Ring transformation of spirocyclopropanepyrazoles into pyrano[2,3-c] pyrazoles

Article abstract of DOI:10.1002/jhet.117

(Chemical Equation Presented) An approach to pyrano[2,3-c]pyrazoles starting from spirocyclopropanepyrazoles via a ring-opening/cyanomethylation and intramolecular cyclization is described. Reactions of spirocyclopropanepyrazoles 1a-d with chloroacetonitr

Full text of DOI:10.1002/jhet.117

782
Ring Transformation of Spirocyclopropanepyrazoles
into Pyrano[2,3-c]pyrazoles
Vol 46
Hiroshi Maruoka,* Eiichi Masumoto, Takafumi Eishima, 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 12, 2009
DOI 10.1002/jhet.117
Published online 7 July 2009 in Wiley InterScience (www.interscience.wiley.com).
An approach to pyrano[2,3-c]pyrazoles starting from spirocyclopropanepyrazoles via a ring-opening/
cyanomethylation and intramolecular cyclization is described. Reactions of spirocyclopropanepyrazoles
1a-d with chloroacetonitrile in the presence of sodium hydride gave the corresponding cyanomethoxy-
pyrazoles 4a-d. Treatment of 4a-d with sodium hydride at room temperature caused intramolecular
Michael addition reaction to afford the corresponding pyrano[2,3-c]pyrazoles 5a-d.
J. Heterocyclic Chem., 46, 782 (2009).
INTRODUCTION
RESULTS AND DISCUSSION
In many biologically active compounds, the pyrazole
core is a privileged substructure. Compounds containing
this ring system are known to display diverse pharmaco-
logical activities such as analgesic, antidepressant, anti-
bacterial, plant growth regulatory, anti-inflammatory and
antihyperglycemic activities [1–10]. In this context, the
synthesis of pyrazole derivatives continues to attract
attention and provides an interesting challenge [11–16].
In connection with our current research interests in this
area, we have reported the synthesis of 1-acyl-1,2-dihy-
dro-3H-pyrazol-3-ones through Lewis acid-mediated rear-
rangement of 3-acyloxypyrazoles [17]. More recently, we
have also discussed the efficient method for the prepara-
tion of spirocyclopropanepyrazoles [18].
The starting materials, spiro compounds 1a-d, were
prepared by treatment of 2,4-dihydro-5-methyl-2-phenyl-
4-(diphenylmethylene)-3H-pyrazol-3-one and a-chloro
esters according to our previous investigation [18].
When a mixture of 1a-d and sodium hydride in N,N-
dimethylformamide was stirred at room temperature for
1 h, pyrazol-3-ones 2a-d were obtained in excellent
yields (Scheme 1 and Table 1). The IR spectra of 2a-d
display bands near 3100 cmꢀ1 due to the secondary
amino group and in the range of 1650–1690 cmꢀ1 due
1
to the two carbonyl groups. The H NMR spectra of 2a-
d in deuteriochloroform exhibit a D2O exchangeable
signal near d 10 attributable to the secondary amino pro-
ton. The 13C NMR spectra of 2a-d show two signals
near d 120 and 150 due to the olefin carbons, whereas
those of 1a-d show three signals near d 50 due to the
spirocyclopropane carbons. Elemental analyses and
spectral data of 2a-d are consistent with the proposed
structures (see experimental section).
Some heterocyclic compounds containing condensed
pyrazoles such as pyrano[2,3-c]pyrazoles possess a wide
spectrum of pharmacological action, including analgesic,
anti-inflammatory, vasodilating and antihypertensive
activities [19–21]. Hence, the preparation and biological
properties of new substituted pyrano[2,3-c]pyrazoles are
of interest [22–36]. For these reasons, we focused our
attention on the development of a new method for the
preparation of pyrano[2,3-c]pyrazoles starting from spi-
rocyclopropanepyrazoles and now report the results of
our investigation, a ring-opening/cyanomethylation and
intramolecular cyclization of them in the presence of a
base such as sodium hydride.
Fortunately, we found the reaction condition under
which ring-opening products 2a-c could be isolated in
the presence of a Lewis acid. Titanium(IV) chloride-cat-
alyzed ring-opening reactions have already been
reported in the literature [37–39]. Subsequently, thermal
treatment of 1a-c with titanium(IV) chloride in chloro-
form caused ring opening of cyclopropane to give the
corresponding pyrazol-3-ones 2a-c in good yields. The
C
V
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July 2009
Ring Transformation of Spirocyclopropanepyrazoles into Pyrano[2,3-c]pyrazoles
783
Scheme 1
Scheme 2
the formation of 3 is not clear at present, this is prob-
ably because the metal complex containing chelate ring
coordinated by both carboxyl and hydroxyl groups
would be easily formed as an intermediate in this
reaction.
