Synthesis of substituted methyl 5,5-polymethylene-2,4-dioxotetrahydropyran- 3-carboxylates

Article abstract of DOI:10.1134/S1070428010030115

Dimethyl 2-(1-bromocyclohexylcarbonyl)-, 2-(1-bromocyclopentylcarbonyl)-, and 2-(1-bromocyclobutylcarbonyl)-2-methylmalonates reacted with zinc and aromatic aldehydes to give the corresponding methyl 1-aryl-4-methyl-3,5-dioxo-2- oxaspiro[5.5]undecane-4-,

Full text of DOI:10.1134/S1070428010030115

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 3, pp. 368–371. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © N.F. Kirillov, V.S. Melekhin, S.N. Shurov, A.V. Plotnikov, M.I. Vakhrin, O.A. Maiorova, 2010, published in Zhurnal Organicheskoi
Khimii, 2010, Vol. 46, No. 3, pp. 375–378.
Synthesis of Substituted Methyl 5,5-Polymethylene-
2,4-dioxotetrahydropyran-3-carboxylates
N. F. Kirillova, V. S. Melekhina, S. N. Shurova, A. V. Plotnikova,
M. I. Vakhrina, and O. A. Maiorovab
a Perm State University, ul. Bukireva 15, Perm, 614990 Russia
e-mail: kirillov@psu.ru
b Institute of Technical Chemistry, Ural Division, Russian Academy of Sciences, Perm, Russia
Received February 4, 2009
Abstract—Dimethyl 2-(1-bromocyclohexylcarbonyl)-, 2-(1-bromocyclopentylcarbonyl)-, and 2-(1-bromo-
cyclobutylcarbonyl)-2-methylmalonates reacted with zinc and aromatic aldehydes to give the corresponding
methyl 1-aryl-4-methyl-3,5-dioxo-2-oxaspiro[5.5]undecane-4-, 6-aryl-9-methyl-8,10-dioxo-7-oxaspiro[4.5]-
decane-9-, and 5-aryl-8-methyl-7,9-dioxo-6-oxaspiro[3.5]nonane-8-carboxylates.
DOI: 10.1134/S1070428010030115
We found previously [1] that dialkyl 2-(2-bromo-
isobutyryl)malonates react with zinc and aldehydes to
give the corresponding alkyl 2,4-dioxotetrahydropyr-
an-3-carboxylates [1]. In the present communication
we report on the synthesis of analogous compounds
having a spiro carbon atom. The reactions of dimethyl
2-bromo-2-methylmalonate with zinc and cyclohex-
ane-, cyclopentane-, and cyclobutanecarbonyl chlo-
rides gave dimethyl 2-cycloalkylcarbonyl-2-methyl-
malonates I–III which were subjected to bromination
with molecular bromine to obtain bromo derivatives
IV–VI. The latter reacted with zinc yielding zinc
enolates VII–IX which added at the carbonyl group of
aromatic aldehydes with formation of alkoxides X–
XII. Intramolecular cyclization of X–XII with elimi-
nation of MeOBrZn resulted in the formation of meth-
yl 1-aryl-4-methyl-3,5-dioxo-2-oxaspiro[5.5]undecane-
4-carboxylates XIIIa–XIIId, methyl 6-aryl-9-methyl-
8,10-dioxo-7-oxaspiro[4.5]decane-9-carboxylates
XIVa and XIVb, and 5-aryl-8-methyl-7,9-dioxo-6-
oxaspiro[3.5]nonane-8-carboxylates XVa and XVb
(Scheme 1).
The structure of the isolated compounds was con-
firmed by their elemental compositions and IR and
1H NMR spectra. In the IR spectra of XIII–XV, ab-
sorption bands belonging to stretching vibrations of
Scheme 1.
Me
Me
COOMe
COOMe
COOMe
COOMe
Br
O
Me
O
Br
( )n
Zn
Br2
MeO
OMe
Me
+
COCl
–HBr
( )n
( )n
O
O
I–III
IV–VI
O
COOMe
Me
BrZnO
Ar
O
COOMe
COOMe
COOMe
Me
Zn
ArCHO
( )n
Ar
–MeOZnBr
COOMe
( )n
( )n
O
O
OZnBr
VII–IX
Xa–Xd, XIa, XIb, XIIa, XIIb
XIIIa–XIIId, XIVa, XIVb, XVa, XVb
I, IV, VII, X, XIII, n = 3; II, V, VIII, XI, XIV, n = 2; III, VI, IX, XII, XV, n = 1; X–XV, Ar = 4-BrC6H4 (a), 4-ClC6H4 (b);
X, XIII, Ar = Ph (c), 4-MeOC6H4 (d).
