Dehydrohalogenation of substituted diethyl halocyclopropane-1,1- dicarboxylates

Article abstract of DOI:10.1007/s11178-005-0095-0

The synthesis and dehydrohalogenation of diethyl halocyclopropane-1,1- dicarboxylates prepared from diethyl ethylidene- and benzylidenemalonates are described.

Full text of DOI:10.1007/s11178-005-0095-0

Russian Journal of Organic Chemistry, Vol. 40, No. 12, 2004, pp. 1760–1763. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 12, 2004,
pp. 1811–1814.
Original Russian Text Copyright © 2004 by Boitsov, Kostikov, Molchanov, Stepakov, Baird.
Dehydrohalogenation of Substituted Diethyl
Halocyclopropane-1,1-dicarboxylates
V. M. Boitsov1, R. R. Kostikov1, A. P. Molchanov1, A. V. Stepakov1, and M. S. Baird2
1 St. Petersburg State University, Universitetskii pr. 26, St. Petersburg, 198504 Russia
2 Chemistry Department, University of Wales, Gwynedd, LL57 2UW, United Kingdom
Received April 5, 2004
Abstract—The synthesis and dehydrohalogenation of diethyl halocyclopropane-1,1-dicarboxylates prepared
from diethyl ethylidene- and benzylidenemalonates are described.
Halocyclopropane derivatives containing several
electron-acceptor groups are convenient synthons in
organic chemistry [1]. In the present work we studied
dehydrohalogenation of diethyl halocyclopropanedi-
carboxylates prepared by cyclopropanation of diethyl
ethylidene- and benzylidenemalonates I and II or by
reaction of ethyl diazoacetate with diethyl benzyli-
denemalonate (II) with subsequent halogenation and
denitrogenation of intermediate 4,5-dihydro-1H-pyra-
zole. By reaction of esters I and II with bromoform
in the presence of sodium hydroxide and benzyltri-
ethylammonium chloride as phase-transfer catalyst
(reversed order of mixing the reactants) we obtained
diethyl 2,2-dibromopropane-1,1-dicarboxylates III and
IV, respectively (Scheme 1). Compound III was de-
scribed previously in [2]; however; attempts to repro-
duce the procedure given therein were unsuccessful
sponding 2-cyclopropene-1,1-dicarboxylates VI and
VII in 73 and 15% yield, respectively (Scheme 3).
In the IR spectrum of compound VII we observed
an absorption band at 1870 cm–1, which belongs to
stretching vibrations of the endocyclic double bond.
Carbon atoms in the cyclopropane ring of compounds
VI and VII gave the following signals in the 13C NMR
spectra: δC 85.7 and 37.4 (C1), 113.2 and 99.2 (C2),
40.0 and 120.7 ppm (C3), respectively.
An analogous reaction with compound III resulted
in formation of a mixture of products which, according
Scheme 2.
Ph
COOEt
COOEt
N2CHCOOEt
EtOCO
COOEt
Ph
COOEt
N
NH
1
II
[3]. The H NMR spectra of compounds III and IV
contained signals from the cyclopropane ring CH
proton at δ 2.56 (q, J = 7 Hz) and 3.84 ppm (s),
respectively.
Ph
EtOCO
Cl
COOEt
COOEt
Cl2
N
N
Scheme 1.
Ph
R
CHBr3, NaOH
COOEt
EtOCO
COOEt
COOEt
BTEAC
Br
Br
COOEt
COOEt
–N2
Cl
R
COOEt
I, II
V
III, IV
Scheme 3.
I, III, R = Me; II, IV, R = Ph.
Ph
We also examined dehydrohalogenation of chloro-
cyclopropane derivative V which was synthesized
according to the scheme described in [4] (Scheme 2).
The reactions of compounds IV and V with potassium
tert-butoxide in tetrahydrofuran afforded the corre-
t-BuOK
COOEt
COOEt
IV, V
R
VI, VII
VI, R = Br; VII, R = CO2Et.
1070-4280/04/4012-1760 © 2004 MAIK “Nauka/Interperiodica”

DEHYDROHALOGENATION OF SUBSTITUTED DIETHYL HALOCYCLOPROPANE-...
1761
1
to the H NMR data, contained 51% of compound
from protons on C6 and N1, δ, ppm: XII: 7.02 d (6-H,
J = 3 Hz), 11.14 d (NH, J = 3 Hz); XIII: 7.73 d (6-H,
J = 4 Hz), 11.21 d (NH, J = 4 Hz).
VIII, 21% of initial diester III, and 28% of uniden-
tified compounds (Scheme 4). We failed to separate
this mixture into particular components owing to their
ready polymerization, and it was used in further
experiments without additional purification. The 13C
NMR spectrum of VIII contained signals from carbon
atoms in the cyclopropane ring at δC 35.0 (C2), 39.7
(C1), and 130.1 ppm (C3) and a signal from the
exocyclic methylene carbon atom at δC 111.5 ppm.
Methylenecyclopropane VIII is likely to be formed via
isomerization of methylcyclopropene IX.
The reaction of methylenecyclopropane VIII with
diazomethane gave a complex mixture of products. By
column chromatography we succeeded in isolating
only individual pyrazole derivative XIV in 45% yield.
1
The H NMR spectrum of XIV contained singlet
signals from the pyrazole ring prtons at δ 7.88, 8.06,
and 11.81 ppm, as well as a signal at δ 6.86 ppm from
the exocyclic olefinic proton. The formation of com-
pound XIV may be illustrated by Scheme 6. According
to this scheme, diazomethane adds at the exocyclic
double bond in VIII to give spiro-fused dihydropyra-
zole derivative which loses bromide ion and undergoes
opening of the three-membered ring, thus being con-
verted into an allyl type cation. Elimination of proton
from the latter yields pyrazole structure XIV.
Scheme 4.
Me
Me
t-BuOK
Br
Br
COOEt
COOEt
COOEt
COOEt
Br
III
IX
CH2
Scheme 6.
COOEt
COOEt
Br
COOEt
Br
CH2N2
VIII
VIII
COOEt
N
N
Cyclopropene derivatives VI and VII were brought
into reaction with diazomethane. Treatment of VI with
diazomethane in diethyl ether at room temperature
(reaction time 48 h) gave a mixture of regioisomeric
dihydropyridazines X and XI at a ratio of 1:1.3
COOEt
COOEt
COOEt
COOEt
–Br–
1
(Scheme 5). In the H NMR spectra of X and XI,
N
N
N
N
signals from protons in the pyridazine ring were
located at δ, ppm: X: 6.76 d (6-H, J = 2 Hz), 8.85
(NH); XI: 7.57 d (6-H, J = 3 Hz), 8.43 (NH). Under
analogous conditions, the reaction of VII with diazo-
methane led to formation of triethyl 3-phenyl-1,4-di-
hydropyridazine-4,4,5-tricarboxylate (XII) and triethyl
5-phenyl-1,4-dihydropyridazine-3,4,4-tricarboxylate
(XIII) at a ratio of 1.2:1 (overall yield 61%). The IR
spectrum of the product mixture contained an absorp-
tion band at 3400 cm–1 due to stretching vibrations of
H
XIV
EXPERIMENTAL
The IR spectra were recorded on a UR-20 spectro-
photometer (Carl Zeiss) from 2% solutions in chloro-
form. The H and 13C NMR spectra were obtained on
1
a Bruker DPX-300 instrument at 300 and 75 MHz,
respectively, from 2% solutions in CDCl3. The ele-
mental compositions were determined on a Hewlett–
Packard 185 CHN analyzer. The melting points were
measured on a Boetius device; uncorrected values are
given. The purity of the compounds was checked, and
the reaction mixtures were analyzed, by TLC using
Silufol UV-254 plates.
1
the dihydropyridazine NH group. In the H NMR
spectrum of that mixture, we observed doublet signals
Scheme 5.
EtOCO
Ph
COOEt
R
EtOCO
Ph
COOEt
R
CH2N2
VI, VII
+
N
N
N
N
Diethyl 2,2-dibromo-3-methylcyclopropane-1,1-
dicarboxylate (III). A mixture of 1 g (5.4 mmol) of
diethyl ethylidenemalonate (I) [5], 0.7 ml (8.1 mmol)
of bromoform, 0.1 g of benzyltriethylammonium
H
H
X, XII
XI, XIII
X, XI, R = Br; XII, XIII, R = CO2Et.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 12 2004

BOITSOV et al.
1762
chloride, and 8 ml of methylene chloride was cooled
with an ice–salt mixture, and 4 g of a 50% aqueous
solution of sodium hydroxide was added dropwise
under stirring, maintaining the temperature below 5°C.
The cooling bath was removed, the mixture was stirred
for 2.5 h at room temperature and diluted with an equal
volume of water, and the organic phase was separated
and washed with water. The aqueous phase was
extracted with methylene chloride, the extracts were
combined with the organic phase and dried over anhy-
drous magnesium sulfate, the solvent was evaporated,
and the residue was subjected to column chromatog-
raphy on silica gel using hexane–ethyl acetate (4:1) as
eluent. Yield 0.74 g (38%), Rf 0.67. IR spectrum, ν,
cm–1: 1030, 1070, 1090, 1130, 1270, 1310, 1370, 1450,
1390, 1450, 1470, 1620, 1740 s, 2930, 2950, 2990,
1
3030. H NMR spectrum (CDCl3), δ, ppm: 1.28 t
(6H, CH3, J = 7 Hz), 4.24 q (4H, CH2, J = 7 Hz), 7.40–
7.50 m (3H, Harom), 7.60–7.70 m (2H, Harom). 13C NMR
spectrum (CDCl3), δC, ppm: 14.5 (CH3); 40.0 (C1);
61.3 (CH2); 62.0 (CH2); 85.7 (C2); 113.2 (C3); 123.6,
129.3, 130.0, 130.9 (Carom); 169.4 (CO).
Triethyl 3-phenylcyclopropene-1,1,2-tricarbox-
ylate (VII). Potassium tert-butoxide, 0.35 g (3.1 mmol),
was added over a period of 30 min under argon to
a solution of 0.94 g (2.6 mmol) of triethyl 2-chloro-
3-phenylcyclopropane-1,1,2-tricarboxylate (V) [4] in
6 ml of tetrahydrofuran, cooled to 0°C. The cooling
bath was removed, and the mixture was stirred for
40 min at room temperature, treated with water, and
extracted with diethyl ether. The extract was washed
with two portions of water, dried over magnesium
sulfate, and evaporated, and the residue was subjected
to column chromatography on silica gel using hexane–
ethyl acetate (5:1, by volume) as eluent. Yield 0.13 g
(15%), mp 44–45°C. IR spectrum, ν, cm–1: 880, 1020,
1080, 1290 s, 1370, 1450, 1720 v.s, 1870, 2990.
1H NMR spectrum (CDCl3), δ, ppm: 1.23 t (6H, CH3,
J = 7 Hz), 1.36 t (3H, CH3, J = 7 Hz), 4.20 q (4H, CH2,
J = 7 Hz), 4.36 q (2H, CH2, J = 7 Hz), 7.47 m (3H,
1
1610, 1720 v.s, 2990. H NMR spectrum (CDCl3), δ,
ppm: 1.29–1.35 m (9H, CH3), 2.56 q (1H, CH, J =
7 Hz), 4.25–4.34 m (4H, CH2). 13C NMR spectrum
(CDCl3), δC, ppm: 13.6 (CH3), 14.5 (CH3), 32.0 (C2),
35.7 (CH), 45.0 (C1), 62.4 (CH2), 63.3 (CH2), 163.7
(CO), 165.6 (CO).
Diethyl 2,2-dibromo-3-phenylcyclopropane-1,1-
dicarboxylate (IV). Following an analogous proce-
dure, from 10 g (40 mmol) of diethyl benzylidene-
malonate (II) [6], 7.0 ml (80 mmol) of bromoform,
0.5 g of benzyltriethylammonium chloride, 80 ml of
methylene chloride, and 32.0 g of 50% aqueous
NaOH we obtained 5.0 g (30%) of diester IV (56% on
the reacted II). mp 55–59°C, Rf 0.63 (hexane–ethyl
acetate, 4:1). IR spectrum, ν, cm–1: 1040, 1120, 1200,
1260, 1290, 1370, 1450, 1740 v.s, 2990, 3040.
1H NMR spectrum (CDCl3), δ, ppm: 1.25 t (3H, CH3,
J = 7 Hz), 1.39 t (3H, CH3, J = 7 Hz), 3.84 s (1H, CH),
4.16–4.32 m (2H, CH2), 4.39 q (2H, CH2, J = 7 Hz),
H
arom), 7.81 m (2H, Harom). 13C NMR spectrum
(CDCl3), δC, ppm: 14.5 (CH3); 14.6 (CH3); 37.3 (C1);
61.9 (CH2); 62.4 (CH2); 99.2 (C2); 120.7 (C3); 123.6,
129.5, 132.5, 132.8 (Carom); 158.0 (CO); 169.0 (CO).
Found %: C 65.02, H 6.07. C18H20O6. Calculated, %:
C 65.05, H 6.07.
Diethyl 5-bromo-3-phenyl-1,4-dihydropyrida-
zine-4,4-dicarboxylate (X) and diethyl 3-bromo-5-
phenyl-1,4-dihydropyridazine-4,4-dicarboxylate
(XI). Potassium tert-butoxide, 0.53 g (4.8 mmol), was
added under argon to a solution of 0.50 g (1.2 mmol)
of ester IV in 7 ml of tetrahydrofuran, cooled to 0°C.
The cooling bath was removed, the mixture was stirred
for 20 h at room temperature, and a solution of diazo-
methane prepared from 1.0 g (9.7 mmol) of N-nitroso-
N-methylurea in diethyl ether was added. The mixture
was kept for 48 h at room temperature and treated
with water, the organic phase was separated, and the
aqueous phase was extracted with methylene chloride.
The extracts were combined with the organic phase,
dried over magnesium sulfate, and evaporated, and the
residue (0.46 g) was subjected to column chromatog-
raphy using hexane–ethyl acetate (4:1) as eluent. We
isolated 0.08 g (18%) of a mixture of diesters X and
XI, Rf 0.21 (hexane–ethyl acetate, 4:1). IR spectrum, ν,
cm–1: X+XI: 820, 870, 1040, 1060, 1100, 1120, 1160,
13
7.30–7.40 m (5H, Harom). C NMR spectrum (CDCl3),
δC, ppm: 14.3 (CH3); 14.5 (CH3); 29.0 (C2); 43.9 (CH);
46.7 (C1); 62.6 (CH2); 63.6 (CH2); 128.5, 128.6, 129.7,
132.3 (Carom); 163.4 (CO); 165.6 (CO).
Diethyl 2-bromo-3-phenylcyclopropene-1,1-di-
carboxylate (VI). Potassium tert-butoxide, 0.29 g
(2.6 mmol), was added under argon to a solution of
0.27 g (0.65 mmol) of ester IV in 5 ml of tetrahydro-
furan, cooled to 0°C. The cooling bath was removed,
and the mixture was stirred for 20 h at room tempera-
ture. The mixture was then treated with water, the
organic layer was separated, and the aqueous layer was
extracted with methylene chloride. The extracts were
combined with the organic phase, dried over magne-
sium sulfate, and evaporated to isolate 0.16 g (73%) of
compound VI. IR spectrum, ν, cm–1: 800, 870, 940,
1030, 1070 s, 1090, 1160, 1180, 1260, 1280 s, 1370,
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DEHYDROHALOGENATION OF SUBSTITUTED DIETHYL HALOCYCLOPROPANE-...
1763
1270, 1370, 1400, 1450, 1500, 1760 s, 2950, 2990,
3030, 3440. H NMR spectrum (CDCl3), δ, ppm: X:
of methylene chloride. The extract was combined with
the organic phase, dried over magnesium sulfate, and
evaporated. According to the H NMR data, the
residue, 0.7 g, contained 0.36 g (51%) of diethyl
2-bromo-3-methylenecyclopropane-1,1-dicarboxylate
(VIII) and 0.15 g (21%) of initial compound III.
1
1
1.14 t (6H, CH3, J = 7 Hz), 3.85–4.05 m (2H, CH2),
4.16 q (2H, CH2, J = 7 Hz), 6.76 d (1H, CH, J = 2 Hz),
7.20–7.50 m (5H, Harom), 8.85 br.s (1H, NH); XI:
1.13 t (6H, CH3, J = 7 Hz), 3.85–4.05 m (2H, CH2),
4.16 q (2H, CH2, J = 7 Hz), 7.20–7.50 m (5H, Harom),
7.57 d (1H, CH, J = 3 Hz), 8.43 br.s (1H, NH).
13C NMR spectrum (CDCl3), δC, ppm: X: 14.0 (CH3);
62.9 (CH2); 63.7 (C4); 106.3 (C5); 119.3, 128.4, 128.7,
128.8 (Carom); 129.6 (CH); 136.7 (C3); 167.8 (CO); XI:
14.0 (CH3); 63.7 (C4), 64.0 (CH2); 106.3 (C5); 119.3
(C3); 125.9, 128.7, 128.8 (Carom); 129.9 (CH); 136.7
(Carom); 165.8 (CO).
1
Compound VIII. H NMR spectrum (CDCl3), δ,
ppm: 1.27–1.36 m (6H, CH3), 4.20–4.38 m (5H, CH2,
CH), 5.96 s (2H, CH2). 13C NMR spectrum (CDCl3),
δC, ppm: 14.4 (CH3), 14.6 (CH3), 35.0 (CH), 39.7 (C1),
62.6 (CH2), 62.8 (CH2), 111.5 (CH2), 130.1 (C3), 164.5
(CO), 166.2 (CO).
Diethyl 2-(1H-pyrazol-4-yl)methylenemalonate
(XIV). A solution of diazomethane in diethyl ether,
prepared from 2.0 g of N-nitroso-N-methylurea, was
added at room temperature to a mixture (see above)
containing 0.35 g (1.3 mmol) of ester VIII in 10 ml of
diethyl ether. The mixture was kept for 48 h at room
temperature, and the solvent was distilled off. The
residue, 0.71 g, was subjected to column chromatog-
raphy using hexane–ethyl acetate (4:1) as eluent to
isolate 0.138 g (45%) of ester XIV, mp 113–116°C. IR
spectrum, ν, cm–1: 870, 1020, 1040, 1080, 1160, 1200,
1270 s, 1300, 1380, 1400, 1470, 1740 s, 2990, 3040,
Triethyl 3-phenyl-1,4-dihydropyridazine-4,4,5-
tricarboxylate (XII) and triethyl 5-phenyl-1,4-
dihydropyridazine-3,4,4-tricarboxylate (XIII). A so-
lution of diazomethane in diethyl ether, prepared from
0.31 g (3.0 mmol) of N-nitroso-N-methylurea, was
added to a solution of 0.088 g (0.3 mmol) of ester VII
in diethyl ether, and the mixture was kept for 48 h at
room temperature. The precipitate was filtered off and
washed with cold diethyl ether. Yield of mixture
XII/XIII 0.062 g (61%), mp 144–146°C. IR spectrum,
ν, cm–1: XII+XIII: 870, 1040, 1130, 1270, 1310,
1
1
3450. H NMR spectrum (CDCl3), δ, ppm: 1.36 t
1380, 1470, 1630, 1740 v.s, 3050, 3440. H NMR
(3H, CH3, J = 7 Hz), 1.37 t (3H, CH3, J = 7 Hz), 4.36 q
(2H, CH2, J = 7 Hz), 4.41 q (2H, CH2, J = 7 Hz),
6.86 s (1H, CH), 7.88 s (1H, CH), 8.06 s (1H, CH),
11.81 s (1H, NH). 13C NMR spectrum (CDCl3), δC,
ppm: 14.4 (CH3), 63.1 (CH2), 108.3 (CH), 124.9 (CH),
133.7 [=C(CO2Et)2], 134.0 (CH), 140.3 (C4), 162.8
(CO), 165.0 (CO).
spectrum (CDCl3), δ, ppm: XII: 0.95 t (6H, CH3, J =
7 Hz), 1.23 t (3H, CH3, J = 7 Hz), 3.95 q (4H, CH2, J =
7 Hz), 4.18 q (2H, CH2, J = 7 Hz), 7.02 d (1H, CH,
J = 3 Hz), 7.25–7.64 m (5H, Harom), 11.14 d (1H, NH,
J = 3 Hz); XIII: 0.95 t (6H, CH3, J = 7 Hz), 1.19 t
(3H, CH3, J = 7 Hz), 3.95 q (4H, CH2, J = 7 Hz),
4.09 q (2H, CH2, J = 7 Hz), 7.20–7.64 m (5H, Harom),
7.73 d (1H, CH, J = 4 Hz), 11.21 d (1H, NH, J =
4 Hz). 13C NMR spectrum (CDCl3), δC, ppm: XII: 14.0
(CH3); 14.8 (CH3); 56.2 (C4); 60.7 (CH2); 62.5 (CH2);
96.7 (C5); 124.2 (C6); 128.6, 129.0, 134.7, 136.3
(Carom); 141.7 (C3), 165.9 (CO); 169.3 (CO); XIII:
14.0 (CH3); 14.7 (CH3); 56.2 (C4), 62.2 (CH2); 62.5
(CH2); 114.4 (C5); 124.9, 126.9, 127.3, 127.8 (Carom);
134.6 (C6); 136.4 (C3); 164.1 (CO); 169.1 (CO).
Found, %: C 60.97; H 5.90; N 7.47. C19H22N2O6. Cal-
culated, %: C 60.95; H 5.92; N 7.48.
This study was performed under financial support
by the INTAS program (grant no. 00.549).
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