Synthesis and characterization of 1,3,5-triarylpyrazol-4-ols and 3,5-diarylisoxazol-4-ols from chalcones and theoretical studies of the stability of pyrazol-4-ol toward acid dehydration

Article abstract of DOI:10.1016/j.molstruc.2019.127536

The synthesis of diverse pyrazol-4-ol and isoxazole-4-ol heterocycles involving only 3 reaction steps is reported in this study. However, the synthesis of carboxamide pyrazol-4-ol has failed in the conditions used in the synthesis, acid methanol solution. The carboxamide pyrazol-4-ol decomposes via dehydration, forming the respective pyrazol. Theoretical calculations were used to elucidate the dehydration reaction. We have found a mechanism for acid-catalyzed dehydration that can explain the experimental observations. The calculated free energy profile for acid-catalyzed dehydration of the carboxamide pyrazol-4-ol and phenylpyrazole-4-ol point out that the latter is more stable in relation dehydration, with a dehydration rate 100 times smaller in acid methanol solution.

Full text of DOI:10.1016/j.molstruc.2019.127536

Journal Pre-proof
Synthesis and characterization of 1,3,5-triarylpyrazol-4-ols and 3,5-diarylisoxazol-4-
ols from chalcones and theoretical studies of the stability of pyrazol-4-ol toward acid
dehydration
Edna Carolina Cipagauta Esquivel, Virgínia Camila Rufino, Matheus Henrique
Trindade Nogueira, Ana Carolina Carbonaro Souza, Josefredo Rodriguez Pliego
Júnior, Marcelo Siqueira Valle
PII:
S0022-2860(19)31645-X
DOI:
https://doi.org/10.1016/j.molstruc.2019.127536
MOLSTR 127536
Reference:
To appear in: Journal of Molecular Structure
Received Date: 7 October 2019
Revised Date: 2 December 2019
Accepted Date: 3 December 2019
Please cite this article as: E.C. Cipagauta Esquivel, Virgí.Camila. Rufino, M.H. Trindade Nogueira,
A.C. Carbonaro Souza, J.R. Pliego Júnior, M.S. Valle, Synthesis and characterization of 1,3,5-
triarylpyrazol-4-ols and 3,5-diarylisoxazol-4-ols from chalcones and theoretical studies of the stability of
pyrazol-4-ol toward acid dehydration, Journal of Molecular Structure (2020), doi: https://doi.org/10.1016/
j.molstruc.2019.127536.
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Synthesis and Characterization of 1,3,5-Triarylpyrazol-4-ols and 3,5-
Diarylisoxazol-4-ols from Chalcones and Theoretical Studies of the
Stability of Pyrazol-4-ol Toward Acid Dehydration
Edna Carolina Cipagauta Esquivel, Virgínia Camila Rufino, Matheus Henrique
Trindade Nogueira, Ana Carolina Carbonaro Souza, Josefredo Rodriguez Pliego Júnior
and Marcelo Siqueira Valle*
Departamento de Ciências Naturais, Universidade Federal de São João del-Rei, São
João del-Rei, MG,. Brazil, 36301-160.
*marcelovalle@ufsj.edu.br
J. R. Pliego ORCID : 0000-0002-2944-5332

Keywords
heterocycles, pyrazol, theoretical calculations, DFT, dehydration mechanism
Abstract
The synthesis of diverse pyrazol-4-ol and isoxazole-4-ol heterocycles involving only 3
reaction steps is reported in this study. However, the synthesis of carboxamide pyrazol-
4-ol has failed in the conditions used in the synthesis, acid methanol solution. The
carboxamide pyrazol-4-ol decomposes via dehydration, forming the respective pyrazol.
Theoretical calculations were used to elucidate the dehydration reaction. We have found
a mechanism for acid-catalyzed dehydration that can explain the experimental
observations. The calculated free energy profile for acid-catalyzed dehydration of the
carboxamide pyrazol-4-ol and phenylpyrazole-4-ol point out that the latter is more
stable in relation dehydration, with a dehydration rate 100 times smaller in acid
methanol solution.
1. Introduction
Heterocycles are widely distributed in nature, many of which are fundamental to
living systems. These classes of substances play key roles in biological processes and
have a wide range of applications in the agrochemical, pharmaceutical and veterinary
industries.[1] In the pharmaceutical industry they have been prepared to act as
antipyretics, antivirals, antifungals, anti-inflammatories, antioxidants, antidiabetic,
antibacterial, anticonvulsant, antiallergic and anticancer.[2] The most diverse
heterocycle class belongs to the group of five membered rings containing more than one
heteroatom, generally derived from furan, thiophene and pyrrole.[3] Pyrazole and
isoxazole rings are two examples of heterocycles which generally have excellent

therapeutic response.[4] The compounds of these classes are part of the N-heterocycle
class azois which have the a nitrogen atom as heteroatom at the 2 position of the ring.
Of these, pyrazols constitute a wide range of synthetic and natural products.[4] These
compounds are widely exploited as medicines and are marketed as antitumor drugs such
as Celecoxib (1)[5] and Pyrazofurin (2) (Figure 1).[6] On the other hand, isoxazoles,
besides being used as dyes, oils, electrical insulators and lubricants, have a large
number of pharmacological and agrochemical applications and are considered key
molecules for obtaining new compounds in organic synthesis.[7] The pharmacological
properties of isoxazoles may be altered according to the ring substituent. Among the
most representative examples are Parecoxib (3), having anti-inflammatory effect, and
the antibiotic Sulfamethoxazole (4) (Figure 1).[7][8]
Figure 1. Pyrazols and isoxazoles used as pharmaceuticals.
Among the most important methods for obtaining pyrazols are the
cyclocondensation of hydrazines with dicarbonyl compounds (Knorr's method),[9] and
cycloaddition between dipolar compounds and alkenes or alkynes [10][11]. In order to
obtain isoxazoles, the cyclocondensation between a 1,3-dieletrophil and hydroxylamine,
Claisen's method, have been employed[12] and 1,3-dipolar cycloaddition between
alkenes or alkynes with nitrile oxides.[13][7]
In this paper, we describe the synthesis and characterization of pyrazole
derivatives and isoxazoles, phenylpyrazol-4-ols (7) e isoxazol-4-ols (8), respectively,
from substituted chalcones prepared from Claisen-Schmidt aldol condensation. We also

