Aza-Henry Reaction with CF3-Ketimines: An Efficient Approach to Trifluoromethylated β-Nitroamines, 1,2-Diamines, α-Aminooximes, and Imidazolidinones

Article abstract of DOI:10.1002/ejoc.201500898

CF₃-Substituted ketimines synthesized from trifluoroacetone, hexafluoroacetone, and trifluoroacetophenones were studied in aza-Henry reactions with nitroalkanes. We found that nitromethane and nitropropane react with CF₃-substituted

Full text of DOI:10.1002/ejoc.201500898

FULL PAPER
DOI: 10.1002/ejoc.201500898
Aza-Henry Reaction with CF3-Ketimines: An Efficient Approach to
Trifluoromethylated β-Nitroamines, 1,2-Diamines, α-Aminooximes, and
Imidazolidinones
Irina V. Kutovaya,[a] Olga I. Shmatova,[a] Viktor M. Tkachuk,[b] Nina V. Melnichenko,[b]
Mikhail V. Vovk,*[b] and Valentine G. Nenajdenko*[a,c]
Keywords: Synthetic methods / Reduction / Nucleophilic addition / Nitro compounds / Schiff bases / Amines / Fluorine
CF3-Substituted ketimines synthesized from trifluoroacetone,
hexafluoroacetone, and trifluoroacetophenones were studied
in aza-Henry reactions with nitroalkanes. We found that ni-
tromethane and nitropropane react with CF3-substituted ket-
imines to form the target β-nitroamines in high yield. The
aza-Henry reaction proceeded under mild conditions in the
presence of an appropriate base. A new simple method for
the synthesis of β-nitroamines bearing CF3 group was devel-
oped. α-CF3-β-nitroamines can easily be converted into tri-
fluoromethylated 1,2-diamines, α-aminooximes, and imid-
azolidinones.
Introduction
The importance of fluorinated organic compounds for
medicine and modern materials science is commonly
known. Psychotropic and neuroleptic drugs, as well as
many antiviral medications, often bear fluorine atoms (Fig-
ure 1). Nearly 25% of all pharmaceuticals contain a fluor-
ine atom or a CF3 group. Fluorinated compounds have in-
creased metabolic stability compared to their nonfluorin-
ated analogues, due to the fact that the carbon–fluorine
bond is one of the strongest in organic chemistry.[1] The
presence of a CF3 group in a molecule also significantly
increases the lipophilic properties, and can improve the
binding affinity of the molecule, thereby enhancing the ef-
fectiveness of drugs. The steric effects of fluorination are
also very important, and can bring about a change of pre-
ferred conformation (gauche effect for fluorinated frag-
ments, and high conformation energy of CF3 group).[2] As
a result, research into convenient methods for the prepara-
tion of fluorine-containing molecules is very important.
Figure 1. Examples of drugs containing a CF3 group.
Fluoroorganic compounds occur only rarely in nature.
The number of methods and reagents that allow the direct
introduction of fluorine or fluorinated groups are limited.[3]
Thus, methods that make use of fluorine-containing build-
ing blocks to incorporate a fluorinated fragment into a mol-
ecule are widely used for the preparation of target fluorin-
ated compounds.[1,4]
Trifluoromethyl-substituted imines are interesting sub-
strates for this purpose. Due to the electron-withdrawing
effect of the CF3 fragment, such imines are much more re-
active than their nonfluorinated counterparts. Moreover, as
a rule, ketimines are less reactive compounds, and a lot of
the reactions that take place with aldimines do not proceed
or have restricted use with ketimines. To date, only a few
examples of the addition of aliphatic nitroalkanes to ket-
imines are known.[5] This is also true for fluorinated imines.
[a] Department of Chemistry, Lomonosov Moscow State
University,
Moscow 119991, Russia
E-mail: nen@acylium.chem.msu.ru
www.msu.ru
[b] Institute of Organic Chemistry of the National Academy of
Sciences of Ukraine,
5, Murmanska Str., Kyiv 02660, Ukraine
www.ioch.kiev.ua
[c] A. N. Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences,
119991 Moscow, Russia
www.ineos.ac.ru
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500898.
Eur. J. Org. Chem. 2015, 6749–6761
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6749

M. V. Vovk, V. G. Nenajdenko et al.
FULL PAPER
The aza-Henry reaction allows the creation of new car- imines derived from trifluoroacetone or trifluoroaceto-
bon–carbon bonds with fluorinated imines, and leads to at- phenone.
tractive structures containing not only a CF3 group, but
4-Methoxy-N-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl-
also an amine moiety. The β-nitroamine products are very idene]aniline (1a) was chosen as a model compound. To
attractive from a synthetic point of view, because both of find optimal reaction conditions, a wide range of catalysts
their nitrogen-containing groups can be easily converted [ZnCl2 + iPr2NEt, BF3·Et2O, BF3·Et2O + K2CO3, 1,8-di-
into various other functional groups.[6] The most commonly azabicycloundec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]-
used activators in aza-Henry reactions are organic[7] and octane (DABCO), K2CO3, KOH, CsF, iPr2NEt, ZnCl2 +
inorganic[8] bases for the activation of the nitroalkane, and DBU, ZnCl2, ZnCl2 + DABCO, 1,5-diazabicyclo[4.3.0]non-
Lewis acids[9] for the activation of the imine.
5-ene (DBN), triazabicyclodecene (TBD)], solvents (tolu-
First, we decided to study the interaction of fluorinated ene, acetonitrile, nitromethane), and amounts of the cata-
ketimines with nitroalkanes in detail. Imines derived from lyst and of nitromethane were tested (Table 1).
hexafluoroacetone, trifluoroacetone, and trifluoroaceto-
phenones have not been studied before as substrates in the
aza-Henry reaction with nitroalkanes. This is the first sys-
tematic investigation of this reaction.
Table 1. The aza-Henry reaction of 1a with various catalysts.
The reduction of α-CF3-β-nitroamines to vicinal di-
amines is of special interest, as this structural fragment
often occurs in different medicines, catalysts, and natural
products (Figure 2). Due to the presence of strongly elec-
tron-withdrawing CF3 group, the basicity and nucleophilic-
ity of the two amine groups in such diamines is dramatically
different; this opens up the possibility of selective subse-
quent transformations of the trifluoromethylated diamines.
Catalyst
Amount of
catalyst [equiv.]
Solvent
Reaction Yield of
time [h]
2a [%]
ZnCl2 + iPr2NEt
ZnCl2 + iPr2NEt
ZnCl2 + iPr2NEt
ZnCl2 + DBU
DBU
DBU
DBU
DBU
DBU
DBN
TBD
iPr2NEt
iPr2NEt
1
0.1
0.05
0.1
0.1
0.2
1
0.2
0.2
0.2
0.2
0.1
0.2
0.1
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
toluene[a]
toluene/MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
44
6
20
2
1.5
1
2.67
0.1
1
0.5
48
2
2
48
46
71
68
74
73
88
43
45
75
66
27
78
68
23
K2CO3
[a] 10 equiv. of MeNO2 was used.
The use of BF3·Et2O + K2CO3, ZnCl2, BF3·Et2O, KOH,
ZnCl2 + DABCO, CsF, or DABCO as the catalyst in the
reaction in nitromethane gave no reaction. When ZnCl2 +
iPr2NEt, DBU, iPr2NEt, DBN, TBD, or K2CO3 was ued,
the target compound (i.e., 2a) was isolated in good yield
(Table 1). The best yield after a reasonable reaction time
was achieved using DBU (0.2 equiv.) in nitromethane. In-
creasing the amount of DBU to 1 equiv. led to side-reac-
tions, and the product (i.e., 2a) could not be isolated in
good yield. We also tried to use lower amounts of DBU,
but when 0.1 equiv. of DBU was used, the transformation
proceeded much more slowly.
Figure 2. 1,2-Diamines.
We also tested different solvents. In toluene, the reaction
finished within minutes, but there were a lot of by-products,
Results and Discussion
Ketimines derived from hexafluoroacetone,[10] trifluo- and the target compound (i.e., 2a) could not be isolated in
roacetone,[11] and trfluoroacetophenones[12] were synthe- good yield. In acetonitrile, no reaction between imine 1a
sized according to published methods, and were used as and nitromethane was observed at all.
starting materials for the reaction with nitromethane. We
Thus, the reaction of hexafluoroacetone imine 1a with
began our investigation by searching for an appropriate cat- nitromethane was found to proceed in maximal yield when
alyst and solvent for the reaction of hexafluoroacetone 0.2 equiv. of DBU was used as catalyst in nitromethane,
imines with nitromethane. It should be noted that due to with a reaction time of 1 h. Having identified these optimal
the presence of two electron-withdrawing groups, imines de- conditions for substance 1a, we carried out aza-Henry reac-
rived from hexafluoroacetone are much more reactive than tions of nitromethane with other imines 1b–1e (Table 2; to
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Aza-Henry Reaction with CF3-Ketimines
give compounds 2a–2e). The reactions were monitored by DABCO, K2CO3, KOH, CsF, iPr2NEt, DBU + ZnCl2,
TLC, and the reaction times were less than 2 h.
DBN, Py, Na2CO3, Cs2CO3, Et3N, and TBD), solvents (tol-
uene, DMSO, MeOH, Et2O, acetonitrile, dichloromethane,
and nitromethane) and different concentrations of nitro-
methane were tested to find optimal conditions.
Table 2. The aza-Henry reaction of imines 1a–1e.
The target product (i.e., 2f) could only be detected in the
reaction mixture when a rather strong base such as DBN
(pKa = 12.7), TBD (pKa = 15.2), or DBU (pKa = 12.5[13]
)
was used as the catalyst. The use of DBU, even in small
quantities, resulted in the formation of the product (i.e., 2f)
in low yield (40%), although the process proceeded very
quickly. Using a polar solvent or a large excess of nitro-
methane also led to a lot of side-reactions. The use of TBD
as a catalyst gave satisfactory results (60% yield). The best
results for this reaction were observed when DBN (1 equiv.)
was used as an activator in an excess of nitromethane
(Table 3).
Nitroamine R1 (imine)
R2 (nitroalkane)
Catalyst
Yield [%]
2a
2b
2c
2d
2e
2e
4a
4b
4c
4d
4e
4-MeOC6H4
4-MeC6H4
4-ClC6H4
C6H5
4-MeC6H4CO
4-MeC6H4CO
4-MeOC6H4
4-MeC6H4
4-ClC6H4
C6H5
H
H
H
H
H
H
Et
Et
Et
Et
DBU
DBU
DBU
DBU
DBU
iPr2NEt
DBU
DBU
DBU
DBU
DBU
88
84
96
89
54
98
62
60
60
80
64
Table 3. The aza-Henry reaction of 1f with various catalysts.
4-MeC6H4CO Et
However, we found that these conditions were unsuitable
for imine 1e, which has an additional electron-withdrawing
group at the nitrogen atom. In this case, we observed not
only the formation of the target nitroamine, but also of
product 3e, resulting from the reaction of 1e with DBU.
The formation of 3e can be explained by enhanced electro-
philicity of 1e. As a result, the 8-nitrogen of DBU can react
as a nucleophile with the imine carbon of 1e (Scheme 1).
Subsequent ring opening and reaction with traces of water
finally leads to the formation of 3e. The use of iPr2NEt
with this substrate resulted in the formation of the required
nitroamine (i.e., 2e) in excellent yield.
Catalyst
Amount of
catalyst [equiv.]
Solvent
Reaction
time [h]
Yield of
2f [%]
DBU
DBU
DBU
DBN
DBN
TBD
TBD
0.2
1
0.2
0.2
1
toluene[a]
toluene[a]
MeNO2
22
2
0.5
12
5
40
21
23
48
78
35
60
toluene[a]
toluene[a]
toluene[a]
toluene[a]
0.2
1
20
6
[a] 10 equiv. of MeNO2 was used.
We went on to test the reaction with other imines derived
from trifluoroacetone (i.e., 1g–1i) using this system (DBN/
toluene/nitromethane). The target compounds (i.e., 2g–2i)
were obtained in 70–84% yield (Table 4). In a similar man-
ner, the reaction of imines 1f–1i with nitropropane was car-
ried out. However, DBU was used as a catalyst, because
DBN and TBD required longer reaction times in this case.
The nitroamine products (i.e., 4f–4i) contain two
stereocentres, and according to NMR spectroscopy, each of
these compounds was formed as a mixture of two dia-
stereomers in a 1:1 ratio.
Scheme 1. Aza-Henry reaction of imine 1e with nitromethane and
DBU.
To determine the scope and limitations of aza-Henry re-
To obtain more general information about this reaction,
action with fluorinated imines, we also studied the reaction imines derived from some trifluoroacetophenones were
of ketimines 1a–1e with nitropropane. We also optimized studied. Starting 1-alkyl-aryl-2,2,2-trifluoroethylidene-
the conditions for this reaction using 1a as a model com- carbamates 1j–1r are highly electrophilic due to the pres-
pound, and once again the best results were obtained with ence of two electron-withdrawing groups (trifluoromethyl
DBU. The reaction proceeded at room temperature for 1 d and alkoxycarbonyl; Table 5). It was found that the reaction
to give slightly lower yields (60–80%) than those obtained of compounds 1j–1r with nitromethane proceeds cleanly in
with nitromethane (2a–2e).
DMSO solution in the presence of catalytic amounts of tri-
Next, we investigated the reaction between nitromethane ethylamine to give alkyl-N-(2-aryl-3-nitro-1,1,1-trifluoro-
and imines derived from trifluoroacetone. To screen the re- propane-2-yl) carbamates 2j–2r in excellent yields (82–
action conditions, 4-methoxy-N-[2,2,2-trifluoro-1-methyl- 90%).
ethylidene] aniline (1f) was chosen as a model imine. Vari-
Thus, we have found that trifluoromethyl-substituted
ous catalysts (ZnCl2 + iPr2NEt, BF3·Et2O + K2CO3, DBU, imines of any type can be effectively transformed into the
Eur. J. Org. Chem. 2015, 6749–6761
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M. V. Vovk, V. G. Nenajdenko et al.
FULL PAPER
Table 4. The aza-Henry reaction of imines 1f–1i.
6.98–7.12, pKa2 = –0.54–0.47 for diamines 5h, 6h; pKa1 ≈
5.79–6.85, pKa2 = –4.00–3.38 for diamines 5j–5p, as calcu-
lated with ACDlabs[15]).[16]
Table 6. Reduction of nitroamines 2a–2h and 4a–4h to give 1,2-
diamines.
Nitroamine R1 (imine)
R2 (nitroalkane) Catalyst
Yield [%]
2f
2g
2h
2i
4f
4g
4h
4i
4-MeOC6H4
4-MeC6H4
4-ClC6H4
C6H5
H
H
H
H
DBN, 1 equiv.
78
70
84
DBN, 1 equiv.
DBN, 1 equiv.
DBN, 1 equiv.
DBU, 0.2 equiv.
DBU, 0.2 equiv.
DBU, 0.2 equiv.
DBU, 0.2 equiv.
70
66[a]
52[a]
98
Diamine R1
R2
R3
Yield [%]
4-MeOC6H4 Et
4-MeC6H4
4-ClC6H4
C6H5
Et
Et
Et
5a
5b
5c
5d
5g
6a
6b
6c
6d
6g
CF3
4-MeOC6H4
4-MeC6H4
4-ClC6H4
C6H5
4-ClC6H4
4-MeOC6H4
4-MeC6H4
4-ClC6H4
C6H5
H
H
H
H
97
80
98
82
88
96
80
94
89
82
CF3
CF3
CF3
CH3
CF3
CF3
CF3
CF3
CH3
37[a]
[a] The yield was calculated from the 19F NMR spectra.
H
Et
Et
Et
Et
Et
Table 5. The aza-Henry reaction of imines 1j–1r with nitromethane.
4-ClC6H4
Reduction under acidic conditions is unsuitable for
nitroamines 2j–2p, due to the fact that carbamate groups
(especially Boc) are not stable in acidic media. Therefore, in
these cases we used reduction with NaBH4 in the presence
of an equimolar amount of NiCl2·6H2O. This reductive sys-
tem was also shown to be highly effective, and the corre-
sponding monoprotected diamines (i.e., 5j–5r) were ob-
tained in high yields (Table 7).
Nitroamine Ar (imine)
R (nitroalkane)
Yield [%]
2j
2k
2l
4-FC6H4
4-MeC6H4
C6H5
Me
Me
Et
Et
Et
tBu
tBu
tBu
84
84
90
82
84
85
86
82
2m
2n
2o
2p
2q
4-FC6H4
4-MeOC6H4
C6H5
4-MeC6H4
4-FC6H4
Table 7. Reduction of nitroamines 2j–2p to give 1,2-diamines.
corresponding nitroamines using an aza-Henry reaction.
However, it is necessary to use different bases as the cata-
lyst, depending on the electrophilicity of the starting imines.
As compounds based on diamines are widely used in
medicine and organic synthesis, we decided to study the re-
duction of nitroamine products 2a–2q and 4a–4h to give the
corresponding 1,2-diamines. For this reduction, we added
zinc powder portionwise to a solution of the nitroamine in
methanol containing hydrochloric acid (8 m).[14]
In some cases, full conversion was not observed, and it
was necessary to add additional zinc and hydrochloric acid.
We found that this approach was general, and no limita-
tions were observed. As a result, a number of diamines 5a–
Diamine
Ar
R
Yield [%]
5j
5k
5l
5m
5n
5o
5p
4-FC6H4
4-MeC6H4
C6H5
4-FC6H4
4-MeOC6H4
C6H5
Me
Me
Et
Et
Et
tBu
tBu
81
86
86
81
88
84
82
4-MeC6H4
We also found that trifluoromethylated nitroamine deriv-
5h and 6a–6h were obtained in excellent yields (82–98%), atives can be subjected to a partial reduction to obtain the
irrespective of the substituents on the amine nitrogen and corresponding aminooximes. This reaction was carried out
the carbon skeleton (Table 6). The 1,2-diamine products in methanol solution with the addition of a small amount
(i.e., 5a–5h and 6a–6h) containing a trifluoromethyl group of saturated aqueous ammonia under an atmosphere of
are stable compounds. In contrast, nitroamines 2a–2q and hydrogen (1 atm.) using palladium on charcoal (10%) as a
4a–4h should be stored in a refrigerator due to their limited catalyst for 1–2 d.[17] It is worth noting that in the absence
stability. These trifluoromethylated diamines are attractive of ammonia, or using 5% palladium on charcoal, the reac-
building blocks bearing a CF3 group. It is quite important tion proceeded very slowly. Compounds 7a–7h and 8a–8h
to point out that the two nitrogen atoms in these com- were obtained in 72–94% yield (Table 8). Such aminoox-
pounds have very different nucleophilicities (pKa1 = 3.89– imes are very interesting in terms of their possible applica-
4.61, pKa2 = –6.63–5.16 for diamines 5a–5d, 6a–6d; pKa1
≈
tions, because they are protected aminoaldehydes.
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Aza-Henry Reaction with CF3-Ketimines
Table 8. Reduction of nitroamines 2a–2h and 4a–4h to give ami-
nooximes.
Scheme 2. Preparation of diamines 10k and 10l.
Conclusions
Aminooxime R1
R2
R3
Yield [%]
In summary, the reaction of nitroalkanes and fluorinated
ketimines derived from hexafluoroacetone, trifluoroaceto-
phenone, and trifluoroacetone was systematically investi-
gated. We found that the best catalysts for this reaction are
strong organic bases such as DBU, DBN, Et3N, and
iPr2NEt. Complete and partial reduction of the prepared
nitroamines to give diamines and aminooximes was carried
out. These reactions give access to attractive trifluoro-
methylated building blocks Ϫ diamines and aminooximes
Ϫ in good and excellent yields, irrespective of the structure
of the starting materials.
7a
7b
7c
7d
7h
8a
8c
8d
8h
CF3
4-MeOC6H4
4-MeC6H4
4-ClC6H4
C6H5
4-ClC6H4
4-MeOC6H4
4-ClC6H4
C6H5
H
H
H
H
H
Et
Et
Et
Et
82
80
94
76
90
76
82
72
82
CF3
CF3
CF3
CH3
CF3
CF3
CF3
CH3
4-ClC6H4
The presence in the structure of compounds 7 of two
functional groups (amine and alkoxycarbonyl groups) cre-
ates favourable conditions for their intramolecular cycliza-
tion to the corresponding imidazolidin-2-ones (i.e., 9;
Table 9). This kind of cyclization is relatively easy to im-
plement. Heating 7 in refluxing toluene in the presence of
DBU resulted in clean heterocyclization. Previously, one
compound of this type (Ar = C6H5) was synthesized by a
three-step transformation from the corresponding α-amino-
nitrile.[18]
Experimental Section
General Remarks: 1D NMR (1H, 19F, and 13C) spectra were ob-
tained with Bruker VRX-400, Varian VXR-300, Bruker Avance
DRX-500, and Agilent 400-MR spectrometers. Chemical shifts for
1H NMR spectroscopic data were referenced to internal tetrameth-
ylsilane (δ = 0.0 ppm); chemical shifts for 13C NMR spectroscopic
data were referenced to CDCl3 (δ = 77.0 ppm); chemical shifts for
19F NMR spectroscopic data were referenced to PhCF3 (δ =
–63.90 ppm) or CFCl3 (δ = 0.0 ppm). TLC was carried out on pre-
coated silica plates (Silufol UV-254), which were visualized with
UV light and/or staining with ninhydrin solution or aqueous
Ce(SO4)2 solution with phosphomolybdic and sulfuric acids. Flash
chromatography was carried out using MP Silica 60 (320–
630 mesh) with the solvents indicated. All solvents and reagents for
the reactions were of reagent grade, and were dried and distilled
immediately before use as follows: dichloromethane from P2O5, tri-
ethylamine and pyridine from calcium hydride, diethyl ether and
benzene from sodium.
Table 9. Cyclization of diamines 5j–5l and 5n to give imidazoline-2-
ones 9j–9l and 9n.
Diamine Imidazoline-2-one Ar
R
Yield [%]
General Procedure for the Preparation of Imines 1a–1e: In a 250 mL
flask, a solution of aniline (0.1 mol) in dichloromethane (150 mL)
was cooled to about –40 °C. Hexafluoroacetone gas, generated by
the slow, dropwise addition of hexafluoroacetone trihydrate (26.5 g,
0.12 mol) to concentrated sulfuric acid (15 mL) at 90 °C, was then
bubbled into the aniline solution over a period of 2 h. A moisture-
sensitive precipitate, the adduct of hexafluoroacetone with aniline,
was gradually formed. Then, triethylamine (41.5 mL, 0.3 mol) was
added to the solution, and the precipitate dissolved. After that, the
flask was equipped with a condenser, and phosphorus oxychloride
(15.3 g, 0.1 mol) was added dropwise at such a rate that gentle re-
flux was maintained. The solution turned yellow, and a precipitate
formed. The solvent and the tertiary amine were removed under
vacuum, and the resulting residue was distilled under reduced pres-
sure to give the crude product.[10]
5j
9j
9j
9k
9k
9l
4-FC6H4
4-FC6H4
4-MeC6H4
4-MeC6H4
C6H5
Me
Et
Me
tBu
Et
90
88
92
90
87
90
82
5m
5k
5p
5l
5o
5n
9l
9n
C6H5
4-MeOC6H4
tBu
Et
Carbamates 4k and 4l, containing an O-tert-butyl sub-
stituent, may be considered as N-Boc-monosubstituted de-
rivatives, and under the action of a saturated solution of
hydrogen chloride in dioxane, they were smoothly converted
into the dihydrochloride salts of 2-aryl-3,3,3-trifluoro-
propane-1,2-diamines 10k and 10l (Scheme 2). The method
described here for the synthesis of these important com-
pounds complements existing approaches described in the
literature.[19]
4-Methoxy-N-[2,2,2-trifluoro-1-(trifluoromethyl)ethylidene]aniline
(1a): Yellow liquid (52%). b.p. 80–82 °C/ 28 Torr; ref.[10] b.p. 78–
81 °C/ 28 Torr. 1H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3 H, CH3-
O), 6.93–6.95 (m, 2 H, Ar), 6.99–7.01 (m, 2 H, Ar) ppm. 19F NMR
Eur. J. Org. Chem. 2015, 6749–6761
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6753

M. V. Vovk, V. G. Nenajdenko et al.
FULL PAPER
(376.5 MHz, CDCl3): δ = –64.80 (CF3), –72.09 (CF3) ppm, in substances 2a–2e; nitropropane (0.5 mL) for substances 4a–4e] and
agreement with the literature data.[10]
base [DBU (0.05 mol, 8.5 μL) for substances 2a–2d, 4a–4e; Hünig’s
base (0.05 mol, 8.5 μL) for substance 2e] were added to the imine
(0.25 mmol). The reaction was monitored by TLC (ca. 1.5 h), then
the mixture was concentrated under reduced pressure, and the
product was isolated by column chromatography (eluent: hexane/
dichloromethane, 3:1, for substances 2a–2e; hexane/dichlorometh-
ane, 1:1, for substances 4a–4e).
4-Methyl-N-[2,2,2-trifluoro-1-(trifluoromethyl)ethylidene]aniline
(1b): Yellow liquid (49%). b.p. 96–97 °C /80 Torr; ref.[20] b.p. 85–
86 °C/ 53 Torr. 1H NMR (400 MHz, CDCl3): δ = 2.39 (s, 3 H,
CH3), 6.84–6.86 (m, 2 H, Ar), 7.22–7.24 (m, 2 H, Ar) ppm.
4-Chloro-N-[2,2,2-trifluoro-1-(trifluoromethyl)ethylidene]aniline
(1c): Yellow liquid (68%). b.p. 66–67 °C /20 Torr; ref.[20] b.p. 65–
4-Methoxy-N-[2,2,2-trifluoro-1-(nitromethyl)-1-(trifluoromethyl)eth-
yl]aniline (2a): Yellow oil (88%). 1H NMR (400 MHz, CDCl3): δ =
3.80 (s, 3 H, CH3-O), 4.27 (br. s, 1 H, H-N), 4.86 (s, 2 H, CH2),
6.84–6.86 (m, 2 H, Ar), 7.17–7.19 (m, 2 H, Ar) ppm. 13C NMR
1
66 °C/ 21 Torr. H NMR (400 MHz, CDCl3): δ = 6.84–6.86 (m, 2
H, Ar), 7.38–7.40 (m, 2 H, Ar) ppm.
N-[2,2,2-Trifluoro-1-(trifluoromethyl)ethylidene]aniline (1d): Yellow
liquid (65%). b.p. 68–71 °C /60 Torr; ref.[20] b.p. 75–76 °C/ 91 Torr.
1H NMR (400 MHz, CDCl3): δ = 6.93–6.95 (m, 2 H, Ar), 7.29–
7.31 (m, 1 H, Ar), 7.41–7.45 (m, 2 H, Ar) ppm. 13C NMR
(100 MHz, CDCl3): δ = 117.0 (Ar), 126.4 (Ar), 128.5 (Ar), 141.9
2
(100 MHz, CDCl3): δ = 55.4 (CH3-O), 67.3 (sept, JC,F = 27.1 Hz,
1
C-CF3), 72.6 (CH2), 114.4 (Ar), 122.3 (q, JC,F = 290.8 Hz, CF3),
129.0 (Ar), 131.5 (Cq, Ar), 158.3 (Cq, Ar) ppm. 19F NMR
(376.5 MHz, CDCl ): δ = –70.86 (CF ) ppm. IR (neat): ν = 3373
˜
3
3
1
2
(q, JC,F = 270.0 Hz, CF3), 144.3 (Cq, Ar), 170.3 (sept, JC,F
=
(br., NH) , 1159 (CF), 1149 (CF) cm–1. HRMS (ESI): calcd. for
35.0 Hz, C-CF3) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –71.89
C11H13F6N2O3 [M + H]+ 333.0669; found 333.0666.
(CF3), –64.90 (CF3) ppm.
4-Methyl-N-[2,2,2-trifluoro-1-(nitromethyl)-1-(trifluoromethyl)eth-
yl]aniline (2b): Brown oil (84%). 1H NMR (400 MHz, CDCl3): δ =
2.34 (s, 3 H, CH3), 4.35 (br. s, 1 H, H-N), 4.89 (s, 2 H, CH2), 7.09–
7.15 (m, 4 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.4
4-Methyl-N-[2,2,2-trifluoro-1-(trifluoromethyl)ethylidene]benzamide
(1e): White solid (88 %), m.p. 31–32 °C. 1H NMR (400 MHz,
CDCl3): δ = 2.38 (s, 3 H, CH3), 7.23–7.83 (m, 4 H, Ar) ppm, in
agreement with the literature data.[21]
2
(CH3), 67.3 (sept, JC,F = 29.9 Hz, C-CF3), 72.2 (CH2), 114.4 (Cq,
Ar), 121.9 (q, 1JC,F = 303.6 Hz, CF3), 126.2 (Ar), 129.5 (Ar), 136.1
(Cq, Ar) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –71.14 (CF3)
General Procedure for the Preparation of Imines 1f–1i: Trifluoro-
acetone (0.12 mol, 11 mL) and a solution of titanium tetrachloride
(0.08 mol, 8.8 mL) in hexane (8 mL) were added to a vigorously
stirred mixture of the appropriate aniline (0.2 mol) and anhydrous
diethyl ether (100 mL) at 0 °C. The reaction mixture was stirred at
room temperature for 1 h, then the precipitate of titanium dioxide
was removed by filtration, and the filtrate was concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, dichloromethane/hexane, 1:1) to give the target
imine.[22]
ppm. IR (neat): ν = 3300 (br., NH) cm–1. C H F N O : C 41.78,
˜
11 10
6
2
2
H 3.19, N 8.86; found C 41.84, H 3.26, N 8.92.
4-Chloro-N-[2,2,2-trifluoro-1-(nitromethyl)-1-(trifluoromethyl)eth-
yl]aniline (2c): Yellow oil (94%). 1H NMR (400 MHz, CDCl3): δ =
4.55 (br. s, 1 H, H-N), 4.91 (s, 2 H, CH2), 7.14–7.17 (m, 2 H, Ar),
7.28–7.32 (m, 2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ =
2
1
67.1 (sept, JC,F = 25.5 Hz, C-CF3), 72.1 (CH2), 121.8 (q, JC,F
=
288.2 Hz, CF3), 127.1 (Ar), 129.0 (Ar), 131.4 (Cq, Ar), 137.6 (Cq,
Ar) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –70.82 (CF3) ppm.
4-Methoxy-N-[2,2,2-trifluoro-1-methylethylidene]aniline (1f): Brown
oil (98%). 1H NMR (400 MHz, CDCl3): δ = 2.06 (s, 3 H, CH3),
3.81 (s, 3 H, CH3-O), 6.78–6.80 (m, 2 H, Ar), 6.91–6.93 (m, 2 H,
Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.6 (CH3), 55.6
(CH3), 114.5 (Ar), 120.5 (q, 1JC,F = 273.0 Hz, CF3), 121.1 (Cq, Ar),
IR (neat): ν = 3420 (br., NH) cm–1. C H ClF N O : C 35.68, H
˜
10
7
6
2
2
2.10, N 8.32; found C 35.84, H 2.26, N 8.34.
N-[2,2,2-Trifluoro-1-(nitromethyl)-1-(trifluoromethyl)ethyl]aniline
1
(2d): Yellow oil (88%). H NMR (400 MHz, CDCl3): δ = 4.49 (br.
2
121.5 (Ar), 140.5 (Cq, Ar), 158.3 (q, JC,F = 33.0 Hz, C-CF3) ppm,
s, 1 H, H-N), 4.92 (s, 2 H, CH2), 7.20–7.24 (m, 3 H, Ar), 7.32–7.36
(m, 2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 67.3 (sept,
2JC,F = 28.5 Hz, C-CF3), 72.2 (c, CH2), 118.9 (q, 1JC,F = 292.3 Hz,
CF3), 123.3 (Ar), 125.7 (Ar), 128.9 (Ar), 139.0 (Cq, Ar) ppm. 19F
in agreement with the literature data.[23]
4-Methyl-N-[2,2,2-trifluoro-1-methylethylidene]aniline (1g): Brown
oil (78%). 1H NMR (400 MHz, CDCl3): δ = 2.07 (s, 3 H, CH3),
2.36 (s, 3 H, CH3), 6.70–6.72 (m, 2 H, Ar), 6.83–6.85 (m, 2 H, Ar)
ppm, in agreement with the literature data.[24]
NMR (376.5 MHz, CDCl ): δ = –71.04 (CF ) ppm. IR (neat): ν =
˜
3
3
3373 (br., NH) , 1159 (CF), 1149 (CF) cm–1. C10H8F6N2O2: C
39.75, H 2.67, N 9.27; found C 39.84, H 2.65, N 9.46.
4-Chloro-N-[2,2,2-trifluoro-1-methylethylidene]aniline (1h): Pale yel-
low oil (80%). 1H NMR (400 MHz, CDCl3): δ = 2.02 (s, 3 H, CH3),
4-Methyl-N-[2,2,2-trifluoro-1-(nitromethyl)-1-(trifluoromethyl)eth-
yl]benzamide (2e): Yellow solid (98%), m.p. 72–74 °C. 1H NMR
(400 MHz, CDCl3): δ = 2.43 (s, 3 H, CH3), 5.66 (s, 2 H, CH2), 6.47
(br. s, 1 H, H-N), 7.28–7.30 (m, 2 H, Ar), 7.66–7.68 (m, 2 H, Ar)
ppm. 13C NMR (100 MHz, CDCl3): δ = 21.1 (CH3), 67.2 (sept,
6.72–6.74 (m, 2 H, Ar), 7.34–7.36 (m, 2 H, Ar) ppm. 13C NMR
1
(100 MHz, CDCl3): δ = 14.4 (CH3), 118.2 (Ar), 119.7 (q, JC,F
=
278.5 Hz, CF3), 129.3 (Cq, Ar), 130.7 (Ar), 146.1 (Cq, Ar), 158.1
2
(q, JC,F = 34.7 Hz, C-CF3) ppm. 19F NMR (376.5 MHz, CDCl3):
δ = –74.60 (CF3) ppm, in agreement with the literature data.[25]
1
2JC,F = 29.3 Hz, C-CF3), 67.3 (CH2), 119.9 (Ar), 122.8 (q, JC,F
=
289.3 Hz, CF3), 126.8 (Ar), 129.3 (Cq, Ar), 143.5 (Cq, Ar), 167.2
N-[2,2,2-Trifluoro-1-methylethylidene]aniline(1i): Yellow oil (70%).
(C=O) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –72.61 (CF3)
4
1H NMR (400 MHz, CDCl3): δ = 2.03 (q, JH,F = 0.4 Hz, 3 H,
ppm. IR (neat): ν = 3350 (br., NH) , 1725 (C=O) cm–1. HRMS
˜
CH3), 6.78–6.81 (m, 2 H, Ar), 7.17–7.20 (m, 1 H, Ar), 7.37–7.41
(m, 2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.4 (CH3),
118.6 (Ar), 119.7 (q, 1JC,F = 278.3 Hz, CF3), 125.2 (Ar), 129.2 (Ar),
(ESI): calcd. for C12H10F6N2NaO3 [M + Na]+ 367.0488; found
367.0482.
2
147.2 (Cq, Ar), 157.4 (q, JC,F = 34.0 Hz, C-CF3) ppm. 19F NMR
4-Methoxy-N-[2-nitro-1,1-bis(trifluoromethyl)butyl]aniline (4a): Yel-
(376.5 MHz, CDCl3): δ = –75.00 (CF3) ppm, in agreement with the
1
low solid (62%), m.p. 69–73 °C. H NMR (400 MHz, CDCl3): δ =
literature data.[24]
3
1.02 (t, JH,H = 7.4 Hz, 3 H, CH3-CH2), 2.16–2.24 (m, 1 H, CH3-
General Procedure for the Aza-Henry Reaction of Hexafluoracetone
Imines with Nitroalkanes: Nitroalkane [nitromethane (1 mL) for
CH2), 2.41–2.53 (m, 1 H, CH3-CH2), 3.79 (s, 3 H, CH3-O), 4.76
(br. s, 1 H, H-N), 5.02 (dd, 3JH,H = 12.0, 3JH,H = 3.1 Hz, 1 H, CH),
6754
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Eur. J. Org. Chem. 2015, 6749–6761

Aza-Henry Reaction with CF3-Ketimines
6.80–6.84 (m, 2 H, Ar), 7.06–7.08 (m, 2 H, Ar) ppm. 13C NMR (m, 2 H, CH2), 1.94–2.02 (m, 2 H, CH2), 2.35 (s, 3 H, CH3), 2.74–
(100 MHz, CDCl3): δ = 10.3 (CH3-CH2), 22.4 (CH3-CH2), 55.8
2.80 (m, 6 H, 3 CH2), 3.38–3.51 (m, 6 H, 3 CH2), 6.23 (br. s, 1 H,
2
(CH3-O), 67.3 (sept, JC,F = 26.0 Hz, C-CF3), 88.5 (CH), 114.1 H-N), 7.15–7.22 (m, 2 H, Ar), 7.84–7.91 (m, 2 H, Ar) ppm. 13C
1
(Ar), 122.6 (q, JC,F = 290.4 Hz, CF3), 127.7 (Cq, Ar), 132.8 (Ar), NMR (100 MHz, CDCl3): δ = 19.2, 21.0, 23.6, 26.4, 28.6, 31.9,
157.6 (Cq, Ar) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –64.53
37.9, 48.2, 53.9, 64.2 (sept, 2JC,F = 29.3 Hz, C-CF3), 122.6 (q, 1JC,F
(q, 4JF,F = 11.6 Hz, 3 F, CF3), –67.59 (q, 4JF,F = 11.6 Hz, 3 F, CF3) = 289.3 Hz, CF3), 127.3 (Ar), 128.6 (Cq, Ar), 131.6 (Ar), 141.5 (Cq,
ppm. IR (neat): ν = 3353 (br., NH) cm–1. HRMS (ESI): calcd. for
Ar), 164.9 (c, C=O), 165.7 (c, C=O) ppm. 19F NMR (376.5 MHz,
˜
C13H15F6N2O3 [M + H]+ 360.0909; found 360.0903.
CDCl ): δ = –70.55 (CF ) ppm. IR (nujol): ν = 3110 (br., NH) ,
˜
3 3
1690 (C=O), 1670 (C=O) cm–1. C20H25F6N3O2: C 52.98, H 5.56,
N 9.27; found C 52.84, H 5.71, N 9.18.
4-Methyl-N-[2-nitro-1,1-bis(trifluoromethyl)butyl]aniline (4b): Yel-
1
3
low oil (60%). H NMR (400 MHz, CDCl3): δ = 1.03 (t, JH,H
=
7.3 Hz, 3 H, CH3-CH2), 2.16–2.21 (m, 1 H, CH3-CH2), 2.32 (s, 3
H, CH3), 2.42–2.51 (m, 1 H, CH3-CH2), 4.91 (br. s, 1 H, H-N),
General Procedure for the Aza-Henry Reaction of Trifluoracetone
Imines with Nitroalkanes: Nitroalkane [nitromethane (2.5 mmol,
0.14 mL) for substances 2f–2i; nitropropane (2.5 mmol, 0.26 mL)
3
3
5.03 (dd, JH,H = 12.0, JH,H = 3.0 Hz, 1 H, CH), 6.98–7.00 (m, 2
H, Ar), 7.08–7.10 (m, 2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): for substances 4f–4i] and base [DBN (0.25 mmol, 31 μL) for sub-
δ = 10.3 (CH3-CH2), 20.8 (CH3-CH2), 29.7 (CH3), 67.8 (sept, 2JC,F
stances 2f–2i; DBU (0.05 mmol, 8.5 μL) for substances 4f–4i] were
1
= 25.6 Hz, C-CF3), 88.5 (CH), 122.4 (q, JC,F = 293.6 Hz, CF3), added to a solution of the imine (0.25 mmol) in toluene (1 mL).
125.0 (Ar), 129.7 (Ar), 135.0 (Cq, Ar), 137.8 (Cq, Ar) ppm. 19F
The reaction was monitored by TLC (over about 20 h), then the
reaction mixture was concentrated under reduced pressure. The
4
NMR (376.5 MHz, CDCl3): δ = –65.39 (q, JF,F = 11.1 Hz, 3 F,
CF3), –68.89 (q, 4JF,F = 11.1 Hz, 3 F, CF ) ppm. IR (neat): ν = 3280 product was isolated by column chromatography (hexane/dichloro-
˜
3
(br., NH) cm–1. C13H14F6N2O2: C 45.36, H 4.10, N 8.14; found C methane, 1:1).
45.25, H 4.04, N 8.17.
4-Methoxy-N-[2,2,2-trifluoro-1-methyl-1-(nitromethyl)ethyl]aniline
1
4-Chloro-N-[2-nitro-1,1-bis(trifluoromethyl)butyl]aniline (4c): (2f): Yellow oil (78%). H NMR (400 MHz, CDCl3): δ = 1.45 (s, 3
1
2
Brownish-yellow solid (80%), m.p. 56–58 °C. H NMR (400 MHz,
H, CH3), 3.79 (s, 3 H, CH3-O), 4.56 (d, JH,H = 11.4 Hz, 1 H,
CDCl3): δ = 1.05 (t, 3JH,H = 7.3 Hz, 3 H, CH3-CH2), 2.15–2.17 (m, CH2), 4.68 (d, 2JH,H = 11.4 Hz, 1 H, CH2), 6.80–6.83 (m, 2 H, Ar),
3
1 H, CH3-CH2), 2.41–2.48 (m, 1 H, CH3-CH2), 5.03 (dd, JH,H
=
7.01–7.04 (m, 2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ =
3
2
12.0, JH,H = 3.3 Hz, 1 H, CH), 5.11 (br. s, 1 H, H-N), 7.01–7.03
17.4 (CH3), 55.0 (CH3-O), 61.0 (q, JC,F = 25.0 Hz, C-CF3), 77.5
(m, 2 H, Ar), 7.23–7.26 (m, 2 H, Ar) ppm. 13C NMR (100 MHz, (CH2), 113.8 (Ar), 122.6 (q, 1JC,F = 288.6 Hz, CF3), 127.2 (Cq, Ar),
2
CDCl3): δ = 9.8 (CH3-CH2), 22.0 (CH3-CH2), 69.2 (sept, JC,F
=
133.6 (Ar), 156.7 (Cq, Ar) ppm. 19F NMR (376.5 MHz, CDCl3): δ
27.9 Hz, C-CF3), 87.8 (CH), 122.9 (q, 1JC,F = 295.9 Hz, CF3), 125.4 = –77.48 (CF ) ppm. IR (neat): ν = 3120 (br., NH) cm–1
.
˜
3
(Ar), 128.8 (Ar), 130.2 (Cq, Ar), 138.2 (Cq, Ar) ppm. 19F NMR
C11H13F3N2O3: C 47.49, H 4.71, N 10.07; found C 47.67, H 4.88,
N 10.10.
4
(376.5 MHz, CDCl3): δ = –65.17 (q, JF,F = 11.6 Hz, 3 F, CF3),
–69.11 (q, 4JF,F = 11.6 Hz, 3 F, CF ) ppm. IR (neat): ν = 3358 (br.,
˜
3
4-Methyl-N-[2,2,2-trifluoro-1-methyl-1-(nitromethyl)ethyl]aniline
(2g): Brownish-yellow oil (70%). 1H NMR (400 MHz, CDCl3): δ
= 1.51 (s, 3 H, CH3), 2.31 (s, 3 H, CH3), 3.91 (br. s, 1 H, H-N),
NH) cm–1. C12H11ClF6N2O2: C 39.52, H 3.04, N 7.68; found C
39.62, H 3.09, N 7.55.
2
2
N-[2-Nitro-1,1-bis(trifluoromethyl)butyl]aniline (4d): Brown oil
4.55 (d, JH,H = 11.2 Hz, 1 H, CH2), 4.67 (d, JH,H = 11.2 Hz, 1
1
3
(60%). H NMR (400 MHz, CDCl3): δ = 1.04 (t, JH,H = 7.2 Hz,
3 H, CH3-CH2), 2.18–2.21 (m, 1 H, CH3-CH2), 2.42–2.51 (m, 1 H,
H, CH2), 6.94–6.96 (m, 2 H, Ar), 7.07–7.09 (m, 2 H, Ar) ppm. 13C
NMR (100 MHz, CDCl3): δ = 17.5 (CH3), 20.3 (CH3), 60.9 (q,
3
3
1
CH3-CH2), 5.06 (dd, JH,H = 11.7, JH,H = 3.4 Hz, 1 H, CH), 5.07 2JC,F = 27.3 Hz, C-CF3), 77.6 (CH2), 124.6 (Ar), 125.2 (q, JC,F
=
(br. s, 1 H, H-N), 7.08–7.15 (m, 2 H, Ar), 7.28–7.32 (m, 2 H, Ar)
286.0 Hz, CF3), 129.2 (Cq, Ar), 133.7 (Ar), 138.5 (Cq, Ar) ppm.
ppm. 13C NMR (100 MHz, CDCl3): δ = 9.8 (CH3-CH2), 22.0
19F NMR (376.5 MHz, CDCl3): δ = –78.67 (CF3) ppm. IR (neat):
2
(CH3-CH2), 69.3 (sept, JC,F = 25.3 Hz, C-CF3), 88.0 (CH), 122.2 ν = 3219 (br., NH) , 1120 (CF) cm–1. C H F N O : C 50.38, H
˜
11 13
3
2
2
(q, 1JC,F = 290.3 Hz, CF3), 123.9 (Ar), 124.5 (Ar), 128.7 (Ar), 140.2
(Cq, Ar) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –65.18 (q, 4JF,F
5.00, N 10.68; found C 50.18, H 4.88, N 10.56.
4-Chloro-N-[2,2,2-trifluoro-1-methyl-1-(nitromethyl)ethyl]aniline
4
= 11.6 Hz, 3 F, CF3), –69.11 (q, JF,F = 11.6 Hz, 3 F, CF3) ppm.
1
(2h): Yellow oil (84%). H NMR (400 MHz, CDCl3): δ = 1.54 (s,
IR (neat): ν = 3325 (br., NH) cm–1. C H F N O : C 43.65, H
˜
2
12 12
6
2
2
3 H, CH3), 4.03 (br. s, 1 H, H-N), 4.58 (d, JH,H = 12.0 Hz, 1 H,
3.66, N 8.48; found C 43.84, H 3.67, N 8.64.
CH2), 4.74 (d, 2JH,H = 12.0 Hz, 1 H, CH2), 6.95–6.97 (m, 2 H, Ar),
4-Methyl-N-[2-nitro-1,1-bis(trifluoromethyl)butyl]benzamide (4e): 7.22–7.25 (m, 2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ =
1
3
Yellow oil (64%). H NMR (400 MHz, CDCl3): δ = 1.25 (t, JH,H
17.4 (CH3), 61.0 (q, 2JC,F = 30.2 Hz, C-CF3), 78.0 (CH2), 125.0 (q,
= 7.3 Hz, 3 H, CH3-CH2), 1.99–2.04 (m, 2 H, CH3-CH2), 2.43 (s, 1JC,F = 287.9 Hz, CF3), 125.1 (Ar), 128.7 (Ar), 129.1 (Cq, Ar),
3 H, CH3), 4.76 (br. s, 1 H, H-N), 4.77–4.81 (m, 1 H, CH), 7.25– 139.9 (Cq, Ar) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –78.65
7.27 (m, 2 H, Ar), 7.91–7.94 (m, 2 H, Ar) ppm. 13C NMR (CF ) ppm. IR (neat): ν = 3380 (br., NH) cm–1. C H ClF N O :
˜
3
10 10
3
2
2
(100 MHz, CDCl3): δ = 9.8 (CH3-CH2), 21.4 (CH3-CH2), 23.6
C 42.49, H 3.57, N 9.91; found C 42.64, H 3.45, N 9.95.
2
(CH3), 68.2 (sept, JC,F = 25.0 Hz, C-CF3), 90.1 (CH), 115.3 (Ar),
N-[2,2,2-Trifluoro-1-methyl-1-(nitromethyl)ethyl]aniline (2i): Brown
oil (70%). 1H NMR (400 MHz, CDCl3): δ = 1.56 (s, 3 H, CH3),
1
123.6 (q, JC,F = 286.0 Hz, CF3), 128.9 (Cq, Ar), 133.5 (Ar), 141.2
(Cq, Ar), 157.6 (C=O) ppm. 19F NMR (376.5 MHz, CDCl3): δ =
2
4.05 (br. s, 1 H, H-N), 4.60 (d, JH,H = 12.8 Hz, 1 H, CH2), 4.75
4
4
–64.53 (q, JF,F = 11.6 Hz, 3 F, CF3), –64.59 (q, JF,F = 11.6 Hz, 3
2
(d, JH,H = 12.8 Hz, 1 H, CH2), 7.01–7.11 (m, 3 H, Ar), 7.26–7.29
F, CF ) ppm. IR (nujol): ν = 3420 (br., NH) , 1670 (C=O), 1230
˜
(m, 2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.6 (CH3),
3
(CF) cm–1. C14H14F6N2O3: C 45.17, H 3.79, N 7.53; found C 45.04,
2
61.0 (q, JC,F = 25.0 Hz, C-CF3), 77.5 (CH2), 123.7 (Ar), 124.8 (q,
H 3.67, N 7.64.
1JC,F = 285.0 Hz, CF3), 128.7 (Ar), 128.9 (Ar), 141.4 (Cq, Ar) ppm.
19F NMR (376.5 MHz, CDCl3): δ = –76.26 (CF3) ppm. IR (neat):
4-Methyl-N-(2,2,2-trifluoro-1-{[3-(2-oxoazepane-1-yl)prop-
yl]amino}-1-(trifluoromethyl)ethyl)benzamide (3e): Pale yellow solid
ν = 3349 (br., NH) cm–1. C H F N O : C 48.39, H 4.47, N 11.29;
˜
10 11
3
2
2
1
(47%), m.p. 90–93 °C. H NMR (400 MHz, CDCl3): δ = 1.61–1.76
found C 48.51, H 4.48, N 11.31.
Eur. J. Org. Chem. 2015, 6749–6761
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6755

M. V. Vovk, V. G. Nenajdenko et al.
FULL PAPER
4-Methoxy-N-[1-methyl-2-nitro-1-(trifluoromethyl)butyl]aniline (4f):
123.3 (Ar), 123.4 (Ar), 125.7 (q, 1JC,F = 289.2 Hz, CF3), 128.5 (Ar),
Yellow oil (66 %), diastereomeric mixture (1:1). 1H NMR
128.7 (Ar), 141.6 (Cq, Ar), 141.9 (Cq, Ar) ppm. 19F NMR
3
(400 MHz, CDCl3): δ = 1.01 (t, JH,H = 7.5 Hz, 3 H, CH3-CH2), (376.5 MHz, CDCl3): δ = –76.11 (CF3), –77.07 (CF3) ppm. IR
3
1.10 (t, JH,H = 7.5 Hz, 3 H, CH3-CH2), 1.24–1.27 (m, 2 H, CH3- (neat): ν = 3305 (br., NH) , 1238 (CF) cm–1. 2C H F N O ·H O:
˜
12 15
3
2
2
2
CH2), 1.28–1.31 (m, 2 H, CH3-CH2), 1.37 (s, 3 H, CH3), 1.39 (s, 3
H, CH3), 2.59–2.65 (m, 1 H, CH), 2.65–2.70 (m, 1 H, CH), 3.78 (s,
3 H, CH3-O), 3.82 (s, 3 H, CH3-O), 6.69–6.74 (m, 2 H, Ar), 6.77–
6.80 (m, 2 H, Ar), 6.85–6.90 (m, 2 H, Ar), 6.91–6.93 (m, 2 H, Ar)
ppm. 13C NMR (100 MHz, CDCl3): δ = 11.8 (CH3-CH2), 11.9
(CH3-CH2), 14.6 (CH3-CH2), 14.8 (CH3-CH2), 18.2 (CH3), 18.6
C 46.70, H 4.70, N 10.89; found C 46.81, H 4.68, N 10.81.
General Procedure for the Aza-Henry Reaction of Trifluoraceto-
phenone Imines with Nitroalkanes: N-Alkylidencarbamate 1j–1q
(4 mmol) was added to a solution of nitromethane (1.1 mL,
0.02 mol) and triethylamine (0.055 mL, 0.4 mmol) in anhydrous
DMSO (6 mL), and the mixture was kept at room temperature for
12 h. The mixture was then poured into water (30 mL), and ex-
tracted with CH2Cl2 (2 ϫ 15 mL). The combined organic layers
were dried with Na2SO4, and the solvent was evaporated. The resi-
due was purified by crystallization from hexane/2-propanol, 6:1
(compounds 2j–2n), or hexane (compounds 2p and 2q).
2
(CH3), 54.9 (CH3-O), 55.0 (CH3-O), 62.7 (q, JC,F = 25.2 Hz, C-
1
CF3), 92.1 (CH), 92.8 (CH), 113.7 (Ar), 113.9 (Ar), 115.3 (q, JC,F
= 270.0 Hz, CF3), 120.1 (Ar), 120.4 (Ar), 134.1 (Cq, Ar), 134.3 (Cq,
Ar), 140.0 (Cq, Ar), 140.3 (Cq, Ar) ppm. 19F NMR (376.5 MHz,
CDCl ): δ = –76.66 (CF ), –77.65 (CF ) ppm. IR (neat): ν = 3418
˜
3
3
3
(br., NH) cm–1. C12H16F3N2O3: C 46.39, H 4.54, N 9.02; found C
Methyl [2,2,2-Trifluoro-1-(4-fluorophenyl)-1-(nitromethyl)ethyl]-
46.53, H 4.74, N 9.12.
carbamate (2j): Pale yellow solid (84%), m.p. 116–117 °C. 1H NMR
2
4-Methyl-N-[1-methyl-2-nitro-1-(trifluoromethyl)butyl]aniline (4g):
(400 MHz, CDCl3): δ = 3.73 (s, 3 H, CH3), 5.39 (d, JH,H
=
Brownish-yellow oil (52%), diastereomeric mixture (1:1). 1H NMR
2
12.2 Hz, 1 H, CH2), 5.53 (d, JH,H = 12.2 Hz, 1 H, CH2), 5.62 (br.
3
(400 MHz, CDCl3): δ = 0.88 (t, JH,H = 7.7 Hz, 3 H, CH3-CH2),
s, 1 H, H-N), 7.12–7.14 (m, 2 H, Ar), 7.35–7.42 (m, 2 H, Ar) ppm.
3
2
13C NMR (100 MHz, CDCl3): δ = 52.7 (CH3), 63.3 (q, JC,F
=
1.02 (t, JH,H = 7.2 Hz, 3 H, CH3-CH2), 1.27–1.35 (m, 2 H, CH3-
2
CH2), 1.43–1.47 (m, 2 H, CH3-CH2), 1.99 (s, 3 H, CH3), 2.04 (s, 3
H, CH3), 2.30 (s, 3 H, CH3), 2.36 (s, 3 H, CH3), 4.47–4.61 (m, 1
H, CH), 4.72–4.77 (m, 1 H, CH), 6.70–6.72 (m, 2 H, Ar), 6.83–
6.87 (m, 2 H, Ar), 7.03–7.07 (m, 2 H, Ar), 7.17–7.20 (m, 2 H, Ar)
ppm. 13C NMR (100 MHz, CDCl3): δ = 10.0 (CH3-CH2), 10.2
(CH3-CH2), 13.7 (CH3), 13.9 (CH3), 21.7 (CH3-CH2), 21.9 (CH3-
27.5 Hz, C-CF3), 72.6 (CH2), 115.9 (d, JC,F = 22.5 Hz, Ar), 123.5
1
4
(q, JC,F = 283.8 Hz, CF3), 127.6 (d, JC,F = 2.5 Hz, Ar), 127.8 (d,
3JC,F = 8.7 Hz, Ar), 154.6 (C=O), 162.9 (d, JC,F = 250.0 Hz, Ar)
1
ppm. 19F NMR (280 MHz, CDCl3): δ = –76.32 (CF3), –112.25 (F)
ppm. IR (KBr): ν = 3360–3450 (NH), 1750 (CO), 1575 (NO ) cm–1.
˜
2
C11H10F4N2O4: C 42.59, H 3.25, N 9.03; found C 42.67, H 3.28,
N 9.14.
2
CH2), 29.3 (CH3), 29.7 (CH3), 63.5 (q, JC,F = 22.2 Hz, C-CF3),
1
91.8 (CH), 91.9 (CH), 118.5 (Ar), 118.6 (Ar), 123.0 (q, JC,F
=
Methyl [2,2,2-Trifluoro-1-(4-methylphenyl)-1-(nitromethyl)ethyl]-
carbamate (2k): Pale yellow solid (86 %), m.p. 114–115 °C. 1H
NMR (400 MHz, CDCl3): δ = 2.35 (s, 3 H, CH3), 3.73 (s, 3 H,
CH3), 5.38 (d, 2JH,H = 12.4 Hz, 1 H, CH2), 5.50–5.70 (m, 2 H, CH,
NH), 7.21–7.25 (m, 2 H, Ar), 7.22–7.38 (m, 2 H, Ar) ppm. 13C
NMR (100 MHz, CDCl3): δ = 20.7 (CH3), 52.6 (CH3), 63.4 (q,
271.6 Hz, CF3), 129.0 (Ar), 129.3 (Ar), 134.4 (Cq, Ar), 135.1 (Cq,
Ar), 151.0 (Cq, Ar), 151.2 (Cq, Ar) ppm. 19F NMR (376.5 MHz,
CDCl ): δ = –74.80 (CF ), –75.72 (CF ) ppm. IR (neat): ν = 3420
˜
3
3
3
(br., NH) cm–1. C13H17F3N2O2: C 53.79, H 5.90, N 9.65; found C
53.60, H 5.78, N 9.55.
1
2JC,F = 27.5 Hz, C-CF3), 72.6 (CH2), 123.5 (q, JC,F = 285.0 Hz,
4-Chloro-N-[1-methyl-2-nitro-1-(trifluoromethyl)butyl]aniline (4h):
Yellow oil (98 %), diastereomeric mixture (1:1). 1H NMR
CF3), 125.5 (Ar), 128.7 (Ar), 129.5 (Ar), 139.7 (Ar), 154.6 (C=O)
ppm. 19F NMR (280 MHz, CDCl3): δ = –76.27 (CF3) ppm. IR
3
(400 MHz, CDCl3): δ = 0.89 (t, JH,H = 7.0 Hz, 3 H, CH3-CH2),
3
(KBr): ν = 3350–3450 (NH), 1735 (CO), 1575 (NO ), 1370 (NO )
˜
1.02 (t, JH,H = 7.1 Hz, 3 H, CH3-CH2), 1.44 (s, 3 H, CH3), 1.49
2
2
cm–1. C12H13F3N2O4: C 47.06, H 4.28, N 9.15; found C 46.90, H
(s, 3 H, CH3), 1.80–1.87 (m, 1 H, CH3-CH2), 1.90–1.96 (m, 1 H,
CH3-CH2), 2.12–2.18 (m, 1 H, CH3-CH2), 2.23–2.31 (m, 1 H, CH3-
CH2), 3.72 (br. s, 1 H, H-N), 4.31 (br. s, 1 H, H-N), 4.72–4.74 (m,
1 H, CH), 4.75–4.77 (m, 1 H, CH), 6.73–6.76 (m, 2 H, Ar), 6.87–
6.90 (m, 2 H, Ar), 7.09–7.11 (m, 2 H, Ar), 7.19–7.23 (m, 2 H, Ar)
ppm. 13C NMR (100 MHz, CDCl3): δ = 10.0 (CH3-CH2), 10.1
(CH3-CH2), 15.7 (CH3), 15.9 (CH3), 21.4 (CH3-CH2), 21.8 (CH3-
4.19, N 9.04.
Ethyl [2,2,2-Trifluoro-1-phenyl-1-(nitromethyl)ethyl]carbamate (2l):
Pale yellow solid (90 %), m.p. 92–94 °C. 1H NMR (400 MHz,
CDCl3): δ = 1.27 (t, 3JH,H = 6.8 Hz, 3 H, CH3-CH2), 4.11–4.17 (m,
2 H, CH3-CH2), 5.44 (2JH,H = 12.0 Hz, 1 H, CH2), 5.58 (br. s, 1
2
H, H-N), 5.60 (d, JH,H = 12.0 Hz, 1 H, CH2), 7.36–7.48 (m, 5 H,
2
Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0 (CH3-CH2), 61.7
(CH3-CH2), 63.6 (q, 2JC,F = 28.8 Hz, C-CF3), 72.6 (CH2), 123.5 (q,
1JC,F = 285.0 Hz, CF3), 125.7 (Ar), 128.8 (Ar), 129.5 (Ar), 131.9
(Ar), 154.2 (C=O) ppm. 19F NMR (280 MHz, CDCl3): δ = –76.25
CH2), 62.6 (q, JC,F = 26.7 Hz, C-CF3), 91.9 (CH), 92.4 (CH),
1
119.8 (Ar), 120.0 (Ar), 124.7 (Ar), 124.8 (Ar), 125.5 (q, JC,F
=
291.1 Hz, CF3), 128.5 (Ar), 128.6 (Ar), 140.2 (Cq, Ar), 140.5 (Cq,
Ar) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –75.03 (CF3), –75.93
(CF ) ppm. IR (neat): ν = 3283 (br., NH) cm–1. C H ClF N O :
˜
3
12 14
3
2
2
(CF ) ppm. IR (KBr): ν = 3380–3450 (NH), 1750 (CO), 1580
˜
3
(NO2), 1320 (NO2) cm–1. C12H13F3N2O4: C 47.06, H 4.28, N 9.15;
C 46.39, H 4.54, N 9.09; found C 46.21, H 4.48, N 9.14.
found C 47.24, H 4.32, N 9.09.
N-[1-Methyl-2-nitro-1-(trifluoromethyl)butyl]aniline (4i): Brown oil
(37%), diastereomeric mixture (1:1). 1H NMR (400 MHz, CDCl3): Ethyl [2,2,2-Trifluoro-1-(4-fluorophenyl)-1-(nitromethyl)ethyl]carb-
δ = 0.88 (t, 3JH,H = 7.2 Hz, 3 H, CH3-CH2), 1.02 (t, 3JH,H = 7.3 Hz, amate (2m): Pale yellow solid (82 %), m.p. 74–76 °C. 1H NMR
3
3 H, CH3-CH2), 1.48 (s, 3 H, CH3), 1.52 (s, 3 H, CH3), 1.91–1.98 (400 MHz, CDCl3): δ = 1.28 (s, JH,H = 6.8 Hz, 3 H, CH3-CH2),
(m, 2 H, CH3-CH2), 2.19–2.34 (m, 2 H, CH3-CH2), 4.74–4.79 (m, 4.12–4.17 (m, 2 H, CH3-CH2), 5.41 (d, 2JH,H = 12.4 Hz, 1 H, CH2),
2
1 H, CH), 4.81–4.82 (m, 1 H, CH), 6.85–6.90 (m, 2 H, Ar), 6.93– 5.51 (d, JH,H = 12.4 Hz, 1 H, CH2), 5.56 (br. s, 1 H, H-N), 7.06–
6.97 (m, 2 H, Ar), 7.03–7.09 (m, 1 H, Ar), 7.11–7.14 (m, 1 H, Ar),
7.18 (m, 2 H, Ar), 7.38–7.43 (m, 2 H, Ar) ppm. 13C NMR
7.22–7.28 (m, 2 H, Ar), 7.30–7.37 (m, 2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0 (CH3-CH2), 61.8 (CH3-CH2), 63.3 (q,
2
(100 MHz, CDCl3): δ = 10.1 (CH3-CH2), 10.2 (CH3-CH2), 15.9
2JC,F = 28.8 Hz, C-CF3), 72.6 (CH2), 115.9 (d, JC,F = 22.5 Hz,
(CH3), 16.0 (CH3), 21.4 (CH3-CH2), 21.9 (CH3-CH2), 62.7 (q, 2JC,F Ar), 123.3 (q, 1JC,F = 283.8 Hz, CF3), 127.7 (d, 4JC,F = 1.3 Hz, Ar),
3
1
= 26.8 Hz, C-CF3), 91.9 (CH), 92.6 (CH), 123.0 (Ar), 123.2 (Ar),
127.8 (d, JC,F = 8.7 Hz, Ar), 154.1 (C=O), 162.9 (d, JC,F =
6756
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6749–6761

Aza-Henry Reaction with CF3-Ketimines
248.8 Hz, Ar) ppm. 19F NMR (280 MHz, CDCl3): δ = –76.16 3,3,3-Trifluoro-N2-(4-methoxyphenyl)-2-(trifluoromethyl)propane-
1
(CF ), –112.19 (F) ppm. IR (KBr): ν = 3350–3450 (NH), 1750
1,2-diamine (5a): Brown oil (97%). H NMR (400 MHz, CDCl3):
˜
3
(CO), 1575 (NO2), 1340 (NO2) cm–1. C12H12F4N2O4: C 44.45, H δ = 3.47 (s, 2 H, CH2), 3.78 (s, 3 H, CH3-O), 4.14 (br. s, 1 H, H-
3.73, N 8.64; found C 44.61, H 3.64, N 8.46.
N), 6.79–6.81 (m, 2 H, Ar), 6.95–6.97 (m, 2 H, Ar) ppm. 13C NMR
(100 MHz, CDCl3): δ = 40.7 (CH2), 55.4 (CH3-O), 67.2 (sept, 2JC,F
Ethyl [2,2,2-Trifluoro-1-(4-methylphenyl)-1-(nitromethyl)ethyl]carb-
1
= 29.3 Hz, C-CF3), 114.2 (Ar), 122.7 (q, JC,F = 289.3 Hz, CF3),
amate (2n): Pale yellow solid (84 %), m.p. 74–75 °C. 1H NMR
126.1 (Ar), 133.5 (Cq, Ar), 156.8 (Cq, Ar) ppm. 19F NMR
3
(400 MHz, CDCl3): δ = 1.29 (t, JH,H = 6.6 Hz, 3 H, CH3-CH2),
(376.5 MHz, CDCl ): δ = –71.77 (CF ) ppm. IR (KBr): ν = 3250
˜
2
3
3
3.82 (s, 3 H, CH3), 4.13–4.18 (m, 2 H, CH3-CH2), 5.41 (d, JH,H
=
(br., NH) , 1360 (CF) cm–1. HRMS (ESI): calcd. for C11H14F6N2O
12.3 Hz, 1 H, CH2), 5.58 (br. s, 1 H, H-N), 5.59 (d, 2JH,H = 12.4 Hz,
[M + H]+ 303.0927; found 303.0937.
1 H, CH2), 6.91–6.99 (m, 2 H, Ar), 7.31–7.35 (m, 2 H, Ar) ppm.
13C NMR (100 MHz, CDCl3): δ = 14.0 (CH3-CH2), 55.0 (CH3),
3,3,3-Trifluoro-N2-(4-methylphenyl)-2-(trifluoromethyl)propane-1,2-
2
1
61.6 (CH3-CH2), 63.3 (q, JC,F = 28.8 Hz, C-CF3), 72.6 (CH2), diamine (5b): Brown oil (80%). H NMR (400 MHz, CDCl3): δ =
114.1 (Ar), 123.5 (q, 1JC,F = 285.0 Hz, CF3), 123.6 (Ar), 127.1 (Ar), 1.34 (br. s, 2 H, NH2), 2.30 (s, 3 H, CH3), 3.32 (s, 2 H, CH2), 4.79
154.2 (C=O), 160.1 (Ar) ppm. 19F NMR (280 MHz, CDCl3): δ =
(br. s, 1 H, H-N), 6.95–6.97 (m, 2 H, Ar), 7.06–7.08 (m, 2 H, Ar)
–76.33 (CF ) ppm. IR (KBr): ν = 3380–3450 (NH), 1740 (CO),
ppm. 13C NMR (100 MHz, CDCl3): δ = 20.2 (CH3), 29.3 (CH2),
˜
3
1590 (NO2), 1320 (NO2) cm–1. C13H15F3N2O5: C 46.43, H 4.50, N 65.7 (sept, JC,F = 24.4 Hz, C-CF3), 122.5 (Ar), 123.8 (q, JC,F
=
2
1
8.33; found C 46.27, H 4.61, N 8.21.
291.1 Hz, CF3), 129.2 (Ar), 132.5 (Cq, Ar), 139.1 (Cq, Ar) ppm.
19F NMR (376.5 MHz, CDCl3): δ = –71.49 (CF3) ppm. IR (KBr):
ν = 3295 (br., NH) cm–1. HRMS (ESI): calcd. for C H F N [M
tert-Butyl [2,2,2-Trifluoro-1-phenyl-1-(nitromethyl)ethyl]carbamate
(2o): Pale yellow solid (85%), m.p. 87–88 °C. H NMR (400 MHz,
˜
1
11 14
6
2
+ H]+ 287.0975; found 287.0977.
CDCl3): δ = 1.44 (s, 9 H, 3 CH3), 5.30–5.60 (3 H, m. NH, CH2),
7.40–7.42 (m, 5 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 3,3,3-Trifluoro-N2-(4-chlorophenyl)-2-(trifluoromethyl)propane-1,2-
2
1
27.7 (CH3-C), 63.6 (q, JC,F = 27.5 Hz, C-CF3), 72.8 (CH2), 81.4
diamine (5c): Brown oil (98%). H NMR (400 MHz, CDCl3): δ =
1
(CH3-C), 123.5 (q, JC,F = 286.3 Hz, CF3), 125.8 (Ar), 128.6 (Ar),
1.29 (br. s, 2 H, NH2), 3.31 (s, 2 H, CH2), 5.19 (br. s, 1 H, H-N),
129.3 (Ar), 132.2 (Ar), 153.2 (C=O) ppm. 19F NMR (280 MHz, 6.95–6.98 (m, 2 H, Ar), 7.20–7.22 (m, 2 H, Ar) ppm. 13C NMR
2
CDCl ): δ = –76.18 (CF ) ppm. IR (KBr): ν = 3350–3450 (NH), (100 MHz, CDCl3): δ = 29.3 (CH2), 65.3 (sept, JC,F = 25.2 Hz, C-
˜
3
3
1735 (CO), 1575 (NO2), 1375 (NO2) cm–1. C14H17F3N2O4: C 50.30, CF3), 122.6 (Ar), 126.4 (q, JC,F = 248.3 Hz, CF3), 128.6 (Ar),
1
H 5.13, N 8.38; found C 50.45, H 5.27, N 8.51.
128.7 (Cq, Ar), 140.7 (Cq, Ar) ppm. 19F NMR (376.5 MHz,
CDCl ): δ = –71.31 (CF ) ppm. IR (KBr): ν = 3340 (br., NH) cm–1.
˜
3
3
tert-Butyl [2,2,2-Trifluoro-1-(4-methylphenyl)-1-(nitromethyl)ethyl]-
carbamate (2p): Pale yellow solid (86%), m.p. 77–79 °C. H NMR
C10H9ClF6N2·H2O: C 35.05, H 3.82, N 8.08; found C 35.18, H
3.93, N 8.02.
1
(400 MHz, CDCl3): δ = 1.44 (s, 9 H, 3 CH3), 2.34 (s, 3 H, CH3),
5.38 (br. s, 1 H, NH), 5.43 (2JH,H = 12.0 Hz, 1 H, CH2), 5.52 (2JH,H 3,3,3-Trifluoro-N2-(phenyl)-2-(trifluoromethyl)propane-1,2-diamine
1
= 12.0 Hz, 1 H, CH2), 7.16–7.28 (m, 2 H, Ar), 7.25–7.33 (m, 2 H, (5d): Brown oil (82%). H NMR (400 MHz, CDCl3): δ = 1.86 (br.
Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.7 (CH3-C), 63.6
s, 2 H, NH2), 2.99 (s, 2 H, CH2), 3.36 (br. s, 1 H, H-N), 6.92–6.94
2
(q, JC,F = 27.5 Hz, C-CF3), 72.8 (CH2), 81.4 (CH3-C), 123.5 (q, (m, 1 H, Ar), 7.03–7.05 (m, 2 H, Ar), 7.23–7.28 (m, 2 H, Ar) ppm.
1JC,F = 286.3 Hz, CF3), 125.8 (Ar), 128.6 (Ar), 129.3 (Ar), 132.2
(Ar), 153.2 (C=O) ppm. 19F NMR (280 MHz, CDCl3): δ = –76.22
13C NMR (100 MHz, CDCl3): δ = 27.8 (CH2), 66.1 (sept, JC,F
=
2
1
20.9 Hz, C-CF3), 119.4 (q, JC,F = 296.2 Hz, CF3), 120.9 (Ar),
(CF ) ppm. IR (KBr): ν = 3350–3450 (NH), 1740 (CO), 1575 121.4 (Ar), 122.7 (Cq, Ar), 128.7 (Ar) ppm. 19F NMR (376.5 MHz,
˜
3
(NO2), 1370 (NO2) cm–1. C15H19F3N2O4: C 51.72, H 5.50, N 8.04; CDCl ): δ = –71.56 (CF ) ppm. IR (KBr): ν = 3273 (br., NH) ,
˜
3
3
found C 51.55, H 5.37, N 8.21.
1250 (CF) cm–1. HRMS (ESI): calcd. for C10H11F6N2 [M + H]+
273.0813; found 273.0821.
tert-Butyl [2,2,2-Trifluoro-1-(4-fluorophenyl)-1-(nitromethyl)ethyl]-
carbamate (2q): Pale yellow solid (82%), m.p. 71–72 °C. H NMR
N2-(4-Chlorophenyl)-3,3,3-trifluoro-2-methylpropane-1,2-diamine
1
1
(400 MHz, CDCl3): δ = 1.44 (s, 9 H, 3 CH3), 5.38 (br. s, 1 H, H- (5h): Brown oil (88%). H NMR (400 MHz, CDCl3): δ = 1.37 (s,
N), 5.56 (br. s, 2 H, CH2), 7.09–7.15 (m, 2 H, Ar), 7.38–7.43 (m, 2
3 H, CH3), 1.56 (br. s, 2 H, NH2), 2.70–2.73 (m, 1 H, CH2), 3.21–
H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.1 (3 CH3), 63.6 3.24 (m, 1 H, CH2), 4.66 (br. s, 1 H, H-N), 6.82–6.84 (m, 2 H, Ar),
2
(q, JC,F = 28.2 Hz, C-CF3), 73.1 (CH2), 82.1 (CH3-C), 116.1 (d, 7.14–7.17 (m, 2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ =
1
2JC,F = 22.1 Hz, Ar), 123.8 (q, JC,F = 285.7 Hz, CF3), 128.3 (d,
17.9 (CH3), 29.3 (CH2), 59.3 (q, 2JC,F = 25.6 Hz, C-CF3), 119.7 (q,
1JC,F = 376.5.7 Hz, CF3), 121.1 (Ar), 125.5 (Cq, Ar), 128.4 (Ar),
1
4JC,F = 9.0 Hz, Ar), 128.4 (Ar), 153.6 (C=O), 163.3 (d, JC,F
=
250.5 Hz, Ar) ppm. 19F NMR (280 MHz, CDCl3): δ = –76.40 142.8 (Cq, Ar) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –77.03
(CF ), –112.19 (F) ppm. IR (KBr): ν = 3350–3450 (NH), 1750
(CF ) ppm. IR (KBr): ν = 3205 (br., NH) cm–1. C ClH F N : C
˜
3 10 12 3 2
˜
3
(CO), 1575 (NO2), 1340 (NO2) cm–1. C12H12F4N2O4: C 44.45, H 47.54, H 4.79, N 11.09; found C 47.45, H 4.93, N 11.05.
3.73, N 8.64; found C 44.61, H 3.64, N 8.46.
1,1,1-Trifluoro-N2-(4-methoxyphenyl)-2-(trifluoromethyl)pentane-
1
Reduction of Nitroamines 2a–2i to Diamines: Concentrated hydro-
chloric acid (3.65 mL) and water (4.2 mL) were added to a solution
of the nitroamine (0.2 mmol) in methanol (15 mL). Then, zinc pow-
der (3.2 mmol, 208 mg) was added in portions over 1 h with vigor-
ous stirring under argon. The reaction mixture was stirred over-
night at room temperature, then saturated aqueous sodium
hydrogen carbonate solution was added (to pH 8). The aqueous
phase was extracted with ethyl acetate (3ϫ 50 mL), and then the
combined organic layers were dried with sodium sulfate, and con-
centrated under reduced pressure. The residue was purified by col-
umn chromatography (dichloromethane/methanol, 100:3).
2,3-diamine (6a): Yellow oil (96%). H NMR (400 MHz, CDCl3):
3
δ = 1.06 (t, JH,H = 7.1 Hz, 3 H, CH3-CH2), 1.25–1.28 (m, 2 H,
CH3-CH2), 3.20–3.23 (m, 1 H, CH), 3.78 (s, 3 H, CH3), 4.66 (br.
s, 1 H, H-N), 6.79–6.81 (m, 2 H, Ar), 7.01–7.04 (m, 2 H, Ar) ppm.
13C NMR (100 MHz, CDCl3): δ = 11.4 (CH3-CH2), 24.8 (CH3-
2
CH2), 54.3 (CH), 54.9 (CH3), 69.7 (sept, JC,F = 28.3 Hz, C-CF3),
1
113.6 (Ar), 122.6 (q, JC,F = 294.5 Hz, CF3), 125.8 (Cq, Ar), 134.5
(Ar), 156.1 (Cq, Ar) ppm. 19F NMR (376.5 MHz, CDCl3): δ =
4
4
–66.35 (q, JF,F = 9.2 Hz, CF3), –68.28 (q, JF,F = 9.2 Hz, CF3)
ppm. IR (KBr): ν = 3300 (br., NH) cm–1. HRMS (ESI): calcd. for
˜
C13H17F6N2O [M + H]+ 331.1240; found 331.1244.
Eur. J. Org. Chem. 2015, 6749–6761
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6757

M. V. Vovk, V. G. Nenajdenko et al.
FULL PAPER
1,1,1-Trifluoro-N2-(4-methylphenyl)-2-(trifluoromethyl)pentane-2,3- was washed with ammonia (15% aqueous solution; 10 mL), water
1
diamine (6b): Brown oil (80%). H NMR (400 MHz, CDCl3): δ =
(20 mL), dried with Na2SO4, and evaporated. The residue was
3
1.08 (t, JH,H = 7.4 Hz, 3 H, CH3-CH2), 1.27 (s, 3 H, CH3), 1.42 recrystallized from hexane.
(br. s, 2 H, NH2), 2.02–2.08 (m, 2 H, CH3-CH2), 3.22–3.25 (m, 1
Methyl [1-(Aminomethyl)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]-
H, CH), 5.17 (br. s, 1 H, H-N), 7.00–7.03 (m, 2 H, Ar), 7.38–7.40
1
carbamate (5j): Pale yellow solid (81%), m.p. 87–89 °C. H NMR
(m, 2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.4 (CH3-
2
(400 MHz, CDCl3): δ = 1.42 (br. s, 2 H, NH2), 3.19 (d, JH,H
=
2
CH2), 20.2 (CH3), 24.7 (CH3-CH2), 54.4 (CH), 69.5 (sept, JC,F
=
12.8 Hz, 1 H, CH2), 3.55–3.70 (m, 4 H, CH3, CH), 6.02 (br. s, 1
H, H-N), 7.06–7.08 (m, 2 H, Ar), 7.37–7.42 (m, 2 H, Ar) ppm. 13
NMR (100 MHz, CDCl3): δ = 52.0 (CH3), 46.5 (CH2), 64.2 (C-
1
27.8 Hz, C-CF3), 122.7 (Ar), 126.2 (q, JC,F = 279.0 Hz, CF3),
C
129.1 (Cq, Ar), 132.4 (Ar), 139.3 (Cq, Ar) ppm. 19F NMR
4
(376.5 MHz, CDCl3): δ = –66.38 (q, JF,F = 8.9 Hz, CF3), –68.41
2
1
CF3), 115.2 (d, JC,F = 21.3 Hz, Ar), 125.5 (q, JC,F = 286.3 Hz,
(q, 4JF,F = 8.9 Hz, CF ) ppm. IR (KBr): ν = 3373 (br., NH) , 1159
˜
CF3), 127.8 (d, 4JC,F = 7.5 Hz, Ar), 131.5 (Ar), 154.8 (C=O), 162.2
3
(CF), 1149 (CF) cm–1. HRMS (ESI): calcd. for C13H17F6N2 [M +
(d, JC,F = 247.5 Hz, Ar) ppm. 19F NMR (280 MHz, CDCl3): δ =
1
H]+ 315.1292; found 315.1290.
–72.72 (CF ), –114.88 (F) ppm. IR (KBr): ν = 3300–3420 (NH),
˜
3
1735 (CO) cm–1. C11H12F4N2O2: C 47.15, H 4.32, N 10.00; found
1,1,1-Trifluoro-N2-(4-chlorophenyl)-2-(trifluoromethyl)pentane-2,3-
1
C 47.27, H 4.28, N 10.14.
diamine (6c): Brown oil (94%). H NMR (400 MHz, CDCl3): δ =
3
1.07 (t, JH,H = 7.3 Hz, 3 H, CH3-CH2), 1.45 (br. s, 2 H, NH2),
Methyl [1-(Aminomethyl)-2,2,2-trifluoro-1-(4-methylphenyl)ethyl]-
carbamate (5k): Pale yellow solid (86 %), m.p. 121–122 °C. 1H
NMR (400 MHz, CDCl3): δ = 1.44 (br. s, 2 H, NH2), 2.35 (s, 3 H,
CH3), 3.25–3.29 (m, 1 H, CH), 3.60–3.80 (m, 4 H, CH, CH3), 5.91
(br. s, 1 H, NH), 7.13–7.27 (m, 2 H, Ar), 7.26–7.40 (m, 2 H, Ar)
ppm. 13C NMR (100 MHz, CDCl3): δ = 20.6 (CH3), 52.0 (CH3),
1.65–1.68 (m, 2 H, CH3-CH2), 3.25–3.27 (m, 1 H, CH), 5.45 (br. s,
1 H, H-N), 6.93–6.96 (m, 2 H, Ar), 7.17–7.20 (m, 2 H, Ar) ppm.
13C NMR (100 MHz, CDCl3): δ = 11.4 (CH3-CH2), 24.8 (CH3-
2
CH2), 54.7 (CH), 68.3 (sept, JC,F = 24.8 Hz, C-CF3), 122.6 (Ar),
1
125.3 (Ar), 127.0 (q, JC,F = 206.4 Hz, CF3), 128.4 (Cq, Ar), 141.2
(Cq, Ar) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –66.05 (q, 4JF,F
1
46.0 (CH2), 64.6 (C-CF3), 125.6 (q, JC,F = 286.3 Hz, CF3), 125.7
4
(Ar), 129.0 (Ar), 132.1 (Ar), 138.0 (Ar), 154.8 (C=O) ppm. 19F
= 9.1 Hz, CF3), –68.58 (q, JF,F = 9.1 Hz, CF ) ppm. IR (KBr): ν
˜
3
= 3263 (br., NH) cm–1. 4C12ClH13F6N2·5H2O: C 40.35, H 4.37, N
NMR (280 MHz, CDCl ): δ = –72.47 (CF ) ppm. IR (KBr): ν =
˜
3
3
3300–3420 (NH), 1740 (CO) cm–1. C12H15F3N2O2: C 52.17, H 5.47,
7.84; found C 40.20, H 4.17, N 7.62.
1,1,1-Trifluoro-N2-(phenyl)-2-(trifluoromethyl)pentane-2,3-diamine
N 10.14; found C 52.37, H 5.38, N 10.19.
1
(6d): Yellow oil (89%). H NMR (400 MHz, CDCl3): δ = 1.10 (t,
Ethyl [1-(Aminomethyl)-2,2,2-trifluoro-1-(phenyl)ethyl]carbamate
3JH,H = 7.9 Hz, 3 H, CH3-CH2), 1.80–1.88 (m, 1 H, CH3-CH2),
1.97–2.07 (m, 1 H, CH3-CH2), 3.39–3.42 (m, 1 H, CH), 7.03–7.09
(m, 3 H, Ar), 7.23–7.29 (m, 2 H, Ar) ppm. 13C NMR (100 MHz,
CDCl3): δ = 11.4 (CH3-CH2), 29.3 (CH3-CH2), 54.5 (CH), 69.3
(5l): Pale yellow solid (86 %), m.p. 119–120 °C. 1H NMR
3
(400 MHz, CDCl3): δ = 1.22 (t, JH,H = 7.2 Hz, 3 H, CH3-CH2),
2
1.42 (br. s, 2 H, NH2), 3.27 (d, JH,H = 13.8 Hz, 1 H, CH2), 3.68
(d, 2JH,H = 13.8 Hz, 1 H, CH2), 4.10 (q, 2JH,H = 7.2 Hz, 2 H, CH3-
CH2), 5.90 (br. s, 1 H, H-N), 7.30–7.55 (m, 5 H, Ar) ppm. 13C
NMR (100 MHz, CDCl3): δ = 14.0 (CH3-CH2), 60.9 (CH3-CH2),
2
1
(sept, JC,F = 25.8 Hz, C-CF3), 116.5 (Ar), 122.3 (q, JC,F
=
232.3 Hz, CF3), 122.7 (Ar), 128.6 (Ar), 141.7 (Cq, Ar) ppm. 19F
4
2
1
NMR (376.5 MHz, CDCl3): δ = –66.48 (q, JF,F = 8.3 Hz, CF3),
46.3 (CH2), 64.8 (q, JC,F = 25.0 Hz, C-CF3), 125.6 (q, JC,F
=
–68.20 (q, 4JF,F = 8.3 Hz, CF ) ppm. IR (KBr): ν = 3220 (br., NH)
˜
3
286.3 Hz, CF3), 125.9 (Ar), 128.1 (Ar), 128.3 (Ar), 135.3 (Ar),
cm–1. C12H14F6N2: C 48.00, H 4.70, N 9.33; found C 48.20, H 4.63,
154.5 (C=O) ppm. 19F NMR (280 MHz, CDCl3): δ = –72.30 (CF3)
ppm. IR (KBr): ν = 3300–3420 (NH), 1740 (CO) cm– 1
.
N 9.22.
˜
N2-(4-Chlorophenyl)-3,3,3-trfluoromethyl-2-methylpentane-2,3-di-
amine (6h): Brown oil (82 %), diastereomeric mixture (1:1). 1H
C12H15F3N2O2: C 52.17, H 5.47, N 10.14; found C 52.37, H 5.38,
N 10.05.
3
NMR (400 MHz, CDCl3): δ = 1.01 (t, JH,H = 7.4 Hz, 3 H, CH3-
Ethyl [1-(Aminomethyl)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]carb-
3
amate (5m): Pale yellow solid (81 %), m.p. 89–90 °C. 1H NMR
CH2), 1.05 (t, JH,H = 7.3 Hz, 3 H, CH3-CH2), 1.37 (s, 3 H, CH3),
3
1.40 (s, 3 H, CH3), 1.63–1.71 (m, 2 H, CH3-CH2), 1.87–1.95 (m, 2
(400 MHz, CDCl3): δ = 1.23 (s, JH,H = 7.2 Hz, 3 H, CH3-CH2),
3
3
2
H, CH3-CH2), 2.68 (dd, JH,H = 11.5, JH,H = 2.6 Hz, 1 H, CH),
1.42 (br. s, 2 H, NH2), 3.23 (d, JH,H = 13.0 Hz, 1 H, CH2), 3.64
3
3
(d, 2JH,H = 13.0 Hz, 1 H, CH2), 4.10 (q, 2JH,H = 7.2 Hz, 2 H, CH3-
CH2), 6.01 (br. s, 1 H, H-N), 7.00–7.16 (m, 2 H, Ar), 7.28–7.36 (m,
2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0 (CH3-CH2),
3.15 (dd, JH,H = 10.1, JH,H = 2.7 Hz, 1 H, CH), 4.67 (br. s, 1 H,
H-N), 4.99 (br. s, 1 H, H-N), 6.68–6.60 (m, 2 H, Ar), 6.78–6.83 (m,
2 H, Ar), 7.08–7.10 (m, 2 H, Ar), 7.11–7.16 (m, 2 H, Ar) ppm. 13
C
2
NMR (100 MHz, CDCl3): δ = 10.6 (CH3-CH2), 11.8 (CH3-CH2),
16.3 (CH3), 16.5 (CH3), 22.7 (CH3-CH2), 24.8 (CH3-CH2), 55.6
61.0 (CH3-CH2), 46.5 (CH2), 64.4 (q, JC,F = 25.0 Hz, C-CF3),
2
1
115.2 (d, JC,F = 21.3 Hz, Ar), 125.5 (q, JC,F = 286.3 Hz, CF3),
2
4
(CH), 59.4 (CH), 61.6 (q, JC,F = 23.6 Hz, C-CF3), 120.7 (Ar),
127.8 (d, JC,F = 7.5 Hz, Ar), 131.1 (Ar), 154.4 (C=O), 162.2 (d,
1
1JC,F = 246.3 Hz, Ar) ppm. 19F NMR (280 MHz, CDCl3): δ =
121.5 (Ar), 124.2 (q, JC,F = 230.0 Hz, CF3), 124.7 (Cq, Ar), 125.3
(Cq, Ar), 128.3 (Ar), 128.9 (Ar), 142.9 (Cq, Ar), 143.3 (Cq, Ar)
–72.70 (CF ), –114.86 (F) ppm. IR (KBr): ν = 3300–3420 (NH),
˜
3
ppm. 19F NMR (376.5 MHz, CDCl3): δ = –72.91 (CF3), –75.27
1740 (CO) cm–1. C12H14F4N2O2: C 48.98, H 4.80, N 9.52; found C
(CF ) ppm. IR (KBr): ν = 3373 (br., NH) , 1159 (CF), 1149 (CF)
˜
48.78, H 4.64, N 9.66.
3
cm–1. C12ClH13F6N2: C 51.34, H 5.74, N 9.98; found C 51.17, H
Ethyl [1-(Aminomethyl)-2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl]-
carbamate (5n): Pale yellow solid (88%), m.p. 78–80 °C. H NMR
(400 MHz, CDCl3): δ = 1.22 (t, JH,H = 7.2 Hz, 3 H, CH3-CH2),
5.94, N 9.76.
1
3
Reduction of Nitroamines 2j–2r to Diamines: NiCl2·6H2O (0.48 g,
2 mmol) and NaBH4 (0.38 g, 10 mmol) were successively added to 1.47 (br. s, 2 H, NH2), 3.26 (d, JH,H = 14.0 Hz, 1 H, CH2), 3.66
2
2
2
a cooled (0 °C) solution of carbamate 2j–2r (2 mmol) in methanol
(10 mL), and the resulting mixture was stirred for 30–40 min. The
solvent was evaporated at room temperature. Ammonia (15 %
aqueous solution; 20 mL) was added to the residue, and the mix-
ture was extracted with CH2Cl2 (3ϫ 15 mL). The organic layer
(d, JH,H = 14.0 Hz, 1 H, CH2), 3.79 (s, 3 H, CH3), 4.09 (q, JH,H
= 7.2 Hz, 2 H, CH3-CH2), 5.77 (br. s, 1 H, H-N), 6.81–6.97 (m, 2
H, Ar), 7.26–7.42 (m, 2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3):
δ = 14.1 (CH3-CH2), 54.9 (CH3), 60.9 (CH3-CH2), 45.9 (CH2), 64.5
(q, 2JC,F = 25.0 Hz, C-CF3), 113.7 (Ar), 125.6 (q, 1JC,F = 286.3 Hz,
6758
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6749–6761

Aza-Henry Reaction with CF3-Ketimines
1
1
CF3), 127.0 (Ar), 127.1 (Ar), 154.5 (C=O), 159.1 (Ar) ppm. 19F
CF3), 122.0 (q, JC,F = 252.5 Hz, CF3), 122.5 (q, JC,F = 235.9 Hz,
CF3), 122.6 (Ar), 128.8 (Ar), 139.1 (Cq, Ar), 140.8 (Cq, Ar), 184.6
NMR (280 MHz, CDCl ): δ = –72.96 (CF ) ppm. IR (KBr): ν =
˜
3
3
3300–3420 (NH), 1735 (CO) cm–1. C13H17F3N2O3: C 50.98, H 5.59, (C=N) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –72.20 (CF3)
N 9.15; found C 50.79, H 5.71, N 9.34.
ppm. IR (KBr): ν = 3420 (br., OH, NH) cm–1. C H ClF N O: C
˜
10 7 6 2
37.46, H 2.20, N 8.74; found C 37.50, H 2.17, N 8.86.
tert-Butyl [1-(Aminomethyl)-2,2,2-trifluoro-1-(phenyl)ethyl]carb-
amate (5o): Pale yellow solid (84 %), m.p. 77–78 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.20–1.60 (m, 11 H, 3 CH3, NH2), 3.27 (d,
3,3,3- Trifluoro-2-[(phenyl)amino]-2-(trfluoromethyl)propanal Ox-
1
ime (7d): Brown oil (76%). H NMR (400 MHz, CDCl3): δ = 4.34
2
2JH,H = 14.1 Hz, 1 H, CH2), 3.65 (d, JH,H = 14.1 Hz, 1 H, CH2),
(br. s, 1 H, H-N), 6.93–6.95 (m, 2 H, Ar), 7.05–7.07 (m, 1 H, Ar),
7.24–7.28 (m, 2 H, Ar), 7.54 (s, 1 H, CH), 8.26 (br. s, 1 H, H-O)
ppm. 13C NMR (100 MHz, CDCl3): δ = 67.2 (sept, 2JC,F = 31.0 Hz,
5.69 (br. s, 1 H, H-N), 7.32–7.58 (m, 5 H, Ar) ppm. 13C NMR
(100 MHz, CDCl3): δ = 27.7 (CH3-C), 46.4 (CH2), 64.9 (C-CF3),
2
1
C-CF3), 121.0 (Ar), 122.7 (q, JC,F = 292.1 Hz, CF3), 122.9 (Ar),
80.1 (CH3-C), 125.7 (q, JC,F = 285.0 Hz, CF3), 125.9 (Ar), 127.9
128.8 (Ar), 141.4 (Cq, Ar), 167.2 (C=N) ppm. 19F NMR
(Ar), 128.1 (Ar), 135.6 (Ar), 153.7 (C=O) ppm. 19F NMR
(376.5 MHz, CDCl ): δ = –72.23 (CF ) ppm. IR (KBr): ν = 3415
˜
3
3
(280 MHz, CDCl ): δ = –72.51 (CF ) ppm. IR (KBr): ν = 3300–
˜
3
3
(br., OH, NH) cm–1. 2C10H8F6N2O·3H2O: C 38.35, H 3.54, N 8.94;
3420 (NH), 1740 (CO) cm–1. C14H19F3N2O2: C 55.26, H 6.29, N
found C 38.55, H 3.52, N 9.03.
9.21; found C 55.38, H 6.11, N 9.37.
2-[(4-Chlorophenyl)amino]-3,3,3-trifluoro-2-methylpropanal Oxime
(7h): Yellow oil (90%). H NMR (400 MHz, [D6]DMSO): δ = 1.50
tert-Butyl [1-(Aminomethyl)-2,2,2-trifluoro-1-(4-methylphenyl)eth-
yl]carbamate (5p): Pale yellow solid (82 %), m.p. 93–94 °C. 1H
NMR (400 MHz, CDCl3): δ = 1.38 (s, 9 H, 3 CH3), 1.45 (br. s, 2
H, NH2), 2.32 (s, 3 H, CH3), 3.24–3.28 (m, 1 H, CH2), 3.61–3.65
(m, 1 H, CH2), 5.59 (br. s, 1 H, NH), 7.09–7.25 (m, 2 H, Ar), 7.22–
7.38 (m, 2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.6
(CH3-C), 27.8 (CH3), 46.0 (CH2), 64.6 (q, 2JC,F = 25.0 Hz, C-CF3),
1
(s, 3 H, CH3), 4.54 (br. s, 1 H, H-N), 5.68 (s, 1 H, CH), 6.81–6.85
(m, 2 H, Ar), 7.13–7.17 (m, 2 H, Ar) ppm. 13C NMR (100 MHz,
2
[D6]DMSO): δ = 17.7 (CH3), 59.5 (q, JC,F = 25.8 Hz, C-CF3),
2
127.2 (q, JC,F = 276.4 Hz, CF3), 120.3 (Ar), 120.8 (Cq, Ar), 128.9
(Ar), 144.7 (Cq, Ar), 166.7 (C=N) ppm. 19F NMR (376.5 MHz,
[D ]DMSO): δ = –72.20 (CF ) ppm. IR (KBr): ν = 3408 (br., OH,
˜
1
6
3
80.0 (CH3-C), 125.7 (q, JC,F = 286.3 Hz, CF3), 125.9 (Ar), 128.9
NH) cm–1. 3C10ClH10F3N2O·H2O: C 40.68, H 3.32, N 8.03; found
(Ar), 132.5 (Ar), 137.8 (Ar), 153.7 (C=O) ppm. 19F NMR
C 40.79, H 3.50, N 7.94.
(280 MHz, CDCl ): δ = –72.59 (CF ) ppm. IR (KBr): ν = 3300–
˜
3
3
3420 (NH), 1740 (CO) cm–1. C15H21F3N2O2: C 56.59, H 6.65, N
2-[(4-Methoxyphenyl)amino]-1,1,1-trfluoro-2-(trifluoromethyl)pent-
ane-3-one Oxime (8a): Yellow oil (76 %). 1H NMR (400 MHz,
CDCl3): δ = 1.03 (t, 3JH,H = 7.3 Hz, 3 H, CH3-CH2), 1.24 (m, 2 H,
CH3-CH2), 1.86 (br. s, 1 H, H-O), 3.80 (s, 3 H, CH3), 4.74 (br. s, 1
8.80; found C 56.80, H 6.70, N 8.64.
Reduction of Nitroamines 2a–2h, 3a–3h to Oximes: Nitroamine 2a–
2h, 3a–3h (0.2 mmol) was dissolved in methanol (15 mL), and satu-
rated aqueous ammonia (2 mL) and palladium on carbon (10%;
50 mg) as catalyst were added. The suspension was stirred under a
hydrogen atmosphere for 28 h, then it was filtered through a Celite
plug. The filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography (dichloromethane/
methanol, 100:1).
H, H-N), 6.77–6.84 (m, 2 H, Ar), 7.05–7.08 (m, 2 H, Ar) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 9.9 (CH3-CH2), 22.0 (CH3-CH2),
2
55.4 (CH3-O), 69.5 (sept, JC,F = 22.4 Hz, C-CF3), 113.7 (Ar),
1
124.0 (q, JC,F = 220.0 Hz, CF3), 127.3 (Ar), 131.6 (Cq, Ar), 157.2
(Cq, Ar), 167.2 (C=N) ppm. 19F NMR (376.5 MHz, CDCl3): δ =
–69.42 (CF ) ppm. IR (KBr): ν = 3380 (br., OH, NH) cm–1. HRMS
˜
3
(ESI): calcd. for C13H14F6N2NaO2-OH– [M + Na]+ 367.0852;
3,3,3-Trifluoro-2-[(4-methoxyphenyl)amino]-2-(trfluoromethyl)pro-
found 367.0852.
p
a
n
-
2-[(4-Chlorophenyl)amino]-1,1,1-trfluoro-2-(trifluoromethyl)pentane-
3-one Oxime (8c): Yellowish-brown oil (82%). 1H NMR (400 MHz,
CDCl3): δ = 1.18 (t, 3JH,H = 7.4 Hz, 3 H, CH3-CH2), 2.48 (q, 3JH,H
= 7.4 Hz, 2 H, CH3-CH2), 4.34 (br. s, 1 H, H-N), 6.75–6.77 (m, 2
H, Ar), 7.03–7.09 (m, 2 H, Ar), 9.26 (br. s, 1 H, H-O) ppm. 13C
NMR (100 MHz, CDCl3): δ = 11.5 (CH3-CH2), 20.1 (CH3-CH2),
al Oxime (7a): Brown oil (82%). 1H NMR (400 MHz, CDCl3): δ
= 3.78 (s, 3 H, CH3-O), 4.14 (br. s, 1 H, H-N), 6.79–6.81 (m, 2 H,
Ar), 6.95–6.97 (m, 2 H, Ar), 7.47 (s, 1 H, CH) ppm. 13C NMR
2
(100 MHz, CDCl3): δ = 55.4 (CH3-O), 67.2 (sept, JC,F = 29.3 Hz,
1
C-CF3), 114.2 (Ar), 122.7 (q, JC,F = 289.3 Hz, CF3), 126.1 (Cq,
Ar), 133.5 (Ar), 141.3 (Cq, Ar), 156.8 (C=N) ppm. 19F NMR
2
69.3 (sept, JC,F = 26.4 Hz, C-CF3), 116.5 (Ar), 120.8 (Ar), 122.5
(376.5 MHz, CDCl ): δ = –71.77 (CF ) ppm. IR (KBr): ν = 3400
˜
1
3
3
(q, JC,F = 221.9 Hz, CF3), 128.7 (Cq, Ar), 141.6 (Cq, Ar), 153.6
(br., OH, NH) cm–1. C10H10F6N2O2: C 41.78, H 3.19, N 8.86;
(C=N) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –69.63 (CF3)
found C 41.88, H 2.99, N 8.72.
p p m . I R ( K B r ) : ν = 3 3 8 0 ( b r . , O H , N H ) c m – 1
.
˜
3C12H11ClF6N2O·H2O: C 40.68, H 3.32, N 8.03; found C 40.79, H
3.50, N 7.94.
3,3,3-Trifluoro-2-[(4-methylphenyl)amino]-2-(trfluoromethyl)propan-
al Oxime (7b): Reddish-brown oil (80 %). 1H NMR (400 MHz,
CDCl3): δ = 2.29 (s, 3 H, CH3), 4.20 (br. s, 1 H, H-N), 6.85–6.87
(m, 2 H, Ar), 7.05–7.07 (m, 2 H, Ar), 7.51 (s, 1 H, CH), 8.05 (br.
s, 1 H, H-O) ppm. 13C NMR (100 MHz, CDCl3): δ = 29.3 (CH3),
2-[Phenylamino]-1,1,1-trfluoro-2-(trifluoromethyl)pentane-3-one
Oxime (8d): Yellowish-brown oil (82 %). 1H NMR (400 MHz,
CDCl3): δ = 1.17 (t, 3JH,H = 7.4 Hz, 3 H, CH3-CH2), 2.46 (m, 2 H,
CH3-CH2), 4.34 (br. s, 1 H, H-N), 6.74–6.76 (m, 2 H, Ar), 6.90–
6.93 (m, 1 H, Ar), 7.18–7.20 (m, 2 H, Ar), 8.29 (br. s, 1 H, H-O)
ppm. 13C NMR (100 MHz, CDCl3): δ = 9.4 (CH3-CH2), 20.5
2
1
67.4 (sept, JC,F = 21.2 Hz, C-CF3), 120.7 (q, JC,F = 282.7 Hz,
CF3), 121.2 (Ar), 129.3 (Cq, Ar), 141.5 (Ar), 155.0 (Cq, Ar), 164.7
(C=N) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –72.21 (CF3)
ppm. IR (KBr): ν = 3400 (br., OH, NH) cm–1. C H F N O: C
2
˜
10 10
6
2
(CH3-CH2), 70.0 (sept, JC,F = 26.3 Hz, C-CF3), 117.0 (Ar), 121.2
1
40.00, H 5.19, N 8.48; found C 40.28, H 5.23, N 8.52.
(Ar), 123.7 (q, JC,F = 247.6 Hz, CF3), 129.1 (Ar), 141.9 (Cq, Ar),
154.4 (C=N) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –69.66
3,3,3-Trifluoro-2-[(4-chlorophenyl)amino]-2-(trfluoromethyl)propan-
al Oxime (7c): Yellowish-brown oil (94%). 1H NMR (400 MHz,
CDCl3): δ = 4.37 (br. s, 1 H, H-N), 6.86–6.88 (m, 2 H, Ar), 7.21–
(CF ) ppm. IR (KBr): ν = 3380 (br., OH, NH) cm–1. C H F N O:
˜
3
12 12
6
2
C 37.46, H 2.20, N 8.74; found C 37.28, H 2.23, N 8.62.
2-[(4-Chlorophenyl)amino]-1,1,1-trifluoro-2-methylpentane-3-one
7.23 (m, 2 H, Ar), 7.52 (s, 1 H, CH), 8.98 (br. s, 1 H, H-O) ppm.
13C NMR (100 MHz, CDCl3): δ = 67.2 (sept, JC,F = 27.6 Hz, C- Oxime (8h): Yellowish-brown oil (82%). H NMR (400 MHz, [D6]
2
1
Eur. J. Org. Chem. 2015, 6749–6761
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6759

M. V. Vovk, V. G. Nenajdenko et al.
FULL PAPER
DMSO): δ = 1.00 (t, JH,H = 7.2 Hz, 3 H, CH3-CH2), 1.40 (s, 3 H,
3
C11H11F3N2O2: C 50.77, H 4.26, N 10.77; found C 50.62, H 4.36,
CH3), 1.55–1.59 (m, 2 H, CH3-CH2), 3.36 (br. s, 1 H, H-N), 6.94– N 10.69.
6.96 (m, 2 H, Ar), 7.14–7.17 (m, 2 H, Ar), 7.38 (br. s, 1 H, H-O)
General Procedure for the Preparation of 1,2-Diamines 10k and 10l:
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 11.3 (CH3-CH2), 15.2
(CH3), 21.6 (CH3-CH2), 62.7 (q, 2JC,F = 24.7 Hz, C-CF3), 117.0 (q,
1JC,F = 263.3 Hz, CF3), 119.7 (Ar), 120.8 (Ar), 128.6 (Cq, Ar),
144.5 (Cq, Ar), 155.0 (C=N) ppm. 19F NMR (376.5 MHz, [D6]
Carbamate 2k or 2l (0.5 mmol) was added to a saturated solution
of hydrogen chloride in dioxane (2 mL). The mixture was stirred
for 4 h. The resulting precipitate was collected by filtration and
dried under reduced pressure.
DMSO): δ = –73.25 (CF ) ppm. IR (KBr): ν = 3400 (br., OH, NH)
˜
3
3,3,3-Trifluoro-2-(phenyl)propane-1,2-diamine Dihydrochloride
cm–1. C12H14ClF3N2O: C 48.91, H 4.79, N 9.51; found C 48.88, H
(10k): Pale yellow solid (90 %), m.p. ca. 170 °C. 1H NMR
4.73, N 9.52.
2
(400 MHz, [D6]DMSO): δ = 3.55 (d, JH,H = 13.4 Hz, 1 H, CH2),
3.88 (d, JH,H = 13.4 Hz, 1 H, CH2), 3.80–6.00 (m, 6 H, 2 NH3+),
2
General Procedure for the Preparation of Imidazoline-2-ones 9j–9n:
DBU (0.031 g, 0.02 mmol) was added to a solution of carbamate
4j–4n (0.7 mmol) in toluene (5 mL). The mixture was heated for
2 h, then it was cooled to room temperature. The resulting precipi-
tate was collected by filtration and dried in air.
7.45–7.51 (m, 3 H, Ar), 7.66–7.71 (m, 2 H, Ar) ppm. 13C NMR
2
(100 MHz, [D6]DMSO): δ = 41.4 (CH2), 61.2 (q, JC,F = 27.5 Hz,
1
C-CF3), 124.9 (q, JC,F = 285.0 Hz, CF3), 127.5 (Ar), 128.5 (Ar),
129.5 (Ar), 131.4 (Ar) ppm. 19F NMR (280 MHz, [D6]DMSO): δ
= –75.77 (CF ) ppm. IR (KBr): ν = 3320–3420 (NH) cm–1
.
˜
3
4-(4-Fluorophenyl)-4-(trifluoromethyl)imidazoline-2-one (9j): Pale
yellow solid [90% (from 5j), 88% (from 5m)], m.p. Ͼ220 °C (de-
C9H13Cl2F3N2: C 41.25, H 5.19, N 9.62; found C 41.46, H 5.35, N
9.41.
2
comp.). 1H NMR (400 MHz, [D6]DMSO): δ = 3.65 (d, JH,H
=
2
3,3,3-Trifluoro-2-(4-methylphenyl)propane-1,2-diamine Dihydro-
chloride (10l): Pale yellow solid (88%), m.p. ca. 180 °C (decomp.).
1H NMR (400 MHz, [D6]DMSO): δ = 2.33 (s, 3 H, CH3), 3.61 (d,
10.4 Hz, 1 H, CH2), 4.00 (d, JH,H = 10.4 Hz, 1 H, CH2), 6.79 (br.
s, 1 H, H-N), 7.20–7.36 (m, 2 H, Ar), 7.53–7.56 (m, 2 H, Ar), 8.30
(br. s, 1 H, H-N) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 47.7
2
2JH,H = 15.0 Hz, 1 H, CH2), 3.95 (d, JH,H = 15.0 Hz, 1 H, CH2),
(CH2), 64.1 (q, JC,F = 27.5 Hz, C-CF3), 115.4 (d, 2JC,F = 21.3 Hz,
2
4.05–7.10 (br. s, 6 H, 2 NH3+), 7.26 (m, 2 H, Ar), 7.49 (m, 2 H,
Ar), 125.8 (q, 1JC,F = 283.8 Hz, CF3), 129.2 (d, 4JC,F = 8.8 Hz, Ar),
Ar) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 20.7 (CH3), 41.3
4
1
133.4 (d, JC,F = 2.5 Hz, Ar), 161.2 (C=O), 162.2 (d, JC,F
=
2
245.0 Hz, Ar) ppm. 19F NMR (280 MHz, [D6]DMSO): δ = –79.71
(CH2), 61.3 (q, JC,F = 28.8 Hz, C-CF3), 80.0 (CH3-C), 126.0 (q,
1JC,F = 285.0 Hz, CF3), 127.6 (Ar), 128.0 (Ar), 129.4 (Ar), 139.3
(Ar) ppm. 19F NMR (280 MHz, [D6]DMSO): δ = –70.04 (CF3)
(CF ), –114.17 (F) ppm. IR (KBr): ν = 3240–3320 (NH), 1740 (CO)
˜
3
cm–1. C10H8F3N2O: C 48.40, H 3.25, N 11.29; found C 48.26, H
ppm. IR (KBr): ν = 3310–3420 (NH) cm–1. C H Cl F N : C
˜
10 15
2
3
2
3.40, N 11.18.
41.25, H 5.19, N 9.62; found C 41.36, H 5.35, N 9.48.
4-(4-Methylphenyl)-4-(trifluoromethyl)imidazoline-2-one (9k): Pale
yellow solid [92% (from 5k), 90% (from 5p)], m.p. Ͼ230 °C (de-
1
Acknowledgments
comp.). H NMR (400 MHz, [D6]DMSO): δ = 2.30 (s, 3 H, CH3),
2
2
3.62 (d, JH,H = 10.0 Hz, 1 H, CH2), 3.97 (d, JH,H = 10.0 Hz, 1
H, CH2), 6.72 (br. s, 1 H, H-N), 7.16–7.30 (m, 2 H, Ar), 7.29–7.43
(m, 2 H, Ar), 8.22 (br. s, 1 H, H-N) ppm. 13C NMR (100 MHz,
This work was supported by the Russian Science Foundation
(RSCF) (grant number 10 14-13-00083).
2
[D6]DMSO): δ = 20.7 (CH3), 47.7 (CH2), 64.2 (q, JC,F = 27.5 Hz,
1
C-CF3), 125.9 (q, JC,F = 283.8 Hz, CF3), 126.7 (Ar), 129.0 (Ar),
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134.2 (Ar), 134.3 (Ar), 161.3 (C=O) ppm. 19F NMR (280 MHz,
[D ]DMSO): δ = –79.47 (CF ) ppm. IR (KBr): ν = 3140–3320
˜
6
3
(NH), 1740 (CO) cm–1. C11H11F3N2O: C 54.10, H 4.54, N 11.47;
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found C 54.31, H 4.36, N 11.58.
4-Phenyl-4-(trifluoromethyl)imidazoline-2-one (9l): Pale yellow solid
[87% (from 5l), 90% (from 5o)], m.p. Ͼ230 °C (decomp.). 1H NMR
2
(400 MHz, [D6]DMSO): δ = 3.66 (d, JH,H = 10.4 Hz, 1 H, CH2),
2
4.01 (d, JH,H = 10.4 Hz, 1 H, CH2), 6.77 (br. s, 1 H, H-N), 7.00–
7.16 (m, 2 H, Ar), 7.36–7.60 (m, 5 H, Ar), 8.29 (br. s, 1 H, H-N)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 47.6 (CH2), 64.3 (q,
1
2JC,F = 27.5 Hz, C-CF3), 125.8 (q, JC,F = 285.0 Hz, CF3), 126.8
(Ar), 128.4 (Ar), 128.8 (Ar), 137.1 (Ar), 161.2 (C=O) ppm. 19F
NMR (280 MHz, [D6]DMSO): δ = –79.15 (CF3) ppm. IR (KBr):
ν = 3220–3320 (NH), 1750 (CO) cm–1. C H ClF N O: C 52.18,
˜
12 14
3
2
H 3.94, N 12.17; found C 52.01, H 3.80, N 11.98.
4-Methoxyphenyl-4-(trifluoromethyl)imidazoline-2-one (9n): Pale
1
yellow solid (82%), m.p. Ͼ230 °C (decomp.). H NMR (400 MHz,
[D6]DMSO): δ = 3.62 (d, 2JH,H = 10.4 Hz, 1 H, CH2), 3.76 (s, 3 H,
2
CH3), 3.97 (d, JH,H = 10.4 Hz, 1 H, CH2), 6.73 (br. s, 1 H, H-N),
6.90–7.04 (m, 2 H, Ar), 7.34–7.48 (m, 2 H, Ar), 8.22 (br. s, 1 H,
H-N) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 47.7 (CH3),
2
55.2 (CH2), 64.0 (q, JC,F = 28.8 Hz, C-CF3), 113.8 (Ar), 125.9 (q,
1JC,F = 283.8 Hz, CF3), 128.1 (Ar), 129.0 (Ar), 159.4 (Ar), 161.3
(C=O) ppm. 19F NMR (280 MHz, [D6]DMSO): δ = –79.23 (CF3)
ppm. IR (KBr): ν = 3150–3320 (NH), 1740 (CO) cm– 1
.
˜
6760
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6749–6761

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Received: July 7, 2015
Published Online: September 16, 2015
Eur. J. Org. Chem. 2015, 6749–6761
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6761