Synthesis and chemistry of N-arylated pyrano[2,3-c]pyrazoles

Article abstract of DOI:10.1002/jhet.5570440623

(Chemical Equation Presented) Novel N2-arylated pyrano[2,3-c]pyrazol-6-ones 2 can be prepared in a selective manner by generating the anion of 1 (R=H) with lithium hexamethyldisilazide in DMF and quenching with activated aryl halides. Sterically demanding

Full text of DOI:10.1002/jhet.5570440623

Nov-Dec 2007
1389
Synthesis and Chemistry of N-Arylated Pyrano[2,3-c]pyrazoles
J. Geno Samaritoni, Scott Thornburgh, Paul R. Graupner*, and David H. Cooper
Discovery Research, Dow AgroSciences,
9330 Zionsville Road, Indianapolis, IN, 46268, USA;
E-mail: prgraupner@dow.com
Received January 4, 2007
R
R
O
R
4
3
LHMDS,
ArX
MeOH/OH-
COX
5
N
Ar
N
2
N
Ar
N
N
DMF/THF
R= Me, CF3, Ph
(8-61%)
or NHMe2
N
O
O
O
6
1
H
(31%-quant.)
[1]
[2]
X = OMe, NMe2
Novel N2-arylated pyrano[2,3-c]pyrazol-6-ones 2 can be prepared in a selective manner by generating
the anion of 1 (R=H) with lithium hexamethyldisilazide in DMF and quenching with activated aryl halides.
Sterically demanding groups such as phenyl as in 5 reduce reactivity significantly while electron-
withdrawing substituents such as trifluoromethyl and phenyl at C4 of the pyranone ring as in 10 and 15
render the pyranone carbonyl particularly susceptible to attack by nucleophiles resulting in ring-opening to
give novel crotonyl derivatives. Proof of structure required a variety of nmr methods involving proton,
carbon, and nitrogen nuclei.
J. Heterocyclic Chem., 44, 1389 (2007).
chemical shift of this N2 nitrogen is consistent with the
chemical shift of the substituted sp3 nitrogen of pyrazoles
[4].
INTRODUCTION
Since the early 1980s pyrano[2,3-c]pyrazoles 1 have
been reported to possess a wide spectrum of biological
activity of pharmaceutical interest [1]. We became
interested in this fused ring system for potential
agrichemical use as part of our discovery program.
Although there are numerous examples of substitution at
N1 of 1 [2], which are prepared using substituted
hydrazines, there are few reports which discuss alkyl
substitution at N2 [1a,1c,3] and the literature is silent on
the synthesis and characterization of N2-arylated pyrano-
[2,3-c]pyrazol-6-ones 2 which were of particular interest
to us. Two studies featuring the N-alkylation of 1 indicate
a preference for incorporation of the alkyl group at N2,
but reaction is by no means selective with ratios of N2:N1
alkylation approximately 2:1 [1a,1c]. In contrast we have
found that incorporation of an aryl group at N2 can be
accomplished with much greater selectivity which has
allowed access to novel N2-arylated pyrano[2,3-c]-
pyrazoles 2.
These results were corroborated with those obtained
from its regioisomer 1b which was synthesized in an
unequivocal manner from 5-trifluoromethyl-2-hydrazino-
pyridine and ethyl acetoacetate. The 1H-15N HMBC
spectrum of 1b shows a correlation between the C3
methyl protons at 2.51 ppm with a nitrogen at 281.1 ppm
consistent with an sp2 nitrogen atom at N2 of the pyrazole
ring.
The hexamethyldisilazide-generated anion of 1a was
also quenched with aryl halides to give N2-arylated
pyrano[2,3-c]pyrazol-6-ones 2b-d in moderate yields as
the only isolated arylation products. Although use of
additional aryl halide had minimal effect on product yield,
the use of DMF as co-solvent had resulted in enhanced
yields relative to THF alone in initial experiments.
We next turned our attention to the N-arylation of 5 in
which C3 is now occupied by the more sterically-
demanding phenyl ring (Scheme 1). Pyrano[2,3-c]-
pyrazol-6-one 5 was prepared from 4 [5] by the method
of Khan and coworkers [2]. Due to the greater steric
demand of the phenyl group at C3 and its electron-
withdrawing nature, N-arylation proceeded in very low
yield (10%) with 80% of the starting material
recovered. The ratio of 7:6 was found to be 4:1.
