New investigation of Vilsmeier-type reaction using pyrazolones with various amides

Article abstract of DOI:10.1016/j.tetlet.2011.05.055

New investigation of Vilsmeier-type reaction was evaluated to realize the solvent effect by using pyrazolones to react with various of amides, including formamide, N-methylformamide, N-propylformamide, N-tert-butylformamide, N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), N,N-dipropylformamide (DPF), N,N-diisopropylformamide, N,N-dibutylformamide, piperidine-1- carbaldehyde, and pyrrolidine-1-carbaldehyde, in the presence of phosphorous oxychloride POCl₃. The unexpected resulting products were observed in this work according to the difference chemoseletivities of substituted amides. The plausible reactive pathways were proposed to explain the experimental result. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2011.05.055

Tetrahedron Letters 52 (2011) 3786–3792
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New investigation of Vilsmeier-type reaction using pyrazolones
with various amides
Yu-Ying Huang a, Kimiyoshi Kaneko b, Hiroyuki Takayama b, Masayuki Kimura b, Fung Fuh Wong a,
⇑
a Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
b Department of Medico Pharmaceutical Science, Nihon Pharmaceutical University, 10281, Komuro, Inamachi, Kita-Adachigun, Saitama, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 January 2011
Revised 4 May 2011
Accepted 13 May 2011
Available online 19 May 2011
New investigation of Vilsmeier-type reaction was evaluated to realize the solvent effect by using pyraz-
olones to react with various of amides, including formamide, N-methylformamide, N-propylformamide,
N-tert-butylformamide, N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), N,N-dipropylfor-
mamide (DPF), N,N-diisopropylformamide, N,N-dibutylformamide, piperidine-1-carbaldehyde, and pyr-
rolidine-1-carbaldehyde, in the presence of phosphorous oxychloride POCl3. The unexpected resulting
products were observed in this work according to the difference chemoseletivities of substituted amides.
The plausible reactive pathways were proposed to explain the experimental result.
Key words:
Vilsmeier-type reaction
Pyrazolones
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Amides
Formylation
Dipyrazolylmethane
1. Introduction
products resulted from the different reactivity of the substituted
amides serving as the Vilsmeier reagent by reacting with POCl3.
Functionalized N-arylpyrazole moiety has been shown to exhi-
bit antihyperglycemic, analgesic, anti-inflammatory, sedative, and
hypnotic activities.1–3 More specifically, 5-alkyl/arylamino substi-
tuted pyrazoles have been exploited in the design of pharmaceuti-
cals and agrochemical agents exhibiting a range of biological
activities.2,4–6
Vilsmeier-type reaction belongs to electrophilic aromatic sub-
stitution reaction for the formylation9 of activated aromatic sub-
strates and carbonyl compounds by halomethyleniminium salt. It
is a powerful synthetic tool for the construction of many heterocy-
clic compounds.10–12 Formylpyrazoles are prepared by this reac-
tion and attract attention for its being powerful building blocks
for the design of complex pyrazolic assemblies in the agrochemis-
try and biomedical chemistry fields.7,8 Herein, we are greatly inter-
ested in the study of the reactivity of various amides in the
presence of phosphorous oxychloride POCl3 as the reactants13 with
pyrazolones. These amides include formamide, N-methylforma-
mide, N-propylformamide, N-tert-butylformamide, N,N-dimethyl-
We provided the plausible reactive pathways to explain our exper-
imental result.
2. Result and discussion
5-Pyrazolone derivatives were prepared as the substrates
following the reported procedure via tandem condensation and
thermal cyclization.14 In this new investigation, we chose a series
of 1,3-disubstituted-1H-pyrazol-5-ones 1a–1h as the substrates
to react with various amides, including formamide, N-methylfor-
mamide, N-propylformamide, N-tert-butylformamide, N,N-dimeth-
ylformamide
(DMF),
N,N-diethylformamide
(DEF),
N,
N-dipropylformamide (DPF), N,N-diisopropylformamide, N,N-dibu-
tylformamide, piperidine-1-carbaldehyde, and pyrrolidine-1-carb-
aldehyde with POCl3 in CH2Cl2 co-solution. For improving the
previous procedure of the Vilsmeier reaction, we modified the sol-
vent system by using amide/CH2Cl2 co-solvent system (see Scheme
1). Initially, compounds 1a–1f were allowed to react with N,N-
dimethylformamide (DMF) or N,N-diethylformamide (DEF,
3.0 equiv) with POCl3 (5.0 equiv) in CH2Cl2 solution at reflux
(ꢀ50–60 °C) within 0.5–1 h. After aqueous worked-up and purified
by column chromatography on silica gel, we isolated the corre-
sponding formylated product 2a–2f in >87% yields (see Scheme 1
and Table 1). In this modified solvent system (amide/CH2Cl2 = 1:1),
the reaction time was decreased from ꢀ12 h to 0.5–1 h. All of the
4-formylpyrazolone products 2a–2f were fully characterized by
formamide
(DMF),
N,N-diethylformamide
(DEF),
N,
N-dipropylformamide (DPF), N,N-diisopropylformamide, N,N-dibu-
tylformamide, piperidine-1-carbaldehyde, and pyrrolidine-1-carb-
aldehyde. In this Letter, we found the formation of unexpected
⇑
Corresponding author. Tel.: +886 4 2205 3366x5603; fax: +886 4 2207 8083.
E-mail addresses: wongfungfuh@yahoo.com.tw, ffwong@mail.cmu.edu.tw (F.F.
Wong).
0040-4039/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.055

Y.-Y. Huang et al. / Tetrahedron Letters 52 (2011) 3786–3792
3787
O
O
O
H
NR3R4, POCl3, CH2Cl2
NR3R4 = NMe2, NEt2, NPr2, NBu2
R1
N
H
H
N
R2
2
O
NR3R4
R2
O
O
O
H
NR3R4, POCl3, CH2Cl2
R1
N
R1
N
R1
N
N
+
N
N
NR3R4 = N(
i-Pr)2, N
N
R2
R2
,
1
2
3, 4 or 5
O
OH
N R1
OH
H
NR3R4, POCl3, CH2Cl2
NR3R4 = NH2, NHMe, NH(
-Bu)
R1
N
t
N
N
R2 R2
6
Scheme 1.
Table 1
Reaction of the pyrazolones with N,N-dimethylformamide, N,N-diethylformamide,
N,N-dipropylformamide, or N,N-dibutylformamide in the presence of POCl3
Table 2
Reactions of the pyrazolones with N,N-diisopropylformamide, piperidine-1-carbalde-
hyde or pyrrolidine-1-carbaldehyde in the presence of POCl3
Pyrazolones (1a–1f)
Amides HCONR3R4
Products
4-Formylpyrazolones
(2a–2f)
Pyrazolones (1a–1h)
Amides
Products
HCONR3R4
4-
5-
S.M.
N1-R1
C3-R2
NR3R4
No.
Yields (%)
Formylpyrazolones Aminopyrazoles
S.M. N1-R1
C3-R2 –NR3R4
No.
