Optimizing the structure of 4-dialkylamino-α,α-diarylprolinol ethers as catalysts for the enantioselective cyclopropanation of α,β-unsaturated aldehydes in water

Article abstract of DOI:10.1002/cctc.201300097

We optimized the structure of a new family of chiral diarylprolinol-type organocatalysts with improved performances in conjugate addition reactions performed in water and proceeding under the iminium activation manifold. The principles behind the catalyst

Full text of DOI:10.1002/cctc.201300097

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DOI: 10.1002/cctc.201300097
Optimizing the Structure of 4-Dialkylamino-a,a-
diarylprolinol Ethers as Catalysts for the Enantioselective
Cyclopropanation of a,b-Unsaturated Aldehydes in Water
Jose I. Martꢀnez, Efraim Reyes, Uxue Uria, Luisa Carrillo, and Jose L. Vicario*[a]
We optimized the structure of a new family of chiral diarylpro-
linol-type organocatalysts with improved performances in con-
jugate addition reactions performed in water and proceeding
under the iminium activation manifold. The principles behind
the catalyst design were, firstly, the incorporation of a tertiary
amino group at the 4-position of the pyrrolidine scaffold,
which can facilitate the reaction by providing a basic site that
favors deprotonation of the pronucleophile, and, secondly,
a bulky diaryltrialkylsilyloxymethyl group maintained at the 2-
position to control the iminium ion geometry and to provide
the required steric bias for face stereoselection. The nature of
this 4-dialkylamino group and the relative 2,4-configuration
was optimized and the resulting catalyst proved its efficiency
in the catalytic enantioselective cyclopropanation of a,b-unsa-
turated aldehydes using water as the reaction solvent. More-
over, the reaction was studied by computational methods,
which indicated that the overall transformation proceeded
through a cascade Michael/a-alkylation sequence, in which the
first iminium-mediated Michael addition reaction was the rate-
determining step and also the step at which stereochemical in-
formation was transferred from the catalyst to the products.
Introduction
The development of more environmentally acceptable chemi-
cal processes has led to increased interest in both academic
and industrial research. In particular, replacing the commonly
used volatile organic compounds by solvents with lower vapor
pressures or by liquids that are believed to be more environ-
mentally benign has been a field of remarkable activity in the
last few years. Especially, the use of water as the solvent has
received substantial attention,[1] not only because of its inher-
ent friendliness towards environment but also owing to the
fact that it is the cheapest and most widely available solvent.
In this sense, aminocatalysis, which is known as the ability of
primary or secondary amines to promote an organic transfor-
mation through the reversible formation of azomethine inter-
mediates such as iminium ions or enamines, constitutes a privi-
leged manifold for developing processes that can take place in
water because of the compatibility of the catalysts and the re-
active intermediates that participate in the catalytic cycle to-
wards aqueous media and ambient oxygen. Moreover, amino-
catalytic processes have demonstrated their high level of per-
formance in reactions that involve functionalization of carbonyl
compounds with exceptional levels of regio- diastereo- and
enantiocontrol. In addition, the ability of these catalysts to pro-
mote tandem or domino reactions that combine different
transformations in a single manipulation leading to a high
degree of molecular complexity in a fast and reliable way and
starting from simple starting materials is another positive
aspect related to aminocatalysis and to the environmental
benefits associated to these domino processes.
In this sense, several chiral primary and secondary amines
have been designed and employed in different transformations
by using an aqueous environment, mostly focused on reac-
tions such as the aldol, Mannich, Michael, or other related ones
that proceed under enamine activation.[2] In this sense, the
main tendency in the catalyst design has focused on the intro-
duction of long hydrophobic alkyl side chains in the catalyst
structure. The concept behind this design is based on the fact
that aggregation of the organocatalyst with the hydrophobic
reagents participating in the Michael reaction reduces the con-
tact between these reagents and bulk water as the reaction
proceeds, therefore, the reagents behave as if they were dis-
solved in an organic solvent.[3] Alternatively, the use of catalysts
with improved solubility in water achieved by introducing per-
fluorinated alkyl side chains[4] or lateral quaternary ammonium
moieties[5] on their structure has also been explored and also
several surfactant-type organocatalysts have been found to ef-
ficiently catalyze several of these reactions in water with excel-
lent results.[6] Other authors have focused on the development
of recyclable chiral amine catalysts that can also be used in
aqueous media, such as modified chiral ionic liquid-type orga-
nocatalysts[7] and some examples of chiral secondary amines
attached to solid supports[8] or incorporated into dendrimeric
structures.[9]
[a] J. I. Martꢀnez, Prof. E. Reyes, Dr. U. Uria, Prof. L. Carrillo, Prof. J. L. Vicario
Department of Organic Chemistry II
University of the Basque Country (UPV/EHU)
P.O. Box 644, 48080 Bilbao (Spain)
Fax: (+34)601-2748
E-mail: joseluis.vicario@ehu.es
On the other hand, and as previously mentioned, although
a wide variety of such modified catalysts have been developed
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201300097.
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to promote reactions under the enamine activation manifold,
only a few examples based on the iminium activation ap-
proach as the operating organocatalytic activation mechanism
in an organic reaction proceeding in an aqueous medium have
been reported in the recent literature.[10] Moreover, and despite
the fact that the iminium activation manifold is an outstanding
platform for developing cascade processes,[11] only a few exam-
ples that proceed in water as the reaction solvent have been
reported up to date.[12] In particular, our group has demonstrat-
ed in a preliminary way (Scheme 1) that the enantioselective
Figure 1. Relevant features associated to the catalyst design.
the modulation of the ability of the catalyst to form micellar
aggregates in disperse aqueous solutions by means of intro-
ducing linear alkyl side chains of different lengths at the nitro-
gen atom. In addition, the presence of this additional Brønsted
basic site would also cooperate in the reaction because it af-
fords a slightly basic initial reaction medium that could facili-
tate activation of the bromomalonate by assisting its deproto-
nation. Moreover, as it was also expected that the reaction
medium would become increasingly acidic as the reaction
moved towards completion because of the continuous genera-
tion of HBr eliminated after the intramolecular a-alkylation
step, it was also envisaged that protonation of the tertiary
amine site would result in a catalyst architecture with im-
proved ambiphilic character. On the other hand, the bulky dia-
ryl(trialkylsilyloxy)methyl group at the 2-position of the pyrroli-
dine structure was maintained as key element for achieving
stereocontrol, because it was known that these types of diary-
lprolinol-based catalysts control the iminium ion geometry
(preferential formation of E iminium ion), and also because of
their performance in exerting a very effective degree of stereo-
induction during the conjugate addition step by blocking one
of the diastereotopic faces of the Michael acceptor through
steric bias.[14] It has also to be pointed out that the incorpora-
tion of the additional 4-dialkylamino substituent at the catalyst
scaffold results in an additional stereogenic center with poten-
tial implications in the performance of the new catalyst in
terms to stereocontrol and, therefore, the influence of the con-
figuration of this stereocenter is another issue that has to be
studied in order to identify the best catalyst architecture.
Scheme 1. “In water” organocatalytic enantioselective cyclopropanation of
enals developed by our group.
cyclopropanation of a,b-unsaturated aldehydes with diethyl
bromomalonate can be performed by using an O-TMS protect-
ed a,a-diarylprolinol derivative as the catalyst in a reaction in-
volving a cascade sequence that consists of an initial Michael
reaction under iminium activation followed by intramolecular
a-alkylation under enamine catalysis.[12a] We have also demon-
strated that, although other methodologies require the incor-
poration of one equivalent of a Brønsted base to quench the
HBr formed as the reaction proceeds forward,[13] performing
the reaction in water led to the formation of the final cyclopro-
panes in good yields and stereoselectivities without the need
of such an stoichiometric additive, which, on the other hand, is
known to lead to undesired side-reactions.[13i]
However, this methodology reported in our preliminary
study suffered from a very important drawback, associated to
the need of an important excess of a,b-unsaturated aldehyde
reagent (three-fold excess with respect to ethyl bromomalo-
nate) to obtain good yields of the final cyclopropanation prod-
uct. This requirement resulted in a problematic situation when
we tried to conduct the reaction on a larger scale because the
reaction mixture appeared as an emulsion and not as a homo-
geneous solution and could not be properly stirred. For this
reason, we decided to synthesize a modified version of the ini-
tial diarylprolinol catalyst aiming to identify a new structurally
related chiral secondary amine with improved performances in
this reaction if working in a purely aqueous environment.
The synthesis of this family of highly modular catalysts was
performed according to the synthetic pathway shown in
Scheme 2, by starting from the commercially available and
cheap reagent trans-4-hydroxyproline. The synthesis begins
with the esterification and N-carbamoylation of the starting
material followed by reaction with the required aryl Grignard
reagent, which led to the formation of bicyclic adduct 1 in
good yield without the need to previously protect the secon-
dary hydroxy group of the starting 4-hydroxyproline. Next, the
amino functionality was installed by initial mesylation followed
by nucleophilic displacement by the azide anion (taking place
with no epimerization) and subsequent hydrogenation and N-
alkylation with a set of alkyl halides. Finally, a family of differ-
ent catalysts 4a–g was obtained by hydrolysis and a final O-si-
lylation (or O-methylation) step. In addition, diastereomeric cis-
configured catalyst 4h was prepared as representative model
for studying the influence of the relative stereochemistry of
the two stereocenters present at the catalyst structure starting
Results and Discussion
The key aspects of our catalyst design are shown in Figure 1
and rely on the incorporation of a tertiary amine moiety at the
4-position of the diarylprolinol skeleton. This would allow us
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Table 1. Performance of catalysts 4a–g and 4h in the model reaction.[a]
Entry
Catalyst
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4 f
4g
4h
4e[e]
4e[f]
4e[e,g]
88
85
85
82
94
75
75
99
94
36
93
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
80
92
93
94
96
93
88
86
96
84
96
9
10
11
[a] The reaction was conducted with an aliquot (0.125 mmol) of 5 and
a threefold excess of 6a in the presence of the catalyst (20 mol%) in
water (1 mL) at room temperature. [b] Yield of pure product after flash
column chromatography. [c] Diastereomeric ratio determined by NMR
analysis of the crude reaction mixture. [d] Determined by HPLC analysis
after reduction to the corresponding primary alcohol (see Experimental
Section). [e] 10 mol% of catalyst was employed. [f] 5 mol% of catalyst
was employed. [g] Reaction performed by using a 1:1.2 ratio of 5 and 6a.
similar levels of enantiocontrol with the only exception of the
O-methyl derivative 4a that furnished cyclopropane 7a at
a moderate 80% ee (entry 1). We therefore decided to use the
triethylsilyl substituent as the most convenient O-protecting
group in terms of better stability towards hydrolysis and we
next evaluated the role played by the alkyl groups placed at
the tertiary amine moiety. In this sense, we observed that the
smallest dimethylamino group at the 4-position of the catalyst
(catalyst 4e) led to a notable improvement in the yield of the
reaction, also observing that it proceeded with slightly higher
enantioselectivity (entry 5). Importantly, if the length of these
alkyl chains was increased, the performance of the catalysts
decreased notably (entries 6 and 7). The influence of the rela-
tive configuration of the two stereocenters at the catalysts was
also evaluated by observing that the trans-2,4-disubstituted
analogue of 4e performed very well in terms of catalytic activi-
ty but led to the formation of the final cyclopropane adduct
with a somewhat lower degree of enantiocontrol (entry 8).
Once catalyst 4e had been identified as the most effective
architecture for this transformation, we also found that the cat-
alyst loading could be lowered down to 10 mol% without sig-
nificantly affecting the results (entry 9) but if the reaction was
conducted by using 5 mol% of 4e, the yield dropped down
drastically. Remarkably, we also found that the good perfor-
mance of this catalyst in water also enabled us to perform the
reaction by using a 1:1.2 ratio of cinnamaldehyde and diethyl
bromomalonate, which resulted in an important improvement
with respect to the original conditions reported. Finally, it
should be pointed out that in all the reactions evaluated, the
final cyclopropane adducts were formed as single diastereoiso-
mers, as NMR analysis of the crude reaction mixtures indicated.
Scheme 2. Synthesis of catalysts 4a–h. The N-methylation for the synthesis
of 3a and the final O-methylation step for the synthesis of catalyst 4a were
performed by using a modified procedure (see the Supporting Information).
from 1. In this sense, trans-configured derivative 4h was pre-
pared from 1 by standard Mitsunobu inversion followed by the
same set of transformations as used before for converting
1 into 4.
With this family of different catalysts in hand, we proceeded
to evaluate their performance in the projected cyclopropana-
tion reaction using the reaction between cinnamaldehyde and
diethyl bromomalonate as a model system (Table 1). In all
cases we applied the conditions initially set up by us in our
preliminary report, which involve the use of 20 mol% of cata-
lyst in water as the only solvent and using a 3:1 ratio of diethyl
bromomalonate to cinnamaldehyde. We started by evaluating
the nature of the protecting group at the oxygen atom main-
taining a common di-n-butylamino group as 4-substituent of
the a,a-diarylprolinol architecture and keeping a 2,4-cis relative
configuration for all cases (entries 1–4). As it can be seen in
Table 1, this O-protecting group had little influence on the
yield of the reaction and also all these catalysts 4a–d furnished
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Table 2. Scope of the reaction
Entry
R
Product
Yield [%][a]
dr[b]
ee [%][c]
1
2
3
4
5
6
Ph
7a
7b
7c
7d
7e
7 f
93
83
80
60
70
83
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
97
>99
94
>99
93
2-CH3OC6H4
4-CH3OC6H4
4-NO2C6H4
4-FC6H4
2-furyl
>99
[a] Yield of pure product after column chromatography purification. [b]
Determined by NMR analysis of crude reaction mixture. [c] Determined
by HPLC analysis after reduction to the corresponding primary alcohol
(see the Supporting Information).
Scheme 3. Proposed catalytic cycle for the enantioselective cyclopropana-
tion of a,b-unsaturated aldehydes with diethylbromomalonate catalyzed by
a chiral secondary amine.
With these notably improved reaction conditions in hand,
we proceeded to study the scope of the reaction with respect
to the possibility of using other a,b-unsaturated aldehydes as
substrates (Table 2). As it can be seen in this table, all
enals 6a–f tested performed well in the reaction regardless of
the electronic nature of the b-substituent which includes the
reaction using electron-rich (entries 2 and 3) and electron-poor
(entries 4 and 5) substrates. Moreover, heteroaryl substituents
were also tolerated (entry 6). In all cases the yields were high,
the formation of one single diastereoisomer was observed, and
the final cyclopropanation products were obtained in higher
than 90% ee It should be pointed out that all these adducts
were found to be somewhat unstable compounds and, there-
fore, they were subjected to reduction under standard condi-
tions (NaBH4, MeOH, 08C) to obtain the more stable primary al-
cohols that were isolated and fully characterized. At this point,
we additionally found the conditions for the HPLC separation
of both enantiomers using chiral stationary phase HPLC col-
umns. Therefore, ee determinations were performed at this
stage.
onate. Accordingly, we started by calculating the energies of
the two possible diastereomeric Z and E iminium salts that
could be eventually formed after the condensation reaction
between the catalyst and cinnamaldehyde. As in other studies,
the E iminium ion (E)-I was 5.02 kcalmolÀ1 more stable than
the corresponding Z iminum ion (Z)-I (Figure 2).
Mechanistic aspects
Figure 2. Main geometrical features and DGreact values of the iminium ion
(Z)-I and (E)-I obtained at the B3LYP/6-31G(d) level of theory using the PCM
model.
We also decided to study the reaction using computational
tools to unveil the most relevant aspects associated to the re-
action pathway and to the factors that govern the stereoselec-
tivity. We assumed a catalytic cycle as shown in Scheme 3, in
which the reaction would start by the activation of the enal by
the catalyst through iminium ion formation which should be
followed by a Michael addition step with diethyl bromomalo-
nate (with the participation of the corresponding enolate) gen-
erating an enamine intermediate, and this would subsequently
undergo intramolecular a-alkyation reaction and final hydroly-
sis that would release the product and would account for cata-
lyst turnover.
We next proceeded to calculate the transition states associ-
ated to the initial Michael reaction that leads to the formation
of enamine intermediate II (Figure 3). We observed that the ap-
proach of the bromomalonate reagent to this E-iminium ion
(E)-I through its less hindered face resulted in a transition state
(TS-1a) significantly lower in energy than the transition state
corresponding to the reaction through its most hindered face
(TS-1b). The latter reaction would eventually result in the for-
mation of the final product with the opposite absolute config-
uration at the stereogenic center that was formed in this initial
step (DG° =12.20 and 16.35 kcal molÀ1, respectively). We also
calculated the energy of the transition state associated to the
For the first study of the energetic profile of the reaction we
decided to perform our calculations by using the more struc-
turally simple O-TMS a,a-diphenylprolinol chiral catalyst for the
reaction between cinnamic aldehyde and dimethyl bromomal-
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Figure 3. Optimized transition states for the Michael addition to (E)-I and
(Z)-I and optimized structures and DGreact values for enamines II. Activation
energies are given in kcalmolÀ1
.
conjugate addition of the bromomalonate reagent to the imi-
nium ion (Z)-I through its less hindered face (TS-1c), which
would also lead to the formation of the final product with the
opposite configuration at the Michael-generated stereocenter
to that obtained experimentally (enamine intermediate (R)-II),
and this transition state was also higher in energy (DG° =
17.74 kcalmolÀ1) than the two transition states of the reactions
involving the E-iminium ion TS-1a and TS-1b. However, inter-
estingly, the calculated activation energy (Ea) was comparable
to the activation barrier needed to reach (R)-II (DDG° =
12.72 kcalmolÀ1 for the formation of (R)-II through the partici-
pation of iminium ion (Z)-I versus DDG° =12.20 kcalmolÀ1 for
the formation of (S)-II through participation of iminium ion
(E)-I).
Figure 4. Optimized transition states for the SN2 reaction step and DGreact
values for intermediates III. Activation energies are given in kcalmolÀ1
.
We next analyzed the subsequent intramolecular a-alkyla-
tion step involving SN2-type reaction between the nucleophilic
enamine moiety and the alkyl bromide. (Figure 4). At this
point, four different situations could be taken into account.
The first two arise if starting from the enamine intermediate
(S)-II and consist of a direct SN2 reaction (TS-2a-trans) or a SN2
reaction after a 1808 turn in the CÀC bond created in the pre-
vious step (TS-2a-cis) to afford the desired cyclopropane with
a (2R,3S)-configuration or a (2R,3R)-configuration, respectively.
In the same way, the intermediate (R)-II could undergo the re-
action through the same two channels (TS-2b-trans and TS-
2b-cis) generating the (2S,3R)- or (2S,3S)-configured cyclopro-
panes, respectively. As it can be seen in Figure 4, the formation
of the (2R,3S)-III product is favored in terms of energy
(DDG° =10.37 kcalmolÀ1 versus DDG° =14.33, 10.97, and
12.45 kcalmolÀ1), which also agrees with the experimental
observation.
These calculated data also indicated that, for the preferred
pathway which generates iminium ion (2R,3S)-III through inter-
mediate (S)-II, the activation energy associated to the first step
of the cascade (the Michael reaction) was higher than the one
required for the subsequent intramolecular SN2 reaction
(DDG° =12.20 kcalmolÀ1 and 10.37 kcalmolÀ1, respectively).
This also indicated that this first Michael reaction was indeed
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which stereochemistry is placed. The catalyst belongs to
a novel class of catalysts that are active in reactions in aqueous
media, involving activation of enals through iminium ion for-
mation. The activity results are in contrast to that of most of
the other related structures reported, which have been exclu-
sively employed in reactions under enamine activation. Thus,
this novel catalyst structure may pave the way for its applica-
tion in other related transformations.
Experimental Section
General methods
NMR spectra were acquired on a Bruker 300 spectrometer, running
1
at 300 and 75 MHz for H and 13C, respectively. Chemical shifts (d)
are reported in ppm relative to residual solvent signals (CHCl3,
7.26 ppm for 1H NMR, CDCl3, 77.0 ppm for 13C NMR). IR spectra
were measured in a PerkinElmer 1600 apparatus and only charac-
teristic bands are given. Mass spectra were recorded on a Waters
micromass GCT spectrometer by using electronic impact (EI, 70 eV).
Analytical thin-layer chromatography was performed by using pre-
coated aluminum-backed plates (Merck Kieselgel 60 F254) and vi-
sualized by UV irradiation or phosphomolibdic acid. Melting points
were measured in a Bꢂchi B-540 apparatus and were uncorrected.
Optical rotations were measured on a PerkinElmer 241 polarimeter.
The enantiomeric excesses (ee) of the products were determined
by chiral stationary phase HPLC in a Waters 2695 with a Waters
2998 photodiode array detector and by using the indicated chiral
column and conditions in each case. Analytical-grade solvents and
commercially available reagents were used without further purifica-
tion. Silica gel (Silica gel 60, 230–400 mesh, Merck) was employed
for flash column chromatography.
Figure 5. Optimized transition states for the Michael addition and intramo-
lecular alkylation reaction TS-1a’ and TS-2a’-trans and optimized structure,
and DGreact value for enamines (S)-II’ in the 4e-catalyzed reaction.
the rate-limiting step of the process (and also irreversible as
we envisioned in the catalytic cycle in Scheme 3). Additionally,
it was the step at which the stereochemical information was
transferred from the catalyst to the product. In this sense, our
calculations also indicated that the eventual formation of the
opposite enantiomer to the one experimentally observed
should occur most probably through the attack of the bromo-
malonate reagent to the iminium ion intermediate (Z)-I and
not as a consequence of poor face stereodiscrimination of the
O-TMS a,a-diarylprolinol catalyst.
Synthesis of catalyst 4e
(6R,7aS)-1,1-bis[3,5-bis(trifluoromethyl)phenyl]-6-
Finally, we also calculated the energetic profile for the reac-
tion by using the newly designed organocatalyst 4e (Figure 5).
These calculations indicated that the initial Michael reaction
step was slightly more exothermic than the parent reaction
using the simpler O-TMS-a,a-diphenylprolinol and also that
lower activation energy barriers were required for both the
hydroxytetrahydropyrrolo[1,2-c]oxazol-3(1H)-one (1): Methyl chloro-
formate (22.4 mL, 0.289 mol) was dropwise added to a suspension
of trans-4L-hydroxyproline (17.21 g, 0.138 mol) and K2CO3 (18.0 g,
0.138 mol) in MeOH (70 mL) at 08C. The mixture was stirred at this
temperature for 8–10 h, after which the solvent was removed
under reduced pressure. The obtained solid was redissolved in
CH2Cl2 and washed with water. The aqueous layer was then ex-
tracted with CH2Cl2 (2ꢃ25 mL) and the combined organic layers
were dried over anhydrous Na2SO4 and filtered. After the removal
of the solvent (2S,4R)-dimethyl 4-hydroxypyrrolidine-1,2-dicarboxy-
late, was isolated as a yellowish solid (27.83 g, 0.137 mol, quantita-
tive). 1H NMR (CDCl3, 300 MHz): d=4.42–4.35 (m, 2H), 3.67–3.52
(m, 7H), 3.47–3.30 (m, 2H), 2.40–2.13 (m, 1H), 2.03–1.93 ppm (m,
1H). 13C NMR (CDCl3, 75.4 MHz) (*denotes minor rotamer signals):
d=173.2, 173.1*, 155.6, 155.3*, 69.6, 68.8, 57.8, 57.5*, 54.9, 54.4*,
52.7, 52.6*, 38.9, 38.2* ppm. Anal. calcd. for C8H13NO5: C, 47.29; H,
6.45; N, 6.89. Found: C, 47.59; H, 6.68; N, 6.95. Next, a solution of
1-bromo-3,5-bis(trifluoromethyl)benzene (14.9 mL, 0.086 mol) in
THF (15 mL) was dropwise added to a suspension of Mg (2.1 g,
0.086 mol) in dry THF (25 mL) at 08C. The mixture was stirred at
reflux for 1 h and then it was allowed to reach RT, after which a so-
lution of (2S,4R)-dimethyl 4-hydroxypyrrolidine-1,2-dicarboxylate
(5.01 g, 0.025 mol) in dry THF (15 mL) was dropwise added at 08C.
The mixture was heated to reflux for 2 h and it was afterwards
poured into an NH4Cl ice bath and filtered. The mixture was then
rate-limiting initial Michael reaction (DDG° =11.68 kcalmolÀ1
)
and also for the subsequent intramolecular SN2-type reaction
(DDG° =7.47 kcalmolÀ1). These data are also in agreement
with the higher activity of catalyst 4e compared to the activity
of the O-TMS-protected a,a-diphenylprolinol catalyst used in
our previous work.
Conclusion
We showed that incorporating a 4-dimethylamino group in the
structure of O-TMS-a,a-diarylprolinol results in an aminocata-
lyst with improved abilities to catalyze the enantioselective cy-
clopropanation of a,b-unsaturated aldehydes with diethyl bro-
momalonate in water. A computational study also indicated
that the reaction proceeded through a cascade Michael/intra-
molecular a-alkylation process, in which the initial Michael re-
action is the rate-determining step and also the moment at
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extracted with EtOAc (3ꢃ20 mL) and the combined organic layers
were dried over anhydrous Na2SO4 and filtered. After the removal
of the solvent, the obtained solid was purified through flash chro-
matography (hexane/EtOAc 6: 4) to yield 1 as a brownish solid
FTIR: n˜ =2112 cmÀ1 (N3 st), 1758 (C=O st). [a]2D0: À155.9 (c=1.0,
CH2Cl2). M.p.: 119–1228C (hexane/EtOAc 8:2).
(6S,7aS)-1,1-bis[3,5-bis(trifluoromethyl)phenyl]-6-
(dimetylamino)tetrahydropyrrolo[1,2-c]oxazol-3(1H)-one (3a): A so-
lution of 2 (888 mg, 1.568 mmol) in MeOH was shaken under H2
(90 psi) atmosphere for 10–12 h in the presence of Pd(OH2) (44 mg,
5%wt). Afterwards, the solution was filtered through a Celite path
and the solvent was removed, affording (6S,7aS)-6-amino-1,1-
bis[3,5-bis(trifluoromethyl)phenyl]tetrahydropyrrolo-[1,2-c]oxazol-
3(1H)-one as a brownish solid (849 mg, quantitative). 1H NMR
(CDCl3, 300 MHz): d=7.97 (s, 2H), 7.91 (s, 1H), 7.88 (s, 1H), 7.87 (s,
2H), 4.68 (dd, 1H, J=9.4, 6.4 Hz), 3.90–3.69 (m, 1H), 3.51–3.43 (m,
2H), 2.07 (ddd, 1H, J=12.3, 6.4, 6.2 Hz), 1.34 (bs, 2H), 0.97 ppm
(ddd, 1H, J=12.3, 9.4, 7.5 Hz). 13C NMR (CDCl3, 75.4 MHz): d=
159.1, 144.6, 141.5, 132.8 (q, JCF =33.8 Hz), 132.6 (q, JCF =34.0 Hz),
125.9 (d, JCF =3.5 Hz), 125.8 (d, JCF =3.5 Hz), 123.8–123.1 (m, 1C),
1
(9.50 g, 0.017 mol, 67%). H NMR (CDCl3, 500 MHz): d=7.99 (s, 2H),
7.92 (s, 1H), 7.90 (s, 1H), 7.87 (s, 2H), 4.97 (dd, 1H, J=11.5, 4.7 Hz),
4.64–4.62 (m, 1H), 4.12 (dd, 1H, J=12.8, 5.5 Hz), 3.26 (d, 1H, J=
12.8 Hz), 2.03 (bs, 1H), 1.81 (dd, 1H, J=13.0, 4.7 Hz), 1.22 ppm
(ddd, 1H, J=13.0, 11.5, 5.2 Hz). 13C NMR (CDCl3, 125.7 MHz): d=
158.8, 144.2, 141.4, 132.8 (q, JCF =33.8 Hz), 132.7 (q, JCF =34.0 Hz),
125.8 (d, JCF =2.4 Hz), 125.4 (d, JCF =2.4 Hz), 123.5–123.4 (m, 1C),
122.9–122.8 (m, 1C), 122.8 (q,
JCF =273.3 Hz), 122.7 (q, JCF =
272.8 Hz), 83.5, 71.0, 67.1, 56.7, 39.2 ppm. Anal calcd. for
C22H13F12NO3: C, 46.58; H, 2.31; N, 2.47. Found: C, 46.67; H, 2.21; N,
2.30. MS (70 eV) m/z (%): 567 (6, M+), 548 (21), 478 (58), 439 (15),
369 (22), 241 (27), 213 (21). FTIR: n˜ =3459 (OH st), 1759 (C=O
st) cmÀ1. [a]D20: +104.9 (c=1.0, CH2Cl2). M.p.: 75–788C (hexanes/
EtOAc 8:2).
122.9–122.3 (m, 1C), 122.8 (q,
JCF =273.3 Hz), 122.7 (q, JCF =
272.9 Hz), 83.9, 68.2, 55.6, 52.8, 39.2 ppm. HRMS: Calcd. for
[C22H15F12N2O2]+: 567.0942 ([M+H]+); found: 567.0950. MS (70 eV)
m/z (%): 567 (100, [M+H]+), 566 (7, M+), 548 (20), 549 (80) 523 (29).
FTIR (cmÀ1): 3468, 3459 (NH2 st), 1764 (C=O st). [a]2D0: À116.5 (c=
1.0, MeOH). M.p.: 123–1258C (hexanes/EtOAc 8:2). Next, this com-
pound (200 mg, 0.35 mmol) was dissolved in MeOH (20 mL) and
aqueous formaldehyde (37%) (1.2 mL, 15.9 mmol) and formic acid
(306 mL, 8.1 mmol) were added. The solution was stirred at reflux
for 10–12 h and then 6m NaOH (15 mL) was added. The mixture
was extracted with CH2Cl2 (3ꢃ15 mL) and the combined organic
layers were dried over anhydrous Na2SO4 and filtered. After the re-
moval of the solvent, the obtained oil was purified through flash
chromatography (hexane/EtOAc 4:6) and the product 3a was iso-
lated as a white solid (190 mg, 0.33 mmol, 94%). 1H NMR (CDCl3,
300 MHz): d=7.95 (s, 2H), 7.91 (s, 2H), 7.85 (s, 2H), 4.65 (dd, 1H,
J=11.4, 5.4 Hz), 3.67 (dd, 1H, J=11.5, 6.9 Hz), 3.47 (dd, 1H, J=11.5,
8.0 Hz), 3.21–3.01 (m, 1H), 2.15 (s, 6H), 1.90–180 (m, 1H), 1.19–
1.04 ppm (m, 1H). 13C NMR (CDCl3, 75.4 MHz): d=158.2, 144.5,
(6S,7aS)-6-azido-1,1-bis[3,5-bis(trifluoromethyl)phenyl]-
tetrahydropyrrolo[1,2-c]oxazol-3(1H)-one (2): Pyridine (197 mL,
2.317 mmol) was added to a solution of 1 (730 mg, 1.287 mmol) in
dry CH2Cl2 (60 mL). The reaction mixture was cooled to 08C and
methanesulfonyl chloride (108 mL, 2.317 mmol) was dropwise
added. The solution was stirred for 6 h at RT and the reaction was
then quenched with H2O (30 mL). The aqueous layer was extracted
with CH2Cl2 (3ꢃ20 mL) and the combined organic layers were
dried over anhydrous Na2SO4 and filtered. The removal of the sol-
vent afforded (6R,7aS)-1,1-bis[3,5-bis(trifluoromethyl)phenyl]-3-
oxohexahydropyrrolo[1,2-c]oxazol-6-yl methanesulfonate as color-
less oil after flash column chromatography purification (hexanes/
1
EtOAc 6:4). (807 mg, 1.248 mmol, 97%). H NMR (CDCl3, 300 MHz):
d=8.01 (s, 2H), 7.94 (s, 1H), 7.91 (s, 1H), 7.89 (s, 2H), 5.34–5.29 (m,
1H), 4.91 (dd, 1H, J=11.4, 4.6 Hz), 4.30 (dd, 1H, J=13.9, 6.1 Hz),
3.52 (d, 1H, J=13.9 Hz), 3.09 (s, 3H), 2.14 (dd, 1H, J=14.0, 4.6 Hz),
1.41 ppm (ddd, 1H, J=14.0, 11.4, 5.6 Hz). 13C NMR (CDCl3,
75.4 MHz): d=158.5, 143.9, 140.9, 132.8 (q, JCF =33.8 Hz), 132.7 (q,
141.3, 132.8 (q, JCF =33.8 Hz), 132.7 (q, JCF =33.9 Hz), 125.8 (d, JCF
=
J
CF =34.0 Hz), 125.9 (d, JCF =2.9 Hz), 125.5 (d, JCF =2.9 Hz), 123.5–
3.0 Hz), 125.5 (d, JCF =3.0 Hz), 123.9–123.1 (m, 1C), 123.0–122.6 (m,
1C), 122.8 (q, JCF =273.1 Hz), 122.7 (q, JCF =273.1 Hz), 83.5, 68.1,
66.9, 50.3, 43.7, 33.9 ppm. HRMS: Calcd. for [C24H19F12N2O2]+:
595.1255 ([M+H]+); found: 595.1257. MS (70 eV) m/z (%): 598 (40,
[M+H]+), 581 (56), 566 (10), 549 (60), 523 (29), 126 (25), 112 (14).
FTIR: n˜ =1749 cmÀ1 (C=O st). [a]D20: À122.0 (c=1.0, CH2Cl2). M.p.:
78–808C (hexane/EtOAc 8:2).
123.4 (m, 1C), 122.9–122.8 (m, 1C), 122.8 (q, JCF =273.0 Hz), 122.7
(q, JCF =273.2 Hz), 83.7, 79.3, 66.8, 54.3, 38.7, 37.1 ppm. Anal. calcd.
for C23H15F12NO5S: C, 42.80; H, 2.34; N, 2.17. Found: 42.88; H, 2.42;
N, 2.05. MS (70 eV) m/z (%): 646 (32, [M+H]+), 627 (25), 626 (100),
603 (15) 602 (60), 506 (81) 439 (17). FTIR: n˜ =1769 cmÀ1 (C=O st).
[a]2D0: +106.2 (c=1.0, CH2Cl2). M.p.: 95–978C (hexane/EtOAc 8:2).
Next, this compound (993 mg, 1.539 mmol) was dissolved in DMF
(30 mL) and sodium azide (300 mg, 4.617 mmol) was added at
once. The mixture was stirred at 708C for 8–10 h, after which water
(20 mL) was added and the mixture was extracted with Et2O (2ꢃ
20 mL). The combined organic layers were washed with saturated
NaHCO3 (2ꢃ20 mL), brine (2ꢃ20 mL), and H2O (2ꢃ20 mL), dried
over anhydrous Na2SO4, and filtered. Compound 2 was isolated as
a white solid (911 mg, 1.538 mmol, quantitative) after the removal
of the solvent and was found to be analytically pure by NMR spec-
troscopy. 1H NMR (CDCl3, 300 MHz): d=7.96 (s, 2H), 7.93 (s, 2H),
7.85 (s, 2H), 4.83–4.62 (m, 1H), 4.43–4.14 (m, 1H), 3.88 (dd, 1H, J=
12.7, 3.4 Hz), 3.46 (dd, 1H, J=12.7 Hz, 6.6 Hz), 2.31–2.21 (m, 1H),
1.40–1.17 ppm (m, 1H). 13C NMR (CDCl3, 75.4 MHz): d=158.3,
144.2, 140.9, 132.88 (q, JCF =33.7 Hz), 132.86 (q, JCF =34.0 Hz), 125.8
(d, JCF =2.6 Hz), 125.7 (d, JCF =2.8 Hz), 123.8–123.3 (m, 1C), 123.3–
122.8 (m, 1C), 122.72 (q, JCF =273.2 Hz), 122,67 (q, JCF =273.4 Hz),
84.1, 67.4, 60.8, 52.7, 35.4 ppm. HRMS: Calcd. for [C22H13F12N2O2]+:
565.0785 ([M+H]+ÀN2); found: 565.0791. MS (70 eV) m/z (%): 479
(18), 478 (40), 369 (18), 192 (26), 257 (65), 213 (31), 188 (14), 187
(10), 174 (15), 149 (12), 148 (70), 130 (28), 95 (13), 76 (17), 67 (100).
(2S,4S)-2-[bis[3,5-bis(trifluoromethyl)phenyl]triethylsilyl-oxy]methyl-
4-dibutylaminopyrrolidine, (4e): 4m NaOH (1.4 mL, 5.7 mmol) was
added to a solution of 3a (340 mg, 0,572 mmol) in MeOH (30 mL)
and stirred at reflux for 12 h. Then H2O (20 mL) was added and the
mixture was extracted with EtOAc (1ꢃ20 mL) and with CH2Cl2 (2ꢃ
20 mL). The combined organic layers were dried over anhydrous
Na2SO4 and after filtration the removal of the solvent afforded
(2S,4S)-2-[bis[3,5-bis(trifluoromethyl)phenyl]-hydroxymethyl]-4-(di-
methylamino)pyrrolidine as colorless oil (300 mg, 0,572 mmol,
quantitative). 1H NMR (CDCl3, 300 MHz): d=8.08 (s, 2H), 8.00 (s,
2H), 7.74 (s, 2H), 4.53 (dd, 1H, J=9.0, 3.5 Hz), 3.28 (d, 1H, J=
11.9 Hz), 2.92 (dd, 1H, J=11.9, 4.7 Hz), 2.61–2.41 (m, 1H), 2.28 (s,
6H), 1.88 (ddd, 1H, J=14.0, 9.0, 5.0 Hz), 1.66 ppm (d, 1H, J=
14.0 Hz). 13C NMR (CDCl3, 75.4 MHz): d=149.1, 148.6, 131.9 (q, JCF
33.2 Hz), 131.7 (q, JCF =33.2 Hz), 126.6 (d, JCF =3.1 Hz), 125.8 (d,
CF =3.3 Hz), 123.3 (q, CF =272.8 Hz), 123.2 (q, CF =272.8 Hz),
=
J
J
J
121.3–120.8 (m, 2C), 77.4, 65.5, 63.6, 50.6, 42.7, 32.4 ppm. HRMS:
Calcd. for [C23H21F12N2O]+: 569.1462 ([M+H]+). Found: 569.1456. MS
(70 eV) m/z (%): 525 (60, [M+H]+), 468 (11), 435 (32), 220 (18), 113
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(100), 73 (16), 71 (10), 68 (46). FTIR: n˜ =3335 cmÀ1 (OH st). [a]D
:
20
[1] a) R. Breslow, C. J. Rizzo, J. Am. Chem. Soc. 1991, 113, 4340; b) R. Bre-
slow, Acc. Chem. Res. 1991, 24, 159; c) S. Narayan, J. Muldoon, M. G.
Finn, V. V. Fokin, H. C. Kolb, K. B. Sharpless, Angew. Chem. 2005, 117,
3339; Angew. Chem. Int. Ed. 2005, 44, 3275.
[2] a) M. Raj, V. K. Singh, Chem. Commun. 2009, 6687; b) J. Paradowska, M.
Stodulski, J. Mlynarsi, Angew. Chem. 2009, 121, 4352; Angew. Chem. Int.
Ed. 2009, 48, 4288; c) M. Gruttadauria, F. Giacalone, R. Noto, Adv. Synth.
Catal. 2009, 351, 33. For a discusion of the role of water in organocata-
lytic reactions see: d) D. G. Blackmond, A. Armstrong, V. Coombe, A.
Wells, Angew. Chem. 2007, 119, 3872; Angew. Chem. Int. Ed. 2007, 46,
3798; e) Y. Hayashi, Angew. Chem. 2006, 118, 8281; Angew. Chem. Int. Ed.
2006, 45, 8103.
À16.9 (c=1.0, CH2Cl2). Next, this compound (300 mg, 0.573 mmol)
was solved in dry CH2Cl2 (20 mL), and pyridine (115 mL,
1.432 mmol) and TESOTf (259 mL, 1.146 mmol) were added at 08C.
The reaction mixture was stirred for 12 h at this temperature, after
which it was quenched with H2O (15 mL). The mixture was extract-
ed with CH2Cl2 (3ꢃ15 mL) and the combined organic fractions
were dried over anhydrous Na2SO4 and filtered. The solvent was re-
moved and the residue was purified trough flash column chroma-
tography (hexane/EtOAc 8:2), isolating 4e as a colorless oil
1
(305 mg, 0.447 mmol, 78%). H NMR (CDCl3, 300 MHz): d=8.10 (s,
[3] a) Z. Zheng, B. L. Perkins, B. Ni, J. Am. Chem. Soc. 2010, 132, 50; b) H. W.
Moon, D. Y. Kim, Tetrahedron Lett. 2010, 51, 2906; c) C. Palomo, A.
Landa, A. Mielgo, M. Oiarbide, A. Puente, S. Vera, Angew. Chem. Int. Ed.
2007, 46, 8431; d) N. Mase, K. Watanabe, H, Yoda, K, Takabe, F. Tanaka,
C. F. Barbas III, J. Am. Chem. Soc. 2006, 128, 4966.
[4] a) L. Zu, H. Xie, H. Li, J. Wang, W. Wang, Org. Lett. 2008, 10, 1211; b) L.
Zu, J. Wang, H. Li, W. Wang, Org. Lett. 2006, 8, 3077.
[5] a) V. Singh, V. K. Singh, Org. Lett. 2007, 9, 1117; b) Z. Zheng, B. L. Perkins,
B. Ni, J. Am. Chem. Soc. 2010, 132, 50.
[6] S. Luo, X. Mi, S. Liu, H. Xu, J.-P. Cheng, Chem. Commun. 2006, 3687.
[7] Review: a) P. Domꢀnguez de Marꢀa, Angew. Chem. 2008, 120, 7066;
Angew. Chem. Int. Ed. 2008, 47, 6960. Highlight articles: b) O. V. Maltsev,
A. S. Kucherenko, A. L. Chimishkyan, S. G. Zlotin, Tetrahedron: Asymmetry
2010, 21, 2659; c) D.-Z. Xu, Y. Liu, S. Shi, Y. Wang, Tetrahedron: Asymme-
try 2010, 21, 2530; d) B. Ni, Q. Zhang, K. Dhungana, A. D. Headley, Org.
Lett. 2009, 11, 1037; e) D.-Q. Xu, B.-T. Wang, S.-P. Luo, H.-D. Yue, L.-P.
Eang, Z.-Y. Xu, Tetrahedron: Asymmetry 2007, 18, 1788; f) M. Lombardo,
F. Pasi, S. Easwar, C. Trombini, Adv. Synth. Catal. 2007, 349, 2061; g) W.
Miao, T. H. Chan, Adv. Synth. Catal. 2006, 348, 1711; h) L. Zhou, L. Wang,
Chem. Lett. 2007, 36, 628.
[8] a) D. Font, S. Sayalero, A. Bastero, C. Jimeno, M. A. Pericꢄs, Org. Lett.
2008, 10, 337; b) E. Alza, X. C. Cambeiro, C. Jimeno, M. A. Pericꢄs, Org.
Lett. 2007, 9, 3717; c) M. Gruttadauria, F. Giacalone, A. M. Marculescu, P.
Lo Meo, S. Riela, R. Noto, Eur. J. Org. Chem. 2007, 4688; d) F. Giacalone,
M. Gruttadauria, A. M. Marculescu, R. Noto, Tetrahedron Lett. 2007, 48,
255; e) D. Font, C. Jimeno, M. A. Pericꢄs, Org. Lett. 2006, 8, 4653.
[9] a) G. R. Krishnan, J. Thomas, K. Sreekumar, ARKIVOC 2009, 10, 106; b) E.
Bellis, G. Kokotos, J. Mol. Catal. A: Chem. 2005, 241, 166.
2H), 7.92 (s, 2H), 7.71 (s, 2H), 4.31 (dd, 1H, J=10.0, 6.5 Hz), 3.16–
2.89 (m, 1H), 2.68–2.47 (m, 1H), 2.35–2.11 (m, 1H), 2.07 (s, 6H),
2.04–1.87 (m, 1H), 1.79 (bs, 1H), 1.20–1.02 (m, 1H), 0.84 (t, 9H),
0.46–0.02 ppm (m, 6H). 13C NMR (CDCl3, 75.4 MHz): d=147.5,
145.7, 131.6 (q, JCF =33.4 Hz), 130.8 (q, JCF =33.3 Hz), 128.9 (d, JCF
2.7 Hz), 128.5 (d, JCF =2.5 Hz), 123.4 (q, JCF =272.7 Hz), 123.1 (q,
CF =272.8 Hz), 122.0–121.9 (m, 1C), 121.8–121.6 (m, 1C), 82.0, 67.1,
=
J
64.2, 51.0, 44.2, 33.1, 6.8, 6.2 ppm. HRMS: Calcd. for
[C29H35F12N2OSi]+: 683.2327 ([M+H]+); found: 683.2315. MS (70 eV)
m/z (%): 478 (16), 435 (36), 113 (100), 73 (18), 71 (10), 68 (46). FTIR:
n˜ =3352 cmÀ1 (NH st). [a]D20: À5.7 (c=1.0, CH2Cl2).
Cyclopropanation reaction: General procedure
The starting a,b-unsaturated aldehyde (0.150 mmol) was added to
a mixture of catalyst 4e (0.013 mmol) and water (1 mL) under vigo-
rous stirring. The mixture was cooled down to 08C and after
30 min, diethylbromalonate (0.125 mmol) was added at once. The
reaction was stirred until TLC analysis indicated complete con-
sumption of the malonate. Next, the mixture was extracted with
CH2Cl2 (3ꢃ1 mL) and the combined organic layers were dried, the
solvent was removed, and the mixture was purified through flash
column chromatography (hexane/EtOAc 8: 2).
[10] a) J. McNulty, D. McLeod, Chem. Eur. J. 2011, 17, 8794; b) J. Lu, F. Liu, T.-
P. Loh, Adv. Synth. Catal. 2008, 350, 1781. See also ref. [3c].
(2R,3S)-diethyl
2-formyl-3-phenylcyclopropane-1,1-dicarboxylate,
[11] a) H. Pellissier, Adv. Synth. Catal. 2012, 354, 237; b) C. Grondal, D. Enders,
Nat. Chem. 2010, 2, 167; c) B. Westermann, M. Ayaz, S. S. van Berkel,
Angew. Chem. 2010, 122, 858; Angew. Chem. Int. Ed. 2010, 49, 846; d) X.
Yu, W. Wang, Org. Biomol. Chem. 2008, 6, 2037; e) D. Enders, C. Grondal,
M. R. M. Hꢂttl, Angew. Chem. 2007, 119, 1590; Angew. Chem. Int. Ed.
2007, 46, 1570.
[12] a) U. Uria, J. L. Vicario, D. Badꢀa, L, Carrillo, E. Reyes, A. Pesquera, Syn-
thesis 2010, 701; b) A. Carlone, M. Marigo, C. North, A. Landa, K. A. Jør-
gensen, Chem. Commun. 2006, 4928.
[13] a) M. Rueping, H. Sundꢅn, L. Hubener, E. Sugiono, Chem. Commun.
2012, 48, 2201; b) A. Russo, S. Meninno, C. Tedesco, A. Lattanzi, Eur. J.
Org. Chem. 2011, 5096; c) V. Terrasson, A. van der Lee, R. M. de Figueire-
do, J. M. Campagne, Chem. Eur. J. 2010, 16, 7875; d) A. Russo, A. Lattan-
zi, Tetrahedron: Asymmetry 2010, 21, 1155; e) X. Companyꢆ, A.-N. Alba,
F. Cꢇrdenas, A. Moyano, R. Rios, Eur. J. Org. Chem. 2009, 3075; f) I. Ibra-
hem, G.-L. Zhao, R. Rios, J. Vesely, H. Sundꢅn, P. Dziedzic, A. Cꢆrdova,
Chem. Eur. J. 2008, 14, 7867; g) J. Vesely, G.-L. Zhao, A. Bartoszewicz, A.
Cꢆrdova, Tetrahedron Lett. 2008, 49, 4209; h) R. Rios, H. Sundꢅn, J.
Vesely, G.-L. Zhao, P. Dziedzic, A. Cꢆrdova, Adv. Synth. Catal. 2007, 349,
1028; i) H. Xie, L. Zu, H. Li, J. Wang, W. Wang, J. Am. Chem. Soc. 2007,
129, 10886.
(7a): The cyclopropane 7a was prepared according to the general
procedure after 7 d by using trans-4-fluorocinnamaldehyde
(19.8 mL, 0.150 mmol), diethyl bromomalonate (92%, 22,9 mL,
0.125 mmol) and the catalyst 4e (6.9 mg, 0.0125 mmol). The pro-
duct 7a was isolated after flash chromatography purification as
a
colorless oil (33.7 mg, 0.116 mmol, 70%). 1H NMR (CDCl3,
300 MHz): d=9.45 (d, 1H, J=4.7 Hz), 7.58–7.40 (m, 5H), 4.58–4.15
(m, 2H), 3.92 (q, 2H, J=7.0 Hz), 3.82 (d, 1H, J=7.4 Hz), 3.37 (dd,
1H, J=7.4, 4.7 Hz), 1.30 (t, 3H, J=7.0 Hz), 0.93 ppm (t, 3H, J=
7.0 Hz). 13C NMR (CDCl3, 75.4 MHz): d=196.0, 166.0, 164.5, 132.2,
128.5, 128.4, 128.0, 62.4, 61.9, 44.7, 38.1, 35.2, 14.0, 13.6 ppm. The
other spectroscopic and physical properties matched with those
reported in the literature.[12a]
Acknowledgements
The authors thank the Spanish MICINN (CTQ2011-22790), the
Basque Government (IT328-10 and fellowships to J.I.M. and U.U.)
and UPV/EHU (UFI QOSYC 11/22) for financial support. Member-
ship in the COST Action CM0905 is also acknowledged.
[14] a) K. L. Jensen, G. Dickmeiss, J. Hao, L. Albrecht, K. A. Jørgensen, Acc.
Chem. Res. 2012, 45, 248; b) A. Mielgo, C. Palomo, Chem. Asian J. 2008,
3, 922.
Keywords: aldehydes
· density functional calculations ·
Received: February 4, 2013
enantioselectivity · Michael addition · organocatalysis
Published online on && &&, 0000
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ChemCatChem 0000, 00, 1 – 9
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FULL PAPERS
J. I. Martꢀnez, E. Reyes, U. Uria, L. Carrillo,
J. L. Vicario*
&& – &&
Optimizing the Structure of 4-
Dialkylamino-a,a-diarylprolinol Ethers
as Catalysts for the Enantioselective
Cyclopropanation of a,b-Unsaturated
Aldehydes in Water
Be water my friend: A new family of
chiral diarylprolinol-type organocatalysts
with improved performances in conju-
gate addition reactions in water and
proceeding under the iminium activa-
tion manifold were studied. Once the
optimized catalyst structure had been
found, it proved its efficiency in the cat-
alytic enantioselective cyclopropanation
of a,b-unsaturated aldehydes using
water as the only reaction medium.
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 0000, 00, 1 – 9
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