Synthesis and reactions of 4-(arylhydrazino)coumarins

Article abstract of DOI:10.1007/s10593-010-0428-y

The interaction of 4-hydroxycoumarin with phenyl-, 2-chlorophenyl- and 4-bromophenyhydrazine hydrochlorides in the presence of triethylamine led in all cases to the corresponding 4-(arylhydrazino)-coumarins and 1-aryl-3-(2- hydroxyphenyl)-2H-pyrazolin-5-o

Full text of DOI:10.1007/s10593-010-0428-y

Chemistry of Heterocyclic Compounds, Vol. 45, No. 11, 2009
SYNTHESIS AND REACTIONS OF
4-(ARYLHYDRAZINO)COUMARINS
I. Strakova1, A. Strakovs1*, M. Petrova2, and S. Belyakov2
The interaction of 4-hydroxycoumarin with phenyl-, 2-chlorophenyl- and 4-bromophenyhydrazine
hydrochlorides in the presence of triethylamine led in all cases to the corresponding 4-(arylhydrazino)-
coumarins and 1-aryl-3-(2-hydroxyphenyl)-2H-pyrazolin-5-ones. 4-(Arylhydrazino)coumarins reacted
with 4-chlorobenzaldehyde in the presence of piperidine acetate to give the corresponding 2-aryl-3-(4-
chlorophenyl)[1]benzopyrano[4,3-b]pyrazol-4-ones. The reaction of 4-(4-bromophenylhydrazino)-
coumarin with 4-chlorobenzaldehyde in the presence of piperidine acetate and an excess of piperidine
gave 2-(4-bromophenyl)-5-(4-chlorophenyl)-3-(2-hydroxyphenyl)-4-(piperidinocarbonyl)pyrazole, but
the reaction of phenyl- and 4-(2-chlorophenylhydrazino)coumarins with 4-chlorobenzaldehyde gave
1-aryl-5-(4-chlorophenyl)-3-(2-hydroxyphenyl)-4-(1-piperidino)carbonyl-4,5-dihydropyrazoles.
Keywords: 4-(arylhydrazino)coumarins, 1-aryl-3-(2-hydroxyphenyl)-2H-pyrazin-5-ones, aromatic
aldehydes, 2,3-diaryl[1]benzopyrano[4,3-b]pyrazol-4-ones.
In a development of work on the synthesis of coumarins with heterocycles at the C(3)–C(4) bond [1-3]
we have synthesized pyrazolocoumarins by the reactions of 4-(arylhydrazino)coumarins with aromatic
aldehydes. We reverted to pyrazolocoumarins [4-6] which, like other 3,4-heteroannelated coumarins, were
observed to have biological activity [7-13].
The reactions of phenyl-, 2-chlorophenyl- and 4-bromophenylhydrazine hydrochlorides with 4-hydroxy-
coumarin 1 in the presence of triethylamine were carried out by heating in the absent of solvent (1h 30 min,
90-100ºC). In all cases, 1-aryl-3-(2-hydroxyphenyl)pyrazol-5-ones 3a-c were formed along with the
corresponding 4-(arylhydrazino)coumarins 2a-c. Pyrazolone 3a was obtained previously [14] by boiling
4-hydroxycoumarin with phenylhydrazine in benzene. On boiling the same reagents in toluene with a catalytic
amount of p-toluenesulfonic acid we obtained 4-(phenylhydrazino)coumarin (2a) as the main product (50%) and
the pyrazolone 3a in a yield of only 18%. Boiling the pyrazolones 3a-c in acetic anhydride in the presence of
p-toluenesulfonic acid gave the diacetyl derivatives 4a-c.
The reaction of (4-arylhydrazino)coumarins 2a-c with 4-chlorobenzaldehyde in DMF solution in the
presence of equimolar catalytic amounts of piperidine and acetic acid gave the corresponding 2-aryl-3-(4-
chlorophenyl)[1]benzopyrano[4,3-b]pyrazol-4-ones 5a-c.
_______
* To whom correspondence should be addressed, e-mail: strakovs@latnet.lv.
1Riga Technical University, Riga LV-1048, Latvia.
2Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia; e-mail: marina@osi.lv.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, 1643-1650, November, 2009.
Original article submitted June 16, 2006. Revised version submitted May 23, 2009.
0009-3122/09/4511-1319©2009 Springer Science+Business Media, Inc.
1319