discuss the studies performed by theoretical calculations of the relative stability of
phenyl pyrazol-4-ol (7c) and carboxamide pyrazol-4-ol (9c) (See Scheme 1). This
theoretical analysis was critical for undertanding why some pyrazolol products were not
observed in the reaction condictions used in this work.
Experimental
1.1. Materials
Melting points were determined on a Digital Melting Point Apparatus (MQAPF-
302, Microquímica). The infrared spectra were recorded in potassium bromide disks on
1
a. ALPHAFT-IR MB 102 and Agilent FTIR Cary 630 in 400 to 4000 cm-1 region. H
and 13C NMR spectra were recorded on Bruker 400 NMR or 500 NMR spectrometers at
the Universidade Federal de Juiz de Fora (UFJF) or Universidade Estadual de Campinas
(UNICAMP.
1.2. Methodologies of synthesis
Preparation of chalcones (5a-i): Acetophenone (0.06 mL, 5.0 mmol) was
solubilized in ethanol (10.0 mL) and cooled in an ice bath for 15 minutes and was added
a solution of sodium hydroxide (200.0 mg, 5.0 mmol) in water (10.0 mL). Then
benzaldehyde (5.0 mmol) was added. The reaction mixture was remained under stirring
during one hour and monitored by TLC (thin layer chromatography) (ethyl
acetate:hexane 3:7 v/v as eluent; UV lamp was used to visualize the plates). The solids
formed were vacuum filtered and purified by recrystallization in ethanol, furnishing the
respective chalcone as crystals.
Preparation of epoxichalcones (6a-i): Chalcone (5a-i) (0.5 mmol) was
solubilized in methanol (5.00 mL) and an aqueous solution of sodium hydroxide 25%
w/v (1.00 mL, 0.6 mmol) and added hydrogen peroxide 30% w/v (0.35 mL, 15.0

mmol). The reaction mixture was remained under stirring during two hours and
monitored by TLC (ethyl acetate:hexane 7:3 v/v as eluent; UV lamp was used to
visualize the plates). The solution was vacuum filtered, then was isolated epoxichalcone
crystals. The solids formed were vacuum filtered and purified by recrystallization in
ethanol, furnishing the respective epoxichalcone as crystals.
Preparation of phenyl-pyrazol-4-ols (7b-i): Epoxichalcone (6a-i) (0.5 mmol)
was solubilized in methanol (5.00 mL) and was added phenylhydrazine hydrochloride
(0.06 mL, 0.5 mmol). The reaction mixture was remained under stirring and reflux
during two hours and monitored by TLC (ethyl acetate:hexane 7:3 v/v as eluent; UV
lamp was used to visualize the plates). After evaporation of the solvent, the amount of
sample subjected to column chromatography (ethyl acetate:hexane 2:8) and the amount
of product phenyl-pyrazol-4-ol (7b-i) was obtained. The product formation (7a) was not
observed using this methodology.
Preparation of isoxazol-4-ols (8b,c,e,h): Epoxichalcone (6a-i) (0.5 mmol)
was solubilized in methanol (20.00 mL) and was added hydroxylamine hydrochloride
(0.035 g, 0.6 mmol). The reaction mixture was remained under stirring and reflux about
two hours and monitored by TLC (ethyl acetate:hexane 2:8 v/v as eluent; UV lamp was
used to visualize the plates). After evaporation of the solvent, After evaporation of the
solvent, the amount of sample subjected to column chromatography (ethyl
acetate:hexane 1:9) and the amount of product isoxazol-4-ol was obtained. The
isoxazol-4-ols (8a,d,f,g and I) could not be isolated using this methodology.
Preparation of phenylpyrazol (11b): Phenyl-pyrazol-4-ol (7b) (172 mg, 0.5
mmol) was solubilized in methanol (20.00 mL) and was added a solution of chloridric
acid 37% w/v (1.00 mL). The reaction mixture was remained under stirring and reflux
during twenty hours and monitored by TLC (ethyl acetate/hexane 2:8 v/v as eluent, UV

lamp was used to visualize the plates). The reactional mixture was neutralized and
washed using a saturated solution of sodium bicarbonate (3 x 15 mL) and was added
dichloromethane (20 mL). The layers were separated and the aqueous layer was
extracted with dichloromethane (2 × 20 mL). The organic extracts were combined, dried
over anhydrous sodium sulfate and evaporated to dryness under vacuum. After
evaporation of the solvent, the amount of sample subjected to column chromatography
(ethyl acetate:hexane 2:8) and the amount of product pyrazol (11b) was obtained in
80% yield (131 mg, 0.4 mmol) as a yellow oil.
Procedure of attempting to preparation of the carboxamide-pyrazol-4-ol
(9a-i): Epoxichalcone (6a-i) (0.5 mmol) was solubilized in methanol (15.00 mL) and
was added semicarbazide hydrochloride (0.034 mg, 3.0 mmol). The reaction mixture
was remained under stirring and reflux during five hours and monitored by TLC (ethyl
acetate/hexane 2:8 v/v as eluent; UV lamp was used to visualize the plates, revealed
using an acid solution of 2,4-dinitrophenylhydrazine) the bicarbonate saturated solution
was added and the mixture was extracted with diethyl ether (3 x 20 mL). The combined
organic phases were dried with anhydrous sodium sulfate, filtered and the solvent
removed by rotary evaporation, resulting in a slightly yellow solid, in which was
analyzed by NMR and no desired product was detected in all cases.
(2E)-1,3-diphenyl-2-propen-1-one (5a). Yellow solid; yield: 88%; mp: 54-56
1
°C; IR (KBr) ν (1/cm-1): 1665, 1608, 1571, 1453; H NMR (400 MHz, CDCl3): δ 7.54
(d, 1H, J 15.7 Hz, CH), 7.80 (d, 1H J 15.9 Hz, CH), 7.38 – 8.02 (m, 12H, aromatic
13
hydrogens); C NMR (100 MHz, CDCl3): δ 122.3, 128.6, 128.7, 128.8, 129.2, 130.7,
132.9, 135.1, 138.4, 145.0, 190.7.
(2E)-3-(2-methoxyphenyl)-1-phenylprop-2-en-1-one (5b). Yellow solid; yield:
88%; mp: 54-57 °C; IR (KBr) ν (1/cm-1): 1659, 1597, 1575, 1488, 1247, 1016; 1H NMR

