A divergent synthesis of dihydropyridazinones, N-substituted dihydropyrazoles, and O-substituted pyrazoles

Article abstract of DOI:10.1002/jhet.519

Dihydropyridazinones 4a,b, N-substituted dihydropyrazoles 5b-d, and O-substituted pyrazoles 6a-d have been synthesized starting from spirocyclopropanepyrazole derivative 2. Treatment of 2 with α-chloro esters, e.g., methyl chloroacetate, ethyl chloroacetate, isopropyl chloroacetate, and tert-butyl chloroacetate, in potassium carbonate/sodium iodide system caused ring opening and subsequent C- or N-attack nucleophilic substitution to give the corresponding dihydropyridazinones 4a,b and N-substituted dihydropyrazoles 5b-d. On the other hand, in the absence of sodium iodide, O-substituted pyrazoles 6a-d were obtained from 2 via an O-attack nucleophilic substitution.

Full text of DOI:10.1002/jhet.519

96
A Divergent Synthesis of Dihydropyridazinones, N-Substituted
Dihydropyrazoles, and O-Substituted Pyrazoles
Vol 48
Eiichi Masumoto, Hiroshi Maruoka,* Fumi Okabe, Sho Nishida,
Yuki Yoshimura, Toshihiro Fujioka, and Kenji Yamagata
Faculty of Pharmaceutical Sciences, Fukuoka University, Jonan-ku, Fukuoka 814-0180, Japan
*E-mail: maruoka@fukuoka-u.ac.jp
Received January 18, 2010
DOI 10.1002/jhet.519
Published online 2 September 2010 in Wiley Online Library (wileyonlinelibrary.com).
Dihydropyridazinones 4a,b, N-substituted dihydropyrazoles 5b–d, and O-substituted pyrazoles 6a–d
have been synthesized starting from spirocyclopropanepyrazole derivative 2. Treatment of 2 with a-
chloro esters, e.g., methyl chloroacetate, ethyl chloroacetate, isopropyl chloroacetate, and tert-butyl
chloroacetate, in potassium carbonate/sodium iodide system caused ring opening and subsequent C- or
N-attack nucleophilic substitution to give the corresponding dihydropyridazinones 4a,b and N-substi-
tuted dihydropyrazoles 5b–d. On the other hand, in the absence of sodium iodide, O-substituted pyra-
zoles 6a–d were obtained from 2 via an O-attack nucleophilic substitution.
J. Heterocyclic Chem., 48, 96 (2011).
INTRODUCTION
buster drugs such as Celebrex [12] and Viagra [13], that
find a wide range of applications in pharmaceutical [14–
16]. Many synthetic methods for pyrazoles are available
[17–23], among which notable methods involve the
reactions between 1,3-difunctional compounds with
hydrazines or their derivatives [24,25] and 1,3-dipolar
cycloadditions of diazo compounds onto triple bonds
[26–28]. Although the synthesis of functionalized pyra-
zoles such as O- and C-substituted pyrazoles (types A
and B) starting from dihydropyrazole 1 has been
reported [29–31], there are relatively few methods in the
The pyridazine nucleus and derived 3-oxo-derivatives,
pyridazin-3(2H)-ones, are versatile pharmacophores in many
biologically active molecules of contemporary interest [1–4].
For example, these molecules have been previously reported
to be platelet aggregation inhibitor [5], a-adrenoceptor antag-
onists [6], and antisecretory/antiulcer agents [7]. In this con-
text, the synthesis of pyridazin-3(2H)-ones continues to
attract attention and provides an interesting challenge [8–11].
Pyrazole motif makes up the core structure of numer-
ous biologically active compounds, including block-
C
V
2010 HeteroCorporation

January 2011
A Divergent Synthesis of Dihydropyridazinones, N-Substituted Dihydropyrazoles,
and O-Substituted Pyrazoles
97
Scheme 1
chloropropionitrile according to our previous investiga-
tion [38]. In our initial studies, to check something
about the reactivity of spirocyclopropanepyrazole 2, we
examined a sodium iodide–promoted ring transformation
of 2. Fortunately, we found the reaction condition under
which pyrano[2,3-c]pyrazole derivative 3 could be iso-
lated. Indeed, thermal treatment of 2 with sodium iodide
in N,N-dimethylformamide caused a ring opening/recyc-
lization to give the fused pyrazole derivative 3 in 78%
yield (Scheme 2). The structure of 3 was confirmed by
elemental analysis and spectroscopic data (1H NMR,
13C NMR, and mass). This result suggests that a ring-
opening reaction of spirocyclopropanepyrazole 2 easily
occurs in the presence of nucleophiles and then the in-
termediate anion would be produced. Moreover, in our
previous article [39], we have shown that the ring-open-
ing reaction of spirocyclopropanepyrazole derivatives
with sodium hydride provided the corresponding ring-
opened products.
literature describing the selective preparation of N-sub-
stituted pyrazoles (type C) (Scheme 1). In connection
with our current research interests in this area, we have
reported the synthesis of N-acyl-1,2-dihydro-3H-pyrazol-
3-ones through Lewis acid–mediated rearrangement of
O-acyloxypyrazoles [32].
With these results in hand, we next investigated a di-
vergent method for the synthesis of pyrazole derivatives
from spirocyclopropanepyrazole 2 in detail. When a
mixture of 2, methyl chloroacetate, and sodium iodide
in the presence of potassium carbonate in N,N-dimethyl-
formamide was stirred at 120ꢀC for 1 h, the dihydropyr-
idazinone 4a was obtained in 38% yield as the only iso-
lated product (Scheme 3 and entry 1 in Table 1). While,
the reaction with isopropyl and/or tert-butyl chloroace-
tate afforded the corresponding N-substituted dihydro-
pyrazoles 5c,d in 62 and 45% yields, respectively
(entries 3 and 4). In the case of ethyl chloroacetate, the
reaction gave the N-substituted dihydropyrazole 5b
(38%) together with the dihydropyridazinone 4b (15%)
as minor product (entry 2). These products 4a,b and
5b–d gave satisfactory spectroscopic data consistent
with their assigned structures (see Experimental section).
On the other hand, the utility of cyclopropane deriva-
tives in organic synthesis has been recognized for their
ready accessibility originating from the inherent ring
strain that can lead to a variety of ring-opening reactions
under the influence of a wide range of chemicals, for
example, electrophiles, nucleophiles, and radicals [33–
37]. In our recent work, we achieved the synthesis of
spirocyclopropanepyrazoles, followed by the reaction of
4-arylidene-3H-pyrazol-3-one with a-chloro esters, e.g.,
methyl chloroacetate, ethyl chloroacetate, isopropyl
chloroacetate, and tert-butyl chloroacetate [38]. More
recently, we have also discussed the ring-opening reac-
tion of spirocyclopropanepyrazoles in the presence of
sodium hydride [39]. Thus, we hypothesized that if the
O-, C-, or N-anion-containing intermediate could be pro-
duced readily from spirocyclopropanepyrazole derivative
through a ring-opening reaction under appropriate reac-
tion conditions, the synthesis of O-, C-, or N-substituted
pyrazoles would then be possible.
