Synthesis and characterization of 8-(2-((trimethylsilyl)ethynyl) phenylamino)-7H-naphtho[1,8-bc]acridin-7-one

Article abstract of DOI:10.1080/00397910802369539

An unexpected heterocyclic cyclization reaction of acenaphthenequinone and 2-(trimethylsilylethynyl)aniline in the presence of p-toluenesulfonic acid is reported. A new heterocyclic aromatic compound, 8-(2-((trimethylsilyl)ethynyl) phenylamino)-7H-naphtho[1,8-bc]acridin-7-one, was synthesized as the sole isolated reaction product and characterized by elemental analysis; NMR, IR, and UV spectroscopies; mass spectrometry, and single-crystal x-ray diffraction. Copyright Taylor & Francis Group, LLC.

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Synthesis and
Characterization of 8-(2-
((Trimethylsilyl)ethynyl)phenylamin
naphtho[1,8-bc]acridin-7-one
Lidong Li a , Clara S. B. Gomes a , Pedro T. Gomes a
& M. Teresa Duarte a
a Centro de Química Estrutural, Departamento de
Engenharia Química e Biológica, Instituto Superior
Técnico, Lisboa, Portugal
Published online: 08 Nov 2008.
To cite this article: Lidong Li , Clara S. B. Gomes , Pedro T. Gomes
& M. Teresa Duarte (2008) Synthesis and Characterization of 8-(2-
((Trimethylsilyl)ethynyl)phenylamino)-7H-naphtho[1,8-bc]acridin-7-one, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:24, 4415-4425, DOI: 10.1080/00397910802369539
To link to this article: http://dx.doi.org/10.1080/00397910802369539
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Synthetic Communications1, 38: 4415–4425, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802369539
Synthesis and Characterization
of 8-(2-((Trimethylsilyl)ethynyl)phenylamino)-
7H-naphtho[1,8-bc]acridin-7-one
Lidong Li, Clara S. B. Gomes, Pedro T. Gomes,
and M. Teresa Duarte
´
´
Centro de Quımica Estrutural, Departamento de Engenharia Quımica e
ꢀ
Biologica, Instituto Superior Tecnico, Lisboa, Portugal
´
Abstract: An unexpected heterocyclic cyclization reaction of acenaphthenequi-
none and 2-(trimethylsilylethynyl)aniline in the presence of p-toluenesulfonic
acid is reported. A new heterocyclic aromatic compound, 8-(2-((trimethylsilyl)-
ethynyl)phenylamino)-7H-naphtho[1,8-bc]acridin-7-one, was synthesized as
the sole isolated reaction product and characterized by elemental analysis;
NMR, IR, and UV spectroscopies; mass spectrometry, and single-crystal
x-ray diffraction.
Keywords: Acenaphthenequinone, acridine, cyclization, heterocycle, 2-(trimethyl-
silylethynyl)aniline
INTRODUCTION
Compounds of the acridine family constitute a large class of cytotoxic
agents available from natural sources.[1] Some of their derivatives have
demonstrated antitumor, antibacterial, or anticancer activities.[2] Their
cytotoxicities have been proven to stem from their abilities to bind
DNA by intercalation and interface with various metabolic processes in
both prokaryotic and eukaryotic cells. It has been demonstrated that
Received March 17, 2008.
Address correspondence to Pedro T. Gomes, Centro de Quımica Estrutural,
´
Departamento de Engenharia Quımica e Biologica, Instituto Superior Tecnico,
ꢀ
Av. Rovisco Pais, 1049-001 Lisboa, Portugal. E-mail: pedro.t.gomes@ist.utl.pt
´
´
4415

4416
L. Li et al.
the structural extension of the planar aromatic rings of the acridine series,
via fusing five- or six-membered heterocyclic rings as part of the
molecule, may substantially improve their cytotoxicities.[3] In addition,
the structural extension of the planar rings also has contributed to
overcoming multidrug resistance of this kind of antitumor agents.[4]
Therefore, many efforts have been devoted to design new cytotoxic agents
through expanding the planar structures of the acridine series, for exam-
ple, 7H-pyrido[4,3,2-kl]acridine (A), 11H-pyrido[4,3,2-mn]acridine (B),[5]
pyrido[2,3,4-kl]acridin-4-one (C),[6] 2,7-dihydro-3H-pyridazino[5,4,3-kl]-
acridin-3-one (D),[7] or (1,3-benzothiazol-2-yl)amino-9-(10H)-acridinone
(E) (Chart 1).[8] However, the syntheses of these compounds generally
need several synthetic steps and time-consuming repeated separations.
In this report, we describe a new heterocyclic acridine derivative, 8-
(2-((trimethylsilyl)ethynyl)phenylamino)-7H-naphtho[1,8-bc]acridin-7-one
(1), containing an aromatic five-fused ring heterocyclic system, which was
prepared by a single-step reaction of two commercially available
reagents, acenaphthenequinone and 2-(trimethylsilylethynyl)aniline, via
an unexpected heterocyclic cyclization reaction.
RESULTS AND DISCUSSION
Reaction of acenaphthenequinone with 2 equivalents of 2-(trimethylsily-
lethynyl)aniline catalyzed by p-toluenesulfonic acid gave the new hetero-
cyclic compound 8-(2-((trimethylsilyl)ethynyl)phenylamino)-7H-naphtho
[1,8-bc]acridin-7-one (1) (Scheme 1). After 3 days in refluxing toluene,
Chart 1. Some cytotoxic agents of the acridine series.