(500 MHz, CDCl3): δ 3.83 (s, 3H, CH3), δ 7.39 (d, 1H. J 15.6 Hz, CH), 7.76 (d, 1H, J
15.7 Hz, CH), 6.91 – 7.99 (m, 11H, aromatic hydrogens); 13C NMR (125 MHz, CDCl3):
δ 55.6, 113.9, 114.6, 119.9, 127.8, 128.6, 128.7, 130.4, 132.2, 132.8, 138.7, 144.9,
161.9, 190.8.
(2E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (5c). Yellow solid; yield:
98%; mp: 69-71 °C; IR (KBr) ν (1/cm-1):1665, 1603, 1578, 1510, 1269, 1021; 1H NMR
(500 MHz, CDCl3) δ 3.83 (s, 3H, CH3), 7.39 (d, 1H, J 15.6 Hz, CH), 7.76 (d, 1H, J 15.7
Hz, CH), 6.90 – 7.99 (m, 11H, aromatic hydrogens); 13C NMR (125 MHz, CDCl3) δ
55.6, 114.6, 119.9, 127.8, 128.6, 128.8, 130.4, 132.8, 138.7, 144.9, 161.9, 190.8.
(2E)-3-(3,4-dimethoxyphenyl)-1-phenylprop-2-en-1-one (5d). Yellow solid;
yield: 97%; mp: 85-86 °C; IR (KBr) ν (1/cm-1): 1652, 1591, 1576, 1510, 1128, 1016;.
NMR 1H (400 MHz, CDCl3) δ 3.90 (s, 3H, CH3), 3.92 (s, 3H, CH3), 7.38 (d, 1H, J 15.7
13
Hz, CH), 7.70 (d, 1H, J 15.4 Hz, CH), δ 6.86 – 7.99 (m, 9H, aromatic hydrogens); C
NMR (100 MHz, CDCl3) δ 56.1, 56.2, 120.3, 123.4, 128.0, 128.6, 128.7, 132.7, 138.4,
145.2, 149.4, 151.6, 190.8.
(2E)-3-(3,4,5-trimethoxyphenyl)-1-phenylprop-2-en-1-one (5e). Yellow solid;
yield: 98%; mp: 129-132 °C; IR (KBr) ν (1/cm-1): 1659, 1603, 1575, 1505, 1282, 1129;
1H NMR (500 MHz, CDCl3) δ 3.87 (s, 3H, CH3), 3.88 (s, 6H, CH3), 7.39 (d, 1H, J 15.6
13
Hz, CH), 7.70 (d, 1H, J 15.7 Hz, CH), 6.83 – 7.99 (m, 9H, aromatic hydrogens); C
NMR (125 MHz, CDCl3) δ 56.4, 61.2, 105.8, 121.6, 128.6, 128.8, 130.5, 132.9, 138.4,
140.6, 145.2, 153.6, 190.7.
(2E)-3-(4-nitrophenyl)-1-phenylprop-2-en-1-one (5f). Yellow solid; yield: 96%;
1
mp: 155-157 °C; IR (KBr) ν (1/cm-1): 1658, 1609, 1598, 1447, 1516, 1337 ; H NMR
(500 MHz, CDCl3) δ 7.62 (d, 1H, J 15.7 Hz, CH), 7.79 (d, 1H, J 15.9 Hz, CH), 7.49 –

8.26, (m, 11H, aromatic hydrogens); 13C NMR (125 MHz, CDCl3) δ 124.4, 125.9,
128.8, 129.0, 120.1, 133.6, 137.7, 141.7, 141.2, 148.8, 189.8.
(2E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (5g). Yellow solid; yield:
1
98%; mp: 109-110 °C; IR (KBr) ν (1/cm-1): 1660, 1607, 1597, 1448, 1098; H NMR
(400 MHz, CDCl3) δ 7.48 (d, 1H, J 15.7 Hz, CH), 7.75 (d, 1H, J 15.9 Hz, CH), 7.36 –
8.00 (m, 11H, aromatic hydrogens); 13C NMR (100 MHz, CDCl3) δ 122.7, 128.7, 128.9,
129.43, 129.8, 133.1, 133.6, 136.6, 138.2, 143.4, 190.4.
(2E)-3-(4-bromophenyl)-1-phenylprop-2-en-1-one (5h). Yellow solid; yield:
95%; mp: 113-115 °C; IR (KBr) ν (1/cm-1): 1654, 1603, 1572, 1481, 977; 1H NMR (500
MHz, CDCl3) δ 7.50 (d, 1H, J 16.6 Hz, CH), 7.73 (d, 1H, J 15.7 Hz, CH), 7.45 – 8.00
(m, 11H, aromatic hydrogens); 13C NMR (125 MHz, CDCl3) δ 122.8, 125.0, 128.7,
128.9, 129.9, 132.4, 133.2, 134.0, 138.2, 143.6, 190.4.
(2E)-3-(4-fluorophenyl)-1-phenylprop-2-en-1-one (5i). Yellow solid; yield:
94%; mp: 80-82 °C; IR (KBr) ν (1/cm-1): 1659, 1606, 1577, 1509, 1215; 1H NMR (400
MHz, CDCl3) δ 7.44 (d, 1H, J 15.7 Hz, CH), 7.77 (d, 1H, J 15.9 Hz, CH), 7.06 – 8.00
13
(m, 11H, aromatic hydrogens); C NMR (100 MHz, CDCl3) δ 116.3 (d, J 22.0 Hz, C
orto), 121.9, 128.7, 128.8, 130.5 (d, J 8.8 Hz, C meta), 131.3 (d, J 3.7 Hz, C para),
133.0, 138.3, 143.7, 163.3 (d, J 251.6 Hz, C ipso), 190.5.
phenyl(3-phenyloxyran-2-yl)methanone (6a). White solid; yield: 90%; mp: 80-
82 °C; IR (KBr) ν (1/cm-1): 1687, 1595, 1497, 893, 753; 1H NMR (400 MHz, CDCl3) δ
4.06 (d, 1H, J 2.0 Hz, CH), 4.28 (d, 1H, J 1.7 Hz, CH), 7.34 – 8.00 (m, 10H, aromatic
hydrogens); 13C NMR (125 MHz, CDCl3) δ 59.6, 125.9, 128.3, 128.6, 128.9, 129.1,
134.2, 135.7, 193.3.

