A facile synthesis of (E)-3-styryl-1-phenyl cyclohepta[c]pyrazol-8(1H)-ones

Article abstract of DOI:10.1007/s11164-012-0785-5

A facile synthesis of some novel (E)-3-styryl-1-phenylcyclohepta[c]pyrazol- 8(1H)-ones via the condensation reaction of 3-cinnamoyltropolones with phenylhydrazine is described. All the synthesized compounds were obtained in good yields of 62-69 % and their structures were characterized by IR, ¹H NMR, MS, and elemental analysis. This procedure offers easy access to tropone-fused pyrazole derivatives in short reaction times, and the products are achieved in good yields.

Full text of DOI:10.1007/s11164-012-0785-5

Res Chem Intermed (2013) 39:2621–2627
DOI 10.1007/s11164-012-0785-5
A facile synthesis of (E)-3-styryl-1-phenyl
cyclohepta[c]pyrazol-8(1H)-ones
•
Yang Li Minqin Chang Rui Liu
•
•
•
Guihai Lin Wentao Gao
Received: 23 May 2012 / Accepted: 18 August 2012 / Published online: 7 September 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A facile synthesis of some novel (E)-3-styryl-1-phenylcyclohepta[c]pyr-
azol-8(1H)-ones via the condensation reaction of 3-cinnamoyltropolones with phen-
ylhydrazine is described. All the synthesized compounds were obtained in good yields
1
of 62–69 % and their structures were characterized by IR, H NMR, MS, and ele-
mental analysis. This procedure offers easy access to tropone-fused pyrazole deriv-
atives in short reaction times, and the products are achieved in good yields.
Keywords Tropone Á Pyrazole Á Condensation reaction Á 3-Cinnamoyltropolone Á
Phenylhydrazine
Introduction
The pyrazole ring system, one of the most valuable nitrogen heterocycles, has been the
subject of considerable research due to its usefulness in synthetic organic chemistry
and also because of its pharmacological properties [1–5]. Especially, the important
role of ring-fused pyrazoles in medicinal and pharmaceutical chemistry is indisputable
and well reflected by a large number of recent publications [5–9], including some
excellent reviews [10, 11]. As a consequence, over recent years great efforts have been
devoted to the synthesis of interesting types of ring-fused pyrazole derivatives
[12–16]. Most fused pyrazole compounds reported in the literature comprise a
common heterocyclic ring moiety fused with a pyrazole ring, such as pyrimidopy-
razole [9, 12], pyrazoloquinoline [13, 17], pyrazoloindole [18], benzofuropyrazole
[19], pyridopyrazole [8, 20], and synthetic analogues thereof. However, there are very
few reports in which the heterocyclic moiety is replaced with a tropone unit.
Y. Li Á M. Chang Á R. Liu Á G. Lin Á W. Gao (&)
Institute of Superfine Chemicals, Bohai University, Jinzhou 121000, China
e-mail: bhuzh@163.com
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Y. Li et al.
On the other hand, tropone natural products and synthetic tropone derivatives
have attracted considerable interest due to the unique structure and properties of the
tropone ring [21–23]. Recent studies have suggested that a combination of a
heterocycle moiety fused with a tropone ring may increase their biological activities
or create new medicinal properties [24–26]. For example, structural variations of
established drugs with the tropone ring resulted in enhanced anticancer activity [26].
Therefore, there is much current interest in assembling a tropone ring by fusing with
heterocyclic systems, which represent privileged moieties in medicinal chemistry,
and are ubiquitous sub-structures associated with biologically active natural
products [27–29].
In light of these findings, and in view of structural diversity playing a prominent
role in medicinal and combinatorial chemistry for a faster and more efficient route
towards new drug discovery [30], we assumed that incorporation of the tropone
moiety instead of an aromatic or heteroaromatic ring fused with a pyrazole ring
would be much more attractive and valuable for medicinal chemistry and drug
discovery. Thus, the aim of the present work was to synthesize novel compounds
combining these two systems in a molecular framework as in fused forms.
Results and discussion
Recently, we have reported the intramolecular oxidation cyclization reaction of
3-cinnamoyltropolone by the treatment with the I2/DMSO/H2SO4 system for the
synthesis of flavone-like tropones [31–33]. We have also developed an efficient
synthesis of 5,7-dibromotropono[c]pyrazole derivatives via the condensation reaction
of 3-acetyl-5,7-dibromotropolone with aromatic hydrazines [34]. In the context of our
ongoing studies on troponoid chemistry and further extending the diversity of our
previous work, we have become interested in the synthesis of novel 3-styryltropon-
o[c]pyrazole derivatives (2a–g). Our strategy to reach this goal is outlined in
Scheme 1. 3-Cinnamoyltropolones 1a–g are easily synthesized in high yields and high
purity as well as being based on our previous reported procedures [35].
