On the Michael addition of water to α,β-unsaturated ketones using amino acids

Article abstract of DOI:10.1002/ejoc.201301230

The use of water as a nucleophile for Michael additions is still a challenge in organic chemistry. In this report we describe the use of amino acids as catalysts for the Michael addition of water to α,β- unsaturated ketones. All 20 proteinogenic amino aci

Full text of DOI:10.1002/ejoc.201301230

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301230
On the Michael Addition of Water to α,β-Unsaturated Ketones Using Amino
Acids
[a]
[a]
[a]
[a]
Verena Resch,* Christiane Seidler, Bi-Shuang Chen, Ian Degeling, and
Ulf Hanefeld[
a]
Keywords: Organocatalysis / Amino acids / Water chemistry / Green chemistry / Michael addition
The use of water as a nucleophile for Michael additions is
still a challenge in organic chemistry. In this report we de-
scribe the use of amino acids as catalysts for the Michael ad-
dition of water to α,β-unsaturated ketones. All 20 proteino-
as the best candidate. To obtain a better insight and to deter-
mine the minimum requirements of the catalyst, several
structurally related compounds were tested. The reaction
was characterized in terms of conditions and equilibrium.
genic amino acids were screened and L-lysine was identified
Introduction
However, most of the methods furnishing racemic products
suffer from complex, cumbersome or expensive preparation
of the catalysts.
The Michael addition of water to α,β-unsaturated
ketones still seems to be a difficult task to achieve by using
chemical methods. Although in nature this reaction is ubiq-
uitous due to its presence in many metabolic cycles, only
a few methods using non-enzymatic approaches have been
reported. Apart from enzymatic methods using hy-
In the last few years, amino acids have played an impor-
tant role in organocatalysis. In particular, proline and its
derivatives have been established as versatile catalysts for a
variety of different reactions including Michael additions
[9]
[10]
(
for selected examples see ref. and for reviews see ref.
[
1]
dratases, for example, fumarase, malease, citraconase and
enoyl-CoA hydratase, which are used on an industrial scale,
the only enantioselective direct catalytic example described
so far was published recently and involved the use of a
and references cited therein). In some of these methods, the
use of water or mixtures of water and organic solvent as
reaction media was highlighted, but the addition of water
was not reported. This gives an indication of the difficulty
of using water as a nucleophile in Michael additions. More-
over, the use of an amino acid as catalyst and water as both
solvent and nucleophile has so far not been reported.
We report herein the use of amino acids as catalysts for
the Michael addition of water to α,β-unsaturated ketones
[
2]
DNA-based catalyst for the hydration of enones in water.
The indirect asymmetric addition of water by hydrobor-
ation, that is a two-step approach, has also been described
recently using a Taniaphos catalyst.[ Another method in-
volving the use of a palladium-wool complex to convert 2-
cyclohexen-1-one into 3-hydroxycyclohexanone in a non-
asymmetric fashion has been reported.[ This method pro-
vides high conversions, however, earlier studies and theo-
retical calculations indicated that the reaction equilibrium
lies on the substrate side. Furthermore, the use of acidic
3]
(Scheme 1). As a result of its rigid character and its fre-
4]
quent use in earlier studies, 2-cyclohexen-1-one (1a) was
chosen as the main test substrate. The study focused on l-
lysine and l-histidine as the most promising catalysts.
Furthermore, the reaction conditions and reaction equilib-
rium were evaluated and different α,β-unsaturated ketones
were tested. To obtain more insight into this reaction, the
[5]
[
6]
[7]
ion-exchange resins has been reported and the use of
phosphine catalysts has been described for the addition of
water and other nucleophiles to α,β-unsaturated ketones.
[
8]
[
a] Gebouw voor Scheikunde, Afdeling Biotechnologie, Technische
Universiteit Delft,
Julianalaan 136, 2628 BL Delft, The Netherlands
E-mail: v.a.resch@tudelft.nl
u.hanefeld@tudelft.nl
http://www.bt.tudelft.nl/boc
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301230.
©
2013 The Authors. Published by Wiley-VCH Verlag GmbH &
Co. KGaA. This is an open access article under the terms of
the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the
original work is properly cited.
Scheme 1. Michael addition of water to α,β-unsaturated ketones
catalysed by lysine.
Eur. J. Org. Chem. 2013, 7697–7704
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7697

V. Resch, C. Seidler, B.-S. Chen, I. Degeling, U. Hanefeld
SHORT COMMUNICATION
minimum requirements of the catalysts were determined by cause the consumption of 2-cyclohexen-1-one without the
reducing the number of functional groups on both l-histi- formation of the desired Michael addition product leading
dine and l-lysine.
to a slight decrease in the mass balance. l-Glutamine
showed good activity, but again the mass balance was not
as good as with l-lysine (90% compared with 97%). Based
Results and Discussion
[
11]
on these results, l-lysine and l-histidine were further in-
We started our investigation by screening the 20 pro- vestigated as two structurally different amino acids. In gene-
teinogenic amino acids as potential catalysts for the ral, however, it can be noted that the three basic amino
Michael addition of water to 2-cyclohexen-1-one (1a) as the acids, l-arginine, l-histidine and l-lysine, are among the
main test substrate. Because the reactions were carried out best catalysts tested. Also, l-glutamine, an amino acid with
in water as the only solvent, the pH needs to be considered a polar uncharged side-chain, showed good catalytic abili-
an important parameter. The dissolution of amino acids ties. It should be emphasized that no changes in the pH of
alone in water leads to a change in the pH of the reaction the buffer system were ensured after dissolution of the
medium. Therefore all reactions were buffered to pH 7 by amino acids. Grouping the amino acids by their structural
using sodium phosphate (250 mm). To avoid the presence of and electronic properties showed no clear trend. Also, a
additional amines, no nitrogen-containing buffer systems or plot of the pK values of the α-amino groups against con-
a
salts were used. To compare the rate of the reaction, the version showed no correlation between the reaction rate
initial rates (reaction time 3 h) were measured well before and pK (see the Supporting Information).
a
the maximum yield was reached. Blank reactions contain-
ing only substrate and the corresponding buffer were per- reaction medium might have an influence on the reaction
formed in parallel. rate and should therefore be considered. To quantify this
Because the reaction takes place in water, the pH of the
As shown in Figure 1, most of the 20 amino acids cata- effect, the initial rates were measured at different pH values
lyse the addition of water to 2-cyclohexen-1-one (1a), except by using sodium phosphate buffer (pH 6–8) and borate
for tyrosine, which shows no acceleration compared with buffer (pH 9 and 10) to control the pH of the reaction me-
the background reaction caused by buffer alone. This might dium.
be caused by the fact that tyrosine is barely soluble in water
and therefore no homogeneous reaction system could be of the reaction on the pH of the medium (pH axis, Fig-
established. ure 2). The conversion of 2-cyclohexen-1-one into 3-hy-
The results of pH screening clearly show the dependency
The four fastest reactions were observed with l-histidine, droxycyclohexanone increased with increasing pH. Because
–
l-lysine, l-glutamine and l-cysteine. The fastest reaction OH ions might be the active species attacking the Michael
–
rate was achieved with l-cysteine, but taking the mass bal- acceptor, the concentration of OH plays an important role
ance into account, this system is not competitive with, for in the reaction rate and therefore higher pH values lead to
example, l-lysine. Side-reactions such as polymerization an acceleration of the reaction. In parallel, it can be noted
Figure 1. Screening of the 20 proteinogenic amino acids for their ability to catalyse the Michael addition of water to 2-cyclohexen-1-one
(
1a) yielding 3-hydroxycyclohexanone. The bars represent conversion. The blank reaction is represented by the striped bar. Dots represent
the mass balance.
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Michael Addition of Water to α,β-Unsaturated Ketones
that by increasing the pH, the mass balance decreases and catalysed (Figure 2), the focus was set on the primary amine
more side-reactions occur due to the harsher reaction con- group rather than on the carboxylic acid functionality. Sev-
ditions. Here again, polymerization products form, as is evi- eral structurally reduced catalysts based on l-histidine and
dent by the change in colour of the reaction mixture; the l-lysine were tested. Decreasing the number of functional
colourless reaction mixture turned yellowish over time at groups should indicate which functionalities are involved in
pH values higher than 8.
the catalysis. On this basis, cadaverine, butylamine, propyl-
amine, ethylamine and methylamine were tested as possible
truncated l-lysine analogues (Figure 3).
Figure 3. Study of the minimum requirement for the catalyst l-
lysine: primary amines cadaverine, butylamine, propylamine, ethyl-
amine and methylamine were used.
The same principle was applied to l-histidine. As pos-
sible catalysts, histamine, 4-methyl-1H-imidazole, imidazole
and pyrrole were tested. The small amino acids glycine and
l-alanine, representing catalysts in which both the primary
amine and the carboxylic acid are retained but not the sec-
ond primary amine or imidazole moiety, were included for
comparison (Figure 4).
Figure 2. Temperature and pH profile for the addition of water to
2-cyclohexen-1-one (1a). Reactions were carried out at the given
temperatures and pH values for a reaction time of 3 h (initial rates).
Full bars represent reactions with l-lysine as catalyst, striped bars
represent blank reactions (buffer only, no l-lysine added).
At pH values of around 10, no beneficial effect of the
amino acid could be detected because the background reac-
tion caused by the buffer is equally fast. An approximately
neutral pH gave the best results in terms of reaction rate
and mass balance, for example, at pH 7, the l-lysine-cata-
lysed reaction is around six times faster than the back-
ground reaction mediated by buffer only.
The dependence on temperature was also evaluated be-
tween 20 and 50 °C. A clear trend towards a higher reaction
rate was detected at higher temperatures. Experiments re-
Figure 4. Study of the minimum requirement for the catalyst l-
histidine: imidazole derivatives histamine, 4-methyl-1H-imidazole,
imidazole and pyrrole were used. Glycine and l-alanine as catalysts
with both the carboxylic acid moiety and the primary amine re-
vealing the temperature dependence were also carried out tained have also been studied.
as initial rate experiments (reaction time 3 h). All tempera-
tures were tested at pH values from 6 to 10, including blank
The use of propylamine, ethylamine, 4-methyl-1H-imid-
experiments with buffer only. It can be noted that at higher azole, imidazole or pyrrole showed no significant effect over
temperatures the reaction seems to be more prone to the buffer alone. Note also that none of the reactions with the
polymerization side-reaction. This is again evident by the structurally reduced catalysts were as fast as with l-hist-
change in colour from colourless to yellowish and by the idine or l-lysine. The same holds true for glycine, which can
incomplete mass balance. Compromising between mass bal- be seen as a structurally reduced version of l-leucine and
ance and reaction velocity, the best results were achieved at l-histidine.
40 °C.
Comparison of the results obtained with the truncated
After optimizing the reaction conditions, the minimal catalysts and with l-lysine and l-histidine showed that in
requirement of the catalyst was investigated. Contemplating principle a primary amino group is essential (Figure 5).
the catalytically active moiety, amino acids have several po- Nevertheless, when no carboxylic acid moiety is present, as
tential reactive centres. On the one hand, the primary amine for cadaverine or histamine, the rate of the reaction is al-
or the carboxylic acid group might play an important role, most reduced by half and no acceleration of the reaction
on the other hand, the imidazole moiety of l-histidine rate was observed with ethylamine or propylamine. Thus it
might be an important feature. In another scenario, both can be concluded that the carboxylic acid moiety also has
moieties may need to be present. As the reaction is base- an important influence on the reaction. This is supported
Eur. J. Org. Chem. 2013, 7697–7704
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V. Resch, C. Seidler, B.-S. Chen, I. Degeling, U. Hanefeld
SHORT COMMUNICATION
by the findings of Ramachary and Mondal, who used a
nitrogen-containing base, in general, proline or pyrrolidine
derivatives, in combination with an acid for the addition of
methanol and longer-chain alcohols to a variety of different
α,β-unsaturated ketones.[ Amino acids combine both of
these features in one molecule and because the carboxylic
acid moiety is deprotonated under neutral conditions, it
might also serve as a proton acceptor and deprotonation of
water might occur. Our findings support the assisting effect
of the acid functionality, and based on the mechanism pro-
posed by Ramachary and Mondal, the following mecha-
nism can be assumed for the addition of water to 2-cy-
clohexen-1-one (1a; Scheme 2). Starting with the formation
of aminal 3, the iminium cation 4, which is in equilibrium
9d]
–
with 5, is formed by the elimination of OH . The mecha-
Figure 5. Conversions achieved with structurally different catalysts
for the addition of water to 2-cyclohexen-1-one (1a). Non-amino
–
nism proceeds via the attack of the OH species at the 3-
–
position. The formation of the OH ion from water is as- acid catalysts are shown as striped bars, l-lysine as a grey bar, l-
sisted by the deprotonated carboxylic acid moiety. Upon histidine as a black bar, and l-alanine and glycine as light-grey
bars. Conversions were measured in the linear phase of the reac-
tion. The conversion with buffer only (white bar) is shown for com-
parison.
hydrolysis, the Michael product 2a is released and the free
amino acid is formed ready to enter the next catalytic cycle.
A closer look at how enzymes, and therefore nature, per-
form the addition of water reveals that the water molecule
is often deprotonated and coordinated by a carboxylate res- small synthetic β-turn tetrapeptides as catalysts led to a
idue in the active site. For example, in the case of enoyl- similar mechanism in which again both the amino and car-
CoA hydratase, a hydratase that is involved in the degrada- boxylic acid functionality are involved.[13]
tion of fatty acids, the water is deprotonated/coordinated
The position of the equilibrium was investigated by fol-
by two glutamic acid residues.[ Furthermore, a very re- lowing the reaction over time and the equilibrium constant
12]
cent study of the dehydration of β-hydroxy ketones using was calculated from the final conversion. Given an equilib-
Scheme 2. Proposed catalytic cycle for the hydration reaction.
7700
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Michael Addition of Water to α,β-Unsaturated Ketones
Figure 6. Time course of both the hydration and dehydration reaction catalysed by l-lysine. ᭹: hydration reaction of 2-cyclohexen-1-one
with 25 mol-% catalyst; ᭺: hydration reaction with 50 mol-% catalyst; ᭿: dehydration reaction of 3-hydroxycyclohexanone with 25 mol-
%
catalyst.
rium constant of 0.36Ϯ0.04, the reaction lies on the sub-
strate side allowing a maximum conversion of 25%. Al-
though water is present in huge excess, the substrate side is
still preferred as a result of the conjugation of the double
bond to the ketone.
Further proof of the equilibrium was evidenced by doub-
ling the amount of catalyst, which still led to a conversion
at 25% (Figure 6). The equilibrium constant calculated
[
5]
from our data is in accord with previous investigations,
however, our data does not support the results reported by
Wang et al., who claimed yields of 92.0% by using a palla-
Figure 7. Substrates tested for the addition of water to 2-cy-
clohexen-1-one (1a) using l-lysine as catalyst.
dium–wool complex as catalyst for the addition of water to
4]
2
-cyclohexen-1-one.[
Attempts to obtain higher yields by employing a biphasic
Table 1. Isolated yields from preparative-scale hydration reac-
tions.
system using different organic solvents to achieve concur-
rent extraction of the product did not provide a solution to
the problem. In fact, the opposite was the case. By using a
biphasic system, the substrate immediately migrates into the
organic phase and is therefore no longer available for the
addition of water. Because the reaction proceeds very
cleanly, both the product and the remaining substrate can
be isolated in pure form after simple silica gel chromatog-
raphy. This allows the reuse of the remaining substrate in
additional reaction cycles and therefore an economically
improved reaction system.
[a]
Substrate
Isolated yield [%][a]
1
1
a
b
21.0
9.8
14.3
n.c.
n.c.
n.c.
n.c.
1
c
1
1e
1
1
d
f
g
[a] n.c.: no conversion.
To elucidate the substrate scope, six further α,β-unsatu- amino acids can promote the hydration reaction. Because
rated ketones structurally closely related to the main test no ee was detected for product 2a, and considering the sim-
substrate 1a were tested by using l-lysine as catalyst (Fig- plicity of l-lysine, there is still room for improvement in
ure 7). The results are presented in Table 1.
terms of asymmetric induction. However, the small size of
Because the addition of water creates a new chiral centre, water might make the asymmetric Michael addition with
the ee of the product 2a was determined after conversion low molecular weight catalysts challenging. For example,
to the corresponding acetate.[
16b]
Although optically pure Ramachary and Mondal reported the asymmetric Michael
amino acids were used, the addition of water did not pro- addition of benzyl alcohol as a nucleophile to 3-nonen-2-
ceed in an asymmetric fashion and no ee could be deter- one using l-proline as catalyst, which resulted in an ee of
[
9d]
mined.
11%.
The low ee obtained in the reaction with a bulky
Given that water is considered to be a poor nucleophile, nucleophile like benzyl alcohol shows the challenge of the
it is even more astonishing that simple compounds like asymmetric addition.
Eur. J. Org. Chem. 2013, 7697–7704
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V. Resch, C. Seidler, B.-S. Chen, I. Degeling, U. Hanefeld
SHORT COMMUNICATION
accordance with literature[16b]). Electrospray Ionization (ESI) high-
resolution mass spectrometry was performed with a Bruker micrO-
Conclusions
β-Hydroxy ketones are an important class of compounds TOF-Q instrument in positive ion mode (capillary potential of
often found as a common structural motif in natural prod- 4500 V).
ucts. Although the molecules themselves look rather simple,
their synthesis can be challenging. One-step synthetic stra-
tegies commonly used for the preparation of β-hydroxy
General Procedure for Initial Rate Measurements: Reactions were
carried out in 1.5 mL screw-capped glass vials to prevent evapora-
tion of substrate/product. Shaking was performed in a heated table-
ketones structurally closely related to 3-hydroxycyclohexan- top shaker at the given temperature. Buffers in the range pH 6–8
one are, for example, the desymmetrization of the corre- were prepared as sodium phosphate buffers, buffers at pH 9 and 10
sponding diol by using, for example, molecular oxygen, N- were prepared as borate buffers (all at a buffer strength of 250 mm).
[
14]
l-Histidine or l-lysine monohydrochloride (0.05 mmol) was dis-
solved in the required buffer (1 mL) and 2-cyclohexen-1-one
hydroxyphthalimide and [Co(acac) ],
dimethyldioxir-
3
ane[ or sodium dichromate. Starting the desymmetriz-
ation from the diketone rather than from the diol by using
a biocatalytic approach has also been described.[ Another
route involves the hydrogenolysis of β-epoxy ketones using,
for example, Bu SnH/Bu SnI/phosphine oxide
Cp TiCl]. Also, the pyridinium-assisted ring-opening of
15]
[16]
(
20 mg, 0.21 mmol) was added. For blank reactions the set-up was
the same but without the addition of the amino acid. Reactions
were allowed to proceed at the given temperature for 3 h. For work-
up, the aqueous reaction mixtures were saturated with NaCl and
extracted with ethyl acetate (2ϫ 0.5 mL). The combined organic
layers were dried with Na SO and analysed by GC (for method
17]
[
18]
or
3
3
[
19]
[
2
2
4
epoxide rings followed by NaBH reduction has been de- see General Methods).
4
[
20]
scribed. Although intramolecular aldolization of keto al-
dehydes is rarely employed, good results have been obtained
by using triazabicyclo[4.4.0]dec-5-ene (TBD) as base.
General Procedure for Catalyst Screening: The reaction set-up for
the catalyst screening was the same as used to determine the initial
rates. l-Arginine, l-histidine, l-lysine monohydrochloride, l-as-
partic acid, l-glutamic acid, l-serine, l-threonine, l-aspargine, l-
glutamine, l-cysteine, glycine, l-proline, d-alanine, l-isoleucine, l-
[
21]
However, a straightforward approach starting from the α,β-
unsaturated ketone by the direct Michael addition of water
to the conjugated double bond still had not been described. leucine, l-methionine, l-phenylalanine, l-tryptophan, l-tyrosine, l-
Thus, we have investigated the use of amino acids, in par- valine, histamine, 4-methyl-1H-imidazole, imidazole, pyrrole, ca-
ticular, l-lysine, as novel catalysts for the Michael addition daverine dihydrochloride, butylamine, propylamine, ethylamine and
methylamine (0.05 mmol) were dissolved in sodium phosphate
buffer (pH 7, 1 mL, 250 mm). After the addition of 2-cyclohexen-
of water to α,β-unsaturated ketones by using 2-cyclohexen-
1-one (1a) as the main test substrate. The reaction proceeds
1-one (1a; 20 mg, 0.21 mmol), the reaction was allowed to proceed
under mild conditions by using water both as substrate and
green solvent following the principle of “the best solvent is
for 3 h at 40 °C. Work-up and analysis were performed as described
above.
[
22]
no solvent”.
Furthermore, l-lysine represents a cheap,
Time Study and Equilibrium Reaction: Samples for the time study
were prepared and analysed as described above in General Pro-
cedure for Initial Rate Measurements. Reactions were performed
at 40 °C and sodium phosphate buffer (pH 7, 250 mm) was used.
readily available and sustainable catalyst.
Experimental Section
General Procedure for Substrate Screening: Reactions were carried
out as described in the General Procedure for Initial Rate Measure-
ments. Whenever the substrate was not soluble in buffer, acetoni-
trile was used as co-solvent. After extraction with ethyl acetate, the
1
13
General Methods: H and C NMR spectra were recorded with a
1
13
4
00 MHz spectrometer ( H: 400 MHz, C: 100 MHz) and chemi-
cal shifts (δ) are given in ppm. Column chromatography was per-
formed by using silica gel 60 (particle size 0.063–0.2 mm). Ethyl
acetate and petroleum ether used for column chromatography were
distilled before use. Silica gel plates 60 F254 were used for TLC. The
conversion from 2-cyclohexen-1-one (1a) to 3-hydroxycyclohexan-
one (2a) was determined by GC (column: Varian CP-Wax 52 CB,
samples were dried with Na
by GC–MS (Varian
5 mϫ0.25 mmϫ0.4 μm, with He as carrier gas).
2
SO
4
and crude samples were analysed
FactorFour
VF-1ms column,
2
Preparative-Scale Synthesis of 3-Hydroxycyclohexanone (2a): For
isolation and characterization of the Michael addition product, the
reaction was carried out on a preparative scale. 2-Cyclohexen-1-
one (1a; 3.02 g, 31.3 mmol) was dissolved in sodium phosphate
buffer (pH 7, 150 mL, 250 mm). l-Lysine monohydrochloride
(1.37 g, 7.5 mmol) was added and the reaction was stirred for 24 h
at 40 °C. Work-up was performed by continuous liquid–liquid ex-
traction overnight (200 mL of ethyl acetate was continuously
5
0ϫ0.53ϫ2.0 μm) using an internal standard (dodecane) and cali-
bration lines for both substrate (2-cyclohexen-1-one) and product
3-hydroxycyclohexanone) with the following specifications and
temperature program: start 80 °C hold for 5 min, to 140 °C at
0 °C/min, hold for 3 min, to 200 °C at 50 °C/min, hold for 3 min,
to 250 °C at 50 °C/min, hold for 1 min; injector temperature:
50 °C, detector temperature: 270 °C, total nitrogen flow: 20 mL/
(
5
2
min; retention times: 2-cyclohexen-1-one: 7.22 min, 3-hydroxy- bubbled through the aqueous phase). The organic phase was dried
cyclohexanone: 12.90 min, dodecane: 3.89 min. GC–MS analysis
was performed with a mass-selective detector using He as carrier
2 4
with Na SO and evaporated under reduced pressure. The crude
product mixture was purified by flash chromatography on silica
gas
and
a
Varian
FactorFour
VF-1ms
column
gel (ethyl acetate/petroleum ether, 1:1) to yield 0.74 g (21%) of a
1
(25 mϫ0.25 mmϫ0.4 μm). The ee of 3-oxocyclohexyl acetate was
colourless oil. H NMR (CDCl
3
, 400 MHz): δ = 1.64–1.80 (m, 2
measured by GC with a chiral stationary phase (Chiradex GTA)
using the following temperature program: injector temperature:
H), 1.96–2.11 (m, 2 H), 2.29 (t, J = 6.6 Hz, 2 H), 2.39 (dd, J = 7.5,
14.1 Hz, 1 H), 2.46 (s, 1 H), 2.63 (dd, J = 4.1, 14.1 Hz, 1 H), 4.14–
4.21 (m, 1 H) ppm (in accord with the literature[ ). C NMR
16b]
13
200 °C, detector temperature: 220 °C, split 60, start 150 °C, hold
for 10 min, to 170 °C at 25 °C/min, hold 1.2 min. Retention times
for racemic acetylated alcohol: 6.2 min and 6.7 min (R and S; in
(CDCl
accord with the literature
3
, 100 MHz): δ = 20.5, 32.4, 40.7, 50.1, 69.3, 210.8 ppm (in
[16b]
+
). MS: m/z (%) = 114 (24) [M] , 73
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Michael Addition of Water to α,β-Unsaturated Ketones
(
(
13), 71 (33), 69 (13), 68 (45), 60 (46), 58 (30), 57 (19), 55 (66), 54 2-Chlorocyclohex-2-enone (1e):[23] 2-Cyclohexen-1-one (1 g,
15), 44 (99), 43 (100), 42 (94), 41 (48), 40 (13).
10.40 mmol) was dissolved in DMF/c.HCl (15 mL, 1:1) followed
by the addition of m-CPBA (2.68 g, 15.54 mmol). The reaction was
allowed to proceed for 30 min at room temperature and was then
Preparative-Scale Synthesis of 3-Hydroxy-4,4-dimethylcyclohexan-
one (2b): For isolation and characterization of the Michael addition
product, the reaction was carried out on a preparative scale. 4,4-
Dimethylcyclohexanone (1b; 0.97 g, 7.69 mmol) was dissolved in
sodium phosphate buffer (pH 7, 35 mL, 250 mm) and acetonitrile
quenched with 1 n NaHCO
tracted with EtOAc (3ϫ 10 mL) and the combined organic layers
were dried with Na SO . The organic solvent was evaporated under
3
(10 mL). The aqueous phase was ex-
2
4
reduced pressure and the crude reaction product purified by flash
chromatography on silica gel (ethyl acetate/petroleum ether, 1:8) to
yield 0.73 g (54%) of a pale-rosy solid (m.p. 69–72 °C). H NMR
(
15 mL). l-Lysine monohydrochloride (0.45 g, 2.5 mmol) was
added and the reaction mixture was stirred for 24 h at 40 °C. Work-
up was performed by continuous extraction with ethyl acetate
(
evaporated under reduced pressure. The crude product mixture was
purified by flash chromatography on silica gel (ethyl acetate/petro-
leum ether, 1:1) to yield 0.11 g (9.8%) of a colourless oil. H NMR
1
(
5
CDCl
3
, 400 MHz): δ = 2.03–2.09 (m, 2 H), 2.48 (dt, J = 5.0,
2 4
200 mL) overnight. The organic phase was dried with Na SO and
.4 Hz, 2 H), 2.59 (t, J = 6.6 Hz, 2 H), 7.14 (t, J = 4.5 Hz, 1
1
3
H) ppm. C NMR (CDCl
146.5, 191.4 ppm (in accord with the literature ). MS: m/z (%) =
1
8
5
3
, 100 MHz): δ = 22.6, 27.0, 38.5, 132.2,
[23]
1
+
+
30 (68) [M] , 132 (23) [M] , 104 (26), 102 (75), 91 (14), 89 (46),
8 (18), 76 (19), 74 (58), 67 (98), 65 (23), 63 (11), 61 (16), 55 (100),
3 (23), 51 (18), 50 (12), 42 (17), 41 (27), 40 (10).
(CDCl
3
, 400 MHz): δ = 1.07 (s, 3 H), 1.12 (s, 3 H), 1.44–1.52 (ddd,
J = 6.7, 7.9, 14.2 Hz, 1 H), 1.86 (ddd, J = 6.6, 7.0, 13.6 Hz, 1 H),
1
2
.94 (s,1 H), 2.31–2.43 (m, 2 H), 2.40 (dd, J = 8.1, 14.6 Hz, 1 H),
.64 (dd, J = 4.2, 14.8 Hz, 1 H), 3.69 (dd, J = 4.3, 8.1 Hz, 1
Supporting Information (see footnote on the first page of this arti-
cle): The plot of pK against conversion from amino acid screening,
H and C NMR spectra and HRMS spectrum.
1
3
H) ppm. C NMR (CDCl
3
, 100 MHz): δ = 21.0, 26.1, 34.1, 34.7,
a
+
1
13
3
8
5
7.7, 46.4, 50.4, 210.1. ppm. MS: m/z (%) = 142 (13) [M] , 86 (86),
2 (12), 72 (11), 71 (25), 70 (55), 69 (28), 67 (12), 58 (40), 57 (54),
6 (100), 55 (59), 53 (13), 44 (22), 43 (97), 42 (24), 41 (80).
Acknowledgments
Preparative-Scale Synthesis of 3-Hydroxycycloheptanone (2c): For
isolation and characterization of the Michael addition product, the
reaction was carried out on a preparative scale. Cyclohept-2-enone
Financial support was provided by the Austrian Science Fund
(
FWF) through an Erwin-Schroedinger Fellowship (J3292, to
(
(
1c; 1.03 g, 9.41 mmol) was dissolved in sodium phosphate buffer
pH 7, 35 mL, 250 mm) and acetonitrile (15 mL). l-Lysine monohy-
V. R.). A senior research fellowship from the China Scholarship
Council/Delft University of Technology Joint Program (to B.-S.C.)
is gratefully acknowledged. The authors would like to thank J. H.
Schrittwieser for fruitful discussions and M. Gorseling and R.
van Oosten for the technical assistance. Furthermore, E. Janssen
and Prof. R. V. A. Orru are gratefully acknowledged for HRMS
measurements.
drochloride (0.45 g, 2.5 mmol) was added and the reaction mixture
was stirred for 24 h at 40 °C. Work-up was performed by con-
tinuous extraction with ethyl acetate (200 mL) overnight. The or-
ganic phase was dried with Na SO and evaporated under reduced
2 4
pressure. The crude product mixture was purified by flash
chromatography on silica gel (ethyl acetate/petroleum ether, 1:1) to
yield 0.17 g (14.3%) of a yellowish oil. H NMR (CDCl
4
1
3
,
[
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3
13
0.8 Hz, 1 H) ppm. C NMR (CDCl
3
, 100 MHz): δ = 23.7, 24.2,
+
8.7, 44.3, 51.6, 67.4, 212.2 ppm. MS: m/z (%) = 128 (7) [M] , 110
(
(
12), 86 (25), 82 (14), 71 (45), 70 (14), 69 (39), 68 (56), 67 (32), 60
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H12NaO [M + Na] 151.0735; found 151.0733.
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2
stopped by extraction with acidified water (3 mL) and Et
0 mL). The combined organic layers were washed with water and
brine, dried with Na SO , and evaporated under reduced pressure.
2
O (3ϫ
1
5
2
4
[
[
The crude product mixture was purified by flash chromatography
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1
2
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1
3
, 400 MHz): δ =
.74–1.98 (m, 4 H), 2.08 (s, 3 H), 2.37 (t, J = 6.5 Hz, 2 H), 2.48
(
5
dd, J = 6.3, 14.8 Hz, 1 H), 2.61 (dd, J = 4.3, 14.8 Hz, 1 H), 5.20–
.25 (m, 1 H) ppm (in accord with the literature[
16b]
13
). C NMR
(CDCl
3
, 100 MHz): δ = 20.6, 21.1, 29.2, 40.9, 46.5, 71.5, 170.1,
[16b]
2
(
8
5
(
08.3 ppm (in accord with the literature
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1 (2), 73 (3), 71 (4), 70 (2), 69 (7), 68 (33), 67 (5), 60 (3), 58 (5),
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Eur. J. Org. Chem. 2013, 7697–7704
© 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7703

V. Resch, C. Seidler, B.-S. Chen, I. Degeling, U. Hanefeld
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Received: August 15, 2013
[
Published Online: October 15, 2013
2011, 22, 1736–1739.
7704
www.eurjoc.org
© 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2013, 7697–7704