Novel Preparation of 1-Aryl-3-(2-hydroxyphenyl)-2-pyrazolin-5-ones and their Conversion into 2-Aryl-4-methyl[1] benzopyrano[4,3-c] pyrazol-3(2H)-ones

Article abstract of DOI:10.1039/a605456k

1-Aryl-3-(2-hydroxyphenyl)-2-pyrazolin-5-ones are prepared from 4-hydroxycoumarin and arylhydrazines and then cyclised with triethyl orthoacetate to give 2-aryl-4-methyl[1]benzopyrano[4,3-c]pyrazol-3(2H)-ones.

Full text of DOI:10.1039/a605456k

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30 J. CHEM. RESEARCH (S), 1997
J. Chem. Research (S),
1997, 30–31†
Novel Preparation of 1-Aryl-3-(2-hydroxyphenyl)-
2-pyrazolin-5-ones and their Conversion into 2-Aryl-
4-methyl[1]benzopyrano[4,3-c]pyrazol-3(2H)-ones†
Jayne A. Froggett, Michael H. Hockley* and Roger B. Titman
Knoll Pharmaceuticals Research and Development Department, Pennyfoot Street, Nottingham
NG1 1GF, UK
1-Aryl-3-(2-hydroxyphenyl)-2-pyrazolin-5-ones are prepared from 4-hydroxycoumarin and arylhydrazines and then
cyclised with triethyl orthoacetate to give 2-aryl-4-methyl[1]benzopyrano[4,3-c]pyrazol-3(2H)-ones.
In the search for routes to 1-aryl-3-(2-hydroxyphenyl)-2-pyr-
azolin-5-ones it was found that one possibility, the reaction of
4-hydroxycoumarin with arylhydrazines, was not well docu-
mented.
Whereas Chantegrel and Gelin1 described the synthesis of
3-(2-hydroxyaryl)-1-methyl-2-pyrazolin-5-ones by the regio-
selective reaction of methylhydrazine with 4-hydroxycou-
marin 1a, Heubner and Link2 reported, and we have con-
firmed, that phenylhydrazine 2b on reaction with 1a at 120 °C
gave 3-(2-hydroxyphenyl)-1-phenyl-4-phenylazo-3-pyrazolin-
5-one 4. In contrast to this we now report a simple one-
pot preparation of 1-aryl-3-(2-hydroxyphenyl)-2-pyrazolin-
5-ones 3a,b from the reaction of 4-chlorophenylhydrazine 2a
or phenylhydrazine 2b with 4-hydroxycoumarin 1a. This
avoids the only other, lengthier, route to 3 published by
Colotta et al.,3 which involves reaction of the b-ketoester 5
with arylhydrazines followed by debenzylation.
Thus reaction of 4-hydroxycoumarin 1a with a 1.5 molar
excess of arylhydrazines 2a,b in toluene under reflux, with
azeotropic removal of water, gave the 1-aryl-3-(2-hydroxy-
phenyl)-2-pyrazolin-5-ones 3a,b (Scheme 1) in 60–70%
1
yield.4 The melting points and H NMR data for 3a,b are in
agreement with those reported by Colotta et al.3
carried out on a Carlo-Erba 1106/1 elemental analyser. IR spectra
were recorded on a Unicam FTIR 3020 spectrometer and 1H NMR
spectra on a Bruker AC 250 spectrometer using tetramethylsilane
as internal standard. Mass spectra were recorded on a Finnegan
MAT 8200 mass spectrometer.
Typical
Procedure.—1-(4-Chlorophenyl)-3-(2-hydroxyphenyl)-
2-pyrazolin-5-one 3a. 5
M
Sodium hydroxide (50 cm3) was added to
Scheme 1
a suspension of 4-chlorophenylhydrazine hydrochloride (22.7 g,
0.138 mol) in water (600 cm3), maintaining the temperature at
20 °C. The mixture was extracted with diethyl ether (3Å200 cm3)
and the extracts were washed with water (200 cm3), dried (MgSO4)
and evaporated under reduced pressure below 40 °C. To the thus
isolated 4-chlorophenylhydrazine (18.90 g, 0.133 mol) was added
immediately 4-hydroxycoumarin (14.25 g, 0.088 mol) and dry
toluene (150 cm3) and the resultant mixture was stirred under
reflux with a Dean–Stark trap. After 2 h, water separated (1.6 cm3,
0.088 mol) and the solution was allowed to cool to yield the title
compound 3a as orange crystals, mp 190–191 °C (19.8 g, 72.5%)
(Found: C, 63.1; H, 4.0; Cl, 12.8; N, 10.1%; Mǹ, 286.0494.
C15H11ClN2O2 requires C, 63.1; H, 4.0; Cl, 12.8; N, 10.1%; M,
286.0509); dH (CDCl3) 3.9 (2 H, s, CH2), 6.9–7.8 (8 H, m, aromatic
protons), 10.0 (1 H, s, OH).
Arylhydrazinocoumarins 6a,b are intermediates in the
one-pot reaction and, as by products, can be removed by
virtue of their insolubility in dichloromethane. Coumarin 6a
was isolated as a major reaction product when 1 equiv. of the
arylhydrazine was used in the reaction.
In contrast, the reaction of 4-hydroxy-3-methylcoumarin
1b with 4-chlorophenylhydrazine 2a gave the arylhydrazino-
coumarin 6c as the sole product. Rearrangement to the pyr-
azolinone is presumably prevented due to steric hindrance by
the methyl group.
Heating the pyrazolin-5-ones 3a,b with triethyl ortho-
acetate1 at 140–150 °C gave cyclisation to 4-methyl[1]benzo-
pyrano[4,3-c]pyrazol-3(2H)-ones 7a,b.3,4 Compound 7a is a
potent immunosuppressant.5
1-Phenyl-3-(2-hydroxyphenyl)-2-pyrazolin-5-one
3b.
Mp
129–131 °C (56% yield) (Found: C, 71.8; H, 4.9; N, 11.35; Mǹ,
252.0900. C15H12N2O2 requires C, 71.4; H, 4.8; N, 11.1%; M,
252.0899); dH (CDCl3) 3.9 (2 H, s, CH2), 6.9–7.8 (8 H, m, aromatic
protons), 10.1 (1 H, s, OH).
4-(4-Chlorophenylhydrazino)coumarin 6a. Repetition of the pro-
cedure for 3a but with only an equimolar amount of 4-chloro-
phenylhydrazine (12.5 g, 0.088 mol) gave a mixture of 3a and 6a on
filtration of the cooled reaction mixture. Digestion of the solid with
boiling dichloromethane (250 cm3), followed by recrystallisation
from industrial methylated spirits, gave 6a as a colourless solid
(2.1 g, 8% yield) (Found: C, 63.0; H, 3.9; Cl, 12.7; N, 8.9%; Mǹ,
286.0494. C15H11ClN2O2 requires C, 63.1; H, 4.0; Cl, 12.8; N, 10.1%;
Experimental
Melting points were determined on a Gallenkamp melting
point apparatus and are uncorrected. Elemental analyses were
*To receive any correspondence.
†This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1996, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

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J. CHEM. RESEARCH (S), 1997 31
M, 286.0509); dH [(CD3)2SO] 5.4 (1 H, s, CH), 6.8–8.3 (8 H, m,
aromatic protons), 8.45 (1 H, s, NH), 9.85 (1 H, s, NH).
276.0899); dH [(CD3)2SO] 2.8 (3 H, s, Me), 7.2–8.1 (9 H, m, aro-
matic protons).
4-(4-Chlorophenylhydrazino)-3-methylcoumarin 6c. Repetition of
the procedure for 3a but starting from 4-hydroxy-3-methyl-
coumarin gave 6c, mp 218–220 °C (85% yield) (Found: C, 63.7; H,
4.1; Cl, 11.5; N, 9.1%; Mǹ, 300.0662. C16H13ClN2O2 requires C,
63.9; H, 4.3; N, 9.3; Cl, 11.8%; M, 300.0665); dH [(CD3)2SO] 2.0
(3 H, s, Me), 3.35 (1 H, brs, NH), 6.9–7.9 (8 H, m, aromatic
protons), 10.7 (1 H, brs, NH).
We thank Dr R. V. Davies for helpful discussions.
Received, 5th August 1996; Accepted, 18th October 1996
Paper E/6/05456K
2-(4-Chlorophenyl)-4-methyl[1]benzopyrano[4,3-c]pyrazol-
3(2H)-one 7a. A mixture of 3a (60 g, 0.21 mol) and triethyl ortho-
acetate (115 cm3, 101.8 g, 0.63 mol) was stirred and heated at
140–150 °C for 30 min. The reaction mixture was allowed to cool to
room temperature and was then diluted with diethyl ether (20 cm3).
The product was filtered to afford the title compound 7a as yellow
crystals (62.4 g, 96%), mp 204–206 °C (Found: C, 65.8; H, 3.55; Cl,
11.6; N, 8.9%; Mǹ, 310.0513. C17H11ClN2O2 requires C, 65.7; H,
3.5; Cl, 11.1; N, 9.0%; M, 310.0509); dH [(CD3)2SO] 2.83 (3 H, s,
Me), 7.5–8.3 (8 H, m, aromatic protons).
References
1 B. Chantegrel and S. Gelin, Synthesis, 1985, 548.
2 C. F. Heubner and K. P. Link, J. Am. Chem. Soc., 1945, 67, 102.
3 (a) V. Colotta, L. Cecchi, F. Melani, G. Palazzino and G. Fillac-
chioni, Tetrahedron Lett., 1987, 28, 5165; (b) V. Colotta, L. Cecchi,
F. Melani, G. Palazzino, G. Gilacchioni, C. Martini, G. Giannac-
cini and A. Lucacchini, J. Pharm. Sci., 1989, 78, 239.
4 J. G. Bowen, M. H. Hockley, J. R. Housley, I. M. Hunneyball, R.
B. Titman and D. G. Wbber, Eur. Pat. Appl. 354 693, 1990.
5 P. Appleby, J. G. Bowen, D. G. Webber, G. Naylor, G. Telford
and J. K. Wilkinson, Clin. Exp. Immunol., 1993, 93, 313.
2-Phenyl-4-methyl[1]benzopyrano[4,3-c]pyrazol-3(2H)-one
7b.
Mp 163–165 °C (57% yield) (Found: C, 73.9; H, 4.5; N, 10.2%; Mǹ,
276.0899. C17H12N2O2 requires C, 73.9; H, 4.35; N, 10.1%; M,