Chemistry of keto acetals: III. Stereochemical features of the addition of triethyl orthoformate to 6-(diethoxymethyl)-1-trimethylsiloxycyclohexene

Article abstract of DOI:10.1134/S1070428014030063

Stereochemistry of the addition of triethyl orthoformate to 6-(diethoxymethyl)-1-trimethylsiloxycyclohexene has been studied. The reaction yields a mixture of isomeric 2,6-bis(diethoxymethyl)cyclohexanones with diequatorial and axial/equatorial orientations of the acetal fragments, the latter prevailing. The stereochemistry of the addition is determined by the transition state structure rather than by thermodynamic stability of the resulting keto diacetal.

Full text of DOI:10.1134/S1070428014030063

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 3, pp. 342–345. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © O.V. Kharitonova, O.V. Osipenko, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 3, pp. 353–356.
Chemistry of Keto Acetals: III.* Stereochemical Features
of the Addition of Triethyl Orthoformate to 6-(Diethoxymethyl)-
1-trimethylsiloxycyclohexene
O. V. Kharitonova and O. V. Osipenko
Lomonosov Moscow State University of Fine Chemical Technology, pr. Vernadskogo 86, Moscow, 119571 Russia
e-mail: khov@orc.ru
Received January 30, 2013
Abstract—Stereochemistry of the addition of triethyl orthoformate to 6-(diethoxymethyl)-1-trimethylsiloxy-
cyclohexene has been studied. The reaction yields a mixture of isomeric 2,6-bis(diethoxymethyl)cyclo-
hexanones with diequatorial and axial/equatorial orientations of the acetal fragments, the latter prevailing. The
stereochemistry of the addition is determined by the transition state structure rather than by thermodynamic
stability of the resulting keto diacetal.
DOI: 10.1134/S1070428014030063
Keto diacetals are interesting but still difficultly
accessible polyfunctional intermediate products in fine
organic synthesis. Keto diacetals were used to obtain
numerous heterocyclic compounds [1, 2] and hydroxy
diacetals as starting materials for the synthesis of
cyanine dyes [3, 4]. The synthesis of keto diacetals
was described in several publications [5–7]. The most
general procedure for the synthesis of β,β′-keto di-
acetals is based on the addition of triethyl orthoformate
to silyl enol ethers containing an acetal fragment
(Scheme 1).
2,6-Bis(diethoxymethyl)cyclohexanone can be
formed as optically inactive cis isomer and two
optically active trans isomers, and the cis isomer can
exist as diequatorial (ee) and diaxial (aa) conformers.
Unfortunately, stereochemistry of the above reactions
remained beyond the scope of all relevant publications.
We decided to explore this problem in the present
work. Scheme 2 illustrates the general scheme of syn-
thesis of 2,6-bis(diethoxymethyl)cyclohexanone (III).
Scheme 2.
Me3SiCl
NaI, Et3N
O
OEt
OEt
Me3SiO
OEt
OEt
Scheme 1.
CH(OEt)3
ZnCl2
OEt OSiMe3
OEt
O
OEt
OEt
EtO
EtO
I
II
R1
R2
R1
R2
OEt
O
OEt
R1 = R2 = H, R1R2 = (CH2)3.
CH(OEt)3, ZnCl2
EtO
OEt
(EtO)2CH
O
O
H
CH(OEt)2
H
III
H
H
(EtO)2CH
CH(OEt)2
Initial 2-(diethoxymethyl)cyclohexanone (I) was
prepared by condensation of 1-(trimethylsiloxy)cyclo-
hexene with triethyl orthoformate [8]. As expected, the
addition of diethoxymethyl group was stereoselective,
and the product was a single isomer with equatorial
orientation of the acetal fragment (according to the
cis Isomers
(EtO)2CH
O
O
H
CH(OEt)2
H
H
(EtO)2CH
H
CH(OEt)2
trans Isomers
1
1H NMR data). The H NMR spectrum of I contained
* For communication II, see [1].
only one one-proton signal at about δ 4.8 ppm (d, 1-H).
342