The formation of the pyrazole-3-ones 2 could be
explained by possible mechanism presented in Scheme
1. Thus, the reaction of spiro compounds 1 with sodium
hydride probably causes the ring opening of cyclopro-
pane via deprotonation to give the sodium salts A of
pyrazole, which could then undergo protonation of A to
afford the pyrazoles 2. On the other hand, treatment of
1 with titanium(IV) chloride probably causes ring open-
ing reaction via an attack of chloride ion to cyclopro-
pane ring, giving the intermediate chlorine-containing
compound B. The pyrazol-3-ones 2 would then be pro-
duced easily from B through an elimination of hydrogen
chloride.
Based on these results, we hypothesized if a cyano-
methylation of sodium salts A of pyrazole could
undergo readily under an appropriate reaction condition,
the synthesis of cyanomethylated pyrazoles would be
possible. Thus, we carried out the cyanomethylation of
spiro compounds 1 with chloroacetonitrile by use of a
sodium hydride/N,N-dimethylformamide system. Con-
trary to our expectation, when a mixture of 1a-d and
sodium hydride in N,N-dimethylformamide was stirred
at room temperature for 1 h and then the reaction mix-
ture was treated with chloroacetonitrile at 60ꢁC for 1 h,
the O-cyanomethylated pyrazoles 4a-d were obtained in
moderate to good yields (Scheme 3 and entries 1–4 in
Table 2). By comparison of the NMR, mass spectra and
elemental analyses of 4a-d it seems that the structural
assignments given to these compounds are correct. In
this reaction, C- and/or N-cyanomethylated pyrazoles
were not detected.
melting points and IR spectra of these compounds 2a-c
coincided with those of samples prepared from 1a-c and
sodium hydride as described above. Interestingly, in the
case of the reaction of 1d as the substrate, the expected
product 2d could not be produced but instead the car-
boxylic acid 3 was obtained in 93% yield (Scheme 2
and see ‘‘Experimental’’ section). To confirm the struc-
ture of 3, we carried out the hydrolysis of compound
2b. Thus, thermal treatment of 2b with potassium
hydroxide in aqueous ethanol afforded the carboxylic
acid 3 (73%), which was confirmed by direct compari-
son with an authentic sample prepared from 1d and tita-
nium(IV) chloride. Although the detailed mechanism for
Table 1
Synthesis of compounds 2a-d according to Scheme 1.
Entry
1
Substrate
Product
Yield (%)
1a
2a
99a
99b
99a
99b
99a
99b
86a
0b
Scheme 3
2
3
4
1b
1c
1d
2b
2c
2d
a NaH/DMF, r.t., 1 h.
b TiCl4/CHCl3, reflux, 1h.
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H. Maruoka, E. Masumoto, T. Eishima, F. Okabe, S. Nishida, Y. Yoshimura, T. Fujioka,
and K. Yamagata
Vol 46
Table 2
equivalent of 1a-d and 1.0 equivalent of sodium hydride
in N,N-dimethylformamide was stirred at room tempera-
ture for 1 h, the reaction mixture was treated with 1.0
equivalent of chloroacetonitrile at 60ꢁC for 1 h and then
with 0.5 equivalent of sodium hydride at room tempera-
ture, the corresponding pyrano[2,3-c]pyrazoles 5a-d
were obtained in moderate yields (Table 3).
Synthesis of compounds 4a-d and 5a-d according to Scheme 3.
Entry
Substrate
Product
Yield (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
4a
4b
4c
4d
4a
4b
4c
4d
5a
5b
5c
5d
67
58
76
85
35
61
56
58
In conclusion, we have developed a novel method for
the construction of pyrano[2,3-c]pyrazole derivatives 5a-
d, proceeding by a ring-opening/cyanomethylation and
intramolecular cyclization when spirocyclopropane-
pyrazoles 1a-d are treated with chloroacetonitrile in the
presence of sodium hydride. This methodology offers
significant advantages with regard to the supply of pyr-
ano[2,3-c]pyrazoles, which may exhibit biological activ-
ities such as analgesic, anti-inflammatory, vasodilating
and antihypertensive activities. Functionalized pyr-
ano[2,3-c]pyrazoles are important synthons in organic
synthesis and for the preparation of biologically active
compounds with interest in medicinal chemistry. Further
studies on the synthesis of new substituted pyrano[2,3-
c]pyrazoles are under way.
To confirm the O-cyanomethylated pyrazoles 4, we
next examined the conversion of 4 into the fused pyraz-
ole derivatives in the presence of a base. After some
optimization, the best result was obtained when 4a-d
were treated with sodium hydride in N,N-dimethylfor-
mamide at room temperature, the expected pyrano[2,3-
c]pyrazoles 5a-d was isolated in moderate yields
(Scheme 3 and entries 5–8 in Table 2). Although, we
tested the reactions under the other conditions such as
a potassium tert-butoxide/N,N-dimethylformamide and
potassium tert-butoxide/tert-butyl alcohol system, those
attempts were unacceptable with respect to yield. It
makes us believe that the intramolecular Michael addi-
tion reaction of 4 can only be promoted by using a
sodium hydride/N,N-dimethylformamide system.
