Synthesis of conjugated (E,E)-1,3-diene-containing troponoid-based compounds

Article abstract of DOI:10.2478/s11696-012-0155-1

Through exploration of the electrophilic substitution reaction of 3-((2E,4E)-5-phenylpenta-2,4-dienoyl)-2-hydroxy-2,4,6-cycloheptatrien-1-one (3-((2E,4E)-5-phenylpenta-2,4-dienoyl)tropolone) with halogen and diazonium salts as well as the nucleophilic cyclisation reaction with hydroxylamine hydrochloride and substituted phenylhydrazine hydrochlorides by employing our reliable methods, we have synthesised a series of new (E,E)-1,3-diene-bearing troponoid-based compounds. All the newly synthesised molecules represent an issue of great interest, since the presence of conjugated 1,3-diene moiety can be developed further via other reactions.

Full text of DOI:10.2478/s11696-012-0155-1

Chemical Papers 66 (7) 691–698 (2012)
DOI: 10.2478/s11696-012-0155-1
ORIGINAL PAPER
Synthesis of conjugated ( , )-1,3-diene-containing troponoid-based
compounds
Wen-Tao Gao*, Yan Yan, Yang Li
Institute of Superfine Chemicals, Bohai University, 121000 Jinzhou, China
Received 13 September 2011; Revised 22 December 2011; Accepted 17 January 2012
Through exploration of the electrophilic substitution reaction of 3-((2E,4E)-5-phenylpenta-2,4-
dienoyl)-2-hydroxy-2,4,6-cycloheptatrien-1-one (3-((2E,4E)-5-phenylpenta-2,4-dienoyl)tropolone)
with halogen and diazonium salts as well as the nucleophilic cyclisation reaction with hydroxylamine
hydrochloride and substituted phenylhydrazine hydrochlorides by employing our reliable methods,
we have synthesised a series of new (E,E)-1,3-diene-bearing troponoid-based compounds. All the
newly synthesised molecules represent an issue of great interest, since the presence of conjugated
1,3-diene moiety can be developed further via other reactions.
c
ꢀ 2012 Institute of Chemistry, Slovak Academy of Sciences
Keywords: troponoid, 1,3-diene, electrophilic substitution, nucleophilic cyclisation
Introduction
troponoid-based molecules, the interest surrounding
the troponoid moiety continues to be a vector in the
development of efficient and practical synthesis of new
troponoid-based compounds (Adlington et al., 2002;
Albrecht et al., 2004; Hong et al., 2010; Azizian et al.,
2011).
Conjugated dienes are important intermediates in
organic synthesis and biologically active natural com-
pounds; they have been used extensively as reactive
species for building chemical diversity (Xiao et al.,
2000; Bhargava et al., 2008; Nishimura et al., 2010).
As a consequence, there have been many efforts to syn-
thesise different types of organic molecules containing
conjugated 1,3-diene moiety (Ramazani & Bodaghi,
2004; Cai et al., 2006; Ignatowska & Dmowski, 2006;
Liu et al., 2007; Bazin et al., 2008). For example,
Conti and Desideri (2010) reported the synthesis of
new 3-((1E,3E)-4-phenylbuta-1,3-dienyl)-substituted
chromenes and chromen-4-ones as anti-picornavirus
capsid-binders. On the other hand, troponoid-based
natural products and synthetic compounds have been
studied in such varied fields as medicinal and mate-
rial sciences because of their multiple biological activi-
ties such as anti-tumour (Yamato et al., 1984; Bentley,
2008; Wakabayashi et al., 2003), antifungal (Angawi
et al., 2003), anti-HCV (Boguszewska-Chachulska et
al., 2006), and antimicrobial activities (Seephonkai et
al., 2001), as well as their ability to form liquid crys-
tal materials or metallomesogens (Mori et al., 2005;
Mazzeo et al., 2005). Given the high significance of
Our research group has gained substantial abil-
ity in the synthesis of troponoid-based compounds
through previous experience (Gao et al., 1989, 2009a,
2009b, 2010a, 2010b; Gao & Zheng, 2000; Li & Gao,
2010; Chang et al., 2011). Building on this evolving
expertise and in the light of the above findings, our
research group is actively involved in exploring the
reactivity of 3-((2E,4E)-5-phenylpenta-2,4-dienoyl)-2-
hydroxy-2,4,6-cycloheptatrien-1-one ((3-((2E,4E)-5-
phenylpenta-2,4-dienoyl) tropolone) (I) and its appli-
cation in the synthesis of new (E,E)-1,3-diene-bearing
troponoid-based compounds, which represent poten-
tially useful synthetic building blocks in medicinal
chemistry or in designing novel troponoid drugs. Our
earlier report detailed the synthesis of compound I by
the direct Claisen–Schmidt condensation reaction be-
tween 3-acetyl-2-hydroxy-2,4,6-cycloheptatrien-1-one
(3-acetyltropolone) with (2E)-3-phenylprop-2-enal
(cinnamaldehyde) (Zhang et al., 1995; Gao & Zheng,
2000). However, the report is of episodic character
*Corresponding author, e-mail: bhuzh@163.com

692
W. T. Gao et al./Chemical Papers 66 (7) 691–698 (2012)
and no work has been done on the further trans-
formation of I. As a consequence, our present work
was directed towards an extension of this work to in-
clude further examples of conjugated (E,E)-1,3-diene-
containing troponoid-based compounds.
