Synthesis and characterization of bromo-, arylazo-, and heterocyclic-fused troponoids containing a 1,3-benzodioxole system

Article abstract of DOI:10.1002/jhet.702

A facile synthesis of a series of novel bromo-, arylazo-, and heterocyclic fused troponoid compounds containing 1,3-benzodioxole system is described. The 7-bromo-, 5,7-dibromo-, and 5-arylazo-substituted 3-[(2E)-3-(1,3-benzodioxol-5- yl)prop-2-enoyl]tropolones (2, 3, and 5-7) were obtained by direct bromination or azo-coupling reactions of 3-[(2E)-3-(1,3-benzodioxol-5-yl)prop- 2-enoyl]tropolone (1) with bromine, and diazonium salts of aniline derivatives, respectively. 3-[(2E)-3-(1,3-Benzodioxol-5-yl)prop- 2-enoyl]-5-bromotropolone (4) was obtained from 3-acetyl-5-bromotropolone via one-pot aldol dehydration reaction with piperonal. Tropolones 2, 3, and 4 were subjected to nucleophilic cyclization with bifunctional hydroxylamine hydrochloride and phenylhydrazine hydrochloride to give the corresponding isoxazolo- and pyrazolo-fused tropones (8-13), respectively..

Full text of DOI:10.1002/jhet.702

January 2012
Synthesis and Characterization of Bromo-, Arylazo-, and
Heterocyclic-Fused Troponoids Containing a 1,3-Benzodioxole
System
167
Yang Li, Mingchun Sun, and Wentao Gao*
Institute of Superfine Chemicals, Bohai University, Jinzhou, 121000 China
*E-mail: isfcwentao@163.com
Received May 11, 2010
DOI 10.1002/jhet.702
Published online 21 October 2011 in Wiley Online Library (wileyonlinelibrary.com).
A facile synthesis of a series of novel bromo-, arylazo-, and heterocyclic fused troponoid compounds
containing 1,3-benzodioxole system is described. The 7-bromo-, 5,7-dibromo-, and 5-arylazo-substituted
3-[(2E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]tropolones (2, 3, and 5–7) were obtained by direct bromi-
nation or azo-coupling reactions of 3-[(2E)-3-(1,3-benzodioxol-5-yl)prop- 2-enoyl]tropolone (1) with
bromine, and diazonium salts of aniline derivatives, respectively. 3-[(2E)-3-(1,3-Benzodioxol-5-yl)prop-
2-enoyl]-5-bromotropolone (4) was obtained from 3-acetyl-5-bromotropolone via one-pot aldol dehydra-
tion reaction with piperonal. Tropolones 2, 3, and 4 were subjected to nucleophilic cyclization with
bifunctional hydroxylamine hydrochloride and phenylhydrazine hydrochloride to give the corresponding
isoxazolo- and pyrazolo-fused tropones (8–13), respectively.
J. Heterocyclic Chem., 49, 167 (2012).
INTRODUCTION
On the other hand, 1,3-benzodioxoles, one of the
major subclasses of many natural products such as
safrole [9], Leucettamine B [10], Steganacin [11], and
egonol [12], exhibit a wide variety of biological activ-
ities [13–17], such as cytotoxic activity against several
human tumor cell lines including human colon carci-
noma cells [18] and multidrug-resistant nasopharyngeal
carcinoma cells [19]. The 1,3-benzodioxole framework
can be identified in the clinical antitumour agents eto-
poside, teniposide [20], and lignan lactone podophylo-
toxin [21] and the structure–activity relationships
showed that the 1,3-benzodioxole moiety is fundamen-
tal for the cytotoxic activity because it can be metabo-
lized by CYP to form metallo-carbene intermediates
which could be responsible for the antitumor activity
of lignans [22,23]. In addition, the presence of 1,3-ben-
zodioxole moiety in some other bioactive molecules
drastically alters their pharmacological properties. For
example, among the many compounds isolated, the
1,3-benzodioxole-bearing coumarins show antiplatelet
aggregation activity [24].
Since 1945, when Dewar correctly predicted that nat-
ural products such as colchicine and derivatives of pu-
berulonic acid encompass the troponoid ring [1], the
importance of troponoid and its heterocyclic-fused deriv-
atives has been well recognized and considerable efforts
have been devoted aiming at understanding and exploit-
ing the chemistry of the cyclohepta-2,4,6-trienone (tro-
pone) [2]. Some natural products containing a tropolone
nucleus or bicyclic heterocyclic-fused tropone moiety
exhibit potent biological and pharmacological activities
such as antitumour and antimalarial activities [3]. There
are several reports dealing with the preparation of tropo-
noid derivatives and their corresponding biological eval-
uations [4]. In this regard, the works carried by Yamato
et al. [5] and Crozet and coworkers [6] are of special in-
terest. In addition, the tropolone moiety plays an impor-
tant role in molecular assemblies for a faster and effi-
cient lead generation towards the new drug discovery.
But tropolone derivatives are scarce in nature [7], occur-
ring only in lower plants and fungi [8], and limited in-
formation is available on these compounds. Therefore,
synthesis of troponoid compounds continues to be a con-
siderable synthetic challenge.