Assignment of the structures of 6 and 7 could not be
done from 1H-15N HMBC experiments due to the
absence of protons on the substituent at C3 which
correlate to the nitrogen N2. Experiments designed to
observe a nuclear Overhaeuser effect (nOe) between the
ortho-phenyl protons and H5 of the pyridine ring of
RESULTS AND DISCUSSION
Treatment of a cold solution of 1a in DMF with lithium
hexamethyldisilazide in THF followed by an excess of 2-
fluoro-5-trifluoromethylpyridine afforded a 59% yield of
2a (Scheme 1) with no N1-arylated isomer isolated. The
position of the pyridine ring at N2 of the pyrazole ring
1
was established by a H-15N heteronuclear multiple bond
correlation (HMBC) experiment which clearly indicated a
correlation consistent with a three-bond coupling from the
methyl protons at C3 of the pyrazole ring (3.01 ppm) to
the nitrogen N2 at 205.1 ppm. The relative upfield

1390
J. Samaritoni, S. Thornburgh, P. Graupner, D. Cooper
Vol 44
Scheme 1: Synthesis of N-arylayted Pyrano[2,3-c]pyrazoles
Y
Y
Y
Me
X
X
HO CF3
Me
X
CONH2
CO2Et
O
X
b
d
a
e
N
N
Ar
N
NR
Ar
N
N
N
NR
N
N
H
O
O
O
O
ZO
O
O
CO2Et
Y = CF3, Z = H 11
Y = Ph, Z = Ar 16
R = H, Ar
R = H, Ar
X = Ph, R = H
Me, R = H
9
X = Y = Me 2a-d
X = Me, Y = CF3 12
X = Ph, Y = Me 7
X = Y = Me 1a-e
X = Ph, Y = Me 5
X = Me, Y = CF3 10
X = Me, Y = Ph 15
4
8
d
c
a) CF3COCH2CO2Et, 170 °C/2.5h (81%), b) 180 °C/2h (65% from 8), c) ref. 2 (X = Ph), d) LHMDS, aryl halide, DMF/THF, e) 175 °C (Y = CF3)
both structures were unsuccessful. Assignment of
proton signals at 7.2 and 6.8 were attached to a single
nitrogen atom, confirming the presence of a primary
amide group. This was confirmed by IR which showed
an amide stretch at 1682 cm-1 and by mass spectral
analysis which gave a molecular ion 17 amu above that
of 12 consistent with addition of ammonia to 12. It was
found that heating 11 slightly above its melting point
resulted in cyclization to 12.
It is believed that 13 (Scheme 2) is initially formed but
the electron-withdrawing capacity of the trifluoromethyl
group at C4 enhances the electrophilicity of pyranone
carbonyl carbon rendering it susceptible to attack by
hexamethyldisilylamine to afford 14. Solvolysis of the
disilylamide then yields the observed primary amide 11.
Pyranone ring opening was also observed when the 4-
phenylpyranopyrazole 15 was arylated under these
conditions affording the primary amide 16. The reasons
cited above for the ring opening of 13 apply here, but in
this case the ring-opened hydroxypyrazole was also O-
arylated.
structure 6 was based on the substantial downfield shifts
1
of the pyridyl and otho phenyl protons in the H NMR
spectrum of 6 versus those observed for 7. Downfield
shifts of this type have been found to be indicative of
the degree of interannular conjugation and dihedral
angles between the aromatic rings in phenyl substituted
pyrazoles [6]. Steric interactions between the pyridinyl
protons at N-2 and the ortho phenyl protons at C3 of the
pyrazole ring impede coplanarity in 7 resulting in a
larger dihedral angle between the rings, reduced
interannular conjugation, and relative upfield shifts of
the pyridinyl and ortho-phenyl protons.
Me
Ph
N
N
O
O
Ar
6
Unexpected results were obtained from the N-
arylation of 10 in which a trifluoromethyl group is now
at C4 (Scheme 1). Pyranopyrazole 10 was prepared by
treatment of commercially available 5-methylpyrazol-3-
one 8 with ethyl trifluoroacetate. The initially formed
carbinol 9 is quite stable at 170 °C and was isolated and
fully characterized but will undergo cyclization to 10
when heated slightly above its melting point. When the
anion of 10 is treated with an excess of the aryl halide,
N-arylation takes place at N2, however, the pyranone
ring is also opened giving the primary amide 11 as the
major product. The proton NMR spectrum for 11
showed three broad exchangeable singlets at 9.6, 7.2,
and 6.8 ppm, while in the carbon NMR spectrum, there
were two downfield signals not attributable to the
pyridine. An HMBC spectrum indicated a long-range
4-bond cross-peak to the signal at 160 ppm, while the
olefinic singlet at 7.0 ppm was the only proton signal
that showed correlation to the other signal at 165 ppm -
suggesting a carbonyl from an acid or amide group. A
1H-15N-HMBC experiment determined that the two
Scheme 2
CF3
(Me3Si)2NH
10
N
Ar
N
O
O
13
CF3
OH
solvolysis
(Me3Si)2NOC
11
N
Ar
N
14
Although pyranone ring-opening had not been observed
during the arylations of 1a described above, we were
prompted to examine the behavior of the 4-methyl
derivatives 1c-d and 2c toward other nucleophiles.
