2-Aminobenzaldehyde, a common precursor to acridines and acridones endowed with bioactivities

Article abstract of DOI:10.1016/j.tet.2020.131435

By starting from a common substrate, 2-aminobenzaldehyde, both acridines and acridones were prepared. The former were generated in high yields by copper-catalyzed N-arylation followed by acid-mediated cyclization while the latter were obtained by double copper-catalyzed N-arylation followed by cyclization under the same reaction conditions. Moreover, acridine was subjected to deprotometalation by recourse to a lithium-zinc base and converted to the corresponding 4-iodo derivative, which was involved in copper-catalyzed couplings with pyrrolidinone and pyrazole. Finally, addition of pyrazole, indole and carbazole onto the 9 position of bare acridine was improved. While moderate biological activity was noticed in melanoma cells growth inhibition, the newly prepared compounds feature interesting photophysical properties which were evaluated in a preliminary study.

Full text of DOI:10.1016/j.tet.2020.131435

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2-Aminobenzaldehyde, a common precursor to acridines and acridones endowed
with bioactivities
Sarah Zeghada, Ghenia Bentabed-Ababsa, Olivier Mongin, William Erb, Laurent
Picot, Valérie Thiéry, Thierry Roisnel, Vincent Dorcet, Florence Mongin
PII:
S0040-4020(20)30607-4
https://doi.org/10.1016/j.tet.2020.131435
TET 131435
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 June 2020
Revised Date: 17 July 2020
Accepted Date: 20 July 2020
Please cite this article as: Zeghada S, Bentabed-Ababsa G, Mongin O, Erb W, Picot L, Thiéry Valé,
Roisnel T, Dorcet V, Mongin F, 2-Aminobenzaldehyde, a common precursor to acridines and acridones
endowed with bioactivities, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131435.
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Graphical Abstract
_________________________________________________
2-Aminobenzaldehyde, a common precursor to acridines and
acridones endowed with bioactivities
Sarah Zeghada,a,b,c Ghenia Bentabed-Ababsa,b,* Olivier Mongin,a William Erb,a Laurent Picot,d,*
Valérie Thiéry,d Thierry Roisnel,a Vincent Dorceta and Florence Mongina,*
a Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) - UMR 6226,
F-35000 Rennes, France
b Laboratoire de Synthèse Organique Appliquée, Faculté des Sciences Exactes et Appliquées,
Université Oran 1 Ahmed Ben Bella, BP 1524, El M’Naouer, 31000 Oran, Algeria
c Ecole Supérieure en Génie Electrique et Energétique d’Oran (ESGEE), BP CH 2,
Achaba Hanifi, Technopole USTO, 31000 Oran, Algeria
d La Rochelle Université, Laboratoire Littoral Environnement et Sociétés, UMRi CNRS 7266,
Université de La Rochelle, 17042 La Rochelle, France
* Corresponding authors.
E-mail addresses: bentabedg@gmail.com (G. Bentabed-Ababsa),
laurent.picot@univ-lr.fr (L. Picot), florence.mongin@univ-rennes1.fr (F. Mongin).
Keywords: acridine; acridone; N-arylation; copper; antiproliferative activity; melanoma cells
1

Abstract:
By starting from a common substrate, 2-aminobenzaldehyde, both acridines and acridones were
prepared. The former were generated in high yields by copper-catalyzed N-arylation followed by acid-
mediated cyclization while the latter were obtained by double copper-catalyzed N-arylation followed
by cyclization under the same reaction conditions. Moreover, acridine was subjected to
deprotometalation by recourse to a lithium-zinc base and converted to the corresponding 4-iodo
derivative, which was involved in copper-catalyzed couplings with pyrrolidinone and pyrazole. Finally,
addition of pyrazole, indole and carbazole onto the 9 position of bare acridine was improved. While
moderate biological activity was noticed in melanoma cells growth inhibition, the newly prepared
compounds feature interesting photophysical properties which were evaluated in a preliminary study.
1.
Introduction
Heteroaromatic units such as acridines and acridones play an important role in various molecules
exhibiting biological properties as well as in organic materials for a wide range of applications (e.g.
related to fluorescence).1 For example, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide (DACA)
and amsacrine (m-AMSA) are topoisomerase II inhibitors and, while the former has been used in trials
for the treatment of lung cancer or brain and CNS tumors, the latter is also a potent intercalating
antineoplastic agent used for the treatment of acute myeloid leukemia (Figure 1, left).1b
Figure 1. Structures of biologically active acridines (left) and acridones (right).
Other biological activities can be found in acridone-based compounds. For example, 1,5,6-
trimethoxyacridone is known for its ability to inhibit aromatase and glycosyltransferase, and its
2

moderate cytotoxic activity against liver cancer cell line WRL-68 (IC50 = 86 µM). Finally, citrusinine-I
is a natural acridone reported as herbicide model due to its ability to inhibit photosynthesis (Figure 1,
right).1b
Acridines and acridones are traditionally prepared by using as key step copper-catalyzed C-N bond
formation reactions between 2-halogenobenzoic acids and anilines.1a,b Among other methods reported
to access acridines,2 we can cite (i) the Bernthsen synthesis in which diphenylamine and carboxylic
acids are heated in the presence of zinc chloride as catalyst to furnish 9-substituted acridines,3 (ii)
palladium-catalyzed N-arylation/intramolecular Heck reaction of 2-bromostyrenes with 2-
chloroanilines developed by Buchwald and co-workers,4 (iii) [4+2] annulation of 2-aminoaryl ketones
with in situ formed arynes (by treating 2-(trimethylsilyl)aryl triflates with cesium fluoride) documented
by Larock and co-workers to afford unsymmetrical acridines,5 (iv) palladium-catalyzed consecutive
C=C bond and C-N bond formations between 1,2-dibromobenzenes and N-tosyl hydrazones of 2-
aminophenyl ketones reported by Wang and co-workers,6 (v) the appoach of Ellman and co-workers
who employed aromatic azides with aromatic imines in a [3+3] annulation reaction (Rh(III)-catalyzed
amination followed by intramolecular electrophilic aromatic substitution and aromatization),7 (vi)
palladium-catalyzed N-arylation/Friedel-Crafts reactions of anilines reported by Guo, Wang and co-
workers from 2-formylphenyl triflates and anilines,8 and by Xu and co-workers from 2-
bromobenzaldehydes,9 both in the presence of copper salts, (vii) tandem N-arylation/Friedel-Crafts
reactions of 2-aminophenones with diaryliodonium salts10 and arylboronic acids,11 (viii) Wang’s12 and
Wu’s13 annulation-aerobic oxidative dehydrogenation and Deng’s palladium-catalyzed reaction14 of 2-
aminophenones with cyclohexanones, and (ix) Jiang’s nitrogen/iodine exchange of diaryliodonium
salts with sodium azide15 (Scheme 1).
3

Scheme 1. General ways reported in the literature to access acridines.
Among a few other specific syntheses,16 the general ways to access acridones include (i) acid-
induced cyclization of N-aryl anthranilic acids (or amides),16a,17 (ii) hydrolysis of 9-chloroacridines18
and oxidation of acridines18-19 or acridinium salts,20 (iii) copper-catalyzed (first reported by Deng,21
Cheng,22 Xu,23 Zhu23 and co-workers) or potassium tert-butoxide-mediated (reported by Zou and co-
workers)24 intramolecular N-arylation of N-substituted 2-aminobenzophenones,25 (iv) copper-catalyzed
oxidative cyclization of 2-(phenylamino)acetophenones studied in parallel by Zhou,26 Fu,19 Zhang27
and co-workers, as well as Yang’s scandium triflate-catalyzed28 and Du/Zhao’s
(diacetoxyiodo)benzene-mediated29 dehydrogenative cyclization of 2-(phenylamino)benzaldehydes, (v)
Chen’s tandem copper-catalyzed N-arylation/Friedel-Crafts reaction of methyl 2-aminobenzoates with
diaryliodonium salts,10 (vi) reactions involving in situ generated arynes (from 2-(trimethylsilyl)aryl
triflates) such as Jiang’s palladium-catalyzed multicomponent with 2-iodoanilines and carbon
monoxide,30 and Larock’s cesium fluoride-mediated coupling with methyl 2-aminobenzoates,31 (vii)
Lei’s palladium-copper co-catalyzed oxidative double C-H carbonylation of diphenylamines,16d (viii)
palladium-catalyzed carbonylation/C-H activation sequence developed by Song, Liu and co-workers
4