Initially, we examined the reaction of 1a with free phenylhydrazine in refluxing
EtOH. However, the reaction was found to be very complex and we could not obtain
any pyrazole derivatives in appreciable yields. Instead, we found that the reaction of
1a and phenylhydrazine hydrochloride was performed smoothly and gave the
O
Ph
N
N
OH
O
phenyldrazine hydrochloride
EtOH, reflux, 24 h
R
R
O
2a-g
1a-g
R=Me, OMe, Cl, Br, CN, NO2
Scheme 1 Synthesis of (E)-3-styryl-1-phenylcyclohepta[c]pyrazol-8(1H)-ones (2a–g)
123

Synthesis of (E)-3-styryl-1-phenyl cyclohepta[c]pyrazol-8(1H)-ones
2623
desired (E)-3-(4-methylstyryl)-1-phenyltropono[c]pyrazole (2a) in good yield of
69 %. The reaction result we obtained is very similar to that reported by Lee et al.
[36]. In addition, we also tried using other solvents such as MeOH, MeCN, and 1,2-
dichloroethane. But the yield could not be improved further. Some representative
results are summarized in Table 1.
As shown in Table 1, the effect of substituents on the benzene ring is not very
strong, showing little distinction and giving about the same yields. For example, the
troponyl-substituted chalcones 2a–c (Entries 1–3) bearing electron-donating methyl
and methoxy groups were obtained in 69, 65 and 66 % yields, respectively. On the
other hand, compounds 2d–g (Entries 4–7) bearing electron-withdrawing groups
were obtained in the comparable yields of 62–67 %.
The structures of (E)-3-styryl-1-phenylcyclohepta[c]pyrazol-8(1H)-ones deriva-
tives were deduced from their spectral data and elemental analysis as described for
2a. The IR spectrum of reaction product 2a showed a typical stretching vibration
band at 1,636 cm-1 due to the tropone carbonyl group. The main features of its 1H
NMR spectrum showed a pair of AB doublets appearing at 7.47 and 7.69 ppm,
consistent with the two vinylic protons with a large coupling constant J = 16.0 Hz,
which indicated the expected E-configuration. Its ESI–MS spectrum (positive-ion
mode) exhibited a characteristic quasi-molecular ion peak at m/z 339.3 ([M ? H]?).
Further, the structure assigned for this reaction product 2a was fully supported by its
elemental analysis, which established its molecular formula in accordance with the
suggested molecular structure. The other synthesized compounds exhibited similar
spectral characteristics except the substituents, which exhibited characteristic
signals with appropriate chemical shifts. Additionally, it is worth noting that the
structures of products 2 contain styryl group p-electron systems tethered to a
pyrazole ring, which can be used as promising precursors for the synthesis of
complex compounds, for example, via Diels–Alder reaction [37].
Conclusions
It can be concluded that the present investigation has demonstrated a facile syn-
thesis of novel (E)-3-styryl-1-phenylcyclohepta[c]pyrazol-8(1H)-one derivatives.
The molecules we have synthesized should allow us, in the future, to investigate
structure–activity relationships over various biotests. Moreover, all these synthe-
sized molecules can be used for the synthesis of more complex heterocyclic
compounds, since a styryl group tethered to a pyrazole ring can be further
elaborated, for example, via Diels–Alder reaction.
Experimental
The chemicals used in this work were obtained from Fluka and were used without
purification. The melting points were determined by using WRS-1B melting points
apparatus and were uncorrected. 1H NMR was measured with a BRUKER BRX 400
at 400 MHz. The reported chemical shifts were against TMS. The mass spectra
123

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Y. Li et al.
Table 1 Yields and physical properties of the compounds 2a–g
Entry
1
Product
2a–g
Yield/%a
69
M.p./°C
2a
234–235
Ph
N
N
O
2
2b
65
203–205
Ph
N
N
O
MeO
3
4
5
2c
2d
2e
66
64
62
244–246
216–218
209–211
Ph
N
N
O
OMe
Cl
Ph
N
N
O
Ph
N
N
O
Br
6
7
2f
67
63
225–227
238–240
Ph
N
N
N
O
CN
2 g
Ph
N
O
NO2
a
Isolated yields
were determined using a MSD VL ESI1 spectrometer. Elemental analyses were
recorded on an Elementar vario EL-III element analyzer.
General procedure for synthesis (E)-3-styryl-1-phenylcyclohepta[c]pyrazol-
8(1H)-one derivatives (2a–g)
To a solution of 3-cinnamoyltropolone 1 (1 mmol) in 5 mL of EtOH was added
phenylhydrazine hydrochloride (2 mmol). The resulting mixture was heated at
reflux for 24 h. After the reaction was complete (TLC), the mixture was cooled to
room temperature, and then poured into some water and filtered to give the crude
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Synthesis of (E)-3-styryl-1-phenyl cyclohepta[c]pyrazol-8(1H)-ones
2625
products, which were further purified by recrystallization from acetic acid to afford
products 2. The yields and melting points are listed in Table 1 and the spectral and
analytical data are given below.
(E)-3-(4-Methylstyryl)-1-phenylcyclohepta[c]pyrazol-8(1H)-one (2a)
Orange powder; IR (KBr, m, cm-1): 1,636, 1,592, 1,557, 1,520, 1,496, 1,420, 1,400,
1,273, 1,214, 1,167, 1,148, 1,030, 1,014, 960, 896, 852, 801, 700; 1H NMR (CDCl3,
400 MHz) (d, ppm): 2.33 (s, 3H, Me), 6.90 (d, 1H, J = 12.4 Hz, tropone-H),
6.98–7.01 (m, 1H, ArH), 7.23 (d, 2H, J = 8.0 Hz, benzene-H), 7.47 (d, 1H,
J = 16.0 Hz, = CH), 7.41–7.51 (m, 6H, ArH), 7.66 (d, 2H, J = 8.0 Hz, benzene-
H), 7.69 (d, 1H, J = 16.4 Hz, = CH), 8.13 (d, 1H, J = 10.8 Hz, tropone-H); MS
(ESI, m/z): 339.3 [M ? H]?. Anal. Calcd for C23H18N2O: C, 81.63; H, 5.36; N,
8.28. Found: C, 81.24; H; 5.47; N, 8.35.
(E)-3-(2-Methoxystyryl)-1-phenylcyclohepta[c]pyrazol-8(1H)-one (2b)
Yellow solid, IR (KBr, m, cm-1): 1,610, 1,558, 1,519, 1,510, 1,476, 1,410, 1,255,
1
1,217, 1,025, 974, 761, 702; H NMR (CDCl3, 400 MHz) (d, ppm): 3.86 (s, 3H,
OMe), 6.91 (d, 1H, J = 12.4 Hz, tropone-H), 7.02–7.08 (m, 3H, ArH), 7.34–7.37
(m, 1H, ArH), 7.44–7.51 (m, 6H, ArH), 7.69 (d, 1H, J = 16.4 Hz, = CH), 7.86 (d,
1H, J = 16.4 Hz, = CH), 7.92 (d, 1H, J = 7.6 Hz, benzene-H), 8.10 (d, 1H,
J = 10.8 Hz, tropone-H); MS (ESI, m/z): 355.2 [M ? H]?. Anal. Calcd for
C23H18N2O2: C, 77.95; H, 5.12; N, 7.90. Found: C, 78.38; H, 5.17; N 8.14.
(E)-3-(4-Methoxystyryl)-1-phenylcyclohepta[c] pyrazol-8(1H)-one (2c)
Yellow solid, IR (KBr, m, cm-1): 1,630, 1,593, 1,552, 1,521, 1,1488, 1,391, 1,341,
1
1,262, 1,200, 1,110, 1,070, 1,010, 900, 793, 691; H NMR (CDCl3, 400 MHz) (d,
ppm): 3.80 (s, 3H, OMe), 6.89 (d, 1H, J = 12.4 Hz, tropone-H), 6.96–7.00 (m, 3H,
ArH), 7.41–7.53 (m, 6H, ArH), 7.56 (d, 1H, J = 16.0 Hz, = CH), 7.61 (d, 1H,
J = 16.0 Hz, = CH), 7.72 (d, 2H, J = 8.4 Hz, benzene-H), 8.11 (d, 1H,
J = 10.8 Hz, tropone-H); MS (ESI, m/z): 355.2 [M ? H]?. Anal. Calcd for
C23H18N2O2: C, 77.95; H, 5.12; N, 7.90. Found: C, 78.27; H, 5.04; N, 8.09.
(E)-3-(4-Chlorostyryl)-1-phenylcyclohepta[c]pyrazol-8(1H)-one (2d)
Yellow solid, IR (KBr, m, cm-1): 1,630, 1,581, 1,546, 1,515, 1,496, 1,454, 1,397,
1,244, 1,206, 1,120, 1,050, 1,017, 974, 870, 748, 699; 1H NMR (CDCl3, 400 MHz)
(d, ppm): 6.90 (d, 1H, J = 12.4 Hz, tropone-H), 7.41–7.49 (m, 7H, ArH), 7.57 (d,
1H, J = 16.4 Hz, = CH), 7.78–7.83 (m, 5H, ArH and = CH), 8.15 (d, 1H,
J = 10.8 Hz, tropone-H); MS (ESI, m/z): 359.2 [M ? H]?. Anal. Calcd for
C22H15ClN2O: C, 73.64; H, 4.21; N, 7.81. Found: C, 73.50; H, 4.25; N, 7.95.
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Y. Li et al.
(E)-3-(2-Bromostyryl)-1-phenylcyclohepta[c]pyrazol-8(1H)-one (2e)
Yellow solid, IR (KBr, m, cm-1): 1,630, 1,587, 1,550, 1,497, 1,431, 1,395, 1,206,
1
1,017, 961, 802, 771, 748; H NMR (CDCl3, 400 MHz) (d, ppm): 6.91 (d, 1H,
J = 12.4 Hz, tropone-H), 6.97–7.00 (m, 1H, ArH), 7.28–7.30 (m, 1H, ArH), 7.48
(d, 1H, J = 15.9 Hz, = CH), 7.44 (d, 1H, J = 15.9 Hz, = CH), 7.41–7.52 (m, 5H,
ArH), 7.79-7.83 (m, 2H, ArH), 7.68 (d, 1H, J = 8.0 Hz, benzene-H), 8.12–8.15 (m,
2H, ArH); MS (ESI, m/z): 403.1, 405.1 [M ? H]?. Anal. Calcd for C22H15BrN2O:
C, 65.52; H, 3.75; N, 6.95. Found: C, 65.39; H, 3.67; N, 7.01.
(E)-3-(4-Cyanostyryl)-1-phenylcyclohepta[c]pyrazol-8(1H)-one (2f)
Yellow solid, IR (KBr, m, cm-1): 1,637, 1,551, 1,524, 1,443, 1,400, 1,350, 1,302,
1,272, 1,254, 1,236, 1,200, 1,178, 1,056, 1,030, 971, 802, 775, 706; 1H NMR
(CDCl3, 400 MHz) (d, ppm): 6.92 (d, 1H, J = 12.5 Hz, tropone-H), 7.01–7.04 (m,
1H, ArH), 7.42–7.52 (m, 6H, ArH), 7.63 (d, 1H, J = 16.1 Hz, = CH), 7.88 (d, 2H,
J = 8.3 Hz, benzene-H), 7.96–8.00 (m, 3H, ArH and = CH), 8.17 (d, 1H,
J = 11.0 Hz, tropone-H); MS (ESI, m/z): 350.2 [M ? H]?. Anal. Calcd for
C23H15N3O: C, 79.07; H, 4.33; N, 12.03. Found: C, 78.97; H, 4.25; N, 11.99.
(E)-3-(4-Nitrostyryl)-1-phenylcyclohepta[c]pyrazol-8(1H)-one (2g)
Yellow solid, IR (KBr, m, cm-1): 1,634, 1,588, 1,546, 1,497, 1,472, 1,388, 1,349,
1,257, 1,205, 1,139, 1,104, 1,050, 1,019, 970, 805, 790, 761; H NMR (CDCl3,
1
400 MHz) (d, ppm): 6.92 (d, 1H, J = 12.4 Hz, tropone-H), 7.01–7.03 (m, 1H,
ArH), 7.42–7.49 (m, 5H, ArH), 7.52 (d, 1H, J = 16.4 Hz, = CH), 7.70 (d, 1H,
J = 16.4 Hz, = CH), 8.03–8.06 (m, 1H, ArH), 8.07 (d, 2H, J = 8.4 Hz, benzene-
H), 8.19 (d, 1H, J = 11.2 Hz, tropone-H), 8.26 (d, 2H, J = 8.4 Hz, benzene-H);
MS (ESI, m/z): 370.2 [M ? H]?. Anal. Calcd for C22H15N3O3: C, 71.54; H, 4.09;
N, 11.38. Found: C, 71.43; H, 4.00; N, 11.24.
Acknowledgment We would like to acknowledge the financial support from the Natural Science
Foundation of Liaoning Province (Grant No. 201202001).
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