CHEMISTRY OF KETO ACETALS: III.
The 2-H proton also appeared as a single signal at
343
EtO
OEt
CH4
H2
H10
H5
δ 2.64 ppm (broadened doublet of triplets with
coupling constants of 10.2 and 6 Hz). The coupling
constant 10.2 Hz corresponds to diaxial interaction
between 2-H and 8-H. The coupling constants of 2-H
with 7-H and 1-H are approximately equal (J =
5.9 Hz). These findings suggest axial orientation of
2-H and equatorial orientation of the acetal fragment.
H3
O
H9
H7
H6
H8
CH1
OEt
EtO
B
H4
H10
H5
H2
(A) and axial–equatorial (B) orientation of the sub-
H3
H9
stituents.
H7
The more mobile fraction contained 64% of the ee
isomer and 36% of the ae isomer. This followed from
the intensity ratio (4.7:1) of the 2-H and 3-H signals at
δ 2.58–2.68 and 2.69–2.77 ppm, respectively. The 2-H
signal was a broadened doublet of triplets with the
H6
H8
CH1
O
OEt
EtO
Keto acetal I was subjected to silylation with
chloro(trimethyl)silane in the presence of triethylamine
and sodium iodide in pentane–acetonitrile at –10 to
–0°C (5 h; TLC monitoring). After appropriate treat-
ment, we isolated 6-(diethoxymethyl)-1-trimethylsil-
oxycyclohexene (II). In this reaction the acetal frag-
ment remained intact, and its conformation did not
change. Compound II should be characterized by
a high boiling point and should be thermally unstable
(thermal elimination of alcohol should produce cyclic
analog of Danishefsky’s diene [3]). Poorly repro-
ducible yields were obtained previously [7]. Therefore,
in the present work the product, after washing from
sodium chloride and triethylamine (which could bind
the catalyst in the next step), was neither distilled nor
purified by chromatography but was brought into the
condensation with triethyl orthoformate immediately
after removal of the solvent.
2,6-Bis(diethoxymethyl)cyclohexanone (III) was
synthesized by condensation of silyl enol ether II with
triethyl orthoformate at 10°C (48 h) in the presence of
20% zinc chloride in ethyl acetate as catalyst. The
product was purified by chromatography on silica gel.
We thus isolated two fractions with Rf 0.8 and 0.74.
The fraction with Rf 0.8 was a mixture of isomeric 2,6-
bis(diethoxymethyl)cyclohexanones with diequatorial
coupling constants J2,8 = 10.2 Hz and J2,18 ≈ J2,18
≈
6 Hz. The coupling constant J2,8 = 10.2 Hz indicates
axial position of the 2-H proton and hence equatorial
orientation of the diethoxymethyl substituent. The 3-H
signal of stereoisomer B was a doublet of triplets with
coupling constants of 5.6 and 6.9 Hz. The latter con-
stant corresponds to the 3-H–4-H coupling, and the
former, to 3-H–5-H and 3-H–6-H. Their values suggest
equatorial position of 3-H and axial position of the di-
ethoxymethyl group. The acetal CH protons gave rise
to two doublets at 4.83 and 4.86 ppm at a ratio of
14:86. The singlet at δ 8.58 ppm with an intensity of
0.05H was assigned to the CHO proton in the corre-
sponding aldehyde formed as impurity as a result of
partial hydrolysis of the acetal group. Furthermore,
a triplet at δ 7.31 ppm (0.1H, J = 2 Hz) was observed,
which is likely to belong to proton at the double bond
generated by dealkoxylation of the keto diacetal.
Elimination of ethoxy group is also supported by the
presence of a quartet at δ 4.0 ppm due to OCH2
protons. The increased intensity of the equatorial acetal
proton signal as compared to ring methylene protons
(5-H–10-H) indicates more facile elimination of alco-
hol from the axial acetal group, i.e., with predominant
formation of structure C.
H2
H2
H10
H5
H10
H5
H
OEt
H2
C
CH1
OEt
H9
H9
OEt
O
H7
H7
H6
H8
H6
H8
CH1
CH1
O
OEt
OEt
EtO
EtO
A
C
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

KHARITONOVA, OSIPENKO
344
EXPERIMENTAL
1
The H NMR spectra were recorded from solutions
in CDCl3 on a Bruker MSL-300 spectrometer at
300 MHz) using tetramethylsilane as internal refer-
ence. The progress of reactions was monitored, and the
products were identified, by TLC on Silica gel 60 F254
plates using hexane–ethyl acetate (6:1) as eluent; spots
were visualized by treatment with iodine vapor. The
products were isolated by column chromatography on
Merck Silica gel 60 (eluent hexane–ethyl acetate,
100 :1 to 6:1). Zinc(II) chloride was heated to the
melting point, cooled, ground, and dissolved in anhy-
drous ethyl acetate to a concentration of 20%; sodium
iodide was calcined for 1 h at 250°C; triethylamine
was preliminarily kept over potassium hydroxide and
distilled under atmospheric pressure, a fraction with
bp 89–90°C being collected; chloro(trimethyl)silane
was distilled under atmospheric pressure (bp 57°C);
ethyl acetate, acetonitrile, pentane, and hexane (of
dried or ultrapure grade) were used without additional
purification. 2-(Diethoxymethyl)cyclohexanone (I)
was synthesized as described in [8].
6-(Diethoxymethyl)-1-trimethylsiloxycyclohex-
ene (II). A mixture of 200 mL of acetonitrile, 200 mL
of pentane, 59 g (0.39 mol) of sodium iodide, 55 mL
(0.39 mol) of triethylamine, and 50 mL (0.39 mol) of
chloro(trimethyl)silane was cooled to –10°C, 40 g
(0.2 mol) of 2-(diethoxymethyl)cyclohexanone (I) was
added to the resulting solution, and the mixture was
stirred for 3.5 h at a temperature not exceeding –10°C.
The mixture was then allowed to warm up to 0°C and,
after 1.5 h, to 13°C. After 1 h, the acetonitrile layer
was separated from the pentane layer, and the former
was extracted with pentane (3×50 mL). The combined
extracts were washed with 2% aqueous HCl (2×
50 mL) cooled to 0°C, a cold saturated solution of
sodium carbonate (2×50 mL), and water (2×100 mL),
and dried over sodium sulfate. The solvent was
removed under reduced pressure, and the residue
(40 mL) was brought into further transformations with
additional purification.
Structure of the energetically most favorable conformer of
6-(diethoxymethyl)-1-trimethylsiloxycyclohexene (II) and
direction of electrophilic attack thereon.
The fraction with the lower Rf value (0.74) con-
tained only one 2,6-bis(diethoxysimethyl)cyclohexa-
none (III) isomer with axial–equatorial orientation of
the acetal substituents (structure B). This follows from
the equal intensities of the 2-H and 3-H signals in the
region of δ 2.7 ppm and of the doublet acetal proton
signals at δ 4.8 ppm.
The weight ratio of the fractions with Rf 0.80 and
0.74 is 1:0.57, i.e., the major product in the reaction of
6-(diethoxymethyl)-1-trimethylsiloxycyclohexene (II)
with triethylorthoformate is 2,6-bis(diethoxymethyl)-
cyclohexane (III) with axial–equatorial orientation of
the acetal substituents (stereoisomer B). The ratio of
the ae and ee isomers was 59:41. Prevalence of the
isomer with “unfavorable” axial orientation of one
acetal group was rationalized with the aid of quantum
chemical calculations. As might be expected, semiem-
pirical PM3 calculations of the optimal configuration
of 2,6-bis(diethoxymethyl)cyclohexanone predicted di-
equatorial orientation of the acetal substituents in the
most energetically favorable conformer. Therefore, the
factor determining the formation of the ae conformer is
not its thermodynamic stability but kinetic features of
the reaction of silyl enol ether II with triethyl ortho-
formate. Figure shows the most energetically favorable
configuration of 6-(diethoxymethyl)-1-trimethylsiloxy-
cyclohexene (II) according to quantum chemical cal-
culations. Analysis of the given structure indicates that
trans-attack by electrophile on the double bond leading
to the ae isomer should be preferred from the steric
viewpoint; in fact, this was observed experimentally.
2,6-Bis(diethoxymethyl)cyclohexanone (III).
Compound II prepared as described above, 18 mL
(0.06 mol), was added over a period of 1 h to a mixture
of 40 mL (0.08 mol) of a 20% solution of ZnCl2 in
ethyl acetate and 12 mL (0.1 mol) of triethyl ortho-
formate, cooled to 10°C. The mixture was kept for
48 h at that temperature and treated with a saturated
solution of sodium carbonate to pH 9. The abundant
precipitate was filtered off and washed on a filter with
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

CHEMISTRY OF KETO ACETALS: III.
345
diethyl ether (3×50 mL). The aqueous layer was ex-
tracted with diethyl ether (2×25 mL), the extracts were
combined with the organic phase, dried over sodium
sulfate, and evaporated, and the residue was subjected
to column chromatography.
5-H, 6-H, 7-H, 8-H, 9-H, 10-H), 2.64 br.d.t (1H, 2-H,
J = 10.2, 6 Hz), 3.48–3.61 m (4H, CH2), 3.62–3.78 m
(4H, CH2), 4.83 d (1H, 1-H, J = 6.3 Hz).
REFERENCES
ae Isomer. Yield 3.7 g (20%), nD20 = 1.4565.
1H NMR spectrum, δ, ppm: 1.17 t (6H, CH3, J = 7 Hz),
1.19 t (6H, CH3, J = 7 Hz), 1.50–2.50 m (6H, 5-H,
6-H, 7-H, 8-H, 9-H, 10-H), 2.64 br.d.t (1H, 2-H, J =
10.2, 6 Hz), 2.70 d.t (1H, 3-H, J = 5.6, 7 Hz), 3.48–
3.61 m (4H, CH2), 3.62–3.78 m (4H, CH2), 4.83 d (1H,
1-H, J = 6.3 Hz), 4.86 d (1H, 4-H, J = 6.9 Hz). Found,
%: C 63.71; H 9.95. C16H30O5. Calculated, %: C 63.55;
H 10.00.
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Mixture of ae and ee isomers (36:64). Yield
6.48 g (35%), nD20 = 1.4569. Found, %: C 63.83;
H 9.96. C16H30O5. Calculated, %: C 63.55; H 10.00.
1H NMR spectrum of the ee isomer (from the spectrum
of ae/ee isomer mixture), δ, ppm: 1.17 t (6H, CH3, J =
7 Hz), 1.19 t (6H, CH3, J = 7 Hz), 1.50–2.50 m (6H,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014