from 2-bromodiarylamines,32 and (ix) Langer’s palladium-catalyzed double amination of bis(2-
bromophenyl) ketones.33 As far as N-arylated acridones are concerned, they can be obtained either by a
suitable choice of the precursors,16a,21-22,25,32-33 or by post-functionalization of acridones34 (Scheme 2).
Cl or H
R1
O
R2
N
R
R1
R2
R1
R2
HO
O
N
NHR
O
Br
O
R
NH2
R1
(ii)
(i)
(iii)
R2
(ix)
R1
O
H or Me
NH
R1
Br
CO
(iv)
R3
(v)
(viii)
N
R
Br
R2
R2
R1
(vii)
(vi)
N
R
O
R2
R1
CO
I (+CO)
Ar
OMe
NH2
I
R1
R2
R1
R2
OTf
N
NHR
O
TMS
TfO
H
or
R1
OMe
NHR
Scheme 2. General ways reported in the literature to access acridones.
In 2018, we reported an easy synthesis of N-aryl isatins or acridines, both involving a copper-
catalyzed C-N bond formation from 2-aminophenones.35 As part of our studies dedicated to the
development of short syntheses to access aromatic heterocycles of biological interest,36 we here report
our efforts to access both acridines and N-arylated acridones from a common precursor, 2-
aminobenzaldehyde. We also document the photophysical properties of some of the prepared
compounds, as well as their ability to inhibit the growth of melanoma cells.
5

2.
Results and Discussion
2.1. Syntheses of acridines
The secured synthesis of 2-aminobenzaldehyde reported in 201237 allowed organic chemists to
involve it in copper-catalyzed N-arylation reactions, either with iodobenzenes as demonstrated for
example by Li and co-workers by using potassium carbonate together with catalytic copper(I) iodide
and glycine in dimethylformamide at 130 °C,38 or with pinacol boronic esters as reported by Liu and
Xu.39 Inspired by previously reported N-arylation of 2-aminophenones,40 and in line with our previous
study,35 2-aminobenzaldehyde (1) was reacted with iodoarenes (iodobenzene, the three different
iodoanisoles, and 3-iodopyridine) in the presence of potassium carbonate (2 equiv) and catalytic
activated copper41 at the reflux temperature of dibutyl ether to afford the expected products 2a-e in
moderate to good yields (Table 1, left). The diarylamines were next cyclized by using sulfuric acid in
boiling acetic acid,42 providing the acridines 3a-e in high yields (Table 1, right). Our approach to
access substituted acridines is complementary to those already reported in the literature. For example,
Wu and Mu synthesized 3b and 3d them from 2-fluorobenzaldehyde by ZnCl2 promoted
intramolecular cyclization of 2 arylaminophenyl Schi bases,43 and Xu from 2-bromobenzaldehyde
by palladium-catalyzed tandem coupling/cyclization.9 In the case of 3-iodoanisole, two products 3c1
and 3c2 can be formed upon acid-mediated cyclization; they were respectively isolated in a 74:26 ratio
in favor of the less hindered (entry 3). This result is rather consistent with previously reported
trifluoroacetic acid-mediated cyclizations of 2-(3-methoxyphenylamino)benzaldehyde giving 3c1 and
3c2 in a 60:40 ratio.44 In contrast, in the case of 3-iodopyridine for which two possible products can in
theory be obtained, the one resulting from a cyclization at the 2 position of the pyridine ring (3e) was
the only product isolated (entry 5). This result is particularly interesting since at present there is no
efficient access to benzo[b][1,5]naphthyridine (3e) in the literature.15
6

Table 1. N-arylation of 2-aminobenzaldehyde (1) to afford the N-arylamines 2, and subsequent
conversion to the acridines 3.
Entry I-Ar
2, Yield (%)a
2a, 7135
Product 3 (time), Yield (%)a
3a (0.5 h), 94
1
I-Ph
2
2b, 78
2c, 83
3b (1.5 h), 80
3c1 (3 h), 72
3
3c2 (3 h), 25
3d (3 h), 98
4
5
2d, 76
2e, 62
3e (2 h), 83
a After purification (see experimental part).
The efficiency of the reaction led us to consider double N-arylation-cyclization sequences using
diiodides. Kuninobu, Takai and co-workers showed that the pentacycle 3f2 could be synthesized from
2f2 in 76% yield by using catalytic indium(III) triflate in 1,2-dichloroethane at 150 °C for 24 h.45 Wu,
Mu and co-workers prepared both 3f1 and 3f2 from the corresponding 2-arylaminophenyl Schiff bases
in 98 and 50% yield, respectively, by using zinc chloride in excess in tetrahydrofuran at 80 °C for 24
h.43 By using conditions close to those of Table 1 for the N-arylation (0.4 equiv of activated copper, 3
equiv of potassium carbonate, reflux of dibutyl ether), but with an extended reaction time in order to
allow the reaction to go to completion, 1,3-diiodobenzene reacted with an excess of 2-
7

aminobenzaldehyde to directly lead to dibenzo[b,j][1,7]phenanthroline (3f1), isolated in 87% yield
(Scheme 3, top). In contrast, using 1,4-diiodobenzene instead furnished the non-cyclized product 2f2 in
91% yield; the latter was converted to dibenzo[b,j][4,7]phenanthroline (3f2) in 89% yield by
subsequent acid-mediated aromatic electrophilic substitution (sulfuric acid in boiling acetic acid)
(Scheme 3, bottom). All these results are consistent with an easier cyclization from 2f1 which benefits
from an additional well-located mesomeric electron-donating group.
Scheme 3. N-arylation of 2-aminobenzaldehyde (1) to afford,
after cyclization, the pentacycles 3f1 and 3f2. a No other isomer detected.
Our expertise in the field of deprotometalation-electrophilic trapping sequences from sensitive
aromatic heterocycles,46 and in copper-catalyzed N-arylation reactions of amides47 and azoles48 by aryl
iodides, led us to study these reactions from acridine (3a). Indeed, acridine being so sensitive to
nucleophilic attacks at its 9 position49 that its deprotometalation followed by electrophilic trapping has,
to our knowledge, never been reported. As a consequence, multistep approaches need to be followed
8

when halogenated acridones are required, as exemplified with the synthesis of 4-iodoacridine (4a)
prepared from 4-bromoacridine (coming from the corresponding bromoaniline) by halogen/metal
exchange followed by quenching with chlorotributylstannane and subsequent reaction with iodine.50 By
simply starting from acridine (3a), using our lithium-zinc base prepared in situ from ZnCl2·TMEDA51
(0.5 equiv) and lithium 2,2,6,6-tetramethylpiperidide (LiTMP; 1.5 equiv)46 chemoselectively led to the
9-arylmetal derivative which, upon iodolysis, furnished the 4-iodo derivative 4a in 76% yield (Scheme
4, top). However, probably due to several possible deprotonation sites, a mixture was obtained by
applying the same conditions to benzo[b][1,5]naphthyridine (3e); the 4,9-diiodo derivative 4e was the
only product isolated from a mixture also containing traces of the 9-iodo (Scheme 4, bottom).
Scheme 4. Functionalization of the tricycles 3a and 3e by a deprotometalation-iodolysis sequence
and ORTEP diagrams (30% probability) of 4a and 4e.
Scheme 5. N-arylation of pyrrolidinone using 4-iodoacridine (4a).
Because of the paucity of N-(4-acridyl)amides and N-(4-acridyl)azoles in the literature, we were
eager to develop an approach toward them. Therefore, we first attempted the reaction of pyrrolidinone
with 4a in the presence of potassium phosphate and catalytic copper(I) iodide in dimethyl sulfoxide
(DMSO) at 110 °C. Under these conditions,47 the expected coupled product was isolated in 58% yield
9