(3-(2-methoxyphenyl)oxyran-2-yl)(phenyl)methanone (6b). White solid; yield:
1
71%; mp: 80-81 °C; IR (KBr) ν (1/cm-1):1691, 1598, 1493, 1233, 1114, 894, 833; H
NMR (400 MHz, CDCl3) δ 3.81 (s, 3H, CH3), 4.17 (d, 1H, J 2.0 Hz, CH), 4.37 (d, 1H, J
13
2.0 Hz, CH), 6.89 – 8.05 (m, 9H, aromatic hydrogens); C NMR (125 MHz, CDCl3) δ
55.6, 55.9, 60.7, 110.5, 120.9, 124.4, 125.7, 128.6, 128.9, 129.9, 133.9, 135.8, 158.4,
193.8.
(3-(4-methoxyphenyl)oxyran-2-yl)(phenyl)methanone (6c). White solid; yield:
1
67%; mp: 80-81 °C; IR (KBr) ν (1/cm-1): 1683, 1597, 1514, 1251, 1036, 908, 772; H
NMR (400 MHz, CDCl3) δ 3.81 (s, 3H, CH3), 4.00 (d, 1H, J 2.0 Hz, CH), 4.27 (d, 1H, J
13
2.0 Hz, CH), 6.90 – 7.99 (m, 9H, aromatic hydrogens); C NMR (100 MHz, CDCl3) δ
55.6, 59.6, 61.3, 114.5, 127.4, 127.5, 128.5, 129.1, 134.1, 135.7, 160.5, 193.4.
(3-(3,4-dimethoxyphenyl)oxyran-2-yl)(phenyl)methanone (6d). White solid;
yield: 75%; mp: 82-84 °C; IR (KBr) ν (1/cm-1): 1679, 1593, 1512, 1264, 1021, 893,
783; 1H NMR (500 MHz, CDCl3) δ 3.88 (s, 6H, CH3), 4.01 (d, 1H, J 1.8 Hz, CH), 4.26
13
(d, 1H, J 1.8 Hz, CH), 6.81 – 7.99 (m, 8H, aromatic hydrogens); C NMR (125 MHz,
CDCl3) δ 56.2, 56.2, 59.8, 61.3, 108.2, 111.4, 119.1, 128.1, 128.5, 129.1, 134.2, 134.7,
135.7, 149.9, 193.3.
(3-(3,4,5-trimethoxyphenyl)oxyran-2-yl)(phenyl)methanone (6e). White solid;
yield: 75%; mp: 105-107 °C; IR (KBr) ν (1/cm-1): 1669, 1595, 1512, 1236, 1127, 895.
779; 1H NMR (500 MHz, CDCl3) δ 3.83 (s, 3H, CH3), 3.85 (s, 6H, CH3), 4.00 (d, 1H, J
1.3 Hz, CH), 4.22 (d, 1H, J 1.6 Hz, CH), 6.56 – 8.00 (m, 7H, aromatic hydrogens); 13C
NMR (125 MHz, CDCl3) δ 56.2, 59.6, 60.9, 61.0, 102.3, 128.4, 128.9, 131.1, 134.1,
135.5, 138.6, 153.8, 192.9.
(3-(4-nitrophenyl)oxyran-2-yl)(phenyl)methanone (6f). White solid; yield: 85%;
mp: 138-140 °C; IR (KBr) ν (1/cm-1): 1680, 1597, 1518, 1448, 1343, 881, 846; 1H NMR