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-
The IR spectra of 5a-d display bands near 2250 cmꢀ1
due to
a nonconjugated cyano group and near
1730 cmꢀ1 due to a carbonyl group. The H NMR spec-
tra of 5a-d in deuteriochloroform exhibit a signal near d
5.0 attributable to the 4-methine proton and a signal
near d 6.0 attributable to the 6-methine proton. The 13C
NMR spectra of 5a-d show a signal near d 50 due to
the 4-methine carbon, a signal near d 60 due to the
5-quaternary carbon and a signal near d 70 due to the
6-methine carbon, whereas those of 4a-d show a signal
near d 40 due to the methylene carbon and two signals
near d 120 and 150 due to the olefin carbons. Elemental
analyses and spectral data of 4 and 5 are consistent with
the assigned structures (see experimental section). In
addition, for products 5a-d, a clear nuclear Overhauser
effect was not observed between 4-methine proton and
6-methine proton of trans configuration. These results
indicate that trans-pyrano[2,3-c]pyrazoles are more
stable than cis-pyrano[2,3-c]pyrazoles.
1
trometer. The elemental analyses were performed on
YANACO MT-6 CHN analyzer.
a
General Procedure for the Preparation of Ring-Opening
Products 2a-d from 1a-d. Procedure A. To an ice-cooled
and stirred solution of 1a-d [18] (1 mmole) in N,N-dimethyl-
formamide (5 mL) was added 60% sodium hydride (0.04 g,
1 mmole). After the mixture was stirred at room temperature
for 1 h, the solvent was removed 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 chloro-
form-acetone (4:1) as the eluent to afford 2a (0.404 g, 99%),
Table 3
Finally, on the basis of these results, we have tried to
directly construct pyrano[2,3-c]pyrazoles 5 starting from
sipro compounds 1 in a one-pot process. To optimize
the yield of 5, we carried out several further experi-
ments on 1, testing different reaction conditions, e.g.
time, solvent and substrate/base molar ratio. The results
are summarized in Table 3. After a mixture of 1.0
Synthesis of pyrano[2,3-c]pyrazoles 5a-d starting from 1a-d.
Entry
Substrate
Product
Yield (%)
1
2
3
4
1a
1b
1c
1d
5a
5b
5c
5d
28
47
44
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Ring Transformation of Spirocyclopropanepyrazoles into Pyrano[2,3-c]pyrazoles
785
2b (0.420 g, 99%), 2c (0.436 g, 99%) and 2d (0.388 g, 86%),
respectively.
colorless needles, mp 175–177ꢁC (chloroform-petroleum
ether); IR (potassium bromide): m 3106 (NH), 1706, 1683,
1656 cmꢀ1 (C¼¼O); 1H NMR (deuteriochloroform): d 1.14,
1.16 (s, 9H, CO2CMe3), 1.29, 1.69 (s, 3H, 5-Me), 6.65 (d, J ¼
7.3 Hz, 1.35H, PhAH), 6.94–6.96 (m, 1.35H, PhAH), 7.11–
7.46 (m, 10.3H, PhAH), 7.77 (d, J ¼ 7.9 Hz, 0.65H, PhAH),
7.85 (d, J ¼ 7.9 Hz, 1.35H, PhAH), 9.26, 10.74 ppm (s, 1H,
NH); 13C NMR (deuteriochloroform): d 11.9, 13.4 (5-Me),
27.2, 27.4, 27.5 (CO2CMe3), 82.3, 83.8 (CO2CMe3), 97.6,
108.3 (C-4), 117.8, 118.8, 121.4 (PhAC), 124.0
(Ph2C¼¼CACO2CMe3), 124.1, 124.7, 125.7, 127.5, 127.7,
127.8, 127.9, 128.0, 128.2, 128.3, 128.7, 128.8, 128.9, 129.3,
129.6, 129.7, 130.6, 137.5, 138.8, 140.4, 141.2, 141.6,
142.9, 145.4 (PhAC), 146.0, 149.4 (C-5), 149.5, 150.4
(Ph2C¼¼CACO2CMe3), 162.9, 171.3, 171.5, 176.3 ppm
(C¼¼O); ms: m/z 453 [MþH]þ. Anal. Calcd. for
C29H28N2O3ꢂ0.5H2O: C, 75.47; H, 6.33; N, 6.07. Found: C,
75.51; H, 6.27; N, 6.06.
