Synthesis of Diels-Alder adducts of N-arylmaleimides by a multicomponent reaction between maleic anhydride, dienes, and anilines

Article abstract of DOI:10.1007/s00706-011-0515-5

We have carried out the synthesis and characterization of some hexahydroisoindolyl benzoic acids and their corresponding ethyl esters by a multicomponent reaction (MCR) between aminobenzoic acids or aminobenzoates, maleic anhydride, and isoprene in the ab

Full text of DOI:10.1007/s00706-011-0515-5

Monatsh Chem (2011) 142:827–836
DOI 10.1007/s00706-011-0515-5
ORIGINAL PAPER
Synthesis of Diels–Alder adducts of N-arylmaleimides
by a multicomponent reaction between maleic anhydride,
dienes, and anilines
•
J. Alberto Guevara-Salazar Delia Quintana-Zavala
•
•
Hugo A. Jimenez-Vazquez Jose Trujillo-Ferrara
´
´
´
Received: 26 October 2010 / Accepted: 26 April 2011 / Published online: 31 May 2011
Ó Springer-Verlag 2011
Abstract We have carried out the synthesis and character-
ization of some hexahydroisoindolyl benzoic acids and their
corresponding ethyl esters by a multicomponent reaction
(MCR) between aminobenzoic acids or aminobenzoates,
maleic anhydride, and isoprene in the absence of catalysts.
According to additional experiments, the MCR takes place by
sequential formation of N-arylmaleamic acids from the ami-
nobenzoic acids or aminobenzoates and maleic anhydride,
Diels–Alder adducts of the acids and isoprene, and finally the
imides. The 1H NMR data (coupling constants) of the adducts
suggested that the preferred conformation of the correspond-
ing cyclohexene rings is a syn-boat, a fact supported by a
density functional theory (DFT) conformational analysis and
DFT calculations of the spin–spin coupling constants of the
corresponding conformers. Our MCR synthetic methodology
was tested successfully in the synthesis of other adducts, for
which cyclopentadiene and other anilines were employed.
Keywords Cycloadditions Á Conformation Á
Cyclizations Á Hexahydroisoindolediones Á
Computational chemistry
Introduction
Reactions that involve three or more components in a
single synthetic step are useful in the synthesis of relatively
simple or structurally complex organic molecules [1].
These reactions are known, in general, as multicomponent
reactions (MCR); they also include one-pot reactions, in
which additional components are added to the reaction
mixture at subsequent stages. One of the advantages of
these MCR is that they eliminate the need for work-up and
purification at each of the reaction steps, making the
overall process faster, and reducing the amount of solvent
used. In this sense, Diels–Alder reactions are no exception,
as several examples of MCR involving thermal [2–4] and
catalyzed [5, 6] cycloaddition reactions have been reported.
The Diels–Alder cycloaddition reactions of N-substi-
tuted maleimides as dienophiles have been carried out
with a number of different dienes and under different
methodologies [7], including the use of chiral [8, 9] and
achiral catalysts [10], Lewis acid catalysts [11], under
heating [11], or even at room temperature [12, 13]. Other
variations employed for these cycloadditions involve the
use of aqueous buffer solutions [14] or microwaves [15],
which have led to good results in terms of the decrease
in the overall reaction time.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0515-5) contains supplementary
material, which is available to authorized users.
´
´
J. A. Guevara-Salazar Á H. A. Jimenez-Vazquez
´
´
Departamento de Quımica Organica, Escuela Nacional de
Ciencias Biologicas, Instituto Politecnico Nacional, Prol. Carpio
´
´
y Plan de Ayala s/n, 11340 Mexico, DF, Mexico
D. Quintana-Zavala
´
Laboratorio de Quımica Organica, Centro de Investigacion en
Ciencia Aplicada y Tecnologıa Avanzada, Instituto Politecnico
´
´
´
´
Nacional, Calzada Legaria No. 694, 11500 Mexico, DF, Mexico
Herein we introduce an MCR between maleic anhy-
dride, isoprene, and aminobenzoic acids or ethyl
aminobenzoates, in which the final product is that expected
from the [4 ? 2] Diels–Alder cycloaddition of the corre-
sponding N-arylmaleimides and isoprene; in this three-
J. A. Guevara-Salazar Á J. Trujillo-Ferrara (&)
´
Departamento de Bioquımica, Escuela Superior de Medicina,
´
´
´
Instituto Politecnico Nacional, Salvador Dıaz Miron y Plan de
San Luis s/n, 11340 Mexico, DF, Mexico
e-mail: jtrujillo@ipn.mx
123

828
J. A. Guevara-Salazar et al.
R1
Table 1 Yields of adducts 4 obtained through the MCR
O
O
N
O
R2
160 °C, 96 h
Toluene
Product
Yield (%)
R1
+
+
O
R2
4a
4b
4c
4d
90.7
71.9
76.9
96.2
O
NH2
1
2
3a-3e
4a-4e
a: R1 = COOH, R2 = H
: R1 = COOEt, R2 = H
b
c
: R1 = H, R2 = COOH
d: R1 = H, R2 = COOEt
e: R1 = H, R2 = H
Hα
O
Hβ
H
Scheme 1
4
7
3
1
5
6
3a
7a
2
N
Ar
component MCR no catalyst was used. We also carried out,
independently, the preparation of the same adducts in a
conventional synthesis in order to make a direct compari-
son between both methods, and propose the most likely
sequence of events taking place within the MCR. In
H
Hα
O
Hβ
Scheme 2
3
addition, from the JHH coupling constants of the adducts
and from data derived from density functional theory
(DFT) calculations we have determined the preferred
conformation of the fused bicyclic system.
In the particular case of 4b, protons H3a and H7a show
three coupling constants each; the first corresponds to the
interaction between them: JH3aH7a = 9.38 Hz. In addition,
the other two coupling constants involving H3a and the
diasterotopic H4a,4b protons have values of 2.50 and
7.25 Hz. The coupling constants between H7a and the
H7a,7b protons are very similar to the former set, 2.50 and
6.60 Hz. The geminal (2JHH) coupling constants between
the H4a,4b and the H7a,7b protons are both around
15.5 Hz. The fact that the coupling constants between the
bridge protons and the adjacent a and b methylene protons
are so different suggests the predominance of a single
conformer. Furthermore, it does not agree with the idea of a
half-chair as the major conformer, because there is no
apparent reason why one of the two possible half-chair
conformations would be preferred over the other. It is
likely that conformational averaging between the two half-
chair forms would lead to less dissimilar values of these
coupling constants.
Results and discussion
Carboxylic acids 4a and 4c and the corresponding ethyl
esters 4b and 4d were synthesized by an MCR between
maleic anhydride (1), isoprene (2), and the corresponding
para- or meta-aminobenzoic acids or ethyl aminobenzoates
(3a–3d) in toluene under thermal conditions (Scheme 1).
In all cases a single product was detected by TLC and
purified by recrystallization from CH2Cl2/n-hexane. The
characterization of these products was carried out by
1
spectroscopy, particularly by H and 13C one- and two-
dimensional NMR. As shown in Table 1, the yields
obtained in our MCR range from good to excellent.
1
The H and 13C chemical shifts of the products and the
1
coupling patterns of the H signals are in agreement with
To further investigate the preferred conformation of
adducts 4, we carried out theoretical calculations with
Gaussian 09 [27] on some of the possible conformers of
adduct 4b, in the context of DFT, using the 6-31?G(d,p)
basis set in combination with Truhlar’s meta-GGA M06-
2X hybrid functional [28, 29]. As the NMR data was
obtained in CDCl3, we also introduced the effect of sol-
vation (chloroform, e = 4.7113) through Tomasi’s
polarizable continuum model (PCM) model [30], as
implemented in the default self-consistent reaction field
(SCRF) methodology of Gaussian 09 [31]; optimizations
and vibrational frequency analyses were carried out under
the effect of solvation at this level of theory. The optimized
geometries of the conformers investigated, two boats
(b-syn and b-anti) and two half-chairs (hc-1 and hc-2), are
those expected for compounds 4. The coupling constants
(3JHH) of the aliphatic protons of the cyclohexene ring of
adduct 4b were assigned directly from the corresponding
spectrum, according to the numbering shown in Scheme 2.
Even though it is usually assumed that the most stable
conformers of a cyclohexene ring would be half-chairs [16,
17], it is known that in cis-fused [4.3.0]bicyclic systems,
such as the hexahydroisoindole nucleus of our adducts, the
most stable conformation is a boat [17]. However, from
NMR data it has been proposed that out of the two possible
boat forms (syn and anti, see below), the predominance of
one over the other depends on the particular structure of the
system under study [18–23], a fact supported by crystal-
lographic data [24–26].
123

Synthesis of Diels–Alder adducts of N-arylmaleimides by a multicomponent reaction
829
level of theory under solvation effects (PCM) on the M06-
2X/6-31?G(d,p)/PCM geometries previously obtained.
Furthermore, from both sets of calculated coupling con-
stants (empirical and DFT) and the relative energies of the
conformers, we also estimated two sets of calculated aver-
age coupling constants (empirical and theoretical) assuming
a Boltzmann distribution of conformers, according to
methodology described elsewhere [35]. The results are
summarized in Fig. 1 and in Table 2.
Notice that the theoretical calculation also allows for the
2
estimation of the JHH coupling constants for H4a–H4b
and H7a–H7b. In Table 3 we present the average values of
these coupling constants compared with the experimental
ones.
3
2
It can be seen that the J (and J) experimental values
are more similar to those of the most stable conformer
b-syn. However, the agreement is even better if we con-
sider the averaged coupling constant values. In addition, it
is readily apparent that the values derived from the DFT
calculations of spin–spin coupling are in even better
agreement than the empirical ones. Thus, we can conclude
that indeed the most stable conformer of the cyclohexene
fragment in adducts 4, in the gas phase as well as in
solution, is the syn-boat.
Fig. 1 M06-2X/6-31?G(d,p)/PCM optimized geometries, calculated
relative free energies (DG at 25 °C kJ/mol), and proportions of the
conformers assuming a Boltzmann distribution of the boat (b) and
half-chair (hc) geometries of adduct 4b
Table 2 Dihedral angles (h°), empirical (emp), and theoretical
(theor) coupling constants (3JHH, Hz) derived from the M06-2X/6-
31?G(d,p)/PCM optimized geometries of the boat (b) and half-chair
(hc) conformers of adduct 4b (see text)
shown in Fig. 1 in order of relative free energies (calcu-
lated at 25 °C). We did not explore the conformations of
the phenyl ring or the carboethoxy group. Supported by the
NMR data of adducts 4a–4d, we assumed that the con-
formation of the bicyclic moiety was essentially
independent of the geometry of these fragments. Interest-
ingly enough, from the calculations the most stable
conformers turned out to be the boat forms. Most likely this
is the result of the strain introduced into the cyclohexene
ring by the cis-fused five-membered ring in the half-chair
conformations. The fact that the most stable boat con-
former (b-syn) is that in which both carbonyl carbons of the
heterocyclic ring have the axial orientation, can be
explained in terms of a lower torsional strain arising from
the interaction of these carbons with the C4/C7a methylene
protons, with respect to conformer b-anti.
Conformer H3a–H7a H3a–H4a H3a–H4b H7a–H7a H7a–H7b
h
h
h
h
h
b-syn
b-anti
hc-1
1.8
2.2
65.7
159.1
95.6
-50.8
42.7
-68.2
47.9
-44.8
-37.6
20.3
-161.2
-152.8
-94.5
37.7
-37.8
-19.1
37.2
hc-2
152.5
emp
3J
3J
3J
3J
3J
b-syn
b-anti
hc-1
11.1
11.1
6.9
2.2
11.1
1.2
4.3
6.0
9.3
7.0
2.0
11.3
10.2
1.1
4.8
5.6
6.8
9.1
hc-2
6.9
10.2
theor
3J
3J
3J
3J
3J
b-syn
10.2
2.1
7.7
1.7
12.6
11.0
0.9
8.2
7.8
For all four conformers we determined the relevant
H–C–C–H dihedral angles, and from them we estimated
the corresponding empirical vicinal coupling constants
according to the Haasnoot–de Leeuw–Altona equation
[32], as implemented in the ALTONA computer program
[33]. In addition, we also calculated the theoretical spin–
spin coupling constants from DFT data, employing the
two-step methodology described by Deng et al. [34] as
implemented in Gaussian 09, at the B3LYP/6-311?G(d,p)
b-anti
hc-1
11.0
8.7
12.5
0.94
11.1
2.50
2.8
8.2
11.8
8.7
8.6
hc-2
8.6
11.5
6.60
5.0
exp
9.40
11.0
10.2
7.25
4.6
2.50
2.7
avg (emp)
avg (theor)
2.7
7.9
2.5
8.2
3
The experimental (exp) J values are shown for comparison with the
values estimated from the Boltzmann distribution of conformers (avg)
123

830
J. A. Guevara-Salazar et al.
Table 3 Theoretical coupling constants (2JHH, Hz) derived from the
M06-2X/6-31?G(d,p)/PCM optimized geometries of the boat (b) and
half-chair (hc) conformers of adduct 4b (see text)
Table 4 Yields obtained in the synthesis of maleamic acids 5 and
adducts 4, according to the reactions displayed in Scheme 3
Product
Yield (%)
Overall yield (%)
Conformer
H4a–H4b
H7a–H7b
2J
2J
5a
5b
5c
5d
4a
4b
4c
4d
90.3
89.0
95.8
77.7
76.8
82.7
90.2
64.2
–
–
b-syn
b-anti
hc-1
hc-2
avg
-15.61
-15.88
-21.32
-19.10
-15.77
15.5
-15.91
-15.73
-19.18
-21.64
-16.02
15.5
–
–
69.4
73.6
86.4
49.9
exp
2
The experimental (exp) J values are shown for comparison with the
values estimated from the Boltzmann distribution of conformers (avg)
The overall yields of the two steps are also shown
those obtained through the MCR. It is readily apparent that,
at least for the synthesis of adducts 4a and 4d, we obtained
a much better yield in the MCR than in the two-step pro-
cess (Table 1).
R1
R1
R2
O
R2
+
O
It is interesting to note that under the conditions
employed in this second step the cycloaddition takes place
simultaneously with the formation of the imide; thus, it is
not known which of the two reactions takes place first. In
order to investigate this, the second reaction was performed
again, under a different set of conditions. In this case, we
carried out the reaction of acid 3a with isoprene in ethyl
acetate as solvent at 60 °C for 120 h (toluene was not
employed because the maleamic acids 5 are not soluble at
this temperature). This time two types of compounds were
identified and isolated from the reaction mixture, one being
the known adduct 4a, and the other a mixture of regio-
isomeric adducts resulting from the cycloaddition of
isoprene with 3a (6a/7a, Scheme 4). The presence of the
latter was evidenced by two new signals appearing
approximately at 10.0 ppm in the 1H NMR spectrum,
indicative of the amide groups of the new adducts, which
do not exist in adducts 4. In addition, the 1H and 13C
THF, r.t.
O
NH
O
NH2
CO2H
1
3a-3d
5a-5d
Toluene
1
2
160 °C, 96 h
a
b
: R = COOH, R = H
1
2
2
: R = COOEt, R = H
c: R1 = H, R2 = COOH
d: R1 = H, R2 = COOEt
O
N
O
R1
R2
4a 4d
-
Scheme 3
In order to investigate the sequence of events taking
place in our MCR, we carried out the synthesis of adducts
4a–4d through a two-step sequence (Scheme 3). The first
reaction involved the synthesis of N-arylmaleamic acids,
which have been obtained by a number of methodologies
[36–43]. In our particular case we followed that described
by Trujillo-Ferrara et al. [42, 43], which employs anilines
and maleic anhydride. We carried out the reactions in THF
as solvent and at room temperature, conditions under which
acids 5a–5d were obtained in very good yields (Table 3).
THF was employed because the reactants are not soluble in
toluene at this temperature. The fact that the reactions took
place readily suggests that the formation of the maleamic
acids is indeed the first step of the MCR.
O
N
CO2H
CO2H
O
+
4a
CO2H
NH
O
AcOEt
N
+
60 °C, 120 h
H
O
CO2H
6a
7a
CO2H
2
+
CO2H
O
5a
N
H
In the second reaction, acids 5a–5d react with isoprene
under thermal conditions, leading to adducts 4a–4d with
global yields for the two steps (Table 4) that are similar to
CO2H
Scheme 4
123

Synthesis of Diels–Alder adducts of N-arylmaleimides by a multicomponent reaction
831
R1
Table 5 Yields obtained in the MCR synthesis of adducts 4e, 9b, 9e,
and 9f according to the reactions displayed in Schemes 1 and 6
R1
R2
O
R2
Product
Yield (%)
O
+
O
NH
4e
9b
9e
9f
73.2
75.2
83.5
89.9
O
NH2
CO2H
5
1
3
2
R1
R2
O
N
H
O
CO2H
6
7
N
R1
+
R1
R2
- H2O
O
R2
O
N
H
CO2H
4
Scheme 5
R1
O
O
N
O
160 °C, 96 h
Toluene
R1
+
+
O
O
NH2
Fig. 2 Oak Ridge thermal ellipsoid plot (ORTEP) of the structure
obtained by single-crystal X-ray diffraction of adduct 9f. Thermal
ellipsoids drawn at 30% probability
1
3b 3e 3f
8
9b 9e 9f
, ,
,
,
b: R1 = COOEt
1
e
: R = H
f: R1 = F
the corresponding endo adducts 9, also in good yields
(Scheme 6); these results are summarized in Table 5.
The endo stereochemistry of these adducts was further
supported by a single-crystal X-ray diffraction analysis
carried out on a crystal of 9f. The corresponding structure
is shown in Fig. 2.
Scheme 6
spectra of the mixture showed two sets of very similar
signals for the cyclohexene ring, particularly for the vinylic
proton, in a 55:45 proportion.
From the above information, we can propose that the
most likely sequence of events taking place in our MCR is
that shown in Scheme 5. Maleic anhydride (1) reacts rap-
idly under the reaction conditions with the anilines 3 to
yield the corresponding maleamic acids. These intermedi-
ates undergo a Diels–Alder cycloaddition with isoprene (2)
leading to a mixture of adducts 6 and 7, which cyclize to
form imides 4.
Conclusions
The synthesis of adducts 4a–4d took place in a straight-
forward manner and in good to excellent yields through a
three-component MCR. The spectroscopic data are in full
agreement with the proposed structures. The NMR data
suggested that the preferred conformation in the cyclo-
hexene fragment of these adducts is a boat, a fact that was
supported by the comparison with coupling constants
derived from empirical methods and theoretical calcula-
tions. It is readily apparent that the calculation of the
theoretical spin–spin coupling constants and the inclusion
of solvation led to a better agreement between experi-
mental and calculated values. The synthesis of 4a–4d was
In order to test the generality of our MCR methodology,
we carried out additional experiments. The reaction of
aniline 3e with isoprene and maleic anhydride under the
conditions described above led to the formation of 4e in
73% yield (Scheme 1). In a second set of experiments, we
performed the reactions between maleic anhydride, cyclo-
pentadiene (8), and anilines 3b, 3e, or 3f, which furnished
123

832
J. A. Guevara-Salazar et al.
also carried out in a two-step process; in this case, although
the yields of 4b and 4c were comparable to those obtained
in the MCR, the yields of 4a and 4d were much lower. Our
MCR methodology also allowed for the synthesis of
adducts 4e, 9b, 9e, and 9f in good yields, for which dif-
ferent anilines and dienes were used. For the particular case
of adducts 9, they were obtained with endo stereochemis-
try, as evidenced by X-ray diffraction. The MCR has
additional advantages in terms of the overall shorter reac-
tion times, lower cost, and lower environmental impact, as
a result of the reduced amounts of solvents and reactants
used.
was purified and characterized by spectroscopy. 1H and 13
C
spectra of these adducts as well as detailed NMR data of
known compounds 4e, 9e, and 9f are presented in the
Supplementary Material.
4-[(3aR*,7aS*)-1,3,3a,4,7,7a-Hexahydro-5-methyl-1,3-
dioxo-2H-isoindol-2-yl]benzoic acid (4a, C16H15NO4)
From the general method, with 250 mg of 3a (1.823
mmol), 178.8 mg of 1 (1.823 mmol), and 0.37 cm3 of 2
(3.646 mmol); the product was recrystallized from a cold
mixture of CH2Cl2/n-hexane, leading to a white powder in
90.7% yield (471.7 mg, 1.653 mmol). M.p.: 178–180 °C;
Rf = 0.15 (n-hexane/AcOEt 6:4); UV–Vis (CH2Cl2): kmax
(e) = 245.3 0.8 (13,765.8) nm (mol-1 dm3 cm-1); IR
-1
ꢀ
(KBr):m = 3,437, 2,935, 1,712, 1,456 cm
;
1H NMR
Experimental
(500 MHz, CDCl3): d = 8.20 (2H, d, 3J = 8.50 Hz),
7.42 (2H, d, J = 8.50 Hz), 5.63 (1H, br), 3.30 (1H, ddd,
3
All reagents and solvents, except THF and AcOEt, were
purchased and used without additional purification. THF
was distilled from a deep-blue solution of the solvent
containing sodium and benzophenone under nitrogen
atmosphere. Ethyl acetate was purified by fractional dis-
tillation. Cyclopentadiene was obtained by distillation from
bicyclopentadiene and used a short time after. Analytical
thin-layer chromatography (TLC) was carried out on
Merck-DC-F254 aluminum plates, using short-wave UV
light for visualization. The melting points were determined
in a Mel-Temp II apparatus. The IR spectra were deter-
mined in KBr discs, or in solution (CHCl3) for liquid
samples, in a Spectrum One FT-IR spectrophotometer. The
IR absorption frequencies are reported in cm-1. The UV–
Vis spectra were determined in a UV–Vis Beackman
Coulter DU 650 spectrophotometer, using CH3OH or
3J = 9.51 Hz, 3J = 6.68 Hz, 3J = 2.50 Hz), 3.25 (1H,
ddd, 3J = 9.51 Hz, 3J = 7.50 Hz, 3J = 2.50 Hz), 2.66
(1H, ddd, 2J = 15.50 Hz, 3J = 6.68 Hz, 3J = 2.50 Hz),
2.60 (1H, dd, 2J = 15.50 Hz, 3J = 2.50 Hz), 2.33 (1H, m),
2.28 (1H, m), 1.78 (3H, s) ppm; 13C NMR (125 MHz,
CDCl3): d = 179.2, 179.0, 171.2, 137.0, 136.8, 131.2,
129.3, 126.5, 120.4, 40.0, 39.6, 29.1, 24.7, 23.7 ppm;
HRMS (EI): m/z calculated for C16H15NO4 [M?] 285.1001,
found 285.0978.
Ethyl 4-[(3aR*,7aS*)-1,3,3a,4,7,7a-hexahydro-5-methyl-
1,3-dioxo-2H-isoindol-2-yl]benzoate (4b, C18H19NO4)
From the general method, with 250 mg of 3b (1.513
mmol), 148.4 mg of 1 (1.513 mmol), and 0.30 cm3 of 2
(3.027 mmol); the product was recrystallized from a cold
mixture of CH2Cl2/n-hexane, leading to a white powder in
71.9% yield (341.0 mg, 1.088 mmol). M.p.: 139–140 °C;
Rf = 0.55 (n-hexane/AcOEt 6:4); UV–Vis (CH2Cl2): kmax
(e) = 243.4 0.1 (14,641.8) nm (mol-1 dm3 cm-1); IR
1
CH2Cl2 as solvents. The H and 13C NMR spectra were
obtained in a Varian VNMRS-500 spectrometer, at
500 MHz (125.787 MHz for 13C), or in a Varian Mercury
spectrometer operating at 300 MHz (75 MHz for 13C). The
samples were dissolved in CDCl3 or DMSO-d6, using TMS
as internal reference. HRMS data were obtained in a JEOL
GCmateTM II spectrometer in electron impact (EI, 70 eV)
mode.
-1
ꢀ
(KBr): m = 3,450, 2,939, 1,709, 1,456 cm
;
1H NMR
3
(500 MHz, CDCl3): d = 8.12 (2H, d, J = 8.75 Hz), 7.36
(2H, d, J = 8.75 Hz), 5.61 (1H, br), 4.38 (2H, q), 3.28
3
(1H, ddd, 3J = 9.38 Hz, 3J = 6.62 Hz, 3J = 2.50 Hz),
3.21 (1H, ddd, 3J = 9.38 Hz, 3J = 7.25 Hz, 3J =
2.50 Hz), 2.64 (1H, ddd, 2J = 15.50 Hz, 3J = 6.62 Hz,
3J = 2.50 Hz), 2.58 (1H, dd, 2J = 15.50 Hz, 3J =
2.50 Hz), 2.35 (1H, m), 2.28 (1H, m), 1.77 (3H, s), 1.39
(3H, t) ppm; 13C NMR (125 MHz, CDCl3): d = 180.0,
178.2, 166.0, 136.8, 136.2, 130.6, 130.5, 126.3, 120.4,
61.4, 40.0, 39.5, 29.1, 24.7, 23.7, 14.5 ppm; HRMS (EI):
m/z calculated for C18H19NO4 [M?] 313.1314, found
313.1324.
General method for the preparation of Diels–Alder
adducts 4a–4e, 9b, 9e, and 9f by MCR
The corresponding aniline 3a–3f (250 mg) together with 1
equivalent of maleic anhydride (1) and 2 equivalents of
isoprene (2) and 9.0 cm3 of toluene were deposited in a
20-cm3 ACE pressure tube. The tube was closed, intro-
duced into a sand bath at 160 °C, and kept under constant
stirring for 96 h. After this time the product was precipi-
tated with cold n-hexane, filtered, and washed twice with
20 cm3 of n-hexane at room temperature (r.t.). The product
3-[(3aR*,7aS*)-1,3,3a,4,7,7a-Hexahydro-5-methyl-1,3-
dioxo-2H-isoindol-2-yl]benzoic acid (4c, C16H15NO4)
From the general method, with 250 mg of 3c (1.823
mmol), 178.8 mg of 1 (1.823 mmol), and 0.37 cm3 of 2
123

Synthesis of Diels–Alder adducts of N-arylmaleimides by a multicomponent reaction
833
(3.646 mmol); the product was recrystallized from a cold
mixture of CH2Cl2/n-hexane, leading to a white powder in
76.9% yield (399.9 mg, 1.402 mmol). M.p.: 197–199 °C;
Rf = 0.15 (n-hexane/AcOEt 6:4); UV–Vis (CH2Cl2): kmax
(e) = 234.4 1.5 (10,199.5) nm (mol-1 dm3 cm-1); IR
Ethyl 4-[(3aR*,4S*,7R*,7aS*)-1,3,3a,4,7,7a-hexahydro-
1,3-dioxo-4,7-methano-2H-isoindol-2-yl]benzoate
(9b, C18H17NO4)
From the general method, with 250 mg of 3b (1.51 mmol),
148 mg of maleic anhydride (1.51 mmol), and 0.25 cm3 of
cyclopentadiene (8, 3.02 mmol); the product was recrys-
tallized from a cold mixture of CH2Cl2/n-hexane, leading
to a beige powder in 75.2% yield (354 mg, 1.14 mmol).
M.p.: 130–132 °C; Rf = 0.46 (n-hexane/AcOEt 6:4); IR
-1
(KBr): m = 3,451, 2,929, 1,706, 1,454 cm
;
1H NMR
ꢀ
3
(500 MHz, CDCl3): d = 8.13 (1H, d, J = 7.50 Hz), 8.01
(1H, s), 7.58 (1H, t), 7.51 (1H, d, 3J = 8.55 Hz), 5.65 (1H,
br), 3.32 (1H, ddd, 3J = 8.20 Hz, 3J = 7.25 Hz, 3J =
2.62 Hz), 3.26 (1H, ddd, 3J = 8.10 Hz, 3J = 7.94 Hz,
3J = 2.62 Hz), 2.67 (1H, ddd, 2J = 15.38 Hz, 3J =
7.25 Hz, 3J = 2.25 Hz), 2.61 (1H, dd, 2J = 15.38 Hz,
3J = 7.94 Hz), 2.34 (1H, dd, 2J = 15.50 Hz, 3J =
7.50 Hz), 2.30 (1H, m), 1.80 (3H, s) ppm; 13C NMR
(125 MHz, CDCl3): d = 179.5, 179.3, 171.0, 136.8,
132.7, 131.9, 130.8, 130.4, 129.6, 128.4, 120.4, 40.0,
39.6, 29.1, 24.7, 23.7 ppm; HRMS (EI): m/z calculated
for C16H15NO4 [M?] 235.1001, found 285.1001.
ꢀ
(KBr): m = 2,941, 1,731, 1,609, 1,510, 1,478, 1,278, 857,
1
768 cm-1; H NMR (300 MHz, CDCl3): d = 8.08 (2H, d,
3J = 8.40 Hz), 7.23 (2H, d, J = 8.40 Hz), 6.25 (2H, br),
3
3
4.36 (2H, q, J = 7.10 Hz), 3.49 (2H, m), 3.43 (2H, dd,
3J = 3.00 Hz, J = 1.50 Hz), 1.77 (1H, d, J = 8.85 Hz),
1.60 (1H, d, 2J = 8.85 Hz), 1.36 (3H, t, 3J = 7.10 Hz)
ppm; 13C NMR (75 MHz, CDCl3): d = 176.6, 165.9,
135.9, 134.9, 134.88, 130.5, 126.6, 61.4, 52.5, 46.1, 46.09,
14.5 ppm.
4
2
(3aR*,4S*,7R*,7aS*)-3a,4,7,7a-Tetrahydro-2-phenyl-4,
7-methano-1H-isoindole-1,3(2H)-dione (9e)
Ethyl 3-[(3aR*,7aS*)-1,3,3a,4,7,7a-hexahydro-5-methyl-
1,3-dioxo-2H-isoindol-2-yl]benzoate (4d, C18H19NO4)
From the general method, with 250 mg of 3d (1.513 mmol),
148.4 mg of 1 (1.513 mmol), and 0.30 cm3 of 2 (3.027
mmol); the product was dissolved with CH2Cl2 and filtered
through a layer of silica gel. The solvent was removed under
vacuum in a rotary evaporator, leaving a translucent yellow
liquid in 96.2% yield (456.2 mg, 1.456 mmol). Rf = 0.54
(n-hexane/AcOEt 6:4); UV–Vis (CH2Cl2): kmax (e) =
231.3 1.4 (10,965.1) nm (mol-1 dm3 cm-1); IR (CHCl3):
From the general method, with 0.25 cm3 of 3e
(2.68 mmol), 263 mg of maleic anhydride (2.68 mmol),
and 0.45 cm3 of cyclopentadiene (8, 5.36 mmol); the
product was recrystallized from a cold mixture of
CH2Cl2/n-hexane, leading to a yellow powder in 83.5%
yield (536 mg, 2.24 mmol). M.p.: 136–138 °C (Ref. [45]
143 °C).
(3aR*,4S*,7R*,7aS*)-2-(4-Fluorophenyl)-3a,4,7,7a-tetra-
hydro-4,7-methano-1H-isoindole-1,3(2H)-dione (9f)
From the general method, with 0.22 cm3 of 3f
(2.25 mmol), 220 mg of maleic anhydride (2.25 mmol),
and 0.40 cm3 of cyclopentadiene (8, 4.50 mmol); the
product was recrystallized from a cold mixture of AcOEt/
n-hexane, leading to a transparent crystals in 89.9% yield
(520 mg, 2.02 mmol). M.p.: 172–174 °C (Ref. [46]
170–173 °C).
m = 3,451, 2,938, 1,712, 1,450 cm-1; 1H NMR (500 MHz,
ꢀ
CDCl3): d = 7.98 (1H, d, 3J = 9.15 Hz), 7.86 (1H, s), 7.45
(1H, t), 7.36 (1H, d, 3J = 9.15 Hz), 5.54 (1H, br), 4.29 (2H,
q), 3.18 (1H, ddd, 3J = 9.38 Hz, 3J = 6.80 Hz, 3J =
2.50 Hz), 3.12 (1H, ddd, 3J = 9.38 Hz, 3J = 6.80 Hz,
3J = 2.50 Hz), 2.54 (1H, ddd, 2J = 15.62 Hz, 3J =
6.80 Hz, 3J = 2.50 Hz), 2.48 (1H, dd, 2J = 15.50 Hz,
3J = 2.50 Hz), 2.20 (1H, dd, 2J = 15.50 Hz, 3J =
7.13 Hz), 2.16 (1H, m), 1.69 (3H, s), 1.30 (3H, t) ppm;
13C NMR (125 MHz, CDCl3): d = 179.3, 179.2, 163.7,
136.7, 132.6, 131.8, 131.0, 129.6, 129.3, 127.8, 120.4,
61.5, 39.9, 39.5, 29.0, 24.6, 23.6, 14.5 ppm; HRMS (EI):
m/z calculated for C18H19NO4 [M?] 313.1314, found
313.1324.
General method for the preparation
of the N-arylmaleamic acids 5a–5d
The aniline 3a–3d (2 g) and approximately 1.1 equivalents
of maleic anhydride (1) were dissolved separately in
100-cm3 round-bottom flasks fitted with rubber septa, with
approximately 20 cm3 of anhydrous THF each. The flask
with the aniline, which also contained a magnetic stirrer,
was introduced into an ice bath at 0 °C, and the solution of
maleic anhydride was slowly added through a cannula. The
mixture was stirred for 16 h at r.t., after which the product
was filtered and washed twice with 20 cm3 of n-hexane and
characterized by spectroscopy. No further purification was
carried out.
(3aR*,7aS*)-3a,4,7,7a-Tetrahydro-5-methyl-2-phenyl-1H-
isoindole-1,3(2H)-dione (4e)
From the general method, with 0.25 cm3 of 3e (2.68
mmol), 263 mg of 1 (2.68 mmol), and 0.55 cm3 of 2
(5.36 mmol); the product was recrystallized from a cold
mixture of CH2Cl2/n-hexane, leading to a yellow powder in
73.2% yield (474 mg, 1.96 mmol). M.p.: 83–85 °C (Ref.
[44] 85–87 °C).
123

834
J. A. Guevara-Salazar et al.
4-[[(2Z)-3-Carboxy-1-oxo-2-propen-1-yl]amino]benzoic
acid (5a)
Diels–Alder adduct 4b
From the general method, with 250 mg of 5b (0.950 mmol)
and 0.19 cm3 of 2 (1.90 mmol); the product was recrys-
tallized from a cold mixture of CH2Cl2/n-hexane, leading
to a white powder in 82.7% yield (246.2 mg, 0.786 mmol).
From the general method, with 2.0 g of 3a (0.0146 mol)
and 1.57 g of 1 (0.0163 mol); the reaction produced a
yellow powder in 90.3% yield (3.10 g, 0.0132 mol). M.p.:
215–216 °C (Ref. [47]: 214–216 °C).
Diels–Alder adduct 4c
Ethyl 4-[[(2Z)-3-carboxy-1-oxo-2-propen-1-yl]amino]ben-
zoate (5b)
From the general method, with 250 mg of 5c (1.063 mmol)
and 0.21 cm3 of 2 (2.13 mmol); the product was recrys-
tallized from a cold mixture of CH2Cl2/n-hexane, leading
to a beige powder in 90.2% yield (273.5 mg, 0.959 mmol).
From the general method, with 2.0 g of 3b (0.0121 mol)
and 1.30 g of 1 (0.0133 mol); the reaction produced a
white powder in 89.0% yield (2.84 g, 0.0107 mol). M.p.:
177–179 °C (Ref. [48]: 194–196 °C).
Diels–Alder adduct 4d
From the general method, with 250 mg of 5d (0.950 mmol)
and 0.19 cm3 of 2 (1.90 mmol); the product was dissolved
with CH2Cl2 and filtered through a layer of silica gel. The
solvent was removed under vacuum in a rotary evaporator,
leaving a translucent yellow liquid in 64.2% yield
(231.2 mg, 0.738 mmol).
3-[[(2Z)-3-Carboxy-1-oxo-2-propen-1-yl]amino]benzoic
acid (5c)
From the general method, with 2.0 g of 3c (0.0146 mol)
and 1.57 g of 1 (0.0163 mol); the reaction produced a
beige powder in 95.8% yield (3.05 g, 0.0116 mol). M.p.:
215–217 °C (Ref. [42]: 218–220 °C).
Theoretical methodology
Ethyl 3-[[(2Z)-3-carboxy-1-oxo-2-propen-1-yl]amino]-
benzoate (5d, C13H13NO5)
The calculations described herein were carried out using
the Gaussian 09 program package [27]. The optimizations
were carried out using the TIGHT option; all DFT calcu-
lations were done using the INT(GRID = ULTRAFINE)
option. The four conformers under study were drawn with
Molden [49] and optimized first at the HF/STO-3G level of
ab initio theory. The resulting geometries were used as
starting points for subsequent optimizations at the HF/3-
21G, HF/6-31?G(d,p), B3LYP/6-31?G(d,p), M06-2X/6-
31?G(d,p), and M06-2X/6-31?G(d,p)/PCM levels of
theory. For the PCM calculations the keyword SCRF
(SOLVENT = CHLOROFORM) was used. At the highest
levels employed we carried out vibrational analyses
(25 °C, 1 bar) in order to obtain the corresponding free
energy corrections to the electronic energies; no correction
factors were applied to the vibrational frequencies. Only
real frequencies were obtained for all optimized geome-
tries. The dihedral angles relating to the coupling constants
under study were measured with Molden on the geometries
optimized at the highest levels of theory. From these angles
an empirical set of coupling constants were obtained for
each one of the conformers with the ALTONA computer
program [33]. In addition, for each conformer we calcu-
lated the theoretical spin–spin coupling constants at the
B3LYP/6-311?G(d,p)/PCM level of theory, according
to the two-step methodology (Gaussian 09 keyword
NMR = MIXED) described by Deng and co-workers [34];
only the coupling constants corresponding to the protons
shown in Scheme 2 were calculated. For both sets of
coupling constants the corresponding average values were
calculated assuming a Boltzmann distribution of con-
formers from the estimated relative energies. Cartesian
From the general method, with 2.0 g of 3d (0.0121 mol)
and 1.30 g of 1 (0.0133 mol); the reaction produced a
white powder in 77.7% yield (2.47 g, 0.0094 mol). M.p.:
155–158 °C; Rf = 0.75 (AcOEt/MeOH 1:1); UV–Vis
(MeOH): kmax (e) = 217.3 0.6 (37617.1) nm (mol-1
dm3 cm-1); IR (KBr): ꢀm = 3,312, 1,724, 1,683, 1,592,
1
1,580, 1,289, 1,112, 848, 761 cm-1; H NMR (300 MHz,
DMSO-d6): d = 10.56 (1H, s), 8.28 (1H, s), 7.86 (1H, d,
3
3J = 7.80 Hz), 7.66 (1H, d, J = 7.80 Hz), 7.46 (1H, t),
6.47 (1H, d, 3J = 12.00 Hz), 6.32 (1H, d, 3J = 12.00 Hz),
4.30 (2H, q), 1.30 (3H, t) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 167.7, 166.2, 164.2, 139.7, 132.2, 131.4,
131.0, 129.9, 125.0, 124.5, 120.5, 61.8, 14.5 ppm.
General method for the preparation of Diels–Alder
adducts 4a–4d from arylmaleamic acids and isoprene
The corresponding N-arylmaleamic acid 5a–5d (250 mg)
together with 2 equivalents of isoprene (2) and 9.0 cm3
of toluene were deposited in a 20-cm3 ACE pressure
tube. The tube was closed, introduced into a sand bath at
160 °C, and kept under constant stirring for 96 h. After
this time the product was precipitated with cold n-hex-
ane, filtered, and washed twice with 20 cm3 of n-hexane
at r.t. The product was purified and characterized by
spectroscopy.
Diels–Alder adduct 4a
From the general method, with 250 mg of 5a (1.063 mmol)
and 0.21 cm3 of 2 (2.13 mmol); the product was recrys-
talized from a cold mixture of CH2Cl2/n-hexane, leading to
a white powder in 76.8% yield (232.9 mg, 0.816 mmol).
123

Synthesis of Diels–Alder adducts of N-arylmaleimides by a multicomponent reaction
835
coordinates of the conformers of 4a along with absolute
energies and lowest vibrational frequencies are given in the
Supplementary Material.
coordinates refined. Unit weights were used in the refine-
ment. The plot in Fig. 2 was made with ORTEP-3 for
Windows (version 2.02) [52]. Data for adduct 9f are
summarized in Table 6. Supplementary crystallographic
data have been deposited at the Cambridge Crystallo-
graphic Data Centre (CCDC 816697) [53].
Single-crystal X-ray crystallography
Recrystallization of adduct 9f from CH2Cl2/n-hexane led to
the formation of colorless crystals, one of which was
mounted on a glass fiber. Crystallographic measurements
were carried out at room temperature on an Oxford Dif-
fraction Xcalibur S diffractometer using Mo Ka radiation
´
Acknowledgements We thank the Secretarıa de Investigacion y
Posgrado of the Instituto Politecnico Nacional for financial support
(Grants: DQZ, 20110101; HAJV, 20100506; JTF, 20100220). DQZ
and HAJV are fellows of the COFAA and EDI programs of the IPN.
´
´
´
JAGS thanks the Consejo Nacional de Ciencia y Tecnologıa for the
award of a scholarship. We thank Francisco Ayala M.Sc. for the
HRMS measurements and Profs. G. Zepeda and J. Tamariz for helpful
comments.
˚
(graphite monochromator, k = 0.71073 A), and a CCD
detector. No absorption correction was applied. The
structure was solved with SIR92 [50] and refined with
SHELXL [51]. Anisotropic temperature factors were
introduced for all non-hydrogen atoms. Hydrogen atoms
were placed in idealized positions and their atomic
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Formula mass
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C15H12FNO2
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0.21 9 0.23 9 0.30
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P21/c
Crystal dimensions (mm)
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Space group
Z
4
˚
a (A)
6.2846(1)
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c (°)
Collection ranges
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´
´
37. Correa-Basurto J, Vazquez Alcantara I, Espinoza-Fonseca LM,
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