(500 MHz, CDCl3) δ 4.18 (d, 1H, J 1.8 Hz, CH), 4.26 (d, 1H J 1.8 Hz, CH), 7.47 – 8.24
13
(m, 9H, aromatic hydrogens); C NMR (125 MHz, CDCl3) δ 58.1, 60.9, 124.0, 126.7,
128.4, 129.1, 134.4, 135.2, 142.8, 148.3, 192.1.
(3-(4-chlorophenyl)oxyran-2-yl)(phenyl)methanone (6g). White solid; yield:
1
86%; mp: 83-85 °C; IR (KBr) ν (1/cm-1):1686, 1595, 1495, 1090, 893, 821; H NMR
(400 MHz, CDCl3) δ 4.04 (d, 1H J 2.0 Hz, CH), 4.23 (d, 1H J 1.7 Hz, CH), 7.27 – 7.99
13
(m, 9H, aromatic hydrogens); C NMR (100 MHz, CDCl3) δ 58.9, 61.1, 127.3, 128.6,
129.1, 129.2, 134.2, 134.3, 135.2, 135.6, 192.9.
(3-(4-bromophenyl)oxyran-2-yl)(phenyl)metanone (6h). White solid; yield: 75%;
1
mp: 85-87 °C; IR (KBr) ν (1/cm-1): 1660, 1590, 1490, 1009, 890, 803; H NMR (400
MHz, CDCl3) δ 4.34 (d, 1H, J 2.0 Hz, CH), 4.54 (d, 1H, J 2.0 Hz, CH), 7.53 – 8.30 (m,
9H, aromatic hydrogens) ; 13C NMR (125 MHz, CDCl3) δ 58.8, 60.9, 123.1, 127.4,
128.3, 128.9, 132.0, 134.1, 134.6, 135.4, 192.7.
(3-(4-fluorophenyl)oxyran-2-yl)(phenyl)methanone (6i). White solid; yield:
1
84%; mp: 82-84 °C; IR (KBr) ν (1/cm-1): 1686, 1594, 1511, 1216, 892, 846; H NMR
(500 MHz, CDCl3) δ 4.04 (d, 1H, J 1.8 Hz, CH), 4.24 (d, 1H, J 1.8 Hz, CH), 7.06 – 7.99
13
(m, 9H, aromatic hydrogens) ; C NMR (125 MHz, CDCl3) δ 58.9, 61.2, 116.0 (d, J
21.8 Hz, C orto), 127.7 (d, J 8.6 Hz, C meta), 128.5, 129.1, 131.4 (d, J 3.2 Hz, C para),
134.2, 135.6, 162.4 (d, J 248.4 Hz, C ipso), 193.1.
5-(2-methoxyphenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-4-ol (7b). Brown oil;
1
yield: 85%; IR (KBr) ν (1/cm-1): 3361, 1660, 1593, 1494, 1246, 1023, 1147; H NMR
(500 MHz, CDCl3) δ 2.56 (s, 1, OH), 3.95 (s, 3H, CH3), 5.44 (d, J 2.4 Hz, 1H; CH),
5.09 (d, J 2.7 Hz, 1H; CH), 6.74 – 7.82 (m, 14H, aromatic hydrogens) ; 13C NMR (125
MHz, CDCl3) δ 55.9, 68.5, 82.3, 110.9, 113.4, 119.6, 121.7, 125.3, 126.1, 126.7, 128.6,
128.8, 129.1, 129.2, 131.8, 143.9, 147.4, 157.1.

5-(4-methoxyphenyl)-1,3-dyphenyl-4,5-dihydro-1H-pyrazol-4-ol (7c). Brown
oil; yield: 75%; IR (KBr) ν (1/cm-1): 3333, 1685, 1596, 1496, 1246, 1137, 1028; NMR
1H (500 MHz, CDCl3) δ 2.13 (s, 1H, OH), 3.73 (s, 3H, CH3), 5.06 (d, 1H, J 2.8 Hz,
CH), 5.08 (d, 1H, J 2.8 Hz, CH), 6.79 – 7.82 (m, 14H, aromatic hydrogens) ; NMR 13C
(125 MHz, CDCl3) δ 55.5, 73.1, 83.3, 113.6, 114.8, 119.9, 126.1, 126.9, 127.2, 128.8,
129.2, 129.9, 130.2, 131.6, 142.1, 147.0, 159.8.
5-(3,4-dimethoxyphenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-4-ol (7d). Brown
1
oil; yield: 68%; IR (KBr) ν (1/cm-1): 3312, 1680, 1593, 1500, 1258, 1137, 1028; H
NMR (500 MHz, CDCl3) δ 3.77 (s, 3H, CH3), 3.80 (s, 3H, CH3), 5.04 (d, 1H, J 3.1 Hz,
13
CH), 5.12 (d, 1H, J 2.9 Hz, CH), 6.72 – 7.83 (m, 13H, aromatic hydrogens); C NMR
(125 MHz, CDCl3) δ 56.1, 56.1, 73.5, 83.4, 108.8, 111.8, 113.6, 118.1, 120.1, 126.1,
128.8, 128.9, 129.3, 130.8, 131.5, 143.9, 147.2, 148.9, 149.8.
5-(3,4,5-trimethoxyphenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-4-ol
(7e).
Brown solid; yield: 30%; mp: 88-91 °C; IR (KBr) ν (1/cm-1): 3430, 1676, 1593, 1496,
1
1232, 1125, 1023; H NMR (500 MHz, CDCl3) δ 2.12 (s, 1H, OH), 3.73 (s, 6H, CH3),
3.78 (s, 3H, CH3), 4.99 (d, 1H, J 3.5 Hz, CH), 5.13 (d, 1H, J 3.1 Hz, CH), 6.40 – 7.84
13
(m, 12H, aromatic hydrogens); C NMR (125 MHz, CDCl3) δ 55.2, 59.0, 72.9, 82.3,
101.4, 112.5, 119.0, 125.1, 127.7, 128.1, 130.1, 133.1, 136.4, 142.9, 146.2, 152.9.
5-(4-nitrophenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-4-ol (7f). Orange solid;
yield: 35%; mp: 149-151 °C; IR (KBr) ν (1/cm-1): 3343, 1683, 1597, 1498, 1518, 1343,
1
1136, 1052; H NMR (500 MHz, CDCl3) δ 2.67 (s, 1H, OH), 5.11 (d, 1H, J 3.1 Hz,
13
CH), 5.21 (d, 1H, J 2.9 Hz, CH), 6.83 – 8.17 (m, 14H, aromatic hydrogens); C NMR
(125 MHz, CDCl3) δ 72.9, 83.1, 113.5, 120.6, 124.8, 126.2, 127.1, 129.1, 129.3, 129.5,
130.9, 143.3, 145.7, 147.2, 147.9.