O
N
Ar
Ar
MeC
N
HN
N
NHNHAr
OH
O
O
O
(MeCO)2O
.
ArNHNH2 HCl
+
OH
O
O
Et3N
OCOMe
O
2a–c
3a–c
4a–c
1
(CH2)5NH MeCOOH
ClC6H4CHO
.
.
ClC6H4CHO
(CH2)5NH MeCOOH
+ (CH2)5NH
Ar
2a,b
2c
Ar
N
N
Br
N
OH
N
Cl
Cl
O
O
CO
5a–c
N
N
OH
N
Cl
7a,b
CO
N
6
2–5 a Ar = Ph, b Ar = 2-ClC6H4, c Ar = 4-BrC6H4; 7 a Ar = Ph, b Ar = 2-ClC6H4
TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
С
Н
N
Hal
2а
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6
C15H12N2O2
71.49
71.41
62.63
62.84
54.20
54.40
71.30
71.41
62.58
62.84
54.18
54.40
67.66
67.85
61.30
61.54
54.72
54.96
70.70
70.88
64.69
64.88
58.40
58.50
59.91
59.96
70.33
70.50
65.41
65.59
4.69
4.80
3.80
3.87
3.11
3.35
4.66
4.80
3.71
3.87
3.14
3.35
4.70
4.80
3.92
4.08
3.60
3.64
3.55
3.51
2.99
2.97
2.60
2.68
4.35
4.29
5.57
5.70
5.00
5.10
10.95
11.10
9.63
9.77
8.32
8.46
10.87
11.10
9.61
9.77
8.29
8.46
8.11
8.33
7.37
7.55
6.65
6.74
7.40
7.51
6.71
6.88
6.14
6.20
7.60
7.77
9.11
9.14
8.38
8.50
245-246
256-257
254-256
119-121
208-210
196-197
90-91
51
53
52
18
9
C15H11ClN2O2
C15H11BrN2O2
C15H12N2O2
12.20
12.36
23.90
24.13
C15H11ClN2O2
C15H11BrN2O2
C19H16N2O4
12.10
12.36
23.95
24.13
15
43
88
64
30
37
40
70
50
32
C19H15ClN2O4
C19H15BrN2O4
C22H13ClN2O2
C22H12Cl2N2O2
C22H12BrClN2O2
C27H23BrClN3O2
C27H26ClN3O2
C27H25Cl2N3O2
9.40
9.56
19.00
19.24
9.30
9.51
17.50
17.41
122-123
92-93
201-202
207-208
135-137
197-198
221-223
177-178
7a
7b
7.60
7.71
14.10
14.34
1320

