Iodine-promoted five-component reaction using fragment assembly strategy to construct dihydrooxepines

Article abstract of DOI:10.1016/j.tet.2018.06.047

An iodine-promoted fragment assembly strategy for the synthesis of fused heterocycles has been established. It provides an efficient route to construct pyrazolone-oxepine-pyrazoles from phenylhydrazines, aryl methyl ketones and acetoacetate esters. Notably, acetoacetate esters play two distinct pivotal roles in the five-component reaction by realizing the unique reactivities of methyl, methylene and carbonyl groups to construct 3-methyl-5-pyrazolone skeletons and by the reaction of methyl and carbonyl groups to form a C (sp3)-O bond.

Full text of DOI:10.1016/j.tet.2018.06.047

Accepted Manuscript
Iodine-promoted five-component reaction using fragment assembly strategy to
construct dihydrooxepines
Peng Zhao, Xia Wu, Xiao Geng, Can Wang, Yan-Dong Wu, An-Xin Wu
PII:
S0040-4020(18)30747-6
10.1016/j.tet.2018.06.047
TET 29643
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 April 2018
Revised Date: 15 June 2018
Accepted Date: 19 June 2018
Please cite this article as: Zhao P, Wu X, Geng X, Wang C, Wu Y-D, Wu A-X, Iodine-promoted five-
component reaction using fragment assembly strategy to construct dihydrooxepines, Tetrahedron
(2018), doi: 10.1016/j.tet.2018.06.047.
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ACCEPTED MANUSCRIPT
Graphical Abstract
.
Iodine-Promoted Five-Component Reaction
using Fragment Assembly Strategy to
Construct Dihydrooxepines
Leave this area blank for abstract info.
Peng Zhao, Xia Wu, Xiao Geng, Can Wang, Yan-Dong Wu, An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan 430079, P. R. China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Iodine-Promoted Five-Component Reaction using Fragment Assembly Strategy to
Construct Dihydrooxepines
Peng Zhao, Xia Wu, Xiao Geng, Can Wang, Yan-Dong Wu, An-Xin Wu 
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An iodine-promoted fragment assembly strategy for the synthesis of fused heterocycles has been
established. It provides an efficient route to construct pyrazolone-oxepine-pyrazoles from
phenylhydrazines, aryl methyl ketones and acetoacetate esters. Notably, acetoacetate esters play
two distinct pivotal roles in the five-component reaction by realizing the unique reactivities of
methyl, methylene and carbonyl groups to construct 3-methyl-5-pyrazolone skeletons and by the
reaction of methyl and carbonyl groups to form a C(sp3)-O bond.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
five-component reaction
iodine-promoted
C(sp3)-O bond
acetoacetate esters
pyrazolone-oxepine-pyrazoles
1. Introduction
functionalize pyrazolones via formal cycloaddition or
nucleophilic addition reactions (Scheme 1a).[7,8] Furthermore,
Multi-component reactions (MCRs) are powerful tools for
rapidly increasing molecular complexity and diversity, and have
a rich history.[1] In particular, MCRs as novel strategies for
quickly assembling small molecules to construct molecular
libraries have received widespread attention and undergone rapid
development because of the emergence of molecular biology and
high-throughput biological screening for drug discovery.[1,2]
However, the majority of developed MCRs, including named
reactions, are limited to three[3]- or four-component[4] reactions.
MCRs involving five or more components have been a long-
standing challenge in organic synthesis owing to the difficulty in
controlling the reactivity, selectivity, and compatibility with
increasing number of reaction components. Recently,
pyrazolones and their derivatives have emerged as an important
family of five-membered heterocycles, and they are frequently
found in natural products, biologically active molecules and
pharmaceutical agents.[5] Therefore, several methods for the
synthesis of pyrazolone derivatives have been intensively
investigated to diversify the pyrazolone-based structures
available for potential medicinal research. Among these elegant
methods, using 3-methyl-pyrazolin-5-ones as substrates is
especially appealing, because these compounds contain a diverse
array of reactive centers.[6] The main strategy is using 3-methyl-
considerable attention has been paid to the development of
cascade reactions to construct fused pyrazole derivatives by
exploiting the binucleophilic nature of pyrazolones via enol
tautomerism (Scheme 1b).[9] Recently, the prior preparation of
unsaturated pyrazolones has been exploited to develop tandem
reactions to construct heterocycles (Scheme 1c). [10] These elegant
approaches mainly involve methylene and carbonyl groups acting
as O-nucleophiles.
Scheme 1. Applications of pyrazolones and their derivatives in organic
synthesis.
p—yr—azo—lin-5-ones as nucleophiles to build spiropyrazolones or
 Corresponding author. Tel./fax: +86 027 6786 7773.
E-mail address: chwuax@mail.ccnu.edu.cn (A. Wu).

2
Tetrahedron
ACCEPTED MANUSCRIPT
However, directly employing the methyl group of pyrazolone
amount of TfOH had a prominent effect on the yield (Table 1,
formed in-situ has not yet to be exploited in organic synthesis.
Furthermore, implementing identical molecules that can exhibit
distinctly different reaction selectivities simultaneously in the
same chemical system via a fragment assembly strategy remains
a challenge and attractive prospect. To date, examples of methyl,
methylene and carbonyl groups in acetoacetate esters being used
to directly construct C–O bonds for the synthesis of
dihydrooxepine rings have not been reported. Owing to our
interest in the further development of multi-component reactions
and the construction of medium-sized ring compounds, we now
report an iodine-promoted five-component fragment assembly
strategy for the synthesis of multi-heterocyclic compounds, in
which acetoacetate esters not only react with phenylhydrazines to
forge pyrazolones, but also exhibit distinctly different reaction
selectivity to construct C–O bonds for the synthesis of fused
oxepine derivatives.
entry 11). Finally, we tested the effect of different amounts of
iodine on the reaction outcome. The reaction proceeded smoothly
when the amount of iodine was decreased to 50 mmol % (Table
1, entry 12). To our surprise, the optimum yield was still obtained
when the amount of iodine was further decreased to 10 mmol %
(Table 1, entry 13). However, the reaction did not proceed
without iodine (Table 1, entry 14), which confirmed that iodine
played a critical role in this transformation.
With the optimized reaction conditions in hand, we next
investigated the scope of the five-component reaction. To our
satisfaction, a variety of acetophenone derivatives bearing
different functional groups and substitution patterns afforded the
desired products in moderate to good yields (38%–75%), as
shown in Scheme 2. For example, aryl methyl ketones bearing
Scheme 2. Scope of methyl ketones.
2. Results and discussion
Our initial attempt focused on the model reaction of
acetophenone (1a), phenylhydrazine (2a), and ethyl acetoacetate
(3a) in the presence of molecular iodine at 100 °C. The desired
product 2,3-dihydrooxepine product was obtained in 25% yield
when the 1a/2a/3a molar ratios were 1:1.5:2 (Table S1, entry 1).
