Facile synthesis of acridine derivatives by ZnCl2-promoted intramolecular cyclization of o -arylaminophenyl schiff bases

Article abstract of DOI:10.1021/ol402732n

A concise and efficient method for the synthesis of a wide range of acridine derivatives and polycyclic aza-aromatic compounds from a ZnCl ₂-promoted cyclization reaction of readily available o-arylaminophenyl Schiff base compounds under convenient conditions was developed. Reaction conditions and scope of the new method were examined in detail.

Full text of DOI:10.1021/ol402732n

Letter
pubs.acs.org/OrgLett
Facile Synthesis of Acridine Derivatives by ZnCl2‑Promoted
Intramolecular Cyclization of o‑Arylaminophenyl Schiff Bases
Qing Su, Pei Li, Mina He, Qiaolin Wu,* Ling Ye, and Ying Mu*
State Key Laboratory of Supramolecular Structure and Materials, School of Chemistry, Jilin University, 2699 Qianjin Street,
Changchun 130012, People’s Republic of China
S
* Supporting Information
ABSTRACT: A concise and efficient method for the synthesis of a wide range of acridine derivatives and polycyclic aza-aromatic
compounds from a ZnCl2-promoted cyclization reaction of readily available o-arylaminophenyl Schiff base compounds under
convenient conditions was developed. Reaction conditions and scope of the new method were examined in detail.
related polycyclic aza-aromatic compounds, such as benzo[j]-
cridines as an important class of heteroaromatic
Acompounds have attracted considerable interest because [1,7]phenanthroline, dibenzo[b,j][4,7]phenanthroline,
dibenzo[b,j][1,7]phenanthroline, and acridino[4,3-c]acridine,
from a ZnCl2-promoted cyclization reaction of o-arylamino-
phenyl Schiff base compounds.
of their novel hetreocycle chemistry, broad range of properties,
and industrial applications.1 It has been well-known that
acridine derivatives possess versatile biological activities2 such
as antibacterial, antimalarial, and anticancer. Some acridine
compounds have been studied as DNA and RNA intercalating
agents.3 Acridine derivatives and related compounds have been
applied in industry as pigments and dyes for long time.4
Recently, acridine derivatives with extended conjugated systems
were reported to exhibit unusual electronic and photophysical
properties, which are expected to be promising candidates for
organic semiconductor materials.5 Therefore, many efforts have
been focused on the development of synthetic methods for the
construction of a variety of acridine derivatives. The Brenthsen
reaction is one of the earliest used methods for the preparation
of acridines, which is achieved by heating a diphenylamine and
a carboxylic acid together with ZnCl2 under 200−270 °C.6 The
most common method for preparing acridines is by the
reduction of 9-acridanones and 9-chloroacridines, which are
readily available from the cyclization of diphenylamine-2-
carboxylic acids.7 The synthetic methods for acridine
derivatives by cyclization of diphenylamine-2-aldehydes or
diphenylamine-2-ketones were also reported, but the starting
aldehydes and ketones are difficult to prepare.8 A small number
of acridines were also synthesized by dehydrogenation,9 C−H
functionalization,10 or other reactions.11 Most of these known
synthetic methods require either harsh reaction conditions,
such as high temperature, strongly basic or acidic media, or
difficultly obtained starting materials. Therefore, it is highly
desirable to develop new synthetic methods for acridine
derivatives under relatively mild conditions. Herein, we report
an efficient method to synthesize acridine derivatives and
In an attempt to synthesize new Zn complexes chelated by
anilido-imine ligands from reactions of ZnCl2 with o-
arylaminophenyl Schiff base compounds, acridine derivatives
were obtained instead of the expected Zn complexes. We
therefore began to investigate the cyclization reaction of the o-
arylaminophenyl Schiff base compounds in the presence of
ZnCl2 in detail. Treatment of o-C6H4(CHNC6H5)(NC6H5)
1 with 0.5−2 equiv of ZnCl2 in THF at 50−80 °C for 24 h
resulted in acridine 1a in 35−99% yields (Table S1, Supporting
Information). Relatively low yields were obtained when the
reaction was carried out in other common organic solvents,
such as toluene, benzene, CH2Cl2, or CHCl3. (PhNH2)2·ZnCl2
adduct was also obtained from the reaction by concentrating
the reaction solution, and its crystal structure was determined
(Table S2, Supporting Information). High ZnCl2 loadings
(100−200 mol %) were found to accelerate the cyclization
reaction probably because ZnCl2 could be coordinated by both
the amine and imine groups in the starting material and by the
produced acridine and aniline in the reaction system. After the
reaction conditions were briefly optimized, this new synthetic
method has been applied to prepare a range of acridines with
different substituents by varying the o-arylaminophenyl Schiff
base substrates, and the results are listed in Table 1.
The cyclization reactions of the substrates o-C6H4(CH
NC6H4-Me-p)(NC6H4-Me-p) (2) and o-C6H4(CHNC6H3-
Received: September 21, 2013
© XXXX American Chemical Society
A
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Letter
a
Table 1. Results of the ZnCl2-Promoted Cyclization Reactions of o-Arylaminophenyl Schiff Base Compounds
a
b
c
Reactions were performed at 80 °C for 24 h on a 0.20 mmol scale in 2 mL of solvent with 1.0 equiv of ZnCl2. Isolated yield. With 2.0 equiv of
d
ZnCl2. Determined by NMR analysis.
R2-2,6)(NC6H4-Me-p) (R = Me, 3; R = Et, 4) with less
sterically demanding substituents on their imine N atoms
proceeded smoothly to give 2-methylacridine 2a with similar
yields (70−76%, entries 2−4). However, the substrate 5 with a
bulky 2,6-iPr2Ph on the imine N atom was found to be
unsuitable for the cyclization reaction (entry 5). When the o-
methoxy-substituted substrate 6 was employed, 4-methoxyacri-
dine 6a was obtained in a high yield of 95% (entry 6). The
cyclization reaction of the o-methyl-substituted substrate 7
proceeded efficiently to produce 4-methylacridine 7a in similar
yields (entry 7) to those for the reactions of substrates 3 and 4.
Notably, the cyclization of the m-chloro-substituted substrate 8
produced a 3:2 mixture of acridines 8a and 8b in a total yield of
86% (entry 8). Similar to the reaction of 6, the cyclization
reaction of the p-methoxy-substituted substrate 9 produced 2-
methoxyacridine 9a in a high yield of 97% (entry 9). With these
results, it is evident that the reactivity of the o-arylaminophenyl
Schiff base substrates and the regioselectivity of their products
are sensitive to the electronic and steric effects of the aryl
substituents at both the amine and imine N atoms. In
comparison, the steric effect of the aryl substituent at the
imine N atom and the electronic effect of the aryl substituent at
the amine N atom on the reactivity of these substrates seem to
be more remarkable.
Two naphthalene-based substrates 10 and 11 were also
examined for the intramolecular cyclization reaction. As
expected, a tetracyclic acridine derivative benz[c]acridine 10a
was obtained from the reaction of 10 in a yield of 49% (entry
10). In the case of the substrate 11, the cyclization reaction
regioselectively proceeded at the 1-position of the 2-naphthyl-
amine moiety, producing benz[a]acridine 11a in a yield of 62%
(entry 11). In a previously reported example, fluorobenz[c]-
acridines were synthesized by thermolysis of arylenaminoimine
hydrochlorides and subsequent aromatization of the inter-
mediates with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ)-chlorobenzene systems.12
In our further studies, two 7-quinoline-substituted derivatives
12 and 13 were synthesized and used as the substrates of the
cyclization reaction. 2,4-Dimethylbenzo[j][1,7]phenanthroline
12a was obtained in high yields of 96% and 95%, respectively,
from the reactions of 12 and 13 in the presence of 1 equiv of
ZnCl2 in THF (eq 1). The molecular structure of 12a was
confirmed by X-ray diffraction analysis as shown in Figure 1.
The fact that compound 12a was formed as only product in the
reactions indicates that, in comparison to the 6-position, the 8-
position of the 2,4-dimethylquinoline moiety is much more
easily attacked by the electrophilic group. From a structural
point of view, it seems abnormal for the quinoline-containing
substrates 12 and 13 showing higher reactivities than the
B
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Table 2. Synthesis of Dibenzo[b,j][4,7]phenanthrolin,
Dibenzo[b,j][1,7]phenanthrolin, and Acridino[4,3-
a
c]acridine by the Cyclization Reaction
Figure 1. Molecular structure of 12a.
naphthalene-based substrates 10 and 11. The two electron-
donating methyl groups on the quinoline moiety in 12 and 13
are apparently responsible for the high reactivities of the two
compounds. In addition, the two methyl substituents in
product 12a would provide opportunities for further structural
modification such as halogenation, acylation, and carboxyla-
tion.7d,13
a
Reactions were performed on a 0.10 mmol scale in 2 mL of solvent at
b
c
80 °C for 24 h using 2.0 equiv of ZnCl2. Isolated yield. Using 4.0
equiv of ZnCl2.
acridino[4,3-c]acridine 16a was obtained from the double
cyclization reaction of the naphthalene-1,5-diamine-derived
substrate 16. The isolated yield of 16a is lower than those of
14a and 15a, indicating that the reactivity of 16 is relatively low
in comparison to the ones of 14 and 15. Above results
demonstrates that the new cyclization reaction can been applied
to the synthesis of complex polycyclic heteroaromatic
compounds.
On the basis of our investigations and reported similar
results,8a a plausible mechanism for the cyclization reaction of
o-arylaminophenyl Schiff base compounds is shown in Scheme
1. The imine N atom in the o-arylaminophenyl Schiff base
coordinates to ZnCl2 to form a ZnCl2 complex, in which the Zn
atom induces a polarization of the imine CN bond to make
the C atom positively charged. The cyclization reaction then
takes place by an intramolecular electrophilic attack of the C
In order to further screen the scope of this new ZnCl2-
promoted cyclization reaction of o-arylaminophenyl Schiff base
compounds, we have synthesized three new bis(o-arylamino-
phenyl Schiff base) substrates 14−16 as shown in Table 2 and
investigated their intramolecular cyclization reactions under
different conditions. For the reactions of 14, a polycyclic
heteroaromatic compound dibenzo[b,j][4,7]phenanthrolin 14a
was isolated as the only product in all cases. It is not very clear
why the expected linear product quino[2,3-b]acridine was not
formed in the reactions. When the reactions were carried out at
80 °C for 24 h in the presence of 2 or 4 equiv of ZnCl2 (entries
1 and 2, Table 2), 14a was obtained in a yield of 28% or 50%,
respectively. The reaction was found to be quite sensitive to
temperature. When the reaction was run at 60 °C for 48 h in
the presence of 2 equiv of ZnCl2, 14a was obtained in a yield of
only 10%. As in the case of 14, a bent polycyclic heteroaromatic
compound dibenzo[b,j][1,7]phenanthroline 15a was obtained
as the only product from the reactions of substrate 15. No
linear product was obtained. By comparing the yields of 14a
and 15a obtained under similar conditions, it can be seen that
the reactivity of 15 is abviously higher than the one of 14.
The observed regioselectivity for the reactions of 14 and 15
suggests that the double-cyclization reactions in these systems
happen sequentially, and the electrophilic attack for both
cyclization reactions takes place at the most active ortho-
position or one of the equally active ortho-positions of an amine
group in the substrates or intermediates. Attempts to observe
Scheme 1. Plausible Mechanism for the Cyclization Reaction
of ortho-Arylaminophenyl Schiff Base Compounds
1
the intermediates by following the reactions with H NMR
were not successful. Similar regioselectivity has been observed
previously for the acid-catalyzed cyclization of (phenylendi-
amino)bisbenzophenone and (phenylendiamino)bisaceto-
phenone.14 The expected polycyclic heteroaromatic product
C
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Letter
P.; Sun, J.-S.; Garestier, T.; Hel
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atom on the aromatic ring at an ortho-position of the amine
group in the substrate to generate a zwitterionic intermediate.
The allylic carbocation is deprotonated by transferring the
proton to the nitrogen anion to form a substituted 9,10-
dihydroacridine which is unstable and aromatization reaction
happens by splitting off an aniline molecule. Similar
aromatization reactions of 1,4-dihydropyridine derivatives to
form pyrazolo[3,4-b]quinoline, acridine, and pyrimido[4,5-
b]quinoline derivatives have been reported in the literature.15
In summary, we have developed a concise and efficient
method for the synthesis of acridine derivatives by a ZnCl2-
promoted cyclization reaction of readily available o-arylamino-
phenyl Schiff base compounds. This new cyclization reaction
can also be applied to the synthesis of complex polycyclic aza-
aromatic compounds by double cyclization reactions of bis(o-
arylaminophenyl Schiff base) substrates.
ASSOCIATED CONTENT
* Supporting Information
■
S
Synthetic procedures and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) (a) Hounsou, C.; Guittat, L.; Monchaud, D.; Jourdan, M.;
Saettel, N.; Mergny, J.-L.; Teulade-Fichou, M.-P. Chem. Med. Chem.
2007, 2, 655. (b) Kitahara, Y.; Mizuno, T.; Kubo, A. Tetrahedron 2004,
60, 4283. (c) Sakaguchi, S.; Shibamoto, A.; Ishii, Y. Chem. Commun.
2002, 180. (d) Raja, R.; Thomas, J. M.; Greenhill-Hooper, M.; Ley, S.
V.; Paz, F. A. A. Chem.Eur. J. 2008, 14, 2340.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wuql@jlu.edu.cn.
*E-mail: ymu@jlu.edu.cn.
Notes
(14) (a) Hellwinkel, D.; Ittemann, P. Liebigs Ann. Chem. 1985, 7,
1501. (b) Watanabe, M.; Suzuki, H.; Tanaka, Y.; Ishida, T.; Oshikawa,
T.; Torii, A. J. Org. Chem. 2004, 69, 7794.
The authors declare no competing financial interest.
(15) Dzvinchuk, I. B.; Tolmachova, N. A.; Chernega, A. N.; Lozinskii,
M. O. Chem. Heterocycl. Com. 2009, 45, 194.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Grant Nos. 21004026, 21074043,
51173061, and 21274050). Q.S. acknowledges the support of
the Frontiers of Science and Interdisciplinary Innovation
Project from Jilin University (Grant No. 450060445023).
REFERENCES
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