Scheme 2
For these reasons, we focused our attention on the de-
velopment of a new method for the preparation of substi-
tuted pyrazole derivatives; we now report our experimen-
tal results, a ring opening/nucleophilic substitution of spi-
rocyclopropanepyrazole derivative with a-chloro esters in
the presence of a base such as potassium carbonate.
RESULTS AND DISCUSSION
The starting material, spirocyclopropanepyrazole 2,
was prepared by treatment of 2,4-dihydro-5-methyl-2-
phenyl-4-(diphenylmethylene)-3H-pyrazol-3-one and 2-
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E. Masumoto, H. Maruoka, F. Okabe, S. Nishida, Y. Yoshimura, T. Fujioka, and K. Yamagata
Vol 48
Scheme 3
nucleophilic substitution is preferred when the substitu-
ent is a relatively smaller group, such as methyl and
ethyl. Therefore, it is proposed that a ring-opening reac-
tion of 2 probably causes in the presence of potassium
carbonate to give the intermediate C-anion D, which
undergoes C-attack nucleophilic substitution to afford
C-adduct E. Intramolecular nucleophilic addition of acti-
vated methylene group of E to carbonyl group readily
occurs and then the fused pyrazole F would be pro-
duced. Thus, the dihydropyridazinones 4a,b could be
formed via a ring expansion of F. While in the reaction
of isopropyl and/or tert-butyl chloroacetate, an isomeri-
zation of D to the intermediate N-anion G easily occurs,
depending in a large part on the steric effects of the sub-
stituent on the ester group, and then N-substituted dihy-
dropyrazoles 5b–d would be produced from G through
an N-attack nucleophilic substitution.
Furthermore, we found the reaction condition under
which the O-substituted pyrazoles 6a–d could be iso-
lated. Thermal treatment of 2 with a-chloro esters in the
presence of potassium carbonate, without sodium iodide,
gave the corresponding O-substituted pyrazoles 6a–d
and N-substituted dihydropyrazoles 7a–d (Scheme 4 and
Table 2). Interestingly, in this reaction, the dihydropyri-
dazinone derivative such as 4a,b was not detected at all.
The IR spectra of 6a–d display bands near 2220 cmꢁ1
due to a conjugated cyano group and in the range of
1745ꢁ1768 cmꢁ1 due to a carbonyl group. The 1H
NMR spectra of 6a–d in deuteriochloroform exhibit a
two-proton singlet near d 3.7 due to the methylene pro-
tons and two one-proton singlets near d 6.0 due to the
two olefin protons. The 13C NMR spectra of 6a–d show
a signal near d 70 due to the methylene carbon and a
signal near d 166 due to the ester carbonyl carbon. In
addition, mass spectra and elemental analyses of the
N-substituted pyrazole 5b and O-substituted pyrazole 6b
point to the same molecular ion and elemental composi-
tion C30H27N3O3. By comparison of the NMR, mass
spectra and elemental analyses of 5b–d and 6a–d, it
seems that the structural assignments given to these
compounds are correct (see Experimental section).
The IR spectra of 4a,b display bands near 3230 cmꢁ1
due to a secondary amino group near 2220 cmꢁ1 due to
a
conjugated cyano group and in the range of
1605ꢁ1745 cmꢁ1 due to two carbonyl groups, whereas
those of 5b–d show bands near 2225 cmꢁ1 due to a con-
jugated cyano group and in the range of 1610ꢁ1750
cmꢁ1 due to two carbonyl groups. The H NMR spectra
1
of 4a,b in deuteriochloroform exhibit a one-proton sin-
glet near d 5.25 assignable to the 4-methine proton, a
D2O exchangeable signal near d 5.3 attributable to the
secondary amino proton, and two one-proton singlets
near d 6.0 due to the two olefin protons, whereas those
of 5b–d show a two-proton singlet near d 4.3 due to the
methylene protons and two one-proton singlets near d
6.0 due to the two olefin protons. The 13C NMR spectra
of 4a,b show a signal near d 70 due to the 4-methine
carbon and two signals near d 162 and 172 due to the
two carbonyl carbons, whereas those of 5b–d show a
signal near d 48 due to the methylene carbon and two
signals near d 165 due to the two carbonyl carbons.
The reason for this change of behavior is not very
clear at present. One explanation could rely on the fact
that isopropyl and tert-butyl groups are well known as
bulky substituents. When the substituent is a large
group, such as isopropyl and tert-butyl groups, N-attack
nucleophilic substitution is preferred, whereas C-attack
The formation of 6a–d and 7a–d could be explained
by possible mechanism presented in Scheme 4. Thus,
the reaction of spiro compound 2 with potassium
Table 1
Synthesis of 4a,b and 5b–d according to Scheme 3.
Entry
R
Products
Yields (%)
1
2
3
4
Me
Et
Pri
But
4a
4b/5b
5c
38
15/38
62
5d
59
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A Divergent Synthesis of Dihydropyridazinones, N-Substituted Dihydropyrazoles,
and O-Substituted Pyrazoles
99
Scheme 4
Table 2
Synthesis of 6a–d and 7a–d according to Scheme 4.
Entry
R
Products
Yields (%)
1
2
3
4
Me
Et
Pri
But
6a/7a
6b/7b
6c/7c
6d/7d
42/38
36/34
43/28
36/41
Thus, thermal treatment of 4a,b with acetic anhydride in
pyridine afforded the N-acetylated dihydropyridazinones
1
8a,b (55, 35%), which were characterized by H NMR,
13C NMR, mass, IR, and elemental analyses (Scheme
5). Furthermore, to understand better the formation of
7d, compound 5d was reacted with tert-butyl chloroace-
tate in the presence of potassium carbonate to produce
the corresponding N-substituted dihydropyrazole 7d
(72%), which was confirmed by direct comparison with
an authentic sample prepared from 2 and tert-butyl
chloroacetate as described above. In this reaction, the
activated methylene group of tert-butyl chloroacetate
could nucleophilically attack the a,b-unsaturated nitrile
of 5d to result in the formation of the intermediate Mi-
chael adduct J. The chlorine-containing compound J
may be favored due to the hydrogen bond formed
between hydrogen of methine proton and oxygen of
ester carbonyl group. Thus, compound 7d would then be
formed easily from J via an elimination of hydrogen
chloride. In deuteriochloroform, the NMR spectra indi-
cate that compound 7d existed as a geometrical single
Scheme 5
carbonate probably causes the ring opening of cyclopro-
pane to give the intermediate C-anion D, which was fol-
lowed by an isomerization to produce the O-anion H or
N-anion G in the absence of sodium iodide, respec-
tively. The O-anion H could then undergo an O-attack
nucleophilic addition to afford the O-substituted pyra-
zoles 6a–d. In the case of the N-anion G, an N-attack
nucleophilic addition probably occurs and then could
provide 5a–d, which were followed by a Michael addi-
tion of activated methylene group of a-chloro esters to
a,b-unsaturated nitrile of 5a–d, giving the chlorine-con-
taining compound I. Compounds 7a–d would then be
formed easily from I through an elimination of hydro-
gen chloride. On the basis of all of the above results, it
make us believe that compared with a nitrogen atom,
the relatively lower nucleophilicity of the oxygen atom
made the transformation from 5 to 7 proceeded more
efficiently in the absence of sodium iodide.