Procedure B. To an ice-cooled and stirred solution of 1a-c
(1 mmole) in chloroform (5 mL) was added titanium(IV) chlo-
ride (0.38 g, 2 mmoles). After the mixture was refluxed for
1 h, a 5% hydrochloric acid solution (20 mL) was added to
the reaction mixture with stirring and ice-cooling. After work-
up as described above, 2a (0.406 g, 99%), 2b (0.419 g, 99%)
and 2c (0.435 g, 99%) were obtained.
Methyl 2-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-
4-yl)-3,3-diphenylacrylate (2a). This compound was obtained
as pale yellow needles, mp 141–143ꢁC (chloroform-petroleum
ether); IR (potassium bromide): m 3060 (NH), 1714, 1685,
1656 cmꢀ1 (C¼¼O); 1H NMR (deuteriochloroform): d 1.32 (s,
3H, 5-Me), 3.37 (s, 3H, CO2Me), 6.72 (d, J ¼ 7.3 Hz, 2H, Ph-
H), 6.99 (d, J ¼ 3.7 Hz, 2H, PhAH), 7.15–7.44 (m, 9H,
PhAH), 7.79 (d, J ¼ 7.9 Hz, 2H, PhAH), 10.33 ppm (s, 1H,
NH); 13C NMR (deuteriochloroform): d 12.0 (5-Me), 52.3
(CO2Me), 107.9 (C-4), 118.0, 121.6 (PhAC), 122.2
(Ph2C¼¼CACO2Me), 124.6, 125.0, 127.9, 128.0, 128.1, 128.5,
128.7, 128.9, 129.1, 130.4, 137.1, 141.2, 142.4 (PhAC), 149.1
(C-5), 150.2 (Ph2C¼¼CACO2Me), 162.7, 172.9 ppm (C¼¼O);
ms: m/z 411 [MþH]þ. Anal. Calcd. for C26H22N2O3ꢂ0.2H2O:
C, 75.42; H, 5.45; N, 6.77. Found: C, 75.59; H, 5.45; N, 6.75.
Ethyl 2-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-
4-yl)-3,3-diphenylacrylate (2b). This compound was obtained
as pale yellow needles, mp 149–151ꢁC (chloroform-petroleum
ether); IR (potassium bromide): m 3110 (NH), 1711, 1680,
1656 cmꢀ1 (C¼¼O); 1H NMR (deuteriochloroform): d 0.69,
0.91 (t, J ¼ 7.1 Hz, 3H, CO2CH2Me), 1.31, 1.62 (s, 3H, 5-
Me), 3.90, 3.96 (q, J ¼ 7.1 Hz, 2H, CO2CH2Me), 6.68 (d, J ¼
7.3 Hz, 2H, PhAH), 6.97–7.45 (m, 11H, PhAH), 7.70–7.83
(m, 2H, PhAH), 8.43, 10.47 ppm (s, 1H, NH); 13C NMR (deu-
teriochloroform): d 12.0 (5-Me), 13.1, 13.3 (CO2CH2Me), 61.7
(CO2CH2Me), 108.0 (C-4), 117.9, 118.9, 121.5 (PhAC), 122.4
(Ph2C¼¼CACO2CH2Me), 124.4, 127.8, 128.0, 128.1, 128.5,
128.9, 129.0, 129.3, 130.4, 137.2, 141.3, 142.7 (PhAC), 149.3
(C-5), 150.2 (Ph2C¼¼CACO2CH2Me), 162.8, 172.5 ppm
(C¼¼O); ms: m/z 425 [MþH]þ. Anal. Calcd. for C27H24N2O3:
C, 76.39; H, 5.70; N, 6.60. Found: C, 76.46; H, 5.78; N, 6.42.
Isopropyl 2-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-
4-yl)-3,3-diphenylacrylate (2c). This compound was obtained as
pale yellow needles, mp 196–198ꢁC (chloroform-petroleum
ether); IR (potassium bromide): m 3126 (NH), 1706, 1671, 1644
The Preparation of Carboxylic Acid Derivative 3 from
1d and/or 2b. Procedure A. To an ice-cooled and stirred
solution of 1d [18] (0.45 g, 1 mmole) in 1,2-dichloroethane
(5 mL) was added titanium(IV) chloride (0.38 g, 2 mmoles).
