Reformatsky synthesis of 16-aryl-15-oxadispiro[5.1.5.3]-hexadecane-7,14-diones

Article abstract of DOI:10.1023/A:1013150730954

Methyl 1-bromocyclohexanecarboxylate reacts with zinc in the presence of cyclohexanecarbonyl chloride to give methyl 1-(cyclohexylcarbonyl)cyclohexanecarboxylate. Treatment of the latter with bromine leads to formation of methyl 1-(1-bromocyclohexylcarbonyl)cyclohexanecarboxylate which reacts with zinc and aromatic aldehydes, yielding 16-aryl-15-oxadispiro[5.1.5.3]hexadecane-7,14-diones.

Full text of DOI:10.1023/A:1013150730954

Russian Journal of Organic Chemistry, Vol. 37, No. 9, 2001, pp. 1223 1224. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 9, 2001,
pp. 1290 1291.
Original Russian Text Copyright
2001 by Kirillov, Shchepin.
Reformatsky Synthesis of 16-Aryl-15-oxadispiro[5.1.5.3]-
hexadecane-7,14-diones
N. F. Kirillov and V. V. Shchepin
Perm State University, ul. Bukireva 15, Perm, 614600 Russia
Received February 9, 2001
Abstract Methyl 1-bromocyclohexanecarboxylate reacts with zinc in the presence of cyclohexanecarbonyl
chloride to give methyl 1-(cyclohexylcarbonyl)cyclohexanecarboxylate. Treatment of the latter with bromine
leads to formation of methyl 1-(1-bromocyclohexylcarbonyl)cyclohexanecarboxylate which reacts with zinc
and aromatic aldehydes, yielding 16-aryl-15-oxadispiro[5.1.5.3]hexadecane-7,14-diones.
We recently synthesized substituted tetrahydro-
pyran-2,4-diones containing a spiro-carbon atom in
position 3 of the pyran ring [1]. In the present com-
munication we report on the use of Reformatsky reac-
tion to build up the cyclic system of 2,3,5,6-tetra-
hydro-2,4-pyrandiones containing two spiro-carbon
atoms in positions 3 and 5 of the pyran ring. The
target compounds were synthesized as shown in
Scheme 1. The first stage was the reaction of methyl
1-bromocyclohexanecarboxylate (I) with zinc and
cyclohexanecarbonyl chloride which afforded methyl
1-(cyclohexylcarbonyl)cyclohexanecarboxylate (II).
Bromination of ester II gave methyl 1-(1-bromocyclo-
hexylcarbonyl)cyclohexanecarboxylate (III). The latter
was brought into Reformatsky reaction with zinc to
obtain intermediate IV which was treated with aro-
matic aldehydes Va Vd. Alkoxides VIa VId thus
formed underwent spontaneous cyclization in ether
ethyl acetate, yielding 34 40% of 16-aryl-15-oxadi-
spiro[5.1.5.3]hexadecane-7,14-diones VIIa VIId as
final products (Scheme 1).
The structure of compounds VII was proved by
1
elemental analysis and IR and H NMR spectroscopy.
The IR spectra of VII contained absorption bands
1
typical of ketone (1720 cm ) and lactone carbonyl
1
groups (1750 1760 cm ). Signals at 5.51 5.77 and
1
0.57 2.17 ppm in the H NMR spectra were assigned,
respectively, to the CHO proton and methylene
protons of the cyclohexane rings.
EXPERIMENTAL
1
The H NMR spectra of solutions of compounds
II and VIIb in CCl4 were recorded on an RYa-2310
spectrometer at 60 MHz; the spectra of compounds
III, VIIa, VIIc, and VIId were obtained from
Scheme 1.
V VII, R = Ph (a), 4-FC6H4 (b), 4-ClC6H4 (c), 2,4-Cl2C6H3 (d).
1070-4280/01/3709-1223$25.00 2001 MAIK Nauka/Interperiodica

1224
KIRILLOV, SHCHEPIN
solutions in DMSO-d6 on a Bruker AM-300 instru-
ment (300 MHz). Tetramethylsilane was used as
internal reference. The IR spectra were measured on
a UR-20 instrument from neat substances.
zinc (by decanting), and treated with 5% hydrochloric
acid. The organic phase was separated, and the
aqueous phase was extracted with ethyl acetate. The
extract was combined with the organic phase, dried
over anhydrous sodium sulfate, and evaporated. Prod-
ucts VIIa VIId were recrystallized from petroleum
ether ethyl acetate.
Methyl 1-(cyclohexylcarbonyl)cyclohexanecar-
boxylate (II). Fine turnings of zinc, 10 g, were mixed
with 25 ml of anhydrous ether and 5 ml of anhydrous
ethyl acetate, and a mixture of 0.1 mol of methyl
cyclohexanecarboxylate and 0.1 mol of cyclohexane-
carbonyl chloride in 30 ml of the same solvents was
added dropwise. The mixture was refluxed for 1 h,
separated from excess zinc (by decanting), and treated
with water. The organic phase was separated, dried
with anhydrous sodium sulfate, and evaporated. The
product was distilled under reduced pressure. Yield
61%. bp 163 165 C (10 mm), mp 49 50 C (from
16-Phenyl-15-oxadispiro[5.1.5.3]hexadecane-
7,14-dione (VIIa). Yield 34%. mp 158 159 C. IR
1
spectrum, , cm : 1720, 1750 (C O). 1H NMR spec-
trum, , ppm: 7.32 7.64 m (5H, Ph), 5.51 s (1H,
CHO), 0.64 2.16 m (20H, cyclohexyl). Found, %:
C 77.05; H 8.12. C21H26O3. Calculated, %: C 77.27;
H 8.03.
16-(4-Fluorophenyl)-15-oxadispiro[5.1.5.3]hexa-
decane-7,14-dione (VIIb). Yield 38%. mp 176
1
petroleum ether). IR spectrum, , cm : 1715, 1750
1
177 C. IR spectrum, , cm : 1720, 1755 (C O).
(C O). 1H NMR spectrum, , ppm: 3.52 s (3H,
OCH3), 2.38 m (1H, 1 -H), 0.58 2.11 m (20H, cyclo-
hexyl). Found, %: C 71.21; H 9.45. C15H24O3. Cal-
culated, %: C 71.39; H 9.59.
1H NMR spectrum, , ppm: 7.18 7.45 m (4H, C6H4),
5.59 s (1H, CHO), 0.60 2.17 m (20H, cyclohexyl).
Found, %: C 73.08; H 7.28. C21H25FO3. Calculated,
%: C 73.23; H 7.32.
Methyl 1-(1-bromocyclohexylcarbonyl)cyclo-
hexanecarboxylate (III). Bromine, 0.11 mol, was
added with stirring to a solution of 0.1 mol of com-
pound II in 25 ml of acetic acid. The mixture was
heated for 1.5 h on a water bath, excess bromine and
acetic acid were distilled off, and the product was re-
crystallized twice from petroleum ether (bp 40 70 C).
16-(4-Chlorophenyl)-15-oxadispiro[5.1.5.3]hexa-
decane-7,14-dione (VIIc). Yield 40%. mp 211
1
212 C. IR spectrum, , cm : 1720, 1750 (C O).
1H NMR spectrum, , ppm: 7.39 d (2H, Harom), 7.37 d
(2H, Harom), 5.54 s (1H, CHO), 0.57 2.16 m (20H,
cyclohexyl). Found, %: C 69.75; H 7.07; Cl 9.68.
C21H25ClO3. Calculated, %: C 69.89; H 6.98; Cl 9.82.
1
Yield 62%. mp 67 68 C. IR spectrum, , cm : 1720,
1
16-(2,4-Dichlorophenyl)-15-oxadispiro[5.1.5.3]-
1735, 1750, 1760 (C O). H NMR spectrum, , ppm:
hexadecane-7,14-dione (VIId). Yield 36%. mp 220
3.65 s (3H, OCH3), 1.16 2.16 m (20H, cyclohexyl).
Found, %: C 54.53; H 6.82; Br 23.95. C15H23BrO3.
Calculated, %: C 54.39; H 7.00; Br 24.12.
1
221 C. IR spectrum, , cm : 1720, 1760 (C O).
1H NMR spectrum, , ppm: 7.60 d (1H, Harom), 7.53 s
(1H, Harom), 7.49 d (1H, Harom), 5.77 s (1H, CHO),
0.62 2.17 m (20H, cyclohexyl). Found, %: C 63.87;
H 6.05; Cl 17.72. C21H24Cl2O3. Calculated, %:
C 63.80; H 6.12; Cl 17.94.
16-Aryl-15-oxadispiro[5.1.5.3]hexadecane-7,14-
diones VIIa VIId. To a mixture of 6 g of zinc
(prepared as fine turnings), a catalytic amount of
mercury(II) chloride, 10 ml of anhydrous diethyl
ether, and 25 ml of anhydrous ethyl acetate we added
dropwise with stirring a mixture of 0.02 mol of com-
pound III and 0.021 mol of aldehyde Va Vd in 35 ml
of the same solvent mixture. The reaction mixture
was refluxed for 1 h, cooled, separated from excess
REFERENCE
1. Kirillov, N.F., Shchepin, V.V., and Litvinov, D.N.,
Russ. J. Org. Chem., 2000, vol. 36, no. 7, pp. 979 981.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001