5-(4-chlorophenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-4-ol (7g). Brown solid;
yield: 34%; mp: 150-152 °C; IR (KBr) ν (1/cm-1): 3356, 1689, 1601, 1491, 1131, 1091,
1011; 1H NMR (400 MHz, CDCl3) 2.51 (s, 1H, OH), 5.08 (s, 2H, CH), 6.83 – 7.81 (m,
14H, aromatic hydrogens); 13C NMR (100 MHz, CDCl3) δ 72.9, 81.2, 113.5, 120.3,
124.1, 126.1, 127.5, 129.0, 129.4, 129.7, 131.2, 134.0, 136.7, 143.4, 147.5.
5-(4-bromophenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-4-ol (7h). Brown
solid; yield: 53%; mp: 148-150 °C; IR (KBr) ν (1/cm-1): 3283, 1691, 1594, 1491, 1383,
1009; 1H NMR (500 MHz, CDCl3) δ 2.54 (s, 1H, OH), 5.06 (d, 1H, J 2.8 Hz, CH), 5.07
13
(d, 1H, J 2.8 Hz, CH), 6.83–7.81 (m, 14H, aromatic hydrogens); C NMR (125 MHz,
CDCl3) δ 72.9, 83.2, 113.5, 120.3, 122.1, 126.1, 127.8, 129.0, 129.4, 130.9, 131.2,
132.6, 137.3, 143.4, 147.0.
5-(4-fluorophenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-4-ol (7i). Brown oil;
1
yield: 75%; IR (KBr) ν (1/cm-1): 3326, 1697, 1592, 1498, 1223, 1137, 1034; H NMR
(500 MHz, CDCl3) δ 2.13 (s, 1H, OH), 5.08 (d, 1H, J 2.8 Hz, CH), 5.09 (d, 1H, J 2.8
Hz, CH), 6.82 – 7.82 (m, 14H, aromatic hydrogens); 13C NMR (125 MHz, CDCl3) δ
72.8, 83.2, 113.5, 120.1, 126.1, (d, J 21.1.0 Hz, C ortho), 127.7 (d, J 8.0 Hz, C meta),
128.9, 129.3, 131.3, 133.9 (d, J 3.0 Hz, C para), 143.5, 161.1 (d, J 247 Hz, C ipso).
5-(2-methoxyphenyl)-3-phenyl-4,5-dihydro-1H-isoxazol-4-ol (8b). White solid;
yield: 8%; mp: 95-98 °C; IR (KBr) ν (1/cm-1): 3391, 1658, 1599, 1488, 1464, 1236,
1
1018, 1112; H NMR (500 MHz, CDCl3) δ 3.48 (s, 3H, CH3), 5.34 (d, 1H, J 3.2 Hz,
CH), 5.76 (d, 1H, J 2.9 Hz, CH), 6.90 – 7.80 (m, 9H, aromatic hydrogens); 13C NMR δ
55.7, 83.7, 87.0, 110.6, 120.9, 125.6, 126.3, 127.3, 128.3, 128.9, 129.4, 130.3, 156.7,
157.5.
5-(4-methoxyphenyl)-3-phenyl-4,5-dihydro-1H-isoxazol-4-ol (8c). Orange solid;
yield: 6%; mp: 93-96 °C; IR (KBr) ν (1/cm-1): 3372, 1677, 1611, 1510, 1446, 1239,

1
1100, 1031; H NMR (500 MHz, CDCl3) δ 3.76 (s, 3H, CH3), 5.31 (d, 1H, J 3.5 Hz,
CH), 5.46 (d, 1H, J 3.1 Hz, CH), 6.84 – 7.78 (m, 9H, aromatic hydrogens); 13C NMR δ
55.5, 84.6, 90.2, 114.6, 126.9, 127.3, 128.1, 129.0, 129.9, 130.5, 157.5, 159.6.
5-(3,4,5-trimethoxyphenyl)-3-phenyl-4,5-dihydro-1H-isoxazol-4-ol (8e). Orange
solid; yield: 6%; mp: 115-118 °C; IR (KBr) ν (1/cm-1): 3448, 1686, 1595, 1542, 1456,
1240, 1133, 1003; 1H NMR (500 MHz, CDCl3) δ 3.78 (s, 3H, CH3), 3.79 (s, 6H, CH3),
5.35 (d, 1H, J 3.5 Hz, CH), 5.45 (d, 1H, J 3.5 Hz, CH), 6.52 – 7.76 (m, 7H, aromatic
hydrogens); 13C NMR δ 56.1, 60.8, 84.8, 90.0, 102.0, 127.1, 127.8, 128.9, 130.4, 133.5,
137.6, 153.6, 157.5.
5-(4-bromophenyl)-3-phenyl-4,5-dihydro-1H-isoxazol-4-ol (8h). White solid;
yield: 53%; mp: 138-142 °C; IR (KBr) ν (1/cm-1): 3232, 1676, 1591, 1448, 1487, 1133,
1
1063, 1011; H NMR (500 MHz, CDCl3) δ 5.28 (d, 1H, J 2.3 Hz, CH), 5.47 (d, 1H, J
13
2.9 Hz, CH), 7.36 – 7.76 (m, 9H, aromatic hydrogens); C NMR δ 84.5, 89.4, 122.3,
127.0, 127.2, 127.5, 129.0, 130.6, 132.0, 136.7, 157.3.
5-(2-methoxyphenyl)-1,3-diphenyl-4,5-dihydro-1H-pirazol (11b). Brown solid;
1
yield: 80%; mp: 158-162 °C; H NMR (500 MHz, CDCl3) δ 3.43 (s, 3H, CH3), 6.83 –
8.03 (m, 15H, aromatic hydrogens); 13C NMR δ 55.0, 106.2, 111.3, 119.1 120.7, 124.2,
126.3, 127.6, 128.5, 128.6, 128.7, 130.9, 131.2 131.6, 139.6, 142.1, 151.1, 156.5.
2. Theoretical Methods
The acid dehydration reactions of pyrazol-4-ol and phenylpyrazol-4-ol were
investigated by means geometry optimization and harmonic frequency calculations
using the X3LYP[14] functional with the def2-SVP[15] basis set for carbon and
hydrogen, and ma-def2-SVP (including diffuse functions) basis set for oxygen and
nitrogen.[16] The solvent effect was included in the optimizations through the

