Synthesis of heterospirans containing a γ-lactone ring

Article abstract of DOI:10.1134/S1070428008070221

Reactions of α-ketols with diethyl malonate at the molar ratio 2:1 in the presence of K₂CO₃ were investigated. The heterospiranes obtained contained a dihydrofuran and a γ-lactone rings. The optimum conditions for the synthesis of heterospiranes were found by varying the ratio of the initial compounds: α-ketoalcohol (or 2-ethoxycarbonyl-, 2-methoxycarbonyl-, 2-cyano-3,4,4-trimethyl-2-buten-4-olides), diethyl malonate, K₂CO₃, by varying the environment, and also the temperature and the time of the reaction.

Full text of DOI:10.1134/S1070428008070221

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 7, pp. 1077−1081. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © A.A. Avetisyan, G.G. Tokmadzhyan, R.A. Piridzhanyan, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 7,
pp. 1086−1090.
Synthesis of Heterospirans Containing a γ-Lactone Ring
A. A. Avetisyan, G. G. Tokmadzhyan, and R. A. Piridzhanyan
Yerevan State University, Yerevan, 375025 Armenia
e-mail: tokmajyang@yahoo.com
Received July 30, 2007
Abstract—Reactions of α-ketols with diethyl malonate at the molar ratio 2:1 in the presence of K2CO3 were
investigated. The heterospiranes obtained contained a dihydrofuran and a γ-lactone rings. The optimum conditions
for the synthesis of heterospiranes were found by varying the ratio of the initial compounds: α-ketoalcohol (or
2-ethoxycarbonyl-, 2-methoxycarbonyl-, 2-cyano-3,4,4-trimethyl-2-buten-4-olides), diethyl malonate, K2CO3,
by varying the environment, and also the temperature and the time of the reaction.
DOI: 10.1134/S1070428008070221
One of the most general preparation methods of
functionally substituted 2-buten-4-olides [furan-2(5H)-
ones] consists in the condensation of α-ketoalcohols with
compounds containing active methylene groups in the
presence of basic reagents [1]. In the course of the search
of optimum conditions for the preparation of 2-ethoxy-
carbonyl-3,4,4-trimethyl-2-buten-4-olide [ethyl 4,5,5-
trimethyl-2-oxo-2,5-dihydro-furan-3-carboxylate (I)]
from dimethylacetylcarbinol and diethyl malonate [2] in
the presence of potassium carbonate we found that the
heating of the initial reagents at the molar ratio 2:1 at
140–150°C led to the formation of three reaction
products, among which one was the target lactone I (yield
15%), and another was 4,5,5-trimethylfuran-2(5H)-one
(II) (yield 20%). The study of the structure of the third
The attempt to synthesize ethyl-4-methyl-2-oxo-1-
oxaspiro[4.5]dec-3-ene-3-carboxylate (V) from 1-acetyl-
cyclohexanol and diethyl malonate in the presence of
potassium carbonate also gave a similar result. The major
reaction product alongside previously known 4-methyl-
1-oxaspiro[4.5]dec-3-en-2-one (VI) (yield 24%) and com-
pound V (yield 12%) was 19-methyl-7,15-dioxatri-
spiro[5.1.0.5.3.2]nonadec-18-en-16-one (VII) (yield
35%) [3]. In order to define the limits of this fairly
interesting reaction we introduced into the reaction with
diethyl malonate the methylphenylacetylcarbinol. The
reaction was carried out in the previously found optimum
conditions: the molar ratio of diethyl malonate to the
methylphenylacetylcarbinol 2:1, temperature 140°C,
reaction time 10 h. Thus we obtained 4,5-dimethyl-5-
phenylfuran-2(5H)-one (VIII) (33%), ethyl 4,5-dimethyl-
2-oxo-5-phenyl-2,5-dihydrofuran-3-carboxylate (IX)
(6%), and 2,3,6-trimethyl-2,6-diphenyl-1,7-dioxaspiro-
[4.4]non-3-en-8-one (X) (30%). Therefore a method was
1
compound (yield 45%) by means of IR, H NMR
spectroscopy and mass spectrometry permitted its
identification as
2,2,3,6,6-pentamethyl-1,7-
dioxaspiro[4.4]non-3-en-8-one (III) [3].
H3C
H3C
R
COOC2H5
H3C
R
R
R
K2CO3
140_150oC
C
CH2(COOC2H5)2
C CH3
O
'
R’
R
O
'
R’
O
O
R’
'
'
R’
OH
O
O
O
R
O
'
R’
III, VII, X
II, VI, VIII
I, V, IX
I–III, R = R' = CH3; V–VII, R, R' = (CH2)5; VIII–X, R = CH3, R' = C6H5.
1077

AVETISYAN et al.
1078
found for preparation of heterospiranes containing
a γ-lactone and a dihydrofuran rings.
attack of a hydroxy group on the electron-deficient β-
carbon atom by the type of Michael reaction results in
spiro compounds B (Scheme 1). Their further hydrolysis
under the reaction conditions and the decarboxylation
leads to the formation of compounds III, VII, and X.
The assumed reaction pathway [the primary formation
of ethyl 4,5,5-trimethyl-2-oxo-2,5-dihydrofuran-3-carb-
oxylate (I), its condensation with dimethylacetylcarbinol,
intramolecular addition to the activated double bond,
hydrolysis of the ester group, and the decarboxylation]
was tested on a sequence of reactions.
Natural and synthetic derivatives of γ-lactones, among
them also spiro compounds containing the γ-lactone
rings, are endowed with a wide range of biological action
[4–7], many of them are used in the medical practice,
and we believe that the more detailed investigation of
the pathway of the found closure of the dihydrofuran
ring and also of various factors affecting the yield of
heterospiranes possessing the γ-lactone ring would be
rational.
The reaction of compound I with dimethylacetyl-
carbinol under similar conditions resulted as expected
in the formation of the corresponding heterospirane III
in up to 63% yield depending on the reaction temperature.
The condensation of α-ketoalcohol with diethyl
malonate under the conditions of the phase-transfer
catalysis (in the presence of potassium carbonate)
provided not only 4,5-substituted ethyl 2-oxo-2,5-
dihydrofuran-3-carboxylates I, V, and IX, but also to the
products of their further condensation and transformation
under the reaction conditions.
H3C
COOC2H5
K2CO3
(H3C)2C C(O)CH3
OH
III
H3C
H3C
O
O
Apparently the key stage in the synthesis of spiro
compounds III, VII, and X is the nucleophilic attack of
a lactone allyl carbanion generated by the base on the
carbonyl group of the ketoalcohol to form intermediate
compounds A. The water elimination and the nucleophilic
I
However the reaction of 4,5,5-trimethyl-2-oxo-2,5-
dihydrofuran-3-carboxylic acid with dimethylacetyl-
Scheme 1.
R
C
C(O)CH3
CH2(COOC2H5)2
'
R’
OH
_
R
K2CO3
H3C
COOC2H5
O
H2C
COOC2H5
O
C
C(O)CH3
140_150oC
R
R’
R
'
R’
O C(O)CH2COOC2H5
'
R’
O
O
OH
C
OH
R
R
H3C
R
H3C
HO
CH C(O)CH3
C
C
C
'
'
R’
R’
R’
CH
H2C
R
COOC2H5
COOC2H5
_H2O
R
'
R’
O
R’
O
O
O
A
H3C
H3C
H
H
R
R
R’
COOC2H5
O
III, VII, X
COOH
O
'
_CO2
R’
O
O
R
O
R
O
'
R’
R’
B
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008

SYNTHESIS OF HETEROSPIRANS CONTAINING A γ-LACTONE RING
1079
carbinol gave spiro compound III only in 2% yield, and
the reaction of compound II with dimethylacetylcarbinol
did not go at all.
heating varying the molar ratio of the reagents. This
resulted only in transesterification and in obtaining
methyl 4,5,5-trimethyl-2-oxo-2,5-dihydrofuran-3-carb-
oxylate (XII) in 43% yield.
The active role in the reaction under study of the
electron-acceptor fragment [CH3CH=C(COOC2H5)COO]
was proved by involving into the reaction with dimethyl-
acetylcarbinol the diethyl ethylidenemalonate [8].
Compound XII was introduced into the reaction with
dimethylacetylcarbinol in the presence of K2CO3; the
best yield of compound III (50%) was obtained at the
molar ratio compound XII–diethyl malonate–K2CO3
1:1.5:1, at 180°C within 7 h.
The closure of the dihydrofuran ring with the forma-
tion of compound XI proves the validity of our concept
of the chemistry of this process (Scheme 2)
.
From 4,5,5-trimethyl-2-oxo-2,5-dihydrofuran-3-
carbonitrile (XIII) in the presence of K2CO3 like in the
previous cases at various molar ratios of reagents, dif-
ferent temperature modes (from 120 to 180°C) and dif-
ferent time of heating compound III formed in moderate
yields (from 20 to 32%). Consequently, the presence of
a functional group in the position 3 of the 2-oxodi-
hydrofuran ring favored the reaction to proceed along
the above pathway resulting in the formation of com-
pound III.
The effect of various factors on the yield of compound
III we studied by an example of the reaction either of
diethyl malonate or compound I with dimethylacetyl-
carbinol in the presence of K2CO3 (without solvent or in
dimethyl sulfoxide).
The first set of experiments with the variation of
reagents ratio and also of reaction temperature and
duration showed that the yield of target compound III
depended both on the molar reagents ratio and on the
reaction temperature. The optimum reaction conditions
giving compound III in 45% yield were as follows: molar
ratio diethyl malonate–dimethylacetylcarbinol–K2CO3
1:0.5:1, temperature 140–150°C, reaction time 10 h. The
reaction carried out in DMSO gave compound III only
in 30% yield. In the latter case the main reaction product
was compound II.
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer
Specord 75IR from mulls in mineral oil. 1H NMR spectra
were registered on a spectrometer Varian Mercury 300
(300 MHz), internal reference TMS. Mass spectra were
obtained on an instrument MKh-1321A, electron impact,
energy of ionizing electrons 50–70 eV, direct admission
of samples into the ion source. The purity of synthesized
compounds was checked by TLC on Silufol UV-254
plates, eluent acetone–benzene, 1:2, development in
iodine vapor or under UV radiation. Melting points were
measured on a Bo¸tius heating block.
The second set of experiments included the reaction
of compound I in the presence of K2CO3 at heating the
reaction mixture in various manners for 7–8 h both
without solvent and in DMSO. The best yield of
compound III (63%) was obtained at the molar ratio
lactone–ketoalcohol–K2CO3 1:1:1, at 165°C without
solvent.
2,2,3,6,6-Pentamethyl-1,7-dioxaspiro[4.4]non-3-
en-8-one (III). a. To 8 g (0.05 mol) of diethyl malonate
was added 13 g (0.1 mol) of K2CO3 and 10.2 g (0.1 mol)
We tried to replace K2CO3 by sodium methylate; the
reaction was performed both at room temperature and at
Scheme 2.
OH
C
(H3C)2C C(O)CH
OH
3 H3C
HO
CH3
CH3
K2CO3
COOC2H5 120_125oC
C
_
COOC2H5
COOC2H5
COOC2H5
CH3CH C
CH2CH C
_H2O
COOC2H5
CH C
H2C
COOC2H5
OH
CH3
CH3
CH3
CH3
H3C
H3C
H3C
H2O
_CO2
C
C
CH3
O
CH3
O
_H2O
COOC2H5
CH
C
HC
H
H
H
COOC2H5
CH(COOC2H5)2
H
CH2COOC2H5
XI
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008

AVETISYAN et al.
1080
of dimethylacetylcarbinol. The reaction mixture was
heated at 140–150°C for 10 h, on cooling it was acidified
with 10–15% hydrochloric acid till pH 3–4, and the
stirring was continued for 30 min more. The reaction
products were extracted into ether, and the extract was
dried with magnesium sulfate. After distilling off the
solvent the residue was distilled in a vacuum. We obtain-
ed 1.2 g (20%) of compound II, bp 81–83°C (2 mm Hg),
1.3 g (15%)of compound I, bp 127–129°C (2 mm Hg),
and 4.7 g (45%) of compound III, bp 160–165°C (2 mm
Hg), mp 113°C (from hexane). IR spectrum, cm–1: 1770
(C=O lact), 1660 (C=C). 1H NMR spectrum (DMSO-d),
δ, ppm: 1.10 s (12H), 1.60 d (3H, J 2 Hz), 2.2 d and
2.8 d (2H, J 18 Hz), 5.15 q (1H, J 2 Hz). Mass spectrum,
m/z (Irel, %): 210 (5) [M]+, 193 (3), 182 (11), 153 (22),
137 (14), 124 (100), 109 (94), 95 (10), 81 (16), 79 (13),
67 (16). Found, %: C 68.42; H 8.60. C12H19O3.
Calculated, %: C 68.57; H 8.57.
Physicochemical constants and spectra of compound
III obtained by procedures a–e were identical.
19-Methyl-7,15-dioxatrispiro[5.1.0.5.3.2]-
nonadec-18-en-16-one (VII). To 8.0 g (0.05 mol) of
diethyl malonate was added 13.0 g (0.1 mol) of K2CO3
and 14.4 g (0.1 mol) of 1-acetylcyclohexanol. The
reaction mixture was heated at 140–150°C for 10 h, on
cooling it was acidified with 10–15% hydrochloric acid
till pH 3–4, and the stirring was continued for 30 min
more. The reaction products were extracted into ether,
and the extract was dried with magnesium sulfate. After
distilling off the solvent the residue was distilled in
a vacuum. We obtained 1.9 g (24%) of 4-methyl-1-
oxaspiro[4.5]dec-3-en-2-one (VI), bp 98–100°C (1 mm
Hg), 1.3 g (12%) of ethyl 4-methyl-2-oxo-1-oxaspiro-
[4.5]dec-3-ene-3-carboxylate (V), bp 154–155°C (1 mm
Hg), and 5 g (35%) of compound VII, bp 220–225°C
(1 mm Hg, calc.), mp 97–98°C (from hexane). IR
spectrum, cm–1: 1770 (C=O lact), 1660 (C=C). 1H NMR
spectrum (DMSO-d), δ, ppm: 1.20–1.90 m (20H),
2.00 d (3H, J 2 Hz), 2.95 d (2H, J 8 Hz), 5.40 q (1H,
J 2 Hz). Mass spectrum, m/z (Irel, %): 290 (6) [M]+, 274
(3), 262 (10), 192 (25), 164 (100), 149 (45), 135 (11),
121 (93), 108 (93), 69 (95), 55 (44). Found, %: C 74.48;
H 8.96. C18H26O3. Calculated, %: C 74.48; H 8.96.
b. To 19.8 g (0.1 mol) of compound I was added 13.8 g
(0.1 mol) of K2CO3 and 12 g (0.1 mol) of dimethylacetyl-
carbinol. The reaction mixture was heated for 7–8 h, on
cooling it was acidified with diluted (1:1) hydrochloric
acid till pH 3–4, and the stirring was continued for
30 min more. The reaction products were extracted into
ether, and the extract was dried with magnesium sulfate.
After distilling off the solvent the residue was distilled
in a vacuum. Yield 50%.
2,3,6-Trimethyl-2,6-diphenyl-1,7-dioxaspiro-
[4.4]non-3-en-8-one (X). To 4.9 g (0.03 mol) of diethyl
malonate was added 8.4 g (0.06 mol) of K2CO3 and 10 g
(0.06 mol) of methylphenylacetylcarbinol. The reaction
mixture was heated at 140–150°C for 10 h, on cooling it
was acidified with 10–15% hydrochloric acid till pH 3–
4, and the stirring was continued for 30 min more. The
reaction products were extracted into ether, and the
extract was dried with magnesium sulfate.After distilling
off the solvent the residue was distilled in a vacuum. We
obtained 1.9 g (33%) of dimethyl-5-phenylfuran-2(5H)-
one (VIII), bp 145–147°C (2 mm Hg), nD20 1.5430, 0.5 g
(6%) of ethyl 4,5-dimethyl-2-oxo-5-phenyl-2,5-dihydro-
furan-3-carboxylate (IX), bp 175–177°C (2 mm Hg), nD20
1.5355, and 3 g (30%) of compound X, bp 220–222°C
(2 mm Hg), mp 159°C (from hexane). IR spectrum, cm–1:
3100 (=C–H), 1760 (C=O lact), 1660 (C=C), 950, 995
c. To 1.7 g (0.1 mol) of 4,5,5-trimethyl-2-oxo-2,5-di-
hydrofuran-3-carboxylic acid was added 13.8 g (0.1 mol)
of K2CO3 and 12 g (0.1 mol) of dimethylacetyl-carbinol.
After the treatment described in procedure b we obtained
0.4 g (2%) of compound III.
d. To methyl 4,5,5-trimethyl-2-oxo-2,5-dihydrofuran-
3-carboxylate (XII) was added K2CO3 and dimethyl-
acetylcarbinol in a ratio 1:1:1.5. The reaction mixture
was heated for 7 h at 180°, on cooling it was acidified
with diluted (1:1) hydrochloric acid. The reaction
products were extracted into ether, and the extract was
dried with magnesium sulfate. After distilling off the
solvent the residue was distilled in a vacuum. Yield 50%.
e. To 4,5,5-trimethyl-2-oxo-2,5-dihydrofuran-3-carbo-
nitrile (XIII) was added K2CO3 and dimethylacetyl-
carbinol in a ratio 1:1:1.5. The reaction mixture was
heated for 7 h at 180°, on cooling it was acidified with
diluted (1:1) hydrochloric acid. The reaction products
were extracted into ether, and the extract was dried with
magnesium sulfate. After distilling off the solvent the
residue was distilled in a vacuum. Yield 32%.
1
[δ(C–Harom)]. H NMR spectrum (DMSO-d), δ, ppm:
0.64 s (3H, CH3), 1.63 d (3H, =CCH3, J 1.5 Hz), 1.78 s
2
(3H, CH3), 2.55 d (1H, J 2 Hz) and 3.25 d (1H,CH,
2J 17.3 Hz), 5.77 q (1H, =CH, J 1.5 Hz), 7.14–7.38 m
(10H, C6H5). Found, %: C 79.45; H 6.41. C22H22O3.
Calculated, %: C 79.04; H 6.59.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008

SYNTHESIS OF HETEROSPIRANS CONTAINING A γ-LACTONE RING
1081
Ethyl 2-(4,5,5-trimethyl-2,5-dihydrofuran-2-
yl)acetate (XI). To 5.5 g (0.03 mol) of diethyl ethylidene-
malonate was added 4.1 g (0.03 mol) of K2CO3 and 3.6 g
(0.03 mol) of dimethylacetylcarbinol. The reaction mix-
ture was heated at 140–150°C for 10 h, on cooling it was
acidified with 10–15% hydrochloric acid till pH 3–4,
and the stirring was continued for 30 min more. The
reaction products were extracted into ether, and the
extract was dried with magnesium sulfate.After distilling
off the solvent the residue was distilled in a vacuum.
Yield 3.7 g (64%), bp 155–160°C (20 mm Hg), nD20
2.5010. IR spectrum, cm–1: 1725 (C=O ester), 1630
magnesium sulfate. After distilling off the solvent the
residue was distilled in a vacuum. Yield 43%, bp 135–
138°C (2–3 mm Hg), mp 47–48°C (from hexane). IR
spectrum, cm–1: 1780 (C=O lact.), 1730 (C=O ester),
1640 (C=C), 1250 (C–O–C). Found, %: C 58.61; H 6.45.
C9H12O4. Calculated, %: C 58.69; H 6.52.
REFERENCES
1. Avetisyan, A.A. and Dangyan, M.T., Usp. Khim., 1977,
vol. 46, p. 1250.
2. Avetisyan, A.A., Tatevosyan, G.E., Mangasaryan, Ts.E.,
Matsoyan, S.G., and Dangyan, M.T., Zh. Org. Khim., 1970,
vol. 6, p. 962.
3. Avetisyan, A.A., Ovsepyan, V.V., and Tokmadzhyan, G.G.,
Khim. Geterotsikl. Soedin., 1986, p. 1426.
4. Avetisyan, A.A. and Tokmadzhyan, G.G., Arm. Khim. Zh.,
1993, p. 219.
5. Avchibasi, H., Anil, H., and Toprak, M., Phytochem., 1987,
vol. 26, p. 2852.
1
(C=C), 950, 995 [δ(C–Harom)]. H NMR spectrum
(DMSO-d), δ, ppm: 0.95–1.25 m (9H), 2.00–2.25 m (6H),
4.10 q (2H, J 5.5 Hz), 5.60–5.75 m (4H). Found, %:
C 67.50; H 7.55. C11H18O3. Calculated, %: C 67.69; H 7.69.
Methyl 4,5,5-trimethyl-2-oxo-2,5-dihydrofuran-3-
carboxylate (XII). To a solution of sodium methylate in
anhydrous methanol was added first compound I and then
dropwise dimethylacetylcarbinol. The reaction mixture
was stirred at 80–85°C for 12 h (or the mixture was left
standing at room temperature for 18 h). Then the reaction
mixture was acidified with 10% acetic acid, the products
were extracted with ether, and the extract was dried with
6. Itakava, H., Morita, H., Osava, K., Watanabe, K., and Ita-
ka, Y., Chem. Pharm. Bull., 1987, vol. 35, p. 2849.
7. Yamasaki, M., Okuyama, E., and Macbagashi, Y., Chem.
Pharm. Bull., 1979, vol. 27, p. 1611.
8. Knoevenagel, E., Ber., 1898, vol. 31, p. 2585.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 7 2008