Synthesis and some transformations of bicyclic γ-lactones with a fused cyclopropane ring

Article abstract of DOI:10.1134/S1070428008120129

Reductive cyclization of 4-hydroxymethyl-5,5-dimethyl(or pentamethylene)-2,5-dihydrofuran-2-ones by the action of sodium tetrahydridoborate gave bicyclic compounds in which the lactone ring is fused to a cyclopropane ring. Hydrolysis of the products with aqueous sodium hydroxide resulted in the formation of the corresponding disodium cyclopropane-1,1- dicarboxylates, which reacted with alkyl halides to produce the diesters. Acid hydrolysis of the fused systems was accompanied by opening of the cyclopropane ring with formation of 4-chloromethyl-5,5-dimethyl-2-oxotetrahydrofuran-3- carboxylic acid.

Full text of DOI:10.1134/S1070428008120129

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 12, pp. 1795–1798. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © A.A. Avetisyan, G.G. Tokmadzhyan, L.V. Karapetyan, L.S. Balayan, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol.
44, No. 12, pp. 1822–1825.
Synthesis and Some Transformations of Bicyclic γ-Lactones with
a Fused Cyclopropane Ring
A. A. Avetisyan, G. G. Tokmadzhyan, L. V. Karapetyan, and L. S. Balayan
Erevan State University, ul. Aleka Manukyana 1, Erevan, 375025 Armenia
e-mail: tokmajyang@yahoo.com
Received November 12, 2007
Abstract—Reductive cyclization of 4-hydroxymethyl-5,5-dimethyl(or pentamethylene)-2,5-dihydrofuran-2-
ones by the action of sodium tetrahydridoborate gave bicyclic compounds in which the lactone ring is fused to
a cyclopropane ring. Hydrolysis of the products with aqueous sodium hydroxide resulted in the formation of
the corresponding disodium cyclopropane-1,1-dicarboxylates, which reacted with alkyl halides to produce the
diesters. Acid hydrolysis of the fused systems was accompanied by opening of the cyclopropane ring with
formation of 4-chloromethyl-5,5-dimethyl-2-oxotetrahydrofuran-3-carboxylic acid.
DOI: 10.1134/S1070428008120129
Functionally substituted cyclopropane derivatives,
as well as derivatives of saturated γ-lactones, are wide-
spread in nature, and they often exhibit pronounced
biological activity. Apart from monocyclic cyclopro-
pane derivatives, fused bicyclic terpenes containing
a cyclopropane ring, derivatives of carane and carene
[1], thujane and thujene [2], etc., are encountered in
nature. Therefore, synthesis of systems including both
γ-lactone and cyclopropane ring is important.
oxabicyclo[3.1.0]hexane-1-carboxylates Ia and Ib or
the corresponding carboxylic acids Ic and Id rather
than expected saturated γ-butyrolactones (Scheme 1).
The product structure was determined on the basis of
1
their IR, H and 13C NMR, and mass spectra, which
unambiguously showed that the lactone ring in Ia–Id is
fused to a cyclopropane ring, i.e., the reaction was sim-
ilar to that observed for the corresponding 4-bromo-
methyl derivatives. Presumably, initial attack by hy-
dride ion at the activated (electrophilic) β-carbon atom
in 4-hydroxymethyl derivatives gives intermediate
carbanion with localization of the negative charge on
the α-carbon atom (with respect to the carbonyl group),
and the intermediate is stabilized by intramolecular
nucleophilic cyclization.
We previously patented a procedure for the syn-
thesis of bicyclic lactones containing a cyclopropane
ring via reductive cyclization of 5,5-dialkyl(or poly-
methylene)-4-bromomethyl-2-oxo-2,5-dihydrofuran-3-
carboxylic acids or their esters by the action of sodium
tetrahydridoborate [3]. While studying selective hydro-
genation of the endocyclic double bond in 5,5-dialkyl-
(or pentamethylene)-4-hydroxymethyl-2-oxo-2,5-dihy-
drofuran-3-carboxylic acids or their esters [4] with
NaBH4 in tetrahydrofuran we found that the products
were ethyl 4,4-dimethyl(or pentamethylene)-2-oxo-3-
Thus we were the first to obtain bicyclic systems
consisting of cyclopropane and γ-lactone rings by
reductive cyclization of hydroxymethyl-substituted
butenolides. The products may be used as initial com-
pounds for the synthesis of functionally substituted
Scheme 1.