continuum SMD method in the methanol solvent.[17] The imaginary frequency of each
transition state was visualized to verify its connection to the minima. Single point
energy calculations were performed at the M06-2X/ma-def2-TZVPP level of theory to
obtain more accurate energy values.[16,18] The solution phase free energies were
obtained from:
Gsol = Eel + Gn + ΔGsolv
(1)
The terms on the right-side are the electronic energy (Eel) using the M06-2X/ma-
def2-TZVPP level of theory, the translational, vibrational and rotational contributions to
the free energy (Gn) and the solvation free energy (ΔGsolv), both obtained at the
SMD/X3LYP/ma-def2-SVP level of theory. The calculations were done with the Orca 4
program[19,20] and GAMESS program.
3. Results and Discussion
3.1. Synthesis and characterization of compounds 5-9, 11
The reactions performed in this work are described in Schemes 1-3. Chalcones (5a-i)
were obtained as solids in high yields (88 to 98%) by Claisen-Schmidt aldol
condensation (Scheme 1) involving the reaction between acetophenone and
benzaldehyde (substituted with electron withdrawing and donating groups), in basic
medium, in a mixture of ethanol and water. Epoxychalcones (6a-i) were easily obtained
in their racemic form by reacting the respective chalcones by oxidizing the double bond
with 30% oxygen peroxide in alkaline medium. Yields were obtained in the range of 67
to 90%. To obtain phenylpyrazol-4-ol (7b-i), the epoxychalcones (6a-i) were reacted
with phenylhydrazine hydrochloride in methanol under reflux for 20 hours under
constant stirring. After purification by column chromatography, the desired products

were isolated as solids in yields ranging from 30 to 85%. Using hydroxylamine
hydrochloride as nucleophile, their reactions with epoxychalcones were less effective
and led only the isoxazole-4-ols (8b, 8c, 8e, 8h) in low to moderate yields (6 to 53%).
Therefore, 8 examples of 1,3,5-triarylpyrazol-4-ols (or phenylpyrazol-4-ols) and 4 of
3,5-diarylisoxazole-4-ols (or isoxazol-4-ols) were obtained in average to good yields.
These compounds will be evaluated for their possible anticancer activities.
Scheme 1. Synthetic route to the obtention of desired heterocycles.
The elucidations of their chemical structures could be confirmed by FT-IR and
13
1H / C NMR spectra analyzes. As an example, the FT-IR spectrum of phenylpyrazol-
4-ol (7c) (R = 4-OCH3) had a broadened 3333 cm-1 stretch band for the hydroxyl (OH)
group, the (CO) bond was checked by the stretch band at 1028 cm-1, the stretch bands

related to pyrazolic ring formation were identified at 1685 cm-1 for the C = N group and
the band at 1137 cm-1 for the C-N bond, while aromatic carbon bonds (C = C) generated
1
two stretch bands at 1596 and 1496 cm-1. In its H NMR spectrum, two singlets are
observed at δ 2.14 and 3.73 ppm, the first corresponding to the hydroxyl group
hydrogen and the second to the homotopic methyl hydrogens of the methoxyl group.
The 14 aromatic hydrogens appeared in the range of δ 6.8 - 7.8 ppm. The two signals
for the α and β hydrogens appear as two doublets at δ 5.0 and δ 5.1 ppm with a coupling
constant of 3J = 2.8 Hz, a value that follows the Karplus ratio, since the two hydrogens
are at an approximate angle of 60o, thus conferring the trans configuration of the double
13
bond of its structure. In its C NMR spectrum the δ 159.4 ppm signal was assigned to
the carbon of the C = N group. Carbons α and β presented signals at δ 73.1 and 83.3
ppm, while the 14 signals present in the range between δ 113.6 to 147.1 ppm were
attributed to aromatic carbons. Finally, the methyl carbon of the substituent group
generated a chemical shift signal at δ 55.5 ppm.
However, unlike epoxychalcone condensations with phenylhydrazine or
hydroxylamine hydrochlorides, reactions with semicarbazide hydrochloride failed in all
attempts to obtain carboxamide-pyrazol-4-ols (9) (Scheme 2). A complex mixture was
obtained and we could not separate them. The instability of (9) may have led, for
example, to its dehydration product, pyrazole (10), by the catalytic action of the
hydrochloric acid of semicarbazide reagent, as well as other side products.

Scheme 2. Reaction of epoxychalcone (6) with semicarbazide hydrochloride.
In order to verify if the elimination reaction in the pyrazol-4-ol ring could occur,
it was decided to investigate this hypothesis by reacting phenylpyrazol-4-ol (7b) with
hydrochloric acid to obtain its respective phenylpyrazole (11b), since carboxamide
pyrazol-4-ol (9) could not be isolated (Scheme 3). Only after 20 hours of reaction, we
obtained pyrazol (11b) in an optimal yield of 80%, demonstrating a greater stability of
(7b) compared to (9).
Scheme 3. Dehydration of (7b) to acid-promoted pyrazole (11b).
13
1
The compound was characterized by 1H and C NMR spectroscopy. In the H
NMR spectrum, signals in the range of δ 7.9 to 6.7 ppm were observed for the 15
aromatic hydrogen atoms, including the hydrogen that is part of the pyrazole ring, as all
of these hydrogens experience the phenomenon of magnetic anisotropy. The singlet at δ
13
3.43 ppm refers to the three methoxy hydrogens. In the C NMR spectrum, it has a δ
156.5 ppm signal assigned to the C = N group and the 14 aromatic carbons and the two
carbons belonging to the pyrazole ring appear in the range of δ 106.2 to 151.1 ppm.
Finally, the carbon of the methoxyl group generated a signal with chemical shift at δ
55.0 ppm.
3.2. Theoretical investigation of the dehydration mechanism of carboxamide
pyrazol-4-ol and phenylpyrazol-4-ol

