Ene reactions of arylmethylenedihydropyrazoles with 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione

Article abstract of DOI:10.1055/s-2002-33917

2-Acetyl-3-aryl-7-arylmethylene-3,4,5,6,7,9-hexahydro-2H-indazoles enter into the ene reaction with 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione to give the corresponding monoene adducts. Under analogous conditions, 3-aryl-7-arymethylene-2-methyl-3,4,5,6,7,9-hexahydro-2H-indazoles give mono- and polyaddition products. The structures of compounds obtained were established using UV, IR, ¹H and ¹³C NMR spectroscopy and X-ray diffraction analysis.

Full text of DOI:10.1055/s-2002-33917

PAPER
1891
Ene Reactions of Arylmethylenedihydropyrazoles with
4-Phenyl-3H-1,2,4-triazole-3,5(4H)-dione
Ene Reactions
o
.
f
Arylmethy
I
lenedihy
.
dropyrazole
K
limova,a G. M. Martinez,*a B. T. Klimova,a Z. C. Damian,a S. Ortega,a I. D. Mendez,a P. R. Gutiérrez,b
G. R. A. Vazquezb
a
Universidad Nacional Autónoma de México, Instituto de Química and Facultad de Química (UNAM), Circuito exterior, Coyoacán,
México D.F., C.P. 04510, México
E-mail: margarma@chem.ucla.edu; E-mail: margar@servidor.unam.mx
b
Centro de Investigación, Facultad de Ciencias Químicas, Universidad Autónoma de Puebla, Apdo, Postal 1067, C. P. 72001, Puebla, Pue,
México
Received 14 May 2002; revised 20 June 2002
pyrazoles
synthesized
from
mono-
and
Abstract: 2-Acetyl-3-aryl-7-arylmethylene-3,4,5,6,7,9-hexahydro-
2H-indazoles enter into the ene reaction with 4-phenyl-3H-1,2,4-tri-
azole-3,5(4H)-dione to give the corresponding monoene adducts.
Under analogous conditions, 3-aryl-7-arymethylene-2-methyl-
bis(arylmethylene)-cycloalkanones manifest rather high
pharmacological activities.6–8 Ferrocenyl substituted di-
hydropyrazoles also possess biological activities, as is
3,4,5,6,7,9-hexahydro-2H-indazoles give mono- and polyaddition exemplified in antiviral 4-acetyl-3-ferrocenyl-1,4,5- tri-
azatricyclo[5.2.2.02,6]undec-5-ene.9
products. The structures of compounds obtained were established
using UV, IR, 1H and 13C NMR spectroscopy and X-ray diffraction
Introduction of additional nitrogen-containing fragments
into dihydropyrazoles may be promising as regards broad-
analysis.
Key words: chalcones, Diels–Alder reactions, ene reactions, dihy-
er spectrum of valuable biological properties in com-
dropyrazoles
pounds to be synthesized.
In this respect, [4+2] cycloaddition and ene reaction prod-
ucts (compounds 3 and 4, respectively, Scheme 1) recent-
ly prepared10,11 from bi- and monocyclic ferrocenyl-
dihydropyrazoles 3a–d and N-phenylazodicarboximide 2
are of certain interest. The nitrogenous organic com-
pounds 3a–d possess antiviral activities.11–15
, -Chalcones react with hydrazine to form unstable, 1-
unsubstituted 4,5-dihydropyrazoles, which are converted
into stable 1-acetyl derivatives by acetylation.1–5 It is
known that many biologically active compounds incor-
porate pyrazole fragments. Thus bicyclic acetyldihydro-
Scheme 1
Synthesis 2002, No. 13, Print: 20 09 2002.
Art Id.1437-210X,E;2002,0,13,1891,1897,ftx,en;M02202SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1892
E. I. Klimova et al.
PAPER
Poor solubilities of these compounds in different solvents N-Acetylated dihydropyrazoles 10a–c were obtained by
is their major drawback. Thus, the development of the the addition of hydrazine to chalcones 8a–c followed by
methods for the synthesis of this type of compounds with acylation of the 2-unsubstituted bicyclic products 9a–c.
aryl or alkyl substituents and studies of their chemical and N-Methyldihydropyrazoles 12a,b were prepared by the
pharmacological properties is a topical problem. In the addition of methylhydrazine to chalcones 8a and 8b, re-
present work, we have studied the reactions of arylmeth- spectively. Both unsubstituted and 2-substituted dihydro-
ylene substituted dihydropyrazoles with 4-phenyl-3H- pyrazoles were obtained in good yields. The formation of
1,2,4-triazole-3,5(4H)-dione (2).
dihydropyrazoles 9a–c, 10a–c and 12a,b occurs ste-
reospecifically.16,17 These compounds were isolated as
only one diastereoisomeric form with trans-orientation of
the hydrogen atoms H-3 and H-9 of the dihydropyrazole
Chalcones 8a–c prepared by the condensation of benzal-
dehyde or anisaldehyde with cyclohexanone 7a,b or 1-
methyl-4-piperidone (7c) in the presence of alkali in aque-
ous ethanol served as the starting compounds for the syn-
thesis of pyrazoles 9 and 10 (Scheme 2).
1
ring as evidenced from H and 13C NMR spectral data.
Thus chemical shifts for the protons H-3 in 9a–c, 10a–c,
12a, and 12b are, = 4.35, 4.54, 5.59, 4.93, 4.86, 5.63,
3.65, and 3.58, and the spin-spin coupling constants 3JH-3,
Chalcones 8a–c were isolated exclusively as single dia-
stereoisomer forms with E,E-configuration of the arylme-
thylene fragments. Crystals suitable for X-ray structural
analysis of these chalcones could not be grown. However,
indirect proof of their structures was obtained from X-ray
structural analysis of single crystals of alcohols prepared
by the addition of methyllithium, e.g., of 2,5-diaryl-
methylidene-1-methyl-cyclohexanols 11a and 11b.
are equal to 10.2, 10.3, 9.8, 9.3, 9.5, 11.2, 13.8, and
H-9
14.0, respectively, which is characteristic of trans-iso-
mers. It has been shown that cis-isomers are characterized
by smaller coupling constants (3JH-3, H-9 = 5.0–2.0 Hz).18
Dihydropyrazoles 10, 12 contain a C=C double bond con-
jugated with the C=N bond of the dihydropyrazole ring.
They can behave as s-cis-heterodienes in reactions with
active dienophiles. The presence of allylic hydrogen at-
oms in compounds 10, 12 makes it possible to perform
ene synthesis as has been shown in the case of ferrocenyl
substituted analogs.
The general view of the molecules 11a,b are shown in
Figure 1. As follows from X-ray structural data, the aryl-
methylene fragments in the alcohol possess E,E-config-
uration. One may state with high degree of confidence that
the same configurations exist in the respective original
chalcones 8a–c.
Scheme 2
Figure 1 X-ray structure of compounds 11a and 11b.
Synthesis 2002, No. 13, 1891–1897 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Ene Reactions of Arylmethylenedihydropyrazoles with 4-Phenyl-3H-1,2,4-triazole-3,5(4H)-dione
1893
Scheme 3 Ene addition to compounds 13–15 and one of the possible mechanisms of ene product formation20,21
However, dihydropyrazoles 10, 12 do not enter into [4+2] The structures of compounds 13–17 were established on
1
1
cycloaddition with 2, they rather give products of the ene the basis of H and 13C NMR spectra. H NMR spectral
addition. In the case of compounds 10a–c, monoaddition data suggest that these compounds were formed as mix-
products 13–15 are formed (Schemes 3 and 4), this could tures of two diastereomers in ca. 2:1, 2.5:1, or 3:1 ratios
be due to the acceptor character of the substituents.
the major diastereomeric form hereafter is denoted a and
the minor b.
Unlike N-acetyl derivatives, N-methyl analogs 12a,b
1
were found to be able to add up to seven moles of the eno- Characteristic signals in the H NMR spectra include
phile per mole of the starting dihydropyrazole.
broad singlets for the NH protons ( = ca. 9.5–9.9), sin-
glets for the aliphatic methine protons, singlets of an ole-
finic protons of compounds 13a and 13b or triplets of
analogous olefinic protons of compounds 14a–17a and
14b–17b.
Individual diastereomers of compound 15 were separated
by PTLC on silica gel. The spatial structure of the adduct
15a was established using X-ray diffraction analysis of
single crystals grown from 96% aqueous methanol. X-
Ray structural analysis of 15a (Figure 2) has shown that
the orthorhombic crystals of 15a contain in their unit cell
twin asymmetric molecules of the ene adducts corre-
sponding to both diastereomers connected to each other
through crystallized water molecules. The yields of com-
pounds 8–10 and 12–17 are listed in Table 1.
Scheme 4
If the reaction was carried out at –5 to 0 °C with equimolar The water molecules form hydrogen bonds with NH and
ratio of reactants, the ene adducts 16 and 17 were isolated C=O groups (5-oxo) of the 1-phenylurazolyl substituent.
in satisfactory yields. However, one could not suppress The general view of the molecule 15a and packing of the
the formation of polyadducts, which were formed in 20– molecules in a crystal are shown in Figure 2. The key ele-
1
25% yields (TLC, H NMR data). The monoaddition ment in the structure of 15a is the central bicyclic frame-
products 16, 17 were separated from the products of the work. The six-membered ring is fused to the five-
reaction by chromatography on alumina. Also observed membered ring existing in a flattened envelope conforma-
were other compounds apparently mixtures of di-, tri-, and tion. The phenyl substituent at C-7 is pseudo-equatorial.
polyaddition (others) products; their isolation in the indi- The hydrogen atoms H-3 at C-3 and H-9 at C-9 are trans-
vidual form and structural elucidation could not be ac- arranged. Data from the X-ray analysis show that the N-
complished so far because of their poor solubilities in 1–C-8 bond in the the dihydropyrazole ring is somewhat
organic solvents. 1H NMR spectroscopic data suggest the longer [d = 1.260(6) Å], while the N-1–N-2 bond is some-
presence of different diastereoisomers; attempts to sepa- what shorter [d = 1.408(5) Å] than the standard values
rate them by TLC failed. Heavy overlap of signals in all (C=N bond length is 1.23 Å18 and N–N bond length is 1.45
the regions of the 1H NMR spectra precluded their assign- Å19). The geometrical parameters of the cyclohexene and
ments. Data from NMR and mass spectrometry allowed phenyl moieties have standard values.
only rough estimates of the number of the enophile mole-
It was thus shown that reactions of arylmethylene substi-
cules that reacted with one molecule of dihydropyrazole.
tuted bicyclic dihydropyrazoles with active dieno- eno-
Studies in this direction are in progress. It was convinc-
philes follow the ene pathway.20,21 In the case of the acetyl
ingly established that the sequential mole-per-mole addi-
substituent at N-2, mono-ene addition products are
formed. Substitution of the donor methyl group for the ac-
ceptor acetyl group results in enhanced reactivities of the
ene components which can add stepwise several enophile
tion of the enophile to a solution of N-methyl
dihydropyrazole results in the incorporation of 7 moles of
the enophile per mole of the ene component.
Synthesis 2002, No. 13, 1891–1897 ISSN 0039-7881 © Thieme Stuttgart · New York

1894
E. I. Klimova et al.
PAPER
Figure 2 Molecular and Crystal packing of compound 15a. The dihedral angles are C25 N2 C3 C11 –63.1 (7), N1 N2 C3 C11 136.2 (5), C25
N2 C3 C9 176.4 (5), N1 N2 C3 C9 15.7 (5), C9 C3 C11 C16 -85.9 (7), C25 N2 C3 C9 176.4 (5), N1 N2 C3 C9 15.7 (5), C7 C8 C9 C4 –42.2
(7), C7 C8 C9 C3 –167.9 (5), C5 C4 C9 C3 172.5 (4), C11 C3 C9 C8 -138.5 (5), C11 C3 C9 C4 99.4 (6), C9 C3 C11 C12 87.6 (8).
2,6-Bis(arylmethylidene)cyclohexanones 8a–c
Table 1 Compounds 8–17 Prepared
These compounds were synthesized using
a conventional
procedure5 from cyclohexanone and benzaldehyde or p-anisalde-
hyde in the presence of alkali in aq EtOH and purified by column
chromatography on alumina (eluent, hexane–CHCl3, 3:1).
Compound
Yield (%)
68
Compound
Yield (%)
24
8a
8b
13b
65
14 (ca. 2:1),
65
8a
Pale yellow powder; yield: 68%; mp 120–121 °C (Lit.5 mp 121–
122 °C).
8c
71
14a
43
1H NMR: = 1.77 (m, 2 H, CH2), 2.91 (m, 4 H, CH2), 7.31–7.48 (m,
9a
74
14b
22
10 H, C6H5), 7.80 (2 H, CH=, J = 2.0 Hz).
13C NMR: = 22.9 (CH2), 28.3 (2 CH2), 128.2 (2 CH2=), 128.5,
130.2, 136.8 (2 C6H5), 135.8,136.1 (2 Cipso), 190.2 (C=O).
9b
72
15a (ca. 2.5:1)
70
9c
67
15a
50
MS: m/z = 273 [M]+.
10a
10b
10c
12a
12b
13 (ca. 2:1)
13a
73
15b
20
8b
71
16 (ca. 2.5:1.
60
Pale yellow powder; yield: 65%; mp 153–154 °C (Lit.5 mp 155 °C).
69
16a
16b
17
42
1H NMR: = 1.79 (m, 2 H, CH2), 2.91 (m, 4 H, CH2), 3.84 (s, 6 H,
2 CH3), 6.93 (d, 2 H, C6H4), 7.45 (d, 2 H, C6H4, J = 8.8 Hz), 7.76 (s,
2 H, CH=).
13C NMR: = 22.9 (CH2), 28.4 (2 CH2), 55.2 (2 CH3), 113.8 (2
CH=), 132.1, 136.4 (2 C6H4), 128.6 (2 C), 134.2 (2 Cipso), 159.8 (2
C–O), 190.0 (C=O).
72
17
69
58
73
17a
17b
43
MS: m/z = 334 [M]+.
48
14
8c
Pale yellow powder; yield: 71%; mp 210–211 °C.
IR: 1620, 1678, 2826, 3949 cm–1.
molecules depending on the number of the allylic hydro-
gen atoms formed upon each addition step. Studies of the
effects of different factors on the features of the stepwise
additions ene poly-addition and isolation of products of
each step deserve special investigations.
1H NMR: = 2.48 (s, 3 H, CH3), 3.76 (d, 4 H, CH2, J = 1.2 Hz), 3.84
(s, 6 H, CH3), 6.95 (d, 4 H, C6H4, J = 9.0 Hz), 7.37 (d, 4 H, C6H4,
J = 9.0 Hz), 7.77 (s, 2 H, CH=).
13C NMR: = 45.8 (CH3), 55.2 (CH2), 57.1 (2 CH3), 114.0 (2 CH=),
132.2, 135,9 (C6H4), 127.9 (2 C), 131.2 (2 Cipso), 160.1 (2 C–O),
186.7 (C=O).
UV spectra were recorded on a Specord UV-VIS spectrophotome-
ter. IR spectra were obtained for pellets with KBr using a Specord
75-IR spectrophotometer. 1H and 13C NMR spectra were recorded
on a Unity Inova Varian (300 and 75 MHz) spectrometer for solu-
tions in CDCl3 with Me4Si as the internal standard. Mass spectra
were obtained on a Varian MAT CH-6 (70 eV) instrument. Column
chromatography was carried out on alumina (activity III according
to Brockmann) and TLC was carried out on SiO2. The parameters
of the unit cell and the X-ray diffraction intensities were recorded
on Siemens P4/PC spectrometer. The crystallographic data, param-
eters of the X-ray experiment, and refinements are listed in the leg-
end to Figure 2. Structures of compounds 10 and 12a were solved
by the direct method and refined using the least-squares method in
a full-matrix anisotropic approximation for non-hydrogen atoms.
UV (CHCl3): max = 205, 356 nm.
Anal. Calcd for C22H23NO3: C, 75.62; H, 6.63; N, 4.01. Found: C,
75.53; H, 6.75; N, 3.87.
Dihydropyrazoles 9a–c
These compounds were synthesized by a standard procedure5 from
the chalcones 8a–c and hydrazine hydrate in EtOH. The precipitat-
ed dihydropyrazoles were filtered, washed with EtOH on a filter,
and dried over P2O5.
9a
Colorless powder; yield: 74%; mp 84–86 °C (Lit.5 mp 84–86 °C).
Synthesis 2002, No. 13, 1891–1897 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Ene Reactions of Arylmethylenedihydropyrazoles with 4-Phenyl-3H-1,2,4-triazole-3,5(4H)-dione
1895
1H NMR: = 1.43 (m, 1 H, CH2), 1.57 (m, 1 H, CH2), 1.80 (m, 1 H,
CH2), 1.98 (m, 1 H, CH2), 2.48 (m, 1 H, CH2), 2.88 (m, 1 H, CH2),
3.00 (m, 1 H, CH, J = 10.2 Hz), 4.35 (d, 1 H, CH, J = 10.2 Hz), 7.19
(d, 1 H, CH, J = 1.8 Hz), 7.24–7.49 (m, 10 H, 2 C6H5).
1H NMR: = 2.27 (s, 3 H, CH3), 2.42 (s, 3 H, CH3), 2.74 (dd, 1 H,
CH2, J = 6.0, 10.2 Hz), 2.86 (dd, 1 H, CH2, J = 2.54, 10.2 Hz), 3.64
(m, 2 H, CH2, J = 1.5 Hz), 3.78 (s, 3 H, CH3), 3.83 (s, 3 H, CH3),
3.90 (dm, 1 H, CH, J = 11.2 Hz), 5.63 (d, 1 H, CH, J = 11.2 Hz),
6.82–7.25 (m, 8 H, 2 C6H4), 7.34 (br, 1 H,CH=).
MS: m/z = 228 [M]+.
IR: 1024, 1150, 1609, 1628, 1679, 2846, 2894 cm–1.
9b
UV (CHCl3): max = 313 nm.
MS: m/z = 405 [M]+.
Colorless powder; yield: 72%; mp 94–95 °C (Lit.5 mp 93–95 °C).
1H NMR: = 1.47 (m, 1 H, CH2), 1.69 (m, 1 H, CH2), 1.97 (m, 1 H,
CH2), 2.21 (m, 1 H, CH2), 2.56 (m, 1 H, CH2), 2.91 (m, 1 H,CH2),
2.99 (m, 1 H, CH, J = 10.3 Hz),3.77 (s, 3 H, CH3), 4.54 (d, CH,
J = 10.3 Hz), 6.92 (m, 4 H, C6H5), 7.12 (d, 1 H, CH, J = 2.3), 7.21
(m, 4 H, C6H5), 8.61 (s, 1 H, NH).
Anal. Calcd for C24H27N3O3: C, 71.09; H, 6.71; N 10.36. Found: C,
70.93; H, 6.89; N, 10.47.
Methylidenecyclohexanols 11a,b
These compounds were prepared according to the standard proce-
dure by reacting the ketones 8a–c with MeLi in Et2O.
MS: m/z = 316 [M]+.
9c
1-Methyl-2,6-bis(phenylmethylidene)cyclohexanol (11a)
Pale yellow powder; yield: 68%; mp 120–121 °C (Lit.5 mp 121–
122 °C).
1H NMR: = 1.27–1.60 (m, 1 H, CH2), 1.64 (m, 3 H, CH3), 1.72–
1.88 (m, 1 H, CH2), 1.88 (s, 1 H, OH), 2.15–2.31 (m, 2 H, CH3),
2.90–3.02 (m, 2 H, CH2), 7.16–7.36 (m, 10 H, C6H5), 7.79 (2
H,CH=).
Colorless crystals; yield: 67%; mp 169–171 °C.
1H NMR: = 2.25 (s, 3 H, CH3), 2.70 (dd, 1 H, CH2, J = 5.7, 9.8
Hz), 2.88 (dd, 1 H, CH2, J = 2.6, 9.8 Hz), 3.59 (m, 2 H, CH2), 3.77
(s, 3 H, CH3), 3.82 (s, 3 H, CH3), 3.86 (d, 1 H, CH, J = 11.3 Hz),
5.59 (d, 1 H, CH, J = 11.3 Hz), 6.78–7.20 (m, 8 H, 2 C6H5), 7.33 (s,
1 H, CH=), 9.60 (s, 1 H, NH).
Anal. Calcd for C22H25N3O2: C, 72.70; H, 6.93; N, 11.56. Found: C,
72.58; H, 7.09; N, 11.43.
MS: m/z = 363 [M]+.
13C NMR: = 18.5 (CH3), 22.9 (CH2), 28.3 (2 CH2). 128.2 (2 CH=),
128.5, 130.2, 136.8 (2 C6H5), 135.8, 136.10 (2 Cipso), 141.3 (C–O).
1-Methyl-2,6-bis(4-methoxyphenyl)methylidenecyclohexanol
(11b)
N-Acetyldihydropyrazoles 10a–c
These compounds were obtained by treatment of anhyd compounds
9a–c with Ac2O according to a standard procedure and purified by
recrystallization from EtOH.
Pale yellow powder; yield 65%; mp 153–154 °C (Lit.5 mp 155 °C).
1H NMR: = 1.72–1.85 (m, 2 H, CH2), 1.61 (m, 3 H, CH3), 1.73–
1.84 (m, 1 H, CH2), 2.15–2.33 (m, 2 H, CH3), 2.61 (s, 1 H, OH),
7.26–7.48 (m, 10 H, C6H5), 7.79 (2 H, CH=).
13C NMR: = 19.6 (CH3), 22.9 (CH2), 28.9 (2 CH2), 50.6 (2 CH3),
113.8 (2 CH=), 132.1, 136.4 (2 C6H4), 128.6 (2 C), 134.2 (2 Cipso),
137.8 (2 C–O).
2-Acetyl-3-phenyl-7-phenylmethylidene-3,4,5,6,7,9-hexahydro-
2H-indazole (10a)
Colorless crystals; yield: 73%; mp 168–169 °C (Lit.5 mp 168–
169 °C).
1H NMR: = 1.50 (m, 1 H, CH2), 2.38 (s, 3 H, CH3), 3.05 (m, 1 H,
CH, J = 9.3 Hz), 4.93(d, 1 H, CH, J = 9.3 Hz), 7.18 (d, 1 H, CH,
J = 2.0 Hz), 7.24–7.40 (m, 10 H, 2 C6H5).
13C NMR: = 22.2 (CH3), 24.3, 29.0, 30.7 (3 CH2), 57.2, 57.7 (2
CH), 125.5 (CH=), 127.3 (C), 127.5, 127.9, 128.2, 128.7, 129.5,
130.6 (C6H5), 135.9, 141.8 (2 Cipso), 158.6 (C=N), 170.1 (C=O).
N-Methyl Substituted Dihydropyrazoles 12a,b; General Proce-
dure
A mixture of a chalcone 8a or 8b (5 mmol) and methylhydrazine (2
mL) was boiled in MeOH (30 mL) with stirring for 1 h and cooled
to 0 °C. The crystals formed were filtered, washed with aq MeOH,
and purified by recrystallization from MeOH.
MS: m/z = 330 [M]+.
2-Methyl-3-phenyl-7-phenylmethylidene-3,4,5,6,7,9-hexa-
hydro-2H-indazole (12a)
Yellow crystals; yield: 72%; mp 120–121 °C.
2-Acetyl-3-(4-methoxyphenyl)-7-(4-methoxyphenyl)methyl-
idene-3,4,5,6,7,9-hexahydro-2H-indazole (10b)
Colorless crystals; yield: 71%; mp 162–163 °C (Lit.5 mp 162–
163 °C).
1H NMR: = 1.49 (m, 1 H, CH2), 1.63 (m, 1 H, CH2), 1.93 (m, 1 H,
CH2), 2.16 (m, 1 H, CH2), 2.42 (m, 1 H, CH2), 2.97 (m, 1 H, CH2),
2.35 (s, 3 H, CH3), 3.04 (m, 1 H, CH, J = 9.5 Hz), 3.78 (s, 3 H, CH3),
3.83 (s, 3 H, CH3), 4.86 (d, 1 H, CH, J = 9.5 Hz), 6.89 (m, 4 H,
C6H4), 7.14 (d, 1 H, CH, J = 2.6 Hz), 7.22 (m, 4 H, C6H5).
13C NMR: = 22.2 (CH3), 24.3, 29.0, 30.0 (3 CH2), 55.2 (2 CH),
57.2, 67.3 (2 CH), 126.9 (CH=), 127.6 (C), 113.7, 114.2, 131.1 (2
C6H5), 128.8, 144.1 (2 Cipso), 158.8 (2 C–O), 159.1 (C=N), 170.29
(C=O).
1H NMR: = 1.40 (m, 1 H, CH2), 1.52 (m, 1 H, CH2), 1.88 (m, 1 H,
CH2), 2.02 (m, 1 H, CH2), 2.40 (m, 1 H, CH2), 2.86 (m, 1 H, CH2),
2.80 (s, 3 H, CH3), 3.01 (dd, 1 H, CH, J = 13.8 Hz), 3.65 (d, 1 H,
CH, J = 13.8 Hz), 7.20 (d, 1 H, CH=, J = 1.8 Hz), 7.22–7.46 (m, 10
H, C6H5).
13C NMR: = 24.3 (CH2), 26.7 (2 CH2), 42.0 (CH3), 55.2, 81.4 (2
CH), 127.0 (CH=), 127.1 (C), 127.3, 127.7, 128.0, 128.6, 128.6 (2
C6H5), 130.9, 136.6 (2 Cipso), 155.2 (C=N).
Anal. Calcd for C21H22N2: C, 83.41; H, 7.33; N, 9.26. Found: C,
84.53; H, 7.21; N, 9.33.
3-(4-Methoxyphenyl)-7-(4-methoxyphenyl)methylidene-2-
methyl-3,4,5,6,7,9-hexahydro-2H-indazole (12b)
Yellow crystals; yield: 69%; mp 105–106 °C.
1H NMR: = 1.48 (m, 1 H, CH2), 1.88 (m, 1 H, CH2), 1.98 (m, 1 H,
CH2), 2.39 (m, 1 H, CH2), 2.83 (m, 1 H, CH2), 2.87 (m, 1 H, CH2),
2.77 (s, 3 H, CH3), 2.99 (dm, 1 H, CH, J = 14.0 Hz), 3.58 (d, 1 H,
CH, J = 14.0 Hz), 3.81 (s, 3 H, CH3), 3.82 (s, 3 H, CH3), 7.15 (d, 1
MS: m/z = 390 [M]+.
2-Acetyl-3-(4-methoxyphenyl)-7-(4-methoxyphenyl)methyl-
idene-5-methyl-5-aza-3,4,5,6,7,9-hexahydro-2H-indazole (10c)
Colorless crystals; yield: 69%; mp 232–233 °C.
Synthesis 2002, No. 13, 1891–1897 ISSN 0039-7881 © Thieme Stuttgart · New York

1896
E. I. Klimova et al.
PAPER
H, CH=, J = 1.8 Hz), 6.85–6.94 (m, 4 H, C6H4), 7.27–7.38 (m, 4 H,
C6H4).
13C NMR: = 24.2, 28.5, 28.6 (3 CH2), 41.9, 55.1, 55.2 (3 CH3),
54.9, 80.9 (2 CH), 128.5 (CH=), 129.9 (C), 113.7, 114.2, 130.1 (2
C6H4), 130.4, 130.5 (2 Cipso), 156.0 (C=N), 158.6, 159.2 (2 C–O).
J = 9.6 Hz), 6.22 (t, 1 H, CH=, J = 5.1 Hz), 6.34 (s, 1 H, CH), 6.83–
6.93 (m, 4 H, C6H4), 7.14–7.23 (m, 4 H, C6H4), 7.41–7.49 (m, 5 H,
C6H5), 9.48 (br, 1 H, NH).
13C NMR: = 21.6, 55.3, 55.3 (3 CH3), 26.0, 26.9 (2 CH2), 59.5,
65.4, 66.6 (3 CH), 125.3 (CH=), 127.1 (C), 114.2, 114.3, 127.6,
128.0, 128.8, 129.2 (3 C6H5), 131.2, 133.3, 141.5 (3 Cipso), 152.9,
154.5 (2 C–O), 159.5 (C=N), 169.9 (2 C=O), 170.0 (1 C=O).
Anal. Calcd for C23H26N2O2: C, 76.21; H, 7.23; N, 7.73. Found: C,
76.38; H, 7.09; N, 7.84.
2-Acetyl-3-phenyl-7-[phenyl-(4-phenyl-1-urazolyl)methyl]-
3,4,5,9-tetrahydro-2H-indazole (15)
Mixture of two diastereomers 15a and 15b (ca. 2.5:1); pale yellow
powder; yield: 0.4 g (70%).
IR: 1284,1377,1559, 1656, 1699, 2830, 3226, 3331 cm–1.
MS: m/z = 565 [M]+.
Reaction of Dihydropyrazoles 10a–c and 12a,b with 4-Phenyl-
3H-1,2,4-triazole-3,5(4H)-dione (2); General Procedure
A: Imide 2 (0.175 g, 1 mmol) was added to a stirred solution of di-
hydropyrazoles 10a–c or 12a,b (1 mmol) in CHCl3 (20 mL) at
20 °C. Disappearance of bright red coloration of the solution (ca. 5
min) indicated that the reaction was over. The solvent was removed
in vacuo and the residue was chromatographed on alumina (ben-
zene–EtOAc, 4:1).
UV(CHCl3): max =208 nm.
Anal. Calcd for C32H31N5O5: C, 67.95; H, 5.53; N, 12.38. Found: C,
68.03; H, 5.37; N, 12.51.
2-Acetyl-3-(4-methoxyphenyl)-7-[4-methoxyphenyl-(4-phenyl-
1-urazolyl)methyl]-5-methyl-5-aza-3,4,5,9-tetrahydro-2H-in-
dazole (13)
Mixture of two diastereomers 13a and 13b (ca. 2:1); pale yellow
powder; yield: 0.42 g (73%).
15a
Isolated by repeated recrystallization from MeOH; mp 192–193 °C.
1H NMR: = 1.38 (m, 1 H, CH2), 1.87 (m, 1 H, CH2), 2.43 (m, 1 H,
CH2), 3.13 (m, 1 H, CH2), 2.19 (s, 3 H, CH3), 3.19 (m, 1 H, CH,
J = 10.5 Hz), 4.85 (d, 1 H, CH, J = 10.5 Hz), 6.38 (t, 1 H, CH=,
J = 4.8 Hz), 6.45 (s, 1 H, CH), 7.27–7.56 (m, 15 H, 3 C6H5), 8.60
(br, 1 H, NH).
MS: m/z = 580 [M]+.
Anal. Calcd for C32H32N6O5: C, 66.20; H, 5.55; N, 14.77. Found: C,
66.08; H, 5.71; N, 14.63.
13C NMR: = 22.4 (CH3), 26.1, 26.6, (2 CH2), 55.1, 60.3, 67.2 (3
CH), 125.3 (CH=), 125.6 (C), 127.8, 128.1, 128.5, 128.6, 128.8,
Isomer 13a
1H NMR: = 2.24 (s, 3 H, CH3), 2.89 (s, 3 H, CH3), 3.34 (m, 2 H,
CH2), 3.52 (td, 1 H, CH, J = 6.5, 11.7 Hz), 3.77 (s, 3 H, CH3), 3.78
(s, 3 H, CH3), 4.84 (d, 1 H, CH, J = 11.7 Hz), 6.15 (s, 1 H, CH), 6.59
(s, 1 H, CH=), 6.84–7.84 (m, 13 H, 3 ArH), 9.87 (br, 1 H, NH).
128.9, 128.9, 129.1, 129.1 (3 C6H5), 131.4, 136.0, 140.8 (Cipso
)
141.8 (C=N), 152.6, 154.6 (3 C=O).
IR: 1227, 1423, 1601, 1640, 1707, 1771, 3061, 3430 cm–1.
UV (CHCl3): max = 210 nm.
Isomer 13b
1H NMR: 2.39 (s, 3 H, CH3), 2.89 (s, 3 H, CH3), 3.16 (m, 2 H, CH2),
3.55 (td, 1 H, CH, J = 6.0, 12.1 Hz), 3.82 (s, 3 H, CH3), 3.83 (s, 3 H,
CH3), 4.88 (d, 1 H, CH, J = 12.1 Hz), 6.21 (s, 1 H, CH), 6.39 (s, 1
H, CH=), 6.84–7.67 (m, 13 H, 3 ArH), 9.80 (br, 1 H, NH).
Anal. Calcd for C30H27N5O3: C, 71.27; H, 5.38; N, 13.85. Found: C,
71.20; H, 5.41; N, 13.76.
15b
1H NMR: = 1.25 (m, 1 H, CH2), 1.87 (m, 1 H, CH2), 2.41 (m, 1 H,
CH2), 3.10 (m, 1 H, CH2), 2.35 (s, 3 H, CH3), 3.16 (m, 1 H, CH,
J = 9.6 Hz), 4.60 (d, 1 H, CH, J = 9.6 Hz), 6.33 (t, 1 H, CH=, J = 4.5
Hz), 6.40 (s, 1 H, CH), 7.16–7.55 (m, 15 H, 3 C6H5), 8.50–8.60 (br,
1 H, NH).
2-Acetyl-3-(4-methoxyphenyl)-7-[4-methoxyphenyl-(4-phenyl-
1-urazolyl)methyl]-3,4,5,9-tetrahydro-2H-indazole (14)
Mixture of isomers 14a and 14b (ca. 2:1); pale yellow powder;
65%; yield: 0.32 g.
IR: 1230, 1426, 1599, 1463, 1700, 2900, 3063, 3460 cm–1.
13C NMR: = 22.3 (CH3), 26.1, 26.9 (2 CH2), 54.9, 60.3, 67.0 (3
CH), 125.7 (CH=), 127.4 (C), 127.6, 127.8, 128.1, 128.5, 128.6,
128.92, 129.1, 129.4 (3 C6H5), 131.2, 134.8, 140.8 (Cipso) 142.2
(C=N), 153.1, 154.2 (3 C=O).
UV (CHCl3): max = 210 nm.
Anal. Calcd for C30H27N5O3: C, 71.27; H, 5.38; N, 13.85. Found: C,
71.38; H, 5.22; N, 13.94.
2-Methyl-3-phenyl-7-[phenyl-(4-phenyl-1-urazolyl)methyl]-
3,4,5,9-tetrahydro-2H-indazole (16)
Yield: 0.29 g (60%) and polyadducts related 16 (0.10 g). The prod-
uct 16 was a mixture of two diastereomers
Isomer 14a
1H NMR: = 1.77 (m, 1 H, CH2), 2.07 (m, 1 H, CH2), 2.36 (m, 1 H,
CH2), 2.91 (m, 1 H, CH2), 2.20 (s, 3 H, CH3), 3.18 (m, 1 H, CH,
J = 9.6 Hz), 3.78 (s, 3 H, CH3), 3.82 (s, 3 H, CH3), 4.78 (d, 1 H, CH,
J = 9.6 Hz), 6.31 (t, 1 H, CH=, J = 4.6 Hz), 6.40 (s, 1 H, CH), 6.78–
6.83 (m, 4 H, C6H4), 7.16–7.25 (m, 4 H, C6H4), 7.29–7.40 (m, 5 H,
C6H5), 9.20 (br, 1 H, NH).
16a and 16b (ca. 2.5:1); pale yellow powder.
IR: 1284, 1357, 1423, 1601, 1656, 1699, 3206, 3364 cm–1.
MS: m/z = 477 [M]+.
13C NMR: = 21.7, 54.6, 54.9 (3 CH3), 26.0, 26.6 (2 CH2), 59.5,
65.8, 66.2 (3 CH), 125.3 (CH=), 127.0 (C), 114.3, 114.6, 127.6,
128.0, 128.8, 129.0 (3 C6H5), 130.4, 132.9, 140.4 (3 Cipso), 151.6,
152.7 (2 C–O), 158.9 (C=N), 168.0, 169.1, 169.2 (2 C=O).
UV (CHCl3): max = 213 nm.
Anal. Calcd for C29H27N5O2: C, 72.95; H, 5.70; N, 14.65. Found: C,
73.03; H, 5.93; N, 14.39.
Polyadduct related to 16 was a colorless powder; mp ca. 250 °C
(dec.).
MS: m/z = 625, 827, 1050 [M]+.
Isomer 14b
1H NMR: = 1.79 (m, 1 H, CH2), 2.11 (m, 1 H, CH2), 2.34 (m, 1 H,
CH2), 2.75 (m, 1 H, CH2), 2.18 (s, 3 H, CH3), 3.20 (m, 1 H, CH,
J = 9.6 Hz), 3.77 (s, 3 H, CH3), 3.83 (s, 3 H, CH3), 4.80 (d, 1 H, CH,
Synthesis 2002, No. 13, 1891–1897 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Ene Reactions of Arylmethylenedihydropyrazoles with 4-Phenyl-3H-1,2,4-triazole-3,5(4H)-dione
1897
16a
B: Ene Polyaddition of the Imide 2 to the Dihydropyrazole 12a
N-Phenylimide 2 was added in 17.5-mg portions with stirring at
20 °C to a solution of compound 12a (30 mg) in CHCl3 (20 mL) af-
ter discoloration of the reaction mixture. Discoloration occurred vir-
tually instantaneously after addition of the first two portions and
retarded with each subsequent portion of the enophile. The addition
of the seventh molar equivalent took ca. 3 h. The mixture was dilut-
ed with Et2O (100 mL), the colorless precipitate was filtered and
washed with Et2O.
1H NMR: = 1.80–2.21 (m, 2 H, CH2), 2.43 (m, 2 H, CH2), 2.75 (s,
3 H, CH3), 3.10 (td, 1 H, CH, J = 7.18 Hz), 7.32–7.60 (m, 15 H, 3
C6H5), 9.99 (br, 1 H, NH).
13C NMR: = 25.6 (2 CH2), 41.7 (CH3), 54.4, 61.7, 79.6 (3 CH),
125.6 (CH=), 127.4 (C), 127.3, 127.8, 128.1, 128.2, 128.5, 128.8,
128.9, 129.0, (3 C6H5), 136.6, 138.4, 138.56 (3 Cipso), 139.4, (C=N),
151.9, 152.1 (3 C=O).
16b
1H NMR: = 1.58–2.08 (m, 2 H, CH2), 2.35 (m, 2 H, CH2), 2.77 (s,
3 H, CH3), 2.95 (td, 1 H, CH, J = 5.8, 13.6 Hz), 3.65 (d, 1 H, CH,
J = 13.6 Hz), 6.32 (s, 1 H,CH), 7.09 (t, 1 H, CH=, J = 7.02 Hz),
7.20–7.60 (m, 15 H, 3 C6H5), 9.59 (br, 1 H, NH).
13C NMR: = 25.4 (2 CH2), 41.5 (CH3), 53.9, 61.1, 79.9 (3 CH),
125.5 (CH=), 126.2 (C), 127.4, 127.8, 127.8, 127.9, 128.2, 128.3,
128.6, 128.8, 129.0, 129.1 (3 C6H5), 131.6, 132.4, 136.1 (3 Cipso),
140.2 (C=N), 151.8, 152.2 (3 C=O).
Acknowledgement
This investigation was supported by a grant DGAPA IN 203599.
We want to thank Messrs L.Velasco, J. Perez, E. R. Patiño, and H.
Rios and A. Peña for their technical assistance.
References
(1) Freudenberg, K.; Stoll, W. Liebigs Ann. Chem. 1924, 440,
38.
3-(4-Methoxyphenyl)-7-[4-methoxyphenyl-(4-phenyl-1-
urasolyl)methyl]-2-methyl-3,4,5,9-tetrahydro-2H-indazole (17)
Yield: 0.31 g (58%) and polyadducts-related 17 (0.13 g). The prod-
uct 17 was a mixture of two diastereomers 17a and 17b (ca. 3:1);
pale yellow powder.
IR: 1269, 1382, 1562, 1670, 1701,2827, 3219, 3341 cm–1.
MS: m/z = 537 [M]+.
(2) Auwers, K.; Heimke, P. Liebigs Ann. Chem. 1927, 458, 186.
(3) Raiford, L. C.; Tanzer, L. K. J. Org. Chem. 1941, 6, 722.
(4) Sayed, G. H. Indian J. Chem. 1980, 19b, 364.
(5) Oszbach, Gy.; Szabo, D. Acta Chim. Acad. Sci. Hung. 1975,
86, 449; Chem. Abstr. 1976, 84, 30958.
(6) Krapcho, C. J.; Turk, C. F. US Patent 3 957 762, 1976;
Chem. Abstr. 1976, 85, 63066.
(7) Krapcho, C. J.; Turk, C. F. US Patent 4 004 007, 1977;
Chem. Abstr. 1977, 86, 171443.
UV (CHCl3): max = 209 nm.
Anal. Calcd for C31H31N5O4: C, 69.26; H, 5.81; N, 13.02. Found: C,
69.38; H, 5.74; N, 12.94.
(8) Krapcho, C. J.; Turk, C. F. J. Med. Chem. 1979, 22, 270.
(9) Klimova, E.; Ruiz, L.; Martinez, G. M.; Espinosa, P.;
Meleshonkova, N. Russ. Chem. Bull. 1996, 45, 2740.
(10) Klimova, E.; Martinez, M.; Klimova, T.; Alvarez, T.;
Toscano, A.; Ruiz, L. J. Organomet. Chem. 1999, 585, 106.
(11) Klimova, E.; Martinez, M.; Klimova, T.; Ruiz, L. Russ.
Chem. Bull. 2000, 49, 906.
(12) Tose, N.; Nakaya, H.; Takeda, Y. Brit. J. Pharmacol. 1995,
114, 1076.
(13) Regan, J.; Bruno, J.; Mc Garry, D. Bioorg. Med. Chem. Lett.
1998, 8, 2737.
(14) Mock, C.; Puscasu, I.; Rauterkus, M. J. Inorg. Chim. Acta
2000, 319, 109.
(15) Chimirri, A.; Monforte, P.; Musumeci, L. Arch. Pharm.
(Weinheim, Ger.) 2001, 334, 203.
(16) Zimmermann, D.; Janin, Y. L.; Brehm, L.; Brauner-
Osborne, H.; Ebert, B.; Johansen, T. N.; Madsen, U.;
Krogsgaard-Larsen, P. Eur. J. Med. Chem. 1999, 34, 967.
(17) Malinka, W. Pharmazie 2001, 56, 384.
(18) Chang, C. H.; Porter, R. F.; Bauer, S. H. J. Am. Chem. Soc.
1970, 92, 5313.
(19) Tables of Interatomic Distances and Configuration in
Molecules and Ions; Suttonm, L. E., Ed.; Chemical Society:
London, 1965.
The polyadducts-related 17 was a colorless powder.
MS: m/z = 702, 887, 1063 [M]+.
17a
1H NMR: = 1.76–2.00 (m, 2 H, CH2), 2.40 (m, 2 H, CH2), 2.74 (s,
3 H, CH3), 3.06 (td, 1 H, CH, J = 5.1, 13.8 Hz), 3.65 (d, 1 H, CH,
J = 13.8 Hz), 3.82 (s, 3 H, CH3), 3.83 (s, 3 H, CH3), 6.29 (s, 1 H,
CH), 6.79 (t, 1 H, CH=, J = 7.6 Hz), 6.88 (d, 2 H, C6H4, J = 8.7 Hz),
6.93 (d, 2 H, C6H4, J = 8.7 Hz), 7.35 (d, 2 H, C6H4, J = 8.7 Hz), 7.35
(d, 2 H, C6H4, J = 8.7 Hz), 7.54 (d, 2 H, C6H4, J = 8.7 Hz), 7.38–
7.50 (m, 5 H, 3 C6H5), 9.99 (br, 1 H, NH).
13C NMR: = 25.5, 25.6 (2 CH2), 41.6, 55.2, 55.3 (3 CH3), 54.2,
61.5, 79.1 (3 CH), 125.6 (CH=), 126.2 (C), 113.9, 114.1, 127.8,
128.4, 128.9, 129.0, 129.1 (3 C6H5), 131.6, 138.2, 139.1 (3 Cipso),
151.9, 152.3 (2 C–O), 159.1, (C=N), 159.3, 159.5, 159.7 (3 C=O).
17b
1H NMR: = 1.56–1.78 (m, 2 H, CH2), 2.06 (m, 2 H, CH2), 2.75 (s,
3 H, CH3), 2.93 (td, 1 H, CH, J = 5.1,14.4 Hz), 3.62 (d, 1 H, CH,
J = 14.4 Hz), 3.81 (s, 3 H, CH3), 3.82 (s, 3 H, CH3), 6.31 (s, 1 H,
CH), 6.76 (t, 1 H, CH=, J = 8.0 Hz), 6.86 (d, 2 H, C6H4, J = 8.4 Hz),
6.91 (d, 2 H, C6H4, J = 8.4 Hz), 7.44 (d, 2 H, C6H4, J = 8.4 Hz), 7.70
(d, 2 H, C6H4, J = 8.4 Hz), 7.22–7.35 (m, 5 H, 3 C6H5), 10.12 (br, 1
H, NH).
(20) Gau, A. H.; Lein, G. L.; Uang, B. J.; Liao, F. L. J. Org.
Chem. 1999, 64, 2194.
(21) Vassilikogiannakis, G.; Stratakis, M.; Karabatsos, G. J.;
Orfanopoulos, M. J. Heterocycl. Chem. 1996, 33, 993.
13C NMR: = 25.4, 25.4 (2 CH2), 41.3, 55.2, 55.3 (3 CH3), 53.7,
61.0, 79.4 (3 CH), 125.5 (CH=), 125.6 (C), 114.0, 114.1, 127.9,
128.1, 128.7, 128.7, 129.0 (3 C6H5), 131.5, 138.2, 139.9 (3 Cipso),
151.7, 152.2 (2 C–O), 159.0, (C=N), 159.7, 159.9, 160.2 (3 C=O).
Synthesis 2002, No. 13, 1891–1897 ISSN 0039-7881 © Thieme Stuttgart · New York