Conditions used were 1) sodium hydroxide (one
equivalent) in methanol at room temperature and 2)
excess 40% aqueous dimethylamine in THF at room

Nov-Dec 2007
Synthesis and Chemistry of N-Arylated Pyrano[2,3-c]pyrazoles
1391
Starting materials and reagents which were obtained from
commercial sources were used without further purification.
Proton, carbon-13 and nitrogen-15 NMR spectra were obtained
on Bruker UltaShield 600 MHz, Bruker 400 MHz, or Varian
Gemini 300 MHz spectrometers and are reported in parts per
million (ꢀ) downfield from tetramethylsilane or aqueous
ammonia as internal reference. Mass spectra were obtained
using an LC/MS system consisting of a Waters SunFire C18 5μ
4.6x50 mm column, Waters 2996 photodiode array and Alltech
2420 ELSD detectors, and a Waters Micromass ZQ mass
spectrometer. Infrared spectra were obtained on a Digilab FTS
40 Pro spectrophotomer. Elemental analyses were provided by
Midwest Microlabs of Indianapolis, IN.
temperature. The results shown in Scheme 3 and Table 1
illustrate the ease with which the pyranone ring is opened
under mild conditions to afford methyl esters 17a-b and
N,N-dimethylamides 18a-b and 19 in moderate to good
yields.
Scheme 3: Reaction of pyranones with nucleophiles.
O
Me
HO
Me
NaOH
MeOH
OMe
N
N
17
Ar
General procedure for the preparation of pyrazol-6-ones
1b-1e. A 1-2 M solution of the hydrazine in ethyl acetoacetate
was heated under reflux for two to four hours in a round-
bottomed flask fitted with a Dean-Stark trap. Upon cooling the
precipitated pyrazolone was collected.
N
N
O
O
O
Me
Me
Ar
NMe2
1c-d
N
aq Me2NH
THF
N
HO
3,4-Dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-1H-pyrano-
[2,3-c]pyrazol-6-one (1b).
Ar
18
Obtained using 2-hydrazino-5-
trifluoromethylpyridine. Yield: 1.775 g (51%), tan solid, mp
214.5-216.5 °C; 1H nmr ꢀ (dimethyl sulfoxide-d6) 9.00 (m, 1H),
8.41 (dd, 1H, J = 8.9 Hz and J = 2.3 Hz), 8.00 (d, 1H, J = 8.6
Hz), 6.03 (q, 1H, J = 1.3 Hz), 2.50 (s, 3H), 2.45 (d, 3H, J = 1.3
Hz); ms (API-ES+) m/z 310 ([M+H+]+, 100). A portion was
recrystallized from ethyl acetate giving the following
microanalytical data: Anal. Calcd. for C14H10F3N3O2: C, 54.37;
H, 3.26; N, 13.59. Found: C, 54.14; H, 3.20; N, 13.43.
O
Me
Me
aq Me2NH
THF
NMe2
N
Ar
N
N
Ar
N
O
O
HO
2c
19
Table 1
1-(4-Chloro-phenyl)-3,4-dimethyl-1H-pyrano[2,3-c]pyrazol-
6-one (1c). Obtained using 4-chlorophenylhydrazine. Yield:
Results from scheme 3
1
2.68 g (58%), tan powder, mp 176-9 °C; H nmr ꢀ (dimethyl
Compound
Ar
Yield %
sulfoxide-d6) 7.83 (d, 2H, J = 9.1 Hz), 7.65 (d, 2H, J = 9.1 Hz),
5.97 (q, 1H, J = 1.4 Hz), 2.48 (s, 3H), 2.45 (d, 3H, J = 1.1 Hz);
ms (API-ES+) m/z 277 ([M+2+H+]+, 32), 275 ([M+H+]+, 100).
Anal. Calcd. for C14H11ClN2O2: C, 61.21; H, 4.04; N, 10.20.
Found: C, 61.22; H, 4.04; N, 10.08.
17a
17b
18b
19c
2-pyridyl
31
Quant
87
p-Chlorophenyl
p-Chlorophenyl
6-CF3-2-pyrimidinyl
70
3,4-Dimethyl-1-pyridin-2-yl-1H-pyrano[2,3-c]pyrazol-6-one
(1d). Obtained using 2-hydrazino-pyridine. Yield: 2.84 g
(64%), pink solid, mp 229-233.5 °C; 1H nmr (dimethyl
sulfoxide-d6) ꢀ 8.56 (m, 1H), 8.03 (m, 1H), 7.89 (m, 1H), 7.42
(m, 1H), 5.97 (d, 1H, J = 1.3 Hz), 2.48 (s, 3H), 2.44 (d, 3H, J =
1.3 Hz); 13C nmr ꢀ (CDCl3) 160.0, 153.4, 151.3, 149.9, 149.5,
145.7, 139.1, 122.7, 115.3, 106.4, 103.3, 20.2, 15.3; ms (API-
ES+) m/z 242 ([M+H+]+, 100). Anal. Calcd. for C13H11N3O2: C,
64.72; H, 4.60; N, 17.42. Found: C, 64.79; H, 4.46; N, 17.22.
