Novel Vilsmeier-type methylenation for synthesis of dipyrazolylmethane derivatives using formamide or N-methylformamide

Article abstract of DOI:10.1016/j.tet.2011.03.089

A novel Vilsmeier-type methylenation for synthesis of dipyrazolylmethanes was developed by reacting pyrazolones with formamide or N-methylformamide in the presence of phosphorous oxychloride POCl₃ coupling agent. This method can efficiently provide a series of dipyrazolylmethane derivatives as the main products in excellent yields without the formylated products. Our experimental result was different with the classical Vilsmeier-type reaction.

Full text of DOI:10.1016/j.tet.2011.03.089

Tetrahedron 67 (2011) 3863e3867
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Tetrahedron
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Novel Vilsmeier-type methylenation for synthesis of dipyrazolylmethane
derivatives using formamide or N-methylformamide
*
Fung Fuh Wong , Yu-Ying Huang
Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel Vilsmeier-type methylenation for synthesis of dipyrazolylmethanes was developed by reacting
pyrazolones with formamide or N-methylformamide in the presence of phosphorous oxychloride POCl3
coupling agent. This method can efficiently provide a series of dipyrazolylmethane derivatives as the
main products in excellent yields without the formylated products. Our experimental result was different
with the classical Vilsmeier-type reaction.
Received 27 December 2010
Received in revised form 23 March 2011
Accepted 25 March 2011
Available online 31 March 2011
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Keywords:
Vilsmeier-type reaction
Methylenation
Dipyrazolylmethane
Pyrazolone
Formylation
1. Introduction
O
O
P
Cl
Cl
H
R3
R3
C
N
+
Cl
Cl
H
N
R4
In 1927, the Vilsmeier or VilsmeiereHaack reaction was first
published and applied to an immense variety of substrates, from
substituted benzenes to complex heterocycles.1,2 The classical
Vilsmeier reagent, involves electrophilic substitution of an acti-
vated aromatic ring with a halomethyleniminium salt, which re-
sults from the reaction between an acid chloride (e.g., POCl3, SOCl2
(COCl)2, and COCl2) and an amide, usually DMF (see Scheme 1).
When DMF was used in the reaction, the product of Vilsmeier re-
action is an aldehyde. Thus, Vilsmeier reaction is often called as
Vilsmeier formylation.3
R4
1. Reactive Specie
Scheme 1.
reaction solvent, which are important key functional14 or bioactive
materials.15
2. Result and discussion
Vilsmeier reagent serves not only as a formylating agent,3 but
also as an activating reagent for carboxylic acids to give esters,4
amides5 and acid chlorides,6 and for alcohols to give alkyl chlo-
rides,7 esters,8 alkyl aryl sulfides,9 and imides.10 Since, it is now
used as a powerful organic synthetic tool for the formylation1e3 or
construction11,12 of many aromatic and heterocyclic compounds.
Herein, we have a lot of interests in the study of reactive ability of
various amides.13 Thus, we attempted to investigate the reactivity
of pyrazolones with various amides including formamide,
N-methylformamide, N,N-dimethylformamide (DMF), and N,N-
diethylformamide (DEF). Eventually, we have successfully provided
the new Vilsmeier-type methylenation to prepare dipyrazolyl-
methane derivatives by using formamide or N-methylformamide as
5-Pyrazolone derivatives were prepared as the starting mate-
rials by following the previous literature reported procedure via
tandem condensation and thermal cyclization.16 In this newly de-
veloped method, we chose 1,3-diphenyl-1H-pyrazol-5-one (2) as
the model for the selection of best conditions for the new Vils-
meier-type methylenation reaction (see Scheme 1). To search for
optimum conditions and establish
a reproducible procedure,
compound 2 was allowed to react with formamide (3.0 equiv) and
phosphorous oxychloride (POCl3, 5.0 equiv) in CH2Cl2 solution at
reflux (w50e60 ꢀC) within 0.5e1 h. After aqueous worked-up and
purification by column chromatography on silica gel, we isolated
the corresponding methylenated product 3 in 96% yield without
the formylated product 4 (see Scheme 2).
To examine the solvent effects, we applied the same condition
to 1,3-diphenyl-1H-pyrazol-5-one 2a and various amides con-
taining N-methylformamide N,N-dimethylformamide (DMF), and
* Corresponding author. Tel.: þ886 4 2205 3366x5603; fax: þ886 4 2207 8083;
e-mail addresses: wongfungfuh@yahoo.com.tw, ffwong@mail.cmu.edu.tw(F.F.Wong).
0040-4020/$ e see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.089

3864
F.F. Wong, Y.-Y. Huang / Tetrahedron 67 (2011) 3863e3867
OH
OH
O
O
O
HCONH2, POCl3
N
N
Ph
Ph
N
Ph
N
N
Ph N
H
CH2Cl2, at reflux
N
N
Ph
Ph
Ph Ph
3a
2a
4
Scheme 2.
N,N-diethylformamide (DEF) in the presence of POCl3. Based on the
experimental result, up to 86% yields of the formylated product 4
have been achieved when the pyrazolone 2a was reacted with DMF
and DEF (see entries 3 and 4 of Table 1). When pyrazolone 2a was
usedtoward N-methylformamidewithin 0.5e1.0h, wealsofoundthe
methylenated product 3a was obtained in 71% yield without the
formylated product. Otherwise, the starting material 2a was re-
covered in same condition (see entry 2 in Table 1).
N,N-dimethylformamide (DMF) and N,N-diethylformamide (DEF)
as the reactants, the Vilsmeier formylation was very smooth to
generate the corresponding formylated product 10.
When formamide and N-methylformamide, were used in this
procedure, the imidination intermediate 9 was effectively trans-
ferred to the more stable aminomethylidene derivatives 11
according to the formation of the intramolecular hydrogen-bond-
ing. Consequently, the Michel addition of intermediate 11 with
another equivalent of pyrazole 6 leads to dipyrazolyl-amino-
methane 11. After the protonation and hydrolysis two reactions
were completed, the final product 13 was usefully obtained in ex-
cellent yield (see Scheme 3).
Table 1
The amide agents study of new Vilsmeier methylenation via 1,3-diphenyl-1H-pyr-
azol-5-one (2a)
Entry HCONR3R4 Products
For the further investigation of the reliable procedure of the new
developed Vilsmeier-type methylenation, we also extended the
pyrazolone scopes to 3-phenyl-pyrazolones 2bei bearing N1-
substituted aryl group with various mono-substituents, including
o-, m-, p-ClPh, o-, m-, p-MePh, p-BrPh, and p-OMePh with form-
amide. When employing the condition was shown in Scheme 4, all
of substrates can be successfully converted to the corresponding
methylenation dipyrazolylmethane products 3bei in ꢁ84% yields
(see Table 2). 1-(2,4-Dinitrophenyl)-3-phenyl-1Hpyrazol-5-one (2j)
own two strong withdrawing NO2 groups in N1-aromatic ring, the
corresponding dipyrazolylmethanes 3j did not detected in the same
condition. 1-(2,4,6-Trichlorophenyl)-3-phenyl-1H-pyrazol-5-one
(2k) having three chloro-substituents was also reacted with
HCONH2 and produced the corresponding dipyrazolylmethanes 3k
in 87% yield (see Table 2). The dipyrazolylmethanes 3aek were
reported and fully characterized by spectroscopic methods.14aed For
R3
R4
Dipyrazoylmethanes Yields 4-Formylpyrazolones Yields
(%)
(%)
1
2
3
4
H
H
H
Me
Et
3a
3a
d
d
96
d
d
4
da
da
86
Me
Me
Et
71
db
db
4
89
a
The formulated product was not detectable.
The methylenated product was not detectable.
b
Furthermore, we propose the plausible mechanism shown in
Schemes 1 and 3, and accounts for the difference between the
classical Vilsmeier formylation and the newly developed Vilsmeier
methylenation. Firstly, amide agents were fast reacted with phos-
phorous oxychloride POCl3 to form the reactive hal-
omethyleniminium salts 1 in situ and side product HCl (see Scheme
1).17 In the presence of acidic species including excess amount of
POCl3 and HCl, pyrazolones 5 performed isomerization to convert
to pyrazoles 6. Further, pyrazoles 6 was reacted with the reactive
iminium species 1 to generate the imidination intermediate 8
example, compound 2a presented a peak at
in 1H NMR. In 13C NMR spectrum, compound 2a possessed char-
acterization absorptions at 109.5 ppm for methylene carbon
13CH]C. The IR absorptions of 2a showed peaks at 2109 cmꢂ1 for
d
8.51 ppm for eC1H]C
d
e
and
9
through the reactive species 7 (see Scheme 3). For
R3
R4
O
O
O
N
NR3R4 = NMe2
, NEt2
Vilsmeier type
reaction
R1
N
R1
N
H
H
..
N
N
R4
R2
10
R2
H
R3
O
N
8
R1
N
N
Cl
R2
H
R
R
O
O
N
N
NR3R4 = NH2
, NHMe
7
Hydrid shift
R = H , Me
R1
N
R1
N
H
H
N
N
R2
R2
11 (more stable
9
intermediate)
+
OH
OH
N R1
OH
O
OH
NHR
1. Protonation
2. Hydrolysis
N R1
N
R1
N
R1
N
R1
N
N
N
N
N
R2 R2
R2 R2
12
R2
13
6
Scheme 3.

F.F. Wong, Y.-Y. Huang / Tetrahedron 67 (2011) 3863e3867
3865
OH
OH
N R1
O
OH
POCl3, HCONH2
R1
N
R1
N
R1
N
CH2Cl2, at reflux, 0.5-1 h
N
N
N
N
R2 R2
R2
2a-2o
R2
R1 = Ph, o-, m-, p-MePh, o-, m-, p-ClPh, p-BrPh,
p-OMePh, 2,4,di-NO2Ph, 2,4,6,tri-ClPh
R2 = Me, CF3, i-Pr, n-Pr, Ph
3a-3o
Scheme 4.
Table 2
The result of synthesis of dipyrazolylmethanes 3aeo
and POCl3 coupling agent. Based on our experimental data, the
result was different with the classical Vilsmeier-type reaction and
the yielding dipyrazolylmethane products without formylated
compounds seemed to determinate the solvents involved form-
amide and N-methylformamide.
Pyrazolones
Substrates
Dipyrazoylmethanes
N1-R1
C3-R2
Products
Yields (%)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
CF3
n-Pr
i-Pr
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
96
90
92
94
94
96
95
93
o-MePh
o-ClPh
m-MePh
m-ClPh
p-MePh
p-ClPh
p-BrPh
p-OMePh
2,4-Di-NO2Ph
2,4,6-Tri-ClPh
Ph
3. Experimental section
3.1. General procedure
All chemicals were reagent grade and used as purchased. All
reactions were carried out under nitrogen atmosphere and moni-
tored by TLC analysis. Flash column chromatography was carried
out on silica gel (230e400 mesh). Commercially available reagents
were used without further purification unless otherwise noted.
Dichloromethane, ethyl acetate, hexanes, and methanol were pur-
chased from Mallinckrodt Chemical Co. The following compounds
were purchased from Acros Chemical Co: ethyl butyrylacetate,
ethyl acetoacetate, 2,4-dinitrophenyl hydrazine, formamide, phe-
nylhydrazine, o-tolylhydrazine hydrochloride, m-tolylhydrazine
hydrochloride, and p-tolylhydrazine hydrochloride. 2,4,6-Tri-
chlorophenyl hydrazine was purchased from TCI Chemical Co.
4-Bromophenylhydrazine hydrochloride, 2-chlorophenylhydrazine
hydrochloride, 3-chlorophenylhydrazine hydrochloride, 4-chlor-
ophenylhydrazine hydrochloride, ethyl benzoylacetate, ethyl
isobutyrylacetate, ethyl trifluoroacetoacetate, and 4-methox-
yphenylhydrazine hydrochloride were purchased from Alfa
Chemical Co. Phosphorylchloride was purchased from FERAK
Chemical Co. Purification by gravity column chromatography was
carried out by use of Merck Reagents Silica Gel 60 (particle size
0.063e0.200 mm, 70e230 mesh ASTM). Infrared (IR) spectra were
measured on a Bomem Michelson Series FT-IR spectrometer. The
wavenumbers reported are referenced to the polystyrene
1601 cmꢂ1 absorption. Absorption intensities are recorded by the
following abbreviations: s, strong; m, medium; w, weak. Proton
NMR spectra were obtained on a Bruker (200 or 400 MHz) spec-
trometer by use of CDCl3 as solvent. Carbon-13 NMR spectra were
obtained on a Bruker (50 or 100 MHz) spectrometer by use of CDCl3
as solvent. Carbon-13 chemical shifts are referenced to the center of
84
Not detectable
87
93
90
92
91
Ph
Ph
Ph
stretching of the eCH]C group and at 3291 cmꢂ1 for stretching of
the eOH group.
For the further investigation of the substituent effects, we ex-
tended this newly developed method toward 1-phenyl-3-
substituted pyrazolones 2leo, which contained Me, CF3, n-Pr, or
i-Pr groups at the C-3 position on pyrazolic ring. The corresponding
dipyrazolylmethane products 3leo were obtained in 90e93% yields
(see Table 2). Therefore, this efficient Vilsmeier-type methylenation
method can also be successfully applied to synthesize a series of
dipyrazolylmethane derivatives 3aeo.
To search for the optimum condition for N-methylformamide as
reaction solvent, we used 1,3-diphenyl-1H-pyrazol-5-one 2a as mold
and tried to prolong the reaction time from 1.0 h to 2.0 h. Fortunately,
theisolatedyieldofdesiredproduct3awaspromotedfrom71%to95%
(see Scheme 4 and Table 3). As a result, the optimum condition was
extended 1,3-disubstituted-1H-pyrazol-5-ones 2b, c, h, l, and o with
N-methylformamide. The desired dipyrazolylmethane products 3b, c,
h, l, and o were also obtained in good to excellent yields (82e94%, see
Table 3). However, the formylated compounds were also not detect-
able using N-methylformamide as the reaction solvent.
In conclusion, we have successfully developed the newly Vils-
meier-type methylenation method by treating various 1,3-di-
substituted pyrazolones with formamide or N-methylformamide
the CDCl3 triplet (d 77.0 ppm). Multiplicities are recorded by the
following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; J, coupling constant (Hz). Elemental analyses were
carried out on a Heraeus CHNeO RAPID element analyzer.
Table 3
The results of the pyrazolones reacted with N-methylformamide in the presence of
POCl3
3.2. Standard procedure for the synthesis of
dipyrazolylmethane derivatives (3aei and 3keo)
Pyrazolones (2aec, h, l, and o)
Reaction time (h) Dipyrazoylmethanes
S.M.
N1-R1
C3-R2
No.
Yields (%)
2a
2a
2b
2c
2h
2l
Ph
Ph
o-MePh
p-OMePh
p-BrPh
Ph
Ph
Ph
Ph
Ph
Ph
Me
i-Pr
w1.0
2.0
2.0
2.0
2.0
3a
3a
3b
3c
3h
3l
71
95
90
82
91
94
91
The reliable procedure involved the treatment of pyrazolones
(3aei and 3keo, 1.0 equiv) with catalytic amount of POCl3
(w3 equiv) in formamide solution (2 mL) at 50e60 ꢀC within
0.5e1 h. When the reaction was completed, the reaction mixture
was concentrated, added to saturate sodium bicarbonate (15 mL),
and extracted with dichloromethane (15 mL). The organic extracts
2.0
2.0
2o
Ph
3o

3866
F.F. Wong, Y.-Y. Huang / Tetrahedron 67 (2011) 3863e3867
were dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue solution was purified by column chroma-
tography on silica gel to give the corresponding dipyrazolyl-
methane products (3aei and 3keo) in 82e96% yields.
NMR (CD3OD, 200 MHz)
d
7.40 (m, 2H, ArH), 7.48 (m, 2H, ArH), 7.78
120.0,
(m, 2H, ArH), 7.99 (m, 2H, ArH); 13C NMR (50 MHz, CD3OD)
d
126.0, 128.9, 129.0, 130.4, 130.7, 130.9, 154.9, 170.1; IR (KBr) 3293
(m), 3124 (s), 1880 (m), 1537 (s, CeN), 1472 (m), 1305 (m), 1147 (m),
982 (m), 807 (m) cmꢂ1. Anal. Calcd for C31H20Cl2N4O2: C, 67.52; H,
3.66; N, 10.16. Found: C, 67.56; H, 3.62; N, 10.15.
3.2.1. 4,40-Methylidenebis(1,3-diphenyl-2-pyrazolone)
(recrystallized from ethanol) 261.2e262.2 ꢀC; 1H NMR (CDCl3,
200 MHz) 7.24 (t, 1H, J＝7.6 Hz, ArH), 7.44e7.53 (m, 5H, ArH),
7.82e7.86 (m, 2H, ArH), 8.01 (d, 2H, J＝7.6 Hz, ArH); 13C NMR
(50MHz, CDCl3)
(3a). Mp
d
3.2.8. 4,40-Methylidenebis[1-(40-bromophenyl)-3-phenyl-2-pyr-
azolone] (3h). Mp (recrystallized from ethanol) 183e184 ꢀC; 1H
d
39.7,108,119.1 (2ꢃ CH),109.5,125.3,126.0(2ꢃ CH),
NMR (CD3OD, 200 MHz)
d
7.38 (m, 2H, ArH), 7.50 (m, 2H, ArH), 7.81
120.0,
128.9 (2ꢃ CH),130.7,130.9 (2ꢃ CH),134.8,138.1,154.6,170.2; IR (KBr)
3067 (m),1715 (s, C]O),1601 (s, CeN),1496 (m),1383 (m),1326 (m),
1172 (m), 1116 (m), 899 (m) cmꢂ1. Anal. Calcd for C31H22N4O2: C,
77.16; H, 4.60; N, 11.61. Found: C, 77.13; H, 4.62; N, 11.59.
(m, 2H, ArH), 7.99 (m, 2H, ArH); 13C NMR (50 MHz, CD3OD)
d
126.0, 128.9, 129.0, 130.4, 130.7, 130.9, 154.9, 170.1; IR (KBr) 3293
(m), 3124 (s), 1880 (m), 1537 (s, CeN), 1472 (m), 1305 (m), 1147 (m),
982 (m), 807 (m) cmꢂ1. Anal. Calcd for C31H20Br2N4O2: C, 55.15; H,
3.15; N, 8.75. Found: C, 55.17; H, 3.19; N, 8.72.
3.2.2. 4,40-Methylidenebis[1-(20-methylphenyl)-3-phenyl-2-pyr-
azolone] (3b). Mp (recrystallized from ethanol) 205.3e206.3 ꢀC; 1H
3.2.9. 4,40-Methylidenebis[1-(40-methoxylphenyl)-3-phenyl-2-pyr-
NMR (CD3OD, 200 MHz)
ArH), 7.54e7.59 (m, 5H, ArH), 7.82 (d, 2H, J＝7.2 Hz, ArH); 13C NMR
(50 MHz, CD3OD)
d
2.27 (s, 3H, CH3), 7.51 (d, 2H, J＝7.2 Hz,
azolone] (3i). Mp (recrystallized from ethanol) 128e130 ꢀC; 1H
NMR (CDCl3, 200 MHz)
ArH), 7.40e7.44 (m, 3H, ArH), 7.73 (d, 2H, J＝7.2 Hz, ArH), 7.81 (d, 2H,
J＝6.8 Hz, ArH); 13C NMR (50 MHz, CDCl3)
121.0 (2ꢃ CH),125.9 (2ꢃ CH),128.9 (2ꢃ CH),130.6,130.9,131.5,154.5,
157.2, 170.0; IR (KBr) 2927 (m), 1709 (s, C]O), 1512 (s, CeN), 1500
(m),1248 (m),1030 (m), 832 (m) cmꢂ1. Anal. Calcd for C33H26N4O4: C,
73.05; H, 4.83; N, 10.33. Found: C, 73.07; H, 4.85; N, 10.31.
d 3.79 (s, 3H, CH3), 6.90 (d, 2H, J＝6.8 Hz,
d
15.9, 126.3 (2ꢃ CH), 126.6, 127.2, 128.0, 128.5,
129.2 (2ꢃ CH), 131.1, 131.2, 131.5, 131.7, 136.7, 149.6, 157.4; IR (KBr)
3293 (m), 3124 (s),1880 (m),1537 (s, CeN),1472 (m), 1305 (m),1147
(m), 982 (m), 807 (m) cmꢂ1. Anal. Calcd for C33H26N4O2: C, 77.63; H,
5.13; N, 10.97. Found: C, 77.67; H, 5.15; N, 10.96.
d
39.5, 55.5,114.0 (2ꢃ CH),
3.2.3. 4,40-Methylidenebis[1-(20-chlorophenyl)-3-phenyl-2-pyr-
azolone] (3c). Mp (recrystallized from ethanol) 198e199 ꢀC; 1H
3.2.10. 4,40-Methylidenebis[1-(20-40-60-trichorophenyl)-3-phenyl-2-
NMR (CD3OD, 200 MHz)
5H, ArH), 7.82 (d, 2H, J＝7.2 Hz, ArH); 13C NMR (50 MHz, CD3OD)
126.3 (2ꢃ CH),126.6,127.2,128.0,128.5,129.2 (2ꢃ CH),131.1,131.2,
131.5, 131.7, 136.7,149.6,157.4; IR (KBr) 3293 (m), 3124 (s), 1880 (m),
1537 (s, CeN), 1472 (m), 1305 (m), 1147 (m), 982 (m), 807 (m) cmꢂ1
d
7.51 (d, 2H, J＝7.2 Hz, ArH), 7.54e7.59 (m,
pyrazolone] (3k). Mp (recrystallized from ethanol) 144e146 ꢀC; 1H
NMR (CD3OD, 200 MHz)
d
7.34e7.43 (m, 3H, ArH), 7.68e7.72 (m, 4H,
47.1,125.4 (2ꢃ CH),128.4 (2ꢃ CH),
d
ArH); 13C NMR (50 MHz, CD3OD)
d
128.6 (2ꢃ CH),129.1 (2ꢃ CH),130.6,132.1,136.4,152.8,156.9,171.0; IR
(KBr) 3075 (m),1732 (s, C]O),1559 (s, CeN),1461 (s),1380 (m),1157
(m),1097 (m), 983 (m), 829 (m) cmꢂ1. Anal. Calcd for C31H16Cl6N4O2:
C, 54.02; H, 2.34; N, 8.13. Found: C, 54.03; H, 2.36; N, 8.11.
.
Anal. Calcd for C31H20Cl2N4O2: C, 67.52; H, 3.66; N, 10.16. Found: C,
67.49; H, 3.68; N, 10.13.
3.2.4. 4,40-Methylidenebis[1-(30-methylphenyl)-3-phenyl-2-pyr-
3.2.11. 4,40-Methylidenebis(3-methyl-1-phenyl-2-pyrazolone)
azolone] (3d). Mp (recrystallized from ethanol) 190e192 ꢀC; 1H
(3l). Mp (recrystallized from ethanol) 127e129 ꢀC; 1H NMR (CDCl3,
NMR (CD3OD, 200 MHz)
ArH), 7.54e7.59 (m, 5H, ArH), 7.82 (d, 2H, J＝7.2 Hz, ArH); 13C NMR
(50 MHz, CD3OD)
129.2 (2ꢃ CH), 131.1, 131.2, 131.5, 131.7, 136.7, 149.6, 157.4; IR (KBr)
3293 (m), 3124 (s),1880 (m),1537 (s, CeN),1472 (m), 1305 (m),1147
(m), 982 (m), 807 (m) cmꢂ1. Anal. Calcd for C33H26N4O2: C, 77.63; H,
5.13; N, 10.97. Found: C, 77.61; H, 5.09; N, 10.95.
d
2.27 (s, 3H, CH3), 7.51 (d, 2H, J＝7.2 Hz,
200 MHz)
2H, J＝7.8, 2.2 Hz, ArH), 7.81 (d, 2H, J＝7.8 Hz, ArH); 13C NMR
(50 MHz, CDCl3)
137.9, 156.4, 170.6; IR (KBr) 3101 (s), 2802 (m), 1622 (s, C]O), 1584
(s, CeN), 1494 (m), 1412 (m), 1301 (s), 1220 (m), 1035 (m), 967
(m) cmꢂ1. Anal. Calcd for C21H18N4O2: C, 70.38; H, 5.06; N, 8.93.
Found: C, 70.41; H, 5.09; N, 8.96.
d 2.15 (s, 3H, CH3), 7.14 (d, 1H, J＝2.2 Hz, ArH), 7.36 (dd,
d
15.9, 126.3 (2ꢃ CH), 126.6, 127.2, 128.0, 128.5,
d
17.0, 43.1118.9 (2ꢃ CH), 125.1, 128.8 (2ꢃ CH),
3.2.5. 4,40-Methylidenebis[1-(30-chlorophenyl)-3-phenyl-2-pyr-
3.2.12. 4,40-Methylidenebis(1-phenyl-3-trifluoromethyl-2-pyr-
azolone) (3m). Mp (recrystallized from ethanol) 194e196 ꢀC; 1H
azolone] (3e). Mp (recrystallized from ethanol) 190e192 ꢀC; 1H
NMR (CD3OD, 200 MHz)
5H, ArH), 7.82 (d, 2H, J＝7.2 Hz, ArH); 13C NMR (50 MHz, CD3OD)
26.3 (2ꢃ CH), 126.6, 127.2, 128.0, 128.5, 129.2 (2ꢃ CH), 131.1, 131.2,
131.5, 131.7, 136.7,149.6,157.4; IR (KBr) 3293 (m), 3124 (s), 1880 (m),
1537 (s, CeN), 1472 (m), 1305 (m), 1147 (m), 982 (m), 807 (m) cmꢂ1
d
7.51 (d, 2H, J＝7.2 Hz, ArH), 7.54e7.59 (m,
NMR (CDCl3, 200 MHz)
ArH), 7.80 (d, 2H, J＝7.6 Hz, ArH); 13C NMR (50 MHz, DMSO-d6)
85.6, 122.3, 127.2, 129.1, 137.7, 140.4 (q, J＝37.6 Hz), 153.7. Anal.
Calcd for C21H12F6N4O2: C, 54.09; H, 2.59; N, 12.01. Found: C, 54.12;
H, 2.57; N, 12.59.
d 6.61 (s, 1H, ArH), 7.66 (d, 2H, J＝7.8 Hz,
d
d
.
Anal. Calcd for C31H20Cl2N4O2: C, 67.52; H, 3.66; N, 10.16. Found: C,
67.54; H, 3.65; N, 10.18.
3.2.13. 4,40-Methylidenebis(3-n-propyl-1-phenyl-2-pyrazolone)
(3n). Mp (recrystallized from ethanol) 201e202 ꢀC; 1H NMR
3.2.6. 4,40-Methylidenebis[1-(40-methylphenyl)-3-phenyl-2-pyr-
(CDCl3, 200 MHz) d 1.28 (d, J＝7 Hz, 6H), 2.79 (m, 1H), 7.21 (t,
azolone] (3f). Mp (recrystallized from ethanol) 151e152 ꢀC; 1H NMR
J¼7.4 Hz, 1H), 7.41 (dd, J¼7.4, 8 Hz, 2H), 7.92 (d, J¼8 Hz, 2H); 13C
(CD3OD, 200 MHz)
ArH), 7.78 (m, 2H, ArH), 7.99 (m, 2H, ArH); 13C NMR (50 MHz, CD3OD)
39.6, 120.0, 126.0, 128.9, 129.0, 130.4, 130.7, 130.9, 154.9, 170.1; IR
d
2.27 (s, 3H, CH3), 7.40 (m, 2H, ArH), 7.48 (m, 2H,
NMR (50 MHz, CDCl3) d 20.5, 31.2, 40.3, 119.3, 125.4, 129.2, 138.7,
164.7, 171.1; IR (KBr) 3101 (s), 2802 (m), 1622 (s, C]O), 1584 (s,
CeN), 1494 (m), 1412 (m), 1301 (s), 1220 (m), 1035 (m), 967
(m) cmꢂ1. Anal. Calcd for C25H26N4O2: C, 72.44; H, 6.32; N, 13.52.
Found: C, 72.47; H, 6.36; N, 13.49.
d
(KBr) 3293 (m), 3124 (s),1880 (m),1537 (s, CeN),1472 (m),1305 (m),
1147 (m), 982 (m), 807 (m) cmꢂ1. Anal. Calcd for C33H26N4O2: C,
77.63; H, 5.13; N, 10.97. Found: C, 77.62; H, 5.16; N, 10.94.
3.2.14. 4,40-Methylidenebis(3-isopropyl-1-phenyl-2-pyrazolone)
3.2.7. 4,40-Methylidenebis[1-(40-chlorophenyl)-3-phenyl-2-pyr-
(3o). Mp (recrystallized from ethanol) 101e103 ꢀC; 1H NMR (CDCl3,
azolone] (3g). Mp (recrystallized from ethanol) 163e164 ꢀC; 1H
200 MHz) d 1.21 (d, 6H, J＝7.4 Hz, CH(CH3)2), 2.68e2.82 (m, 1H,

F.F. Wong, Y.-Y. Huang / Tetrahedron 67 (2011) 3863e3867
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3867
CHMe2), 7.14 (t, 1H, J＝7.4 Hz, ArH), 7.35 (dd, 2H, J¼8.1, 7.4 Hz, ArH),
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7.84 (d, 2H, J¼8.1 Hz, ArH); 13C NMR (50 MHz, CDCl3)
d
20.1 (2ꢃ
CH3), 30.7, 39.8, 118.8 (2ꢃ CH), 124.9, 128.8 (2ꢃ CH), 138.2, 164.3,
170.6; IR (KBr) 3101 (s), 2802 (m), 1622 (s, C]O), 1584 (s, CeN),
1494 (m), 1412 (m), 1301 (s), 1220 (m), 1035 (m), 967 (m) cmꢂ1
Anal. Calcd for C25H26N4O2: C, 72.44; H, 6.32; N, 13.52. Found: C,
72.41; H, 6.35; N, 13.53.
.
Acknowledgements
We are grateful to the China Medical University (CMU99-Se18)
and the National Science Council of Republic of China for financial
support (NSC-99-2320-B-039-014-MY3).
12. (a) Sivaprasad, S.; Sridhar, R.; Perumal, P. T. J. Heterocycl. Chem. 2006, 43,
389e394; (b) Kumar, K. H.; Perumal, P. T. Chem. Lett. 2005, 34, 1346e1352; (c)
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Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.03.089.
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