(Scheme 5). Next, we tried to N-arylate 4a with pyrazole under conditions previously used for similar
reactions (0.1 equiv of copper(I) source, 2 equiv of cesium carbonate, DMSO at 110 °C for 24 h).48b
While copper(I) oxide proved better than copper(I) iodide, side reactions were observed. Indeed, the
main product isolated (20% yield) was 4,9-di(N-pyrazolyl)acridine (5a2) by using the latter while 4-(N-
pyrazolyl)-9-acridone (5a3) was formed as main compound (66% yield) with the former. Even if
scarce, examples of acridine conversion into acridone have already been reported, for example by
employing sodium hydride in DMSO.52 In both cases, 4-iodo-9-acridone (5a4) and 4-iodo-9-(N-
pyrazolyl)acridine (5a5) were also isolated in yields below 10% (Scheme 6).
Scheme 6. Attempts to N-arylate pyrazole using 4-iodoacridine (4a) in the presence of copper(I) salts
and ORTEP diagram (30% probability) of 5a5.
In order to determine if copper plays a role in the conversion of acridine to acridone, we performed
the reaction from acridine (3a) and pyrazole without copper(I) source; under the same conditions,
acridone (5a6) was also the main product (66% yield) while 9-(N-pyrazolyl)acridine (5a7) was isolated
in 29% yield (Scheme 7, top). Formation of acridones could be explained by the sensitivity of acridines
towards nucleophiles, and the presence of either residual water in DMSO53 or carbonate.54 As regards
the addition of pyrazole onto the acridine ring, we replaced cesium carbonate by potassium phosphate
10

to see the impact of the base on the reaction. Under these conditions, the pyrazoloacridine 5a7 turned
out to be the major product (isolated in 53% yield), and its structure was unambiguously established by
X-ray diffraction (Scheme 7, bottom).
Scheme 7. Attempts to N-arylate pyrazole using acridine (3a) without copper(I) salts
and ORTEP diagram (30% probability) of 5a7.
Scheme 8. Attempts to arylate indole and carbazole using acridine (3a)
and ORTEP diagram (30% probability) of 5a9.
Although 9-(N-pyrazolyl)acridine (5a7) is new, the addition of other aromatic compounds onto
acridine has already been documented.55 As early as 1984, Takano and co-workers documented the
reaction of 2,5-dimethylpyrrole, indole, imidazole and 2-methylimidazole with acridine upon heating at
160 °C (yields between 27 and 47%).56 In contrast with the result observed here with pyrazole, there is
11

no C-N bond formed in the reported examples since pyrrole and indole attack by their C3 carbon, and
imidazoles by their C4. Thus, we tried a reaction from acridine and indole in the presence of cesium
carbonate in DMSO at 110 °C. While it similarly led to 9-(3-indolyl)acridine (5a8) after 24 h, it was
isolated in a higher 75% yield (Scheme 8, top).
A careful analysis of the literature data revealed 9-(N-carbazolyl)acridine (5a9) as the only N-(9-
acridyl)azole reported. It was synthesized by photolysis of a 1:1 mixture of acridine and carbazole in
acetonitrile, and isolated in 19% yield.57 By repeating the protocol giving 5a8 but using carbazole
instead of indole, no reaction was observed (starting materials recovered). However, in the presence of
copper(I) iodide (0.2 equiv), the product was obtained in 83% yield after 24 h in DMSO at 110 °C
(Scheme 8, bottom). However, replacing carbazole by 1,2,4-triazole, benzotriazole or azaindole did not
allow the corresponding N-(9-acridyl)azoles to be formed under similar conditions (starting materials
mainly recovered).
2.2. Syntheses of acridones
In the course of a study published recently, we observed that copper-catalyzed N,N-diarylation of
thienylamines is possible by using an excess of aryl iodide in the presence of 1 equivalent of activated
copper and 3 equivalents of base.58 Hence, 2-aminobenzaldehyde (1) was similarly treated by the
different iodoanisoles (2 equiv) at the reflux temperature of dibutyl ether until disappearance of the
starting materials. The expected 2-(diarylamino)benzaldehydes 6b-d were isolated in 14 to 63% yield,
as a result of side reactions/degradation taking place in the course of the second, more difficult N-
arylation step (Table 2, entries 1-3, left). To cyclize 2-(arylamino)benzaldehydes into acridones,
reported methods are based on the use of scandium(III) triflate28 and PhI(OAc)2.29 In our case, we
simply treated 6b-d with sulfuric acid in boiling acetic acid as before, and obtained the expected
acridones 6b-d in 40 to 71% yields (Table 2, entries 1-3, right). By using iodobenzene as aryl halide,
we directly involved the N,N-diarylation crude product in the cyclization step to obtain N-phenyl-9-
acridone (7a) in an overall 89% yield (Table 2, entry 4).
12

Table 2. Double N-arylation of 2-aminobenzaldehyde (1) to afford the diarylamines 6, and subsequent
conversion to the acridones 7. ORTEP diagrams (30% probability) of 7b-d.
Entry I-Ar
1
6, Yield (%)b Product 7 (time), Yield (%)b
6b, 26c
7b (1 h), 71
2
6c, 14d
7c (2 h), 48
7d (1 h), 40
7a (2 h), 89f
3
6d, 63
e
4
I-Ph
-
a Added by portions of 0.2 equivalent every 2 h. b After purification (see experimental part).
c Remaining 2b was only isolated in 1% yield while starting 4-iodoanisole was detected.
d Remaining 2c was only isolated in 9% yield. e Not isolated. f Yield for 2 steps.
Finally, we decided to check if this approach could be suitable to cyclize differently N,N-
disubstituted 2-aminobenzaldehydes. For this purpose, we selected 2-(phenylamino)benzaldehyde (2a)
13

and carried out the second N-arylation with 4-iodoanisole. The cyclization of 6ab, isolated in 38%
yield, was performed as before to logically furnish as major compound the symmetrical N-(4-
methoxyphenyl) derivative in 42% yield. The minor isomer, resulting from a less favored cyclization
through electrophilic aromatic substitution at the 3-position of anisole, was only isolated in 3% yield
(Scheme 9).
Scheme 9. Second N-arylation of 2-aminobenzaldehyde (1) to afford the diarylamine 6ab, and
subsequent conversion to the acridone 7ab. a Added by portions of 0.2 equivalent every 2 h.
b 2-Methoxy-N-phenyl-9-acridone was also isolated in 3% yield.
2.3. Photophysical properties
Acridine and acridone derivatives, especially when substituted with electron-donating groups, can
display interesting fluorescence properties.59 Thus, in view of potential applications as fluorescent
probes in biological media, we performed a preliminary study of the photophysical properties of
selected compounds. Their UV-visible absorption and emission properties were investigated in toluene,
and the results are gathered in Table 3.
The three isomeric methoxyacridines 3c1, 3c2 and 3d exhibit a broad and structured lowest energy
transition absorption band in the 300-450 nm range and emit in the violet-blue part of the visible
(Figure 2). The maximum wavelengths of 1- (3c2) and 4-methoxy (3d) isomers are red-shifted by 8 and
9 nm compared with 3-methoxyacridine (3c1) respectively, whereas their emission band is red-shifted
by 27 and 16 nm, respectively. Their fluorescence quantum yields are rather high (15-44%), and 3c2,
which is the most red-shifted is also the most emissive of the series.
14

