Synthesis of some pyrano[2,3-c]pyrazoles

Article abstract of DOI:10.1002/jhet.562

Synthetic methods have been developed to prepare pyrano[2,3-c]pyrazoles with various substituents at ring positions 1, 3, and 6. The ¹H- and ¹³C-NMR properties of these products and their precursors are presented and discussed.

Full text of DOI:10.1002/jhet.562

710
Synthesis of Some Pyrano[2,3-c]pyrazoles
Vol 48
James W. Pavlik,a* Vuthichai Ervithayasuporn,a and Supawan Tantayanonb
aDepartment of Chemistry and Biochemistry, Worcester Polytechnic Institute,
Worcester, Massachusetts 01609
bDepartment of Chemistry, Chulalongkorn University, Bangkok 10330, Thailand
*E-mail: jwpavlik@wpi.edu
Received December 16, 2009
DOI 10.1002/jhet.562
Published online 4 March 2011 in Wiley Online Library (wileyonlinelibrary.com).
Synthetic methods have been developed to prepare pyrano[2,3-c]pyrazoles with various substituents
at ring positions 1, 3, and 6. The 1H- and 13C-NMR properties of these products and their precursors
are presented and discussed.
J. Heterocyclic Chem., 48, 710 (2011).
INTRODUCTION
Inspection of Scheme 1 shows that the C3 substituent
in pyranopyrazole 4 is determined by the R2 group in
the acyl side chain of 1. To synthesize pyranopyrazoles
with different R2 substituents, dehydroacetic acid deriva-
tives 1f and 1g, where R2 ¼ ethyl or propyl, were syn-
thesized from commercially available 4-hydroxy-6-
methyl-2-pyrone by acylation using propionic or butyric
anhydride, respectively, using the method of Marcus
et al. [5]. These known dehydroacetic acid derivatives
1f and 1g were converted to the previously unreported
N-methylhydrazones 2f and 2g as shown in Scheme 2.
In the case of the ethyl derivative, reaction of 1f with
methylhydrazine provided N-methylhydrazone 2f in 56%
yield and bipyrazole 5f in 13% yield, which were sepa-
rated by fractional crystallization from ethyl acetate. As
a result of the similar solubilities of the analogous n-
propyl derivatives, N-methylhydrazone 2g was isolated
in 45% by preparative layer chromatography. In this
case, 5g was not isolated.
Our interest in the mechanistic aspects of the photo-
chemistry of the pyrano[2,3-c]pyrazole ring system [1]
required the availability of a variety of these compounds
bearing different substituents at ring positions 1, 3, and 6.
This article describes the synthesis of these compounds.
RESULTS AND DISCUSSION
Gelin et al. [2] have described the synthesis of N-phe-
nylpyrano[2,3-c]pyrazoles 4a–c in three steps from
dehydroacetic acid 1a or from dehydroacetic acid deriv-
atives 1b–1c as shown in Scheme 1.
Following their three-step approach [2], 3,6-dimethyl-
1-phenylpyrano[2,3-c]pyrazole-4(1H)-one 4a was syn-
thesized in our laboratory in an overall yield of 55%.
As suggested, intermediates, 2a and 3a, were isolated
and purified before proceeding to the next step. Work in
our laboratory, however, revealed that the syntheses of
4a–c can also be carried out in a ‘‘one-pot’’ procedure
described in the Experimental Section. This approach
led to the synthesis of 4a in 74% which is substantially
higher than the yield of 55% which was obtained when
intermediates 2a and 3a were isolated and purified.
According to Scheme 1, the substituent on nitrogen in
the pyranopyrazole is controlled by the hydrazine reagent
used. Thus, to synthesize a series of N-methylpyranopyra-
zoles, we investigated using methylhydrazine in the syn-
thetic procedure. In this respect, we have recently
reported [1] that N-methylhydrazone 2e [3], formed from
reaction of 1e with methylhydrazine [4], can be converted
to 1,3,6-trimethylpyrano[2,3-c]pyrazole-4(1H)-one 4e by
the series of reactions shown in Scheme 1 or in a ‘‘one-
pot’’ procedure described in the Experimental Section.