Table 1. Characterisation data of newly prepared compounds
Yield
%
M.p.
◦C
Compound
Colour and shape
I
II
III
IV
V
yellow needles
yellow crystals
yellow crystals
orange crystals
red crystals
83
51
63
40
62
59
55
53
44
61
54
57
47
51
45
43
45
47
146–148
164–166
201–202
206–207
215–217
221–222
207–209
196–198
251–253
257–258
206–207
257–260
253–254
167–168
257–dec.a
230–232
226–228
216–217
Experimental
All chemicals were commercially available ana-
lytical purity reagents from Merck (Germany) and
Fluka (Switzerland) and used without further purifi-
cation. Melting points (uncorrected, Table 1) were
determined by using WRS-1B melting points appa-
ratus (Shanghai Precision & Scientific Instrument,
China). The IR spectra were obtained as KBr pel-
lets in the range of 400–4000 cm−1 on a Shimadzu
FTIR-8400S spectrophotometer (Shimadzu, Japan).
The 1H NMR (400 MHz) spectra were recorded on
a Bruker AVANCE 400 NMR spectrometer (Bruker,
Germany) with TMS as the internal standard us-
ing CDCl3 as solvent. HRMS (ESI) data were ac-
quired on a Bruker Customer micrOTOF-Q 125 high-
resolution mass spectrometer (Bruker, Germany) with
ESI. Spectral data of the newly prepared compounds
are summarised in Table 2. The progress of the re-
actions was monitored by thin-layer chromatography
(TLC) on Merck Kieselgel 60 PF254 (Merck, Ger-
many) using ethyl acetate as eluent.
VI
red powder
VII
VIII
IX
X
XI
XII
XIII
XIV
XV
XVI
XVII
XVIII
deep red powder
pale brown powder
golden powder
brown crystals
golden needles
yellow crystals
orange crystals
golden powder
golden crystals
yellow crystals
yellow crystals
brown powder
a) Decomposes.
acid (2 mL) was added drop-wise to a stirred solution
of I (278 mg, 1 mmol) and sodium acetate (125 mg) in
acetic acid (60 mL) at laboratory temperature. After
stirring for 2 h, water (100 mL) was added to the
reaction mixture. The precipitate was collected and
recrystallised from ethyl acetate to give product III.
Synthesis of 3-((2E,4E)-5-phenylpenta-2,4-
dienoyl)tropolone (I)
Synthesis of 7-iodo-3-((2E,4E)-5-
Potassium hydroxide aqueous solution (5 %, 5 mL)
was added to a stirred solution of 3-acetyltropolone
(164 mg, 1 mmol) and cinnamaldehyde (198 mg,
1.5 mmol) in aqueous MeOH (50 %, 8 mL) at labora-
tory temperature. The resulting solution was stirred at
laboratory temperature for 24 h. The reaction mixture
was then quenched by the addition of 5 mL of H2O
and acidification with 1 M HCl (5 mL). The precip-
itated product was collected and recrystallised from
MeOH to give yellow neddles.
phenylpenta-2,4-dienoyl)tropolone (IV)
A solution of iodine (1.27 g, 5 mmol) and potas-
sium iodide (1.22 g, 7.2 mmol) in water (3 mL)
was added to a stirred mixture of compound I
(278 mg, 1 mmol) and potassium carbonate (305 mg,
2.21 mmol) in water (2 mL) in an ice–water bath. Af-
ter 22 h of stirring, the excess iodine was reduced with
sodium hydrogen sulphide. The mixture was acidified
to pH 4 by addition of 6 M HCl to precipitate as an
orange solid. The crude product was collected and re-
crystallised from ethyl acetate to give IV.