Table 3. Absorption and emission properties of selected acridines and acridones in toluene at 25 °C.
Stokes shift (cm-1) e
d
λabs a (nm) εmax b (M-1 cm-1)
λem c (nm)
ΦF
Compound
348
356
-
429
456
0.15
0.44
0.20
0.04
0.56
< 0.01
0.31
0.08
0.12
0.03
0.01
5430
6160
5540
6160
6490
5700
1140
5480
6530
450
3c1
3c2
3d
-
357
5100
50900
6000
11300
8700
8200
10100
9000
9600
445
313, 328
366, 398
362
411, 421, 436, 464
480
3f1
5a2
5a7
5a3
5a8
5a9
7a
456
399
418, 440
450
361, 384
362
474
391
398, 419
390, 409
377
880
7c
a Absorption maximum. b Molar extinction coefficients at λabs. c Emission maximum. d Fluorescence
quantum yield using as a standard quinine bisulfate in 0.5 M H2SO4 (ΦF = 0.546). e Stokes shift =
(1/λabs – 1/λem).
Figure 2. Absorption (solid line) and emission (dotted line)
of methoxyacridines 3c1, 3c2 and 3d in toluene.
Dibenzophenanthroline 3f1 exhibits a structured absorption band with a maximum at 328 nm and
also a structured emission band at 411 nm (Figure 3). However, it is pretty clear that the emission band
15

is not the mirror image of the intense absorption band (ε ~ 50000 M-1 cm-1) at 328 nm, but of a much
less intense band (ε ~ 750 M-1 cm-1) of lower energy with a maximum at 386 nm (see inset of Figure 3).
The 0-0 transition is at 410 nm. The fluorescence quantum yield of 3f1 is low (4%), in agreement with
a weakly allowed lowest-lying transition. As previously observed with other unsubstituted azarenes,60
this weakly allowed absorption band can be assigned to a n-π* transition and the strongly allowed one
to a π-π* transition.
Figure 3. Absorption (solid line) and emission (dotted line)
of dibenzophenanthroline 3f1 in toluene.
Four structurally-related acridines and an acridone with pyrazolyl, indolyl or carbazolyl substituents
(5a2, 5a3, 5a7, 5a8 and 5a9) have then been studied. These five compounds absorb in the near-UV and
emit in the 400-600 nm range of the visible. The two compounds substituted with pyrazolyl groups at
C4 position are better emitters (56% and 31% for 5a2 and 5a3, respectively) than those bearing
pyrazolyl (< 1% for 5a7), indolyl (8% for 5a8) or carbazolyl (12% for 5a9) substituents at C9.
The four acridines (5a2, 5a7, 5a8 and 5a9) exhibit a broad emission band and a large Stokes shift
(5500-6500 cm-1), whereas acridone 5a3 has a structured emission band and a much smaller Stokes
shift (1140 cm-1) (Figure 4). This is indicative that the intramolecular charge transfer (ICT) process is
more efficient with the former than with the latter. In the case of 4,9-dipyrazolylacridine 5a2, this ICT
16

process occurs from the two pyrazolyl groups to the nitrogen atom of the acridine. 9-Pyrazolyl-, 9-
indolyl- and 9-carbazolylacridines have a similar behavior, but substitution at C9 is clearly less
efficient than substitution at C4 to favor fluorescence, especially in the case of 9-pyrazolylacridine
(5a7). 4,9-Dipyrazolylacridine (5a2) exhibits a broad absorption band of lowest energy at 398 nm that
can be attributed to a charge transfer transition, and which is not present with 5a7, explaining the very
different quantum yields of these two compounds (Figure S1, Supporting Info). With acridone 5a3, the
electron-withdrawing group is obviously the carbonyl, and it seems that the nitrogens of the acridine
and the pyrazolyl at C-4 are not donor enough to allow an efficient ICT.
Figure 4. Absorption (solid line) and emission (dotted line)
of acridines 5a2, 5a8, 5a9 and acridone 5a3 in toluene.
Compared to the two N-arylacridones 7a and 7c, 4-pyrazolylacridone 5a3 is red-shifted both in
absorption and emission (Figure 5). It also exhibits a larger Stokes shift and a much higher
fluorescence quantum yield (31%, instead of 3% and 1% for 7a and 7c, respectively). Substitution at
the C-4 position of the acridone seems thus more efficient than N-substitution to favor ICT and
fluorescence.
17

Figure 5. Absorption (solid line) and emission (dotted line)
of acridones 5a3, 7a and 7c in toluene.
Although this is only a preliminary study, the results obtained allowed us to derive some interesting
structure-property relationships, which will help us design new acridines and acridones with optimized
fluorescence properties.
2.4. Biological evaluation on melanoma cell lines
Fifteen compounds among those synthesized (2a, 3e, 2f2, 3f1, 3f2, 5a1, 5a2, 5a3, 5a7, 5a8, 5a9, 6d,
6ab, 7b, 7d) were evaluated for their antiproliferative activity against A2058 melanoma cells that are
highly invasive human epithelial adherent melanoma cells considered as very resistant to anticancer
drugs. With a mortality rate very high,61 there is an important need to identify other pharmacological
targets and to develop new drugs. The selected cell lines possess natural and acquired resistance to
chemotherapy and radiotherapy; hence, they are suitable to evaluate the antiproliferative activity of our
molecules.
Most of the tested compounds exerted an antiproliferative activity in A2058 melanoma cells (Figure
6), the best results being obtained for 9-(3-indolyl)acridine (5a8) and the dibenzophenanthroline 3f1.
When compared with pentacycles already evaluated on the same target,35 the bare analog 3f1 exhibits a
18

similar behavior. As regards the 9-substituted acridines, the 3-indolyl group is responsible for the
highest antiproliferative activity when compared with N-carbazolyl and N-pyrazolyl. These two
compounds can therefore be considered as a promising starting point for further functionalization
toward more active molecules.
Figure 6: Antiproliferative activity of some of the synthesized compounds
at 10-5 M after 72 h in A2058 human melanoma cells.
3.
Conclusion
Thus, by starting from a common substrate, 2-aminobenzaldehyde, we developed a general entry to
both acridines and acridones. Besides, while methods to introduce specific substituents at the 4 position
of acridine exist, for example by Friedel & Crafts alkylation,62 or with recourse to rhodium,63 nickel,64
cobalt65 or iridium66 catalysis, we here reported a short access to the iodo derivative which can be used
for different post-functionalizations, as demonstrated in the present study. In addition, direct
introduction of an aromatic heterocycle at the 9 position of acridine was improved, notably through
copper catalysis.
Finally, the compounds identified as promising for their antiproliferative activity showed significant
fluorescence properties.
4.
Experimental
4.1. General
19

Column chromatography separations were achieved on silica gel (40-63 μm). Melting points were
measured on a Kofler apparatus. IR spectra were taken on a Perkin-Elmer Spectrum 100 spectrometer.
13
1H and C Nuclear Magnetic Resonance (NMR) spectra were recorded either on a Bruker Avance III
spectrometer at 300 MHz and 75 MHz respectively, or on a Bruker Avance III HD spectrometer at 500
MHz and 126 MHz respectively. 1H chemical shifts (δ) are given in ppm relative to the solvent residual
peak and 13C chemical shifts are relative to the central peak of the solvent signal.67 Microanalyses were
performed on a Thermo Fisher Flash EA 1112 elemental analyzer. 2-Aminobenzaldehyde,37 activated
Cu41 and ZnCl2·TMEDA51 were prepared as described previously.
Crystallography. The samples were studied with monochromatized Mo-Kα radiation (λ = 0.71073
Å, multilayered monochromator). The X-ray diffraction data of the compounds 4a, 4e, 5a5, 5a7, 5a9,
7b, 7c and 7d were collected at T = 150(2) K by using a D8 VENTURE Bruker AXS diffractometer
equipped with a (CMOS) PHOTON 100 detector. The structures were solved by dual-space algorithm
using the SHELXT program,68 and then refined with full-matrix least-square methods based on F2
(SHELXL).69 All non-hydrogen atoms were refined with anisotropic atomic displacement parameters. H
atoms were finally included in their calculated positions and treated as riding on their parent atom with
constrained thermal parameters. The molecular diagrams were generated by ORTEP-3 (version 2.02).70
4.2. N-arylation of 2-aminobenzaldehyde (1)
4.2.1. General procedure 1 for the N-arylation reactions. This reaction was performed under an
argon atmosphere. The N-arylated substrates were prepared by slightly modifying a literature
procedure.40 To 2-aminobenzaldehyde (1; 0.12 g, 1.0 mmol) and the required iodide (1 equiv, 1.0
mmol) in Bu2O (1 mL) were successively added activated Cu (0.20 equiv, 13 mg, 0.20 mmol) and
K2CO3 (2 equiv, 0.29 g, 2.0 mmol). The reaction mixture was degassed and refluxed under argon for 24
h. After cooling to room temperature, it was concentrated. Purification by chromatography on silica gel
(the eluent is given in the product description) led to the expected compound.
20

