Synthesis of N1-Substituted Coumarino[4,3-c] pyrazoles

Article abstract of DOI:10.1002/jhet.5570400513

3-Acyl-4-hydroxy-2-oxo-2H-chromen derivatives 1a-d were condensed with (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide 2, (4-methyl-2-oxo-2H-chromen-7-yloxy)-acetic acid hydrazide 3, and (7-hydrazinocarbonylmethoxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide 4, to give corresponding 3-alkyl-1-[2-(7-hydroxy-2-oxo-2H-chromeno-4-yl)-acetyl]-1H-chromeno[4,3-c] pyrazole-4-one 5a-d, 3-alkyl-1-[2-(4-methyl-2-oxo-2H-chromeno-7-yloxy)-acetyl]-1H-chromeno[4,3-c] pyrazole-4-one 6a-d, and 1-{4-[(3-alkyl-1H-chromeno[4,3-c]pyrazole-4-one-1-yl)-carbonylmethyl] -2-oxo-2H-chromen-7-yloxy-acetyl}-3-alkyl-1H-chromeno[4,3-c]pyrazole-4-one 7a-d.

Full text of DOI:10.1002/jhet.5570400513

Sep-Oct 2003
Synthesis of N -Substituted Coumarino[4,3-c] pyrazoles
833
1
ˇ
Milan Cacˇicˇ, Mladen Trkovnik and Elizabeta Has-Schön
Department of Chemistry, Faculty of Food Technology
J.J.Strossmayer University,Franje Kuhaca 18 ,31 000 Osijek, Croatia
PLIVA d.d.-Research Institute, Prilaz baruna Filipovica 25 , 10 000 Zagreb, Croatia
Faculty of Education, J.J. Strossmayer University, Lorenca Jagera 9 , 31000 Osijek, Croatia
Received August 30, 2002
3-Acyl-4-hydroxy-2-oxo-2H-chromen derivatives 1a-d were condensed with (7-hydroxy-2-oxo-2H-
chromen-4-yl)-acetic acid hydrazide 2, (4-methyl-2-oxo-2H-chromen-7-yloxy)-acetic acid hydrazide 3, and
(7-hydrazinocarbonylmethoxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide 4, to give corresponding
3-alkyl-1-[2-(7-hydroxy-2-oxo-2H-chromeno-4-yl)-acetyl]-1H-chromeno[4,3-c]pyrazole-4-one 5a-d,
3-alkyl-1-[2-(4-methyl-2-oxo-2H-chromeno-7-yloxy)-acetyl]-1H-chromeno[4,3-c]pyrazole-4-one 6a-d,
and 1-{4-[(3-alkyl-1H-chromeno[4,3-c]pyrazole-4-one-1-yl)-carbonylmethyl]-2-oxo-2H-chromen-7-
yloxy-acetyl}-3-alkyl-1H-chromeno[4,3-c]pyrazole-4-one 7a-d.
J. Heterocyclic Chem., 40, 833 (2002).
Since the coumarin ring forms a part of many hetero-
2H-chromen-4-yl)-acetic acid hydrazide 4 was obtained
from (7-hydroxy –2-oxo-2H-chromen-4-yl)-acetic acid.
Compounds 1a-d were synthesized from 4-hydroxy-2-
oxo-2H-chromen [21-23]. Structures of compounds 1a-d
are as previously described [24-28]. Within these struc-
tures the α-pyronic form is dominant, while the presence
of the γ-pyronic form is insignificant.
cyclic compounds of pharmacological interest [1-4], these
derivatives are being evaluated for potential biological
activity. Different biological activity of the coumarins fused
with other heterocycles in 3,4-positions [5-13] prompted
the synthesis of coumarino [4,3-c]-N -substituted pyra-
1
zoles. Woulfson and Zhurin [14] reported the synthesis of
coumarino [4,3-c]-N -phenyl-3-methylpyrazoles by cycliz-
Refluxing an equimolar amounts of 3-acyl-4-hydroxy-2-
oxo-2H-chromen 1 and 2 in ethanol led to a new series of
compounds 5a-d. (Scheme I). The same reaction when
carried out by 3 and 4 leads to the fomation of 6a-d and
7a-d (Schemes II and III).
1
ing the phenylhydrazones of 3-acetyl-4-hydroxycoumarins
using p-toluensulphonic acid. Checchi and co-workers [15]
condensed phenylhydrazine with 4-chloro-3-cyano-
coumarins and obtained coumarino[4,3-c]-N -phenyl-3-
1
aminopyrazoles. Moorty and co-workers [16] carried out
the intramolecular cyclization of the phenylhydrazones of
the respective 4-chloro-3-formylcoumarins using pyridine
to which piperidine was added in traces. In this way the
Screening Data.
Derivatives of coumarins 5a-d, 6a-d and 7a-d described
here were examined for their antimicrobial activity. The best
results were obtained in the case of 1-[2-(7-hydroxy-2-oxo-
2H-chromen-4-yl)-acetyl-3-methyl-1H-chromeno[4,3-c]-
pyrazole-4-one 5a, 3-ethyl-1-[2-(7-hydroxy-2-oxo-2H-
chromen-4-yl)-acetyl-1H-chromeno[4,3-c]pyrazole-4-one
5b, 1-[2-(7-hydroxy-2-oxo-2H-chromen-4-yl)-acetyl-3-
propyl-1H-chromeno[4,3-c]pyrazole-4-one 5c and 1-[2-(7-
hydroxy-2-oxo-2H-chromen-4-yl)-acetyl-3-izobuthyl-1H-
chromeno[4,3-c]pyrazole-4-one 5d. These compounds were
found to possess high antimicrobial activity against
Staphyloccocus pneumoniae and were slightly less active
coumarino[4,3-c]-N -phenylpyrazoles were prepared.
1
From 3-acetyl-4-hydroxy-2-oxo-2H-chromen, with
hydrazine hydrate and phenylhydrazine in ethanol, were
obtained 3-(1-hydrazonoethyl)-4-hydroxy-chromen-2-one
and 3-methyl-1H-chromeno[4,3-c]pyrazole-4-one [17].
Klosa [18], under the same conditiones, synthesised only 3-
(1-hydrazono-ethyl)-4-hydroxy-chromen-2-one.
While in experiments performed so far, monopyrazole-
coumarins were prepared [14-18], we succeeded in synthe-
sis of a new pyrazole and dipyrazole, possesing two and
even three coumarin nucleus.
Baker and co-workers [19] reported an unsuccessful
attempt in (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic
acid hydrazide 2 preparation from the corresponding
methyl ester of the carboxylic acid. We succeeded in the
preparation of the corresponding hydrazide [20] from (7-
hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid methyl
ester, which was reacted with 100% hydrazine hydrate in
methanol. (4-Methyl-2-oxo-2H-chromen-7-yloxy)-acetic
acid ethyl ester was prepared by the reaction of
7-hydroxy-4-methyl-2-oxo-2H-chromen and ethylbro-
moacetate, which reacted with hydrazine hydrate in
ethanol to give 3. (7-Hydrazinocarbonylmethoxy-2-oxo-
Scheme I