After the mixture was refluxed for 4 h, a 5% hydrochloric acid
solution (20 mL) was added to the reaction mixture with stir-
ring and ice-cooling. The precipitate was collected by filtra-
tion, washed with water, dried and recrystallized from chloro-
form-methanol to yield 2-(5-hydroxy-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-3,3-diphenylacrylic acid (3) (0.37 g, 93%) as
colorless needles, mp 277–279ꢁC; IR (potassium bromide): m
1
3448 (OH), 1676 cmꢀ1 (C¼¼O); H NMR (dimethyl sulfoxide-
d6): d 1.67 (s, 3H, 3-Me), 7.05–7.07 (m, 2H, PhAH), 7.17–
7.24 (m, 6H, PhAH), 7.39–7.42 (m, 5H, PhAH), 7.63–7.65
(m, 2H, PhAH), 11.04, 12.21 ppm (s, 2H, 2ꢃOH); 13C NMR
(dimethyl sulfoxide-d6): d 12.2 (3-Me), 118.3 (C-4), 124.3
(Ph2C¼¼CACO2H), 124.6, 127.4, 127.6, 127.7, 127.8, 128.8,
129.0, 129.6, 137.4, 141.8 (PhAC), 142.2 (C-3), 147.1 (C-5),
147.5 (Ph2C¼¼CACO2H), 169.9 ppm (C¼¼O); ms: m/z 397
[MþH]þ. Anal. Calcd. for C25H20N2O3: C, 75.74; H, 5.09; N,
7.07. Found: C, 75.62; H, 5.13; N, 6.91.
Procedure B. After a mixture of 2b (0.42 g, 1 mmole) and
potassium hydroxide (0.56 g, 10 mmoles) in ethanol (5 mL)
and water (2 mL) was refluxed for 8 h, the solvent was
removed in vacuo. A 10% hydrochloric acid solution (20 mL)
was added to the residue with stirring and ice-cooling. The
precipitate was collected by filtration, washed with water,
dried and recrystallized from chloroform-methanol to yield 3
(0.289 g, 73%).
General Procedure for the Preparation of Cyanomethox-
ypyrazoles 4a-d from 1a-d and chloroacetonitrile. To an ice-
cooled and stirred solution of 1a-d (5 mmoles) in N,N-dimethyl-
formamide (15 mL) was added 60% sodium hydride (0.20 g,
5 mmoles). After the mixture was stirred at room temperature
for 1 h, chloroacetonitrile (0.76 g, 10 mmoles) was added to the
reaction mixture with stirring and then the resulting mixture was
stirred at 60ꢁC for 1 h. After the solvent was removed in vacuo,
a 5% hydrochloric acid solution (20 mL) was added to the resi-
due 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 resi-
due was purified by column chromatography on silica gel with
chloroform as the eluent to afford 4a-d.
1
cmꢀ1 (C¼¼O); H NMR (deuteriochloroform): d 0.85, 0.91 (d, J
¼ 6.4 Hz, 6H, CO2CHMe2), 1.32, 1.74 (s, 3H, 5-Me), 4.78, 4.84
(sep, J ¼ 6.4 Hz, 1H, CO2CHMe2), 6.69 (d, J ¼ 7.3 Hz, 1.2H,
PhAH), 6.97–6.99 (m, 1.2H, PhAH), 7.13–7.46 (m, 10.6H,
PhAH), 7.73 (d, J ¼ 7.6 Hz, 0.8H, PhAH), 7.82 (d, J ¼ 7.6 Hz,
1.2H, PhAH), 8.74, 10.35 ppm (s, 1H, NH); 13C NMR (deuterio-
chloroform): d 12.7, 13.4 (5-Me), 20.9, 21.01, 21.09, 21.11
(CO2CHMe2), 69.5, 70.1 (CO2CHMe2), 108.3, 118.0 (C-4),
118.8, 121.5, 122.9 (PhAC), 123.2, 124.4 (Ph2C¼¼CA
CO2CHMe2), 124.8, 125.8, 127.6, 127.8, 127.9, 128.0, 128.1,
128.3, 128.4, 128.6, 128.8, 128.9, 129.0, 129.4, 130.4, 137.3,
138.7, 141.2, 141.4, 142.7 (PhAC), 146.3, 147.0 (C-5), 149.4,
149.7 (Ph2C¼¼CACO2CHMe2), 162.8, 171.5, 171.8 ppm
(C¼¼O); ms: m/z 439 [MþH]þ. Anal. Calcd. for C28H26N2O3: C,
76.69; H, 5.98; N, 6.39. Found: C, 76.68; H, 6.03; N, 6.33.
tert-Butyl 2-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-
4-yl)-3,3-diphenylacrylate (2d). This compound was obtained as
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H. Maruoka, E. Masumoto, T. Eishima, F. Okabe, S. Nishida, Y. Yoshimura, T. Fujioka,
and K. Yamagata
Vol 46
Methyl 2-[5-(cyanomethoxy)-3-methyl-1-phenyl-1H-pyrazol-
4-yl]-3,3-diphenylacrylate (4a). This compound was obtained
as colorless prisms (1.51 g, 67%), mp 120–122ꢁC (acetone-
petroleum ether); IR (potassium bromide): m 2251 (CN), 1712
General Procedure for the Preparation of Pyrano[2,3-
c]pyrazoles 5a-d from 4a-d. To an ice-cooled and stirred so-
lution of 4a-d (1 mmole) in N,N-dimethylformamide (5 mL)
was added 60% sodium hydride (0.02 g, 0.5 mmole). After the
mixture was stirred at room temperature for 48 h, a 5% hydro-
chloric acid solution (20 mL) was added to the reaction mix-
ture 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 resi-
due was purified by column chromatography on silica gel with
chloroform as the eluent to give 5a-d.
