Experimental and DFT study of the aza-Diels-Alder reaction between cyclopentadiene and protonated benzylimine derivated from glyoxylates

Article abstract of DOI:10.1016/j.tet.2005.08.099

The Diels-Alder reaction of protonated N-benzyl imine of methyl glyoxylate with cyclopentadiene in different solvents gave mixtures of exo/endo adducts. The exo/endo selectivity of the reaction was elucidated by NMR experiments. Theoretical calculations by means of density functional theory (DFT) at the B3LYP/6-31G(d) level have also been performed to elucidate the molecular mechanism of this reaction. The DFT results suggest a highly asynchronous concerted mechanism, which in turn can explain the preferred exo stereoselectivity of the reaction. Inclusion of solvent effects enhances the exo selectivity, and this effect increases with the polarity of the solvent, in good agreement with the experimental findings.

Full text of DOI:10.1016/j.tet.2005.08.099

Tetrahedron 61 (2005) 10951–10957
Experimental and DFT study of the aza-Diels–Alder reaction
between cyclopentadiene and protonated benzylimine
derivated from glyoxylates
a
Jose Enrique Rodrıguez-Borges, Xerardo Garcıa-Mera, Franco Fernandez,
b,
b
*
V. Hugo C. Lopes, A. L. Magalhaes and M. Natalia D. S. Cordeiro
´
´
´
´
c
c
c,
*
´
˜
a
´ ˆ
CIQ, Departamento de Quımica, Faculdade de Ciencias, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal
b
´ ´
Departamento de Quımica Organica, Facultade de Farmacia, Universidade de Santiago de Compostela,
E-15782 Santiago de Compostela, Spain
c
´ ˆ
REQUIMTE, Departamento de Quımica, Faculdade de Ciencias, Universidade do Porto, Rua do Campo Alegre, 687,
4169-007 Porto, Portugal
Received 9 June 2005; revised 9 August 2005; accepted 30 August 2005
Available online 19 September 2005
Abstract—The Diels–Alder reaction of protonated N-benzyl imine of methyl glyoxylate with cyclopentadiene in different solvents gave
mixtures of exo/endo adducts. The exo/endo selectivity of the reaction was elucidated by NMR experiments. Theoretical calculations by
means of density functional theory (DFT) at the B3LYP/6-31G(d) level have also been performed to elucidate the molecular mechanism of
this reaction. The DFT results suggest a highly asynchronous concerted mechanism, which in turn can explain the preferred exo
stereoselectivity of the reaction. Inclusion of solvent effects enhances the exo selectivity, and this effect increases with the polarity of the
solvent, in good agreement with the experimental findings.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Functionalized 2-azabicyclo[2.2.1]hept-5-enes (1a) are
useful as synthetic intermediates in the preparation of
diverse biologically active compounds,3 including several
carbocyclic nucleosides.3a,e,f For example, lactam 1b (or in
some cases its enantiomer) has been used in the preparation
of herbicides,3b cyclic analogues of GABA,3d the antibiotic
amidomycin,3c and several anti-viral agents, including the
anti-HIV agent (K)-carbovir,3a an anti-viral agent similar to
Zidovudine (AZT).3e,f
The development of synthetic methodologies based on aza-
Diels–Alder reactions of imine derivatives and dienes to
obtain six-membered heterocycles has attracted much
interest in recent years.1 In particular, a wide variety of
imine derivatives has been successfully used as key
intermediates in stereoselective synthesis of ligands and
synthetic precursors.2 These cycloadditions are highly
accelerated by the addition of Lewis acids, which promote
the formation of an iminium cation complex that rapidly
undergoes cycloaddition with dienes even at very low
temperatures.2a
Among the various azadienophiles known to react well with
cyclopentadiene,1a we have chosen iminium ions derived
from glyoxylates because they are easily prepared and
undergo cycloaddition to dienes under mild conditions.2a,d
In the recent past, Diels–Alder (DA) reactions have been the
subject of several theoretical studies, but the mechanism of
cycloaddition of the dienophile to the 1,3-diene system has
remained unexplored for almost two decades.4–6 It has been
shown that the electronic nature of the substituents at the
diene/dienophile pair may strongly influence the reaction
pathways and determine either a concerted mechanism
Keywords: DFT Study; B3LYP/6-31G(d); Aza-Diels–Alder; NMR
spectroscopy.
