Enantioselective organocatalytic reduction of β-trifluoromethyl nitroalkenes: An efficient strategy for the synthesis of chiral β-trifluoromethyl amines

Article abstract of DOI:10.1002/chem.201405730

An efficient organocatalytic stereoselective reduction of β-trifluoromethyl-substituted nitroalkenes, mediated by 3,5-dicarboxylic ester-dihydropyridines (Hantzsch ester type), has been successfully developed. A multifunctional thiourea-based (S)-valine d

Full text of DOI:10.1002/chem.201405730

DOI: 10.1002/chem.201405730
Communication
&
Organic Synthesis
Enantioselective Organocatalytic Reduction of b-Trifluoromethyl
Nitroalkenes: An Efficient Strategy for the Synthesis of Chiral
b-Trifluoromethyl Amines
Elisabetta Massolo,[a] Maurizio Benaglia,*[a] Manuel Orlandi,[a] Sergio Rossi,[a] and
Giuseppe Celentano[b]
reochemically efficient catalytic methods for the synthesis of
chiral fluorinated amines are still deeply needed.[3]
Abstract: An efficient organocatalytic stereoselective re-
After focusing on the preparation of chiral a-trifluoromethyl-
amine, by trichlorosilane-mediated enantioselective catalytic
reduction of trifluoromethyl ketoimines,[4] we turned our atten-
tion to chiral b-trifluoromethylamines. Recent works on innova-
tive, nonstereoselective, methods of trifluoromethylation to
generate b-trifluoromethyl-substituted aza-derivatives clearly
testify for the great interest in the preparation of this class of
compounds.[5] However, really few strategies are available for
the stereoselective synthesis of enantiopure b-trifluoromethyla-
mines. In 2013, a chemo- and enantioselective CF3SiMe3 addi-
tion to a-imino ketones promoted by Cinchona-derived am-
monium salts was reported (up to 71% ee).[6] In the same year,
based on the seminal contributions by the MacMillan group,[7]
the first visible light-driven intermolecular aminotrifluorome-
thylation of alkenes was developed, as efficient and regioselec-
tive one-step access to a variety of b-trifluoromethylamides in
up to 82% yield and 78% d.r.[8]
duction of b-trifluoromethyl-substituted nitroalkenes,
mediated by 3,5-dicarboxylic ester-dihydropyridines
(Hantzsch ester type), has been successfully developed. A
multifunctional thiourea-based (S)-valine derivative was
found to be the catalyst of choice, promoting the reaction
in up to 97% ee. The methodology has been applied to
a wide variety of substrates, leading to the formation of
differently substituted precursors of enantiomerically en-
riched b-trifluoromethyl amines. The mechanism of the re-
action and the mode of action of the metal-free catalytic
species were computationally investigated; on the basis
of DFT transition-state (TS) analysis, a model of stereose-
lection was also proposed.
The introduction of fluorinated residues in a bioactive mole-
cule may have a strong impact on its effectiveness, simultane-
ously modulating electronic, lipophilic and steric parameters,
critically influencing both the pharmacodynamic and pharma-
cokinetic properties.[1] Many drugs are characterized by the
presence of a CF3 group, as in Efavirenz, used against HIV in-
fection, Telcalgepant, employed in the treatment of the neuro-
vascular disorder migraine and Prozac (Figure 1). Among sever-
al trifluoromethylated compounds known in medicinal chemis-
try, a- and b-trifluoromethylamine units are major components
found in this class of bioactive species (Figure 1).[2] Despite the
great interest in the topic and progress in the field, highly ste-
An alternative strategy to obtain chiral trifluoromethyl deriv-
atives relies on the stereoselective transformation of trifluoro-
methylated prochiral, readily available substrates. Fluorinated
nitroalkenes represent an obvious entry for the synthesis of b-
trifluoromethylamino derivatives. They have been widely used
in combination with a chiral reactant partner to diastereoiso-
merically produce b-nitro-trifluoromethylated products; typical
examples include the synthesis of trifluoromethylated peptide
analogues, using enantiopure a-amino acids as nucleophiles.[9]
Fluorinated nitroolefines have been also employed in organo-
catalytic Michael reactions with aldehydes,[10] intermolecular
oxa-Michael addition of oximes,[11] and 3-alkylidene oxin-
doles,[12] and in the addition of indole[13] and b-dicarbonyl com-
pounds.[14]
[a] E. Massolo, Prof. M. Benaglia, M. Orlandi, Dr. S. Rossi
Dipartimento di Chimica
Universita’ degli Studi di Milano
via Golgi 19, 20133 Milano (Italy)
Fax: (+39)0250314159
However, as far as we know, no examples of enantioselective
organocatalytic reduction of trifluoromethylated nitroalkenes
are known. Here we wish to report our preliminary investiga-
tion on the synthesis of enantiomerically enriched-b-trifluoro-
methyl nitroolefins, by organocatalyzed addition of Hantzsch
ester type reducing agents to fluorinated nitroalkenes. Consid-
ering that the starting materials are readily, and often commer-
cially available, trifluoromethyl ketones the methodology offers
an easy, catalytic, and practical entry to chiral b-trifluorome-
thylamines (Scheme 1).
E-mail: maurizio.benaglia@unimi.it
[b] G. Celentano
Dipartimento di Scienze Farmaceutiche
Universitꢀ degli Studi di Milano
Via Mangiagalli, 25, Milano (Italy)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405730. It contains experimental details
for catalysts synthesis, catalytic enantioselective reductions and synthetic
modification for the absolute configuration determination. Analysis and
characterization: NMR and HPLC traces of the reaction products. Cartesian
coordinates, total electronic and Gibbs free energies of all reported struc-
tures.
In 2007, List and co-workers published the organocatalyzed
stereoselective reduction of nitroalkenes affording the corre-
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substituents clearly showed that
an acceptable level of enantio-
control could be achieved only
with sterically hindered residues
on the amino group (Table 1, en-
tries 1–4 vs. 5–6). In particular,
a
pyrrole ring proved to be
more effective than a phtalimide
in shielding one of the two
enantiotopic faces of the nitroal-
kene, probably due to the pres-
ence of the 2,5-dimethyl sub-
stituents, able to extend the in-
fluence of the heterocycle ring
on the region of space just close
to the site at which the sub-
strate is supposed to be coordi-
nated to the thiourea residue of
the catalyst (Figure 3, see below,
Figure 5, for further considera-
tions based on computational
studies). However, with catalyst
Figure 1. Some biologically active trifluoromethylated compounds.
Scheme 2. Organocatalytic reduction of b-trifluoromethyl nitrostyrene.
Scheme 1. Organocatalytic approach to the synthesis of chiral b-trifluorome-
Table 1. Preliminary studies on the catalytic reduction of 12 with organo-
catalysts 1–11.
thylamines.
Entry
Cat.
Conv. [%][a]
ee [%][b]
sponding enantiomerically enriched nitroalkanes in high yields
and up to 96% ee, the most efficient catalyst featuring a thiour-
ea moiety linked to the diethylamide of (S)-tert-leucine and to
the N-pyrrole derivative of (R,R)-diaminocyclohexane.[15] Based
on this previous work we have preliminary explored a variety
of bifunctional, thiourea-based molecules as catalyst for the re-
duction of trifluoromethylated nitroolefins (Figure 2).[16] Cata-
lysts 1–11 were easily synthesized in four steps through con-
version of the N-tert-butoxycarbonyl (Boc) amino acid to the
corresponding amide, followed by N-Boc deprotection, genera-
tion of the isothiocyanate group and reaction with the proper
1,2-diaminocyclohexane derivative.
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
60
>99
60
83
>99
85
>99 (99)[c]
>99
95 (93)[c]
>99 (98)[c]
80
<5
rac.
13
rac.
38
57
59
43
81
9
10
11
9
10
11
77
55
[a] Reaction run in deuterated benzene at RT; conversion determined by
1H and 19F NMR spectra. [b] Enantiomeric excess determined by HPLC
analysis on a chiral stationary phase (for details see the Supporting Infor-
mation). [c] In brackets isolated yields after chromatographic purification.
The reduction of b-trifluoromethyl-b-nitrostyrene 12 was se-
lected as model reaction and typically performed at 258C for
20 h in the presence of a stoichiometric amount of Hantzsch
ester A and a catalytic amount (10 mol%) of the organocata-
lysts, to afford the expected product 13 (Scheme 2). The results
of this preliminary screening are detailed in Table 1.
6 a modest enantioselectivity was obtained. Therefore, we de-
cided to look at the amino acid portion of the catalyst; it was
observed that, when replacing tert-leucine with valine, higher
ee values were obtained. Table 1, entries 7–8, demonstrated
the combination (S)-valine and (R,R)-diaminocyclohexane to be
the match pair, which guarantees higher ee. The 2,5-dimethyl
derivative 9 was able to promote the reduction of b-trifluoro-
In looking for the best catalyst, we systematically investigat-
ed how the different parts constituting the skeleton of these
thiourea-based structures influence their activity and stereose-
lectivity. Thus, the modification of the diaminocyclohexane N-
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tries 9–10). Reductions in polar
or protic solvents led to the
products with low stereocontrol,
while hexanes proved to be
a suitable solvent for the reac-
tion: with catalyst 9 at À508C,
up to 83% ee was reached
(entry 15).
The generality of the method
was
finally
investigated
(Scheme 3); differently 2-aryl-
and 2-alkyl-substituted 3,3,3-tri-
fluoro-1-nitropropene derivatives
14a–g have been prepared and
reacted with dihdropyridine B to
afford the corresponding chiral
trifluoromethyl
nitroalkanes
15a–g, in the presence of
10%mol equivalents of catalyst
10 in toluene, typically at
À508C. Some selected results
are reported in Table 3.
The reduction of differently
substituted
2-aryl-2-trifluoro-
Figure 2. A few selected chiral organocatalysts employed in the present study.
methyl nitroalkenes has been
successfully accomplished, either
methyl nitrostyrene at room tem-
perature in 81% enantioselectivity,
to afford (R)-2-trifluoromethyl-2-
phenyl-nitroethane 13 in 95%
yield; N,N-dibenzyl substituents on
the amide function (catalyst 10) af-
on substrates featuring electron-donating groups or electron-
withdrawing residues; enantioselectivities usually higher than
80% and up to 90% were obtained (Table 3, entries 1–4).
Even better results were achieved with 2-alkyl-substituted
fluorinated nitroalkenes 14e–g; with benzyl derivative 14e the
reduction mediated by catalyst 10 afforded the expected nitro-
alkane 15e in 90% ee. Excellent results were obtained in the
reduction of alkyl-nitroalkenes 14 f–g that afforded products
15 f and 15g in 97 and 93% ee, respectively.
forded only slightly lower ee with
Figure 3. Proposed mode of
action of the bifunctional thi-
ourea-based catalyst.
respect to derivative 9.
Once 9 and 10 had been identi-
fied as the most promising cata-
lysts, a screening of reaction condi-
tions was carried out. When the
Table 2. Screening of experimental conditions in the organocatalyzed re-
duction of 12.
temperature was lowered to 08C, a diminished chemical activi-
ty was observed but no significant improvement in enantio-
control (Table 2, entries 1, 2). To improve the reaction rate and
to allow us to perform the reduction at lower temperature,
tert-butyl ester derivative B (Figure 4), known to be a more
active reducing agent,[17] was employed. Higher ee values
could not be achieved in dichloromethane (entries 3–6) at 0 or
at À508C; however, by running the reaction in toluene, an in-
crease of the enantioselectivity was observed for lower reac-
tion temperatures. In the presence of the Hantzsch-type ester
B at À508C, the stereoselectivity was improved to up to
87% ee with catalyst 9 and up to 93% ee with catalyst 10 (en-
Entry Cat. Solvent
T [8C] Hantzsch ester Conv. [%][a] ee [%][b]
1
2
3
4
5
6
7
8
7
9
9
9
10
9
9
10
9
10
9
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
0
0
0
À15
À15
À50
RT
A (COOEt)
A (COOEt)
50
60
60
80
78
77
74
77
71
81
87
93
9
B (COOtBu)
B (COOtBu)
B (COOtBu)
B (COOtBu)
B (COOtBu)
B (COOtBu)
B (COOtBu)
B (COOtBu)
B (COOtBu)
B (COOtBu)
B (COOtBu)
B (COOtBu)
B (COOtBu)
>99
>99
>99
>99
>99
>99
61
RT
9
toluene À50
toluene À50
10
11
12
13
14
15
71
THF
EtOH
0
0
0
>99
>99
>99
50
6
9
10
9
hexanes
80
71
83
hexanes À50
hexanes À50
70
[a] Conversion determined by 1H and 19F NMR spectra. [b] Enantiomeric
excess determined by HPLC on chiral stationary phase (for details see the
Supporting Information).
Figure 4. Different reducing agents.
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Figure 5. B3LYP/6-31G(d) geometries of the TSs for catalyst 9. In the “balls and springs” pictures, the COOMe groups of the Hantzsch ester are reported in
“transparent” fashion; non-participating hydrogen atoms are omitted for clarity. Below a comparison between catalysts 6 and 9 is reported.
NOESY experiments were not decisive for attributing
the E/Z configuration; however, computational analy-
sis showed the E isomer to be slightly more stable
than the Z isomer (although by less than 2 kcalmol,
see the Supporting Information). However, it is im-
portant to note that almost identical results in terms
of yield, d.r. and ee were obtained in the enantiose-
lective reduction of 16, independently from the dia-
stereoisomeric ratio of the starting nitroalkene.
The b-trifluoromethyl-a-methyl-substituted nitroal-
Scheme 3. Organocatalytic reduction of b-trifluoromethyl nitroalkenes 14a–g.
kanes 17a–c were obtained in modest yields and low
diastereoisomeric ratio, but with an appreciable level
of enantioselectivity, typically about 60–70% ee for
both isomers, and up to 77% ee (Table 4). Further ex-
periments are necessary to determine the configura-
tion of these novel fluorinated nitroalkanes, featuring
two stereocenters. Follow-up studies will be under-
taken to design and develop a stereoselective cata-
lytic system better suited for this transformation.
Scheme 4. Reduction of a-substituted-b-trifluoromethyl nitroalkenes 16a–c.
To establish the absolute configuration of the re-
duction products, 15e was transformed by hydroge-
nation into the corresponding b-trifluoromethyl
Possible extension of this reaction to a,b-disubstituted-b-tri-
fluoromethylnitroalkenes has also been preliminary investigat-
ed (Scheme 4). It is worth mentioning that the stereoselective
reduction of nitrostyrene derivatives featuring an a-substituent
is still considered a challenging transformation that requires
a controlled protonation step[18] and leads to the formation of
a rather labile stereocentre; indeed, to the best of our knowl-
edge, no organocatalytic example has been reported so far.[19]
Substrates were obtained as a differently enriched mixture
of isomers that were shown to not be configurationally stable
and involved an equilibrium.[20] Due to this equilibration, H-H
amine 18 that was converted in the known N-benzyl derivative
19,[21] thus determining the absolute configuration of the
major isomer to be R (Scheme 5).
The different behaviour of tert-leucine derivative 6 and of
the valine-based catalyst 9 was computationally investigated.
The transition states (TSs) leading to the formation of both (R)-
and (S)-13, for the reaction with both catalysts 6 and 9, have
been located at a B3LYP/6-31G(d) level of theory; finer elec-
tronic energies have successively been obtained increasing the
basis set up to 6/311+(2df,2pd) with two different functionals:
B3LYP[22] and M062X.[23]
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Table 3. General applicability of the organocatalyzed reduction of fluori-
nated nitroolefins.[a]
Table 4. Organocatalyzed reduction a-substituted-b-trifluoromethyl nitro-
alkenes.[a]
entry
1
Substrate
t [h]
Conv. [%][b]
ee [%][c]
Entry Substrate
E/Z ratio
starting ma- [8C] (t
terial [h])
React. T conv. d.r.[b] ee [%][c]
[%][b]
36
81
83
1
2
3
71:29
0 (48)
20
51
57
58:42 45–51
60:40 67–70
60:40 65–66
2
3
36
20
75
85
73
81
71:29
95:5
25
25
4
5
54:46
90:10
25
25
66
42
64:36 77–67
4
5
20
20
81
89
90
90
62:38 <5–<5
[a] Reaction run in deuterated toluene, with 10 mol% of catalyst and
1.3 mol equivalents of reducing agent B. [b] Conversion and diastereoiso-
meric ratio determined by 1H and 19F NMR spectroscopy. [c] Enantiomeric
excess determined by HPLC on chiral stationary phase (for details see the
Supporting Information).
6
7
20
36
80
75
97
93
troolefin C2 electrophilic carbon atom in TS-S9 is closer to the
bulky diaminocyclohexane moiety than in TS-R9. Therefore the
reducing agent, in releasing the hydride, is forced in a hindered
zone at which its ester group repulsively interacts with the 2,5-
methyl pyrrole substituents, thus further favouring TS-R9 (see
Figure 5).
[a] Reaction run in deuterated toluene, with 10 mol% of catalyst and
1.3 mol equivalents of reducing agent B. [b] Conversion determined by
1H and 19F NMR spectra. [c] Enantiomeric excess determined by HPLC on
chiral stationary phase (see the Supporting Information for details).
On the other hand, in the attempt to understand and com-
pare the behaviour of catalysts 6 and 9, it should be noted
that in TS-R of both catalysts a further repulsive interaction
may occur between the phenyl ring and iPr or tBu groups. The
competition between this two negative interactions seems to
be responsible for the worst behaviour of catalyst 6 with re-
spect to catalyst 9, in which the less hindered iPr moiety may
avoid a destabilizing interaction with the substrate (compare
TS-R6 and TS-R9 structures in Figure 6).
In an attempt to rationalize the higher ee observed in the re-
duction of alkyl-substituted nitroalkenes it was noticed that in
the disfavoured TSs the methyl group of the 2,5-dimethyl pyr-
role moiety is forced toward the b-substituent of the substrate.
Therefore, when such a substituent is an aryl group, a CH3–p
interaction might take place, reducing the energy difference
between favoured and disfavoured TSs.[24]
Preliminary conformational analysis on the catalysts under-
lined a very rigid structure: only three conformations for cata-
lyst 9 and a unique conformation for catalyst 6 are energetical-
ly allowed. The selected TSs have been found, assuming the
coordination of the nitro group to the thiourea moiety and of
the Hantzsch ester NH group to the catalyst carboxyamide
group (Figure 5). The methyl-substituted Hantzsch ester C (see
Figure 4) was used to reduce possible conformations of the
system. In the tables and figures below, the notation TS-S9
refers to the TS of catalyst 9 leading to the S isomer.
In the case of catalyst 9, a first inspection of the two TSs
clearly highlights the role of the pyrrole moiety, that exerts in
TS-S9 a repulsive interaction on the phenyl group of the nitro-
alkene, thus disfavouring the formation of the S enantiomer.
Additionally, a deeper look at TS-S9 and TS-R9 shows that
upon the coordination of the substrate to the thiourea, the ni-
The presence of this kind of interaction was confirmed by
performing a non-covalent inter-
action (NCI) analysis, as previous-
ly reported by Yang et al., using
the NCIPLOT software;[25] results
are shown in Figure 7. The green
surface between the phenyl ring
and the catalyst’s methyl sub-
Scheme 5. Determination of absolute configuration of product 15e.
stituent evidences a large region
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Figure 6. B3LYP/6-31G(d) geometries of the disfavoured TSs for catalysts 6 and 9. In the “balls and springs” pictures, the COOMe groups of the Hantzsch ester
are reported in “transparent” fashion; non-participating hydrogen atoms are omitted for clarity.
Table 5. Computationally determined energies and enantioselectivities.
B3LYP
M06-2X
Exptl. ee [%][c]
DDG[a]
0.0
2.4
0.0
ee [%][c]
DDG[b]
0.0
0.5
0.0
ee (%)[c]
TS-R6
TS-S6
TS-R9
TS-S9
97
43
57
81
>99
99
4.6
3.0
[a] DDG in kcalmolÀ1 at the B3LYP/6-311+G(2df,2pd)//B3LYP/6-31G(d)
level of theory. The thermal correction to the Gibbs free energy was cal-
culated at the B3LYP/6-31G(d) level. [b] DDG in kcalmolÀ1 at the M062X/
6-311+G(2df,2pd)//B3LYP/6-31G(d) level of theory. The thermal correction
to the Gibbs free energy was calculated at the B3LYP/6-31G(d) level.
[c] ee was calculated according to the formula: ee=100 exp[À(DDGS)/RT].
Figure 7. NCIPLOT analysis performed in a selected cube (Supporting Infor-
mation) using the M06-2X/6-311+G(2df,2pd) electron density calculated on
the B3LYP/6-31G(d) geometry of the disfavoured TS for catalyst 9. Non-par-
ticipating hydrogen atoms are omitted for clarity.
In conclusion, the enantioselective organocatalytic reduction
of b-trifluoromethyl nitroalkenes was successfully accom-
plished, either on b-aryl- or b-alkyl-substituted substrates, in
up to 97% ee The stereochemical outcome of the reaction and
the behaviour of the metal-free, thiourea-based catalyst were
also rationalized and discussed, based on computational stud-
ies and DFT transition-state analysis. This easy to perform
methodology offers a valuable entry for a straightforward syn-
thesis of enantiomerically pure b-trifluoromethyl amines.[27]
of weak positive interaction due to the expected CH3–p stack-
ing. Clearly, when the b-aryl group is replaced by an alkyl one,
this interaction cannot occur. Hence, TSs leading to the R and
S enantiomer should be energetically more differentiated, justi-
fying the experimentally observed higher enantiomeric excess-
es with alkyl derivatives (Table 3, entries 6 and 7).
Experimental Section
The calculated Gibbs free energies and the prediction of the
enantioselectivities are reported in Table 5. Since the B3LYP
functional is known to give a poor description for long-range
dispersive interactions, as expected, a better prediction of the
enantiomeric excesses was obtained with M06-2X. In particular,
a remarkably good agreement between calculated and experi-
mental ee obtained with catalyst 6 has been achieved with
M06-2X (43 vs. 57% ee). Noteworthy, both the DFT functionals
predict higher TSs energy differences for catalyst 9 compared
to 6, thus confirming the valine-derivative 9 to be the best-
performing catalyst.[26]
General methods
All commercially available reagents including dry solvents were
used as received. Organic extracts were dried over sodium sulfate,
filtered and concentrated under vacuum using a rotatory evapora-
tor. Non-volatile materials were dried under high vacuum. Reac-
tions were monitored by TLC on precoated Merck silica gel 60
F254 plates and visualized either by UV or by staining with a solu-
tion of cerium sulfate (1 g) and ammonium heptamolybdate tetra-
hydrate (27 g) in a mixture of water (469 mL) and concentrated sul-
furic acid (31 mL). Flash chromatography was performed on silica
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1
[10] O. Andrey, A. Alexakis, A. Tomassini, G. Bernardinelli, Adv. Synth. Catal.
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[15] N. J. A. Martin, L. Ozores, B. List, J. Am. Chem. Soc. 2007, 129, 8976–
8977. For a recent organometallic-catalyzed nitroalkene reduction with
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Harms, L. Gong, E. Meggers, J. Am. Chem. Soc. 2013, 135, 10598–10601.
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The b-trifluoromethyl nitroalkene derivative (1 equiv) and the cata-
lyst (0.1 equiv) were dissolved in the dry solvent (1m solution)
under a nitrogen atmosphere for 10 min at the desired tempera-
ture; Hantzsch ester (1 equiv) was added as a solid and the mixture
stirred for 20 h at constant temperature. The solvent was then re-
moved under reduced pressure and products were isolated by
flash column chromatography on silica gel (hexane:ethyl acetate)
for their NMR spectroscopic characterization. When low-boiling
substrates were employed—yielding low boiling products—only
the crude mixture was analyzed. Enantiomeric excess was deter-
mined by HPLC on chiral stationary phase.
[16] For experimental details on the synthesis and characterization of the
catalysts, see the Supporting Information.
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Acknowledgements
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place in few days, even when the isomeric mixture was kept neat at
88C.
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of interaction.
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M. B. thanks COST action CM9505 “ORCA” Organocatalysis and
ZaCh Systems (Zambon Group) for financial support. E.M. and
M.O. thank Universita’ degli Studi di Milano for PhD fellow-
ships, S.R. thanks Universita’ degli Studi di Milano for post-doc-
toral fellowship.
Keywords: bifunctional catalyst · chiral fluorinated amines ·
nitroalkenes · reduction · trifluoromethyl derivatives
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Received: October 20, 2014
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 8
www.chemeurj.org
7
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Organic Synthesis
E. Massolo, M. Benaglia,* M. Orlandi,
S. Rossi, G. Celentano
An efficient organocatalytic stereose-
lective reduction of b-trifluoromethyl-
substituted nitroalkenes, mediated by
3,5-dicarboxylic ester-dihydropyridines
(Hantzsch ester type), has been success-
fully developed. A thiourea-based (S)-
valine derivative promoted the reaction
in up to 97% ee, affording immediate
precursors of enantiomerically enriched
b-trifluoromethylamines (see scheme).
&& – &&
Enantioselective Organocatalytic
Reduction of b-Trifluoromethyl
Nitroalkenes: An Efficient Strategy for
the Synthesis of Chiral b-
Trifluoromethyl Amines
&
&
Chem. Eur. J. 2015, 21, 1 – 8
www.chemeurj.org
8
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!