Reaction of 4,5-dihydro-1H-pyrazole-3,5,5-tricarboxylic acids esters with halogens

Article abstract of DOI:10.1023/A:1022574404328

Esters of 4-R-4,5-dihydro-1H-pyrazole-3,5,5-tricarboxylic acids with chlorine yield esters of 4-R-5-chloro-4,5-dihydro-3H-pyrazole-3,3,5-tricarboxylic acids that at thermolysis provide the esters of the corresponding 2-chlorocyclopropanetricarboxylic acid. The same esters react with bromine in dichloromethane at room temperature to give a mixture of esters of the corresponding 1H-pyrazole-3,5-dicarboxylic acids and 5-bromo-4,5-dihydro-3,3,5-tricarboxylic acids. From 5,5-diethyl 3-methyl 4,5-dihydro-1H-pyrazole-3,5,5-tricarboxylate and N-iodosuccinimide or a system iodine - silver trifluoroacetate we obtained 1,1-diethyl 2-methyl 2-iodocyclopropane-1,1,2-tricarboxylate.

Full text of DOI:10.1023/A:1022574404328

Russian Journal of Organic Chemistry, Vol. 38, No. 11, 2002, pp. 1666 1670. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 11, 2002,
pp. 1723 1727.
Original Russian Text Copyright
2002 by Molchanov, Stepakov, Boitsov, Kostikov.
Reaction of 4,5-Dihydro-1H-pyrazole-3,5,5-tricarboxylic
Acids Esters with Halogens
A. P. Molchanov, A. V. Stepakov, V. M. Boitsov, and R. R. Kostikov
St. Petersburg State University, St. Petersburg, 198504 Russia
Received February 28, 2002
Abstract Esters of 4-R-4,5-dihydro-1H-pyrazole-3,5,5-tricarboxylic acids with chlorine yield esters of
4-R-5-chloro-4,5-dihydro-3H-pyrazole-3,3,5-tricarboxylic acids that at thermolysis provide the esters of the
corresponding 2-chlorocyclopropanetricarboxylic acid. The same esters react with bromine in dichloro-
methane at room temperature to give a mixture of esters of the corresponding 1H-pyrazole-3,5-dicarboxylic
acids and 5-bromo-4,5-dihydro-3,3,5-tricarboxylic acids. From 5,5-diethyl 3-methyl 4,5-dihydro-1H-
pyrazole-3,5,5-tricarboxylate and N-iodosuccinimide or a system iodine silver trifluoroacetate we obtained
1,1-diethyl 2-methyl 2-iodocyclopropane-1,1,2-tricarboxylate.
We formerly established that in reaction of bicyclic
or spirocyclic 2-pyrazolines with halogens (Cl2, Br2)
formed esters of the corresponding 1-halocyclopro-
panecarboxylic acids built into 3-azabicyclo[3.1.0]-
hexane or 5-azaspiro[2.4]heptane skeleton [1 3]. In
the present study we investigated reactions of mono-
cyclic 2-pyrazolines with halogens (Cl2, Br2) and
iodinating agents (N-iodosuccinimide and a system
iodine silver trifluoroacetate). The initial 2-pyrazo-
lines were prepared by treating esters of methylene
and benzylidenemalonic acids with alkyl diazoacetates.
In the IR spectra the absorption band correspond-
ing to the stretching vibrations of N H bond is
1
observed at 3370 3390 cm . In the 13C NMR spectra
the carbon atoms of pyrazoline ring appear as signals
at 39.1 and 56.3 ppm for C4 atoms of pyrazolines
IIIa, b respectively. The signals of atoms C3 are
observed in the region 143 145 ppm, and those of
C5 atom at 76 81 ppm.
Reaction of pyrazolines IIIa, b with chlorine in
dichloromethane gave rise to 1-pyrazolines IVa, b in
1
95% yield. In the H NMR spectra the signals from
Methyl diazoacetate (Ia) reacted with ester IIa at
room temperature, and ester Ib reacted with ester IIb
at heating to 80 C, and thus pyrazolines IIIa, b were
obtained in 57 and 34% yield respectively. The
composition and structure of pyrazolines IIIa, b were
established relaying on elemental analyses (Table 1)
and spectral data (Table 2).
methylene protons of compound IVa appear as
doublets at 2.69 ppm (J 15 Hz) and 3.15 ppm (J
15 Hz), and the singlet of the methine proton from
the pyrazoline IVb is observed at 4.62 ppm. In the
13C NMR spectra the signals of carbon atoms from
pyrazoline ring appear at 38.5 ppm for pyrazoline
IVa and at 55.5 ppm for pyrazoline IVb (C4), and
also in the region 102 106 ppm (C3, C5).