*
Corresponding authors. Fax: C34 981594912 (X.G.-M); fax: C351
226082959 (M.N.D.S.C.); e-mail addresses: qoxgmera@usc.es;
ncordeir@fc.up.pt
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.099

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10952
(synchronous or asynchronous) or a stepwise one with the
formation of an intermediate.4,7–13 In addition, experimen-
talists have always employed catalysts to change the
kinetics of this class of reactions. In particular, a wide
range of homogeneous and heterogeneous Lewis acids have
been used to improve the rate and exo/endo selectivities of
these reactions.14,15
configurations of the adducts were confirmed by NOE
difference spectroscopy (see Section 4).
The use of anhydrous dichloromethane as solvent at K78 8C
led to the best reaction yield of adducts (94%) and an exo/
endo stereoselectivity of 85/15. The use of anhydrous DMF
at K50 8C led to a lower yield of adducts (50%) but an exo/
endo ratio of 96/4 although the reaction was carried out at
higher temperature than the former one with dichloro-
methane. Finally, anhydrous THF led to the lowest reaction
yield of adducts (24%) and an exo/endo stereoselectivity of
83/17 similar to that obtained in dichloromethane. (Table 1).
The purpose of the theoretical contribution of this work is to
rationalize the present DA reaction. In order to obtain
reliable results, high-level density functional theory (DFT)
calculations, which include electron correlation effects,
were carried out. The solvent effects have also been taken
into account in this study, in order to get a more realistic
model of the reaction. In particular, a mean electrostatic
field of the bulk was included in the hamiltonian since it
might influence the energetics of such polarized DA
reaction.
2.2. Theoretical section
The cycloaddition between the reactants cyclopentadiene
(CP) and the protonated benzylimine of methyl glyoxylate
(IMIGLX) can take place along two different reaction
pathways depending on the type of approach (exo and endo)
of CP to IMIGLX (see Scheme 1).
2. Results and discussion
2.1. Experimental section
Starting from the fully-optimized reactant’s geometries, a
thorough exploration of the potential energy surface (PES)
of the reaction allowed us to identify two molecular
complexes (MCs) in its early stage, located on a very
shallow minima region, which give access to the different
reactive channels. These MCs correspond to van der Waals
complexes that are characterized by a large distance
Treatment of hemiacetal (3)16 with equimolar amounts of
benzylamine, trifluoroacetic acid and boron trifluoride
etherate, in dry aprotic organic solvents, generated the
corresponding iminiun ion (6), which was reacted in situ
with excess cyclopentadiene at low temperature under an
argon atmosphere (Scheme 1). Following work-up of the
resulting cycloadducts (7/8), obtained as a racemic mixture
of the (G)-exo/(G)-endo isomers, the major racemic exo
adduct [(G)-7] was easily separated by chromatography
and the minor racemic endo adduct [(G)-8] was obtained
after a second chromatographic purification. 1H NMR
studies allowed to determine the exo/endo ratio of the
reaction mixture by comparing the most cleanly observed
characteristic signals [(G)-7]: 3.88 d (s, 1-H); 2.32 d (s,
3endo-H); 3.09 d (s, 4-H); 6.24 d (dd, 5-H); 1.96 d (d, 7syn-
H); (G)-8: 3.72 d (s, 1-H); 3.39 d (s, 2H, 3exo-H and 4-H);
6.15 d (dd, 5-H); 1.84 d (d, 7syn-H)]. The exo- and endo-
˚
between the reactants (2.9–3.6 A) and were found to be
lower in energy by ca. 12–13 kcal/mol in relation to the
isolated reactants (CP and IMIGLX). Notice also that, for
both the exo and endo approaches, the MCs can adopt two
different geometrical orientations (enantiomers) depending
on the relative positions of the CP and IMIGLX reactants.
However, these enantiomeric species have the same
electronic energy and vibrational behavior. In fact, our
DFT calculations in vacuum confirmed that the reactions
involving those MC enantiomers are undistinguishable in
terms of energetic barriers and products formed. Therefore,
only the results for one of the enantiomers are considered
here. Figure 1 shows the most relevant geometrical
Scheme 1.

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10953
Table 1. Aza-Diels–Alder reaction of iminium salt (6) with cyclopenta-
diene: influence of reaction conditions (Scheme 1).
Solvent
Temperature
(8C)
Time (h)
Yield (%)a
[exo/endo]
exo:endo
[7:8]a,b
CH2Cl2
DMF
THF
K78
K50
K78
6
8
8
80/14
48/2
20/4
85:15
96:4
83:17
a The yields of adducts (G)exo/(G)endo were determined by separation
and isolation of the diastereoisomers and by integration of the signals on
the crude 1H NMR.
b The exo/endo configurations of 7 and 8, respectively, were confirmed by
1D NOE NMR data (see Section 4).
parameters of the reactants, including the labeling of the
atoms, while Figure 2 depicts those of the full-optimized
MCs found along the two reactive channels.
By further analysis of the PES, we were able to characterize
two transition states (TS-endo and TS-exo) and two
cycloadducts (PROD-endo and PROD-exo) related to the
two approach reactive channels. Notice that any attempt to
find on the PES intermediates preceding the formation of the
products was unsuccessful. Moreover, the computed IRCs
starting from the TSs demonstrated that such points connect
nicely the MCs with the cycloadduct products. As an
example, the IRC for the endo approach channel is depicted
in Figure 3. Therefore, our results revealed that these
cycloadditions follow a concerted mechanism.
The relative energies of the stationary points along the
different reaction pathways are listed in Table 2, together
with the relative enthalpies at TZ183, 195 K, while Figure 4
displays the optimized geometries of the TSs. In the gas-
phase, formation of the cycloadducts PROD-endo and
Figure 2. Predicted structures for the molecular complexes for the endo
(MC-endo) and exo (MC-exo) approach channels optimized at the B3LYP/
6-31G(d) level. Bond lengths are given in angstroms.
PROD-exo are exothermic processes; for instance, at 195K,
DHendoZK25.7 kcal/mol and DHexoZK28.0 kcal/mol.
Looking at the values of the relative energies of TS-endo
and TS-exo with respect to the corresponding molecular
complexes (MC-endo and MC-exo), one can also realize
that this cycloaddition is exo-stereoselective in the gas-
phase. Furthermore, the lengths of the C4–C7 forming
˚
˚
bonds, 1.985 A at TS-endo and 2.030 A at TS-exo, are
Table 2. Total energies, relative energies and enthalpiesa (in parentheses)
for the stationary points corresponding to the cycloaddition reactions of
cyclopentadiene (CP) with the protonated benzylimine of methyl
glyoxylate (IMIGLX) in vacuum
Energies
Enthalpies (kcal/mol)
(au)
(kcal/mol)
183 K
195 K
CP
K194.10106
K593.24198
K787.35602
K787.34919
K787.38380
K787.35767
K787.35255
K787.38746
IMIGLX
MC-endo
TS-endo
PROD-endo
MC-exo
TS-exo
(0.00)
(5.13)
(0.00)
(4.58)
(0.00)
(4.54)
(K12.91)
(0.00)
(3.95)
(K13.93)
(0.00)
(3.41)
(K14.02)
(0.00)
(3.37)
PROD-exo
(K14.22)
(K15.22)
(K15.30)
a Energies and enthalpies are relative to the MC-endo and MC-exo
molecular complexes and include the zero-point vibrational corrections.