4.2.2. 2-(Phenylamino)benzaldehyde (2a) was obtained according to the general procedure 1 by
using iodobenzene (0.11 mL) as reported previously.35 Purification by column chromatography over
silica gel (heptane-CH2Cl2 85:15; Rf (petroleum ether-ethyl acetate 90:10) = 0.76) gave 2a in 71%
yield (0.20 g) as a yellow solid: mp 78 °C (lit.71 74-76 °C, after similar purification by column
chromatography); IR (ATR): 698, 748, 822, 899, 1118, 1155, 1185, 1314, 1185, 1314, 1398, 1422,
1
1450, 1491, 1519, 1571, 1591, 1649, 2757, 2837, 2925, 3038, 3279 cm-1; H NMR (CDCl3) δ 6.84 (t,
1H, J = 7.3 Hz), 7.16 (t, 1H, J = 7.1 Hz), 7.23-7.42 (m, 6H), 7.58 (d, 1H, J = 7.6 Hz), 9.92 (s, 1H,
CHO), 10.04 (br s, 1H, NH); 13C NMR (CDCl3) δ 113.0 (CH), 117.2 (CH), 119.5 (C), 123.2 (2CH),
124.5 (CH), 129.5 (2CH), 135.6 (CH), 136.7 (CH), 139.7 (C), 147.8 (C), 194.3 (CH, CHO). The NMR
data are close to those reported previously.72
4.2.3. 2-(4-Methoxyphenylamino)benzaldehyde (2b) was obtained according to the general
procedure 1 by using 4-iodoanisole (0.23 g). Purification by column chromatography over silica gel
(petroleum ether-AcOEt 70:30) gave 2b in 78% yield (0.19 g) as a yellow solid: mp 61-62 °C (lit.44 62-
63 °C, after similar purification by column chromatography); IR (ATR): 659, 748, 795, 839, 899, 1032,
1117, 1155, 1180, 1239, 1295, 1323, 1398, 1438, 1457, 1509, 1574, 1605, 1652, 2746, 2834, 2933,
3001, 3290 cm-1; 1H NMR (CDCl3) δ 3.83 (s, 3H, OMe), 6.77 (ddd, 1H, J = 7.9, 7.1 and 1.0 Hz, H5),
6.90-6.95 (m, 2H), 6.97 (d, 1H, J = 8.6 Hz, H3), 7.17-7.22 (m, 2H), 7.31 (dddd, 1H, J = 8.7, 7.1, 1.7
and 0.4 Hz, H4), 7.54 (dd, 1H, J = 7.8 and 1.6 Hz, H6), 9.83 (br s, 1H, NH), 9.90 (d, 1H, J = 0.5 Hz,
CHO); 13C NMR (CDCl3) δ 55.7 (CH3), 112.7 (CH), 114.9 (2CH), 116.5 (CH), 119.0 (C), 126.2
(2CH), 132.4 (C), 135.7 (CH), 136.6 (CH), 149.4 (C), 157.3 (C), 194.2 (CH, CHO). The 1H NMR data
are close to those reported previously.44
4.2.4. 2-(3-Methoxyphenylamino)benzaldehyde (2c) was obtained according to the general
procedure 1 by using 3-iodoanisole (0.23 g). Purification by column chromatography over silica gel (Rf
(petroleum ether-AcOEt 85:15) = 0.63) gave 2c in 83% yield (0.20 g) as a yellow solid: mp 72-74 °C
(lit.44 68-69 °C, after recrystallization from MeOH-H2O); IR (ATR): 660, 693, 747, 763, 789, 846, 870,
21

958, 1039, 1080, 1116, 1153, 1166, 1184, 1196, 1261, 1306, 1327, 1397, 1405, 1435, 1454, 1470,
1489, 1521, 1574, 1592, 1652, 2757, 2834, 2933, 2957, 2996, 3272 cm-1; 1H NMR (CDCl3) δ 3.81 (s,
3H, OMe), 6.70 (dd, 1H, J = 8.2 and 2.3 Hz), 6.81-6.89 (m, 3H), 7.24-7.30 (m, 2H), 7.37 (ddd, 1H, J =
8.4, 7.0 and 1.4 Hz, H4), 7.57 (dd, 1H, J = 7.7 and 1.5 Hz, H6), 9.90 (s, 1H, CHO), 10.00 (br s, 1H,
13
NH); C NMR (CDCl3) δ 55.5 (CH3), 108.8 (CH), 110.1 (CH), 113.4 (CH), 115.4 (CH), 117.4 (CH),
119.6 (C), 130.2 (CH), 135.7 (CH), 136.7 (CH), 141.1 (C), 147.7 (C), 160.8 (C), 194.4 (CH, CHO).
The 1H NMR data are close to those reported previously.44
4.2.5. 2-(2-Methoxyphenylamino)benzaldehyde (2d) was obtained according to the general
procedure 1 by using 2-iodoanisole (0.23 g). Purification by column chromatography over silica gel
(petroleum ether-AcOEt 90:10) gave 2d in 76% yield (0.19 g) as a yellow solid: mp 68-70 °C (lit.44 67-
69 °C); IR (ATR): 669, 749, 782, 835, 905, 1021, 1040, 1115, 1163, 1186, 1250, 1294, 1328, 1407,
1
1452, 1492, 1515, 1573, 1590, 1652, 2770, 2837, 2937, 3010, 3062, 3269 cm-1; H NMR (CDCl3) δ
3.88 (s, 3H, OMe), 6.83 (ddd, 1H, J = 7.9, 7.0 and 1.1 Hz), 6.94-6.99 (m, 2H), 7.08-7.13 (m, 1H), 7.28
(d, 1H, J = 8.6 Hz), 7.37 (ddd, 1H, J = 8.3, 7.0 and 1.3 Hz), 7.46-7.49 (m, 1H), 7.56 (dd, 1H, J = 7.7
and 1.5 Hz), 9.93 (d, 1H, J = 0.4 Hz, CHO), 10.03 (br s, 1H, NH); 13C NMR (CDCl3) δ 55.7 (CH3),
111.4 (CH), 113.1 (CH), 117.1 (CH), 120.0 (C), 120.5 (CH), 121.8 (CH), 124.4 (CH), 129.0 (C), 135.3
1
(CH), 136.6 (CH), 147.2 (C), 151.8 (C), 194.0 (CH, CHO). The H NMR data are close to those
reported previously.44
4.2.6. 2-(3-Pyridylamino)benzaldehyde (2e) was obtained according to the general procedure 1 by
using 3-iodopyridine (0.205 g). Purification by column chromatography over silica gel (Rf (AcOEt-
petroleum ether 50:50) = 0.41) gave 2e in 62% yield (0.13 g) as a yellow oil: IR (ATR): 666, 707, 750,
784, 833, 899, 1021, 1042, 1117, 1158, 1187, 1224, 1315, 1398, 1456, 1481, 1512, 1570, 1582, 1659,
2748, 2830, 3035, 3276 cm-1; 1H NMR (CDCl3) δ 6.90 (ddd, 1H, J = 7.8, 7.3 and 0.93 Hz, H4 or H5),
7.17 (d, 1H, J = 8.5 Hz, H3), 7.30 (dd, 1H, J = 8.1 and 4.7 Hz, H5’), 7.39 (ddd, 1H, J = 8.5, 7.2 and 1.4
Hz, H4 or H5), 7.59-7.62 (m, 2H, H6 and H4’), 8.39 (d, 1H, J = 3.6 Hz, H6’), 8.60 (br s, 1H, H2’), 9.92
22