Refluxing in acetic acid resulted in the isomerization
of 2f and 2g to the previously unreported diketopyra-
1
zoles 3f and 3g. The H- and 13C-NMR spectra of these
compounds, given in the Experimental Section, could be
explained in terms of a mixture of keto and enol tauto-
mers as shown in Scheme 3. Further isomerization of 3f
and 3g by refluxing in acetic acid containing concen-
trated sulfuric acid provided pyranopyrazoles 4f and 4g.
Their elemental analyses and spectral data are consistent
with their proposed structures.
To utilize this approach to synthesize pyranopyrazole
4h that is unsubstituted at position 3 of the pyrazole
ring, the formylated dehydroacetic acid derivative 1h
was required. This was prepared in 71% yield by
regiospecific formylation 4-hydroxy-6-methyl-2-pyrone
C
V
2011 HeteroCorporation

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Synthesis of Some Pyrano[2,3-c]pyrazoles
711
Scheme 1
Scheme 3
or N-phenylhydrazine with commercially available di-
methyl methoxymethylenemalonate followed by saponi-
fication and decarboxylation of the resulting esters
according to the procedure reported by Tietze et al. [8]
and Claisen and Haase [9], respectively.
Based on the synthetic approach developed by Heinish
et al. [10], pyrazolones 6i and 6h were then converted to N-
methyl- and N-phenylpyranopyrazoles 4i and 4j by the
sequence of reactions shown in Scheme 4. Thus, C-acyla-
tion of pyrazolones 6i or 6j with cinnamoyl chloride 7 in a
slurry of Ca(OH)2 in dioxane gave the a,b-unsaturated
ketones 8i or 8j. Bromination using bromine in acetic acid
at 40ꢀC gave previously unreported monobromo products
9i or 9j, which were assigned the cis-sterochemistry based
on 1H-NMR analysis. Thus, in the case of 9i, the protons at
C5 and C6 appeared as a pair of doublets (J ¼ 11.7 Hz) at
d 5.49 and 5.26. Based on the Karplus equation, the magni-
tude of the coupling constant indicated a very small dihe-
dral angle (y ꢁ 0ꢀ) and the assigned cis-stereochemistry.
Interestingly, when the bromination of N-methyl 8i was
carried out at temperatures above 60ꢀC, the unexpected
5,5-dibromo-1-methyl-6-phenyl-5,6-dihydropyran[2,3-c]
pyrazol-4(1H)-one 10 (Scheme 5) was obtained in 33%
using the procedure developed by Shimizu et al. [6].
This compound was then converted to the previously
1
unreported N-phenylhydrazone 2h in 81%. The H- and
13C-NMR spectra were consistent with the structure of
2h. In particular, the protons of the C6 methyl group
were observed as a 3H singlet at d 2.20 while the C5
and amino protons appear as 1H singlets at d 6.05 and
7.95, respectively. The 13C-NMR spectrum showed the
presence of 11 sets of carbon atoms of which five sets
were confirmed by the DEPT-135 spectrum to be qua-
ternary. The isomerization of 2h to diketopyrazole 3h,
however, was not successful. Thus, refluxing 2h in ace-
tic acid for 1 h led only to the recovery of starting mate-
rial whereas more prolonged refluxing led only to the
decomposition of the N-phenylhydrazone 2h without
formation of any distinguishable product.
Because of the failure of the above synthetic proce-
dure, a different approach to the synthesis of 4i and 4j
was explored. Colatta et al. [7] have reported that 1,3-
disubstituted pyrazolones are useful starting materials
for the synthesis of pyranopyrazoles substituted at C3 of
the pyrazole ring. Although it has not been demonstrated
that this approach can also be used to synthesize pyrano-
pyrazoles unsubstituted at C3 of the pyrazole ring, this
possibility was explored.
Scheme 4
The required N-methyl- and N-phenylpyrazolones 6i
and 6j were synthesized by condensation of N-methyl-
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

712
J. W. Pavlik, V. Ervithayasuporn, and S. Tantayanon
Vol 48
Scheme 5
added dropwise to a solution of 4-hydroxy-6-methyl-3-propio-
nyl-2H-pyran-2-one 1f [5] (1.00 g, 5.49 mmol) in ethanol at
room temperature during a period of 10 min. After complete
addition, the solution was stirred at room temperature for 2 h.
Evaporation of the solvent gave a crude mixture of 2f and 5-
hydroxy-3-ethyl-1-methyl-4-(1,3-dimethylpyrazol-5-yl) pyraz-
ole 5f. The mixture was dissolved in hot ethyl acetate (20 mL)
and allowed to cool to give 2f (0.20 g), which was recrystal-
lized from ethyl acetate to give colorless crystals of 2f: mp
162–163ꢀC; yield 0.16 g (0.734 mmol, 13%); 1H-NMR (deu-
teriochloroform) d 5.75 (s, 1H), 3.63 (s, 3H), 3.49 (s, 3H),
2.36 (q, J ¼ 7.6 Hz, 2H), 2.04 (s, 3H), 1.02 (t, J ¼ 7.8 Hz,
3H); 13C-NMR (deuteriochloroform) d 151.9, 151.4, 148.4,
137.6, 107.5, 89.2, 36.4, 33.4, 21.2, 13.8, 13.5; MS (ESI): (M
þ Na)þ ¼ 242.7. Anal. Calcd for C10H14N2O2: C, 59.98; H,
7.32; N, 25.44. Found: C, 60.21; H, 7:19, N, 25.41.
yield. Dehydrobromination of 9j or 9i with DBU in
refluxing dioxane resulted in the formation of pyranopyr-
azoles 4j or the previously unreported 4i, respectively.
The approach shown in Scheme 5 thus provides a path-
way for the synthesis of pyranopyrazoles unsubstituted
in the pyrazole ring. Presumably, the use of other a,b-un-
saturated acyl chlorides would also allow control of the
substituents in the 4-pyrone ring.
Evaporation of the mother liquor gave 5f (1.12 g), which
was recrystallized from toluene and hexane to give 5f (1.12 g),
which was recrystallized from toluene and hexane to give 5f
as a white crystalline solid: mp 97–98ꢀC; yield 0.65 g (3.10
mmol; 56%); 1H-NMR (deuteriochloroform) d 15.2 (s, 1H),
5.68 (s, 1H), 4.03 (br, NH), 3.26 (q, J ¼ 6.1 Hz, 2H), 2.82 (d,
J ¼ 5.5 Hz, 3H), 2.11 (s, 3H), 1.21 (t, J ¼ 7.3 Hz, 3H); 13C-
EXPERIMENTAL
Melting points were determined using a MEL-TEMP appa-
ratus and are uncorrected. 1H- and 13C-NMR spectra were
recorded at 400.1 and 100.6 MHz, respectively, in deuterio-
chloroform on a Brucker FTNMR system. 1H- and 13C-NMR
chemical shifts were measured relative to internal tetramethyl-
silane and chloroform, respectively. All 13C-NMR spectra are
proton decoupled. Mass spectra were recorded on a Waters
Micromass model ZMD spectrometer using electrospray ioni-
zation and 1:1 acetonitrile:water solvent flow.
3,6-Dimethyl-1-phenylpyrano[2,3-c]pyrazole-4(1H)-one (4a)
‘‘one-pot approach.’’ Phenylhydrazine (1.1 g, 1.0 mL, 10.2
mmol) was added dropwise to a hot (80ꢀ) solution of dehydro-
acetic acid 1a (1.66 g, 10.0 mmol) in ethanol (50 mL). After
several minutes, a yellow solid precipitated that was filtered to
give yellow crystals (2.51 g). Without further purification the
crystals were dissolved in glacial acetic acid (50 mL) and
refluxed for 1 h. Concentrated sulfuric acid (1.0 mL) was
added dropwise and the resulting solution was refluxed for 1
additional hour, cooled to room temperature, and poured into
cold water (100 mL). The resulting precipitate was filtered,
washed with 5% aqueous sodium carbonate, water, and dried
to furnish crude 4a (2.31 g), which was recrystallized from
actonitrile to give 4a as colorless crystals: mp 148–149ꢀC (lit.