In the reactions of 4-(arylhydrazino)coumarins 2a-c with 4-chlorobenzaldehyde in the presence of
piperidine acetate and an excess of piperidine 1-(4-bromophenyl)-5-(4-chlorophenyl)-3-(2-hydroxyphenyl)-
4-(piperidinocarbonyl)pyrazole (6) was obtained in the case of 2c, whereas in the cases of 2a,b under the same
conditions the corresponding 1-aryl-5-(4-chlorophenyl)-3-(2-hydroxyphenyl)-4-(piperidinocarbonyl)- 4,5-dihydro-
pyrazoles 7a,b were obtained.
1
The structures of the compounds synthesized were confirmed by IR and H NMR spectroscopy and, in
the case of the dihydropyrazole 7a, by X-ray crystallography (Tables 1-3).
The signals of the NH protons for the arylhydrazinocoumarins 2a-c appear in the ranges δ 8.13-8.35 and
δ 9.67-9.77 ppm in the 1H NMR spectra of DMSO solutions, while the signals of the NH and OH protons of the
pyrazolones 3a-c appear correspondingly at δ 10.65-10.83 and δ 11.97-12.34 ppm. The frequencies of the three
carbonyl groups of the diacetylpyrazolones 4a-c were observed at 1740-1750, 1760-1764, and 1775-1777 cm-1.
TABLE 2. 1H NMR Spectra of the Compounds Synthesized
Com-
pound
Chemical shifts, δ, ppm (SSCC, J, Hz)
2a
2b
2c
3a
5.35 (1Н, s, Н-3); 6.76-8.10 (9Н, m, С6Н4, С6Н5); 8.14 (1Н, s, NH); 9.67 (1H, s, NH)
5.25 (1Н, s, Н-3); 6.77-8.10 (8Н, m, 2С6Н4); 8.13 (1Н, s, NH); 9.77 (1H, s, NH)
5.29 (1Н, s, Н-3); 6.70-8.10 (8Н, m, 2С6Н4); 8.35 (1Н, s, NH); 9.72 (1H, s, NH)
6.16 (1Н, s, Н-4); 6.90-7.78 (9Н, m, С6Н4, С6Н5); 10.84 (1Н, s, NH);
12.20 (1H, br. s, ОH)
3b
3c
4a
4b
4c
5a
6.11 (1Н, s, Н-4); 6.88-7.70 (8Н, m, 2С6Н4); 10.73 (1Н, s, NH); 11.95 (1H, br. s, ОH)
6.16 (1Н, s, Н-4); 6.88-7.76 (8Н, m, 2С6Н4); 10.65 (1Н, s, NH); 12.34 (1H, br. s, ОH)
2.29 (3Н, s, СН3); 2.33 (3H, s, CH3); 6.73 (1H, s, Н-4); 7.20-7.97 (9Н, m, С6Н4, С6Н5)
2.19 (3Н, s, СН3); 2.24 (3H, s, CH3); 6.69 (1H, s, Н-4); 7.10-7.92 (8Н, m, 2С6Н4)
2.28 (3Н, s, СН3); 2.34 (3H, s, CH3); 6.74 (1H, s, Н-4); 7.20-7.96 (8Н, m, 2С6Н4)
7.45-7.51 (11Н, m, 2С6Н4, С6Н5); 7.61 (1H, dt, J = 6, J = 2, C6H4);
8.12 (1H, dd, J = 6, J = 2, C6H4)
5b
5c
6
7.38-7.62 (10Н, m, 3С6Н4); 7.88 (1H, m, С6Н4); 8.10 (1H, dd, J = 6.5, J = 1.5, C6H4)
7.31-7.72 (11Н, m, 3С6Н4); 8.10 (1H, d, J = 7.4, C6H4)
1.40 (6H, m, С5Н10N); 3.02 и 3.41 (4Н, m, С5Н10N); 6.85-7.64 (12 Н, m, 3С6Н4);
9.87 (1Н, br. s, ОН)
7a
7b
1.55 (6Н, m, С5Н10N); 3.44 (4Н, br. s, С5Н10N); 5.00 (1H, d, J = 5, Н-4);
5.45 (1H, d, J = 5, H-5); 5.49 (4Н, m, С5Н10N); 6.76-7.42 (13Н, m, 2С6Н4, C6H5);
10.28 (1H, s, OH)
1.52 (6Н, m, С5Н10N); 5.21 (1H, d, J = 5, Н-4); 5.49 (4Н, m, С5Н10N);
5.58 (1H, d, J = 5, H-5); 6.82-7.41 (12Н, m, 3С6Н4); 10.44 (1H, br. s, OH)
TABLE 3. Basic Bond Lengths (l) and Valence Angles (ω) in Molecule 7a
Bond
l, Å
Angle
ω, deg
N(1)–N(2)
N(1)–C(5)
N(1)–C(6)
N(2)–C(3)
C(3)–C(4)
1.372(4)
1.466(4)
1.392(4)
1.298(4)
1.507(5)
1.464(5)
1.572(5)
1.514(5)
1.509(5)
1.358(5)
1.206(4)
1.350(5)
1.743(4)
N(2)–N(1)–C(5)
N(2)–N(1)–C(6)
C(5)–N(1)–C(6)
N(1)–N(2)–C(3)
N(2)–C(3)–C(4)
C(3)–C(4)–C(5)
C(4)–C(5)–N(1)
C(12)–C(13)–O(18)
112.1(3)
119.2(3)
126.5(3)
110.9(3)
112.6(3)
101.9(3)
102.4(3)
122.2(3)
C(3)–C(12)
C(4)–C(5)
C(4)–C(19)
C(5)–C(27)
C(13)–O(18)
C(19)–O(20)
C(19)–N(21)
C(30)–Cl(33)
1321

1
Only signals of the aromatic protons were observed in the H NMR spectra of the pyrazolocoumarins 5a-c,
whereas additional signals of the methylene groups of piperidine were observed at δ 1.5 and 3.0-3.5 ppm in the
case of the 5-(piperidinocarbonyl) derivative 6. In compounds 7 doublet signals of the trans protons on C(4) and
C(5) with a coupling constant of J = 5 Hz were observed. The trans positions of the protons on C(4) and C(5) in
pyrazolinone 7a were confirmed by X-ray crystallography (Figure 1, Table 3).
Fig. 1. Spatial model of the molecule 7a with numbering of atoms and thermal vibrational ellipsoids.
TABLE 4. Crystallographic Data for Compound 7a
Empirical formula
Molecular mass, M
Crystal system
C27H26ClN3O2
459.977
Monoclinic
P21/n
Space group
Unit cell parameters:
a, Å
9.3045(3)
21.4232(7)
11.8452(4)
96.661(2)
2345.2(1)
4
b, Å
c, Å
β, deg
Unit cell volume, V, Ǻ3
Molecules per unit cell, Z
Crystal density, d, g/cm3
Coefficient of absorption, µ, mm-1
Number of independent reflections
Number of reflections with I > 3σ(I)
Number of parameters refined
Final residual factor, R
Programs used
1.303
0.19
6213
2366
298
0.078
SIR97 [1], maXus [2]
1322

The five-membered ring in molecule 7a is planar within the limits of experimental error, despite the two
tetrahedral atoms C(4) and C(5). The three phenyl rings of the molecule are also planar. The piperidine ring has
a chair configuration.
An intramolecular hydrogen bond was observed in the molecule of 7a with length of 2.620(4) Ǻ
(H···N(2) 1.89 Ǻ, angle O(18)-H···N(2) 132°). An additional six-membered ring is formed in the molecule 7a by
the presence of this bond.
EXPERIMENTAL
IR spectra were recorded with a Specord IR-75 instrument with suspensions of the substances in nujol
(1800-1500 cm-1 range) and hexachlorobutadiene (3600-2000 cm-1). Frequencies of C–H stretching vibrations in
1
the range 3050-2800 cm-1 were not recorded. H NMR spectra of CDCl3 and DMSO-d6 solutions with TMS as
internal standard were recorded on a Varian-Mercury BB spectrometer (200 MHz).
4-(2-Phenylhydrazino)- (2a), 4-[2-(2-Chlorophenyl)hydrazino]- (2b), 4-[2-(4-Bromophenyl)-
hydrazino]coumarins (2c), and 1-Phenyl- (3a), 1-(2-Chlorophenyl)- (3b), 1-(4-Bromophenyl)-3-(hydroxy-
phenyl)-2H-pyrazolin-5-ones (3c). Mixture of 4-hydroxycoumarin 1 (10 mmol) and arylhydrazine
hydrochloride (10 mmol) was ground in a mortar, transferred to a flask, triethylamine (20 mmol) was added, and
the mixture was heated under reflux on an oil bath at a temperature of 90-100°C for 1 h 30 min. The mixture
was cooled, ethanol (30 ml) was added, returned to the boil with shaking, cooled, and compound 2 was filtered
off. Dilution of the filtrate with water gave an additional small amount of compounds 2 and 3. Compounds 3
were dissolved at 20°C in 1% sodium hydroxide solution and precipitate on acidification. Compounds 2a, 3a-c
were recrystallized from ethanol, 2b from a mixture of ethanol and DMF, and 2c from a mixture of ethanol and
acetic acid.
1-Phenyl- (4a), 1-(2-Chlorophenyl)- (4b), and 1-(4-Bromophenyl)-2-acetyl-3-(2-acetoxyphenyl)-
2H-pyrazolin-5-ones (4c). Pyrazolinone 3 (5 mmol) in acetic anhydride (20 ml) in the presence of a catalytic
amount of p-toluenesulfonic acid was heated for 3 h on a boiling water bath, cooled and poured onto crushed
ice. Diacetylated 4 was filtered off and recrystallized from ethanol.
1-Phenyl- (5a), 2-(2-Chlorophenyl)- (5b), and 2-(4-Bromophenyl)-3-(4-chlorophenyl)[1]benzo-
pyrano[4,3-b]pyrazol-4-ones (5c). A mixture of 4-(arylhydrazino)coumarin (10 mmol), 4-chloro-benzaldehyde
(10 mmol), piperidine (4 mmol), and acetic acid (4 mmol) in DMSO (30 ml) was heated on a boiling water bath
for 6 h. The mixture was cooled, poured into water, the precipitate of pyrazolocoumarin was filtered off and
recrystallized from ethanol.
1-(4-Bromophenyl)-5-(4-chlorophenyl)3-(2-hydroxyphenyl)-4-(piperidinocarbonyl)pyrazole (6). A
mixture of 4-(4-bromophenylhydrazino)coumarin (2c) (5 mmol), 4-chlorobenzaldehyde (5 mmol), acetic acid (4
mmol), and piperidine (15 mmol) in DMSO (15 ml) was heated on a boiling water bath for 6 h. The mixture was
cooled, poured into water, the precipitate of 6 was filtered off, carefully washed with water on the filter and
recrystallized from ethanol.
1-Phenyl- and 1-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-(2-hydroxyphenyl)-4-(piperidinocarbonyl)-
4,5-dihydropyrazoles (7a) and (7b), respectively were obtained analogously to the previous experiment from
4-(arylhydrazino)coumarins 2a,b, 4-chlorobenzaldehyde, piperidine acetate, and an excess of piperidine.
Compounds 7a,b were recrystallized from ethanol.
X-ray Crystallographic Analysis. The diffraction pattern was taken of a monocrystal of compound 7a,
0.04×0.06×0.37 mm, on a Nonius KappaCCD automatic diffractometer to 2θmax = 55° (λMo = 0.71073 Ǻ) at
room temperature. The basic crystallographic characteristics of compound 7a and the parameters of the refined
structure are given in Table 4. Calculations were carried out using programs [15] and [16].
1323

REFERENCES
1.
2.
3.
I. Strakova, M. Petrova, S. Belyakov, and A. Strakovs, Khim. Geterotsikl. Soed., 1827 (2003). [Chem.
Heterocycl. Comp., 39, 1608 (2003)].
I. Strakova. M. Petrova, S. Belyakov, and A. Strakovs, Khim. Geterotsikl. Soed., 660 (2006). [Chem.
Heterocycl. Comp., 42, 574 (2006)].
I. Strakova. M. Petrova, S. Belyakov, and A. Strakovs, Khim. Geterotsikl. Soed., 935 (2007). [Chem.
Heterocycl. Comp., 43, 793 (2007)].
4.
5.
6.
M. Čačič, M. Trkovnik, and E. Has-Schön, J. Heterocycl. Chem., 40, 833 (2002).
V. V. Mulwad and J. M. Shirodkar, Indian. J. Chem.,41B, 1263 (2002).
V. Colotta, L. Cecchi, F. Melani, G. Filaccioni, C. Martini, S. Gelli, and A. Lucacchini, J. Pharm. Sci.,
80, 276 (1991).
7.
8.
A. A. Shestopalov and V. P. Litvinov, Izv. AN, Ser. Khim., 968 (2005).
I. A. Khan, M. V. Kukarni, M. Gopal, M. S. Shahabuddin, and C.-M. Sun, Bioorg. Med. Chem. Lett., 15,
3584 (2005).
9.
10.
11.
E. M. Becalli, A. Contini, and P. Trimerco, Tetrahedron. Lett., 45, 3447 (2004).
F. H. Havaldar and S. S. Bhise, Indian J. Heterocycl. Chem., 13, 15 (2003).
V. L. Savel'ev, O. L. Samsonov, V. P. Lezina, V. S. Troitskaya, I. I. Kozlovskii, A. Beshimov, and
M. M. Kozlovskaya. Khim.-farm. Zh., 37, No. 9, 25 (2003).
12.
13.
14.
15.
F. Al-Omran, A.-Z. A. Elassar, and A. A. El-Khair, J. Heterocycl. Chem., 40, 249 (2003).
A. Alberol, L. Calvo, A. Gonzlez-Ortega, E. F. Encabo, and M. C. Sanudo, Synthesis, 194 (2001).
J. A. Frogget, M. H. Hockley, and R. B. Titman, J. Chem. Res. (S), 30 (1997).
A. Altomare, M. Burla, M. Camalii, G. Cascarano, C. Giacovazzo, A. Guagliardi, A. Moliterni, and
R. Spagna, J. Appl. Crystallogr., 32, 115 (1999).
16.
S. Mackay, C. Edwards, A. Henderson, C. J. Gilmore, N. Stewart, K. Shankland, and A Donald, maXus
Computer Program for the Solution and Refinement of Crystal Structures, Bruker Nonius, The
Netherlands; MacSci., Japan, 1999.
1324