13
(d, 1H, J = 0.5 Hz, CHO), 10.00 (br s, 1H, NH); C NMR (CDCl3) δ 112.7 (CH), 118.3 (CH), 120.0
(C), 123.9 (C), 129.8 (CH), 135.7 (CH), 136.6 (CH), 136.7 (CH), 144.8 (CH), 145.2 (CH), 146.9 (C),
194.5 (CH, CHO). The NMR data are close to those reported previously.73
4.2.7. Dibenzo[b,j][1,7]phenanthroline (3f1). To 2-aminobenzaldehyde (1; 0.48 g, 4.0 mmol) and
1,3-diiodobenzene (1 equiv, 1.0 mmol) in Bu2O (1 mL) were successively added, under an argon
atmosphere, activated Cu (0.40 equiv, 26 mg, 0.40 mmol) and K2CO3 (3 equiv, 0.43 g, 3.0 mmol). The
reaction mixture was degassed and refluxed under argon for 48 h. After cooling to room temperature, it
was concentrated. Purification by column chromatography over silica gel (Rf (CH2Cl2-AcOEt 95:5) =
0.30) gave 3f1 in 87% yield (0.24 g) as a yellow solid: mp 208-210 °C (lit.74 219 °C, after
recrystallization from ligroin); IR (ATR): 737, 748, 810, 820, 856, 921, 950, 1014, 1077, 1117, 1230,
1
1315, 1424, 1453, 1493, 1558, 1608, 1679, 2925, 3044 cm-1; H NMR (CDCl3) δ 7.65 (dtd, 2H, J =
8.1, 7.0 and 1.1 Hz), 7.87 (dddd, 2H, J = 8.5, 6.8, 3.1 and 1.5 Hz), 7.93 (s, 2H), 8.03 (dd, 1H, J = 8.2
and 0.6 Hz), 8.22 (d, 1H, J = 8.2 Hz), 8.31 (dd, 1H, J = 8.6 and 0.7 Hz), 8.39 (d, 1H, J = 8.6 Hz), 8.59
13
(s, 1H), 10.19 (s, 1H); C NMR (CDCl3) δ 124.6 (C), 125.8 (C), 126.5 (CH), 126.7 (CH), 127.1 (C),
127.5 (C), 128.1 (CH), 129.2 (CH), 129.3 (CH), 129.4 (CH), 129.7 (CH), 130.3 (CH), 130.9 (CH),
131.3 (CH), 133.9 (CH), 135.3 (CH), 147.8 (C), 147.9 (C), 149.1 (C), 151.2 (C). The NMR data are
close to those reported previously.43 N,N’-(1,3-phenylene)bis(2-aminobenzaldehyde) (2f1)75 was
similarly isolated (Rf (petroleum ether-AcOEt 85:15) = 0.63) in 12% yield (40 mg) as a yellow oil: IR
(ATR): 662, 691, 748, 812, 841, 871, 910, 990, 1041, 1062, 1080, 1117, 1156, 1194, 1261, 1314, 1397,
1
1456, 1473, 1514, 1576, 1653, 2745, 2833, 3059, 3273 cm-1; H NMR (CDCl3) δ 6.86 (ddd, 2H, J =
7.9, 7.1 and 1.1 Hz, H5 and H5’), 7.05 (dd, 2H, J = 8.0 and 2.1 Hz, H3 and H3’), 7.21 (t, 1H, J = 2.0
Hz, H1”), 7.29 (d, 2H, J = 8.5 Hz, H3”), 7.35 (t, 1H, J = 7.9 Hz, H4”), 7.39 (ddd, 2H, J = 8.6, 7.1 and
1.3 Hz, H4 and H4’), 7.58 (dd, 2H, J = 7.7 and 1.6 Hz, H6 and H6’), 9.90 (d, 2H, J = 0.5 Hz, CHO),
10.03 (br s, 2H, NH); 13C NMR (CDCl3) δ 113.3 (2CH), 117.0, 117.6 (2CH), 118.8 (2CH), 119.7,
130.4, 135.7 (2CH), 136.8 (2CH), 141.1, 147.5, 194.5 (2CH, CHO). In addition, N-(3-iodophenyl)-2-
23

aminobenzaldehyde was detected by NMR: 1H NMR (CDCl3) δ 6.89 (td, 1H, J = 7.4 and 0.9 Hz), 7.08
(t, 1H, J = 7.9 Hz), 7.22-7.25 (m, 2H), 7.40 (ddd, 1H, J = 8.6, 7.2 and 1.4 Hz), 7.46 (d, 1H, J = 7.8 Hz),
7.59 (dd, 1H, J = 7.7 and 1.6 Hz), 7.65 (t, 1H, J = 1.7 Hz), 9.90 (s, 1H, CHO), 9.99 (br s, 1H, NH); 13C
NMR (CDCl3) δ 94.7 (C, C3’), 113.2 (CH), 118.1 (CH), 119.9 (C), 122.1 (CH), 131.0 (CH), 131.5
(CH), 133.2 (CH), 135.8 (CH), 136.8 (CH), 141.3 (C), 147.0 (C), 194.5 (CH, CHO).
4.2.8. N,N’-(1,4-phenylene)-2,2’-bis(2-aminobenzaldehyde) (2f2).45 To 2-aminobenzaldehyde
(0.48 g, 4.0 mmol) and 1,4-diiodobenzene (1 equiv, 1.0 mmol) in Bu2O (1 mL) were successively
added, under an argon atmosphere, activated Cu (0.40 equiv, 26 mg, 0.40 mmol) and K2CO3 (3 equiv,
0.43 g, 3.0 mmol). The reaction mixture was degassed and refluxed under argon for 48 h. After cooling
to room temperature, it was concentrated. Purification by column chromatography over silica gel (Rf
(petroleum ether-AcOEt 85:15) = 0.68) gave 2f2 in 91% yield (0.30 g) as a yellow solid: mp 214 °C;
IR (ATR): 666, 707, 729, 784, 833, 899, 1021, 1042, 1117, 1158, 1187, 1224, 1315, 1398, 1456, 1481,
1512, 1570, 1582, 1659, 2748, 2830, 3035, 3276 cm-1; 1H NMR (CDCl3) δ 6.84 (ddd, 2H, J = 7.9, 7.4
and 1.0 Hz, H5 and H5’), 7.20 (d, 2H, J = 8.5 Hz, H3 and H3’), 7.29 (s, 4H, H2”), 7.38 (ddd, 2H, J =
8.6, 7.2 and 1.6 Hz, H4 and H4’), 7.58 (dd, 2H, J = 7.8, 1.6 Hz, H6 and H6’), 9.91 (s, 2H, CHO), 10.00
(br s, 2H, NH); 13C NMR (CDCl3) δ 113.0 (2CH), 117.2 (2CH), 119.5 (2C), 124.6 (4CH, C2”), 135.7
(2CH), 136.3 (2C), 136.8 (2CH), 148.1 (2C), 194.4 (2CH, CHO).
4.3. Conversion of the N-arylated 2-aminobenzaldehydes (2) into acridines
4.3.1. General procedure 2 for the cyclization reactions giving acridines. The cyclized products
were prepared by adapting a literature procedure.42 To the required N-arylated 2-aminobenzaldehyde
(2; 1.0 mmol) in CH3CO2H (3 mL) was added 96% H2SO4 (2.8 mmol, 0.15 mL). The reaction mixture
was stirred at 110 °C. The reaction time is given in the product description. After cooling to room
temperature, water (5 mL) was added and the reaction mixture was basified using 25% NH4OH.
Extraction using AcOEt (3x20 mL), drying over MgSO4, removal of the solvent and purification by
24

