Condensation of pyrazol-5-ones unsubstituted in the position 1 with β-keto esters. Synthesis of pyrano[2,3-c]pyrazol-6-ones

Article abstract of DOI:10.1007/s10593-005-0159-7

The thermal condensation of β-keto esters and N-unsubstituted pyrazol-5-ones gives good yields of pyrano[2,3-c]pyrazol-6-ones. Other potential routes for the condensation are not realized. The β-diketones react via another scheme to form noncyclic reactio

Full text of DOI:10.1007/s10593-005-0159-7

Chemistry of Heterocyclic Compounds, Vol. 41, No. 3, 2005
CONDENSATION OF PYRAZOL-5-ONES
UNSUBSTITUTED IN THE POSITION 1
WITH β-KETO ESTERS. SYNTHESIS OF
PYRANO[2,3-c]PYRAZOL-6-ONES
N. L. Nam and I. I. Grandberg
The thermal condensation of β-keto esters and N-unsubstituted pyrazol-5-ones gives good yields of
pyrano[2,3-c]pyrazol-6-ones. Other potential routes for the condensation are not realized. The
β-diketones react via another scheme to form noncyclic reaction products.
Keywords: pyrazol-5-ones, pyranopyrazol-6-ones, β-keto esters.
We have previously carried out a detailed investigation of the condensation of aminopyrazoles with
β-dicarbonyl compounds which gives pyrazolopyridines or pyrazolopyrimidines depending on the structure of
the aminopyrazoles [1, 2]. In this work we have studied the potential for 5-hydroxypyrazoles (pyrazol-5-ones)
which are unsubstituted in the position 1 to take part in a similar type of condensation.
3,4-Dimethylpyrano[2,3-c]pyrazol-6-one (3) was prepared for the first time by Wolf [3] by heating 3-
methylpyrazol-5-one with an excess of acetoacetic ester. Later, the preparation and some reactions (nitration,
chlorination, and bromination) of pyrano[2,3-c]pyrazol-6-ones were reported in [4] in which the synthesis of the
latter was also carried out using the Wolf method. The authors based this on the use of various pyrazol-5-ones
with different substituents in position 1 and only aceto- and benzoylacetic esters as the β-keto esters.
Me
Me
N
N
O
N
H
HO
N
H
2
1
III
I
II
O
Me
Me
Me
Me
N
O
N
N
N
Me
O
N
O
O
N
H
H
O
Me
5
3
4
_________________________________________________________________________________________
K. A. Timiryazev Agricultural Academy, Moscow 127550, Russia, e-mail: intelbioscan@mtu-net.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 444-449, March, 2005. Original article
submitted March 1, 2002; revision submitted December 4, 2004.
0009-3122/05/4103-0387©2005 Springer Science+Business Media, Inc.
387

In this work we have studied the behavior of 5-hydroxypyrazoles (pyrazol-5-one) unsubstituted in
position 1 with different β-keto esters in similar type condensations. The reaction between acetoacetic ester (1)
and 3-methylpyrazol-5-one can occur via several routes (I, II, or III). Compound 5 is not formed under these
conditions. 3,6-Dimethylpyrazol-4-one 5 has been obtained by another scheme. It has different characteristics
and its structure has been rigorously proved [5]. The problem of the choice between structures 3 and 4 was
1
resolved by H NMR spectroscopic analysis, the condensation product actually corresponding to structure 3,
which is in agreement with data in [3, 4]. For a final proof of this question we attempted to use 4-ethyl-3-methyl-
and 4-isopropyl-3-methylpyrazol-5-ones (6 and 7) in this condensation. In this case the reaction can only occur
via route II since position 4 is occupied in both pyrazolones. However, the condensation did not occur and the
pyrazolones 6 and 6a were recovered unchanged from the reaction.
R2
i-Pr
R1
Me
R3
Me
Et
N
N
N
O
O
O
O
N
N
H
N
H
H
7a–i
6a
6
7 a R1 = R2 = Me, R3 = H; b R1 = R2 = R3 = Me; c R1 = R2 = Me, R3 = Et; d R1 = R2 = Me,
R3 = n-Pr; e R1 = Me, R2 = Ph, R3 = H; f R1 = Me, R2 = p-MeOC6H4; R3 = H; g R1 = R2 = Me,
R3 = CH2COOEt; h R1 = Ph, R2 = Me, R3 = H; i R1 = p-MeOC6H4, R2 = Me, R3 = H
Hence the reaction proceeds with the participation of a free 4 position and oxygen function in the
position 5 with the NH group in position 1 being unaffected.
As has been shown [3], the first stage of the reaction is condensation with the separation of water
involving the CH2 group of the pyrazol-5-one. A molecule of alcohol is then lost to form the pyranopyrazol-6-
one.
Me
– H2O
+
MeCOCH2COOEt
N
O
N
H
Me
Me
O
Me
N
N
H
Me
EtOOC–CH
_
EtOH
N
HO
N
H
O
We have used 3-methyl-, 3-phenyl-, and 3-p-methoxyphenylpyrazol-5-ones and the acetoacetic,
methylacetoacetic, ethylacetoacetic, propylacetoacetic, isopropylacetoacetic, benzoylacetoacetic,
p-methoxybenzoylacetoacetic, and acetylsuccinic β-keto esters and α-acetylbutyrolactone in the reaction. In all
cases the condensation was carried out similarly by heating in a temperature bath at 145-190°C (see
Experimental) for 2-4 h to give the products 7a-i. The yields varied from 20 to 90% (particularly low yields
being noted for the benzoylacetic ester). Substituents in the acetoacetic ester markedly decreased the yield and
for the isopropylacetoacetic ester it was overall not possible to separate pure material, even though it was present
1
in the mixture according to H NMR spectroscopic data. This is evidently connected to the steric hindrance to
1
condensation. The H NMR spectra were quite informative. The proton in position 5 of the pyran
388