Enthalpies include additionally the thermal translational, rotational and
vibrational contributions computed at TZ183 or 195 K.
Figure 1. Predicted structures for the reactants protonated benzylimine of
methyl glyoxylate (IMIGLX) and cyclopentadiene (CP) optimized at the
B3LYP/6-31G(d) level. Bond lengths are given in angstroms and the
0
dihedral angles, tZ:C1 –C1–C2–N3 and uZ:C1–C2–N3–C4, in degrees.

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10954
Figure 3. B3LYP/6-31G(d) IRC plots for the endo approach channel of the DA reaction.
shorter than the lengths of the N3–C10 forming bonds,
˚
˚
2.820 A at TS-endo and 2.879 A at TS-exo. These data point
up to concerted but highly asynchronous bond formation
processes where the C4–C7 bond is being formed in a larger
extent than the N3–C10 one. On the other hand, the
computed imaginary wave numbers for the TS-endo is
245 cmK1, while that for the TS-exo is 224 cmK1, and this
follows the degree of asynchronicity of the respective
channels (endo!exo).
The polar nature of the two processes can be assessed by a
charge transfer analysis at the corresponding TSs. The
atomic charges have been partitioned between the donor CP
and the acceptor IMIGLX. The negative charge transferred
from CP to IMIGLX along the concerted processes is 0.51e
at TS-endo and 0.53e at TS-exo. The large amount of charge
transfer denotes the high polar nature of both processes. It
correlates with the asynchronicity of the channels (endo!
exo) and with the lowering of the energy barrier on going
from the endo approach mode to the exo one. Alternatively,
the cycloaddition reaction can be analyzed in terms of the
global electronic index—the electrophilicity power u—that
might be defined within the DFT. This static index may
roughly explain the global reactivity pattern observed in
Diels–Alder reactions and is easily estimated using the
frontier molecular orbitals of the reactants.17a The reactant
IMIGLX has a much higher electrophilicity power (uZ
14 eV) than the reactant CP (uZ0.83 eV), the former being
classified as a strong electrophile and the latter as the
nucleophile. On the other hand, the difference between the
electrophilicities of IMIGLX and CP (DuZ13 eV) con-
firms the polar character of the present cycloaddition, which
in turn is much higher than that, for instance, of the
archetypal butadiene/ethylene one (DuZ0.32 eV), that is
classified as a non-polar pericyclic process.17
Concerning the solvent effects, Table 3 presents the relative
energies for the reactions in the solvents tetrahydrofuran,
dichloromethane and dimethylformamide. These energies
Figure 4. Predicted structures for the transition states for the endo (TS-
endo) and exo (TS-exo) approach channels optimized at the B3LYP/6-
31G(d) level. Bond lengths are given in angstroms.

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10955
Table 3. Total energies and relative energiesa (in parentheses) for the cycloaddition reactions of cyclopentadiene (CP) with the protonated benzylimine of
methyl glyoxylate (IMIGLX) in solution
Solvent
Tetrahydrofuran (3Z7.58)
Dichloromethane (3Z8.93)
Dimethylformamide (3Z38.3)
(au)
(kcal/mol)
(au)
(kcal/mol)
(au)
(kcal/mol)
CP
K194.10211
K593.30462
K787.41106
K787.40437
K787.43960
K787.41245
K787.40865
K787.44356
K194.10215
K593.30625
K787.41244
K787.40576
K787.44105
K787.41383
K787.41007
K787.44501
K194.10493
K593.33380
K787.43710
K787.43069
K787.46518
K787.43662
K787.43492
K787.46874
IMIGLX
MC-endo
TS-endo
PROD-endo
MC-exo
TS-exo
(0.00)
(5.04)
(K13.39)
(0.00)
(3.11)
(0.00)
(5.03)
(K13.43)
(0.00)
(3.09)
(0.00)
(4.87)
(K13.09)
(0.00)
(1.80)
PROD-exo
(K15.05)
(K15.09)
(K15.68)
a Energies are relative to the MC-endo and MC-exo molecular complexes and include the zero-point vibrational corrections computed in the gas-phase.
were obtained by performing single-point energy calcu-
lations on top of the gas-phase stationary points, and
modeling the solvent as a polarizable continuum. As can be
seen, the inclusion of the solvent stabilizes more the TSs
than the MCs because large charge transfers occur along
these cycloadditions. Therefore, the more polar the solvents
are, the lower the reaction barriers (see Tables 2 and 3).
Since this outcome is more pronounced for the exo channel,
the solvent effects increase the exo selectivity of the process
when compared to the one found in the gas-phase. Actually,
the activation energy of the endo approach is lowered only
by ca. 0.1–0.3 kcal/mol, whereas that of the exo approach is
by ca. 0.8–2 kcal/mol. Besides, the polarity of the solvent
enhances the exo-selectivity of this reaction. Most likely this
stems from the greater dipole moment of the exo species
(MC-exo: 1.5 D; TS-exo: 5.2 D) over those of the endo
counterparts (MC-endo: 0.7 D; TS-endo: 3.4 D), as stressed
by Cativiela et al.18 Moreover, the theoretical results follow
the experimentally observed trends (THF: exo/endo ratioZ
83/17; CH2Cl2: exo/endo ratioZ85/15; DMF: exo/endo
ratioZ96/4). Finally, as the solvent effects stabilize more the
reactants CPCIMIGLX than the products, the exothermicity
of both reactions in solution is expected to decrease.
instance, one obvious step forward would be a completely
relaxation of the molecular structures inside the solvent
continuum, but previous studies on DA cycloadditions of
strong polar nature have shown that the inclusion of solvent
effects does not significantly modify the gas-phase geome-
tries.17 Further, tuning the value of the dielectric constant for
the experimental temperature and, specially, including a few
explicit individual solvent molecules in the reactants’ first
solvation shell, to take into account local molecular solvent-
solute interactions, might as well introduce interesting effects
on the predictions. Finally, though the present study tried to
mimic the effect of the catalyst by considering the charged
reactant IMIGLX, an explicit inclusion of the catalyst may
well alter both bond-formation processes in a different manner
and, therefore, allow a more refined selectivity prediction.
4. Experimental
4.1. General
Silica gel was purchased from Merck. The efficient drying
of DMF is achieved by standing with powdered CaSO4,
followed by distillation under reduced pressure. The DMF
˚
distillate is stored over Type 3A molecular sieve. All other
3. Conclusion
chemicals used were of reagent grade and were obtained
from Aldrich Chemical Co. Flash column chromatography
was performed on silica gel (Merck 60, 230–240 mesh) and
analytical thin-layer chromatography (TLC) on pre-coated
silica gel plates (Merck 60 GF254) using iodine vapour and/
or UV light for visualization. Melting points were
determined on a Reichert Kofler Thermopan or in capillary
tubes on a Bu¨chi 510 apparatus, and are uncorrected.
Infrared spectra were recorded on a Perkin-Elmer 1640-FT
The formation of methyl glyoxylate (5), in situ, from
hemiacetal (3) was confirmed through the isolation of the
corresponding 2,4-dinitrophenylhydrazone (4) in acidic
conditions. The cycloaddition reaction between cyclopenta-
diene and the iminium cation (6), generated by treatment of
benzylamine with methyl glyoxylate (5) in the presence of
TFA and BF3$Et2O, afforded racemic exo-adduct (majority)
and racemic endo-adduct. The exo/endo ratio increased with
the polarity of the solvent.
spectrophotometer and the main bands are given in cmK1
.
1H NMR spectra (300 MHz) and 13C NMR spectra
(75.47 MHz) were recorded on a Bruker WM AMX
spectrometer using TMS as internal standard (chemical
shifts (d) in ppm, J in Hz). The 1D difference NOE
experiments were all performed on a Varian Inova 750 MHz
spectrometer using 6 K data files. In these experiments a 908
pulse width was used with an irradiation time corresponding
to 5!T1. Elemental analyses were obtained on a Perkin-
Elmer 240B microanalyser by the Microanalysis Service of
the University of Santiago de Compostela. Mass spectra
were performed on a Hewlett-Packard HP5988A mass
spectrometer by electron impact (EI). Optical rotations at
the sodium D-line were determined using a Perkin-Elmer
241 thermostated polarimeter.
Theoretical calculations at B3LYP/6-31G(d) level enabled
us to characterize two reaction paths that lead to the exo and
endo final products. The analysis of the reaction kinetics
suggests a concerted mechanism with a prior formation of a
stable molecular complex, similar to previous theoretical
studies on reactions of the same type.6,17 The exo/endo ratio
of epimers 7/8 was predicted to increase with the solvent
polarity in good agreement with the experimental findings.
Even though a qualitative interpretation of the experimental
results has been achieved with the model adopted for
studying the reaction, there is still room for improvement in
the quantitative prediction of its stereoselectivity. For

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10956
4.1.1. Methyl glyoxylate hemiacetal, 3.5 A solution of
glyoxylic acid monohydrate (2) (23.0 g; 250 mmol) in dry
methanol (125 mL) was refluxed overnight. The solution
was cooled to room temperature and neutralized with solid
KHCO3. The neutral solution was evaporated in vacuo and
the oily residue was dissolved in CH2Cl2 and dried with
Na2SO4. Evaporation of the solvent afforded the methyl
glyoxylate hemiacetal in 82% yield. [a]2D5 0 (c 1, CHCl3). IR
(NaCl): 3383 (O–H), 2959, 1748 (CO), 1449, 1360, 1231,
1086, 799 cmK1. 1H NMR (CDCl3): 3.54 (s, 3H, 2-OCH3),
3.84 (s, 4H, 1-OCH3), 4.90 (s, 1H, 2-H), 5.40 (s, D2O exch.,
1H, OH). 13C NMR (CDCl3): 53.35 (2-OCH3), 55.82
(1-OCH3), 93.61 (C-2), 170.13 (C-1). MS (EI, m/z): 120
(MC). Anal. Calcd for C4H8O4 C 40.00, H 6.71, found C
39.88, H 6.84.
an oily residue (ca. 45 g) that upon chromatography on
silica gel (900 g) with 6:1 hexane/EtOAc as eluent afforded
(G)-7 (29.19 g; 80%) in the early fractions as a colorless oil
and compound (G)-8 in the later fractions (not homogenous
by TLC). Compound 8 was further purified by column
chromatography on silica gel (170 g) with 4:1 hexane/
EtOAc as eluent, affording (G)-8 as a yellow oil (5.11 g;
14%). The procedure with THF and DMF as solvents at low
temperature is similar (Table 1).
4.2.1. Compound (G)-7. [a]2D5 0 (c 1, CHCl3). IR (NaCl):
3060, 2993, 2950, 1743, 1603, 1562, 1434, 1235, 1167, 909,
845, 736 cmK1. 1H NMR (CDCl3): 1.395 (d, 1H, JZ8.3 Hz,
7anti-H), 1.96 (d, 1H, JZ8.3 Hz, 7syn-H), 2.32 (s, 1H, 3endo-H),
3.09 (s, 1H, 4-H), 3.43 and 3.58 (AB system, 2H, JZ
12.63 Hz, NCH2Ph), 3.59 (s, 3H, CO2CH3), 3.88 (s, 1H,
1-H), 6.24 (dd, 1H, JZ5.5, 1.6 Hz, 5-H), 6.47 (dd, 1H, JZ
5.5, 2.7 Hz, 6-H), 7.19–7.38 (m, 5H, C6H5). 13C NMR
(CDCl3): 46.85 (C-7), 48.72 (C-4), 52.10 (CO2CH3), 59.16
(NCH2Ph), 64.47 (C-1), 65.04 (C-3), 127.28 (C-40), 128.41
(C-20CC-60), 129.35 (C-30CC-50), 133.88 (C-5), 136.80
(C-6), 139.23 (C-10), 174.78 (COO). MS (EI, m/z): 243
(MC). Anal. Calcd for C15H17NO2 C 74.05, H 7.04, N 5.76,
found C 73.91, H 7.17, N 5.79.
The crude oily product was used in the following reactions
without further purification.
4.1.2. Methyl glyoxylate 2,4-dinitrophenylhydrazone, 4.
To a solution of 2,4-dinitrophenylhydrazine (0.10 g;
0.50 mmol) in absolute methanol (5 mL) and concn
H2SO4. (0.4 mL) that had been warmed and filtered, was
added a solution of 3 (48 mg; 0.40 mmol) in 5 mL of
absolute methanol. The solid formed was filtered, washed
several times with cold absolute methanol, and recrystallized
from methanol affording methyl glyoxylate 2,4-dinitro-
phenylhydrazone. Yield 106 mg (99%). Mp 199–201 8C
(MeOH). [a]2D5 0 (c 1, CHCl3). IR (KBr): 3288 (N–H), 3088,
1731 (CO), 1619 (CN), 1576, 1498 (arom. C]C), 1429,
1316, 1236, 1204, 1138, 1105, 925, 850, 744, 709, 630,
535 cmK1. 1H NMR (DMSO-d6): 3.78 (s, 3H, CH3), 7.89 (d,
1H, JZ9.5 Hz, arom., 6-H), 8.06 (s, 1H, 2-H), 8.44 (dd, 1H,
JZ9.5, 2.65 Hz, arom., 5-H), 8.80 (d, 1H, JZ2.65 Hz,
arom., 3-H), 11.90 (s, 1H, D2O exch., –NH–). 13C NMR
(DMSO-d6): 52.48 (OCH3), 117.68, 122.82, 130.33, 131.78,
137.75, 139.30, 144.04, 163.41 (C-1). MS (EI, m/z): 268
(MC). Anal. Calcd for C9H8N4O6 C 40.31, H 3.01, N 20.89,
found C 40.15, H 3.22, N 20.79.
4.2.2. Compound (G)-8. [a]2D5 0 (c 1, CHCl3). IR (NaCl):
3062, 2992, 1747, 1603, 1435, 1198, 909, 857, 700 cmK1
.
1H NMR (CDCl3): 1.57 (d, 1H, JZ8.5 Hz, 7anti-H), 1.83 (d,
1H, JZ8.5 Hz, 7syn-H), 3.57 (s, 3H, CO2CH3), 3.83 and
3.89 (AB system, 2H, JZ12.9 Hz, NCH2Ph), 6.15 (dd, 1H,
JZ5.5, 2.4 Hz, 5-H), 6.49 (dd, 1H, JZ5.5, 2.9 Hz, 6-H),
7.20–7.44 (m, 5H, C6H5). MS (EI, m/z): 243 (MC). Anal.
Calcd for C15H17NO2 C 74.05, H 7.04, N 5.76, found C
74.19, H 7.10, N 5.84.
The stereochemistry of adducts 7 and 8 was determined
through 1 D NOE NMR experiments at room temperature.
The NOE effects were observed between 7-Hsyn and 3-H and
protons in a close vicinity, as shown in the following figure.
4.2. Methyl [2-benzyl-2-azabicyclo[2.2.1]hept-5-ene]-3-
carboxylate, (G)-(exo)-7 and methyl [2-benzyl-2-azabi-
cyclo[2.2.1]hept-5-ene]-3-carboxylate, (G)-(endo)-8
A solution of benzylamine (16.4 mL; 16.0 g; 150 mmol) in
dry CH2Cl2 (100 mL) was added under argon to a stirred
˚
suspension of 3 (18.01 g; 150 mmol) and 3 A molecular
sieve pearls (100 g) in dry CH2Cl2 (400 mL) at 0 8C. When
the addition was complete the reaction mixture was cooled
to K78 8C and treated successively with trifluoroacetic acid
(11.5 mL; 17.1 g; 150 mmol), boron trifluoride etherate
(18.8 mL; 21.3 g; 150 mmol) and freshly distilled cyclo-
pentadiene (25 mL; ca. 300 mmol). After 6 h a mixture of
saturated aqueous NaHCO3 solution (300 mL) and then
solid NaHCO3 (35 g) were added, the mixture was allowed
to reach room temperature and filtered. The organic layer
was separated from the filtrate and washed with water and
CH2Cl2 on a celite pad, after which the organic layer of the
resulting mixture was separated and put aside, and the
aqueous layer was extracted with CH2Cl2 (3!150 mL). The
pooled organic layers were washed with saturated NaHCO3
solution (150 mL) and brine (150 mL), and were dried with
Na2SO4. Removal of the solvent in a rotary evaporator left
4.3. Computational methods
In this work, DFT calculations have been carried out using
the B3LYP19,20 exchange-correlation functionals, together
with the standard 6-31G(d) basis set. The PES for the
cycloaddition reaction was scanned systematically for all
possible intermediates and transition state structures.

´
J. E. Rodrıguez-Borges et al. / Tetrahedron 61 (2005) 10951–10957
10957
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Stationary points found on the PES were optimized without
any geometrical constraint by the Berny analytical gradient
optimization algorithm.21 Harmonic frequencies were
computed at the full-optimized geometries, allowing the
assignment of stationary points as minima or transition
states and the determination of zero-point vibrational
energies and thermal vibrational contributions (TZ183
and 195 K). To verify that each saddle point connects two
putative minima, intrinsic reaction coordinate (IRC)
calculations were performed in forward and backward
directions, that is, by following the eigenvector associated to
´ ´
4. Domingo, L. R.; Arno, M.; Contreras, R.; Perez, P. J. Phys.
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the unique negative eigenvalue of the Hessian matrix, using
´
22
the Gonzalez and Schlegel integration method. The
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electronic structures of stationary points were analyzed by
the natural bond orbital method,23 and global electronically
indexes,17 defined in the context of the DFT, were also
computed for the reactants. In addition, solvent effects have
been considered by performing, on top of the optimized
geometries, single-point energy calculations using the self-
consistent reaction field method based on the polarizable
continuum model of Tomasi and co-workers.24 The
dielectric constants used in the latter calculations, 3Z7.58,
8.93 and 38.3, correspond to the solvents employed in the
experiments, namely tetrahydrofuran, dichloromethane and
dimethylformamide, respectively. Finally, thermodynamic
properties were evaluated at the experimental temperatures
TZ183 and 195 K. All calculations were carried out with
Gaussian 98 package of programs.25
8. Houk, K. N.; Loncharich, R. J.; Blake, J. F.; Jorgensen, W. L.
J. Am. Chem. Soc. 1989, 111, 9172.
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17. (a) Domingo, L. R.; Aurell, M. J.; Perez, P.; Contreras, R.
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Acknowledgements
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Andres, J. J. Org. Chem. 1999, 64, 5867. (c) Domingo, L. R.;
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Andres, J.; Alves, C. N. Eur. J. Org. Chem. 2002, 15, 2557. (d)
The authors would like to thank the Xunta de Galicia and
also the Ministry of Education of Portugal for financial
support of this work under project XUGA
PGIDT02BTF20305PR and Program PRODEP III/action
3.2, respectively.
Domingo, L. R. J. Org. Chem 2001, 66, 3211.
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