Methyl 3-cyclopropyl-3-oxopropanoate in the synthesis of heterocycles having a cyclopropyl substituent

Article abstract of DOI:10.1134/S1070428010060199

Reactions of methyl 3-cyclopropyl-3-oxopropanoate with chloroacetone and ammonia, benzaldehyde and ammonia, and benzoquinone gave, respectively, methyl 2-cyclopropyl-5-methyl-1H-pyrrole-3-carboxylate, dimethyl 2,6-dicyclopropyl-4- phenyl-1,4-dihydropyridi

Full text of DOI:10.1134/S1070428010060199

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 6, pp. 894–897. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © N.T. Pokhodylo, V.S. Matiichuk, N.D. Obushak, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 6,
pp. 898–901.
Methyl 3-Cyclopropyl-3-oxopropanoate in the Synthesis
of Heterocycles Having a Cyclopropyl Substituent
N. T. Pokhodylo, V. S. Matiichuk, and N. D. Obushak
Ivan Franko Lviv National University, ul. Kirilla i Mefodiya 6, Lviv, 79005 Ukraine
e-mail: obushak@in.lviv.ua
Received October 5, 2009
Abstract—Reactions of methyl 3-cyclopropyl-3-oxopropanoate with chloroacetone and ammonia, benzalde-
hyde and ammonia, and benzoquinone gave, respectively, methyl 2-cyclopropyl-5-methyl-1H-pyrrole-3-car-
boxylate, dimethyl 2,6-dicyclopropyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate, and methyl 2-cyclo-
propyl-5-hydroxy-1-benzofuran-3-carboxylate. Cyclization of methyl 3-cyclopropyl-3-oxopropanoate with
ethyl chloro(arylhydrazono)ethanoates and other halohydrazones led to the formation of 3-substituted 1-aryl-5-
cyclopropyl-1H-pyrazole-4-carboxylic acids, and 5-cyclopropyl-1-(quinolin-5-yl)-1H-1,2,3-triazole-4-carbox-
ylic acid was obtained by reaction of the title compound with 5-azidoquinolines.
DOI: 10.1134/S1070428010060199
Due to unusual structure and steric strain cyclo-
propane derivatives are unique compounds in the
series of carbocycles [1]. Cyclopropane derivatives are
widely used as building blocks in organic synthesis
and for creation of combinatorial libraries. Many natu-
ral and synthetic compounds containing a cyclopro-
pane fragment exhibit versatile biological activity
[2, 3]. Studies in the field of biosynthesis and meta-
bolism of cyclopropane derivatives provide informa-
tion necessary for the design of new drugs [4]. Of
particular interest are heterocyclic compounds having
a cyclopropyl group as substituent [5].
In the present work we used methyl 3-cyclopropyl-
3-oxopropanoate (I) to obtain various cyclopropyl-
substituted heterocyclic compounds. It should be taken
into account that some experimental conditions could
Scheme 1.
O
OMe
ClCH2C(O)Me, NH3, EtOH
Me
N
H
II
O
Ph
O
O
O
PhCHO, NH3, EtOH
MeO
OMe
OMe
N
H
I
III
O
OMe
O
O, ZnCl2
HO
O
IV
894

METHYL 3-CYCLOPROPYL-3-OXOPROPANOATE IN THE SYNTHESIS
895
promote opening of labile cyclopropane ring. Methyl
3-cyclopropyl-3-oxopropanoate (І) readily reacted
with chloroacetone and benzaldehyde in the presence
of ammonia to give pyrrole and dihydropyridine
derivatives II and ІІІ, respectively (Hantzsch synthe-
sis; Scheme 1). Substituted pyrrole ІІ was synthesized
according to the procedure described in [6]. The
reaction was carried out at room temperature, and the
product crystallized from the reaction mixture in high
yield. Ester І reacted with benzaldehyde and ammonia
on heating in boiling ethanol; the cyclopropane frag-
ment remained intact under these conditions, and no
tarring was observed.
sodium methoxide, and the subsequent hydrolysis gave
pyrazolecarboxylic acids IXa–IXe in 54–83% yield
(Scheme 3).
Scheme 3.
O
N2 Cl–
R3
+
R2
R1
Y
VIIa–VIIc
VIa–VIc
X
H
N
R2
AcONa, AcOH
N
O
O
R1
We also found conditions ensuring cyclization of
methyl 3-cyclopropyl-3-oxopropanoate (I) with benzo-
quinone to produce benzofuran IV (Scheme 1). The
reaction was performed by heating the reactants in
isopropyl alcohol in the presence of Lewis acid
(ZnCl2) [7]. The reaction time was 1 h; prolonged
heating resulted in formation of tars. The product,
compound IV should be thoroughly purified from im-
purities of zinc compounds by double recrystallization.
VIIIa–VIIIe
O
R2
N
N
I, MeONa
MeOH
OH
R1
We failed to synthesize aminothiophene V accord-
ing to the classical Gewald procedure [8]. Unlike ethyl
acetoacetate which readily gives rise to thiophene ring
[9], the reaction of methyl 3-cyclopropyl-3-oxopropan-
oate (І) with ethyl cyanoacetate and elemental sulfur
resulted in tarring in a short time (Scheme 2).
IXa–IXe
VI, R1 = H (a), Me (b), Cl (c); VII, Y = Cl, R3 = Ac,
R2 = Me (a), EtO (b); Y = H, R3 = Me2S+ Br–, R2 = Ph (c);
VIII, X = Cl: R1 = H, R2 = OEt (a); R1 = Me, R2 = OEt (b);
R1 = Cl, R2 = OEt (c); R1 = H, R2 = Me (d); X = Br, R1 = H,
R2 = Ph (e); IX, R1 = H, R2 = OH (a); R1 = Me, R2 = OH (b);
R1 = Cl, R2 = OH (c); R1 = H, R2 = Me (d), Ph (e).
Scheme 2.
Cyclization of ester І with aromatic azides was
studied using 5-azidoquinoline (XI) as example. It was
prepared from quinolin-5-amine (X) via diazotization
and subsequent treatment of the diazonium salt with
sodium azide. The reaction of azide XI with methyl
3-cyclopropyl-3-oxopropanoate (I) gave triazolecar-
boxylic acid XII as the major product (yield 74%,
O
O
O
N
OMe
+
+
S8
OEt
O
I
OEt
NH2
Morpholine, EtOH
MeO
Scheme 4.
S
O
NH2
N3
(1) H2SO4, NaNO2
(2) NaN3
V
Taking into account considerable interest in pyra-
zole derivatives [10], compound І was brought into
reaction analogous to the reaction of chlorohydrazones
with β-keto esters [11]. Such reactions were performed
previously using ethyl acetoacetate [12]. We prelimi-
narily synthesized a series of halohydrazones VIIIa–
VIIIe by coupling of arenediazonium salts VIa–VIc
with compounds VIIa–VIIc. Hydrazones VIIIa–VIIIe
reacted with keto ester І in methanol in the presence of
N
N
X
XI
N
O
N
N
N
I, MeONa, MeOH
OH
XII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 6 2010

POKHODYLO et al.
896
Scheme 4). Some by-products were also formed, but
they were not identified. Acid XII is a bioisoster of
5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-car-
boxylic acid which is used in the synthesis of pharma-
ceutical agent Zoniporide [13].
Methyl 2-cyclopropyl-5-hydroxy-1-benzofuran-
3-carboxylate (IV). A solution of 3.2 g (22.5 mmol) of
ester І and 2 g (15 mmol) of anhydrous zinc(II)
chloride in 6 ml of propan-2-ol was heated to the
boiling point, 2.2 g (20 mmol) of 1,4-benzoquinone
was added in portions over a period of 20–30 min, and
the mixture was heated for 30 min more under reflux,
cooled, and left to stand for 24 h. The precipitate was
filtered off, washed with alcohol, and purified by
double recrystallization from ethanol. Yield 2.8 g
We can conclude that methyl 3-cyclopropyl-3-oxo-
propanoate (І) is a convenient reagent for the prepara-
tion of triazole, benzofuran, pyrazole, pyrrole, and
pyridine derivatives having a cyclopropyl substituent
in addition to various other substituents in the hetero-
ring. However, the presence of a cyclopropane ring
affects the reactivity of keto ester I, so that we plan to
examine the behavior of compound I in more detail.
1
(61%), mp 154–155°C. H NMR spectrum, δ, ppm:
1.14–1.22 m (4H, CH2), 2.90–2.99 m (1H, CH), 3.88 s
(3H, CH3O), 6.59–6.67 m (1H, Harom), 7.08–7.22 m
(2H, Harom), 9.01 s (1H, OH). Mass spectrum: m/z 233
[M + H]+. Found, %: C 67.09; H 5.39. C13H12O4. Cal-
culated, %: C 67.23; H 5.21. M 232.24.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
Pyrazoles IXa–IXe (general procedure). A solution
of 0.6 g (26 mmol) of sodium in 20 ml of methanol
was added on cooling to a solution of 1.42 g
(10 mmol) of ester І in 10 ml of methanol, 10 mmol of
the corresponding hydrazone VIIIa–VIIIe was added
under vigorous stirring, and the mixture was kept for
30 min at room temperature and then heated for 30 min
under reflux. The mixture was diluted with 20 ml of
water, heated for 1 h at the boiling point, cooled to
room temperature, and acidified, and the precipitate
was filtered off and recrystallized from ethanol.
Unity Plus 400 spectrometer at 400 MHz from solu-
tions in DMSO-d6 using TMS as internal reference.
The mass spectra (chemical ionization) were obtained
on an Agilent 1100 LC/MSD instrument. Hydrazones
VIIIa–VIIIe were synthesized as described in [11].
Methyl 2-cyclopropyl-5-methyl-1H-pyrrole-3-
carboxylate (II). Chloroacetone, 1.4 g (15 mmol), was
added to a mixture of 2.1 g (15 mmol) of ester І, 7 ml
of 25% aqueous ammonia, and 10 ml of ethanol, and
the mixture was left to stand for 48 h. The precipitate
was filtered off and recrystallized from diethyl ether–
petroleum ether (1:1). Yield 2.0 g (74%), mp 111–
5-Cyclopropyl-1-phenyl-1H-pyrazole-3,4-dicar-
1
boxylic acid (IXa). Yield 83%, mp 176°C. H NMR
1
spectrum, δ, ppm: 1.07 m (2H, CH2), 1.19 m (2H,
CH2), 3.57–3.67 m (1H, CH), 7.22 t (1H, p-H, J =
8.4 Hz), 7.42 t (2H, m-H, J = 8.4 Hz), 7.94 d (2H, o-H,
J = 8.4 Hz). Mass spectrum: m/z 273 [M + H]+. Found,
%: C 61.52; H 4.76; N 10.21. C14H12N2O4. Calculated,
%: C 61.76; H 4.44; N 10.29. M 272.26.
112°C. H NMR spectrum, δ, ppm: 0.77 m (2H, CH2),
0.88 m (2H, CH2), 2.09 s (3H, CH3), 2.61 m (1H, CH),
3.66 s (3H, CH3O), 5.90 s (1H, 4-H), 10.22 s (1H,
NH). Mass spectrum: m/z 180 [M + H]+. Found, %:
C 67.14; H 7.20; N 7.99. C10H13NO2. Calculated, %:
C 67.02; H 7.31; N 7.82. M 179.22.
5-Cyclopropyl-1-(4-methylphenyl)-1H-pyrazole-
3,4-dicarboxylic acid (IXb). Yield 85%, mp 181–
182°C. H NMR spectrum, δ, ppm: 1.06 m (2H, CH2),
1.19 m (2H, CH2), 2.27 s (3H, Me), 3.56–3.66 m (1H,
CH), 7.36 d (2H, m-H, J = 8.4 Hz), 7.93 d (2H, o-H,
J = 8.4 Hz). Mass spectrum: m/z 287 [M + H]+. Found,
%: C 62.83; H 4.74; N 9.62. C15H14N2O4. Calculated,
%: C 62.93; H 4.93; N 9.79. M 286.29.
Dimethyl 2,6-dicyclopropyl-4-phenyl-1,4-dihy-
dropyridine-3,5-dicarboxylate (III). A mixture of
4.8 g (0.034 mol) of ester І, 1.8 g (0.017 mol) of
benzaldehyde, 2 ml (~0.03 mol) of a concentrated
ammonia solution, and 4 ml of ethanol was heated for
2 h under reflux. After cooling to room temperature,
the mixture was poured into 50 ml of ice water, and the
precipitate was filtered off, washed with water, dried
under reduced pressure, and recrystallized from hex-
ane–benzene. Yield 1.4 g (23%), light yellow crystals,
mp 87–88°C. 1H NMR spectrum, δ, ppm: 0.75–1.10 m
(8H, CH2), 2.6–2.7 m (2H, CH), 3.62 s (6H, CH3O),
4.91 s (1H, CH), 6.64 s (1H, NH), 7.07–7.20 m (5H,
Ph). Mass spectrum: m/z 354 [M + H]+. Found, %:
C 71.21; H 6.42; N 3.72. C21H23NO4. Calculated, %:
C 71.37; H 6.56; N 3.96. M 353.42.
1
1-(4-Chlorophenyl)-5-cyclopropyl-1H-pyrazole-
3,4-dicarboxylic acid (IXc). Yield 87%, mp 188–
1
189°C. H NMR spectrum, δ, ppm: 1.07 m (2H, CH2),
1.19 m (2H, CH2), 3.64–3.72 m (1H, CH), 7.37 d (2H,
m-H, J = 8.8 Hz), 8.06 d (2H, o-H, J = 8.8 Hz). Mass
spectrum: m/z 307 [M + H]+. Found, %: C 54.48;
H 3.60; N 9.22. C14H11ClN2O4. Calculated, %:
C 54.83; H 3.62; N 9.13. M 306.71.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 6 2010

METHYL 3-CYCLOPROPYL-3-OXOPROPANOATE IN THE SYNTHESIS
897
3. Donaldson, W.A., Tetrahedron, 2001, vol. 57, p. 8589;
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vol. 44, p. 2049; Brandl, M., Kozhushkov, S.I.,
3-Acetyl-5-cyclopropyl-1-phenyl-1H-pyrazole-4-
carboxylic acid (IXd). Yield 76%, mp 146–148°C.
1H NMR spectrum, δ, ppm: 1.20–1.37 m (4H, CH2),
2.69 s (3H, CH3), 3.60–3.70 m (1H, CH), 7.32 t (1H,
p-H, J = 7.6 Hz), 7.48 t (2H, m-H, J = 7.6 Hz), 7.92 d
(2H, o-H, J = 7.6 Hz). Mass spectrum: m/z 271 [M +
H]+. Found, %: C 66.54; H 5.37; N 10.18. C15H14N2O3.
Calculated, %: C 66.66; H 5.22; N 10.36. M 270.29.
Loscha,
K.,
Kokoreva,
O.V.,
Yufit,
D.S.,
3-Benzoyl-5-cyclopropyl-1-phenyl-1H-pyrazole-
4-carboxylic acid (IXe). Yield 78%, mp 110–112°C.
1H NMR spectrum, δ, ppm: 1.04 m (2H, CH2), 1.15 m
(2H, CH2), 3.73–3.82 m (1H, CH), 7.36 m (1H, p-H),
7.49 t (2H, m-H, J = 7.6 Hz), 7.55 t (2H, m′-H, J =
7.2 Hz), 7.68 m (1H, p′-H), 7.83 d (2H, o-H, J =
7.6 Hz), 8.06 d (2H, o′-H, J = 7.2 Hz). Mass spectrum:
m/z 333 [M + H]+. Found, %: C 72.02; H 4.68; N 8.49.
C20H16N2O3. Calculated, %: C 72.28; H 4.85; N 8.43.
M 332.36.
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Vasilishin, R.Ya., Farm. Zh., 2002, no. 6, p. 45.
5-Cyclopropyl-1-(quinolin-5-yl)-1H-1,2,3-tri-
azole-4-carboxylic acid (XII). A solution of 1.4 g
(10 mmol) of quinolin-5-amine (X) in a mixture of
2.5 ml of concentrated sulfuric acid and 7 ml of water
was cooled to 0°C, and a saturated solution of 0.83 g
(0.012 mol) of sodium nitrite was added, maintaining
the temperature below 5°C. The mixture was stirred
for 5 min, a solution of 0.65 g (0.01 mol) of sodium
azide in 5 ml of water was added, and the mixture was
kept for 10 min at room temperature and neutralized
with a solution of ammonia. The precipitate was
filtered off. Azide XI thus obtained was used without
additional purification. Yield 57%, decomposes at 49–
51°C. Mass spectrum: m/z 171 [M + H]+.
8. Gewald, K., Schinke, E., and Bottcher, H., Chem. Ber.,
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Ester I, 1.42 g (10 mmol), and azide XI, 1.7 g
(10 mmol), were added under vigorous stirring to a so-
lution of sodium methoxide prepared from 0.3 g of
sodium and 20 ml of methanol. The mixture was
stirred at room temperature until a solid separated, and
the precipitate was filtered off and recrystallized from
1
12. Bernard, A., Cocco, M.T., Maccioni, A., and Plumital-
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ethanol–DMF. Yield 74%, mp 189–190°C. H NMR
spectrum, δ, ppm: 1.02–1.25 m (4H, CH2), 2.45–
2.52 m (1H, CH), 7.56–7.83 m (3H, 3-H, 4-H, 7-H),
8.22–8.38 m (2H, 6-H, 8-H), 8.89 m (1H, 2-H), 11.11 s
(1H, COOH). Found, %: C 64.04; H 4.22; N 18.07.
C15H12N4O2. Calculated, %: C 64.28; H 4.32; N 19.99.
13. Clements-Jewery, H., Sutherland, F.J., Allen, M.C.,
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