3,4-Dimethyl-1-(4-trifluoromethyl-phenyl)-1H-pyrano[2,3-
c]pyrazol-6-one (1e). Obtained using 4-trifluoromethylphenyl-
hydrazine. Yield: 630 mg (38%), off-white powder, mp 152-4
CONCLUSIONS
Novel N2-arylated pyrano[2,3-c]pyrazol-6-ones 2 can
be prepared in a selective manner by generating the anion
of 1 with lithium hexamethyldisilazide in DMF and
quenching with activated aryl halides.
Sterically-demanding groups such as phenyl as in 5
reduce selectivity somewhat while electron-withdrawing
substituents such as trifluoromethyl and phenyl at C4 of
the pyranone ring as in 10 and 15 render the pyranone
carbonyl particularly susceptible to attack by nucleophiles
resulting in ring-opening to give novel crotonyl
derivatives. Proof of structure required a variety of nmr
methods involving proton, carbon, and nitrogen nuclei.
1
°C; H nmr ꢀ (dimethyl sulfoxide-d6) 8.03 (d, 2H, J = 8.9 Hz),
7.94 (d, 2H, J = 8.6 Hz), 5.99 (q, 1H, J = 1.0 Hz), 2.48 (s, 3H),
2.44 (d, 3H, J = 1.0 Hz); MS (API-ES+) m/z 309 ([M+H+]+,
100). A portion was recrystallized from ethyl acetate giving the
following microanalytical data: Anal. Calcd. for C15H11F3N2O2:
C, 58.44; H, 3.60; N, 9.10. Found: C, 57.92; H, 3.59; N, 8.86.
General procedure for the preparation of pyrazolones 2a-
2d. To a mixture cooled in a dry ice-isopropanol bath of 1
mmol of 1a (R = H) in 0.5-1.0 mL of dimethylformamide was
added dropwise via syringe 1.0 mmol of a 1.0 M solution of
lithium hexamethyldisilazide in tetrahydrofuran. After 30-90
minutes a solution of 2.6-3.0 equivalents of aryl halide in 0.5-1.0
mL in dimethylformamide was added dropwise via syringe.
After stirring overnight at room temperature, the mixture was
EXPERIMENTAL
Melting points were obtained on a Thomas Hoover Unimelt
capillary melting point apparatus and are uncorrected.
Chromatography was performed on silica gel (230-400 mesh
ASTM) obtained from EM Science, Darmstadt, Germany.

1392
J. Samaritoni, S. Thornburgh, P. Graupner, D. Cooper
Vol 44
concentrated to a residue which was partitioned between
saturated sodium carbonate and dichloromethane. The layers
were separated, the aqueous phase was extracted once with
dichloromethane and the combined extracts were dried
(MgSO4). Concentration gave crude material which was purified
by trituration, recrystallization, or chromatography.
([M+H+]+, 100). Anal. Calcd. for C19H12F3N3O2: C, 61.45; H,
3.26; N, 11.32. Found: C, 61.28; H, 3.01; N, 11.12.
Titled compound 6 was eluted first affording 8 mg (2%) of a
1
solid, mp 170-4 °C; H nmr ꢀ (deuteriochloroform) 8.92 (m,
1H), 8.13 (m, 2H), 7.63-7.52 (m, 5H), 6.00 (q, 1H, J = 1.1 Hz),
2.20 (d, 3H, J = 1.4 Hz), 1.58 (s, 3H); ms (API-ES+) m/z 372
([M+H+]+, 100).
