00 (d, J = 8.4 Hz, 1H),
284.0925.
7.83–7.78 (m, 1H), 7.59–7.52 (m, 2H), 4.12 (s, 3H).
1,3-Dimethoxy-6-methylacridine (3g). Yellow solid (43.6 mg,
4-Methoxyacridine (3p).12e Brown solid (39.7 mg, 95%); 1H
86%); 1H NMR (300 MHz, CDCl3) δ 8.92 (s, 1H), 7.87 (s, 1H), NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 8.40 (d, J = 9.0 Hz, 1H),
7.82 (d, J = 8.4 Hz, 1H), 7.27 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.79–7.74 (m, 1H), 7.59–7.52 (m, 2H),
7.04 (d, J = 1.8 Hz, 1H), 6.38 (d, J = 2.1 Hz, 1H), 3.99 (s, 3H), 3.97 7.45 (dd, J1 = 7.5 Hz, J2 = 7.5 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H),
(s, 3H), 2.57 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 162.5, 156.6, 4.16 (s, 3H).
151.2, 149.9, 141.4, 131.4, 128.7, 127.5, 127.1, 123.5, 117.2, 98.2,
97.5, 56.1, 56.0, 22.6; ESI-MS (m/z, %) 254 [M + H]+; ESI-HRMS 1H NMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 8.29 (d, J = 9.0 Hz,
calcd for C16H16O2N [M + H]+ 254.1176, found 254.1179.
1H), 7.98 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H),
4-Methylacridine (3q).12e Yellow solid (34.2 mg, 88%);
6-Fluoro-1,3-dimethoxyacridine (3h). Yellow solid (43.3 mg, 7.79–7.74 (m, 1H), 7.62 (d, J = 6.6 Hz, 1H), 7.53 (dd, J1 = 7.5 Hz,
1
85%); H NMR (300 MHz, CDCl3) δ 8.97 (s, 1H), 7.93 (dd, J1 = J2 = 7.5 Hz, 1H), 7.42 (dd, J1 = 7.5 Hz, J2 = 7.5 Hz, 1H), 2.96
9.0 Hz, J2 = 6.3 Hz, 1H), 7.69 (dd, J1 = 10.5 Hz, J2 = 1.8 Hz, 1H), (s, 3H).
7.28–7.22 (m, 1H), 7.02 (s, 1H), 6.42 (s, 1H), 4.02 (s, 3H), 3.98
Benzo[c]acridine (3r).12e Light yellow solid (45.9 mg, 98%);
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 164.2 (d, JC–F = 250.3 Hz), 1H NMR (300 MHz, CDCl3) δ 9.53 (d, J = 8.4 Hz, 1H), 8.65 (s,
163.2, 156.7, 151.9, 150.4 (d, JC–F = 13.3 Hz), 131.9, 131.4 (d, 1H), 8.39 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.90–7.69
JC–F = 10.5 Hz), 122.4, 117.1, 116.4 (d, JC–F = 26.9 Hz), 111.3 (d, (m, 6H), 7.60 (dd, J1 = 7.5 Hz, J2 = 7.5 Hz, 1H).
JC–F = 19.9 Hz), 98.1, 97.8, 56.2, 56.1; ESI-MS (m/z, %) 258
[M + H]+; ESI-HRMS calcd for C15H13O2NF [M + H]+ 258.0925, NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.23 (s, 1H), 8.20 (d, J =
found 258.0928. 9.0 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H),
3-Chloroacridine (3s).12e Yellow solid (22.9 mg, 54%); 1H
8-Fluoro-1,3-dimethoxyacridine (3i). Yellow solid (51.2 mg, 7.83–7.78 (m, 1H), 7.55 (dd, J1 = 7.5 Hz, J2 = 7.5 Hz, 1H), 7.46
99%); 1H NMR (300 MHz, CDCl3) δ 9.29 (s, 1H), 7.90 (d, J = (dd, J1 = 9.0 Hz, J2 = 0.9 Hz, 1H).
8.7 Hz, 1H), 7.69–7.62 (m, 1H), 7.10 (dd, J1 = 9.9 Hz, J2
=
1-Chloroacridine (3s′).12e Yellow solid (14.3 mg, 33%); 1H
7.8 Hz, 1H), 7.05 (d, J = 1.8 Hz, 1H), 6.46 (d, J = 2.1 Hz, 1H), NMR (300 MHz, CDCl3) δ 9.17 (s, 1H), 8.24 (d, J = 9.0 Hz, 1H),
4.04 (s, 3H), 3.99 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 163.3, 8.16 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.86–7.80 (m,
158.9 (d, JC–F = 255.3 Hz), 156.7, 151.7, 150.1, 130.0 (d, JC–F
=
1H), 7.71–7.56 (m, 3H).
9.4 Hz), 125.6 (d, JC–F = 4.3 Hz), 124.6 (d, JC–F = 4.0 Hz), 117.5,
2,7-Dichloroacridine (3t). Light yellow solid (48.2 mg, 97%);
116.6 (d, JC–F = 16.8 Hz), 107.4 (d, JC–F = 19.1 Hz), 98.3, 98.2, 1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 8.14 (d, J = 9.3 Hz,
56.3, 56.1; ESI-MS (m/z, %) 258 [M + H]+; ESI-HRMS calcd for 2H), 7.95 (d, J = 2.1 Hz, 2H), 7.70 (dd, J1 = 9.3 Hz, J2 = 2.4 Hz,
C15H13O2NF [M + H]+ 258.0925, found 258.0933.
2H); 13C NMR (125 MHz, CDCl3) δ 147.6, 134.3, 132.6, 132.2,
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131.5, 127.3, 126.5; ESI-MS (m/z, %) 248 [M + H]+; ESI-HRMS
calcd for C13H8NCl2 [M + H]+ 248.0028, found 248.0026.
1,2,3,4-Tetrahydroacridine (6).10 Yellow oil (26.8 mg, 73%);
1H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 1H), 7.80 (s,
1H), 7.69 (d, J = 7.8 Hz, 1H), 7.63–7.58 (m, 1H), 7.43 (dd, J1 =
7.5 Hz, J2 = 7.5 Hz, 1H), 3.13 (t, J = 6.6 Hz, 2H), 2.97 (t, J = 6.3
Hz, 2H), 2.04–1.96 (m, 2H), 1.93–1.85 (m, 2H).
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Acknowledgements
Financial support from the National Natural Science Foun-
dation of China (21325209) and the Shanghai Municipal Com-
mittee of Science and Technology (14XD1404400) are gratefully
acknowledged.
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