Subsequent studies showed that a 1a/2a/3a molar ratio of 1:2:2
increased the yield of 4a to 30% (Table 1, entry 1). Different
temperatures were also applied to this multi-component reaction,
with 140 °C found to give the best yield (Table 1, entries 2–4).
Table 1. Optimization of the reaction conditions.
entry
temp
(°C)
I2
additive
yield/%b
(time/h)
(equiv)
1
2
100
110
130
140
140
140
140
140
140
140
140
140
140
140
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.1
30 (24 h)
35 (24 h)
42 (12 h)
46 (12 h)
52 (7 h)
21 (12 h)
47 (7 h)
54 (7 h)
65 (7 h)
37 (12 h)
72 (7 h)
71 (7 h)
73 (7 h)
NRd
3
4
5
TsOH.H2O
FeCl3
6
7
ZnCl2
8
Cu(OTf)2
CF3SO3H
HCl
9
(4-H), electron-rich (4-Me, 4-OMe, 3,4-OCH2O, 3,4-
OCH2CH2O), and electron-deficient (3-NO2, 4-NO2, 4-CN, 4-
COOMe) groups exhibited excellent reactivity, affording the
corresponding products in moderate to good yields (58%–75%,
4a–4k). The substrate was further also successfully extended to
various halogenated (4-Cl, 4-Br, 4-F) substrates (57%–75%, 4l–
4n). Notably, 2-naphthyl methyl ketone and 1-naphthyl methyl
ketone were also tolerated in this transformation (68%–72%, 4o–
4p). Furthermore, various heteroaryl ketones, including thienyl,
benzofuryl, and furyl ketones, were found to be compatible under
the optimal conditions, giving the corresponding products in
moderate yields (38%–67%, 4q–4t).
10
11c
12c
13c
14c
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
aReaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), 3a (2.0 mmol),
I2, and additive (1.0 mmol) heated in DMSO (4 mL). bIsolated yields.
d
c2.5 mmol TfOH was used instead of 1.0 mmol TfOH. NR = No
Reaction
The scope of the study was then extended to substituted
phenylhydrazines, with the results shown in Scheme 3. Various
substituted phenylhydrazines were found to be compatible in the
reaction. For example, electron-rich (4-CH3) and halogen (3-Cl,
and 4-Cl) groups on the phenyl rings were tolerated, affording
Next, a series of Brønsted and Lewis acids were screened as
additives for the reaction, with TfOH determined to be the
optimal additive for the five-component reaction (Table 1, entries
5–10). The effect of different amounts of TfOH on the outcome
of the reaction was also investigated. The results showed that the

3
the corresponding products in moderate to good yields (4u–4y,
35%–73%). The scope of β-keto esters was also investigated.
Various β-keto esters (3aa–3ae) performed smoothly in this
transformation, affording 4a in 56%–65% yields. Finally, the
reaction of 1a, 2a and 2u gave the expected four products. (see
Supporting Information).
transformation. Subsequently, the reaction of hydrated species
ACCEPTED MANUSCRIPT
1ac with 5a in the absence of iodine afforded product 7a in 42%
yield. Notably, when the pyrazolone was substituted by –C(CH3)3,
the reaction did not proceed, possibly due to steric hindrance
(Scheme 4d). Subsequently, product 7a was reacted smoothly
under the optimized conditions, affording hydrooxepine ring 4a
in 85% yield (Scheme 4e).
Scheme 3. Scope of phenylhydrazines and acetoacetate esters.
Based on the results described above, and those of previous
reports,[11] a possible mechanism for this transformation was
proposed, as shown in Scheme 5. Acetophenone (1a) was
converted into phenylglyoxal 1ab via an iodination/Kornblum
oxidation sequence. Next, 1ab was converted into 1ab′ in the
presence of TfOH. Meanwhile phenylhydrazine (2a) and ethyl
acetoacetate (3a) were converted into key intermediate
pyrazolone
5a
via
a
rapid
dehydration
condensation/aminolysis.[12] Activated aldehyde intermediate
1ab′ was then trapped in-situ by 5a to give A, which underwent
further dehydration to form B. Intermediate B reacted with
another equivalent of 5a via a Michael addition to form 7a.
Subsequent the 7a could be iodinated to obtained C or C′, which
underwent an in-situ iodine-based oxidative coupling to generate
4a.
Scheme 5. Possible mechanism.
To gain insight into the reaction mechanism, a series of control
experiments were performed. Acetophenone (1a, 1.0 mmol) was
4. Control experiments.
3. Conclusions
In summary, we have developed a novel approach to the
synthesis of fused heterocycles. This iodine-promoted five-
component reaction demonstrates the diverse reactivity of a
single molecule, with acetoacetate esters playing two vital yet
distinct roles in constructing pyrazolones and C–O bonds.
Furthermore, the fragment assembly strategy is facile and
provides an efficient route to construct pyrazolone-oxepine-
pyrazole skeletons. A plausible mechanism is proposed, which
could provide a basis for the discovery of new methodologies for
reactions co-promoted by iodine and TfOH. Further studies on
the applications of this strategy will be reported in due course.
heated with iodine (0.1 mmol) in DMSO at 140 °C to afford
phenylglyoxal 1ab and the corresponding hydrated species 1ac in
quantitative yield (Scheme 4a). Acetophenone (1a) was replaced
with α-iodoacetophenone 1aa and reacted with 5a under the
optimized conditions to afford desired product 4a in 85% yield
(Scheme 4b). Hydrated species 1ac was also subjected to the
optimized reaction condition, affording 4a in 85% yield (Scheme
4c). These results confirmed that pyrazolone 5a, phenacyl iodine
1aa and phenylglyoxal 1ab were intermediates in this
4. Experimental
General Synthesis Information: Unless otherwise noted, materials
were obtained from commercial suppliers and used without
purification. All reactions were performed in pressure tubings,

4
Tetrahedron
TLC analysis was performed using pre-coated glass plates.
overall spectroscopic data are in complete agreement with
ACCEPTED MANUSCRIPT
Column chromatography was performed using silica gel (200–
assigned structures and consistent with literature6a
300 mesh). IR spectra were recorded on a Perkin-Elmer PE-983
4-(4-methoxybenzoyl)-5-methyl-2,7-diphenyl-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one
1
infrared spectrometer as KBr pellets with absorption in cm–1. H
(4c):
spectra were recorded in CDCl3/DMSO-d6 on 400/600 MHz
NMR spectrometers and resonances (δ) are given in parts per
million relative to tetramethylsilane. Data are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m
= multiplet), coupling constants (Hz) and integration. 13C spectra
were recorded in CDCl3/DMSO-d6 on 75/100/150 MHz NMR
spectrometers and resonances (δ) are given in ppm. HRMS were
obtained on a Bruker 7-tesla FT-ICR. MS equipped with an
electrospray source. Trace MS spectrometer (EI, 70 eV).
