Synthesis of 4-Arylidenepyrazolones by a Gold-Catalyzed Cyclization/Arylidene Group Transfer Cascade of N-Propioloyl Hydrazones

Article abstract of DOI:10.1021/acs.joc.5b01366

An efficient gold-catalyzed cyclization/arylidene group transfer cascade reaction of N-propioloyl hydrazones has been developed. This method provides a novel approach for the synthesis of various functionalized 4-arylidenepyrazolones.

Full text of DOI:10.1021/acs.joc.5b01366

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Note
Synthesis of 4-Arylidenepyrazolones by a Gold-Catalyzed Cyclization/
Arylidene Group Transfer Cascade of N-Propioloyl Hydrazones
Zong-Cang Ding, Hai-Tao Tang, Ren-Hao Li, Lu-Chuan Ju, and Zhuang-Ping Zhan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01366 • Publication Date (Web): 25 Aug 2015
Downloaded from http://pubs.acs.org on September 1, 2015
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Synthesis of 4-Arylidenepyrazolones by a Gold-Catalyzed
Cyclization/Arylidene Group Transfer Cascade of
N-Propioloyl Hydrazones
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ZongꢀCang Ding, HaiꢀTao Tang, RenꢀHao Li, LuꢀChuan Ju, and
ZhuangꢀPing Zhan*
Department of Chemistry, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, Fujian, P. R. China
ABSTRACT: An efficient gold catalyzed cyclization/arylidene group transfer cascade
reaction of Nꢀpropioloyl hydrazones has been developed. This method provides a
novel approach for the synthesis of various functionalized 4ꢀarylidenepyrazolones.
Pyrazolone is an important molecular motif and exists in many natural products, drugs,
pharmaceutical candidates, and biologically important compounds.1 Among those
pyrazolone derivatives, 4ꢀarylidenepyrazolones have been used as antagonists for a
variety of biological targets (Figure 1)2 such as effective inhibitors for HIVꢀ1
integrase,2a orthopoxvirus,2b inhibitor of H1N1 and H5N1 neuraminidases,2c as well as
Farnesoid X Receptor.2d To date, the preparation of 4ꢀarylidenepyrazolone derivatives
usually relies on the condensation of substituted aldehydes3 (or their acetal4 or imine5
precursors) with 2ꢀpyrazolinꢀ5ꢀones, which are in turn obtained by the Knorr
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condensation of βꢀketoesters with substituted hydrazines. To the best of our
knowledge, the use of a πꢀacidic transitionꢀmetal catalyzed cyclization to access this
family of compounds has not been disclosed.
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Figure 1. Biologically active 4ꢀarylidenepyrazolone derivatives.
Metalꢀcatalyzed skeletal rearrangements provide an effective pathway for the
construction of complex molecules.6 In particular, the [3,3] rearrangement of various
propargylic compounds have been well studied,7 including the unique Nꢀpropargylic
hydrazone derivatives. Such rearrangement reactions can be channeled to form
different types of products by proper choice of substituents on the substrates. For
example, we have reported the [3,3] sigmatropic rearrangement of Nꢀpropargylic
sulfonylhydrazones for the stereoselective synthesis of sufonyldienes (Scheme 1, eq
1).8 However, switching the Nꢀsulfonyl group for an Nꢀphenyl or Nꢀalkyl group led
to the formation of polysubstituted pyrazoles via a PtCl4ꢀcatalyzed [3,3] sigmatropic
rearrangement/cyclization cascade (Scheme 1, eq 2).9 As part of our ongoing efforts in
expanding the synthetic utility of Nꢀpropargylic hydrazones, we prepared the
Nꢀpropioloyl hydrazones and envisioned that similar rearrangement/cyclization
sequence from these structures might afford pyridazinones (Scheme 1, eq 3).10
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However, when 1 was treated with a gold catalyst, the 4ꢀarylidenepyrazolone 2 was
obtained instead of the expected pyridazinone (Scheme 1, eq 4). 11ꢀ12 We report herein
a novel method for the synthesis of various 4ꢀarylidenepyrazolones from Nꢀpropioloyl
hydrazones by gold catalyzed cyclization/1,3ꢀmigration cascade.
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Scheme 1. [3,3]-Rearrangement of N-Propargylhydrazones and Arylidene Group
Transfer of N-Propioloyl Hydrazones
We began our studies by reacting 1a under the reaction conditions that we
previously employed to convert Nꢀpropargylphenylhydrazones to pyrazoles (Scheme
1, eq 2). Treating 1a with a catalytic amount of PtCl4 in reflux toluene gave 2a in 36%
yield (Table 1, entry 1). A range of other transitionꢀmetal catalysts, including
Rh2(Oct)4, Rh2(OAc)4, Sc(OTf)3, CuI, Cu(OAc)2, CuBr, CuBr·SMe2 were tested to
increase the yield of 2a but the results were unsatisfactory (Table 1, entries 2ꢀ8).