Yields (%)
No. Yields (%)
1a
1b
1c
1d
1e
1f
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Me
i-Pr
Ph
Ph
Ph
Ph
Me
i-Pr
Ph
Ph
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NEt2
NEt2
NEt2
NEt2
NEt2
2a
2b
2c
2d
2e
2f
2a
2b
2c
2d
2e
2f
95
96
93
93
96
94
93
91
87
93
94
91
88
83
o-MePh
p-OMePh
p-BrPh
Ph
Ph
Ph
o-MePh
p-OMePh
p-BrPh
Ph
Ph
Ph
1a
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
N(i-Pr)2
2a
63
62
59
56
51
53
54
51
59
53
49
54
57
58
54
3a
4a
4b
4c
4d
4e
4f
28
33
37
42
46
38
37
32
34
33
39
35
34
31
36
Pyrrolidinyl 2a
Pyrrolidinyl 2b
Pyrrolidinyl 2c
Pyrrolidinyl 2d
Pyrrolidinyl 2e
Pyrrolidinyl 2f
Pyrrolidinyl 2g
Piperidinyl 2a
Piperidinyl 2b
Piperidinyl 2c
Piperidinyl 2d
Piperidinyl 2e
Piperidinyl 2f
Piperidinyl 2g
o-MePh
p-OMePh Ph
p-BrPh
Ph
Ph
Ph
Me
i-Pr
n-Pr
Ph
1g
1a
1b
1c
1d
1e
1f
Ph
Ph
4g
5a
5b
5c
5e
5e
5f
o-MePh
p-OMePh Ph
p-BrPh
Ph
Ph
Ph
NEt2
NPr2
NBu2
1a
1a
2a
2a
Ph
Ph
Me
i-Pr
n-Pr
1g
Ph
5g
spectroscopic methods (see Table 1) and the data were consistence
with the previous literature reported.7,8 Furthermore, we extended
the reaction condition to 1,3-diphenyl-1H-pyrazol-5-one (1a) by
using N,N-dipropylformamide (DPF) and N,N-dibutylformamide
with CH2Cl2 as the reaction solvent. The corresponding 4-form-
ylpyrazolone product 2a was also obtained in excellent yields
(>83%, see Table 1 and Scheme 1).
To investigate the steric effect and ring stress effect in amide
functional groups, the bulky N,N-diisopropylformamide, or flexible
cyclic piperidine-1-carbaldehyde and pyrrolidine-1-carbaldehyde
were selected as the reaction solvents. We carried out the same
reaction condition toward pyrazolones 1a–1d, which owned N1-
substituted phenyl and aryl group, with various mono-substituents
including o-MePh, p-BrPh, and p-OMePh. The 4-formylpyrazolones
2a–2d were obtained as the major products in 63%, 51–62% and
54–59% yields, respectively (see Table 2). Particularly, unexpected
amination15 products 3a, 4a–4d or 5a–5d were observed and iso-
lated in 28%, 32–46% or 31–39% yields, respectively (see Scheme 1
and Table 2). However, we also preformed the above strategy to
pyrazolones 1e–1g bearing C-3 Me, n-Pr, or i-Pr group. The tradi-
tional Vilsmeier formylated products 2e–2g were achieved in 51–
54% and 54–58% yields, respectively. Similarly, the unexpected
amination15 products 4e–4g or 5e–5g were also provided in 32–
38% or 31–36% yields (see Scheme 1 and Table 2).
To examine solvent effect of other amide, we applied the same
condition to 1,3-disubstituted-1H-pyrazol-5-ones 1a–1f with ori-
ginal formamide. Particularly, we did not isolate and detect the
4-formylpyrazolones product 2 in this solvent system. When we
fully identified and characterized the isolated products by spectro-
scopic methods, the dipyrazolylmethane products 6a–6f were
obtained in 84–96% isolated yields under the reaction condition
(see Scheme 1 and Table 3). For example, compound 6a presented
a peak at d 8.51 ppm for –C1H@C in 1H NMR. In 13C NMR spectrum,
compound 6a possessed characterization absorptions at
d
109.5 ppm for methylene carbon –13CH@C. The IR absorptions of
6a showed peaks at 2109 cmꢁ1 for stretching of the –CH@C group
and at 3291 cmꢁ1 for stretching of the –OH group.
For the further investigation of other amide agents, pyrazolones
1a–1f were reacted with N-methylformamide. Fortunately, the
dipyrazolylmethane products 6a–6f were also obtained as the only
corresponding products in 82–95% yields. Whatever, the formylat-
ed compounds 2 were also not detectable in the presence of N-
methylformamide as the reaction solvent (see Scheme 1 and Table
3). When applying N-tert-butylformamide toward 1,3-diphenyl-
1H-pyrazol-5-ones 1a under the same condition, we obtained the

3788
Y.-Y. Huang et al. / Tetrahedron Letters 52 (2011) 3786–3792
Table 3
O
R3
R4
O
P
Cl
Cl
H
Reaction of pyrazolones with formamide, N-methylformamide, or N-tert-butylforma-
mide in the presence of POCl3
R3
+
C N
Cl
Cl
H
N
R4
Pyrazolones (1a–1g)
Amides HCONR3R4
Products
Dipyrazoylmethanes
7. Reactive specie
S.M.
N1-R1
C3-R2
NR3R4
No.
Yields (%)
Scheme 2.
1a
1b
1c
1d
1e
1f
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Me
i-Pr
Ph
Ph
Ph
NH2
NH2
NH2
NH2
NH2
NH2
NHMe
NHMe
NHMe
NHMe
NHMe
NHMe
NH(t-Bu)
6a
6b
6c
6d
6e
6f
6a
6b
6c
6d
6e
6f
96
90
84
93
93
91
95
90
82
91
94
91
47
o-MePh
p-OMePh
p-BrPh
Ph
Ph
Ph
o-MePh
p-OMePh
p-BrPh
Ph
Ph
Ph
butylformamide as reactants, the more stable b-ketoamide inter-
mediate 9 possessed enough the life-time to react with secondary
equivalent of 5-hydroxypyrazole 8 to proceed the Michel addition
and generate dipyrazolyl-aminomethane 12. After the protonation
and hydrolysis reactions were simultaneously performed, the final
dipyrazolylmethane products 6 were usefully obtained in good to
excellent yields under formamide and N-methylformamide two
systems (see Scheme 3 and Table 3). When N-tert-butylformamide
was applied in the same condition, the steric effect of tert-butyl
group on the nitrogen atom is not favoring the hydrogen bonding
formation of b-ketoamide intermediate 9. Since, the corresponding
dipyrazolylmethane product 6 was obtained in the lower yield
(47%, see Table 3).
In conclusion, the different chemosetectivity of Vilsmeier reac-
tion was completely explored by using pyrazolones with variety of
amides, including formamide, N-methylformamide, N-propylfor-
mamide, N-tert-butylformamide, N,N-dimethylformamide (DMF),
N,N-diethylformamide (DEF), N,N-dipropylformamide (DPF), N,N-
diisopropylformamide, N,N-dibutylformamide, piperidine-1-carb-
aldehyde, and pyrrolidine-1-carbaldehyde in the presence of POCl3.
We believed the steric effect of substituted amide play a key role to
control the chemoselctive results. Furthermore, three plausible
pathways were also provided to describe the chemoselective
reactions.
Ph
Me
i-Pr
Ph
1a
6a
corresponding dipyrazolylmethane product 6a in lower yield
(47%). The result indicated that the bulky functional alkyl group
on the nitrogen atom is not in favor for the formation of
dipyrazolylmethane product (see Scheme 3 and Table 3).
Following the experimental result, we tried to realize the reac-
tivity and reaction mechanism on various amide solvent systems.
Since, we propose the plausible reaction mechanism as shown in
Schemes 2 and 3 to account the formation of the different resulting
products. At first, amide agents were treated with phosphorous
oxychloride POCl3 to in situ form the very reactive species Vilsme-
ier reagent halomethyleniminium salts 7 (see Scheme 2).16
In acid catalytic condition, pyrazolones
1 was efficiently
converted to 5-hydroxypyrazole 8. Simultaneously, 5-hydroxy pyr-
azoles 8 was preliminarily reacted with the active iminium species
7 by means of C-enolization (A and C) and O-substitution B in three
probably reaction pathways. In the A reaction pathway, the active
iminium species 7 was generated from various amides including
N,N-dimethylformamide, N,N-diethylformamide, N,N-dipropylfor-
mamide, and N,N-dibutylformamide. 5-Hydroxy pyrazoles 8 was
allowed to react with an active iminium species 7 by following
the normal Vilsmeier reaction to form b-ketoamide intermediate
9. After the hydrolysis was completed, the traditional Vilsmeier
products 2 were obtained.7,8
When N,N-diisopropylformamide, piperidine-1-carbaldehyde,
and pyrrolidine-1-carbaldehyde were used as the reactants to gen-
erate active iminium species 7, the competitive pathway A and B
were provided to describe the resulting data. In the pathway B,
the activated b-ketoamide intermediate 10 was formed by O-sub-
stitution from 5-hydroxypyrazole 8 with active iminium species 7.
