Organocatalytic Enantioselective Decarboxylative Protonation Reaction of Meldrum's Acid Derivatives under PTC Conditions

Article abstract of DOI:10.1002/ejoc.201800331

An original organocatalyzed enantioselective protonation sequence of a transient quaternary ammonium enolate species has been developed by starting from readily available disubstituted Meldrum's acid derivatives and phenols. Under phase-transfer-catalytic (PTC) conditions, chiral nonracemic 2-aryl propionic ester derivatives were obtained in good isolated yields with enantioselectivities up to 70 % ee. The usefulness of the approach was demonstrated by the synthesis of enantioenriched (S)-ibuprofen.

Full text of DOI:10.1002/ejoc.201800331

A Journal of
Accepted Article
Title: Organocatalytic enantioselective decarboxylative protonation
reaction of Meldrum's acid derivatives under PTC conditions
Authors: Fabien Legros, Thomas Martzel, Jean-François Brière,
Sylvain Oudeyer, and Vincent Levacher
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800331
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800331
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10.1002/ejoc.201800331
European Journal of Organic Chemistry
FULL PAPER
Organocatalytic enantioselective decarboxylative protonation
reaction of Meldrum’s acid derivatives under PTC conditions
Fabien Legros,[a] Thomas Martzel,[a] Jean-François Brière,[a] Sylvain Oudeyer[a]* and Vincent
Levacher[a]
Dedication ((optional))
Abstract: An original organocatalyzed enantioselective protonation
sequence of transient quaternary ammonium enolate species was
developed starting from readily available disubstituted Meldrum’s acid
derivatives and phenols. Chiral non-racemic 2-aryl propionic ester
derivatives were obtained in good isolated yields and up to 70% ee
under PTC conditions. The usefulness of the reaction was
demonstrated in the course of the synthesis of enantioenriched (S)-
ibuprofen.
nucleophiles such as phenol or benzhydrol derivatives to ketenes
was developed. Using either Brønsted or Lewis base catalysts
provided 2-aryl propionic acid derivatives in high yields and
enantioselectivities up to 95% (Figure 1a, left part).[8]
Nevertheless, the use of reactive ketene precursors, that are by
nature quite unstable, limit the attractiveness of this approach.
a) Previous work:
O
Hemi-malonates
HO2C
o
o
o o
OR1
ee
Scope
Stability
o
o
Alk Ar
Introduction
Ref. 7 Decarboxylation
Enantioselective protonation (EP) of enolates for accessing
enantiomerically enriched a,a-disubstituted carbonyl compounds
remains a challenging area of research due to the difficulty of
introducing the smallest element of the periodic classification in a
stereocontrolled manner. Nevertheless, this methodology gives
access to ubiquitous enantiomerically enriched a,a-disubstituted
carbonyl motifs and, consequently, several research groups have
developed elegant and efficient strategies based on either
enzymatic, organometallic or organocatalytic approaches over
the years.[1] The usefulness of such strategies has been
demonstrated during the course of the total synthesis of natural
products such as (S)-a-Damascone,[2] or homoisoflavones
isolated from Chlorophytum Inornatum and Scilla Nervosa[3]
together with drugs derived from 2-aryl propionic acid such as (S)-
Naproxen.[4] The later architecture is of particular interest due to
its wide range of biological properties.[5] Thus, organocatalyzed
EP reaction is a synthetic approach of choice for the 2-aryl
propionic acid derivatives despite the catalytic formation of
transient acyclic ketene enolate for which the complete control of
the configuration remains challenging.[6] Several organocatalytic
EP approaches were developed providing highly reactive non-
cyclic intermediates (Figure 1a). From an historical point of view,
enantioselective decarboxylative protonation of alkyl aryl
substituted malonic or hemi-malonic acids was first tackled
(Figure 1a, upper part).[7] These approaches suffered from a lack
of enantioselectivity (ees below 40%) and generally required the
use of stoichiometric amount of a chiral base. Several years later,
the two steps 1,2-addition-protonation sequence of protic
O
1,2-Nucleophilic
addition
O
O
•
EP
OR1
Alk
Ar
OR1
OR1
Alk
Ar
Ref. 8
*
H Ar
H
Alk
Ketene
Chiral 2-aryl
propionic acid
derivatives
o
o
o
o
o o
ee
Scope
Stability
1,4-Nucleophilic
addition
Ref. 9-10
Ar
Alk = CH2SR,
CH2COAr
Acrylate derivatives
ee
Scope
Nu
o
o
o
o
OR1
Stability
o
o
O
b) This work: Enantioselective decarboxilative protonation of
Meldrum's acid (MA) derivatives under PTC conditions
Alk Ar
*
*
R4N+ArO− ArOH
O
EP
O
NR4
O
O
(cat.)
ArOH
Alk
Ar
OAr
OAr
OAr
*
- Me2CO
- CO2
− R4N+ArO−
O
O
H Ar
Alk
o
o
High ee?
Scope?
Chiral ammonium
enolate
MA derivatives
Stable
Easy accessible
o
o
o
o
o
o
Figure 1. Context of this work.
Lastly, the domino 1,4-addition-protonation sequence of
thiol or aldehydes[10] (under the form of Breslow intermediate)
nucleophiles to a-aryl acrylates furnished the corresponding
products in modest to high enantioselectivities by implementing
Brønsted base or NHC organocatalysts respectively (Figure 1a,
lower part). Noteworthy, the major limitation relies on the lack of
reactivity of a-aryl acrylates derivatives which requires the use of
[9]
[a]
F. Legros, T. Martzel, J.-F. Brière, S. Oudeyer* and V. Levacher
Normandie Université, Université de Rouen, INSA Rouen, CNRS,
COBRA, 76000 Rouen, France
a
strong nucleophile such as benzenethiol or Breslow
E-mail: sylvain.oudeyer@univ-rouen.fr
intermediate thus hampering the scope of this approach. In this
context, the development of an enantioselective and more
general protonation approach for the synthesis of a large array of
http://www.lab-cobra.fr/thematique/lorganocatalyse
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800331
European Journal of Organic Chemistry
FULL PAPER
scope of 2-aryl propionic acid derivatives using stable and readily
accessible substrates is still of particular interest.
yield but at the expense of the ee, which dropped to 22%. Finally,
moving to other ethereal solvents raised the enantioselectivity up
to 54% ee in CPME but in low NMR yield of around 20% (entries
16-17).
Meldrum’s acid (MA) has emerged as a readily available,
bench stable and versatile building block in organocatalysis.[11] In
line with our recent work dealing with the synthesis and
*
applications of chiral ammonium aryloxides (R4 NOAr)[12] as
Table 1. Initial attempts for the addition of 4-methoxyphenoxide 2a to
Meldrum’s acid derivative 3a.[a]
cooperative ion pairs organocatalysts,[13] we reasoned that
aryloxides could add to non-symmetrical 5,5-disubstituded MA
*
R4N+X- (10 mol%)
OH
derivatives in order to trigger
a domino fragmentation-
Me Ph
O
4-MeOC6H4ONa
H
Ph
O
O
decarboxylation-EP sequence to afford enantioenriched 2-aryl
propionic derivatives. In the presence of stoichiometric amount of
OAr
(10 mol%)
+
Me
(S)
O
O
solvent, t, T
phenol, the key enantioselective protonation of a transient chiral
13a]
quaternary ammonium enolate[14,
occurs along with the
OMe
2a
1a
3a
regeneration of the catalytically active R*4NOAr species (Figure
1b). Although mono-substituted MA derivatives have been
already used as nucleophiles in enantioselective organocatalytic
protonation reaction,[15],[16] Worthy of note, the 5,5-disubstituted
MA derivatives with two different substituents remain unexplored
in organocatalytic processes, and this despite opportunity
afforded by the markedly electrophilic properties of their carbonyl
functional groups.[11] To the best of our knowledge, a single
example described the enantioselective desymmetrisation of 5,5-
disubstitued MA by means of the nucleophilic addition of a
stoichiometric amount of chiral ammonium alkoxides to form
chiral hemi-malonate derivatives with fair level of
enantioselectivity up to 51%.[17]
R1
*
R4N+X-
R1
OH
N
Cl
R2
N
Cl
R2
OH
N
A: R1 = OMe, R2 = Ph
B: R1 = H, R2 = Ph
E: R1 = OMe, R2 = 9-anth
C: R1 = OMe, R2 = Ph
D: R1 = H, R2 = Ph
N
F
F
F
F
F
F
Br
N
Br
n-Bu
N
n-Bu
F
F
Results and Discussion
G
F
F
F
F
At the onset, we studied the addition of 4-methoxyphenol 2a
to MA derivatives 1a in the presence of 10 mol% of quaternary
ammonium halide (R*4N+X-) and 10 mol% of sodium 4-
methoxyphenoxide in THF at -20 °C for 24 h. We sought thereby
to firstly generate in situ the required chiral ammonium phenoxide
through an ion metathesis event thus avoiding its tedious and
time-consuming preparation (Table 1).
F
F
F
OMe
Ph
BF4
Me
Tol
F
N
O
O
Tol
Tol
N
N
Br
Tol
Me
Several catalysts derived from Cinchona alkaloids were
screened under these conditions but unfortunately low yields and
almost racemic mixtures of ester 3a were obtained (entries 1-5).
We thus turned our attention to the 2nd generation of Maruoka’s
catalyst F (5 mol%) for which a promising 46% ee could be
reached albeit in a poor 10% NMR yield providing that the reaction
was performed at room temperature (entries 6-7). We observed
that the yields gradually increased with the temperature without
any loss of the ee allowing to reach 47% NMR yield and 45% ee
at 50 °C (entries 8-9). The reaction time was increased to 48 h
furnishing the product 3a in 66% NMR yield (54% isolated yield)
and 43% ee (entry 10). Among other catalysts such as tartrate-
derived catalyst I (entry 13) or axially chiral ammonium salts G
and H (entries 11-12), the Lygo’s catalyst H allowed to reach a
49% ee along with a 62% NMR yield. Having in hands two suitable
catalysts (entries 10 and 12), we studied the influence of the
solvent using commercially available Maruoka’s catalyst F
(entries 14-17). Whereas polar aprotic solvents such as ACN led
to a better yield, the product was obtained in a racemic form (entry
14). Less polar solvents such as toluene provided decent NMR
F
F
Ph
BF4
I
OMe
H
F
NMR
ee
entry
solvent
R*4NX
t (h)
T (°C)
(%)[c]
yield
(%)[b]
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
THF
THF
THF
A
24
24
24
24
24
24
24
24
-20
-20
-20
-20
-20
-20
rt
19
9
14
6
B
C
18
17
14
3
5
D
1
E
16
-
F[d]
F[d]
F[d]
10
23
46
45
30
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10.1002/ejoc.201800331
European Journal of Organic Chemistry
FULL PAPER
tested providing 3a in 39% yield and 54% ee (Table 2, entry 2).
Lastly, by using K3PO4 as a base, a 62% ee could be reached
along with a 24% yield (Table 2, entry 3). In order to improve the
yield, we turned our attention to the use of additives. By adding a
catalytic amount of CsCl, previously reported by Maruoka to
enhance the rate of PT catalyzed reaction,[18] we observed a slight
improvement of the yield to 35% with a comparable level of
enantioselectivity (Table 2, entry 4). As previously observed
(Table 1, entry 10 vs 12), the Lygo’s catalyst H gave similar results
to those obtained with Maruoka’s catalyst F, we thus decided to
evaluate its performance under PT conditions. Pleasingly, we
were able to double the yield (79%) compared to the use of
Maruoka’s catalyst F (Table 2 entry 5 vs 4) while maintaining
comparable level of enantioselectivity (64% ee). The catalyst
loading could be decreased to 2 mol% without affecting the ee
while providing acceptable 57% yield (Table 2, entry 6).
9
THF
F[d]
F[d]
G[d]
H[d]
I[d]
24
48
48
48
48
48
48
48
48
50
50
50
50
50
50
50
50
50
47
66
52
62
56
86
68
21
23[e]
45
43
0
10
11
12
13
14
15
16
17
THF
THF
THF
49
4
THF
ACN
F[d]
F[d]
F[d]
F[d]
0
toluene
dioxane
CPME
22
51
54
[a] The reaction was performed on 0.2 mmol scale using 1 equivalent of 1a
and 2a. [b] Yield determined by NMR using Bn2O as internal standard. [c]
Measured by HPLC equipped with column containing chiral stationary
phase. The absolute configurations were established by comparison with
literature data (see supporting information). [d] 5 mol% of catalyst was used.
[e] 16% isolated yield.
Having in hands our optimized conditions, we then moved
to the survey of the scope and limitations of this methodology
(Table 3).
Then, we moved to a solid-liquid phase transfer (PT) catalysis
starting from 4-methoxyphenol 2a in the presence of a mineral
base in order to secure a more convenient generation of the
phenoxide species by deprotonation (Table 2).
Table 3. Scope and limitations.[a]
R2
R2
R1
O
Cat. H (5 mol%)
K3PO4 (30 mol%)
CsCl (30 mol%)
OH
H
O
O
O
R1
+
(S)
O
CPME (0.2 M)
20 °C, 48 h
O
R3
Table 2. Optimization of the PT catalyzed addition of 4-methoxyphenoxide
to Meldrum’s acid derivative 3a.[a]
R3
3
1
2
*
R4N+X- (5 mol%)
Base (30 mol%)
additive (30 mol%)
entry
1
1:R1/R2
2:R3
3:yield (%)[b]
3a:79
ee (%)[c]
64
OH
Me Ph
O
H
Ph
O
1a:Me/H
1b:Et/H
2a:4-MeO
2a:4-MeO
2a:4-MeO
2a:4-MeO
2a:4-MeO
2a:4-MeO
2a:4-MeO
2a:4-MeO
2a:4-MeO
2a:4-MeO
2a:4-MeO
2a:4-MeO
2a:4-MeO
2b:H
O
+
Me
(S)
O
O
CPME (0.2 M)
20 °C, 48 h
2
3b:30
58
O
OMe
OMe
2a
3
1c:Bn/H
1d:Me/4-F
3c:25
44
1a
3a
yield
ee
entry
R*4NX
base
additive
4
3d:99
67
(%)[b]
(%)[c]
5
1e:Me/4-Cl
1f:Me/4-Br
1g:Me/3-Br
1h:Me/4-Me
1i:Me/2-Me
1j:Me/4-iBu
1k:Me/4-tBu
1l:Me/4-OMe
1m:Me/4-CF3
1a:Me/H
3e:91
66
1
2
3
4
5
6
F
K2CO3
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
-
11
59
6
3f:88
65
F
-
39
54
7
3g:96 (83)[d]
3h:59
30 (58)[d]
66
F
-
24
62
8
F
CsCl
CsCl
CsCl
35
62
9
3i:34
25
H
H[d]
79
64
10
11
12
13
14
15
16
3j:64
59
57
65
3k:64
57
[a] The reaction was performed on 0.2 mmol scale using 1 equivalent of 1a
and 2a. [b] Isolated yields. [c] Measured by HPLC equipped with column
containing chiral stationary phase. The absolute configurations were
established by comparison with literature data (see supporting information).
[d] 2 mol% of catalyst were used.
3l:68
65
3m:92 (84)[d]
3n:52
27 (53)[d]
68
By performing the reaction in CPME (0.2 M) at 20 °C for 48 h in
the presence of Maruoka’s catalyst F (5 mol%) and K2CO3 (30
mol%), we were able to improve the level of enantioselectivity to
59% (Table 2, entry 1 vs Table 1, entry 17) but at the expense of
the isolated yield. Encouraged by this result, Cs2CO3 was also
1e:Me/4-Cl
1e:Me/4-Cl
2b:H
3o:72
70
2c:2-Me
3p:79
52
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10.1002/ejoc.201800331
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The enantiomeric excess rapidly reached a plateau (i.e. 64% after
8 h) and remained at this level until the end of the reaction after
48 h while conversion was ranged from 52 to 79%. In
consequence, one may assume that there is no racemization
during the course of the reaction.
In order to push forward our investigation, the enantioenriched
product 3a (64% ee) was engaged into the classical reaction
conditions for 48 h with 1 equivalent of 4-MeOphenol but in the
absence of Meldrum’s acid derivative (Scheme 1).
[a] The reaction was performed on 0.15 or 0.2 mmol scale using 1 equivalent
of 1 and 2. [b] Isolated yields. [c] Measured by HPLC equipped with column
containing chiral stationary phase. [d] Reaction time: 8 h.
We first studied the influence of the alkyl group on the Meldrum’s
acid derivatives (Table 3, entries 1-3). The replacement of a
methyl by an ethyl or a benzyl resulted in a dramatic drop in the
yields along with an erosion of the ees from 64% to 44% for the
benzyl group. We then examined the influence of the substitution
pattern in the aromatic ring (Table 3, entries 4-13). The
substitution at the para position by an halogen atom (F, Br or Cl)
gave the corresponding products 3d-f in high yields (88-99%),
meanwhile maintaining the enantiomeric excesses around 64%
(Table 3, entries 4-6 vs 1). Derivatives 1g possessing a meta-
bromo substituted phenyl underwent a smooth reaction yielding
product 3g in 83% yield and 58% ee as long as the reaction time
was shortened to 8 hours (Table 3, entry 7). Otherwise a drastic
drop of the ee to 30% was observed in 48 hours, likely due to
racemization issue caused by the presence of residual K3PO4 or
phenoxide. Whereas the introduction of a methyl group at the para
position was well-tolerated (3h, 59%, 66% ee), the introduction of
this substituent at the ortho-position was detrimental to both yield
and ee (Table 3, entry 9 vs 8). Interestingly, these conditions
tolerated other alkyl chains at the para position such as iBu or tBu
(Table 3, entry 10 and 11) without influencing the outcome of the
reaction (3j-k, 64%, 57-59% ee). Product 1l with an electro-
donating functional group such as a p-OMe afforded the
corresponding product 3l with acceptable 68% yield and 64% ee
(Table 3, entry 12). On the other hand, substrate 1m with p-CF3
phenyl pendant was also well tolerated provided that the reaction
time was reduced to 8 hours furnishing the desired product 3m in
84% yield and 53% ee (Table 3, entry 13). Lastly, we briefly
examined the influence of the substitution pattern in the phenol
derivatives. Whereas phenol 2b gave the best level of
enantioselectivity (68 and 70% ee, Table 3, entries 14-15), phenol
2c bearing a bulky substituent at the ortho position afforded the
corresponding product 3p in 52% ee (Table 3, entry 16).
Cat. H (5 mol%)
K3PO4 (30 mol%)
CsCl (30 mol%)
OH
H
Ph
H
Ph
OAr
OAr
∗
∗
Me
Me
+
CPME (0.2 M)
20 °C, 48 h
O
O
Ar = 4-MeOC H
OMe
2a
1 equiv
6
4
3a
96%, 33% ee
92%, 0% ee
3a
64% ee
0 equiv
Scheme 1. Racemization issue.
After 48 h, the initial enantiomeric excess was divided by two
reaching 33% ee. Moreover, the same reaction in the absence of
phenol resulted in a complete racemization after 48 h. Accordingly,
there is a clear competition between the deprotonation of
4-methoxyphenol and the product 3a in favour of the former one.
Then, during the course of the reaction, the generated phenoxide
species is more prone to attack the markedly electrophilic MA
derivatives 1 rather than acting as a Brønsted base thus
preventing any racemization reaction. Such an explanation is in
agreement with the fact that 3g and 3m that are formed
quantitatively in 8 h due to the better reactivity of their
corresponding Meldrum’s acids 1g and 1m (and likely better
electrophilic character) start to racemize during the last 40 h in the
absence of 1 (Table 3, entries 7 and 13 respectively).
Regarding the mechanism of this reaction, we propose that a
solid-liquid PT-catalyzed deprotonation of the phenol 2 occurs in
order to generate in situ a chiral ammonium aryloxide reactive
species (Figure 3, step a), which subsequently adds to the
electrophilic carbonyl of the MA derivatives 1, thus triggering the
fragmentation along with the elimination of a molecule of acetone
to provide an hemi-malonate derived ion pair (Figure 3, step b).
Then, a decarboxylation step (Figure 3, step c) provides a more
basic enolate flanked by the chiral ammonium which undergoes
an asymmetric protonation by an incoming molecule of phenol
derivative 2 thus providing the product 3 with the concomitant
regeneration of the chiral ammonium phenoxide that is actually
the catalytically active species (Figure 3, step d).
Aware of a possible racemization issue, we decided to follow the
ee during the course of the formation of compound 3a was
realized (Figure 2).
ee (%)
100
90
80
70
64
64
64
64
60
50
40
30
20
10
0
time(h)
0
8
16
24
48
Figure 2. Evolution of the ee (%) during the course of the formation of 3a.
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10.1002/ejoc.201800331
European Journal of Organic Chemistry
FULL PAPER
Ar2OH
We feel this original methodology might find further applications
in organocatalysis.
2
*
R4N+X−
K3PO4(s)
CsCl(s)
(a) solid-
liquid PT
deprotonation
R1 Ar1−OAr2
O
R1 Ar1
O
OAr2
∗
H
*
O
O
+NR4
2
Experimental Section
Ar O−
3
O
1
(b)
General information: Reactions were performed using oven dried
glassware under inert atmosphere of argon. Unless otherwise noticed, all
reagent-grade chemicals were commercially available and used as
received. THF, Toluene and CH2Cl2 were dried over MBRAUN MB SPS-
800 apparatus. Dry acetonitrile, dry 1,4-Dioxane, dry DMF and dry
methanol were purchased from Aldrich, CPME was purchased from TCI
and all were used as received. Reactions were monitored by thin-layer
chromatography with silica gel 60 F254 pre-coated aluminium plates
(0.25 mm). Visualization was performed under UV light and
phosphomolybdic acid or KMO4 staining. Flash chromatographic
purifications of compounds were achieved with 60 silica gel (40-63 μm) or
with C18-HP 15 μm F0004 Flash Column on an Interchim Puriflash 430
apparatus. Melting points were measured on a WME Köfler hot-stage
(Stuart SMP3). Infrared spectra (IR) were recorded on a PerkinElmer
Spectrum 100 Series FT-IR spectrometer. Liquids and solids were applied
on a Single Reflection Attenuated Total Reflectance (ATR) accessory.
Data are reported in cm-1. Optical rotations were determined with a Perkin
Elmer 341 mircropolarimeter with a 10 cm cell. Specific rotations are
reported in 10-1 deg cm² g-1 and concentrations in g per 100 mL. 1H NMR
spectra (300 MHz), 13C NMR spectra (75 MHz) and 19F NMR (282 MHz)
were recorded on a Bruker Advance300. Data appear in the following
order: chemical shift in ppm (referenced to the internal solvent signal for
1H and 13C NMR, or to CFCl3 as internal standard for 19F NMR), multiplicity
(s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet) and coupling
(d)
Enantioselective
protonation
Me2CO
Ar2OH
2
Nucleophilic
addition/
fragmentation
Ar1
R1 Ar1
*
+NR4
O−
O
*
O
R1
OAr2
−O
OAr2
R4N+
(c)
Decarboxylation
CO2
Figure 3. Mechanism proposal for the nucleophilic addition / fragmentation /
decarboxylation / enantioselective protonation sequence.
Finally, in order to demonstrate the synthetic utility of this
methodology, we turned our attention to the synthesis of
enantioenriched ibuprofen,
a commercially available anti-
inflammatory drug. Starting from compound 3j (59% ee), a simple
saponification step in the presence of LiOH and H2O2[8b] afforded
the ibuprofen in 70% yield without racemization (Scheme 2). A
comparison of the optical rotation with literature value allowed us
to establish a S-configuration of the ibuprofen (see supporting
information for transition state proposal).
constant
J in Hertz. Accurate Mass measurements (HRMS) were
performed with a Waters LCP 1er XR spectrometer. HPLC analyses were
performed using a Daicel Chiralpak® column (250 mm x 4.6 mm, 5 μm or
3 μm) on a ThermoFisher Scientific Dionex Ultimate 3000 apparatus with
UV-vis diode array detector. Elemental analyses were performed on a
Thermo Fisher Flash 2000 Series apparatus.
H
H
General procedure for the synthesis of enantioenriched 2-aryl
propionic ester derivatives 3
O
OH
LiOH/H2O2
∗
∗
Me
Me
Aq THF, 0 °C
O
O
In a glass vial were sequentially introduced K3PO4 (30 mol%), CsCl
(30 mol%), catalyst H (5 mol%), phenol 2 and 5,5-disubstituted Meldrum’s
acid 1 (0.15 or 0.2 mmol, 1 equiv). CPME (0.2 M) was added, and the
resulting heterogeneous mixture was stirred under argon atmosphere at
20 °C for 8 or 48 h. The reaction mixture was then diluted with CH2Cl2
(5 mL) and filtered over a silica gel pad (eluent: CH2Cl2). The filtrate was
concentrated under vacuum, and the crude product was purified by silica
gel column chromatography to give the desired enantioenriched phenolic
ester 3.
3j
(S)-ibuprofen
70%
OMe
59% ee
60% ee
Scheme 2. Synthesis of enantioenriched (S)-ibuprofen starting from ester 3j.
Conclusions
In conclusion, we have developed an original organocatalyzed
enantioselective protonation reaction of acyclic enolates leading
to several enantioenriched 2-aryl propionic derivatives 3 with
good isolated yields and ees up to 70%. This process takes
advantage of the readily availability of 5,5-disubstituted MA
derivatives as stable starting materials with a marked electrophilic
character. This poorly exploited reactivity allows a domino
4-methoxyphenyl 2-phenylpropanoate (3a): Following the general
procedure, Meldrum’s acid 1a (46.8 mg, 0.2 mmol, 1 equiv.),
4-methoxyphenol 2a (24.8 mg, 0.2 mmol, 1 equiv.), K3PO4 (12.7 mg,
0.06 mmol, 30 mol%), CsCl (10.1 mg, 0.06 mmol, 30 mol%) and catalyst
H (8.8 mg, 0.01 mmol, 5 mol%) were stirred in CPME (1 mL) for 48 h. The
title compound was obtained as a white solid (40.5 mg, 79%) after silica
gel flash column chromatography (Petroleum ether/EtOAc 95:5). Rf = 0.37
(Petroleum ether/EtOAc 95:5). mp = 52-54 °C. IR (neat) νmax = 2985, 2953,
2828, 1744, 1596, 1504, 1453, 1246, 1191, 1141, 1075, 1028, 1007, 935,
addition-fragmentation-decarboxylation-protonation
reaction
triggered by a chiral ammonium phenoxide cooperative ion pair.
The synthetic usefulness of this methodology was demonstrated
in the course of the synthesis of enantioenriched (S)-ibuprofen.
1
889, 818, 751, 702, 538, 525, 507 cm-1. H NMR (300 MHz, CDCl3): δ =
7.43-7.25 (m, 5H), 6.95-6.80 (m, 4H), 3.94 (q, 1H, J = 7.1 Hz), 3.77 (s, 3H),
1.61 (d, 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ = 173.5, 157.3, 144.4,
140.3, 128.9 (2 C), 127.7 (2 C), 127.5, 122.3 (2 C), 114.5 (2 C), 55.7, 45.7,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800331
European Journal of Organic Chemistry
FULL PAPER
18.7. HRMS (EI+) m/z: [M]+ Calcd for C16H16O3 256.1094; Found: 256.1090.
HPLC analysis: 64% ee (column DAICEL Chiralpak IA 3μm, heptane/i-
4-methoxyphenyl 2-(4-chlorophenyl)propanoate (3e) : Following the
general procedure, Meldrum’s acid 1e (53.7 mg, 0.2 mmol, 1 equiv.),
4-methoxyphenol 2a (24.8 mg, 0.2 mmol, 1 equiv.), K3PO4 (12.7 mg,
0.06 mmol, 30 mol%), CsCl (10.1 mg, 0.06 mmol, 30 mol%) and catalyst
H (8.8 mg, 0.01 mmol, 5 mol%) were stirred in CPME (1 mL) for 48 h. The
title compound was obtained as a white solid (53.2 mg, 91%) after silica
gel flash chromatography (Petroleum ether/EtOAc 95:5). Rf = 0.27
(Petroleum ether/EtOAc 95:5). mp = 57-60 °C. IR (neat) νmax = 2982, 2936,
1750, 1597, 1504, 1492, 1456, 1248, 1191, 1134, 1092, 1071, 1033, 1014,
890, 834, 820, 769, 521 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.34 (s, 4H),
6.93-6.81 (m, 4H), 3.92 (q, 1H, J = 7.2 Hz), 3.78 (s, 3H), 1.59 (d, 3H, J =
7.2 Hz). 13C NMR (75 MHz, CDCl3): δ = 173.1, 157.4, 144.3, 138.7, 133.3,
129.1 (2 C), 129.0 (2 C), 122.1 (2 C), 114.5 (2 C), 55.6, 45.1, 18.6. HRMS
(ESI-) m/z: [M - H]- Calcd for C16H15ClO3 289.0637; Found: 289.0627.
HPLC analysis: 66% ee (column DAICEL Chiralpak IA 3μm,
heptane/EtOH 98:2, flow rate 1 mL/min, 20 °C, UV 220 nm, tmin = 10.6 min,
tmajor = 13.0 min). [α]D20 +61.6 (c 0.50, CHCl3).
PrOH 98:2, flow rate 1 mL/min, 20 °C, UV 230 nm, tmajor = 11.4 min, tmin
13.5 min). [α]D20 +67.8 (c 0.50, CHCl3).
=
4-methoxyphenyl 2-phenylbutanoate (3b): Following the general
procedure, Meldrum’s acid 1b (49.7 mg, 0.2 mmol, 1 equiv.),
4-methoxyphenol 2a (24.8 mg, 0.2 mmol, 1 equiv.), K3PO4 (12.7 mg,
0.06 mmol, 30 mol%), CsCl (10.1 mg, 0.06 mmol, 30 mol%) and catalyst
H (8.8 mg, 0.01 mmol, 5 mol%) were stirred in CPME (1 mL) for 48 h. The
title compound was obtained as a colourless oil (16.3 mg, 30%) after silica
gel flash column chromatography (Cyclohexane/EtOAc 95:5). Rf = 0.28
(Cyclohexane/EtOAc 95:5). IR (neat) νmax = 2966, 2935, 1749, 1598, 1505,
1455, 1442, 1298, 1248, 1191, 1132, 1101, 1031, 947, 907, 840, 797, 744,
698, 509 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.43-7.25 (m, 5H), 6.95-
6.80 (m, 4H), 3.78 (s, 3H), 3.68 (t, 1H, J = 7.7 Hz), 2.30-2.13 (m, 1H), 1.98-
1.82 (m, 1H), 0.99 (t, 3H, J = 7.4 Hz). 13C NMR (75 MHz, CDCl3): δ = 173.0,
157.3, 144.4, 138.8, 128.8 (2 C), 128.1 (2 C), 127.5, 122.3 (2 C), 114.5 (2
C), 55.7, 53.6, 26.9, 12.3. HRMS (ESI+) m/z: [M + NH4]+ Calcd for
C17H22NO3 288.1600; Found: 288.1594. HPLC analysis: 58% ee (column
DAICEL Chiralpak IA 3μm, heptane/i-PrOH 98:2, flow rate 1 mL/min, 20 °C,
UV 220 nm, tmajor = 12.2 min, tmin = 13.6 min). [α]D20 +48.2 (c 0.50, CHCl3).
4-methoxyphenyl 2-(4-bromophenyl)propanoate (3f) : Following the
general procedure, Meldrum’s acid 1f (62.6 mg, 0.2 mmol, 1 equiv.),
4-methoxyphenol 2a (24.8 mg, 0.2 mmol, 1 equiv.), K3PO4 (12.7 mg,
0.06 mmol, 30 mol%), CsCl (10.1 mg, 0.06 mmol, 30 mol%) and catalyst
H (8.8 mg, 0.01 mmol, 5 mol%) were stirred in CPME (1 mL) for 48 h. The
title compound was obtained as an off-white solid (59.2 mg, 88%) after
silica gel flash column chromatography (Petroleum ether/EtOAc 95:5).
4-methoxyphenyl 2,3-diphenylpropanoate (3c): Following the general
procedure, Meldrum’s acid 1c (62.1 mg, 0.2 mmol, 1 equiv.),
4-methoxyphenol 2a (24.8 mg, 0.2 mmol, 1 equiv.), K3PO4 (12.7 mg,
0.06 mmol, 30 mol%), CsCl (10.1 mg, 0.06 mmol, 30 mol%) and catalyst
H (8.8 mg, 0.01 mmol, 5 mol%) were stirred in CPME (1 mL) for 48 h. The
title compound was obtained as a white solid (16.9 mg, 25%) after silica
gel flash column chromatography (EP/EtOAc 95:5) and C18-HP 15 μm
F0004 Flash Column chromatography using an Interchim Puriflash
apparatus (gradient ACN/H2O 20:80 to 100:0). Rf = 0.29 (EP/EtOAc 95:5).
mp = 79-82 °C. IR (neat) νmax = 2988, 2936, 2839, 1752, 1593, 1503, 1455,
1355, 1278, 1242, 1192, 1138, 1087, 1031, 860, 821, 753, 703, 521 cm-1.
1H NMR (300 MHz, CDCl3): δ = 7.46-7.18 (m, 10H), 6.84-6.70 (m, 4H),
4.08 (dd, 1H, J = 9.4, 6.3 Hz), 3.76 (s, 3H), 3.49 (dd, 1H, J = 13.7, 9.4 Hz),
3.12 (dd, 1H, J = 13.7, 9.4 Hz). 13C NMR (75 MHz, CDCl3): δ = 172.4,
157.3, 144.2, 138.9, 138.4, 129.2 (2 C), 128.9 (2 C), 128.6 (2 C), 128.1 (2
C), 127.7, 126.7, 122.2 (2 C), 114.4 (2 C), 55.7, 53.8, 40.1. HRMS (ESI+)
m/z: [M + NH4]+ Calcd for C22H24NO3 350.1751; Found: 350.1759. HPLC
analysis: 44% ee (column DAICEL Chiralpak IA 3μm, heptane/i-PrOH 98:2,
flow rate 1 mL/min, 20 °C, UV 215 nm, tmajor = 22.7 min, tmin = 23.9 min).
[α]D20 +16.8 (c 0.50, CHCl3).
Rf = 0.26 (Petroleum ether/EtOAc 95:5). mp = 52-54 °C. IR (neat) νmax
=
2980, 2936, 1751, 1596, 1505, 1489, 1463, 1298, 1248, 1192, 1162, 1136,
1074, 1010, 891, 820, 769, 520 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.54-
7.46 (m, 2H), 7.32-7.23 (m, 2H), 6.94-6.81 (m, 4H), 3.83 (q, 1H, J = 7.2
Hz), 3.70 (s, 3H), 1.51 (d, 3H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): δ =
173.1, 157.4, 144.3, 139.2, 132.0 (2 C), 129.4 (2 C), 122.2 (2 C), 123.4,
114.5 (2 C), 55.7, 45.2, 18.6. HRMS (EI+) m/z: [M]+ Calcd for C16H15BrO3
334.0199; Found: 334.0201. HPLC analysis: 65% ee (column DAICEL
Chiralpak IA 3μm, heptane/EtOH 95:5, flow rate 1 mL/min, 20 °C,
UV 220 nm, tmin = 8.8 min, tmajor = 10.6 min). [α]D20 +54.0 (c 0.50, CHCl3).
4-methoxyphenyl 2-(3-bromophenyl)propanoate (3g): Following the
general procedure, Meldrum’s acid 1g (62.6 mg, 0.2 mmol, 1 equiv.),
4-methoxyphenol 2a (24.8 mg, 0.2 mmol, 1 equiv.), K3PO4 (12.7 mg,
0.06 mmol, 30 mol%), CsCl (10.1 mg, 0.06 mmol, 30 mol%) and catalyst
H (8.8 mg, 0.01 mmol, 5 mol%) were stirred in CPME (1 mL) for 8 h. The
title compound was obtained as a yellowish oil (55.4 mg, 83%) after silica
gel flash column chromatography (Petroleum ether/Et2O 9:1). Rf = 0.31
(Petroleum ether/Et2O 9:1). IR (neat) νmax = 2980, 2936, 2836, 1750, 1594,
1569, 1503, 1464, 1298, 1190, 1135, 1102, 1073, 1033, 892, 821, 765,
692, 519, 438 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.57-7.53 (m, 1H),
7.47-7.40 (m, 1H), 7.36-7.30 (m, 1H), 7.27-7.20 (m, 1H), 6.95-6.81 (m, 4H),
3.91 (q, 1H, J = 7.2 Hz), 3.78 (s, 3H), 1.60 (d, 3H, J = 7.2 Hz). 13C NMR
(75 MHz, CDCl3): δ = 172.9, 157.4, 144.2, 142.4, 130.8, 130.6, 130.5,
126.3, 127.9, 122.2 (2 C), 114.5, 55.7, 45.3, 18.6. HRMS (EI+) m/z: [M]+
Calcd for C16H15O3 334.0199; Found: 334.0210. HPLC analysis: 58% ee
(column DAICEL Chiralpak IA 3μm, heptane/EtOH 98:2, flow rate
4-methoxyphenyl 2-(4-fluorophenyl)propanoate (3d): Following the
general procedure, Meldrum’s acid 1d (50.4 mg, 0.2 mmol, 1 equiv.),
4-methoxyphenol 2a (24.8 mg, 0.2 mmol, 1 equiv.), K3PO4 (12.7 mg,
0.06 mmol, 30 mol%), CsCl (10.1 mg, 0.06 mmol, 30 mol%) and catalyst
H (8.8 mg, 0.01 mmol, 5 mol%) were stirred in CPME (1 mL) for 48 h. The
title compound was obtained as an off-white solid (54.5 mg, 99%) after
silica gel flash column chromatography (Petroleum ether/EtOAc 95:5). Rf
= 0.27 (Petroleum ether/EtOAc 95:5). mp = 37-38 °C. IR (neat) νmax = 2980,
2938, 1750, 1602, 1504, 1457, 1298, 1222, 1191, 1132, 1102, 1070, 1033,
890, 837, 819, 788, 761, 724, 535, 520 cm-1. 1H NMR (300 MHz, CDCl3):
δ = 7.42-7.31 (m, 2H), 7.12-7.01 (m, 2H), 6.95-6.80 (m, 4H), 3.93 (q, 1H,
J = 7.2 Hz), 3.78 (s, 3H), 1.60 (d, 3H, J = 7.2 Hz). 13C NMR (75 MHz,
20
1 mL/min, 20 °C, UV 220 nm, tmajor = 8.1 min, tmin = 9.7 min). [α]D +44.8
(c 0.50, CHCl3).
4-methoxyphenyl 2-(p-tolyl)propanoate (3h): Following the general
procedure, Meldrum’s acid 1h (49.7 mg, 0.2 mmol, 1 equiv.),
4-methoxyphenol 2a (24.8 mg, 0.2 mmol, 1 equiv.), K3PO4 (12.7 mg,
0.06 mmol, 30 mol%), CsCl (10.1 mg, 0.06 mmol, 30 mol%) and catalyst
H (8.8 mg, 0.01 mmol, 5 mol%) were stirred in CPME (1 mL) for 48 h. The
title compound was obtained as a white solid (31.8 mg, 59%) after silica
gel flash column chromatography (Petroleum ether/Et2O 10:1). Rf = 0.33
(Petroleum ether/Et2O 10:1). mp = 77-80 °C. IR (neat) νmax = 2982, 2931,
1750, 1594, 1506, 1454, 1343, 1250, 1193, 1150, 1075, 1025, 891, 814,
1
4
CDCl3): δ = 173.4, 162.2 (d, J = 246 Hz), 157.4, 144.3, 135.9 (d, J = 3
Hz), 129.3 (d, 2 C, 3J = 8 Hz), 122.2 (2 C), 115.8 (d, 2 C, 2J = 21 Hz), 114.5
(2 C), 55.7, 44.9, 18.8. 19F{1H} NMR (282 MHz, CDCl3, CFCl3) δF -115.85
(tt, 1F, J = 8.6, 5.3 Hz). HRMS (EI+) m/z: [M]+ Calcd for C16H15FO3
274.1000; Found: 274.1006. HPLC analysis: 67% ee (column DAICEL
Chiralpak IA 3μm, heptane/i-PrOH 98:2, flow rate 1 mL/min, 20 °C,
UV 220 nm, tmajor = 13.0 min, tmin = 14.2 min). [α]D20 +51.6 (c 0.50, CHCl3).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800331
European Journal of Organic Chemistry
FULL PAPER
784, 762, 532, 487 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.26 (m, 2H),
7.17 (m, 2H), 6.94-6.79 (m, 4H), 3.91 (q, 1H, J = 7.1 Hz), 3.77 (s, 3H), 2.35
(s, 3H), 1.58 (d, 3H, J = 7.1 Hz). 13C NMR (75 MHz; CDCl3): δ = 173.7,
157.2, 144.4, 137.3, 137.0, 129.6 (2 C), 127.5 (2 C), 122.2 (2 C), 114.4 (2
C), 55.6, 45.3, 21.2, 18.7. HRMS (EI+) m/z: [M]+ Calcd for C17H16O3
270.1250; Found: 270.1262. HPLC analysis: 66% ee (column DAICEL
Chiralpak IA 3μm, heptane/i-PrOH 98:2, flow rate 1 mL/min, 20 °C,
UV 220 nm, tmajor = 14.3 min, tmin = 15.0 min). [α]D20 +66.0 (c 0.50, CHCl3).
4-methoxyphenyl 2-(4-methoxyphenyl)propanoate (3l): Following the
general procedure, Meldrum’s acid 1l (52.9 mg, 0.2 mmol, 1 equiv.),
4-methoxyphenol 2a (24.8 mg, 0.2 mmol, 1 equiv.), K3PO4 (12.7 mg,
0.06 mmol, 30 mol%), CsCl (10.1 mg, 0.06 mmol, 30 mol%) and catalyst
H (8.8 mg, 0.01 mmol, 5 mol%) were stirred in CPME (1 mL) for 48 h. The
title compound was obtained as a pale yellow oil (39.2 mg, 68%) after silica
gel flash column chromatography (Petroleum ether/EtOAc 9:1). Rf = 0.24
(Petroleum ether/EtOAc 9:1). IR (neat) νmax = 2936, 2837, 1749, 1611,
1504, 1463, 1442, 1301, 1245, 1192, 1178, 1133, 1072, 1031, 889, 834,
820, 784, 759, 540, 520 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.35-7.28
(m, 2H), 7.95-7.86 (m, 2H), 6.94-6.80 (m, 4H), 3.89 (q, 1H, J = 7.2 Hz),
3.81 (s, 3H), 3.77 (s, 3H), 1.58 (d, 3H, J = 7.2 Hz). 13C NMR (75 MHz,
CDCl3): δ = 173.8, 158.9, 157.3, 144.5, 132.3, 128.7 (2 C), 122.3 (2 C),
114.4 (2 C), 114.3 (2 C), 55.7, 55.4, 44.8, 18.7. HRMS (ESI+) m/z:
[M + NH4]+ calcd for C17H22NO4 304.1543; Found: 304.1557. HPLC
analysis: 65% ee (column DAICEL Chiralpak IA 3μm, heptane/EtOH 95:5,
flow rate 1 mL/min, 20 °C, UV 225 nm, tmin = 11.6 min, tmajor = 12.6 min).
[α]D20 +65.5 (c 0.20, CHCl3).
4-methoxyphenyl 2-(o-tolyl)propanoate (3i): Following the general
procedure, Meldrum’s acid 1i (49.7 mg, 0.2 mmol, 1 equiv.),
4-methoxyphenol 2a (24.8 mg, 0.2 mmol, 1 equiv.), K3PO4 (12.7 mg,
0.06 mmol, 30 mol%), CsCl (10.1 mg, 0.06 mmol, 30 mol%) and catalyst
H (8.8 mg, 0.01 mmol, 5 mol%) were stirred in CPME (1 mL) for 48 h. The
title compound was obtained as a colourless oil (18.6 mg, 34%) after silica
gel flash column chromatography (Petroleum ether/EtOAc 95:5). Rf = 0.26
(Petroleum ether/EtOAc 95:5). IR (neat) νmax = 2978, 2936, 2837, 1751,
1597, 1504, 1463, 1248, 1191, 1146, 1109, 1074, 1032, 890, 823, 750,
727, 541, 519, 452 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.37-7.31 (m, 1H),
7.27-7.15 (m, 3H), 6.94-6.80 (m, 4H), 4.18 (q, 1H, J = 7.2 Hz), 3.78 (s, 3H),
2.45 (s, 3H), 1.56 (d, 3H, J = 7.2 Hz). 13C NMR (75 MHz; CDCl3): δ = 173.9,
157.2, 144.4, 138.9, 135.8, 130.8, 127.2, 126.8, 126.5, 122.2 (2 C), 114.4
(2 C), 55.6, 41.6, 19.8, 18.0. HRMS (EI+) m/z: [M]+ calcd for C17H16O3
270.1250; Found: 270.1262. HPLC analysis: 25% ee (column DAICEL
Chiralpak IA 3μm, heptane/i-PrOH 95:5, flow rate 1 mL/min, 20 °C,
UV 220 nm, tmajor = 7.7 min, tmin = 10.0 min). [α]D20 +29.4 (c 0.50, CHCl3).
4-methoxyphenyl
2-(4-(trifluoromethyl)phenyl)propanoate
(3m):
Following the general procedure, Meldrum’s acid 1m (60.5 mg, 0.2 mmol,
1 equiv.), 4-methoxyphenol 2a (24.8 mg, 0.2 mmol, 1 equiv.), K3PO4
(12.7 mg, 0.06 mmol, 30 mol%), CsCl (10.1 mg, 0.06 mmol, 30 mol%) and
catalyst H (8.8 mg, 0.01 mmol, 5 mol%) were stirred in CPME (1 mL) for
8 h. The title compound was obtained as a colourless oil (54.2 mg, 84%)
after silica gel flash column chromatography (Petroleum ether/Et2O 9:1).
Rf = 0.27 (Petroleum ether/Et2O 9:1). IR (neat) νmax = 2936, 2845, 1752,
1619, 1504, 1323, 1249, 1190, 1162, 1114, 1067, 1034, 1018, 891, 842,
822, 761, 603, 518 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.64 (d, 2H, J =
8.2 Hz), 7.52 (d, 2H, J = 8.2 Hz), 6.95-6.81 (m, 4H), 4.01 (q, 1H, J = 7.2
Hz), 3.78 (s, 3H), 1.63 (d, 3H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): δ =
172.8, 157.5, 144.2 (m, 2 C), 129.8 (q, 2J = 32 Hz), 128.1 (2 C), 125.9 (q,
2 C, 3J = 4 Hz), 124.2 (q, 1J = 270 Hz), 122.1 (2 C), 114.5 (2 C), 55.6, 45.6,
18.6. 19F{1H} NMR (282 MHz, CDCl3, CFCl3) δF -61.03 (s, 3F). HRMS
(ESI-) m/z: [M - H]- Calcd for C17H14F3O3 323.0901; Found: 323.0898.
HPLC analysis: 53% ee (column DAICEL Chiralpak IA 3μm,
heptane/EtOH 98:2, flow rate 1 mL/min, 20 °C, UV 220 nm, tmin = 9.7 min,
tmajor = 10.3 min). [α]D20 +40.0 (c 0.50, CHCl3).
4-methoxyphenyl 2-(4-iso-butylphenyl)propanoate (3j): Following the
general procedure, Meldrum’s acid 1j (58.1 mg, 0.2 mmol, 1 equiv.),
4-methoxyphenol 2a (24.8 mg, 0.2 mmol, 1 equiv.), K3PO4 (12.7 mg,
0.06 mmol, 30 mol%), CsCl (10.1 mg, 0.06 mmol, 30 mol%) and catalyst
H (8.8 mg, 0.01 mmol, 5 mol%) were stirred in CPME (1 mL) for 48 h. The
title compound was obtained as a colourless oil (40.1 mg, 64%) after silica
gel flash column chromatography (Petroleum ether/Et2O 9:1). Rf = 0.38
(Petroleum ether/Et2O 9:1). IR (neat) νmax = 2955, 2869, 2838, 1752, 1504,
1464, 1249, 1193, 1162, 1135, 1071, 1036, 890, 842, 766, 546, 520 cm-1.
1H NMR (300 MHz, CDCl3): δ = 7.33-7.26 (m, 2H), 7.17-7.10 (m, 2H), 6.95-
6.80 (m, 4H), 3.91 (q, 1H, J = 7.1 Hz), 3.78 (s, 3H), 2.47 (d, 2H, J = 7.2
Hz), 1.97-1.80 (m, 1H), 1.59 (d, 3H, J = 7.1 Hz), 0.91 (d, 6H, J = 7.2 Hz).
13C NMR (75 MHz, CDCl3): δ = 173.7, 157.3, 144.5, 140.9, 137.5, 129.6
(2 C), 127.3 (2 C), 122.3 (2 C), 114.4 (2 C), 55.7, 45.3, 45.2, 30.3, 22.5
(2 C), 18.7. HRMS (AP+) m/z: [M + H]+ Calcd for C20H25O3 313.1798;
Found 313.1789. HPLC analysis: 59% ee (column DAICEL Chiralpak IA
phenyl 2-phenylpropanoate (3n): Following the general procedure,
Meldrum’s acid 1a (46.8 mg, 0.2 mmol, 1 equiv.), phenol 2b (18.8 mg,
0.2 mmol, 1 equiv.), K3PO4 (12.7 mg, 0.06 mmol, 30 mol%), CsCl
(10.1 mg, 0.06 mmol, 30 mol%) and catalyst H (8.8 mg, 0.01 mmol,
5 mol%) were stirred in CPME (1 mL) for 48 h. The title compound was
obtained as colourless crystals (23.4 mg, 52%) after silica gel flash column
chromatography (Petroleum ether/Et2O 9:1). Rf = 0.29 (Petroleum
ether/Et2O 9:1). mp < 30 °C. IR (neat) νmax = 3031, 2980, 2935, 1752, 1592,
1492, 1454, 1327, 1193, 1161, 1136, 1072, 917, 774, 748, 729, 689, 540,
496 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.45-7.27 (m, 7H), 7.23-7.16 (m,
1H), 7.03-6.95 (m, 2H), 3.97 (q, 1H, J = 7.2 Hz), 1.62 (d, 3H, J = 7.2 Hz).
13C NMR (75 MHz, CDCl3): δ = 173.2, 150.9, 140.2, 129.5 (2 C), 128.9 (2
C), 127.7 (2 C), 127.5, 125.9, 121.5 (2 C), 45.8, 18.7. HRMS (EI+) m/z:
[M]+ Calcd for C15H14O2 226.0988; Found: 226.0985. HPLC analysis:
68% ee (column DAICEL Chiralpak IA 3μm, heptane/i-PrOH 99:1, flow
3μm, heptane/i-PrOH 95:5, flow rate 0.5 mL/min, 20 °C, UV 220 nm, tmin
16.9 min, tmajor = 17.9 min). [α]D20 +60.0 (c 0.10, CHCl3).
=
4-methoxyphenyl 2-(4-(tert-butyl)phenyl)propanoate (3k): Following
the general procedure, Meldrum’s acid 1k (58.1 mg, 0.2 mmol, 1 equiv.),
4-methoxyphenol 2a (24.8 mg, 0.2 mmol, 1 equiv.), K3PO4 (12.7 mg,
0.06 mmol, 30 mol%), CsCl (10.1 mg, 0.06 mmol, 30 mol%) and catalyst
H (8.8 mg, 0.01 mmol, 5 mol%) were stirred in CPME (1 mL) for 48 h. The
title compound was obtained as a white solid (40.1 mg, 64%) after silica
gel flash column chromatography (Petroleum ether/Et2O 9:1). Rf = 0.33
(Petroleum ether/Et2O 9:1). mp = 58-60 °C. IR (neat) νmax = 2960, 2906,
2871, 2835, 1748, 1596, 1504, 1456, 1250, 1191, 1138, 1070, 1029, 891,
832, 777, 744, 574, 554, 520 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.42-
7.28 (m, 4H), 6.96-6.80 (m, 4H), 3.92 (q, 1H, J = 7.2 Hz), 1.59 (d, 3H, J =
7.2 Hz), 1.33 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 173.7, 157.2, 150.2,
144.5, 137.1, 127.2 (2 C), 125.8 (2 C), 122.3 (2 C), 114.4 (2 C), 55.67,
45.2, 34.6, 31.5 (3 C), 18.8. HRMS (AP+) m/z: [M + H]+ Calcd for C20H25O3
313.1798; Found 313.1807. HPLC analysis: 57% ee (column DAICEL
Chiralpak IA 3μm, heptane/i-PrOH 98:2, flow rate 1 mL/min, 20 °C,
UV 220 nm, tmin = 8.2 min, tmajor = 9.7 min). [α]D20 +48.4 (c 0.50, CHCl3).
20
rate 1 mL/min, 20 °C, UV 215 nm, tmajor = 6.8 min, tmin = 8.1 min). [α]D
+58.8 (c 0.58, CHCl3).
phenyl 2-(4-chlorophenyl)propanoate (3o): Following the general
procedure, Meldrum’s acid 1e (53.7 mg, 0.2 mmol, 1 equiv.), phenol 2b
(18.8 mg, 0.2 mmol, 1 equiv.), K3PO4 (12.7 mg, 0.06 mmol, 30 mol%),
CsCl (10.1 mg, 0.06 mmol, 30 mol%) and catalyst H (8.8 mg, 0.01 mmol,
5 mol%) were stirred in CPME (1 mL) for 48 h, the title compound was
obtained as a colourless oil (37.5 mg, 72%) after silica gel chromatography
(Petroleum ether/Et2O 9:1). Rf = 0.49 (Petroleum ether/Et2O 9:1). IR (neat)
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10.1002/ejoc.201800331
European Journal of Organic Chemistry
FULL PAPER
νmax = 2982, 2936, 1752, 1593, 1492, 1456, 1331, 1193, 1135, 1092, 1070,
1015, 918, 830, 766, 744, 691, 528, 499 cm-1. 1H NMR (300 MHz, CDCl3):
δ = 7.31-7.21 (m, 6H), 7.24-7.16 (m, 1H), 7.02-6.94 (m, 2H), 3.94 (q, 1H,
J = 7.2 Hz), 1.60 (d, 3H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3) δC 172.8,
190.8, 138.6, 133.4, 129.5 (2 C), 129.1 (4 C), 126.0, 122.4 (2 C), 45.2,
18.6. HRMS (EI+) m/z: [M]+ Calcd for C15H13ClO2 260.0599; Found:
260.0614. HPLC analysis: 70% ee (column DAICEL Chiralpak IA 3μm,
Asymmetry 2004, 15, 3653-3691; c) J. Blanchet, J. Baudoux, M. Amere,
M.-C. Lasne, J. Rouden, Eur. J. Org. Chem. 2008, 5493-5506; d) J. T.
Mohr, A. Y. Hong, B. M. Stoltz, Nat. Chem. 2009, 1, 359-369; e) T.
Poisson, S. Oudeyer, J.-F. Brière, V. Levacher, in Enantioselective
Organocatalyzed Reactions I (Ed.: R. Mahrwald), Springer, Dordrecht
Heidelberg London New York, 2011, pp. 67-106; f) A. Claraz, S. Oudeyer,
V. Levacher, Curr. Org. Chem. 2012, 16, 2192-2205; g) S. Oudeyer, J.-
F. Brière, V. Levacher, Eur. J. Org. Chem. 2014, 6103-6119; h) J. P.
Phelan, J. A. Ellman, Beilstein J. Org. Chem. 2016, 12, 1203-1228; i) N.
Fu, L. Zhang, S. Luo, Org. Biomol. Chem. 2018, 16, 510-520.
C. Fehr, J. Galindo, Angew. Chem. Int. Ed. 1994, 33, 1888-1889.
T. Poisson, V. Gembus, V. Dalla, S. Oudeyer, V. Levacher, J. Org. Chem.
2010, 75, 7704-7716.
heptane/EtOH 95:5, flow rate 0.5 mL/min, 20 °C, UV 220 nm, tmin
10.1 min, tmajor = 10.6 min). [α]D20 +54.5 (c 0.49, CHCl3).
=
[2]
[3]
o-tolyl 2-(4-chlorophenyl)propanoate (3p): Following the general
procedure, Meldrum’s acid 1e (53.7 mg, 0.2 mmol, 1 equiv.), o-cresol 2c
(21.6 mg, 0.2 mmol, 1 equiv.), K3PO4 (12.7 mg, 0.06 mmol, 30 mol%),
CsCl (10.1 mg, 0.06 mmol, 30 mol%) and catalyst H (8.8 mg, 0.01 mmol,
5 mol%) were stirred in CPME (1 mL) for 48 h. The title compound was
obtained as a colourless oil (43.3 mg, 79%) after silica gel flash column
chromatography (Petroleum ether/EtOAc 96:4). Rf = 0.35 (Petroleum
ether/EtOAc 96:4). IR (neat) νmax = 2981, 2935, 1750, 1490, 1457, 1330,
1220, 1172, 1135, 1110, 1091, 1070, 1043, 1014, 940, 894, 833, 778, 746,
712, 527, 448 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.41-7.31 (m, 4H),
7.22-7.07 (m, 3H), 6.95-6.87 (m, 1H), 3.98 (q, 1H, J = 7.2 Hz), 1.95 (s, 3H),
1.63 (d, 3H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): δ = 174.2, 149.3,
138.6, 133.4, 131.3, 130.2, 129.2 (2 C), 129.0 (2 C), 127.0, 126.2, 127.7,
45.1, 18.4, 16.0. HRMS (EI+) m/z: [M]+ Calcd for C16H15ClO4 274.0755;
Found: 274.0758. HPLC analysis: 52% ee (column DAICEL Chiralpak IA
[4]
[5]
H. Brunner, P. Schmidt, Eur. J. Org. Chem. 2000, 2119-2133.
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2001, 2, 37-51.
[6]
[7]
For a discussion on the influence of the double bond geometry of enolate
in protonation reactions, see: P. Duhamel, Bull. Soc. Chim. Fr. 1996, 133,
457-459.
a) L. Verbit, T. R. Halbert, R. B. Patterson, J. Org. Chem. 1975, 40, 1649-
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a) H. Pracejus, Justus Liebigs Ann. Chem. 1960, 634, 9-22; b) S. L.
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2009, 7, 346-350.
3μm, heptane/EtOH 99:1, flow rate 1 mL/min, 20 °C, UV 220 nm, tmin
=
6.2 min, tmajor = 7.5 min). [α]D20 +40.6 (c 0.50, CHCl3).
Synthesis of (S)-ibuprofen: To a solution of ester 3j (33.7 mg, 0.12 mmol,
1 equiv.) in THF (0.8 mL) and water (0.12 mL) were successively added
LiOH (2.0 M, 0.2 mL) and H2O2 (30% in water, 0.1 mL) at 0 °C. The
reaction mixture was stirred for 8 h at 0 °C, then quenched by the addition
of Na2S2O3 (0.7 M, 1 mL) and NaHCO3 (0.5 M, 1.6 mL). The resulting
mixture was allowed to stir for 15 minutes, and HCl (20%) was added until
the mixture was acidic. The organic layer was extracted with EtOAc (3 x
10 mL), and the combined organic layers were dried over Na2SO4 then
concentrated. The crude product was purified by silica gel flash column
chromatography (Petroleum ether/Acetone/AcOH 90:10:1) to give the title
compound as a white solid (18.1 mg, 70%). Rf = 0.22 (Petroleum
ether/Acetone/AcOH 90:10:1). 1H NMR (300 MHz, CDCl3): δ = 7.25-7.19
(m, 2H), 7.14-7.07 (m, 2H), 3.71 (q, 1 H, J = 7.2 Hz), 2.44 (d, 2H, J = 7.2 Hz),
1.92-1.76 (m, 1H), 1.50 (d, 3 H, J = 7.2 Hz), 0.89 (d, 6 H, J = 6.6 Hz). HPLC
analysis: 59% ee (column DAICEL Chiralpak IA 5μm, MeOH/H2O (0.1%
a) K. M. Johnson, M. S. Rattley, F. Sladojevich, D. M. Barber, M. G.
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[11] For reviews, see: a) A. M. Dumas, E. Fillion, Acc. Chem. Res. 2010, 43,
440-454; b) E. Pair, T. Cadart, V. Levacher, J.-F. Brière, Chem. Cat.
Chem. 2016, 8, 1882-1890.
[12] For reviews, see : a) J.-F. Brière, S. Oudeyer, V. Dalla, V. Levacher,
Chem. Soc. Rev. 2012, 41, 1696-1707; b) J. Godemert, S. Oudeyer, V.
Levacher, Chem. Cat. Chem. 2016, 8, 74-85.
[13] For selected examples, see : a) A. Claraz, G. Landelle, S. Oudeyer, V.
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Oudeyer, V. Levacher, Tetrahedron: Asymmetry 2013, 24, 764-768; d)
M. Decostanzi, J. Godemert, S. Oudeyer, V. Levacher, J.-M. Campagne,
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Oudeyer, V. Levacher, ChemistrySelect 2016, 1, 3184-3188.
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ammonium enolates, see : a) E. Yamamoto, A. Nagai, A. Hamasaki, M.
Tokunaga, Chem. Eur. J. 2011, 17, 7178-7182; b) E. Yamamoto, D.
Gokuden, A. Nagai, T. Kamachi, K. Yoshizawa, A. Hamasaki, T. Ishida,
M. Tokunaga, Org. Lett. 2012, 14, 6178-6181.
AcOH) 75:25, flow rate 1mL/min, 20 °C, UV 220 nm, tmin= 8.6 min, tmajor
9.6 min). [α]D20 +34.0 (c 0.50, CHCl3).
=
Acknowledgements
This work has been partially supported by Rouen University, INSA
Rouen, CNRS, EFRD and Labex SynOrg (ANR-11-LABX-0029)
and region Normandie (CRUNCh network). F.L. thanks the MESR
for a doctoral fellowship.
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Weaver, M. Lee, J. A. Ellman, J. Am. Chem. Soc. 2012, 134, 9058-9061;
b) S. Luo, N. Fu, Y. Guo, L. Zhang, Synthesis 2015, 47, 2207-2216.
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11571.
Keywords: Asymmetric catalysis • Meldrum’s acid • Nucleophilic
addition • Organocatalysis • Protonation
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2587; b) L. Duhamel, P. Duhamel, J.-C. Plaquevent, Tetrahedron:
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10.1002/ejoc.201800331
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Entry for the Table of Contents (Please choose one layout)
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Enantioselective protonation
F. Legros, T. Martzel, J.-F. Brière, S.
Oudeyer* and V. Levacher
Page No. – Page No.
Organocatalytic enantioselective
decarboxylative protonation reaction
of Meldrum’s acid derivatives under
PTC conditions
An original organocatalyzed enantioselective protonation sequence starting from
readily available disubstituted Meldrum’s acid derivatives and phenols was
developed providing chiral non-racemic 2-aryl propionic ester derivatives in good
isolated yields and up to 70% ee under PTC conditions. The usefulness of the
reaction was demonstrated in the course of the synthesis of enantioenriched (S)-
ibuprofen.
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