Enantioselective addition of aryl ketones and acetone to nitroalkenes organocatalyzed by carbamate-monoprotected cyclohexa-1,2-diamines

Article abstract of DOI:10.1016/j.tetasy.2015.07.011

Enantiomerically pure carbamate-monoprotected trans-cyclohexane-1,2-diamines are used as chiral organocatalysts for the addition of aryl ketones and acetone to nitroalkenes to give enantioenriched β-substituted γ-nitroketones. The reaction was performed i

Full text of DOI:10.1016/j.tetasy.2015.07.011

Tetrahedron: Asymmetry 26 (2015) 970–979
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective addition of aryl ketones and acetone to nitroalkenes
organocatalyzed by carbamate-monoprotected cyclohexa-1,2-
diamines
a,
Jesús Flores-Ferrándiz a, Alexander Stiven a, Lia Sotorríos b, Enrique Gómez-Bengoa b, , Rafael Chinchilla
⇑
⇑
a Departamento de Química Orgánica, Facultad de Ciencias, and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
b Departamento de Química Orgánica I, Universidad del País Vasco, Apdo. 1072, 20080 San Sebastíán, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiomerically pure carbamate-monoprotected trans-cyclohexane-1,2-diamines are used as chiral
organocatalysts for the addition of aryl ketones and acetone to nitroalkenes to give enantioenriched b-
substituted c-nitroketones. The reaction was performed in the presence of 3,4-dimethoxybenzoic acid
as an additive, in chloroform as the solvent at room temperature, achieving enantioselectivities up to
96%. Theoretical calculations are used to justify the observed sense of the stereoinduction.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 7 July 2015
Accepted 17 July 2015
Available online 31 July 2015
1. Introduction
nitroalkenes involve the use of chiral primary amine-containing
NH-functionalized species, such as amides,14 sulfonamides15 and
The enantioselective preparation of
c
-nitrocarbonyl compounds
thioureas,16 the last achieving the best results. Using these primary
amine-containing bifunctional organocatalysts, the enantioselec-
tivity is induced by the addition of a transient enamine to the
nitroolefin, which is hydrogen bond-coordinated by the NH group
of the additional functionality.
is an interesting synthetic topic, since they are precursors of
important compounds such as alkaloids,1 aminoacids,2 antitu-
morals,3 antibiotics,4 peptidomimetics5 and marine metabolites6,
among others.7 The direct conjugate addition of carbonyl com-
pounds to conjugated nitroalkenes by means of metal-free organic
catalysts represents a convenient access to this type of compounds.
Therefore, over the past few years, much progress has been made
in the development of organocatalytic-based methodologies for
accomplishing this task.8
Nonetheless, the direct organocatalytic asymmetric conjugate
addition of aromatic ketones to nitroalkenes is still considered a
‘difficult’ process and is much less explored. The enantioselective
addition of aromatic ketones to b-nitrostyrenes is particularly
We have recently reported the use of primary amines from chi-
ral trans-cyclohexane-1,2-diamines 1–3, monosubstituted with the
common Boc, Cbz and Fmoc protecting groups, respectively, as
organocatalysts in the enantioselective Michael addition reactions
of aldehydes to maleimides.17 Herein we report the use of these
simple primary amine-containing species as chiral organocatalysts
in the conjugate addition reactions of arylated ketones, or even
acetone, to nitroalkenes, leading to enantioenriched b-substituted
c-nitroketones. Theoretical calculations have been used to explain
interesting, as the corresponding
intermediates in the preparation of b-arylated
c
-nitroketones can be used as
-aminobutyric
the observed sense of enantioselectivity.
c
acids, which are pharmacologically important GABAB agonists.9
Commercial examples include baclofen,10 used in the treatment
of spasticity, and phenibut,11 a tranquilizer and nootropic drug.
Although the enantioselective addition of particular aryl
ketones, such as acetophenone, to b-nitrostyrene has been
described using proline12 or proline-derived organocatalysts,13
most of the reported procedures using arylated ketones and
O
O
N
H
OBn
N
H
OtBu
NH2
NH2
2
1
O
N
H
O
NH2
⇑
Corresponding authors. Tel.: +34 96 5903728; fax: +34 96 5903549.
E-mail addresses: enrique.gomez@ehu.es (E. Gómez-Bengoa), chinchilla@ua.es
3
(R. Chinchilla).
http://dx.doi.org/10.1016/j.tetasy.2015.07.011
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

J. Flores-Ferrándiz et al. / Tetrahedron: Asymmetry 26 (2015) 970–979
971
aldehydes to maleimides organocatalyzed by 1,17 gave poor enan-
tioselection (Table 1, entry 10).
2. Results and discussion
We next explored the effect of the addition of some additives to
the reaction, employing chloroform as the reaction solvent. Thus,
the addition of the basic imidazole (20 mol %), which has previ-
ously been shown to be beneficial in some conjugate addition reac-
tions,18 was detrimental for the enantioselectivity in this case,
compared to when no additive was used (Table 1, compare entries
5 and 11). Therefore, we switched to the use of carboxylic acids as
additives (20 mol %), since it is known that they can facilitate the
interconversion of different intermediates of the catalytic enamine
cycle.8g,19 Thus, the addition of benzoic acid (20 mol %) resulted in
a slight improvement in the yield and enantioselectivity compared
to when no additive was used (Table 1, compare entries 5 and 12).
This positive result prompted us to explore if a modulation of the
pKa of the additive by changing the substituent in the aromatic
ring could be beneficial.
The presence of electron-withdrawing groups in the aromatic
ring of the acid additive, such as chloro or nitro, increased the yield
of adduct (R)-6aa, although it reduced the enantioselectivity of the
process (Table 1, entries 13 and 14). Therefore, the presence of
additives bearing electron-releasing groups, such as a methyl or
methoxy group, was explored (Table 1, entries 15–17). Among
them, the best results were achieved when 3,4-dimethoxybenzoic
Carbamate-monoprotected primary amines 1–3 were employed
as organocatalysts and were prepared by monoprotection of
(1S,2S)-cyclohexane-1,2-diamine with the common tert-butoxy-
carbonyl (Boc), benzyloxycarbonyl (Cbz) and fluorenylmethoxycar-
bonyl (Fmoc) groups as previously reported.17b The search for the
most appropriate organocatalyst and reaction conditions
(Table 1) began using the model conjugate addition reaction of
acetophenone
4a
(2 equiv)
to
(E)-b-nitrostyrene
5a,
organocatalyzed by 1 (20 mol %) in toluene as the solvent at
room temperature, which afforded the corresponding adduct (R)-
6aa in 62% isolated yield and with 88% ee after 5 d reaction time
(Table 1, entry 1). The (R)-absolute configuration of the final
adduct was determined by comparison of the elution order of the
corresponding enantiomers in chiral HPLC with those in the
literature.16c This adduct (R)-6aa is a precursor of the drug
baclofen.16h
When the Cbz-monoprotected diamine 2 was used as the
organocatalyst under these reaction conditions, the enantioselec-
tivity of the process remained unchanged, although the isolated
yield of the final adduct decreased (Table 1, entry 2). In addition,
when the Fmoc-monoprotected primary amine 3 was employed,
the enantioselectivity decreased to 68% (Table 1, entry 3).
Therefore, we chose the Boc-containing primary amine 1 as the
organocatalyst for the rest of the study.
The use of others solvents was also explored. Thus, dichloro-
methane and chloroform were tested, with the latter slightly
increasing both the yield and enantioselectivity (Table 1, entries
4 and 5), whereas the use of hexane or ether diminished both val-
ues (Table 1, entries 6 and 7). In addition, a polar solvent such as
DMF afforded only 50% ee of (R)-6aa, while a protic one such as
water proved not beneficial (Table 1, entries 8 and 9). Moreover,
the use of a combination of DMF/water (2:1, v/v), a solvent mixture
that has proven effective in enantioselective conjugate additions of
acid was used as the additive (Table 1, entry 17), giving rise to c-
nitroketone (R)-6aa with 93% ee (Table 1, entry 17). Although not
spectacular, the presence of this acid additive was slightly positive
for the enantioselectivity, but also improved the chemical yield.
Keeping the most effective reaction conditions [1 (20 mol %),
3,4-dimethoxybenzoic acid (20 mol %), CHCl3, 25 °C], other param-
eter changes were explored. Thus, the stoichiometry of the reaction
was modified and 5 equiv of acetophenone were used; no signifi-
cant changes were observed in either the yield or stereoselectivity
(Table 1, entry 18). In addition, the organocatalyst loading was
reduced to 10 mol %, but the former values diminished (Table 1,
Table 1
Screening and optimization of the reaction conditions for the enantioselective addition reaction of acetophenone to (E)-b-nitrostyrene
cat.
O
O
Ph
additive
NO2
NO2
+
Ph
Ph
Me
Ph
*
solvent, T, 5 d
6aa
5a
4a
Entry
Catalyst (mol %)
Additivea (mol %)
Solvent
T (°C)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
1 (20)
2 (20)
3 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (10)
1 (20)
ent-1 (20)
—
—
—
—
—
—
—
—
PhMe
PhMe
PhMe
CH2Cl2
CHCl3
Hexane
Et2O
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
10
25
62
55
60
63
65
58
50
60
53
60
60
65
78
70
67
80
73
70
60
65
71
88 (R)
88 (R)
68 (R)
87 (R)
89 (R)
86 (R)
82 (R)
50 (R)
60 (R)
42 (R)
80 (R)
90 (R)
85 (R)
83 (R)
87 (R)
82 (R)
93 (R)
92 (R)
88 (R)
90 (R)
93 (S)
DMF
H2O
9
—
—
10
11
12
13
14
15
16
17
18d
19
20
21
DMF/H2Oc
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Imidazole (20)
PhCO2H
4-ClC6H4CO2H
4-O2NC6H4CO2H
4-MeC6H4CO2H
2,4,6-(Me)3C6H2CO2H
3,4-(MeO)2C6H3CO2H
3,4-(MeO)2C6H3CO2H
3,4-(MeO)2C6H3CO2H
3,4-(MeO)2C6H3CO2H
3,4-(MeO)2C6H3CO2H
a
b
c
Isolated yield after flash chromatography.
Enantioselectivities and absolute stereochemistry determined by chiral HPLC (Ref. 16c).
2/1, v/v.
5 equiv of 4a were used.
d

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J. Flores-Ferrándiz et al. / Tetrahedron: Asymmetry 26 (2015) 970–979
most favourable reaction conditions [1 (20 mol %), 3,4-dimethoxy-
benzoic acid (20 mol %), CHCl3, 25 °C], the obtained results are sum-
marized in Table 2.
entry 19). This also happened when the reaction temperature was
lowered to 10 °C (Table 1, entry 20).
In an attempt to achieve opposite enantioselection, we also per-
formed the reaction using organocatalyst ent-1, which was pre-
pared similarly but using (1R,2R)-cyclohexane-1,2-diamine as the
chirality source.17b Using this primary amine as organocatalyst
(20 mol %) under the most effective reaction conditions [3,4-
dimethoxybenzoic acid (20 mol %), CHCl3, 25 °C], the expected
adduct (S)-6a was isolated in 93% ee (Table 1, entry 21).
First, we performed the reaction of arylated ketones 4, differ-
ently substituted on the aromatic ring, to (E)-b-nitrostyrene 5a.
Thus, when an electron-releasing group such as a methyl was pre-
sent at the 3- or 4-position of the aromatic ring 4b and 4c, the
resulting adducts (R)-6ba and (R)-6ca were obtained with 86%
and 91% ee, respectively (Table 2, entries 2 and 3), whereas the
presence of a 4-methoxy substituent 4d yielded (R)-6da with
91% ee (Table 2, entry 4). The presence of halogens in the aromatic
ring, as in the case of ketones 4e–i, gave the corresponding adducts
(R)-6ea–ia, with 85–88% enantioselectivities (Table 2, entries 5–9).
In addition, the presence of other electron-withdrawing sub-
stituents, such as the trifluoromethyl 4j, 4k and nitro 4l groups,
resulted in lower enantioselections for the corresponding adducts
(R)-6ja, (R)-6ka and (R)-6la (Table 2, entries 10–12). Moreover,
the use of a polyaromatic ketone, such as 1-(naphthalen-2-
O
N
H
OtBu
NH2
ent-1
yl)ethan-1-one 4m afforded the
ee (Table 2, entry 13), whereas the use of a heteroaromatic ketone,
c-nitroketone (R)-6ma with 89%
Next we explored the scope of this organocatalyzed conjugate addi-
tion reaction by modifying the ketone and the nitroalkene under the
Table 2
Enantioselective addition of ketones to nitroalkenes organocatalyzed by 1
1 (20 mol%)
3,4-(MeO)2C6H3CO2H
(20 mol%)
R2
O
O
NO2
NO2
+
R2
R1
Me
R1
CHCl3, rt
5
4
6
Entry
Ketonea
Nitroalkene
t (d)
Adduct No.
Yieldb (%)
eec,d (%)
R1
No.
R2
No.
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5a
5b
5c
5f
5h
5j
5l
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
3
3
3
3
3
3
3
3
(R)-6aa
(R)-6ba
(R)-6ca
(R)-6da
(R)-6ea
(R)-6fa
(R)-6ga
(R)-6ha
(R)-6ia
(R)-6ja
(R)-6ka
(R)-6la
(R)-6ma
(R)-6na
(R)-6ab
(R)-6ac
(R)-6ad
(R)-6ae
(R)-6af
(R)-6ag
(R)-6ah
(R)-6ai
(R)-6aj
(R)-6ak
(R)-6al
(R)-6am
(S)-6an
(R)-6oa
(R)-6ob
(R)-6oc
(R)-6of
(R)-6oh
(R)-6oj
(R)-6ol
(S)-6on
73
70
70
63
68
68
70
70
67
71
68
58
71
85
70
72
60
56
75
77
73
70
68
75
69
70
74
92
85
85
79
87
70
71
78
93
86
91
91
88
85
86
88
88
82
83
75
89
68
90
89
90
89
87
93
90
86
87
88
90
86
96
70
67
70
74
78
69
62
84
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-FC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
3-F3CC6H4
4-F3CC6H4
4-O2NC6H4
2-Naphthyl
2-Pyridinyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
4j
4k
4l
4m
4n
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4o
4o
4o
4o
4o
4o
4o
4o
4-MeC6H4
4-MeOC6H4
3,4-(OCH2O)C6H3
3,4,5-(MeO)3C6H2
4-FC6H4
2-ClC6H4
4-ClC6H4
4-BrC6H4
4-F3CC6H4
4-O2NC6H4
2-Naphthyl
3-Pyridinyl
2-Furanyl
Ph
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-F3CC6H4
2-Naphthyl
2-Furanyl
5n
a
b
c
2 equiv of 4a–n were used; 5 equiv of 4o were used.
Isolated yield after flash chromatography.
Enantioselectivities determined by chiral HPLC.
d
Absolute configuration assigned by the order of elution of the enantiomers in chiral HPLC (see Section 4).

J. Flores-Ferrándiz et al. / Tetrahedron: Asymmetry 26 (2015) 970–979
973
such as 1-(pyridin-2-yl)ethan-1-one 4n yielded the corresponding
adduct (R)-6na with a much lower 68% ee (Table 2, entry 14).
We next explored the influence of changing the substituent on
the nitroalkene 5. Thus, when a 4-methyl was present on the
aromatic ring 5b, the resulting (R)-6ab was isolated with 90% ee,
a similar value to when a 4-methoxy group 5c was present
[(R)-6ac, 89% ee] (Table 2, entries 15 and 16). In addition, when
other electron-releasing systems were present, as in the case of
the dioxole moiety 5d and 3,4,5-trimethoxy groups 5e, the
enantioselectivities for the obtained adducts (R)-6ad and (R)-6ae
were 90% and 89%, respectively (Table 2, entries 17 and 18).
When halogen groups were present on the aromatic ring of 5
would lead to opposite results, but according to Seebach’s model
and our initial calculations, this alternative is not operative and
can be safely discarded.
O
O
H
H
N
N
N
O
O
X
endo
exo
Re face nitroalkene
(R)-product
Si face nitroalkene
(S)-product
(5f-i), the corresponding
c-nitroketones (R)-6af–ai were isolated
with enantioselectivities ranging from 86% to 93% (Table 2, entries
19–22). Adduct (R)-6ah is particularly interesting, since it is an
intermediate in the preparation of the commercial drug
phenibut.16h In addition, the presence of other electron-
withdrawing substituents such as the 4-trifluoromethyl 5j and 4-
nitro 5k afforded adducts (R)-6aj and (R)-6ak with 87% and 88%
ee, respectively (Table 2, entries 23 and 24). Moreover, the
presence of a system such as 2-naphthyl 5l allowed us to prepare
(R)-6al with 90% ee (Table 2, entry 25), while the use of
heteroaromatic systems such as a 3-pyridyl 5m and 2-furanyl 5n
lower face enamine
lower face enamine
Figure 1. Seebach’s synclinal model (left) for the reaction of the enamine model
and nitrostyrene.
We have previously studied a related reaction (enamine and
maleimide), which was also catalyzed by 1,17b determining that
the polarity of the solvent had an effect on the conformation of
the catalyst, and more significantly, on the differential
stabilization of the diastereomeric transition states. Thus, in the
simplest alternative, the electrophile can be activated by an
intramolecular H-bond with the NHBoc hydrogen of the catalyst
(TSAMe-R and TSAPh-R, Fig. 2). Due to the relative disposition of
the NH groups of the enamine and the NHBoc moieties, the
electrophile showed a clear preference for the approach through
the lower face of the enamine, leading to the formation of the
(R)-products. This effect is independent of the source of the
enamine, either coming from acetone or acetophenone.
yielded
c-nitroketones (R)-6am and (S)-6an (no change in the
enantioselectivity sense, just an effect of the CIP rules), with
enantioselectivities of 86% and 96%, respectively (Table 2, entries
26 and 27).
Finally, we explored the use of organocatalyst 1, under the for-
mer reaction conditions, in the conjugate addition of the simple
acetone (5 equiv), to these nitroalkenes (Table 2). Thus, when ace-
tone 4o was reacted with (E)-b-nitrostyrene 5a, the corresponding
c-nitroketone (R)-6oa was isolated in a 92% yield and in 70% ee
(Table 2, entry 28). When a 4-methyl or a 4-methoxy group was
present in the nitroalkene, the corresponding adducts (R)-6ob
and (R)-6oc were obtained with 67 and 70% ee, respectively
(Table 2, entries 29 and 30), whereas the presence of a halogen
group such as a 4-fluoro and 4-chloro gave rise to higher enantios-
elections of the isolated adducts (R)-6of and (R)-6oh, respectively
(Table 2, entries 31 and 32). However, the reaction with a 4-triflu-
oromethylated nitroalkene 5j produced a lower enantioselectivity
The presence of the internal hydrogen bond makes this transi-
tion state very apolar, and thus quite insensitive to the polarity
of the solvent. When computed in the gas phase (as the extreme
case for an apolar environment), the Gibbs Free activation energy
was as low as 14.6 kcal/mol for the acetone derived enamine
TSAMe-R, and 20.3 kcal/mol for the acetophenone TSAPh-R. As
expected, the energies in water were similar to the gas phase,
increasing slightly to 15.3 kcal/mol for acetone, and staying ca.
20.0 kcal/mol for acetophenone.
for the c-nitroketone (R)-6oj (Table 2, entry 33), as well as when
using the 2-naphthyl-nitroalkene 5j (Table 2, entry 34). Finally, a
higher enantioselectivity for adduct (S)-6on (84%) was observed
when using 2-furanyl as the substituent in nitroalkene 5n
(Table 2, entry 35).
A second main approach was found, wherein the nucleophile
attacks from the upper face of the enamine (Fig. 3), in the distal
position from the NHBoc group, and thus, without the possibility
of forming any intramolecular H-bond. In TSBMe-S and TSBPh-S,
the attack takes place from the left side (from our point of view
in Fig. 3) of the enamine, thorough the Si face of the nitroalkene
[(S)-product], whereas the approach of the nitroalkene from the
right side of the enamine (hypothetical TSC) is strongly disfavoured
due to steric repulsion with the large Boc group, which blocks that
face. We could not actually find any transition state for this
approach without severely distorting the structure. The transition
structures in Figure 3 are very polar, showing a clear separation
of the developing positive and negative charges on the enamine
and the nitroalkene, respectively. This type of situation is very sen-
sitive to the environment; highly favoured in polar solvents, and
especially in protic solvents (water) which are able to solvate
and activate the electrophile by the formation of intermolecular
H-bonds. Consequently, the computed energies in water (16.9
and 19.3 kcal/mol) are lower than in the gas phase (17.8 and
21.7 kcal/mol).
In order to justify the origin and sense of the observed enantios-
electivity, we carried out theoretical calculations on the reactions
of acetophenone 4a and acetone 4o with nitrostyrene 5a, catalyzed
by the NHBoc derivative 1. We made use of different computa-
tional methods (M06-2X and B3LYP-D3, see the Section 4.3), and
conditions, such as a gas phase system and a water solvent model,
as extreme situations of apolar and very polar environments. The
choice of solvent was seen to have a significant impact on the
enantioselectivity (Table 1), and we were intrigued by the high
ee’s that were obtained in chloroform and other apolar solvents,
while the use of water or DMF was seen to be detrimental for
the observed selectivity.
Following the literature evidence, and our own previous calcu-
lations, we assumed that the reaction took place through Seebach’s
synclinal model,20 where the nitroalkene approached the enamine
through an endo-type transition state (Fig. 1, left). In that model,
the attack from the lower face of the enamine (from our point of
view) stereo-specifically determines the formation of the (R)-pro-
duct through reaction with the Re face of nitrostyrene.
Consequently, the approach from the upper face of the enamine
(not shown) gave the (S)-product. The exo variant of the reaction
These computational data are thus able to explain the experi-
mental findings. If the reaction is performed in an apolar system,
the lowest-in-energy transition states are TSAMe-R and TSAPh-R,
bearing the internal H-bond activation, which explains the highly
enantioselective formation of the (R)-product. As the polarity of

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J. Flores-Ferrándiz et al. / Tetrahedron: Asymmetry 26 (2015) 970–979
apolar TS
O
O
tBu
tBu
N
N
N
H
N
H
H
H
O
O
O
O
intramolecular
H-bond
N
N
activation
O
O
(R)
(R)
TSAMe-R
TSAPh-R
acetone Re approach
gas phase: 14.6 kcal/mol
water: 15.3 kcal/mol
acetophenone Re approach
gas phase: 20.3 kcal/mol
water: 20.0 kcal/mol
Figure 2. Computed Gibbs Free activation energies for the TSA-type transition states in the gas phase and water models.
of aryl ketones to nitroalkenes, leading to enantiomerically
enriched b-substituted -nitroketones. Good yields and enantiose-
O
O
H
δ+
H
c
δ+
N
tBu
N
tBu
N
H
lectivities can be achieved in the presence of 3,4-dimethoxyben-
zoic acid as the additive. Furthermore, acetone can also be used
as pro-nucleophile, but affording lower enantioselections.
Theoretical calculations suggest that the presence of an
intramolecular H-bond activation of the nitrostyrene with the
NHBoc moiety of the catalyst is responsible for the preferential for-
mation of the (R)-product in apolar solvents such as chloroform.
The partial rupture of the H-bond in polar solvents, such as water
or DMF, induces the formation of a more polar transition state
[(S)-enantiomer], thus explaining the deleterious effect of the
solvent polarity on the enantioselectivity of the reaction.
N
H
O
O
O
O
O
O
N
N
Ph
Me
δ-
δ-
Nitroalkene
approach blocked
(S)
(S)
Hypothetical TSC
TSBMe-S
TSBPh-S
Acetone Si face approach
Acetophenone Si face approach
gas phase: 21.7 kcal/mol
water: 19.3 kcal/mol
gas phase: 17.8 kcal/mol
water: 16.9 kcal/mol
Figure 3. Computed Gibbs Free activation energies for the TSB-type transition
states in the gas phase and water models.
4. Experimental
4.1. General
the solvent increases, the polar transition states (TSB-type, Fig. 3)
gain relative significance, inducing a deleterious effect on the
enantioselectivity (Table 1, entries 8, 9 and 10). Furthermore, these
results also agree with the common chemical sense, by which
intramolecular H-bonds are stronger in apolar solvents, while
intermolecular H-bonds with surrounding water molecules are
present in aqueous systems. Finally, 3D representations29 of the
operative transition states for acetophenone in the gas phase and
in the water model are shown in Figure 4.
All reagents and solvents were of the best grade available and
used without further purification. IR data were collected with a
Nicolet Impact 400D-FT spectrometer. The 1H and 13C NMR spec-
troscopic data were recorded at 25 °C with a Bruker AC-300 at
300 and 75 MHz, respectively, or a Bruker AC-400 at 400 and
101 MHz, respectively, with TMS as the internal standard. MS spec-
tra were registered with an Agilent MS 5973 (GC). HRMS analyses
were performed with an Agilent 7200 Accurate-Mass Q-TOF instru-
ment (DIP probe), using chemical ionization (methane).
Nitroalkenes 5 were purchased or prepared according to a reported
procedure,21 except for 5m, which was obtained following another
methodology.22 Absolute configurations for adducts 6 were deter-
mined according to the described order of elution of their enan-
tiomers in chiral HPLC, whereas in the case of new compounds, it
was assigned by analogy. In the case of compounds 6aa and 6on,
the employed HPLC chiral columns were the same than those
reported in the literature (Chiralpak AS-H and AD-H, respectively).
It has been assured for the rest of the adducts that the employed
Chiralpak AS-H column maintains the same elution order of the
enantiomers than when using a Chiralpak AD-H column, but giving
cleaner determinations in the reaction crude. Reference racemic
samples of adducts 6 were obtained by performing the reaction
using an equimolecular mixture of 1 and ent-1 (20 mol %) as
organocatalyst in toluene as solvent at 25 °C.
Boc
acetophenone
Boc
acetophenone
nitrostyrene
nitrostyrene
TSBPh-S
TSAPh-R
Figure 4. 3-D representation of the transition states for the reaction of acetophe-
none and nitrostyrene
4.2. General procedure for the enantioselective conjugate
addition reaction
3. Conclusions
In conclusion that primary amine-containing carbamates,
prepared easily by monoprotection of enantiomerically pure trans-
cyclohexane-1,2-diamines with the common Boc, Cbz and Fmoc
groups, can act as organocatalysts in the enantioselective addition
To a solution of 1 (8.6 mg, 0.04 mmol), the nitroalkene
(0.2 mmol) and 3,4-dimethoxybenzoic acid (7.3 mg, 0.04 mmol)
in CHCl3 (0.5 mL) was added the ketone (0.4 mmol for 4a–n, 74
L, 1 mmol for 4o) and the mixture was stirred at 25 °C for the
l

J. Flores-Ferrándiz et al. / Tetrahedron: Asymmetry 26 (2015) 970–979
975
time shown in Table 2. The reaction was quenched with HCl 2 M
(10 mL) and the mixture was extracted with AcOEt (3 Â 10 mL).
The organic phase was dried over MgSO4, and the solvent was
evaporated (15 Torr) to give the crude product, which was purified
by silica gel chromatography (n-hexane/AcOEt gradients).
Adducts 6 were identified by comparison of their spectroscopic
data with those of the literature. Their enantiomeric excesses were
determined by chiral HPLC.
4.2.6. (R)-1-(3-Chlorophenyl)-4-nitro-3-phenylbutan-1-one
6fa16e
Colourless oil; 1H NMR (400 MHz, CDCl3): dH = 7.87 (t, J = 1.8 Hz,
1H), 7.53 (ddd, J = 7.9, 2.1, 1.0 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.35–
7.31 (m, 2H), 7.30–7.25 (m, 3H), 4.80 (dd, J = 12.5, 6.8 Hz, 1H), 4.68
(dd, J = 12.5, 7.8 Hz, 1H), 4.25–4.17 (m, 1H), 3.46 (dd, J = 17.8,
6.6 Hz, 1H), 3.40 (dd, J = 17.8, 7.2 Hz, 1H) ppm; 13C NMR
(101 MHz, CDCl3): dC = 195.5, 138.8, 137.8, 135.0, 133.4, 130.0,
129.1, 128.1, 127.9, 127.4, 126.0, 79.4, 41.6, 39.1 ppm; HPLC:
4.2.1. (R)-4-Nitro-1,3-diphenylbutan-2-one 6aa16c
Chiralpak AS-H,
k = 210 nm,
n-hexane/2-propanol,
70:30,
White solid, mp 88–89 °C; 1H NMR (300 MHz, CDCl3): dH = 7.92
(dd, J = 8.4, 1.3 Hz, 2H), 7.57 (d, J = 7.4 Hz, 1H), 7.46 (dd, J = 8.2,
6.9 Hz, 2H), 4.84 (dd, J = 12.5, 6.7 Hz, 1H), 4.70 (dd, J = 12.4,
7.9 Hz, 1H), 4.29–4.17 (m, 1H), 3.50 (dd, J = 16.3, 5.0 Hz, 1H), 3.42
(dd, J = 16.3, 6.0 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3):
dC = 196.8, 139.1, 136.4, 133.6, 129.1, 128.7, 128.0, 127.9, 127.4,
79.6, 41.5, 39.3 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-hex-
ane/2-propanol, 70:30, 1.0 mL/min, tr (minor) = 8.7 min, tr
(major) = 10.3 min.
1.0 mL/min, tr (minor) = 8.5 min, tr (major) = 10.6 min.
4.2.7. (R)-1-(4-Chlorophenyl)-4-nitro-3-phenylbutan-1-one
6ga16c
White solid, mp 67–68 °C; 1H NMR (400 MHz, CDCl3): dH = 7.84
(d, J = 8.7 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.35–7.31 (m, 2H), 7.30–
7.24 (m, 3H), 4.81 (dd, J = 12.5, 6.8 Hz, 1H), 4.68 (dd, J = 12.5,
7.8 Hz, 1H), 4.24–4.17 (m, 1H), 3.44 (dd, J = 17.7, 6.6 Hz, 1H), 3.39
(dd, J = 17.7, 7.3 Hz, 1H) ppm; 13C NMR (101 MHz, CDCl3):
dC = 195.6, 140.00, 138.9, 134.6, 129.4, 129.1, 129.0, 127.9, 127.4,
79.4, 41.4, 39.2 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-hex-
ane/2-propanol, 70:30, 1.0 mL/min, tr (minor) = 10.5 min, tr
(major) = 12.6 min.
4.2.2. (R)-4-Nitro-3-phenyl-1-(m-tolyl)butan-1-one 6ba16c
Colourless oil; 1H NMR (300 MHz, CDCl3): dH = 7.72–7.70 (m,
2H), 7.40–7.25 (m, 7 H), 4.81–4.86 (dd, J = 6.8 Hz, 12.8 Hz, 1H),
4.83 (dd, J = 12.5, 6.6 Hz, 1H), 4.68 (dd, J = 12.5, 8.1 Hz, 1H), 4.27–
4.17 (m, 1H), 3.47 (dd, J = 17.9, 6.5 Hz, 1H), 3.40 (dd, J = 17.9,
7.7 Hz, 1H), 2.39 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3):
dC = 197.0, 139.1, 138.5, 136.3, 134.3, 129.0, 128.5, 128.5, 127.8,
127.4, 125.2, 79.5, 41.5, 39.2, 21.3 ppm; HPLC: Chiralpak AS-H,
k = 210 nm, n-hexane/2-propanol, 70:30, 1.0 mL/min, tr (min-
or) = 7.2 min, tr (major) = 8.9 min.
4.2.8. (R)-1-(4-Bromophenyl)-4-nitro-3-phenylbutan-1-one
6ha16e
White solid, mp 86–87 °C; 1H NMR (400 MHz, CDCl3): dH = 7.76
(d, J = 8.7 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.36–7.29 (m, 2H), 7.28–
7.24 (m, 3H), 4.81 (dd, J = 12.5, 6.8 Hz, 1H), 4.68 (dd, J = 12.5,
7.8 Hz, 1H), 4.24–4.17 (m, 1H), 3.44 (dd, J = 17.7, 6.5 Hz, 1H), 3.38
(dd, J = 17.7, 7.3 Hz, 1H) ppm; 13C NMR (101 MHz, CDCl3):
dC = 195.8, 138.8, 135.0, 132.0, 129.5, 129.1, 128.8, 127.9, 127.4,
79.4, 41.4, 39.2 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-hex-
ane/2-propanol, 70:30, 1.0 mL/min, tr (minor) = 11.8 min, tr
(major) = 14.5 min.
4.2.3. (R)-4-Nitro-3-phenyl-1-(p-tolyl)butan-1-one 6ca16e
Colourless oil; 1H NMR (300 MHz, CDCl3): dH = 7.86–7.78 (m,
2H), 7.35–7.23 (m, 7H), 4.83 (dd, J = 12.5, 6.5 Hz, 1H), 4.67 (dd,
J = 12.5, 8.1 Hz, 1H), 4.26–4.15 (m, 1H), 3.45 (dd, J = 17.6, 6.4 Hz,
1H), 3.37 (dd, J = 17.6, 7.6 Hz, 1H), 2.40 (s, 3H) ppm; 13C NMR
(75 MHz, CDCl3): dC = 196.4, 144.4, 139.2, 133.8, 129.3, 129.0,
128.1, 127.8, 127.4, 79.5, 41.3, 39.3, 21.6 ppm; HPLC:
4.2.9. (R)-1-(4-Iodophenyl)-4-nitro-3-phenylbutan-1-one 6ia15b
White solid, mp 98–99 °C; 1H NMR (300 MHz, CDCl3): dH = 7.81
(d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.40–7.17 (m, 5H), 4.80
(dd, J = 12.5, 6.8 Hz, 1H), 4.67 (dd, J = 12.5, 7.8 Hz, 1H), 4.25–4.15
(m, 1H), 3.45 (dd, J = 17.7, 6.6 Hz, 1H), 3.38 (dd, J = 17.7, 7.3 Hz,
1H) ppm; 13C NMR (75 MHz, CDCl3): dC = 196.1, 138.8, 138.0,
135.5, 129.3, 129.1, 127.9, 127.4, 101.6, 79.4, 41.3, 39.2 ppm;
HPLC: Chiralpak AS-H, k = 210 nm, n-hexane/2-propanol, 70:30,
1.0 mL/min, tr (minor) = 14.4 min, tr (major) = 17.9 min.
Chiralpak AS-H,
k = 210 nm,
n-hexane/2-propanol,
70:30,
1.0 mL/min, tr (minor) = 8.9 min, tr (major) = 10.5 min.
4.2.4. (R)-1-(4-Methoxyphenyl)-4-nitro-3-phenylbutan-1-one
6da16c
White solid, mp 90–91 °C; 1H NMR (300 MHz, CDCl3): dH = 7.94
(d, J = 9.0 Hz, 4H), 7.38–7.23 (m, 5H), 6.93 (d, J = 8.9 Hz, 4H), 4.84
(dd, J = 12.5, 6.5 Hz, 1H), 4.68 (dd, J = 12.5, 8.1 Hz, 1H), 4.27–4.15
(m, 1H), 3.87 (s, 3H), 3.43 (dd, J = 17.5, 6.4 Hz, 1H), 3.35 (dd,
J = 17.5, 7.6 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): dC = 195.3,
163.8, 139.3, 130.3, 129.4, 129.00, 127.8, 127.4, 113.8, 79.6, 55.5,
41.1, 39.4 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-hexane/2-
4.2.10. (R)-4-Nitro-3-phenyl-1-(3-(trifluoromethyl)phenyl)-
butan-1-one 6ja
Colourless oil; IR (ATR):
m = 3066, 2922, 1690, 1550, 1409, 1321,
propanol,
70:30,
1.0 mL/min,
tr
(minor) = 18.9 min,
tr
1167, 1126, 1065 cm-1; 1H NMR (400 MHz, CDCl3): dH = 8.10 (d,
J = 7.9 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H),
7.39–7.21 (m, 5H), 4.83 (dd, J = 12.5, 7.0 Hz, 1H), 4.71 (dd,
J = 12.5, 7.6 Hz, 1H), 4.28–4.21 (m, 1H), 3.52 (dd, J = 17.8, 6.6 Hz,
1H), 3.46 (dd, J = 17.8, 7.1 Hz, 1H) ppm; 13C NMR (101 MHz,
CDCl3): dC = 195.5, 138.7, 136.8, 131.4 (q, J = 33.3 Hz), 131.12,
129.9 (q, J = 3.4 Hz), 129.5, 129.2, 128.0, 127.4, 124.8 (q,
J = 3.9 Hz), 123.5 (q, J = 273.7 Hz), 79.4, 41.6, 39.2 ppm; MS (EI,
70 ev): m/z (%) = 287 (100), 275 (46), 185 (54), 173 (28), 145
(41), 130 (17), 103 (21), 77 (15); HRMS (CI-CH4): m/z calcd for
(major) = 23.1 min.
4.2.5. (R)-1-(4-Fluorophenyl)-4-nitro-3-phenylbutan-1-one
6ea23
Colourless oil; 1H NMR (300 MHz, CDCl3): dH = 7.98–7.93 (m,
2H), 7.37–3.32 (m, 2H), 7.31–7.24 (m, 3H), 7.16–7.10 (m, 2H),
4.83 (dd, J = 12.4, 6.8 Hz, 1H), 4.69 (dd, J = 12.4, 7.7 Hz, 1H), 4.27–
4.17 (m, 1H), 3.47 (dd, J = 17.7, 6.6 Hz, 1H), 3.40 (dd, J = 17.7,
7.3 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): dC = 195.2, 165.6 (d,
J = 254.6 Hz), 138.9, 132.7 (d, J = 2.8 Hz), 130.8 (d, J = 9.3 Hz),
129.0, 127.8, 127.3, 115.5 (d, J = 21.8 Hz), 79.4, 41.3, 39.2 ppm;
HPLC: Chiralpak AS-H, k = 210 nm, n-hexane/2-propanol, 70:30,
1.0 mL/min, tr (minor) = 9.4 min, tr (major) = 11.3 min.
C
17H15F3NO3 [M+H]+: 338.0999, found: 338.1005; HPLC:
Chiralpak AS-H, k = 210 nm, n-hexane/2-propanol, 80:20,
1.0 mL/min, tr (minor) = 7.8 min, tr (major) = 9.7 min.

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J. Flores-Ferrándiz et al. / Tetrahedron: Asymmetry 26 (2015) 970–979
4.2.11. (R)-4-Nitro-3-phenyl-1-(4-(trifluoromethyl)phenyl)-
butan-1-one 6ka16g
(s, 1H), 3.45 (dd, J = 17.6, 6.5 Hz, 1H), 3.39 (dd, J = 17.6, 7.3 Hz,
1H) ppm; 13C NMR (101 MHz, CDCl3): dC = 196.9, 159.0, 136.4,
133.5, 130.9, 128.7, 128.5, 128.0, 114.4, 79.8, 55.2, 41.6,
38.6 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-hexane/2-propa-
nol, 70:30, 1.0 mL/min, tr (minor) = 14.6 min, tr (major) = 17.6 min.
Colourless oil; 1H NMR (300 MHz, CDCl3): dH = 8.00 (d,
J = 8.2 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.37–7.17 (m, 5H), 4.81
(dd, J = 12.5, 7.0 Hz, 1H), 4.69 (dd, J = 12.5, 7.6 Hz, 1H), 4.27–4.18
(m, 1H), 3.51 (dd, J = 17.9, 6.7 Hz, 1H), 3.45 (dd, J = 17.9, 7.1 Hz,
1H) ppm; 13C NMR (75 MHz, CDCl3): dC = 195.9, 139.0, 138.7,
134.7 (q, J = 32.7 Hz), 129.1, 128.3, 128.0, 127.4, 125.7 (q,
J = 3.6 Hz), 123.4 (q, J = 272.9 Hz), 79.4, 41.8, 39.2 ppm; HPLC:
4.2.17. (R)-3-(Benzo[d][1,3]dioxol-5-yl)-4-nitro-1-phenylbutan-
1-one 6ad23
White solid, mp 82–83 °C; 1H NMR (400 MHz, CDCl3):
dH = 7.94–7.91 (m, 2H), 7.61–7.54 (m, 1H), 7.50–7.43 (m, 2H),
6.76 (d, J = 1.1 Hz, 1H), 6.74 (d, J = 1.3 Hz, 2H), 5.93 (s, 2H), 4.78
(dd, J = 12.4, 6.5 Hz, 1H), 4.62 (dd, J = 12.4, 8.1 Hz, 1H), 4.18–4.11
(m, 1H), 3.44 (dd, J = 17.6, 6.5 Hz, 1H), 3.37 (dd, J = 17.6, 7.4 Hz,
1H) ppm; 13C NMR (101 MHz, CDCl3): dC = 196.8, 148.1, 147.1,
136.3, 133.6, 132.7, 128.7, 128.0, 120.7, 108.7, 107.7, 101.2, 79.7,
41.6, 39.1 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-hexane/2-
Chiralpak AS-H,
k = 210 nm,
n-hexane/2-propanol,
70:30,
1.0 mL/min, tr (minor) = 7.1 min, tr (major) = 8.4 min.
4.2.12. (R)-4-Nitro-1-(4-nitrophenyl)-3-phenylbutan-1-one
6la16g
Pale yellow solid, mp 91–92 °C; 1H NMR (400 MHz, CDCl3):
dH = 8.28 (d, J = 8.9 Hz, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.37–7.31 (m,
2H), 7.31–7.24 (m, 3H), 4.81 (dd, J = 12.5, 7.1 Hz, 1H), 4.71 (dd,
J = 12.5, 7.5 Hz, 1H), 4.26–4.19 (m, 1H), 3.55 (dd, J = 17.8, 6.7 Hz,
1H), 3.50 (dd, J = 17.8, 7.0 Hz, 1H) ppm; 13C NMR (101 MHz,
CDCl3): dC = 195.4, 140.6, 138.5, 129.1, 129.0, 128.0, 127.3, 123.9,
79.3, 42.0, 39.1 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-hex-
ane/2-propanol, 70:30, 1.0 mL/min, tr (minor) = 32.8 min, tr
(major) = 36.7 min.
propanol,
70:30,
1.0 mL/min,
tr
(minor) = 20.0 min,
tr
(major) = 25.9 min.
4.2.18. (R)-4-Nitro-1-phenyl-3-(3,4,5-trimethoxyphenyl)butan-
1-one 6ae16f
White solid, mp 142–143 °C; 1H NMR (300 MHz, CDCl3):
dH = 7.95–7.90 (m, 2H), 7.63–7.54 (m, 1H), 7.50–7.42 (m, 2H),
4.83 (dd, J = 12.5, 6.6 Hz, 1H), 4.69 (dd, J = 12.5, 8.0 Hz, 1H), 4.23–
4.12 (m, 1H), 3.84 (s, 6H), 3.81 (s, 3H), 3.47 (dd, J = 17.6, 6.3 Hz,
1H), 3.38 (dd, J = 17.6, 7.5 Hz, 1H) ppm; 13C NMR (75 MHz,
CDCl3): dC = 196.9, 153.5, 137.6, 136.4, 134.7, 133.6, 128.7, 128.0,
104.6, 79.4, 60.7, 56.2, 41.6, 39.6 ppm; HPLC: Chiralpak AS-H,
k = 210 nm, n-hexane/2-propanol, 80:20, 1.0 mL/min, tr (min-
or) = 14.9 min, tr (major) = 17.1 min.
4.2.13. (R)-1-(Naphthalen-2-yl)-4-nitro-3-phenylbutan-1-one
6ma15b
White solid, mp 78–79 °C; 1H NMR (400 MHz, CDCl3): dH = 8.41
(s, 1H), 7.96 (dd, J = 8.7, 1.6 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.86
(dd, J = 8.1, 4.1 Hz, 2H), 7.62–7.52 (m, 2H), 7.38–7.29 (m, 4H),
7.28–7.25 (m, 1H), 4.87 (dd, J = 12.5, 6.6 Hz, 1H), 4.72 (dd,
J = 12.5, 8.0 Hz, 1H), 4.32–4.24 (m, 1H), 3.60 (dd, J = 18.3, 7.1 Hz,
1H), 3.54 (dd, J = 18.3, 8.2 Hz, 1H) ppm; 13C NMR (101 MHz,
CDCl3): dC = 196.7, 139.1, 135.7, 133.6, 132.4, 129.8, 129.5, 129.0,
128.7, 128.6, 127.8, 127.6, 127.4, 126.9, 123.5, 79.6, 41.5,
39.4 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-hexane/2-propa-
nol, 70:30, 1.0 mL/min, tr (minor) = 10.6 min, tr (major) = 11.9 min.
4.2.19. (R)-3-(4-Fluorophenyl)-4-nitro-1-phenylbutan-1-one
6af16h
Colourless oil; 1H NMR (400 MHz, CDCl3): dH = 7.95–7.87 (m,
2H), 7.62–7.54 (m, 1H), 7.49–7.42 (m, 2H), 7.30–7.23 (m, 2H),
7.02 (t, J = 8.7 Hz, 2H), 4.82 (dd, J = 12.5, 6.5 Hz, 1H), 4.66 (dd,
J = 12.5, 8.2 Hz, 1H), 4.26–4.19 (m, 1H), 3.46 (dd, J = 17.7, 6.7 Hz,
1H), 3.41 (dd, J = 17.7, 7.3 Hz, 1H) ppm; 13C NMR (101 MHz,
CDCl3): dC = 196.6, 162.1 (d, J = 246.6 Hz), 136.2, 134.8 (d,
J = 3.2 Hz), 133.6, 129.1 (d, J = 8.1 Hz), 128.7, 128.0, 115.9 (d,
J = 21.5 Hz), 79.5, 41.5, 38.6 ppm; HPLC: Chiralpak AS-H,
k = 210 nm, n-hexane/2-propanol, 70:30, 1.0 mL/min, tr (min-
or) = 9.6 min, tr (major) = 11.1 min.
4.2.14. (R)-4-Nitro-3-phenyl-1-(pyridin-2-yl)butan-1-one 6na24
White solid, mp 59–61 °C; 1H NMR (400 MHz, CDCl3): dH = 8.65
(ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.98 (dt, J = 7.7, 0.9 Hz, 1H), 7.80 (td,
J = 7.7, 1.7 Hz, 1H), 7.46 (ddd, J = 7.7, 4.8, 0.9 Hz, 1H), 7.34–7.28 (m,
4H), 7.27–7.19 (m, 1H), 4.79 (dd, J = 12.4, 6.7 Hz, 1H), 4.68 (dd,
J = 12.4, 8.3 Hz, 1H), 4.28–4.21 (m, 1H), 3.83 (dd, J = 18.2, 7.0 Hz,
1H), 3.62 (dd, J = 18.2, 7.2 Hz, 1H) ppm; 13C NMR (101 MHz,
CDCl3): dC = 198.5, 152.6, 148.9, 139.2, 136.9, 128.9, 127.6, 127.5,
121.8, 79.8, 40.7, 39.2 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-
hexane/2-propanol, 70:30, 1.0 mL/min, tr (minor) = 8.5 min, tr
(major) = 9.4 min.
4.2.20. (R)-3-(2-Chlorophenyl)-4-nitro-1-phenylbutan-1-one
6ag16c
Colourless oil; 1H NMR (400 MHz, CDCl3): dH = 7.94 (dd, J = 8.4,
1.3 Hz, 2H), 7.62–7.54 (m, 1H), 7.49–7.43 (m, 2H), 7.43–7.39 (m,
1H), 7.31–7.27 (m, 1H), 7.27–7.18 (m, 2H), 4.89 (dd, J = 12.8,
6.9 Hz, 1H), 4.85 (dd, J = 12.8, 6.7, 1H), 4.72–66 (m, 1H), 3.58 (dd,
J = 17.9, 7.4 Hz, 1H), 3.52 (dd, J = 17.9, 6.4 Hz, 1H) ppm; 13C NMR
(101 MHz, CDCl3): dC = 196.7, 136.2, 133.7, 133.6, 130.4, 129.0,
128.7, 128.4, 128.0, 127.3, 77.5, 39.8, 36.1 ppm; HPLC:
4.2.15. (R)-4-Nitro-1-phenyl-3-(p-tolyl)butan-1-one 6ab16c
White solid, mp 72–73 °C; 1H NMR (400 MHz, CDCl3):
dH = 7.94–7.88 (m, 2H), 7.60–7.52 (m, 1H), 7.48–7.41 (m, 2H),
7.19–7.09 (m, 4H), 4.80 (dd, J = 12.4, 6.6 Hz, 1H), 4.65 (dd,
J = 12.4, 8.0 Hz, 1H), 4.22–4.14 (m, 1H), 3.45 (dd, J = 17.6, 6.4 Hz,
1H), 3.39 (dd, J = 17.6, 7.4 Hz, 1H), 2.30 (s, 3H) ppm; 13C NMR
(101 MHz, CDCl3): dC = 196.9, 137.5, 136.3, 136.0, 133.5, 129.7,
128.7, 128.0, 127.2, 79.7, 41.5, 38.9, 21.0 ppm; HPLC:
Chiralpak AS-H,
k = 210 nm,
n-hexane/2-propanol,
70:30,
1.0 mL/min, tr (minor) = 8.3 min, tr (major) = 9.4 min.
4.2.21. (R)-3-(4-Chlorophenyl)-4-nitro-1-phenylbutan-1-one
6ah16c
Chiralpak AS-H,
1.0 mL/min, tr (minor) = 7.9 min, tr (major) = 10.1 min.
k = 210 nm,
n-hexane/2-propanol,
70:30,
White solid, mp 48–49 °C; 1H NMR (400 MHz, CDCl3): dH = 7.91
(dd, J = 8.4, 1.3 Hz, 2H), 7.62–7.55 (m, 1H), 7.50–7.44 (m, 2H), 7.30
(d, J = 8.4 Hz, 2H), 7.27–7.21 (m, 2H), 4.81 (dd, J = 12.6, 6.5 Hz, 1H),
4.66 (dd, J = 12.6, 8.2 Hz, 1H), 4.25–4.18 (m, 1H), 3.46 (dd, J = 17.8,
6.7 Hz, 1H), 3.40 (dd, J = 17.8, 7.2 Hz, 1H) ppm; 13C NMR (101 MHz,
CDCl3): dC = 196.4, 137.6, 136.2, 133.7, 129.2, 128.8, 128.7,
128.0, 79.3, 41.3, 38.6 ppm; HPLC: Chiralpak AS-H, k = 210 nm,
4.2.16. (R)-3-(4-Methoxyphenyl)-4-nitro-1-phenylbutan-1-one
6ac16c
White solid, mp 69–70 °C; 1H NMR (400 MHz, CDCl3):
dH = 7.96–7.85 (m, 2H), 7.63–7.52 (m, 1H), 7.47–7.41 (m, 2H),
7.20 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.79 (dd, J = 12.3,
6.6 Hz, 1H), 4.64 (dd, J = 12.3, 8.0 Hz, 1H), 4.21–4.14 (m, 1H), 3.77

J. Flores-Ferrándiz et al. / Tetrahedron: Asymmetry 26 (2015) 970–979
977
n-hexane/2-propanol, 70:30, 1.0 mL/min, tr (minor) = 9.4 min, tr
(major) = 11.7 min.
4.2.27. (S)-3-(Furan-2-yl)-4-nitro-1-phenylbutan-1-one 6an16c
Colourless oil; 1H NMR (400 MHz, CDCl3): dH = 8.01–7.91 (m,
2H), 7.63–7.56 (m, 1H), 7.52–7.44 (m, 2H), 7.34 (dd, J = 1.9,
0.8 Hz, 1H), 6.29 (dd, J = 3.3, 1.9 Hz, 1H), 6.19 (d, J = 3.3 Hz, 1H),
4.81 (dd, J = 12.6, 6.1 Hz, 1H), 4.75 (dd, J = 12.6, 7.3 Hz, 1H), 4.37–
4.30 (m, 1H), 3.53 (dd, J = 17.9, 6.1 Hz, 1H), 3.43 (dd, J = 17.9,
7.5 Hz, 1H) ppm; 13C NMR (101 MHz, CDCl3): dC = 196.5, 151.9,
142.3, 136.2, 133.6, 128.7, 128.0, 110.5, 107.1, 77.2, 38.9,
33.1 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-hexane/2-propa-
nol, 70:30, 1.0 mL/min, tr (minor) = 8.7 min, tr (major) = 9.7 min.
4.2.22. (R)-3-(4-Bromophenyl)-4-nitro-1-phenylbutan-1-one
6ai16e
White solid, mp 66–67 °C; 1H NMR (400 MHz, CDCl3): dH = 7.90
(d, J = 8.4 Hz, 2H), 7.61–7.55 (m, 1H), 7.49–7.41 (m, 4H), 7.17 (d,
J = 8.4 Hz, 2H), 4.81 (dd, J = 12.6, 6.4 Hz, 1H), 4.65 (dd, J = 12.6,
8.2 Hz, 1H), 4.23–4.16 (m, 1H), 3.45 (dd, J = 17.8, 6.7 Hz, 1H), 3.40
(dd, J = 17.8, 7.2 Hz, 1H) ppm; 13C NMR (101 MHz, CDCl3):
dC = 196.4, 138.1, 136.1, 133.7, 132.1, 129.2, 128.7, 127.9, 121.7,
79.2, 41.2, 38.7 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-hex-
ane/2-propanol, 70:30, 1.0 mL/min, tr (minor) = 9.8 min, tr
(major) = 12.7 min.
4.2.28. (R)-5-Nitro-4-phenylpentan-2-one 6oa25
White solid, mp 113–114 °C; 1H NMR (300 MHz, CDCl3):
dH = 7.34–7.19 (5H, m), 4.68 (dd, J = 12.3, 6.9 Hz, 1H), 4.58 (dd,
J = 12.3, 7.9 Hz, 1H), 4.06–3.96 (m, 1H), 2.90 (d, J = 7.0 Hz, 2H),
2.09 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): dC = 205.4, 138.8,
129.0, 127.8, 127.3, 79.4, 46.0, 39.0, 30.3 ppm; HPLC:
4.2.23. (R)-4-Nitro-1-phenyl-3-(4-(trifluoromethyl)phenyl)-
butan-1-one 6aj16g
Colourless oil; 1H NMR (300 MHz, CDCl3): dH = 7.93–7.89 (m,
2H), 7.61–7.58 (m, 3H), 7.49–7.42 (m, 4H), 4.86 (dd, J = 12.7,
6.4 Hz, 1H), 4.71 (dd, J = 12.7, 8.2 Hz, 1H), 3.51 (dd, J = 17.9,
6.7 Hz, 1H), 3.44 (dd, J = 17.9, 7.2 Hz, 1H) ppm; 13C NMR
(75 MHz, CDCl3): dC = 196.3, 143.2, 136.1, 133.8, 130.15 (q,
J = 32.8 Hz), 128.8, 128.0, 126.34, 126.0 (q, J = 3.8 Hz), 123.85 (q,
J = 272.1 Hz), 79.0, 41.2, 39.0 ppm; HPLC: Chiralpak AS-H,
k = 210 nm, n-hexane/2-propanol, 70:30, 1.0 mL/min, tr (min-
or) = 6.7 min, tr (major) = 8.0 min.
Chiralpak AS-H,
1.0 mL/min, tr (minor) = 9.5 min, tr (major) = 11.4 min.
k = 210 nm,
n-hexane/2-propanol,
75:25,
4.2.29. (R)-5-Nitro-4-(p-tolyl)pentan-2-one 6ob25
White solid, mp 66–68 °C; 1H NMR (300 MHz, CDCl3):
dH = 7.16–7.06 (m, 4H), 4.67 (dd, J = 12.2, 6.9 Hz, 1H), 4.57 (dd,
J = 12.2, 7.7 Hz, 1H), 4.01–3.92 (m, 1H), 2.89 (d, J = 7.1 Hz, 2H),
2.31 (s, 3H), 2.11 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3):
dC = 205.5, 137.6, 135.7, 129.7, 127.2, 79.6, 46.2, 38.7, 30.4,
21.0 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-hexane/2-propa-
nol, 80:20, 1.0 mL/min, tr (minor) = 9.4 min, tr (major) = 12.4 min.
4.2.24. (R)-4-Nitro-3-(4-nitrophenyl)-1-phenylbutan-1-one
6ak16h
White solid, mp 102–103 °C; 1H NMR (300 MHz, CDCl3):
dH = 8.25–8.18 (m, 2H), 7.94–7.88 (m, 2H), 7.63–7.56 (m, 1H),
7.53–7.40 (m, 4H), 4.89 (dd, J = 12.9, 6.2 Hz, 1H), 4.75 (dd,
J = 12.9, 8.3 Hz, 1H), 4.43–4.35 (m, 1H), 3.54 (dd, J = 18.0, 6.8 Hz,
1H), 3.47 (dd, J = 18.0, 7.0 Hz, 1H) ppm; 13C NMR (75 MHz,
CDCl3): dC = 195.9, 147.4, 146.6, 135.9, 133.9, 128.8, 128.6, 128.0,
124.2, 78.8, 41.0, 38.9 ppm; HPLC: Chiralpak AD-H, k = 210 nm, n-
hexane/2-propanol, 80:20, 1.0 mL/min, tr (minor) = 22.2 min, tr
(major) = 36.5 min.
4.2.30. (R)-4-(4-Methoxyphenyl)-5-nitropentan-2-one 6oc25
White solid, mp 93–94 °C; 1H NMR (300 MHz, CDCl3):
dH = 7.13 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H) 4.66 (dd,
J = 12.2, 6.9 Hz, 1H), 4.55 (dd, J = 12.2, 7.8 Hz, 1H), 4.00–3.91 (m,
1H), 2.88 (d, J = 7.1 Hz, 2H), 3.78 (s, 3H), 2.11 (s, 3H) ppm; 13C
NMR (75 MHz, CDCl3): dC = 205.6, 159.1, 130.6, 128.4, 114.4, 79.7,
55.3, 46.3, 38.4, 30.4 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-
hexane/2-propanol, 70:30, 1.0 mL/min, tr (minor) = 15.9 min, tr
(major) = 29.1 min.
4.2.25. (R)-3-(Naphthalen-2-yl)-4-nitro-1-phenylbutan-1-one
6al16c
4.2.31. (R)-4-(4-Fluorophenyl)-5-nitropentan-2-one 6of26
White solid, mp 81–82 °C; 1H NMR (300 MHz, CDCl3):
dH = 7.22–7.18 (m, 2H), 7.04–6.99 (m, 2H), 4.68 (dd, J = 12.4,
6.6 Hz, 1H), 4.57 (dd, J = 12.4, 7.9 Hz, 1H), 4.05–3.95 (m, 1H), 2.90
(d, J = 7.0 Hz, 2H), 2.12 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3):
dC = 205.1, 162.2 (d, J = 246.7 Hz), 134.6 (d, J = 3.4 Hz), 129.0 (d,
J = 8.2 Hz), 115.97 (d, J = 21.6 Hz), 79.4, 46.1, 38.3, 30.3 ppm;
HPLC: Chiralpak AS-H, k = 210 nm, n-hexane/2-propanol, 70:30,
1.0 mL/min, tr (minor) = 9.2 min, tr (major) = 11.8 min.
White solid, mp 89–90 °C; 1H NMR (400 MHz, CDCl3): dH = 7.91
(dd, J = 8.4, 1.3 Hz, 2H), 7.85–7.74 (m, 3H), 7.72 (d, J = 1.3 Hz, 1H),
7.58–7.51 (m, 1H), 7.51–7.35 (m, 5H), 4.89 (dd, J = 12.5, 6.6 Hz,
1H), 4.76 (dd, J = 12.5, 8.0 Hz, 1H), 4.43–4.35 (m, 1H), 3.56 (dd,
J = 17.7, 6.4 Hz, 1H), 3.49 (dd, J = 17.7, 7.5 Hz, 1H) ppm; 13C NMR
(101 MHz, CDCl3): dC = 196.7, 136.5, 136.3, 133.5, 133.3, 132.8,
128.9, 128.7, 128.0, 127.8, 127.6, 126.5, 126.4, 126.2, 125.1, 79.5,
41.5, 39.4 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-hexane/2-
propanol,
(major) = 13.1 min.
70:30,
1.0 mL/min,
tr
(minor) = 10.3 min,
tr
4.2.32. (R)-4-(4-Chlorophenyl)-5-nitropentan-2-one 6oh25
White solid, mp 90–92 °C; 1H NMR (300 MHz, CDCl3):
dH = 7.31 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 4.68 (dd,
J = 12.4, 6.6 Hz, 1H), 4.57 (dd, J = 12.4, 7.9 Hz, 1H), 4.04–3.96 (m,
1H), 2.90 (d, J = 7.0 Hz, 2H), 2.13 (s, 3H) ppm; 13C NMR (75 MHz,
CDCl3): dC = 205.0, 137.3, 133.8, 129.2, 128.8, 79.2, 45.9, 38.4,
30.4 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-hexane/2-propa-
nol, 70:30, 1.0 mL/min, tr (minor) = 11.2 min, tr (major) = 15.5 min.
4.2.26. (R)-4-Nitro-1-phenyl-3-(pyridin-3-yl)butan-1-one 6am
Colourless oil; IR (ATR): = 3035, 2929, 2857, 1684, 1549, 1428,
1267, 1177, 1024 cm-1 1H NMR (300 MHz, CDCl3): dH = 8.62 (d,
m
;
J = 2.2 Hz, 1H), 8.54 (dd, J = 4.8, 1.5 Hz, 1H), 7.96–7.88 (m, 2H),
7.66 (dt, J = 8.0, 2.0 Hz, 1H), 7.62–7.57 (m, 2H), 7.50–7.44 (m,
2H), 7.31–7.28 (m, 1H), 4.88 (dd, J = 12.8, 6.4 Hz, 1H), 4.73 (dd,
J = 12.8, 8.1 Hz, 1H), 4.27 (dd, J = 14.6, 6.8 Hz, 1H), 3.50 (d,
J = 6.9 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): dC = 196.1, 149.2,
149.0, 136.1, 135.3, 134.9, 133.8, 128.8, 128.0, 123.8, 78.9, 41.0,
36.9 ppm; MS (EI, 70 ev): m/z (%) = 207 (69), 131 (11), 117 (34),
105 (100), 77 (51), 51 (17); HRMS (CI-CH4): m/z calcd for
4.2.33. (R)-5-Nitro-4-(4-(trifluoromethyl)phenyl)pentan-2-one
6oj27
Colourless oil; 1H NMR (400 MHz, CDCl3): dH = 7.60 (d,
J = 8.1 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 4.73 (dd, J = 12.6, 6.5 Hz,
1H), 4.62 (dd, J = 12.6, 8.0 Hz, 1H), 4.14–4.03 (m, 1H), 2.94 (dd,
J = 6.9, 0.9 Hz, 2H), 2.14 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3):
dC = 204.7, 142.9, 130.2 (q, J = 32.8 Hz), 127.9, 126.0, 123.8 (d,
J = 272.2 Hz), 78.8, 45.8, 38.6, 30.3 ppm; HPLC: Chiralpak AS-H,
C
15H15N2O3 [M+H]+: 271.1077, found: 271.1070; HPLC:
Chiralpak AS-H, k = 210 nm, n-hexane/2-propanol, 70:30,
1.0 mL/min, tr (major) = 22.0 min, tr (minor) = 38.2 min.

978
J. Flores-Ferrándiz et al. / Tetrahedron: Asymmetry 26 (2015) 970–979
3. Szanto, G.; Hegedus, L.; Mattyasovszky, L.; Simon, A.; Simon, A.; Bitter, I.; Toth,
G.; Toke, L.; Kadas, I. Tetrahedron 2009, 65, 8412–8417.
4. Andrey, O.; Vidonne, A.; Alexakis, A. Tetrahedron Lett. 2003, 44, 7901–7904.
5. Yu, Z.; Liu, X.; Zhou, L.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2009, 48, 5195–
5198.
k = 210 nm, n-hexane/2-propanol, 70:30, 1.0 mL/min, tr (min-
or) = 6.5 min, tr (major) = 7.8 min.
4.2.34. (R)-4-(Naphthalen-2-yl)-5-nitropentan-2-one 6ol27
White solid, mp 101–103 °C; 1H NMR (300 MHz, CDCl3):
dH = 7.86–7.78 (m, 3H), 7.68 (d, J = 1.5 Hz, 1H), 7.53–7.45 (m, 2H),
7.34 (dd, J = 8.5, 1.8 Hz, 1H), 4.78 (dd, J = 12.4, 6.9 Hz, 1H), 4.70
(dd, J = 12.4, 7.7 Hz, 1H), 4.25–4.14 (m, 1H), 3.00 (d, J = 7.0 Hz,
2H), 2.13 (s, 3H); 13C NMR: (75 MHz, CDCl3): dC = 205.3, 136.1,
133.3, 132.8, 128.9, 127.8, 127.6, 126.5, 126.2, 125.0, 79.3, 46.1,
39.1, 30.4 ppm; HPLC: Chiralpak AS-H, k = 210 nm, n-hexane/
2-propanol, 70:30, 1.0 mL/min, tr (minor) = 10.4 min, tr
(major) = 14.4 min.
6. Hong, B.-C.; Kotame, P.; Tsai, C.-W.; Liao, J.-H. Org. Lett. 2010, 12, 776–779.
7. (a) Elsner, P.; Jiang, H.; Nielsen, J. B.; Pasi, F.; Jorgensen, K. A. Chem. Commun.
2008, 5827–5829; (b) Karthikeyan, T.; Sankararaman, S. Tetrahedron:
Asymmetry 2008, 19, 2741–2745; (c) Ruiz, N.; Reyes, E.; Vicario, J. L.; Badia,
D.; Carrillo, L.; Uria, U. Chem. Eur. J. 2008, 14, 9357–9367; (d) Krayer, M.;
Ptaszek, M.; Kim, H.-J.; Meneely, K. R.; Fan, D.; Secor, K.; Lindsey, J. S. J. Org.
Chem. 2010, 75, 1016–1039.
8. (a) Sulzer-Mosse, S.; Alexakis, A. Chem. Commun. 2007, 3123–3135; (b) Almasi,
D.; Alonso, D. A.; Nájera, C. Tetrahedron: Asymmetry 2007, 18, 299–365; (c)
Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–1716; (d) Peng, F.; Shao, Z. J. Mol.
Catal. A: Chem. 2008, 285, 1–13; (e) Roca-Lopez, D.; Sadaba, D.; Delso, I.;
Herrera, R. P.; Tejero, T.; Merino, P. Tetrahedron: Asymmetry 2010, 21, 2561–
2601; (f) Somanathan, R.; Chavez, D.; Servin, F. A.; Romero, J. A.; Navarrete, A.;
Parra-Hake, M.; Aguirre, G.; Anaya, d. P. C.; Gonzalez, J. Curr. Org. Chem. 2012,
16, 2440–2461; (g) Serdyuk, O. V.; Heckel, C. M.; Tsogoeva, S. B. Org. Biomol.
Chem. 2013, 11, 7051–7071; (h) Aitken, L. S.; Arezki, N. R.; Dell’Isola, A.; Cobb,
A. J. A. Synthesis 2013, 45, 2627–2648.
4.2.35. (S)-4-(Furan-2-yl)-5-nitropentan-2-one 6on25
Colourless oil; 1H NMR (300 MHz, CDCl3): dH = 7.35–7.33 (m,
1H), 6.30 (dd, J = 3.2, 1.9 Hz, 1H), 6.15 (d, J = 3.3 Hz, 1H), 4.68 (dd,
J = 6.6, 1.6 Hz, 2H), 4.15–406 (m, 1H), 2.94 (dd, J = 8.3, 7.0 Hz,
2H), 2.18 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): dC = 205.0,
151.6, 142.3, 110.5, 107.1, 77.2, 43.5, 32.9, 30.2 ppm; HPLC:
9. Kerr, D. I. B.; Ong, J. Med. Res. Rev. 1992, 12, 593–636.
10. (a) Olpe, H. R.; Demieville, H.; Baltzer, V.; Bencze, W. L.; Koella, W. P.; Wolf, P.;
Haas, H. L. Eur. J. Pharmacol. 1978, 52, 133–136; (b) Berthelot, P.; Vaccher, C.;
Flouquet, N.; Debaert, M.; Luyckx, M.; Brunet, C. J. Med. Chem. 1991, 34, 2557–
2560; (c) Kerr, D. I. B.; Ong, J.; Doolette, D. J.; Abbenante, J.; Prager, R. H. Eur. J.
Pharmacol. 1993, 236, 239–245.
Chiralpak AD-H,
k = 210 nm,
n-hexane/2-propanol,
90:10,
11. Lapin, I. CNS Drug Rev. 2001, 7, 471–481.
12. Enders, D.; Seki, A. Synlett 2002, 26–28.
1.0 mL/min, tr (major) = 26.4 min, tr (minor) = 29.3 min.
13. (a) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III
Synthesis 2004, 1509–1521; (b) Xu, D.-Z.; Shi, S.; Wang, Y. Eur. J. Org. Chem.
2009, 4848–4853; (c) Barbayianni, E.; Bouzi, P.; Constantinou-Kokotou, V.;
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Chandrasekhar, S.; Kumar, T. P.; Haribabu, K.; Reddy, C. R.; Kumar, C. R.
Tetrahedron: Asymmetry 2011, 22, 697–702.
4.3. Calculations
The structures were optimized using density functional theory
(DFT) with the B3LYP28 and the 6-31G⁄ basis set as implemented
in Gaussian 09.29 The structures were re-optimized at M06-2X/6-
311+G⁄⁄ level of theory30 on the previously optimized structures,31
including polarization functions for better description of hydrogen
bond activations and to better account for the dispersion forces of
such large systems. Besides, solvation factors were introduced with
the IEF-PCM method,32 using water as indicated in the text and
figures.
We also performed single-point calculations at B3LYP-D3/
6-311+G⁄⁄ level of theory, including Grimme’s dispersion with
the original D3 damping function, and the relative values were
similar to those of the M06-2X energies.33 The stationary points
were characterized by frequency calculations in order to verify
that they have the right number of imaginary frequencies. The
intrinsic reaction coordinates (IRC)34 were followed to verify
the energy profiles connecting each TS to the correct associated
local minima. 3D structures were drawn using the CyL view
software.35
14. Liu, J.; Yang, Z.; Liu, X.; Wang, Z.; Liu, Y.; Bai, S.; Lin, L.; Feng, X. Org. Biomol.
Chem. 2009, 7, 4120–4127.
15. (a) Xue, F.; Zhang, S.; Duan, W.; Wang, W. Adv. Synth. Catal. 2008, 350, 2194–
2198; (b) Rasappan, R.; Reiser, O. Eur. J. Org. Chem. 2009, 1305–1308.
16. (a) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170–7171; (b) Liu, K.;
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Acknowledgments
We thank the financial support from the Spanish Ministerio de
Economía y Competitividad (project CTQ2011-24151), FEDER, the
COST Action CM0905 ‘Organocatalysis’, the FP7 Marie Curie
Action of the European Commission via the ITN ECHONET
Network (FP7-MCITN-2012-316379), and the universities of
Alicante and the Basque Country. We also thank SGI/IZO-SGIker
(UPV/EHU) for allocation of computational resources. J.F.-F.
acknowledges the Vicerrectorado de Investigación, Desarrollo e
Innovación of the University of Alicante for a fellowship. A.S.
thanks the University of Edinburgh for an ERASMUS fellowship.
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