Synthesis and structure of acetyl-substituted oxocyclohexanecarboxylates

Full text of DOI:10.1134/S1070428010040287

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 4, pp. 594–596. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © V.E. Subbotin, V.V. Sorokin, A.G. Golikov, A.P. Kriven’ko, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 4,
pp. 601–603.
SHORT
COMMUNICATIONS
Synthesis and Structure of Acetyl-Substituted
Oxocyclohexanecarboxylates
V. E. Subbotin, V. V. Sorokin, A. G. Golikov, and A. P. Kriven’ko
Chernyshevskii Saratov State University, ul. Astrakhanskaya 83, Saratov, 410012 Russia
e-mail: Ubique@rambler.ru
Received July 7, 2009
DOI: 10.1134/S1070428010040287
Dicarbonyl-substituted hydroxycyclohexanones
with similar substituents (Ac or COOR) have been
studied in sufficient detail [1]. Much less data are
available on analogous compounds having different
substituent groups (COR and COOR) [2]. However,
such derivatives are promising from the viewpoint of
their biological activity and design of carbo- and hetero-
cyclic systems with specified functionalization pattern.
spectral methods and chemical transformations. Com-
pounds Ia–Ic were synthesized by condensation of
aromatic aldehydes with ethyl acetoacetate or acetyl-
acetone to give ethyl 2-benzylidene-3-oxobutanoate
(IIa) or 3-arylmethylidenepentane-2,4-diones IIb and
IIc, followed by Michael addition. Intramolecular al-
dolization of intermediate A gave cyclohexanecarbox-
ylates Ia–Ic in up to 80% yield.
1
We now report on the synthesis of new ethyl
3-acetyl-2-aryl-4-hydroxy-4-methyl-6-oxocyclohexane-
carboxylates Ia–Ic whose structure was determined by
The spectral data (IR and H NMR) for the synthe-
sized compounds confirmed only the presence of car-
bonyl-containing fragments but not their position, so
O
O
MeC(O)CH2C(O)Me
piperidine
O
O
O
O
PhCHO, piperidine
Me
OEt
O
Me
Me
OEt
Ar
Ph
O
Ac
OEt
IIa
O
Me
Me
MeC(O)CH2C(O)OEt
piperidine
O
O
ArCHO, piperidine
Me
Me
A
Me
Ar
IIb, IIc
Ar
O
Ar
O
Ac
Ac
NH2OH
OEt
OEt
HO
Me
HO
Me
O
NOH
Ia–Ic
IIIa–IIIc
O
Ar
Ac
O
EtO
HO
Me
A
B
Ar = Ph (a), 3-O2NC6H4 (b), 4-MeOC6H4 (c).
594

SYNTHESIS AND STRUCTURE OF ACETYL-SUBSTITUTED OXOCYCLOHEXANE...
595
δ, ppm
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
4.0 3.5
3.0 2.5
2.0 1.5
δ, ppm
Two-dimensional NOESY spectrum of ethyl 3-acetyl-4-hydroxy-4-methyl-6-oxo-2-phenylcyclohexanecarboxylate (Ia).
that alternative structure B cannot be ruled out. The
structure of the products was unambiguously deter-
mined on the basis of the two-dimensional NOESY
spectrum of compound Ia, which displayed coupling
between methyl protons in the acetyl substituent and
protons in the 4-methyl group. Such coupling is pos-
sible only if the above groups are attached to neighbor-
ing carbon atoms. In addition, cross peaks with 2-Hax,
3-Hax, 5-Hax, and 5-Heq were observed (see figure).
Ethyl 3-acetyl-2-aryl-4-hydroxy-4-methyl-6-oxo-
cyclohexanecarboxylates Ia–Ic (general procedure).
A mixture of 18 mmol of compound IIa–IIc and
18 mmol of acetylacetone or ethyl acetoacetate was
cooled to 10–15°C, a solution of 2 ml of piperidine in
10 ml of ethanol was added dropwise, and the mixture
was kept for 78 h at room temperature. The precipitate
was filtered off and recrystallized from ethanol.
Ethyl 3-acetyl-4-hydroxy-4-methyl-6-oxo-2-
phenylcyclohexanecarboxylate (Ia). Yield 72%,
mp 104–105°C. IR spectrum, ν, cm–1: 3434 (OH),
Mutual arrangement of the ester and acetyl groups
was also proved by chemical transformation, specifi-
cally by reaction of cyclohexanecarboxylates Ia–Ic
with hydroxylamine. It is known that reactions of
diacetylhydroxycyclohexanones with hydroxylamine
involve heterocyclization with participation of the
1,3-dioxo fragment and formation of isoxazoles and
that bis(ethoxycarbonyl)-substituted analogs react via
nucleophilic replacement at the endocyclic carbonyl
group with formation of oximes [2]. The reactions of
compounds Ia–Ic with hydroxylamine gave the corre-
sponding oximes, ethyl 3-acetyl-2-aryl-4-hydroxy-6-
hydroxyimino-4-methylcyclohexanecarboxylates IIIa–
1
1722 (C=O, ester), 1705 (C=O), 1602 (Ac). H NMR
spectrum, δ, ppm: 1.03 s (3H, CH3CO), 1.31 s (3H,
CH3), 1.68 t (3H, CH2CH3), 2.02 s (1H, OH), 2.49 d
(1H, 5-Hax), 2.63 d (2H, 5-Heq), 3.27 d (1H, 3-H),
3.71 d (1H, 1-H), 3.93 t (1H, 2-H), 4.04 m (2H,
OCH2). Found, %: C 67.58; H 7.24. C18H22O5. Calcu-
lated, %: C 67.91; H 6.97.
Ethyl 3-acetyl-4-hydroxy-4-methyl-2-(3-nitro-
phenyl)-6-oxocyclohexanecarboxylate (Ib). Yield
80%, mp 127–130°C. IR spectrum, ν, cm–1: 3430
(OH), 1724 (C=O, ester), 1707 (C=O), 1696 (Ac),
1
1
IIIc, whose IR and H NMR spectra were consistent
1528 (NO2). H NMR spectrum, δ, ppm: 1.05 s (3H,
with the assumed structure.
CH3CO), 1.32 s (3H, CH3), 1.68 t (3H, CH2CH3),
2.02 s (1H, OH), 2.60 d (1H, 5-Hax), 2.68 d (1H,
5-Heq), 3.23 d (1H, 3-H), 3.64 d (1H, 1-H), 3.86 t (1H,
2-H), 4.05 m (2H, OCH2). Found, %: C 59.26; H 6.05;
Ethyl 2-benzylidene-3-oxobutanoate (IIa) and
3-arylmethylidenepentane-2,4-diones IIb and IIc were
reported in [3, 4].
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 4 2010

SUBBOTIN et al.
596
N 4.05. C18H20O7N. Calculated, %: C 59.50; H 5.83;
N 3.85.
ppm: 1.11 s (3H, CH3CO), 1.32 s (3H, CH3), 1.72 t
(3H, CH2CH3), 2.02 s (1H, OH), 2.46 d (1H, 5-Hax),
2.64 d (1H, 5-Heq), 3.24 d (1H, 3-H), 3.65 d (1H, 1-H),
3.82 s (1H, NHOH), 3.88 t (1H, 2-H), 4.08 m (2H,
OCH2). Found, %: C 57.12; H 5.81; N 7.01.
C18H22N2O7. Calculated, %: C 57.14; H 5.86; N 7.40.
Ethyl 3-acetyl-4-hydroxy-2-(4-methoxyphenyl)-
4-methyl-6-oxocyclohexanecarboxylate (Ic). Yield
78%, mp 137–140°C. IR spectrum, ν, cm–1: 3416
(OH), 1726 (C=O, ester), 1696 (C=O), 1589 (Ac).
1H NMR spectrum, δ, ppm: 1.09 s (3H, CH3CO),
1.32 s (3H, CH3), 1.69 t (3H, CH2CH3), 2.02 s (1H,
OH), 2.45 d (1H, 5-Hax), 2.60 d (1H, 5-Heq), 3.23 d
(1H, 3-H), 3.64 d (1H, 1-H), 3.83 s (3H, OCH3), 3.86 t
(1H, 2-H), 4.05 m (2H, OCH2). Found, %: C 65.32;
H 6.94. C19H24O6. Calculated, %: C 65.50; H 6.94.
Ethyl 3-acetyl-4-hydroxy-6-hydroxyimino-
2-(4-methoxyphenyl)-4-methylcyclohexanecarbox-
ylate (IIIc). Yield 57%, mp 65–67°C. IR spectrum, ν,
cm–1: 3501 (OH), 3360 (NHOH), 1728 (C=O, ester),
1
1703 (Ac), 1644 (N=C). H NMR spectrum, δ, ppm:
1.07 s (3H, CH3CO), 1.30 s (3H, CH3), 1.70 t (3H,
CH2CH3), 2.01 s (1H, OH), 2.65 d (1H, 5-Hax), 2.67 d
(1H, 5-Heq), 3.12 d (1H, 3-H), 3.65 d (1H, 1-H), 3.81 s
(1H, NHOH), 3.83 s (3H, OCH3), 3.86 t (1H, 2-H),
4.02 m (2H, OCH2). Found, %: C 62.88; H 6.93;
N 4.05. C19H25NO6. Calculated, %: C 62.80; H 6.93;
N 3.85.
Ethyl 3-acetyl-2-aryl-4-hydroxy-6-hydroxy-
imino-4-methylcyclohexanecarboxylates IIIa–IIIc
(general procedure). A solution of 2.5 mmol of hy-
droxylamine hydrochloride in 3 ml of water was added
dropwise over a period of 5 min to a solution of
2.5 mmol of cyclohexanecarboxylate Ia–Ic in 15 ml of
ethanol. The mixture was heated for 3 h under reflux
and was kept for 78 h at room temperature. The precip-
itate was filtered off, washed with water and diethyl
ether, and recrystallized from ethanol.
The IR spectra were measured in KBr on a Specord
1
M-80 spectrometer. The H NMR spectra were
recorded on a Varian-400 instrument at 400 MHz using
CDCl3 as solvent and tetramethylsilane as internal
reference. The progress of reactions and the purity of
products were monitored by TLC on Silufol UV-254
plates; spots were visualized under UV light or by
treatment with iodine vapor. The melting points were
determined using glass capillaries and were not
corrected.
Ethyl 3-acetyl-4-hydroxy-6-hydroxyimino-4-
methyl-2-phenylcyclohexanecarboxylate (IIIa).
Yield 51%, mp 109–112°C. IR spectrum, ν, cm–1: 3475
(OH), 3220 (NHOH), 1725 (C=O, ester), 1703 (Ac),
1
1656 (N=C). H NMR spectrum, δ, ppm: 1.09 s (3H,
CH3CO), 1.31 s (3H, CH3), 1.70 t (3H, CH2CH3),
2.00 s (1H, OH), 2.44 d (1H, 5-Hax), 2.60 d (1H,
5-Heq), 3.23 d (1H, 3-H), 3.64 d (1H, 1-H), 3.81 s (1H,
NHOH), 3.86 t (1H, 2-H), 4.05 m (2H, OCH2). Found,
%: C 64.68; H 7.01; N 4.20. C18H23NO5. Calculated,
%: C 64.85; H 6.95; N 4.20.
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Ethyl 3-acetyl-4-hydroxy-6-hydroxyimino-
4-methyl-2-(3-nitrophenyl)cyclohexanecarboxylate
(IIIb). Yield 45%, mp 96–98°C. IR spectrum, ν, cm–1:
3507 (OH), 3320 (NHOH), 1726 (C=O, estert), 1638
1
(Ac), 1527 (NO2), 1652 (N=C). H NMR spectrum, δ,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 4 2010