Following general procedure A using 4-methoxyacetophenone
(1c, 150 mg, 1.0 mmol), Phenylhydrazine (2a, 216 mg, 2.0
mmol), ethyl acetoacetate (3a, 260 mg, 2.0 mmol) and purified
by silicagel column chromatography, afforded the compound as
orange solid (343 mg, Yield 70%); Mp. 249-251 °C, (literature
249-251 °C); 1H NMR (600 MHz, DMSO-d6): δ (ppm): 8.02 (d, J
= 7.2 Hz, 2H), 7.73 (t, J = 9.0 Hz, 4H), 7.57 (t, J = 7.8 Hz, 2H),
7.46 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.8 Hz, 2H), 7.16 (t, J = 7.2
Hz, 1H), 7.10 (d, J = 7.8 Hz, 2H), 5.62-5.52 (m, 2H), 3.86 (s, 3H),
1.89 (s, 3H); 13C NMR (150 MHz, DMSO-d6): δ (ppm) 192.2,
164.4, 161.6, 155.7, 149.4, 148.8, 146.2, 137.9, 136.3,131.2,
129.4, 128.9, 128.3, 128.2, 124.9, 123.1, 118.1, 117.4, 114.7,
104.0, 69.7, 55.8, 14.9; MS (EI): m/z 490.15 the overall
spectroscopic data are in complete agreement with assigned
structures and consistent with literature6a
Representative procedure for the synthesis of 4 (A): A mixture
of acetophenone 1 (1a 120 mg, 1.0 mmol), 2 (2a, 216 mg, 2.0
mmol), 3 (3a, 260 mg, 2.0 mmol), TfOH (375 mg, 2.5 mmol) and
iodine (25.4 mg, 0.1 mmol) in DMSO (4 mL), the mixture was
stirred at 140 °C till almost completed conversion of the
substrates by TLC analysis, the mixture was quenched with
saturation Na2S2O3 solution (50 mL), extracted with EtOAc (3 ×
50 mL). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by column
chromatography on silica gel (eluent: petroleum ether/EtOAc =
8/1) to afford the product 4 (4a-4x).
4-(2,4-dimethoxybenzoyl)-5-methyl-2,7-diphenyl-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one
(4d):
2,4-
mmol),
Following
Dimethoxyacetophenone
general
procedure
(1d, 180
A
mg,
using
1.0
Phenylhydrazine (2a, 216 mg, 2.0 mmol), ethyl acetoacetate (3a,
260 mg, 2.0 mmol) and purified by silicagel column
chromatography, afforded the compound as red solid; (353.6 mg,
Representative procedure for the synthesis of 2 (B): To a
solution of phenylhydrazine hydrochloride in proper amount of
water, then stirred for 30 min at 50 °C. Next, 30% sodium
hydroxide solution was added to the mixture until pH = 10
followed by continued stirring 30 min. Finally, the mixture was
extracted with EtOAc (200 mL). The combined organic layers
were dried over Na2SO4 and the solvent was removed under
pressure.
1
Yield 68%); Mp. 203-205 °C, (literature 205-207 °C); H NMR
(600 MHz, CDCl3): δ (ppm) 8.16 (s, 1H), 7.86 (d, J = 7.8 Hz,
2H), 7.68 (d, J = 7.8 Hz, 2H), 7.48 (t, J = 7.8 Hz, 2H), 7.37 (t, J =
7.2 Hz, 1H), 7.30 (t, J = 7.8 Hz, 2H), 7.10 (t, J = 7.2 Hz, 1H),
6.64 (d, J = 8.4 Hz, 1H), 6.39 (s, 1H), 5.25-5.14 (m, 2H), 3.81 (s,
3H), 3.66 (s, 3H), 2.10 (s, 3H); 13C NMR (150 MHz, CDCl3): δ
(ppm) 190.6, 166.1, 162.2, 161.7, 155.4, 149.8, 145.3, 138.0,
136.5, 133.1, 129.0, 128.4, 127.8, 124.6, 122.5, 118.6, 118.4,
116.3, 106.8, 103.7, 98.2, 69.9, 55.6, 55.5, 15.0; MS (EI): m/z
520.36 the overall spectroscopic data are in complete agreement
with assigned structures and consistent with literature6a
4-benzoyl-5-methyl-2,7-diphenyl-7,9-dihydrooxepino[2,3-c:6,5-
c']dipyrazol-3(2H)-one (4a): Following general procedure A
using acetophenone (1a, 120 mg, 1.0 mmol), Phenylhydrazine
(2a, 216 mg, 2.0 mmol), ethyl acetoacetate (3a, 260 mg, 2.0
mmol) and purified by silicagel column chromatography,
afforded the compound as deep yellow solid (335.8 mg, Yield
4-(4-ethoxybenzoyl)-5-methyl-2,7-diphenyl-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one
(4e):
1
73%); Mp, 265-267 °C, (literature 264-266 °C); H NMR (600
Following general procedure A using 4'-Ethoxyacetophenone (1e,
164 mg, 1.0 mmol), Phenylhydrazine (2a, 216 mg, 2.0 mmol),
ethyl acetoacetate (3a, 260 mg, 2.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
orange solid (327.6 mg, Yield 65%); Mp. 232-234 °C, (literature
229-231 °C); 1H NMR (600 MHz, CDCl3): δ (ppm) 7.99 (s, 2H),
7.83 (d, J = 7.8 Hz, 2H), 7.69 (d, J = 7.8 Hz, 2H), 7.51 (t, J = 7.8
Hz, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.8 Hz, 2H), 7.13 (t,
J = 7.2 Hz, 1H), 6.95 (d, J = 7.8 Hz, 2H), 5.34-5.18 (m, 2H),
4.11-4.06 (m, 2H), 2.05 (s, 3H), 1.43 (t, J = 6.6 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ (ppm) 192.6, 164.2, 162.0, 155.1,
150.1, 149.8, 144.8, 138.0, 136.5, 131.2, 129.2, 128.7, 128.2,
128.1, 125.0, 122.9, 118.7, 118.4, 114.9, 104.2, 70.0, 63.9, 15.2,
14.6; MS (EI): m/z 504.31 the overall spectroscopic data are in
complete agreement with assigned structures and consistent with
literature6a
MHz, DMSO-d6): δ (ppm) 8.08 (d, J = 7.2 Hz, 2H), 7.73 (d, J =
7.8 Hz, 4H), 7.63-7.54 (m, 4H), 7.49-7.45 (m, 2H), 7.37 (t, J =
7.2 Hz, 2H), 7.19-7.14 (m, 1H), 5.64-5.54 (m, 2H), 1.87 (s, 3H);
13C NMR (150 MHz, DMSO-d6): δ (ppm) 194.2, 161.7, 155.8,
148.9, 148.6, 146.1, 137.8, 136.3, 134.9, 129.4, 129.3, 128.9,
128.7, 128.3, 125.0, 123.1, 118.1, 117.7, 103.9, 69.7, 14.9; MS
