Asymmetric conjugate addition of α,α-disubstituted aldehydes to nitroalkenes organocatalyzed by chiral monosalicylamides from trans-cyclohexane-1,2-Diamines

Article abstract of DOI:10.3390/molecules23010141

Primary amine-salicylamides derived from chiral trans-cyclohexane-1,2-diamines are used as organocatalysts for the enantioselective conjugate addition of α,α-disubstituted aldehydes to arylated and heteroarylated nitroalkenes. The reaction is performed in

Full text of DOI:10.3390/molecules23010141

molecules
Article
Asymmetric Conjugate Addition of α,α-Disubstituted
Aldehydes to Nitroalkenes Organocatalyzed by
Chiral Monosalicylamides from
trans-Cyclohexane-1,2-Diamines
José R. Martínez-Guillén 1, Jesús Flores-Ferrándiz 1, Cecilia Gómez 1, Enrique Gómez-Bengoa 2,
*
ID
and Rafael Chinchilla 1,
*
ID
1
Department of Organic Chemistry, Faculty of Sciences, and Institute of Organic Synthesis (ISO),
University of Alicante, P.O. Box 99, 03080 Alicante, Spain; jramonimg@gmail.com (J.R.M.-G.);
jfloresf@gmail.com (J.F.-F.); cgomez@ua.es (C.G.)
Department of Organic Chemistry I, University of the Basque Country, P.O. Box 1072,
20080 San Sebastíán, Spain
2
*
Correspondence: enrique.gomez@ehu.es (E.G.-B.); chinchilla@ua.es (R.C.); Tel.: +34-965903822 (R.C.)
Received: 25 December 2017; Accepted: 9 January 2018; Published: 11 January 2018
Abstract: Primary amine-salicylamides derived from chiral trans-cyclohexane-1,2-diamines are
used as organocatalysts for the enantioselective conjugate addition of -disubstituted aldehydes
α,α
to arylated and heteroarylated nitroalkenes. The reaction is performed in the presence of
4-dimethylaminopyridine as an additive in dichloromethane as a solvent at room temperature.
The corresponding enantioenriched γ-nitroaldehydes are obtained with enantioselectivities up to
95%. Theoretical calculations are used to justify the reasons of the stereoinduction.
Keywords: organocatalysis; asymmetric synthesis; Michael addition; nitroalkenes
1. Introduction
The asymmetric synthesis of
years. They are precursors of -aminobutyric acid analogues (GABAs), which exhibit a range
of pharmacological activities including antidepressant, anticonvulsant, anxiolytic and others [
In addition, GABA derivatives can be potent drugs in the treatment of neurodegenerative disorders [
γ-nitroaldehydes has gained great importance during recent
γ
1
,
2
3
].
].
Moreover, the presence of the versatile nitro group allows for further transformations to valuable
compounds. This is largely due to the utility of the nitro group as a masked functionality to be
transformed to a variety of other useful functional groups [
with the term ‘synthetic chameleon’ [6].
4,5], which was well described by Seebach
Nowadays, the enantioselective 1,4-addition reaction of enolizable aldehydes to nitroalkenes
promoted by a chiral organocatalyst is one of the most common and convenient procedures for
achieving the synthesis of
bifunctional organocatalysts derived from enantiopure trans-cyclohexane-1,2-diamine, a commonly
employed chiral auxiliary [13 14], bearing a primary amine and an additional H-bond-forming
functionality, have been employed successfully in this transformation (Figure 1). Thus, the use of primary
amine-thioureas has been frequent, as exemplified in organocatalyst 15], 16] and 17], as well as
the Cinchona-derived 18], the isosteviol- and rosin-derived 19] and 20], respectively, and even
calix[4]arene-derived compounds [21]. In addition, primary-amine squaramides have been used, as is the
case of isosteviol-derived compound 22], and the primary-amine-containing benzimidazole 23] and
guanidine 24]. In all these primary-amine organocatalysts, the enantioselectivity is induced by addition
γ-nitroaldehydes in an enantiomerically enriched form [7–12]. Particularly,
,
1
[
2
[
3 [
4
[
5
[
6 [
7
[
8 [
9
[
Molecules 2018, 23, 141; doi:10.3390/molecules23010141
www.mdpi.com/journal/molecules

Molecules 2018, 23, 141
2 of 13
of a transient enamine to the nitroolefin, which is H-bond-coordinated by the NO2 group to the NH’s of
the catalyst functionality.
Figure 1. Chiral trans-cyclohexa-1,2-diamine-based organocatalysts employed in the enantioselective
conjugate addition of aldehydes to nitroalkenes.
In the last years, our group has been involved in the use of small-size trans-cyclohexane-
1,2-diamine-derived monocarbamates, such as the mono-Boc-protected diamine 10 as organocatalysts
in the enantioselective conjugate addition reactions of carbonyl compounds to electron-deficient
olefins (Figure 2) [25–28]. This paper shows now that a simple monoamidation of a chiral
trans-cyclohexane-1,2-diamine with salicylic acid affords a primary amine-bearing salicylamide 11
(Figure 2), suitable to organocatalyze the asymmetric conjugate addition reaction of the ‘difficult’
α
,
α
-disubstituted aldehydes to nitroalkenes, leading to enantioenriched
γ-nitroaldehydes. Theoretical
calculations can explain the observed enantioselectivity of the process.
Figure 2. Organocatalysts employed in this study.
2. Results and Discussion
The primary amine-salicylamide 11 employed as organocatalyst in this study was prepared by
monoamidation of (1S,2S)-cyclohexane-1,2-diamine with phenyl salicylate in refluxing propan-2-ol [29].
The search for the most appropriate reaction conditions (Table 1) was carried out using the model
conjugate addition reaction of isobutyraldehyde (12a) to trans-
organocatalyzed by 11 (20 mol %) in toluene as a solvent at room temperature afforded the
corresponding -nitroaldehyde (S)-14aa in 79% ee but in a very low yield after 2 d reaction time
β-nitrostyrene (13a). Thus, this reaction
γ
(Table 1, entry 1). The (S) 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 [24].
The use of dimethylformamide (DMF) as solvent lowered down dramatically the stereoselectivity of

Molecules 2018, 23, 141
3 of 13
the process (Table 1, entry 2), whereas the use of dichloromethane raised the enantioselectivity again
up to 84%, but with almost negligible yield (Table 1, entry 3).
Table 1. Screening and optimization of the reaction conditions for the model enantioselective
conjugate addition.
Yield (%) b
Entry
Catalyst (mol %)
Additive (mol %) a
Solvent
t (d)
ee (%) c
10 d
26
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
11 (20)
11 (20)
11 (20)
11 (20)
11 (20)
11 (20)
11 (20)
11 (20)
11 (20)
11 (20)
11 (20)
11 (20)
11 (10)
11 (20)
11 (20)
ent-11 (20)
15 (20)
10 (20)
-
-
-
PhMe
DMF
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
79 (S)
9 (S)
10 d
81
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
84 (S)
92 (S)
76 (S)
81 (S)
91 (S)
38 (S)
93 (S)
71 (S)
78 (S)
75 (S)
94 (S)
94 (S)
95 (S)
95 (R)
79 (S)
65 (S)
DMAP (20)
Imidazole (20)
Pyridine (20)
TMG (20)
10 d
10 d
43
DBU (20)
31
47
DABCO (20)
PhCO2H (20)
4-O2NC6H4CO2H (20)
3,4-(MeO)2C6H3CO2H (20)
DMAP (20)
DMAP (10)
DMAP (30)
DMAP (30)
DMAP (30)
DMAP (30)
10 d
10 d
10 d
17
41
72
74
40
30
a
DMAP: 4-Dimethylaminopyridine; TMG: 1,1,3,3-Tetramethylguanidine; DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene;
b
c
DABCO: 1,4-Diazabicyclo[2.2.2]octane. Isolated yield after flash chromatography. Enantioselectivities and
absolute stereochemistry determined by chiral HPLC (see Experimental Section). Estimated by 1H-NMR
d
(400 MHz).
The addition of acid or basic additives frequently has proven beneficial in the organocatalyzed
conjugate addition of carbonyl compounds to nitroalkenes, not only accelerating the formation
of the transient enamine, but supposedly avoiding the formation of stable catalyst-derived
byproducts [12]. Therefore, we assayed the model conjugate addition reaction in the presence of
4-dimethylaminopyridine (DMAP, 20 mol %) as a basic additive in dichloromethane as a solvent,
now obtaining adduct (S)-14aa in an 81% isolated yield and with an enantioselectivity of 92% (Table 1,
entry 4). However, the use of other basic additives resulted in being not so effective. Thus, the presence
of imidazole or pyridine as additives gave lower enantioselections and very poor yields (Table 1,
entries 5 and 6), whereas other basic species such as TMG, DBU or DABCO showed less efficiency than
DMAP, considering the isolated yield of (S)-14aa (Table 1, entries 7–9). In addition, we also attempted
the use of aromatic carboxylic acids as additives, but, in all cases, the achieved enantioselectivities
were just moderate and yields were very low (Table 1, entries 10–12).
Considering the couple 11/DMAP as the most efficient catalytic combination, we explore the
influence of the ratio between both components. Thus, lowering the organocatalyst loading down to
10 mol % and keeping the additive loading to 20 mol % gave rise to (S)-14aa in only 17% yield but
in 94% ee (Table 1, entry 13), whereas keeping the catalyst loading in 20 mol % and diminishing the
amount of DMAP to 10 mol % maintained the ee unaltered, increasing the final yield (Table 1, entry 14).
However, loadings of 20 mol % of 11 and 30 mol % of DMAP allowed to obtain (S)-14aa in 72% yield
and 95% ee (Table 1, entry 15).
Expecting to achieve an opposite enantioselection, we also performed the reaction using as
organocatalyst ent-11, which was prepared similarly to its enantiomeric counterpart, but using
(1R,2R)-cyclohexane-1,2-diamine as chirality source (Figure 3). Using this primary amine as

Molecules 2018, 23, 141
4 of 13
organocatalyst (20 mol %) under the most effective reaction conditions (DMAP (30 mol %), CH2Cl2,
rt), adduct (R)-14aa was isolated in the same 95% enantioselectivity than its opposite (S)-enantiomer
(Table 1, entry 16).
We were intrigued to determine if the presence of the phenolic OH on the organocatalyst
was a determinant for the high enantioselectivity obtained. Thus, we prepared the primary
amine-containing benzamide 15 by reaction of (1S,2S)-cyclohexane-1,2-diamine with phenyl benzoate
under similar conditions as 11 (Figure 3). However, under the above optimal reaction conditions,
this organocatalyst 15 gave rise to adduct (S)-14aa in only a 79% ee (Table 1, entry 17). Therefore,
the presence of the phenolic OH in organocatalyst 10 results as being important for achieving a good
enantioinduction. It is interesting to note that the use of the monocarbamate 10 as an organocatalyst
was not particularly successful, giving rise to the corresponding adduct in low yield and only 65%
ee (Table 1, entry 18), whereas it has been able to reach up to 96% ee when employed in a related
enantioselective Michael addition of aromatic ketones to nitroalkenes [27].
Figure 3. Organocatalysts employed in this study.
Next, we extended the addition reaction of isobutyraldehyde to other trans-
under the most favorable reaction conditions (11 (20 mol %), DMAP (30 mol %), CH2Cl2, rt), the results
being summarized in Table 2. The absolute configuration of the known -nitroaldehydes 14 was
β-nitroalkenes 13
γ
assigned in accordance with the elution order of the enantiomers in chiral HPLC when compared to
the literature (see Experimental Section).
Thus, when nitroalkenes 13b and 13c, bearing electron-releasing groups such as methyl or
methoxy in the aromatic ring, were used, the corresponding Michael adducts (S)-14ab and (S)-14ac
were both isolated in enantioselectivities of 92% (Table 2, entries 2 and 3). In addition, the presence of
a dioxolane system on the aromatic ring, as in the nitroolefin 13d, lowered the enantioselection down
to 85% (Table 2, entry 4), whereas this was raised up to 94% when 13e containing three methoxy groups
was used as electrophile (Table 2, entry 5). When halogen groups were present onto the aromatic
ring of the nitroalkene, the achieved enantioselectivities were rather uneven. Thus, a fluoro group
(13f) gave rise to (S)-14af in 92% ee, whereas chloro groups at 2- (13g) and 4-positions (13h) afforded
adducts (R)-14ag and (S)-14ah in similar 87 and 88% ee, respectively (Table 2, entries 6–8), and a bromo
group (13i) gave (S)-14ai in 94% ee (Table 2, entry 9). Moreover, an electron-withdrawing group such
as the trifluoromethyl (13j) gave also a good enantioselectivity for (S)-14aj (93%) (Table 2, entry 10).
When nitroalkene 13k bearing a 2-naphthyl group was employed as Michael acceptor,
the corresponding adduct (S)-14ak was obtained in 91% ee (Table 2, entry 11). In addition, the influence
of the presence of heteroarylated rings in the nitroalkene was also explored with the use as Michael
acceptors of the 3-pyridinyl- and 2-furanyl-containing nitroalkenes 13l and 13m, which gave rise to
adducts (S)-14al and (S)-14am in 91 and 92% ee, respectively (Table 2, entries 12 and 13).

Molecules 2018, 23, 141
5 of 13
Table 2. Enantioselective conjugate addition of aldehydes to nitroalkenes organocatalyzed by 11.
Entry
Aldehyde
β-Nitroalkene
t (d)
γ-Nitroaldehyde
R1,R2
No.
R3
No.
No.
Yield (%) a
eeb (%) b
1
2
3
4
5
Me,Me
Me,Me
Me,Me
Me,Me
Me,Me
12a
12a
12a
12a
12a
Ph
4-MeC6H4
4-MeOC6H4
3,4-(OCH2O)C6H3
3,4,5-(MeO)3C6H2
13a
13b
13c
13d
13e
2
2
2
2
2
(S)-14aa
(S)-14ab
(S)-14ac
(S)-14ad
(S)-14ae
72
67
91
64
85
95
92
92
85
94
6
7
8
Me,Me
Me,Me
Me,Me
Me,Me
Me,Me
Me,Me
Me,Me
Me,Me
-(CH2)4-
12a
12a
12a
12a
12a
12a
12a
12a
12b
4-FC6H4
2-ClC6H4
4-ClC6H4
4-BrC6H4
4-F3CC6H4
2-Naphthyl
3-Pyridinyl
2-Furanyl
Ph
13f
13g
13h
13i
13j
13k
13l
2
2
2
2
2
2
2
2
3
(S)-14af
(R)-14ag c
(S)-14ah
(S)-14ai
(S)-14aj
(S)-14ak
(S)-14al
(S)-14am
(S)-14ba
62
50
70
50
51
68
43
82
60
92
87
88
94
93
91
91
92
94
9
10
11
12
13
14
13m
13a
a
b
Isolated yield after flash chromatography.
Enantioselectivities determined by chiral HPLC. Absolute
configuration assigned by the order of elution of the enantiomers in chiral HPLC (See Experimental Section).
c
Apparent change in the sense of the enantioselectivity because of the application of the Cahn-Ingold-Prelog rules.
We also explored the conjugate addition reaction of other
α,α-disubstituted aldehydes with
nitroalkene 13a Thus, when cyclopentanecarbaldehyde (12b) was used, the corresponding
.
Michael adduct (S)-14ba was isolated in an excellent 94% ee (Table 2, entry 14). However, when
diphenylacetaldehyde or 2-phenylpropionaldehyde were used as pro-nucleophiles, almost negligible
amounts (5%) of the corresponding adducts were detected as racemates.
To get further insight into the origin of the enantioselectivity, we carried out theoretical calculations
on the reaction between isobutyraldehyde 12a and nitroalkene 13a in the presence of catalyst 11
A salient feature of this catalyst is the presence of a phenolic OH in the ortho position, which seems to
play a key role to enhance the activity and/or selectivity of the process. To understand this intriguing
behavior, the results obtained with 11 were compared with those of the less active catalyst 15, and also
with the model system 16 (Figure 4), which bears the OH group para to the carbonyl substituent.
This species was not checked experimentally but would give us a better understanding of the relevance
of the ortho substitution for the reactivity.
.
Figure 4. Model catalysts employed in the computational study.
As expected, the initial formation of an enamine between the catalyst free amine and the aldehyde
is followed by attack to the nitrostyrene according to Seebach’s synclinal model (endo attack) [30,31],
which was confirmed by the much higher energy of other possible approaches, like exo depicted in
Figure 5. The synclinal model secures a diastereoselective approach of the reacting faces of enamine
and alkene, meaning that the lower face (in our view) of the enamine reacts with the Re face of alkene
and the opposite, the upper face of enamine with the Si face of alkene. As a direct consequence,
the approach of the alkene from each side of the enamine produces a single diastereoisomer.

Molecules 2018, 23, 141
6 of 13
Figure 5. Seebach’s synclinal model for the approach of enamine and nitroalkene faces.
The different conformations of the both cyclohexyl-amine substituents in the catalysts were taken
into consideration. The amine side arms of cyclohexane possess several free rotating bonds, and,
among all the possibilities checked, we selected the most stable ones, outlined in Figure 6. In them,
the enamine and amide groups occupy the equatorial positions of the cyclohexane, pointing up and
down, respectively. The fragment NH-C-C-NH is in staggered conformation. We then located the
transition states for 11, corresponding to the different approaches, taking into account all possible
H-bonding activation networks of the NH and OH groups (Figure 6). As expected, the amide NH
group in 11 is H-binding the nitro group of the electrophile, activating it for the nucleophilic attack,
and inducing a good differentiation of both faces of the enamine. The lower face approach in TS1 is
much lower in energy (9.8 kcal/mol) than TS2 (15.8 kcal/mol), justifying the experimental selectivity.
The origin of the selectivity is clearly linked to the high strain developing in TS2 to accommodate
the H-bond between the nitro and amide groups. We could demonstrate that OH is not actively
participating in the activation of the nitro group, since the barrier in TS3 is clearly higher (18.4 kcal/mol)
than in TS1, even if the amide-NH in TS3 is slightly contributing to increase the acidity of the OH
through Brønsted assistance (δO–H = 1.98 Å). Interestingly, this H-bonding network alternative is more
flexible, and the energy difference between TS3 and TS4 is fairly reduced to only 2.0 kcal/mol.
Figure 6. Computed Free energies and structures of the diastereoselective transition states for the C-C
bond formation in the presence of catalyst 11.
Initially, the tentative role of OH in promoting the reaction was assigned to its suitability to
enhance the H-bond donor ability of the amide group through an extra activation by Brønsted
acid-assistance (δO–H = 1.62 Å in TS1). However, to our surprise, the calculations predicted a similar
reactivity and selectivity for species 15 and 16 (Figure 4), where the OH group is lacking or cannot
interact with the amide because it is positioned at the para position. In fact, the activation energies

Molecules 2018, 23, 141
7 of 13
of transition states TS5 and TS7 are undistinguishable from TS1 (Figure 7), and a similar situation is
found comparing TS2 TS6 and TS8. Thus, the presence or absence of the ortho OH group in 11 is not
,
predicted computationally to have a significant effect on both reactivity and selectivity.
In this regard, there is an increasing number of studies indicating that C-C bond formation
between enamine and nitroalkene is facile and might not be the rate-determining step in catalyzed
processes [32–34]. Instead, the highest energy along the reaction coordinate would correspond to the
protonation of the highly stable cyclic intermediates that arise after the C-C bond formation. Thus,
the rate- and stereodetermining steps might not be identical. We checked this alternative in our
case, and could locate two cyclic intermediates, 17 and 18 (Figure 8), showing energies of
−
8.6 and
−
6.1 kcal/mol with respect to the starting materials. Furthermore, the lowest transition state for their
protonation (TS9) would be the rate limiting step of our cycle, presenting a Free energy barrier of
28.0 kcal/mol (from 17).
Figure 7. Computed Free energies and structures of the diastereoselective transition states for the C-C
bond formation in the presence of the catalysts 15 and 16.
Figure 8. Computed Free energies and structures for the formation of the cyclic intermediates and their
protonation to the final products.
A similar protonation cannot obviously be envisioned for catalytic species lacking ortho-phenol,
like 15 and 16, and, in those cases, adventitious water must be responsible for the cleavage and

Molecules 2018, 23, 141
8 of 13
protonation of the proposed intermediates, although at a higher energetic cost. As a confirmation,
we were able to locate some transition states involving a molecule of water, which are in every case
at least 1.5–2.0 kcal/mol higher in energy than TS9. Thus, we can confirm that also in our case the
stereoselectivity is controlled during the C-C bond formation event, but the reaction rate is governed
by the protonation and cleavage of the stable cyclic intermediates. It is at this point where the phenol
moiety plays a crucial role, nicely explaining the experimental results.
3. Experimental Section
3.1. General Information
All the reagents and solvents employed were of the best grade available and were used without
further purification. The 1H- and 13C-NMR spectra were recorded at room temperature on a Bruker
(Bruker, Billerica, MA, USA) AC-400 at 400 MHz and 101 MHz, respectively, using TMS as internal
standard. IR spectra were measured on a Nicolet Impact 400D-FT instrument (Thermo Fisher Scientific,
Waltham, MA, USA). Electron Ionized Mass Spectrometry (EIMS) spectra were obtained on an Agilent
Technologies GC/MS-5973N equipment (Agilent Technologies, Santa Clara, CA, USA) at 70 eV. HR-MS
spectra were obtained on an Agilent Technologies 7200 Accurate-Mass Q-TOF GC/MS equipment
at using EI at 70 eV. Compounds 11 and ent-11 were obtained as described [29]. Nitroalkenes 13
were purchased or prepared following a reported procedure [35], except 13l, which was obtained
differently [36]. Absolute configuration for adducts 14 was determined according to the order of elution
of their enantiomers in chiral HPLC. The absolute configuration of the not described compounds
14ad and 14ae was assigned by analogy. Reference racemic samples of adducts 14 were obtained by
performing the conjugate addition reaction using 4-methylbenzylamine (20 mol %) as organocatalyst
in toluene as a solvent at room temperature.
3.2. General Procedure for the Asymmetric Conjugate Addition Reaction
To a solution of 10, 11, ent-11 or 15 (0.04 mmol), the nitroalkene 13 (0.2 mmol) and DMAP (7.3 mg,
0.06 mmol) in CH2Cl2 (0.3 mL) was added the aldehyde 12 (0.4 mmol) and the mixture was stirred
at rt until completion (TLC). The reaction was quenched with HCl 2N (10 mL) and the mixture was
extracted with AcOEt (3
×
10 mL). The organic phase was washed with sat. NaHCO3 (2
×
10 mL),
dried over MgSO4, and the solvent was evaporated (15 Torr) to get the crude product, which was
purified by silica gel chromatography (n-hexane/AcOEt gradients). Known adducts 14 were identified
by comparison of their NMR data with those of the literature (Supplementary Materials NMR spectra).
Their enantiomeric excesses were determined by chiral HPLC using the conditions described in each
case (Supplementary Materials HPLC chromatograms). Not described compounds 14ad and 14ae
have been fully characterized.
1
2,2-Dimethyl-4-nitro-3-phenylbutanal (14aa) [24]. Colorless oil; H-NMR (CDCl3): δH = 9.52 (s, 1H),
7.35–7.28 (m, 3H), 7.22–7.17 (m, 2H), 4.85 (dd, J = 13.1, 11.3 Hz, 1H), 4.69 (dd, J = 13.1, 4.2 Hz, 1H),
3.79 (dd, J = 11.3, 4.2 Hz, 1H), 1.12 (s, 3H), 0.99 (s, 3H) ppm; 13C-NMR (CDCl3): δC = 204.2, 135.3, 129.0,
128.6, 128.0, 76.2, 48.3, 48.1, 21.5, 18.7 ppm; HPLC: Chiralpak OD-H,
λ = 210 nm, n-hexane/2-propanol,
80:20, 1.0 mL/min, tr (R) = 13.4 min, tr (S) = 19.2 min.
2,2-Dimethyl-4-nitro-3-(p-tolyl)butanal (14ab) [24]. Colorless oil; 1H-NMR (CDCl3): δH = 9.52 (s, 1H),
7.13 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.2 Hz, 2H), 4.83 (dd, J = 12.9, 11.4 Hz, 1H), 4.67 (dd, J = 12.9, 4.2 Hz,
1H), 3.74 (dd, J = 11.4, 4.2 Hz, 1H), 2.32 (s, 3H), 1.12 (s, 3H), 1.00 (s, 3H) ppm; 13C-NMR (CDCl3):
δC = 204.4, 137.8, 132.1, 129.3, 128.9, 76.3, 48.2, 48.1, 21.5, 21.0, 18.8 ppm; HPLC: Chiralpak OD-H,
λ = 210 nm, n-hexane/2-propanol, 80:20, 1.0 mL/min, tr (R) = 9.7 min, tr (S) = 13.2 min.
3-(4-Methoxyphenyl)-2,2-dimethyl-4-nitrobutanal (14ac) [24]. Colorless oil; 1H-NMR (CDCl3): δH = 9.51
(s, 1H), 7.12 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 4.81 (dd, J = 12.8, 11.4 Hz, 1H), 4.66 (dd, J = 12.8
,
4.2 Hz, 1H), 3.78 (s, 3H), 3.73 (dd, J = 11.4, 4.2 Hz, 1H), 1.11 (s, 3H), 0.99 (s, 3H) ppm; 13C-NMR (CDCl3):

Molecules 2018, 23, 141
9 of 13
δC = 204.4, 159.2, 130.0, 127.0, 114.0, 76.4, 55.1, 48.3, 47.7, 21.4, 18.7 ppm; HPLC: Chiralpak OD-H,
λ = 210 nm, n-hexane/2-propanol, 80:20, 1.0 mL/min, tr (R) = 12.0 min, tr (S) = 16.1 min.
3-(Benzo[d][
1
,
3
]dioxol-5-yl)-2,2-dimethyl-4-nitrobutanal (14ad). Colorless oil; IR (ATR):
ν
= 2972, 2904,
2817, 1722, 1552, 1491, 1444, 1376, 1241, 1038, 931, 816 cm−1; H-NMR (CDCl3): δH = 9.51 (s, 1H),
6.75 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 1.8 Hz, 1H), 6.65 (dd, J = 8.0, 1.8 Hz, 1H), 5.96 (s, 2H),
4.78 (dd, J = 13.0, 11.4 Hz, 1H), 4.65 (dd, J = 13.0, 4.2 Hz, 1H), 3.70 (dd, J = 11.4, 4.2 Hz, 1H), 1.13 (s, 3H),
1.02 (s, 3H) ppm; 13C-NMR (CDCl3): δC = 204.2, 147.9, 147.4, 128.8, 122.6, 109.1, 108.3, 101.2, 76.5, 48.3,
21.6, 19.0 ppm; MS (EI, 70 eV): m/z (%) = 265 (M+, 10), 148 (100); HR-MS (EI): m/z calcd. for C13H15NO5
1
[M]+: 265.0952, found: 265.0947; HPLC: Chiralpak OD-H,
λ = 210 nm, n-hexane/2-propanol, 80:20,
1.0 mL/min, tr (R) = 17.2 min, tr (S) = 23.0 min.
2,2-Dimethyl-4-nitro-3-(3,4,5-trimethoxyphenyl)butanal (14ae). Colorless oil; IR (ATR):
ν = 2972, 2939,
2835, 1722, 1589, 1552, 1460, 1242, 1124, 1005, 729 cm−1; 1H-NMR (CDCl3): δH = 9.52 (s, 1H), 6.38 (s, 2H)
,
4.85 (dd, J = 13.1, 11.3 Hz, 1H), 4.69 (dd, J = 13.1, 4.2 Hz, 1H), 3.85 (s, 6H), 3.83 (s, 3H), 3.70 (dd, J = 11.3,
4.2 Hz, 1H), 1.16 (s, 3H), 1.06 (s, 3H) ppm; 13C-NMR (CDCl3): δC = 204.3, 153.1, 137.7, 131.0, 106.2, 76.3,
60.7, 56.1, 48.9, 48.2, 21.7, 19.3 ppm; MS (EI, 70 eV): m/z (%) = 311 (M+, 16), 194 (100), 179 (35); HR-MS
(EI): m/z calcd. for C15H21NO6 [M]+: 311.1369, found: 311.1367; HPLC: Chiralpak OD-H,
n-hexane/2-propanol, 80:20, 1.0 mL/min, tr (R) = 18.2 min, tr (S) = 20.7 min.
λ = 210 nm,
3-(4-Fluorophenyl)-2,2-dimethyl-4-nitrobutanal (14af) [24]. Colorless oil; 1H-NMR (CDCl3): δH = 9.51 (s, 1H),
7.21–7.17 (m, 2H), 7.05–7.01 (m, 2H), 4.82 (dd, J = 13.1, 11.4 Hz, 1H), 4.69 (dd, J = 13.1, 4.2 Hz,
1H), 3.78 (dd, J = 11.4, 4.2 Hz, 1H), 1.12 (s, 3H), 1.01 (s, 3H) ppm; 13C-NMR (CDCl3): δC = 204.0,
162.4 (d, J = 247.4 Hz), 131.2 (d, J = 3.1 Hz), 130.6 (d, J = 8.2 Hz), 115.7 (d, J = 21.5 Hz), 76.3, 48.2, 47.7, 21.6,
18.8 ppm; HPLC: Chiralpak OD-H, λ = 210 nm, n-hexane/2-propanol, 80:20, 1.0 mL/min, tr (R) = 11.1 min,
tr (S) = 17.8 min.
3-(2-Chlorophenyl)-2,2-dimethyl-4-nitrobutanal (14ag) [37]. Colorless oil; 1H-NMR (CDCl3): δH = 9.55 (s, 1H)
,
7.44–7.40 (m, 1H), 7.31–7.21 (m, 3H), 4.89–4.80 (m, 1H), 4.73 (dd, J = 13.3, 4.1 Hz, 1H), 4.63 (dd, J = 11.3,
3.5 Hz, 1H), 1.17 (s, 3H), 1.08 (s, 3H) ppm; 13C-NMR (CDCl3): δC = 203.8, 135.8, 133.7, 130.4, 129.1, 128.2,
127.1, 76.2, 49.0, 42.4, 20.9, 18.6 ppm; HPLC: Chiralpak OD-H, λ = 210 nm, n-hexane/2-propanol, 80:20,
1.0 mL/min, tr (S) = 11.1 min, tr (R) = 27.9 min.
3-(4-Chlorophenyl)-2,2-dimethyl-4-nitrobutanal (14ah) [24]. Colorless oil; 1H-NMR (CDCl3): δH = 9.50
(s, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 4.83 (dd, J = 13.1, 11.4 Hz, 1H), 4.69 (dd, J = 13.1
,
4.2 Hz, 1H), 3.77 (dd, J = 11.4, 4.2 Hz, 1H), 1.12 (s, 3H), 1.01 (s, 3H) ppm; 13C-NMR (CDCl3):
δC = 203.8, 134.1, 133.9, 130.4, 128.9, 76.1, 48.1, 47.8, 21.7, 18.8 ppm; HPLC: Chiralpak OD-H, λ = 210 nm
n-hexane/2-propanol, 80:20, 1.0 mL/min, tr (R) = 11.9 min, tr (S) = 17.6 min.
,
1
3-(4-Bromophenyl)-2,2-dimethyl-4-nitrobutanal (14ai) [24]. Colorless oil; H-NMR (CDCl3): δH = 9.50
(s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 4.82 (dd, J = 13.2, 11.4 Hz, 1H), 4.69 (dd, J = 13.2
,
4.1 Hz, 1H), 3.76 (dd, J = 11.4, 4.1 Hz, 1H), 1.12 (s, 3H), 1.01 (s, 3H) ppm; 13C-NMR (CDCl3):
δC = 203.8, 134.5, 131.9, 130.7, 122.2, 76.0, 48.1, 47.9, 21.7, 18.9 ppm; HPLC: Chiralpak OD-H, λ = 210 nm
n-hexane/2-propanol, 80:20, 1.0 mL/min, tr (R) = 14.0 min, tr (S) = 19.6 min.
,
1
2,2-Dimethyl-4-nitro-3-(4-(trifluoromethyl)phenyl)butanal (14aj) [38]. Colorless oil; H-NMR (CDCl3):
δH = 9.50 (s, 1H), 7.61 (d, J = 8.2 Hz, 3H), 7.36 (d, J = 8.2 Hz, 2H), 4.89 (dd, J = 13.3, 11.4 Hz, 1H),
4.74 (dd, J = 13.3, 4.1 Hz, 1H), 3.88 (dd, J = 11.4, 4.1 Hz, 1H), 1.14 (s, 3H), 1.02 (s, 3H) ppm; 13C-NMR
(CDCl3): δC = 203.5, 139.8, 130.4 (q, J = 32.7 Hz), 125.7 (q, J = 3.6 Hz), 123.8 (q, J = 272.2 Hz), 75.9,
48.1, 21.8, 18.9 ppm; HPLC: Chiralpak OD-H,
λ = 210 nm, n-hexane/2-propanol, 80:20, 1.0 mL/min,
tr (R) = 11.7 min, tr (S) = 18.5 min.
2,2-Dimethyl-3-(naphthalen-2-yl)-4-nitrobutanal (14ak) [24]. Colorless oil; 1H-NMR (CDCl3): δH = 9.57
(s, 1H), 7.84–7.82 (m, 3H), 7.68 (d, J = 1.3 Hz, 1H), 7.54–7.46 (m, 2H), 7.34 (dd, J = 8.5, 1.9 Hz, 1H),
5.00 (dd, J = 13.1, 11.3 Hz, 1H), 4.79 (dd, J = 13.1, 4.1 Hz, 1H), 3.97 (dd, J = 11.3, 4.1 Hz, 1H), 1.19 (s, 3H)
,

Molecules 2018, 23, 141
10 of 13
1.05 (s, 3H) ppm; 13C-NMR (CDCl3): δC = 204.2, 133.0, 132.9, 132.8, 128.4, 128.3, 127.8, 127.6, 126.5,
126.5, 126.3, 76.3, 48.6, 48.4, 21.7, 19.0 ppm; HPLC: Chiralpak OD-H,
λ = 210 nm, n-hexane/2-propanol,
70:30, 1.0 mL/min, tr (R) = 16.4 min, tr (S) = 29.6 min.
2,2-Dimethyl-4-nitro-3-(pyridin-3-yl)butanal (14al) [24]. Colorless oil; 1H-NMR (CDCl3): δH = 9.50 (s, 1H),
8.56 (d, J = 3.9 Hz, 1H), 8.51 (s, 1H), 7.63–7.57 (m, 1H), 7.30 (dd, J = 8.3, 5.2 Hz, 1H), 4.89 (dd, J = 13.3,
11.4 Hz, 1H), 4.75 (dd, J = 13.3, 4.1 Hz, 1H), 3.83 (dd, J = 11.4, 4.1 Hz, 1H), 1.15 (s, 3H), 1.04 (s, 3H)
ppm; 13C-NMR (CDCl3): δC = 203.3, 150.4, 149.4, 136.2, 131.5, 123.5, 75.7, 48.2, 46.0, 21.8, 18.8 ppm;
HPLC: Chiralpak AD-H,
λ = 210 nm, n-hexane/2-propanol, 80:20, 1.0 mL/min, tr (S) = 12.6 min,
tr (R) = 14.6 min.
3-(Furan-2-yl)-2,2-dimethyl-4-nitrobutanal (14am) [39]. Colorless oil; 1H-NMR (CDCl3): δH = 9.52 (s, 1H),
7.37 (dd, J = 1.8, 0.6 Hz, 1H), 6.32 (dd, J = 3.3, 1.8 Hz, 1H), 6.22 (dd, J = 3.3, 0.6 Hz, 1H), 4.76 (dd, J = 12.9
,
11.1 Hz, 1H), 4.59 (dd, J = 12.9, 3.9 Hz, 1H), 3.93 (dd, J = 11.1, 3.9 Hz, 1H), 1.18 (s, 3H), 1.05 (s, 3H) ppm;
13C-NMR (CDCl3): δC = 203.4, 149.7, 142.7, 110.4, 109.6, 74.8, 48.1, 42.2, 21.1, 19.0 ppm; HPLC: Chiralpak
OD-H, λ = 210 nm, n-hexane/2-propanol, 80:20, 1.0 mL/min, tr (R) = 9.0 min, tr (S) = 13.2 min.
1-(2-Nitro-1-phenylethyl)cyclopentanecarbaldehyde (14ba) [40]. Colorless oil; 1H-NMR (CDCl3): δH = 9.49
(s, 1H), 7.34–7.19 (m, 5H), 4.96 (dd, J = 13.1, 11.4 Hz, 1H), 4.68 (dd, J = 13.1, 3.8 Hz, 1H), 3.70 (dd, J = 11.4
,
,
3.8 Hz, 1H), 2.07–2.03 (m, 1H), 1.90–1.86 (m, 1H), 1.68–1.50 (m, 6H) ppm; 13C-NMR (CDCl3): δC = 204.4
136.4, 128.80, 128.78, 128.07, 77.3, 60.2, 49.3, 32.6, 31.5, 24.8, 24.6 ppm; HPLC: Chiralpak OD-H,
λ = 210 nm, n-hexane/2-propanol, 80:20, 1.0 mL/min, tr (S): 11.0 min, tr (R): 14.4 min.
3.3. Computational Methods
All reported structures were optimized at Density Functional Theory level by using the B3LYP [41–43]
functional as implemented in Gaussian 09 [44]. Optimizations were carried out with the 6-31G (d,p) basis
set. The stationary points were characterized by frequency calculations in order to verify that they have
the right number of imaginary frequencies. The reported energy values correspond to Gibbs Free energies,
including single point refinements at M06-2X/6-311 + G (d,p) [45] level of theory in a solvent model
(IEFPCM, dichloromethane) [46–48] on the previously optimized structures (Supplementary Materials
computed structures).
4. Conclusions
We conclude that readily available primary amine-salicylamides, prepared by a simple
monoamidation of enantiomerically pure trans-cyclohexane-1,2-diamines, act as efficient organocatalysts
in the enantioselective conjugate addition of aldehydes to nitroalkenes, leading to enantiomerically
enriched γ-nitroaldehydes. Good yields and high enantioselectivities can be achieved working in the
presence of DMAP as a rate-accelerating additive. Theoretical calculations suggest that the stereoselectivity
is defined during the C-C bond forming event, through a H-bond activation of the nitroalkene with
the NH of the amide. The approach of the alkene happens preferentially through the lower face of the
enamine, where the amide group is located. Meanwhile, the rate-determining step occurs at a later stage,
corresponding to the protonation of downstream stable cyclic intermediates. The ortho phenolic moiety
of the catalyst is able to act as an internal proton source, and its presence increases the protonation rate,
accelerating the reaction.
Supplementary Materials: The following are available online, NMR spectra, HPLC chromatograms and cartesian
coordinates of the computed structures.
Acknowledgments:
We thank the financial support from the Spanish Ministerio de Economía,
Industria y Competitividad (CTQ2015-66624-P) and the University of Alicante (VIGROB-173, UAUSTI17-06). J.F.-F.
thanks the Vicerrectorado de Investigación y Transferencia del Conocimiento de la Universidad de Alicante for
a fellowship. We also thank the Basque Government (GIC15/03, IT1033-16) for financial support, and the General
Research Services (IZO/SGI SGIker) of the University of the Basque Country for human and technical support.

Molecules 2018, 23, 141
11 of 13
Author Contributions: J.R.M.-G. and J.F.-F. performed the experiments; C.G. analyzed the results; R.C. conceived,
designed the experiments and wrote the paper; and E.G.-B. carried out the theoretical calculations and wrote
the paper.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Aboul-Enein, M.N.; El-Azzouny, A.A.; Saleh, O.A.; Maklad, Y.A. On chemical structures with potent
antiepileptic/anticonvulsant profile. Mini Rev. Med. Chem. 2012, 12, 671–700. [CrossRef] [PubMed]
Andresen, H.; Aydin, B.E.; Mueller, A.; Iwersen-Bergmann, S. An overview of gamma-hydroxybutyric acid:
Pharmacodynamics, pharmacokinetics, toxic effects, addiction, analytical methods, and interpretation of
results. Drug Test. Anal. 2011, 3, 560–568. [CrossRef] [PubMed]
2.
3.
Gajcy, K.; Lochynski, S.; Librowski, T. A role of GABA analogues in the treatment of neurological diseases.
Curr. Med. Chem. 2010, 17, 2338–2347. [CrossRef] [PubMed]
4.
5.
Ono, N. The Nitro Group in Organic Synthesis; John Wiley Sons, Inc.: New York, NY, USA, 2001.
Goksu, H.; Sert, H.; Kilbas, B.; Sen, F. Recent advances in the reduction of nitro compounds by heterogenous
catalysts. Curr. Org. Chem. 2017, 21, 794–820. [CrossRef]
6.
Calderari, G.; Seebach, D. Asymmetric Michael additions. Stereoselective alkylation of chiral, non-racemic
enolates by nitro olefins. Preparation of enantiomerically pure γ-aminobutyric and succinic acid derivatives.
Helv. Chim. Acta 1985, 68, 1592–1604. [CrossRef]
7.
8.
Berner, O.M.; Tedeschi, L.; Enders, D. Asymmetric Michael additions to nitroalkenes. Eur. J. Org. Chem. 2002,
1877–1894. [CrossRef]
Sulzer-Mosse, S.; Alexakis, A. Chiral amines as organocatalysts for asymmetric conjugate addition to
nitroolefins and vinyl sulfones via enamine activation. Chem. Commun. 2007, 14, 3123–3135. [CrossRef]
[PubMed]
9.
Roca-López, D.; Sadaba, D.; Delso, I.; Herrera, R.P.; Tejero, T.; Merino, P. Asymmetric organocatalytic
synthesis of
γ-nitrocarbonyl compounds through Michael and Domino reactions. Tetrahedron Asymmetry
2010, 21, 2561–2601. [CrossRef]
10. Somanathan, R.; Chávez, D.; Servin, F.A.; Romero, J.A.; Navarrete, A.; Parra-Hake, M.; Aguirre, G.;
Anaya, d.P.C.; González, J. Bifunctional organocatalysts in the asymmetric Michael additions of carbonylic
compounds to nitroalkenes. Curr. Org. Chem. 2012, 16, 2440–2461. [CrossRef]
11. Aitken, L.S.; Arezki, N.R.; Dell’Isola, A.; Cobb, A.J.A. Asymmetric organocatalysis and the nitro group
functionality. Synthesis 2013, 45, 2627–2648.
12. Alonso, D.A.; Baeza, A.; Chinchilla, R.; Gómez, C.; Guillena, G.; Pastor, I.M.; Ramón, D.J. Recent advances
in asymmetric organocatalyzed conjugate additions to nitroalkenes. Molecules 2017, 22, 895. [CrossRef]
[PubMed]
13. Bennani, Y.L.; Hanessian, S. trans-1,2-Diaminocyclohexane derivatives as chiral reagents, scaffolds,
and ligands for catalysis: Applications in asymmetric synthesis and molecular recognition. Chem. Rev. 1997
97, 3161–3195. [CrossRef] [PubMed]
,
14. Kouklovsky, C.; Langlois, Y.; Aguilar, E.; Fernández-García, J.M.; Sikervar, V. (1S,2S)-1,2-Diaminocyclohexane.
In Encyclopedia of Reagents for Organic Synthesis; John Wiley Sons, Ltd.: New York, NY, USA, 2014.
15. Zhang, X.-J.; Liu, S.-P.; Lao, J.-H.; Du, G.-J.; Yan, M.; Chan, A.S.C. Asymmetric conjugate addition of carbonyl
compounds to nitroalkenes catalyzed by chiral bifunctional thioureas. Tetrahedron Asymmetry 2009, 20,
1451–1458. [CrossRef]
16. Uehara, H.; Barbas, C.F., III. anti-Selective asymmetric Michael reactions of aldehydes and nitroolefins
catalyzed by a primary amine/thiourea. Angew. Chem. Int. Ed. 2009, 48, 9848–9852. [CrossRef] [PubMed]
17. Lalonde, M.P.; Chen, Y.; Jacobsen, E.N. A chiral primary amine thiourea catalyst for the highly enantioselective
direct conjugate addition of
α,α-disubstituted aldehydes to nitroalkenes. Angew. Chem. Int. Ed. 2006, 45,
6366–6370. [CrossRef] [PubMed]
18. Chen, J.-R.; Zou, Y.-Q.; Fu, L.; Ren, F.; Tan, F.; Xiao, W.-J. Highly enantioselective Michael addition of
aldehydes to nitroolefins catalyzed by primary amine thiourea catalysts. Tetrahedron 2010, 66, 5367–5372.
[CrossRef]

Molecules 2018, 23, 141
12 of 13
19. Ma, Z.-W.; Liu, Y.-X.; Zhang, W.-J.; Tao, Y.; Zhu, Y.; Tao, J.-C.; Tang, M.-S. Highly enantioselective
Michael additions of isobutyraldehyde to nitroalkenes promoted by amphiphilic bifunctional primary
amine-thioureas in organic or aqueous medium. Eur. J. Org. Chem. 2011, 2011, 6747–6754. [CrossRef]
20. Guo, X.-T.; Sha, F.; Wu, X.-Y. Highly enantioselective Michael addition of α,α-disubstituted aldehydes to
nitroolefins. Res. Chem. Intermed. 2016, 42, 6373–6380. [CrossRef]
21. Durmaz, M.; Sirit, A. Calixarene-based highly efficient primary amine-thiourea organocatalysts for
asymmetric Michael addition of aldehydes to nitrostyrenes. Supramol. Chem. 2013, 25, 292–301. [CrossRef]
22. Ma, Z.-W.; Liu, X.-F.; Sun, B.; Huang, X.-H.; Tao, J.-C. Chiral primary amine-squaramide catalyzed highly
enantioselective Michael addition of isobutyraldehyde to nitroolefins. Synthesis 2017, 49, 1307–1314.
[CrossRef]
23. Fernandes, T.d.A.; Vizcaíno-Milla, P.; Ravasco, J.M.J.M.; Ortega-Martinez, A.; Sansano, J.M.; Nájera, C.; Costa, P.R.R.;
Fiser, B.; Gómez-Bengoa, E. Bifunctional primary amine 2-aminobenzimidazole organocatalyst anchored to
trans-cyclohexane-1,2-diamine in enantioselective conjugate additions of aldehydes. Tetrahedron Asymmetry 2016
,
27, 118–122. [CrossRef]
24. Avila, A.; Chinchilla, R.; Fiser, B.; Gómez-Bengoa, E.; Nájera, C. Enantioselective Michael addition of
isobutyraldehyde to nitroalkenes organocatalyzed by chiral primary amine-guanidines. Tetrahedron Asymmetry
2014, 25, 462–467. [CrossRef]
25. Flores-Ferrándiz, J.; Chinchilla, R. Solvent-dependent enantioswitching in the Michael addition of
α,α-disubstituted aldehydes to maleimides organocatalyzed by mono-N-Boc-protected cyclohexa-1,2-
diamines. Tetrahedron Asymmetry 2014, 25, 1091–1094. [CrossRef]
26. Flores-Ferrándiz, J.; Fiser, B.; Gómez-Bengoa, E.; Chinchilla, R. Solvent-induced reversal of enantioselectivity
in the synthesis of succinimides by the addition of aldehydes to maleimides catalysed by carbamate-
monoprotected 1,2-diamines. Eur. J. Org. Chem. 2015, 1218–1225. [CrossRef]
27. Flores-Ferrandiz, J.; Stiven, A.; Sotorrios, L.; Gómez-Bengoa, E.; Chinchilla, R. Enantioselective addition of aryl
ketones and acetone to nitroalkenes organocatalyzed by carbamate-monoprotected cyclohexa-1,2-diamines.
Tetrahedron Asymmetry 2015, 26, 970–979. [CrossRef]
28. Flores-Ferrándiz, J.; Chinchilla, R. Organocatalytic enantioselective conjugate addition of aldehydes to
maleimides in deep eutectic solvents. Tetrahedron Asymmetry 2017, 28, 302–306. [CrossRef]
29. Costes, J.-P.; Duhayon, C.; Mallet-Ladeira, S.; Shova, S.; Vendier, L. Does the sign of the Cu-Gd magnetic
interaction depend on the number of atoms in the bridge? Chem. Eur. J. 2016, 22, 2171–2180. [CrossRef]
[PubMed]
30. Seebach, D.; Golinski, J. Synthesis of open chain 2,3-disubstituted 4-nitroketone by diastereoselective Michael
addition of (E)-enamines to (E)-nitroolefins. A topological rule for C,C-bond forming processes between
prochiral centers. Helv. Chim. Acta 1981, 64, 1413–1423. [CrossRef]
31. Seebach, D.; Beck, A.K.; Golinski, J.; Hay, J.N.; Laube, T. Über den sterischen Verlauf von Enaminen aus
offenkettigen Aldehyden und Ketonen mit Nitroolefinen zu 2,3-disubstituierten 4-Nitroketonen. Helv. Chim. Acta
1985, 68, 162–172. [CrossRef]
32. Földes, T.; Madarász, A.; Révész, Á.; Dobi, Z.; Varga, S.; Hamza, A.; Nagy, P.R.; Pihko, P.M.; Pápai, I.
Stereocontrol in diphenylprolinol silyl ether catalyzed Michael additions: Steric shielding or Curtin-Hammett
scenario? J. Am. Chem. Soc. 2017, 139, 17052–17063. [CrossRef] [PubMed]
33. Burés, J.; Armstrong, A.; Blackmond, D. Explaining anomalies in enamine catalysis: “Downstream species”
as a new paradigm for stereocontrol. Acc. Chem. Res. 2016, 49, 214–222. [CrossRef] [PubMed]
34. Sahoo, G.; Rahaman, H.; Madarász, A.; Pápai, I.; Melarto, M.; Valkonen, A.; Pihko, P.M. Dihydrooxazine
oxides as key Intermediates in organocatalytic Michael additions of aldehydes to nitroalkenes. Angew. Chem.
Int. Ed. 2012, 51, 13144–13148. [CrossRef] [PubMed]
35. Rodríguez, J.M.; Pujol, M.D. Straightforward synthesis of nitroolefins by microwave- or ultrasound-assisted
Henry reaction. Tetrahedron Lett. 2011, 52, 2629–2632. [CrossRef]
36. Kuster, G.J.T.; Steeghs, R.H.J.; Scheeren, H.W. Novel five/five- and six/five-membered bicyclic nitroso acetals
from high-pressure-promoted cyclization reactions of p-methoxybenzyl vinyl ether, 1-nitro-2-heteroaryl
ethenes, and mono- and di-substituted olefins. Eur. J. Org. Chem. 2001, 553–560. [CrossRef]
37. Bai, J.-F.; Xu, X.-Y.; Huang, Q.-C.; Peng, L.; Wang, L.-X. Highly asymmetric Michael additions of
α
,
α
-disubstituted aldehydes to
β-nitroalkenes promoted by chiral pyrrolidine-thiourea bifunctional catalysts.
Tetrahedron Lett. 2010, 51, 2803–2805. [CrossRef]

Molecules 2018, 23, 141
13 of 13
38. Porta, R.; Coccia, F.; Annunziata, R.; Puglisi, A. Comparison of different polymer- and silica-supported
9-amino-9-deoxy-epi-quinines as recyclable organocatalysts. ChemCatChem 2015, 7, 1490–1499. [CrossRef]
39. Rasappan, R.; Reiser, O. Cyclohexane-1,2-diamines: Efficient catalysts for the enantioselective conjugate
addition of ketones to nitro olefins. Eur. J. Org. Chem. 2009, 1305–1308. [CrossRef]
40. Ting, Y.-F.; Chang, C.; Reddy, R.J.; Magar, D.R.; Chen, K. Pyrrolidinyl-camphor derivatives as a new class of
organocatalyst for direct asymmetric Michael addition of aldehydes and ketones to β-nitroalkenes. Chem. Eur. J.
2010, 16, 7030–7038. [CrossRef] [PubMed]
41. Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti correlation-energy formula into a functional
of the electron density. Phys. Rev. B 1988, 37, 785–789. [CrossRef]
42. Becke, A.D. Density functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 1993, 98, 5648.
[CrossRef]
43. Kohn, W.; Becke, A.D.; Parr, R.G. Density functional theory of electronic structure. J. Phys. Chem. 1996, 100,
12974–12980. [CrossRef]
44. Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.
Gaussian 09, Revision D.01; Gaussian, Inc.: Wallingford, CT, USA, 2013.
45. Zhao, Y.; Truhlar, D.G. The M06 suite of density functionals for main group thermochemistry, thermochemical
kinetics, noncovalent interactions, excited states, and transition elements: Two new functional and systematic
testing of four M06-class functional and 12 other functional. Theor. Chem. Acc. 2008, 120, 215–241. [CrossRef]
46. Cancès, E.; Mennucci, B.; Tomasi, J. A new integral equation formalism for the polarizable continuum model:
Theoretical background and applications to isotropic and anisotropic dielectrics. J. Chem. Phys. 1997, 107,
3032–3047. [CrossRef]
47. Cossi, M.; Barone, V.; Mennuci, B.; Tomasi, J. Ab initio study of ionic solutions by a polarizable continuum
model. Chem. Phys. Lett. 1998, 286, 253–260. [CrossRef]
48. Tomasi, J.; Mennucci, B.; Cancès, E. The IEF versión of the PCM solvation method: An overview of a new
method addressed to study molecular solutes at the QM ab initio level. J. Mol. Struct. (Theochem) 1999, 464,
211–226. [CrossRef]
Sample Availability: Samples of the compounds 11 and ent-11 are available from the authors.
©
2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).