In light of these findings and in view of structural di-
versity playing a prominent role in medicinal and com-
binatorial chemistry for a faster and efficient lead
C
V
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168
Y. Li, M. Sun, and W. Gao
Vol 49
Scheme 1. Synthesis of 7-bromo- and 5,7-dibromo-substituted tropolones 2,3.
generation toward the new drug discovery [25], we wish
to report herein the synthesis of novel 1,3-benzodioxole-
bearing tropolone as well as heterocyclic-fused tropone
derivatives.
pound 1, indicating that the bromination reaction
occurred selectively on the tropolone ring. In the 1H
NMR spectrum of 2, the signals from two hydrogens of
C4 and C6 appeared as two doublet signals at 7.74 (d,
1H, J ¼ 11.0 Hz) and 8.26 (d, 1H, J ¼ 11.0 Hz),
which arose a result of coupling with the C5 hydrogen.
The signal corresponding to the C5 hydrogen appears
as a doublet of doublets at 7.27 ppm (dd, 1H, J ¼
11.0, 10.8 Hz), which arose from coupling with both
the C4 and C6 hydrogen atoms. These observations
clearly indicated the formation of a 7-bromo-substi-
tuted product 2. The molecular formula was established
to be C17H11BrO5 by its HRMS spectrum, which shows
RESULTS AND DISCUSSION
As far as we know, 3-[(2E)-3-(1,3-benzodioxol-5-
yl)prop-2-enoyl]-tropolone (1) has been synthesized con-
veniently for many years [26a]. However, further modi-
fication of it is very limited [26b], despite its important
potential biological activities. In this regard we previ-
ously reported the synthesis of isoxazolo- and pyrazolo-
fused tropones containing 1,3-benzodioxole system [27].
However, the report is of episodic character and no
efforts have been made to develop a general synthesis
of this type of compounds. Thus, we are very interested
in transforming compound 1 into various interesting 1,3-
benzodioxole-bearing troponoid derivatives, which
should be useful precursors for the synthesis of new bio-
logically active tropolone derivatives.
a
pseudþo-molecular-ion peak at m/z 396.9686
([MþNa] ; calc. for C17H7119BrNaO5þ: 396.9682), indi-
cating the presence of twelve degrees of unsaturation.
Similarly, the structure of 3 was fully characterized
1
using H NMR and HRMS spectra. The main feature
1
of its H NMR spectrum shows two doublet signals at
7.82 and 8.49 ppm with a coupling constant J ¼ 1.95
Hz, which is a typical value (1–3 Hz) for meta-protons
coupling in tropolone ring. The molecular formula of
compound 3 was deduced to be C17H10Br2O5 from its
HRMS, which shows a þpseudo-molecular-ion peak at
m/z 474.8781 ([MþNa] ; calc. for C17H7109Br2NaO5þ:
474.8785), indicating the presence of 12ꢀ of unsatura-
tion. These observations supported that two bromine
atoms were substituted at the 5- and 7-positions of the
tropolone ring.
We first carried out the bromination reaction of 1
with bromine as shown in Scheme 1. When treated with
an equimolar amount of bromine in acetic acid in the
presence of sodium acetate, 7-bromo-substituted tropo-
lone 2 was obtained in 72% yields. Under the same
reaction conditions the bromination reaction with two
equivalents of bromine gave 5,7-dibromotropolone 3 in
67% yield.
However, 5-bromo-substituted tropolone 4 could not
obtained by direct bromination from compound 1 using
bromine because of the occurrence of bromination on 7-
position. Thus, we selected 3-acetyl-5-bromotropolone
(10) as a starting compound to react with 1.5 equimolar
The structures of 2 and 3 were established based on
1
spectral data. In the H NMR spectra of compounds 2,
3, the signals for the two vinyl protons and the five
1,3-benzodioxol protons were observed and their spec-
tral pattern is very similar to that of the starting com-
Scheme 2. Synthesis of the desired 5-bromo-substituted tropolone 4.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2012
Synthesis and Characterization of Bromo-, Arylazo-, and Heterocyclic-Fused Troponoids
Containing a 1,3-Benzodioxole System
169
Scheme 3. Synthesis of 5-arylazo-substituted target compounds 5–7.
piperonal (20) to give the desired 5-bromo product 4 in
89% yield via one-pot aldol dehydration reaction in
50% aq. methanol in the presence of 5% aq. KOH. The
synthetic route was shown in Scheme 2.
Thus, we are interested in the synthesis of arylazo-sub-
stituted 1,3-benzodioxol-bearing tropolones. The synthe-
sis of so far unreported 5-aryldiazenyl-substituted tropo-
lones was shown in Scheme 3. The azo-coupling
reactions of 3-[(2E)-3-(1,3-benzodioxol-5-yl)prop-2-
enoyl]-tropolone (1) with diazonium salts of aniline
derivatives in pyridine took place selectively at the 5-
position of the tropolone ring to give the corresponding
arylazo derivatives 5–7 in the yields of 63%, 72%, 52%,
respectively. The resulting products of the reactions
were easily identifiable by proton NMR. For example,
The spectral data of 4 are in accordance with the
assumed structure. Its 1H NMR spectrum exhibited a
singlet at 6.01 (2H), a doublet at 6.81 (1H, J ¼ 1.6 Hz),
a doublet at 6.93 (1H, J ¼ 7.9 Hz), and a doublet of
doublets at 7.05 (1H, J ¼ 7.9, 1.6 Hz), two doublets
centered at 7.08 and 7.62 with a coupling constant 15.9
Hz, representing the side-chain seven protons of (3-ben-
zo[1,3]dioxol-5-yl)acryloyl moiety. The splitting pattern
of the tropolone protons showed a doublet at 8.18, a
doublet at 7.71, and a doublet of doublets at 7.43.
