Cyclization of chalcones to isoxazole and pyrazole derivatives

Article abstract of DOI:10.1007/s10593-010-0455-8

A series of pyrazole and isoxazole derivatives were obtained by the condensation of the chalcones with hydrazine, phenylhydrazine, and hydroxylamine. All compounds were characterized using NMR, IR, and MS techniques.

Full text of DOI:10.1007/s10593-010-0455-8

Chemistry of Heterocyclic Compounds, Vol. 45, No. 12, 2009
CYCLIZATION OF CHALCONES
TO ISOXAZOLE AND PYRAZOLE
DERIVATIVES
A. Voskienė1 and V. Mickevičius1*
A series of pyrazole and isoxazole derivatives were obtained by the condensation of the chalcones with
hydrazine, phenylhydrazine, and hydroxylamine. All compounds were characterized using NMR, IR, and
MS techniques.
Keywords: β-alanines, chalcones, isoxazoles, pyrazoles, pyrazolines.
Chalcones are convenient intermediate compounds for the synthesis of five-, six-, and seven-membered
heterocycles often exhibiting biological activity. Pyrazole and isoxazole derivatives constitute an interesting
class of heterocycles due to their synthetic versatility and effective biological activities. Isoxazole derivatives
represent a unique class of nitrogen- and oxygen-containing five-membered heterocycles, and they are
associated with a wide spectrum of biological effects such as antiviral [1], anthelmintic [2], anti-inflammatory
[3], anticonvulsant [4], anticancer [5], etc. Pyrazolines display various biological activities such as antimicrobial
[6], antifungal [7], antidepressant [8], immunosuppressive [9], anticonvulsant [10], antitumor [11], antiamoebic
[12], antibacterial [13], and anti-inflammatory [14]. β-Aminopropionic acid (β-alanine) is the simplest β-amino
acid. It is the most important component of numerous biologically active compounds such as vitamin B5
(pantothenic acid), penicillins, cephalosporins, and peptides [15]. The synthetic N-substituted β-alanines are
growth stimulators for agricultural crops [16-18]. It is probable that the new compounds containing fragments of
the above-mentioned compounds exhibit biological activity themselves.
We continue our study of the chemistry of N-substituted amino acids and their derivatives. The starting
compounds 1-3 were synthesized by condensation of N-(4-acetylphenyl)-β-alanine with aromatic aldehydes
[19]. In this work, heating chalcones 1 and 2 under reflux with hydroxylamine in ethanol in the presence of
sodium ethoxide gave disubstituted dihydroisoxazoles 5 and 6. Under different conditions, when pyridine was
used as a base, we succeeded in synthesizing isoxazole derivative 7.
In the IR spectrum of compound 7, the absorption band of the C=N group appeared at 1563 cm–1. The
1H NMR spectrum for compound 6 showed proton signals of the isoxazoline moiety as an ABX type spin
system, and the proton signals were observed as double doublets due to the spin coupling. The signal of
heterocyclic proton in compound 7 was observed at 7.02 ppm.
_______
* To whom correspondence should be addressed, e-mail: Vytautas.Mickevicius@ktu.lt.
1Department of Organic Chemistry, Kaunas University of Technology, Kaunas LT-50254, Lithuania.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1842-1846, December, 2009.
Original article received November 10, 2009.
0009-3122/09/4512-1485©2009 Springer Science+Business Media, Inc.
1485