To confirm the structure of the dihydropyridazinone
derivatives 4a,b, we carried out the acetylation of 4a,b.
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E. Masumoto, H. Maruoka, F. Okabe, S. Nishida, Y. Yoshimura, T. Fujioka, and K. Yamagata
Vol 48
78%), mp 185ꢁ187ꢀC (acetone-petroleum ether); IR (potas-
isomer of Z configuration. In addition, for product 7d, a
clear nuclear Overhauser effect was observed between
two olefin protons of Z configuration.
1
sium bromide): m 2242 cmꢁ1 (CN); H NMR (deuteriochloro-
form): d 1.60 (s, 3H, 3-Me), 4.02 (dd, J ¼ 2.4, 7.6 Hz, 1H, 5-
H), 4.29 (dd, J ¼ 7.6, 11.0 Hz, 1H, 6-H), 4.37 (dd, J ¼ 2.4,
11.0 Hz, 1H, 6-H), 7.24–7.26 (m, 1H, Ph-H), 7.31–7.49 (m,
12H, Ph-H), 7.76–7.78 ppm (m, 2H, Ph-H); 13C NMR (deuter-
iochloroform): d 14.2 (3-Me), 39.7 (C-5), 50.1 (C-4), 66.9 (C-
6), 101.5 (C-3a), 117.5 (CN), 120.5, 126.0, 127.8, 128.1,
128.3, 128.7, 128.8, 129.0, 130.1, 138.2, 139.6, 141.3, (Ph-C),
147.5 (C-3), 148.3 ppm (C-7a); ms: m/z 392 [M þ H]þ. Anal.
Calcd. for C26H21N3O: C, 79.77; H, 5.41; N, 10.73. Found: C,
79.77; H, 5.64; N, 10.61.
General procedure for the preparation of dihydropyrida-
zinones 4a,b and N-substituted dihydropyrazoles 5b–d from
2 and a-chloro esters in the presence of sodium iodide and
potassium carbonate. A mixture of 2 (0.391 g, 1 mmol),
methyl chloroacatate (0.326 g, 3 mmol), ethyl chloroacatate
(0.368 g, 3 mmol), isopropyl chloroacatate (0.410 g, 3 mmol)
or tert-butyl chloroacatate (0.452 g, 3 mmol), sodium iodide
(0.450 g, 3 mmol), and potassium carbonate (0.276 g, 2 mmol)
in N,N-dimethylformamide (5 mL) was stirred at 120ꢀC for
1 h. After removal of the solvent in vacuo, a saturated aqueous
sodium thiosulfate solution (30 mL) was added to the residue
with stirring and ice cooling. The resulting mixture was extracted
with chloroform (60 mL). The extract was dried over anhydrous
sodium sulfate and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel with chloroform
as the eluent and recrystallization from an appropriate solvent
(a fractional recrystallization) to afford 4a,b and 5b–d.
Finally, on the basis of these results, we examined the
conversion of the O-substituted pyrazoles 6a–d into the
fused pyrazole derivatives in the presence of a base.
Although, we carried out several experiments on 6a–d,
testing different reaction conditions, e.g., time, solvent,
and substrate/base molar ratio, those attempts were
unacceptable with respect to yield. Contrary to our ex-
pectation, when 6a–d were treated with potassium tert-
butoxide in tert-butyl alcohol to result in the formation
of the carboxylic acid 9 (41% from 6a, 29% from 6b,
26% from 6c, and 48% from 6d). To confirm the struc-
ture of 9, we carried out the hydrolysis of compound
6a. Thus, thermal treatment of 6a with potassium hy-
droxide in aqueous ethanol afforded the carboxylic acid
9 in 56% yield. The melting point and IR spectrum of
this compound coincided with those of samples prepared
from 6a–d in a potassium tert-butoxide/tert-butyl alco-
hol condition.
In conclusion, we have developed a novel method for
the construction of dihydropyridazinones 4a,b, N-substi-
tuted dihydropyrazoles 5b–d, and O-substituted pyra-
zoles 6aꢁd, proceeding by a ring opening and C-, N-,
or O-attack nucleophilic substitution when spirocyclo-
propanepyrazole 2 are treated with a-chloro esters and
potassium carbonate, with or without sodium iodide.
Functionalized pyrazole derivatives are important syn-
thons in organic synthesis and for the preparation of bio-
logically active compounds with interest in medicinal
chemistry. Further synthetic applications for pyridazine
and pyrazole derivatives are in progress.
1,2,3,4-Tetrahydro-6-methyl-3-oxo-2-phenyl-5-(a-methylene-
b,b-diphenylpropanenitril-3-yl)-4-pyridazinecarboxylic acid
methyl ester (4a). This compound was obtained as colorless
needles (0.176 g, 38%), mp 216ꢁ217ꢀC (chloroform-petro-
leum ether); IR (potassium bromide): m 3232 (NH), 2220
(CN), 1742, 1613 cmꢁ1 (C¼¼O); 1H NMR (deuteriochloro-
form): d 1.56 (s, 3H, 6-Me), 3.92 (s, 3H, CO2Me), 5.31 (s, 1H,
4-H), 5.33 (br. s, 1H, NH), 5.70 (s, 1H, olefin H), 5.85 (s, 1H,
olefin H), 7.17–7.45 (m, 13H, Ph-H), 7.62–7.64 ppm (m, 2H,
Ph-H); 13C NMR (deuteriochloroform): d 21.3 (6-Me), 53.6
(CO2Me), 58.9 [Ph2C-C(CN)¼¼CH2], 69.8 (C-4), 109.7 (C-5),
119.8 (CN), 126.46, 126.49, 126.6, 126.7 (Ph-C), 127.5 [Ph2C-
C(CN)¼¼CH2], 127.85, 127.91, 128.2, 129.0, 129.3, 129.6,
130.0 (Ph-C), 132.2 [Ph2C-C(CN)¼¼CH2], 141.0, 141.3, 143.1
(Ph-C), 155.2 (C-6), 162.1 (C-3), 172.3 ppm (C¼¼O); ms: m/z
464 [M þ H]þ. Anal. Calcd. for C29H25N3O3ꢂ0.15H2O: C,
74.71; H, 5.47; N, 9.01. Found: C, 74.72; H, 5.53; N, 8.91.