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Table 1. Optimization of the Reaction Conditionsa
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entry
1
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catalyst
PtCl4
Rh2(Oct)4
Rh2(OAc)4
Sc(OTf)3
CuI
Cu(OAc)2
CuBr
CuBr·SMe2
AuCl3
solvent
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCF3
DCE
t/h
6
6
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6
6
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6
6
1
1
6
1
1
1
1
6
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1
1
resultb
36%
NRc
NR
NR
NR
NR
Trace
Trace
41%
44%
60%
83%
50%
78%
70%
33%
30%
50%
57%
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17d
18d
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Au(PPh3)NTf2
AuPPh3Cl/AgOTf
IPrAuCl/ AgOTf
IPrAuCl/AgBF4
IPrAuCl/AgSbF6
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
DMSO
DMF
CCl4
1,4ꢀdioxane
THF
Complex
Complex
aReaction conditions: The reaction was carried out using 1a (0.3 mmol) and catalyst
(5 mol %) in the solvent (3 mL) at reflux unless otherwise noted. bIsolated yield.
cNR= no reaction. dThe reaction was performed at 110 oC.
Recently, gold catalysis of organic reactions has become a highly active field. 13 The
fact that gold has the unique catalytic activity on alkynes leads us to try gold catalysts.
Interestingly, an improved 41% yield was obtained when AuCl3 was used as the
catalyst (Table 1, entry 9). Encouraged by these results, different gold catalyst systems
(Table 1, entries 10ꢀ14) were screened leading to the discovery that an optimal yield
of 83% could be obtained by the use a combination of the gold catalyst IPrAuCl and
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AgOTf (Table 1, entry 12). Other solvents, such as PhCF3, DCE, DMSO, DMF,
CCl4, 1, 4ꢀdioxane and THF, are less effective (entries 15ꢀ21). Therefore, the optimum
reaction conditions were determined to be performing the reaction in toluene at reflux
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with 5 mol % IPrAuCl/AgOTf as the catalyst (Table 1, entry 12).
Scheme 2. Gold Catalyzed Synthesis of 4-Arylidenepyrazolonesa, b
aReaction conditions: The reaction was carried out using 1 (0.3 mmol) and catalyst (5 mol %) in
PhCH3 (3 mL) at reflux in Schlenk tube. bIsolated yields. cTs= pꢀtoluenesulfonyl
The substrate scope was explored and the results were summarized in Scheme 2.
Hydrazones derived from phenyl aldehydes bearing electronꢀdonating groups (ꢀOMe,
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ꢀMe), or electronꢀwithdrawing halogen (Br) at different positions of the phenyl group,
were successfully employed to give corresponding products in moderate to good
yields (Scheme 2, products 2aꢀ2f, 50ꢀ83% yields). The structure of 2d was further
confirmed by single crystal Xꢀray structure analysis (Figure 2，see SI). Heteroaryl
aldehydeꢀderived hydrazones were also viable substrates (Scheme 2, products 2gꢀ2h,
51ꢀ61% yields). Hydrazone derived from 2ꢀformylanaphthalene gave product 2i in
63% yield. Substrates with both electronꢀrich (ꢀOMe) and electron–poor (ꢀNO2, ꢀBr)
phenyl groups at the R3 position reacted smoothly to afford the desired products
(Scheme 2, products 2jꢀ2l, 52ꢀ57% yields). Replacing the R3 phenyl group with tosyl
or a methyl group completely abolished the formation of the corresponding products
due to the decomposition of the starting materials under the reaction conditions
(Scheme 2, products 2m and 2n, 0% yield). The reaction seemed to be insensitive to
the R1 subsitutent. Hence, phenyl groups substituted with –Me, ꢀCOOMe and –Cl, and
numerous alkyl groups, such as nꢀpropyl, cyclopropyl, cyclohexenyl and the bulky
tꢀbutyl were all tolerated (Scheme 2, products 2oꢀ2u, 40ꢀ70% yields). However,
introducing a trimethylsilyl group at this position led to no reaction perhaps owing to
the triple bond could not be attacked by the nitrogen atom of the imine moiety
because the trimethylsilyl group made it less electrophilic (Scheme 2, product 2v, 0%
yield). Interestingly, the present method was also compatible with the use of
ketohydrazone as the substrate albeit with moderate efficiency (Scheme 2, product 2w,
41% yield). In addition, product 2x was also prepared in moderate yield, which would
be useful in the mechanism study experiment (Scheme 2, product 2x, 51% yield).
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To gain insight into the mechanism, a crossover experiment between equimolar
amounts of reactants 1x and 1c was carried out which yields the corresponding
products 2x and 2c and the crossover products 2a and 2m were also detected (Scheme
3, eq 1, determined by HPLC, Figure 3, see SI). This result clearly indicated the
1,3ꢀarylidene migration proceeds in an intermolecular manner. Moreover, the result
leaded us to conjecture that trace amounts of water may participate in the reaction and
2ꢀpyrazolinꢀ5ꢀone 6 may be a reactive intermediate. In order to verify our hypothesis,
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the reaction of 1c with an equivalent of water was carried out, and 6a was isolated as
Scheme 3. Mechanism Study.
expected in 70% yield, together with the minor corresponding product 2c and
benzaldehyde (Scheme 3, eq 2). In addition, in the presence of 6a, the reaction of 1p
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afforded a nearly 1:1 mixture of 2c and 2p (Scheme 3, eq 3), these results indicated
that 6 was produced as the reactive intermediate. It is noteworthy that the major
product 2a rather than the corresponding 2c was obtained when 1a reacted with
equimolar amounts of pꢀanisaldehyde (Scheme 3, eq 4). Additionally, 6a and
pꢀanisaldehyde could smoothly give the condensation product 2a in 84% yield under
the optimized conditions (Scheme 3, eq 5), thus confirming the fact that the
condensation reaction procedure of 6 with an aldehyde was included in the arylidene
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group transfer process.
Scheme 4. Proposed Mechanism
Based on the above results, a proposed mechanism is illustrated in Scheme 4.
Firstly, coordination of the gold catalyst with the alkyne activates the triple bond of 1
for nucleophilic attack by the nitrogen atom of the hydrazone leading to the cyclized
vinyl gold intermediate 4. In this process, the pyridazinone is not formed perhaps
because the weaker nucleophilicity of the carbon atom of the imine than the nitrogen
atom. Then, 4 is hydrolyzed by advantageous water in the reaction system to give an
aldehyde 7 and 5 which is the enamine tautomer of 6 and the gold catalyst is
regenerated by protodemetalation of 4 at the same time. The in situ generated 5 then
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undergoes intermolecular nucleophilic attack at the carbonyl moiety of 7 affords the
final product 2 and regenerates the water. As a note, the trace amounts of water plays
a crucial role in the arylidene group transfer course. What’s more, the high Z
selectivity of 2 is probably owing to the E isomer is destabilized because of the steric
repulsion between R1and R2.
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In summary, we have developed a novel approach for the synthesis of
4ꢀarylidenepyrazolone derivatives from Nꢀpropioloylhydrazones by a gold catalyzed
cyclization/1,3ꢀmigration cascade. The reaction is broad in substrate scope and
provides convenient access to
a
variety of highly functionalized
4ꢀarylidenepyrazolones. The present method complements traditional condensation
reactions to prepare this family of compounds, and shall find its potential applications
in medicinal chemistry.
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all reagents were obtained
commercially and used without further purification. Propargylic acid were prepared
according to known references.14All reaction mixtures were stirred with a magnetic
1
bar in flameꢀdried tube. H and 13C spectra were recorded on a 400 or 500 MHz
spectrometer. Chemical shifts were reported in ppm. 1H NMR spectra were referenced
to CDCl3 (7.26 ppm), and 13CꢀNMR spectra were referenced to CDCl3 (77.0 ppm).
All 13CꢀNMR spectra were measured with complete proton decoupling. Peak
multiplicities were designated by the following abbreviations: s, singlet; d, doublet; t,
triplet; m, multiplet; brs, broad singlet and J, coupling constant in Hz. IR spectra were
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recorded on a FTIR spectrometer as thin film. Absorptions were given in
wavenumbers (cmꢀ1). HRMS spectra were recorded with Micromass QTOF2
Quadrupole/TimeꢀofꢀFlight Tandem mass spectrometer using electron spray
ionization. HPLC Separation and purification of the crossover experimental products
were all conducted on a HPLC instrument at room temperature using toluene as
elution solvent and the chromatogram was monitored at 450 nm.
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General procedure for synthesis of N-propioloyl hydrazones 1. A propynoic acid
(5.5 mmol, 1.1 eq) in SOCl2 (5 mL) was heated at 60 ºC for 3 h, then the excess
SOCl2 was removed under reduced pressure. The resulting acid chloride was used
without further purification. To the solution of the corresponding hydrazone (5 mmol,
1.0 eq) in 15 mL THF was added 1.6 M nꢀbutyl lithium in hexane (4.68 mL, 7.5 mmol,
1.5 eq) at ꢀ78 °C under the protection of N2. A yellow solid was formed during the
addition. The mixture was stirred for 15 min, then propynoic acid chloride in 5 mL
THF was added. The resulting solution was warmed to rt over 30 min and quenched
by adding H2O. The solution was extracted with diethyl ether. The extracts were
combined, washed with H2O and dried over anhydrous Na2SO4. The solvent was
removed by vacuum and the crude residue was purified by silica gel column
chromatography (eluent: petroleum ether/ EtOAc = 20/1), and the resulting
Nꢀpropioloyl hydrazones 1 was further purified by recrystallyzation from ethyl acetate
and hexane.
General procedure for synthesis of 4-Arylidenepyrazolones 2. Corresponding
Nꢀpropioloyl hydrazones 1 (0.3 mmol), IPrAuCl (0.015 mmol, 9.3mg) and AgOTf
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(0.015mmol, 3.85mg) were added to 10 mL schlenk tube followed by the adding of
PhCH3 (3 mL), and the reaction mixture was stirred at reflux under the protection of
N2. Upon completion (monitored by TLC), the reaction mixture was cooled to room
temperature and purified by silica gel column chromatography to afford the
corresponding 4ꢀarylidenepyrazolones 2. (eluent: petroleum ether/ EtOAc = 30/1).
