Aza-Henry reactions on C-Alkyl substituted aldimines

Article abstract of DOI:10.3390/molecules21060723

The reactivity of C-CH₃ substituted N-protected aldimines in aza-Henry addition reactions was compared with that of the analogous trifluoromethylated compounds. C-Alkyl aldimines easily reacted with nitro alkanes under solvent-free conditions and in the absence of catalyst, despite being worse electrophiles than C-CF₃ aldimines, they gave the aza-Henry addition only when ZrCl₄ was added. The presence of a bulky group on the imine carbon deeply influenced the reactivity.

Full text of DOI:10.3390/molecules21060723

molecules
Article
Aza-Henry Reactions on C-Alkyl
Substituted Aldimines
Alessia Pelagalli, Lucio Pellacani, Elia Scandozza and Stefania Fioravanti *
Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, P.le Aldo Moro 5, I-00185 Roma, Italy;
alessia.pelagalli@uniroma1.it (A.P.); lucio.pellacani@uniroma1.it (L.P.); eliasca93@gmail.com (E.S.)
* Correspondence: stefania.fioravanti@uniroma1.it; Tel.: +39-064-991-3098
Academic Editor: Alessandro Palmieri
Received: 3 May 2016; Accepted: 26 May 2016; Published: 2 June 2016
Abstract: The reactivity of C-CH3 substituted N-protected aldimines in aza-Henry addition reactions
was compared with that of the analogous trifluoromethylated compounds. C-Alkyl aldimines easily
reacted with nitro alkanes under solvent-free conditions and in the absence of catalyst, despite being
worse electrophiles than C-CF3 aldimines, they gave the aza-Henry addition only when ZrCl4 was
added. The presence of a bulky group on the imine carbon deeply influenced the reactivity.
Keywords: nitro compounds; amines; carbon–carbon bond formation
1. Introduction
The development of stereoselective reactions to create carbon–carbon bonds between compounds
bearing a heteroatom functionality can provide valuable building blocks for organic synthesis. Starting
from this purpose and considering the importance of the 1,2-diamine structural motif in biologically
active natural products, drugs, and more recently as chiral auxiliaries and chiral ligands in asymmetric
catalysis, general methods to synthesize this class of compounds are most relevant. Among them, the
aza-Henry reaction [
alkanes to aldimines and leads to the synthesis of
two vicinal nitrogenated functionalities with different oxidation states. Also for this, the aza-Henry
reaction presents important synthetic applications [ ], providing access to a wide variety of other
1
–4
], also called nitro-Mannich reaction, involves the nucleophilic addition of nitro
β-nitro amines, valuable compounds containing
5–8
organic compounds by functional transformations of the nitro group into other chemical functionalities,
such as amines, carbonyl groups, hydroxylamines, oximes, and nitriles.
While only recently, C-CF3 substituted aldimines [9–11] are reported in the aza-Henry reactions
as interesting trifluoromethyl nitrogen-containing starting materials; the reactivity of C-aryl analogues
has been well documented in the literature, while very few data are reported on the reactivity of C-alkyl
substituted aldimines [2]. Classically, non-enantioselective nucleophilic addition of nitro alkanes to
C-aryl substituted aldimines usually required the presence of a base as catalyst [12]. On the contrary,
the same reaction on C-trifluoromethyl imines takes place only in the presence of a Lewis acid, namely
ZrCl4, which was found to be the best catalyst for that reaction [9,10].
Stimulated by this difference of reactivity, we thought it might be interesting to deepen the study
of the behavior of C-alkyl substituted aldimines in nitro-Mannich reactions, especially to compare their
reactivity with that of fluorinated analogues. In fact, as is well known [13–20], the presence of fluorine
atoms influences both the reactivity and biological properties of compounds in which they are present.
2. Results and Discussion
Different C-alkyl substituted N-protected aldimines 3a
equimolar direct condensation reactions between primary amines 1a
following the methodology previously reported by us to obtain trifluomethylated substrates in high
–
i
were synthesized by solvent-free
–c
and aldehydes 2a (Table 1)
–c
Molecules 2016, 21, 723; doi:10.3390/molecules21060723
www.mdpi.com/journal/molecules

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yields [21]. The reactions proceeded with high stereoselectivity, leading, in high yields and purity,
only to (E)-aldimines, which can be used in the subsequent aza-Henry additions without further
purification.
Table 1. Solvent-free synthesis of C-alkyl substituted N-protected aldimines.
Entry
1
a
R
2
R1
Product 3
Yield (%)
1
2
3
a
b
b
Me
Cy
t-Bu
a
b
c
85
90
95
Bn
4
5
6
a
b
c
Me
Cy
t-Bu
d
e
f
78
80
83
b
c
Ph
7
8
9
a
b
c
Me
Cy
t-Bu
g
h
i
80
88
95
The nitro-Mannich addition of nitromethane (4) on aldimine 3a, which were selected as suitable
reactants to fix the best reaction conditions, was tested under solvent-free conditions either in the
presence or in the absence of a catalyst (base or acid). The reactions carried out by using different
organic (TEA, DABCO) or inorganic (K2CO3, KF) bases did not give any product of addition, leading
only to a very complex reaction mixture with the disappearance of all reagent signals in the NMR
spectra. On the contrary, performing the reaction with ZrCl4, while the nitromethane was quantitatively
recovered, the 1H-NMR spectrum of the crude mixture showed only the disappearance of the imine
signals, whose hydrolysis is mainly promoted by the presence of Lewis acid. Only working without
added catalyst, the expected product 5a was obtained after 1 h of stirring at room temperature by a
self-catalyzed addition in which aldimine 3a acts as both base and electrophile [22,23] (Scheme 1).
Scheme 1. Best reaction conditions for the aza-Henry addition.
To the best of our knowledge, neither the C-aryl nor the C-trifluoromethyl substituted aldimines
have been reported to react in the absence of catalyst, thus confirming the strong influence of the
imido carbon substituent on the reactivity of aldimines, that may affect the reaction outcome by
influencing the electrophilicity of the sp2 carbon and/or making the nitrogen lone pair more or less
available. To partially confirm this, we decided to test the reactivity of anil 3d. While similar N-aryl
trifluoromethyl aldimines did not give nitro-Mannich addition either without catalyst or in the presence
of ZrCl4 [9], N-phenyl C-methyl aldimine (3d) lead to the expected β-nitro amine 5d, in the absence of
catalyst, although in longer times and lower yields with respect to N-alkyl substituted 3a (Scheme 2).

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Scheme 2. Aza-Henry addition on anil 3d.
The last result seems to confirm the relevant role of the substituent nature on imine carbon. In fact,
the EDG methyl (electron donating group, EDG), counteracting the mesomeric aromatic effect of the
phenyl residue, permitted that the self-catalyzed addition reaction also takes place on an aldimine
derived from a primary aromatic amine.
Then, by turning to match the diastereoselective reaction outcome, the chiral imine (R)-3g was
reacted with nitro alkanes 4 and 6 to study both the syn/anti and the stereoselective facial outcome
of the nitro-Mannich additions. The results were compared with those already reported for the same
aza-Henry reactions performed on chiral trifluoromethyl aldimine 3j [9] (Table 2).
Table 2. Stereoselective comparison between the aza-Henry additions on C-alkyl substituted aldimines.
Entry
R
R1
Product
Time (h)
Yield (%)
syn/anti a
Dr a
b
1
2
3
4
a
CH3
CF3
7/71g
1
3
8
18
b
90
80
84
70
´
´
3:7
8:2
2:8
7.2:2.8
c
H
c
7/71j
CH3
syn-8/81g; anti-9/91g
1:1
3:7
CH3
c
CF3
syn-8/81j; anti-9/91j
Determined by 1H-NMR performed on the crude mixtures. After flash chromatography on silica gel.
Reaction performed in the presence of ZrCl4 as catalyst, see ref. [10].
The replacement of the
´
CF3 group with the
´
CH3 group on the imine carbon seems to partially
influence time and yields of additions (Table 1, entries 1, 3), but much more the syn/anti reaction
control, probably due to the different involved mechanism. In fact, while nitro alkanes added to
imine 3g through an intermolecular self-catalyzed reaction, imine 3j undergoes addition only in the
presence of ZrCl4 by an intramolecular process involving the in situ formation of a chiral zirconated
intermediate (Figure 1).
Figure 1. Different possible mechanisms.

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As shown in Table 2, the chiral intermediate permits a partial control of the syn/anti
diastereoselectivity that was completely lost by an intermolecular reaction approach. On the contrary,
the aldimine chiral resident center leads to the same stereoselective facial attack, the
β-nitro amines
always being obtained with the same dr. By 2D NOESY analyses (see Supplementary Materials) [10
]
1
1
1
the R configuration to the new chiral center of major isomers 7 g (entry 2), syn-8/8 g, and anti-9/9 g
were assigned. The obtained data showed that the nucleophilic intermolecular attack takes place
preferentially on the methyl aldimine Si face (Figure 2), just like the intramolecular addition proceeds
preferentially on the analogous trifluoromethyl aldimine Si face.
O
O
Si
N
Me
face
+
R'
H
N
R
Ph
H
Figure 2. Stereoselective intermolecular attack.
Finally, the temperature effect was considered. As previously reported [10], the stereoselective
outcome of addition reactions carried out on trifluoromethyl imines was not affected by the
˝
temperature. In fact, while working at low temperatures (from 0 to
´
20 C) only a significant
decrease in yields and no changes in diastereoselectivity was observed. Instead, a very high
complete stereoselectivity control was registered when the nitro-Mannich reactions were performed
1 1
on (R)-3g under low temperature and the chiral β-nitro amines 7 g and anti-9 g were obtained as
diastereomerically pure compounds, although in lower yields and longer reaction times (Scheme 3).
Scheme 3. Temperature effect on the stereoselective aza-Henry additions.
The stereochemical results can be due to different steric and electronic effects of two considered
groups. In fact, the volume of the fluorine atom is close to that of the hydrogen atom and, above all,
the –CF3 group is one of the strongest electron-withdrawing groups able to increase the carbon
electrophilicity [24–26]. As a possible consequence, it seems to be more difficult to control the
nucleophilic attack rate and even stereoselectivity starting from trifluoromethyl aldimine 3j.
Continuing our study, we decided to consider the influence of two other different alkyl groups on
the reactivity of C-alkyl substituted aldimines with nitro alkanes.
Therefore, imines 3b
from pivalaldehyde (Table 1) were reacted under solvent-free conditions with nitromethane (
Unexpectedly, while C-hexyl imines reacted without catalyst giving the corresponding -nitro amines
5b (Scheme 4, ), the presence of the tert-butyl group on the imine carbon required ZrCl4 as catalyst
to lead to the expected compounds 5c (Scheme 4, ), with no reaction taking place either without
catalyst or in the presence of a base (K2CO3 or Et3N), or also by changing other reaction parameters
,
e
derived from cyclohexanecarbaldehyde and imines 3c
,
f, derived
4).
β
,e
A
,f
B
˝
(molar ratios, temperature (from 25 to 60 C), presence of a solvent (THF, CH2Cl2)).

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Scheme 4. Reactivity of different C-alkyl substituted aldimines with CH3NO2 (4).
The different reactivity of aldimines 3c
In fact, the tert-butyl group, characterized by an electron-donating effect but even by a strong steric
hindrance, seems to influence the C=N reactivity in the same way of the CF3 group, that on the
,f, derived from pivalaldehyde appeared very intriguing.
´
contrary, as reported before, is a well-known strong EWG (electron withdrawing group, EWG)
although with limited steric hindrance. Therefore, trifluoromethyl aldimines can be considered
good electrophiles, unlike their unfluorinated analogues.
A possible explanation for this unexpected similar reactivity can be proposed.
As already reported by us [10] in the reaction of trifluoromethyl aldimine 3j the catalyst is required
to increase the acidity of the nitro alkane
CF3 group increases the C=N double bond electrophilicity, but at the same time drastically decreases
the lone pair nitrogen availability so that the nucleophile may not be formed.
On the contrary, the presence of a tert-butyl group in 3c favors the nitronate formation but
could decrease the reactivity of the C=N carbon due to both steric and electronic effects. Therefore,
the ZrCl4-coordination with aldimine and nitromethane
) increases the sp2 carbon reactivity
α-proton by ZrCl4-coordination, since the presence of the
´
,f
3
4 (I
but, above all, allows the reaction to be able to occur through an intramolecular addition (Figure 3),
as already proposed to explain the reactivity of C-CF3 substrates, thereby probably minimizing the
tert-butyl steric effect.
Figure 3. Proposed outcome for the ZrCl4-catalyzed addition.

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Finally, the stereoselective reaction outcome was even studied on C-alkyl substituted (E)-aldimines
3h,i. The reactions were performed at low temperature and starting from 3i in the presence of ZrCl4 as
catalyst. The results are reported in Table 3.
Table 3. Diastereoselective additions on different C-alkyl substituted aldimines.
Entry
R
R'
H
Product
Time (h)
syn/anti a
Dr a
99:1
99:1
Yield (%) b
1
2
7/71h
24
48
45
56
´
1:1
Cy
syn-8/81h;
CH3
anti-9/91h
3
4
H
CH3
7/71i
´
8
´
55
´
´
´
99:1
´
t-Bu c
Determined by 1H-NMR performed on the crude mixtures; After purification on silica gel; Reaction
a
b
c
performed in the presence of ZrCl4 (50 mol %).
The increase of steric hindrance on the imine carbon influenced the course of the aza-Henry
additions. Besides determining an increase of reaction time and a decrease in the yields, the addition of
6
failed in the syn/anti stereocontrol on the aldimine 3h (entry 2) and does not take place starting from
the highly hindered tert-butyl aldimine 3i (entry 3). Only the stereoselectivity of attack remains very
high giving only one diastereomer by addition of nitromethane ( ) (entries 1, 3). The same selectivity
was observed in the reaction of with aldimine 3g (entry 3), with only one diastereomer of syn/anti
4
6
geometric isomers being formed.
3. Experimental Section
IR spectra were recorded on a Perkin-Elmer 1600 FT/IR spectrophotometer in CHCl3 as solvent.
1H-NMR and 13C-NMR spectra were recorded on a VARIAN XL-300 spectrometer at 300 and 75 MHz
or on a Bruker Avance III at 400 and 101 MHz, respectively, at room temperature. CDCl3 was used
1
as solvent and CHCl3 and CDCl3 as internal standard for H and 13C, respectively. The NOESY
experiments were performed with a Bruker Avance III spectrometer at 400 MHz using CDCl3 as
solvent and CHCl3 as internal standard and used to assist in structure elucidation [27]. HPLC analyses
were performed with a Varian 9001 instrument using an analytical column (3.9
ˆ
300 mm, flow rate
1.3 mL/min; detector: 254 nm) equipped with a Varian RI-4 differential refractometer, or a Varian
9050 UV/VIS detector. Eluents were HPLC grade. HR-MS analyses were performed using a Micromass
Q-TOF Micro quadrupole-time of flight (TOF) mass spectrometer equipped with an ESI source and
a syringe pump. ˝The experiments were conducted in the positive ion mode. Optical rotation was
determined at 25 C with a JASCO DIP-370 polarimetry at a wavelength of 589 nm, using a quartz cell
of 1 cm length.
3.1. General Procedure for the Synthesis of C-alkyl Imines (3a–i)
Equimolar amounts (5 mmol) of aldehyde and amine were reacted under solvent free conditions.
The reaction mixtures were stirred at room temperature for 15 min, then CH2Cl2 (3 mL) and anhydrous
sodium sulfate (Na2SO4) were added and the mixtures were filtered off. The organic solvent was

Molecules 2016, 21, 723
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evaporated under vacuum to give the expected aldimines which were used without further purification.
3a–i [28–35] are known compounds.
3.2. General Procedure for the Synthesis of C-alkyl β-nitro Amines
Procedure A. (E)-Aldimines
3 (1 mmol) were stirred at room temperature (1–18 h) with a five-fold
excess of nitro compound (eight-fold excess of nitro compound 6) under solvent-free conditions.
4
After removal of nitro compound excess under vacuum, the crude mixtures were purified by flash
chromatography on silica gel.
˝
Procedure B. As procedure A, but at ´20 C.
Procedure C. ZrCl4 (0.5 mmol) was added to a mixture of (E)-aldimine 3i (1 mmol) and nitro
compound
4 (5 mmol) or 6 (8 mmol). The reactions were performed under solvent-free conditions and
stirred at room temperature (1–2 h). Then, after addition of water (5 mL), the crude mixtures were
extracted three times with Et2O. The collected organic layers were dried over anhydrous Na2SO4 and
the solvent evaporated under vacuum. The crude mixtures were purified by flash chromatography on
silica gel.
˝
Procedure D. Same as procedure C, but at ´20 C.
N-Benzyl-1-nitropropan-2-amine (5a, Procedure A). Yellow oil; (0.165 g, 85%); purified by flash
chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); IR
(CDCl3, 300 MHz) 7.31–7.18 (5H, m), 4.37–4.26 (m, 2H), 3.83–3.67 (2H, m), 3.43–3.32 (1H, m), 1.59
ν
max 3355, 1571 cm´1; 1H-NMR
δ
(1H, br), 1.15 (3H, d, J = 6.6 Hz); 13C-NMR (CDCl3, 75 MHz)
δ 139.6, 128.4 (2C), 127.9 (2C), 127.1, 80.2,
51.2, 50.8, 18.2; HRMS m/z [M + H]+ 195.1139 (calcd for C10H15N2O2, 195.1134).
N-Benzyl-1-cyclohexyl-2-nitroethanamine (5b, Procedure A). Yellow oil; (0.223 g, 85%); purified by flash
chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); IR
(CDCl3, 300 MHz) 7.31–7.18 (5H, m), 4.43 (1H, dd, J = 11.5, 5.0 Hz), 4.34 (1H, dd, J = 11.7, 7.8 Hz),
3.75 (2H, s, J = 10.3 Hz), 3.14–3.08 (1H, m), 1.78–1.45 (7H, m), 1.25–0.90 (5H, m); 13C-NMR (CDCl3,
ν
max 3353, 1562 cm´1; 1H-NMR
δ
75 MHz)
δ 139.8, 128.3 (2C), 128.0 (2C), 127.0, 77.1, 60.8, 51.5, 39.7, 29.0, 28.8, 26.2, 26.1 (2C); HRMS m/z
[M + H]+ 263.1758 (calcd for C15H23N2O2, 263.1760).
N-Benzyl-3,3-dimethyl-1-nitrobutan-2-amine (5c, Procedure C). Pale yellow oil; (0.189 g, 80%); purified by
flash chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); IR
ν
3359, 1571 cm´1
;
max
1H-NMR (CDCl3, 300 MHz)
8.8 Hz), 3.87–3.77 (2H, m,), 3.16 (1H, dd, J = 8.8, 4.0 Hz), 1.75 (1H, br), 0.97 (9H, s); 13C-NMR (CDCl3,
75 MHz)
140.1, 128.4 (2C), 128.3 (2C), 127.2, 78.3, 65.5, 54.5, 35.4, 26.6 (3C); HRMS m/z [M + H]+
δ = 7.35–7.22 (5H, m), 4.59 (1H, dd, J = 11.8, 4.0 Hz), 4.32 (1H, dd, J = 11.8,
δ
237.1601 (calcd for C13H21N2O2, 237.1603).
N-(1-Nitropropan-2-yl)aniline (5d, Procedure A). Yellow oil; (0.09 g, 50%); purified by flash
chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); IR
(CDCl3, 300 MHz) 7.22 (2H, t, J = 7.8 Hz) 6.79 (1H, t, J = 7.3 Hz), 6.67
1H NMR (CDCl3, 300 MHz)
(2H, d, J = 7.9 Hz), 4.58 (1H, dd, J = 12.2, 4.5 Hz), 4.38 (1H, dd, J = 11.7, 8.3 Hz), 4.26–4.20 (1H, m), 3.71
ν
max 3355, 1567 cm´1; 1H-NMR
δ
δ
(1H, br), 1.38 (3H, d, J = 6.3 Hz); 13C-NMR (CDCl3, 75 MHz)
δ 145.6, 129.6 (2C), 118.9, 113.7 (2C), 79.2,
47.8, 18.6; HRMS m/z [M + H]+ 181.0982 (calcd for C9H13N2O2, 181.0977).
N-(1-Cyclohexyl-2-nitroethyl)aniline (5e, Procedure A). Pale yellow oil; (0.134 g, 54%); purified by flash
1
chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); IR
NMR (CDCl3, 300 MHz)
4.63–4.39 (2H, m), 4.12–3.88 (1H, m), 3.72 (1H, br), 1.98–1.50 (6H, m), 1.38 –0.95 (5H, m); 13C NMR
ν
3356, 1564 cm´1; H
max
δ
7.19 (2H, t, J = 7.8 Hz), 6.75 (1H, t, J = 7.3 Hz), 6.66 (2H, d, J = 7.9 Hz),
(CDCl3, 75 MHz)
δ 146.5, 129.5 (2C), 118.4, 113.4 (2C), 76.4, 56.9, 40.6, 29.6, 28.8, 26.1, 25.9 (2C); HRMS
m/z [M + H]+ 249.1601 (calcd for C14H21N2O2, 249.1603).
N-(3,3-Dimethyl-1-nitrobutan-2-yl)aniline (5f, Procedure C). Pale yellow oil; (0.122 g, 55%); purified by
flash chromatography on silica gel (eluent: hexane/ethyl acetate = 90:10); IR
ν
3350, 1563 cm´1
;
max

Molecules 2016, 21, 723
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1H-NMR (CDCl3, 400 MHz)
δ
7.16 (2H, t, J = 7.9 Hz), 6.72 (1H, t, J = 7.3 Hz), 6.67 (2H, d, J = 7.8 Hz),
4.63 (1H, dd, J = 12.1, 4.8 Hz), 4.36 (1H, dd, J = 12.1, 8.6 Hz), 4.10 (1H, m), 3.63 (1H, br), 1.02 (9H, s);
13C-NMR (CDCl3, 100 MHz)
δ 147.4, 129.5 (2C), 118.4, 113.4 (2C), 77.2, 61.2, 29.8, 26.6 (3C); HRMS m/z
[M + H]+ 223.1451 (calcd for C12H19N2O2, 223.1447).
(S)-1-Nitro-N-[(R)-1-phenylethyl]propan-2-amine (7g, Procedure A). Yellow oil; (0.135 g, 65%); separated
by HPLC (eluent: hexane/ethyl acetate = 90:10); [
1555 cm´1; 1H-NMR (CDCl3, 300 MHz)
7.37–7.27 (5H, m), 4.41 (1H, dd, J = 11.4, 5.4 Hz), 4.23 (1H,
dd, J = 11.4, 5.4 Hz), 3.93 (1H, q, J = 6.5 Hz), 3.28–3.14 (1H, m), 1.79 (1H, br), 1.34 (3H, d, J = 6.5 Hz),
1.15 (3H, d, J = 6.6 Hz); 13C-NMR (CDCl3, 75 MHz)
144.7, 128.6 (2C), 127.2, 126.5 (2C), 81.2, 55.3, 49.2,
25.1, 17.6; HRMS m/z [M + H]+ 209.1297 (calcd for C11H17N2O2, 209.1290).
α
]D:
´55.4 (c = 40 g/100 mL, CHCl3); IR νmax 3358,
δ
δ
1
(R)-1-Nitro-N-[(R)-1-phenylethyl]propan-2-amine (7 g, Procedure B). Yellow oil; (0.168 g, 81%); purified by
flash chromatography on silica gel (eluent: hexane/ethyl acetate = 90:10); [
α
]D: -70.4 (c = 40 g/100 mL,
1
CHCl3); IR
ν
3358, 1555 cm´1; H-NMR (CDCl3, 300 MHz)
δ
7.37–7.22 (5H, m), 4.42 (1H, dd,
max
J = 11.4, 5.4 Hz), 4.33 (1H, dd, J = 11.3, 5.3 Hz), 3.90 (1H, q, J = 6.5 Hz), 3.32–3.14 (1H, m), 1.58 (1H, br),
1.33 (3H, d, J = 6.5 Hz), 1.12 (3H, d, J = 6.6 Hz); 13C-NMR (CDCl3, 75 MHz)
δ 145.1, 128.6 (2C), 127.2,
126.4 (2C), 79.63, 55.4, 49.5, 24.6, 19.2; HRMS m/z [M + H]+ 209.1288 (calcd for C11H17N2O2, 209.1290).
(S)-1-Cyclohexyl-2-nitro-N-[(R)-1-phenylethyl]ethanamine (7h, Procedure A). Pale yellow oil; (0.153 g,
55.3%); separated by HPLC (eluent: hexane/ethyl acetate = 85:25); [
α
]D: +13.8 (c = 40 g/100 mL,
1
CHCl3); IR
ν
3361, 1558 cm´1; H-NMR (CDCl3, 300 MHz)
δ
7.38–7.20 (5H, m), 4.28 (1H, dd,
max
J = 11.6, 5.1 Hz), 4.19 (1H, dd, J = 11.6, 8.0 Hz), 3.87 (1H, q, J = 6.5 Hz), 3.07–2.99 (1H, m), 1.86–0.87
(12H, m), 1.31 (3H, d, J = 6.5 Hz); 13C-NMR (CDCl3, 75 MHz)
δ 145.0, 128.4 (2C), 127.2, 126.7 (2C), 77.6,
58.8, 55.5, 39.3, 29.2, 28.3, 26.4, 26.3 (2C), 24.6; HRMS m/z [M + H]+ 277.1923 (calcd for C16H25N2O2,
277.1916).
1
(R)-1-Cyclohexyl-2-nitro-N-[(R)-1-phenylethyl]ethanamine (7 h, Procedure B). Pale yellow oil; (0.065 g,
23.7%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 85:25); [
α
]D:
1
+18.5 (c = 40 g/100 mL, CHCl3); IR
ν
3361, 1558 cm´1; H-NMR (CDCl3, 300 MHz)
δ
7.37–7.19
max
(5H, m), 4.51 (1H, dd, J = 11.6, 5.0 Hz), 4.40 (1H, dd, J = 11.5, 5.6 Hz), 3.88 (1H, q, J = 6.5 Hz), 2.86 (1H, q,
J = 5.5 Hz), 1.32 (3H, d, J = 6.5 Hz), 1.97–0.81 (12H, m); 13C -NMR (CDCl3, 75 MHz)
δ 145.1, 128.4 (2C),
127.2, 126.8 (2C), 76.1, 58.8, 55.5, 40.2, 29.3, 29.0, 26.3, 26.1 (2C), 24.7; HRMS m/z [M + H]+ 277.1913
(calcd for C16H25N2O2, 277.1916).
(S)-3,3-dimethyl-1-nitro-N-[(R)-1-phenylethyl]butan-2-amine (7i, Procedure C). Pale yellow oil; (0.063 g,
25%); separated by HPLC (eluent: hexane/ethyl acetate = 85:25); [
1H-NMR (CDCl3, 300 MHz)
7.29–7.18 (5H, m), 4.33 (1H, dd, J = 11.9, 4.6 Hz), 4.06 (1H, dd, J = 11.9,
7.5 Hz), 3.75 (1H, q, J = 6.5 Hz), 3.05 (1H, dd, J = 7.5 Hz, 4.6 Hz), 1.25 (3H, d, J = 6.5 Hz), 1.20 (1H, br,
J = 2.1 Hz), 0.90 (9H, s); 13C NMR (CDCl3, 75 MHz)
145.7, 128.5 (2C), 127.4, 126.9 (2C), 78.3, 63.2, 57.4,
35.7, 26.7 (3C), 23.6; HRMS m/z [M + H]+ 251.1765 (calcd for C14H23N2O2, 251.1760).
α
]D:
´85.4 (c = 40 g/100mL, CHCl3);
δ
δ
1
(R)-3,3-dimethyl-1-nitro-N-[(R)-1-phenylethyl]butan-2-amine (7 i, Procedure D). Pale yellow oil; (0.138
g, 55%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 85:25); [ ]D:
43.6 (c = 40 g/100 mL, CHCl3); IR 7.33–7.24 (5H,
3359 1553 cm´1; 1H-NMR (CDCl3, 300 MHz)
m), 4.59 (1H, dd, J = 11.8, 4.5 Hz), 4.34 (1H, dd, J = 11.7, 6.4 Hz), 3.82 (1H, q, J = 6.5 Hz), 2.86 (1H, dd,
α
´
ν
δ
max
J = 6.3 Hz, 4.6 Hz), 1.59 (1H, br), 1.32 (3H, d, J = 6.5 Hz), 0.85 (9H, s); 13C-NMR (CDCl3, 75 MHz)
δ
144.9, 128.3 (2C), 127.2 (2C), 127.1, 77.5, 62.7, 56.3, 35.1, 26.4 (3C), 24.5; HRMS m/z [M + H]+ 251.1763
(calcd for C14H23N2O2, 251.1760).
1 1
3-Nitro-N-[(R)-1-phenylethyl]butan-2-amine (syn-8g/8 g;anti-9g/9 g, Procedure A) Yellow oil; (0.186 g,
84%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); IR
ν
max
1
3355, 1567 cm´1; H -NMR (CDCl3, 300 MHz)
δ 7.48–7.07 (20H, m), 4.76–4.62 (2H, m), 4.56–4.30
(2H, m), 3.99–3.86 (3H, m), 3.87–3.70 (1H, m), 3.24–3.08 (1H, m), 3.03–2.83 (3H, m), 1.54–1.35 (4H, m),

Molecules 2016, 21, 723
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1.48 (3H, d, J = 7.0 Hz), 1.44 (6H, d, J = 6.6 Hz), 1.40 (3H, d, J = 6.4 Hz), 1.33 (9H, d, J = 6.4 Hz), 1.30
(3H, d, J = 6.5 Hz), 1.12 (3H, d, J = 6.5 Hz), 1.11 (3H, d, J = 6.4 Hz), 1.01 (3H, d, J = 6.7 Hz), 0.98 (3H,
d, J = 6.8 Hz); 13C-NMR (CDCl3, 75 MHz)
δ 145.5, 145.2, 144.7, 144.6, 128.4 (4C), 128.3, 128.2 (4C),
126.9 (4C), 126.6, 126.5, 126.3 (4C), 126.2, 87.8, 87.3, 87.0, 84.4, 55.7, 55.1, 54.9, 53.8 (2C), 53.7, 53.1, 52.9,
25.1, 24.7, 24.4, 23.7, 16.6, 16.5 (2C), 15.8, 15.6, 15.3, 14.5 (2C); HRMS m/z [M + H]+ 223.1450 (calcd for
C12H19N2O2, 223.1447).
1
(2R,3S)-3-Nitro-N-[(R)-1-phenylethyl]butan-2-amine (anti-9 g, Procedure B). Yellow oil; (0.133 g, 60%);
purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20); [ ]D: 9.9
(c = 40 g/100 mL, CHCl3); IR 7.37–7.22 (5H, m),
max 3353, 1566 cm´1; 1H-NMR (CDCl3, 300 MHz)
4.75–4.63 (1H, m), 3.94 (1H, q, J = 6.5 Hz), 2.95 (1H, m), 2.00 (1H, br), 1.44 (3H, d, J = 6.7 Hz), 1.32 (3H,
α
´
ν
δ
d, J = 6.5 Hz), 1.00 (3H, d, J = 6.6 Hz); 13C-NMR (CDCl3, 75 MHz)
δ 145.3, 128.5 (2C), 127.1, 126.4 (2C),
84.5, 55.2, 54.0, 24.5, 16.7, 14.7; HRMS m/z [M + H]+ 223.1445 (calcd for C12H19N2O2, 223.1447).
(R)-1-Cyclohexyl-2-nitro-N-[(R)-1-phenylethyl]propan-1-amine (syn-8'h/anti-9'h, Procedure B). Pale yellow
oil; (0.162 g, 56%); purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate = 80:20);
IR ν δ 7.36–7.21 (10H, m), 4.62 (1H, q, J = 6.9 Hz, syn),
max 3357, 1568 cm´1; 1H-NMR (CDCl3, 300 MHz)
4.25 (1H, q, J = 6.5 Hz, anti), 3.76 (1H, q, J = 6.8 Hz, anti), 3.74 (1H, q, J = 6.2 Hz, syn), 2.93 (1H, dd,
J = 5.9 Hz, 4.2 Hz, anti), 2.83 (1H, dd, J = 7.5 Hz, 4.1 Hz, syn), 1.52 (3H, d, J = 3.9 Hz, syn), 1.48 (3H,
d, J = 6.8 Hz, anti), 1.83–0.94 (24H, m), 1.27 (6H, d, J = 6.5 Hz); 13C NMR (CDCl3, 75 MHz)
δ 145.4,
145.2, 128.4 (2C), 128.3 (2C), 127.2, 127.1, 126.9 (2C), 126.5 (2C), 86.6, 83.8, 69.4, 62.8, 57.0, 56.7, 41.1, 40.2,
30.8, 30.7, 29.8 (2C), 26.1 (2C), 25.4 (2C), 24.7, 23.9, 21.7, 21.4, 16.8, 13.5; HRMS m/z [M + H]+ 291.2074
(calcd for C17H27N2O2 291.2073).
4. Conclusions
In summary, a first direct comparison in aza-Henry addition reactions between the C-CF3 and
C-CH3 substituted N-protected aldimines was reported. The different inductive effect of the two groups
greatly influence the reaction outcome acting both on the electrophilicity of the imino carbon and on
the nitrogen lone pair availability. The presence of a strong steric hindrance on the imine carbon due
to the tert-butyl group unexpectedly required the reaction conditions already fixed for trifluoromethyl
aldimines, although for different reactivity reasons.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/
21/6/723/s1.
Acknowledgments: We thank the Università degli Studi di Roma “La Sapienza” for financial support.
Author Contributions: S.F. and A.P. conceived and designed the experiments, A.P. and E.S. performed the
experiments, and S.F. and L.P. analyzed the data and wrote the paper. All authors discussed the results and
approved the final version.
Conflicts of Interest: The authors declare no conflict of interest.
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2016 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/).