(EI): m/z 460.22 the overall spectroscopic data are in complete
agreement with assigned structures and consistent with literature
6a
5-methyl-4-(4-methylbenzoyl)-2,7-diphenyl-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one
(4b):
Following general procedure A using 4'-Methylacetophenone (1b,
134 mg, 1.0 mmol) Phenylhydrazine (2a, 216 mg, 2.0 mmol),
ethyl acetoacetate (3a, 260 mg, 2.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
orange solid (341.8 mg, yield 72%); Mp. 290-292 °C, (literature
293-295 °C); 1H NMR (600 MHz, DMSO-d6): δ (ppm) 7.95 (d, J
= 7.2 Hz, 2H), 7.77-7.68 (m, 3H), 7.61-7.54 (m, 2H), 7.50-7.43
(m, 2H), 7.41-7.33 (m, 4H), 7.19-7.13 (m, 1H), 5.63-5.52 (m,
2H), 2.40 (s, 3H), 1.87 (s, 3H); 13C NMR (150 MHz, DMSO-d6):
δ (ppm) 193.6, 161.7, 155.8, 149.2, 148.7, 146.2, 145.7, 137.9,
136.3, 132.6, 130.0, 129.3, 128.9, 128.3, 124.9, 123.2, 118.2,
118.1, 117.6, 103.9, 69.7, 21.4, 14.9; MS (EI): m/z 474.34 the
4-(benzo[d][1,3]dioxole-5-carbonyl)-5-methyl-2,7-diphenyl-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one (4f): Following
general procedure A using 1-(1,3-benzodioxol-5-yl)ethanone (1f,
164 mg, 1.0 mmol), Phenylhydrazine (2a, 216 mg, 2.0 mmol),
ethyl acetoacetate (3a, 260 mg, 2.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
orange solid (302 mg, Yield 60%); Mp. 285-287 °C, (literature
287-289 °C); 1H NMR (600 MHz, DMSO-d6): δ (ppm) 7.79-7.72
(m, 4H), 7.67 (d, J = 7.2 Hz, 1H), 7.61-7.56 (m, 3H), 7.48 (t, J =

5
7.2 Hz, 1H), 7.40 (t, J = 7.2 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H),
7.08 (d, J = 7.8 Hz, 1H), 6.21 (d, J = 5.4 Hz, 2H), 5.62-5.52 (m,
2H), 1.92 (s, 3H); 13C NMR (150 MHz, DMSO-d6): δ (ppm)
191.8, 161.6, 155.7, 152.9, 149.0, 148.7, 148.5, 146.2, 137.9,
136.3, 129.9, 129.3, 128.9, 128.3, 124.9, 123.1, 118.1, 117.5,
108.7, 103.9, 102.5, 98.8, 98.7, 69.6, 14.8; MS (EI): m/z 504.18
the overall spectroscopic data are in complete agreement with
assigned structures and consistent with literature6a
column chromatography, afforded the compound as orange
ACCEPTED MANUSCRIPT
solid (291 mg, Yield 60%); Mp > 320 °C, (literature > 320 °C );
1H NMR (600 MHz, CDCl3): δ (ppm) 8.14 (d, J = 7.8 Hz, 2H),
7.82 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 7.8
Hz, 2H), 7.52 (t, J = 7.8 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H), 7.33 (t,
J = 7.8 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 5.37-5.19 (m, 2H), 1.98
(s, 3H). 13C NMR (150 MHz, CDCl3): δ (ppm) 193.49, 193.43,
161.9, 155.2, 149.4, 147.5, 144.6, 137.7, 136.3, 133.1, 129.3,
129.0, 128.8, 128.4, 125.4, 122.9, 119.0, 118.7, 117.7, 117.5,
103.8, 69.9, 15.4; MS (EI): m/z 485.37 the overall spectroscopic
data are in complete agreement with assigned structures and
consistent with literature6a
4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carbonyl)-5-methyl-2,7-
diphenyl-7,9-dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one
(4g): Following general procedure A using 1-(2,3-dihydro-1,4-
benzodioxin-6-yl)ethanone (1g, 178 mg, 1.0 mmol),
Phenylhydrazine (2a, 216 mg, 2.0 mmol), ethyl acetoacetate (3a,
260 mg, 2.0 mmol) and purified by silicagel column
chromatography, afforded the compound as red solid (326.3 mg,
4-(5-methyl-3-oxo-2,7-diphenyl-2,3,7,9-tetrahydrooxepino[2,3-
c:6,5-c']dipyrazole-4-carbonyl)benzoate (4k): Following general
procedure A using Methyl 4-acetylbenzoate (1k, 178 mg, 1.0
mmol), Phenylhydrazine (2a, 216 mg, 2.0 mmol), ethyl
acetoacetate (3a, 260 mg, 2.0 mmol) and purified by silicagel
column chromatography, afforded the compound as orange solid
(300 mg, Yield 58%); Mp, 248-250 °C; (literature 247-249 °C);
1H NMR (600 MHz, DMSO-d6): δ (ppm) 8.21 (d, J = 7.8 Hz, 2H),
8.14 (d, J = 7.8 Hz, 2H), 7.73 (t, J = 9.6 Hz, 4H), 7.58 (t, J = 7.8
Hz, 2H), 7.48 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.8 Hz, 2H), 7.17 (t,
J = 7.2 Hz, 1H), 5.65-5.56 (m, 2H), 3.89 (s, 3H), 1.86 (s, 3H);
13C NMR (150 MHz, DMSO-d6): δ (ppm) 194.1, 165.4, 161.7,
155.9, 148.5, 148.06, 148.02 146.13, 146.08, 137.9, 137.8, 136.3,
134.6, 130.1, 129.3, 128.9, 128.4, 125.0, 123.1, 118.1, 103.8,
69.7, 52.6, 15.0; MS (EI): m/z 518.41 the overall spectroscopic
data are in complete agreement with assigned structures and
consistent with literature6a
1
Yield 63%); Mp. 303-305 °C, (literature 303-305 °C); H NMR
(600 MHz, DMSO-d6): δ (ppm) 7.79-7.71 (m, 7.8 Hz, 4H), 7.61-
7.53 (m, 4H), 7.49-7.45 (m, 1H), 7.39 (t, J = 7.8 Hz, 2H), 7.18 (t,
J = 7.2 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 5.63-5.51 (m, 2H) ,
4.37 (s, 2H), 4.32 (s, 2H), 1.9 (s, 3H); 13C NMR (150 MHz,
DMSO-d6): δ (ppm) 192.1, 161.6, 155.7, 149.3, 149.1, 148.7,
146.2, 143.7, 137.9, 136.3, 129.3, 128.9, 128.7, 128.3, 124.9,
123.1, 118.1, 117.9, 117.85, 117.84, 117.5, 103.9, 69.6, 64.7,
63.9, 14.9; MS (EI): m/z 518.34 the overall spectroscopic data are
in complete agreement with assigned structures and consistent
with literature6a
5-methyl-4-(3-nitrobenzoyl)-2,7-diphenyl-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one
(4h):
Following general procedure A using 3-Nitroacetophenone (1h,
165 mg, 1.0 mmol), Phenylhydrazine (2a, 216 mg, 2.0 mmol),
ethyl acetoacetate (3a, 260 mg, 2.0 mmol) and purified by
silicagel column chromatography, afforded the compound as red
solid (378.8 mg, Yield 75%); Mp. 170-172 °C, (literature 168-
4-(4-chlorobenzoyl)-5-methyl-2,7-diphenyl-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one (4l): Following
general procedure A using 4'-Chloroacetophenone (1l, 154.5 mg,
1.0 mmol), Phenylhydrazine (2a, 216 mg, 2.0 mmol), ethyl
acetoacetate (3a, 260 mg, 2.0 mmol) and purified by silicagel
column chromatography, afforded the compound as orange solid
(281.6 mg, Yield 57%); Mp. 277-279 °C; (literature 282-284 °C);
1H NMR (600 MHz, CDCl3): δ (ppm) 7.99 (d, J = 7.8 Hz, 2H),
7.81 (d, J = 7.8 Hz, 2H), 7.69 (d, J = 7.8 Hz, 2H), 7.56-7.46 (m,
4H), 7.42 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 7.8 Hz, 2H), 7.14 (t, J =
7.2 Hz, 1H), 5.35-5.18 (m, 2H), 2.02 (s, 3H).; 13C NMR (150
MHz, CDCl3): δ (ppm) 193.3, 161.9, 155.2, 149.7, 148.5, 144.7,
141.2, 137.8, 136.4, 133.4, 130.1, 129.7, 129.2, 128.7, 128.3,
125.2, 122.9, 118.7, 103.9, 69.9, 15.3; MS (EI): m/z 494.37 the
overall spectroscopic data are in complete agreement with
assigned structures and consistent with literature6a
1
170 °C); H NMR (600MHz, CDCl3): δ (ppm) 8.82 (s, 1H), 8.49
(d, J = 7.8 Hz, 1H), 8.38 (d, J = 6.6 Hz, 1H), 7.81-7.73 (m, 3H),
7.70 (d, J = 7.8 Hz, 2H), 7.53 (t, J = 7.8 Hz, 2H), 7.46-7.41 (m,
1H), 7.33 (t, J = 7.8 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 5.41-5.21
(m, 2H), 2.01 (s, 3H); 13C NMR (150 MHz, CDCl3): δ (ppm)
192.7, 161.9, 155.3, 149.3, 148.7, 147.2, 144.6, 137.7, 136.3,
134.1, 130.6, 129.3, 128.8, 128.7, 128.4, 125.4, 123.3, 123.0,
119.0, 118.8, 103.7, 69.9, 15.5; MS (EI): m/z 505.29 the overall
spectroscopic data are in complete agreement with assigned
structures and consistent with literature6a
5-methyl-4-(4-nitrobenzoyl)-2,7-diphenyl-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one (4i): Following
general procedure A using 4-nitroacetophenone (1i, 165 mg, 1.0
mmol), Phenylhydrazine (2a, 216 mg, 2.0 mmol), ethyl
acetoacetate (3a, 260 mg, 2.0 mmol) and purified by silicagel
column chromatography, afforded the compound as orange solid
(328.3 mg, Yield 65%); Mp, 298-300 °C, (literature 298-300 °C);
1H NMR (600 MHz, DMSO-d6): δ (ppm) 8.33 (d, J = 7.8 Hz, 2H),
8.28 (d, J = 7.8 Hz, 2H), 7.69-7.63 (m, 4H), 7.55-7.49 (m, 2H),
7.45-7.39 (m, 1H), 7.34-7.27 (m, 2H), 7.14-7.07 (m, 1H), 5.58-
5.47 (m, 2H), 1.81 (s, 3H); 13C NMR (150 MHz, DMSO-d6): δ
(ppm) 193.6, 161.7, 155.9, 150.9, 148.4, 147.3, 146.1, 138.8,
137.7, 136.2, 130.0, 129.4, 128.9, 128.4, 125.1, 124.6, 123.2,
118.1, 103.7, 69.6, 15.0; MS (EI): m/z 505.39 the overall
spectroscopic data are in complete agreement with assigned
structures and consistent with literature6a
4-(4-bromobenzoyl)-5-methyl-2,7-diphenyl-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one
(4m):
Following general procedure A using 4'-Bromoacetophenone
(1m, 199 mg, 1.0 mmol), Phenylhydrazine (2a, 216 mg, 2.0
mmol), ethyl acetoacetate (3a, 260 mg, 2.0 mmol) and purified
by silicagel column chromatography, afforded the compound as
orange solid (388 mg, Yield 72%); Mp, 282-284 °C; (literature
1
283-285°C); H NMR (600 MHz, DMSO-d6): δ (ppm) 8.33 (d, J
= 7.8 Hz, 2H), 8.28 (d, J = 7.8 Hz, 2H), 7.69-7.63 (m, 4H), 7.55-
7.49 (m, 2H), 7.45-7.39 (m, 1H), 7.34-7.27 (m, 2H), 7.14-7.07
(m, 1H), 5.58-5.47 (m, 2H), 1.81 (s, 3H); 13C NMR (150 MHz,
DMSO-d6): δ (ppm) 193.6, 161.7, 155.9, 150.9, 148.4, 147.3,
146.1, 138.8, 137.7, 136.2, 130.0, 129.4, 128.9, 128.4, 125.1,
124.6, 123.2, 118.1, 103.7, 69.6, 15.0; MS (EI): m/z 538.16 the
overall spectroscopic data are in complete agreement with
assigned structures and consistent with literature6a
4-(5-methyl-3-oxo-2,7-diphenyl-2,3,7,9-tetrahydrooxepino[2,3-
c:6,5-c']dipyrazole-4-carbonyl)benzonitrile
(4j):
Following
general procedure A using 4-Acetylbenzonitrile (1j, 145 mg, 1.0
mmol), Phenylhydrazine (2a, 216 mg, 2.0 mmol), ethyl
acetoacetate (3a, 260 mg, 2.0 mmol) and purified by silicagel
4-(4-fluorobenzoyl)-5-methyl-2,7-diphenyl-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one
Following general procedure A using 4-Fluoroacetophenone (1n,
(4n):

6
Tetrahedron
138 mg, 1.0 mmol), Phenylhydrazine (2a, 216 mg, 2.0 mmol),
5-methyl-2,7-diphenyl-4-(thiophene-2-carbonyl)-7,9-
ACCEPTED MANUSCRIPT
ethyl acetoacetate (3a, 260 mg, 2.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
orange solid (358.5 mg, Yield 75%); Mp, 220–223 °C; IR (KBr):
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one
(4r):
Following general procedure A using 2-Acetylthiophene (1r, 126
mg, 1.0 mmol), Phenylhydrazine (2a, 216 mg, 2.0 mmol), ethyl
acetoacetate (3a, 260 mg, 2.0 mmol) and purified by silicagel
column chromatography, afforded the compound as orange solid
(302.2 mg, Yield 65%); Mp, 189-191 °C; (literature 189-191 °C);
1H NMR (600 MHz, DMSO-d6): δ (ppm) 8.24 (d, J = 4.8 Hz, 1H),
7.97 (d, J = 3.0 Hz, 1H), 7.77 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 7.8
Hz, 2H), 7.58 (t, J = 7.8 Hz, 2H), 7.48 (t, J = 7.2 Hz, 2H), 7.40 (t,
J = 7.8 Hz, 2H), 7.28-7.26 (m, 1H), 7.19 (d, J = 7.2 Hz, 1H),
5.61-5.53 (m, 2H), 1.98 (s, 3H); 13C NMR (150 MHz, DMSO-d6):
δ (ppm) 185.7, 161.5, 155.8, 148.7, 147.5, 146.2, 142.0, 137.8,
137.7, 136.5, 136.3, 129.3, 128.9, 128.3, 125.0, 123.1, 118.2,
117.6, 103.7, 69.7, 14.6; MS (EI): m/z 466.09 the overall
spectroscopic data are in complete agreement with assigned
structures and consistent with literature6a
1607, 1478, 1432, 1371, 1272, 749 cm–1; H NMR (400 MHz,
1
CDCl3): δ (ppm) 8.12-8.04 (m, 2H), 7.81 (d, J = 8.0 Hz, 2H),
7.69 (d, J = 8.0 Hz, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.2
Hz, 1H), 7.33 (t, J = 8.0 Hz, 2H), 7.23-7.11 (m, 3H), 5.36-5.17
(m, 2H), 2.04 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ (ppm) 192.8, 167.8, 165.3, 162.0, 155.2, 149.8, 148.7, 144.7,
137.9, 136.5, 131.6, 131.5, 129.2, 128.8, 128.3, 125.2, 122.9,
118.8, 118.7, 116.7, 116.5, 104.0, 70.0, 15.3; HRMS (ESI): m/z
[M+H]+ calcd for C28H19FN4O3: 517.10728; found: 517.10817
4-(2-naphthoyl)-5-methyl-2,7-diphenyl-7,9-dihydrooxepino[2,3-
c:6,5-c']dipyrazol-3(2H)-one (4o): Following general procedure
A
Phenylhydrazine (2a, 216 mg, 2.0 mmol), ethyl acetoacetate (3a,
260 mg, 2.0 mmol) and purified by silicagel column
chromatography, afforded the compound as red solid (367 mg,
using 2-acetylnaphthalene (1o, 170 mg, 1.0 mmol),
4-(benzofuran-2-carbonyl)-5-methyl-2,7-diphenyl-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one
(4s):
1
Yield 72%); Mp. 252-254 °C; (literature 252-254 °C); H NMR
Following general procedure A using 1-(benzofuran-2-yl)ethan-
1-one (1s, 160 mg, 1.0 mmol), Phenylhydrazine (2a, 216 mg, 2.0
mmol), ethyl acetoacetate (3a, 260 mg, 2.0 mmol) and purified
by silicagel column chromatography, afforded the compound as
orange solid (306.8 mg, Yield 66%); Mp, 240-242 °C; (literature
(600 MHz, DMSO-d6): δ (ppm) 8.73 (s, 1H), 8.14 (s, 3H), 8.08-
8.01 (m, 1H), 7.79-7.68 (m, 5H), 7.64-7.55 (m, 3H), 7.51-7.43
(m, 1H), 7.39-7.30 (m, 2H), 7.18-7.07 (m, 1H), 5.71-5.57 (m,
2H), 1.88 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ (ppm):
194.1, 161.7, 155.8, 149.0, 148.7, 146.2, 137.8, 136.3, 135.8,
132.4, 132.3, 129.9, 129.5, 129.3, 129.2, 128.9, 128.3, 127.9,
127.3, 124.9, 123.1, 118.0, 117.9, 104.1, 69.7, 14.9; MS (EI): m/z
510.30 the overall spectroscopic data are in complete agreement
with assigned structures and consistent with literature6a
1
240-242 °C); H NMR (600 MHz, CDCl3): δ (ppm) 7.82 (d, J =
7.8 Hz, 2H), 7.69 (d, J = 7.8 Hz, 3H), 7.65 (s, 1H), 7.60 (d, J =
8.4 Hz, 1H), 7.55-7.48 (m, 3H), 7.44-7.40 (m, 1H), 7.39-7.29 (m,
3H), 7.14 (t, J = 7.2 Hz, 1H), 5.36-5.22 (m, 2H), 2.13 (s, 3H).;
13C NMR (150 MHz, CDCl3): δ (ppm) 183.6, 162.0, 156.3, 155.3,
151.2, 149.9, 146.8, 144.8, 137.8, 136.4, 129.2, 128.8, 128.3,
126.8, 125.2, 124.3, 123.7, 122.9, 119.4, 118.7, 115.9, 112.9,
104.0, 69.9, 40.6, 15.3; MS (EI): m/z 500.01 the overall
spectroscopic data are in complete agreement with assigned
structures and consistent with literature6a
4-(1-naphthoyl)-5-methyl-2,7-diphenyl-7,9-dihydrooxepino[2,3-
c:6,5-c']dipyrazol-3(2H)-one (4p): Following general procedure
A
Phenylhydrazine (2a, 216 mg, 2.0 mmol), ethyl acetoacetate (3a,
260 mg, 2.0 mmol) and purified by silicagel column
chromatography, afforded the compound as red solid (346.8 mg,
using 1-acetylnaphthalene (1p, 170 mg, 1.0 mmol),
4-(furan-2-carbonyl)-5-methyl-2,7-diphenyl-7,9-
1
Yield 68%); Mp. 227-229 °C; (literature 228-230 °C); H NMR
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one (4t): Following
general procedure A using 2-acetylfuran (1t, 110 mg, 1.0 mmol),
Phenylhydrazine (2a, 216 mg, 2.0 mmol), ethyl acetoacetate (3a,
260 mg, 2.0 mmol) and purified by silicagel column
chromatography, afforded the compound as orange solid (135 mg,
(600 MHz, DMSO-d6): δ (ppm) 9.22 (d, J = 8.4 Hz, 1H), 8.09 (d,
J = 7.2 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz,
1H), 7.62-7.58 (m, 1H), 7.51 (d, J = 7.8 Hz, 2H), 7.46 (t, J = 9.0
Hz, 3H), 7.36-7.30 (m, 3H), 7.25-7.17 (m, 2H), 7.07 (t, J = 7.8
Hz, 2H), 6.87 (t, J = 7.2 Hz, 1H), 5.39-5.31 (m, 2H), 1.65 (s, 3H);
13C NMR (150 MHz, DMSO-d6): δ (ppm) 195.8, 161.9, 155.8,
150.0, 148.9, 146.3, 138.9, 137.8, 136.3, 136.0, 134.1, 133.7,
130.0, 129.5, 129.3, 129.0, 128.9, 128.3, 127.0, 125.1, 124.9,
123.1, 118.1, 117.5, 104.5, 69.7, 14.9; MS (EI): m/z 510.34 the
overall spectroscopic data are in complete agreement with
assigned structures and consistent with literature6a
1
Yield 38%); Mp. 260–262 °C; (literature 257-259 °C); H NMR
(600 MHz, DMSO-d6): δ (ppm) 8.19 (s, 1H), 7.80-7.70 (m, 4H),
7.64 (s, 1H), 7.57 (t, J = 7.8 Hz, 2H), 7.48-7.45 (m, 1H), 7.40 (t,
J = 7.8 Hz, 2H), 7.21-7.15 (m, 1H), 6.84-6.78 (m, 1H), 5.58-5.50
(m, 2H), 1.96 (s, 3H); 13C NMR (150 MHz, DMSO-d6): δ (ppm)
180.3, 161.7, 155.8, 150.9, 149.9, 148.7, 146.9, 146.2, 137.8,
136.3, 129.3, 129.0, 128.3, 125.0, 123.1, 118.2, 118.1, 113.4,
103.8, 69.7, 14.7; MS (EI): m/z 449.92 the overall spectroscopic
data are in complete agreement with assigned structures and
consistent with literature6a
5-methyl-2,7-diphenyl-4-(thiophene-3-carbonyl)-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one
(4q):
Following general procedure A using 3-Acetylthiophene (1q, 126
mg, 1.0 mmol), Phenylhydrazine (2a, 216 mg, 2.0 mmol), ethyl
acetoacetate (3a, 260 mg, 2.0 mmol) and purified by silicagel
column chromatography, afforded the compound as orange solid
(312.2 mg, Yield 67%); Mp. 227-229 °C; (literature 229-231 °C);
1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.61 (s, 1H), 7.78 (d, J
= 8.0 Hz, 2H), 7.74 (d, J = 7.2 Hz, 3H), 7.70 (d, J = 5.2 Hz, 1H),
7.56 (t, J = 7.6 Hz, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6
Hz, 2H), 7.16 (t, J = 7.2 Hz, 1H), 5.59-5.49 (m, 2H), 1.93 (s, 3H);
13C NMR (150 MHz, DMSO-d6): δ (ppm) 187.4, 161.6, 155.8,
148.72, 148.66, 146.3, 140.3, 137.9, 137.2, 136.3, 129.3, 128.93,
128.86, 128.3, 126.1, 124.9, 123.1, 118.1, 117.3, 103.7, 69.7,
14.8; MS (EI): m/z 466.80 the overall spectroscopic data are in
complete agreement with assigned structures and consistent with
literature6a
4-benzoyl-5-methyl-2,7-di-p-tolyl-7,9-dihydrooxepino[2,3-c:6,5-
c']dipyrazol-3(2H)-one (4u): Following general procedure A
using acetophenone (1a, 120 mg, 1.0 mmol), 4-
Methylphenylhydrazine (2b, 244 mg, 2.0 mmol), ethyl
acetoacetate (3a, 260 mg, 2.0 mmol) and purified by silicagel
column chromatography, afforded the compound as orange solid
(356 mg, Yield 73%); Mp. 231-233 °C; (literature 232-234 °C);
1H NMR (600 MHz, DMSO-d6): δ (ppm) 8.06 (d, J = 7.2 Hz, 2H),
7.74 (t, J = 7.2 Hz, 1H), 7.63-7.56 (m, 6H), 7.36 (d, J = 7.8 Hz,
2H), 7.17 (d, J = 8.4 Hz, 2H), 5.59-5.50 (m, 2H), 2.37 (s, 3H),
2.25 (s, 3H), 1.85 (s, 3H); 13C NMR (150 MHz, DMSO-d6): δ
(ppm) 194.2, 161.5, 155.5, 148.8, 148.4, 145.9, 138.0, 135.5,
134.9, 134.8, 134.1, 133.9, 129.7, 129.4, 129.3, 128.7, 123.0,
118.1, 117.7, 103.8, 69.6, 20.7, 20.4, 14.9; MS (EI): m/z 488.33

7
the overall spectroscopic data are in complete agreement with
assigned structures and consistent with literature6a
7.55-7.39 (m Hz, 8H), 7.22 (s, 2H), 5.48 (s, 1H), 2.35 (s, 6H);
ACCEPTED MANUSCRIPT
13C NMR (150 MHz, DMSO-d6): δ (ppm) 196.1, 146.2, 137.2,
136.6, 132.4, 129.0, 128.7, 128.3, 128.2, 125.6, 120.2, 117.8,
38.4, 11.7; MS (EI): m/z 464.34 the overall spectroscopic data are
in complete agreement with assigned structures and consistent
with literature6a
5-methyl-4-(4-nitrobenzoyl)-2,7-di-p-tolyl-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one
(4v):
Following general procedure A using 4-nitroacetophenone (1i,
165 mg, 1.0 mmol), 4-Methylphenylhydrazine (2b, 244 mg, 2.0
mmol), ethyl acetoacetate (3a, 260 mg, 2.0 mmol) and purified
by silicagel column chromatography, afforded the compound as
orange solid (239.8 mg, Yield 45%); Mp. 279-281 °C; (literature
281-283 °C); 1H NMR (600 MHz, DMSO-d6): δ (ppm) 8.39 (d, J
= 9.0 Hz, 2H), 8.33 (d, J = 9.0 Hz, 2H), 7.59 (t, J = 8.4 Hz, 4H),
7.37 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 5.60-5.54 (m,
2H), 2.38 (s, 3H), 2.26 (s, 3H), 1.86 (s, 3H); 13C NMR (150 MHz,
DMSO-d6): δ (ppm) 193.6, 161.5, 155.7, 150.8, 148.2, 147.2,
145.9, 138.8, 138.1, 135.3, 134.2, 133.8, 130.0, 129.7, 129.3,
124.6, 123.0, 118.11, 118.07, 103.6, 69.5, 20.7, 20.4, 15.0; MS
(EI): m/z 533.67 the overall spectroscopic data are in complete
agreement with assigned structures and consistent with
literature6a
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Grants 21472056, 21602070 and
21702091). We thank Dr. Chuanqi Zhou, Hebei University, for
analytical support. This work was supported by “The
Fundamental Research Funds for the Central Universities”
(CCNU15ZX002). This work was also supported by the 111
Project B17019.
References
1 (a) Posner, G. H. Chem. Rev. 1986, 86, 831–844; (b) Ramo´n,
D. J.; Yus, M. Angew. Chem., Int. Ed., 2005, 44, 1602; (c)
Brauch, S.; van Berkel, S. S.; Westermann, B. Chem. Soc. Rev.,
2013, 42, 4948–4962; (d) Rotstein, B. H.; Zaretsky, S.; Rai, V.;
Yudin, A. K. Chem. Rev. 2014, 114, 8323; (e) Cioc, R. C.;
Ruijter, E.; Orru, R.V. A. Green Chem. 2014, 16, 2958; (f)
Ravichandiran, P.; Lai, B. B.; Gu, Y. L. Chem. Rec. 2017, 17,
142.