The heating in a vacuum of pyrazoline IVa to
80 C and of pyrazoline IVb to 130 C resulted in
formation of cyclopropanes Va, b in 95% yield. In
1
the H NMR spectrum of cyclopropane Va are seen
the doublet signals from methylene protons of the
three-membered ring at 2.20 ppm (J 7 Hz) and
2.40 ppm (J 7 Hz). The signals of carbon atoms of
the three-membered ring of cyclopropane Va appear
at 26.1 (C3), 43.6 (C1) and 46.2 (C2) ppm.
I, R = Me (a), Et (b); II, R = H (a), Ph (b); III,
R = Me, R = H (a); R = Et, R = Ph (b).
1
In the H NMR spectrum of pyrazoline IIIa is
present a singlet from methylene protons of the pyr-
azoline ring at 3.54 ppm and a signal from NH proton
at 7.13 ppm, and in the H NMR spectrum of pyr-
azoline IIIb singlet of the methine proton appears at
5.63 ppm, and NH signal at 9.0 ppm.
Cyclopropane Vb formed as a mixture of E and
Z-isomers in 4.7 : 1 ratio. In the H NMR spectrum of
compound Vb the methine singlet from cyclopropane
ring of E-isomer appears at 3.89 ppm, that of Z-iso-
mer at 3.84 ppm. In this spectrum are also observed
1
1
1070-4280/02/3811-1666$27.00 2002 MAIK Nauka/Interperiodica

REACTION OF 4,5-DIHYDRO-1H-PYRAZOLE-3,5,5-TRICARBOXYLIC
1667
Table 1. Yields, melting points and elemental analyses of compounds synthesized
Found, %
Calculated, %
H
Compd.
Yield, %
mp,
C
Formula
no.
C
H
N
C
N
a
IIIa
IIIb
IVa
IVb
Va
57
34
95
96
95
96
16
27
15
90
54
48.47
59.69
43.88
54.39
47.53
58.57
48.57
62.43
49.05
52.29
35.54
6.03
6.03
5.12
5.36
5.39
5.81
4.99
5.44
4.63
5.04
4.17
10.17
7.59
8.89
6.89
C11H16N2O6
C18H22N2O6
C11H15ClN2O6
C18H21ClN2O6
C11H15ClO6
C18H21ClO6
C8H10N2O4
C15H16N2O4
C18H21BrN2O6
C18H21BrO6
C11H15IO6
48.53
59.66
43.08
54.48
47.41
58.62
48.49
62.49
48.99
52.32
35.70
5.92
6.12
4.93
5.33
5.42
5.74
5.09
5.59
4.80
5.12
4.08
10.29
125 126b
7.73
9.13
7.06
a
a
a
a
Vb
VIa
VIb
VII
VIII
IX
80 81
14.01
9.58
6.17
14.14
9.72
6.35
88 89
a
a
a
a
b
Oily substance.
With decomposition.
signals from the aromatic protons and those of ester
groups. In the 13C NMR spectrum the carbon signals
from the cyclopropane ring appear at 43.0 (C3),
47.5 (C1) and 49.3 (C2) ppm for E-isomer and at 38.1
(C3), 45.4 (C1) and 51.5 (C2) ppm for Z-isomer.
Carbonyl carbons of E-isomer give rise to signals at
164.4, 164.6, and 165.1 ppm, those of Z at 163.2,
166.3, and 166.1 ppm. The signals of carbon atoms
from OCH2CH3 group in E-isomer are located at 62.5,
62.8, and 63.4 ppm whereas those of Z-isomer appear
at 62.9, 63.5, and 63.6 ppm. The configuration of
isomeric cyclopropanes Va, b was assigned relying
on upfield shift as compared to E-isomer of carbon
signals from C=O and OCH2CH3 in the Z-isomer
which is due to shielding of the ester group by a
phenyl located cis to it. In E-isomer the ester group
and phenyl are in trans-position [4].
complex mixtures that were subjected to column
chromatography to isolate pyrazoles VIa, b, 1-pyr-
azoline VII, and cyclopropane VIII in 16, 20, 15,
1
and 3% respectively. The H NMR spectrum of pyr-
azoline VII shows that the compound contains E- and
Z-isomers in 1: 2.2 ratio. The signal of methine
proton at C4 appears at 4.65 in the spectrum of Z-iso-
mer and at 4.73 ppm in that of E-isomer.
VI, R = Me, R = H (a), R = Et, R = Ph (b).
At heating pyrazoline VII in a vacuum at 110 C
in 90% yield formed bromocyclopropane VIII also as
IV, V, R = Me, R = H (a), R = Et, R = Ph (b).
The reaction of pyrazolines IIIa, b with bromine
in dichloromethane at room temperature gave rise to
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 11 2002

1668
MOLCHANOV et al.
1
Table 2. IR, H and 13C NMR spectra of compounds synthesized
1
Compd.
no.
IR spectrum, , cm
1H NMR spectrum, , ppm (J, Hz) 13C NMR spectrum, , ppm (J, Hz)
IIIa
870, 900, 1020, 1070, 1140, 1270 s, 1.25 t (6H, 7), 3.54 s (2H), 3.80 s 14.3, 39.1, 52.7, 63.3, 75.6, 142.7,
1370, 1410, 1450, 1590, 1740 v.s, (3H), 4.22 q (4H, 7), 7.13 s (1H) 162.2, 168.3
3040, 3370
IIIb
880, 1040, 1100, 1120, 1280, 1380, 1.24 t (3H, 7), 1.56 t (3H, 7), 1.72 13.7, 14.3, 56.3, 61.6, 62.7, 63.4,
1410, 1580, 1740 v.s, 3020, 3390 t (3H, 7), 4.11 m (2H), 4.52 m (2H), 80.9, 128.5, 128.9, 129.0, 135.3,
4.72 m (2H), 5.63 s (1H), 7.59 145.0, 161.3, 166.6, 167.9
7.79 (5H), 8.99 s (1H)
IVa
IVb
1020, 1100, 1140, 1270s, 1370,
1450, 1600, 1730 v.s, 3050
1.32 m (6H), 2.69 d (1H, 14), 3.15 d 14.3, 38.5, 54.8, 63.9, 102.9,
(1H, 14), 3.89 s (3H), 4.33 m (4H) 104.0, 164.7, 164.9, 165.5
880, 970, 1030, 1070, 1130, 1280 s, 0.81 t (3H, 7), 0.87 t (3H, 7), 1.34 13.6, 14.3, 55.5, 63.0, 63.2, 64.3,
1370, 1470, 1750 v.s., 2990
t (3H, 7), 3.83 q (2H, 7), 3.90 q 102.1, 106.3, 128.9, 129.2, 129.3,
(2H, 7), 4.35 m (2H), 4.62 s (1H), 133.4, 163.4, 163.6, 164.1
6.88 m (2H), 7.25 m (3H)
Va
870, 980, 1020, 1090, 1140, 1270 s, 1.26 t (3H, 7), 1.31 t (3H, 7), 2.20 14.3, 14.4, 26.1, 43.6, 46.2, 54.1,
1380, 1440, 1740 v.s, 2990
d (1H, 7), 2.40 d (1H, 7), 3.81 s 62.8, 63.2, 164.4, 165.6, 166.8
(3H), 4.18 q (2H, 7), 4.27 m (2H)
a
E-Vb
Z-Vb
870, 1040, 1130, 1270 s, 1370, 1.10 t (3H, 7), 1.19 t (3H, 7), 1.37 13.9, 14.2, 14.5, 43.0, 47.5, 49.3,
t (3H, 7), 3.89 s (1H), 4.11 m (4H), 62.5, 62.8, 63.4, 127.9, 128.2,
4.38 m (2H), 7.26 7.40 (5H) 129.8, 131.4, 164.4, 164.6, 165.2
1450, 1730 v.s, 2990
1.10 t (3H, 7), 1.19 t (3H, 7), 1.32 14.0, 14.2, 14.4, 38.1, 45.4, 51.5,
t (3H, 7), 3.84 s (1H), 4.18 m (4H), 62.9, 63.5, 63.6, 129.1, 129.8,
4.32 m (2H), 7.26 7.40 (5H)
950, 1020, 1090, 1170, 1270s, 1330, 1.38 t (3H, 7), 3.94 s (3H), 4.40 q 14.5, 52.8, 62.1, 111.7, 140.1,
1450, 1570, 1730 v.s, 3050, 3420 (2H, 7), 7.33 s (1H), 10.5 s (1H) 140.6, 160.6, 161.3
1020, 1100, 1180, 1390, 1450, 1610, 1.20 t (6H, 7), 4.23 q (4H, 7), 7.35 m 14.2, 61.7, 127.6, 128.2, 128.3,
130.2, 131.1, 163.2, 166.3, 166.4
VIa
VIb
1720 v.s, 3050, 3420
(5H), 13.0 br.s (1H)
130.7, 131.0, 132.5, 137.6, 160.8
a
Z-VII
870, 970, 1020, 1070, 1120, 1290s, 0.83 t (3H, 7), 1.31 t (3H, 7), 1.37 13.9, 14.2, 52.1, 63.0, 64.1, 64.2,
1380, 1470, 1740 v.s, 2990
t (3H, 7), 3.87 q (2H, 7), 4.32 m 99.8, 106.7, 128.8, 129.1, 129.5,
(4H), 4.65 s (1H), 7.21 7.32 (5H) 133.6, 162.7, 164.9, 165.1
E-VII
0.82 t (3H, 7), 1.37 m (6H), 3.82 13.7, 14.4, 55.3, 62.8, 63.1, 64.5,
q (2H, 7), 4.26 m (4H), 4.73 s (1H), 101.9, 105.8, 128.7, 129.1, 129.4,
7.21 7.32 (5H)
133.4, 163.2, 163.3, 164.4
a
Z-VIII 870, 1040, 1100, 1270 s, 1370 s 1.22 t (3H, 7), 1.35 t (6H, 7), 3.70 13.6, 14.3, 14.8, 39.1, 45.9, 51.4,
1450, 1730 v.s, 2990 s
s (1H), 4.28 m (6H), 7.28 7.44 62.7, 63.7, 63.9, 126.9, 127.7,
(5H) 128.9, 130.1, 163.4, 166.1, 166.3
E-VIII
1.13 t (3H, 7), 1.36 t (6H, 7), 3.85 s 13.7, 14.5, 14.7, 43.2, 47.4, 49.6,
(1H), 4.12 m (4H), 4.41 m (2H), 62.6, 62.9, 63.8, 127.4, 127.9,
7.28 7.44 (5H)
129.5, 131.2, 164.1, 164.3, 165.0
IX
970, 1020, 1090, 1270s, 1350, 1380, 1.21 t (3H, 7), 1.31 t (3H, 7), 1.89 2.7, 14.3, 14.6, 28.4, 41.7, 54.0,
1450, 1730 v.s, 3050
d (1H, 7), 2.30 d (1H, 7), 3.72 s 62.8, 63.1, 165.5, 165.9, 167.9
(3H), 4.13 m (2H), 4.28 m (2H)
a
Mixture of E- and Z-isomers.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 11 2002

REACTION OF 4,5-DIHYDRO-1H-PYRAZOLE-3,5,5-TRICARBOXYLIC
1669
a mixture of E- and Z-isomers. In the 1H NMR
spectrum of cyclopropane VIII signals of the methine
proton of the cyclopropane ring are observed at
3.70 ppm for Z-isomer and at 3.85 ppm for E-isomer.
Triethyl 4,5-dihydro-4-phenyl-5-chloro-3H-pyr-
azole-3,5,5-tricarboxylate (IV) was obtained in a
similar way from 1 g (2.8 mmol) of pyrazoline IIIb.
Yield 1.05 g.
1,1-Diethyl 2-methyl 2-chlorocyclopropane-
1,1,2-tricarboxylate (Va). Pyrazoline IVa (0.96 g,
3.1 mmol) was heated in a vacuum at 80 C to the end
of nitrogen liberation (10 min). Yield 83 g.
The reaction of pyrazoline IIIa with N-iodosuc-
cinimide or CF3CO2I (from iodine and CF3CO2Ag)
gave rise to iodocyclopropane IX in 50% yield.
1
In the H NMR spectrum of ester IX appear the
Triethyl 2-chloro-3-phenylcyclopropane-1,1,2-
tricarboxylate (Vb). Pyrazoline IVb (1.05 g,
2.6 mmol) was heated in a vacuum at 130 C to the
end of nitrogen liberation (10 min). Yield 94 g.
methylene protons of cyclopropane ring as doublets
at 1.89 and 2.30 ppm (J 7 Hz), and also signals from
the protons of ester groups. In the 13C NMR spectrum
the carbon atoms of the cyclopropane ring are observ-
ed at 2.7 (C2), 28.4 (C3) and 41.7 (C1) ppm. We
failed to synthesize iodocyclopropane in reaction of
ester IIIb with N-iodosuccinimide: 65% of the initial
pyrazolone was obtained alongside a mixture of
intractable products.
Pyrazoline IIIa reaction with bromine. To a
solution of 0.43 g (1.6 mmol) of pyrazoline IIIa in
5 ml of dichloromethane was added 0.3 ml of
bromine, and the mixture was kept for 3 days at room
temperature. Then the reaction mixture was washed
with 5% solution of Na2SO3, and dried over MgSO4.
The solvent was evaporated, the reaction products
were subjected to column chromatography on silica
gel to isolate 0.048 g (16%) of ester VIa, 0.062 g
(14%) of the initial pyrazoline IIIa, and 0.391 g of
unidentified products.
EXPERIMENTAL
IR spectra were recorded on spectrophotometer
UR-20 from 2% solutions of compounds in chloro-
1
form. H and 13C NMR spectra were registered on
spectrometer Bruker DPX-300 at operating frequ-
encies 300.13 and 75.47 MHz respectively. The
purity of substances was checked and reaction mix-
tures were analyzed by TLC on Silufol UV-254
plates.
Pyrazoline IIIb reaction with bromine. (a) The
process was performed as described above for pyrazo-
line IIIa with 0.32 g (0.9 mmol) of pyrazoline IIIb
and 0.21 ml of bromine in chloroform. We obtained
0.051 g (20%) of ester VIb, 0.058 g (15%) of ester
VII and 0.011 g (3%) of ester VIII. (b) To a solution
of 0.5 g (1.4 mmol) of pyrazoline IIIb in 5 ml of
glacial acetic acid was added 0.3 ml of bromine, and
the mixture was heated to 80 C for 2 h. The solvent
was distilled off, the residue was dissolved in ether,
washed with 5% solution of Na2SO3, and dried on
MgSO4. The ether was evaporated, and the residue
was subjected to column chromatography on silica gel
(eluent hexane ethyl acetate, 1: 1) Yield 0.11 g.
5,5-Diethyl 3-methyl 4,5-dihydro-1H-pyrazole-
3,5,5-tricarboxylate (IIIa). To a solution of 2 g
(11.6 mmol) of ester IIa in 20 ml of ethyl ether was
added 1 g (10 mmol) of ester Ia, the mixture was
kept for 1 h at room temperature. The solvent was
evaporated, the residue was purified by column
chromatography on silica gel (eluent hexane ethyl
acetate, 1.8 : 1). On evaporation of the eluent 1.8 g of
oily substance IIIa was obtained.
Triethyl
4,5-dihydro-4-phenyl-3H-pyrazole-
Triethyl 2-bromo-3-phenylcyclopropane-1,1,2-
tricarboxylate (VIII). Pyrazoline VII (0.04 g,
0.1 mmol) was heated in a vacuum to 110 C till the
end of nitrogen liberation (5 min). Yield 0.03 g.
3,5,5-tricarboxylate (IIIb). To a solution of 2 g
(8 mmol) of ester IIb in 20 ml of benzene was added
2 g (17,5 mmol) of ester Ib. The mixture was heated
to 80 C for 8 h. The benzene was distilled off, and
hexane was added to the residue for crystallization.
The separated precipitate was filtered off and washed
with hexane. Yield 1 g.
1,1-Diethyl 2-methyl 2-iodo-1,2,2-cyclopropane-
tricarboxylate (IX). (a) To a solution of 0.41 g
(1.5 mmol) of pyrazoline IIIa in 10 ml of glacial
acetic acid was added 0.42 g (1.9 mmol) of N-iodo-
succinimide. The mixture was heated for 1 h to 70 C.
The solvent was distilled off in a vacuum, the residue
was dissolved in ether, washed with 5% solution of
Na2SO3, and dried on MgSO4. The ether was
evaporated, and the residue was subjected to column
chromatography on silica gel (eluent hexane ethyl
acetate, 2: 1) Yield 0.28 g. (b) To a stirred mixture
5,5-Diethyl 3-methyl 4,5-dihydro-5-chloro-1H-
pyrazole-3,5,5-tricarboxylate (IVa). Through
solution of 0.9 g (3.3 mmol) of pyrazoline IIIa in
10 ml of dichloromethane at room temperature was
passed a flow of chlorine till the initial pyrazoline was
totally consumed (TLC monitoring). The solvent was
evaporated at room temperature. Yield 0.96 g.
a
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 11 2002

1670
MOLCHANOV et al.
of 0.30 g (1.1 mmol) of pyrazoline IIIa and 0.82 g
(3.3 mmol) of silver trifluoroacetate in 8 ml of 1,2-di-
chloroethane heated to 70 C was added a solution of
0.42 g (1.6 mmol) of iodine in 6 ml of 1,2-dichloro-
ethane. The mixture was stirred for another 30 min,
cooled, and the precipitated AgI was filtered off. The
organic layer was washed with 5% solution of
Na2SO3, and dried on MgSO4. The solvent was
distilled off, and the residue was subjected to column
chromatography on silica gel (eluent hexane ethyl
acetate, 2: 1 by volume) Yield 0.22 g (54%).
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