1
in the H NMR spectrum of compound 6, the character-
istic chemical shifts of the three protons attached to the
tropolone ring were found at 7.55 ppm as a doublet (J
¼ 11.2 Hz) for C7 proton, at 8.26 ppm as a doublet of
doublets (J ¼ 11.3, 2.1 Hz) because of C6 proton, and
at 8.45 ppm as a doublet (J ¼ 2.10 Hz) assignable to C4
proton. The splitting pattern is very similar to that of
the 5-brom tropolone 1. The four protons of p-tolylazo
moiety resonated as two doublets at 7.31 (2H, d, J ¼
8.2 Hz) and 7.82 ppm (2H, d, J ¼ 8.2 Hz).
It is well known that arylazo compounds, which have
been widely utilized over the years in various fields
such as dyes [28], biomedicine [29], and organic synthe-
sis [30], have recently found advanced potential applica-
tions as photosensitive species in photographic or elec-
trophotographic systems and are the dominant organic
photoconductive materials in commercial copiers [31].
Scheme 4. Synthesis pyrazolo- and isoxazolo-fused target compounds 8–13.
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Y. Li, M. Sun, and W. Gao
Vol 49
(C¼¼O); 1H NMR (dimethyl sulfoxide [DMSO]-d6, 500 MHz)
(d, ppm): 6.04 (s, 2H, OCH2O), 6.85 (d, 1H, J ¼ 1.6 Hz, 1,3-
benzodioxol H-40), 6.99 (d, 1H, J ¼ 7.9 Hz, 1,3-benzodioxol
H-70), 7.06 (dd, 1H, J ¼ 7.9, 1.6 Hz, 1,3-benzodioxol H-60),
7.13 (d, 1H, J ¼ 15.9 Hz, ¼¼CH), 7.27 (dd, 1H, J ¼ 11.0, 11.0
Hz, tropolone H-5), 7.62 (d, 1H, J ¼ 15.9 Hz, ¼¼CH), 7.74 (d,
1H, J ¼ 11.0 Hz, tropone H-6), 8.26 (d, 1H, J ¼ 11.0 Hz,
tropolone H-4), 9.78 (s, 1H, OH). ESI-HRMS calc. for
C17H7191BrNaOþ5 [MþNa]þ: 396.9682; found: 396.9686.
Recently, we have reported the synthesis of some new
heterocyclic-fused tropone compounds such as cyclohep-
ta[b]pyran-4,9-diones [32]. In continuation of our studies
on the synthesis of novel and interesting heterocyclic
tropone derivatives, we herein synthesized six novel iso-
xazolo- and pyrazolo-fused tropones 8–13 by refluxing
compounds 2, 3, or 4 with hydroxylamine hydrochloride
or phenylhydrazine hydrochloride in EtOH as shown in
Scheme 4. Completion of the reactions was monitored
by thin layer chromatography (TLC).
Synthesis of 3-[(2E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]-
5,7-dibromotropolone (3). To a stirred solution of 3-[(2E)-3-
(1,3-benzodioxol-5-yl)prop-2-enoyl]-tropolone (1) (0.296 g,
1 mmol) and sodium acetate in acetic acid (50 mL) was added
dropwise a solution of bromine (0.320 g, 2 mmol) in acetic
acid (2 mL) at room temperature. After stirring for 2 h, water
(100 mL) was added. The precipitate was collected and recrys-
tallized from ethyl acetate. Yield 67%; mp: 179–180ꢀC. IR
(KBr, m, cmꢁ1): 3433 (OH), 1651 (C¼¼O), 1607 (C¼¼O); 1H
NMR (CDCl3, 500 MHz) (d, ppm): 6.02 (s, 2H, OCH2O), 6.82
(d, 1H, J ¼ 7.9 Hz, 1,3-benzodioxol H-70), 6.96 (d, 1H, J ¼
15.85 Hz, ¼¼CH), 7.06 (d, 1H, J ¼ 1.6 Hz, 1,3-benzodioxol H-
40), 7.08 (dd, 1H, J ¼ 7.9, 1.6 Hz, 1,3-benzodioxol H-60), 7.53
(d, 1H, J ¼ 15.85 Hz, ¼¼CH), 7.82 (d, 1H, J ¼ 1.95 Hz, tropo-
lone H-6), 8.49 (d, 1H, J ¼ 1.95 Hz, tropolone H-4), 9.74 (s,
1H, OH). ESI-HRMS calc. for C17H7109Br2NaO5þ [MþNa]þ:
474.8785; found: 474.8781.
