Condensation of N-3-substituted 5-pyrazolones with esters of β-keto acids. Synthesis of pyrano[2,3-c]pyrazol-6-ones

Article abstract of DOI:10.1007/s10593-006-0089-z

N-Substituted 5-pryazolones undergo thermal condensation with esters of β-keto acids, losing water and alcohol molecules, to form N-substituted pyrano[2,3-c]pyrazol-6-ones. The pyran ring in these products is readily cleaved by the action of alkali to give the corresponding salts of unsaturated acids. 2006 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-006-0089-z

Chemistry of Heterocyclic Compounds, Vol. 42, No. 3, 2006
CONDENSATION OF N-3-SUBSTITUTED
5-PYRAZOLONES WITH ESTERS OF β-KETO ACIDS.
SYNTHESIS OF PYRANO[2,3-c]PYRAZOL-6-ONES
N. L. Nam and I. I. Grandberg
N-Substituted 5-pryazolones undergo thermal condensation with esters of β-keto acids, losing water and
alcohol molecules, to form N-substituted pyrano[2,3-c]pyrazol-6-ones. The pyran ring in these products
is readily cleaved by the action of alkali to give the corresponding salts of unsaturated acids.
Keywords: 5-pyrazolones, pyrano[2,3-c]pyrazol-6-ones, esters of β-keto acids.
In previous work [1], we found that the condensation of β-keto acids with 5-pyrazolones unsubstituted at
the nitrogen atom leads to pyrano[2,3-c]pyrazol-6-ones, which are heteroanalogs of coumarin. The high
analgesic and anti-inflammatory activity found for these compounds [2] led us to study the behavior of
N-substituted 5-pyrazolones with esters of β-keto acids. As early at 1905, Stolle [3] showed that the first step in
the condensation of 3-methyl-1-phenyl-5-pyrazolone (1a) with ethyl acetoacetate (2a) proceeds even at 100°C
with the loss of water and formation of 3, which is the product of condensation at C(4). Ester 3 then loses an
ethanol molecule at 140°C to give pyrano[2,3-c]pyrazol-6-one (4a).
R2
O
R3
R1
R1
O
R2–CO–CH–COOEt
+
N
R3
N
O
N
2a–d
Me
R1
N
O
R4
R4
3
1a–c
R2
R3
O
N
O
N
R4
4a–h
1 a R1 = Me, R4 = Ph, b R1 = R4 = Me, c R1 = Me, R4 = CH2CH2OH; 2 a R2 = Me, R3 = H,
b R2 = Me, R3 = Et, c R2 = Ph, R3 = H, d α-acetylbutyrolactone; 4 a-h R1 = Me, a R2 = Me,
R3 = H, R4 = Ph, b R2 = R4 = Ph, R3 = H, c R2 = Me, R3 = Et, R4 = Ph, d R2 = R4 = Me, R3 = H,
e R2 = R4 = Me, R3 = CH2CH2OH, f R2 = Me, R3 = H, R4 = CH2CH2OCOCH2COMe,
g R2 = Me, R3 = H, R4 = CH2CH2OH, h R2 = Me, R3 = CH2CH2OH, R4 = Ph
__________________________________________________________________________________________
K. A. Timiryazev Moscow Agricultural Academy, 127550 Moscow, Russia; e-mail:
intelbioscan@mtu.net.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 367-372, March,
2006. Original article submitted March 22, 2002; revision submitted November 11, 2005.
326
0009-3122/06/4203-0326©2006 Springer Science+Business Media, Inc.

After using 1a in this reaction, we also studied 1,3-dimethyl-5-pyrazolone (1b) and 1-(β-hydroxyethyl)-
3-methyl-5-pyrazolone (1c). The β-keto esters examined were ethyl acetoacetate (2a), ethyl ethylacetoacetate
(2b), ethyl benzoylacetate (2c), and α-acetylbutyrolactone (2d). We should note that N-alkyl-5-pyrazolones
undergo condensation with subsequent cyclization even at 90-100°C. Thus, for example, Elguero et al. [4]
studied the reaction of methylhydrazine and ethyl acetoacetate (2a) in an attempt to prepare 5-pyrazolone but
found that this compound was not obtained at 100°C but rather 4d. The preparation of 5-pyrazolone required
lowering the reaction temperature to 70°C. The low yields of N-alkyl-5-pyrazolones in the condensation of
alkylhydrazines with β-keto esters may specifically be related to this side-condensation. We have found that the
reaction should be carried out in methanol without excess β-keto ester by slowly adding the β-keto ester to a
solution of the hydrazine in methanol at reflux (see Experimental). Further complications arise in the preparation
of pyranopyrazole 4g. Transesterification of ethyl acetoacetate present in excess occurs already in the synthesis
of starting 1-(β-hydroxyethyl)-3-methyl-5-pyrazolone (1c) in addition to the side-condensation to give a pyran
ring and leads to a mixture of products (see Scheme).
Me
4g
4f
+
+
HOCH2CH2NHNH2
+
2a
N
O
N
CH2CH2OH
1c
The reaction of hydrazine with a three-fold excess of ethyl acetoacetate gives only acylated
pyranopyrazolone 4f in satisfactory yield. Acid hydrolysis of 4f gives pure hydroxyethylpyranopyrazolone 4g
(see also the work of Kuo et al. [2]).
All pyrano-6-pyrazolones do not give a positive test with FeCl3, while 5-hydroxypyrazoles, which are
tautomers of 5-pyrazolones, turn dark brown upon adding FeCl3.
The reaction between 1a and 2d gives the product of the usual condensation as well as about 15% of an
1
impurity, which proved difficult to isolate. H NMR spectroscopy indicated that this impurity was uncyclized
lactone 5.
5
Me
14
13
Me
4
Me
1
Me
HOCH2CH2
Me
6
O
2
3
∆
∆
7
1a
+
N
N
O
HO
8
O
O
N
9
N
O
O
O
Ph
10
2d
5
11
4h
12
1
13
13
The H and C NMR spectra of 4h correspond to the structure presented and the C NMR spectra of
pyrano-6-pyrazolones [5] (see Experimental).
As heteroanalogs of coumarin, pyranopyrazolones undergo opening of the pyran ring by the action of
alkali to give salts of unsaturated acids, which partially recyclize upon acidification. However, complete
cyclization required heating to 160-180°C. Treatment of 4h with alkali in 1:1 water–methanol leads to opening
of the pyran ring and formation of an unsaturated acid salt 6. Contrary to expectation, cyclization to restore the
pyran ring dos not occur upon acidification of the salt solution. Instead, a 15:85 mixture of E-butyrolactone 5a
and Z-butyrolactone 5b is obtained. However, we should note that the conversion of the Z-isomer to the
E-isomer and vice versa may occur upon tautomeric transformations through an oxo form by means of rotation
about the C–C axis.
327

Me
HOCH2CH2
Me
NaOH
4h
NaOOC
NaO
water,
methanol
N
N
6
Ph
HCl
O
O
Me
Me
Me
N
Me
O
N
O
HO
N
N
HO
5a
E-isomer (15%)
Ph
Ph
5b
(85%)
Z-isomer
H
Me
Me
O
N
O
N
O
Ph
The mass spectrum of 5b shows a strong [M - CH2OH]+ (M - 31) peak, which is not characteristic for
lactones. At high temperatures (up to 300°C) upon direct inlet into the ionization chamber, lactone 5b rearranges
to pyranopyrazole 4h, which decomposes, giving the [M - CH2OH]+ ion characteristic of aromatic alcohols Ar–
CH2CH2OH.
EXPERIMENTAL
1
13
The H NMR spectra (in DMSO-d6) and C NMR spectra (in CDCl3) were taken on a Bruker AM-300
spectrometer at 300 and 75 MHz, respectively. The UV spectra were taken on a Specord M-40 spectrometer in
ethanol. The IR spectra were taken on a Perkin–Elmer spectrometer for KBr pellets.
1,3-Dimethyl-5-pyrazolone (1b). A sample of methylhydrazine sulfate (14.4 g, 100 mmol) was added
to a stirred solution of NaOH (8 g, 100 mmol) in a mixture of water (10 ml) and methanol (100 ml). Then, ethyl
acetoacetate (13 g, 100 mmol) was added dropwise slowly over 1 h with stirring and heating to 50°C on a water
bath. The mixture was stirred for an additional 6 h at this temperature and then evaporated to dryness in vacuum.
The residue was extracted with ethyl acetate in a Soxhlet apparatus. The solvent was evaporated off and the
residue recrystallized from 3:1 ethyl acetate–hexane to give 9.3 g (83%) 1b; mp 116°C (mp 118°C [4]).
Pyrano[2,3-c]pyrazol-6-ones (4) (General Method). A mixture of N-substituted 5-pyrazolone
(50 mmol) and corresponding β-keto ester (55 mmol) was heated on a metal bath at 150-190°C for 2-4 h,
distilling off the eliminated water and alcohol. After cooling, ethyl acetate (20 ml) was added and the mixture
was heated at reflux for 15 min. The mixture was cooled. The precipitate formed was filtered off and
recrystallized from a suitable solvent.
328

3,4-Dimethyl-1-phenylpyrano[2,3-c]pyrazol-6-one (4a). Heating a mixture of pyrazolone 1a and ester
2a at 160-165°C for 3 h gave 4a in 72% yield; mp 146°C (1:4 benzene–hexane) (mp 145°C [5]). IR spectrum,
1
ν, cm-1: 1615, 1755 (C=O). UV spectrum, λmax, nm (log ε): 239 (4.08), 250 (4.10), 317 (3.98). H NMR
spectrum, δ, ppm, (J, Hz): 2.47 (3H, d, 4-CH3); 2.51 (3H, s, 3-CH3); 5.84 (1H, q, J = 1.1, H-5); 7.41 (1H, m,
p-HPh); 7.58 (2H, m, m-HPh); 7.85 (2H, m, o-HPh).
3-Methyl-1,4-diphenylpyrano[2,3-c]pyrazol-6-one (4b). Heating a mixture of pyrazolone 1a and ethyl
benzoylacetate at 150°C for 3 h gave 4b in 48% yield, mp 136°C (after heating, the mixture was heated at reflux
in 2:1 hexane–ethyl acetate and then recrystallized from this mixed solvent) (mp 140°C [5]). IR spectrum,
1
ν, cm-1: 1525, 1595, 1730 (C=O). UV spectrum, λmax, nm (log ε): 232 (4.27), 254 (4.44), 330 (4.03). H NMR
spectrum, δ, ppm, (J, Hz): 2.11 (3H, s, 3-CH3); 5.94 (1h, s, H-5); 7.54 (5H, m, 4-C6H5); 7.42 (1H, m, p-H, 1-
C6H5); 7.26 (2H, m, m-H, 1-C6H5); 7.83 (2H, m, o-H, 1-C6H5).
5-Ethyl-3,4-dimethyl-1-phenylpyrano[2,3-c]pyrazol-6-one (4c). Heating a mixture of pyrazolone 1a
and ethyl ethylacetoacetate at 175-180°C for 4 h gave 4c in 30% yield; mp 144°C (ethyl acetate) (mp 142°C [3]).
IR spectrum, ν, cm-1: 1515, 1605, 1725 (C=O). UV spectrum, λmax, nm (log ε): 232 (4.13), 240 sh (4.12), 258
1
(4.13), 319 (4.12). H NMR spectrum, δ, ppm, (J, Hz): 1.12 (3H, t, J = 7.8, 5-CH3); 2.40 (3H, s, 4-CH3); 2.52
(3H, s, 3-CH3); 2.56 (2H, m, 5-CH2); 7.36 (1H, m, p-H, 1-C6H5); 7.56 (2H, m, m-H, 1-C6H5); 7.80 (2H, m, o-H,
1-C6H5).
1,3,4-Trimethylpyrano[2,3-c]pyrazol-6-one (4d). Heating a mixture of pyrazolone 1b and ester 2a at
150°C for 2 h gave 4d in 80% yield; mp 170°C (ethyl acetate) (mp 167-168°C [4]). IR spectrum, ν, cm-1: 1520,
1
1600, 1720 (C=O). UV spectrum, λmax, nm (log ε): 225 (3.89), 314 (4.17). H NMR spectrum, δ, ppm, (J, Hz):
2.40 (3H, s, 4-CH3); 2.44 (3H, s, 3-CH3); 3.69 (3H, s, 1-CH3); 5.74 (1H, s, H-5).
5-(β-Hydroxyethyl)-1,3,4-trimethylpyrano[2,3-c]pyrazol-6-one (4e). Heating a mixture of pyrazolone
1b and α-acetylbutyrolactone 2d at 165°C for 3 h gave 4e in 88% yield; mp 189°C (5:1 ethyl acetate–hexane
and then methanol). IR spectrum, ν, cm-1: 1630, 1720 (C=O). UV spectrum, λmax, nm (log ε): 227 (3.88), 237 sh
1
(3.84), 311 (3.93). H NMR spectrum, δ, ppm, (J, Hz): 2.40 (3H, s, 4-CH3); 2.50 (3H, s, 3-CH3); 2.64 (2H, t,
J = 7.9, 5-CH2CH2OH); 3.45 (2H, m, 5-CH2CH2OH); 3.70 (3H, s, 1-CH3); 4.43 (1H, m, 5-OH). Found, %:
C 59.8; H 6.6; N 12.1. C11H14N2O3. Calculated, %: C 59.4; H 6.3; N 12.6.
1-(β-Acetoacetoxyethyl)-3,4-dimethylpyrano[2,3-c]pyrazol-6-one (4f) was obtained in 76% yield
from β-hydroxyethylhydrazine (50 mmol) and ester 2a (180 mmol) upon heating at 150°C for 2 h; mp 120°C
(2:1 ethyl acetate–hexane) (mp 120-122°C [2]). IR spectrum, ν, cm-1: 1705 (C=O), 1725 (C=O). UV spectrum,
1
λ
max, nm (log ε): 225 (3.83), 314 (4.16). H NMR spectrum, δ, ppm, (J, Hz): 2.12 (3H, s, COCH3); 2.34 (3H, s,
4-CH3); 2.36 (3H, s, 3-CH3); 3.48 (2H, s, COCH2); 4.29 (2H, t, J = 7.6, N–CH2); 4.42 (2H, t, J = 7.7, O–CH2);
5.77 (1H, s, H-5).
1-(β-Hydroxyethyl)-3,4-dimethylpyrano[2,3-c]pyrazol-6-one (4g). Crude condensation product 4f
obtained in the above procedure was hydrolyzed by heating with concentrated hydrochloric acid (35 ml) for
90 min at 50°C with vigorous stirring. The reaction mixture was evaporated in vacuum to dryness maintaining
the external bath temperature at 60°C. The residue was heated with water (12 ml) to 60°C and cooled. The
crystalline precipitate was filtered off washed with water (3 ml), and dried to give 3.5 g (31%) 4g; mp 158°C
(mp 158-160°C [2]). IR spectrum, ν, cm-1: 1715 (C=O), 2600-3200. UV spectrum, λmax, nm (log ε): 26 (3.70),
315 (4.01). 1H NMR spectrum, δ, ppm, (J, Hz): 2.38 (6H, s, 3,4-CH3), 3.70 (2H, t, J = 7.7, 1-CH2CH2OH); 3.98
(2H, m, 1-CH2CH2OH); 4.78 (1H, br. s, OH); 5.76 (1H, s, H-5).
5-(β-Hydroxyethyl)-3,4-dimethyl-1-phenylpyrano[2,3-c]pyrazol-6-one (4h). A mixture of pyrazolone
1a (8.7 g, 50 mmol) and α-acetylbutyrolactone 4h (6.5 g) was heated at 195°C for 4 h. After cooling, ethyl
acetate (40 ml) and activated charcoal (1 g) were added. The mixture was heated at reflux for 15 min and filtered
while hot. After cooling, the crystalline precipitate was filtered off and dried to give 10.4 g crude product with
1
mp 140-146°C. The H NMR spectrum showed the presence of about 15% unsaturated lactone impurity (see
text). The product was purified by repeated crystallization from benzene, from ethyl acetate, and,
329

finally, from methanol to give 2.4 g pure 4h; mp 157°C. IR spectrum, ν, cm-1: 1740 (C=O), 2900, 3200.
1
UV spectrum, λmax, nm (log ε): 233 (3.98), 241 (3.97), 258 (3.98), 319 (3.97). H NMR spectrum, δ, ppm,
(J, Hz): 2.40 (3H, s, 3-CH3); 2.49 (3H, s, 4-CH3); 2.80 (2H, t, J = 7.8, 5-CH2CH2OH); 3.78 (2H, m,
13
5-CH2CH2OH); 7.30 (1H, m, p-HPh); 7.46 (2H, m, m-HPh); 7.81 (2H, o-HPh). C NMR spectrum, δ, ppm: 15.1
(C-1), 149.5 (C-2), 102.6 (C-3), 136.9 (C-4), 19.2 (C-5), 113.6 (C-6), 169.3 (C-7), 161.6 (C-8), 144.4 (C-9),
120.3 (C-10), 129.3 (C-11), 126.9 (C-12), 30.3 (C-13); 6.1.3 (C-14) (numbering of the atoms given in the text).
Found, %: C 67.8; H 5.3; N 10.0. C16H16N2O3. Calculated, %: C 67.6; H 5.6; N 9.9.
3-[1-(5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)ethylidene]dihydro-2-furanone (5) (Mixture
of E- and Z-isomers). A sample of pyranopyrazolone 4h (3.5 g, 12.3 mmol) was added to a solution of KOH
(1.5 g) in a mixture of water (20 ml) and methanol (20 ml) and stirred for 30 min. The solution was filtered and
acidified by adding a mixture of acetic acid (4 ml) and concentrated hydrochloric acid (2 ml). The mixture was
evaporated in vacuum to half volume and cooled. The crystalline precipitate was filtered off, washed with water
(4 ml), and dried. Recrystallization from benzene–ethanol gave 1.4 g (40%) mixture of 5a and 5b;
mp 124-127°C, which gives a positive test with FeCl3. IR spectrum, ν, cm-1: 1750 (C=O), 2700, 3300. UV
1
spectrum, λmax, nm (log ε): 247 (4.02), 288 sh (3.76). H NMR spectrum, δ, ppm, (J, Hz): 2.16 (3H, s, 3-CH3);
2.38 (3H, s, α-CH3); 2.78 (2H, t, J = 7.9, CH2CH2O); 4.22 (2H, t, J = 7.8, CH2CH2O); 7.22 (1H, m, p-H,
1-C6H5); 7.45 (2H, m, m-H, 1-C6H5); 7.72 (2H, m, o-H, 1-C6H5).
Repeated crystallization from benzene–ethanol gave pure Z-isomer 5b; mp 129°C. The IR and UV
1
spectra and elemental analysis were identical to those described for the mixture. H NMR spectrum, δ, ppm,
(J, Hz): 2.02 (3H, s, 3-CH3); 2.09 (3H, s, α-CH3); 3.00 (2H, t, J = 7.7, CH2CH2O); 4.22 (2H, t, J = 7.8,
CH2CH2O); 7.22 (1H, m, p-H, 1-C6H5); 7.45 (2H, m, m-H, 1-C6H5); 7.72 (2H, m, o-H, 1-C6H5). Mass spectrum,
m/z (Irel, %): 284 [M]+ (75), 269 (31), 253 [M+ - CH2OH] (81), 255 (47), 91 (70), 77 (100). Found, %: C 67.3;
H 5.7; N 9.6. C16H10N2O3. Calculated, %: C 67.6; H 5.6; N 9.9.
Heating 500 mg 5b at 180°C for 30 min and subsequent recrystallization from methanol gave 310 mg
pure 4h, identical in all characteristics to the sample described above.
Reaction of 3,4-Dimethyl-1-phenylpyrano[2,3-c]pyrazol-6-one with Alkali.
A
sample of
pyranopyrazolone 4 (3.6 g, 15 mmol) in was dissolved in a solution of NaOH (1.4 g, 35 mmol) in a mixture of
water (20 ml) and methanol (20 ml) and stirred for 30 min. The solution was filtered and methanol was distilled
off in vacuum. The residue was acidified by adding formic acid (3 ml). The semicrystalline mass was separated,
washed with water, and dried in vacuum. The crude product was recrystallized from 1:2 ethyl acetate–hexane to
give 2.6 g brown crystals with a broad melting range from 96 to 110°C. Chromatography using 5:1 benzene–
acetone as the eluent showed three spots with Rf 0.55 (starting pyranopyrazole); 0.37 and 0.76 (E-isomer 5a and
Z-isomer 5b). Heating 1.5 g of this product for 30 min at 180°C gave a crystalline mass, which was
recrystallized from 1:2 benzene–hexane to give 1.1 g pure 4h identical to the sample described above.
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