Synthesis of 5-hydroxy- and 5-amino-1-tosyl-5-phenyl-3-(2-arylvinyl)-4,5- dihydropyrazoles

Article abstract of DOI:10.1055/s-2005-862353

The reaction of β-arylacryloyloxiranes with tosylhydrazine leads to unexpected 5-hydroxysubstituted Δ²-pyrazolines. A series of 3-styryl substituted pyrazoles and 5-amino-Δ²-pyrazolines were synthesized from the 5-hydroxy-Δ²-pyrazolines. The mechanism of this process has been proposed based on current and previous results. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-862353

LETTER
485
Synthesis of 5-Hydroxy- and 5-Amino-1-tosyl-5-phenyl-3-(2-arylvinyl)-4,5-
dihydropyrazoles
5
-Hydroxy- and 5-
i
A
mino
n
-1-tosyl-5-ph
a
e
nyl-3-(2-arylvin
M
yl)-4,5-dihydropyraz
o
.
les Kuz’menok, Tatyana A. Koval’chuk,* Alexander M. Zvonok
Department of Organic Chemistry, Belarusian State Technologycal University, 13A, Sverdlova str., Minsk, 220050, Belarus
Fax +375(17)2276217; E-mail: kovtatale@yahoo.com
Received 28 October 2004
∆, H+
Abstract: The reaction of b-arylacryloyloxiranes with tosylhydra-
Ar
Ar
zine leads to unexpected 5-hydroxysubstituted D2-pyrazolines. A
O
Ph
Ar
series of 3-styryl substituted pyrazoles and 5-amino-D2-pyrazolines
TsNHNH2
were synthesized from the 5-hydroxy-D2-pyrazolines. The mecha-
nism of this process has been proposed based on current and previ-
ous results.
+
Ph
N
N
O
H+, THF
Ph
N
N
1a–f
HO
2a–f
3a–f
Ts
Ts
Key words: epoxy enones, hydrazones, rearrangements
RNH2
Ar
a Ar = Ph
b Ar = 4-Cl-C6H4
c Ar = 3-Cl-C6H4
d Ar = 4-F-C6H4
e Ar = 4-Br-C6H4
f Ar = 4-NO2-C6H4
g Ar = Ph, R = Pr
h Ar = 3-Cl-C6H4, R = Pr
i Ar = Ph, R = c-Hexyl
Ph
HN
The reaction of hydrazine and its derivatives with a,b-un-
saturated ketones and a,b-epoxy ketones is one of the pre-
parative methods for the synthesis of pyrazolines and
pyrazoles. Pyrazolines are typical products of these reac-
tions, when a,b-unsaturated ketones are used, and 4-hy-
droxy pyrazolines in the case where a,b-epoxy ketones
are applied.1 Combination of the functionalities of the b-
arylacryloyloxiranes allowed evaluation of the reactivity
of the carbonyl group, oxirane ring and conjugated double
bond to nucleophilic reagents such as hydrazine.
N
N
Ts
R
j Ar = 4-NO2-C6H4, R = CH2Ph
4g–j
Scheme 1
The structures of 5-hydroxy-3-styrylpyrazolines (2a–f)
were determined by IR, 1H NMR and 13C NMR spectros-
copy.7 Thus, the hydroxyl, azomethine and vinyl group
absorptions were observed in IR spectra, but there was no
presence of the carbonyl band.
Earlier, we found that the reaction of b-arylacryloyl-
oxiranes with hydrazine gives the oxiranylpyrazoline
intermediates, stable enough for isolation. However, in
solution these compounds undergo further intramolecular
oxidative–reductive transformation to b-hydroxyalkyl-
pyrazoles.2 These data indicate that hydrazine reacts pref-
erentially with the conjugated double bond of b-
arylacryloyloxiranes. Reaction of phenylhydrazine with
b-arylacryloyloxiranes in proton solvents gives b-aryl-
vinylpyrazoles, which shows participation of the oxirane
ring in the cyclization process.3
The 1H NMR spectra indicated the presence of the meth-
ylene diastereotopic protons at d = 3.20–3.50 ppm
(J = 17.6–17.9 Hz), consistent with 5-hydroxypyrazoline
structures.8,9 The chemical shift of the double bond pro-
tons appeared in the range of d = 6.55–6.66 ppm and 6.92–
7.14 ppm (J = 16.4–16.7 Hz). Compared to the initial
enones, they are displayed at the higher field as an AB-
system. The tosyl group protons are shown in the 1H NMR
spectrum as a characteristic singlet at d = 2.4 ppm (for the
methyl group) and AB-system of aromatic protons signals
in the low field at the range of d = 7.22 and 7.68 ppm
In this paper, the reaction of b-arylacryloyloxiranes with
tosylhydrazine is reported. Pyrazoles and pyrazolines
with aromatic substituents are interesting as potential bio-
receptor ligands.4
1
(J = 8.3 Hz). The H NMR spectra of pyrazoles 3a–f
showed analogous pattern of chemical shifts to those of
pyrazolines 2a–f with an exception of the protons at the
4-position. A singlet signal at d = 6.5 ppm is indicative for
the pyrazole.
Although 4-hydroxypyrazolines are the typical products
of the reaction of a,b-epoxy ketones with tosylhydrazine5
and other hydrazines,1 we found that the reaction of
3-aryl-1-(3-phenyloxiran-2-yl)-prop-2-en-1-ones (1a–f)
with tosylhydrazine under acid catalysis leads to forma-
tion of 3-(2-arylvinyl)-5-hydroxy-5-phenyl-1-tosyl-2-
pyrazolines (2a–f) with 58–83% yield (Scheme 1). Addi-
tionally, 3-(2-arylvinyl)-5-phenyl-1-tosyl-1H-pyrazoles
(3a–f) were isolated with 7–21% yield by chromatogra-
phy after crystallization of the major products.6
It is known that 1-acyl-5-hydroxy-2-pyrazolines can react
with various amines yielding 1-acyl-5-alkylamino-2-
pyrazolines.10 Thus, pyrazolines 2a,c were subjected to
the reactions with primary amines, yielding the corre-
sponding 5-alkylamino-2-pyrazolines (4g–j).11 The struc-
tures 4g–j were confirmed by H NMR spectroscopy.7
1
Unlike reported 1-phenyl-5-hydroxy-2-pyrazolines12
which do not undergo dehydration, pyrazoline 2a pro-
duced the corresponding pyrazole 3a when heated in the
presence of hydrochloric acid for 6 hours in THF.13 These
results indicate that the formation of pyrazoles 3a–f pro-
ceeds via dehydration of the 5-hydroxypyrazolines 2a–f,
and not through the competitive 4-hydroxypyrazolines.
SYNLETT 2005, No. 3, pp 0485–0486
1
6.
0
2.
2
0
0
5
Advanced online publication: 17.01.2005
DOI: 10.1055/s-2005-862353; Art ID: G38804ST
© Georg Thieme Verlag Stuttgart · New York

486
N. M. Kuz’menok et al.
LETTER
H
Ar
H+
Ar
+
O
O
HO
Ph
Ar
Ar
O
Ph
Ph
TsNHNH2
H+
Ph
H
H
- H+
N
+
N
N
..
N
O
HN
Ts
N
H
1
Ts
Ts
Ar
Ar
Ph
HO
Ar
Ar
Ph
HO
Ph
H
N
N
N
N
- H2O
N
HN
Ts
HO
Ph
N
N
B
A
Ts
Ts
Ts
2
3
Scheme 2
(KBr): nmax = 3504 (OH), 1600 (C=N), 1364, 1168 (S=O),
960 (HC=) cm–1. 1H NMR (400 MHz, CDCl3): d = 2.39 (3 H,
s, CH3), 3.23 (1 H, d, J = 17.6 Hz, CH2), 3.51 (1 H, d,
J = 17.6 Hz, CH2), 6.63 (1 ,H d, J = 16.4 Hz, CH=), 7.02 (1
H, d, J = 16.4 Hz, CH=), 7.23 (2 H, d, J = 8.3 Hz, C6H4),
7.29–7.50 (10 H, m, arom.), 7.69 (2 H, d, J = 8.3 Hz, C6H4).
MS: m/z (%) = 418 (5.4) [M+], 91 (100).
Formation of pyrazolines 2a–f proceeded through the ox-
irane ring-opening at the a-carbon, then probably through
the intramolecular rearrangement of azadiene intermedi-
ate (A). The azadiene A is further transformed through a
hydride [1,5] sigmatropic shift to 1,3-diketone monohy-
drazone (B, Scheme 2). Intramolecular cyclization leads
finally to 5-hydroxypyrazolines 2a–f.
Compound 2c: yield 83%, mp 98–100 °C (C6H6). 1H NMR
(400 MHz, CDCl3): d = 2.39 (3 H, s, CH3), 3.21 (1 H, d,
J = 17.6 Hz, CH2), 3.49 (1 H, d, J = 17.6 Hz, CH2), 6.55 (1
H, d, J = 16.4 Hz, CH=), 7.00 (1 H, d, J = 16.4 Hz, CH=),
7.22 (2 H, d, J = 8.3 Hz, C6H4), 7.25 (5 H, m, C6H5), 7.32–
It has been shown that 1,3-diketone hydrazones form
stable 5-hydroxy-2-pyrazolines only if an electron-with-
drawing group, i.e. acyl, is at the 1-position, or if a per-
fluoroalkyl group is present at the 5-position of the
pyrazoline ring.8
7.50 (4 H, m, C6H4), 7.68 (2 H, d, J = 8.3 Hz, C6H4). 13
C
NMR (125.77 MHz, CDCl3): d = 21.61 (CH3), 50.50 (CH2),
97.82 (C-OH), 121.91 (CH=), 125.02 (CH=), 125.05,
126.90, 127.96, 128.33, 128.59, 128.94, 129.38, 130.08,
135.15, 137.6, 142.8 (arom.),153.02 (C-3).
Compound 3a: yield 12%, mp 122–124 °C (EtOH). IR
(KBr): nmax = 1383, 1176 (S=O), 970 (HC=) cm–1. 1H NMR
(400 MHz, CDCl3): d = 2.37 (3 H, s, CH3), 6.53 (1 H, s, 4-
H), 7.08 (1 H, d, J = 16.6 Hz, CH=), 7.16 (1 H, d, J = 16.6
Hz, CH=), 7.20 (2 H, d, J = 8.2 Hz, arom.), 7.27–7.52 (10 H,
m, arom.), 7.56 (2 H, d, J = 8.2 Hz, C6H4).
Compound 4i: yield 79%, mp 190–192 °C (MeOH). IR
(KBr): nmax = 3385 (NH), 2928, 2856 (CH), 1344, 1160
(S=O) cm–1. 1H NMR (400 MHz, CDCl3): d = 1.20–2.25 (10
H, m, C6H11), 2.38 (3 H, s, CH3), 2.81 (1 H, m, C6H11), 3.17
(1 H, d, J = 18.0 Hz, CH2), 3.56 (1 H, d, J = 18.0 Hz, CH2),
6.60 (1 H, d, J = 16.4 Hz, CH=), 7.10 (1 H, d, J = 16.4 Hz,
CH=), 7.12–7.45 (14 H, m, arom.).
Synthesis of the series of stable 3-(2-arylvinyl)-5-hy-
droxy-5-phenyl-1-tosyl-2-pyrazolines 2a–f expands our
knowledge about structure-stability dependence of 5-hy-
droxysubstituted pyrazolines.
References
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33, 647.
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(3) Kuz’menok, N. M.; Zvonok, A. M. Chem. Heterocycl.
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(11) Amine (propyl-, cyclohexyl- or benzylamines) (1 mmol)
was added to the colorless solution of the pyrazoline 2 (1
mmol) in 10 mL THF or MeOH (the color of the solution
becomes brightly orange). Reaction mixture was left at r.t.
for 12 h. After evaporation of the solvent in vacuo, the
residue was diluted with a mixture of CHCl3–MeOH.
Further solid 5-aminopyrazoline 4 was filtered off or taken
as an oil.
(12) Igidov, N. M.; Koz’minykh, E. N.; Kolotova, N. V.;
Koz’minykh, V. O. Russ. Chem. Bull. 1999, 7, 1383.
(13) Pyrazoline 2 (1 mmol) was dissolved in 10 mL THF with
catalytic amount of the concentrated HCl and left at 50 °C
for 6 h. After solvent evaporation in vacuo, the oil was
diluted with Et2O from which pyrazole 3 was crystallized.
(5) Padwa, A. J. Org. Chem. 1965, 30, 1274.
(6) Typical Procedure:
Tosylhydrazine (1.02 g, 5.5 mmol) and catalytic amount of
the concentrated HCl were added to a solution of 3-aryl-1-
(3-phenyloxiran-2-yl)prop-2-en-1-one (1, 5 mmol) in 20 mL
THF. The reaction was carried out at r.t. for 12–18 h (control
by TLC). After evaporation of the solvent in vacuo the
residue was diluted with a mixture of Et2O-benzene (1:3).
Further solid pyrazoline 2 was filtered off and purified by
recrystallization using EtOH or benzene. The residue
mixture was divided on a column and pyrazole 3 and
additional pyrazolines 2 were taken.
(7) Selected physical and spectroscopic data.
Compound 2a: yield 77%, mp 169–172 °C (EtOH). IR
Synlett 2005, No. 3, 485–486 © Thieme Stuttgart · New York