Synthesis of 6-arylspiro[tetrahydropyran-3,1′-cyclobutane]-2,4-diones

Article abstract of DOI:10.1134/S1070428007110073

Methyl 1-(2-bromo-2-methyl-1-oxopropyl)-, 1-(1-bromocyclopentylcarbonyl)-, and 1-(1-bromocyclohexylcarbonyl) cyclobutanecarboxylates reacted with zinc and aromatic aldehydes to give, respectively, 7-aryl-2,2-dimethyl-6-oxaspiro[3.5] nonane-5,9-diones, 11-

Full text of DOI:10.1134/S1070428007110073

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 11, pp. 1628–1631. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © N.F. Kirillov, V.V. Shchepin, V.S. Melekhin, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 11,
pp. 1633–1636.
Synthesis of 6-Arylspiro[tetrahydropyran-3,1′-cyclobutane]-
2,4-diones
N. F. Kirillov, V. V. Shchepin†, and V. S. Melekhin
Perm State University, ul. Bukireva 15, Perm, 614990 Russia
Received September 10, 2006
Abstract—Methyl 1-(2-bromo-2-methyl-1-oxopropyl)-, 1-(1-bromocyclopentylcarbonyl)-, and 1-(1-bromocy-
clohexylcarbonyl)cyclobutanecarboxylates reacted with zinc and aromatic aldehydes to give, respectively,
7-aryl-2,2-dimethyl-6-oxaspiro[3.5]nonane-5,9-diones, 11-aryl-12-oxadispiro[3.1.4.3]tridecane-5,13-diones,
and 12-aryl-13-oxadispiro[3.1.5.3]tetradecane-5,14-diones.
DOI: 10.1134/S1070428007110073
In continuation of our previous studies on the syn-
thesis of substituted tetrahydropyran-2,4-diones having
spiro carbon atoms in positions 3 and 5 of the hetero-
ring [1–3], we now report on the preparation of anal-
ogous compounds in which the C3 atom is shared with
cyclobutane ring. By the Reformatsky reaction of
methyl 1-bromocyclobutanecarboxylate (I) with zinc
and isobutyryl chloride we obtained methyl 1-(2-meth-
yl-1-oxo-propyl)cyclobutanecarboxylate (II) whose
bromination gave methyl 1-(2-bromo-2-methyl-1-oxo-
propyl)cyclobutanecarboxylate (III) as the key inter-
mediate product. The reaction of bromo derivative III
with zinc and aromatic aldehydes involved addition of
zinc enolate IV at the carbonyl group of the aldehyde,
followed by spontaneous cyclization of intermediate V
into tetrahydropyran-2,4-dione spiro-fused with cyclo-
butane ring at the 3-position. We thus isolated 7-aryl-
8,8-dimethyl-6-oxaspiro[3.5]nonane-5,9-diones VIa–
VId (Scheme 1).
Likewise, from bromocyclobutane I, zinc, and
cyclopentanecarbonyl chloride we obtained methyl
1-(cyclopentylcarbonyl)cyclobutanecarboxylate (VII),
bromination of the latter gave methyl 1-(1-bromo-
cyclopentylcarbonyl)cyclobutanecarboxylate (VIII),
and compound VIII was brought into reaction with zinc
and aromatic aldehydes. As a result, we isolated tetrahy-
dropyran-2,4-dione derivatives with two spiro carbon
atoms in positions 3 and 5 of the heteroring, 11-aryl-12-
oxadispiro[3.1.4.3]tridecane-5,13-diones IXa–IXc
(Scheme 2).
Following an analogous scheme, 1-(cyclohexyl-
carbonyl)cyclobutanecarboxylate (X) obtained by the
Reformatsky reaction of bromo derivative I with zinc
Scheme 1.
O
Me
Me
O
Me
BrZnO
Me
Me
Br
Zn, Me2CHCOCl
–ZnBrCl
Br2
Zn
Br
Me
–HBr
COOMe
COOMe
II
COOMe
COOMe
IV
I
III
O
O
Me
Me
Me
Ar
H
ArCHO
Me
–MeOZnBr
OZnBr
Ar
O
O
COOMe
Va–Vd
VIa–VId
V, VI, Ar = 4-BrC6H4 (a), 4-ClC6H4 (b), 2,4-Cl2C6H3 (c), 3-O2NC6H4 (d).
†
Deceased.
1628

SYNTHESIS OF 6-ARYLSPIRO[TETRAHYDROPYRAN-3,1′-CYCLOBUTANE]-2,4-DIONES
1629
Scheme 2.
O
O
O
Zn,
COCl
Br2
Zn, ArCHO
–MeOZnBr
I
Br
–ZnBrCl
–HBr
COOMe
COOMe
Ar
O
O
VII
VIII
IXa–IXc
IX, Ar = 4-BrC6H4 (a), 4-ClC6H4 (b), 2,4-Cl2C6H3 (c).
Scheme 3.
O
O
O
Zn,
COCl
Br2
Zn, ArCHO
–MeOZnBr
I
Br
–ZnBrCl
–HBr
Ar
O
O
COOMe
COOMe
X
XI
XIIa–XIIf
XII, Ar = Ph (a), 4-BrC6H4 (b), 4-ClC6H4 (c), 2,4-Cl2C6H3 (d), 4-MeOC6H4 (e), 4-O2NC6H4 (f).
and cyclohexanecarbonyl chloride was converted into
methyl 1-(1-bromocyclohexylcarbonyl)cyclobutane-
carboxylate (XI). The subsequent Reformatsky reac-
tion of bromide XI with zinc and aromatic aldehydes
gave 12-aryl-13-oxadispiro[3.1.5.3]tetradecane-5,14-
diones XIIa–XIIf in which the tetrahydropyran ring is
substituted at C3 and C5 by tri- and pentamethylene
groups, respectively (Scheme 3).
mixture was heated for 1 h under reflux, the liquid
phase was separated by decanting and hydrolyzed 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 12.0 g (65%), bp 80–82°C (4 mm), d420 = 1.0953,
nD20 = 1.4592. IR spectrum, ν, cm–1: 1715, 1725 (C=O).
1H NMR spectrum, δ, ppm: 3.69 s (3H, OMe), 2.69 m
(1H, CHCO), 1.58–2.59 m (6H, CH2), 1.05 d (6H, Me,
J = 6.5 Hz). Found, %: C 65.41; H 8.88. C10H16O3.
Calculated, %: C 65.19; H 8.75
The structure of compounds VIa–VId, IXa–IXc,
and XIIa–XIIf was proved by elemental analysis and
1
1H NMR and IR spectroscopy. In the H NMR spectra
of these compounds, we observed a characteristic sin-
glet at δ 5.06–5.82 ppm from the OCH proton. Their
IR spectra contained absorption bands at 1705–1720
and 1720–1755 cm–1 due to stretching vibrations of the
ketone and lactone carbonyl groups, respectively.
Methyl 1-(1-bromo-2-methyl-1-oxopropyl)cyclo-
butanecarboxylate (III). Compound II, 0.1 mol, was
dissolved in 25 ml of acetic acid, 0.11 mol of bromine
was added dropwise under stirring, and 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 19.7 g (75%),
bp 111–113°C (4 mm), d420 = 1.4015, nD20 = 1.4940. IR
EXPERIMENTAL
1
spectrum, ν, cm–1: 1715, 1735 (C=O). H NMR spec-
The IR spectra of compounds II, III, VIa–VId,
VII, VIII, IXa–IXc, X, XI, and XIIa–XIIf were
recorded on a Spesord 75IR spectrophotometer from
samples dispersed in mineral oil. The 1H NMR spectra
were measured on a Tesla BS-576A instrument at
100 MHz in CDCl3 relative to hexamethyldisiloxane as
internal reference.
trum, δ, ppm: 3.68 s (3H, OMe), 1.72–2.60 m (6H,
CH2), 1.86 s (6H, Me). Found, %: C 45.52; H 5.64;
Br 30.51. C10H15BrO3. Calculated, %: C 45.65; H 5.75;
Br 30.37.
7-Aryl-8,8-dimethyl-6-oxaspiro[3.5]nonane-5,12-
diones VIa–VId (general procedure). A mixture of
0.02 mol of compound III and 0.017 mol of the corre-
sponding aldehyde in 30 ml of anhydrous ethyl acetate
was added dropwise under stirring to a mixture of
3 g of fine zinc turnings and a catalytic amount of
mercury(II) chloride in 30 ml of anhydrous ethyl
acetate (in the synthesis of VId, ester III was initially
Methyl 1-(2-methyl-1-oxopropyl)cyclobutane-
carboxylate (II). A solution of 0.1 mol of methyl
1-bromocyclobutanecarboxylate and 0.1 mol of iso-
butyryl chloride in 50 ml of anhydrous benzene was
added dropwise to a mixture of 10 g of fine zinc
turnings and 10 ml of anhydrous ethyl acetate. The
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 11 2007

KIRILLOV et al.
1630
heated with zinc over a period of 30 min, and 3-ni-
trobenzaldehyde was then added). The mixture was
heated for 2 h under reflux and cooled, the liquid phase
was separated by decanting and hydrolyzed 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 and dried over anhydrous sodium sul-
fate, most part of the solvent was distilled off, and the
product was recrystallized from ethyl acetate.
%: C 68.74; H 8.71. C12H18O3. Calculated, %: C 68.54;
H 8.63.
Methyl 1-(1-bromocyclopentylcarbonyl)cyclo-
butanecarboxylate (VIII) was synthesized by bromi-
nation of II according to the procedure described
above for the synthesis of compound III. Yield 23.1 g
(80%), bp 147–149°C (7 mm), d427 = 1.3522, nD27
=
1.5020. IR spectrum, ν, cm–1: 1715, 1725 (C=O).
1H NMR spectrum, δ, ppm: 3.69 s (3H, OMe), 1.48–
2.75 m (14H, CH2). Found, %: C 49.70; H 6.02;
Br 27.48. C12H17BrO3. Calculated, %: C 49.84; H 5.93;
Br 27.63.
7-(4-Bromophenyl)-8,8-dimethyl-6-oxaspiro-
[3.5]nonane-5,12-dione (VIa). Yield 5.33 g (93%),
mp 163–164°C. IR spectrum, ν, cm–1: 1710, 1725
11-Aryl-12-oxadispiro[3.1.4.3]tridecane-5,13-di-
ones (IXa–IXc) were synthesized as described above
for VIa–VId using compound VIII as starting
material.
1
(C=O). H NMR spectrum, δ, ppm: 7.43 d and 7.13 d
(2H each, 4-BrC6H4, J = 8.3 Hz), 5.20 s (1H, CHO),
1.92–2.84 m (6H, CH2), 1.10 s (3H, Me), 0.88 s
(3H, Me). Found, %: C 56.77; H 5.20; Br 23.92.
C16H17BrO3. Calculated, %: C 56.99; H 5.08; Br 23.70.
11-(4-Bromophenyl)-12-oxadispiro[3.1.4.3]tri-
decane-5,13-dione (IXa). Yield 5.13 g (83%),
mp 168–169°C. IR spectrum, ν, cm–1: 1715, 1730
7-(4-Chlorophenyl)-8,8-dimethyl-6-oxaspiro-
[3.5]nonane-5,12-dione (VIb). Yield 4.48 g (90%),
mp 171–172°C. IR spectrum, ν, cm–1: 1710, 1720
1
(C=O). H NMR spectrum, δ, ppm: 7.42 d and 7.14 d
(2H each, 4-BrC6H4, J = 8.3 Hz), 5.25 s (1H, CHO),
0.90–2.77 m (14H, CH2). Found, %: C 59.69; H 5.19;
Br 21.88. C18H19BrO3. Calculated, %: C 59.52; H 5.27;
Br 22.00.
1
(C=O). H NMR spectrum, δ, ppm: 7.17–7.29 m (4H,
4-ClC6H4), 5.20 s (1H, CHO), 1.90–2.88 m (6H, CH2),
1.09 s (3H, Me), 0.87 s (3H, Me). Found, %: C 65.79;
H 5.69; Cl 12.23. C16H17ClO3. Calculated, %: C 65.64;
H 5.85; Cl 12.11.
11-(4-Chlorophenyl)-12-oxadispiro[3.1.4.3]tri-
decane-5,13-dione (IXb). Yield 4.93 g (91%),
mp 162–163°C. IR spectrum, ν, cm–1: 1715, 1725
7-(2,4-Dichlorophenyl)-8,8-dimethyl-6-oxaspiro-
[3.5]nonane-5,12-dione (VIc). Yield 4.45 g (80%),
mp 104–105°C. IR spectrum, ν, cm–1: 1710, 1730
1
(C=O). H NMR spectrum, δ, ppm: 7.08–7.34 m (4H,
4-ClC6H4), 5.27 s (1H, CHO), 0.98–2.76 m (14H,
CH2). Found, %: C 67.67; H 5.90; Cl 11.31.
C18H19ClO3. Calculated, %: C 67.82; H 6.01; Cl 11.12.
1
(C=O). H NMR spectrum, δ, ppm: 7.15–7.50 m (3H,
C6H3), 5.82 s (1H, CHO), 1.95–2.85 m (6H, CH2),
1.14 s (3H, Me), 0.97 s (3H, Me). Found, %: C 58.91;
H 5.09; Cl 21.83. C16H16Cl2O3. Calculated, %: C 58.73;
H 4.93; Cl 21.67.
11-(2,4-Dichlorophenyl)-12-oxadispiro[3.1.4.3]-
tridecane-5,13-dione (IXc). Yield 4.38 g (73%),
mp 107–108°C. IR spectrum, ν, cm–1: 1715, 1730
(C=O). 1H NMR spectrum, δ, ppm: 7.40 d, 7.34 s, and
7.22 d (1H each, C6H3, J = 8.0 Hz); 5.81 s (1H, CHO);
1.08–2.78 m (14H, CH2). Found, %: C 61.32; H 5.29;
Cl 19.89. C18H18Cl2O3. Calculated, %: C 61.20;
H 5.14; Cl 20.07.
8,8-Dimethyl-7-(3-nitrophenyl)-6-oxaspiro[3.5]-
nonane-5,12-dione (VId). Yield 4.38 g (85%),
mp 158–159°C. IR spectrum, ν, cm–1: 1715, 1730
1
(C=O). H NMR spectrum, δ, ppm: 7.40–7.65 m (4H,
3-O2NC6H4), 5.35 s (1H, CHO), 1.50–2.89 m (6H,
CH2), 1.16 s (3H, Me), 0.91 s (3H, Me). Found, %:
C 63.49; H 5.58; N 4.43. C16H17NO5. Calculated, %:
C 63.36; H 5.65; N 4.62.
Methyl 1-(cyclohexylcarbonyl)cyclobutanecar-
boxylate (X) was synthesized from ester I and cyclo-
hexanecarbonyl chloride as described above for com-
pound II. Yield 14.6 g (65%), bp 122–123°C (4 mm),
d420 = 1.0638, nD20 = 1.4760. IR spectrum, ν, cm–1: 1715,
Methyl 1-(cyclopentylcarbonyl)cyclobutanecar-
boxylate (VII) was synthesized as described above for
compound II using cyclopentanecarbonyl chloride.
1
1730, 1750 (C=O). H NMR spectrum, δ, ppm: 3.65 s
(3H, OMe), 2.32–2.65 m (1H, CHCO), 1.05–2.27 m
(16H, CH2). Found, %: C 69.82; H 9.09. C13H20O3.
Calculated, %: C 69.61; H 8.99.
Yield 11.6 g (55%), bp 118–120°C (7 mm), d425
=
1.0673, nD25 = 1.4710. IR spectrum, ν, cm–1: 1710, 1725
(C=O). 1H NMR spectrum, δ, ppm: 3.65 s (3H, OMe),
2.78 m (1H, CHCO), 1.30–2.60 m (14H, CH2). Found,
Methyl 1-(1-bromocyclohexylcarbonyl)cyclo-
butanecarboxylate (XI) was obtained by bromination
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SYNTHESIS OF 6-ARYLSPIRO[TETRAHYDROPYRAN-3,1′-CYCLOBUTANE]-2,4-DIONES
1631
of X according to the procedure described above for
the synthesis of bromo ester III. Yield 26.1 g (86%),
bp 156–158°C (4 mm), mp 49°C (from hexane). IR
12-(2,4-Dichlorophenyl)-13-oxadispiro[3.1.5.3]-
tetradecane-5,14-dione (XIId). Yield 5.43 g (87%),
mp 138–139°C. IR spectrum, ν, cm–1: 1720, 1755
1
spectrum, ν, cm–1: 1715, 1735, 1755 (C=O). H NMR
1
(C=O). H NMR spectrum, δ, ppm: 7.12–7.40 m (3H,
spectrum, δ, ppm: 3.65 s (3H, OMe), 1.05–2.88 m
(16H, CH2). Found, %: C 51.69; H 6.44; Br 26.53.
C13H19BrO3. Calculated, %: C 51.50; H 6.32; Br 26.35.
C6H3), 5.70 s (1H, CHO), 0.80–2.82 m (16H, CH2).
Found, %: C 61.98; H 5.35; Cl 19.48. C19H20Cl2O3.
Calculated, %: C 62.13; H 5.49; Cl 19.31.
12-Aryl-13-oxadispiro[3.1.5.3]tetradecane-5,14-
diones XIIa–XIIf. The procedures for the synthesis of
compounds XIIa–XIIe and XIIf were analogous to
those described above for the synthesis of VIa–VIc
and VId, respectively; compound XI was used as start-
ing material.
12-(4-Methoxyphenyl)-13-oxadispiro[3.1.5.3]-
tetradecane-5,14-dione (XIIe). Yield 4.58 g (82%),
mp 96–97°C. IR spectrum, ν, cm–1: 1715, 1750 (C=O).
1H NMR spectrum, δ, ppm: 6.96 d and 6.77 d (2H
each, 4-MeOC6H4, J = 8.4 Hz), 5.07 s (1H, CHO),
3.76 s (3H, MeO), 0.80–2.81 m (16H, CH2). Found, %:
C 73.02; H 7.44. C20H24O3. Calculated, %: C 73.14;
H 7.37.
12-Phenyl-13-oxadispiro[3.1.5.3]tetradecane-
5,14-dione (XIIa). Yield 4.21 g (83%), mp 136–
137°C. IR spectrum, ν, cm–1: 1705, 1745 (C=O).
1H NMR spectrum, δ, ppm: 6.96–7.33 m (5H, Ph),
5.11 s (1H, CHO), 0.70–2.95 m (16H, CH2). Found, %:
C 76.68; H 7.49. C19H22O3. Calculated, %: C 76.48;
H 7.43.
12-(4-Nitrophenyl)-13-oxadispiro[3.1.5.3]tetra-
decane-5,14-dione (XIIf). Yield 5.25 g (90%),
mp 178–179°C. IR spectrum, ν, cm–1: 1720, 1755
1
(C=O). H NMR spectrum, δ, ppm: 8.13 d and 7.30 d
(4H, 4-O2NC6H4, J = 8.4 Hz), 5.19 s (1H, CHO),
0.70–2.88 m (16H, CH2). Found, %: C 66.28; H 6.29;
N 3.94. C19H21NO5. Calculated, %: C 66.45; H 6.17;
N 4.08.
12-(4-Bromophenyl)-13-oxadispiro[3.1.5.3]tetra-
decane-5,14-dione (XIIb). Yield 5.96 g (83%),
mp 135–136°C. IR spectrum, ν, cm–1: 1715, 1750
1
(C=O). H NMR spectrum, δ, ppm: 7.40 d and 6.95 d
(2H each, 4-BrC6H4, J = 8.3 Hz), 5.06 s (1H, CHO),
0.80–2.80 m (16H, CH2). Found, %: C 60.69; H 5.70;
Br 21.43. C19H21BrO3. Calculated, %: C 60.48; H 5.61;
Br 21.18.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 04-03-96036, 04-03-97505).
REFERENCES
12-(4-Chlorophenyl)-13-oxadispiro[3.1.5.3]tetra-
decane-5,14-dione (XIIc). Yield 4.81 g (85%),
mp 127–128°C. IR spectrum, ν, cm–1: 1720, 1745
1. Kirillov, N.F. and Shchepin, V.V., Russ. J. Org. Chem.,
1
2001, vol. 37, p. 1223.
(C=O). H NMR spectrum, δ, ppm: 7.24 d and 6.99 d
2. Kirillov, N.F., Shchepin, V.V., and Vakhrin, M.I., Russ. J.
Org. Chem., 2004, vol. 40, p. 578.
(2H each, 4-ClC6H4, J = 6.5 Hz), 5.07 s (1H, CHO),
0.80–2.79 m (16H, CH2). Found, %: C 68.78; H 6.49;
Cl 10.42. C19H21ClO3. Calculated, %: C 68.56; H 6.36;
Cl 10.65.
3. Shchepin, V.V., Kirillov, N.F., and Vakhrin, M.I., Russ. J.
Gen. Chem., 2004, vol. 74, p. 933.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 11 2007