chromatography on silica gel (the eluent is given in the product description) led to the expected
compound.
4.3.2. Acridine (3a) was obtained according to the general procedure 2 (reaction time: 30 min) from
2a (0.20 g). Purification by column chromatography over silica gel (heptane-AcOEt 70:30) gave 3a in
1
94% yield (0.17 g) as a yellow solid: mp 110 °C; H NMR (CDCl3) δ 7.55 (ddd, 2H, J = 8.2, 6.6 and
1.1 Hz, H2 and H7), 7.79 (ddd, 2H, J = 8.8, 6.6 and 1.4 Hz, H3 and H6), 8.02 (d, 2H, J = 8.5 Hz, H1
and H8), 8.25 (dd, 2H, J = 8.8 and 0.8 Hz, H4 and H5), 8.79 (s, 1H, H9). These data are similar to
those obtained for a commercial sample.
4.3.3. 2-Methoxyacridine (3b) was obtained according to the general procedure 2 (reaction time: 1.5
h) from 2b (0.23 g). Purification by column chromatography over silica gel (heptane-AcOEt 70:30)
gave 3b in 80% yield (0.17 g) as a beige solid: mp 92-94 °C (lit.76 89-91 °C, after recrystallization from
Et2O-hexane); IR (ATR): 749, 782, 826, 845, 907, 959, 1026, 1114, 1136, 1169, 1217, 1275, 1313,
1
1408, 1431, 1470, 1481, 1520, 1564, 1582, 1633, 2925, 3371 cm-1; H NMR (CDCl3) δ 3.99 (s, 3H,
OMe), 7.17 (d, 1H, J = 2.7 Hz, H1), 7.48 (dd, 1H, J = 9.5 and 2.8 Hz, H3), 7.50-7.55 (m, 1H, H7),
7.69-7.75 (m, 1H, H6), 7.96 (dt, 1H, J = 8.4 and 0.6 Hz, H8), 8.14 (d, 1H, J = 9.5 Hz, H4), 8.21 (d, 1H,
J = 8.6 Hz, H5), 8.63 (s, 1H, H9); 13C NMR (CDCl3) δ 55.6 (CH3), 103.2 (CH), 125.7 (CH), 125.9
(CH), 127.0 (C), 127.6 (C), 127.7 (CH), 129.2 (CH), 129.5 (CH), 131.1 (CH), 133.8 (CH), 146.4 (C),
147.6 (C), 157.2 (C). The 1H NMR data are close to those reported previously.76
4.3.4. 3-Methoxyacridine (3c1) was obtained according to the general procedure 2 (reaction time: 3
h) from 2c (0.23 g). Purification by column chromatography over silica gel (Rf (petroleum ether-AcOEt
80:20) = 0.25) gave 3c1 in 72% yield (0.15 g) as an orange solid: mp 87-88 °C (lit.44 88-89 °C); IR
(ATR): 745, 777, 805, 844, 855, 914, 958, 968, 1015, 1131, 1144, 1173, 1208, 1278, 1294, 1309, 1409,
1
1433, 1449, 1481, 1519, 1563, 1615, 1633, 1724, 2925, 3052 cm-1; H NMR (CDCl3) δ 4.01 (s, 3H,
OMe), 7.21 (dd, 1H, J = 9.2 and 2.4 Hz), 7.46-7.51 (m, 2H), 7.76 (ddd, 1H, J = 8.7, 6.7 and 1.4 Hz),
7.86 (d, 1H, J = 9.2 Hz), 7.96 (dd, 1H, J = 8.4 and 1.2 Hz), 8.18 (d, 1H, J = 8.8 Hz), 8.67 (s, 1H, H9);
25

13C NMR (CDCl3) δ 55.8 (CH3), 105.1 (CH), 121.4 (CH), 124.9 (CH), 125.6 (C), 128.4 (CH), 128.6
1
(CH), 128.9 (C), 129.5 (CH), 130.6 (CH), 131.0 (C), 136.1 (CH), 150.8 (C), 161.7 (C). The H NMR
data are close to those reported previously.44 1-Methoxyacridine (3c2) was similarly obtained (Rf
(petroleum ether-AcOEt 80:20) = 0.40) in 25% yield (52 mg) as a yellow solid: mp 114-115 °C (lit.44
121-122 °C, after similar purification by column chromatography); IR (ATR): 736, 751, 809, 862, 914,
923, 963, 972, 1059, 1085, 1135, 1180, 1233, 1251, 1264, 1315, 1385, 1402, 1438, 1453, 1469, 1524,
1560, 1619, 1628, 1722, 1823, 1941, 2851, 2923, 2963, 3015, 3048 cm-1; 1H NMR (CDCl3) δ 4.09 (s,
3H, OMe), 6.78 (d, 1H, J = 7.4 Hz), 7.53 (ddd, 1H, J = 8.1, 6.6, 1.0 Hz), 7.68 (dd, 1H, J = 8.9 and 7.5
Hz), 7.79 (ddd, 1H, J = 8.7, 6.6 and 1.4 Hz), 7.82 (dt, 1H, J = 8.9 and 0.7 Hz), 8.03 (dt, 1H, J = 8.4 and
0.6 Hz), 8.22 (dd, 1H, J = 8.8 and 0.8 Hz), 9.21 (s, 1H, H9); 13C NMR (CDCl3) δ 56.0 (CH3), 101.8
(CH), 120.5 (C), 121.7 (CH), 125.6 (CH), 126.1 (C), 128.9 (CH), 129.3 (CH), 130.5 (CH), 130.7 (CH),
131.7 (CH), 149.2 (C), 149.8 (C), 155.5 (C). The 1H NMR data are close to those reported previously.44
4.3.5. 4-Methoxyacridine (3d) was obtained according to the general procedure 2 (reaction time: 3
h) from 2d (0.23 g). Purification by column chromatography over silica gel (Rf (heptane-AcOEt 60:40)
= 0.34) gave 3d in 98% yield (0.21 g) as a yellow solid: mp 134-136 °C (lit.77 131-135 °C); IR (ATR):
719, 735, 757, 768, 854, 937, 965, 978, 1011, 1068, 1094, 1126, 1144, 1179, 1225, 1245, 1267, 1320,
1
1367, 1403, 1464, 1491, 1523, 1560, 1626, 1719, 1919, 2925, 3005, 3058 cm-1; H NMR (CDCl3) δ
4.16 (s, 3H, OMe), 7.04 (d, 1H, J = 7.5 Hz), 7.44 (t, 1H, J = 8.0 Hz), 7.54 (ddd, 1H, J = 8.1, 6.6 and 0.9
Hz), 7.57 (dd, 1H, J = 7.6 and 0.8 Hz), 7.76 (ddd, 1H, J = 8.8, 6.6 and 1.4 Hz), 7.98 (d, 1H, J = 8.4
Hz), 8.40 (d, 1H, J = 8.8 Hz), 8.73 (s, 1H, H9); 13C NMR (CDCl3) δ 56.3 (CH3), 106.7 (CH), 120.2
(CH), 125.8 (CH), 126.2 (CH), 127.0 (C), 127.7 (C), 128.0 (CH), 130.0 (CH), 130.4 (CH), 135.9 (CH),
142.3 (C), 148.3 (C), 155.3 (C).
4.3.6. Benzo[b][1,5]naphthyridine (3e) was obtained according to the general procedure 2 (reaction
time: 2 h) from 2e (0.20 g). Purification by column chromatography over silica gel (AcOEt-heptane
50:50) gave 3e in 83% yield (0.15 g) as a white solid: mp 106 °C (lit.78 106-107 °C); IR (ATR): 666,
26

707, 751, 784, 833, 899, 1021, 1042, 1117, 1158, 1187, 1224, 1315, 1398, 1456, 1481, 1512, 1570,
1582, 1659, 2748, 2830, 3035, 3276 cm-1; 1H NMR (CDCl3) δ 7.60 (ddd, 1H, J = 8.0, 7.5 and 0.78 Hz,
H7), 7.68 (dd, 1H, J = 8.8 and 3.9 Hz, H3), 7.84 (ddd, 1H, J = 8.1, 6.6 and 1.3 Hz, H6), 8.09 (d, 1H, J
= 8.5 Hz, H8), 8.26 (d, 1H, J = 8.8 Hz, H5), 8.53 (d, 1H, J = 8.8 Hz, H4), 9.01 (s, 1H, H9), 9.06 (dd,
1H, J = 3.8 and 1.5 Hz, H2); 13C NMR (CDCl3) δ 124.9 (CH), 126.8 (CH), 128.8 (CH), 128.8 (C),
129.6 (CH), 131.2 (CH), 136.8 (CH), 137.5 (CH), 140.6 (C), 145.0 (C), 149.5 (C), 152.1 (CH). The 1H
NMR data are close to those reported previously.78
4.3.7.
Dibenzo[b,j][4,7]phenanthroline
(3f2).
To
N,N’-(1,4-phenylene)-2,2’-bis(2-
aminobenzaldehyde) (2f2; 0.33 g, 1.0 mmol) in CH3CO2H (3 mL) was added 96% H2SO4 (5.6 mmol,
0.30 mL). The reaction mixture was stirred at 110 °C for 1 h. After cooling to room temperature, water
(5 mL) was added and the reaction mixture was basified using 25% NH4OH. Extraction using AcOEt
(3x20 mL), drying over MgSO4, removal of the solvent and purification by column chromatography
over silica gel (heptane-AcOEt 80:20) gave 3f2 in 89% yield (0.25 g) as a yellow solid: mp 240 °C
(lit.45 244-245 °C); IR (ATR): 666, 752, 782, 804, 834, 859, 903, 957, 1013, 1095, 1131, 1190, 1259,
1
1322, 1378, 1455, 1480, 1504, 1556, 1620, 1663, 1734, 2853, 2920, 3053 cm-1; H NMR (CDCl3) δ
7.68 (t, 2H, J = 7.4 Hz, H2 and H11), 7.87 (ddd, 2H, J = 8.2, 7.7 and 1.2 Hz, H3 and H10), 8.14 (d, 2H,
J = 8.2 Hz, H1 and H12), 8.22 (s, 2H, H6 and H7), 8.31 (d, 2H, J = 8.7 Hz, H4 and H9), 9.46 (s, 2H,
H13 and H14); 13C NMR (CDCl3) δ 123.8 (2C), 126.8 (2C), 127.0 (2CH), 128.3 (2CH), 129.5 (2CH),
130.6 (2CH), 130.6 (2CH), 134.4 (2CH), 148.5 (2C), 149.2 (2C). The NMR data are close to those
reported previously.45
4.4. Deprotometalation-iodolysis of acridine (3a) and benzo[b][1,5]naphthyridine (3e)
4.4.1. 4-Iodoacridine (4a)50 was obtained by adapting a procedure reported previously.48a To a
stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperidine (0.25 mL, 1.5 mmol) in THF (2-3 mL)
were successively added BuLi (about 1.6 M hexanes solution, 1.5 mmol) and, 5 min later,
ZnCl2·TMEDA (0.13 g, 0.50 mmol). The reaction mixture was stirred for 15 min at 0 °C before
27