3,4-Dimethyl-2-(5-trifluoromethyl-pyridin-2-yl)-2H-pyrano-
[2,3-c]pyrazol-6-one (2a). Obtained using 2-fluoro-5-trifluoro-
methylpyridine. Chromatography on silica gel using 1:1 hexanes/
4,4,4-Trifluoro-3-hydroxy-3-(5-hydroxy-3-methyl-1H-
pyrazol-4-yl)-butyric acid ethyl ester (9). A mixture of 508
mg (5.18 mmol) of 8 and 2.81 g (15.3 mmol) of 3,3,3-
trifluoroethylacetoacetate was heated at 170 °C for 2.5 h and
was allowed to cool and stand overnight. The mixture was
triturated under diethyl ether to afford 919 mg (63%) of 9 as a
light pink solid; ir (potassium bromide) 3499, 3367, 2518, 1712
cm-1; 1H nmr ꢀ (dimethyl sulfoxide-d6) 11.45 (br s, 1H), 9.90 (br
s, 1H), 6.40 (br s, 1H), 3.98 (q, 2H, J = 7.1 Hz), 3.37 (d, 1H, J =
Hz), 2.83 (d, 1H, J = 15.7 Hz), 2.19 (s, 3H), 1.11 (t, 3H, J = 7.1
Hz); ms (API-ES+) m/z 283 ([M+H+]+, 100);. A portion was
recrystallized from methanol to give an analytical sample, mp
171-4. Anal. Calcd. for C10H13F3N2O4: C, 42.55; H, 4.64; N,
9.93. Found: C, 42.43; H, 4.64; N, 9.88.
1
ethyl acetate as eluant: Yield 186 mg (59%), mp 198-201 °C; H
nmr ꢀ (deuteriochloroform) 8.75 (m, 1H), 8.11 (m, 2H), 5.97 (q,
1H, J = 1.1 Hz), 3.03 (s, 3H), 2.49 (d, 3H, J = 1.4 Hz); ms (API-
ES+) m/z 310 ([M+H+]+, 100). Anal. Calcd. for C14H10F3N3O2: C,
54.37; H, 3.26; N, 13.59. Found: C, 54.42; H, 3.37; N, 13.51.
3,4-Dimethyl-2-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-
2H-pyrano[2,3-c]pyrazol-6-one (2b). Obtained using 2-chloro-
5-trifluoromethyl-1,3,4-thiadiazole. Chromatography on silica
gel using 1:1 hexanes/ethyl acetate as eluant to afford 86 mg
1
(27%), mp 169-72 °C; H nmr ꢀ (deuteriochloroform) 6.05 (q,
1H, J = 1.4 Hz), 3.12 (s, 3H), 2.50 (d, 3H, J = 1.4 Hz); ms (70
eV, electron impact) m/z 316 (M+, 100). Anal. Calcd. for
C11H7F3N4O2S: C, 41.77; H, 2.23; N, 17.72. Found: C, 41.55;
H, 2.17; N, 17.35.
3-Methyl-4-trifluoromethyl-1H-pyrano[2,3-c]pyrazol-6-
one (10). A mixture of 483 mg (4.92 mmol) of 8 and 2.70 g
(14.7 mmol) of 3,3,3-trifluoroethylacetoacetate was heated in an
oil bath held at 180 °C for 2 h after all solids had disappeared.
Upon cooling the mixture was triturated under diethyl ether to
3,4-Dimethyl-2-(4-trifluoromethyl-pyrimidin-2-yl)-2H-
pyrano[2,3-c]pyrazol-6-one (2c). Obtained using 2-chloro-4-
trifluoromethylpyrimidine. Recrystallized from ethyl acetate:
1
1
190 mg (61%) of the titled compound, mp 193-5 °C; H nmr ꢀ
give 696 mg (65%) of a pink solid, mp 175-182 °C; H nmr ꢀ
(deuteriochloroform) 9.13 (d, 1H, J = 5.0 Hz), 7.60 (d, 1H, J =
4.9 Hz), 6.00 (q, 1H, J = 1.3 Hz), 3.00 (s, 3H), 2.48 (d, 3H, J =
1.3 Hz); ms (70 eV, electron impact) m/z 310 (M+, 100). Anal.
Calcd. for C13H9F3N4O2: C, 50.33; H, 3.25; N, 18.06. Found:
C, 50.20; H, 2.96; N, 17.58.
(deuteriochloroform) 11.2 (br s, 1H), 6.45 (s, 1H), 2.58 (s, 3H);
13C nmr ꢀ (CDCl3) 160.2, 159.5, 138.9 (q, J = 36.3 Hz, C-CF3),
137.5, 121.0 (q, J = 273.8 Hz, CF3), 109.6 (q, J = 5.5 Hz,
HC=CCF3), 94.8, 11.6; ms (API-ES+) m/z 219 ([M+H+]+, 100).
Anal. Calcd. for C8H5F3N2O2: C, 44.04; H, 2.31; N, 12.84.
Found: C, 43.92; H, 2.39; N, 12.74.
4,4,4-Trifluoro-3-[3-hydroxy-5-methyl-1-(5-trifluoromethyl-
pyridin-2-yl)-1H-pyrazol-4-yl]-but-2-enoic acid amide (11)
and 3-Methyl-4-trifluoromethyl-2-(5-trifluoro–methyl-
3,4-Dimethyl-2-(4-nitro-3-trifluoromethyl-phenyl)-2H-
pyrano[2,3-c]pyrazol-6-one (2d). Obtained using 4-nitro-3-
(trifluoromethyl)fluorobenzene. Trituration under diethyl ether:
1
161 mg (46%), mp 195-200 °C; H nmr ꢀ (dimethyl sulfoxide-
d6) 8.40 (d, 1H, J = 8.6 Hz), 8.17-8.23 (m, 2H), 6.07 (q, 1H, J =
1.4 Hz), 2.68 (s, 3H), 2.47 (d, 3H, J = 1.4 Hz); ms (API-ES-)
m/z 352 ([M-H+]+, 100). Anal. Calcd. for C15H10F3N3O4: C,
51.00; H, 2.85; N, 11.89. Found: C, 50.78; H, 2.88; N, 11.57.
4-Methyl-3-phenyl-1-(5-trifluoromethyl-pyridin-2-yl)-1H-
pyrano[2,3-c]pyrazol-6-one (6) and 4-Methyl-3-phenyl-2-(5-
trifluoromethyl-pyridin-2-yl)-2H-pyrano[2,3-c]pyrazol-6-one
(7). To a solution of 226 mg (1.00 mmol) of 5 (R = H) in 1.0
mL of dry DMF cooled in a dry ice/isopropanol bath was added
dropwise via syringe 1.0 mL of 1.0 M lithium hexa-methyl-
disilazide in THF. After 45 min a solution of 500 mg (3.03
mmol) of 2-fluoro-5-trifluoromethylpyridine in 0.5 mL of DMF
was added dropwise via syringe. The contents were allowed to
gradually warm to room temperature and were stirred overnight.
The THF was removed in vacuo and the resulting oil was treated
with ice water and diethyl ether. The layers were separated and
the aqueous phase was extracted once with diethyl ether. The
combined extracts were dried (MgSO4) and concentrated to give
204 mg which consisted of approximately 80% starting material
as indicated by lc/ms. This material was chromatographed on
silica gel using dichloromethane and 95:5 dichlorome-thane/
ethyl acetate to elute the N-arylated isomers separately giving 31
mg (8%) of 7, mp 192-194.5 °C; 1H nmr ꢀ (deuteriochloroform)
8.32 (m, 1H), 7.99 (dd, 1H, J = 8.7 Hz and J = 2.5 Hz), 7.92 (d,
1H, J = 8.7 Hz), 7.50-7.35 (m, 5H), 5.96 (q, 1H, J = 1.4 Hz),
1.88 (d, 3H, J = 1.4 Hz), 1.55 (s, 3H); ms (API-ES+) m/z 372
pyridin-2-yl)-2H-pyrano[2,3-c]pyrazol-6-one (12).
To a
solution cooled in a dry ice/isopropanol bath of 218 mg (1.00
mmol) of 10 (R = H) in 1.0 mL of dry DMF was added dropwise
via syringe 1.0 mL (1.00 mmol) of 1.0 M lithium hexamethyl–
disilazide in THF. After 45 min a solution of 500 mg (3.03
mmol) of 2-fluoro-5-trifluoromethylpyridine in 1.0 mL of DMF
was added dropwise. The solution was allowed to warm to
room temperature and was stirred overnight. The solution was
concentrated in vacuo and the residue was partitioned between
diethyl ether and saturated sodium bicarbonate. The layers were
separated, the aqueous phase was extracted once with
chloroform and the combined organics were dried (MgSO4).
Concentration gave 161 mg consisting predominately of DMF.
This material was treated with 1 mL of chloroform causing
precipitation of a white solid. The mixture was chilled in ice
and the solid was collected affording 46 mg of the amide 11, mp
169-72 °C; ir (potassium bromide) 3409, 3187, 1682 cm-1; H
1
nmr ꢀ (dimethyl sulfoxide-d6) 10.85 (br s, 1H), 8.78 (m, 1H),
8.29 (m, 1H), 7.86 (d, 1H, J = 8.6 Hz), 7.72 (br s, 1H), 7.38 (br
s, 1H), 6.92 (m, 1H), 2.47 (s, 3H); ms (API-ES-) m/z 379 ([M-
H+]+, 100); Anal. Calcd. for C14H10F6N4O2: C, 44.22; H, 2.65;
N, 14.73. Found: C, 44.28; H, 2.78; N, 14.56.
Compound 11 was heated at 170-5 °C for 15min and was
allowed to cool forming 12 as a white solid, mp 156-9 °C; H
nmr ꢀ (deuteriochloroform) 8.77 (m, 1H), 8.13 (dd, 1H, J = 8.9
Hz and J = 2.3 Hz), 8.07 (d, 1H, J = 8.6 Hz), 6.54 (s, 1H), 2.93
1

Nov-Dec 2007
Synthesis and Chemistry of N-Arylated Pyrano[2,3-c]pyrazoles
1393
(s, 3H); ms (API-ES+) m/z 364 ([M+H+]+, 100). Anal. Calcd.
for C14H7F6N3O2: C, 46.29; H, 1.94; N, 11.57. Found: C,
46.18; H, 2.00; N, 11.51.
temperature. After 3 h no starting remained (tlc). The solution
was then treated with 1.0 N hydrochloric acid (approximately 10
mL) to give a Ph of 3-4. The mixture was diluted to 40 mL with
water, was chilled in ice, and the solid was collected and
vacuum dried to give 1.01 g (87%) of the titled compound; ir
(potassium bromide) 1679 (s), 1649 (s) cm-1; 1H nmr ꢀ
(deuteriochloroform) pyrazolone tautomer 7.85 (d, 2H, J = 8.9
Hz), 7.33 (d, 2H, J = 8.9 Hz), 4.23 (s, 2H), 3.12 (s, 3H), 2.97 (s,
3H), 2.46 (s, 3H), 2.44 (s, 3H); ms (API-ES-) ms 320 ([M+2-
H+]+, 30), 318 ([M-H+]+, 100);. A portion was recrystallized
from hexanes/ethyl acetate to give the analytical sample, mp
130-1 °C. Anal. Calcd. for C16H18ClN3O2: C, 60.09; H, 5.67; N,
13.14. Found: C, 59.93; H, 5.56; N, 12.98.
3-[5-Methyl-1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-3-
(5-trifluoromethyl-[1,3,4]thiadiazol-2-yloxy)-1H-pyrazol-4-
yl]-3-phenyl-acrylamide (16). To a solution of 116 mg (0.513
mmol) of 15 (R = H) in 0.8 mL of dry DMF cooled in a dry
ice/isopropanol bath was added dropwise 0.500 mL (0.500
mmol) of 1.0 M lithium hexamethyldisilazide in THF. After 30
min a solution of 188 mg (1.00 mmol) of the 2-chloro-5-
trifluoromethyl-1,3,4-thiadiazole [7] in 0.5 mL of DMF was
added dropwise via syringe. The contents were stirred overnight
at room temperature. The volatiles were removed in vacuo, the
residue was partitioned between diethyl ether and saturated
sodium bicarbonate and the layers were separated. The aqueous
phase was extracted once with diethyl ether and the combined
organics were dried (MgSO4). Concentration gave 224 mg
which was chromatographed on silica gel to give 47 mg (17%)
of 16; 1H nmr ꢀ deuteriochloroform) 7.59-7.34 (m, 5H), 6.90 (s,
1H), 5.88 (br s, 1H), 5.36 (br s, 1H), 2.53 (s, 3H); ms (API-ES+)
m/z 548 ([M+H+]+, 100). Anal. Calcd. for C19H11F6N7O2S2: C,
41.68; H, 2.03; N, 17.91. Found: C, 41.95; H, 2.07; N, 17.42.
3-(5-Hydroxy-3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-but-
2-enoic acid methyl ester (17a). To a mixture of 121 mg (0.501
mmol) of 1d in 3 mL of methanol was added 1.0 mL (1.0 mmol) of
1.0 N sodium hydroxide. After stirring at room temperature for one
hour, tlc indicated no starting material remaining. Hydrochloric acid
(1.0N, 1.00 mmol) was added and the methanol was removed in
vacuo. The residue was extracted two times with diethyl ether, the
combined extracts were washed with brine and were dried (MgSO4).
Concentration gave a material which was chromatographed by
reverse-phase (C18 amide linker-modified) using gradient elution
(0.1% acetic acid in 60:40 water/acetonitrile to 100% acetonitrile) to
give 65 mg (47%) of the titled compound, mp 91-5 °C; ir
3-[1-(4-Chloro-phenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-
(4)-ylidene]-butyric acid methyl ester (17b). To a mixture
cooled in ice of 1.0 g (3.64 mmol) of 1c in 22 mL of methanol
was added dropwise 7.4 mL (14.8 mmol) of 2.0 N sodium
hydroxide. The contents were stirred at room temperature
overnight, were cooled, and were treated with 7.4 mL of 2.0 N
hydrochloric acid to give pH 4. The mixture was concentrated
in vacuo to remove most of the methanol and was then diluted
with water and extracted two times with diethyl ether. The
combined extracts were dried (MgSO4). Concentration gave
1
1.15 g (quantitative); H nmr ꢀ (CDCl3) pyrazolone tautomer
7.90 (d, 2H, J = 8.9 Hz), 7.33 (d, 2H, J = 8.9 Hz), 4.19 (s, 2H),
3.74 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H); ms (API-ES-) m/z 307
([M+2-H+]+, 36), 305 ([M-H+]+, 100).
A portion was
recrystallized from ethyl acetate to give the analytical sample,
mp 121-123.5 °C. Anal. Calcd. for C15H15ClN2O3: C, 58.73; H,
4.93; N, 9.13. Found: C, 58.80; H, 5.01; N, 9.14.
REFERENCES
[1] a) Kuo, S.; Huang, L.; Nakamura, H. J. Med. Chem., 1984, 27,
539; (b) Hogale M. B.; Pawar, B. N. J. Indian. Chem. Soc., 1989, 66,
206; (c) Sato, Y.; Shimoji, Y.; Endo, K.; Nishino, H.; Koike, H.;
Kumakura, S. Yakugaku Zasshi, 1978, 98, 335; Chem. Abstr., 1978, 89,
43223; (d) Guo, M. Chinese Patent, CN 1,093,088, 1994; Chem. Abstr.,
1995, 124, 176084; (e) Honna, T.; Ogawa, K.; Hashimoto, S.; Suzue, T.