1
cmꢀ1 (C¼¼O); H NMR (deuteriochloroform): d 2.05 (s, 3H, 3-
Me), 3.55 (s, 3H, CO2Me), 4.62 (s, 2H, OCH2CN), 7.08–7.10
(m, 2H, PhAH), 7.20–7.30 (m, 6H, PhAH), 7.34–7.43 ppm
(m, 7H, PhAH); 13C NMR (deuteriochloroform): d 13.3 (3-
Me), 52.1 (CO2Me), 57.9 (OCH2CN), 105.1 (C-4), 114.0 (CN),
121.5 (Ph2C¼¼CACO2Me), 122.7, 127.3, 128.1, 128.4, 128.6,
129.1, 129.2, 137.6, 140.5, 141.5 (PhAC), 148.3 (C-3), 148.4
(C-5), 150.8 (Ph2C¼¼CACO2Me), 170.2 ppm (C¼¼O); ms: m/z
450 [MþH]þ. Anal. Calcd. for C28H23N3O3: C, 74.82; H,
5.16; N, 9.35. Found: C, 74.98; H, 5.22; N, 9.29.
Methyl 6-cyano-3-methyl-1,5,5-triphenyl-1,4,5,6-tetrahydro-
pyrano[2,3-c]pyrazole-4-carboxylate (5a). This compound was
obtained as colorless prisms (0.155 g, 35%), mp 218–220ꢁC
(chloroform-petroleum ether); IR (potassium bromide): m 2255
(CN), 1740 cmꢀ1 (C¼¼O); 1H NMR (deuteriochloroform): d
2.28 (s, 3H, 3-Me), 3.26 (s, 3H, CO2Me), 4.40 (s, 1H, 4-H),
6.54 (s, 1H, 6-H), 7.15–7.38 (m, 13H, PhAH), 7.59–7.61 ppm
(m, 2H, PhAH); 13C NMR (deuteriochloroform): d 12.6 (3-
Me), 47.3 (C-4), 50.5 (C-5), 52.2 (CO2Me), 71.2 (C-6), 96.3
(C-3a), 115.4 (CN), 120.4, 126.3, 128.0, 128.3, 129.1, 137.8,
139.4, 140.5, (PhAC), 145.2 (C-3), 148.1 (C-7a), 171.8 ppm
(C¼¼O); ms: m/z 450 [MþH]þ. Anal. Calcd. for C28H23N3O3:
C, 74.82; H, 5.16; N, 9.35. Found: C, 74.96; H, 5.26; N, 9.34.