Synthesis of 7-bromo-3-((2E,4E)-5-
phenylpenta-2,4-dienoyl)tropolone (II)
General procedure for azo-coupling reaction of
3-((2E,4E)-5-phenylpenta-2,4-dienoyl)
tropolone (I) with diazonium salts of anilines
A solution of bromine (160 mg, 1 mmol) in acetic
acid (2 mL) was added drop-wise to a stirred solution
of I (278 mg, 1 mmol) and sodium acetate (125 mg) in
acetic acid (60 mL) at laboratory temperature. After
stirring for 2 h, water (100 mL) was added to the
reaction mixture. The precipitate was collected and
recrystallised from ethyl acetate to give product II.
An arenediazonium chloride solution (2 mL), pre-
pared from anilines (2 mmol) and sodium nitrite
(139 mg, 2 mmol) was added drop-wise to an ice-
cooled stirred solution of compound I (278 mg,
1 mmol) in pyridine (5 mL). After 3 h of stirring,
the precipitate was collected and recrystallised from
benzene or ethyl acetate to give 5-(aryldiazenyl)-3-
((2E,4E)-5-phenylpenta-2,4-dienoyl)tropolones
V–VII in good yields.
Synthesis of 5,7-dibromo-3-((2E,4E)-5-
phenylpenta-2,4-dienoyl)tropolone (III)
A solution of bromine (320 mg, 2 mmol) in acetic

W. T. Gao et al./Chemical Papers 66 (7) 691–698 (2012)
Table 2. Spectral data of newly prepared compounds
693
Compound
Spectral data
—
—
I
IR, ν˜/cm−1: 3182 (OH), 1650 (C O), 1611 (C O)
—
—
1
—
—
—
H NMR (CDCl3), δ: 6.80 (1H, d, J = 15.2 Hz, CH), 6.97 (1H, d, J = 15.2 Hz, CH), 7.11 (1H, dd, J = 15.2 Hz,
—
—
—
—
—
J = 10.8 Hz, CH), 7.14–7.16 (1H, m, tropolone-H), 7.26–7.32 (2H, m, CH and benzene-H), 7.34–7.39 (2H, m,
benzene-H), 7.42 (2H, d, J = 8.4 Hz, benzene-H), 7.46 (1H, d, J = 10.0 Hz, tropolone-H), 7.50 (1H, dd, J = 9.5 Hz,
J = 10.0 Hz, tropone-H), 7.66 (1H, d, J = 9.5 Hz, tropolone-H), 9.55 (1H, s, OH)
HRMS (ESI): m/z (calc./found): 301.0833/301.0829 ((M+Na)+, C18H14NaO3)
—
—
II
IR, ν˜/cm−1: 3179 (OH), 1641 (C O), 1611 (C O)
—
—
1
—
—
—
H NMR (CDCl3), δ: 6.72 (1H, d, J = 15.2 Hz, CH), 6.81 (1H, d, J = 15.2 Hz, CH), 6.98 (2H, d, J = 7.2 Hz,
—
—
—
benzene-H), 7.16 (1H, dd, J = 15.2 Hz, J = 10.8 Hz,
CH), 7.34–7.38 (m, 3H, benzene-H), 7.40 (1H, dd, J =
—
15.6 Hz, J = 10.4 Hz,
CH), 7.48 (1H, dd, J = 11.0 Hz, J = 11.2 Hz, tropone-H), 7.67 (1H, d, J = 11.0 Hz,
—
tropone-H), 8.48 (1H, d, J = 11.2 Hz, tropone-H), 9.37 (1H, br s, OH)
HRMS (ESI): m/z (calc./found): 378.9938/378.9930 ((M+Na)+, C18H13BrNaO3)
—
—
III
IV
V
IR, ν˜/cm−1: 3183 (OH), 1639 (C O), 1612 (C O)
—
—
1
—
—
—
H NMR (CDCl3), δ: 6.69 (1H, d, J = 15.2 Hz, CH), 6.75 (1H, d, J = 15.2 Hz, CH), 6.99 (1H, dd, J = 15.2 Hz,
—
—
—
—
—
J = 10.8 Hz, CH), 7.35–7.43 (4H, m, benzene-H, CH), 7.53–7.56 (2H, m, benzene-H), 7.81 (1H, d, J = 2.0 Hz,
tropone-H), 8.49 (1H, d, J = 2.0 Hz, tropone-H), 9.45 (1H, s br, OH)
HRMS (ESI): m/z (calc./found): 456.9043/456.9039 ((M+Na)+, C18H12Br2NaO3)
IR, ν˜/cm−1: 3185 (OH), 1665 (C O), 1611 (C O)
—
—
—
—
1
—
—
—
H NMR (CDCl3), δ: 6.85 (1H, d, J = 15.6 Hz, CH), 7.02 (1H, d, J = 15.6 Hz, CH), 7.18 (1H, dd, J = 15.6 Hz,
—
—
—
—
—
J = 10.4 Hz, CH), 7.33–7.46 (6H, m, benzene-H, CH), 7.52 (1H, dd, J = 10.8 Hz, J = 10.8 Hz, tropolone-H),
7.89 (1H, d, J = 10.8 Hz, tropone-H), 8.39 (1H, d, J = 10.8 Hz, tropone-H), 9.58 (br s, 1H, OH)
HRMS (ESI): m/z (calc./found): 426.9800/426.9794 ((M+Na)+, C18H13INaO3)
IR, ν˜/cm−1: 3182 (OH), 1651 (C O), 1610 (C O)
—
—
—
—
1
—
—
—
H NMR (CDCl3), δ: 6.80 (1H, d, J = 15.2 Hz, CH), 6.99 (1H, d, J = 15.2 Hz, CH), 7.06 (1H, dd, J = 15.2 Hz,
—
—
—
—
—
J = 10.4 Hz, CH), 7.34–7.40 (6H, m, benzene-H, CH), 7.48–7.54 (5H, m, benzene-H), 7.57 (1H, d, J = 11.2 Hz,
tropolone-H), 8.30 (1H, dd, J = 11.2 Hz, J = 2.0 Hz, tropolone-H), 8.47 (1H, d, J = 2.0 Hz, tropone-H), 9.25 (1H,
br s, OH)
HRMS (ESI): m/z (calc./found): 405.1208/405.1205 ((M+Na)+, C24H18N2NaO3)
—
—
VI
VII
VIII
IR, ν˜/cm−1: 3172 (OH), 1648 (C O), 1618 (C O)
—
—
1H NMR (CDCl3), δ: 2.44 (3H, s, CH3), 6.79 (1H, d, J = 15.2 Hz, CH), 7.00 (2H, d, J = 6.0 Hz, benzene-H),
—
—
—
—
—
—
7.09 (1H, d, J = 15.2 Hz, CH), 7.31–7.37 (5H, m, benzene-H, CH), 7.41–7.47 (2H, m, benzene-H), 7.55 (1H, d,
J = 11.2 Hz, tropolone-H), 7.83 (2H, d, J = 8.4 Hz, benzene-H), 8.29 (1H, dd, J = 11.2 Hz, J = 2.0 Hz, tropone-H),
8.45 (1H, d, J = 2.0 Hz, tropone-H), 9.50 (1H, br s, 1H, OH)
HRMS (ESI): m/z (calc./found): 419.1364/419.1371 ((M+Na)+, C25H20N2NaO3)
IR, ν˜/cm−1: 3286 (OH), 1697 (C O), 1628 (C O)
—
—
—
—
1
—
—
—
H NMR (CDCl3), δ: 6.69 (1H, d, J = 15.2 Hz, CH), 6.99 (1H, d, J = 15.2 Hz, CH), 7.10 (1H, dd, J = 15.2 Hz,
—
—
—
—
—
J = 10.4 Hz, CH), 7.36–7.44 (6H, m, benzene-H, CH), 7.59–7.66 (m, 4H, benzene-H), 7.80 (1H, dd, J = 11.0 Hz,
J = 2.0 Hz, tropolone-H), 8.13 (1H, d, J = 11.0 Hz, tropolone-H), 8.49 (1H, d, J = 2.0 Hz, tropolone-H), 9.45 (1H,
br s, OH)
HRMS (ESI): m/z (calc./found): 450.1074/450.1068 ((M+Na)+, C24H17N3NaO5)
IR, ν˜/cm−1: 1634 (C O), 1581 (C N)
—
—
—
—
1
—
—
—
H NMR (CDCl3), δ: 6.68 (1H, d, J = 15.6 Hz, CH), 6.90 (1H, d, J = 15.6 Hz, CH), 7.02 (1H, dd, J = 15.6 Hz,
—
—
—
J = 10.8 Hz, CH), 7.11 (1H, dd, J = 10.8 Hz, J = 10.8 Hz, tropone-H), 7.32 (2H, t, J = 7.2 Hz, benzene-H), 7.38
(1H, t, J = 7.2 Hz, benzene-H), 7.42–7.50 (5H, m, ArH, CH), 7.54 (1H, d, J = 10.8 Hz, tropone-H)
HRMS (ESI): m/z (calc./found): 298.0815/298.0814 ((M+Na)+, C18H13NNaO2)
—
—
—
—
IX
X
IR, ν˜/cm−1: 1680 (C O), 1556 (C N)
—
—
1
—
—
—
H NMR (CDCl3), δ: 6.87 (1H, d, J = 15.6 Hz, CH), 7.03 (1H, d, J = 15.6 Hz, CH), 7.15 (1H, dd, J = 15.6 Hz,
J = 10.8 Hz, CH), 7.32–7.44 (5H, m, ArH, CH), 7.51–7.55 (3H, m, ArH), 7.67 (1H, d, J = 11.2 Hz, tropone-H)
HRMS (ESI): m/z (calc./found): 375.9941/375.9934 ((M+Na)+, C18H12BrNNaO2)
—
—
—
—
—
IR, ν˜/cm−1: 1685(C O), 1566 (C N)
—
—
—
—
1
—
—
—
—
H NMR (CDCl3), δ: 6.97 (1H, d, J = 15.2 Hz, CH), 7.11 (1H, d, J = 15.2 Hz, CH), 7.36 (1H, dd, J = 15.2 Hz,
J = 10.4 Hz, CH), 7.58–7.62 (3H, m, benzene-H, CH), 7.65–7.67 (1H, m, benzene-H), 8.07 (1H, d, J = 8.4 Hz,
—
—
—
—
benzene-H), 8.32 (1H, d, J = 8.4 Hz, benzene-H), 8.51 (1H, d, J = 1.8 Hz, tropolone-H), 8.54 (1H, d, J = 1.8 Hz,
tropolone-H)
HRMS (ESI): m/z (calc./found): 453.0963/453.0958 ((M+Na)+, C18H11Br2NNaO2)
—
—
XI
IR, ν˜/cm−1: 1630 (C O), 1593 (C N)
—
—
1
—
—
—
—
H NMR (CDCl3), δ: 6.78 (1H, d, J = 15.6 Hz, CH), 6.86 (1H, dd, J = 15.6 Hz, J = 10.8 Hz, CH), 6.94 (1H,
d, J = 15.6 Hz, CH), 7.03 (1H, d, J = 11.0 Hz, tropone-H), 7.25–7.30 (3H, m, ArH), 7.35 (2H, t, J = 7.2 Hz,
benzene-H), 7.41–7.44 (2H, m, ArH), 7.46–7.51 (6H, m, ArH, CH), 7.68 (1H, d, J = 10.8 Hz, tropone-H)
HRMS (ESI): m/z (calc./found): 373.1310/373.1321 ((M+Na)+, C24H18N2NaO)
—
—
—
—

694
W. T. Gao et al./Chemical Papers 66 (7) 691–698 (2012)
Table 2. (continued)
Compound
Spectral data
—
—
XII
IR, ν˜/cm−1: 1640 (C O), 1586 (C N)
—
—
1
—
—
—
—
H NMR (CDCl3), δ: 6.82 (1H, d, J = 15.6 Hz, CH), 6.98 (1H, d, J = 15.6 Hz, CH), 7.09 (1H, dd, J = 15.2 Hz,
J = 10.2 Hz, CH), 7.35–7.45 (8H, m, ArH, CH), 7.48–7.56 (5H, m, ArH), 7.69 (1H, d, J = 10.8 Hz, tropolone-H)
HRMS (ESI): m/z (calc./found): 451.0414/451.0406 ((M+Na)+, C24H17BrN2NaO)
—
—
—
—
—
—
XIII
IR, ν˜/cm−1: 1672 (C O), 1594 (C N)
—
—
1
—
—
—
—
H NMR (CDCl3), δ: 6.88 (1H, d, J = 15.6 Hz, CH), 6.95 (1H, dd, J = 15.6 Hz, J = 10.8 Hz, CH), 7.06 (1H,
d, J = 15.6 Hz, CH), 7.29 (2H, t, J = 7.2 Hz, benzene-H), 7.35–7.41 (7H, m, benzene-H, CH), 7.41–7.44 (2H,
—
—
—
—
m, benzene-H), 7.53 (1H, d, J = 2.0 Hz, tropone-H), 7.72 (1H, d, J = 2.0 Hz, tropone-H)
HRMS (ESI): m/z (calc./found): 528.9519/528.9524 ((M+Na)+, C24H16Br2N2NaO)
—
—
XIV
XV
IR, ν˜/cm−1: 1631 (C O), 1597 (C N)
—
—
1
—
—
H NMR (CDCl3), δ: 3.88 (3H, s, OMe), 6.78 (1H, d, J = 15.6 Hz, CH), 6.82 (2H, dd, J = 8.4 Hz, J = 2.5 Hz,
benzene-H), 6.88 (1H, d, J = 15.4 Hz, CH), 6.94 (1H, d, J = 11.0 Hz, tropone-H), 6.98 (2H, dd, J = 6.7 Hz, J =
2.4 Hz, benzene-H), 7.02 (1H, dd, J = 15.6 Hz, J = 10.7 Hz, CH), 7.33–7.37 (5H, m, ArH, CH), 7.42–7.47 (3H,
m, ArH), 7.64 (1H, d, J = 11.0 Hz, tropone-H)