(Z)-4-(4-methoxybenzylidene)-2,5-diphenyl-2,4-dihydro-3H-pyrazol-3-one (2a)
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1
an orange solid (88 mg, 83% yield, mp: 175ꢀ176 oC); H NMR (400 MHz, CDCl3) δ
3.87 (s, 3H), 6.97ꢀ7.00 (m, 2H), 7.20ꢀ7.24 (m, 1H), 7.42ꢀ7.46 (m, 2H), 7.52ꢀ7.55 (m,
4H), 7.66ꢀ7.68 (m, 2H), 8.08 (dd, 2H, J1 = 8.8 Hz, J2=1.1 Hz ), 8.53ꢀ8.56 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 55.6, 114.2, 119.5, 123.71, 125.0, 126.4, 128.8, 128.9,
129.0, 131.2, 136.9, 138.7, 139.8, 149.8, 153.3, 162.5, 164.0; IR (film): 3080, 2839,
1682, 1585 cmꢀ1; HRMS (ESI) m/z Calculated for C23H19N2O2 [M+H]+ 355.1441,
found: 355.1443.
(Z)-4-(4-methylbenzylidene)-2,5-diphenyl-2,4-dihydro-3H-pyrazol-3-one (2b)
a red solid (82 mg, 81% yield, mp: 154ꢀ155 oC); 1H NMR (400 MHz, CDCl3) δ 2.44
(s, 3H), 7.20ꢀ7.25 (m, 1H) 7.31 (d, 2H, J=8.1 Hz), 7.43ꢀ7.47 (m, 2H), 7.54ꢀ7.56 (m,
3H), 7.61(s, 1H), 7.67ꢀ7.70 (m, 2H), 8.08 (dd, 2H, J1 = 8.5 Hz, J2=1.0 Hz ), 8.39 (d,
2H, J=8.2 Hz); 13C NMR (100 MHz, CDCl3) δ 22.0, 118.9, 119.5, 125.1, 125.5, 128.8,
128.9, 129.5, 129.8, 130.6, 130.9, 134.2, 138.5, 144.7, 150.2, 153.1, 162.2; IR (film):
3063, 2959, 1687, 1593 cmꢀ1; HRMS (ESI) m/z Calculated for C23H19N2O [M+H]+
339.1492, found: 339.1495.
(Z)-4-benzylidene-2,5-diphenyl-2,4-dihydro-3H-pyrazol-3-one (2c)
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a red solid (73.8 mg, 76% yield, mp: 144ꢀ145 C); H NMR (500 MHz, CDCl3) δ
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7.22ꢀ7.25 (m, 1H) 7.44ꢀ7.57 (m, 8H), 7.64(s, 1H), 7.69ꢀ7.71 (m, 2H), 8.09 (dd, 2H, J1
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= 8.7 Hz, J2=1.1 Hz )， 8.44ꢀ8.46 （m, 2H; C NMR (125 MHz, CDCl3) δ 119.3,
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125.0, 126.4, 128.5, 128.7, 128.8, 128.9, 129.7, 130.7, 132.8, 133.1, 133.7, 138.3,
149.9, 152.8, 161.9; IR (film): 3062, 1683, 1593 cmꢀ1; HRMS (ESI) m/z Calculated
for C22H17N2O [M+H]+ 325.1335, found: 325.1331.
(Z)-4-(4-bromobenzylidene)-2,5-diphenyl-2,4-dihydro-3H-pyrazol-3-one (2d)
o
1
a red solid (78.6 mg, 65% yield, mp: 167ꢀ169 C); H NMR (500 MHz, CDCl3) δ
7.21ꢀ7.24 (m, 1H), 7.42ꢀ7.46 (m, 2H), 7.54ꢀ7.56 (m, 4H), 7.61ꢀ7.64 (m, 2H),
7.66ꢀ7.68 (m, 2H), 8.03 (dd, 2H, J1 = 8.7 Hz, J2=1.0 Hz ), 8.31ꢀ8.34 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 119.4, 125.3, 126.9, 128.3, 128.8, 128.9， 129.0, 129.9,
130.5, 131.7, 131.9, 135.0, 138.2, 148.2, 152.8, 161.8; IR (film): 3063, 1686, 1596
cmꢀ1; HRMS (ESI) m/z Calculated for C22H16BrN2O [M+H]+ 403.0441 and 405.0420,
found: 403.0446 and 405.0425.
(Z)-4-(2-bromobenzylidene)-2,5-diphenyl-2,4-dihydro-3H-pyrazol-3-one (2e)
o
1
a red solid (66.5 mg, 55% yield, mp: 150ꢀ151 C); H NMR (500 MHz, CDCl3) δ
7.22ꢀ7.23 (m, 1H), 7.35ꢀ7.37 (m, 1H), 7.42ꢀ7.47 (m, 3H), 7.55ꢀ7.56 (m, 3H),
13
7.66ꢀ7.68 (m, 1H), 7.75ꢀ7.77 (m, 2H), 8.01ꢀ8.06 (m, 3H), 8.73 (d, 1H, J=7.6Hz); C
NMR (125 MHz, CDCl3) δ 119.3, 125.3, 126.8, 127.1, 127.3, 128.7, 128.8, 129.0,
130.0, 130.5, 132.0, 132.9, 133.3, 133.4, 138.2, 147.5, 152.4, 161.7; IR (film): 3092,
1687, 1597 cmꢀ1; HRMS (ESI) m/z Calculated for C22H16BrN2O [M+H]+ 403.0441
and 405.0420, found: 403.0446 and 405.0425.
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(Z)-4-(3-bromobenzylidene)-2,5-diphenyl-2,4-dihydro-3H-pyrazol-3-one (2f)
5
6
o
1
a red solid (60.5 mg, 50% yield, mp: 112ꢀ113 C); H NMR (400 MHz, CDCl3) δ
7.21ꢀ7.25 (m, 1H), 7.35ꢀ7.39 (m, 1H), 7.42ꢀ7.46 (m, 2H), 7.53 (s, 1H), 7.55ꢀ7.56 (m,
3H), 7.65ꢀ7.67 (m, 3H), 8.03 (d, 2H, J = 8.2 Hz), 8.43 (d, 1H, J=7.7 Hz), 8.55 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 119.5, 122.5, 125.3, 127.8, 128.8, 128.9, 129.0, 129.9,
130.0, 130.5, 131.9, 134.7, 135.6, 136.0, 138.2, 147.7, 152.6, 161.7; IR (film): 3062,
1686, 1596 cmꢀ1; HRMS (ESI) m/z Calculated for C22H16BrN2O [M+H]+ 403.0441
and 405.0420, found: 403.0446 and 405.0425.
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(Z)-4-(furan-2-ylmethylene)-2,5-diphenyl-2,4-dihydro-3H-pyrazol-3-one (2g)
o
1
a red solid (48.1 mg, 51% yield, mp: 162ꢀ163 C); H NMR (500 MHz, CDCl3) δ
6.73ꢀ6.74 (m, 1H), 7.21ꢀ7.24 (m, 1H), 7.43ꢀ7.47 (m, 2H), 7.52ꢀ7.54 (m, 3H), 7.59(s,
1H), 7.68ꢀ7.70 (m, 2H), 7.75 (dd, 1H, J1 = 1.5 Hz, J2=0.5 Hz ), 8.06ꢀ8.08 (m, 2H),
13
8.84 (d, 1H, J=3.8Hz) ; C NMR (125 MHz, CDCl3) δ 114.9, 119.3, 121.2, 125.1,
125.5, 128.6, 128.8, 129.0, 129.7, 130.9, 131.7, 138.5, 148.8, 150.9, 151.8, 162.3; IR
(film): 3134, 1682, 1609 cmꢀ1; HRMS (ESI) m/z Calculated for C20H15N2O2 [M+H]+
315.1128, found: 315.1133.
(Z)-2,5-diphenyl-4-(thiophen-2-ylmethylene)-2,4-dihydro-3H-pyrazol-3-one (2h)
o
1
a brownness solid (60.4 mg, 61% yield, mp: 139ꢀ140 C); H NMR (400 MHz,
CDCl3) δ 7.20ꢀ7.24 (m, 2H), 7.42ꢀ7.47 (m, 2H), 7.52ꢀ7.57 (m, 3H), 7.67ꢀ7.70 (m, 2H),
7.83(s, 1H), 7.86ꢀ7.88 (m, 1H), 7.95 (dd, 1H, J1 = 3.8 Hz, J2=0.5 Hz ), 8.09ꢀ8.13 (m,
13
2H); C NMR (100 MHz, CDCl3) δ 119.1, 121.0, 124.9, 128.1, 128.6, 128.7, 128.9,
129.6, 130.9, 136.8, 138.4, 138.7,138.9, 141.4, 151.9, 162.4; IR (film): 3062, 1682,
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1593 cmꢀ1; HRMS (ESI) m/z Calculated for C20H15N2OS [M+H]+ 331.0900, found:
331.0904.
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(Z)-4-(naphthalen-2-ylmethylene)-2,5-diphenyl-2,4-dihydro-3H-pyrazol-3-one (2i)
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o
1
a red solid (70.8 mg, 63% yield, mp: 151ꢀ152 C); H NMR (500 MHz, CDCl3) δ
7.22ꢀ7.25 (m, 1H), 7.45ꢀ7.48 (m, 2H), 7.51ꢀ7.62 (m, 5H), 7.71ꢀ7.73 (m, 2H), 7.77(s,
1H), 7.86 (d, 1H, J=8.1 Hz), 7.91 (d, 1H, J=8.6 Hz ), 7.98 (d, 1H, J=8.0 Hz), 8.09 (dd,
2H, J1=8.6 Hz, J2=1.0 Hz), 8.58 (dd, 1H, J1=8.7 Hz, J2=1.6 Hz), 8.94 (s, 1H); 13C
NMR (125 MHz, CDCl3); δ 119.5, 125.1, 126.3, 126.7, 127.7, 128.2, 128.8, 128.9,
129.0, 129.7, 129.8, 130.7, 130.9, 132.8, 135.4, 136.2, 138.4, 149.9, 153.0, 162.0; IR
(film): 3057, 1684, 1595 cmꢀ1; HRMS (ESI) m/z Calculated for C26H19N2O [M+H]+
375.1492, found: 375.1493.
(Z)-4-benzylidene-2-(4-methoxyphenyl)-5-phenyl-2,4-dihydro-3H-pyrazol-3-one
(2j)
o
1
a red solid (60.6 mg, 57% yield, mp: 153ꢀ154 C); H NMR (400 MHz, CDCl3) δ
3.83 (s, 3H), 6.97 (d, 2H, J= 8.7 Hz), 7.49ꢀ7.54 (m, 6H), 7.64 (s, 1H), 7.67ꢀ7.68 (m,
2H), 7.93 (d, 2H, J=8.7 Hz), 8.45 (d, 2H, J=7.3 Hz ); 13C NMR (100 MHz, CDCl3) δ
55.5, 114.0, 121.3, 126.5, 128.6, 128.9, 129.0, 129.7, 130.8, 131.8, 133.0, 133.1,
133.8, 149.9, 152.7, 157.2, 161.7; IR (film): 3066, 2932, 1683, 1615 cmꢀ1; HRMS
(ESI) m/z Calculated for C23H19N2O2 [M+H]+ 355.1441, found: 355.1443.
(Z)-4-benzylidene-2-(4-nitrophenyl)-5-phenyl-2,4-dihydro-3H-pyrazol-3-one (2k)
a bisque solid (58.7 mg, 53% yield, mp: 192ꢀ193 oC); 1H NMR (500 MHz, CDCl3) δ
7.51ꢀ7.55 (m, 2H), 7.58ꢀ7.61 (m, 4H), 7.68ꢀ7.70 (m, 3H), 8.28ꢀ8.30 (m, 2H),
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8.33ꢀ8.35(m, 2H), 8.41 (d, 2H, J=7.4 Hz ); 13C NMR (125 MHz, CDCl3) δ 118.0,
124.7, 125.4, 128.7, 128.8, 129.0, 130.1, 130.3, 132.5, 133.8, 133.9, 143.5, 143.8,
151.5, 154.5, 162.4; IR (film): 3113, 1697, 1590 cmꢀ1; HRMS (ESI) m/z Calculated
for C22H16N3O3 [M+H]+ 370.1186, found: 370.1188.
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(Z)-4-benzylidene-2-(4-bromophenyl)-5-phenyl-2,4-dihydro-3H-pyrazol-3-one (2l)
o
1
a red solid (63 mg, 52% yield, mp: 171ꢀ173 C); H NMR (500 MHz, CDCl3) δ
7.48ꢀ7.53 (m, 3H), 7.54ꢀ7.59 (m, 5H), 7.64ꢀ7.69 (m, 3H), 7.98ꢀ8.02 (m, 2H),
8.40ꢀ8.42(m, 2H);
13C NMR (125 MHz, CDCl3) δ 117.9, 120.6, 126.2, 128.6, 128.9,
129.0, 129.9, 130.5, 131.7, 132.8, 133.3, 133.8, 137.5, 150.5, 153.3, 161.9; IR (film):
3063, 1689, 1597 cmꢀ1; HRMS (ESI) m/z Calculated for C22H16BrN2O [M+H]+
403.0441 and 405.0420, found: 403.0446 and 405.0425.
(Z)-4-benzylidene-2-phenyl-5-(p-tolyl)-2,4-dihydro-3H-pyrazol-3-one (2o)
a red solid (52 mg, 51% yield, mp: 162ꢀ163 oC); 1H NMR (500 MHz, CDCl3) δ 2.47
(s, 3H), 7.21ꢀ7.24 (m, 1H), 7.36 (d, 2H, J=7.7 Hz), 7.43ꢀ7.46 (m, 2H), 7.49ꢀ7.52 (m,
2H), 7.54 (d, 1H, J=7.0 Hz), 7.58 (d, 2H, J=7.78 Hz), 7.64 (s, 1H), 8.07 (d, 2H, J=7.9
Hz), 8.44 (d, 2H, J=7.3 Hz); 13C NMR (125 MHz, CDCl3) δ 21.4, 119.4, 125.0, 126.6,
127.9, 128.6, 128.7, 128.8, 129.6, 132.9, 133.0, 133.7, 138.4, 139.9, 149.9, 152.9,
161.9; IR (film): 3065, 2919, 1684, 1615 cmꢀ1; HRMS (ESI) m/z Calculated for
C23H19N2O [M+H]+ 339.1492, found: 339.1496.
methyl (Z)-4-(4-benzylidene-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)benzoate
(2p)
o
an orange solid (76.8 mg, 67% yield, mp: 199ꢀ200 C); 1H NMR (500 MHz, CDCl3)
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δ 3.97 (s, 3H), 7.21ꢀ7.24 (m, 1H), 7.42ꢀ7.45 (m, 2H), 7.48ꢀ7.51 (m, 2H), 7.54ꢀ7.55 (m,
5
6
7
1H), 7.62 (s, 1H), 7.76 (d, 2H, J=8.2 Hz), 8.03 (m, 2H), 8.21 (d, 2H, J=8.3 Hz), 8.43
8
9
13
(d, 2H, J=7.4 Hz); C NMR (125 MHz, CDCl3) δ 52.3, 119.4, 125.3, 126.0, 128.6,
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128.7, 128.8, 130.1, 131.2, 132.7, 133.4, 133.8, 135.0, 138.2, 150.0, 151.7, 161.8,
166.4; IR (film): 3069, 2950, 1725, 1687, 1594 cmꢀ1; HRMS (ESI) m/z Calculated for
C24H19N2O3 [M+H]+ 383.1390, found: 383.1395.
(Z)-4-benzylidene-5-(4-chlorophenyl)-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (2q)
o
1
a red solid (75 mg, 70% yield, mp: 180ꢀ181 C); H NMR (500 MHz, CDCl3) δ
7.21ꢀ7.24 (m, 1H), 7.42ꢀ7.45 (m, 2H), 7.49ꢀ7.52 (m, 3H), 7.53 (s, 1H), 7.55 (s, 1H),
7.58 (s, 1H), 7.62 (d, 2H, J=8.3 Hz), 8.03 (d, 2H, J=7.8 Hz), 8.43 (d, 2H, J=7.4 Hz);
13C NMR (125 MHz, CDCl3) δ 119.4, 125.3, 126.2, 128.7, 128.8, 129.2, 129.3, 130.1,
132.8, 133.4, 133.8, 136.0, 138.3, 150.0, 151.8, 161.8; IR (film): 3070, 1686, 1593
cmꢀ1; HRMS (ESI) m/z Calculated for C22H16ClN2O [M+H]+ 359.0946, found:
359.0947.
(Z)-4-benzylidene-2-phenyl-5-propyl-2,4-dihydro-3H-pyrazol-3-one (2r)
o
1
a orange solid (61 mg, 70% yield, mp: 108ꢀ109 C); H NMR (400 MHz, CDCl3) δ
1.10 (t, 3H, J=7.4 Hz), 1.83 (sext, 2H, J=7.4 Hz), 2.65 (t, 2H, J=7.3 Hz), 7.17ꢀ7.21 (m,
1H), 7.38ꢀ7.44 (m, 3H), 7.47ꢀ7.55 (m, 3H), 8.01 (d, 2H, J=7.7 Hz), 8.48 (dd, 2H,
J1=8.0 Hz, J2=1.4 Hz); 13C NMR (100 MHz, CDCl3) δ 13.9, 20.6, 29.1, 119.0, 124.7,
127.1, 128.5, 128.6, 132.7, 132.8, 133.5, 138.4, 146.3, 153.7, 161.9; IR (film): 3068,
2957, 1678, 1614 cmꢀ1; HRMS (ESI) m/z Calculated for C19H19N2O [M+H]+
291.1492, found: 291.1493.
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(Z)-4-benzylidene-5-cyclopropyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (2s)
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7
8
o
1
a red solid (48 mg, 55% yield, mp: 123ꢀ124 C); H NMR (500 MHz, CDCl3) δ
1.00ꢀ1.04 (m, 2H), 1.07ꢀ1.13 (m, 2H), 1.86ꢀ1.92 (m, 1H), 7.15ꢀ7.19 (m, 1H),
7.38ꢀ7.42 (m, 2H), 7.49ꢀ7.55 (m, 3H), 7.66 (s, 1H), 7.96ꢀ7.98 (m, 2H), 8.51 (dd, 2H,
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13
J1=8.3 Hz, J2=1.0 Hz); C NMR (125 MHz, CDCl3) δ 6.8, 7.3, 119.0, 124.7, 127.8,
128.7, 132.9, 133.0, 133.6, 138.5, 146.6, 154.8, 162.1; IR (film): 3071, 3005, 1683,
1597 cmꢀ1; HRMS (ESI) m/z Calculated for C19H17N2O [M+H]+ 289.1335, found:
289.1338.
(Z)-4-benzylidene-5-(cyclohex-1-en-1-yl)-2-phenyl-2,4-dihydro-3H-pyrazol-3-one
(2t)
o
1
a red solid (40 mg, 40% yield, mp: 129ꢀ130 C); H NMR (500 MHz, CDCl3) δ
1.73ꢀ1.78 (m, 2H), 1.81ꢀ1.85 (m, 2H), 2.30ꢀ2.32 (m, 2H), 2.52ꢀ2.55 (m, 2H),
6.16ꢀ6.18 (m, 1H), 7.17ꢀ7.20 (m, 1H), 7.39ꢀ7.43(m, 2H), 7.48ꢀ7.55 (m, 3H), 7.68 (s,
13
1H), 8.01 (dd, 2H, J1=8.7 Hz, J2=1.0 Hz), 8.40 (dd, 2H, J1=8.2 Hz, J2=1.4 Hz); C
NMR (125 MHz, CDCl3) δ 21.9, 22.4, 25.9, 26.9, 119.3, 124.9, 126.3, 128.5, 128.7,
129.7, 132.7, 132.9, 133.6, 138.5, 149.3, 153.9, 162.0; IR (film): 3065, 2931, 2857,
1687, 1596 cmꢀ1; HRMS (ESI) m/z Calculated for C22H21N2O [M+H]+ 329.1648,
found: 329.1645.
(Z)-4-benzylidene-5-(tert-butyl)-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (2u)
1
a red liquid (39 mg, 43% yield); H NMR (500 MHz, CDCl3) δ 1.52 (s, 9H),
7.17ꢀ7.21 (m, 1H), 7.41ꢀ7.44(m, 2H), 7.48ꢀ7.54 (m, 3H), 7.85 (s, 1H), 8.02ꢀ8.04 (m,
2H), 8.35 (dd, 2H, J1=8.0 Hz, J2=1.4 Hz); 13C NMR (125 MHz, CDCl3) δ 29.5, 34.9,
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118.9, 124.6, 125.9, 128.3, 128.6, 132.3, 132.5, 133.1, 138.4, 147.8, 158.8, 162.3; IR
(film): 3067, 2971, 2930, 1688, 1597 cmꢀ1; HRMS (ESI) m/z Calculated for
C20H21N2O [M+H]+ 305.1648, found: 305.1648.
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4-(bis(4-methoxyphenyl)methylene)-2,5-diphenyl-2,4-dihydro-3H-pyrazol-3-one
(2w)
o
1
a purple solid (56 mg, 41% yield, mp: 203ꢀ204 C); H NMR (400 MHz, CDCl3) δ
3.69 (s, 3H), 3.90 (s, 3H), 6.51 (d, 2H, J=8.5 Hz), 6.96ꢀ6.99 (m, 4H), 7.02ꢀ7.08 (m,
3H), 7.15ꢀ7.17 (m, 3H), 7.35ꢀ7.40 (m, 2H), 7.51 (d, 2H, J=8.7 Hz), 8.06 (d, 2H, J=7.8
Hz); 13C NMR (100 MHz, CDCl3) δ 55.3, 55.4, 113.1, 113.4, 119.2, 120.5, 124.2,
124.5, 127.6, 127.7, 127.9, 128.6, 129.8, 131.8, 132.8, 135.1, 135.4, 138.8, 152.6,
162.4, 163.4, 165.7; IR (film): 3061, 2931, 1680, 1597 cmꢀ1; HRMS (ESI) m/z
Calculated for C30H25N2O3 [M+H]+ 461.1860, found: 461.1863.
(Z)-4-(4-methoxybenzylidene)-2-phenyl-5-(p-tolyl)-2,4-dihydro-3H-pyrazol-3-one
(2x)
a red solid (56 mg, 51% yield, mp: 178ꢀ179 oC); 1H NMR (500 MHz, CDCl3) δ 2.45
(s, 3H), 3.87 (s, 3H), 6.97ꢀ7.00 (m, 2H), 7.19ꢀ7.22 (m, 1H), 7.34 (d, 2H, J=8.1 Hz),
7.42ꢀ7.46 (m, 2H), 7.55ꢀ7.57 (m, 3H), 8.07ꢀ8.10 (m, 2H), 8.52ꢀ8.55(dd, 2H, J1=7.1
Hz, J2=1.8 Hz); 13C NMR (125 MHz, CDCl3) δ 21.3, 55.4, 114.1, 119.4, 123.8, 124.8,
126.4, 128.2, 128.6, 128.8, 129.5, 136.8, 138.6, 139.7, 149.6, 153.2, 162.4, 163.8; IR
(film): 3084, 2847, 1687, 1584 cmꢀ1; HRMS (ESI) m/z Calculated for C24H21N2O2
[M+H]+ 369.1598, found: 369.1601.
2,5-diphenyl-2,4-dihydro-3H-pyrazol-3-one (6a)
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a white solid (49.7 mg, 70% yield, mp: 88ꢀ90 °C); H NMR (500 MHz, CDCl3) δ
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6
7
3.79 (s, 2H), 7.20ꢀ7.24 (m, 1H), 7.40ꢀ7.47 (m, 5H,), 7.74ꢀ7.77 (m, 2H), 7.96ꢀ7.99 (m,
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9
13
2H), C NMR (125 MHz, CDCl3) δ 39.6, 119.0, 125.3, 125.9, 128.8, 128.9, 130.7,
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130.8, 138.1, 154.6, 170.2. IR (film): 2965, 1705, 1593 cmꢀ1. HRMS (ESI) m/z
Calculated for C15H13N2O [M+H]+ 237.1022, found: 237.1026.
Supporting Information.
1H and13C NMR spectra of all products and crystallographic data (CIF) of 2d and the
HPLC experiment. This material is available free of charge via the Internet at
http://pubs.acs.org.
Corresponding Author.
*Eꢀmail: zpzhan@xmu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the National Natural Science Foundation of China (No.
21272190) NFFTBS (No. J1310024), and PCSIRT in University is gratefully
acknowledged.
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