The activated intermediate 10 replaced by the chloride anion as a
nucleophile17 to lead to 5-chloropyrazole 11.12j Due to the steric
effect of di-iso-propyl group or large ring-stress effect of piperidi-
nyl and pyrrolidinyl groups between the nitrogen and the carbon
substituent on halomethyleniminium salts, the dissociation of
iminium 7 happened and released the amino anion and CO+ spe-
cies.18,19 After the further amination was performed between 5-
chloropyrazole 11 and amino anion (di-iso-propyl, piperidinyl
and pyrrolidinyl groups), the final 5-aminopyrazole products 3a,
4a–4g and 5a–5g were usefully obtained in 31–46% yields (see
Scheme 3 and Table 2). Consequently, the classical Vilsmeier-type
reaction (Pathway A) was also observed to afford the correspond-
ing products 2a–2g in 49–62% yields as the major products.
For formamide, N-methylformamide, and N-tert-butylforma-
mide solvent systems, the pathway C was used to describe the for-
mation of dipyrazoylmethanes 6. Since the intramolecular
hydrogen-bonding was sequentially formed on b-ketoamide inter-
mediate 9 by using formamide N-methylformamide, and N-tert-
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 (230–400 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 Acoros Chemical Co: ethyl Butyrylacetate,
2,4-dinitrophenyl hydrazine, formamide, N,N-diethylformamide,
ethyl acetoacetate, N-formylpiperidine, N-methylformamide,
phenylhydrazine, o-tolylhydrazine hydrochloride, m-tolylhydr-
azine hydrochloride, p-tolylhydrazine hydrochloride. N-Formyl-
pyrrolidine was purchased from Aldaich Chemical Co. N,N-
Diethylformamide was purchased from Scharlau Chemical Co.
2,4,6-Trichlorophenyl hydrazine was purchased from TCI Chemical
Co. 4-Bromophenylhydrazine hydrochloride, 2-chlorophenylhy-
drazine hydrochloride, 3-chlorophenylhydrazine hydrochloride,
4-chlorophenylhydrazine hydrochloride, ethyl benzoylacetate,
ethyl isobutyrylacetate, ethyl trifluoroacetoacetate, 4-methoxy-
phenylhydrazine hydrochloride were purchased from Alfa Chemi-
cal Co. Phosphorylchloride were purchased from FERAK Chemical
Co. Purification by gravity column chromatography was carried
out by use of Merck Reagents Silica Gel 60 (particle size 0.063–
0.200 mm, 70–230 mesh ASTM). Infrared (IR) spectra were mea-
sured on a Bomem Michelson Series FT-IR spectrometer. The wave
numbers reported are referenced to the polystyrene 1601 cmꢁ1
absorption. Absorption intensities are recorded by the following
abbreviations: s, strong; m, medium; w, weak. Proton NMR spectra

Y.-Y. Huang et al. / Tetrahedron Letters 52 (2011) 3786–3792
3789
Path B
O
OH
Cl
R3
R1
N
N
R1
N
N
+
C
N
R4
H
R2
R2
Path A and C
8
1
7
Path A
Path B
NR3R4 = N(
Path C
NR3R4 = NMe2, NEt2
NPr2, NBu2
i
-Pr)2,
NR3R4 = NH2, NHMe
NH( -Bu)
R4 = H, Me, or
-Bu
t
n
t
N
Vilsmeier-type
Reaction
n = 1. 2
R3
H
R4
O
N
N
O
R4
R1
N
H
R3
R2
R1
N
N
R4
O
N
R2
N
10
R1
N
N
R2
Cl
H
OH
9
R1
N
9
N
O C NR3R4
R2
8
OH
4 O
Cl
NHR
N R1
N
R1
N
N
R1
N
N
N
Hydrolysis
R2 R2
R2
11
12
HC O NR3R4
1. Protonation
2. Hydrolysis
NR3R4
O
OH
OH
O
R1
N
N
N R1
N
R1
R1
N
N
H
N
R2
R2 R2
R2
2
3, 4 or 5
Scheme 3.
6
were obtained on a Bruker (200 or 400 MHz) spectrometer 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 the CDCl3
triplet (d 77.0 ppm). Multiplicities are recorded by the following
abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multi-
plet; J, coupling constant (Hz). Elemental analyses were carried out
on a Heraeus CHN–O RAPID element analyzer.
products 3a, 4a–4g and 5a–5g, dipyrazolylmethane products 6a–
6f were obtained.
3.1.1. 1,3-Diphenyl-4-formyl-2-pyrazolin-5-one (2a)
Mp (recrystallized from ethanol) 241–242 °C; 1H NMR (CDCl3,
200 MHz) d 7.13 (t, 1H, J = 7.6 Hz, ArH), 7.37–7.46 (m, 5H, ArH),
7.71–7.75 (m, 2H, ArH), 7.82 (d, 2H, J = 7.6 Hz, ArH), 10.1 (s, 1H,
CHO); 13C NMR (50 MHz, CDCl3) d 116.3, 125.3 (2 ꢂ CH), 128.4
(2 ꢂ CH), 128.8 (2 ꢂ CH), 129.1 (2 ꢂ CH), 129.3 (2 ꢂ CH), 130.7,
133.1, 136.8, 154.1, 183.6; IR (KBr) 3067 (m), 1698 (s, C@O),
1591 (s, C–N), 1482 (m), 1386 (m), 1331 (m), 1179 (m), 1121
(m), 901 (m) cmꢁ1. Anal. Calcd for C16H12N2O2: C, 72.72; H, 4.58;
N, 10.60. Found: C, 72.76; H:4.56; N, 10.62.
Standard procedure for the preparation of 4-formylpyrazolone
products (2a–2g), amination products (3a, 4a–4g and 5a–5g) and
dipyrazolylmethane products (6a–6f).
The reliable procedure involved the treatment of pyrazolones
(1a–1g, 1.0 equiv) with catalytic amount of POCl3 (ꢀ3 equiv) with
various amides (2 mL) including formamide, N-methylformamide,
N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF),
piperidine-1-carbaldehyde, and pyrrolidine-1-carbaldehyde in
CH2Cl2 solution (2 mL) at 50–60 °C within 0.5–1 h. When the reac-
tion was completed, the reaction mixture was concentrated, added
to saturate sodium bicarbonate (15 mL) and extracted with dichlo-
romethane (15 mL). The organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure. The residues
were purified by column chromatography on silica gel to give the
corresponding 4-formylpyrazolone products 2a–2g, amination
3.1.2. 1-(20-Methylphenyl)-3-phenyl-4-formyl-2-pyrazolin-5-
one (2b)
Mp (recrystallized from ethanol) 231–233 °C; 1H NMR (CD3OD,
200 MHz) d 2.31 (s, 3H, CH3), 7.46 (d, 2H, J = 7.2 Hz, ArH), 7.49–7.55
(m, 5H, ArH), 7.73 (d, 2H, J = 7.2 Hz, ArH), 9.92 (s, 1H, CHO); 13C
NMR (50 MHz, CD3OD) d 16.3, 125.9 (2 ꢂ CH), 126.2, 127.2,
128.1, 128.3, 129.1 (2 ꢂ CH), 131.1, 131.2, 131.5, 131.7, 135.9,
136.7, 149.6, 157.4; IR (KBr) 3293 (m), 3124 (s), 1880 (m), 1537
(s, C–N), 1472 (m), 1305 (m), 1147 (m), 982 (m), 807 (m) cmꢁ1
.