Japanese Patent, JP 52077088, 1977; H Chem. Abstr., 1977, 87, 201529;
(f) Sato, Y.; Shimoji, Y.; Kumakura, S.; Takagi, H. Japanese Patent, JP
50151896, 1975; Chem. Abstr., 1976, 84, 164771; (g) El-Ahl, A. A.;
Metwally, M. A.; Amer, F. A. Bollettino Chimico Farmaceutico, 1995,
134, 369; Chem. Abstr., 1995, 124, 86982; (h) Huang, L. J.; Hour, M. J.;
Teng, C. M.; Kuo, S. C. Chem. Pharm. Bull., 1992, 40, 2547; (i) Vaid,
R. K.; Dhindsa, G. S.; Kaushik, B.; Singh, S. P.; Dhawan, S. N. Indian
J. Chem., Sec. B, 1986, 25B, 569; (j) Ueda, T.; Mase, H.; Oda, N.;Ito, I.
Chem. Pharm. Bull., 1981, 29, 3522.
[2] Khan, M. A.; Cosenza, A. G.; Ellis, G. P. J. Heterocyclic
Chem., 1982, 19, 1077 and references cited therein.
[3] Huang, L. J.; Kuo, S. C.; Hwang, J. C.; Chan, S. C.; Wu, L.
T.; Ko, F. N.; Teng, C. M. Zhonghua Yaoxue Zazhi, 1993, 45, 409;
Chem. Abstr., 1994, 121, 57377.
[4] Berger, S.; Braun, S.; Kalinowski, H.-O. NMR Spectroscopy
of the Non-Metallic Elements,” John Wiley & Sons, New York, NY,
1997, pp. 161-163.
[5] Baddar, F. G.; El-Newaihy, M. F.; Salem, M. R. J. Chem. Soc.
(C), 1969, 5, 836.
1
(potassium bromide) 3433 (br), 1705 cm-1; H nmr ꢀ (deuterio-
chloroform) 13.5 (br s, 1H), 8.26 (m,1H), 7.89 (m, 2H), 7.19 (m,
1H), 6.02 (q, 1H, J = 1.3 Hz), 3.73 (s, 3H), 2.59 (d, 3H, J = 1.3 Hz),
2.38 (s, 3H); MS (API-ES-) 272 ([M-H+]+, 100);. A portion was
recrystallized from diethyl ether/ethyl acetate to give the analytical
sample, mp 97-98.5 °C. Anal. Calcd. for C14H15N3O3: C, 61.52; H,
5.53; N, 15.38. Found: C, 61.27; H, 5.35; N, 15.16.
3-[3-Hydroxy-5-methyl-1-(4-trifluoromethyl-pyrimidin-2-
yl)-1H-pyrazol-4-yl]-but-2-enoic acid dimethylamide (19c).
To a mixture of 94 mg (0.303 mmol) of 2c in 1.0 mL of THF
was added 136 mg (1.21 mmol) of 40% aqueous dimethylamine.
After 2 h at room temperature tlc indicated no starting material
remaining. The solution was treated with 1.21 mL of 1.0 N
hydrochloric acid causing precipitation of a white solid which
was collected and dried in vacuo to give 75 mg (70%) of the
titled compound; 1H nmr ꢀ (deuteriochloroform) 8.93 (d, 1H, J =
5.0 Hz), 7.36 (d, 1H, J = 4.9 Hz), 6.21 (br s, 1H), 2.90 (s, 3H),
2.61 (s, 3H), 2.14 (d, 3H, J = 1.6 Hz); ms (API-ES-) m/z 354
([M-H+]+, 100). A portion was recrystallized from chloroform/
hexanes to give the analytical sample, mp 178 °C (dec). Anal.
Calcd. for C15H16F3N5O2: C, 50.70; H, 4.54; N, 19.71. Found:
C, 50.87; H, 4.53; N, 19.17.
3-[1-(4-Chloro-phenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-
(4)-ylidene]-N,N-dimethyl-butyramide (18b). To a mixture
cooled in an ice bath of 1.00 g (3.64 mmol) of 1c in 5 mL of
THF was added dropwise 1.64 g (14.6 mmol) of 40% aqueous
dimethylamine. The contents were allowed to warm to room
[6] Carrillo, J. R.; Cossio, F. P.; Diaz-Ortiz, A.; Gomez-
Escalonilla, M. J.; de la Hoz, A.; Lecea, B.; Moreno, A.; Prieto, P.
Tetrahedron 2001, 57, 4179.
[7] Forster, H; Hofer, W. J.; Schmidt, R. R.; Ene, L. German
Patent DE 3,218,482, 1983; Chem. Abstr. 1984, 100, 85705.