4-benzoyl-2,7-bis(3-chlorophenyl)-5-methyl-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one
(4w):
Following general procedure A using acetophenone (1a, 120 mg,
1.0 mmol), (3-Chlorophenyl)hydrazine (2c, 284 mg, 2.0 mmol),
ethyl acetoacetate (3a, 260 mg, 2.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
orange solid (295.7 mg, Yield 56%); Mp, 246-248 °C; (literature
244-246 °C); 1H NMR (600 MHz, DMSO-d6): δ (ppm) 8.07 (d, J
= 7.2 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.75-7.68 (m, 3H), 7.62-
7.55 (m, 3H), 7.52-7.48 (m, 1H), 7.37 (t, J = 8.4 Hz, 1H), 7.18 (d,
J = 7.8 Hz, 1H), 5.66-5.53 (m, 2H), 1.85 (s, 3H); 13C NMR (150
MHz, DMSO-d6): δ (ppm) 193.8, 161.7, 156.1, 149.2, 149.0,
146.5, 139.0, 137.4, 134.9, 134.8, 133.5, 133.3, 131.0, 130.7,
129.4, 128.7, 128.1, 124.5, 122.6, 121.4, 117.7, 117.1, 116.0,
104.1, 69.7, 14.9; MS (EI): m/z 528.85 the overall spectroscopic
data are in complete agreement with assigned structures and
consistent with literature6a
2 Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112,
3083.
3 (a) Gong, L. Z.; Chen, X. H.; Xu, X. Y. Chem.–Eur. J.,2007,
13, 8920; (b) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett.,
1993, 34, 583; (c) Arraya′s, R. G.; Carretero, J. C. Chem. Soc.
Rev., 2009, 38, 1940. (d) Denmark, S. E.; Fan, Y. J. Org. Chem.,
2005, 70, 9667.
4 (a) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org.
Chem., 2004, 4957; ( b) Dondoni, A.; Massi, A. Acc. Chem. Res.,
2006, 39, 451; (c) Flagstad, T.; Petersen, M. T.; Nielsen, T. E.
Angew. Chem. Int. Ed. 2015, 54, 8395–8397; (d) Mercalli, V.;
Nyadanu, A.; Cordier, M.; Tron, G. C.; Grimaud, L.; Kaim, L. E.
Chem. Commun., 2017, 53, 2118–2121; (e) Ariza, G. M.; Ayaz,
M.; Roberts, S. A.; León, W. A. R.; Pérez, R. A.; Hulme, C.
Angew. Chem. Int. Ed. 2015, 54, 11672 –11676.
4-benzoyl-2,7-bis(4-chlorophenyl)-5-methyl-7,9-
dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(2H)-one
(4x):
Following general procedure A using acetophenone (1a, 120 mg,
1.0 mmol), (4-Chlorophenyl)hydrazine (2d, 284 mg, 2.0 mmol),
ethyl acetoacetate (3a, 260 mg, 2.0 mmol) and purified by
silicagel column chromatography, afforded the compound as
orange solid (185 mg, Yield 35%); Mp. 297-299 °C; (literature
5 (a) “Pyrazol-3-ones. Part IV: Synthesis and Applications”:
Varvounis, G. in Advances in Heterocyclic Chemistry, Vol. 98
(Ed.: Katritzky, A. R.), Academic Press, New York, 2009, p. 143;
(b) Varvounis, G.; Adv. Heterocycl. Chem., Elsevier, 2009, vol.
98, pp. 143–224; (c) Horton, D. A.; Bourne, G. T.; Smythe, M. L.
Chem. Rev. 2003, 103, 893; (d) Zhang, B. H.; Lei, L. S.; Liu, S.
Z.; Mou, X. Q.; Liu, W. T.; Wang, S. H.; Wang, J.; Bao, W.;
Zhang, K. Chem. Commun. 2017, 53, 8545-8548. (e) Tang, M.;
Kong, Y. f.; Chu, B. j.; Feng, D. Adv. Synth. Catal., 2016, 358,
926–939.
1
298-300 °C); H NMR (600 MHz, CDCl3): δ (ppm) 7.98 (d, J =
7.2 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 3H),
7.47 (t, J = 7.2 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4
Hz, 2H), 5.31-5.15 (m, 2H), 1.95 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ (ppm) 194.2, 161.9, 155.1, 150.2, 149.5, 144.8, 136.5,
135.0, 134.83, 134.79, 133.9, 130.1, 129.4, 129.3, 128.7, 123.9,
119.7, 118.6, 104.2, 70.0, 15.3; MS (EI): m/z 529.67 the overall
spectroscopic data are in complete agreement with assigned
structures and consistent with literature6a
6 (a) Wu, X.; Geng, X.; Zhao, P.; Wu, Y. D.; Wu, A. X. Org. Lett.
2017, 19, 4584; (b) Chauhan, P.; Mahajan, S.; Enders, D. Chem.
Commun. 2015, 51, 12890.
Representative procedure for the synthesis of 2-oxo-2-
phenylethane-1,1-diyl)bis(3-methyl-1-phenyl-1H-pyrazol-5(4H)-
one) (7a): using acetophenone (1a, 120 mg, 1.0 mmol), 3-
methyl-5-pyrazolone (5a, 348 mg, 2.0 mmol), TfOH (375 mg,
2.5 mmol) in DMSO (4 mL), the mixture was stirred at 140 °C
for 3 h and then extracted with EtOAc (3 × 50 mL). The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography on silica
gel (eluent: petroleum ether/EtOAc = 1/1. red solid (194.9 mg,
7 (a) Wang, L.; Li, S.; Chauhan, P.; Hack, D.; Philipps, A. R.;
Puttreddy, R.; Rissanen, K.; Raabe, G.; Enders, D. Chem. Eur. J.
2016, 22, 5123; (b) Han, X. Y.; Yao, W. J.; Wang, T. L.; Tan, Y.
R.; Yan, Y. Z.; Kwiatkowski, J.; Lu, Y. X. Angew. Chem. Int. Ed.
2014, 53, 5643; (c) Hack, D.; Dürr, A. B.; Deckers, K.; Chauhan,
P.; Seling Nico, B. Sc.; Rübenach Lukas, B. Sc.; Mertens Lucas,
B. Sc.; Raabe, G.; Schoenebeck, F.; Enders, D. Angew. Chem. Int.
Ed. 2016, 55, 1797.
1
Yield 42%); Mp.170-172 °C; (literature 166-168 °C); H NMR
(600 MHz, DMSO-d6): δ (ppm) 7.88 (s, 2H), 7.70-7.64 (m, 4H),

8
Tetrahedron
ACCEPTED MANUSCRIPT
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