3790
Y.-Y. Huang et al. / Tetrahedron Letters 52 (2011) 3786–3792
Anal. Calcd for C17H14N2O2: C, 73.37; H, 5.07; N, 10.07. Found: C,
73.35; H, 5.11; N, 10.09.
126.9 (2 ꢂ CH), 128.1 (2 ꢂ CH), 128.7, 129.6, 133.1, 140.4, 150.7,
162.8; IR (KBr) 3050 (s), 2814 (m), 1558 (s, C–N), 1432 (m), 1409
(m), 1298 (s), 1256 (m), 1183 (m), 975 (m) cmꢁ1. Anal. Calcd for
C19H19N3: C, 78.86; H, 6.62; N, 14.52. Found: C, 78.82; H, 6.65; N,
14.49.
3.1.3. 1-(40-Methoxylphenyl)-3-phenyl-4-formyl-2-pyrazolin-5-
one (2c)
Mp (recrystallized from ethanol) 152–153 °C; 1H NMR (CDCl3,
200 MHz) d 3.81 (s, 3H, CH3), 6.87 (d, 2H, J = 6.8 Hz, ArH), 7.36–
7.40 (m, 3H, ArH), 7.68 (d, 2H, J = 7.2 Hz, ArH), 7.72 (d, 2H,
J = 6.8 Hz, ArH), 10.2 (s, 1H, CHO); 13C NMR (50 MHz, CDCl3) d
38.1, 114.0 (2 ꢂ CH), 121.0 (2 ꢂ CH), 125.9 (2 ꢂ CH), 128.9
(2 ꢂ CH), 129.8, 130.4, 130.7, 131.3, 131.6, 153.5, 156.2, 179.1; IR
(KBr) 2972 (m), 1691 (s, C@O), 1492 (s, C–N), 1497 (m), 1238
(m), 1032 (m), 851 (m) cmꢁ1. Anal. Calcd for C17H14N2O3: C,
69.38; H, 4.79; N, 9.52. Found: C, 69.34; H, 4.83; N, 9.51.
3.1.9. 1-(20-Methylphenyl)-3-phenyl-5-pyrrolidinopyrazole (4b)
Mp (recrystallized from ethanol) 93–94 °C; 1H NMR (CDCl3,
200 MHz) d 2.37 (m, 4H), 3.53 (m, 4H), 2.36 (s, 3H, CH3), 5.97
(s, 1H), 7.46 (d, 2H, J = 7.2 Hz, ArH), 7.51–7.58 (m, 5H, ArH),
7.72 (d, 2H, J = 7.2 Hz, ArH); 13C NMR (50 MHz, CDCl3) d 15.3,
23.8 (2 ꢂ CH), 54.6 (2 ꢂ CH), 89.5, 125.8 (2 ꢂ CH), 126.1, 126.8,
128.5, 129.3 (2 ꢂ CH), 131.2, 131.8, 132.7, 135.6, 136.9, 149.1,
158.3; IR (KBr) 3079 (m), 2984 (s), 1617, 1587 (s, C–N), 1479
(m), 1334 (m), 1130 (m), 988 (m), 815 (m) cmꢁ1. Anal. Calcd
for C20H21N3: C, 79.17; H, 6.98; N, 13.85. Found: C, 79.14; H,
6.95; N, 13.87.
3.1.4. 1-(40-Bromophenyl)-4-formyl-2-pyrazolin-5-one (2d)
Mp (recrystallized from ethanol) 201–203 °C; 1H NMR (CD3OD,
200 MHz) d 7.27 (m, 2H, ArH); 7.46 (m, 2H, ArH); 7.78 (m, 2H,
ArH); 7.93 (m, 2H, ArH); 9.8 (s, 1H, CHO); 13C NMR (50 MHz,
CD3OD) d 119.3, 125.1 (2 ꢂ CH), 128.6 (2 ꢂ CH), 128.9 (2 ꢂ CH);
130.1 (2 ꢂ CH), 130.5, 130.7, 130.9, 154.9, 178.4; IR (KBr) 3133
(m), 3025 (s), 1790 (m), 1483 (s, C–N), 1456 (m), 1307 (m), 1139
(m), 977 (m), 794 (m) cmꢁ1. Anal. Calcd for C16H11BrN2O2: C,
56.00; H, 3.23; N, 8.16. Found: C, 55.98; H, 3.27; N, 8.15.
3.1.10. 1-(40-Methoxylphenyl)-3-phenyl-5-pyrrolidinopyrazole
(4c)
Mp (recrystallized from ethanol) 129–130 °C; 1H NMR (CDCl3,
200 MHz) d 2.42 (m, 4H), 3.61 (m, 4H), 3.79 (s, 3H, CH3), 5.93 (s,
1H), 6.69 (d, 2H, J = 6.8 Hz, ArH), 7.20–7.25 (m, 3H, ArH), 7.43 (d,
2H, J = 7.2 Hz, ArH), 7.48 (d, 2H, J = 6.8 Hz, ArH); 13C NMR
(50 MHz, CDCl3) d 23.2 (2 ꢂ CH), 38.9, 53.9 (2 ꢂ CH), 89.2, 113.9
(2 ꢂ CH), 122.3 (2 ꢂ CH), 126.7 (2 ꢂ CH), 128.2 (2 ꢂ CH), 129.5,
130.1, 131.3, 131.6, 152.5, 161.3; IR (KBr) 3109 (m), 1566 (s, C–
N), 1479 (m), 1251 (m), 1023 (m), 874 (m) cmꢁ1. Anal. Calcd for
3.1.5. 1-Phenyl-3-methyl-4-formyl-2-pyrazolin-5-one (2e)
Mp (recrystallized from ethanol) 175–176 °C; 1H NMR (CDCl3,
200 MHz) d 1.2 (s, 3H, CH3), 7.3–7.9 (m, 6H, Ph), 9.85 (s, 1H,
CHO); 13C NMR (50 MHz, CDCl3) d 17.0, 116.9, 125.5 (2 ꢂ CH),
129.8 (2 ꢂ CH), 133.9, 134.6, 137.1, 155.7, 181.5; IR (KBr) 3152
(s), 2812 (m), 1659 (s, C@O), 1598 (s, C–N), 1463 (m), 1408 (m),
1296 (s), 1230 (m), 1029 (m), 958 (m) cmꢁ1. Anal. Calcd for
C20H21N3O: C, 75.21; H, 6.63; N, 13.16. Found: C, 75.18; H, 6.65;
N, 13.20.
3.1.11. 1-(40-Bromophenyl)-3-phenyl-5-pyrrolidinopyrazole
(4d)
C
11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.32; H, 4.94;
N, 13.86.
Mp (recrystallized from ethanol) 125–126 °C; 1H NMR (CDCl3,
200 MHz) d 2.39 (m, 4H), 3.51 (m, 4H), 5.88 (s, 1H), 7.12 (m, 2H,
ArH); 7.29 (m, 2H, ArH); 7.57 (m, 2H, ArH); 7.76 (m, 2H, ArH);
13C NMR (50 MHz, CD3OD) d 23.7 (2 ꢂ CH), 53.7 (2 ꢂ CH), 89.6,
118.1, 126.2 (2 ꢂ CH), 128.7 (2 ꢂ CH), 129.2 (2 ꢂ CH); 130.5
(2 ꢂ CH), 131.4, 132.3, 154.2, 162.7; IR (KBr) 3172 (m), 3061 (s),
1582 (s, C–N), 1431 (m), 1323 (m), 1221 (m), 961 (m), 798 (m)
cmꢁ1. Anal. Calcd for C19H18BrN3: C, 61.97; H, 4.93; N, 11.41.
Found: C, 61.94; H, 4.89; N, 11.38.