1,2,3,4-Tetrahydro-6-methyl-3-oxo-2-phenyl-5-(a-methylene-
b,b-diphenylpropanenitril-3-yl)-4-pyridazinecarboxylic acid
ethyl ester (4b). This compound was obtained as colorless
needles (0.072 g, 15%), mp 215–216ꢀC (chloroform-petroleum
ether); IR (potassium bromide): m 3275 (NH), 2226 (CN),
1733, 1609 cmꢁ1 (C¼¼O); 1H NMR (deuteriochloroform): d
1.37 (t, J ¼ 7.0 Hz, 3H, CO2CH2Me), 1.54 (s, 3H, 6-Me),
4.32–4.41 (m, 2H, CO2CH2Me), 5.27 (s, 1H, 4-H), 5.33 (br. s,
1H, NH), 5.74 (s, 1H, olefin H), 5.89 (s, 1H, olefin H), 7.15–
7.29 (m, 7H, Ph-H), 7.34–7.44 (m, 6H, Ph-H), 7.58–7.60 ppm
EXPERIMENTAL
All melting points are uncorrected. The IR spectra were
recorded on a JASCO FT/IR-4100 spectrometer. The 1H and
13C NMR spectra were recorded on a JEOL JNM-A500 spec-
trometer at 500 and 125 MHz, respectively. The 1H and 13C
chemical shifts (d) are reported in parts per million (ppm) rela-
tive to tetramethylsilane as internal standard. The positive
FAB mass spectra were obtained on a JEOL JMS-700T spec-
trometer. The elemental analyses were performed on
YANACO MT-6 CHN analyzer.
a
The preparation of fused pyrazole 3 from 2 and sodium
iodide. A mixture of 2 [38] (0.782 g, 2 mmol) and sodium
iodide (0.600 g, 4 mmol) in N,N-dimethylformamide (5 mL)
was stirred at 140ꢀC for 1 h. After removal of the solvent
in vacuo, cold water was added to the residue. The resulting
mixture was extracted with chloroform (60 mL). The extract
was dried over anhydrous sodium sulfate and concentrated
in vacuo. The residue was purified by column chromatography
on silica gel with chloroform as the eluent to give 3-methyl-1,4,4-
triphenyl-1,4,5,6-tetrahydropyrano[2,3-c]pyrazole-5-carbonitrile
(3). This compound was obtained as colorless prisms (0.607 g,
(m, 2H, Ph-H); 13C NMR (deuteriochloroform):
d 14.1
(CO2CH2Me), 21.4 (6-Me), 58.9 [Ph2C-C(CN)¼¼CH2], 63.1
(CO2CH2Me), 69.8 (C-4), 109.5 (C-5), 119.9 (CN), 126.39,
126.40, 126.6, 126.9, 127.8, 127.9 (Ph-C), 128.3 [Ph2C-
C(CN)¼¼CH2], 129.0, 129.36, 129.4, 130.0 (Ph-C), 131.7
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[Ph2C-C(CN)¼¼CH2], 141.2, 141.7, 143.5 (Ph-C), 155.2 (C-6),
162.1 (C-3), 171.6 ppm (C¼¼O); ms: m/z 478 [M þ H]þ. Anal.
Calcd. for C30H27N3O3ꢂ0.2H2O: C, 74.89; H, 5.74; N, 8.73.
Found: C, 74.74; H, 5.57; N, 8.94.
3-Methyl-4-(a-methylene-b,b-diphenylpropanenitril-3-yl)-5-
oxo-1-phenyl-3-pyrazoline-2-acetic acid ethyl ester (5b). This
compound was obtained as colorless prisms (0.181 g, 38%),
mp 157–159ꢀC (chloroform-petroleum ether); IR (potassium
bromide): m 2228 (CN), 1748, 1646 cmꢁ1 (C¼¼O); 1H NMR
(deuteriochloroform): d 1.24 (t, J ¼ 7.0 Hz, 3H, CO2CH2Me),
1.68 (s, 3H, pyrazoline 3-Me), 4.18 (q, J ¼ 7.0 Hz, 2H,
CO2CH2Me), 4.23 (s, 2H, NCH2), 6.00 (s, 1H, olefin H), 6.11
(s, 1H, olefin H), 7.20–7.46 ppm (m, 15H, Ph-H); 13C NMR
mmol), isopropyl chloroacatate (0.410 g, 3 mmol) or tert-butyl
chloroacatate (0.452 g, 3 mmol), and potassium carbonate
(0.276 g, 2 mmol) in N,N-dimethylformamide (5 mL) was
stirred at 120ꢀC for 1 h. After removal of the solvent in vacuo,
cold water was added to the residue. The resulting mixture
was extracted with chloroform (60 mL). The extract was dried
over anhydrous sodium sulfate and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
with chloroform as the eluent to yield 6a–d. Further the elu-
tion gave 7a–d.
{[3-Methyl-4-(a-methylene-b,b-diphenylpropanenitril-3-yl)-
1-phenyl-1H-pyrazol-5-yl]oxy}acetic acid methyl ester
(6a). This compound was obtained as colorless prisms (0.195
g, 42%), mp 126–128ꢀC (chloroform-petroleum ether); IR (po-
(deuteriochloroform):
d
13.8 (pyrazoline 3-Me), 14.2
1
tassium bromide): m 2224 (CN), 1762 cmꢁ1 (C¼¼O); H NMR
(CO2CH2Me), 48.3 (NCH2), 57.1 [Ph2C-C(CN)¼¼CH2], 61.9
(CO2CH2Me), 112.1 (pyrazoline C-4), 119.4 (CN), 124.7, 126.9,
127.1 (Ph-C), 127.5 [Ph2C-C(CN)¼¼CH2], 128.2, 129.3, 129.4
(Ph-C), 131.3 [Ph2C-C(CN)¼¼CH2], 134.7, 141.4 (Ph-C), 154.8
(pyrazoline C-3), 164.7 (pyrazoline C-5), 166.5 ppm (C¼¼O);
ms: m/z 478 [M þ H]þ. Anal. Calcd. for C30H27N3O3: C,
75.45; H, 5.70; N, 8.80. Found: C, 75.41; H, 5.75; N, 8.64.
3-Methyl-4-(a-methylene-b,b-diphenylpropanenitril-3-yl)-5-
oxo-1-phenyl-3-pyrazoline-2-acetic acid isopropyl ester
(5c). This compound was obtained as colorless prisms (0.305
g, 62%), mp 169–171ꢀC (chloroform-petroleum ether); IR (potas-
sium bromide): m 2221 (CN), 1737, 1612 cmꢁ1 (C¼¼O); 1H
NMR (dimethyl sulfoxide-d6): d 1.16 (d, J ¼ 6.4 Hz, 6H,
CO2CHMe2), 1.66 (s, 3H, pyrazoline 3-Me), 4.41 (s, 2H, NCH2),
4.94 (sep, J ¼ 6.4 Hz, 1H, CO2CHMe2), 5.82 (s, 1H, olefin H),
6.16 (s, 1H, olefin H), 7.24–7.29 (m, 4H, Ph-H), 7.34–7.39 (m,
9H, Ph-H), 7.47–7.50 ppm (m, 2H, Ph-H); 13C NMR (dimethyl
sulfoxide-d6): d 13.3 (pyrazoline 3-Me), 21.3 (CO2CHMe2), 48.1
(NCH2), 56.4 [Ph2C-C(CN)¼¼CH2], 68.9 (CO2CHMe2), 109.9
(pyrazoline C-4), 119.1 (CN), 124.5, 125.9, 126.8, 126.9, 127.9
(Ph-C), 128.1 [Ph2C-C(CN)¼¼CH2], 129.0, 129.1 (Ph-C), 130.5
[Ph2C-C(CN)¼¼CH2], 134.6, 141.1 (Ph-C), 154.6 (pyrazoline C-
3), 164.0 (pyrazoline C-5), 166.3 ppm (C¼¼O); ms: m/z 492 [M
þ H]þ. Anal. Calcd. for C31H29N3O3ꢂ0.2H2O: C, 75.19; H, 5.98;
N, 8.49. Found: C, 75.23; H, 5.99; N, 8.41.
(deuteriochloroform): d 1.72 (s, 3H, pyrazole 3-Me), 3.55 (s,
3H, CO2Me), 3.72 (s, 2H, OCH2), 5.96 (s, 1H, olefin H), 6.27
(s, 1H, olefin H), 7.27–7.43 (m, 13H, Ph-H), 7.69–7.71 ppm
(m, 2H, Ph-H); 13C NMR (deuteriochloroform): d 15.8 (pyraz-
ole 3-Me), 51.8 (CO2Me), 56.9 [Ph2C-C(CN)¼¼CH2], 69.7
(OCH2), 108.2 (pyrazole C-4), 119.4 (CN), 122.9, 127.3,
127.4, 128.1 (Ph-C), 129.1 [Ph2C-C(CN)¼¼CH2], 129.2, 130.0
(Ph-C), 131.9 [Ph2C-C(CN)¼¼CH2], 138.2, 140.8 (Ph-C), 148.7
(pyrazole C-3), 149.3 (pyrazole C-5), 167.1 ppm (C¼¼O); ms:
m/z 464 [M þ H]þ. Anal. Calcd. for C29H25N3O3: C, 75.14;
H, 5.44; N, 9.07. Found: C, 74.93; H, 5.49; N, 9.06.
{[3-Methyl-4-(a-methylene-b,b-diphenylpropanenitril-3-yl)-
1-phenyl-1H-pyrazol-5-yl]oxy}acetic acid ethyl ester (6b). This
compound was obtained as colorless prisms (0.172 g, 36%),
mp 120–122ꢀC (chloroform-petroleum ether); IR (potassium
1
bromide): m 2219 (CN), 1768 cmꢁ1 (C¼¼O); H NMR (deuter-
iochloroform): d 1.15 (t, J ¼ 7.3 Hz, 3H, CO2CH2Me), 1.71
(s, 3H, pyrazole 3-Me), 3.70 (s, 2H, OCH2), 4.03 (q, J ¼ 7.3
Hz, 2H, CO2CH2Me), 5.96 (s, 1H, olefin H), 6.27 (s, 1H, olefin
H), 7.27–7.42 (m, 13H, Ph-H), 7.70–7.72 ppm (m, 2H, Ph-H);
13C NMR (deuteriochloroform): d 14.0 (CO2CH2Me), 15.8 (pyr-
azole 3-Me), 56.9 [Ph2C-C(CN)¼¼CH2], 61.0 (CO2CH2Me),
69.8 (OCH2), 108.3 (pyrazole C-4), 119.4 (CN), 122.8, 127.2,
127.4, 128.1 (Ph-C), 129.1 [Ph2C-C(CN)¼¼CH2], 129.2, 130.0
(Ph-C), 131.8 [Ph2C-C(CN)¼¼CH2], 138.1, 140.7 (Ph-C), 148.7
(pyrazole C-3), 149.3 (pyrazole C-5), 166.6 ppm (C¼¼O); ms:
m/z 478 [M þ H]þ. Anal. Calcd. for C30H27N3O3: C, 75.45; H,
5.70; N, 8.80. Found: C, 75.55; H, 5.78; N, 8.83.
3-Methyl-4-(a-methylene-b,b-diphenylpropanenitril-3-yl)-5-
oxo-1-phenyl-3-pyrazoline-2-acetic acid tert-butyl ester
(5d). This compound was obtained as colorless prisms (0.298
g, 59%), mp 171–173ꢀC (chloroform-petroleum ether); IR (po-
1
tassium bromide): m 2226 (CN), 1746, 1664 cmꢁ1 (C¼¼O); H
{[3-Methyl-4-(a-methylene-b,b-diphenylpropanenitril-3-yl)-
1-phenyl-1H-pyrazol-5-yl]oxy}acetic acid isopropyl ester
(6c). This compound was obtained as colorless needles (0.212
g, 43%), mp 124–126ꢀC (chloroform-petroleum ether); IR (po-
NMR (dimethyl sulfoxide-d6): d 1.37 (s, 9H, CO2CMe3), 1.63
(s, 3H, pyrazoline 3-Me), 4.33 (s, 2H, NCH2), 5.81 (s, 1H, ole-
fin H), 6.16 (s, 1H, olefin H), 7.25–7.29 (m, 4H, Ph-H), 7.34–
7.38 (m, 9H, Ph-H), 7.47–7.50 ppm (m, 2H, Ph-H); 13C NMR
1
tassium bromide): m 2223 (CN), 1756, 1740 cmꢁ1 (C¼¼O); H
NMR (deuteriochloroform) d 1.14 (d, J ¼ 6.4 Hz, 6H,
CO2CHMe2), 1.72 (s, 3H, pyrazole 3-Me), 3.66 (s, 2H, OCH2),
4.92 (sep, J ¼ 6.4 Hz, 1H, CO2CHMe2), 5.96 (s, 1H, olefin
H), 6.27 (s, 1H, olefin H), 7.25–7.43 (m, 13H, Ph-H), 7.72–
7.73 ppm (m, 2H, Ph-H); 13C NMR (deuteriochloroform): d
15.8 (pyrazole 3-Me), 21.6 (CO2CHMe2), 56.9 [Ph2C-
C(CN)¼¼CH2], 68.8 (CO2CHMe2), 69.8 (OCH2), 108.3 (pyraz-
ole C-4), 119.4 (CN), 122.6, 127.1, 127.4, 128.1 (Ph-C), 129.1
[Ph2C-C(CN)¼¼CH2], 129.2, 130.0 (Ph-C), 131.8 [Ph2C-
C(CN)¼¼CH2], 138.2, 140.8 (Ph-C), 148.7 (pyrazole C-3),
149.2 (pyrazole C-5), 166.1 ppm (C¼¼O); ms: m/z 492 [M þ
H]þ. Anal. Calcd. for C31H29N3O3: C, 75.74; H, 5.95; N, 8.55.
Found: C, 75.84; H, 6.03; N, 8.54.
(dimethyl sulfoxide-d6):
d 13.2 (pyrazoline 3-Me), 27.5
(CO2CMe3), 48.7 (NCH2), 56.5 [Ph2C-C(CN)¼¼CH2], 82.1
(CO2CMe3), 109.7 (pyrazoline C-4), 119.1 (CN), 124.5, 126.8,
126.9, 127.9 (Ph-C), 128.1 [Ph2C-C(CN)¼¼CH2], 129.1 (Ph-C),
130.6 [Ph2C-C(CN)¼¼CH2], 134.7, 141.1 (Ph-C), 154.3 (pyra-
zoline C-3), 163.9 (pyrazoline C-5), 165.9 ppm (C¼¼O); ms:
m/z 506 [M þ H]þ. Anal. Calcd. for C32H31N3O3: C, 76.02;
H, 6.18; N, 8.31. Found: C, 76.06; H, 6.22; N, 8.20.
General procedure for the preparation of O-substituted
pyrazoles 6a–d and N-substituted dihydropyrazoles 7a–d
from 2 and a-chloro esters in the presence of potassium
carbonate. A mixture of 2 (0.391 g, 1 mmol), methyl chloroa-
catate (0.326 g, 3 mmol), ethyl chloroacatate (0.368 g, 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

102
E. Masumoto, H. Maruoka, F. Okabe, S. Nishida, Y. Yoshimura, T. Fujioka, and K. Yamagata
Vol 48
cmꢁ1 (C¼¼O); H NMR (deuteriochloroform): d 1.12, 1.15 (d,
J ¼ 6.1 Hz, 6H, CO2CHMe2), 1.32, 1.39 (d, J ¼ 6.4 Hz, 6H,
CO2CHMe2), 1.59 (s, 3H, pyrazoline 3-Me), 3.93 (d, J ¼ 17.7
Hz, 1H, NCH2), 4.33 (d, J ¼ 17.7 Hz, 1H, NCH2), 5.01, 5.13
(sep, J ¼ 6.4 Hz, 2H, 2 ꢃ CO2CHMe2), 5.35 (s, 1H, methine
H), 5.69 (s, 1H, olefin H), 5.88 (s, 1H, olefin H), 7.14–7.32
(m, 7H, Ph-H), 7.36–7.39 (m, 2H, Ph-H), 7.47–7.51 (m, 4H,
Ph-H), 7.61–7.63 ppm (m, 2H, Ph-H); 13C NMR (deuterio-
chloroform): d 19.6 (pyrazoline 3-Me), 21.56, 21.64, 21.7,
21.8 (2 ꢃ CO2CHMe2), 52.6 (NCH2), 59.6 [Ph2C-CH(CN)],
69.9, 71.8 (2 ꢃ CO2CHMe2), 76.2 (methine C), 111.5 (pyrazo-
line C-4), 119.9 (CN), 126.4, 126.5, 126.6, 127.0 (Ph-C),
127.8, 127.9 (olefin C), 128.9, 129.4, 130.2, 141.37, 141.43,
144.1 (Ph-C), 154.6 (pyrazoline C-3), 161.7 (pyrazoline C-5),
168.0, 169.8 ppm (C¼¼O); ms: m/z 592 [M þ H]þ. Anal.
Calcd. for C36H37N3O5ꢂ0.2H2O: C, 72.63; H, 6.33; N, 7.06.
Found: C, 72.59; H, 6.35; N, 7.08.
1
{[3-Methyl-4-(a-methylene-b,b-diphenylpropanenitril-3-yl)-
1-phenyl-1H-pyrazol-5-yl]oxy}acetic acid tert-butyl ester
(6d). This compound was obtained as colorless needles (0.182
g, 36%), mp 161–163ꢀC (chloroform-petroleum ether); IR (po-
1
tassium bromide): m 2231 (CN), 1748 cmꢁ1 (C¼¼O); H NMR
(deuteriochloroform): d 1.35 (s, 9H, CO2CMe3), 1.71 (s, 3H,
pyrazole 3-Me), 3.60 (s, 2H, OCH2), 5.96 (s, 1H, olefin H),
6.26 (s, 1H, olefin H), 7.25–7.43 (m, 13H, Ph-H), 7.72–7.74
ppm (m, 2H, Ph-H); 13C NMR (deuteriochloroform): d 15.8
(pyrazole 3-Me), 27.9 (CO2CMe3), 56.9 [Ph2C-C(CN)¼¼CH2],
67.0 (OCH2), 82.0 (CO2CMe3), 108.4 (pyrazole C-4), 119.4
(CN), 122.6, 127.1, 127.4, 128.1 (Ph-C), 129.18 [Ph2C-
C(CN)¼¼CH2], 129.21, 130.0 (Ph-C), 131.7 [Ph2C-
C(CN)¼¼CH2], 138.2, 140.7 (Ph-C), 148.6 (pyrazole C-3),
149.3 (pyrazole C-5), 165.6 ppm (C¼¼O); ms: m/z 506 [M þ
H]þ. Anal. Calcd. for C32H31N3O3: C, 76.02; H, 6.18; N, 8.31.
Found: C, 76.06; H, 6.24; N, 8.29.
(Z)-4-Cyano-5-[3-methyl-2-(methoxycarbonylmethylene)-5-
oxo-1-phenyl-3-pyrazolin-4-yl]-5,5-diphenyl-2-pentenoic acid
methyl ester (7a). This compound was obtained as colorless
needles (0.203 g, 38%), mp 209–210ꢀC (acetone-petroleum
ether); IR (potassium bromide): m 2224 (CN), 1750, 1736,
1639 cmꢁ1 (C¼¼O); 1H NMR (deuteriochloroform): d 1.58 (s,
3H, pyrazoline 3-Me), 3.67, 3.89 (s, 6H, 2 ꢃ CO2Me), 4.01
(d, J ¼ 18.0 Hz, 1H, NCH2), 4.35 (d, J ¼ 18.0 Hz, 1H,
NCH2), 5.41 (s, 1H, methine H), 5.57 (s, 1H, olefin H), 5.80
(s, 1H, olefin H), 7.17–7.45 (m, 11H, Ph-H), 7.50–7.52 (m,
2H, Ph-H), 7.69–7.70 ppm (m, 2H, Ph-H); 13C NMR (deuterio-
chloroform): d 19.3 (pyrazoline 3-Me), 51.6 (NCH2), 52.6,
53.7 (2 ꢃ CO2Me), 59.6 [Ph2C-CH(CN)], 76.0 (methine C),
112.5 (pyrazoline C-4), 119.7 (CN), 126.5, 126.6 (olefin C),
126.7, 127.9, 129.1, 129.8, 130.4, 133.3, 140.6, 141.0, 143.4
(Ph-C), 154.7 (pyrazoline C-3), 161.8 (pyrazoline C-5), 168.9,
171.2 ppm (C¼¼O); ms: m/z 536 [M þ H]þ. Anal. Calcd. for
C32H29N3O5: C, 71.76; H, 5.46; N, 7.85. Found: C, 71.75; H,
5.65; N, 7.73.
(Z)-5-[2-(Tert-butoxycarbonylmethylene)-3-methyl-5-oxo-1-
phenyl-3-pyrazolin-4-yl]-4-cyano-5,5-diphenyl-2-pentenoic acid
tert-butyl ester (7d). This compound was obtained as colorless
needles (0.254 g, 41%), mp 149–151ꢀC (chloroform-petroleum
ether); IR (potassium bromide): m 2224 (CN), 1737, 1639
1
cmꢁ1 (C¼¼O); H NMR (deuteriochloroform): d 1.35, 1.53 (s,
18H, 2 ꢃ CO2CMe3), 1.55 (s, 3H, pyrazoline 3-Me), 3.84 (d,
J ¼ 18.0 Hz, 1H, NCH2), 4.28 (d, J ¼ 18.0 Hz, 1H, NCH2),
5.27 (s, 1H, methine H), 5.58 (s, 1H, olefin H), 5.83 (s, 1H,
olefin H), 7.14–7.26 (m, 5H, Ph-H), 7.29–7.39 (m, 4H, Ph-H),
7.48–7.53 (m, 4H, Ph-H), 7.64–7.66 ppm (m, 2H, Ph-H); 13C
NMR (deuteriochloroform): d 19.5 (pyrazoline 3-Me), 28.0 (2
ꢃ
CO2CMe3), 53.5 (NCH2), 59.6 [Ph2C-CH(CN)], 76.6
(methine C), 83.0, 84.7 (2 ꢃ CO2CMe3), 111.1 (pyrazoline C-
4), 120.0 (CN), 122.8, 126.4, 126.6 (Ph-C), 127.0, 127.1 (ole-
fin C), 127.2, 127.5, 127.8, 127.9, 128.8, 129.6, 130.5, 140.8,
141.6, 144.3 (Ph-C), 154.9 (pyrazoline C-3), 161.7 (pyrazoline
C-5), 167.7, 169.7 ppm (C¼¼O); ms: m/z 620 [M þ H]þ. Anal.
Calcd. for C38H41N3O5ꢂ0.8H2O: C, 71.97; H, 6.77; N, 6.63.
Found: C, 71.97; H, 6.59; N, 6.63.
(Z)-4-Cyano-5-[2-(ethoxycarbonylmethylene)-3-methyl-5-
oxo-1-phenyl-3-pyrazolin-4-yl]-5,5-diphenyl-2-pentenoic acid
ethyl ester (7b). This compound was obtained as colorless
needles (0.192 g, 34%), mp 124–126ꢀC (chloroform-petroleum
ether); IR (potassium bromide): m 2224 (CN), 1743, 1638
cmꢁ1 (C¼¼O); 1H NMR (deuteriochloroform): d 1.15, 1.34 (t,
J ¼ 7.3 Hz, 6H, 2 ꢃ CO2CH2Me), 1.59 (s, 3H, pyrazoline 3-
Me), 3.99 (d, J ¼ 18.0 Hz, 1H, NCH2), 4.13 (q, J ¼ 7.3 Hz,
2H, CO2CH2Me), 4.36 (d, J ¼ 18.0 Hz, 1H, NCH2), 4.32–4.38
(m, 2H, CO2CH2Me), 5.39 (s, 1H, methine H), 5.62 (s, 1H,
olefin H), 5.83 (s, 1H, olefin H), 7.18–7.52 (m, 13H, Ph-H),
7.66–7.68 ppm (m, 2H, Ph-H); 13C NMR (deuteriochloroform):
d 13.96, 14.0 (2 ꢃ CO2CH2Me), 19.4 (pyrazoline 3-Me), 52.0
(NCH2), 59.6 [Ph2C-CH(CN)], 61.9, 63.3 (2 ꢃ CO2CH2Me),
76.1 (methine C), 112.0 (pyrazoline C-4), 119.7 (CN), 126.5,
126.6 (olefin C), 126.8, 127.0, 127.8, 127.9, 129.0, 129.7,
130.3, 141.0, 141.2, 143.6 (Ph-C), 154.8 (pyrazoline C-3),
161.8 (pyrazoline C-5), 168.5, 170.7 ppm (C¼¼O); ms: m/z 564
[M þ H]þ. Anal. Calcd. for C34H33N3O5: C, 72.45; H, 5.90;
N, 7.46. Found: C, 72.25; H, 6.09; N, 7.33.
The preparation of N-acetylated dihydropyridazinones
8a,b from 4a,b and acetic anhydride. A mixture of 4a
(0.463 g, 1 mmol) or 4b (0.477 g, 1 mmol) and acetic anhy-
dride (0.306 g, 3 mmol) in pyridine (5 mL) was stirred at
100ꢀC for 2 h. After removal of the solvent in vacuo, cold
water was added to the residue. The resulting mixture was
extracted with chloroform (60 mL). The extract was dried over
anhydrous sodium sulfate and concentrated in vacuo. The resi-
due was purified by column chromatography on silica gel with
chloroform as the eluent to provide 8a,b.
1-Acetyl-1,2,3,4-tetrahydro-6-methyl-3-oxo-2-phenyl-5-(a-
methylene-b,b-diphenylpropanenitril-3-yl)-4-pyridazinecarbox-
ylic acid methyl ester (8a). This compound was obtained as
colorless prisms (0.278 g, 55%), mp 214–216ꢀC (chloroform-
petroleum ether); IR (potassium bromide): m 2224 (CN), 1747,
1
1686, 1660 cmꢁ1 (C¼¼O); H NMR (dimethyl sulfoxide-d6): d
1.76 (s, 3H, 6-Me), 2.21 (s, 3H, COMe), 3.86 (s, 3H, CO2Me),
5.60 (s, 1H, olefin H), 6.00 (s, 1H, olefin H), 6.75 (s, 1H, 4-
H), 7.27–7.47 ppm (m, 15H, Ph-H); 13C NMR (dimethyl sulf-
oxide-d6): d 21.8 (6-Me), 23.1 (COMe), 53.5 (CO2Me), 59.4
[Ph2C-C(CN)¼¼CH2], 71.0 (C-4), 118.9 (CN), 125.3 (C-5),
126.5, 126.8, 127.00, 127.01, 127.9 (Ph-C), 128.0 [Ph2C-
C(CN)¼¼CH2], 128.1, 128.9, 129.1, 129.5 (Ph-C), 131.0 [Ph2C-
C(CN)¼¼CH2], 139.38, 139.40, 141.6 (Ph-C), 149.3 (C-6),
(Z)-4-Cyano-5-[2-(isopropoxycarbonylmethylene)-3-methyl-
5-oxo-1-phenyl-3-pyrazolin-4-yl]-5,5-diphenyl-2-pentenoic acid
isopropyl ester (7c). This compound was obtained as colorless
needles (0.166 g, 28%), mp 122–124ꢀC (chloroform-petroleum
ether); IR (potassium bromide): m 2224 (CN), 1733, 1637
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011
A Divergent Synthesis of Dihydropyridazinones, N-Substituted Dihydropyrazoles,
and O-Substituted Pyrazoles
103
160.5 (C-3), 169.2, 169.9 ppm (C¼¼O); ms: m/z 506 [M þ
H]þ. Anal. Calcd. for C31H27N3O4ꢂ1.0H2O: C, 71.11; H, 5.58;
N, 8.03. Found: C, 71.16; H, 5.48; N, 7.80.
described for the preparation of 9 from 6a–d and potassium
tert-butoxide, carboxylic acid derivative 9 was obtained in
56% yield (0.252 g).
1-Acetyl-1,2,3,4-tetrahydro-6-methyl-3-oxo-2-phenyl-5-(a-
methylene-b,b-diphenylpropanenitril-3-yl)-4-pyridazinecarbox-
ylic acid ethyl ester (8b). This compound was obtained as col-
orless prisms (0.182 g, 35%), mp 212–214ꢀC (chloroform-pe-
troleum ether); IR (potassium bromide): m 2224 (CN), 1751,
Acknowledgment. The authors thank Mr. Hiroshi Hanazono
and Ms. Yukiko Iwase for obtaining mass and NMR spectra and
to Ms. Junko Honda for her valuable help with elemental
analyses.
1
1688, 1656 cmꢁ1 (C¼¼O); H NMR (dimethyl sulfoxide-d6): d
1.28 (t, J ¼ 7.0 Hz, 3H, CO2CH2Me), 1.75 (s, 3H, 6-Me), 2.20
(COMe), 4.25–4.38 (m, 2H, CO2CH2Me), 5.60 (s, 1H, olefin
H), 6.00 (s, 1H, olefin H), 6.71 (s, 1H, 4-H), 7.25–7.48 ppm
(m, 15H, Ph-H); 13C NMR (dimethyl sulfoxide-d6): d 13.7
(CO2CH2Me), 21.9 (6-Me), 23.1 (COMe), 59.5 [Ph2C-
C(CN)¼¼CH2], 62.9 (CO2CH2Me), 70.9 (C-4), 119.0 (CN),
125.5 (C-5), 126.7, 126.9, 127.04, 127.07, 127.9, 128.0 (Ph-
C), 128.2 [Ph2C-C(CN)¼¼CH2], 128.9, 129.1, 129.5 (Ph-C),
131.0 [Ph2C-C(CN)¼¼CH2], 139.4, 139.5, 141.7 (Ph-C), 149.3
(C-6), 160.5 (C-3), 168.7, 170.0 ppm (C¼¼O); ms: m/z 520 [M
þ H]þ. Anal. Calcd. for C32H29N3O4ꢂ0.15H2O: C, 73.59; H,
5.65; N, 8.05. Found: C, 73.61; H, 5.77; N, 7.97.
The preparation of compound 7d from 5d and tert-butyl
chloroacetate. A mixture of 5d (0.505 g, 1 mmol), tert-butyl
chloroacatate (0.452 g, 3 mmol), and potassium carbonate
(0.276 g, 2 mmol) in N,N-dimethylformamide (5 mL) was
stirred at 120ꢀC for 1 h. After work-up as described for the
preparation of 7a–d, compound 7d was obtained in 72% yield
(0.446 g). The melting point and IR spectrum of this com-
pound coincided with an authentic sample prepared from 2
and tert-butyl chloroacatate.
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The preparation of carboxylic acid 9 from 6a–d and po-
tassium tert-butoxide. A mixture of 6a–d (1 mmol) and po-
tassium tert-butoxide (0.112 g, 1 mmol) in tert-butyl alcohol
(5 mL) was refluxed for 5 h. After removal of the solvent in
vacuo, a 5% hydrochloric acid solution (20 mL) was added to
the residue with stirring and ice cooling. The resulting mixture
was extracted with chloroform (60 mL). The extract was dried
over anhydrous sodium sulfate and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
with chloroform as the eluent to afford {[3-methyl-4-(a-meth-
ylene-b,b-diphenylpropanenitril-3-yl)-1-phenyl-1H-pyrazol-5-
yl]oxy}acetic acid (9) [from 6a: 0.184 g (41%), from 6b:
0.130 g (29%), from 6c: 0.117 g (26%), and from 6d: 0.216 g
(48%)]. This compound was obtained as colorless needles, mp
80–83ꢀC (chloroform-petroleum ether); IR (potassium bro-
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1
mide): m 3447 (OH), 2224 (CN), 1744 cmꢁ1 (C¼¼O); H NMR
(deuteriochloroform): d 1.72 (s, 3H, pyrazole 3-Me), 3.76 (s,
2H, OCH2), 5.96 (s, 1H, olefin H), 6.26 (s, 1H, olefin H), 6.63
(br, 1H, CO2H), 7.23–7.50 (m, 13H, Ph-H), 7.61–7.69 ppm
(m, 2H, Ph-H); 13C NMR (deuteriochloroform): d 15.7 (pyraz-
ole 3-Me), 56.9 [Ph2C-C(CN)¼¼CH2], 69.1 (OCH2), 108.3
(pyrazole C-4), 119.4 (CN), 123.0, 127.5, 127.6, 128.2 (Ph-C),
128.9 [Ph2C-C(CN)¼¼CH2], 129.4, 129.9 (Ph-C), 131.9 [Ph2C-
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148.83 (pyrazole C-5), 169.8 ppm (C¼¼O); ms: m/z 450 [M þ
H]þ. Anal. Calcd. for C28H23N3O3ꢂ0.4H2O: C, 73.64; H, 5.25;
N, 9.20. Found: C, 73.75; H, 5.64; N, 8.89.
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