OH
N
H
EtONa,
EtOH
.
N
NH2OH HCI
R
O
O
R
HO
N
H
OH
O
N
4
5, 6
Py,
R
H
MeCH(OH)Me
N
O
O
R
HO
O
N
7
H
N
O
HN
R
.
OH
N2H4 H2O,
EtOH
O
N
N
H
H
O
OH
OH
8
N
PhNHNH2,
EtOH
1–3
R
N
N
Ph
9–11
1, 5, 10 R = Ph; 2, 6-9 R = 4-MeOC6H4; 3, 11 R = 4-ClC6H4
One of the most convenient methods for the synthesis of pyrazolines is the reaction of α,β-unsaturated
ketones or aldehydes with hydrazine hydrate and its derivatives [20]. In this work, condensation of
N-(styrylcarbonylphenyl)-β-alanines 1-3 with hydrazine hydrate and phenylhydrazine was carried out in alcohol
under reflux. It was noticed that in the reaction with hydrazine hydrate pyrazoline ring 8 was formed already
after 4 h, while the reaction with phenylhydrazine lasted for 12-20 h. When ethanol was used as a solvent in this
reaction the yield of pyrazolines 9-11 was lower (30-61%), but they were more pure, and there was no need to
purify them by column chromatography.
EXPERIMENTAL
The 1H and 13C NMR spectra were recorded on a Varian Unity Inova 300 spectrometer (300 and 75 MHz
respectively) in DMSO-d6 operating in the Fourier transform mode with TMS as an internal standard. Melting
points were determined on an automatic melting point apparatus APA1 and are uncorrected. The IR spectra were
determined in potassium bromide pellets on a Perkin-Elmer FT-IR system spectrum GX spectrometer. Mass
spectra were obtained on a Waters (Micromas) ZQ 2000 spectrometer, APCI, 20 V. Silica gel plates (Silufol
UV-254) were used for analytical purposes. Elemental analysis was carried out on the CHN analyzer CE 440.
3-[4-(5-Aryl-4,5-dihydroisoxazol-3-yl)phenylamino]propanoic Acids 5, 6. (General Method). To a
freshly prepared sodium alkoxide solution (0.30 g, 13 mmol of sodium metal in 20 ml of absolute ethanol)
4.6 mmol of the corresponding chalcone (1, 2) and hydroxylamine (0.32 g, 4.6 mmol) were added. The mixture
was heated under reflux for 6 h, then diluted with 20 ml of water and acidified with acetic acid to pH 6. The
precipitate was filtered off and washed with water. The crude product was purified by twice-repeated
precipitation from 10% NaOH solution with acetic acid to pH 6.
1486