The structures of all these newly synthesized tropones
were established based on spectral data. The main fea-
1
tures of the H NMR data of compounds 8–13 showed
the absence of the signal at d 9.69–9.74 belonging to
OH moiety of the precursor. Their IR spectra were also
devoid of the stretching vibration bands resembling the
OH moiety of the precursor, and exhibited only one typ-
ical carbonyl absorption for the tropone ring at 1624–
1656 cmꢁ1. Further, the structures assigned for these
reaction products were fully supported by their HRMS,
which established their molecular formulas in accord-
ance with their suggested molecular structures. In addi-
tion, all the compounds 8–13 had the negative coloring
test with iron(III) chloride in methanol solution.
Synthesis of 3-[(2E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]-
5-bromotropolone (4). To a stirred solution of 3-acetylt-5-bro-
motropolone (0.60 g, 2.4 mmols) and piperonal (0.225 g,1.5
mmol) was added dropwise an aqueous solution of 5% KOH
(12 mL). The resulting reaction mixture was stirred at room
temperature for 24 h followed by acidification with 1 M HCl.
The resulting precipitate was collected by filtration, washed
with water, dried, and recrystallized from methanol to give
product 4 in 89% yield; mp: 207–208ꢀC. IR (KBr, m, cmꢁ1):
In summary, the synthesis of a series of hitherto unre-
ported bromo-, arylazo-, and heterocyclic-fused tropo-
noids containing 1,3-benzodioxol system has been
achieved. The novel synthesized compounds should
allow us, in the future, to investigate structure-activity
relationships over various biotests. In addition, the prod-
ucts represent potentially useful synthetic building
blocks in medicinal chemistry.
1
3443 (OH), 1663 (C¼¼O), 1597 (C¼¼O); H NMR (DMSO-d6,
500 MHz) (d, ppm): 6.02 (s, 2H, OCH2O), 6.81 (d, 1H, J ¼
1.6 Hz, 1,3-benzodioxol H-40), 6.93 (d, 1H, J ¼ 7.9 Hz, 1,3-
benzodioxol H-70), 7.05 (dd, 1H, J ¼ 7.9, 1.6 Hz, 1,3-benzo-
dioxol H-60), 7.08 (d, 1H, J ¼ 15.9 Hz, ¼¼CH), 7.43 (dd, 1H, J
¼ 11.2, 2.0 Hz, tropolone H-6), 7.62 (d, 1H, J ¼ 15.9 Hz,
¼¼CH), 7.71 (d, 1H, J ¼ 11.1 Hz, tropolone H-7), 8.18 (d, 1H,
J ¼ 1.9 Hz, tropolone H-4), 9.83 (s, 1H, OH). ESI-HRMS
calc. for C17H1719BrNaOþ5 [MþNa]þ: 396.9682; found:
396.9691.
EXPERIMENTAL
General. All chemicals (AR graded) were commercially
available and used without further purification. Melting points
(uncorrected) were determined by using WRS-1B melting
points apparatus. 1H NMR was measured with a BRUKER
BRX 600 at 400 or 500 MHz. The reported chemical shifts
were against TMS. Mass spectra were recorded on a Micro-
mass Platform liquid chromatography mass spectrometry-elec-
trospray ionization. HRMS (ESI) data were acquired on a
Bruker Customer micrOTOF-Q 125 high-resolution mass spec-
trometer with ESI. The progress of the reactions was moni-
tored by TLC on silica gel GF254 using ethyl acetate as
eluent.
General procedure for the azo-coupling reaction of 3-
[(2E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]-tropolone
(1)
with diazonium salts of anilines. To an ice-cooled stirred so-
lution of compound 1 (0.296 g, 1 mmol) in pyridine (4 mL),
was added dropwise arenediazonium chloride solution (2 mL),
prepared from anilines (2.0 mmols) and NaNO2 (0.139 g, 2.0
mmol). After additional stirring for 3 h, the precipitate was
collected and recrystallized from benzene or ethyl acetate to
give 3-[(2E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]-5-arylazo-
tropolones 5–7.
Synthesis of 3-[(2E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]-
7-bromotropolone (2). To a stirred solution of 3-[(2E)-3-(1,
3-benzodioxol-5-yl)prop-2-enoyl]-tropolone (1) (0.296 g,
1
3-[(2E)-3-(1,3-Benzodioxol-5-yl)prop-2-enoyl]-5-phenyldia-
zenyltropolone (5). Yield 63%; mp: 191–192ꢀC. IR (KBr, m,
cmꢁ1): 3238 (OH), 1651(C¼¼O), 1602 (C¼¼O); 1H NMR
(CDCl3, 400 MHz) (d, ppm): 6.01 (s, 2H, OCH2O), 6.82 (d,
1H, J ¼ 8.2 Hz, 1,3-benzodioxol H-70), 7.09 (d, 1H, J ¼ 15.8
Hz, ¼¼CH), 7.13 (dd, 1H, J ¼ 8.1, 1.6 Hz, 1,3-benzodioxol H-
mmol) and sodium acetate (0.125 g) in acetic acid (50 mL)
was added dropwise a solution of bromine (0.160 g, 1 mmol)
in acetic acid (2 mL) at room temperature. After stirring for 2
h, water (100 mL) was added. The precipitate was collected
and recrystallized from ethyl acetate. Yield 62%; mp: 171–
172ꢀC. IR (KBr, m, cmꢁ1): 3421 (OH), 1654 (C¼¼O), 1610
Journal of Heterocyclic Chemistry
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January 2012
Synthesis and Characterization of Bromo-, Arylazo-, and Heterocyclic-Fused Troponoids
Containing a 1,3-Benzodioxole System
171
60), 7.16 (d, 1H, J ¼ 1.6 Hz, 1,3-benzodioxol H-40), 7.35–7.51
(m, 5H, ArH), 7.58 (d, 1H, J ¼ 11.2 Hz, tropolone H-7), 7.62
(d, 1H, J ¼ 15.8 Hz, ¼¼CH), 8.21 (dd, 1H, J ¼ 11.0, 2.1 Hz,
tropolone H-6), 8.33 (d, 1H, J ¼ 2.10 Hz, tropolone H-4),
9.50 (s, 1H, OH). ESI-HRMS calc. for C23H16N2NaO5þ
[MþNa]þ: 423.0951; found: 423.0955.
253ꢀC. IR (KBr, m, cmꢁ1): 1624 (C¼¼O), 1587 (C¼¼N); 1H
NMR (DMSO-d6, 400 MHz) (d, ppm): 5.99 (s, 2H, OCH2O),
7.05 (d, 1H, J ¼ 2.4 Hz, 1,3-benzodioxol H-40), 7.13 (d, 1H, J
¼ 11.0 Hz, tropone H-7), 7.26 (d, 1H, J ¼ 8.2 Hz, 1,3-benzo-
dioxol H-70), 7.31–7.57 (m, 7H, benzene-H, tropone H-6, and
1,3-benzodioxol H-60), 7.60 (d, 1H, J ¼ 16.0 Hz, ¼¼CH), 7.81
(d, 1H, J ¼ 16.0 Hz, ¼¼CH), 8.42 (d, 1H, J ¼ 2.1 Hz, tropone
H-4). ESI-HRMS calc. for C23H7159BrN2NaO3þ [MþNa]þ:
469.0159; found: 469.0152.
General procedure for the preparation of 3-[(E)-2-(1,3-
benzodioxol-5-yl)vinyl]-8H-cyclohepta[d]isoxazol-8-one
derivatives (11–13). A solution of compound 2, 3, or 4 (1
mmol) and hydroxylamine hydrochloride (2.0 mmols) in absolute
ethanol (15 mL) was refluxed for 12 hours. After the reaction
was over as monitored by TLC, the precipitate was collected and
recrystallized from ethanol to give the products 11–13.
3-[(E)-2-(1,3-Benzodioxol-5-yl)vinyl]-7-bromo-8H-cyclo-
hepta[d]isoxazol-8-one (11). Yield 52%; mp: 275–276ꢀC. IR
(KBr, m, cmꢁ1): 1640 (C¼¼O), 1582 (C¼¼N); 1H NMR
(DMSO-d6, 400 MHz) (d, ppm): 6.01 (s, 2H, OCH2O), 6.98
(d, 1H, J ¼ 2.1 Hz, 1,3-benzodioxol H-40), 7.22 (d, 1H, J ¼
8.2 Hz, 1,3-benzodioxol H-70), 7.33 (dd, 1H, J ¼ 8.2, 2.1 Hz,
1,3-benzodioxol H-60), 7.39 (d, 1H, J ¼ 16.4 Hz, ¼¼CH), 7.57–
7.64 (m, 3H, tropone H), 7.72 (d, 1H, J ¼ 16.4 Hz, ¼¼CH).
ESI-HRMS calc. for C17H7109BrNNaO4þ [MþNa]þ: 393.9685;
found: 393.9692.
3-[(E)-2-(1,3-Benzodioxol-5-yl)vinyl]-5,7-dibromo-8H-
cyclohepta[d]isoxazol-8-one (12). Yield 49%; mp: 287–
288ꢀC. IR (KBr, m, cmꢁ1): 1630 (C¼¼O), 1575 (C¼¼N); 1H
NMR (CDCl3, 400 MHz) (d, ppm): 5.98 (s, 2H, OCH2O),
6.81 (d, 1H, J ¼ 8.0 Hz, 1,3-benzodioxol H-70), 7.09 (d, 1H, J
¼ 1.6 Hz, 1,3-benzodioxol H-40), 7.31 (d, 1H, J ¼ 16.0 Hz,
¼¼CH), 7.35 (dd, 1H, J ¼ 8.0, 1.6 Hz, 1,3-benzodioxol H-60),
7.77 (d, 1H, J ¼ 16.0 Hz, ¼¼CH), 8.14 (d, 1H, J ¼ 2.0 Hz, tro-
pone H-6), 8.43 (d, 1H, J ¼ 2.0 Hz, tropone H-4). ESI-HRMS
calc. for C17H799Br2NNaOþ4 [MþNa]þ: 471.8789; found:
471.8783.
3-[(2E)-3-(1,3-Benzodioxol-5-yl)prop-2-enoyl]-5-p-tolyla-
zotropolone (6). Yield 72%; mp: 193–195ꢀC. IR (KBr, m,
cmꢁ1): 3307 (OH), 1644(C¼¼O), 1609 (C¼¼O); 1H NMR
(CDCl3, 400 MHz) (d, ppm): 2.44 (s, 3H, CH3), 6.01 (s, 2H,
OCH2O), 6.81 (d, 1H, J ¼ 8.1 Hz, 1,3-benzodioxol H-70), 7.06
(d, 1H, J ¼ 15.8 Hz, ¼¼CH), 7.08 (dd, 1H, J ¼ 8.1, 1.6 Hz,
1,3-benzodioxol H-60), 7.11 (d, 1H, J ¼ 1.6 Hz, 1,3-benzo-
dioxol H-40), 7.31 (d, 2H, J ¼ 8.2 Hz, benzene-H), 7.55 (d,
1H, J ¼ 11.2 Hz, tropolone H-7), 7.58 (d, 1H, J ¼ 15.8 Hz,
¼¼CH), 7.82 (d, 2H, J ¼ 8.3 Hz, benzene-H), 8.26 (dd, 1H, J
¼ 11.3, 2.1 Hz, tropolone H-6), 8.45 (d, 1H, J ¼ 2.10 Hz,
tropolone H-4), 9.58 (s, 1H, OH). ESI-HRMS calc. for
C24H18N2NaOþ5 [MþNa]þ: 437.1109; found: 437.1114.
3-[(2E)-3-(1,3-Benzodioxol-5-yl)prop-2-enoyl]-5-(4-nitro-
phenyl)diazenyltropolone (7). Yield 52%; mp: 292–294ꢀC.
1
IR (KBr, m, cmꢁ1): 3320 (OH), 1649 (C¼¼O), 1611 (C¼¼O); H
NMR (CDCl3, 400 MHz) (d, ppm): 6.04 (s, 2H, OCH2O), 6.85
(d, 1H, J ¼ 8.1 Hz, 1,3-benzodioxol H-70), 7.12 (d, 1H, J ¼
15.8 Hz, ¼¼CH), 7.17 (dd, 1H, J ¼ 8.1, 1.6 Hz, 1,3-benzo-
dioxol H-60), 7.22 (d, 1H, J ¼ 1.6 Hz, 1,3-benzodioxol H-40),
7.43 (d, 2H, J ¼ 8.4 Hz, benzene-H), 7.62 (d, 1H, J ¼ 15.8
Hz, ¼¼CH), 7.65 (d, 1H, J ¼ 11.2 Hz, tropolone H-7), 7.88 (d,
2H, J ¼ 8.3 Hz, benzene-H), 8.34 (dd, 1H, J ¼ 11.3, 2.1 Hz,
tropolone H-6), 8.55 (d, 1H, J ¼ 2.10 Hz, tropolone H-4),
9.95 (s, 1H, OH). ESI-HRMS calc. for C23H15N3NaO7þ
[MþNa]þ: 468.0802; found: 468.0785.
General procedure for the preparation of 3-[(E)-2-(1,3-
benzodioxol-5-yl)vinyl]-1-phenylcyclohepta[c]pyrazol-
8(1H)-ones (8–10). A mixture of compound 2, 3, or 4 (1
mmol) and phenyldrazine hydrochloride (2.0 mmols) in etha-
nol (10 mL) was refluxed for 24 h. After the reaction was over
as monitored by TLC, the precipitate was collected and recrys-
tallized from ethyl acetate to give products 8–10.
3-[(E)-2-(1,3-Benzodioxol-5-yl)vinyl]-7-bromo-1-phenyl-
cyclohepta[c]pyrazol-8(1H)-one (8). Yield 64%; mp:
247–248ꢀC. IR (KBr, m, cmꢁ1): 1635 (C¼¼O), 1592 (C¼¼N);
1H NMR (DMSO-d6, 400 MHz) (d, ppm): 6.02 (s, 2H,
OCH2O), 6.89 (d, 1H, J ¼ 8.2 Hz, 1,3-benzodioxol H-70), 6.96
(d, 1H, J ¼ 2.4 Hz, 1,3-benzodioxol H-40), 7.31 (dd, 1H, J ¼
8.2, 2.4 Hz, 1,3-benzodioxol H-60), 7.39–7.51 (m, 8H, ben-
zene-H and tropone-H), 7.55 (d, 1H, J ¼ 16.0 Hz, ¼¼CH), 7.77
3-[(E)-2-(1,3-Benzodioxol-5-yl)vinyl]-5-bromo-8H-cyclo-
hepta[d]isoxazol-8-one (13). Yield 48%; mp: 272–273ꢀC. IR
(KBr, m, cmꢁ1): 1656 (C¼¼O), 1590 (C¼¼N); 1H NMR
(DMSO-d6, 400 MHz) (d, ppm): 6.10 (s, 2H, OCH2O), 6.91
(d, 1H, J ¼ 2.2 Hz, 1,3-benzodioxol H-40), 6.97 (d, 1H, J ¼
8.1 Hz, 1,3-benzodioxol H-70), 7.04 (d, 1H, J ¼ 11.2 Hz, tro-
pone H-7), 7.34 (d, 1H, J ¼ 16.2 Hz, ¼¼CH), 7.43 (dd, 1H, J
¼ 8.1, 2.2 Hz, 1,3-benzodioxol H-60), 7.53 (dd, 1H, J ¼ 11.2,
2.0 Hz, tropone H-6), 7.67 (d, 1H, J ¼ 16.2 Hz, ¼¼CH), 8.40
(d, 1H, J ¼ 2.1 Hz, tropone H-4). ESI-HRMS calc. for
C17H7190BrNNaOþ4 [MþNa]þ: 393.9685; found: 393.9680.
(d, 1H,
J
¼
þ 16.4 Hz,þ ¼¼CH). ESI-HRMS calc. for
C23H7195BrN2NaO3 , [MþNa] : 469.0159; found: 469.0164.
3-[(E)-2-(1,3-Benzodioxol-5-yl)vinyl]-5,7-dibromo-1-phe-
nylcyclohepta[c]pyrazol-8(1H)-one (9). Yield: 42%; mp:
225–228ꢀC. IR (KBr, m, cmꢁ1): 1643 (C¼¼O), 1595 (C¼¼N);
1H NMR (CDCl3, 400 MHz) (d, ppm): 6.05 (s, 2H, OCH2O),
6.95 (d, 1H, J ¼ 8.2 Hz, 1,3-benzodioxol H-70), 7.12 (d, 1H, J
¼ 2.0 Hz, 1,3-benzodioxol H-40), 7.41–7.65 (m, 7H, benzene-
H, ¼¼CH, and 1,3-benzodioxol H-60), 7.83 (d, 1H, J ¼ 16.0
Hz, ¼¼CH), 8.16 (d, 1H, J ¼ 1.6 Hz, tropone H-6), 8.52 (d,
Acknowledgments. The authors thank the Foundation of Liaon-
ing Province Key Laboratory of Applied Chemistry (Grant No.
2008s001) for financial support.
REFERENCES AND NOTES
[1] (a) Dewar, M. J. S. Nature 1945, 155, 50; (b) Dewar, M. J.
S. Nature 1945, 155, 141.
1H,
J
¼
1.6 Hz, tropone H-4). ESI-HRMS calc. for
[2] (a) Pietra, F. Acc Chem Res 1979, 12, 132; (b) Banwell,
M. G.; Lambert, J. N.; Richards, S. L. Aust J Chem 1991, 44, 939.
[3] (a) Cai, P., Smith, D., Cunningham, B., Brown-Shimer, S.,
Katz, B., Pearce, C.; Venables, D.; Houck, D. J Nat Prod 1998, 61,
C23H1749Br2N2NaOþ3 , [MþNa]þ: 546.9264; found: 546.9273.
3-[(E)-2-(1,3-Benzodioxol-5-yl)vinyl]-5-bromo-1-phenyl-
cyclohepta[c]pyrazol-8(1H)-one (10). Yield 51%; mp: 252–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

172
Y. Li, M. Sun, and W. Gao
Vol 49
`
[13] Micale, N.; Zappala, M.; Grasso, S. Il Farmaco 2002, 57, 853.
´
[14] Leite, A. C. L.; da Silva, K. P.; de Souza, I. A.; de Araujo,
791; (b) Lee, J. C.; Jin, S. J.; Cha, J. K. J Org Chem 1998, 63, 2804;
(c) Boger, D. L.; Ichikawa, S.; Jiang, H. J Am Chem Soc 2000, 122,
12169; (d) Seephonkai, P.; Isaka, M.; Kittakoop, P.; Trakulnaleamsai,
S.; Rattanajak, R.; Tanticharoen, M.; Thebtaranonth, Y. J Antibiot
J. M.; Brondani, D. J. Eur J Med Chem 2004, 39, 1059.
[15] Bezerra-Netto, H. J. C.; Lacerda, D. I.; Miranda, A. L. P.;
Alves, H. M.; Barreiro, E. J.; Fraga, C. A. M. Bioorg Med Chem
2006, 14, 7924.
´
2001, 54, 751; (e) Mesa-Siverio, D.; Estevez-Braun, A.; Ravelo, A.
´
´
G.; Murguia, J. R.; Rodrıguez-Afonso, A. Eur J Org Chem 2003,
¨
4243; (f) Baldwin, J. E.; Mayweg, A. V. W.; Pritchard, G. J.; Adling-
ton, R. M. Tetrahedron Lett 2003, 44, 4543.
[16] Oztu¨rk, S. E.; Akgu¨, Y.; Anil, H. Bioorg Med Chem 2008,
16, 4431.
[4] (a) Maeda, Y.; Imafuku, K. J Heterocycl Chem 1995, 32,
349; (b) Nasu, T.; Tagawa, T.; Imafuku, K. J Heterocycl Chem 1998,
35, 389; (c) Houte, H.; Valnot, J. Y.; Piettre, S. R. Tetrahedron Lett
2002, 43, 9217; (d) Gu¨ney, M.; Dastan, A.; Balci, M. Helv Chim
Acta 2008, 88, 830; (e) Feldman, K. S.; Cutarelli, T. D.; Florio, R. D.
J Org Chem 2002, 67, 8528; (f) Potenziano, J.; Spitale, R.; Janik, M.
E. Synth Commun 2005, 35, 2005.
[17] Debdab, M.; Renault, S.; Lozach, O.; Meijer, L.;
Paquin, L.; Carreaux, F.; Bazureau, J. P. Eur J Med Chem 2010,
45, 805.
[18] Yokota, S.; Kitahara, M.; Nagata, K. Cancer Res 2000, 60,
2942.
[19] Xia, Y.; Yang, Z.; Xia, P.; Bastow, K. F.; Nakanishi, Y.;
Lee, K. Bioorg Med Chem Lett 2000, 10, 699.
[5] (a) Yamato, M.; Hashigaki, K.; Kokubu, N.; Tsuruo, T.;
Tashiro, T. J Med Chem 1984, 27, 1749; (b) Yamato, M.; Hashigaki,
K.; Ishikawa, S.; Kokubu, N.; Inoue, Y.; Tsuruo, T.; Tashiro, T. J Med
Chem 1985, 28, 1026; (c) Yamato, M.; Hashigaki, K.; Kokubu, N.;
Tashiro, T.; Tsuruo, T. J Med Chem 1986, 29, 1202; (d) Yamato, M.;
Hashigaki, K.; Sakai, J.; Kawasaki, Y.; Tsukagoshi, S.; Tashiro, T.
J Med Chem 1987, 30, 117; (e) Yamato, M.; Hashigaki, K.; Sakai, J.;
Takeuchi, Y.; Tsukagoshi, S.; Tashiro, T.; Tsuruo, T. J Med Chem
1987, 30, 1245; (f) Yamato, M.; Ando, J.; Sakai, J.; Hashigaki, K.;
Wataya, Y.; Tsukagoshi, S.; Tashiro, T.; Tsuruo, T. J Med Chem
1992, 35, 267.
[20] Chen, G. L.; Yang, L.; Rowe, T. C.; Halligan, B. D.;
Tewey, K.; Liu, L. J Biol Chem 1984, 259, 13560.
[21] Capilla, A. S.; Sanchez, I.; Caignard, D. H.; Renard, P.;
Pujol, M. D. Eur J Med Chem 2001, 36, 389.
[22] Castro, A.; Miguel del Corral, J. M.; Gordaliza, M.; Grande,
´
´ ´
C.; Gomez-Zurita, A.; Garcıa-Gravalos, D.; San Feliciano, A. Eur J
Med Chem 2003, 38, 65.
[23] Imperio, D.; Pirali, T.; Galli, U.; Pagliai, F.; Cafici, L.;
Canonico, P. L.; Sorba, G.; Genazzani, A. A.; Tron, G. C. Bioorg Med
Chem 2007, 15, 6748.
[24] Wu, T. S.; Tsang, Z. J.; Wu, P. L.; Lin, F. W.; Li, C. Y.;
Teng, C. M.; Lee, K. H. Bioorg Med Chem 2001, 9, 77.
[25] Dolle, R. E.; Nelson, K. H., Jr. J Comb Chem 1999, 1,
235.
[6] (a) Tamburlin-Thumin, I.; Crozet, M. P.; Barriere, J. C.;
Barreau, M.; Riou, J. F.; Lavelle, F. Eur J Med Chem 2001, 36, 561;
(b) Tamburlin-Thumin, I.; Crozet, M. P.; Barriere, J. C. Synthesis
1999, 1149.
[26] (a) Yamaguchi, K.; Imafuku, K.; Matsumura, H. J. Syn.
Chem. Org. 1980, 998; (b) Imafuku, K.; Yamaguchi, K. Bull Chem
Soc Jpn 1981, 54, 2855.
[7] Ellington, E.; Bastida, J.; Viladomat, F.; Simanek, V.;
Codina, C. Biochem Syst Ecol 2003, 31, 715.
[8] Angawi, R. F.; Swenson, D. C.; Gloer, J. B.; Wicklow, D.
T. Tetrahedron Lett 2003, 44, 7593.
[27] Gao, W. T.; Zheng, Z. Chin Chem Lett 2000, 11, 503.
[28] Peters, A. T.; Chisowa, E. Dyes Pigm 1993, 22, 223.
[29] Singh, A. K.; Das, J.; Mjumdar, N. J. J Am Chem Soc
1996, 118, 6185.
[9] Lages, A. S.; Silva, K. C. M.; Miranda, A. L. P.; Fraga, C.
A. M.; Barreiro, E. J. Bioorg Med Chem Lett 1998, 8, 183.
[10] Chan, G. W.; Mong, S.; Hemling, M. E.; Freyer, A. J.;
Offen, P. M.; De Brosse, C. W.; Sarau, H. M.; Westley, J. W. J Nat
Prod 1993, 56, 116.
[30] Little, R. D.; Venegas, M. G. J Org Chem 1978, 43, 2921.
[31] Raposo, M. M. M.; Sousa, A. M. R. C.; Fonseca, A. M. C.;
Kirsch, G. Tetrahedron 2005, 61, 8249.
[11] Kupchan, S. M.; Britton, R. W.; Ziegler, M. F.; Gilmore, C.
J.; Restivo, R. J.; Bryan, R. F. J Am Chem Soc 1973, 95, 1335.
[12] Akgul, Y. Y.; Anil, H. Phytochemistry 2003, 63, 939.
[32] (a) Li, Y.; Chang, M, Q.; Sun, M. S.; Li, W.; Gao, W. T.
Chin J Chem 2009, 27, 2073; (b) Gao, W. T.; Li, Y.; Zhang, H.;
Chang, M. Q.; Imafuku, K. J Heterocycl Chem 2009, 46, 1107.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet