Retro-aldol reactions in micellar media

Article abstract of DOI:10.1007/s00706-012-0811-8

Convenient methods for retro-aldol reactions of a, β-unsaturated ketones in micellar media under acidic or basic conditions are proposed that enable obtaining optically pure (3R)-methylcyclohexanone and (1R,4R)-4- methylmenthone in high yields. Springer-V

Full text of DOI:10.1007/s00706-012-0811-8

Monatsh Chem
DOI 10.1007/s00706-012-0811-8
ORIGINAL PAPER
Retro-aldol reactions in micellar media
•
Elena V. Vashchenko Irina V. Knyazeva
•
•
Alexander I. Krivoshey Valerii V. Vashchenko
Received: 19 December 2011 / Accepted: 25 June 2012
Ó Springer-Verlag 2012
Abstract Convenient methods for retro-aldol reactions of
a, b-unsaturated ketones in micellar media under acidic or
basic conditions are proposed that enable obtaining opti-
cally pure (3R)-methylcyclohexanone and (1R,4R)-4-
methylmenthone in high yields.
been proposed [7, 13–15]. However, this method has not
found widespread use because of the difficulties of the
removal of a benzylidene moiety. Thus, in the synthesis of
2-methyldecal-1-one, the benzylidene group has been
removed in several steps including chlorination followed
by treatment with sodium ethylate and aqueous alkali
[7, 8].
Keywords Retro reactions Á Ketones Á Micelles Á
Surfactants
Obviously, the retro-aldol reaction requires media with
high water content (either under acidic or basic catalysis
conditions), whereas the solubility of arylidene derivatives
in such media is extremely low, and this causes low
reaction rates and thus leads to low yields of the products.
Generally, the use of surfactants, which means carrying out
the reaction in micellar media, could result in substantial
enhancement of the process performance [16, 17]. How-
ever, only a few examples of the use of such an approach
for the retro-aldolization of pulegone and cinnamaldehyde
are known at this time [18, 19].
Introduction
Aldol and crotonic condensation reactions are powerful
organic synthesis tools for the formation of a carbon–car-
bon bond [1, 2]. Although the reverse process, the retro-
aldol reaction, is less widespread, it nevertheless plays an
important role in solving of certain synthetic tasks. Thus,
retro-aldol reaction is a simple and useful method for
obtaining (3R)-methylcyclohexanone from naturally
occurring (?)-pulegone [3–6]. Moreover, the retro-aldol
reaction is used in the total synthesis of steroids when
introducing an angular methyl group [7, 8], for obtaining
optically pure 4-methylmentone [9–11], and in the asym-
metric synthesis of optically pure 2-phenylethanols [12].
The lack of a general and effective method for the retro-
aldol reaction is often a restriction for its more widespread
use in organic synthesis. For example, in the synthesis of
steroids and some model compounds, using the benzyli-
dene group as both a blocking and activating group has
In this work, convenient methods for retro-aldol reac-
tions in micellar media under either acidic or basic
conditions are proposed. These methods are especially
useful for the ketones possessing steam volatility. (3R)-
Methylcyclohexanone and (1R,4R)-4-methylmenthone
have been taken as examples to obtain optically pure target
compounds in high yields.
Results and discussion
Retro-aldol reaction in micellar medium under acidic
conditions. Synthesis of (3R)-methylcyclohexanone
from (?)-pulegone
E. V. Vashchenko Á I. V. Knyazeva Á A. I. Krivoshey Á
V. V. Vashchenko (&)
SSI ‘‘STC’’ ‘‘Institute for Single Crystals’’ of NAS
of the Ukraine, 60 Lenin ave., Kharkov 61001, Ukraine
e-mail: vvv6517@mail.ru; valeravv@isc.kharkov.com
The most practical method for the synthesis of optically pure
(3R)-methylcyclohexanone (2) is the retro-aldolization of
123

E. V. Vashchenko et al.
surfactant cetylpyridinium chloride (CPC) was used to
obtain the micellar medium. Retro-aldolization of 1 in
diluted aqueous H2SO4 in the presence of CPC with frac-
tional distillation of the forming acetone followed by steam
distillation of the target compound 2 allows a shortening of
the reaction time to 2 h and an improvement in the yield of
pure 2 up to 85 % (Table 1, entry 4). Moreover, it should
be noted that (3R)-methylcyclohexanone (2) steam distilled
in such a way from the reaction mixture possesses a rather
high purity (more than 95 % according to GC; Table 1,
entry 4); thus, it can be used in further transformations
without additional purification.
Water
O
+
O
H+ or OH-
O
1
2
Scheme 1
naturally occurring (?)-pulegone (1), which is the main
component of pennyroyal oil (Scheme 1).
Conventionally, this reaction is carried out under acidic
conditions by heating (?)-pulegone in hydrochloric acid
[3–5] (Table 1, entry 1) or in diluted aqueous sulfuric acid
[6] (Table 1, entry 2). The reaction is accelerated by dis-
tillation of the forming acetone followed by steam
distillation of the main product 2, which shifts the equi-
librium of the reaction favorably. Nevertheless, even in the
case of distillation of the products, the reaction time is
7–8 h, and the yield of the target compound 2 does not
exceed 70 % (Table 1, entry 1). It seems that these results
are caused by the low solubility of (?)-pulegone in the
aqueous medium. In turn, the low solubility of 1 causes a
relatively low rate of the main reaction and the accumu-
lation of by-products of acid-catalyzed side processes in
the reaction mixture with time. In order to solubilize
compound 1 in the reaction mixture, the industrial method
for carrying out the reaction under basic conditions in a
micellar medium with the use of sodium dodecylsulfate
(SDS) as the surfactant has been proposed [18] (Table 1,
entry 3). The use of this method enables obtaining the
target compound in better yields up to 73 %. However, the
reaction time is much longer (up to 6 days) in comparison
to acidic conditions. The need to maintain a desired pH of
the reaction mixture by addition of fresh NaOH portions
should also be considered as a disadvantage of this method.
In order to overcome the aforementioned problems, we
combined the advantages of the acid-catalyzed process
providing a high reaction rate with the ability of micellar
media to solubilize the starting material, which also
enables a more rapid reaction. The well-known cationic
Retro-aldol reaction in micellar medium under basic
conditions. Synthesis of (1R,4R)-4-methylmenthone
from (1R,4R)-2-benzylidene-p-menthane-3-ones
It has been shown previously [9–11] that the synthesis of
optically pure (1R,4R)-4-methylmenthone can be achieved
by the reaction sequence shown in Scheme 2.
Crotonic condensation of menthone (3) with aromatic
aldehydes 4a–4c gives corresponding arylidene derivatives
5a–5c in 78–84 % yield [20]. The following methylation of
compounds 5a–5c with MeI/tert-BuOK occurs with high
stereoselectivity to give the corresponding (1R,4R)-2-ary-
lidene-4-methyl-p-menthan-3-ones 6a–6c [9–11]. We were
confronted with difficulties when carrying out the last step
of removal of the arylidene group. In contrast to their non-
methylated analogues 5a–5c, the methylated arylidene-
menthanones 6a–6c appear to be very stable in aqueous
alkaline and alcoholic aqueous alkaline media, and
undergo only slow retro-aldolization even with long-term
heating (Table 2, entry 1). Sequential treatment of 6a–6c
with an alcoholic aqueous HCl solution followed by an
alkaline solution results in formation of (1R,4R)-4-meth-
ylmenthone (7) in a very low yield (Table 2, entry 2),
which is probably caused by acid-catalyzed rearrangement
of 6a–6c accompanied with by migration of the arylidene
double bond into the ring [1, 21, 22]. The rearrangement is
also believed to be the main reason for the formation of the
Table 1 The retro-aldolization of (?)-pulegone (1)
Entry
Catalyst/solvent
Surfactant
Reaction timea/h
Yield/%
Purity (GC)/%
Ref.
1
2
3
4c
a
HCl/H2O
None
None
SDS
7–8
15
*144b
62–70
65
n/a
[3–5]
[6]
H2SO4/H2O
NaOH/H2O
H2SO4/H2O
n/a
73
n/a
[18]
CPC
2
85 (91)
98 ([95)
The reaction time is considered to be the time required for the complete acetone distillation
b
Restricted capacity and performance of a fractionating column should be taken into account in this case of large amounts of materials at the
industrial scale
c
The yield and purity of (3R)-methylcyclohexanone (2) steam distilled directly from the reaction mixture are given in brackets
123

Retro-aldol reactions in micellar media
Scheme 2
R
O
R
O
R
R
CH3I
H2O
H
+
+
H
KOH/
DMSO
O
O
tert -BuOK/
tert -BuOH
O
O
3
4a-4c
5a-5c
R = H (a), OMe (b), Br (c)
6a-6c
7
To separate 4a from the target compound 7, we used
transformation of 4a into a non-volatile compound, i.e.,
base-catalyzed oxidation of 4a to the corresponding ben-
zoic acid with potassium permanganate. The target
4-methylmenthone (7) is stable at such conditions, and it
can be steam distilled from the reaction mixture after short-
term heating. According to GC-MS, the product thus
obtained is almost individual. However, taking into
account that intermediate 2-arylidene derivatives 5a and 6a
are oils and thus they were used without additional purifi-
cation, the yield of 7 (46 %) is given per starting menthone 3.
It is worth mentioning that it is more convenient to use
4-methoxybenzylidene derivative 6b instead of 6a for the
synthesis of 7 since compound 6b possesses a higher
melting point and can be easily separated by crystallization
from both unreacted menthone (3) and products of its
alkylation (in contrast to the arylidene derivatives 5,
alkylation of menthone occurs non-selectively [9–11];
Scheme 2, second step), which could decrease the optical
purity of the target compound 7. Moreover, anisaldehyde
(4b) appears to be much less steam volatile than benzal-
dehyde (4a); thus, it can be separated much more easily. By
using compound 6b for the retro-aldolization reaction
(1R,4R)-4-methylmenthone (7) is obtained with an almost
quantitative yield (Table 2, entry 6). The total yield of
three steps is 67 % per starting menthone (3).
Table 2 Synthesis of (1R,4R)-4-methylmenthone (7) from (1R,4R)-
2-arylidene-4-methyl-p-menthan-3-ones 6a–6c
Entry Starting Reaction conditions
material
Reaction Yield/%
time/h
1
2
6c
6c
KOH, EtOH
*168
8
32 [9]
5 [9]
1. HCl, EtOH
2. KOH, EtOH
72
72
24
8
3
4
5
6a
6a
6a
H2SO4, CPC
Tracesa
7a, b
46c
1. NaOH, SDS
1. NaOH, DMSO, SDS
2. KMnO4, Na2CO3, H2O
1. NaOH, DMSO, SDS
2. KMnO4, Na2CO3, H2O
6
6b
8
96d (67c)
a
b
c
d
According to GC-MS
The yield is calculated from compound 6a
The yield is calculated from starting menthone 3
The yield is calculated from compound 6b
target compound 7 only in trace amounts (Table 2, entry 3)
by carrying out the reaction similarly to the retro-aldol-
ization of pulegone described and discussed above
(Table 1, entries 6, 7).
Addition of the anionic surfactant SDS to the aqueous
alkaline solution (similarly to the description in [18]) also
does not improve the yield considerably (Table 2, entry 4).
Addition of a small amount of isopropyl alcohol acting as
anti-foaming agent also did not affect the yield of the target
compound.
In conclusion, carrying out the retro-aldol reaction under
acidic conditions in the micellar medium of the cationic
surfactant CPC enables obtaining optically pure (3R)-
methylcyclohexanone with a relatively short reaction time in
high yield and purity. In the case of a,b-unsaturated ketones,
e.g., arylidene derivatives of (1R,4R)-4-methylmenthone,
which are prone to acid-catalyzed rearrangements, basic
reaction conditions in the micellar medium of the anionic
surfactant SDS in combination with the addition of a polar
aprotic solvent (DMSO) are preferable. In the last case,
separation of the ketone from the accompanying aromatic
aldehyde can be effectively achieved by oxidation of the
aldehyde in mild conditions. In both cases, steam volatility of
the target ketone simplifies their isolation.
Based on the assumption that addition of DMSO to the
reaction mixture will promote not only direct condensation
(as described in [20]) but also the reverse retro-aldolization
process, we used a 6:8:1 mixture of water/DMSO/i-PrOH
(v/v) along with SDS as the reaction medium. Indeed,
combined addition of DMSO and SDS has a synergic effect
that enables the completion of the reaction in 7–8 h
(Table 2, entry 5), and the products of the reaction (4a
and 7) are steam distilled from the reaction mixture.
123

E. V. Vashchenko et al.
intensively refluxed, and the mixture of volatile products
and water was collected in a dropping funnel. Water
(bottom layer) was periodically returned to the reaction
mixture. After distillation had finished (normally 7–8 h),
the water-DMSO reaction mixture was substituted with a
solution of 7.5 g potassium permanganate (0.048 mol) and
7.5 g sodium carbonate (0.070 mol) in 250 cm3 water, and
the collected organic layer was transferred from the
dropping funnel to the flask. The resulting mixture was
refluxed for 30 min, and then (1R,4R)-4-methylmenthan-3-
one was steam distilled from the mixture, separated from
water, and dried over Na2SO4. The obtained product is pure
enough (purity 99.2 % according to GC–MS) to be further
used without additional purification. An analytically pure
sample (purity 99.8 % according to GC-MS) could be
obtained by distillation (b.p.: 220–221 °C) as a colorless
oil. TLC (hexane–ethyl acetate 25:1): Rf = 0.35; MS (EI):
Experimental
1H and 13C NMR spectra were recorded on a Varian
Mercury VX-200 (200 MHz) spectrometer in CDCl3 or
DMSO-d6 using the signal of residual protons of undeu-
terated solvent as the internal standard [23]. Mass spectra
were recorded on a Varian 1200 L GC-MS instrument
either in GC-MS mode or with the use of the direct
exposure probe (DEP) method with EI at 70 eV. Elemental
analyses were performed with an EA-3000 analyser (Eu-
rovector, Italy). IR spectra were recorded on a FT-IR
‘‘Spectrum One’’ instrument (Italy); samples were placed
between ZnSe plates. TLC was performed using TLC
aluminum sheet silica gel 60 F254 (Merck), and detection
was done in an iodine chamber. (?)-Pulegone (1),
(–)-menthone (3), and aromatic aldehydes 4a–4c are
commercially available. Arylidene-p-menthan-3-ones 5a–
5c were obtained according to [20]; (1R,4R)-2-arylidene-4-
methyl-p-menthan-3-ones 6a–6c were synthesized from
substances 5a–5c as described in [9–11].
1
m/z = 168, 153, 135, 126, 109, 97; H NMR (200 MHz,
DMSO-d6): d = 0.60 (3H, d), 0.72 (3H, s), 0.83 (3H, d),
0.97 (3H, d), 1.15–1.35 (1H, m), 1.41–1.60 (2H, m),
1.61–1.86 (1H, m), 1.86–2.00 (1H, m), 2.00–2.15 (1H, m),
2.17–2.37 (2H, m) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 15.64, 17.57, 19.01, 22.01, 23.92, 29.45, 35.08, 36.90,
47.24, 51.19, 214.91 ppm; [a]1D5 = ?12.7° cm2 g-1
(c = 3.3, CHCl3); IR (neat): = 2950 (s), 2910 (s), 2855
(s), 1709 (s), 1455 (s), 1362 (s), 1278 (m), 1222 (m), 1120
(3R)-Methylcyclohexanone (2)
(?)-Pulegone (58.7 g, available from Acros Organics,
purity 92 %, 54.0 g of pure pulegone), 250 cm3 water,
60 cm3 sulfuric acid, and 1 g cetylpyridinium chloride
(CPC) were mixed in a round-bottom flask equipped with a
distillation column (50 9 2 cm, packed with stainless steel
helices and a variable take off head), and gently heated
with stirring. The acetone fraction (b.p.: 56–60 °C) was
slowly distilled off for approximately 2 h. Then the
distillation column was substituted with a dropping funnel,
the reaction mixture was refluxed, and steam distilled (3R)-
methylcyclohexanone together with water was collected in
the funnel. The separated water layer was returned into the
reaction mixture. When steam distillation had finished (in
approximately 2 h), the mixture was cooled, and the
organic layer was collected and diluted with dichlorometh-
ane. The resultant solution was dried with CaCl2, filtered,
and evaporated to give the crude product (36.2 g, 91 %,
purity 95.4 % according to GC–MS) as a slightly yellow
oil. Distillation under atmospheric pressure gives pure
(3R)-methylcyclohexanone (33.8 g, 85 % yield) as a
colorless oil. B.p.: 167.0–167.5 °C; purity 97.8 % (accord-
ing to GC–MS); [a]D20 = ?12.5° cm2 g-1 (neat) (Ref. [24]:
?12.01° cm2 g-1). The 1H NMR spectrum of compound 2
was found to agree with the reported data [25].
(m), 1105 (m) cm-1
.
Acknowledgments Financial support from from the National
Academy of Science of the Ukraine (project no. 0107U003550) is
gratefully acknowledged.
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