introduction of acridine (3a; 0.18 g, 1.0 mmol) at 0-10 °C. After 2 h at room temperature, a solution of
I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. The reaction mixture was stirred overnight before
addition of an aqueous saturated solution of Na2S2O3 (4 mL) and extraction with AcOEt (3 x 20 mL).
The combined organic layers were dried over MgSO4, filtered and concentrated under reduced
pressure. Purification by column chromatography over silica gel (Rf (AcOEt-heptane 20:80) = 0.73)
gave 4a in 76% yield (0.23 g) as a yellow solid: mp 120-124 °C; IR (ATR): 660, 735, 756, 921, 1307,
1456, 1505, 1609 cm-1; 1H NMR (CDCl3) δ 7.21 (dd, 1H, J = 8.3 and 7.1 Hz, H2), 7.55 (ddd, 1H, J =
8.0, 6.7 and 1.0 Hz, H7), 7.80 (ddd, 1H, J = 8.8, 6.6 and 1.4 Hz, H6), 7.95 (dd, 1H, J = 8.5 and 1.2 Hz,
H1), 7.99 (d, 1H, J = 8.5 Hz, H8), 8.36 (dd, 1H, J = 8.8 and 0.7 Hz, H5), 8.44 (dd, 1H, J = 7.1 and 1.2
Hz, H3), 8.66 (s, 1H, H9); 13C NMR (CDCl3) δ 104.2 (C, C4), 126.5 (C), 126.5 (CH), 126.6 (CH),
127.1 (C), 127.9 (CH), 129.3 (CH), 130.1 (CH), 130.7 (CH), 137.0 (CH), 140.8 (CH), 147.1 (C), 149.8
(C). Crystal data for 4a. C13H8IN, M = 305.10, monoclinic, P 21/c, a = 4.6787(7), b = 12.4539(17), c
= 18.228(3) Å, β = 94.359(5) °, V = 1059.0(3) Å3, Z = 4, d = 1.914 g cm-3, μ = 2.985 mm-1. A final
refinement on F2 with 2426 unique intensities and 136 parameters converged at ωR(F2) = 0.0543 (R(F)
= 0.0240) for 2177 observed reflections with I > 2σ(I). CCDC 2011443.
4.4.2. 4,9-Diiodobenzo[b][1,5]naphthyridine (4e) was obtained by adapting a procedure reported
previously.48a To a stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperidine (0.25 mL, 1.5 mmol)
in THF (2-3 mL) were successively added BuLi (about 1.6 M hexanes solution, 1.5 mmol) and, 5 min
later, ZnCl2·TMEDA (0.13 g, 0.50 mmol). The reaction mixture was stirred for 15 min at 0 °C before
introduction of benzo[b][1,5]naphthyridine (3e; 0.18 g, 1.0 mmol) at 0-10 °C. After 2 h at room
temperature, a solution of I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. The reaction mixture was
stirred overnight before addition of an aqueous saturated solution of Na2S2O3 (4 mL) and extraction
with AcOEt (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered and
concentrated under reduced pressure. Purification by column chromatography over silica gel (Rf
(petroleum ether-AcOEt 85:15) = 0.60) gave 4e in 15% yield (65 mg) as an orange solid: mp 232 °C;
28

IR (ATR): 679, 751, 793, 847, 857, 927, 1046, 1120, 1147, 1173, 1239, 1260, 1311, 1373, 1393, 1456,
1
1492, 1532, 1579, 1619, 1695, 1948, 2851, 2919, 3061 cm-1; H NMR (CDCl3) δ 7.72 (ddd, 1H, J =
8.4, 6.7 and 1.0 Hz, H6 or H7), 7.88 (ddd, 1H, J = 8.3, 6.7 and 1.2 Hz, H6 or H7), 8.34 (d, 1H, J = 8.7
Hz, H5 or H8), 8.39 (d, 1H, J = 4.2 Hz, H3), 8.45 (d, 1H, J = 8.8 Hz, H5 or H8), 8.65 (d, 1H, J = 4.2
13
Hz, H2); C NMR (CDCl3) δ 117.2 (C), 124.0 (C), 129.3 (CH), 130.5 (CH), 131.7 (CH), 133.0 (C),
133.2 (CH), 136.2 (CH), 140.6 (C), 143.1 (C), 149.4 (C), 152.0 (CH). Crystal data for 4e. C12H6I2N2,
M = 431.99, monoclinic, P 21/n, a = 14.3375(16), b = 4.2116(5), c = 20.411(2) Å, β = 109.389(4) °, V =
1162.6(2) Å3, Z = 4, d = 2.468 g cm-3, μ = 5.381 mm-1. A final refinement on F2 with 2661 unique
intensities and 128 parameters converged at ωR(F2) = 0.1050 (R(F) = 0.0571) for 2029 observed
reflections with I > 2σ(I). CCDC 2011444. 9-Iodobenzo[b][1,5]naphthyridine was identified by NMR
1
(<10% estimated yield) from a mixture similarly obtained: H NMR (CDCl3) δ 7.66-7.74 (m, 2H, H3
and H7), 7.82-7.88 (m, 1H, H6), 8.22 (d, 1H, J = 8.7 Hz, H5 or H8), 8.45 (d, 1H, J = 8.8 Hz, H5 or
H8), 8.50 (dd, 1H, J = 8.7 and 1.4 Hz, H4), 9.14 (d, 1H, J = 2.7 Hz, H2).
4.5. N-Arylation of pyrrolidinone using 4-iodoacridine (4a)
N-(4-acridyl)-2-pyrrolidinone (5a1) was obtained by adapting a procedure reported previously.47 A
mixture of CuI (19 mg, 0.10 mmol), K3PO4 (0.42 g, 2.0 mmol), 2-pyrrolidinone (0.17 g, 2.0 mmol) and
4-iodoacridine (4a; 0.31 g, 1.0 mmol) in DMSO (2 mL) was degassed and stirred under argon at 110
°C for 24 h. After cooling to room temperature, the reaction mixture was filtered over celite®. After
addition of H2O (25 mL) to the filtrate and extraction with Et2O (3x10 mL), the combined organic
layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by
column chromatography over silica gel (Rf (AcOEt) = 0.44) gave 5a1 in 58% yield (0.15 g) as a yellow
solid: mp 182-184 °C; IR (ATR): 666, 733, 766, 808, 858, 916, 1042, 1074, 1129, 1149, 1223, 1260,
1
1287, 1323, 1415, 1467, 1523, 1579, 1617, 1681, 2878 cm-1; H NMR (CDCl3) δ 2.37 (quint, 2H, J =
7.5 Hz, H4’), 2.76 (t, 2H, J = 8.0 Hz, H3’), 4.30 (t, 2H, J = 7.0 Hz, H5’), 7.51-7.57 (m, 2H, H2 and
H7), 7.76 (ddd, 1H, J = 8.1, 6.7 and 1.1 Hz, H6), 7.82 (dd, 1H, J = 7.1 and 1.0 Hz, H3), 7.95 (d, 1H, J
29