A. Fedotova et al. / C. R. Chimie xxx (2018) 1e5
3
Next, we assumed that if the initial aniline contains a
phenolic hydroxy group, the conjugate addition of such
hydroxyaniline will take place without any promotor. To
confirm this hypothesis, we carried out an experiment with
Michael acceptor 1. To confirm this assumption, we per-
formed an experiment using an excess of aniline. To our
delight, when 1 was treated with 4 equiv of aniline 4d
(instead of 0.5 equiv as previously) in methanol (instead of
HFIP), the target adduct 5d was obtained in very good yield
(Table 3, entry 4).
In summary, we describe in this article suitable condi-
tions to promote the conjugate nucleophilic addition of
functionally substituted aromatic amines to enoates. These
preliminary researches show that, contrary to unsubstituted
2
-hydroxyaniline (2b). Interestingly, and in contrast to the
previous results on the conjugate addition of anilines in
HFIP, the 2b (10 times less acidic than HFIP) added to
methyl crotonate is better in MeOH (conversion is 25%)
than in HFIP (10%) (Table 1, entries 5 and 6). This result is
difficult to explain but can be partially due to the low sol-
ubility of 2-hydroxyaniline in HFIP at room temperature.
Complementary quantum chemical calculations suggest
that 2b plays simultaneously a role of promoter and weak
nucleophile (Scheme 2).
Thus, according to density functional theory (DFT) cal-
culations run in the gas phase at the B3LYP/6-311þG** level
of theory [18], the complex A displays a strong intermo-
lecular H-bond between the aminophenol hydroxy group
2
anilines, their analogues bearing OH or NH groups are good
hydrogen bond donors. In these cases, no expensive fluori-
nated alcohols are required and the reaction can be carried
out in usual protic solvents under very mild conditions.
Further works on the chemoselectivity of the hetero-
Michael reaction with aromatic amines are in progress.
3. Experimental part
and the carbonyl oxygen atom (d[OH/O]C] ¼ 1.823 Å,
dE
1H and 13C NMR spectra were recorded using a Bruker
AVANCE 400 MHz (at 400 and 100 MHz, respectively) and
Bruker AVANCE 300 MHz (at 300 and 75 MHz, respectively)
¼
ꢀ7.2 kcal/mol). At the transition state B corresponding to
the addition of the amino group on the C
b
olefinic atom,
this intermolecular H-bond strengthens (dH/O ¼ 1.667 Å
only). The activation barrier for the first reaction step
spectrometers for solution in CDCl . Chemical shifts (
d) in
3
(
addition of the primary amine to the C]C double bond) is
parts per million are reported using residual chloroform
1
13
equal to þ29.7 kcal/mol for 2b, whereas for 2a it increases
to þ32.1 kcal/mol. It is likely that in HFIP the fluorous
alcohol disrupts this interaction and thus deactivates the
process (Table 1, entry 5).
(7.24 for H NMR and 77.2 for C NMR) as an internal
reference. The coupling constants (J) are given in Hertz. The
IR spectra were measured using a PerkineElmer 16PC FT-IR
Instrument. ESI-MS spectra were obtained by direct injec-
tion of the sample solution using a Thermo LCQ Advantage
Max with methanol as a solvent. High-pressure reactions
were performed using a piston-cylinder type apparatus
(Ollivaud/Lebas, France) for pressures up to 14 kbar. The
silica gel used for flash chromatography was 230e400
mesh. All reagents were of reagents grade and were either
used as such or distilled before use.
On the basis of these results, we decided to test the
reaction of 1 with anilines bearing a second amino group.
These reactions were conducted in fluorinated and non-
fluorinated alcohols at room temperature and under high
pressure. It should be emphasized that high pressure is
necessary for the reaction to occur [16]. Thus, in our ex-
periments, when ester 1 (2 equiv) was refluxed with 1,4-
diaminobenzene 4a in methanol overnight under atmo-
spheric pressure, only starting materials were recovered.
To our surprise, and in contrast to the previous results
obtained for the aza-Michael reaction with primary and
secondary anilines, methanol is the best choice to promote
the conjugate addition of arylamines 4aec to Michael
acceptor 1 under high-pressure conditions. The conversion
All reactions under consideration were carried out in
an appropriate solvent under exactly the same conditions.
1
The H NMR spectra of the reaction mixture were recor-
ded immediately after the end of reaction time without
elimination of the solvent. The conversion of initial ester
was calculated using toluene signals as the internal
standard.
2
of 1 depends slightly on the position of the NH group, the
more nucleophilic 2- and 4-amino anilines giving, expect-
edly, the best results. In HFIP, the conversion reached only
4
. General procedure for the reaction of methyl
crotonate 1 with substituted anilines 2a,b and 4aec
10e25% (Table 2). Note that the treatment of 1 with
diamine 4a leads to bis-adduct 6a only; monoadduct 5a
was never observed.
These results led us to the conclusion that the acidity of
the aniline amino group is high enough to activate the
The mixture of functionally substituted aniline 2a,b or
4
(
aec (1 mmol) and 1 (2 mmol) in the corresponding solvent
0.5e1.5 mL) was placed in a Teflon reaction vessel and
allowed to stand for 2e17 h under 10e14 kbar at room
O
O
H
O
.
.
O
NH
N
O
H
NH
O
NH
O
2
H
O
H
H
O
O
OH
OH
A
B
Scheme 2. Aza-Michael addition of 2-hydroxyaniline 2b onto methyl crotonate.
Please cite this article in press as: A. Fedotova, et al., Solvent effects in the aza-Michael addition of anilines, Comptes Rendus
Chimie (2018), https://doi.org/10.1016/j.crci.2018.03.006
Fedotova, Alena