Ethyl 6-cyano-3-methyl-1,5,5-triphenyl-1,4,5,6-tetrahydro-
pyrano[2,3-c]pyrazole-4-carboxylate (5b). This compound was
obtained as pale yellow prisms (0.282 g, 61%), mp 187–189ꢁC
(chloroform-petroleum ether); IR (potassium bromide): m 2255
(CN), 1723 cmꢀ1 (C¼¼O); 1H NMR (deuteriochloroform): d
0.87 (t, J ¼ 7.3 Hz, 3H, CO2CH2Me), 2.29 (s, 3H, 3-Me),
3.62–3.69 (m, 1H, CO2CH2Me), 3.75–3.82 (m, 1H,
CO2CH2Me), 4.39 (s, 1H, 4-H), 6.59 (s, 1H, 6-H), 7.17–7.38
(m, 13H, PhAH), 7.59–7.62 ppm (m, 2H, PhAH); 13C NMR
(deuteriochloroform): d 12.7 (3-Me), 13.7 (CO2CH2Me), 47.2
(C-4), 50.5 (C-5), 61.3 (CO2CH2Me), 65.8 (C-6), 96.4 (C-3a),
115.5 (CN), 120.3, 126.2, 127.9, 128.2, 128.4, 129.1, 137.8,
139.6, 140.6 (PhAC), 145.1 (C-3), 148.1 (C-7a), 171.5 ppm
(C¼¼O); ms: m/z 464 [MþH]þ. Anal. Calcd. for
C29H25N3O3ꢂ0.5CH3CH2OCH2CH3: C, 74.38; H, 6.04; N,
8.39. Found: C, 74.53; H, 6.03; N, 8.39.
Ethyl 2-[5-(cyanomethoxy)-3-methyl-1-phenyl-1H-pyrazol-
4-yl]-3,3-diphenylacrylate (4b). This compound was obtained
as colorless prisms (1.35 g, 58%), mp 98–100ꢁC (acetone-petro-
leum ether); IR (potassium bromide): m 2244 (CN), 1713 cmꢀ1
1
(C¼¼O); H NMR (deuteriochloroform): d 0.95 (t, J ¼ 7.1 Hz,
3H, CO2CH2Me), 2.06 (s, 3H, 3-Me), 4.02 (q, J ¼ 7.1 Hz, 2H,
CO2CH2Me), 4.64 (s, 2H, OCH2CN), 7.09–7.10 (m, 2H,
PhAH), 7.20–7.44 ppm (m, 13H, PhAH); 13C NMR (deuterio-
chloroform):
d
13.4 (3-Me), 13.6 (CO2CH2Me), 57.9
(OCH2CN), 61.2 (CO2CH2Me), 105.1 (C-4), 114.0 (CN), 121.9
(Ph2C¼¼CACO2CH2Me), 122.7, 127.3, 128.1, 128.2, 128.4,
128.5, 129.2, 129.9, 137.6, 140.5, 141.7 (PhAC), 148.36 (C-3),
148.43 (C-5), 150.5 (Ph2C¼¼CACO2CH2Me), 169.8 ppm
(C¼¼O); ms: m/z 464 [MþH]þ. Anal. Calcd. for C29H25N3O3: C,
75.14; H, 5.44; N, 9.07. Found: C, 75.14; H, 5.52; N, 9.04.
Isopropyl 2-[5-(cyanomethoxy)-3-methyl-1-phenyl-1H-pyrazol-
4-yl]-3,3-diphenylacrylate (4c). This compound was obtained as
colorless needles (1.54 g, 65%), mp 143–145ꢁC (acetone-
petroleum ether); IR (potassium bromide): m 2244 (CN), 1716
cmꢀ1 (C¼¼O); 1H NMR (deuteriochloroform): d 0.97 (d, J ¼
6.4 Hz, 6H, CO2CHMe2), 2.09 (s, 3H, 3-Me), 4.68 (s, 2H,
OCH2CN), 4.88 (sep, J ¼ 6.4 Hz, 1H, CO2CHMe2), 7.19–7.23
(m, 2H, PhAH), 7.25–7.30 (m, 6H, PhAH), 7.33–7.35 (m, 3H,
PhAH), 7.37–7.43 ppm (m, 4H, PhAH); 13C NMR (deuterio-
chloroform):
d
13.4 (3-Me), 21.2 (CO2CHMe2), 58.0
(OCH2CN), 69.0 (CO2CHMe2), 105.0 (C-4), 114.0 (CN),
122.2 (Ph2C¼¼CACO2CHMe2), 122.7, 127.3, 128.1, 128.3,
128.4, 129.1, 129.3, 129.9, 137.5, 140.5, 141.6 (PhAC), 148.3
(C-3), 148.4 (C-5), 149.9 (Ph2C¼¼CACO2CHMe2), 169.3 ppm
(C¼¼O); ms: m/z 478 [MþH]þ. Anal. Calcd. for C30H27N3O3:
C, 75.45; H, 5.70; N, 8.80. Found: C, 75.43; H, 5.77; N, 8.75.
tert-Butyl 2-[5-(cyanomethoxy)-3-methyl-1-phenyl-1H-pyrazol-
4-yl]-3,3-diphenylacrylate (4d). This compound was obtained
as colorless needles (2.09 g, 85%), mp 85–87ꢁC (diethyl ether-
petroleum ether); IR (potassium bromide): m 2251 (CN), 1711
cmꢀ1 (C¼¼O); 1H NMR (deuteriochloroform): d 1.24 (s, 9H,
CO2CMe3), 2.13 (s, 3H, 3-Me), 4.70 (s, 2H, OCH2CN), 7.06–
7.08 (m, 2H, PhAH), 7.19–7.21 (m, 3H, PhAH), 7.25–7.29
(m, 3H, PhAH), 7.34–7.42 ppm (m, 7H, PhAH); 13C NMR
(deuteriochloroform): d 13.5 (3-Me), 27.6 (CO2CMe3), 58.0
(OCH2CN), 81.9 (CO2CMe3), 105.1 (C-4), 114.1 (CN), 122.8
(PhAC), 123.4 (Ph2C¼¼CACO2CMe3), 127.2, 128.0, 128.2,
129.1, 129.4, 129.8, 137.7, 140.6, 141.7 (PhAC), 148.4 (C-3),
148.5 (C-5), 149.5 (Ph2C¼¼CACO2CMe3), 168.6 ppm (C¼¼O);
ms: m/z 492 [MþH]þ. Anal. Calcd. for C31H29N3O3ꢂ0.3CH3-
CH2OCH2CH3: C, 75.27; H, 6.28; N, 8.18. Found: C, 75.26;
H, 6.47; N, 8.01.