HRMS (ESI): m/z (calc./found): 403.1415/403.1412 ((M+Na)+, C25H20N2NaO2)
—
—
—
—
—
—
IR, ν˜/cm−1: 1629 (C O), 1552 (C N)
—
—
—
—
1
—
—
—
—
H NMR (CDCl3), δ: 6.80 (1H, d, J = 15.2 Hz, CH), 6.85 (1H, d, J = 15.2 Hz, CH), 6.87–6.89 (1H, m, ArH),
7.02 (1H, dd, J = 15.2 Hz, J = 10.2 Hz, CH), 7.29–7.33 (2H, m, ArH), 7.36 (2H, t, J = 7.6 Hz, benzene-H), 7.41–
7.46 (5H, m, ArH, CH), 7.48 (1H, dd, J = 1.6 Hz, J = 2.0 Hz, benzene-H), 7.36 (2H, t, J = 7.6 Hz, benzene-H),
—
—
—
—
7.66 (1H, d, J = 10.8 Hz, tropolone-H)
HRMS (ESI): m/z (calc./found): 407.0919/407.0916 ((M+Na)+, C24H17ClN2NaO)
—
—
XVI
XVII
XVIII
IR, ν˜/cm−1: 1650 (C O), 1592 (C N)
—
—
1
—
—
—
—
—
H NMR (CDCl3), δ: 6.81 (1H, d, J = 15.6 Hz, CH), 6.90 (1H, d, J = 15.6 Hz, CH), 7.01 (1H, dd, J = 15.6 Hz,
J = 10.8 Hz, CH), 7.26–7.32 (5H, m, ArH, CH), 7.34 (2H, dd, J = 8.4 Hz, J = 2.0 Hz, benzene-H), 7.41–7.47
(6H, m, ArH), 7.68 (1H, d, J = 11.2 Hz, tropone-H)
HRMS (ESI): m/z (calc./found): 407.0919/407.0926 ((M+Na)+, C24H16ClN2NaO)
—
—
—
IR, ν˜/cm−1: 1630 (C O), 1590 (C N)
—
—
—
—
1
—
—
—
H NMR (CDCl3), δ: 6.80 (1H, d, J = 15.6 Hz, CH), 6.89 (1H, dd, J = 15.6 Hz, J = 10.8 Hz, CH), 7.02 (1H,
d, J = 15.6 Hz, CH), 7.28–7.36 (9H, m, ArH, CH), 7.47 (2H, dd, J = 8.8 Hz, J = 2.0 Hz, benzene-H), 7.61 (2H,
dd, J = 8.8 Hz, J = 2.0 Hz, benzene-H), 7.65 (1H, d, J = 11.2 Hz, tropolone-H)
HRMS (ESI): m/z (calc./found): 451.0414/451.0416 ((M+Na)+, C24H17BrN2NaO)
—
—
—
—
—
IR, ν˜/cm−1: 1592 (C O), 1550 (C N)
—
—
—
—
1
—
—
—
—
—
H NMR (CDCl3), δ: 6.16 (1H, dd, J = 15.6 Hz, J = 10.7 Hz, CH), 6.52 (1H, d, J = 15.2 Hz, CH), 6.79 (1H, d,
J = 15.6 Hz, CH), 6.95 (1H, dd, J = 15.6 Hz, J = 10.8 Hz, CH), 7.08 (2H, d, J = 7.6 Hz, benzene-H), 7.30–7.39
—
—
—
(7H, m, ArH), 7.53 (1H, d, J = 10.8 Hz, tropone-H), 7.59–7.66 (2H, m, ArH), 8.13–8.16 (1H, m, ArH)
HRMS (ESI): m/z (calc./found): 418.1160/418.1157 ((M+Na)+, C24H17N3NaO3)
General procedure for preparation of 3-
((1E,3E)-4-phenylbuta-1,3-dien-1-yl)-8H-
cyclohepta[d]isoxazol-8-one derivatives
(VIII–X)
drochloride (2 mmol) in ethanol (10 mL) was refluxed
for 24 h. Once the reaction was complete, as moni-
tored by TLC, the precipitate was collected and re-
crystallised from ethyl acetate to give products XI–
XVIII in acceptable yields.
A solution of each of 2-hydroxy-2,4,6-cyclohepta-
trien-1-one (tropolone) derivatives I–III (1 mmol) and
hydroxylamine hydrochloride (2 mmol) in absolute
ethanol (15 mL) was refluxed for 12 h. Once the reac-
tion was complete, as monitored by TLC, the precip-
itate was collected and recrystallised from ethanol to
give the corresponding products VIII–X in acceptable
yields.
Results and discussion
Due to the unique structure of compound I, it was
thought worthwhile to compare the α,β-γ,δ-dienone
properties of I with α,β-enonic tropolones in elec-
trophilic substitution and nucleophilic cyclisation re-
action. In our previous report, we observed that the
electrophilic substitution reaction of tropolyl chalcone
with bromine, iodine, and diazonium salts of anilines
took place for preference on the tropolone ring, due to
the tropolone ring being more electron-rich than that
of the α,β-enones moiety (Gao et al., 1989, 2009b,
2010a). Hence, we considered whether the presence of
α,β-γ,δ-dienone moiety at position 3 of the tropolone
I could be involved in the electrophilic substitution
General procedure for preparation of 1-phenyl-
3-((1E,3E)-4-phenylbuta-1,3-dien-1-yl)
cyclohepta[c]pyrazol-8(1H)-one derivatives
(XI–XVIII)
A mixture of each tropolone derivatives I–III
(1 mmol) and the corresponding phenyldrazine hy-

W. T. Gao et al./Chemical Papers 66 (7) 691–698 (2012)
695
Fig. 1. Bromination reaction of tropolone I using bromine as a bromine source.
Fig. 2. Synthesis of 7-iodo-substituted tropolone derivative IV.
Fig. 3. Synthesis of 5-arylazo-substituted tropolones V–VII.
reaction. In order to determine the reactivity of I,
we first investigated the bromination, iodination, and
diazo-coupling reactions of I. As shown in Fig. 1, when
I was treated with bromine in acetic acid at laboratory
temperature with a mole ratio of 1 : 1 or 1 : 2 based on
our previous methods (Gao et al., 1989, 2009b, 2010a),
the products obtained were identified as monobromo
derivative II and dibromo derivative III in 51 % and
63 % yields, respectively. The α,β-γ,δ-dienone moiety
was not involved in the electrophilic substituted reac-
tion. In addition, it is worth noting that in our earlier
report the reaction of 3-cinnamoyltropolone with three
equivalent of bromine afforded 6,8-dibromo-2-phenyl-
4,9-dihydrocyclohepta[b]pyran-4,9-dione (Gao et al.,
1989). However, in this case, when I was treated with
three equivalents of bromine, no oxidative cyclisation
was observed.
The iodination reaction proceeded as shown in
Fig. 2. We found that the iodination reaction of I with
excess iodine (5 mole eq.) in the presence of potassium
carbonate as a catalyst proceeded exclusively at posi-
tion 7 of the tropolone ring to give IV in 40 % yield.
Hence, it may be deduced from these results that,
as per our previous reports, the electrophilic substi-
tution reaction of I proceeded with the regioselectiv-
ity of substitution at the more electrophilic position 7
and/or position 5 of the troponoid ring, confirmed by
1
the H NMR spectra associated with the presence of
the α,β-γ,δ-dienone moiety. This was especially clear
in the case of the diazo-coupling reaction of I with
diazonium salts of anilines in pyridine as shown in
Fig. 3. The reaction took place exclusively at position
5 of the tropolone ring to give the corresponding ary-
lazo derivatives V–VII in yields of 62 %, 59 %, 55 %,

696
W. T. Gao et al./Chemical Papers 66 (7) 691–698 (2012)
Fig. 4. Synthesis of pyrazolo- and isoxazolo-fused tropones VIII–XVIII.
1
respectively. These observations were consistent with
our previous reports. In addition to the above reac-
tions, we attempted to conduct the nitration reaction
of I in the presence of concentrated or fuming nitric
acid, but with no success; only an intractable mixture
was obtained.
ring. In the H NMR spectra of 5-arylazo-substituted
tropolones V–VII, the characteristic splitting pattern
of the three protons attached to the tropolone ring
showed a doublet for C-7proton with the coupling con-
stant J = 11.0 Hz, indicating a value typical of ortho-
proton coupling, a doublet due to C-4 proton with the
coupling constant J = 2.0 Hz, which is clear evidence
of meta-proton coupling, and a doublet of doublets
because of the C-6 proton with coupling constants J
= 11.0 Hz, J = 2.0 Hz, which resulted from coupling
with both C-4 and C-7 hydrogens. The coupling con-
stant analysis demonstrated that the arylazo group is
at the 5-position of the tropolone ring.
The structures of the newly synthesised com-
pounds II–VII were established based on the spectral
1
data. For example, in their H NMR spectra, the sig-
nals for the four vinyl protons and benzene ring pro-
tons were observed and their spectral patterns were
very similar to that of the starting compound I, in-
dicating that these reactions occurred selectively on
the tropolone ring. The substitution position was es-
tablished on the basis of the coupling constants of the
protons in the tropolone ring. As for the 7-substituted
tropolones II and IV, the signals from two hydrogens
of C-4 and C-6 appeared as two doublet signals with
the coupling constant value J = 11.0 Hz, which re-
sulted from coupling with the C-5 hydrogen. The sig-
nal corresponding to C-5 hydrogen appears as a dou-
blet of doublets (dd, J = 11.0 Hz, J = 11.0 Hz), which
results from coupling with both the C-4 and C-6 hy-
drogen atoms. These observations clearly indicated
the formation of 7-substituted products. The 1H NMR
spectrum of 5,7-dibromotropolone III showed two hy-
drogen atoms of C-4 and C-6 as two doublet signals
with the coupling constant value J = 2.0 Hz, which
is a value (1–3 Hz) typical of meta-protons coupling
in the tropolone ring. These observations supported
the hypothesis that two bromine atoms were substi-
tuted at the positions 5 and position 7 of the tropolone
Because compounds containing the pyrazole or
isoxazole moiety have been readily applied to drug
design (Barceló et al., 2007; Noshiranzadeh & Ra-
mazani, 2008b) as well as them exhibiting the abil-
ity to form metal complexes (Morsali et al., 2003;
Morsali & Ramazani, 2005), such compounds have
been the frequent targets of synthesis (Ramazani et
al., 2006; Ganjeie et al., 2007; Noshiranzadeh & Ra-
mazani, 2008a). As a consequence, we focused our at-
tention on the issue of the reactivity of compound
I with bi-functional agents such as hydroxylamine
hydrochloride and substituted phenylhydrazine hy-
drochloride for the synthesis of new troponoid-based
heterocycles. We also considered whether the presence
of α,β-γ,δ-dienone function could affect the reaction.
To this end, we made further use of our reliable ap-
proach to conduct the nucleophilic cyclisation reaction
as shown in Fig. 4. Under the same experimental con-
ditions as in our previous methods (Gao et al., 1989,

W. T. Gao et al./Chemical Papers 66 (7) 691–698 (2012)
697
2009b, 2010a), tropolones I–III reacted readily with
substituted phenylhydrazine hydrochloride or hydrox-
ylamine hydrochloride in refluxing ethanol, to afford,
in each case, a single product, as identified by TLC
analysis. After preparation and recrystallisation from
ethanol, the products were obtained in 43–61 % yields.
We deemed that the relatively low yield was ascribed
to the loss of the product during the preparation and
purification procedures, as TLC analysis did not indi-
cate the formation of any distinct by-product. Based
on the spectral data, the structure of the isolated
products was identified as 3-((1E,3E)-4-phenylbuta-
1,3-dien-1-yl)-8H-cyclohepta[d]isoxazol-8-ones (VIII–
X ) and 1-phenyl-3-((1E,3E)-4-phenylbuta-1,3-dien-1-
yl)cyclohepta[c]pyrazol-8(1H )-ones (XI–XVIII ).
Clearly, the nucleophilic cyclisation reaction in-
volved a nucleophilic attack to the more electrophilic
carbonyl of α,β-γ,δ-dienone and subsequent intra-mo-
lecular cyclo-addition to the hydroxyl carbon of the
tropolone ring, as proposed in our previous papers
(Gao et al., 1989, 2009b, 2010a), whereas the conju-
gated 1,3-diene remained unreacted. To the best of
our knowledge, this is the first example of genera-
tion of diene-bearing π-electron systems tethered to
hetero-fused tropone skeletons, which can be used as
promising precursors in the introduction of a range of
other functional groups. The greatest synthetic possi-
bilities offered by the (E,E)-1,3-diene moiety are the
Diels–Alder reaction, since the synthesis of dienes for
use in the Diels–Alder reaction is still an important
challenge in organic synthesis although other uses of
these compounds have been developed.
moiety always remained unchanged. Thus, all these
newly synthesised molecules should be suitable for, fu-
ture use as highly versatile building blocks in the syn-
thesis of more complex troponoid-based compounds,
since the presence of conjugated 1,3-diene moiety can
be further developed via other reactions, for example,
Diels–Alder reactions. We anticipate that this work
will promote more interest in the chemistry of tro-
ponoids. Further examinations of this transformation
are currently in progress, to be reported in due course.
Acknowledgements. The authors wish to thank the Founda-
tion of Liaoning Province Key Laboratory of Applied Chemistry
(Grant No. 2008s001) for its financial support.
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