ˇ
834
M. Cacˇicˇ, M. Trkovnik and E. Has-Schön
Vol. 40
Scheme III
against Bacillus subtilis, Bacillus cereus and Salmonela
panama. In case of 3-alkyl-1-[2-(4-methyl-2-oxo-2H-
chromeno[4,3-c]pyrazole-4-one 6a-d and 1-{4-[(3-alkyl-
1H-chromeno[4,3-c]pyrazole-4-one-1-yl)-carbonylmethyl]-
2-oxo-2H-chromen-7-yloxy-acetyl}-3-alkyl-1H-chromeno-
[4,3-c]pyrazole-4-one 7a-d, we have found them to have
very weak activity against all the tested microorganisms.
Scheme II
300 spectrometer (300 MHz) with tetramethylsilane as internal
-1
standard. The IR spectra (ν/cm ) were recorded as potassium bro-
mide pellets on a Magna FT-IR 760 Nicolet spectrometer.
Starting from 4-hydroxy-2-oxo-2H-chromen using a known
procedure, we have prepared 3-acyl-4-hydroxy-2-oxo-2H-
chromen 1a-d [21-23]. We have also used known procedures for
the preparation of (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic
acid hydrazide 2.
Table I
Physical and Analytical Data for Compounds 5a-d, 6a-d and 7a-d
Compound
R
Yield
(%)
Mp
(°C)
Formula
(MW)
Analysis Calcd./
Found (%)
N
C
H
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
-CH
82
76
70
63
78
68
72
58
80
82
75
48
262
(402.6)
265
(416.1)
271
(430.4)
279
(444.4)
249
(416.4)
253
(430.4)
259
(444.4)
265
(458.4)
246
(642.57)
248
(670.62)
255
(698.68)
268
(726.73)
C
C
C
C
C
C
C
C
C
C
C
C
H
N O
65.67
3.80
66.34
4.06
66.97
4.36
67.54
4.48
66.34
4.10
66.97
4.48
67.54
4.51
68.11
4.74
65.42
3.40
66.27
4.15
67.04
4.23
67.76
4.84
3.51
6.80
3.87
6.57
4.22
6.24
4.54
6.41
3.87
6.62
4.22
6.44
4.54
6.22
4.84
5.98
3.45
8.92
3.91
8.42
4.33
8.04
4.72
7.80
6.96
6.73
6.51
6.30
6.73
6.51
6.30
6.11
8.72
8.35
8.02
7.71
3
22 14
2
6
6
6
6
6
6
6
6
9
9
9
9
65.43
H N O
23 16 2
66.31
H N O
24 18 2
66.94
H N O
25 20 2
67.47
H N O
23 16 2
66.31
H N O
24 18 2
66.73
H N O
25 20 2
67.30
H N O
26 22 2
68.20
H N O
35 22 4
65.57
H N O
37 26 4
66.20
H N O
39 30 4
67.06
H N O
41 34 4
67.87
-CH CH
2
3
-CH CH CH
2
2
3
-CH CH(CH )
2
3 2
-CH
3
-CH CH
2
3
-CH CH CH
2
2
3
-CH CH(CH )
2
3 2
-CH
3
-CH CH
2
3
-CH CH CH
2
2
3
-CH CH(CH )
2
3 2
EXPERIMENTAL
(4-Methyl-2-oxo-2H-chromen-7-yloxy)-acetic acid hydrazide
(3).
General Information.
A mixture of (4-methyl-2-oxo-2H-chromen-7-yloxy)-acetic
acid ethyl ester (2.6 g, 0.01 mol) and 100% hydrazine hydrate ( 1
ml, 0.02 mol) in absolute ethanol (30 ml) was refluxed for 1.5 to
2.0 hours. The white precipitate which was formed during the reac-
tion was collected by filtration, washed with water and crystallized
Melting points were determined on a Fisher-Johns apparatus
and are uncorrected. Microanalyses for C, H and N were per-
formed on a Perkin-Elmer Analyzer 2400. The H NMR spectra
1
(δ values; DMSO-d solutions) were recorded on a Varian Gemini
6

Sep-Oct 2003
Synthesis of N -Substituted Coumarino[4,3-c] pyrazoles
835
1
1
Table II
1617(C=C, arom.); H NMR (DMSO-d ): δ 9.34 (s, 1H, NH), 7.64
6
(d, 1H, H-5), 6.81(d, 1H, H-6), 6.78(s, 1H, H-8), 6.24 (s, 1H, H-3),
IR Data of Compounds 5a-d, 6a-d and 7a-d
5.32 (s,2H, CH ), 3.24 (d, 2H, NH ), 2.40 (s, 3H, CH ).
2
2
3
-1
Compounds
IR (cm )
3
Anal.Calcd. for C H N O : C, 58.06; H, 4.87; N, 11.29.
12 12
2 4
ν OH
ν CH
ν CH
ν C=O ν C=C ν C=N
2
Found: C, 58.12; H, 4.82; N, 10.98.
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
3422
w
3448
w
3420
w
3432
w
3128
w
3175
w
3181
w
3160
w
3170
w
3165
w
3147
w
3160
w
3142
w
3120
w
3130
w
3140
w
3008
s
3012
sh
3163
sh
3142
sh
3120
sh
3134
sh
3020
sh
3080
sh
3004
sh
2980
sh
2995
sh
3000
sh
1708
s
1709
s
1711
s
1706
s
1651
s
1692
s
1641
s
1654
s
1611
sh
1610
sh
1608
sh
1612
sh
1605
sh
1600
sh
1610
sh
1600
sh
1612
sh
1600
sh
1600
sh
1610
sh
(7-Hydrazinocarbonylmethoxy-2-oxo-2H-chromen-4-yl)-acetic
Acid Hydrazide (4).
In a solution containing methanol (120 ml ) and 100%
hydrazine hydrate (12 ml )was dissolved (7-ethoxycarbonyl-
methoxy-2-oxo-2H-chromen-4-yl)-acetic acid methyl ester (3.2
g, 0.01 mol) and the mixture was left to stand over night at 5 °C.
The product was separated, was collected by suction filtration,
washed with methanol, and recristallized from dil. acetic acid.
-
1712
s
1712
1665
s
1690
-
-
-
-
-
-
-
M.p. >300°C, yield 2.14 g, (70%); IR (potassium bromide):ν 3325;
s
1705
s
1710
s
1718
s
1715
s
1712
s
1710
s
s
1695
s
1694
s
1700
s
1695
s
1700
s
1705
s
1
3263 (NH),(NH ),1707;1690 (C=O), 1623 (C=C,arom.). H NMR
2
(DMSO-d ): δ 9.41 (s, 1H, NH), 9.34 (s, 1H, NH), 7.76 (d, 1H, H-5),
6
7.04 (d, 1H, H-6), 7.02 (s, 1H, H-8), 6.34 (s, 1H, H-3), 4.69 (s, 2H,
CH ), 4.34 (s, 2H, NH ), 4.08 (s, 2H,CH ), 3.38 (s, 2H,NH ).
2
2
2
2
Anal. Calcd. For C H N O : C, 50.98; H, 4.61; N, 18.29.
13 14
4 5
Found: C, 51.02; H, 4.38; N, 18.15.
General Procedure for Condensation and Cyclization of 3-Acyl-
4-hydroxy-2-oxo-2H-chromen with Hydrazide 2,3 and
Dihydrazide 4.
A mixture of 3-acyl- 4-hydroxy-2-oxo-2H-chromen 1a-d (0.01
mole) and the corresponding hydrazide 2,3 (0.01 mole) in
Table III.
H NMR Data for Compounds 5a-d, 6a-d and 7a-d
1
Compound
H-3
H-5
H-6
H-7
H-8
R
-CH -
CH
2
3
H-3′
H-5′
H-6′
H-7′
H-8′
R′
-CH -
2
5a
5b
5c
5d
6a
6b
6c
6d
7a
-
7.96(d)
7.32(d)
7.95(d)
7.31(d)
7.96(d)
7.31(d)
7.97d(d)
7.34(d)
7.98(d)
7.32(d)
7.98(d)
7.32(d)
7.96(d)
7.32(d)
7.94(d)
7.31(d)
8.25(d)
8.04(d)
7.96(d)
8.02(d)
7.98(d)
7.93(d)
8.05(d)
7.98(d)
7.94(d)
7.99(d)
7.96(d)
7.90(d)
7.66(d)
6.82(d)
7.67(q)
6.78(q)
7.65(d)
6.81(d)
7.66(d)
6.80(d)
7.72(d)
7.29(d)
7.74(d)
7.28(d)
7.72(d)
7.29(d)
7.74(d)
7.30(d)
7.84(d)
7.68-
7.78(m)
7.84(d)
7.64-
7.80(m)
7.84(d)
7.64-
7.81(m)
7.87(d)
7.62-
7.64(d)
10.62(s)
7.63(d)
10.63(s)
7.64(d)
10.55(s)
7.64(d)
10.58(s)
-
7.63(d)
-
7.70(d)
-
7.66(d)
-
7.78(d)
-
7.40-
7.60(m)
-
7.38-
7.63(m)
-
7.29(d)
6.75(d)
7.29(d)
6.76(d)
7.26(d)
6.75(d)
7.31(d)
6.72(d)
7.17(s)
7.05(d)
7.30(s)
7.00d)
7.29(s)
7.06(d)
7.26(s)
7.00(d)
7.22(s)
7.09(d)
7.17(d)
7.28(s)
7.08(d)
7.16(d)
7.28(s)
7.08(d)
7.12(d)
7.25(s)
7.00(d)
7.14(d)
2.50(s)
-
3.15(q), 1.12(t)
-
-
-
-
-
-
-
-
-
-
6.74(s)
-
6.30(s)
-
6.29(s)
-
6.26(s)
-
6.24(s)
-
6.24(s)
-
6.24(s)
-
6.26(s)
-
3.94(s)
-
3.95(s)
-
3.94(s)
-
3.93(s)
4.94(s)
-
4.96(s)
-
4.94(s)
-
-
3.07(t), 1.51(q), 0.94(t)
-
3.9(d); 0.89(d); 0.87(d)
-
2.65(s)
-
3.11(q); 1.12(t)
2.40(s)
-
2.40(s)
-
-
2.65(t); 2.50(q); 1.40(t)
-
2.40(s)
3.8(d), 0.92(d); 0.89(d)
4.94(s)
-
4.96(s)
4.02(s)
-
2.40(s)
-
-
2.29(s)
2.50(s)
6.40(s)
7b
7c
7d
-
2.67(t); 1.16(t)
-
4.97(s)
4.08(s)
-
-
-
6.38(s)
-
2.60(t); 2.42(q); 1.40(t)
-
4.97(s)
4.02(s)
6.37(s)
7.35-
7.60(m)
-
7.32-
7.57(m)
-
3.52(s); 1.15(d); 1.07(d)
5.11(s)
4.00(s)
6.39
7.75(m)
from ethanol, m.p. 201-202 °C, yield 2.3 g (92.6%); IR (potassium
absolute ethanol ( 50 ml ) was refluxed for 2 hours or at the end
of the reaction (monitored by TLC). The reaction mixture was
bromide):ν 3269; 3100 (NH), (NH ), 1713; 1683 (C=O),
2

ˇ
836
M. Cacˇicˇ, M. Trkovnik and E. Has-Schön
Vol. 40
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cooled and solid was collected by filtration and recrystallized
from ethanol.
In a similar manner to that described for the preparation of
compounds 5a-d and 6a-d. By the action of 3-acyl-4-hydroxy-2-
oxo-2H-chromen 1a-d (0.02 mole) and dihydrazide 4 (0.01 mole)
in absolute ethanol (75 ml), compounds 7a-d were obtained. Data
for yields, melting points, molecular formula and analyses are
1
given in Table I. IR and H NMR data are given in Table II and
Table III.
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