[2], 150ꢀC), yield, 1.75 g (7.35 mmol, 74%).
NMR (deuteriochloroform)
d 184.2, 178.6, 162.7, 162.6,
106.8, 93.9, 39.0, 22.0, 19.8, 11.5; MS (ESI): (M þ Na)þ
¼
233.0. Anal. Calcd for C10H14N2O2: C, 57.13; H, 6.71; N,
13.83. Found: C, 57.26; H, 6.71; N, 13.24.
1-(3-Ethyl-5-hydroxy-1-methyl-1H-pyrazol-4-yl)butane-1,3-
dione (3f). A solution of 2f (1.23 g, 5.86 mmol) in glacial ace-
tic acid (15 mL) was refluxed for 1 h. Evaporation of the solvent
gave 3f (1.31 g), which was recrystallized from acetonitrile to
give 3f as white crystals: mp 123–124ꢀC; yield 0.86 g (4.10
mmol, 70%); 1H-NMR (deuteriochloroform) enol (major), d
15.0 (s, 1H), 11.5 (br, OH), 5.59 (s, 1H), 3.57 (s, 3H), 2.78 (q, J
¼ 7.6 Hz, 2H), 2.06 (s, 3H), 1.32 (t, J ¼ 7.3 Hz, 3H); keto
(minor) d 11.5 (br, OH), 3.80 (s, 2H), 3.57 (s, 3H), 2.78 (q, J ¼
7.6 Hz, 2H), 2.30 (s, 3H), 1.32 (t, J ¼ 7.3 Hz, 3H); 13C-NMR
(deuteriochloroform) enol (major), d 188.1, 180.9, 158.8, 151.3,
98.6, 96.7, 32.5, 22.7, 22.5, 12.6; keto (minor), d 188.6, 180.9,
158.8, 151.3, 98.6, 55.2, 32.5, 30.8, 22.4, 12.5; MS (ESI): (M þ
Na)þ ¼ 232.9; Anal. Calcd for C10H14N2O2: C, 57.13; H, 6.71;
N, 13.33. Found: C, 57.13; H, 7.04; N, 13.17.
3-Ethyl-1,6-dimethylpyrano [2,3-c] pyrazole-4(IH)-one
(4f). Concentrated sulfuric acid (0.20 mL) was added drop-
wise to a solution of 3f (0.35 g, 1.67 mmol) in glacial acetic
acid (10 mL) and the resulting mixture was heated at reflux
for 1 h. The solution was allowed to cool to room temperature,
neutralized with aqueous sodium carbonate, and extracted with
dichloromethane (30 mL). The organic layer was dried (anhy-
drous sodium sulfate) and evaporated to yield crude 4f (0.29
g), which was recrystallized from cyclohexane to give 4f as
white crystalline product; mp 99–100ꢀC; yield 0.26 g (1.33
mmol, 79%); 1H-NMR (deuteriochloroform) d 5.92 (s, 1H),
3.79 (s, 3H), 2.91 (q, J ¼ 7.6 Hz, 2H), 2.32 (s, 3H), 1.29 (t, J
¼ 7.8 Hz, DH); 13C-NMR (deuteriochloroform) d 175.9,
161.3, 154.9, 151.4, 112.5, 104.9, 34.1, 22.3, 19.8, 13.4; MS
(ESI): (M þ Na)þ ¼ 214.9; Anal. Calcd for C10H20N2O2: C,
62.49; H, 6.29; N, 14.57. Found: C, 62.63; H, 6.34; N, 14.78.
3-Ethyl-1,6-dimethylpyrano[2,3-c]pyrazole-4(1H)-one (4f)
‘‘one-pot approach.’’ A solution of N-methylhydrazone 2f
(0.30 g, 1.43 mmol) in glacial acetic acid (10 mL) was heated
1,3,6-Trimethylpyrano-[2,3-c]pyrazole-4(1H)-one (4e) ‘‘one-
pot approach.’’ N-methylhydrazone 3e (1.00 g, 5.10 mmol) in
glacial acetic acid (20 mL) was refluxed for 1 h. Concentrated
sulfuric acid (1.0 mL) was added dropwise and the resulting
mixture was refluxed for 1 additional hour. The resulting mix-
ture was allowed to cool to room temperature, neutralized with
a
saturated aqueous solution of sodium carbonate, and
extracted with dichloromethane (40 mL). The organic phase
was dried (anhydrous sodium sulfate) and evaporated to give
4e (0.71 g), which was recrystallized from ethyl acetate to
give 4e as a white crystalline product: mp 154–155ꢀC (lit. [1]
154–155ꢀC); yield 0.49 g (2.78 mmol; 55%).
3-Ethyl-1,6-dimethylpyrano[2,3-c]pyrazole-4(1H)-one
(4f). 4-Hydroxy-6-methyl-3-[1-(2-methylhydrazano)propyl]-
3,4-dihydro-2H-pyran-2-one (2f). A solution of methylhydra-
zine (0.25 g, 0.29 mL, 5.50 mmol) and ethanol (5 mL) was
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Synthesis of Some Pyrano[2,3-c]pyrazoles
713
at reflux for 1 h. Concentrated sulfuric acid (0.20 mL) was
added dropwise and the resulting mixture was refluxed for 1
additional hour. After cooling, the mixture was neutralized
with aqueous saturated sodium carbonate and extracted with
dichloromethane (30 mL). The organic layer was dried (anhy-
drous sodium sulfate) and evaporated to provide crude 4f
(0.26 g), which was recrystallized from cyclohexane to give 4f
as a white crystalline product: mp 99–100ꢀC; yield 0.18 g
(0.94 mmol, 66%).
4-Hydroxy-6-methyl-3-[1-(2-phenylhydrazazono)methyl]-2H-
pyran-2-one (2h). Phenylhydrazine (0.26 mL, 0.29 g, 2.70
mmol) was added to a hot (80ꢀC) solution of 4-hydroxy-6-
methyl-2-oxo-2H-pyran-3-carbaldehyde 1h (0.34 g, 2.70
mmol) in ethanol (20 mL). After several minutes of heating,
the solution turned yellow. It was allowed to cool to room
temperature and then placed in a refrigerator overnight. Suc-
tion filtration gave yellow crystals (0.151 g), which were
recrystallized from ethanol to give 2h as yellow crystals: mp
212–213ꢀC; yield 0.47 g (1.93 mmol, 71%); 1H-NMR (dime-
thylsulfoxide-d6) d 13.2 (s, 1H), 10.2 (s, 1H), 7.95 (s, 1H),
7.12 (t, J ¼ 8.1 Hz, 2H), 6.67 (m, 3H), 2.30 (s, 3H); 13C-
NMR (dimethylsulfoxide-d6) d 171.5, 163.6, 162.4, 144.4,
141.6, 129.5, 119, 9, 111.9, 102.0, 95.9, 19.6: (ESI): (M þ
Na)þ ¼ 267.1; Anal. Calcd for C13H12N2O3: C, 63.93; H,
4.95; N, 11.47. Found: C, 64.05; H, 4.81, N, 11.47.
1,6-Dimethyl-3-propylpyrano[2,3-c]pyrazole-4(1H)-one
4-Hydroxy-6-methyl-3-[1-(2-methylhydrazano)butryl]-
(4g).
3,4-dihydro-2H-pyran-2-one (2g). A solution of methylhydra-
zine (0.95 mL, 0.83 g, 18.1 mmol) in ethanol (10 mL) was
added dropwise to a solution of 3-butyryl-4-hydroxy-6-methyl-
2H-pyran-2-one 1g [5] (3.38 g, 17.2 mmol) in ethanol (40 mL)
at room temperature over a period of 10 min and the resulting
mixture was stirred at room temperature for 2 h. Evaporation of
the solvent gave the crude product (4.15 g), which was purified
by preparative layer chromatography: silica gel, dichlorome-
thane (10): ethanol (1). The band at Rf ¼ 0.30 gave a solid
which was recrystallized from toluene–hexane to give 2g as
white crystals: mp 70–71ꢀC; yield 1.73 g (7.72 mmol, 45%):
1H-NMR (deuteriochloroform) d 15.3 (s, 1H), 5.67 (s, 1H), 4.02
(q, J ¼ 5.1 Hz, NH), 3.21 (t, J ¼ 7.6 Hz, 2H), 2.80 (d, J ¼ 5.8
Hz, 3H), 2.10 (s, 3H), 1.57 (sextet, J ¼ 7.8 Hz, 2H), 1.04 (t, J ¼
7.3 Hz, 3H); 13C-NMR (deuteriochloroform) d 184.6, 177.7,
163.1, 163.2, 107.2, 39.3, 30.6, 21.4, 20.2, 14.8; MS (ESI): (M
þ Na)þ ¼ 247.1; Anal. Calcd for C11H16N2O3: C, 58.91; H,
7.19; N, 12.49. Found: C, 58.94; H, 6.97; N, 12.46.
1-Methyl-6-phenylpyrano[2,3-c]pyrazole-4(1H)-one (4i).
5-
Bromo-1-methyl-6-phenyl-5,6-dihydropyrano[2,3-c]pyrazole-4(1H)-
one (9i). A solution of bromine (0.10 mL, 0.31 g, 2.0 mmol)
in glacial acetic acid (10 mL) was added dropwise during a
period of 1 h to a stirred solution of (E)-1-(5-hydroxy-1-
methyl-1H-pyrazol-4-yl)-3-phenylprop-2-ene-1-one 8i [11]
(0.41 g, 1.80 mmol) in glacial acetic acid (30 mL) at 40ꢀC.
Stirring was continued for 2 additional hours after which the
solution was cooled, treated with water (50 mL), neutralized
with saturated aqueous sodium carbonate, and extracted with
dichloromethane (20 mL). The organic phase was dried (anhy-
drous sodium sulfate) and evaporated to give crude 9i (0.55 g),
which was recrystallized from acetonitrile to give 9i as a white
solid: mp 177–178ꢀC; yield 0.44 g (1.59 mmol), 88%; 1H-
NMR (deuteriochloroform) d 7.77 (s, 1H), 7.42 (m, 2H), 7.37
(m, 3H), 5.49 (d, J ¼ 11.7 Hz, 1H) 5.26 (d, J ¼ 11.7 Hz, 1H)
3.69 (s, 3H); 13C-NMR (deuteriochloroform) d 188.1, 158.3,
137.9, 137.2, 129.4, 128.9, 128.2, 101.9, 49.0, 48.6, 33.3; MS
(ESI): (M þ Na)þ ¼ 331.2. Anal. Calcd for C13H11N2O2Br:
C, 50.84; H, 3.61; N, 9.12. Found: C, 50.86; H, 3.62; N, 9.18.
1-Methyl-6-phenylpyrano[2,3-c]pyrazole-4-(1H)-one (4i). 1,8-
Diazabicyclo[5.4.0]undec-7-ene (0.06 mL, 0.06 g, 0.40 mmol)
was added to a solution of 9i (0.10 g, 0.326 mmol) in dioxane
(10 mL) and the solution was stirred for 1 h at 90ꢀC. After
cooling, water (15 mL) was added and stirring was continued
for 30 min. The solution was extracted with dichloromethane
(30 mL) and the organic phase was washed with 2N hydro-
chloric acid (10 mL), dried (anhydrous sodium sulfate), and
evaporated to give 4i (0.091 g), which was recrystallized from
ethyl acetate to give 4i as white crystals: mp 147–148ꢀC; yield
0.051 g (0.226 mmol, 69%); 1H-NMR (deuteriochloroform) d
7.95 (s, 1H), 7.77 (m, 2H), 7.52 (m, 3H), 6.64 (s, 1H), 3.99 (s,
3H); 13C-NMR (deuteriochloroform) d 175.3, 160.4, 154.4,
134.8, 131.9, 131.2, 129.6, 126.5, 109.9, 107.9, 34.8; MS
(ESI); (M þ Na)þ ¼ 249.2; Anal. Calcd for C13H10N2O2: C,
69.00; H, 4.46; N, 12.39. Found: C, 68.79; H, 4.77; N, 12.43.
1,6-Diphenylpyrano[2,3-c]pyrazole-4(1H)-one (4i). 5-Bromo-
1,6-diphenyl-5,6-dihydropyrano[2,3-c]pyrazole-4(1H)-one (9j). A
solution of bromine (0.13 mL, 0.40 g, 2.54 mmol) in glacial
acetic acid (15 mL) was added dropwise during 1 h to a stirred
solution of (E)-1-(5-hydroxy-1-phenyl-1H)-pyrazole-4-yl)-3-
phenylprop-2-ene-1-one 8j [11] (0.37 g, 1.27 mmol) in glacial
acetic (30 mL) at 60ꢀC and the reaction mixture was stirred
for 2 additional hours. After cooling to room temperature and
addition of water (50 mL), filtration gave crude 9j (0.37 g).
1-(3-Ethyl-5-hydroxyl-1-methyl-1H-pyrazole-4-yl)butane-1,3-
dione (3g). A solution of 2g (0.18 g, 0.80 mmol) in glacial
acetic acid (5 mL) was heated at reflux for 1 h. Evaporation of
the solvent gave 3g (0.19 g), which was recrystallized from
ethyl acetate–hexane to give 3g as a white crystalline solid:
1
mp 96–97ꢀC; yield 0.11 g (0.49 mmol, 61%); H-NMR (deu-
teriochloroform) enol (major) d 15.0 (s, 1H), 11.5 (br OH),
5.57 (s, 1H), 3.56 (s, 3H), 2.63 (t, J ¼ 7.6 Hz, 2H), 2.06 (s,
3H), 1.67 (sextet, J ¼ 7.8 Hz, 2H), 0.98 ( t, J ¼ 7.3 Hz, 3H);
keto (minor) d 11.5 (br, OH), 3.80 (s, 2H), 3.57 (s, 3H), 2.63
(t, J ¼ 7.6 Hz, 2H), 2.29 (s, 3H), 1.67 (sextet, J ¼ 7.8 Hz,
2H), 0.98 (t ¼ 7.3 Hz, 3H); 13C-NMR (deuteriochloroform)
enol (major) d 188.6, 181.3, 159.2, 150.5, 99.2, 97.1, 33.0,
31.7, 22.9, 22.2, 14.4: keto (minor) d 188.6, 181.3, 159.2,
150.5, 102.9, 55.6, 31.4, 31.2, 22.4, 14.4; MS (ESI): (M þ
Na)þ ¼ 242.0; Anal. Calcd for C11H16N2O3: C, 58.91; H,
7.19; N, 12.49. Found: C, 58.60, H, 6.93; N, 12.30.
1,6-Dimethyl-3-propylpyrano[2,3-c]pyrazole-4-(1H)-one
(4g). Concentrated sulfuric acid (0.10 mL) was added drop-
wise to a solution of 3g (0.12 g, 0.54 mmol) in glacial acetic
acid (5 mL), the mixture was refluxed for 1 h, neutralized with
aqueous sodium carbonate, and extracted with dichloromethane
(20 mL). The organic layer was dried and evaporated to give
crude 4g (0.10 g), which was recrystallized from cyclohexane
to give 4g as white crystals: mp 61–62ꢀC; yield 0.082 g
(0.398 mmol, 74%); 1H-NMR (deuteriochloroform) d 5.92 (s,
1H), 3.79 (s, 3H), 2.82 (t, J ¼ 7.6 Hz, 2H), 2.32 (s, 3H), 1.76
(sextet, J ¼ 7.6 Hz, 2H), 0.95 (t, J ¼ 7.3 Hz, 3H); 13C-NMR
(deuteriochloroform) d 175.9, 161.3, 154.9, 150.2, 112.6,
105.1, 34.1, 30.8, 30.8, 22.3, 19.7, 14.2; MS (ESI): (M þ H)þ
¼ 207.1. Anal. Calcd for C11H14N2O2: C, 64.06; H, 6.84; N,
13.58. Found: C, 63.86; H 6.58; N, 13.53.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

714
J. W. Pavlik, V. Ervithayasuporn, and S. Tantayanon
Vol 48
[3] Cantos, A.; de March, P.; Moreno-Manas, M.; Pla, A.;
Sanchez-Fernando, F.; Virgili, A. Bull Chem Soc Jpn 1987, 60,
4425.
The crude material was dissolved in dichloromethane (20 mL),
treated with decolorizing carbon, and evaporated to give crude
9j (0.35 g), which was recrystallized from acetonitrile to give
9j as white crystals: mp 195–196ꢀC; yield 0.22 g (0.60 mmol,
[4] Reaction of methylhydrazine with dehydroacetic acid 1 led
to a mixture of N-methylhydrazone 2e and 5-hydroxy-1,3-dimethyl-4-
(1,3-dimethylpyrazol-5yl)pyrazole which were separated on the basis
of their very different solubilities in ethyl acetate.
[5] Marcus, E.; Stephen, J. F.; Chan, J. K. J Org Chem 1969,
34, 2527.
1
47%); H-NMR (deuteriochloroform) d 7.96 (s, 1H), 7.81 (d, J
¼ 7.8 Hz, 2H), 7.46 (m, 2 H), 7.37 (m, 3H), 7.35 (m, 1H),
5.53 (d, J ¼ 11.4 Hz, 1H), 5.09 (d, J ¼ 11.4 Hz, 1H); 13C-
NMR (deuteriochloroform)
d 189.1, 158.8, 138.5, 138.3,
137.3, 129.9, 129.7, 129.4, 128.7, 128.1, 121.8, 103.2, 49.3,
49.1; MS (ESI); (M þ Na)þ ¼ 393.3. Anal. Calcd for
C18H13N2O2Br: C, 58.26; H, 3.53; N, 7.59. Found: C, 58.34;
H, 3.63; N, 7.30.
[6] Shimizu, T.; Hiranuma, S.; Watanabe, T.; Kirihara, M. Het-
erocycles 1994, 38, 243.
[7] Colatta, V.; Catarzi, D.; Varano, F.; Filacchioni, G.; Cecci,
L.; Trincavelli, L.; Martini, C.; Lucacchini, A. Il Farmaco 1998, 53,
189.
[8] Tietze, L. F.; Brumby, T.; Pretor, M.; Remberg, G. J Org
Chem 1988, 53, 810.
REFERENCES AND NOTES
[9] Claisen, L.; Haase, E. Chem Ber 1889, 28, 35.
[10] Heinish, G.; Hellub, D.; Holzer, W. J Heterocyclic Chem
1991, 28, 1047.
[1] Pavlik, J. W.; Ervithayasuporn, V.; MacDonald, J. C.;
Tantayanon, S. Arkivoc 2009, 8, 57.
[2] Gelin, S.; Chantegrel, B.; Nadi, A. I. J Org Chem 1983, 48,
4078.
[11] Holzer, W.; Krca, I. Heterocycles 2003, 60, 2323.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet