Lewis acid activated aza-diels-alder reaction of N-(3-Pyridyl)aldimines: An experimental and computational study

Article abstract of DOI:10.1002/ejoc.200901325

A combined theoretical and experimental study of a Povarovtype cycloaddition reaction, suggests an asynchronous concerted process that is favored by double Lewis acid activation with BF₃·Et ₂O; endo selectivity was observed in the re

Full text of DOI:10.1002/ejoc.200901325

FULL PAPER
DOI: 10.1002/ejoc.200901325
Lewis Acid Activated Aza-Diels–Alder Reaction of N-(3-Pyridyl)aldimines:
An Experimental and Computational Study
[
a]
[a]
[b]
[b]
Francisco Palacios,* Concepción Alonso, Ana Arrieta, Fernando P. Cossío,*
[c]
[a]
[a]
Jose M. Ezpeleta, María Fuertes, and Gloria Rubiales
Keywords: Povarov reaction / Cycloaddition / Imines / Alkenes / Heterocycles / Aldimines
A combined theoretical and experimental study of a Povarov-
between N-(3-pyridyl)aldimines and styrene, cyclopentadi-
type cycloaddition reaction suggests an asynchronous con- ene, or indene, and substituted tetrahydro-1,5-naphthyridine
certed process that is favored by double Lewis acid activation
with BF ·Et O; endo selectivity was observed in the reactions
derivatives were obtained in a regio- and stereoselective
fashion.
3
2
Introduction
Nitrogen-containing heterocycles are important com-
pounds widely employed in the fields of biochemistry, phar-
maceutics, and materials science.[ Consequently, reactions,
including those of carbonyl compounds with amines, in
which nitrogen-containing heterocycles can be prepared
both chemo- and stereoselectively, have often attracted the
attention of organic chemists. The Povarov reaction is such
an example. Povarov initially described the participation of
aldimines 1a (X = CH; Scheme 1), derived from aniline and
aromatic aldehydes, in a formal [4+2] cycloaddition reac-
tion with electron-rich alkenes in the presence of a Lewis
acid catalyst and the subsequent tautomerization of the ini-
1]
Scheme 1. Povarov reaction of imines and alkenes.
However, no attention has been paid to theoretical stud-
ies nor to the elucidation of the Povarov reaction mecha-
[
3e]
nism. In previous studies a stepwise reaction mechanism
was suggested for the lanthanide triflate catalyzed imino-
Diels–Alder reaction of imines derived from anilines with
[
2]
tial adduct to give 1,2,3,4-tetrahydroquinoline derivatives.
Since Povarov’s original report and for nearly three decades,
this reaction did not attract very much attention until it was
[
4a]
alkenes. In addition, experimental evidence
towards a concerted asynchronous cycloaddition.
Taking into account the fact that we have been involved
points
[
3]
developed into a multicomponent reaction (MCR). In
fact, this development triggered an ongoing period of con-
[
6]
[7]
siderable interest in the Povarov reaction.[4] Moreover, the
in the chemistry of 1- and 2-azadienes as well as in the
development of new methods for the preparation of three-
,
Povarov reaction has also found applications in total syn-
[
8]
[9]
[10]
five-, and six-membered nitrogen-containing hetero-
thesis, for example, in the synthesis of (Ϯ)-martinelline, (Ϯ)-
martinellic acid, luotonin A, and camptothecin.[
5]
cycles, we envisaged that the application of the Povarov-
type reaction to amines other than anilines would provide
not only a new family of polycyclic azaheterocycles but also
a substantial increase in molecular diversity. Thus, we re-
port herein the first stereoselective preparation of tetra-
hydro-1,5-naphthyridine derivatives 3 (X = N; Scheme 1)
with control of the relative configuration of the three ste-
reocenters, and a combined theoretical and experimental
[
[
[
a] Departamento de Química Orgánica I, Facultad de Farmacia,
Universidad del País Vasco,
Apartado 450, 01080 Vitoria, Spain
Fax: +34-945-013049
E-mail: francisco.palacios@.ehu.es
b] Departamento de Química Orgánica I, Kimika Fakultatea,
Universidad del País Vasco – Euskal Herriko Unibertsitatea,
Manuel de Lardizabal 3, 20018 San Sebastián-Donostia, Spain study of the Povarov-type reaction between imines and
Fax: +34-943-135270
alkenes as well as the effects of the use of a Lewis acid
E-mail: fp.cossio@ehu.es
c] Departamento de Física Aplicada, Facultad de Farmacia, Uni- (BF
versidad del País Vasco,
·Et O) in a modified Povarov reaction involving N-(3-
2
3
pyridyl)aldimines 1b–d (X = N; Scheme 1) and alkenes such
as ethylene (2a), styrene (2b), cyclopentadiene (2c), and in-
dene (2d).
Apartado 450, 01080 Vitoria, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901325.
Eur. J. Org. Chem. 2010, 2091–2099
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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F. Palacios, F. P. Cossío et al.
FULL PAPER
Results and Discussion
Experimental Study
Table 1. Experimental reaction conditions and compounds 3 ob-
tained from the reactions of aldimines 1 with alkenes 2.
First, the hetero-Diels–Alder reaction between N-(3-pyr-
idyl)aldimine 1c (R = Ph) and styrene (2b) was performed.
No reaction was observed in the absence of a Lewis acid at
room temperature or in chloroform at reflux. In contrast,
when the reaction was performed at room temperature in
the presence of 1 equiv. of BF ·Et O, bicyclic endo com-
3
2
pound 3bc was regioselectively obtained after 216 h
Scheme 2, Table 1, Entry 1), and when the same reaction
(
was carried out in chloroform at reflux at 60 °C, the same
compound 3bc was obtained but in a shorter reaction time
of 24 h (Table 1, Entry 2). In this context, it has been pre-
viously reported that the pyridine nitrogen atom of azin-
ylformamidines is the preferred site of protonation and for
[
a] Percentage of consumption of the starting material by NMR
analysis of the crude reaction mixture. [b] By using 1.2 equiv. of
BF ·Et O, a time of 53 h was required for complete reaction. [c]
No reaction was observed at room temperature. [d] By using
[
11]
3
2
this reason we believed that the use of 2 equiv. of Lewis 1.2 equiv. of BF ·Et O, a time of 50 h was required for complete
acid could accelerate the reaction rate. Thus, with 2 equiv. reaction.
3
2
of BF ·Et O at room temperature or in chloroform at reflux
3
2
2
.41 ppm with coupling constants of 2JHH = 12.6 Hz and
at 60 °C (Scheme 2, Table 1, Entries 3 and 4) the expected
compound 3bc was obtained in considerably shorter reac-
tion times compared with the reactions in which 1 equiv. of
3
JHH = 6.1 and 2.3 Hz corresponding to one of the methyl-
ene protons 3-H, and a decoupled double doublet at δ =
2.26 ppm with coupling constants of J
2
BF ·Et O was used (Scheme 2, Table 1, Entries 1 and 2).
3
2
= 12.6 Hz and
HH
3
Note that almost quantitative conversion of the starting
JHH = 12.2 and 11.3 Hz corresponding to the other meth-
ylene proton 3-H. An HMBC study of compound 3bc
showed, among others, cross-signals between NH and the
methylene carbon atom C-3, which confirms the regiochem-
istry of the process. In the 1D-NOESY spectrum of com-
pound 3bc, the selective saturation of the multiplet at δ =
materials was observed when 2 equiv. of BF ·Et O were
3
2
used (Table 1, Entries 3 and 4) to give 1,2,3,4-tetrahydro-
,5-naphthyridine 3bc with regio- and stereoselective con-
trol of the two stereocenters (Scheme 2). The use of
.2 equiv. of BF ·Et O was not sufficient to give optimal
1
1
3
2
conditions; the required reaction time decreases, but not as
2
.41 ppm (see Figure 1 and the Supporting Information)
much as with the use of 2 equiv. of BF ·Et O.
3
2
corresponding to one of the methylene protons 3-H af-
forded a positive NOESY with protons 2-H (2.54%) and 4-
H at δ = 4.45 ppm (3.52%). This observation together with
1
the coupling constants observed in the H NMR spectrum
of compound 3bc is consistent with the relative cis configu-
ration of all these protons.
Figure 1. Relative configuration assigned by 1D-NOESY analysis
of compound 3bc.
The reaction was then performed with styrene (2b) and
N-(3-pyridyl)aldimine 1d derived from acetaldehyde (R =
Me) in the presence of 1 or 2 equiv. of BF ·Et O at room
Scheme 2. Cycloaddition reactions of 1c,d with 2b–d in the pres-
ence of BF ·Et O.
3
2
3
2
The structure of compound 3bc was assigned on the ba- temperature (Scheme 2, Table 1, Entries 5 and 6) and com-
sis of 1D and 2D NMR spectroscopy, including 1D- pound 3bd was obtained in a very high yield in a regio- and
NOESY, HMQC, and HMBC experiments, and mass spec- stereoselective manner. The reaction times were consider-
1
trometric data. The H NMR spectrum of compound 3bc ably shorter than the reactions of imine 1c derived from
showed one double doublet at δ = 4.59 ppm with coupling benzaldehyde (R = Ph).
3
constants of J
= 11.3 and 2.3 Hz corresponding to the
Next, the hetero-Diels–Alder reactions of N-(3-pyridyl)-
HH
proton 2-H, one double doublet at δ = 4.45 ppm with cou- aldimines 1c (R = Ph) and 1d (R = Me) with cyclic olefins
3
pling constants of J
= 12.2 and 6.1 Hz corresponding cyclopentadiene (2c) and indene (2d) were studied. No reac-
HH
to the proton 4-H, one decoupled double doublet at δ = tion was observed between 2c,d and N-(3-pyridyl)aldimines
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Aza-Diels–Alder Reaction of N-(3-Pyridyl)aldimines
1
c,d in the absence of a Lewis acid. However, almost quan-
titative conversion of the starting materials was observed
with exception of compound 3cd; Table 1, Entry 10) when
(
2
equiv. of BF ·Et O were used (Table 1, Entries 7–9 and
3 2
11–13) with only one isomer obtained, the tricyclic endo-
tetrahydro-1,5-naphthyridine derivatives 3cc,cd or the tetra-
cyclic endo-tetrahydro-1,5-naphthyridine derivatives 3dc,dd,
with regio- and stereoselective control of the three ste-
reocenters (Scheme 2). As before, when using 2 equiv. of
BF ·Et O at room temperature or in chloroform at reflux
Scheme 3. Cycloaddition reactions of imines 1a–d and ethene (2a).
3
2
at 60 °C (Scheme 2, Table 1, Entries 8, 10, 11, and 13), the
reaction time was reduced considerably compared with the
reactions in which 1 equiv. of BF ·Et O was used
3
2
According to our results, the reaction is exothermic, but
(
Scheme 2, Table 1, Entries 7, 9, and 12).
The structures of compounds 3cd,cc,dc,dd were assigned and is quite asynchronous (Figure 3, Table 2, Entry 1). This
the transition-state structure TS1aa lies at 28.1 kcal/mol
on the basis of 1D and 2D NMR spectroscopy and mass disfavored reaction may be a consequence of a significant
spectrometric data. The structure of compound 3dc was decrease in the aromatic stabilization energy in the transi-
also confirmed unambiguously by X-ray analysis (Fig- tion state. We therefore considered that the weaker aromatic
ure 2).
character of N-(3-pyridyl)aldimines 1b–d (X = N) could ac-
celerate the reaction between the imines and alkenes. Thus,
the [4+2] cycloaddition reaction between N-(3-pyridyl)ald-
imines 1b–d (X = N) and ethylene (2a) was studied compu-
tationally (Scheme 3). The calculations indicate that the for-
mation of the cycloadducts 4ab–ad via transition-state
structures TS1 is more favorable (Table 2, Entries 2, 4, and
6) than the formation of the regioisomers 4Јab–ad, respec-
tively, via transition-state structures TS1Ј (Table 2, En-
tries 3, 5, and 7) under conditions of kinetic control (Fig-
Figure 2. ORTEP view of molecular structure of the 1,2,3,4-tetra-
hydro-1,5-naphthyridine derivative 3dc.
As far as we know, this strategy represents the first syn-
thesis of bicyclic cis-2,4- (3bc,bd) as well as tricyclic (3cc,cd)
and tetracyclic (3dc,dd) cis-2,3,4-substituted tetrahydro-1,5-
naphthyridine derivatives. All these results suggest that the
formation of compounds 3 can be explained by a [4+2] cy-
cloaddition reaction of imines 1 with dienophiles 2
(Scheme 2) via endo-A cycloadducts 4 followed by proto-
tropic tautomerization under the reaction conditions. How-
ever, a nonconcerted stepwise reaction mechanism cannot
be discarded. For this reason we performed a computa-
tional study of this process to confirm our experimental
results and to try to predict a computational model consis-
tent with the reaction.
Computational Studies
Figure 3. Fully optimized transition-state structures TS1aa from
the reaction of 1a with 2a, and TS1 and TS1Ј from the reactions
of imines 1b–d with 2a. Selected bond lengths are given in Å. The
First, the simple parent reaction between imine 1a
(
Scheme 3, R = H, X = CH) and ethene (2a) to give 4aa numbers given in parentheses are the relative energy differences (in
(
Scheme 3) was examined. All structures were optimized by kcal/mol) between the transition state TS1Ј and the corresponding
[
12]
transition state TS1 of the same starting imine, calculated at the
B3LYP/6-31G*+∆ZPVE level of theory. Numbers in square brack-
ets correspond to the same relative energy differences (in kcal/mol)
calculated at the M06-2X/6-31G*//B3LYP/6-31G*+∆ZPVE level of
density functional theory (DFT) using the B3LYP
and
[
13]
M06-2X
hybrid functionals as implemented in the
[
14]
[15]
Gaussian 03 and Jaguar software packages. The stan-
[16]
dard split-valence 6-31G* basis set was used in all cases. theory.
Eur. J. Org. Chem. 2010, 2091–2099
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F. Palacios, F. P. Cossío et al.
FULL PAPER
ure 3). In addition, the similar relative energies found for compounds 5 in which BF is coordinated to the imine ni-
3
both the B3LYP and M06-2X functionals indicate that the trogen atom. The activation barriers for the [4+2] cycload-
former is accurate enough for the study of these reactions.
dition reactions of 2a with 7b–d via transition states
TS3ab–ad, in which the Lewis acid is coordinated to the
pyridinic nitrogen atom, are consistently lower (Table 2, En-
tries 12–14) than in the noncoordinated case through transi-
tion states TS1ab–ad (Scheme 4, Table 2, Entries 2, 4, and
[
a]
), reaction energies[a] (∆Erxn),
and synchronicities (Sy) associated with the formation of the
[4+2] cycloadducts in Schemes 3, 4, and 5.
Table 2. Activation energies (∆E
a
[
b]
Entry
Reaction
TS
∆E
a
[kcal/mol] ∆Erxn [kcal/mol] Sy[c]
6). Nevertheless, in these theoretical studies we could ob-
1
2
3
4
5
6
7
8
9
1a + 2a Ǟ 4aa TS1aa
1b + 2a Ǟ 4ab TS1ab
1b + 2a Ǟ 4Јab TS1Јab
1c + 2a Ǟ 4ac TS1ac
1c + 2a Ǟ 4Јac TS1Јac
1d + 2a Ǟ 4ad TS1ad
1d + 2a Ǟ 4Јad TS1Јad
5a + 2a Ǟ 6aa TS2aa
5b + 2a Ǟ 6ab TS2ab
5c + 2a Ǟ 6ac TS2ac
5d + 2a Ǟ 6ad TS2ad
7b + 2a Ǟ 8ab TS3ab
7c + 2a Ǟ 8ac TS3ac
7d + 2a Ǟ 8ad TS3ad
9b + 2a Ǟ 10ab TS4ab
9c + 2a Ǟ 10ac TS4ac
9d + 2a Ǟ 10ad TS4ad
28.1
27.0
28.2
31.3
32.9
30.3
31.5
20.1
18.8
30.9
25.5
22.6
27.3
26.1
14.3
27.2
21.5
–8.4
–10.8
–7.9
0.9
0.85
0.85
0.84
0.92
0.91
0.88
0.87
0.78
0.77
0.84
0.84
0.86
0.94
0.91
0.76
0.83
0.93
serve that if BF coordinates preferentially to the imine ni-
3
trogen atom in the [4+2] cycloaddition reactions of 5a–d
with 2a via transition states TS2, the activation barriers
could be even lower (Table 2, Entries 8–11). This led us to
3.9
–4.5
–1.7
–14.1
–16.1
–4.0
–8.7
–12.5
–1.8
–6.8
–16.5
–3.7
–9.0
believe that a second equivalent of BF could accelerate
3
even more the reaction by the coordination of this second
molecule of BF to the imine nitrogen atom. In accord with
3
1
0
what we had thought, the computational studies showed
that when compounds 9b–d, in which one Lewis acid mole-
cule is coordinated to the imine nitrogen atom and the other
to the pyridine nitrogen atom, reacted with 2a to give cy-
cloadducts 10 via transition structures TS4 (Scheme 5), the
relative activation energies (Table 2, Entries 15–17) de-
creased considerably compared with the reactions between
1
1
1
2
1
3
1
4
1
5
1
6
17
[
a] Computed at the B3LYP/6-31G*+∆ZPVE level of theory. [b] 7 and 2a via transition states TS3.
Computed at the B3LYP/6-31G* level of theory according to the
approach and equations described previously.[ [c] For a perfectly
synchronous reaction, Sy = 1.
7a]
The use of Lewis acids in these reactions minimizes com-
petitive side-reactions, thereby allowing good to excellent
yields and high regio- and diastereoselectivities. For this
reason, to determine the influence of the Lewis acid
(
BF ·Et O), we first examined whether 1 equiv. of BF co-
3
2
3
ordinates preferentially with either the imine or the pyridine
[
11]
ring
nitrogen atom in compounds 1b–d to give 5b–d or
Scheme 5. Cycloaddition reactions of 1b–d in the presence of
equiv. of BF ·Et O.
7b–d, respectively (Scheme 4).
2
3
2
The molecular DFT-based parameters reported in
Table 3 indicate that the double-coordinated compounds 9
Scheme 4, Table 3, Entries 4, 8, and 12) are more electro-
(
philic than the noncoordinated compounds 1 (Table 3, En-
tries 1, 5, and 9), as well as the single-coordinated com-
pounds 5 (Scheme 4, Table 3, Entries 2, 6, and 10) and 7
(Scheme 4, Table 3, Entries 3, 7, and 11). Thus, the chemical
potentials are lower for compounds 9, the computed elec-
trophilicities of compounds 9 are larger than those com-
puted for 1, 5, and 7, and the ∆Nmax values for 5 and 9 are
the largest. This data reflects the enhanced electron-with-
drawing effect of BF bonded to both the imine and pyr-
3
idine nitrogen atoms.
Next, we extended the computational calculations to the
study of the regio- and diastereoselectivities of the [4+2]
cycloaddition reactions of imines 1b (R = H), 1c (R = Ph),
and 1d (R = Me) with the nonsymmetrical dienes styrene
(
2b), cyclopentadiene (2c), and indene (2d), because it had
been observed that the reaction of olefins 2b–d with imines
c,d gave only the cycloadducts 3bc–3dd regio- and dia-
3 2
Scheme 4. Cycloaddition reactions with 1 equiv. of BF ·Et O.
1
The computational results indicate that the coordination stereoselectively (see above) with control of the two or three
of BF to the pyridine nitrogen atom results in compounds stereocenters. The diverse approach of the dienophiles 2b–
3
7, which are more stable (see the table in Scheme 4) than d to the heterodienes 1b–d may lead to eight different cy-
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Aza-Diels–Alder Reaction of N-(3-Pyridyl)aldimines
Table 3. Hardnesses (η), chemical potentials[a] (µ), global electro-
[
a]
[
a]
[a]
philicities (ω), and maximun number of accepted electrons
∆Nmax) of compounds 1b–d and products 5b–d, 7b–d, and 9b–d
coordinated to BF
(
3
.
Entry Compound
η [a.u.]
µ [a.u.]
ω [eV] ∆Nmax [a.u.]
1
2
3
4
5
6
7
8
9
1b
5b
7b
9b
1c
5c
7c
9c
1d
5d
7d
9d
0.19301
0.18531
0.19445
0.20065
0.16414
0.16410
0.16707
0.16762
0.19717
0.19474
0.19400
0.20864
–0.14308
–0.18679
–0.17986
–0.22056
–0.14607
–0.17755
–0.17075
–0.19819
–0.13497
–0.17549
–0.17250
–0.20791
0.053
0.094
0.083
0.121
0.065
0.096
0.087
0.117
0.046
0.079
0.077
0.104
0.741
1.008
0.925
1.099
0.890
1.082
1.022
1.182
0.683
0.898
0.889
0.997
1
0
1
1
12
[
a] Computed at the B3LYP/6-31G* level of theory according to
[17]
the approach and equations described previously.
cloadducts (Scheme 6). These cycloadducts are identified as
endo/exo on the basis of the orientation of the phenyl group
in styrene (2b), the double bond of cyclopentadiene (2c),
and the benzene moiety of indene (2d) and as A/B with
respect to the regiochemistry of the reaction. Moreover, the
imines 1b–d could react with the dienophiles 2b–d via tran-
sition-state structures TS5 to give the corresponding
endo/exo-A and endo/exo-B cycloadducts 4bb–4dd or via
transition-state structures TS5Ј to give the corresponding
endo/exo-A and endo/exo-B cycloadducts 4Јbb–4Јdd
(Scheme 6). However, we found that the pathways involving
endo transition-state structures TS5bb–dd-endo-A, which Scheme 6. Possible [4+2] cycloadducts from the reactions of 1b–d
give the corresponding endo-A adducts 4bb–4dd, exhibit the with the nonsymmetric alkenes 2b–d.
lowest activation barriers (details of the relative activation
barriers for endo/exo selectivity and A/B regiochemistry are
The influence of the Lewis acid on the reactions of the
[
18]
presented in Table 1 of the Supporting Information). All activated imines 7 and 9 with the dienes 2b–d (Scheme 7)
the reactions occur in a concerted manner, but the bond was similar to that observed in their reactions with ethylene
formation is quite asynchronous with the C(dienophile)– (2a). Thus, the computational data indicate that the reac-
C(imine) bond being more advanced in all cases (Scheme 6, tions of double-coordinated compounds 9 with 2b–d to give
Table 4, Entries 1–9, noncoordinated pathway, and Table 1 the endo-A adducts 10bb–dd via TS7 have lower activation
of the Supporting Information).
barriers (Scheme 7, Figure 4, Table 4, double-coordinated
Table 4. Activation energies[a] (∆E
[kcal/mol]), reaction energies[a] (∆Erxn [kcal/mol]), and synchronicities[a] (Sy) associated with the
a
formation of the [4+2] endo-A cycloadducts 4, 8, and 10.
[a] Computed at the B3LYP/6-31G*+∆ZPVE level of theory.
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F. Palacios, F. P. Cossío et al.
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pathway) not only when imines 1b–d react through the tran-
sition states TS5-endo-A to give endo-A adducts 4bb–dd
(Scheme 6, Figure 4, Table 4, noncoordinated pathway), but
also when single-coordinated imines 7 react via transition
states TS6 to give endo-A adducts 8bb–dd (Scheme 7, Fig-
ure 4, Table 4, single-coordinated pathway). As in the pre-
ceding cases, all the reactions occur in a concerted asyn-
chronous manner with the C(dienophile)–C(imine) bond
being more advanced in all cases (see Table 4 and Figure 4).
These computational predictions are consistent with our ex-
perimental results, given that in our hands the reactions of
imines 1c,d with olefins 2b–d gave only the endo cycload-
ducts 3bc–dd.
Conclusions
The computational studies performed on imines 1a (X =
CH) and the computational and experimental studies on
imines 1b–d (X = N) suggest that the Povarov reactions
with olefins 2 take place in an asynchronous concerted pro-
cess. In addition, the Povarov reactions between imines 1b–
d (X = N) and olefins 2b–d take place via endo transition
states to give tetrahydro-1,5-naphthyridine derivatives 3
with regio- and stereoselective control of the three
stereocenters. Moreover, the use of 2 equiv. of BF ·Et O ac-
Scheme 7. Cycloaddition reactions of 1b–d with 2b–d in the pres-
ence of BF ·Et O.
3 2
3
2
tivates the azadiene system, accelerating the reaction more
than when only 1 equiv. is used.
Experimental Section
General Experimental: Solvents for extraction and chromatography
were of technical grade. All solvents used in reactions were freshly
distilled from appropriate drying agents before use. All other rea-
gents were distilled as necessary. All reactions were performed un-
der dry nitrogen. Visualization was accomplished by UV light or
1
13
KMnO
ian Unity Plus 300 and Bruker Avance 400 spectrometer by using
CDCl . Low-resolution mass spectra (MS) were obtained at 50–
0 eV by electron impact (EIMS) with a Hewlett–Packard 5971 or
973 spectrometer. Data are reported in the form m/z (intensity
4
. H, C, and 2D NMR spectra were recorded with a Var-
3
7
5
relative to baseϫ100). High-resolution mass spectra (HRMS) were
obtained by chemical ionization (CI) with an Agilent GC–MS spec-
trometer model 6890N with a TOF (Micromass) analyzer. Infrared
spectra (IR) were recorded with a Nicolet iS10 spectrometer.
CCDC-737355 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Preparation of Imine 1c: A solution of 3-aminopiridine (2 mmol,
0
.19 g) and freshly distilled benzaldehyde (2 mmol, 0.20 mL) in
CHCl (15 mL) with molecular sieves was stirred at room tempera-
ture until TLC indicated the disappearance of the starting materials
48 h). The resulting solution was filtered. The solvent was evapo-
3
(
Figure 4. Fully optimized transition-state structures TS5, TS6, and
TS7 from the reactions of imines 1c, 7c, and 9c with 2b and imines
rated under reduced pressure to give compound 1c as an oil. The
reaction product is unstable during distillation and/or chromatog-
raphy and was used without purification in the following reactions.
1
d, 7d and 9d with 2d as examples. Selected bond lengths are given
in Å. The numbers given in parentheses correspond to the relative
energy differences (in kcal/mol) of TS5 and TS6 with respect to
double-coordinated transition-state structures TS7 calculated at
the B3LYP/6-31G*+∆ZPVE level of theory.
Preparation of Imine 1d: A solution of 3-aminopyridine (2 mmol,
0.19 g) and freshly distilled acetaldehyde (2 mmol, 0.28 mL) in
CHCl (15 mL) with molecular sieves was stirred at room tempera-
3
2096
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2091–2099

Aza-Diels–Alder Reaction of N-(3-Pyridyl)aldimines
ture until TLC indicated the disappearance of the starting materials
(m, 5 H, CHAr), 7.80 (d, 3
J
HH = 4.5 Hz, 1 H, CHAr) ppm. 13
), 42.2 (CH ), 47.3 (CH-
C
(3 h). The molecular sieves were removed by filtration under dry
NMR (75 MHz, CDCl ): δ = 22.6 (CH
3
3
2
nitrogen, and the resulting solution was used without purification
in the following reactions, because the reaction product is unstable
during distillation and/or chromatography.
Ph), 47.6 (HN-CH), 120.9, 122.2, 126.1, 128.8, 139.2 (CHAr), 141.9,
145.2, 145.3 (CAr) ppm. IR: ν˜ = 3228.69, 2958.84, 2938.54, 1588.72,
–
1
+
1451.24, 1335.02 cm . HRMS (CI): calcd. for C20
2
18 2
H N [M]
24.1313; found [M]+ 224.1307.
General Procedure for the Preparation of Compounds 3: Diene 2
(
3 mmol) and one or more equivalents of BF
a solution of the previously prepared imine 1 (2 mmol) in CHCl
15 mL). The mixture was stirred at the appropriate temperature
3
·Et
2
O were added to
6-Phenyl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c][1,5]naphthyridine
(3cc): The procedure was carried out as described in the main text
by using freshly distilled cyclopentadiene (2c; 3 mmol, 0.20 mL)
3
(
1
until TLC and H NMR spectroscopy indicated the disappearance
3 2
and imine 1c. When 2 mmol (0.36 mL) of BF ·Et O was used and
of imine 1. The reaction mixture was diluted with dichloromethane
the mixture was stirred at reflux temperature for 96 h (70% con-
sumption of the starting materials by NMR analysis of the crude
(20 mL), washed with a 2  NaOH aqueous solution (20 mL) and
water (20 mL), extracted with dichloromethane (2ϫ20 mL), and reaction mixture), 0.328 g of compound 3cc (66%) was obtained.
dried (MgSO ). Removal of the solvent under vacuum afforded an When 4 mmol (0.72 mL) of BF ·Et O was used and the mixture
oil that was purified by silica gel flash column chromatography
eluent: hexane/Et O) to afford compounds 3.
4
3
2
was stirred at reflux temperature for 30 h (90% consumption of the
starting materials by NMR analysis of the crude reaction mixture),
(
2
0
.407 g of compound 3cc (82%) was obtained as a brown solid.
2
,4-Diphenyl-1,2,3,4-tetrahydronaphthyridine (3bc): The procedure
was carried out by using freshly distilled styrene (2b; 3 mmol,
.31 mL) and imine 1c. When 2 mmol (0.36 mL) of BF ·Et O was
used and the mixture was stirred at room temperature for 216 h
74% consumption of the starting materials by NMR analysis of
1
M.p. 156–158 °C. H NMR (400 MHz, CDCl
3
): δ = 1.89 (ddd,
2
3
3
J
J
HH = 16.4,
J
HH = 8.8,
J
HH = 1.5 Hz, 1 H, CH
2
), 2.64 (ddd,
), 3.12 (ddd,
0
3
2
2
HH = 16.4, 3JHH = 9.4, 3JHH = 2.4 Hz, 1 H, CH
2
2JHH = 8.8, JHH = 3.1, JHH = 2.4 Hz, 1 H, CH
3
3
2
-CH), 3.75 (s, 1
(
H, NH), 4.24 (dd, JHH = 8.8, 3JHH = 2.4 Hz, 1 H, =CH-CH), 4.71
3
the crude reaction mixture), 0.350 g of compound 3bc (61%) was
obtained. If the mixture was stirred at reflux temperature for 24 h
3
3
3
(
d,
JHH = 3.1 Hz, 1 H, Ph-CH), 5.73 (dd,
HH
JHH = 4.3, J =
1.5 Hz, 1 H, =CH), 6.03–6.06 (m, 1 H, =CH), 6.89–6.95 (m, 2 H,
(
76% consumption of the starting materials by NMR analysis of
the crude reaction mixture), 0.355 g of compound 3bc (62%) was
obtained. When 4 mmol (0.72 mL) of BF ·Et O was used and the
3
CHAr), 7.28–7.47 (m, 5 H, CHAr), 8.05 (d,
J
HH = 4.4 Hz, 1 H,
): δ = 31.7 (CH ), 46.1
-CH), 49.4 (=CH-CH), 57.6 (Ph-CH), 121.4, 122.3, 126.4,
27.5, 128.6 (CHAr), 131.0 (=CH-CH ), 133.5 (=CH-CH), 140.3
CHAr), 141.6, 142.1, 147.1 (CAr) ppm. IR: ν˜ = 3366, 3049, 2923,
13
CHAr) ppm. C NMR (100 MHz, CDCl
CH
1
3
2
3
2
(
2
mixture was stirred at room temperature for 41 h (98% consump-
tion of the starting materials by NMR analysis of the crude reac-
tion mixture), 0.412 g of compound 3bc (71%) was obtained. If
the same mixture was stirred at reflux temperature for 4 h (99%
consumption of the starting materials by NMR analysis of the
crude reaction mixture), 0.435 g of compound 3bc (76%) was ob-
2
(
–1
+
1
584, 1448 cm . MS (EI): m/z (%) = 248 (100) [M] . HRMS (CI):
+
16 2
calcd. for C17H N [M] 248.1313; found 248.1319.
6-Methyl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c][1,5]naphthyridine
(3cd): The procedure was carried out by using freshly distilled cy-
clopentadiene (2c; 3 mmol, 0.20 mL) and imine 1d. When 2 mmol
1
tained as a yellow solid. M.p. 136–138 °C. H NMR (400 MHz,
2
3
3
CDCl
H, CH
CH ), 3.99 (s, 1 H, NH), 4.45 (dd, JHH = 12.2, JHH = 6.1 Hz, 1 room temperature for 46 h (55% consumption of the starting mate-
3
): δ = 2.26 (ddd, JHH = 12.6, JHH = 12.2, JHH = 11.3 Hz,1
2
3
3
2
), 2.41 (ddd, JHH = 12.6, JHH = 6.1, JHH = 2.3 Hz, 1 H,
3 2
(0.36 mL) of BF ·Et O was used and the mixture was stirred at
3
3
2
3
3
H, Ph-CH), 4.59 (dd, JHH = 11.3, JHH = 2.3 Hz, 1 H, HN-CH-
rials by NMR analysis of the crude reaction mixture), 0.120 g of
Ph), 6.86 (dd, JHH = 8.06, 3JHH = 1.48 Hz, 1 H, CHAr), 6.94 (dd, compound 3cd (30%) was obtained as a brown solid. When 4 mmol
3
3
HH = 8.04, 3
J
J
HH = 4.55 Hz, 1 H, CHAr), 7.18–7.46 (m, 10 H,
(0.72 mL) of BF
room temperature for 23 h (65% consumption of the starting mate-
), 47.5 (CH-Ph), 56.9 (N-CH), rials by NMR analysis of the crude reaction mixture), 0.192 g of
21.0, 122.1, 126.3, 126.6, 127.9, 128.5, 128.7, 139.4 (CHAr), 141.8, compound 3cd (48%) was obtained as a brown solid. M.p. 115–
43.0, 144.7, 144.8 (CAr) ppm. IR: ν˜ = 3192, 3154, 2980, 1584,
3 2
·Et O was used and the mixture was stirred at
CHAr), 7.94 (d, 3JHH = 4.55 Hz, 1 H, CHAr) ppm. C NMR
13
(100 MHz, CDCl ): δ = 42.8 (CH
3
2
1
1
1
1
117 °C. H NMR (400 MHz, CDCl
3
): δ = 1.21–1.23 (m, 3 H, CH
HH = 9.3, 3
HH = 2.4 Hz, 1 H, CH
2.53 (ddd, 2JHH = 16.2, 3JHH = 9.0, 3JHH = 2.3 Hz, 1 H, CH
3
2
2
),
),
),
–1
+
2
3
451, 1286 cm . MS (EI): m/z (%) = 286 (10) [M] . HRMS (CI): 2.31 (ddd,
J
HH = 16.3,
J
J
+
calcd. for C20
18 2
H N [M] 286.1470; found 286.1474.
3
3
2
2
.86 (dd, JHH = 9.0, JHH = 3.2 Hz, 1 H, CH-CH ), 3.36 (s, 1 H,
2-Methyl-4-phenyl-1,2,3,4-tetrahydronaphthyridine (3bd): The pro-
3
NH), 3.60–3.62 (m, 1 H, HN-CH-CH
H, =CH-CH) 5.75–5.77 (m, 1 H, =CH), 5.97–5.99 (m, 1 H, =CH),
3
), 4.08 (d, JHH = 9.1 Hz, 1
cedure was carried out by using freshly distilled styrene (2b;
mmol, 0.31 mL) and imine 1d. When 2 mmol (0.36 mL) of
BF ·Et O was used and the mixture was stirred at room tempera-
3
13
6
.75–6.88 (m, 2 H, CHAr) 7.94–7.96 (m, 1 H, CHAr) ppm.
NMR (75 MHz, CDCl ): δ = 19.5 (CH ), 31.1 (CH ), 44.0 (CH-
CH ), 48.3 (HN-CH), 49.0 (=CH-CH), 121.0, 121.4 (CHAr), 130.5
=CH-CH ), 133.6 (=CH-CH), 139.2 (CHAr), 141.6, 147.0 (CAr
ppm. IR: ν˜ = 3254.47, 2985.07, 2908.91, 1577.59, 1448.12 cm .
C
3
2
3
3
2
ture for 2 h (99% consumption of the starting materials by NMR
analysis of the crude reaction mixture), 0.233 g of compound 3bd
2
(
2
)
(52%) was obtained. When 4 mmol (0.72 mL) of BF
3
·Et
2
O was
–1
used and the mixture was stirred at room temperature for 2 h (99%
consumption of the starting materials by NMR analysis of the
crude reaction mixture), 0.322 g of compound 3bd (72%) was ob-
+
16 2
HRMS (CI): calcd. for C17H N [M] 186.1157; found 186.1159.
6-Phenyl-6,6a,7,11b-tetrahydro-5H-indeno[2,1-c][1,5]naphthyridine
(3dc): The procedure was carried out as described in the main text
by using freshly distilled indene (2d; 3 mmol, 0.35 mL), imine 2c,
and 4 mmol (0.72 mL) of BF ·Et O. The mixture was stirred at
3 2
reflux temperature for 48 h (99% consumption of the starting ma-
terials by NMR analysis of the crude reaction mixture), and 0.77 g
1
tained as a brown solid. M.p. 130–132 °C. H NMR (400 MHz,
3
2
CDCl
2.0, 3
3
): δ = 1.21 (d, JHH = 6.2 Hz, 3 H, CH
3
), 1.89 (ddd, JHH
), 2.20 (ddd,
), 3.50–3.56 (m,
=
3
1
J
HH = 12.4,
JHH = 12.0 Hz, 1 H, 1 H, CH
2
2
3
3
J
HH = 12.0, JHH = 6.4, JHH = 2.3 Hz, 1 H, CH
H, HN-CH-Me), 3.6 (s, 1 H, NH), 4.20 (dd, JHH = 12.0, JHH
2
3
3
1
=
3
2
6.4 Hz, 1 H, CH-Ph), 6.73 (dd, JHH = 8.1, JHH = 1.3 Hz, 1 H, of compound 3dc (72%) was obtained as a yellow solid. M.p. 158–
CHAr), 6.83 (dd, JHH = 8.1, JHH = 4.6 Hz, 1 H, CHAr), 7.08–7.26 160 °C. H NMR (400 MHz, CDCl
3
3
1
2
3
): δ = 2.46 (dd, JHH = 20.2,
Eur. J. Org. Chem. 2010, 2091–2099 © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org 2097

F. Palacios, F. P. Cossío et al.
FULL PAPER
3JHH = 12.6 Hz, 1 H, CH
g) S. Kobayashi, H. Ishitani, S. Nagayama, Chem. Lett. 1995,
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2
3
2 2
), 3.27–3.34 (m, 2 H, CH -CH, CH ),
3.84 (s, 1 H, NH), 4.70 (d, JHH = 7.4 Hz, 1 H, Ar-CH), 4.80 (s, 1
H, HN-CH-Ph), 6.84–6.93 (m, 3 H, CHAr), 7.08–7.79 (m, 8 H,
CHAr), 8.06 (d, 3
13
[4] For recent and representative examples, see: a) A. A. Kudale, J.
Kendall, D. O. Miller, J. L. Collins, G. J. Bodwell, J. Org. Chem.
J
HH = 4.40 Hz, 1 H, CHAr) ppm. C NMR
): δ = 31.4 (CH ), 47.8 (CH -CH), 49.1 (CAr-CH),
7.6 (CH-Ph), 121.7, 122.1, 124.3, 126.3, 126.5, 126.7, 127.1, 127.6,
28.7, 140.6 (CHAr), 141.4, 141.9, 142.5, 144.6, 145.1 (CAr) ppm.
(75 MHz, CDCl
3
2
2
2008, 73, 8437–8447; b) V. Sridharan, C. Avendaño, J. C.
5
1
Menendez, Synthesis 2008, 1039–1044; c) V. Sridharan, P. T.
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–1
IR: ν˜ = 3356.31, 3021.79, 2912.61, 1574.28, 1457.12 cm . HRMS
2
007, 5, 1351–1353; d) V. Gaddam, R. Nagarajan, Tetrahedron
+
(
CI): calcd. for C17
-Methyl-6,6a,7,11b-tetrahydro-5H-indeno[2,1-c][1,5]naphthyridine
3dd): The procedure was carried out by using freshly distilled in-
dene (2d; 3 mmol, 0.35 mL) and imine 1d. When 2 mmol (0.36 mL)
of BF ·Et O was used and the mixture was stirred at room tem-
H
16
N
2
[M] 298.1470; found 298.1466.
Lett. 2007, 48, 7335–7338; e) R. Manina, J. Jayashankaran, R.
Raghunathan, Tetrahedron Lett. 2007, 48, 4139–4142; f) S. M.
Reddy, M. Srinivasulu, T. S. Reddy, M. Narsimhulu, Y. Venka-
teswarlu, Indian J. Heterocycl. Chem. 2007, 16, 315–316; g) V. V.
Kouznetsov, U. M. Cruz, F. I. Zubkov, E. V. Nikitina, Synthesis
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6
(
3
2
perature for 24 h (99% consumption of the starting materials by
NMR analysis of the crude reaction mixture), 0.335 g of compound
2
004, 6, 4913–4916.
3
dd (70%) was obtained. When 4 mmol (0.72 mL) of BF
used and the mixture was stirred at room temperature for 12 h
99% consumption of the starting materials by NMR analysis of
3 2
·Et O was
[
5] a) M. Hadden, M. Nieuwenhuyzen, D. Osborne, P. J. Steven-
son, N. Thompson, A. D. Walker, Tetrahedron 2006, 62, 3977–
(
3
984; b) H. Twin, R. A. Batey, Org. Lett. 2004, 6, 4913–4916;
the crude reaction mixture), 0.411 g of compound 3dd (84%) was
c) D. A. Powell, R. A. Batey, Org. Lett. 2002, 4, 2913–2916; see
also: d) R. A. Batey, D. A. Powell, Chem. Commun. 2001,
2
1
obtained as a yellow solid. M.p. 143–144 °C. H NMR (400 MHz,
3
2
CDCl
1
3
3
3
): δ = 1.29 (d, JHH = 6.5 Hz, 3 H, CH
3
), 2.90 (dd, JHH
), 3.09–3.16 (m, 2 H, CH -CH, CH
.5 (s, 1 H, NH), 3.66–3.72 (m, 1 H, CH -CH), 4.54 (d, JHH
=
362–2363.
4.0, JHH = 7.1 Hz, 1 H, CH
2
2
2
),
=
[
6] a) J. Vicario, D. Aparicio, F. Palacios, J. Org. Chem. 2009, 74,
452–456; b) F. Palacios, J. Vicario, A. Maliszewska, D. Apar-
icio, J. Org. Chem. 2007, 72, 2682–2685.
3
3
8
.0 Hz, 1 H, Ar-CH), 6.74–7.30 (m, 5 H, CHAr), 7.75–7.77 (m, 1
H, CHAr), 7.99 (d, 3
J
13
HH = 4.6 Hz, 1 H, CHAr) ppm. C NMR [7] a) F. P. Cossío, C. Alonso, B. Lecea, M. Ayerbe, G. Rubiales,
(
4
1
75 MHz, CDCl
8.3 (CH-CH
3
3
): δ = 19.7 (CH
), 48.8 (CAr-CH), 121.36, 121.46, 124.30, 126.21,
26.56, 126.91, 139.84 (CHAr), 141.45, 142.52, 144.78, 145.21 (CAr
3
), 30.9 (CH
2
), 45.8 (CH
2
-CH),
F. Palacios, J. Org. Chem. 2006, 71, 2839–2847; b) F. Palacios,
E. Herrán, C. Alonso, G. Rubiales, Tetrahedron 2006, 62, 7611–
7618; c) F. Palacios, E. Herrán, G. Rubiales, J. M. Ezpeleta, J.
)
–
1
Org. Chem. 2002, 67, 2131–2135; d) F. Palacios, C. Alonso, P.
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Chem. 2006, 71, 6141–6148; b) F. Palacios, D. Aparicio, A. M.
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ppm. IR: ν˜ = 3228.67, 3064.16, 2973.91, 1577.04, 1450.32 cm .
HRMS (CI): calcd. for C17
+
16 2
H N [M] 236.1313; found 236.1308.
[
[
Supporting Information (see footnote on the first page of this arti-
1
13
cle): H and C NMR spectra of compounds 3bc,bd,cc,cd,dc,dd.
D NOESY, HMBC, and HMQC experiments for compounds 3bc
1
9] a) J. M. de los Santos, D. Aparicio, Y. Lopez, F. Palacios, J.
Org. Chem. 2008, 73, 550–557; b) F. Palacios, C. Alonso, M.
Legido, G. Rubiales, M. Villegas, Tetrahedron Lett. 2006, 47,
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putational characterization of all the reported reactions and sta-
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cual, G. Fernández de Troconiz, J. Org. Chem. 2008, 73, 4568–
4
574; b) F. Palacios, E. Herrán, C. Alonso, G. Rubiales, B.
Financial support from the Universidad del Pais Vasco/Euskal
Herriko Unibertsitatea (UPV/EHU) (UPV: GIU06/51, 07/114),
Gobierno Vasco/Eusko Jaurlaritza (GV/EJ) (IT-324-07, IT 277-07)
and the Spanish Ministerio de Ciencia e Innovación (MICINN)
Lecea, M. Ayerbe, F. P. Cossío, J. Org. Chem. 2006, 71, 6020–
6030; c) F. Palacios, C. Alonso, J. Pagalday, A. M.
Ochoa de Retana, G. Rubiales, Org. Biomol. Chem. 2003, 1,
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is gratefully acknowledged.
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[
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Received: November 18, 2009
Published Online: February 24, 2010
Eur. J. Org. Chem. 2010, 2091–2099
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2099