Synthesis of 14-aryl-13-oxadispiro[3.1.5.3]tetradecane-5,12-diones by the Reformatsky reaction

Article abstract of DOI:10.1134/S107036320609012X

Methyl 1-bromocyclohexanecarboxylate reacts with zinc in the presence of cyclobutanecarbonyl chloride to give methyl 1-(cyclobutylcarbonyl) cyclohexanecarboxylate. Bromination of the latter leads to the formation of methyl 1-(1-bromocyclobutylcarbonyl)cyc

Full text of DOI:10.1134/S107036320609012X

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 9, pp. 1421 1422.
Pleiades Publishing, Inc., 2006.
Original Russian Text
pp. 1481 1483.
V.V. Shchepin, N.F. Kirillov, V.S. Melekhin, M.I. Vakhrin, 2006, published in Zhurnal Obshchei Khimii, 2006, Vol. 76, No. 9,
Synthesis of 14-Aryl-13-oxadispiro[3.1.5.3]tetradecane-
5,12-diones by the Reformatsky Reaction
V. V. Shchepin, N. F. Kirillov, V. S. Melekhin, and M. I. Vakhrin
Perm State University, ul. Bukireva 15, Perm, 614990 Russia
Received February 9, 2006
Abstract Methyl 1-bromocyclohexanecarboxylate reacts with zinc in the presence of cyclobutanecarbonyl
chloride to give methyl 1-(cyclobutylcarbonyl)cyclohexanecarboxylate. Bromination of the latter leads to the
formation of methyl 1-(1-bromocyclobutylcarbonyl)cyclohexanecarboxylate which reacts with zinc and
aromatic aldehydes, yielding 14-aryl-13-oxadispiro[3.1.5.3]tetradecane-5,12-diones.
DOI: 10.1134/S107036320609012X
In continuation of our previous studies on the syn-
thesis of substituted tetrahydropyran-2,4-diones spiro-
fused at positions 3 and 5 of the heteroring [1, 2], we
have developed a procedure for the preparation of
analogous compounds having penta- and trimethylene
groups in the above positions. By the Reformatsky
reaction of methyl 1-bromocyclohexanecarboxylate
(I) with zinc and cyclobutanecarbonyl chloride we
obtained methyl 1-(cyclobutylcarbonyl)cyclohexane-
carboxylate (II). Its bromination gave the key bromo
derivative, methyl 1-(1-bromocyclobutylcarbonyl)-
cyclohexanecarboxylate (III). Compound III was
brought into reaction with zinc and aromatic al-
dehydes. The reaction involved intermediate forma-
tion of zinc enolate IV which added at the aldehyde
carbonyl group to form intermediate V, and sponta-
neous cyclization of the latter afforded the target
tetrahydropyran-2,4-dione derivatives having penta-
and trimethylene groups at positions 3 and 5 of the
heteroring, 14-aryl-13-oxadispiro[3.1.5.3]tetradecane-
5,12-diones VIa VIf (Scheme 1).
The structure of compounds VIa VIf was con-
1
firmed by elemental analysis and IR and H NMR
spectroscopy. The IR spectra of VIa VIf contained
absorption bands in the regions 1695 1705 and 1720
1
1740 cm , which are typical of stretching vibrations
of the ketone and lactone carbonyl groups, respec-
tively. Compounds VIa VIf characteristically showed
1
in the H NMR spectra a singlet from the 6-H proton
at 5.78 6.06 ppm. The corresponding signal in the
1H NMR spectra of structurally related compounds
with tetra- and pentamethylene substituents appeared
at
5.17 5.77 ppm [1, 2].
Scheme 1.
Br
O
O
COCl
Zn,
Br
Br2
HBr
ZnBrCl
OMe
MeO
MeO
O
O
O
I
II
III
O
O
OZnBr
ArCHO
Zn
MeOZnBr
Ar
Ar
O
MeO
O
H
O
H
OZnBr
OMe
O
IV
Va Vf
VIa VIf
V, VI, Ar = Ph (a), 4-BrC6H4 (b), 4-ClC6H4 (c), 2,4-Cl2C6H3 (d), 4-MeOC6H4 (e), 4-O2NC6H4 (f).
1421

1422
SHCHEPIN et al.
and partially evaporated. Compounds VIa VIf were
EXPERIMENTAL
recrystallized from ethyl acetate.
The IR spectra were recorded on a Specord 75R
spectrometer from samples dispersed in mineral oil.
The H NMR spectra were measured from solutions
in CDCl3 (compounds II and III) or DMSO-d6
(VIa VIf) on Mercury-300 (300 MHz; II, III, VIb,
VIc) and Tesla BS-576A instruments (100 MHz; VIa,
VId VIf) relative to HMDS as internal reference.
14-Phenyl-13-oxadispiro[3.1.5.3]tetradecane-
1
5,12-dione (VIa). Yield 75%, mp 143 144 C. IR
1
1
spectrum, , cm : 1695, 1720 (C=O). H NMR spec-
trum, , ppm: 7.37 s (5H, C6H5), 5.84 s (1H, CHO),
1.00 2.30 m (16H, CH2). Found, %: C 76.58; H 7.55.
C19H22O3. Calculated, %: C 76.48; H 7.43.
14-(4-Bromophenyl)-13-oxadispiro[3.1.5.3]tetra-
Methyl 1-(cyclobutylcarbonyl)cyclohexanecar-
boxylate (II). A solution of 0.1 mol of methyl
1-bromocyclohexanecarboxylate and 0.1 mol of
cyclobutanecarbonyl chloride in 50 ml of anhydrous
benzene was added dropwise to a mixture of 10 g of
metallic zinc (prepared as fine turnings) and 10 ml
of anhydrous ethyl acetate. The mixture was heated
for 1 h under reflux, and the solution was separated
from zinc by decanting and treated with water. The
organic phase was separated and dried over anhydrous
sodium sulfate, the solvent was distilled off, and the
residue was distilled under reduced pressure. Yield
decane-5,12-dione (VIb). Yield 80%, mp 162 163 C.
1
1
IR spectrum, , cm : 1700, 1720 (C=O). H NMR
spectrum, , ppm: 7.45 d and 7.68 d (4H, 4-BrC6H4,
J = 8.4 Hz), 5.92 s (1H, CHO), 1.00 2.35 m (16H,
CH2). Found, %: C 60.47; H 5.74; Br 21.02. C19H21
BrO3. Calculated, %: C 60.49; H 5.61; Br 21.18.
14-(4-Chlorophenyl)-13-oxadispiro[3.1.5.3]tetra-
decane-5,12-dione (VIc). Yield 84%, mp 149 150 C.
1
1
IR spectrum, , cm : 1700, 1730 (C=O). H NMR
spectrum, , ppm: 7.51 d and 7.54 d (2H each, C6H4,
J = 8.3 Hz), 5.94 s (1H, CHO), 1.00 2.20 m (16H,
CH2). Found, %: C 68.69; H 6.48; Cl 10.50. C19H21
ClO3. Calculated, %: C 68.57; H 6.36; Cl 10.65.
55%, bp 132 135 C (4 mm Hg), d240 = 1.0703, nD201
=
1
1.4803. IR spectrum, , cm : 1705, 1735 (C=O). H
NMR spectrum, , ppm: 3.65 s (3H, OMe), 3.20
3.60 m (1H, CHCO), 1.10 2.40 m (16H, CH2). Found,
%: C 69.48; H 8.85. C13H20O3. Calculated, %: C
69.61; H8.99.
14-(2,4-Dichlorophenyl)-13-oxadispiro[3.1.5.3]-
tetradecane-5,12-dione (VId). Yield 68%, mp 140
1
1
141 C. IR spectrum, , cm : 1700, 1740 (C=O). H
NMR spectrum, , ppm: 7.47 7.73 m (3H, C6H3),
5.94 s (1H, CHO), 1.10 2.25 m (16H, CH2). Found,
%: C 62.37; H 5.62; Cl 19.14. C19H20Cl2O3. Cal-
culated, %: C 62.14; H 5.49; Cl 19.31.
Methyl 1-(1-bromocyclobutylcarbonyl)cyclo-
hexanecarboxylate (III). Bromine, 0.11 mol, was
added dropwise under stirring to a solution of 0.1 mol
of compound II in 25 ml of acetic acid. The mixture
was heated for 1 h on a water bath, excess bromine
and acetic acid were distilled off, and the residue was
distilled under reduced pressure. Yield 75%, bp 156
158 C (4 mm Hg), d240 = 1.3338, nD201 = 1.5110. IR
14-(4-Methoxyphenyl)-13-oxadispiro[3.1.5.3]-
tetradecane-5,12-dione (VIe). Yield 49%, mp 146
1
1
147 C. IR spectrum, , cm : 1700, 1725 (C=O). H
NMR spectrum, , ppm: 7.29 d and 6.93 d (2H each,
C6H4, J = 8.4 Hz), 5.78 s (1H, CHO), 3.75 s (3H,
MeO), 1.00 2.25 m (16H, CH2). Found, %: C 73.01;
H 7.48; C20H24O4. Calculated, %: C 73.15; H 7.37.
1
spectrum, , cm : 1700, 1740 (C=O). H NMR spec-
trum, , ppm: 3.67 s (3H, OMe), 1.10 2.25 m (16H,
CH2). Found, %: C 51.58; H 6.45; Br 26.56. C13H19
BrO3. Calculated, %: C 51.50; H 6.32; Br 26.35.
14-(4-Nitrophenyl)-13-oxadispiro[3.1.5.3]tetra-
decane-5,12-dione (VIf). Yield 85%, mp 171 172 C.
14-Aryl-13-oxadispiro[3.1.5.3]tetradecane-5,12-
diones VIa VIf (general procedure). A solution of
0.02 mol of compound III and 0.017 mol of the
corresponding aldehyde in 30 ml of anhydrous ethyl
acetate was added dropwise under stirring to a mixture
of 3 g of zinc (prepared as fine turnings), a catalytic
amount of HgCl2, and 30 ml of anhydrous ethyl
acetate; in the synthesis of compound VIf, 4-nitro-
benzaldehyde was added after heating compound III
with zinc over a period of 30 min. The mixture was
heated for 2 h under reflux, cooled, separated from
zinc by decanting, and treated with 5% hydrochloric
acid, the organic phase was separated, and the
aqueous phase was extracted with two portions of
ethyl acetate. The extracts were combined with the
organic phase, dried over anhydrous sodium sulfate,
1
1
IR spectrum, , cm : 1705, 1740 (C=O). H NMR
spectrum, , ppm: 8.25 d and 7.71 d (2H each, C6H4,
J = 8.4 Hz), 6.06 s (1H, CHO), 0.85 2.35 m (16H,
CH2). Found, %: C 66.19; H 6.28; N 3.95. C19H21
NO5. Calculated, %: C 66.46; H 6.16; N 4.08.
ACKNOWLEDGMENTS
This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 04-03-96036, 04-03-97505).
REFERENCES
1. Kirillov, N.F. and Shchepin, V.V., Russ. J. Org. Chem.,
2001, vol. 37, no. 9, p. 1223.
2. Shchepin, V.V., Kirillov, N.F., and Vakhrin, M.I., Russ.
J. Gen. Chem., 2004, vol. 74, no. 6, p. 933.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 9 2006