Synthesis of Acridine Derivative
4417
Scheme 1. Reaction of acenaphthenequinone with 2 equivalents of 2-(trimethyl-
silylethynyl)aniline catalyzed by p-toluenesulfonic acid.
bright red crystals of 1 were obtained as the single reaction product, in
35% yield, with the starting material acenaphthenequinone the only
other product recovered in the reaction workup. The experimental
conditions used were similar to those used in typical dehydrating con-
densation reactions for the synthesis of mono- or diimines.[9] However,
compound 1 is apparently very different from the expected diimine. It
can be inferred that this difference should derive from the role played
by the aniline ortho trimethylsilylethynyl substituent, because reactions
of acenaphthenequinone with other ortho-substituted anilines (e.g., 2,6-
dimethylaniline, 2,6-diisopropylaniline, etc.), in the presence of acids,
have been widely used to synthesize a-diimine compounds.[9b–d]
Figure 1. ORTEP diagram of compound 1 using 50% probability level ellipsoids: (a)
top view and (b) side view. Calculated hydrogen atoms are omitted for clarity.
˚
Selected bond distances and torsion angles: O1–C20 1.243(5)A, N2–C18 1.372(5)A,
˚
ꢁ
˚
˚
N2–C21 1.404(5)A, N2–H02ꢀ ꢀ ꢀ O1 1.762(5)A, C21–N2–C18–C17 43.4(6) , C18–
N2–C21–C26 ꢂ 171.1(4)ꢁ, N2–C21–C26–C27 2.8(6)ꢁ, C26–C27–C28–Si1 ꢂ 23(10)ꢁ.

4418
L. Li et al.
The crystal structure of 1 was determined by x-ray diffraction, the
corresponding molecular structure being represented in Fig. 1. It can
be noticed that the 7H-naphtho[1,8-bc]acridin-7-one backbone is vir-
tually planar, being staggered in relation to the aniline plane by 55.8ꢁ
(Fig. 1b). The planarity of the backbone indicates the p-electrons are
delocalized over the whole plane, imparting rigidity to this heterocycle.
A short intramolecular hydrogen bond occurs between the amide
hydrogen atom H02 and the carbonyl oxygen atom O1, consistent
˚
˚
with a distance N2–H02 ꢀ ꢀ ꢀ O1 of 1.760(5) A [N2 ꢀ ꢀ ꢀ O1 2.603(5) A,
N2–H02 ꢀ ꢀ ꢀ O1 144.4(5)ꢁ].
The H and 13C NMR spectra of compound 1 show all the proton
1
and carbon resonances expected. The characteristic carbons of C¼O,
–N¼C, –C–N¼, –C–NH–C6H4–, –NH–C6H4–, Si–CꢃC, and –CꢃC–
C6H4–, whose resonances appear at dC 186.49, 153.08, 150.22, 153.94,
144.12, 101.68, and 101.07, respectively, were identified by using
1
2-dimensional pulse sequences such as H-1H correlation spectroscopy
(COSY), heteronuclear singular quantum coherence (HSQC), and
heteronuclear multiple bond correlation (HMBC) techniques. The NH
proton was readily assigned, in the 1H NMR spectrum, as a broad
low-field shifted resonance, at dH 13.34, at room temperature, consistent
with the intramolecular hydrogen bond observed by x-ray diffraction.
The UV-vis spectra, taken both in dioxane and chloroform, are repre-
sented in Fig. 2. They show a typical p–pꢄ absorption band at
kmax ¼ 320 nm (e ¼ 31960 l ꢀ molꢂ1 ꢀ cmꢂ1) that can be assigned to the
ethynylphenyl conjugated system, which is comparable to those of other
ethynylphenyl groups.[10] The absorption band at kmax ¼ 462 nm
Figure 2. UV-vis absorption spectra of compound 1 in dioxane (black) and
chloroform (gray).

Synthesis of Acridine Derivative
4419
(e ¼ 14160 l ꢀ molꢂ1 ꢀ cmꢂ1) is consistent with the more extended aromatic
system of the 7H-naphtho[1,8-bc]acridin-7-one backbone.
The reactivity of acenaphthenequinone toward nucleophilic
reagents has been studied and discussed,[11] but, to the best of our
knowledge, the cyclization reaction reported herein has never been
described. Although the experimental evidences have not been obtained,
considering the molecular structure of compound 1, a possible reaction
mechanism can be put forward (Scheme 2). One of the carbonyl groups
of acenaphthenequinone reacts with the first equivalent of aniline, lead-
ing to the formation of mono-imine a, which is a well-known condensa-
tion reaction of ketone and aniline.[9a] It can be envisaged that the
trimethylsilylethynyl group, behaving as a nucleophile, further reacts
with the remaining unreacted carbonyl group to undergo an intramole-
cular cycloadditon reaction, giving rise to intermediate b. The latter will
react with a second equivalent of 2-(trimethylsilylethynyl)aniline, by
addition to the alkyne triple bond, giving rise to an enamine intermedi-
ate c, which is a typical reaction of a primary amine with an alkyne.[12]
Generally, enamine intermediates are unstable and would tautomerize
to the more stable imine. However, in this case, an intramolecular rear-
rangement (c0) leads to the elimination of trimethylsilane, producing the
thermodynamically more stable aromatic five-fused ring heterocyclic
compound 1.
Scheme 2. A possible reaction mechanism for the formation of compound 1.

4420
L. Li et al.
In conclusion, the unexpected one-step, acid-catalyzed cycloaddition
reaction of commercially available acenaphthenequione and 2-(trimethyl-
silylethynyl)aniline afforded the new aromatic heterocyclic compound 1.
Characterization of this compound by NMR, UV, IR, MS, and single-
crystal x-ray diffraction shows it contains a large p-electron delocalized
backbone constituted by five fused aromatic rings. Similar to other
acridine analogs, compound 1 may be envisaged as a potential candidate
to exhibit antitumor, antibacterial, or anticancer activities.
EXPERIMENTAL
General
All experiments were conducted under an inert atmosphere using a
dual vacuum=nitrogen line and standard Schlenk techniques, with
the corresponding workup carried out in air. Toluene was purified
over sodium=benzophenone ketyl and distilled prior to use. Acenaphthe-
nequinone, 2-(trimethylsilylethynyl)aniline, and p-toluenesulfonic acid
monohydrate were purchased from Aldrich and used as received.
The melting point was measured on a Leica Galen III hot-stage
apparatus and is uncorrected. NMR spectra were recorded in CDCl3,
1
on a Bruker Avance III 300 (300.13 MHz for H, and 75.47 MHz for
13C), and chemical shifts were reported relative to the internal standard
TMS. Infrared spectra were recorded on a Jasco FT=IR-4100A spectro-
meter. UV-visible spectra of solutions of 1 (10ꢂ5 M), in dioxane and
chloroform, were recorded on a Beckman DU-70 spectrophotometer.
Mass spectra (MS) were recorded on a 500 MS LC ion trap (Varian,
Inc., Palo Alto, Calif., USA) mass spectrometer equipped with an ESI
source, in which the spray voltage was set at ꢅ5 kV and the capillary vol-
tage was set at 10 V. The elemental analysis was obtained from the ITN
´
(Sacavem, Portugal) elemental analysis service.
8-(2-((Trimethylsilyl)ethynyl)phenylamino)-7H-naphtho[1,8-bc]acridin-7-
one (1)
Toluene (60 ml) was added to a mixture of acenaphthenequinone
(0.40 g,
2.20 mmol)
and
2-(trimethylsilylethynyl)aniline
(1.0 g,
5.28 mmol, 2.4 equiv), followed by addition of p-toluenesulfonic acid
monohydrate (41.8 mg, 0.22 mmol, 0.1 equiv). The mixture was refluxed
for 3 days. After removing the solvent in vacuum, a red=brown solid

