Novel synthesis of 1,4-phenylene bridged bis-heterocyclic tropone compounds

Article abstract of DOI:10.3987/COM-12-12431

A facile synthesis of novel 1,4-phenylene bridged bis-isoxazolo-, pyrazolo-, and pyrano-fused tropone compounds (2-6) is described, involving the cyclization reaction of 3,3'-{1,4-phenylenebis[(1E)-3-oxoprop-1-ene-1,3-diyl]}- bis(tropolone) (1) with hydro

Full text of DOI:10.3987/COM-12-12431

HETEROCYCLES, Vol. 85, No. 4, 2012
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HETEROCYCLES, Vol. 85, No. 4, 2012, pp. 911 - 917. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 18th January, 2012, Accepted, 20th February, 2012, Published online, 28th February, 2012
DOI: 10.3987/COM-12-12431
NOVEL SYNTHESIS OF 1,4-PHENYLENE BRIDGED
BIS-HETEROCYCLIC TROPONE COMPOUNDS
Yang Li, Feng Li, and Wentao Gao*
Institute of Superfine Chemicals, Bohai University, Jinzhou 121000, China
bhuzh@163.com
Abstract – A facile synthesis of novel 1,4-phenylene bridged bis-isoxazolo-,
pyrazolo-, and pyrano-fused tropone compounds (2-6) is described, involving the
cyclization reaction of 3,3’-{1,4-phenylenebis[(1E)-3-oxoprop-1-ene-1,3-diyl]}-
bis(tropolone) (1) with hydroxylamine hydrochloride, aromatic hydrazine
hydrochlorides, and I2/DMSO/H2SO4 system, respectively. The substrate 1 was
obtained via the Claisen-Schmidt condensation reaction between
3-acetyl-tropolone and terephthalaldehyde.
Troponoids with heterocyclic substructures are present in a variety of pharmacologically relevant natural
products1-3 and are attractive targets for synthesis since they often exhibit diverse and important
biological activities such as anti-HCV,4 antifungal,5 and antimalarial activities.6 Accordingly, the
synthesis of structurally novel heterocycle-containing troponoids continue to receive considerable
attention in the field of synthetic organic chemistry.7-10
On the other hand, 1,4-phenylene bridged bis-heterocyclic compounds had been widely investigated and
reported to display important biological properties such as antiamoebic11 and antibacterial activities.12
Therefore, extensive synthetic efforts have been devoted to the development of more novel and
interesting 1,4-phenylene-bis-heterocyclic compounds.13-15 The recent progress in the synthesis of such
compounds has been reviewed by Shaker.16 However, to the best of our knowledge, there has no report of
the synthesis of 1,4-phenylene bridged bis-heterocyclic-condensed tropone compounds.
Our research group derives substantial capability in the synthesis of troponoid-based heterocyclic
compounds through previous experiences.17-22 Building on this evolving expertise and in light of the
above findings, we wish to report herein the synthesis of novel 1,4-phenylene bridged
bis-heterocycle-fused tropone compounds, which could be expected to be vitally important for

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HETEROCYCLES, Vol. 85, No. 4, 2012
pharmacological studies or in the realization of new medicinal properties. Recently, we have reported on
the Claisen-Schmidt condensation reaction of 3-acetyltropolones with aromatic and heteroaromatic
aldehydes to synthesize tropolonyl-substituted chalcone derivatives.17,21,22 According to the reports, we
again used the reliable approach in order to achieve the synthesis of the required starting compound
3,3’-{1,4-phenylenebis[(1E)-3-oxoprop-1-ene-1,3-diyl]}bis(tropolone) (1) as shown in Scheme 1. Thus,
under the same experimental conditions, 3-acetyltropolone (2 equiv.) was reacted readily with
terephthalaldehyde (1.5 equv.) in the presence of 5% aqueous KOH as catalyst in 50% aqueous methanol
as solvent at room temperature to afford a single product according to TLC analysis (Scheme 1). After
workup and recrystallization from methanol, the product was obtained in 63% yield. Based on the spectral
data, the structure of the isolated product was identified as the desired substrate (1).
Scheme 1. Synthesis of the substrate 1
Subsequently, we attempted to conduct the nucleophilic cyclization reaction of substrate 1 with
bifunctional agents such as hydroxylamine hydrochloride and substituted phenylhydrazine hydrochloride
for the synthesis of the desired 1,4-phenylene bridged bis-heterocyclic-condensed troponoids. Our recent
work has demonstrated the reaction of 3-cinnamoyltropolone derivatives with hydroxylamine and
aromatic hydrazines in refluxing EtOH to afford the corresponding isoxazolo- and pyrazolo-fused
tropones in good yields.20 Unfortunately, following the reaction conditions, the nucleophilic cyclization
reaction in this case did not proceed smoothly, and the products were isolated only in very low yields of
11-20% yields. We deduced that the low reaction temperature might impede the condensation reaction. At
this point, we decided to switch the solvent to a high-boiling solvent, such as butanol. When the reaction
with hydroxylamine hydrochloride was run in refluxing butanol for 24 hours, the desired 1,4-phenylene
bis-isoxazolo-fused tropone (2) was obtained in 58% yield. Similarly, the treatment of substrate 1 with
aromatic hydrazine
hydrochlorides gave the corresponding 3,3'-{1,4-phenylenebis[(E)ethene-
2,1-diyl]}bis[1-(aryl)cyclohepta[c]pyrazol-8(1H)-one]s (3-5) in 50-53% yields (Scheme 2).

HETEROCYCLES, Vol. 85, No. 4, 2012
913
N
O
N
O
NH2OH·HCl
O
1
O
n-BuOH, reflux, 24 h
2
R
R
NHNH2
N
R
N
N
N
O
O
n-BuOH, reflux, 24 h
R=H, Cl, Br
3-5
Scheme 2. Synthesis of 1,4-phenylene bridged bis-isoxazolo- and pyrazolo-fused tropones (2-5)
Our recent work has proved that the use of I2/DMSO/H2SO4 system for the intramolecular oxidation
cyclization reaction of 3-cinnamoyltropolone derivatives is very efficient for the construction of
pyranotropone compounds.17,22 We felt that this approach can be judiciously extended for the synthesis of
1,4-phenylene bridged bis-pyrano-fused tropone. Thus, upon the subjection to the reaction conditions, the
oxidation cyclization reaction of 1 proceeded smoothly and became complete in 12 hours. After usual
workup followed by purification of the crude products by recrystallization from trifluoroacetic acid, the
product 2,2'-(1,4-phenylene)bis(cyclohepta[b]pyran-4,9-dione (6) was obtained in 65% yield.
O
O
O
I2/DMSO/H2SO4
1
O
110 oC, 10 h
O
O
6
Scheme 3. Synthesis of 2,2'-(1,4-phenylene)biscyclohepta[b]pyran-4,9-dione (6)
The structures of all the newly synthesized 1,4-phenylene bridged bis-heterocycle-fused tropone
compounds 2-6 were established based on the spectral data and elemental analysis as described for 2. Its
1H NMR spectrum exhibited the absence of the signal at about 9.50 ppm belonging to OH moiety of the
precursor 1, along with the signals for aromatic protons and vinylic protons exactly matching its structure
in the range of aromatic region between 7.26-8.39 ppm. The IR spectrum was also devoid of the
stretching vibration band resembling the OH moiety of 1, and exhibited only the typical carbonyl
13
absorption for the tropone ring at 1629 cm-1, supporting the signal of its C NMR spectrum at 178.42

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ppm. Further, the ESI-MS (positive-ion mode) spectrum showed a characteristic quasi-molecular ion peak
(M+H)+ at m/z 421.0 suggesting, along with the elemental analysis, a molecular formula C26H16N2O4.
In summary, the present investigation has demonstrated a facile synthesis of a series of new
1,4-phenylene bridged bis-heterocycle-fused tropone compounds. The structures of all the newly
synthesized compounds were confirmed by spectral analysis. All data were fully consistent with the
assigned molecular structure (see Experimental Section). We anticipate that this work would arouse more
interest in the chemistry of troponoid.
EXPERIMENTAL
The melting points were measured on WRS-1B digital melting points apparatus and are uncorrected. The
progress of the reaction was monitored by TLC. Infrared spectra were recorded on KBr pellets on an
1
FT/IR-430 spectrophotometer. H NMR and 13C NMR spectra were recorded on a Bruker AVANCE
NMR spectrometer using DMSO-d6 as the solvent. The reported chemical shifts (δ values) are given in
parts per million downfield from tetrammethylsilane (TMS) as the internal standard. Elemental analyses
were estimated on an Elementar Vario EL-III element analyzer. The mass spectra were determined using
a MSD VL ESI1 spectrometer. The reaction process was monitored by thin-layer chromatography (TLC)
on silica gel GF254 using EtOAc/petroleum ether (1/4).
Procedure for the synthesis of 3,3'-{1,4-phenylenebis[(1E)-3-oxoprop-1-ene-1,3-diyl]}bistropolone
(1). To a stirred solution of 3-acetyltropolone (0.33 g, 2.0 mmol) and terephthalaldehyde (0.27 g, 1.5
mmol) in 50% MeOH (8 mL) was added dropwise a solution of 5% aqueous KOH (8 mL) at room
temperature. The resulting solution was stirred at room temperature for 24 h. After the reaction was
completed, the mixture was acidified with 3 N hydrochloric acid to precipitate yellow solids. The solids
were collected and recrystallized from trifluoroacetic acid (TFA) to give 1 as yellow crystals in 72% yield,
mp 268-269 C. IR (KBr) ν/cm-1: 3192 (OH), 1670 (C=O), 1605 (C=O); 1H NMR (600 MHz, DMSO-d6):
δ (ppm): 7.16-7.21 (m, 2H, ben-H), 7.32 (d, J=15.6 Hz, 2H, =CH), 7.46-7.54 (m, 4H, ben-H and =CH),
7.84 (d, 2H, J=10.8 Hz, tropolone-H), 8.29-8.36 (m, 4H, tropolone-H), 8.42 (d, J=10.8 Hz, 2H,
13
tropolone-H), 9.50 (br s, 2H, OH); C NMR (150 MHz, DMSO-d6): δ (ppm): 119.57, 124.43, 126.31,
128.82, 131.13, 135.25, 143.72, 144.08, 144.34, 158.19, 177.46, 182.77; ESI-MS m/z: 427.1 (M+1)+.
Anal. Calcd for C26H18O6: C, 73.23; H, 4.25. Found: C, 73.03; H, 4.42.
Procedure for the synthesis of 3,3'-((1E,1'E)-1,4-phenylenebis(ethene-2,1-diyl))bis(8H-cyclohepta-
[d]isoxazol-8-one) (2). To
a
solution of 3,3'-{1,4-phenylenebis[(1E)-3-oxoprop-1-ene-1,3-
diyl]}bistropolone (1) (0.43 g, 1 mmol) in 10 mL of n-BuOH was added hydroxylamine hydrochloride
(0.14 g, 2 mmol). The resulting mixture was heated at reflux for 24 h. After the reaction was completed
(TLC), the mixture was cooled to room temperature, and then poured into some water, filtered to give the

HETEROCYCLES, Vol. 85, No. 4, 2012
915
crude products, which were further purified by recrystallization from TFA. This compound was obtained
o
1
as pale yellow powder in 58% yield, mp >300 C. IR (KBr) ν/cm-1: 1629 (C=O), 1433 (C=N); H NMR
(600 MHz, DMSO-d6): δ (ppm): 7.26 (d, J=15.6 Hz, 2H, =CH), 7.33-7.46 (m, 6H, ben-H and =CH), 7.52
(dd, J=10.8, 10.8 Hz, 2H, tropolone-H), 7.79-7.87 (m, 2H, tropone-H), 8.13 (d, J=10.8 Hz, 2H,
tropone-H), 8.39 (d, J=10.8 Hz, 2H, tropone-H); 13C NMR (150 MHz, DMSO-d6): δ (ppm): 116.74,
122.30, 122.94, 126.17, 126.84, 131.98, 140.32, 141.27, 143.79, 152.27, 158.69, 178.42; ESI-MS m/z:
421.0 (M+1)+. Anal. Calcd for C26H16N2O4: C, 74.28; H, 3.84; N, 6.66. Found: C, 74.44; H, 3.64; N, 6.49.
General procedure for the synthesis of 3,3'-{1,4-phenylenebis[(E)ethene-2,1-diyl]}bis[1-(aryl)-
cyclohepta[c]pyrazol-8(1H)-one]s (3-5). To a solution of 3,3'-{1,4-phenylenebis[(1E)-3-oxoprop-1-ene-
1,3-diyl]}bistropolone (1) (0.43 g, 1 mmol) in 10 mL of n-BuOH was added the corresponding
phenylhydrazine hydrochloride (2 mmol). The resulting mixture was heated at reflux for 24 hours. After
the reaction was complete (TLC), the mixture was cooled to room temperature, and then poured into
some water, filtered to give the crude products, which were further purified by recrystallization from
TFA.
3,3'-{1,4-Phenylenebis[(E)ethene-2,1-diyl]}bis[1-(phenyl)cyclohepta[c]pyrazol-8(1H)-one] (3). This
o
compound was obtained as yellow crystals in 53% yield, mp >300 C. IR (KBr) ν/cm-1: 1644 (C=O),
1
1485 (C=N); H NMR (600 MHz, DMSO-d6): δ (ppm): 7.39 (d, J=15.6, 2H, =CH), 7.47-7.51 (m, 6H,
ben-H), 7.58-7.69 (m, 4H, ben-H and =CH), 7.83-7.87 (m, 6H, ben-H and tropone-H), 8.07-8.12 (m, 4H,
ben-H and tropone-H), 8.38 (d, J=10.8 Hz, 2H, tropone-H), 8.54 (d, J=10.8 Hz, 2H, tropone-H); 13C
NMR (150 MHz, DMSO-d6): δ (ppm): 113.96, 115.37, 123.53, 123.89, 124.15, 127.57, 129.88, 132.09,
133.40, 135.68, 136.10, 136.56, 149.07, 151.17, 153.21, 178.82; ESI-MS m/z: 571.1 (M+1)+. Anal. Calcd
for C38H26N4O2: C, 79.98; H, 4.59; N, 9.82. Found: C, 80.20; H, 4.40; N, 9.83.
3,3'-{1,4-Phenylenebis[(E)ethene-2,1-diyl]}bis[1-(4-chlorophenyl)cyclohepta[c]pyrazol-8(1H)-one]
o
(4). This compound was obtained as yellow crystals in 51% yield, mp >300 C. IR (KBr) ν/cm-1: 1644
(C=O), 1485 (C=N); 1H NMR (600 MHz, DMSO-d6): δ (ppm): 7.36 (d, J=15.6, 2H, =CH), 7.43 (d, J=7.2
Hz, 4H, ben-H), 7.61-7.70 (m, 6H, ben-H and =CH), 7.81-7.92 (m, 6H, ben-H and tropone-H), 8.11-8.15
13
(m, 2H, tropone-H), 8.40 (d, J=10.8 Hz, 2H, tropone-H), 8.55 (d, J=10.8 Hz, 2H, tropone-H); C NMR
(150 MHz, DMSO-d6): δ (ppm): 115.55, 116.18, 122.43, 123.48, 124.61, 126.57, 131.68, 132.26, 134.30,
135.85, 136.81, 142.56, 148.92, 150.34, 152.94, 179.36; ESI-MS m/z: 639.3 (M+1)+. Anal. Calcd for
C38H24Cl2N4O2: C, 71.37; H, 3.78; N, 8.76. Found: C, 71.53; H, 3.76; N, 8.81.
3,3'-{1,4-Phenylenebis[(E)ethene-2,1-diyl]}bis[1-(4-bromophenyl)cyclohepta[c]pyrazol-8(1H)-one]
(5). This compound was obtained as yellow crystals in 50%, mp >300 oC. IR (KBr) ν/cm-1: 1642 (C=O),
1
1484 (C=N); H NMR (600 MHz, DMSO-d6): δ (ppm): δ 7.41 (d, J=15.6 Hz, 2H, =CH), 7.45 (d, J=7.2
Hz, 4H, ben-H), 7.49-7.55 (m, 4H, ben-H), 7.63-7.71 (m, 4H, =CH and tropone-H), 7.81 (d, J=7.2 Hz, 4H,

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HETEROCYCLES, Vol. 85, No. 4, 2012
ben-H), 7.89 (dd, J=10.8, 10.8 Hz, 2H, tropone-H), 8.28 (d, J=10.8 Hz, 2H, tropone-H), 8.45 (d, J=10.8
13
Hz, 2H, tropone-H); C NMR (150 MHz, DMSO-d6): δ (ppm): 115.39, 116.63, 123.01, 123.74, 130.35,
131.60, 133.72, 135.38, 135.95, 137.39, 140.86, 141.97, 148.28, 150.16, 153.23, 178.81; ESI-MS m/z:
727.1, 728.9, 731.0 (M+1)+. Anal. Calcd for C38H24Br2N4O2: C, 62.66; H, 3.32; N, 7.69. Found: C, 62.49;
H, 3.41; N, 7.80.
Procedure for the synthesis of 2,2'-(1,4-phenylene)bis(cyclohepta[b]pyran-4,9-dione) (6). To a stirred
solution of 3,3'-{1,4-phenylenebis[(1E)-3-oxoprop-1-ene-1,3-diyl]}bistropolone (1) (0.43 g, 1 mmol) in 8
mL of DMSO was added 3-4 drops of concd. H2SO4. After 15 min of magnetic stirring at 110 oC, I2 was
added carefully and the resulting reaction mixture was reacted under the temperature for 12 h. The
completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature
and added with 5 mL of H2O slowly. And then the resulting precipitate was collected by filtration and
o
recrystallized from TFA. This compound was obtained as yellow crystals in 65% yield, mp >300 C. IR
(KBr) ν/cm-1: 1649 (C=O), 1586 (C=O); 1H NMR (600 MHz, DMSO-d6): δ (ppm): 7.43 (d, J=8.4 Hz, 2H,
ben-H), 7.75 (d, J=8.4 Hz, 2H, ben-H), 7.90 (d, J=10.8 Hz, 2H, tropone-H), 8.03 (dd, J=10.8, 10.8 Hz,
2H, tropone-H), 8.28-8.32 (m, 2H, tropone-H), 8.39 (s, 2H, pyran-H), 8.49 (d, J=10.8 Hz, 2H,
13
tropone-H); C NMR (150 MHz, DMSO-d6): 117.12, 122.91, 123.74, 125.78, 126.16, 133.11, 137.51,
138.50, 145.75, 160.16, 178.42, 180.82; ESI-MS m/z: 422.9 (M+1)+. Anal. Calcd for C26H14O6: C, 73.93;
H, 3.34. Found: C, 74.09; H, 3.48.
ACKNOWLEDGEMENTS
The authors would like to thank the financial support from the Foundation of Liaoning Province Key
Laboratory of Applied Chemistry (Grant No. 2008s001).
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