OH
OH
R1
R1
R1
H–
–OH–
R2
R3
R2
R3
R2
R3
O
O
O
NaBH3
O
O
O
Ia–Id
R1 = EtOCO (a, b), HOCO (c, d); R2 = R3 = Me (a, c), R2R3 = (CH2)5 (b, d).
1795

AVETISYAN et al.
1796
cyclopropane derivatives. Taking into account that
γ-lactone ring is unstable in alkaline medium, com-
pounds Ia and Ib were subjected to alkaline hydrolysis
by heating in aqueous sodium hydroxide; as a result,
the corresponding disodium cyclopropane-1,1-dicar-
boxylates IIa and IIb were formed (Scheme 2).
hydrolysis of compound Ia in the presence of hydro-
chloric acid was accompanied by opening of the cyclo-
propane ring with formation of 4-chloromethyl-5,5-
dimethyl-2-oxotetrahydrofuran-3-carboxylic acid (IV)
(Scheme 5).
EXPERIMENTAL
Scheme 2.
R1
The IR spectra were recorded on a Specord 75IR
spectrometer from samples dispersed in mineral oil.
COONa
NaOH
R2
HO
1
The H and 13C NMR spectra were measured on
Ia, Ib
COONa
1
a Varian Mercury 300 instrument (300 MHz for H)
IIa, IIb
relative to tetramethylsilane as internal reference using
DMSO-d6–CCl4 (1:3) as solvent. The mass spectrum
of compound Ia (electron impact, 50–70 eV) was
obtained on an MKh-1321A instrument with direct
sample admission into the ion source. The purity of the
products was checked by TLC on Silufol UV-254
plates using acetone–benzene (1:2) as eluent; spots
were visualized by treatment with iodine vapor or
under UV light.
R1 = R2 = Me (a), R1R2 = (CH2)5 (b).
However, our attempt to convert salts IIa and IIb
into the diacids resulted in closure of cyclopropane
ring with formation of initial bicyclic systems Ic and
Id (Scheme 3).
Scheme 3.
R1
Ethyl 4,4-dimethyl(or pentamethylene)-2-oxo-3-
oxabicyclo[3.1.0]hexane-1-carboxylates Ia and Ib
and 4,4-dimethyl(or pentamethylene)-2-oxo-3-oxa-
bicyclo[3.1.0]hexane-1-carboxylic acids Ic and Id
(general procedure). Sodium tetrahydridoborate,
0.19 g (5 mmol), was added in small portions to a solu-
tion of 3 mmol of the corresponding hydroxymethyl-
substituted γ-butyrolactone in a mixture of 5 ml of
tetrahydrofuran and 1 ml of water. The mixture was
stirred for 3 h at room temperature, acidified to pH 3
with dilute (1:1) hydrochloric acid, and extracted with
chloroform. The extract was dried over magnesium
sulfate, and the solvent was distilled off to isolate com-
pound Ia–Id as a crystalline substance.
COOH
R2
HO
COOH
H+, H2O
IIa, IIb
COOH
O
R1
R2
O
Ic, Id
Disodium salts IIa and IIb were converted into
diethyl and dipropyl esters IIIa–IIId by treatment with
2 equiv of ethyl or propyl bromide (Scheme 4). Acid
Scheme 4.
Ethyl 4,4-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hex-
ane-1-carboxylate (Ia). Yield 0.5 g (84%), mp 78°C
(from hexane), Rf 0.56. IR spectrum, ν, cm–1: 1740
(C=O, ester), 1780 (C=O, lactone). 1H NMR spectrum,
δ, ppm: 1.31 t (3H, CH2CH3, J = 7.1 Hz), 1.39 s and
1.50 s (3H each, CH3), 1.44 d and 1.46 d (1H, CH2, J =
5.4, 4.9 Hz), 1.83 d and 1.85 d (1H, CH2, J = 8.1,
4.9 Hz), 2.55 d and 2.58 d (1H, CH, J = 8.1, 5.4 Hz),
4.27 q (2H, OCH2, J = 7.5 Hz). 13C NMR spectrum,
δC, ppm: 13.63 (CH3), 23.22 and 28.62 (CH3), 18.14
(CH2), 36.24 (CH), 39.79 (C), 60.61 (OCH2), 79.81
(C4), 165.58 and 16.793 (C=O). Mass spectrum, m/z
(Irel, %): 198 (10), 184 (11), 183 (100), 155 (13), 139
(11), 81 (10), 43 (44). Found, %: C 60.54; H 7.00.
C10H14O4. Calculated, %: C 60.60; H 7.07.
R1
COOR3
COOR3
2R3Br
R2
HO
IIa, IIb
–2NaBr
IIIa–IIId
R1 = R2 = Me (a, c), R1R2 = (CH2)5 (b, d);
R3 = Et (a, b), Pr (c, d).
Scheme 5.
Cl
COOH
O
COOEt
HCl
Me
Me
Me
Me
O
O
O
Ia
IV
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

SYNTHESIS AND SOME TRANSFORMATIONS OF BICYCLIC γ-LACTONES
1797
(1H, CH, J = 8.1, 5.4 Hz). Found, %: C 41.52; H 4.42.
C8H10Na2O5. Calculated, %: C 41.38; H 4.31.
Ethyl 4-oxo-3-oxaspiro[bicyclo[3.1.0]hexane-
2,1′-cyclohexane]-5-carboxylate (Ib). Yield 0.54 g
(75%), mp 79°C (from hexane), Rf 0.54. IR spectrum,
ν, cm–1: 1740 (C=O, ester), 1780 (C=O, lactone).
1H NMR spectrum, δ, ppm: 1.3 t (3H, CH2CH3, J =
7.1 Hz), 1.43 d and 1.45 d (1H, CH2, J = 5.4, 4.9 Hz),
1.6–1.9 m (10H, CH2), 1.83 d and 1.85 d (1H, CH2, J =
8.1, 4.9 Hz), 2.55 d and 2.58 d (1H, CH, J = 8.1,
5.4 Hz), 4.2 q (2H, OCH2, J = 7.5 Hz). 13C NMR spec-
trum, δC, ppm: 23.34 and 28.69 (CH3), 18.08 (CH2),
36.25 (CH), 39.78 (C), 79.64 (Cspiro), 167.28 and
168.63 (C=O). Found, %: C 65.51; H 7.53. C13H18O4.
Calculated, %: C 65.55; H 7.56.
Disodium 2-(1-hydroxycyclohexyl)cyclopropane-
1,1-dicarboxylate (IIb). Yield 0.5 g (73%). IR spec-
trum, ν, cm–1: 1740 (C=O), 3600 (OH). 1H NMR spec-
trum, δ, ppm: 1.2 d and 1.2 d (1H, CH2, J = 5.4,
4.9 Hz), 1.3 d and 1.34 d (1H, CH2, J = 8.1, 4.9 Hz),
1.62–1.9 m (10H, CH2), 2.0 d and 2.2 d (1H, CH, J =
8.1, 5.4 Hz) Found, %: C 48.63; H 5.28. C11H14Na2O5.
Calculated, %: C 48.52; H 5.14.
Dialkyl 2-(1-hydroxy-1-methylethyl)- and
2-(1-hydroxycyclohexyl)cyclopropane-1,1-dicarbox-
ylates IIIa–IIId (general procedure). A mixture of
0.01 mol of disodium salt IIa or IIb and 0.02 mol of
ethyl or propyl bromide in 55 ml of dimethylform-
amide was heated for 3 h at 90–100°C. The solvent
was distilled off under reduced pressure, the residue
was treated with water and extracted with diethyl ether,
the extract was dried over magnesium sulfate, the
solvent was distilled off, and the residue was distilled
under reduced pressure.
4,4-Dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane-1-
carboxylic acid (Ic). Yield 0.35 g (69%), mp 105°C
(from hexane), Rf 0.59. IR spectrum, ν, cm–1: 1730
(C=O, acid), 1770 (C=O, lactone), 2700 (OH, assoc.).
1H NMR spectrum, δ, ppm: 1.36 s and 1.50 s (3H each,
CH3), 1.44 d and 1.46 d (1H, CH2, J = 5.4, 4.8 Hz),
1.83 d and 1.85 d (1H, CH2, J = 8.1, 4.8 Hz), 2.55 d
and 2.58 d (1H, CH, J = 8.1, 5.4 Hz), 12.40 br (1H,
COOH). Found, %: C 56.42; H 5.82. C8H10O4. Calcu-
lated, %: C 56.47; H 5.88.
Diethyl 2-(1-hydroxy-1-methylethyl)cyclopro-
pane-1,1-dicarboxylate (IIIa). Yield 0.35 g (56%),
bp 70–72°C (5 mm), nD20 = 1.4600. IR spectrum, ν, cm–1:
4-Oxo-3-oxaspiro[bicyclo[3.1.0]hexane-2,1′-cyclo-
hexane]-5-carboxylic acid (Id). Yield 0.40 g (64%),
mp 145–146°C (from petroleum ether), Rf 0.58. IR
spectrum, ν, cm–1: 1740 (C=O, acid), 1780 (C=O,
1
1740 (C=O), 3600 (OH). H NMR spectrum, δ, ppm:
1.30 t (6H, CH2CH3, J = 7.4 Hz), 1.44 d and 1.46 d
(1H, CH, J = 5.4, 4.9 Hz), 1.38 s and 1.50 s (3H each,
CH3), 1.82 d and 1.86 d (1H, CH, J = 8.1, 4.9 Hz),
2.55 d and 2.60 d (1H, CH2, J = 8.1, 5.4 Hz), 4.20 q
(2H, OCH2, J = 7.5 Hz). Found, %: C 59.22; H 8.11.
C12H20O5. Calculated, %: C 59.02; H 8.20.
1
lactone), 2700 (OH, assoc.). H NMR spectrum, δ,
ppm: 1.43 d and 1.45 d (1H, CH2, J = 5.4, 4.9 Hz),
1.6–1.9 m (10H, CH2), 1.83 d and 1.85 d (1H, CH2,
J = 8.1, 4.9 Hz), 2.55 d and 2.58 d (1H, CH, J = 8.1,
5.4 Hz), 12.40 br (1H, COOH). Found, %: C 62.52;
H 6.62. C11H14O4. Calculated, %: 62.86; H 6.67.
Diethyl 2-(1-hydroxycyclohexyl)cyclopropane-
1,1-dicarboxylate (IIIb). Yield 1.5 g (53%), bp 93–
96°C (5 mm), nD20 = 1.4610. IR spectrum, ν, cm–1: 1740
1
Disodium 2-(1-hydroxy-1-methylethyl)- and
2-(1-hydroxycyclohexyl)cyclopropane-1,1-dicarbox-
ylates IIa and IIb (general procedure). A mixture of
2.5 mmol of compound Ia and Ib and 6 ml of an aque-
ous solution of 0.2 g (5 mmol) of sodium hydroxide
was heated for 4 h at 75°C. Water was removed from
the reaction mixture under reduced pressure, and di-
sodium salts IIa and IIb were isolated as colorless
crystalline substances which were washed with cold
acetone.
(C=O), 3600 (OH). H NMR spectrum, δ, ppm: 1.0 t
(6H, CH2CH3, J = 7.1 Hz), 1.2 d and 1.22 d (1H, CH2,
J = 5.4, 4.9 Hz), 1.30 d and 1.34 d (1H, CH2, J = 5.4,
4.9 Hz), 1.6–1.9 m (10H, CH2), 2.0–2.2 d (1H, CH, J =
8.1, 5.4 Hz), 4.25 q (4H, OCH2, J = 7.5 Hz). Found,
%: C 63.45; H 8.71. C15H24O5. Calculated, %: C 63.38;
H 8.45.
Dipropyl 2-(1-hydroxy-1-methylethyl)cyclopro-
pane-1,1-dicarboxylate (IIIc). Yield 0.4 g (55%),
bp 92–95°C (5 mm), nD20 = 1.4640. IR spectrum, ν, cm–1:
1
Disodium 2-(1-hydroxy-1-methylethyl)cyclopro-
1740 (C=O), 3600 (OH). H NMR spectrum, δ, ppm:
pane-1,1-dicarboxylate (IIa). Yield 0.45 g (77%). IR
0.99 t (6H, CH2CH2CH3, J = 7.1 Hz), 1.39 s and 1.50 s
(3H each, CH3), 1.44 d and 1.46 d (1H, CH2, J = 5.4,
4.9 Hz), 1.83 d and 1.85 d (1H, CH2, J = 8.1, 4.9 Hz),
2.55 d and 2.58 d (1H, CH, J = 8.1, 5.4 Hz), 1.7–1.8 m
1
spectrum, ν, cm–1: 1740 (C=O), 3600 (OH). H NMR
spectrum, δ, ppm: 1.2 d and 1.22 d (1H, CH2, J = 5.4,
4.9 Hz), 1.32 d and 1.34 d (1H, CH2, J = 8.1, 4.9 Hz),
1.39 s and 1.46 s (3H each, CH3), 1.79 d and 1.82 d
(
4H, CH2CH2CH3) 4.25 t (4H, OCH2, J = 7.1 Hz).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

AVETISYAN et al.
1798
Found, %: C 61.82; H 8.85. C14H24O5. Calculated, %:
C 61.76; H 8.82.
3.76 d (1H, 3-H, J = 11.5 Hz), 12.86 br.s (1H, COOH).
13C NMR spectrum, δC, ppm: 21.599 and 28.187 (CH3),
41.543 (CH2), 50.255 (CH), 50.946 (CH), 83.546 (C5),
167.956 (C=O), 168.62 (C=O). Found, %: C 56.24;
H 6.41; Cl 20.50. C8H11ClO4. Calculated, %: C 56.14;
H 6.43; Cl 20.76.
Dipropyl 2-(1-hydroxycyclohexyl)cyclopropane-
1,1-dicarboxylate (IIId). Yield 1.75 g (56%), bp 180–
181°C (5 mm), nD20 = 1.4850. IR spectrum, ν, cm–1:
1740 (C=O), 3600 (OH). 1H NMR spectrum, δ, ppm:
0.99 t (6H, CH2CH2CH3, J = 7.4 Hz), 1.43 d and
1.45 d (1H, CH2, J = 5.4, 4.9 Hz), 1.6–1.9 m (14H,
CH2CH2CH3, CH2), 1.83 d and 1.85 d (1H, CH2, J =
8.1, 4.9 Hz), 2.55 d and 2.58 d (1H, CH, J = 8.1,
5.4 Hz), 4.25 t (2H, OCH2, J = 7.4 Hz). Found, %:
C 65.45; H 8.92. C17H28O5. Calculated, %: C 65.38;
H 8.97.
This study was performed in the framework of the
State Program “Synthesis of Compounds Possessing
New Properties on the Basis of Armenian Raw Mate-
rials” (project no. 041027).
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furan-3-carboxylic acid (IV). A mixture of 0.49 g
(2.5 mmol) of compound Ia and 10 ml of 10% hydro-
chloric acid was heated for 10 h at 70°C. Excess hy-
drochloric acid was distilled off under reduced pres-
sure. Yield 0.31 g (60%), mp 145°C (from xylene). IR
spectrum, ν, cm–1: 1735 (C=O, acid), 1775 (C=O,
1
lactone), 2600 (OH, assoc.). H NMR spectrum, δ,
ppm: 1.38 s and 1.58 s (3H each, CH3), 2.98 d.t (1H,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008