ring gave a singlet at 5.8-5.9 ppm with a hyperfine splitting of 1.1 Hz to the neighboring CH3 group in position 4
which, in turn, occurs as a doublet with J = 1.1 Hz. Hence, for the 5-substituted compounds it is always possible
to assign the signal for the CH3 groups at positions 3 or 4, these occurring side by side at 2.5-2.3 ppm. All of the
pyranopyrazoles gave a negative reaction with FeCl3 whereas all of the hydroxypyrazoles gave a dark-brown
coloration in aqueous alcoholic FeCl3 solution.
α-Acetylbutyrolactone
reacted
anomalously
in
its
reaction
with
3-phenyl-
and
3-p-methoxyphenylpyrazol-5-ones. Condensation under standard conditions (170°C,
3
h) of
α-acetylbutyrolactone with 3-phenylpyrazol-5-one and 3-p-methoxyphenylpyrazol-5-one gave compounds
whose 1H NMR spectra showed an anomalously large chemical shift for the triplet due to the OCH2 (~4.15 ppm)
whereas, in the alcohols with the expected structures 8 and 9, the shift for the CH2O group occurs at ~3.5 ppm.
Me
R
HOCH2CH2
N
O
O
N
H
8–10
8 R = Ph; 9 R = p-MeOC6H4; 10 R = Me
In compound 10 the chemical shift occurs at 3.48 ppm (see Experimental). Upon acylation of the alcohol
OH group this signal is shifted to low field by ~ 0.5-0.8 ppm which leads us to propose the alternative structures
1
8a and 9a for compounds 8 and 9. This is supported by the presence in the H NMR spectrum of low field
signals at 10-12 ppm (NH and phenolic OH group protons) and the absence of a signal for the alcoholic OH
group at 3-5 ppm (for compound 10 the signal for the OH group proton occurs at 4.4 ppm). In addition,
compounds 8a and 9a gave positive reactions with FeCl3 (the appearance of a dark-brown coloration).
OMe
Me
Me
O
N
O
O
N
O
N
N
HO
HO
H
H
8a
9a
However, the mass spectrum of 8a shows a strong peak for [M-31]+ (second in intensity after [M]+)
corresponding to [M-CH2OH]+, which is not typical of butyrolactones. In this connection we recorded the mass
spectrum of the model compound 11 with known structure and also observed a strong peak for [M-31]+. Further
investigation has shown that compound 11 rearranges to compound 11a upon heating to 180°C. This
rearrangement, occurring in the ionization chamber under direct introduction conditions at high temperature
(300°C), is the reason for the appearance of the [M-31]+ ion.
Me
Me
Me
Me
HOCH2CH2
O
O
N
N
N
O
O
HO
N
Ph
Ph
11a
11
389

To clarify the conditions for the possible rearrangement of the pyrazololactone 8a to the pyranopyrazole
1
8 we have found that the rearrangement occurs partially at 280°C. The H NMR spectrum of the obtained
reaction product showed both the signals for the starting 8a (see Experimental) and those corresponding to
structure 8 at 3.60 (t, OCH2), 2.71 (t, CH2), 2.11 (s, CH3), and 7.50-7.38 ppm (m, Harom). The reasons for the
condensation halting at the first stage (8a and 9a) are the steric hindrance due to the bulky substituent in position
3 of the pyrazolone ring which leads to rotation about the C–C axis and distancing of the OH group from the O–
CO fragment making closure of the ring impossible.
CH2COMe
Me
Me
Me
Me
N
N
N
O
N
H
15
Me
O
12
2
13
Me
Me
Me
Me
Me
Me
Me
Me
N
N
N
N
N
OH HO
N
N
H
O
O
N
H
14a
14
Condensation of acetylacetone 12 with the pyrazolone 2 could have led to the pyranopyrazole 13 but
heating pyrazolone 2 with an excess of 12 for 6 h led only to the product of condensation of two molecules of
the pyrazolone with one molecule of acetylacetone to give compound 14. It was of interest that the product of
monocondensation was not produced despite the excess of acetylacetone. The condensation product 14a
(prepared previously in [3]) was insoluble in alkali but it did not have a C=O group absorption band in the region
1620-1800 cm-1 in the IR spectrum. This can be explained by its existence in the tautomeric form 14 and this is
1
in good agreement with the H NMR spectrum. The hydroxyl groups in compound 14 evidently do not possess
sufficient acidity, hence its insolubility in alkali. However, the material gives a positive reaction with FeCl3
(dark-brown coloration). The pyrazolone 2 does not react with dibenzoylmethane when heated at 160°C for 3 h
and was recovered from the reaction unchanged.
EXPERIMENTAL
1H NMR spectra were taken on a Bruker AM-300 instrument (300 MHz) using DMSO-d6 and TMS as
internal standard. UV spectra were recorded on a Specord M-40 instrument using alcohol and IR spectra on a
Perkin-Elmer apparatus using KBr.
Synthesis of Pyrano[2,3-c]pyrazol-6-ones (General Method). The pyrazol-5-one (0.05 mol) and the
corresponding β-keto ester (0.055 mol) were heated in a flask (50 ml) on a metal bath at 150-190°C for 2-4 h,
distilling off the water and alcohol. After cooling the flask, ethyl acetate (20 ml) was added and the product was
heated to reflux for 15 min. The reaction mixture was cooled and the precipitate was filtered and recrystallized
from the corresponding solvent.
3,4-Dimethylpyrano[2,3-c]pyrazol-6-one (7a). Heated for 2 h at 145-155°C, yield 78%; mp 252°C
(sealed capillary) (60% alcohol). IR spectrum, ν, cm-1: 1520, 1610, 1700 (C=O). UV spectrum, λmax, nm (log ε):
227 (3.31); 299 (4.26). 1H NMR spectrum, δ, ppm (J, Hz): 2.47 (3H, s, CH3-3); 2.36 (3H, d, J = 1.1, CH3-4); 5.8
(1H, q, J = 1.1, H-5); 12.9 (1H, br. s, NH). Negative reaction with FeCl3 (mp 245°C [4]).
390

3,4,5-Trimethylpyrano[2,3-c]pyrazol-6-one (7b). Heated for 3 h at 180°C, yield 65%; mp 257°C
(sealed capillary) (ethyl acetate). IR spectrum, ν, cm-1: 1540, 1610, 1710 (C=O). UV spectrum, λmax, nm (log ε):
1
223 (3.65); 231 (3.65); 282 (4.38). H NMR spectrum, δ, ppm: 1.98 (3H, s, CH3-5); 2.34 (3H, s, CH3-4); 2.49
(3H, s, CH3-3); 12.7 (1H, br. s, NH). Found, %: C 60.3; H 5.8; N 15.9; [M]+ 178. C9H10N2O2. Calculated, %:
C 60.7; H 5.6; N 15.9; [M]+ 178. Negative reaction with FeCl3.
5-Ethyl-3,5-dimethylpyrano[2,3-c]pyrazol-6-one (7c). Heated for 3 h at 180°C, yield 42%; mp 206°C
(ethyl acetate). IR spectrum, ν, cm-1: 1535, 1610, 1715 (C=O). UV spectrum, λmax, nm (log ε): 220 (3.49); 228
1
(3.44); 296 (4.11). H NMR spectrum, δ, ppm: 1.03 (3H, t, CH3-5); 2.32 (3H, s, CH3-4); 2.49 (3H, s, CH3-3);
2.52 (2H, q, CH2-5); 12.7 (1H, br. s, NH). Found, %: C 62.1; H 6.3; N 15.1; [M]+ 192. C10H12N2O2.
Calculated, %: C 62.5; H 6.3; N 14.6; [M]+ 192. Negative reaction with FeCl3.
3,4-Dimethyl-5-propylpyrano[2,3-c]pyrazol-6-one (7d). Heated for 3 h at 180°C, yield 43%;
mp 182°C (ethyl acetate). IR spectrum, ν, cm-1: 1540, 1610, 1710 (C=O). UV spectrum, λmax, nm (log ε): 231
(3.59); 303 (4.19). 1H NMR spectrum, δ, ppm: 0.96 (3H, t, CH3-5); 1.43 (2H, m, CH2-5-β); 2.36 (3H, s, CH3-4);
2.44 (2H, t, CH2-5-α); 2.52 (3H, s, CH3-3); 12.7 (1H, br. s, NH). Found, %: C 64.1; H 6.7; N 13.6. C11H14N2O2.
Calculated, %: C 64.4; H 6.5; N 13.3. Negative reaction with FeCl3.
5-β-Hydroxyethyl-3,4-dimethylpyrano[2,3-c]pyrazol-6-one (10). Heated for 3 h at 175°C, yield 60%;
mp 282-284°C (sealed capillary) (ethanol). IR spectrum, ν, cm-1: 1535, 1610, 1720 (C=O). UV spectrum,
λ
max, nm (log ε): 227 (3.48); 266 (3.62); 303 (4.12). 1H NMR spectrum, δ, ppm: 2.38 (3H, s, CH3-3); 2.52 (3H, s,
CH3-4); 2.63 (2H, t, CH2-5-α); 3.48 (2H, t, CH2-O-5-β); 12.85 (1H, br. s, NH). Found, %: C 57.2; H 5.7; N 13.4.
C10H12N2O3. Calculated, %: C 57.7; H 5.7; N 13.5. Negative reaction with FeCl3.
3-Methyl-4-phenylpyrano[2,3-c]pyrazol-6-one (7e). Heated for 3 h at 155°C, yield 21%;
mp 192-194°C (50% acetic acid). IR spectrum, ν, cm-1 1510, 1595, 1670, 1730 (C=O). UV spectrum, λmax, nm
1
(log ε): 257 (3.81), 312 (4.04). H NMR spectrum, δ, ppm: 2.09 (3H, s, CH3-3); 5.86 (1H, s, H-5); 7.52 (5H, s,
C6H5); 13.0 (1H, br. s, NH). Found, %: C 68.7; H 4.6; N 12.3. C13H10N2O2. Calculated %: C 69.0; H 4.4; N 12.4.
4-p-Methoxyphenyl-3-methylpyrano[2,3-c]pyrazol-6-one (7f). Heated for 3 h at 155°C, yield 17%;
mp 195-197°C (70% acetic acid). IR spectrum, ν, cm-1: 1510, 1585, 1685 (C=O). UV spectrum, λmax, nm (log ε):
303 (4.24). 1H NMR spectrum, δ, ppm: 2.14 (3H, s, CH3-3); 3.84 (3H, s, O-CH3); 5.81 (1H, s, H-5); 7.17 (2H, d,
o-Harom); 7.50 (2H, d, m-Harom); 13.0 (1H, br. s, NH). Found, %: C 66.1; H 4.6; N 10.7. C14H12N2O3.
Calculated, %: C 65.6; H 4.7; N 10.9. Negative reaction with FeCl3.
5-Carbethoxymethyl-3,4-dimethylpyrano[2,3-c]pyrazol-6-one (7g). Heated for 2 h at 175°C,
yield 29%; mp 170-172°C (ethyl acetate). IR spectrum, ν, cm-1: 1580, 1610, 1695 (C=O). UV spectrum, λmax, nm
1
(log ε): 220 (3.65); 302 (4.19). H NMR spectrum, δ, ppm: 1.20 (3H, t, OCH2CH3); 2.44 (3H, s, CH3-4); 2.55
(3H, s, CH3-3); 3.52 (2H, s, CH2-5); 4.10 (2H, q, OCH2CH3); 12.8 (1H, br. s, NH). Found, %: C 57.3; H 5.6; N
11.3. C12H14N2O4. Calculated, %: C 57.6, H 5.6; N 11.3. Negative reaction with FeCl3.
4-Methyl-3-phenylpyrano[2,3-c]pyrazol-6-one (7h). Heated for 3 h at 180°C, yield 69%;
mp 194-195°C (ethanol). IR spectrum, ν, cm-1: 1510, 1590, 1690 (C=O). UV spectrum, λmax, nm (log ε): 250
(3.98); 302 (4.18). 1H NMR spectrum, δ, ppm (J, Hz): 2.14 (3H, d, J = 1.1, CH3-4); 5.83 (1H, q, J = 1.1, H-5);
7.35-7.42 (5H, m, Harom). Found, %: C 69.1; H 4.4; N 12.1. C13H10N2O2. Calculated, %: C 69.0; H 4.4; N 12.0.
Negative reaction with FeCl3 (mp 190°C [4]).
3-p-Methoxyphenyl-4-methylpyrano[2,3-c]pyrazol-6-one (7i). Heated for 3 h at 160°C, yield 86%;
mp 231-233°C (ethyl acetate). IR spectrum, ν, cm-1: 1525, 1600, 1710 (C=O). UV spectrum, λmax, nm (log ε):
229 (4.19); 250 (4.03); 307 (4.40). 1H NMR spectrum, δ, ppm (J, Hz): 2.12 (3H, d, J = 1.1, CH3-4); 3.84 (3H, s,
OCH3); 5.86 (1H, q, J = 1.1, H-5); 7.12 (2H, d, m-Harom); 7.9 (2H, d, J = 6, o-Harom); 11.8 (1H, very br. s, NH).
Found, %: C 66.1; H 4.8; N 11.2. C14H12N2O3. Calculated, %: C 65.6; H 4.7; N 10.9. Negative reaction with
FeCl3.
4,5-Dihydro-3-[1-(5-hydroxy-3-phenyl-1H-pyrazol-4-yl)ethylidene]furan-2-one (8a). Heating for 3 h
at 170°C, yield 69%; mp 282-284°C (ethyl acetate). IR spectrum, ν, cm-1: 1515, 1630, 1710 (C=O).
1
UV spectrum, λmax, nm (log ε): 235 (4.48); 250 (4.42); 290 (4.33). H NMR spectrum, δ, ppm: 2.29 (3H, s,
391

CH3-4); 2.60 (2H, t, CH2-5-α); 4.14 (2H, t, CH2-5-β); 7.35-7.42 (5H, m, Harom). Mass spectrum, m/z (Irel, %): 270
[M]+ (100); 255 (51); 239 [M+-CH2OH] (88); 211 (74); 77 (68). Found, %: C 66.7; H 5.4; N 10.4. C15H14O3N2.
Calculated, %: C 66.7; H 5.4; N 10.4. Negative reaction with FeCl3.
4,5-Dihydro-3-{1-[5-hydroxy-3-(4-methoxyphenyl)-1H-pyrazol-4-yl]ethylidene}furanone (9a).
Heating for 3 h at 170°C, yield 59%; mp 273-275°C (ethyl acetate). IR spectrum, ν, cm-1: 1500, 1525, 1610,
1
1710 (C=O). UV spectrum, λmax, nm (log ε): 251 (4.05); 286 (3.90). H NMR spectrum, δ, ppm: 2.29 (3H, s,
CH3-4); 2.59 (2H, t, CH2-5-α); 3.78 (3H, s, OCH3); 4.13 (2H, t, CH2-5-β); 6.98 (2H, d, m-Harom); 7.37 (2H, d,
o-Harom). Found, %: C 64.0; H 5.3; N 9.4. C16H16N2O4. Calculated, %: C 64.0; H 5.3; N 9.3. Positive reaction
with FeCl3.
2,4-Bis(3-methyl-5-oxopyrazol-4-ylidene)pentanediylidene (14). A mixture of 3-methylpyrazol-5-one
(2.94 g, 0.03 mol) and acetylacetone (4 g, 0.04 mol) was heated in a metal bath for 6 h at 140°C, distilling off the
water. During the heating a further 2 g of acetylacetone was added portionwise. The reaction product was cooled
and then heated to reflux with a mixture of benzene (10 ml) and hexane (4 ml). The precipitate was filtered off,
washed with hexane, and then heated to reflux with acetone (10 ml) to purify it from colored admixtures. It was
then filtered off and recrystallized from ethanol to give compound 14 (2.6 g, 67%);
1
mp 232-234°C (sealed capillary). IR spectrum, ν, cm-1: 1270, 1450, 1505, 1530, 1600, 2800-3180. H NMR
spectrum, δ, ppm: 1.79 (3H, s, CH3-aliph.); 1.98 (2H, s, CH2); 2.31 (3H, s, CH3-pyrazole); 11.5 (1H, br. s, OH).
Found, %: C 60.1; H 6.3; N 21.5. C13H16N4O2. Calculated, %: C 60.0; H 6.15; N 21.5. Positive reaction with
FeCl3 (mp 206°C [3]).
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392