3.1.6. 1-Phenyl-3-isopropyl-4-formyl-2-pyrazolin-5-one (2f)
Mp (recrystallized from ethanol) 149–150 °C; 1H NMR (CDCl3,
200 MHz) d 1.28 (d, 6H, J = 7.4 Hz, CH(CH3)2), 2.59–2.73 (m, 1H,
CHMe2), 7.09 (t, 1H, J = 7.4 Hz, ArH), 7.27 (dd, 2H, J = 8.1, 7.4 Hz,
ArH), 7.65 (d, 2H, J = 8.1 Hz, ArH), 9.92 (s, 1H, CHO); 13C NMR
(50 MHz, CDCl3) d 17.8 (2 ꢂ CH3), 29.5, 35.7, 117.6 (2 ꢂ CH),
121.2, 127.7 (2 ꢂ CH), 138.1, 158.3, 179.7; IR (KBr) 3202 (s),
2799 (m), 1601 (s, C@O), 1581 (s, C–N), 1481 (m), 1423 (m),
1312 (s), 1209 (m), 1036 (m), 956 (m) cmꢁ1. Anal. Calcd for
C
13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.78; H,
3.1.12. 3-Methyl-1-phenyl-5-pyrrolidinopyrazole (4e)
6.11; N, 12.20.
Mp (recrystallized from ethanol) 114–115 °C; 1H NMR (CDCl3,
200 MHz) d 1.19 (s, 3H, CH3), 2.39 (m, 4H), 3.57 (m, 4H), 6.01 (s,
1H), 7.4–7.9 (m, 6H, Ph); 13C NMR (50 MHz, CD3OD) d 19.7, 23.4
(2 ꢂ CH), 53.1 (2 ꢂ CH), 89.6, 114.8, 119.6 (2 ꢂ CH), 123.5
(2 ꢂ CH), 149.5, 162.4; IR (KBr) 3132 (s), 2864 (m), 1501 (s, C–N),
3.1.7. 1,3-Diphenyl-5-di-isopropylaminopyrazole (3a)
Mp (recrystallized from ethanol) 92–93 °C; 1H NMR (CDCl3,
200 MHz) d 1.22–1.24 (m, 12H), 3.54–3.60 (m, 1H), 4.12–4.18 (m,
1H), 6.16 (s, 1H), 7.09–7.12 (m, 1H), 7.33–7.36 (m, 2H), 7.39–
7.52 (m, 4H), 8.01–8.03 (m, 2H), 8.17 (s, H); 13C NMR (50 MHz,
CDCl3) d 20.16 (CH3), 20.96 (CH3), 23.96 (CH3), 29.64 (CH3), 46.51
(CH), 48.28 (CH), 97.92, 120.13, 124.24, 128.28 (3 ꢂ CH), 128.47
(3 ꢂ CH), 128.82, 129.04 (2 ꢂ CH), 139.63, 149.43, 161.54; IR
(KBr) 3048 (s), 2811 (m), 1560 (s, C–N), 1428 (m), 1413 (m),
1309 (s), 1247 (m), 1179 (m), 973 (m) cmꢁ1. Anal. Calcd for
1423 (m), 1410 (m), 1287 (s), 1229 (m), 1017 (m), 951 (m) cmꢁ1
.
Anal. Calcd for C14H17N3: C, 73.98; H, 7.54; N, 18.49. Found: C,
73.95; H, 7.57; N, 18.53.
3.1.13. 3-iso-Propyl-1-phenyl-5-pyrrolidinopyrazole (4f)
Mp (recrystallized from ethanol) 123–124 °C; 1H NMR (CDCl3,
200 MHz) d 1.27 (d, 6H, J = 7.4 Hz, CH(CH3)2), 2.38 (m, 4H), 2.61–
2.75 (m, 1H, CHMe2), 3.52 (m, 4H), 6.31 (s, 1H), 6.98 (t, 1H,
J = 7.4 Hz, ArH), 7.14 (dd, 2H, J = 8.1, 7.4 Hz, ArH), 7.57 (d, 2H,
J = 8.1 Hz, ArH); NMR (50 MHz, CDCl3) d 17.8 (2 ꢂ CH3), 23.4
(2 ꢂ CH), 29.6, 40.6, 53.9 (2 ꢂ CH), 90.1, 118.6 (2 ꢂ CH), 121.7,
126.6 (2 ꢂ CH), 147.2, 162.7; IR (KBr) 3102 (s), 2813 (m), 1581 (s,
C–N), 1471 (m), 1429 (m), 1315 (s), 1199 (m), 1036 (m), 957 (m)
cmꢁ1. Anal. Calcd for C16H21N3: C, 75.26; H, 8.29; N, 16.46. Found:
C, 75.23; H, 8.31; N, 16.50.
C21H25N3: C, 78.96; H, 7.89; N, 13.15. Found: C, 78.93; H, 7.91; N,
13.17.
3.1.8. 1,3-Diphenyl-5-pyrrolidinopyrazole (4a)
Mp (recrystallized from ethanol) 87–88 °C; 1H NMR (CDCl3,
200 MHz) d 2.35 (m, 4H), 3.50 (m, 4H), 5.89 (s, 1H), 7.18–7.25
(m, 2H), 7.35 (t, 2H, J = 7.6 Hz), 7.37(t, 2H, J = 7.6 Hz), 7.71 (d, 2H,
J = 7.4 Hz), 7.82 (d, 2H, J = 7.6 Hz); 13C NMR (50 MHz, CDCl3) d
23.1 (2 ꢂ CH), 53.8 (2 ꢂ CH), 89.3, 122.8 (2 ꢂ CH), 125.2 (2 ꢂ CH),

Y.-Y. Huang et al. / Tetrahedron Letters 52 (2011) 3786–3792
3791
3.1.14. 3-n-Propyl-1-phenyl-5-pyrrolidinopyrazole (4g)
3.1.19. 3-Methyl-1-phenyl-5-N-piperidinopyrazole (5e)
Mp (recrystallized from ethanol) 129–130 °C; 1H NMR (CDCl3,
200 MHz) d 1.06 (t, J = 7.4 Hz, 3H), 1.68–1.76 (m, 2H), 2.36 (m,
4H), 2.50 (t, J = 7.5 Hz, 2H), 3.59 (m, 4H), 5.97 (s, 1H), 7.12 (t,
J = 7.4 Hz, 1H), 7.28 (dd, J = 7.4, 7.7 Hz, 2H), 7.81 (d, J = 7.7 Hz,
2H); 13C NMR (50 MHz, CD3OD) d 14.2, 20.4, 23.9 (2 ꢂ CH), 30.5,
53.1 (2 ꢂ CH), 90.3, 120.3, 125.8, 130.4, 138.5, 156.1, 163.0; IR
(KBr) 3112 (s), 2836 (m), 1541 (s, C–N), 1452 (m), 1412 (m),
1301 (s), 1197 (m), 1041 (m), 955 (m) cmꢁ1. Anal. Calcd for
Mp (recrystallized from ethanol) 101–102 °C; 1H NMR (CDCl3,
200 MHz) d 1.19 (s, 3H, CH3), 1.41–1.44 (m, 2H), 1.48–1.54 (m,
4H), 2.69 (t, 4H, J = 5.4 Hz), 6.11 (s, 1H), 7.3–7.9 (m, 6H, Ph); 13C
NMR (50 MHz, CD3OD) d 19.3, 24.2, 29.5 (2 ꢂ CH), 40.6, 54.2
(2 ꢂ CH), 92.6, 115.8, 124.9 (2 ꢂ CH), 127.6 (2 ꢂ CH), 153.4,
161.3; IR (KBr) 3132 (s), 2864 (m), 1501 (s, C–N), 1423 (m), 1410
(m), 1287 (s), 1229 (m), 1017 (m), 951 (m) cmꢁ1. Anal. Calcd for
C15H19N3: C, 74.65; H, 7.94; N, 17.41. Found: C, 74.63; H, 7.92; N,
C16H21N3: C, 75.26; H, 8.29; N, 16.46. Found: C, 75.29; H, 8.28; N,
17.39.
16.44.
3.1.20. 3-iso-Propyl-1-phenyl-5-N-piperidinopyrazole (5f)
Mp (recrystallized from ethanol) 120–121 °C; 1H NMR (CDCl3,
200 MHz) d 1.27 (d, 6H, J = 7.4 Hz, CH(CH3)2), 1.45–1.49 (m, 2H),
1.51–1.58 (m, 4H), 2.61–2.75 (m, 1H, CHMe2), 2.82 (t, 4H,
J = 5.4 Hz), 6.31 (s, 1H), 6.98 (t, 1H, J = 7.4 Hz, ArH), 7.14 (dd, 2H,
J = 8.1, 7.4 Hz, ArH), 7.57 (d, 2H, J = 8.1 Hz, ArH); NMR (50 MHz,
CDCl3) d 17.8 (2 ꢂ CH3), 24.2, 28.5 (2 ꢂ CH), 29.6, 40.6, 53.2
(2 ꢂ CH), 90.1, 116.6 (2 ꢂ CH), 121.3, 126.8 (2 ꢂ CH), 139.1,
162.7; IR (KBr) 3102 (s), 2813 (m), 1581 (s, C–N), 1471 (m), 1429
(m), 1315 (s), 1199 (m), 1036 (m), 957 (m) cmꢁ1. Anal. Calcd for
3.1.15. 1,3-Diphenyl-5-N-piperidinopyrazole (5a)
Mp (recrystallized from ethanol) 98–99 °C; 1H NMR (CDCl3,
200 MHz) d 1.44–1.47 (m, 2H), 1.50–1.56 (m, 4H), 2.79 (t, 4H,
J = 5.4 Hz), 6.09 (s, 1H), 7.16–7.23 (m, 2H), 7.35 (t, 2H, J = 7.6 Hz),
7.37 (t, 2H, J = 7.6 Hz), 7.77 (d, 2H, J = 7.4 Hz), 7.84 (d, 2H,
J = 7.6 Hz); 13C NMR (50 MHz, CDCl3) d 23.1, 26.5 (2 ꢂ CH), 53.8
(2 ꢂ CH), 91.3, 122.6 (2 ꢂ CH), 125.1 (2 ꢂ CH), 126.4 (2 ꢂ CH),
127.9 (2 ꢂ CH), 128.7, 129.1, 133.6, 140.5, 150.8, 163.9; IR (KBr)
3060 (s), 2944 (m), 1549 (s, C–N), 1450 (m), 1421 (m), 1301 (s),
1251 (m), 1199 (m), 965 (m) cmꢁ1. Anal. Calcd for C20H21N3: C,
79.17; H, 6.98; N, 13.85. Found: C, 79.14; H, 6.95; N, 13.87.
C17H23N3: C, 75.80; H, 8.61; N, 15.60. Found: C, 75.77; H, 8.64; N,
15.58.
3.1.21. 3-n-Propyl-5-N-piperidinopyrazole (5g)
3.1.16. 1-(20-Methylphenyl)-3-phenyl-5-N-piperidinopyrazole
(5b)
Mp (recrystallized from ethanol) 126–127 °C; 1H NMR (CDCl3,
200 MHz) d 1.06 (t, J = 7.4 Hz, 3H), 1.44–1.47 (m, 2H), 1.50–1.56
(m, 4H), 1.68–1.76 (m, 2H), 2.50 (t, J = 7.5 Hz, 2H), 2.79 (t, 4H,
J = 5.4 Hz), 6.14 (s, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.29 (dd, J = 7.4,
7.7 Hz, 2H), 7.87 (d, J = 7.7 Hz, 2H); 13C NMR (50 MHz, CD3OD) d
14.2, 20.4, 24.2, 29.5 (2 ꢂ CH), 33.5, 40.6, 54.2 (2 ꢂ CH), 92.3,
119.3, 125.4, 129.2, 138.6, 158.3, 163.8; IR (KBr) 3112 (s), 2836
(m), 1541 (s, C–N), 1452 (m), 1412 (m), 1301 (s), 1197 (m), 1041
(m), 955 (m) cmꢁ1. Anal. Calcd for C17H23N3: C, 75.80; H, 8.61; N,
15.60. Found: C, 75.81; H, 8.58; N, 15.64.
Mp (recrystallized from ethanol) 103–104 °C; 1H NMR (CDCl3,
200 MHz) d 1.45–1.48 (m, 2H), 1.52–1.58 (m, 4H), 2.36 (s, 3H,
CH3), 2.82 (t, 4H, J = 5.4 Hz), 6.13 (s, 1H), 7.45 (d, 2H, J = 7.2 Hz,
ArH), 7.49–7.56 (m, 5H, ArH), 7.68 (d, 2H, J = 7.2 Hz, ArH); 13C
NMR (50 MHz, CDCl3) d 15.3, 22.9, 27.4 (2 ꢂ CH), 54.3 (2 ꢂ CH),
92.1, 125.9 (2 ꢂ CH), 126.2, 127.2, 128.3, 129.1 (2 ꢂ CH), 131.1,
131.5, 131.7, 135.9, 136.7, 149.6, 159.4; IR (KBr) 3159 (m), 3108
(s), 1607, 1537 (s, C–N), 1472 (m), 1321 (m), 1143 (m), 979 (m),
810 (m) cmꢁ1. Anal. Calcd for C21H23N3: C, 79.46; H, 7.30; N,
13.24. Found: C, 79.49; H, 7.28; N, 13.21.
3.1.22. 4,40-Methylidenebis(1,3-diphenyl-2-pyrazolone) (6a)
Mp (recrystallized from ethanol) 261.2–262.2 °C; 1H NMR
(CDCl3, 200 MHz) d 7.24 (t, 1H, J = 7.6 Hz, ArH), 7.44–7.53 (m, 5H,
ArH), 7.82–7.86 (m, 2H, ArH), 8.01 (d, 2H, J = 7.6 Hz, ArH); 13C
NMR (50 MHz, CDCl3) d 39.7, 108, 119.1 (2 ꢂ CH), 109.5, 125.3,
126.0 (2 ꢂ CH), 128.9 (2 ꢂ CH), 130.7, 130.9 (2 ꢂ CH), 134.8,
138.1, 154.6, 170.2; IR (KBr) 3067 (m), 1715 (s, C@O), 1601 (s, C–
N), 1496 (m), 1383 (m), 1326 (m), 1172 (m), 1116 (m), 899 (m)
cmꢁ1. Anal. Calcd for C31H22N4O2: C, 77.16; H, 4.60; N, 11.61.
Found: C, 77.13; H, 4.62; N, 11.59.
3.1.17. 1-(40-Methoxylphenyl)-3-phenyl-5-N-piperidinopyrazole
(5c)
Mp (recrystallized from ethanol) 124–125 °C; 1H NMR (CDCl3,
200 MHz) d 1.44–1.47 (m, 2H), 1.51–1.57 (m, 4H), 2.23 (s, 3H,
CH3), 2.79 (t, 4H, J = 5.4 Hz), 3.79 (s, 3H, CH3), 6.10 (s, 1H), 6.77
(d, 2H, J = 6.8 Hz, ArH), 7.20–7.26 (m, 3H, ArH), 7.47 (d, 2H,
J = 7.2 Hz, ArH), 7.59 (d, 2H, J = 6.8 Hz, ArH); 13C NMR (50 MHz,
CDCl3) d 23.5, 28.2 (2 ꢂ CH), 39.2, 53.9 (2 ꢂ CH), 90.1, 114.0
(2 ꢂ CH), 121.0 (2 ꢂ CH), 125.9 (2 ꢂ CH), 128.9 (2 ꢂ CH), 129.8,
130.4, 131.3, 131.6, 153.5, 161.1; IR (KBr) 3207 (m), 1562 (s, C–
N), 1487 (m), 1243 (m), 1031 (m), 863 (m) cmꢁ1. Anal. Calcd for
3.1.23. 4,40-Methylidenebis[1-(20-methylphenyl)-3-phenyl-2-
pyrazolone] (6b)
Mp (recrystallized from ethanol) 205.3–206.3 °C; 1H NMR
(CD3OD, 200 MHz) d 2.27 (s, 3H, CH3), 7.51 (d, 2H, J = 7.2 Hz,
ArH), 7.54–7.59 (m, 5H, ArH), 7.82 (d, 2H, J = 7.2 Hz, ArH); 13C
NMR (50 MHz, CD3OD) d 15.9, 126.3 (2 ꢂ CH), 126.6, 127.2,
128.0, 128.5, 129.2 (2 ꢂ 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, C–
N), 1472 (m), 1305 (m), 1147 (m), 982 (m), 807 (m) cmꢁ1 Anal.
Calcd for C33H26N4O2: C, 77.63; H, 5.13; N, 10.97. Found: C,
77.67; H, 5.15; N, 10.96.
C21H23N3O: C, 75.65; H, 6.95; N, 12.60. Found: C, 75.61; H, 6.93;
N, 12.57.
3.1.18. 1-(40-Bromophenyl)-3-phenyl-5-N-piperidinopyrazole
(5d)
Mp (recrystallized from ethanol) 118–119 °C; 1H NMR (CDCl3,
200 MHz) d 1.45–1.48 (m, 2H), 1.53–1.61 (m, 4H), 2.35 (s, 3H,
CH3), 2.84 (t, 4H, J = 5.4 Hz), 6.02 (s, 1H), 7.13 (m, 2H, ArH), 7.37
(m, 2H, ArH), 7.68 (m, 2H, ArH), 7.81 (m, 2H, ArH); 13C NMR
(50 MHz, CDCl3) d 1.46–1.49 (m, 2H), 1.53–1.59 (m, 4H), 2.82 (t,
4H, J = 5.4 Hz), 6.13 (s, 1H), 13C NMR (50 MHz, CD3OD) d 24.2,
29.5 (2 ꢂ CH), 40.6, 54.2 (2 ꢂ CH), 93.6, 119.3, 125.1 (2 ꢂ CH),
128.6 (2 ꢂ CH), 128.9 (2 ꢂ CH); 130.1 (2 ꢂ CH), 130.5, 130.9,
154.9, 163.4; IR (KBr) 3213 (m), 3095 (s), 1472 (s, C–N), 1432
(m), 1314 (m), 1119 (m), 981 (m), 793 (m) cmꢁ1. Anal. Calcd for
3.1.24. 4,40-Methylidenebis[1-(40-methoxylphenyl)-3-phenyl-2-
pyrazolone] (6c)
Mp (recrystallized from ethanol) 128–130 °C; 1H NMR (CDCl3,
200 MHz) d 3.79 (s, 3H, CH3), 6.90 (d, 2H, J = 6.8 Hz, ArH), 7.40–
7.44 (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) d 39.5, 55.5, 114.0
(2 ꢂ CH), 121.0 (2 ꢂ CH), 125.9 (2 ꢂ CH), 128.9 (2 ꢂ CH), 130.6,
C20H20BrN3: C, 62.83; H, 5.27; N, 10.99. Found: C, 62.80; H, 5.29;
N, 11.02.

3792
Y.-Y. Huang et al. / Tetrahedron Letters 52 (2011) 3786–3792
Vol. 3, p 1; (c) Kost, A. N.; Grandberg, I. I. In Advances in Heterocyclic Chemistry;
Katritzky, A. R., Boulton, A. J., Eds.; Academic Press: New York, 1966; Vol. 6, p
347; (d) Lee, K. Y.; Kim, J. M.; Kim, J. N. Tetrahedron Lett. 2003, 44, 6737–6740.
and references therein.
130.9, 131.5, 154.5, 157.2, 170.0; IR (KBr) 2927 (m), 1709 (s, C@O),
1512 (s, C–N), 1500 (m), 1248 (m), 1030 (m), 832 (m) cmꢁ1. Anal.
Calcd for C33H26N4O4: C, 73.05; H, 4.83; N, 10.33. Found: C, 73.07;
H, 4.85; N, 10.31.
2. Sakya, S. M.; Rast, B. Tetrahedron Lett. 2003, 44, 7629–7632. and references
therein.
3. Huang, Y. R.; Katzenellenbogen, J. A. Org. Lett. 2000, 2, 2833–2836. and
references therein.
3.1.25. 4,40-Methylidenebis[1-(40-bromophenyl)-3-phenyl-2-
pyrazolone] (6d)
4. (a) Nishigaki, N. Bioorg. Med. Chem. Lett. 2003, 13, 2985–2988; (b) Braibante, M.
E. F.; Braibante, H. T. S.; da Roza, J. K.; Henriques, D. M. Synthesis 2003, 1160–
1162; (c) Schenone, S.; Bruno, O.; Ranise, A.; Bondavalli, F.; D’Amico, M.;
Filippelli, W.; Falcone, G.; De Novellis, V. Il Farmaco 1995, 50, 179–182; (d)
Cooper, C. B.; Helal, C. J.; Sanner, M. A.; Wagner, T. T. PCT WO 18346 A1, 2002.
5. (a) Ansel, J. E.; El Kaim, L.; Gadras, A.; Grimaud, L.; Jana, N. K. Tetrahedron Lett.
2002, 43, 8319–8321; (b) Atlan, V.; Buron, C.; Elkaim, L. Synlett 2000, 489–490;
(c) Palacios, F.; Aparicio, D.; de los Santos, J. M. Tetrahedron 1996, 52, 4123–
4132; (d) Moreno-Manãs, M.; Sebastián, R. M.; Vallribera, A.; Carini, F. Synthesis
1999, 157–160; (e) Abdel-Rahman, R. M.; Seada, M.; Fawzy, M.; El-Baz, I.
Pharmazie 1994, 49, 729–733.
Mp (recrystallized from ethanol) 183–184 °C; 1H NMR (CD3OD,
200 MHz) d 7.38 (m, 2H, ArH); 7.50 (m, 2H, ArH); 7.81 (m, 2H,
ArH); 7.99 (m, 2H, ArH).; 13C NMR (50 MHz, CD3OD) d 120.0;
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, C–N), 1472 (m), 1305 (m),
1147 (m), 982 (m), 807 (m) cmꢁ1. Anal. Calcd for C31H20Br2N4O2:
C, 55.15; H, 3.15; N, 8.75. Found: C, 55.17; H, 3.19; N, 8.72.
6. Dodd, D. S.; Martinez, R. L. Tetrahedron Lett. 2004, 45, 4265–4267.
7. Salmon, R. WO 9,306,089, 1995.
8. Atkinson, R.N.; Gross, M.F. WO 03,037,274, 2003.
3.1.26. 4,40-Methylidenebis(3-methyl-1-phenyl-2-pyrazolone)
(6e)
9. (a) Campaigne, E.; Archer, W. L. J. Am. Chem. Soc. 1953, 75, 989–991; (b) Treihs,
W.; Neupert, H. J.; Hiebsch, J. Chem. Ber. 1959, 92, 141–154; (c) Damodiran, M.;
Panneer, N.; Paramasivan, S.; Perumal, T. Tetrahedron Lett. 2009, 50, 5474–
5478.
10. (a) Vilsmeier, A.; Haack, A. Ber. Dtsch. Chem. Ges. 1927, 60, 119–122; (b) Jones,
G.; Stanforth, S. P. In Organic Reactions; Paquette, L. A., Ed.; Wiley: New York,
NY, 1997; Vol. 49, pp 1–330; (c) Downie, I. M.; Earle, M. J.; Heaney, H.;
Shuhaibar, K. F. Tetrahedron 1993, 49, 4015–4034.
Mp (recrystallized from ethanol) 127–129 °C; 1H NMR (CDCl3,
200 MHz) d 2.15 (s, 3H, CH3), 7.14 (d, 1H, J = 2.2 Hz, ArH), 7.36
(dd, 2H, J = 7.8 Hz, 2.2 Hz, ArH), 7.81 (d, 2H, J = 7.8 Hz, ArH); 13C
NMR (50 MHz, CDCl3) d 17.0, 43.1, 118.9 (2 ꢂ CH), 125.1, 128.8
(2 ꢂ CH), 137.9, 156.4, 170.6; IR (KBr) 3101 (s), 2802 (m), 1622
(s, C@O), 1584 (s, C–N), 1494 (m), 1412 (m), 1301 (s), 1220 (m),
1035 (m), 967 (m) cmꢁ1. Anal. Calcd for C21H18N4O2: C, 70.38; H,
5.06; N, 8.93. Found: C, 70.41; H, 5.09; N, 8.96.
11. (a) Lilienkampf, A.; Johansson, M. P.; Wahala, K. Org. Lett. 2003, 5, 3387–3890;
(b) Tang, X.-Y.; Shi, M. J. Org. Chem. 2008, 73, 8317–8320; (c) Perumal, P. T.
Indian J. Heterocycl. Chem. 2001, 11, 1–8; (d) Pan, W.; Dong, D.-W.; Liu, Q. Org.
Lett. 2007, 9, 2421–2423; (e) Wang, K.-W.; Xiang, D.-X.; Dong, D.-W. Org. Lett.
2008, 10, 1691–1694; (f) Jones, G.; Stanforth, S. P. Org. React. 2000, 56, 355–
659; (g) Marson, C. M. Tetrahedron 1992, 48, 3659–3762; (h) Chen, L.; Zhao, Y.-
L.; Liu, Q.; Cheng, C.; Piao, C.-R. J. Org. Chem. 2007, 72, 9259–9263; (i) Zhang, R.;
Zhang, D.; Guo, Y.; Zhou, G.; Jiang, Z.; Dong, D. J. Org. Chem. 2008, 73, 9504–
9507; (j) Wuts, P. G. M.; Northuis, J. M.; Kwan, T. A. J. Org. Chem. 2000, 65,
9223–9225; (k) Xiang, D.; Yang, Y.; Zhang, R.; Liang, Y.; Pan, W.; Huang, J.;
Dong, D. D. J. Org. Chem. 2007, 72, 8593–8596; (l) Mahata, P. K.; Venkatesh, C.;
Syam Kumar, U. K.; Ila, H.; Junjappa, H. J. Org. Chem. 2003, 68, 3966–3975.
12. (a) Sivaprasad, S.; Sridhar, R.; Perumal, P. T. J. Heterocycl. Chem. 2006, 43, 389–
394; (b) Kumar, K. H.; Perumal, P. T. Chem. Lett. 2005, 34, 1346–1347; (c)
Kumar, H. K.; Selvi, S.; Perumal, P. T. J. Chem. Res. 2004, 218–219; (d) Sridhar,
R.; Perumal, P. T. Synth. Commun. 2003, 33, 607–611. 1483–1488; (e) Selvi, S.;
Perumal, P. T. Indian J. Chem., Sect. B 2002, 41B, 1887–1893; (f) Selvi, S.;
Perumal, P. T. Synth. Commun. 2001, 31, 2199–2202; (g) Amaresh, R. R.;
Perumal, P. T. Synth. Commun. 2000, 30, 2269–2274; (h) Selvi, S.; Perumal, P. T.
Synth. Commun. 2000, 30, 3925–3928; (i) Selvi, S.; Perumal, P. T. Indian J. Chem.,
Sect. B 2000, 39B, 163–165; (j) Amaresh, R. R.; Perumal, P. T. Tetrahedron 1999,
55, 8083–8094; (k) Perumal, P. T.; Majo, V. J.; Anand, R. V. Indian J. Chem., Sect. B
1999, 38, 763–765; (l) Amaresh, R. R.; Perumal, P. T. Tetrahedron 1998, 54,
14327–14340; (m) Amaresh, R. R.; Perumal, P. T. Tetrahedron Lett. 1998, 39,
3837–3840; (n) Majo, V. J.; Perumal, P. T. J. Org. Chem. 1998, 63, 7136–7142; (o)
Selvi, S.; Perumal, P. T. Tetrahedron Lett. 1997, 38, 6263–6266; (p) Majo, V. J.;
Perumal, P. T. Tetrahedron Lett. 1997, 38, 6889–6892; (q) Majo, V. J.; Perumal, P.
T. Tetrahedron Lett. 1996, 37, 5015–5018; (r) Balasundaram, B.; Venugopal, M.;
Perumal, P. T. Tetrahedron Lett. 1993, 34, 4249–4252.
3.1.27. 4,40-Methylidenebis(3-isopropyl-1-phenyl-2-pyrazolone)
(6f)
Mp (recrystallized from ethanol) 101–103 °C; 1H NMR (CDCl3,
200 MHz) d 1.21 (d, 6H, J = 7.4 Hz, CH(CH3)2), 2.68–2.82 (m, 1H,
CHMe2), 7.14 (t, 1H, J = 7.4 Hz, ArH), 7.35 (dd, 2H, J = 8.1, 7.4 Hz,
ArH), 7.84 (d, 2H, J = 8.1 Hz, ArH); 13C NMR (50 MHz, CDCl3) d
20.1 (2 ꢂ CH3), 30.7, 39.8, 118.8 (2 ꢂ CH), 124.9, 128.8 (2 ꢂ CH),
138.2, 164.3, 170.6; IR (KBr) 3101 (s), 2802 (m), 1622 (s, C@O),
1584 (s, C–N), 1494 (m), 1412 (m), 1301 (s), 1220 (m), 1035 (m),
967 (m) cmꢁ1. Anal. Calcd for C25H26N4O2: C, 72.44; H, 6.32; N,
13.52. Found: C, 72.41; H, 6.35; N, 13.53.
Acknowledgments
We are grateful to the China Medical University (CMU100-S-)
and the National Science Council of Republic of China for financial
support (NSC-99-2320-B-039-014-MY3). This study is supported
in part by Taiwan Department of Health Clinical Trial and Research
Center of Excellence (DOH100-TD-B-111-004).
13. Yilmaz, V. T.; Topcu, Y. Thermochim. Acta 1997, 307, 143–147.
14. (a) Wang, X.-j.; Tan, J.; Grozinger, K. Tetrahedron Lett. 2000, 41, 4713–4716; (b)
DeRuiter, J.; Carter, D. A.; Arledge, W. S.; Sullivan, P. J. J. Heterocycl. Chem. 1987,
Supplementary data
ˇ
24, 149–153; (c) Brana, M. F.; Gradillas, A.; Ovalles, A. G.; López, B.; Acero, N.;
Llinares, F.; Mingarro, D. M. Bioorg. Med. Chem. 2006, 14, 9–16.
15. Tsai, J.-Y.; Huang, L.-J.; Chang, C.-S.; Chen, H.-S.; Lin, S.-K.; Wong, F. F.; Huang,
Y.-F.; Kuo, S.-C. Tetrahedron 2008, 64, 11751–11755.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.055.
16. (a) Srivastava, V.; Negi, A. S.; Kumar, J. K.; Gupta, M. M. Steroids 2006, 71, 632–
638; (b) El-Shishtawy, R. M.; Almeida, P. Tetrahedron 2006, 62, 7793–7798.
17. Akila, S.; Selvi, S.; Balasubramaian, K. Tetrahedron 2001, 57, 3465–3469.
18. Yamada, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1083–1085.
19. Dougan, M. L.; Chin, J. L.; Solt, K.; Hansen, D. E. Bioorg. Med. Chem. Lett. 2004, 14,
4153–4156.
References and notes
1. For the reviews: (a) Elguero, J. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Potts, K. T., Eds.; Pergamon Press: Oxford, 1984;
Vol. 5,
p 167; (b) Elguero, J. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996;