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Ijoc 2014031813242455 PDF
Ijoc 2014031813242455 PDF
Abstract
Six compounds including five proline derivatives have been prepared and tested as chiral orga-
nocatalysts for enantioselective aldol reactions and Michael additions. The enantiomeric excesses,
which are highly dependent on the molecular structure of catalysts as well as experimental condi-
tions, have reached over 98%.
Keywords
Aldol Reactions; Michael Additions; Enantioselective; Organocatalysts; Proline Derivatives
1. Introduction
The aldol reaction and the Michael addition are very precious tools of the synthetic organic chemist. Indeed,
these reactions are widely applied to generate carbon-carbon bonds allowing to link building blocks to generate
large and complex molecules. The steric control of chiral centers created during these reactions was initially at-
tained using chiral auxiliaries as is the case, for instance, of chiral imines in Michael additions [1] [2]. For over a
decade, many studies have been undertaken worldwide to extend the enantioselectivity in catalytic manner using
small organic chiral molecules. These metal-free catalysts, highly efficient, more environmentally friendly, and
often stable under both aerobic and aqueous reaction conditions, are always extensively investigated [3]-[8].
The synthesis of azapyridinomacrocycles N-oxides and their use as organocatalysts for enantioselective ally-
lations of 4-nitrobenzaldehyde with allyltrichlorosilane were reported from our laboratory [9]. The described
asymmetric inductions were interesting and promising but too low to afford synthetic applications. Therefore we
*
Corresponding author.
How to cite this paper: Wagner, M., et al. (2014) Enantioselective Aldol Reactions and Michael Additions Using Proline De-
rivatives as Organocatalysts. International Journal of Organic Chemistry, 4, 55-67.
http://dx.doi.org/10.4236/ijoc.2014.41008
M. Wagner et al.
thought to experiment some of these chiral intermediates themselves as organocatalysts in aldol reactions and
Michael additions. This kind of reactions has been extensively described as model to establish the efficiency of
small molecules regarding the enantioselectivity. Herein we wish to report the results using some new deriva-
tives 1 - 6 (Figure 1) as chiral catalysts in both enantioselective aldol and Michael reactions [10]-[17].
56
M. Wagner et al.
H
H2N N SO2 NO2 N O
H H
HN N SO2 NO2
1 2
N O O
H H
HN N SO2 NO2 N
H N SO2 NO2
HCl H
3 4
N
N H N SO2
H
H N SO2 NO2
H
5 6
NO2
NH2
H
N
2Nos
O N
1 O
N Boc (a)
H 2
OH HN N 2Nos
Boc
7
NH2
H
N
2Nos
N O
Boc (a)
H 3
HN N 2Nos
(e) (a)
N N 5
NH2 HN
Boc 10 Boc 2Nos
(f) (a)
N 6
11 HN
Boc 4Nos
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M. Wagner et al.
N
O
Ar O H Ar
H N
H H OH O
N
O 78 % ee
R
S
S,R,R catalyst O
R = O 2N
N
O
Ar O H Ar
H N
H H OH O
N
R
3 % ee
S,S,S catalyst
58
M. Wagner et al.
vents. Indeed, while no reaction took place in aprotic solvents, excellent results in solvent-free medium were
observed (entries 16 - 19, ee up to 96%). In contrast with catalyst 5 in the same conditions, the reaction provided
aldol products in only 31% ee (entry 27). Again, with a lower catalyst loading (10%), the reaction occurred (en-
tries 18, 19) and provided the corresponding aldol product with the same high enantioselectivity (96% ee). Fi-
nally, the scope and limitation of this process with various aromatic aldehydes under optimized conditions were
explored; the results are displayed in Table 1. In all cases, the enantiomeric excesses were of the same order of
magnitude as those previously observed. However, some significant differences between aldehydes bearing
withdrawing groups and those bearing donor groups can be noted. Indeed, the aldol reaction rate with compound
12h (entry 26, two donor groups) is lower than that observed with other aldehydes; these two donor groups re-
ducing the electrophilicity of the aldehyde function. To conclude this chapter regarding aldol reactions, promis-
ing results were obtained showing, once again, that proline derivatives gave the best results.
59
M. Wagner et al.
3. Conclusion
Among the catalysts we have developed in this study, two of them have proved to be very efficient; catalyst 4
for the aldol reaction and catalyst 6 for the Michael addition. It should be noted that, once again, these two cata-
lysts 4 and 6 both derived from a proline structure [30]. Additional studies are currently in progress in our labor-
atory to investigate further applications of these new catalysts.
4. Experimental
4.1. General
The reactions were monitored by thin-layer chromatography (TLC) on aluminum plates (0.20 mm, 60 F254) us-
60
M. Wagner et al.
O Ph O
NO2
(2S,3R)
HN N
O H H2O
H2O S
Ar O
Ar
H HN
S
N N+ O N
O O H S
O2N Ar
- O
H Ph
O2N
Ar
Ph
S N
O N
O H O
+
H O N
H
O Ph
ing EtOAc/cyclohexane mixture as eluent. The reaction compounds were first visualized under UV light and
then by treatment with iodine vapor. Silica gel (40 - 63 μm) was used for flash chromatographies with EtOAc/
cyclohexane mixtures as eluent. Gas chromatography-mass spectroscopy (GC-MS) was performed with an Agi-
lent 6890N (equipped with a 12 m × 0.20 mm dimethylpolysiloxane capillary column) linked to a Model 5973N
(ionization energy: 70 eV). Enantiomeric ratios were determined by chiral HPLC analysis on Daicel Chiralcel
AS-H and ADH. Melting points were achieved on a Kofler block. Optical rotations were measured on a Per-
kin-Elmer model 241. 1H and 13C NMR spectra were recorded in CDCl3 (except specified) respectively at 400
MHz and 100 MHz (Bruker 400). Reagents and materials were obtained from commercial suppliers and were
used without further purification.
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M. Wagner et al.
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M. Wagner et al.
(m, 3H), 8.04 - 8.14 (m, 1H); 13C NMR (D2O) δ 23.6 (CH2), 29.3 (CH2), 46.4 (CH2), 62.0 (CH), 124.5 (CH),
130.1 (CH), 132.7 (CH), 133.3 (C), 134.2 (CH), 147.3 (C), 174.6 (C).
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M. Wagner et al.
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M. Wagner et al.
(CH), 128.6 (CH), 140.7 (C), 140.8 (C), 145.1 (C), 208.5 (C); HPLC (Chiralcel AS-H, n-hexane/iPrOH: 60:40
v/v, 1.0 mL/min, UV 225 nm): tr(major, R) = 7.35 min, tr(minor, S) = 8.26 min, 92% ee.
References
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