368

SYNTHESIS OF SUBSTITUTED METHYL 5,5-POLYMETHYLENE-2,4-DIOXO...
369
ketone (1695–1710 cm–1), ester (1720–1730 cm–1), and
lactone carbonyl groups (1730–1760 cm–1) were pres-
ent. The H NMR spectra of XIII–XV contained only
one set of signals, the most characteristic signal being
that of the ArCH proton (δ 5.82–5.93 ppm).
data. The results of ROESY and NOESY experiments
indicated coupling of the ArCH proton with protons in
the methyl group, and the HMBC data revealed inter-
action of the same proton with the methyl carbon atom.
These findings suggest that the methyl group and
ArCH hydrogen atom in molecule XIIIc are located at
the same side of the tetrahydropyran ring (structure A).
1
Theoretically, compounds XIII–XV may exist as
four diastereoisomers differing by configuration of
substituents on C3 and C6 in the pyran ring. Structures
of diastereoisomers A–D of compound XIIIc are
shown below; the corresponding total energies are also
given. With a view to determine which of the above
diastereoisomers is the most stable, their structures
were analyzed by nonempirical quantum-chemical cal-
culations usng 6-31(d) basis set with full geometry
optimization. The results showed that isomers C and D
are the least stable, so that their formation is likely to
be improbable. Diastereoisomers A and B are charac-
terized by similar energies; therefore, their stabilities
should be comparable, though structure A is formally
more stable. The C6–Ph bond in stereoisomer A is
equatorial, the 6-H proton and protons in the 3-CH3
group appear spatially close, and the calculated dis-
tance 6-H···H–CH2–C3 is 2.271 Å. The corresponding
fragments in stereoisomer B are distant from each
other. The tetrahydropyran ring in isomer A has
a flattened chair conformation: the C6, O1, C2, and C3
atoms lie almost in one plane, while the C4 and C5
atoms deviate from that plane by 0.678 and 1.048 Å,
respectively. The cyclohexane ring has a chair con-
formation, and the C5–C4 bond in the tetrahydropyran
ring occupies equatorial position in the cyclohexane
ring. The steric structure of compound XIIIc was
EXPERIMENTAL
The IR spectra of compounds I–VI and XIII–XV
were recorded on a Specord 75IR spectrophotometer
1
13
from samples dispersed in mineral oil. The H and C
NMR spectra were measured on a Varian Mercury
Plus-300 instrument (300 MHz) using tetramethyl-
silane as internal reference and CDCl3 (I–VI, XVb) or
DMSO-d6 as solvent (XIIIa–XIIId, XIVa, XIVb,
XVa). Quantum-chemical calculations were performed
using Gaussian-03w software package [2].
Dimethyl 2-(cyclohexylcarbonyl)-2-methylmalo-
nate (I). A mixture of 0.11 mol (24.8 g) of dimethyl
2-bromo-2-methylmalonate and 0.1 mol (14.7 g) of
cyclohexanecarbonyl chloride in 10 ml of ethyl acetate
was added dropwise under stirring to a mixture of 15 g
of fine zinc turnings, a catalytic amount of mercury(II)
chloride, and 80 ml of anhydrous ethyl acetate–diethyl
ether (1:1). The mixture was heated for 2 h under
reflux and cooled, the liquid phase was separated from
excess zinc by decanting and hydrolyzed with
5% acetic acid, the organic phase was separated, the
aqueous phase was extracted with two portions of ethyl
acetate, and the extracts were combined with the or-
ganic phase, washed with water, dried over anhydrous
sodium sulfate, and evaporated. The residue was twice
distilled under reduced pressure. Yield 14.1 g (55%),
bp 136–138°C (3 mm), d420 = 1.1149, nD20 = 1.4641. IR
1
studied in detail by H and 13C NMR spectroscopy,
including two-dimensional experiments (1H–1H COSY,
1
1
1H–1H NOESY, H–13C HSQC, H–1H ROESY,
1H–13C HMBC). Signals from carbon atoms were as-
signed on the basis of the DEPT, HMBC, and HSQC
1
spectrum, ν, cm–1: 1725, 1705 (C=O). H NMR spec-
trum, δ, ppm: 1.10–1.93 m (10H, CH2), 1.63 s (3H,
Me), 2.48–2.82 m (1H, CHCO), 3.74 s (6H, MeO).
Found, %: C 61.11; H 7.72. C13H20O5. Calculated, %:
C 60.92; H 7.87.
MeOCO
Me
COOMe
O
Me
O
O
H
H
O
O
O
Ph
Ph
Dimethyl 2-(cyclopentylcarbonyl)-2-methylmalo-
nate (II) was synthesized in a similar way from di-
methyl 2-bromo-2-methylmalonate and cyclopentane-
carbonyl chloride. Yield 11.4 g (47%), bp 163–165°C
(20 mm), d420 = 1.1177, nD20 = 1.4556. IR spectrum, ν,
A
B
–2913889.94 kJ/mol
–2913888.89 kJ/mol
MeOCO
Me
Ph
COOMe
Me
O
O
Ph
O
O
1
cm–1: 1725, 1705 (C=O). H NMR spectrum, δ, ppm:
O
H
O
H
1.40–1.95 m (8H, CH2), 1.66 s (3H, Me), 3.40–3.50 m
(1H, CHCO), 3.79 s (6H, MeO). Found, %: C 59.62;
H 7.61. C12H18O5. Calculated, %: C 59.49; H 7.49.
C
D
–2913882.83 kJ/mol
–2913878.09 kJ/mol
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 3 2010

KIRILLOV et al.
370
Dimethyl 2-(cyclobutylcarbonyl)-2-methylmalo-
was extracted with two portions of ethyl acetate, the
extracts were combined with the organic phase and
dried over anhydrous sodium sulfate, the solvent was
distilled off, and the residue was recrystallized from
methanol.
nate (III) was synthesized in a similar way from di-
methyl 2-bromo-2-methylmalonate and cyclobutane-
carbonyl chloride. Yield 15.1 g (66%), bp 154–156°C
(25 mm), d420 = 1.1368, nD20 = 1.4548. IR spectrum, ν,
1
cm–1: 1725, 1710 (C=O). H NMR spectrum, δ, ppm:
Methyl 1-(4-bromophenyl)-4-methyl-3,5-dioxo-2-
oxaspiro[5.5]undecane-4-carboxylate (XIIIa). Yield
1.83 g (64%), mp 184–185°C. IR spectrum, ν, cm–1:
1.61 s (3H, Me), 1.80–2.40 m (6H, CH2), 3.52–3.63 m
(1H, CHCO), 3.78 s (6H, MeO). Found, %: C 58.02;
H 6.95. C11H16O5. Calculated, %: C 57.88; H 7.07.
1
1740, 1725, 1700 (C=O). H NMR spectrum, δ, ppm:
Dimethyl 2-(1-bromocyclohexylcarbonyl)-2-
methylmalonate (IV). Bromine, 0.055 mol (8.8 g,
2.8 ml), was added under stirring to a solution of
0.05 mol (12.8 g) of compound I in 30 ml of acetic
acid, the mixture was heated for 1 h on a water bath,
acetic acid and excess bromine were distilled off, and
the product was distilled under reduced pressure. Yield
9.6 g (57%), bp 173–175°C (3 mm), mp 74–75°C
(from hexane). IR spectrum, ν, cm–1: 1725, 1710
(C=O). 1H NMR spectrum, δ, ppm: 1.50–2.30 m (10H,
CH2), 1.86 s (3H, Me), 3.74 s (6H, MeO). Found, %:
C 46.73; H 5.89; Br 23.66. C13H19BrO5. Calculated, %:
C 46.58; H 5.71; Br 23.84.
0.60–2.10 m (10H, CH2), 1.74 s (3H, Me), 3.71 s (3H,
MeO), 5.92 s (1H, CHO), 7.37 d and 7.67 d (2H each,
C6H4, J = 8.4 Hz). Found, %: C 55.58; H 5.35;
Br 19.77. C19H21BrO5. Calculated, %: C 55.76; H 5.17;
Br 19.52.
Methyl 1-(4-chlorophenyl)-4-methyl-3,5-dioxo-2-
oxaspiro[5.5]undecane-4-carboxylate (XIIIb). Yield
1.38 g (54%), mp 171–172°C. IR spectrum, ν, cm–1:
1
1745, 1725, 1700 (C=O). H NMR spectrum, δ, ppm:
0.60–2.10 m (10H, CH2), 1.74 s (3H, Me), 3.71 s (3H,
MeO), 5.93 s (1H, CHO), 7.43 d and 7.53 d (2H each,
ClC6H4, J = 8.7 Hz). Found, %: C 62.37; H 5.98;
Cl 9.60. C19H21ClO5. Calculated, %: C 62.55; H 5.80;
Cl 9.72.
Dimethyl 2-(1-bromocyclopentylcarbonyl)-2-
methylmalonate (V) was synthesized in a similar way
from compound II. Yield 8.7 g (54%), bp 161–163°C
(4 mm), d420 = 1.3830, nD201 = 1.4854. IR spectrum, ν,
cm–1: 1735, 1710 (C=O). H NMR spectrum, δ, ppm:
1.80–2.45 m (8H, CH2), 1.87 s (3H, Me), 3.80 s (6H,
MeO). Found, %: C 45.10; H 5.48; Br 24.59.
C12H17BrO5. Calculated, %: C 44.88; H 5.34; Br 24.88.
Methyl 4-methyl-3,5-dioxo-1-phenyl-2-oxaspiro-
[5.5]undecane-4-carboxylate (XIIIc). Yield 1.30 g
(56%), mp 164–165°C. IR spectrum, ν, cm–1: 1735,
1
1725, 1695 (C=O). H NMR spectrum, δ, ppm: 0.60–
2.10 m (10H, CH2), 1.74 s (3H, Me), 3.71 s (3H,
MeO), 5.89 s (1H, CHO), 7.38–7.50 m (5H, Ph).
13C NMR spectrum, δC, ppm: 20.35 (CH3); 20.48,
21.23, 23.55, 24.70, 28.51 (C7–C11), 49.88 (C6), 53.25
(CH3O), 61.79 (C4), 81.70 (C1), 127.87 (Cm), 128.54
Co), 128.84 (Cp), 133.44 (Ci), 166.75 (COO), 168.89
(C3), 205.08 (C5). Found, %: C 68.83; H 6.89.
C19H22O5. Calculated, %: C 69.07; H 6.71.
Dimethyl 2-(1-bromocyclobutylcarbonyl)-2-
methylmalonate (VI) was synthesized in a similar
way from compound III. Yield 12.0 g (78%), bp 158–
160°C (6 mm), d420 = 1.4131, nD20 = 1.4845. IR spec-
1
trum, ν, cm–1: 1740, 1715 (C=O). H NMR spectrum,
δ, ppm: 1.83 s (3H, Me), 1.85–3.12 m (6H, CH2), 3.80 s
(6H, MeO). Found, %: C 43.28; H 4.99; Br 25.84.
C11H15BrO5. Calculated, %: C 43.02; H 4.92; Br 26.02.
Methyl 1-(4-methoxyphenyl)-4-methyl-3,5-di-
oxo-2-oxaspiro[5.5]undecane-4-carboxylate (XIIId).
Yield 1.08 g (43%), mp 167–168°C. IR spectrum, ν,
1
cm–1: 1730, 1720, 1695 (C=O). H NMR spectrum, δ,
Methyl 1-aryl-4-methyl-3,5-dioxo-2-oxaspiro-
[5.5]undecane-4-carboxylates XIIIa–XIIId (general
procedure). A mixture of 7 mmol (2.35 g) of com-
pound IV and 7 mmol of aromatic aldehyde in 15 ml
of anhydrous ethyl acetate was added dropwise under
stirring to a mixture of 1 g of fine zinc turnings, a cat-
alytic amount of mercury(II) chloride, 10 ml of anhy-
drous diethyl ether, and 10 ml of anhydrous ethyl
acetate. The mixture was heated for 2 h under reflux
and cooled, the solution was separated from excess
zinc by decanting and hydrolyzed with 5% acetic acid,
the organic phase was separated, the aqueous phase
ppm: 0.60–2.10 m (10H, CH2), 1.73 s (3H, Me), 3.70 s
(3H, MeO), 3.79 s (3H, MeO), 5.82 s (1H, CHO),
7.01 d and 7.33 d (2H each, C6H4, J = 8.4 Hz). Found,
%: C 66.88; H 6.56. C20H24O6. Calculated, %: C 66.65;
H 6.71.
Compounds XIVa, XIVb, XVa, and XVb were
synthesized in a similar way from the corresponding
diesters V and VI.
Methyl 5-(4-bromophenyl)-8-methyl-7,9-dioxo-
6-oxaspiro[4.5]decane-9-carboxylate (XIVa). Yield
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 3 2010

SYNTHESIS OF SUBSTITUTED METHYL 5,5-POLYMETHYLENE-2,4-DIOXO...
371
1.55 g (56%), mp 115–117°C. IR spectrum, ν, cm–1:
1750, 1725, 1700 (C=O). H NMR spectrum, δ, ppm:
0.77–2.18 m (8H, CH2), 1.62 s (3H, Me), 3.80 s (3H,
MeO), 5.84 s (1H, CHO), 7.50 d and 7.66 d (2H each,
C6H4, J = 8.7 Hz). Found, %: C 54.88; H 4.93;
Br 20.09. C18H19BrO5. Calculated, %: C 54.70; H 4.85;
Br 20.22.
C6H4, J = 8.7 Hz). Found, %: C 60.81; H 5.18;
Cl 10.34. C17H17ClO5. Calculated, %: C 60.63; H 5.09;
Cl 10.53.
1
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 07-03-96035).
REFERENCES
Methyl 5-(4-chlorophenyl)-8-methyl-7,9-dioxo-
6-oxaspiro[4.5]decane-9-carboxylate (XIVb). Yield
1.28 g (52%), mp 119–120°C. IR spectrum, ν, cm–1:
1. Shchepin, V.V., Fatykhova, Yu.Kh., Kirillov, N.F., Russ-
kikh, N.Yu., and Litvinov, D.N., Russ. J. Org. Chem.,
2000, vol. 36, p. 1120.
1
1755, 1730, 1710 (C=O). H NMR spectrum, δ, ppm:
0.74–2.18 m (8H, CH2), 1.62 s (3H, Me), 3.80 s (3H,
MeO), 5.86 s (1H, CHO), 7.52 d and 7.57 d (2H each,
C6H4, J = 9.0 Hz). Found, %: C 61.45; H 5.33;
Cl 10.32. C18H19ClO5. Calculated, %: C 61.63; H 5.46;
Cl 10.11.
2. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E.,
Robb, M.A., Cheeseman, J.R., Montgomery, J.A., Jr.,
Vreven, T., Kudin, K.N., Burant, J.C., Millam, J.M.,
Iyengar, S.S., Tomasi, J., Barone, V., Mennucci, B.,
Cossi, M., Scalmani, G., Rega, N., Petersson, G.A., Naka-
tsuji, H., Hada, M., Ehara, M., Toyota, K., Fukuda, R.,
Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y.,
Kitao, O., Nakai, H., Klene, M., Li, X., Knox, J.E.,
Hratchian, H.P., Cross, J.B., Bakken, V., Adamo, C.,
Jaramillo, J., Gomperts, R., Stratmann, R.E., Yazyev, O.,
Austin, A.J., Cammi, R., Pomelli, C., Ochterski, J.W.,
Ayala, P.Y., Morokuma, K., Voth, G.A., Salvador, P.,
Dannenberg, J.J., Zakrzewski, V.G., Dapprich, S.,
Daniels, A.D., Strain, M.C., Farkas, O., Malick, D.K.,
Rabuck, A.D., Raghavachari, K., Foresman, J.B.,
Ortiz, J.V., Cui, Q., Baboul, A.G., Clifford, S., Cioslow-
ski, J., Stefanov, B.B., Liu, G., Liashenko, A., Piskorz, P.,
Komaromi, I., Martin, R.L., Fox, D.J., Keith, T., Al-
Laham, M.A., Peng, C.Y., Nanayakkara, A., Challa-
combe, M., Gill, P.M.W., Johnson, B., Chen, W.,
Wong, M.W., Gonzalez, C., and Pople, J.A., Gaussian 03,
Revision D.01, Wallingford CT: Gaussian, 2004.
Methyl 5-(4-bromophenyl)-8-methyl-7,9-dioxo-
6-oxaspiro[3.5]nonane-8-carboxylate (XVa). Yield
1.20 g (45%), mp 134–135°C. IR spectrum, ν, cm–1:
1
1755, 1725, 1705 (C=O). H NMR spectrum, δ, ppm:
1.02–2.58 m (6H, CH2), 1.51 s (3H, Me), 3.76 s (3H,
MeO), 5.89 s (1H, CHO), 7.50 d and 7.71 d (2H each,
C6H4, J = 8.1 Hz). Found, %: C 53.78; H 4.56;
Br 21.14. C17H17BrO5. Calculated, %: C 53.56; H 4.49;
Br 20.96.
Methyl 5-(4-chlorophenyl)-8-methyl-7,9-dioxo-
6-oxaspiro[3.5]nonane-8-carboxylate (XVb). Yield
1.13 g (48%), mp 137–138°C. IR spectrum, ν, cm–1:
1
1760, 1725, 1710 (C=O). H NMR spectrum, δ, ppm:
1.20–2.75 m (6H, CH2), 1.62 s (3H, Me), 3.80 s (3H,
MeO), 5.66 s (1H, CHO), 7.37 d and 7.43 d (2H each,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 3 2010