In order to understand the different stability of the carboxamide pyrazol-4-ol (9)
and phenylpyrazol-4-ol (7), we have investigated the acid-catalyzed dehydration of
these molecules. The steps of the dehydration mechanism catalyzed by acid in methanol
solution are presented in the Scheme 4. The mechanism starts with the protonation of
the nitrogen in the ring (step 1) through a fast equilibrium. The next step is the proton
migration to the hydroxyl group (step 2). Both of these processes are fast equilibria
involving the solvent. The protonated hydroxyl group goes through a transition state
that leads to the formation of a carbocation and a water molecule (step 3). The
carbocation then loses a proton for the solvent, leading to the formation of pyrazole or a
substituted pyrazole (phenylpyrazole) (step 4).
R1
R1
H
N N
OH
N N
OH
R
+
+
CH3OH
(1)
CH3OH2
R
R1
R1
H
N N
N N
(2)
R
R
OH2
OH
R1
R1
N N
N N
TS-H2O
+
(3)
(4)
H2O
R
R
OH2
R1
R1
N N
N N
+
+
CH3OH
CH3OH2
R
R
R = H, 2-OMe, 4-OMe, 3,4-diOMe, 3,4,5-triOMe, 4-NO2, Cl, Br or F
R1 = Ph or CONH2
Scheme 4. Steps of the dehydration mechanism of pyrazol-4-ol.

The support for this mechanism can be better analyzed by means of the free
energie profiles in solution (Figure 2). We start our analysis considering the dehydration
of carboxamide-pyrazole-4-ol. The first stage of the protonation of nitrogen is
+
conducted by CH3OH2 , leading to the formation of MS1H+, with a free energy of 0.8
kcal mol-1. MS1H+ undergoes an isomerization process where the proton in the nitrogen
is transferred to the hydroxyl group, leading to the formation of MS2H+, with a free
energy of 10.1 kcal mol-1 relative to the initial reactants. The next step has a transition
state with elimination of a water molecule, TS-H2O, with a free energy of 16.7 kcal mol-
1
relative to the reagents. This transition state structure is presented in the Figure 2 and
the carbon-oxygen distance is 2.04 Å. The carbocation MS3H+ and the water molecule
formed in this step is1.4 kcal mol-1. The last step is a proton exchange between the
medium and MS3H+, leading to the formation of MS4, the final product, with a free
energy of -24.5 kcal mol-1. Based on the free energy profile, the overall free energy
barrier is 16.7 kcal mol-1.

Figure 2. Free energy profile for the mechanism of carboxamide pyrazol-4-ol
dehydration.
As previously mentioned, the motivation for mechanistic elucidation of pyrazol-
4-ol dehydration was to explain why it has taken place while the same process was not
observed for phenyl substituted pyrazol-4-ol. In this sense, phenylpyrazol-4-ol was
selected and we investigated the feasibility of the similar mechanism, whose steps are
presented in Scheme 4 and the free energy profile is shown in Figure 3.
TS1-H2O
TS2-H2O
Figure 3. TS1-H2O and TS2-H2O structures.
The protonation of phenyl-pyrazol-4-ol (MS5) on the nitrogen forms MS5H+,
which has a free energy of -8.7 kcal mol-1 below of the reactants. This is a remarkable
difference from carboxamide-pyrazol-4-ol, because the protonation in this case is much
more favorable. The next step, isomerization of MS5H+ to MS6H+, has a free energy of
19.4 kcal mol-1 and MS6H+ stay 10.8 kcal mol-1 above of the starting reactants.

Subsequently, a transition state for water elimination, TS2-H2O (Figure 4), has a free
energy of 11.7 kcal mol-1 relative to the reactants. The overall free energy barrier is 20.4
kcal mol-1. This step leads to the formation of a carbocation (MS7H+) and a water
molecule, staying -14.4 kcal mol-1 in relation to initial reactants. A rapid exchange of
protons between MS7H+ and the solvent leads to the formation of the final product with
a free energy of -32.1 kcal mol-1.
Comparing the two free energy profiles (Figures 2 and 4), we can observe that
the overall barrier for water elimination step is 3.7 kcal mol-1 higher for phenylpyrazole-
4-ol than for carboxamide pyrazole-4-ol. Thus, this reaction step is 102 times slower for
phenylpyrazole-4-ol than carboxamide pyrazole-4-ol, providing an explanation for the
instability of carboxamide-pyrazole-4-ol.
G
CH3OH
+
N
N
N
N
OMe
OMe
10.8
OH2
H2O
TS2-H2O
MS6H+
11.7
N
N
OMe
OH
MS5
7c
N
N
H2O
CH3OH
+
+
+
-8.7
H
OMe
MS7H+
CH3OH2
-14.4
N
N
OH
MS5H+
N
N
+
CH3OH2
OMe
+
MS8
CH3OH2
-32.1

Figure 4. Free energy profile of mechanism of dehydration of phenylpyrazole-4-ol.
4. Conclusions
In this work it was possible to synthesize 12 compounds, pyrazol-ols and
isoxazol-4-ols, belonging to the azole class in just 3 steps. Attempts to prepare pyrazol-
4-ols (10) carboxamides have failed and it has been possible by theoretical studies to
verify a significant difference in stability between carboxamide-pyrazol-4-ol (9) and
phenyl pyrazol-4-ol (7). The higher free energy barrier for acid-catalyzed water
elimination from 7 in relation to 9 is consistent with experimental observations.
The dehydration of (7b) to the respective pyrazole (11b) shows us the possibility
of preparing other pyrazoles substituted by this methodology.
5. Acknowledgment
The authors thank the Brazilian agencies CNPq, FAPEMIG and CAPES for
financial support and Rede Mineira de Química.
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•
•
•
The carboxamide pyrazol-4-ol decomposes via dehydration.
Theoretical calculations were performed to explain the acid-catalyzed dehydration.
Phenyl pyrazole-4-ol is more stable than carboxamide pyrazol-4-ol.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: