Synthesis of Substituted Acridines through a Palladium-Catalyzed Condensation/Cyclization/Tautomerization Sequence

Article abstract of DOI:10.1002/ejoc.201601553

Herein, we report an efficient strategy for the synthesis of 9-aryl-substituted acridines from cyclohexanones and 2-aminobenzophenones in the presence of a palladium catalyst. Molecular oxygen is applied as a green oxidant. Various cyclohexanones acted as the aryl source to construct the nitrogen-containing heterocycles through a condensation/cyclization/tautomerization sequence.

Full text of DOI:10.1002/ejoc.201601553

A Journal of
Accepted Article
Title: Facile synthesis of substituted acridines via a palladium-
catalyzed condensation/cyclization/tautomerization sequence
Authors: Xiangui Chen, Yanjun Xie, Cheng Li, Fuhong Xiao, and Guo-
Jun Deng
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COMMUNICATION
Facile synthesis of substituted acridines via a palladium-
catalyzed condensation/cyclization/tautomerization sequence
Xiangui Chen,[a] YanjunXie,[a] Cheng Li, [a] Fuhong Xiao, [a]* Guo-Jun Deng[a],[b]
*
Abstract: An efficient strategy for 9-aryl-substituted acridine
synthesis from cyclohexanones and 2-aminobenzophenones under
palladium-catalyzed conditions has been developed. Using
molecular oxygen as the green oxidant, various cyclohexanones
were acted as aryl source to construct the nitrogen-containing
heterocycles via condensation/cyclization/tautomerization sequence.
intramolecular Heck-type reaction from 2-chloroaniline and 2-
bromostyrene to produce an acridine derivative.[6] Larock et al.
synthesized an acridine derivative from 2-aminoaryl ketones and
arynes in the presence of CsF.[7] 2-Halobenzaldehydes or 2-
formyl-phenyl triflate could be smoothly reacted with anilines to
produce unsymmetrical acridine derivatives.[8] Ellman et al.
developed an Rh-catalyzed [3+3] annulation of aromatic imines
and aromatic azides to provide various substituted acridine
derivatives in reasonable yields.[9] The reaction of o-acylanilines
with diaryliodonium salts via tandem arylation/Friedel-Crafts
procedures offers an efficient alternative approach for rapidly
preparing substituted acridines.[10] The direct C-H bond
functionalization of acridine motif achieves an efficient synthetic
approach, particularly for preparing 9-aryl-substituted acridine
derivatives.[11] Although several methods are already
available,[12] efficient synthetic methods for preparing substituted
acridines under mild conditions are still highly sought-after.
Cyclohexanones are cheap, readily available and easy to
handle. These compounds could be easily dehydrogenated to
yield cyclohexenones or phenols.[13] Recently, we and others
developed various methods using these six-membered cyclic
ketones as the aryl source via the dehydrogenation-
tautomerization process.[14] Cyclohexanones and their reactive
intermediates can be trapped to form C-C,[15] C-hetero bonds,[16]
and heterocycles.[17] Reaction selectivity can be easily controlled
when cyclohexanones are used as cyclization partners to
synthesize heterocycles because the reactivities of the carbonyl
group and its ortho-position carbon are relatively different.
Therefore, using cyclohexanone as a two carbon unit and as an
aryl source for synthesizing heterocycles exhibits considerable
advantage, particularly for selectivity control. In this paper, we
report a facile 9-aryl-substituted acridine synthesis from 2-
aminobenzophenones and cyclohexanones via a palladium-
catalyzed condensation/cyclization/aromatization sequence as a
continuation of our effort to use cyclohexanones as an aryl
source for synthesizing heterocycles. During our investigation on
mechanistic study and the preparation of this manuscript, a
report about acridine synthesis under metal-free conditions is
reported by Wang and coworkers.[18]
Introduction
Acridines comprise an important class of nitrogen-containing
heterocycles that have been widely used as antibacterial,
antileukemic, antimalarial and anticancer agents (Scheme 1).[1]
Certain 9-amino-substituted acridines have been successfully
used as RNA and DNA intercalating agents.[2] Substituted
acridines have long been used as dyes and pigments; recently,
however, these chemicals have been gradually utilized as key
building blocks for electronic application because of their rigid
conjugated structure.[3] Consequently, interest in developing an
efficient approach to produce various substituted acridine
derivatives has been increasing.[4] The classic Brenthsen
reaction which uses diphenylamines and carboxylic acids as
starting materials in the presence of excess Lewis acids at 200-
o
270 C, is the earliest practical synthetic method. [5] In recent
years, numerous novel synthetic routes for generating
substituted acridines under relative mild reaction conditions have
been successfully developed. Buchwald et al. established an
Results and Discussion
Scheme 1. Representative bioactive acridines.
We began the investigation of the reaction of 2-
aminobenzophenone (1a) and cyclohexanone (2a) under
palladium catalysis reaction conditions using oxygen as the
hydrogen acceptor at 160 oC (Table 1). The corresponding 9-
phenylacridine (3a) was observed in 25% yield, as determined
by gas chromatography analysis when PdCl2/xanthphos was
used as the catalyst system and toluene was used as the
solvent (entry 1). A brief solvent screening process showed that
1,1,2,2-tetrachloroethane (TCE) is a suitable reaction medium
[a] Key Laboratory of Environmentally Friendly Chemistry and Application
of Ministry of Education, College of Chemistry, Xiangtan University,
Xiangtan
411105,
China.
E-mail:
fhxiao@xtu.edu.cn;
gjdeng@xtu.edu.cn
[b] Beijing National Laboratory for Molecular Sciences and CAS Key
Laboratory of Molecular Recognition and Function Institute of
Chemistry, Chinese Academy of Sciences (CAS) Beijing 100190
(P.R. China)
Supporting information for this article is given via a link at the end of
the document.
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Table1. Optimization of the reaction conditions.[a]
Table2. Reactions of 2-Aminobenzophenone (1a) with Cyclohexanones and
Cyclohexenone.[a]
[a] Conditions : 1a (0.2 mmol), 2a (0.3 mmol), catalyst (5 mol%), ligand (10
mol %), 1,1,2,2-tetrachloroethane (TCE, 0.6 mL), 160 oC under oxygen for 24 h.
[b] Determined by GC using trimethylbenzene as an internal standard. [c] 1a
(0.4 mmol), 2a (0.2 mmol). [d] Catalyst (10 mol%). [e] At 150 oC.
[a] Reaction conditions: 1a (0.4 mmol), 2 (0.2 mmol), PdCl2 (10 mol%), tri-
ortho-tolylphosphine (10 mol%),1,1,2,2-tetrachloroethane (TCE, 0.6 mL),
toluene (0.2 mL), 160 oC, 24 h, under oxygen atmosphere. [b] Isolated yield
based on 2. [c] 36 hours.
for this type of transformation (entry 2). Several phosphine
ligands were investigated using TCE as the solvent, and (2- Me-
Ph)3P exhibited the best efficiency (entries 3-6). A few nitrogen-
containing ligands were also tested, and good yield was
achieved when bipyridine was used (entry 8). Other palladium
salts were less efficient than PdCl2 and lower yields were
obtained (entries 10-13). The reaction yield was slightly
increased when a mixture of TCE/toluene (v/v = 3/1) was used
as the solvent (entry 15). When the excess of 1a was used, 3a
was obtained in 85% yield (entry 17). Reaction yield was further
increased to 90% when 10 mol% of PdCl2 was used (entry 18).
Reaction efficiency was significantly reduced when the reaction
temperature was decreased (entry 19).
decreased when a bulky or long chain alkyl substituent was
present (entries 5-7). The presence of a phenyl group at the
para position significantly decreased reaction yield to 50% (entry
8). A similar yield was obtained when an ester functional group
was present (entry 9). The position of the substituent profoundly
affected reaction yields. When 2-methylcyclohexanone (2j) and
3-methylcyclohexanone (2k) were used, 3j and 3k were
obtained in 38% and 62% yields, respectively (entries 10 and
11). When 2-chlorocyclohexanone (2l) was used, 3a was
obtained as the only product via the cleavage of the C-Cl bond
(entry 12). Interestingly, a considerably lower yield was obtained
when more reactive cyclohexenone (2m) was used (entry 13).
After screening various cyclohexanones for this type of
reaction, we then investigated different 2- aminobenzophenones
to further explore reaction scope and limitations (Table 3).
Several substituents at the para position of the amino group
were investigated under the aforementioned conditions, and
good yields were obtained when methyl, chloro and bromo
Given these optimized conditions, a variety of cyclohexanones
were examined under optimized reaction conditions, as
summarized in (Table 2). Various cyclohexanones with electron-
donating groups at the para position of the carbonyl group were
able to react efficiently with 1a to provide 9-phenyl-substituted
acridines in good yields (entries 2-7). The reaction yield slightly
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Table 3. Reactions of various 2-aminobenzophenones (1) with cyclohexanone
(2a) a
90% yield when a chloro was located at the meta position of the
carbonyl group. Interestingly, when two halogen substituents
existed in both rings of 2-aminobenzophenone, the
corresponding functionalized products which could be easily
converted further into other useful compounds could be obtained
in
good
yields
(3v-3y).
Furthermore,
2-bromo-9-(2-
fluorophenyl)acridine (3y) could smoothly couple with
phenylacetylene under palladium catalyzed reaction conditions
to provide 9-(2-fluorophenyl)-2-(phenylethynyl)acridine (5a) in
85% yield (Scheme 2).
A plausible reaction pathway to rationalize this reaction is
illustrated in (Scheme 3). The condensation reaction of 2-
aminobenzophenone (1a) with cyclohexanone (2a) yields an
imine intermediate A, which can further isomerize into an
enamine intermediate B. The cyclization of B under acidic
reaction conditions19 affords
C to convert into 4a via
dehydration.8a,20 A dehydrogenative-tautomerization sequence
under palladium-catalyzed conditions used oxygen as the
oxidant to achieve the final product 3a.15a,17c, 21,
Scheme 3 . Plausible reaction mechanism.
[a] Conditions : 1 (0.4 mmol), 2a (0.2 mmol), PdCl2 (10 mol%), tri-ortho-
tolylphosphine (10 mol%), 1,1,2,2-tetrachloroethane (TCE, 0.6 mL), toluene (0.2
mL), 160 oC, 24 h, under oxygen atmosphere. [b] Isolated yield based on 2a.
Conclusions
In summary, we developed a novel approach for 9-aryl-
substituted acridines from 2-aminobenzophenones and
substituents were employed (3b-3m). However, reaction was
inefficient when a strong electron-withdrawing nitro group was
present (3n). When a fluoro group was present at the meta
position of the amino group, the desired product 3o was
obtained in 75% yield. The effect of the substituent under
different phenyl rings was also investigated. Good yield was
obtained when a methyl group existed to provide 3p in 73% yield.
Interestingly, product 3q was obtained in 90% yield when a more
steric tert-butyl substituent was used. Halogen groups such as
fluoro and chloro were compatible to give the desired products
3r-3t with good yields. The desired product 3u was obtained in
cyclohexanones
via
a
sequence
of
condensation/cyclization/aromatization procedure. Cheap and
readily available cyclohexanones were used as the aryl source
via dehydrogenation/tautomerization process in an oxygen
atmosphere. The significant reactivity difference between the
carbonyl group and the ortho carbon in cyclohexanone provided
a simple selectivity control process. This method offered an
efficient alternative approach for rapidly synthesizing of 9-aryl-
substituted acridines from aromatic and non-aromatic substrates.
Experimental Section
General information: All reactions were carried out under an
atmosphere of oxygen unless otherwise noted. Column chromatography
was performed using silica gel 48-75 μm. 1H NMR and 13C NMR spectra
were recorded on Bruker-AV (400 and 100 MHz, respectively) instrument
internally referenced to tetramethylsilane (TMS) or chloroform signals.
Scheme 2. Alkynylation of 3y under palladium-catalysis conditions.
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Mass spectra were measured on Agilent 5975 GC-MS instrument (EI).
High-resolution mass spectra were recorded at the Institute of Chemistry,
Chinese Academy of Sciences. The structures of known compounds
were further corroborated by comparing their 1H NMR, 13C NMR data and
MS data with those of literature. Most reagents were obtained from
commercial suppliers and used without further purification.
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This work was supported by the National Natural Science
Foundation of China (21372187, 21502160, 21572194), the
Program for Innovative Research Cultivation Team in University
of Ministry of Education of China (1337304), and the Hunan
Provincial
Innovative
Foundation
for
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(CX2015B202).
Keywords: acridines; cyclohexanones; 2-aminobenzophenones;
palladium; dehydrogenation.
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COMMUNICATION
Condensation, cyclization
Xiangui Chen, YanjunXie, Cheng Li,
Fuhong Xiao, Guojun Deng.
Page No. – Page No.
Facile synthesis of substituted
acridines via a palladium-catalyzed
condensation/cyclization/tautomerizat
-ion sequence
An efficient strategy for 9-aryl-substituted acridine synthesis from cyclohexanones
and 2-aminobenzophenones under palladium-catalyzed conditions has been
developed. Using molecular oxygen as the green oxidant, various cyclohexanones
were acted as aryl source to construct the nitrogen-containing heterocycles via
condensation/cyclization/tautomerization sequence.
This article is protected by copyright. All rights reserved.