3-[4-(5-Phenyl-4,5-dihydroisoxazol-3-yl)phenylamino]propanoic Acid (5). Yield 0.86 g (60%); mp
1
167-168oC. H NMR spectrum, δ, ppm (J, Hz): 2.50 (2H, t, J = 6.7, CH CO); 3.25 (1H, dd, JAX = 8.3,
2
J
J
AB = 16.8, HA-4); 3.28 (2H, t, J = 6.7, NHCH2); 3.75 (1H, dd, JBX = 10.6, JAB = 16.8, HB-4); 5.60 (1H, dd,
AX = 8.2, JBX = 10.6, HX-5); 6.19 (1H, br. s, NH); 6.59-7.44 (9H, m, H Ar); 11.95 (1H, br. s, COOH). Found,
%: C 69.81; H 5.77; N 9.11. C18H18N2O3. Calculated, %: C 69.66; H 5.85; N 9.03.
3-{4-[5-(4-Methoxyphenyl)-4,5-dihydroisoxazol-3-yl]phenylamino}propanoic Acid (6). Yield 0.97 g
1
(61%); mp 146-147oC. H NMR spectrum, δ, ppm (J, Hz): 2.50-2.53 (2H, m, CH2CO); 3.30-3.31 (3H, m,
NHCH2; HA-4); 3.70 (1H, dd, JBX = 10.5, JAB = 16.8, HB-4); 3.74 (3H, s, CH3); 5.54 (1H, dd, JBX = 10.3,
J
AX = 8.8, HX-5); 6.21 (1H, br. s, NH); 6.61, 7.43 (4H, two d, J = 8.8, H Ar); 6.93, 7.30 (4H, two d, J = 8.7, H Ar);
12.18 (1H, br. s, COOH). Mass spectrum, m/z (I, %): 341 [M+H]+ (100). Found, %: C 67.39; H 5.76; N 8.09.
C19H20N2O4. Calculated, %: C 67.05; H 5.92; N 8.23.
3-{4-[5-(4-Methoxyphenyl)isoxazol-3-yl]phenylamino}propanoic Acid (7). A mixture of chalcone 2
(1.2 g, 3.7 mmol) and hydroxylamine (0.77 g, 11 mmol) was dissolved in 8 ml of 2-propanol, then 2 ml of
pyridine was added and the mixture was heated under reflux for 6 h. The solvent was evaporated under reduced
pressure. The precipitated product was washed with water (3×20 ml) and purified by twice-repeated
precipitation from 10% NaOH solution with acetic acid to pH 5-6. Yield 0.52 g (42%); mp 258-259oC. IR
1
spectrum, ν, cm–1: 1513 (C=N), 1614 (C=O), 3121 (NH), 3393 (OH). H NMR spectrum, δ, ppm (J, Hz):
2.32-2.35 (2H, m, CH2CO); 3.27-3.31 (2H, m, NCH2); 3.79 (3H, s, CH3); 6.34 (1H, br. s, NH); 6.66, 7.55 (4H,
two d, J = 8.1, H Ar); 7.02, 7.76 (4H, two d, J = 8.7, H Ar); 7.02 (1H, s, CH). Mass spectrum, m/z (I, %): 339
[M+H]+ (100). Found, %: C 67.52; H 5.40; N 8.17. C19H18N2O4. Calculated, %: C 67.45; H 5.36; N 8.28.
3-{4-[5-(4-Methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl]phenylamino}propanoic Acid (8).
A
solution of chalcone 2 (1.0 g, 3.1 mmol) and hydrazine hydrate (0.62 g, 12 mmol) in ethanol (10 ml) was
refluxed for 4 h, then left at room temperature for 12 h. The resulting precipitate was filtered off and washed
1
with ethanol and ether. Yield 0.88 g (85%); mp 101-102oC (ethanol). H NMR spectrum, δ, ppm (J, Hz):
2.41-2.53 (2H, m, CH2CO); 2.71 (1H, dd, JAX = 10.6, JAB = 16.1, HA-4); 3.23-3.34 (3H, m, HB-4, NHCH2); 3.73
(3H, s, CH3); 4.68 (1H, t, JAX = 10.4, HX-5); 6.55-7.75 (10H, m, H Ar, NNH, NHCH2). Mass spectrum, m/z
(I, %): 340 [M+H]+ (100). Found, %: C 67.39; H 6.41; N 12.13. C19H21N3O3. Calculated, %: C 67.24; H 6.24;
N 12.38.
3-{4-[5-(4-Methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl]phenylamino}propanoic Acid (9).
A solution of chalcone 2 (1.0 g, 3,1 mmol) and phenylhydrazine (0,49 g, 4,5 mmol) in methanol (15 ml) was refluxed
for 20 h. After cooling, the resulting precipitate was filtered off and washed with methanol and ether. Yield 0.78 g
1
(61%); mp 175-176oC (methanol). IR spectrum, ν, cm–1: 1600 (C=N), 1713 (C=O), 3343–3288 (OH). H NMR
spectrum, δ, ppm (J, Hz): 2.51-2.53 (2H, m, CH2CO); 2.96 (1H, dd, JAX = 6.2, JAB = 17.2, HA-4); 3.29 (2H, t, J = 6.4,
NCH2); 3.70 (3H, s, CH3); 3.78 (1H, dd, JBX = 11.9, JAB = 17.2, HB-4); 5.27 (1H, dd, JAX = 6.2, JBX = 11.7, HX-5);
6.06 (1H, br. s, NH); 6.59-7.50 (13H, m, H Ar); 12.25 (1H, br. s, COOH). 13C NMR spectrum, δ, ppm: 33.55
(CH2COO); 38.46 (NHCH2); 43.32 (C-4); 54.91 (CH3); 62.24 (C-3); 111.66; 112.54, 114.17, 117.57, 119.78, 126.99,
127.03, 128.62, 134.73, 144.83, 149.17, 158.27 (C Ar); 148.02 (C=N); 173.04 (COO). Found, %: C 72.54; H 6.26;
N 9.87. C25H25N3O3. Calculated, %: C 72.27; H 6.06; N 10.11.
3-[4-(1,5-Diphenyl-4,5-dihydro-1H-pyrazol-3-yl)phenylamino]propanoic acid (10). A solution of
chalcone 1 (1.0 g, 3 mmol) and phenylhydrazine (0.49 g, 4.5 mmol) in methanol (15 ml) was refluxed for 12 h. After
cooling, 30 ml of water was added and the resulting precipitate filtered off and washed with water. The obtained
crude material was chromatographed over a silica gel column (acetone–hexane, 1:1.5). Rf 0.65. Yield 0.6 g (46%);
mp 147-148oC. IR spectrum, ν, cm–1: 1596 (C=N), 1713 (C=O), 3362 (NH), 3275 (OH). 1H NMR spectrum, δ, ppm
(J, Hz): 2.51 (2H, t, J = 6.7, CH2CO); 2.99 (1H, dd, JAX = 6.3, JAB = 17.3, HA-4); 3.29 (2H, t, J = 6.7, NCH2); 3.82
(1H, dd, JBX = 12.0, JAB = 17.2, HB-4); 5.32 (1H, dd, JAX = 6.3, JBX = 11.9, HX-5); 6.07 (1H, br. s, NH); 6.59-7.51
(14H, m, H Ar); 12.25 (1H, br. s, COOH). 13C NMR spectrum, δ, ppm: 33.54 (CH2COOH);
1487

38.46 (NCH2); 43.32 (C-4); 62.73 (C-5); 111.67, 112.49, 117.66, 119.67, 125.79, 127.09, 127.17, 128.69, 128.86,
142.90, 144.81, 149.22 (C Ar); 148.06 (C=N); 173.05 (COO). Found, %: C 74.83; H 6.28; N 10.76. C24H23N3O2.
Calculated, %: C 74.78; H 6.01; N 10.90.
3-{4-[5-(4-Chlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl]phenylamino}propanoic acid (11). A
solution of chalcone 3 (1.0 g, 3.2 mmol) and phenylhydrazine (0.43 g, 4 mmol) in ethanol (15 ml) was refluxed for
18 h. After cooling the resulting precipitate was filtered off and washed with ethanol and ether. Yield 0.4 g (30%);
mp 172-173oC (ethanol). IR spectrum, ν, cm–1: 1596 (C=N), 1713 (C=O), 3344 (NH), 3254 (OH). 1H NMR
spectrum, δ, ppm (J, Hz): 2.63 (2H, t, J = 6.6, CH2CO); 3.06 (1H, dd, JAX = 6.6, JAB = 17.2, HA-4); 3.46 (2H, t,
J = 6.7, NCH2); 3.88 (1H, dd, JBX = 12.0, JAB = 17.2, HB-4); 5.34 (1H, dd, JAX = 6.6, JBX = 12.0, HX-5); 6.65-7.58
(13H, m, H Ar). 13C NMR spectrum, δ, ppm: 35.04 (CH2COO); 40.73 (NHCH2); 45.26 (C-4); 64.87 (C-5); 114.01,
114.79, 119.99, 122.88, 129.12, 129.69, 130.53, 130.80, 134.27, 144.17, 149.84, 151.22 (C Ar); 147.23 (C=N);
174.32 (COO). Found, %: C 68.72; H 5.44; N 10.26. C24H22ClN3O2. Calculated, %: C 68.65; H 5.28; N 10.01.
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