Isopropyl 6-cyano-3-methyl-1,5,5-triphenyl-1,4,5,6-tetrahy-
dropyrano[2,3-c]pyrazole-4-carboxylate (5c). This compound
was obtained as colorless prisms (0.267 g, 56%), mp 188–
189ꢁC (chloroform-petroleum ether); IR (potassium bromide):
m 2254 (CN), 1718 cmꢀ1 (C¼¼O); 1H NMR (deuteriochloro-
form): d 0.62, 1.11 (d, J ¼ 6.4 Hz, 6H, CO2CHMe2), 2.30 (s,
3H, 3-Me), 4.36 (s, 1H, 4-H), 4.58 (sep, J ¼ 6.4 Hz, 1H,
CO2CHMe2), 6.65 (s, 1H, 6-H), 7.17–7.38 (m, 13H, PhAH),
7.59–7.61 ppm (m, 2H, PhAH); 13C NMR (deuteriochloro-
form): d 12.7 (3-Me), 21.0, 21.5 (CO2CHMe2), 47.1 (C-4),
50.3 (C-5), 69.0 (CO2CHMe2), 71.2 (C-6), 96.6 (C-3a), 115.5
(CN), 120.4, 126.2, 127.9, 128.2, 128.5, 129.1, 137.8, 139.7,
140.7 (PhAC), 145.0 (C-3), 148.1 (C-7a), 171.1 ppm (C¼¼O);
ms: m/z 478 [MþH]þ. Anal. Calcd. for C30H27N3O3: C, 75.45;
H, 5.70; N, 8.80. Found: C, 75.50; H, 5.84; N, 8.72.
tert-Butyl 6-cyano-3-methyl-1,5,5-triphenyl-1,4,5,6-tetrahy-
dropyrano[2,3-c]pyrazole-4-carboxylate (5d). This compound
was obtained as pale yellow prisms (0.287 g, 58%), mp 225–
227ꢁC (chloroform-petroleum ether); IR (potassium bromide):
m 2251 (CN), 1723 cmꢀ1 (C¼¼O); 1H NMR (deuteriochloro-
form): d 1.07 (s, 9H, CO2CMe3), 2.33 (s, 3H, 3-Me), 4.32 (s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Ring Transformation of Spirocyclopropanepyrazoles into Pyrano[2,3-c]pyrazoles
787
[11] Lamberth, C. Heterocycles 2007, 71, 1467.
1H, 4-H), 6.61 (s, 1H, 6-H), 7.20–7.38 (m, 13H, PhAH), 7.60–
7.62 ppm (m, 2H, PhAH); 13C NMR (deuteriochloroform): d
12.8 (3-Me), 27.5 (CO2CMe3), 47.6 (C-4), 50.4 (C-5), 71.2 (C-
6), 82.1 (CO2CMe3), 96.9 (C-3a), 115.6 (CN), 120.3, 126.2,
127.8, 128.1, 128.2, 128.7, 129.1, 137.9, 140.0, 140.9 (PhAC),
145.1 (C-3), 148.1 (C-7a), 170.6 ppm (C¼¼O); ms: m/z 492
[MþH]þ. Anal. Calcd. for C31H29N3O3: C, 75.74; H, 5.95; N,
8.55. Found: C, 75.74; H, 6.03; N, 8.51.
[12] Kralj, D.; Mecinovic, J.; Bevk, D.; Groselj, U.; Stanovnik,
B.; Svete, J. Heterocycles 2006, 68, 897.
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Heterocyclic Chemistry, Katritzky, A. R., Ed.; Elsevier: San Diego,
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Diego, 2001; Vol. 80, p 73.
General Procedure for the Preparation of Pyrano[2,3-
c]pyrazoles 5a-d from 1a-d and Chloroacetonitrile. To an
ice-cooled and stirred solution of 1a-d (1 mmole) in N,N-
dimethylformamide (5 mL) was added 60% sodium hydride
(0.04 g, 1 mmole). After the mixture was stirred at room tem-
perature for 1 h, chloroacetonitrile (0.075 g, 1 mmole) was
added to the reaction mixture with stirring and then the result-
ing mixture was stirred at 60ꢁC for 1 h. To an ice-cooled and
stirred solution of the reaction mixture was added 60% sodium
hydride (0.04 g, 1 mmole). After the mixture was stirred at
room temperature for 48 h, a 5% hydrochloric acid solution
(20 mL) was added to the reaction mixture with stirring and
ice-cooling. The resulting mixture was extracted with chloro-
form (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 form 5a (0.127 g, 28%), 5b (0.219 g, 47%), 5c
(0.208 g, 44%), and 5d (0.292 g, 59%), respectively.
[15] Elguero, J. In Comprehensive Heterocyclic Chemistry,
Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press: Oxford, 1984;
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Acknowledgments. 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.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet