Deep Eutectic Solvent Choline Chloride/ p-toluenesulfonic Acid and Water Favor the Enthalpy-Driven Binding of Arylamines to Maleimide in Aza-Michael Addition

Article abstract of DOI:10.1021/acs.joc.0c02039

Deep eutectic solvents (DESs) have been considered the organic reaction medium of the century because they can be used as solvents and active catalysts in chemical reactions. However, experimental and theoretical studies are still needed to provide information on the structures of DESs, the kinetics and thermodynamics properties, the interactions between the DESs and the substrates, the effect of water on the DES supramolecular network and its physicochemical properties, and so forth. This information is very useful to understand the essence of the processes that take place in the catalysis of chemical reactions and, therefore, to help in the design of a DES for a specific reaction and sample. This article shows a systematic study of the impact of DES choline chloride/p-toluenesulfonic acid and DES choline chloride/p-toluenesulfonic acid-water in the aza-Michael addition of arylamines to maleimide to obtain aminopyrrolidine-2,5-dione derivatives. The derivatives are obtained under very mild reaction conditions with good yield. The global reaction is exothermic, spontaneous, permitted by enthalpy, and prohibited for entropy. The calculated potential energy surface shows a reaction mechanism of six steps controlled by enthalpy (except the last step that is controlled by entropy). The water incorporated in the supramolecular DES complex stabilizes the transition states and favors the enthalpy-driven binding. A set of H/D exchange NMR experiments validates the transition state existing in the fourth stage of the mechanism.

Full text of DOI:10.1021/acs.joc.0c02039

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Article
Deep Eutectic Solvent Choline Chloride/p‑toluenesulfonic Acid and
Water Favor the Enthalpy-Driven Binding of Arylamines to
Maleimide in Aza-Michael Addition
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́
́
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Abelardo Gutierrez-Hernandez, Arlette Richaud, Luis Chacon-García, Carlos J. Cortes-García,
Francisco Mendez,* and Claudia Araceli Contreras-Celedon*
́
́
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ABSTRACT: Deep eutectic solvents (DESs) have been consid-
ered “the organic reaction medium of the century” because they
can be used as solvents and active catalysts in chemical reactions.
However, experimental and theoretical studies are still needed to
provide information on the structures of DESs, the kinetics and
thermodynamics properties, the interactions between the DESs and
the substrates, the effect of water on the DES supramolecular
network and its physicochemical properties, and so forth. This
information is very useful to understand the essence of the
processes that take place in the catalysis of chemical reactions and,
therefore, to help in the design of a DES for a specific reaction and
sample. This article shows a systematic study of the impact of DES
choline chloride/p-toluenesulfonic acid and DES choline chloride/
p-toluenesulfonic acid−water in the aza-Michael addition of arylamines to maleimide to obtain aminopyrrolidine-2,5-dione
derivatives. The derivatives are obtained under very mild reaction conditions with good yield. The global reaction is exothermic,
spontaneous, permitted by enthalpy, and prohibited for entropy. The calculated potential energy surface shows a reaction
mechanism of six steps controlled by enthalpy (except the last step that is controlled by entropy). The water incorporated in the
supramolecular DES complex stabilizes the transition states and favors the enthalpy-driven binding. A set of H/D exchange NMR
experiments validates the transition state existing in the fourth stage of the mechanism.
DESs is very low or null and DESs19,20 possess high
1. INTRODUCTION
biodegradability and21 negligible vapor pressures, are recycla-
One of the great challenges concerning the chemical industry
ble and reusable, and easily allow the solubility of organic and
in the 21st century is the replacement of conventional toxic
inorganic compounds as a result of their high polarity. In
solvents by sustainable solvents obtained from renewable
addition to the possibility of modifying their viscosity and
density properties varying the composition,22 for example,
adding a third component such as carboxylic acid, halide, or
water23−29 makes DESs very versatile and taken into account
as the ideal solvent for various purposes.30−34 Several papers
have been published in this area,35−38 and the authors have
concluded that systematic studies of the DESs are necessary to
better understand their physicochemical properties and
provide information on the definition, nature, and structure
of DES,39,40 the kinetic, thermodynamic, and dynamic of the
sources, thus trying to minimize industrial waste to promote a
sustainable environment.1 A large part of the development in
chemistry takes place or is carried out in liquid solution;
therefore, the correct choice of the solvent used in a chemical
reaction is of crucial importance2−5 because in addition to the
chemical and physical characteristics of the solvent itself,
several aspects must be taken into account from an ecological
point of view, such as its nature, boiling point, flammability,
toxicity, and biodegradability, among others.6,7 Thus, the so-
called neoteric solvents have emerged as important options,
such as fluorinated solvents, supercritical fluids, ionic liquids,
and deep eutectic solvents (DESs), all of which have a number
of advantages and disadvantages.8−11 DESs are generated with
the highest atomic economy from a mixture of two or more
immiscible solid components (Brønsted or Lewis acids and
bases) under a phase change to liquid at a precise temperature;
their formation is simple,12,13 they do not generate byproducts,
and no purification is required before use.14−18 The toxicity of
Received: August 23, 2020
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© XXXX American Chemical Society
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Table 1. Reaction Condition of Aza-Michael Addition to Maleimide 1
a
b
c
c
entry
1/2a
reaction condition
3a yield (%)
4a yield
g
1
2
3
4
5
6
7
8
9
1:1
1:2
1:3
1:5
1:2
1:2
1:2
1:2
1:2
120 °C, 1 h
120 °C, 0.5 h
120 °C, 1.5 h
120 °C, 20 h
120 °C, 22 h
90 °C, 2 h
9
35
12
19
44
82
93
65
42
n. o.
traces
7%
17%
40%
traces
d
g
50 °C , 1.5 h
n. o.
n. o.
n. o.
e
g
RT , 20 h
f
g
RT , 20 h
a
b
c
d
Maleimide 1, aniline 2a ratio. 0.097 g (1 equiv) maleimide 1, 0.186 g (2 equiv) aniline 2a, 0.5 g DES ChCl/TsOH 1:1. Product yield. 0.3 mL
e
f
g
1
of H2O was added. 1 mL of H2O was added. 1 mL of H2O was used as a solvent. Not observed by H NMR.
interactions with the substrates,41−44 and, specially, the effect
of water on DESs’ supramolecular network. This information is
very valuable and useful to understand the essence of the
processes that take place in the catalysis of chemical reactions
and, therefore, to help in the design of a DES for a specific
reaction and reagents.
maleimides have serious reactivity problems because they
present a high tendency to polymerization as well as a greater
facility to be hydrolyzed under basic conditions, which makes
them difficult to obtain good results in the formation of β-
aminocarbonylic derivatives, thus limiting their usefulness and
application. In recent years, some methods have been
described to obtain selectivity in the addition of amines to
maleimides. Harris and Philp described the use of bis-
(phosphine oxide) as a reagent with polarization effect to
accelerate the nucleophilic addition of amines to maleimides.66
In this article, we make for the first time a systematic study
of the impact of DES choline chloride/p-toluenesulfonic acid
ChCl/TsOH and DES choline chloride/p-toluenesulfonic
acid−water ChCl/TsOH/H2O in the aza-Michael addition of
arylamines 2 to maleimide 1 to obtain aminopyrrolidine-2,5-
dione derivatives 3 under very mild reaction conditions with
high yield. The derivatives are of great importance in biology,
materials science, and chemistry; they are used as synthetic
blocks to obtain small bioactive molecules, natural products,
drugs, and agrochemicals.45−53 This contribution complements
our previous work on nucleophilic addition reactions in α,β-
unsaturated carbonyl compounds (maleimide and maleic
anhydride)54−56 that were made in terms of the local hard
and soft acid and base principle and the density functional
theory.57−60 Now, our experimental and theoretical studies on
the aza-Michael addition have been motived for two
overarching goals: (i) development of a new experimental
methodology under mild reaction conditions for fast and
efficient synthesis of 3, through the aza-Michael additions of 2
to 1 using ChCl/TsOH and water as solvents without the need
of a catalyst, ligand, and/or additive and (ii) understanding the
kinetics and thermodynamics of the interactions between
ChCl/TsOH and the reagents and the effect of water on the
supramolecular network of ChCl/TsOH using spectroscopic
techniques and a potential energy surface.
̈
Papamicael described that the presence of TMEDA or trans-
TMCDA accelerating the speed of the reaction promotes
chemoselectivity to the addition.67 Workentin used AuNPs as a
template macromolecule to modify maleimides under hyper-
baric pressure conditions (11,000 atm).68 Scheidt described
the conjugate addition of alkylamines to maleimides, with Ca2+
complexes69 and under cooperative catalysis with a Lewis acid
and a Brønsted base.70 However, it is very important to
describe new methods that can be used as synthetic tools to
obtain aminopyrrolidine-2,5-dione and that avoid the need of
using drastic conditions and the use of metal catalysts, that
improve the performance of the expected products, and that
avoid the formation of undesirable products.
2. RESULTS AND DISCUSSION
We commenced our investigation with the reaction of
maleimide 1 and aniline 2a in the presence of ChCl/TsOH
(1:1) as a solvent (Table 1) under an open atmosphere. First,
1 equiv maleimide 1 and 1 equiv aniline 2a in ChCl/TsOH
were allowed to react at 120 °C for 1 h, generating the
expected product 3a in 9% yield (entry 1). Encouraged by this
result, various ratios of raw materials were screened, and 3a
was obtained in several yields (entries 2−4), suggesting that 1
equiv maleimide 1 and 2 equiv aniline 2a was the best ratio.
However, increasing the time reaction to 22 h did not improve
the yield of 3a (entry 5) but favored the synthesis of 4a in 40%
yield. When the temperature was decreased to 90 °C for 2 h,
3a was produced in 82% yield (entry 6). To carry out the
reaction at lower temperatures, we added water to the reaction
medium; we observed that when we added 0.3 mL of water,
the reaction was carried out at 50 °C, and after 1.5 h, we
obtained 3a in 93% yield (entry 7). Considering that the
The aza-Michael conjugate addition61,62 is recognized as a
simple synthetic strategy for facilitating the addition of
compounds with nucleophilic nitrogen to compounds α,β-
unsaturated and to encourage the formation of N−C bonds
generally with good yields. This reaction has been widely
studied with different nucleophilic nitrogen and different
acceptors of Michael; however, very few have been performed
with maleimides.63−65 The conjugate addition of primary or
secondary amines to maleimides proceeds with good results
when long reaction times, high temperatures, and high
pressures are used. Under these reaction conditions,
B
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addition of water favored the best agitation of the reaction
mixture and increased the 3a yield, in the following essay, we
decided to add 1 mL of water and carry out the reaction at
room temperature; under these conditions, the formation of 3a
was observed in 65% yield after 20 h (entry 8). In another test,
we used only water as a solvent and observed 42% of 3a (entry
9).
and interactions of ChCl/TsOH and water with the substrate.
To study the principles governing the stability of the species,
we have constructed the model using directly the molecules of
the reagents 1 and 2a and the solvents ChCl, TsOH, and
water. The ground-state geometries and energies of 1, 2a, 3a,
ChCl, TsOH, H2O, complex C, intermediate I, transition states
TSs, and product P (see Scheme 1) were obtained at the
M062X/6-311++G(d,p) level of theory72 using GAUS-
SIAN09.73 M062X is a well-balanced functional that includes
dispersion corrections and properly describes the interaction
energies for charge-transfer complexes.74,75 Frequency calcu-
lations confirmed that the local minimum and transition states
have 0 and 1 imaginary frequencies, respectively. Scheme 1
shows the aza-Michael reaction mechanism of five steps for the
addition of 2a to 1 and six steps for the addition in the
presence of ChCl, TsOH, and H2O.
Next, when the model reaction was screened in different
DES, 3a was produced in 64, 61, and 87% (Table 2). In
Table 2. Reaction Condition of Aza-Michael Addition to
Maleimide 1
Figure 2 shows the energy profiles for the addition (the
relative electronic energies including zero-point energy
corrections); the red line shows the addition in the absence
of molecules of the solvent and water (P is 3a), and the blue
and green lines show the addition in the presence of ChCl/
TsOH and ChCl/TsOH/H2O, respectively. The energy
profiles are almost similar, but they differ mainly in that the
reactions in the presence of ChCl/TsOH and ChCl/TsOH/
H2O occur in the low and deepest energy curves, respectively,
and all the species are more stable than the reagents, including
the transition states.
2.1. First Step: 1 + 2a → C. As the reagents 1 and 2a
approach to form C, the energy decreases −7.0 kcal/mol (red
line in Figure 2), −51.9 kcal/mol (with ChCl/TsOH, blue
line), and −63.0 kcal/mol (with ChCl/TsOH/H2O, green
line). The great stability of C with ChCl/TsOH/H2O occurs
by the interactions between the oxygen atom of the OC
group of maleimide and the hydrogen atoms of the −CH3
group of ChCl, and the −NH2 group of aniline with the H2O
and the sulfonic moiety of TsOH (see Scheme 2). It is
interesting to know that Chandrasekhar and Jorgensen (1985)
have found a (Cl···CH3C)− complex in the nucleophilic
substitution reaction of Cl− + CH3C.76
a
entry
solvent
reaction condition
3a yield
c
1
2
3
4
5
6
7
ChCl/urea 1:2
50 °C, 1.5 h
50 °C, 1.5 h
70 °C, 1.5 h
60 °C, 20 h
60 °C, 20 h
60 °C, 20 h
60 °C, 20 h
64%
61%
c
ChCl/ZnCl2 1:2
ChCl/tartaric Ac. 1:2
87%
21%
18%
11%
b
MeOH
THF
b
b
toluene
b
d
cyclohexane
n. o.
a
0.097 g (1 equiv) maleimide 1, 0.186 g (2 equiv) aniline 2a, 0.5 g
DES. 1 mL of organic solvent. 4a was observed in traces by H
b
c
1
d
1
NMR. Not observed by H NMR.
different polar or nonpolar solvents such as methanol, THF,
and toluene, 3a was produced in 21, 18, and 11% yields,
respectively. No formation of compound 3a was observed in
cyclohexane under the reaction conditions used.
With the optimized conditions in hand, the scope of the
reaction was explored by reacting maleimide 1 with different
aromatic amines 2b−2m. The reaction of 2b or 2c bearing
electron-donating groups as CH3 on the aromatic ring with 1
generated the products 3b and 3c in 80 and 85% yields,
respectively, while that of 2d and 2e afforded 3d and 3e in 42
and 27% yields, respectively. On the other hand, the treatment
of 1 with electron-withdrawing groups as 4-chloro, 2-bromo, 4-
iodo, and 3,4-dichloro, on the amine aromatic ring produced
3f, 3g, 3h, and 3i, gave 84, 43, 91, and 40% yields, respectively.
When 2j, 2k, and 2l were used, 3j, 3k, and 3l were produced in
80, 57, and 37% yields, respectively. When we used 2m, a
secondary aromatic amine, the desired product 3m, was
2.2. Second Step: C → [TS1]⧧. Then, C overcomes an
activation barrier for the addition of 34.6, 21.6 kcal/mol (with
ChCl/TsOH), and 20.2 kcal/mol (with ChCl/TsOH/H2O)
and forms the intermediate I via the first transition state TS1
(Scheme 3). Strictly speaking, the activation energy for the
addition (the difference of energy between TS1 and the
separate reagents) is just 27.6 kcal/mol. However, there is no
activation barrier between separate reagents and TS1 in the
presence of ChCl/TsOH and ChCl/TsOH/H2O; the
activation energy has a negative value of −30.3 and −42.8
kcal/mol, respectively (see Figure 2).
́
obtained with a 90% yield (Figure 1). Ruesgas-Ramon et al.
(2017) pointed out that “the extraction process is affected by
several factors: affinity between DESs and the target
compounds, the water content, the mole ratio between DES’
starting molecules, the liquid/solid ratio between the DES and
sample, and the conditions and extraction method”.71
Fortunately, for our case, the extractions of DES were high
because in most of the reactions, the addition products were
the only ones that were formed. We will return to this point in
the theoretical section.
As we can observe from Table 1, the reaction of maleimide 1
with aniline 2a to obtain 3-(phenylamino)pyrrolidine-2,5-
dione 3a is favored with the presence of ChCl/TsOH and
water. Therefore, we decided to explore the potential energy
surface to obtain the kinetic and thermodynamic properties of
the reaction and identify the structures, degree of participation,
2.3. Third and Fourth Steps: [TS1]⧧ → I→ [TS2]⧧. The
new N−C bond obtained in the intermediate I makes a
tetravalent nitrogen atom and a trivalent carbon atom in the
aniline and maleimide moieties, respectively (see Scheme 4).
Then, the energy increases to get the second transition state
TS2; the activation energies are 11.4, 14.3 kcal/mol (with
ChCl/TsOH), and 2.6 kcal/mol (with ChCl/TsOH/H2O).
Scheme 5 shows TS2 that involves the deprotonation and
protonation of the nitrogen and carbon atoms of the aniline
and maleimide moieties, respectively. The proton transfer
process involves a 1,3-hydrogen shift rearrangement, and it
occurs internally (H−N−C−C → N−C−C−H) with the
formation of a four-membered ring; in general, the process
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Figure 1. Synthetized aminopyrrolidine-2,5-dione 3a−3m. (a) Isolated yield (b) conversions were calculated by GC analysis of the limiting
substrate and final product.
Scheme 1. Reaction Mechanism of Aza-Michael Addition to Maleimide 1
occurs with high energy, and we can observe that TS2 is less
stable than the reagents (maleimide and aniline) by 36.6 kcal/
mol. For TS2 with ChCl/TsOH, the four-membered ring is
stabilized by 16.1 kcal/mol. In the case of TS2 with ChCl/
TsOH/H2O, the process involves a six-membered ring where
the water molecule accepts a proton from the N atom and
donates a proton to the C atom; TS2 is stabilized by 41.9 kcal/
mol.
GAUSSIAN09.73 They were obtained at T = 298.15 K, and
P = 1atm by means of partition functions using statistical
thermodynamic relationships.73 The global reactions (i) 1 +
2a→P (ΔGo = −8.3 kcal/mol and ΔHo = −21.2 kcal/mol),
(ii) 1 + 2a + ChCl/TsOH→P (ΔGo = −23.7 kcal/mol and
ΔHo = −60.4 kcal/mol), and (iii) 1 + 2a + ChCl/TsOH/H2O
→ P (ΔGo = −27.0 kcal/mol and ΔHo = −74.3 kcal/mol) are
spontaneous, permitted by enthalpy and prohibited by entropy.
Figures 3 and 4 show that the formation of the species involved
in the reaction mechanism (C, TS1, I, TS2, and P) is carried
out by nonspontaneous reactions [except P(3a) for (i), and C
and P for (ii) and (iii)] and prohibited by entropy. However,
the formation of all the species in the reactions (ii) and (iii) is
permitted by enthalpy (see Figure 4). Therefore, ChCl/TsOH
and ChCl/TsOH/H2O favor the enthalpy-driven binding of
aniline to maleimide in the aza-Michael addition. The
enthalpy-driven binding can be associated with a “cage effect”
by the ChCl/TsOH and ChCl/TsOH/H2O molecules that
2.4. Fifth Step: [TS2]⧧ → P. As we can observe in Figure 2,
the more stable specie is P; its energy decreases with respect to
the reagents to −20.7, −61.0 kcal/mol (with ChCl/TsOH),
and −73.8 kcal/mol (with ChCl/TsOH/H2O) (see Scheme 6.
Table 3 displays the relative electronic energies ΔE,
enthalpies ΔHo, Gibbs free energies ΔGo, and TΔSo (in
kcal/mol) for all the species involved in the additions: (i) 1 +
2a, (ii) 1 + 2a + ChCl/TsOH, and (iii) 1 + 2a + ChCl/
TsOH/H2O. The thermochemical properties were calculated
at the M062X/6-311++G(d,p) level of theory72 using
D
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Figure 2. Energy profiles for the addition of 2a to 1. The red, blue, and green lines show the addition in the absence of molecules of the solvent and
water and the presence of ChCl/TsOH and ChCl/TsOH/H2O, respectively. The relative electronic energies include zero-point energy corrections.
Scheme 2. C Obtained for the Addition of 2a to 1, (a) in the
Absence of Molecules of the Solvent and Water, (b) in the
Presence of ChCl/TsOH, and (c) in the Presence of ChCl/
TsOH/H2O
Scheme 4. I Obtained for the Addition of 2a to 1, (a) in the
Absence of Molecules of Solvent and Water, (b) in the
Presence of ChCl/TsOH, and (c) in the Presence of ChCl/
TsOH/H2O
Scheme 5. TS2 Obtained for the Addition of 2a to 1, (a) in
the Absence of Molecules of the Solvent and Water, (b) in
the Presence of ChCl/TsOH, and (c) in the Presence of
ChCl/TsOH/H2O
Scheme 3. TS1 Obtained for the Addition of 2a to 1, (a) in
the Absence of Molecules of the Solvent and Water, (b) in
the Presence of ChCl/TsOH, and (c) in the Presence of
ChCl/TsOH/H2O
releases 3a. For ChCl/TsOH/3a → ChCl/TsOH + 3a, the
energy values were ΔE = 1.9 kcal/mol, ΔGo = −9.6 kcal/mol,
ΔHo = 0.8 kcal/mol, and TΔSo = 8.8 kcal/mol, and for ChCl/
TsOH/H2O/3a → ChCl/TsOH/H2O + 3a, the energy values
were ΔE = 3.4 kcal/mol, ΔGo = −8.3 kcal/mol, ΔHo = 2.3
kcal/mol, and TΔSo = 6.0 kcal/mol. Therefore, the separation
of 3a in both cases is spontaneous and is allowed by entropy.
In the experiment, the DES (ChCl/TsOH) was recovered
through evaporation of water, vacuum dried, and reused. The
DES recyclability study revealed that this solvent can be used
generate a transient dynamical confinement of the reagents and
lead to a reduction in their degrees of freedom (spatial,
orientation, and dynamic). The cage creates a “hole” that
benefits the van der Waals interactions and hydrogen bonding
between reagents and ChCl/TsOH or ChCl/TsOH/H2O.77,78
2.5. Sixth Step: P → 3a + ChCl/TsOH (or ChCl/TsOH/
́
H2O). Following the Ruesgas-Ramon et al. suggestion for the
extraction process,71 we analyzed the affinity between the DES
and the target compounds in terms of the disruption of P that
E
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It is interesting to observe that TS2 obtained in the fourth
stage of the reaction mechanism involves a six-membered ring
where the water molecule accepts a proton from the tetravalent
nitrogen atom and donates a proton to the trivalent carbon
atom; with this in mind, we carried out an H/D exchange
NMR experiment to verify the presence of the deuterium atom
in the carbon atom. Reaction 2a + 1 was performed first using
ChCl/TsOH and then ChCl/TsOH/D2O. Reactions were
stopped after 2 h, and product 3a was obtained for each
Scheme 6. P Obtained for the Addition of 2a to 1, (a) in the
Absence of Molecules of the Solvent and Water, (b) in the
Presence of ChCl/TsOH, and (c) in the Presence of ChCl/
TsOH/H2O
1
reaction. Figure 6 shows the H spectrum for the product 3a
for both reactions (in CD3OD at room temperature).
Interestingly, the methine resulting from the reaction after
amine incorporation did not undergo deuterium addition
(Figure 6), whereas the adjacent position was deuterated
which indicates water proton addition in a regioselective
process. Both the integrals of the signals and the appearance of
the signals corroborated this. However, in order to support
that the presence of deuterium in the product is not due to
deuterium exchange with the maleimide under these
conditions, the reaction was carried out in the presence of
D2O, under the same reaction conditions, but without amine,
Table 3. Relative Energies for All the Species Involved in
the Additions (i) 1 + 2a, (ii) 1 + 2a + ChCl + TsOH, and
(iii) 1 + 2a + ChCl + TsOH + H2O
a
b
c
b
c
b
c
(i) ΔE , ΔHo ,
(ii) ΔE , ΔHo ,
(iii) ΔE , ΔHo ,
c
c
c
c
c c
ΔGo , TΔSo
0, 0, 0, 0
species
ΔGo , TΔSo
ΔGo , TΔSo
0, 0, 0, 0
R
C
0, 0, 0, 0
−7.0, −6.6, 3.6,
−10.2
−51.9, −51.2,
−63.0, −62.6, −18.5,
−16.3, −34.9
−44.1
TS1
I
27.6, 26.8, 41.0,
−30.3, −29.9, 6.5,
−36.4
−42.8, −43.3, 2.2,
−45.5
−14.2
1
resulting, as observed in the spectrum of H NMR, in the
25.2, 24.7, 38.1,
−13.4
−30.4, −30.4, 8.7,
−44.5, −45.0, 0.9,
absence of the deuterated product after 2 h of reaction.
The nature of the TS2 transition state was also verified
through calculation of the intrinsic reaction coordinate79,80
using the Gonzalez-Schlegel’s method implemented in
GAUSSIAN0973 at the M062X/6-311++G(d,p) level of
theory72 (see the figures in the Supporting Information).
A final note, the analysis of the mole fractions of the reagents
XR (maleimide 1 + aniline 2a) and the DES XDES (ChCl/
TsOH), shows that in general XR < XDES, except for entries 3
and 4, where XR > XDES (see Table 4). Entries 3 and 4 display
comparable numbers of “solute” as “solvent” molecules, and we
observed that the entries had low yields of 3a (12 and 19%,
respectively). The analysis including the mole fraction of water
−39.1
−45.9
TS2
P
36.6, 35.9, 49.4,
−16.1, −16.1, 20.7, −41.9, −43.4, 6.2,
−13.5
−36.8
−49.6
−20.7, −21.2, −8.3, −61.0, −60.4,
−73.8, −74.3, −27.0,
−12.9 −23.7, −36.7
−47.3
a
b
Values in kcal/mol. The electronic energies including zero-point
energy corrections. The relative electronic energies, enthalpies, and
c
Gibbs free energies values were obtained at T = 298.15 K, and P = 1
atm. The thermochemical values were computed at the M062X/6-
311++G(d,p) level of theory using Gaussian09.
up to five reaction cycles without losing its activity (Figure 5).
In the DES FT-IR spectra, no change between reaction cycles
was observed.
X
H O (entries 7−9) indicates that XH O > XDES > XR. Although
2
2
Figure 3. Gibbs free energy profiles for the addition of 2a to 1. The red, blue, and green lines show the addition in the absence of molecules of the
solvent and water and the presence of ChCl/TsOH and ChCl/TsOH/H2O, respectively.
F
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Figure 4. Enthalpy profiles for the addition of 2a to 1. The red, blue, and green lines show the addition in the absence of molecules of the solvent
and water and the presence of ChCl/TsOH and ChCl/TsOH/H2O, respectively.
addition, and the effect of water on the ChCl/TsOH
supramolecular network and its physicochemical properties.
We have developed an easy synthetic approach to obtain
interesting varieties of pyrrolidinedione through the addition of
aza-Michael of anilines to the maleimide in the DES ChCl/
TsOH, which provides rapid access to the aminopyrrolidines-
2,5-diones. This reaction, which generates the desired
products, has the advantages such as a wide substrate range,
high atom economy, and good tolerance to functional groups.
The key to this reaction was to avoid the use of bases, metal
catalysts, or ligands. The calculated potential energy surface for
the addition of aniline to maleimide suggests a reaction
mechanism of several steps. The energy profiles show that the
reactions in the presence of ChCl/TsOH or ChCl/TsOH/
H2O occur in the lowest energy curve, and all the species
(complex, intermediate, transition states, and product) are
more stable than the reagents. A set of H/D exchange NMR
experiments validates the transition state existing in the fourth
stage of the mechanism. The total reaction is exothermic,
spontaneous, permitted by enthalpy, and prohibited for
entropy. The relative stabilization by the enthalpy contribu-
tions (in kcal/mol) for TS1 and TS2 follows the trends
Figure 5. DES recyclability study.
the relationship between the yield of 3a and XH O is not linear
(R2 = 0.70), the yield of 3a increases when XH O decreases. The
experimental results showed that the higher yields of 3a (see
Table 1) were obtained with DES/H2O (93%, entry 7, XDES
2
2
=
0.155, XH O = 0.715, 50 °C and 1.5 h) and DES (82%, entry 6,
2
XDES = 0.545, XH O = 0, 90 °C, and 2 h). The water increased
2
the yield of 3a by 11% and decreased the time and temperature
of the reaction by ΔT = 40 °C and Δt = 0.5 h. According to
the reaction mechanism, the rate-determining (rate-control-
ling) step of the reaction is the formation of TS1 (see Scheme
1 and Figure 2). Using the conventional transition theory,81,82
we calculated the rate constant k for the reaction in the
absence of DES and H2O (red line, Figure 2), the k(DES) for the
reaction in the presence of DES (blue line, Figure 2), and the
‡
(δΔ H(oDES/H O) = 70.1) > (δΔ⧧H(oDES) = 56.7) > (δΔ⧧Ho =
2
0.0) and (δΔ H(oDES/H O) = 79.3) > (δΔ⧧Ho(DES) = 52.0) >
‡
2
(δΔ⧧Ho = 0.0), respectively. The relative destabilization (in
k
(DES/H2O) for the reaction in the presence of DES/H2O (green
kcal/mol) by the entropy contributions for TS1 and TS2
follows the trends (δTΔ S(oDES/H O) = 31.3) > (δTΔ⧧So(DES)
=
‡
line, Figure 2). The ratio of reaction rates showed the trend
{[k(DES/H2O)/k] = 28.998 × 1011} > {[k(DES)/k] = 2.305 ×
1011} ≫ {[k/k] = 1}. Therefore, the transition state TS1 is
stabilized to a greater extent with DESs and even more with
DES/H2O.
2
22.2) > (δTΔ⧧So = 0.0) and (δTΔ S(oDES/H O) = 36.1) >
‡
2
(δTΔ⧧So(DES) = 23.3) > (δTΔ⧧So = 0.0), respectively. The
relative stabilization by enthalpy contribution for TS1 and TS2
is twice the magnitude of the relative destabilization by
enthalpy contribution (in kcal/mol) for TS1 and TS2.
Therefore, ChCl/TsH and the water incorporated in the
supramolecular ChCl/TsOH complex increases the stabiliza-
tion of TS1 and TS2 and favors the enthalpy-driven binding.
The computational errors in this system using only one of the
3. CONCLUSIONS
We provided experimental and theoretical information about
the structure of DES ChCl/TsOH, the kinetic and
thermodynamic properties and interactions between the DES
and the substrates anilines and maleimides in aza-Michael
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1
Figure 6. H NMR (MeOH-d4) (a) using H2O in the reaction, (b) using D2O in the reaction.
reaction mechanisms (nucleophilic substitution and Diels−
Alder reactions).
Table 4. Mole Fractions of the Reagents, DESs, and Water
entry
XR
XDES
XH O
XR/XDES
XR/(XDES + XH O
)
2
2
1
2
3
4
5
6
7
8
9
0.36
0.45
0.53
0.63
0.45
0.45
0.13
0.13
0.05
0.64
0.55
0.47
0.38
0.55
0.55
0.16
0.16
0.06
0.00
0.00
0.00
0.00
0.00
0.00
0.72
0.72
0.89
0.56
0.83
1.11
1.67
0.83
0.83
0.83
0.83
0.83
0.56
0.83
1.11
1.67
0.83
0.83
0.15
0.15
0.05
4. EXPERIMENTAL SECTION
4.1. General Information. Thin layer chromatography (TLC)
analyses were performed on commercial aluminum plates bearing a
0.25 mm layer of Merck silica gel 60F254, which were visualized with
UV light at 254 nm or under iodine. Column chromatography was
performed with SiO2 [F60 (230−400 mesh)]. High-resolution mass
spectra (HRMS) were recorded on the MStation JMS-700 using
electron impact (EI) ionization. GC/MS analysis were recorded on a
Thermo Scientific ISQ LT Single Quadrupole Gas Chromatograph/
Mass Spectrometer (GC/MS) using a TraceGOLD TG-SQC GC
column (15 m × 0.25 mm × 0.25 μm) and an injection temperature
of 240 °C, a detector temperature of 260 °C, an initial temperature of
50 °C for a 5 min hold, a final temperature of 250 °C for a 10 min
hold, a flow rate of 1.0 mL/min, splitless, and a run time of 30 min.
Infra-red (IR) spectra were recorded on a Thermo Scientific Nicolet
molecules of the solvents ChCl, TsOH, and H2O should be
not significant because the theoretical results are consistent
with the experiments. However, we are working to introduce
explicit solvents in the system and for generalization with other
H
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iS10 spectrometer using attenuated total reflection. Selected
absorption maxima (νmax) are reported in wavenumbers (cm−1).
Melting points were recorded in degrees Celsius (°C), using a
Fisher−Johns melting point apparatus, and are reported uncorrected.
1H and 13C {1H} NMR spectra of solutions in CD3OD and DMSO-d6
were recorded on a Mercury 400 spectrometer. Deuterated methanol
and DMSO-d6 were used as received, and chemical shift values (δ) are
reported in parts per million (ppm) relative to the residual signals of
Me4Si): δC 180.6, 178.4, 159.3, 149.8, 130.9, 106.5, 101.6, 55.0, 38.8;
IR (ν/cm−1): 3383, 3172, 1693, 1603, 1192; HRMS (EI): m/z calcd
for C10H10N2O3, 206.0691; found, 206.0702.
4.8. 3-((4-Hydroxyphenyl)amino)pyrrolidine-2,5-dione 3e.
According to the general procedure and after purification on silica gel
using the mixture of Hex/EtOAc (7:3, v/v) as the eluent, 3e was
obtained in 27% yield (0.055 g). Dark green solid, rf 0.14 (Hex/
1
EtOAc 6:4), melting point (measured) 194−196 °C; H NMR (400
1
MHz, CD3OD; Me4Si): δH 6.64−6.57 (m, 4H), 4.41 (dd, J = 8.5, 5.4
Hz, 1H), 3.09 (dd, J = 17.9, 8.5 Hz, 1H), 2.48 (dd, J = 17.9, 5.4 Hz,
1H); 13C {1H} NMR (100 MHz, CD3OD; Me4Si): δC 180.8, 178.5,
151.3, 141.2, 116.9, 56.2, 38.7; IR (ν/cm−1): 3370, 3274, 1693, 1512;
HRMS (EI): m/z calcd for C10H10N2O3, 206.0691; found, 206.0698.
4.9. 3-((4-Chlorophenyl)amino)pyrrolidine-2,5-dione 3f. Ac-
cording to the general procedure, 3f was obtained by crystallization in
methanol in 84% yield (0.189 g). Pale yellow crystalline solid, rf 0.38
(Hex/EtOAc 6:4), melting point (measured) 164−166 °C; 1H NMR
(400 MHz, CD3OD; Me4Si): δH 7.07 (d, J = 8.9 Hz, 2H), 6.64 (d, J =
8.8 Hz, 2H), 4.52 (dd, J = 8.6, 5.5 Hz, 1H), 3.14 (dd, J = 17.9, 8.6 Hz,
1H), 2.49 (dd, J = 17.9, 5.5 Hz, 1H); 13C {1H} NMR (100 MHz,
CD3OD; Me4Si): δC 180.3, 178.2, 147.4, 129.9, 123.5, 115.6, 54.7,
38.6; IR (ν/cm−1): 3387, 1704, 1599, 1486, 1170, 824.
these solvents [δ 3.30 and 4.90 ppm for H (CD3OD) and δ 49.0
ppm for 13C {1H} (CD3OD) and δ 2.50 ppm for 1H (DMSO-d6) and
δ 39.52 ppm for 13C {1H} (DMSO-d6)]. Abbreviations used in the
NMR follow-up experiments are as follows: s, singlet; d, doublet; t,
triplet, and m, multiplet. The maleimide 1, the arylamines 2a−2m,
ChCl, and TsOH were purchased from Sigma-Aldrich with purities
more than 98%. ChCl was placed in an oven at 100 °C for 5 h to
remove the water content. The other chemicals were used as received.
4.2. Preparation of DESs (ChCl/TsOH). 1.8 mmol ChCl and 1.8
mmol TsOH were mixed in a 10 mL round-bottomed flask and
heated in a sand bath on a hot plate magnetic stirrer for 15 min at 120
°C until a clear liquid appeared; the colorless liquid was used directly
for the reactions without purification.
4.3. Typical Procedure for the Aza-Michael Addition in
ChCl/pTsOH. 0.3 mL of water was added to ChCl/TsOH (0.59 g)
with stirring for 5 min, and then, the maleimide 1 (0.097 g, 1 mmol)
and aniline 2a (0.19 g, 2 mmol) were slowly added to the reaction
mixture. The reaction mixture was stirred at 50 °C in a sand bath on a
hot plate magnetic stirrer for 1.5 h. The reaction was monitored by
TLC. After completion of the reaction, water was added, an extraction
was made with AcOEt, the organic phase was separated, and dried on
anhydrous MgSO4; the solvent was evaporated under vacuum. The
pure 3a product was obtained by crystallization in methanol.
4.4. Characterization Data of Compounds. 3-(Phenyl-
amino)-pyrrolidine-2,5-dione 3a. According to the general
procedure, the pure 3a product was obtained by crystallization in
methanol in 93% yield (0.176 g). Yellow pale solid. rf 0.42 (Hex/
EtOAc 6:4), melting point (measured): 177−179 °C; 1H NMR (400
MHz, CD3OD, Me4Si): δH 7.13−7.08 (m, 2H), 6.66 (dt, J = 7.2, 2.3
Hz, 3H), 4.54 (dd, J = 8.5, 5.5 Hz, 1H), 3.14 (dd, J = 17.9, 8.6 Hz,
1H), 2.49 (dd, J = 17.9, 5.5 Hz, 1H), 13C {1H} NMR (100 MHz,
CD3OD; Me4Si): δC 180.6, 178.4, 148.5, 130.1, 119.2, 114.6, 54.9,
38.7; IR (ν/cm−1): 3387, 1701, 1603, 1194, 753; HRMS (EI): m/z
calcd for C10H10N2O2, 190.0742; found, 190.0745.
4.5. 3-(m-Tolyl-amino)-pyrrolidine-2,5-dione 3b. According
to the general procedure, 3b was obtained by crystallization in
methanol in 80% yield (0.164 g). Pink pale crystalline solid, rf 0.48
(Hex/EtOAc 6:4), melting point (measured): 155−157 °C; 1H NMR
(400 MHz, CD3OD; Me4Si): δH = 7.01 (t, J = 7.9 Hz, 1H), 6.52 (d, J
= 5.3 Hz, 2H), 6.48 (d, J = 8.1 Hz, 1H), 4.54 (dd, J = 8.5, 5.5 Hz,
1H), 3.15 (dd, J = 17.9, 8.6 Hz, 1H), 2.51 (dd, J = 17.9, 5.5 Hz, 1H),
2.23 (s, 3H); 13C {1H} NMR (100 MHz, CD3OD; Me4Si): δC 180.7,
178.4, 148.4, 139.9, 130.0, 120.2, 115.4, 111.8, 55.0, 38.8, 21.6; IR (ν/
cm−1): 3355, 1698, 1609, 1489, 1188, 765; HRMS (EI): m/z calcd
for C11H12N2O2, 204.0899; found, 204.0899.
4.6. 3-(p-Tolylamino)pyrrolidine-2,5-dione 3c. According to
the general procedure, 3c was obtained by crystallization in methanol
in 86% yield (0.175 g). Pale yellow crystalline solid, rf 0.47 (Hex/
EtOAc 6:4), melting point (measured): 139−141 °C; 1H NMR (400
MHz, CD3OD; Me4Si): δH 6.96 (d, J = 8.5 Hz, 2H), 6.60 (d, J = 8.4,
2H), 4.49 (dd, J = 8.5, 5.5 Hz, 1H), 3.13 (dd, J = 17.9, 8.5 Hz, 1H),
2.50 (dd, J = 17.9, 5.5 Hz, 1H), 2.20 (s, 3H); 13C {1H} NMR (100
MHz, CD3OD; Me4Si): δC 180.7, 178.4, 146.0, 130.6, 128.6, 114.9,
55.3, 38.7, 20.5; IR (ν/cm−1): 3390, 1704, 1615, 1521, 1197, 809.
4.7. 3-((3-Hydroxyphenyl)amino)pyrrolidine-2,5-dione 3d.
According to the general procedure and after purification on silica gel
using a mixture of Hex/EtOAc (7:3, v/v) as the eluent, 3d was
obtained in 42% yield (0.087 g). Pale yellow solid, rf 0.17 (Hex/
EtOAc 6:4), melting point (measured): 168−171 °C; 1H NMR (400
MHz, CD3OD; Me4Si): δH 6.93 (t, J = 8.1 Hz, 1H), 6.20−6.14 (m,
3H), 4.51 (dd, J = 8.3, 5.6 Hz, 1H), 3.14 (dd, J = 17.9, 8.6 Hz, 1H),
2.52 (dd, J = 17.9, 5.5 Hz, 1H); 13C {1H} NMR (100 MHz, CD3OD;
4.10. 3-((2-Bromophenyl)amino)pyrrolidine-2,5-dione 3g.
According to the general procedure, 3g was obtained by crystallization
in EtOAc/methanol (6:4, v/v) in 43% yield (0.115 g). Pale orange
crystalline solid, rf 0.54 (Hex/EtOAc 6:4), melting point (measured):
149−152 °C; 1H NMR (400 MHz, CD3OD; Me4Si): δH 7.40 (dd, J =
7.9, 1.4 Hz, 1H), 7.22−7.12 (m, 1H), 6.75 (dd, J = 8.1, 0.8 Hz, 1H),
6.61 (td, J = 7.8, 1.4 Hz, 1H), 4.64 (dd, J = 8.6, 5.9 Hz, 1H), 3.20 (dd,
J = 17.7, 8.6 Hz, 1H), 2.59 (dd, J = 17.7, 5.9 Hz, 1H); 13C {1H} NMR
(100 MHz, CD3OD; Me4Si): δC 180.1, 178.0, 145.3, 133.7, 129.6,
120.1, 113.4, 110.8, 54.7, 38.9; IR (ν/cm−1): 3373, 1701, 1592, 1486,
1188, 735; HRMS (EI): m/z calcd for C10H9BrN2O2, 267.9847;
found, 267.9853 and m/z [M + 2], 269.9821.
4.11. 3-((4-Iodophenyl)amino)pyrrolidine-2,5-dione 3h. Ac-
cording to the general procedure, 3h was obtained by crystallization in
EtOAc/methanol (6:4, v/v) in 91% yield (0.287 g). Colorless
crystalline solid, rf 0.76 (Hex/EtOAc 6:4), melting point (measured):
178−180 °C; 1H NMR (400 MHz, CD3OD; Me4Si): δH 7.36 (d, J =
8.8 Hz, 2H), 6.50 (d, J = 8.8 Hz, 2H), 4.52 (dd, J = 8.6, 5.5 Hz, 1H),
3.14 (dd, J = 17.9, 8.6 Hz, 1H), 2.48 (dd, J = 17.9, 5.5 Hz, 1H); 13C
{1H} NMR (100 MHz, CD3OD; Me4Si): δC 180.3, 178.1, 148.4,
138.8, 116.6, 79.1, 54.5, 38.5; IR (ν/cm−1): 3328, 1783, 1692, 1588;
HRMS (EI): m/z calcd for C10H9IN2O2, 315.9749; found, 315.9749.
4.12. 3-((3,4-Dichlorophenyl)amino)pyrrolidine-2,5-dione
3i. According to the general procedure, 3i was obtained by
crystallization in methanol in 40% yield (0.104 g). Yellow crystalline
solid, rf 0.38 (Hex/EtOAc 6:4), melting point (measured) 192−194
1
°C; H NMR (400 MHz, CD3OD; Me4Si): δH 7.19 (d, J = 8.8 Hz,
1H), 6.84 (d, J = 2.7 Hz, 1H), 6.61 (dd, J = 8.8, 2.7 Hz, 1H), 4.56
(dd, J = 8.7, 5.5 Hz, 1H), 3.17 (dd, J = 17.9, 8.7 Hz, 1H), 2.50 (dd, J
= 17.9, 5.5 Hz, 1H); 13C {1H} NMR (100 MHz, CD3OD; Me4Si): δC
180.1, 178.0, 148.7, 133.5, 131.6, 120.9, 115.4, 114.2, 54.4, 38.4; IR
(ν/cm−1): 3367, 1689, 1595, 1471, 856, 800; HRMS (EI): m/z calcd
for C10H8Cl2N2O2, 257.9963; found, 257.9975.
4.13. 3-((4-Benzoylphenyl)amino)pyrrolidine-2,5-dione 3j.
According to the general procedure and after purification on silica gel
using the mixture of Hex/EtOAc (7:3, v/v) as the eluent, 3j was
obtained in 80% yield (0.236 g). Yellow solid, rf 0.19 (Hex/EtOAc
1
6:4), melting point (measured) 180−183 °C; H NMR (400 MHz,
CD3OD; Me4Si): δH 7.65 (t, J = 8.2 Hz, 4H), 7.56 (t, J = 7.4 Hz, 1H),
7.47 (t, J = 7.7 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H), 4.74 (dd, J = 8.4,
5.8 Hz, 1H), 3.21 (dd, J = 17.9, 8.8 Hz, 1H), 2.57 (dd, J = 17.9, 5.6
Hz, 1H); 13C {1H} NMR (100 MHz, CD3OD; Me4Si): δC 197.5,
179.7, 177.8, 153.5, 140.1, 134.0, 132.7, 130.4, 129.2, 127.2, 113.0,
53.9, 38.3; IR (ν/cm−1): 3324, 1704, 1592, 1558, 1318, 1279, 1191,
1143; HRMS (EI): m/z calcd for C17H14N2O3, 294.1004; found,
294.1023.
4.14. 3-((3-Nitrophenyl)amino)pyrrolidine-2,5-dione 3k. Ac-
cording to the general procedure and after purification on silica gel
I
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using the mixture of Hex/EtOAc (7:3, v/v) as the eluent, 3k was
Michoacana de San Nicolás de Hidalgo, Morelia 58030,
Michoacán, Mexico
obtained in 57% yield (0.133 g). Yellow powder, rf 0.28 (Hex/EtOAc
1
6:4), melting point (measured) 175−177 °C; H NMR (400 MHz,
́
Carlos J. Cortes-García − Departamento de Síntesis Orgánica,
CD3OD; Me4Si): δH 7.53 (t, J = 2.3 Hz, 1H), 7.49 (ddd, J = 8.1, 2.1,
0.8 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H), 7.07−7.04 (m, 1H), 4.70 (dd, J
= 8.7, 5.5 Hz, 1H), 3.21 (dd, J = 17.9, 8.8 Hz, 1H), 2.55 (dd, J = 17.9,
5.5 Hz, 1H); 13C {1H} NMR (100 MHz, CD3OD; Me4Si): δC 180.0,
177.9, 150.7, 150.0, 130.9, 120.1, 113.0, 107.9, 54.3, 38.3; IR (ν/
cm−1): 3353, 1688, 1541, 1343, 1263, 1160, 734; HRMS (EI): m/z
calcd for C10H9N3O4, 235.0593; found, 235.0602.
Instituto de Investigaciones Químico Biológicas, Universidad
Michoacana de San Nicolás de Hidalgo, Morelia 58030,
Michoacán, Mexico
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02039
4.15. 3-((2-Nitrophenyl)amino)pyrrolidine-2,5-dione 3l. Ac-
cording to the general procedure, 3l was obtained by crystallization in
EtOAc/methanol (6:4, v/v) in 37% yield (0.088 g). Orange crystal, rf
Author Contributions
C.A.C.-C. conceived and designed the experiments and wrote
the first draft of the paper; A.G.-H and C.A.C.-C. carried out
the experimental work and provided reagents, materials, and
analysis tools; C.A.C.-C., L.C.-G., and C.J.C.-G. analyzed the
data and participated in the discussion of the obtained
experimental results; A.R. and F.M. carried out the calculations
and analyzed the theoretical results. F.M. conceived and
designed the theoretical work and wrote the last draft of the
document, and all the authors participated in its revision. All
authors have read and accepted the published version of the
manuscript.
1
0.34 (Hex/EtOAc 6:4), melting point (measured) 191−194 °C; H
NMR (400 MHz, DMSO-d6; Me4Si): δH 11.39 (s, 1H), 8.36 (d, J =
8.1 Hz, 1H), 8.08 (dd, J = 8.6, 1.5 Hz, 1H), 7.59−7.53 (m, 1H), 7.13
(d, J = 8.6 Hz, 1H), 6.80−6.73 (m, 1H), 5.04 (dt, J = 8.4, 6.4 Hz,
1H), 3.13 (dd, J = 17.2, 8.8 Hz, 1H), 2.71 (dd, J = 17.2, 6.2 Hz, 1H);
13C {1H} NMR (100 MHz, DMSO-d6; Me4Si): δC 177.8, 175.9,
144.2, 136.5, 131.8, 126.2, 116.3, 114.9, 52.2, 37.3; IR (ν/cm−1):
3356, 1710, 1616, 1510.
4.16. 3-(Methyl(phenyl)amino)pyrrolidine-2,5-dione 3m.
According to the general procedure, 3m was obtained by
crystallization in methanol in 90% yield (0.184 g). Colorless
crystalline solid, rf 0.43 (Hex/EtOAc 6:4), melting point (measured)
165−167 °C; 1H NMR (400 MHz, CD3OD; Me4Si): δH 7.20 (dd, J =
8.8, 7.3 Hz, 2H), 6.86 (d, J = 8 Hz, 2H), 6.75 (t, J = 7.3 Hz, 1H), 5.08
(dd, J = 9, 5.9 Hz, 1H), 3.01 (dd, J = 18.2, 9 Hz, 1H), 2.81 (s, 3H),
2.71 (dd, J = 18.2, 5.9 Hz, 1H); 13C {1H} NMR (100 MHz, CD3OD;
Me4Si): δC 179.8, 178.0, 150.8, 130.2, 119.6, 115.3, 61.7, 34.3, 33.8;
IR (ν/cm−1): 3196, 1689, 1598, 1495, 1241, 759, 694; HRMS (EI):
m/z calcd for C11H12N2O2, 204.0899; found, 204.0904.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
C.A.C.-C. thanks the CIC-UMSNH for financial support of
this project, A.G.-H. thanks CONACyT (grant no. 922285) for
a graduate fellowship. A.R. thanks LE STUDIUM, Loire Valley
́
Institute for Advanced Studies, Orleans & Tours, France, and
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02039.
■
the research fellow and funding from the European Union’s
Horizon 2020 research and innovation program under the
Marie Skłodowska-Curie grant agreement no. 665790. F.M.
sı
́
́
thanks Programa Especial de Apoyo a la investigacion basica
UAM-2019.
Experimental procedures; compound characterization
data and spectra; and details of calculation (PDF)
DEDICATION
■
AUTHOR INFORMATION
Corresponding Authors
́
■
This work is dedicated to Prof. Virgilio Mendoza-Garcia who
introduced us to aza-Michael addition.
́
Francisco Mendez − Departamento de Química, División de
Ciencias Básicas e Ingeniería, Universidad Autónoma
Metropolitana-Iztapalapa, México D. F. 09340, Mexico;
Loire Valley Institute for Advanced Studies, Orléans & Tours,
France CEMHTI, Orléans 45000, France; orcid.org/
0000-0002-0555-1528; Email: fm@xanum.uam.mx
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