Synthesis of Acridine Derivative
4421
was obtained. This solid was dissolved in chloroform (ca. 5 ml), and the
solution was added dropwise into n-hexane (ca. 60 ml) with stirring. A
yellow solid (unreacted acenaphthenequinone, as confirmed by NMR)
was precipitated and filtered. The filtrate was collected, and an oran-
ge=red solid was isolated after removing the solvent in vacuum. This
orange=red solid was purified by recrystallization in ethyl acetate at
ꢂ20 ꢁC. Compound 1 was obtained as bright red crystals, with mp
235–236 ꢁC. Yield: 35%.
1H NMR (CDCl3, 300 MHz): dH 13.34 (s, 1H), 9.36 (d, J ¼ 7.4 Hz,
1H), 8.72 (d, J ¼ 7.3 Hz, 1H), 8.24 (d, J ¼ 8.2 Hz, 1H), 8.09 (m, 2H),
7.79 (m, 4H), 7.56 (d, J ¼ 8.6, 1H), 7.22 (m, 1H), 7.11 (m, 3H), 0.14 (s,
9H). 13C NMR (CDCl3, 75.47 MHz): dC 186.49, 153.94, 153.08, 150.22,
144.12, 134.41, 133.10, 132.48, 131.77, 130.99, 130.12, 129.00, 128.96,
128.81, 128.73, 128.59, 127.57, 127.03, 126.61, 126.33, 124.24, 123.82,
122.10, 118.94, 117.12, 109.95, 101,68, 101.07, 0.30. UV-vis (dioxane or
chloroform): kmax 320 (e ¼ 31960 l ꢀ molꢂ1 ꢀ cmꢂ1), 462 (e ¼ 14160 l ꢀ
molꢂ1 ꢀ cmꢂ1) nm. IR (KBr disc): 3446 (NH), 2153 (CꢃC), 1736
(C ¼ O), 1630 (NH), 1570 (Ar-H) cmꢂ1. ESI-MS: m=z 469 [M þ H]þ
(calcd. for C31H25N2 OSi [M þ H]þ, 469). Anal. calcd. for C31H24N2OSi:
C, 79.45; H, 5.16; N, 5.98%. Found: C, 79.35; H, 4.86; N, 5.90%.
X-Ray Crystallography
Single crystals suitable for x-ray characterization were grown from a
dilute ethyl acetate solution, at ꢂ20ꢁC. Crystal data for compound 1
was collected in a Bruker AXS-Kappa Apex II diffractometer equipped
with an Oxford Cryosystems open-flow nitrogen cryostat, at 150 K,
˚
using graphite monochromated Mo-Ka radiation (k ¼ 0.71069A). Cell
parameters were retrieved using Bruker Smart software and refined
using Bruker Saint on all observed reflections. Absorption corrections
were applied using SADABS.[13] Structure solution and refinement were
performed using direct methods with the programs SIR92[14] and
SHELXL,[15] both included in the package of programs WINGX ver-
sion 1.70.01.[16] Non hydrogen atoms were refined with anisotropic ther-
mal parameters. Except for H02, which was found in the difference
electron density map and was allowed to refine freely, all hydrogens
were inserted in idealized positions and allowed to refine riding in the
parent C atoms. All remaining crystal data and refinement parameters
are presented in Table 1. Graphic presentations were prepared with
ORTEP-III.[17]
CCDC 677331 contains the supplementary crystallographic data for
this article. These data can be obtained free of charge via www.ccdc.

4422
L. Li et al.
Table 1. Crystal data and structure refinement for compound 1
Parameter
Value
Empirical formula
Formula weight
Temperature (K)
C31H24N2OSi
468.62
150
˚
Wavelength (A)
0.71069
Monoclinic
P21=n
Crystal system
Space group
Unit cell dimensions
ꢁ
˚
˚
ꢁ
a ¼ 11.286(2)A, a ¼ 90 , b ¼ 8.1535(15)A,
ꢁ
˚
b ¼ 97.411(11) , c ¼ 25.721(5)A, c ¼ 90
3
˚
V (A )
2347.1(8)
4
1.326
Z
Dcalc (Mg A
ꢂ3
˚
)
Absorption coefficient (mmꢂ1
F(000)
Crystal size (mm)
)
0.128
984
0.02 ꢆ 0.07 ꢆ 0.18
Theta range for data collection (ꢁ)
Index ranges
Reflections collected
Independent reflections
Reflections observed [I > 2r(I)]
Rint
Refinement method
Goodness of fit on F2
R1 [I > 2r (I)]
wR2 [I > 2r(I)]
R1, wR>2 all data
2.62–25.35
ꢂ13 ꢇ h ꢇ 13, ꢂ 9 ꢇ k ꢇ 9, ꢂ30 ꢇ l ꢇ 30
20185
4275
2084
0.1496
Full-matrix least-square on F2
0.969
0.073
0.142
0.179=0.17
0.322= ꢂ 0.365
Largest diffꢂer3ence peak and
˚
hole (e A
)
cam.ac.uk/data_request/cif, by e-mailing data_request@ccdc.cam.ac.uk,
or by contacting the Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB2 1EZ, UK; fax: þ 44 1223 336033.
ACKNOWLEDGMENTS
ˆ
We thank the Fundac¸a˜o para Ciencia e Tecnologia, Portugal, for financial
support (Project POCI=QUI=59025=2004), co-financed by European Funds
for Regional Development (FEDER) and fellowships to L. L. and C. S. B. G.
(SFRH=BPD=30733=2006 and SFRH=BD=16807=2004, respectively).

Synthesis of Acridine Derivative
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