Study of the Hetero-[4+2]-Cycloaddition Reaction of Aldimines and Alkynes. Synthesis of 1,5-Naphthyridine and Isoindolone Derivatives

Article abstract of DOI:10.1021/acs.joc.7b00977

Both experimental and computational studies for the cycloaddition reaction between N-(3-pyridyl)aldimines and acetylenes where 1,5-naphthyridines are obtained are reported. The reaction of benzaldimine with a methoxycarbonyl group in position 2 with phenyl acetylene, styrene, and indene afforded polycyclic isoindolone derivatives. The mechanism of reaction of N-(3-pyridyl)aldimines with olefins can be explained by an asynchronous [4+2] cycloaddition; in the case of acetylenes, the obtained results suggest a stepwise mechanism through a 3-azatriene.

Full text of DOI:10.1021/acs.joc.7b00977

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Article
Study of the Hetero-[4+2]-Cycloaddition Reaction of Aldimines and
Alkynes. Synthesis of 1,5-naphthyridines and Isoindolone Derivatives
CONCEPCION ALONSO, Maria Gonzalez, F Palacios, and Gloria Rubiales
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 May 2017
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Study of the Heteroꢀ[4+2]ꢀCycloaddition Reaction of
Aldimines and Alkynes. Synthesis of 1,5ꢀNaphthyridine
and Isoindolone Derivatives.
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Concepción Alonso, María González, Francisco Palacios* and Gloria Rubiales*
Departamento de Química Orgánica I, Facultad de Farmacia, Centro de Investigaciones y Estudios
Avanzados “Lucio Lascaray”, Universidad del País Vasco UPV/EHU, Paseo de la Universidad 7,
0
1006 Vitoria, Spain.
eꢀmail: francisco.palacios@ehu.es
gloria.rubiales@ehu.es
TOC
ABSTRACT
Both experimental and computational studies for the cycloaddition reaction between Nꢀ(3ꢀ
pyridyl)aldimines and acetylenes where 1,5ꢀnaphtyridines are obtained are reported. The reaction of
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benzaldimine with a methoxycarbonyl group in position 2 with phenyl acetylene, styrene and indene
afforded polycyclic isoindolone derivatives. The mechanism of reaction Nꢀ(3ꢀpyridyl)aldimines with
olefins can be explained by an asynchronous [4+2] cycloaddition, in the case of acetylenes the obtained
results suggest a stepwise mechanism through a 3ꢀazatriene.
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INTRODUCTION
A wide range of applications in biochemistry, pharmacology and material science have been observed
1
for nitrogenated heterocycles. Various strategies for the preparation of nitrogen heterocycles are
described in the literature, among which one of the most straightforward is the heteroꢀDielsꢀAlder
2
reaction (HDAr). By this reaction the formation of the carbonꢀcarbon bond is effectively achieved from
an atom economic point of view, allowing the preparation of sixꢀmembered rings with a high molecular
3
4
5,6
diversity which may have applications in industry. An example of HDAr is the Povarov reaction,
and this process is an tool for the preparation of nitrogenꢀcontaining heterocyclic compounds. The
Povarov reaction has been applied in total synthesis of interesting biologically active compounds, such
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as (±)–martinelline, (±)ꢀmartinellic acid, luotonin A, and camptothecin. This methodology also
represents a direct route to the naphthyridine core structure of interesting biologically active compounds
8
as Topoisomerase I inhibitors and with antiproliferative activity against several cancer cell lines as
reported in our research group.
As Povarov initially described, electron rich olefins are usually used as dienophiles in the reaction with
5
aromatic aldimines I (X = CH, Scheme 1a) derived from aniline, while only scarce examples have been
9
reported with acetylenic compounds III (Scheme 1a) acting as dienophiles and very few examples with
1
0
imines II (X = N, Scheme 1a) derived from heterocyclic amines have been reported. Moreover, if
pyridyl amines are used instead of anilines, a new entry to nitrogenated derivatives such as 1,5ꢀ
naphthyridine derivatives V could be prepared by this strategy. Furthermore, pyridyl substitution instead
of phenyl ring in polycyclic systems may be expected to afford more waterꢀsoluble compounds which
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show better cytotoxic properties. By a combined theoretical and experimental study we previously
reported that the Povarov type cycloaddition reaction between pyridylaldimines IIb and olefins such as
styrene VIa (n = 0, Y = CH
2
, Z = CH, Scheme 1b) and indene VIb (n = 1, Y = CH, Z = C, Scheme 1b)
suggested an asynchronous concerted process favoured by double Lewis acid activation with BF
3
·Et O
2
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and formation of endoꢀcycloadducts VIIa or VIIb.
N
H
R1
N
R
R1
(a)
X
X
I X = CH
II X = N
R2 III
2
IV X = CH , ref 9
V X = N , This work
Ph
Ph
N
n
Z
CHCl , 60ºC
HN
Y
3
n Z
H
Y
(
b)
BF —Et O
3
2
(
2 equiv)
N
VI
a:
N
IIb
VII
,
ref 12
n = 0, Y = CH , Z = CH
b: n = 1, Y = CH, Z = C
2
Scheme 1. Reactions of aldimines and alkynes and/or olefins.
In this sense, if acetylenes are used as dienophiles instead of olefins, the electronic and structural
properties of starting materials and compounds obtained may represent an interesting challenge for their
theoretical and experimentally study, and from a preparative point of view 1,5ꢀnaphtiridines may be
directly obtained. It must be taken into account that pyridine, a πꢀelectron deficient aromatic, is less
reactive than benzene due to the electronegativity of the nitrogen atom, which would greatly affect the
reactivity of Nꢀ(3ꢀpyridyl)aldimines in a Lewis acid activated azaꢀ[4+2]ꢀcycloaddition reaction.
We report herein both experimental (synthetic and NMR) and computational studies of the
cycloaddition reaction between Nꢀ(3ꢀpyridyl)aldimines and alkynes. By means of these studies carried
out in parallel, we were able to get useful information regarding the plausible mechanism for the
synthesis of heterocyclic products according to the dienophile.
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RESULTS AND DISCUSSION
Experimental study
We started with the preparation of the corresponding Nꢀ(3ꢀpyridyl)aldimines 3 by means of a solution of
3ꢀaminopyridine 1 and aromatic aldehydes 2 in chloroform in the presence of molecular sieves (Scheme
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). Afterwards, the obtained aldimines 3 were reacted with acetylenes 4. In the absence of catalyst no
product formation was observed and starting material recovered. However, when trifluorboroetherate as
Lewis acid catalyst was used good results were observed: the optimal ones were when 2 equivalents of
Lewis acid were used. The crude mixture was treated with NaOH 2N and water in order to remove
2 2
easily all inorganic salts and subsequently extracted with CH Cl affording only 2,4ꢀdisubstituted 1,5ꢀ
naphthyridines 5 regioselectively (Table 1), while the formation of the other regioisomers, namely 2,3ꢀ
disubstituted 1,5ꢀnaphthyridines was not observed. The multicomponent reaction of 3ꢀaminopyridine 1,
aromatic aldehydes 2 and acetylenes 4 was also explored. However, a complex mixture of reaction
products was obtained.
Scheme 2. Reactions of aldimines 3 and acetylenes 4 with Lewis acid.
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The structure of aromatic 1,5ꢀnaphthyridines 5 was assigned on basis of NMR spectra and mass
spectrometry. For example, when aldimine 3b (Ar = 4ꢀCF C H ) and 4ꢀmethoxyphenyl acetylene 4b (R
3
6
4
=
OMe) were used the 1,5ꢀnaphthyridine 5d (Table 1, entry 4) was obtained. Its structure was assigned
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by means of NMR experiments and confirmed by HRMS. For instance, in the FꢀNMR spectrum of
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compound 5d one signal was observed at δ
F
= ꢀ 63.1 ppm and in the HꢀNMR spectrum the
corresponding two signals at low field corresponding to two protons of the naphthyridine ring, one
3
4
double doublet at δ = 8.49 ppm with coupling constants J = 8.5 Hz, J = 1.8 Hz and another
H
HH
HH
3
4
double doublet at δ
H
= 9.01 with coupling constants JHH = 4.3 Hz and JHH = 1.8 Hz. Moreover, its
structure has been unequivocally confirmed by Xꢀray analysis (see the Supporting Information).
Formation of naphthyridines 5 could be explained by a formal [4+2] process of imines 3 with alkynes 4
and subsequent aromatization under the reaction conditions to afford corresponding naphthyridines 5
(Scheme 2).
Table 1. Naphthyridines 5 obtained.
Reaction
time (h)
Yield
(%)
75
entry
Product
Ar
R
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2
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4
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6
5a
5b
5c
5d
5e
5f
Ph
H
H
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4ꢀCF C H
3
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4
60
4ꢀNO C H
2
6
4
H
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4ꢀCF C H
3
6
4
MeO
MeO
CF3
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18
36
60
60
60
4ꢀNO C H
2
6
4
4ꢀCF C H
3
6
4
In order to explore the scope of the process, the same synthetic protocol was applied to aldimine 3d
Scheme 3), prepared as before from commercially available 3ꢀpyridylamine 1 and methyl 2ꢀ
formylbenzoate 2d, and used in situ. Subsequent treatment of aldimine 3d with acetylene 4a (R = H)
was performed in chloroform at reflux by using 2 equivalents of BF ·Et O as Lewis acid. However, in
(
3
2
this case, the corresponding naphthyridine 5g was not detected, while the Nꢀ3ꢀpyridyl isoindolinone 6
was obtained in a 60 % yield (Scheme 3). Isoindolinones are ubiquitous in complex natural products and
13,14
pharmaceutical active ingredients.
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1D and 2D NMR experiments and mass spectrometry were used for the characterization of isoindolone
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. The H NMR spectroscopy shows signals of two methylenic protons at δ = 3.25 ppm and at δ = 3.50
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ppm, with coupling constants JHH = 17.4 Hz and JHH = 9.4 Hz for the first methylenic proton and JHH
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=
17.4 Hz and JHH = 2.8 Hz for the second one. Moreover, in C NMR spectrum a signal at δ = 197.1
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ppm which corresponds to a carbonyl carbon was observed. COSY experiment results (see Supporting
Information) are consistent with this structure 6 showing coupling relationship between methylenic
protons and the adjacent proton at three bond distance. The formation of the isoindolinone 6 may be
explained by an initial nucleophilic addition of terminal acetylene 4a over the iminic double bond to
give the intermediate 7, whose intramolecular cyclization would yield 8 followed by loss of methanol
affording derivative 6. As far as we know, this process represents the first example for the synthesis of
Nꢀ3ꢀpyridylisoindolinꢀ1ꢀone containing an alkylcarbonyl substituent at position 6. Taking these
observations into account we wondered if a stepwise mechanism might be implied in the reaction of
aldimines with acetylenes, rather than an asynchronous concerted process via endo transition states as in
12
the case of alkenes.
Scheme 3. Reaction of aldimine 3d and phenylacetylene 4a with Lewis acid.
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So as to check if the mechanism and the behaviour involved in the reaction of aldimines with acetylenes
may be different to the use of olefins, we performed the process with olefins. In this case, the reaction of
aldimine 3d with styrene 9 (n = 0, Y = CH
Scheme 4) in the presence of 2.0 equivalents of BF
corresponding isoindolones fused with an endoꢀdihydroꢀ[1,5]ꢀnaphthyridine 11 (n = 0, Y = CH
CH) and an endoꢀtetrahydroindeno[1,5]ꢀnaphthyridine 12 (n = 1, Y = CH, Z = C) moiety in good yields
80% and 85% respectively, see Supporting Information for characterization data). As far as we know,
2
, Z = CH, Scheme 4) or indene 10 (n = 1, Y = CH, Z = C,
·Et O and chloroform as solvent yielded
, Z =
3
2
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2
(
this process represents the first example of the synthesis of these polycyclic heterocycles 11 and 12
containing an isoindolone moiety.
Scheme 4. Reactions of aldimine 3d and olefins 9 and 10 with Lewis acid.
These experimental results obtained with olefins, which are in accordance with our previously reported
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computational studies, suggest that the [4+2]ꢀcycloaddition reactions between the aldimine 3d and
olefins 9 and 10 occur through an asynchronous concerted process via endo transition states to give
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polycyclic isoindolinone derivatives 13 (Scheme 4), subsequent prototropic tautomerization, posterior
intramolecular cyclization of 14 and subsequent loss of methanol would lead to the formation of
polycyclic indolinones 11 and 12 with regioꢀ and stereoselective control of the two or three
stereocenters, respectively.
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In order to gain insight into what happened in the case of acetylenes 4 we decided to monitor the
reaction by NMR spectroscopy. As an inhomogeneous solution was observed when the reaction was
performed in the presence of BF ·Et O as Lewis acid, we decided to study the reaction by using 2
3
2
2
equivalents of a Brönsted acid such as phosphoric acid diphenyl ester [(PhO) P(O)OH]. The use of a
Brönsted acid instead of a Lewis acid might avoid the heterogeneity complications when performing the
reaction in a NMR tube.
Scheme 5. Reaction of aldimine 3b and acetylene 4b with a Brönsted acid.
In this sense, the reaction between aldimine 3b and acetylene 4b promoted by two equivalents of
Brönsted acid was monitored by NMR spectroscopy (Scheme 5). Phosphonic acid was added to a
solution of aldimine 3b in deuterated chloroform (see Figures S3 and S4 the Supporting Information)
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mixture heated under reflux until the disappearance of signal corresponding to the iminic proton (δ =
1
8
.21 ppm) was observed in the H NMR spectrum. Subsequent treatment with NaOH 2N and extraction
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afforded a crude mixture whose C NMR spectrum (Figure S4d in the Supporting Information) showed
signals at δ = 85.1 and 86.1 ppm corresponding to an internal alkyne. Purification of the crude mixture
allowed the isolation of propargylamine 15 as major compound (Scheme 5) which was characterized by
means of NMR spectroscopy and HRMS. The formation of Nꢀpyridylpropargylamine 15 could be
explained by alkynylation of aldimines 3 with alkynes 4. Often called A3ꢀcoupling, this requires the
presence of a transitionꢀmetal that catalyzes the reaction, resulting in a convenient and general approach
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towards propargylamines. In our case propargylamines 15 were obtained in the presence of Brönsted
acid, in the absence of transitionꢀmetal catalysts.
In previous reports, the electrocyclic ring closure of aromatic propargylamines in the presence of
1
6
transition metal catalysts had been described. However, in our case, all attempts for the electrocyclic
ring closure of aromatic propargylamines 15, such as thermal treatment and/or in presence of copper or
3 2
zinc transition metal catalysts (using CuCl or AgOTf) or BF ·Et O did not give the corresponding
naphthyridines 5d and the starting materials were recovered (Scheme 5). Probably the presence of
nitrogen in the pyridine ring not only deactivates the intramolecular cyclization with respect to the
benzene, but also creates a different reactivity pattern, the α and γ carbons being the most deactivated
ones respect to the nitrogen atom in the pyridine ring. For these reasons the formation of the
corresponding naphthyridine 5d by an intramolecular cyclization of Nꢀpyridylpropargylamine 15 even
when phosphoric acid diphenyl ester [(PhO) P(O)OH] is used as a Brönsted acid would not be favoured.
2
Therefore, these experimental results observed by the monitoring of the reaction of aldimines and
alkynes in NMR and the formation of heterocyclic naphthyridines 5 via reaction of pyridylimines 3 with
3 2
acetylenic dienophiles 4 in the presence of 2 equivalents of BF ·Et O suggest that the reaction could be
initially explained by a stepwise [4+2] process followed by aromatization under the reaction conditions.
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Computational study
To confirm our experimental results and to predict a computational model consistent with the reaction
between Nꢀ(3ꢀpyridyl)aldimines 3 and acetylenes 4 (see Scheme 2, vide supra), we then focused our
attention on the theoretical study of these reactions. As far as we know, this would be the first study
carried out to elucidate the mechanism of the Povarov reaction of imines and acetylenes. We analyzed
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the putative reaction mechanisms employing Gaussian 09 program within the density functional theory
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(
DFT) framework using B3LYP and also performing singleꢀpoint energy calculations with M06ꢀ
2
0
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2
X, hybrid functional were used along with the 6ꢀ311G** basis set. The accuracy of both methods
2
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has been extensively tested for stable molecules and pericyclic reactions (see Supporting Information).
So, after treatment of aldimines 3 with two equivalents of BF ·Et O as Lewis acid, a double
3
2
12
coordination of the two nitrogen atoms may afford the activated Nꢀ(3ꢀpyridyl)aldimines 16 and may
undergo nucleophilic addition of acetylene 4 giving a resonance stabilized zwitterionic intermediate 17
through a transition structure TS1 (see Scheme 6 and Supporting Information). Based on the
experimental results described in Schemes 2 and 3, the first question to determine theoretically would be
whether the formation of 1,5ꢀnaphthyridines 5 involves a concerted [4+2] cycloaddition through a cyclic
intermediate 18 or a stepwise process involving an zwitterionic intermediate 17 (Scheme 6). All our
theoretical attempts to locate transition structures corresponding to the [4+2]ꢀcycloaddition reaction that
would afford intermediate 18 precursor of naphthyridines 5 by means of a concerted process met with
no success. All the starting geometries converged to a transition structure with the Cꢀiminic—C1ꢀ
acetylene bond formed while the distance between C2ꢀpyridine—C2ꢀacetylene was higher than 3Å upon
the optimization at the B3LYP/6ꢀ311G** + ZPVE level, which may support initially the stepwise
pattern.
At this point, three pathways may be conceivable for the formation of 24, precursors of naphthyridines
5
. First, intermediate 17 could cyclise to give the corresponding dihydronaphthyridine 18 prior to 19 and
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finally 24 (path 1, Scheme 6). A second pathway is possible where the zwitterionic intermediate 17 by a
1,3ꢀprotonꢀshift may give the propargylamine 20, whose subsequent ring closure could afford 19 (path
2, Scheme 6). And a third pathway could be the transformation of the zwitterionic intermediate 17 into a
3ꢀazatriene 21 formed by a 1,3ꢀhydrideꢀshift followed by a 6πꢀelectron electrocyclic ring closure
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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50
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60
2
3
(
ERC), whose subsequent prototropic tautomerization and aromatization would result in the formation
of 24 (path 3, Scheme 6) and naphthyridines 5.
Ar
N
Ar
Ar
N
F
3
BN
TS1
3
F BN
+
R
NBF
Ar
3
4a-c
4+2]
NBF
3
R
R
1
6a-c
17
5
[
concerted
Path 1
EAS
TS3
Path 3
1,3ꢀHydrideꢀshift
process
(
Not favored)
F
3
BN
TS2
Path 2
1,3ꢀProtonꢀshift
NBF
3
R
Ar
18
Ar
prototropic
tautomerization
F3BN
Ar
FriedelꢀCraftsꢀtype
reaction
NBF3
F3BHN
R
F3BHN
21
(Not favored)
NBF3
Experimentally
it has no place
NBF3
20
R
R
19
TS4 ERC
Ar
Ar
aromatization
aromatization
Ar
F3BN
F3BN
TS5
prototropic
tautomerization
F3BN
NBF3
NBF3
NBF3
R
R
R
24
23
22
NaOH
H O
2
5
Scheme 6. Reactions of doubly activated aldimines 16 and acetylenes 4.
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2
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2
2
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5
5
5
5
5
5
6
With respect to path 1, if a stepwise [4+2]ꢀcycloaddition takes place an electrophilic aromatic
substitution (EAS) of the pyridine ring at 2 position should occur for the formation of a new C2ꢀ
pyridine—C2ꢀacetylene bond to give cycloadducts 19 which is hard to understand since the pyridine
2
4
ring is disabled and mainly at the α and γ positions respect to the nitrogen atom. Regarding the second
pathway, the formation of propargylamines by direct addition of alkynes to imines derived from aniline
in the presence of a metal catalyst and that these compounds cyclise to give the corresponding quinoline
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
16a,b
16c
derivatives in a copper
or gold catalyzed FriedelꢀCraftsꢀtype process has been previously
15
described. However, in our case, cyclization of propargylamines 15 derived from 3ꢀpyridylamines
(Scheme 5) is not favoured because of the previously mentioned electronic restrictions of the pyridine
ring respect to the phenyl ring. This behaviour has been experimentally confirmed since all attempts for
the cyclization of experimentally obtained propargylamine 15 did not occur (vide supra Scheme 5).
Therefore, a plausible mechanism for the formation of naphthyridines 5 may be indicated by pathway 3
(Scheme 6) which implies a transformation of intermediates 17 into 3ꢀazatrienes 21 whose electrocyclic
23
ring closure (ERC) may give intermediates 22 followed by prototropic tautomerization to lead 23 and
subsequent aromatization to afford compounds 24 and the corresponding naphthyridines 5.
Therefore, we studied whether the formation of propargylamines 20 or 3ꢀazatrienes 21 is favoured
theoretically. In this sense, we have located both a transition structure TS2 connecting zwitterionic
intermediates 17 with propargylamines 20 as well as transition structures TS3 connecting zwitterionic
intermediates 17 with 3ꢀazatrienes 21 (Scheme 6). In gas phase and in the presence of chloroform
(solvent effect), computed results indicate that the activation barriers associated to the formation of
azatrienes 21 through transition structures TS3 are lower than the activation barriers corresponding to
the formation of propargylamines 20 (about 6 to 9 kcal/mol, see Table 3 and Figures S7 and S8 of
Supporting Information). Although, formation of both 20 and 21 are very exothermic either in the gas
phase or in the presence of chloroform, the formation of azatriene 21 is almost twice as exothermic as
the formation of propargylamine 20, and at all calculation levels of theory.
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Next, we investigated whether the electrocyclic closure of the intermediates 21 could lead to the
formation of the compounds 22 and finally to 24 (Scheme 6). In this sense, we located in all cases
transition structures TS4 (Figure 1) connecting the azatrienes 21 with compounds 22 through a
disrotatory electrocyclization mode (6πꢀERC) and also transition structures TS5 corresponding to the
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19
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21
22
23
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[
1,3]ꢀproton shift for the transformation of 22 into theirs tautomeric compounds 23 (Scheme 6 and
Supporting Information), both in gas phase and in the presence of solvent and at all calculation levels.
Figure 1. Fully optimized transition structures TS4aꢀf (B3LYP/6ꢀ311G** level) found into the conversion of
azatrienes 21aꢀf into dihydronaphthyridines 22aꢀf through a disrotatory electrocyclization mode (6πꢀERC).
Selected bond lengths are given in Å.
Therefore, computational calculations suggest that 3ꢀazatrienes 21 undergo an electrocyclic ring closure
(ERC), prototropic tautomerization and aromatization to finally afford compounds 24. As
experimentally observed, the treatment of the crude reaction would give naphthyridines 5. The
activation barriers for the ERC through TS4 are higher (more than 10 kcal/mol, see Table 4, entries 1, 3,
5
, 7, 9 and 11 in the Supporting Information) than the activation barriers corresponding to this step of
the process through TS5 (See Table 4 entries 2, 4, 6, 8, 10 and 12 in the Supporting Information). At all
levels of calculation, both in gas phase and in the presence of chloroform, computational results indicate
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
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5
5
5
5
6
that the formation of 22 is slightly endothermic but its tautomerization into compounds 23, where
aromatic pyridine ring is regenerated, is strongly exothermic (ꢀ30 kcal/mol aprox, see Table S4 in the
Supporting Information). To sum up, this second stage of the reaction as a whole turns out to be
thermodynamically favoured. Moreover, taking into account that the formation of 3ꢀazatrienes 21 is a
highly exothermic process we might think that the formation of 23 is favoured kinetically and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
thermodynamically. As an example, the energy profile
acetylene 4a (R = H) and the double activated aldimine 16b (Ar = 4ꢀCF
at the M06ꢀ2X(PCM)/6ꢀ311G**//B3LYP/6ꢀ311G* + ZPVE level using chloroform as solvent is showed
ꢀ
E in kcal/mol of the reaction between the
3
6 4
C H
, see Scheme 6) computed
(Figure 2).
CF3
CF3
CF3
CF3
CF3
TS1b
TS3b
TS4b
TS5b
F3BN
+
F3BN
F3BN
F3BN
F3BN
ERC
NBF3
NBF3
NBF3
NBF3
NBF3
4
a
1
6b
17b
21b
22b
23b
TS3b
29.8
TS1b
13.9
17b
.7
7
4
a + 16b
0.0
TS4b
TS5b
8.1
E
ꢀ
7.8
ꢀ
22b
ꢀ
30.0
21b
ꢀ 41.7
2
3b
ꢀ 60.0
Figure 2. Energy profile for the catalysed Povarov reaction between 4a (R = H) and 16b (Ar = 4ꢀCF C H ) at
3
6
4
M06ꢀ2X(PCM)/6ꢀ311G**//B3LYP/6ꢀ311G** + ꢁZPVE level (unit: kcal/mol) using chloroform as solvent.
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CONCLUSIONS
In summary, experimental results show different behaviours for the reaction of aldimines derived from
ꢀaminopyridine and alkynes depending on the promoter. Thus, when the reaction was performed in the
presence of a Lewis acid, such as BF ·Et O, the corresponding naphthyridine and isoindolinone
compounds were isolated. Alternatively, in the presence of Brönsted acid, such as phosphoric acid
diphenyl ester [(PhO) P(O)OH], propargylamines were obtained. Moreover, our combined experimental
and computational investigations of the Povarov reaction between ꢀ(3ꢀpyridyl)aldimines and
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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32
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45
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
2
2
N
acetylenes with a Lewis acid suggest a stepwise [4+2]ꢀcycloaddition mechanism. The presence of
nitrogen in the pyridine ring deactivates the SE with respect to the benzene, yielding the formation of a
3
ꢀazatriene whose electrocyclic ring closure (ERC) may give the corresponding heterocyclic
intermediates followed by prototropic tautomerization and subsequent aromatization to afford
naphthyridines.
EXPERIMENTAL SECTION
General Methods. All reagents from commercial suppliers were used without further purification. All
solvents were freshly distilled before use from appropriate drying agents. All other reagents were
recrystallized or distilled when necessary. Reactions were performed under a dry nitrogen atmosphere.
Analytical TLCs were performed with silica gel 60 F254 plates. Visualization was accomplished by UV
light. Column chromatography was carried out using silica gel 60 (230ꢀ400 mesh ASTM). Melting
points were determined with a digital melting point apparatus without correction. NMR spectra were
1
obtained on a 300 MHz and on a 400 MHz spectrometers and recorded at 25 ºC. Chemical shifts for H
1
3
NMR spectra are reported in ppm downfield from TMS, chemical shifts for C NMR spectra are
13
19
recorded in ppm relative to internal chloroform (
δ
= 77.2 ppm for C), chemical shifts for F NMR are
reported in ppm downfield from fluorotrichloromethane (CFCl
3
). Coupling constants ( ) are reported in
J
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5
5
5
5
5
5
5
6
1
3
19
Hertz. The terms m, s, d, t, q refer to multiplet, singlet, doublet, triplet, quartet. C NMR, and F NMR
were broadband decoupled from hydrogen nuclei. High resolution mass spectra (HRMS) was measured
by positiveꢀion electrospray ionization (EI) method using a mass spectrometer QꢀTOF. Aldimines 3aꢀc
8
a
were prepared as previously described.
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Methyl-2-pyridin-3-yliminomethylbenzoate (3d). 3ꢀAminopyridine 1 (10 mmol, 0.941 g) was solved in
CHCl (30 mL) and methylꢀ2ꢀformylbenzoate 2d (10 mmol, 1.390 mL) was added. The mixture was
3
stirred under nitrogen at refluxing chloroform for 12 h. The reaction product is unstable during
1
distillation and/or chromatography and was used in situ for further reactions. H RMN of crude reaction
3
mixture (300 MHz, CDCl3)
δ
: 3.93 (s, 3H), 7.28ꢀ7.39 (m, 1H), 7.56ꢀ7.69 (m, 3H), 8.02 (d, JHH = 7.7
3
13
1
Hz, 1H), 8.25 (d,
reaction mixture (75 MHz, CDCl
43.2, 147.4, 147.7, 161.8, 167.1 ppm.
J
HH = 7.7 Hz, 1H), 8.48ꢀ8.59 (m, 2H), 9.27 (s, 1H) ppm; C { H} NMR of crude
3
) δ
: 52.5, 123.7, 127.9, 128.5, 130.5, 130.9, 132.5, 134.7, 136.7,
1
General procedure for Povarov reaction. Synthesis of naphthyridines 5 and isoindolinone 6. To a
solution of of the in situ prepared aldimine 3 (5 mmol) in chloroform the corresponding acetylenes 4 (7
mmol) and BF ·Et O (10 mmol, 1.230 mL) were added and the mixture was stirred at the opportune
3
2
1
temperature until TLC and H NMR spectroscopy indicated the disappearance of aldimine. The reaction
mixture was washed with 2M aqueous solution of NaOH (25 mL) and water (25 mL), extracted with
4
dichloromethane (2 x 25 mL), and dried over anhydrous MgSO . The removal of the solvent under
vacuum afforded and oil that was purified by silica gel flash column chromatography using a gradient
elution of 10ꢀ40% ethyl acetate in hexane to afford products 5aꢀf and when imine 3d was used
compound 6.
2
,4-Diphenyl-1,5-naphthyridine (5a). The general procedure was followed using imine 3a prepared in
situ and phenylacetylene 4a (7 mmol, 0.768 mL) and the reaction mixture was stirred at refluxing
chloroform for 24 h. Compound 5a (1.057 g, 75 %)was obtained as a white solid; mp 122ꢀ124 ºC (ethyl
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acetate/hexane). H NMR (400 MHz, CDCl
3
)
δ
: 7.48ꢀ7.60 (m, 6H), 7.66 (dd,
J
HH = 8.4 Hz, JHH = 4.0
3
3
3
Hz, 1H), 7.86 (d,
J
HH = 7.6 Hz, 2H), 8.12 (s, 1H), 8.22 (d,
J
HH = 7.8 Hz, 2H), 8.52 (d,
J
HH = 7.9 Hz,
3
13
1
1
H), 8.99 (d, JHH = 4.0 Hz, 1H) ppm; C { H} NMR (75 MHz, CDCl )
δ
: 122.5, 124.5, 127.8, 128.5,
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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59
60
128.9, 129.1, 129.9, 130.6, 137.3, 137.9, 139.2,141.5, 144.6, 149.2, 150.6, 157.9 ppm. HRMS (EI)
+
calculated for C H N [M] 282.1157; found 282.1165.
20
14
2
4
-Phenyl-2-(4-(trifluoromethyl)phenyl)-1,5-naphthyridine (5b). The general procedure was followed
using imine 3b prepared in situ and phenylacetylene 4a (7 mmol, 0.768 mL) and the reaction mixture
was stirred at refluxing chloroform for 18 h. Compound 5b (1.050 g, 60 %)was obtained as a yellowish
1
solid; mp 173ꢀ174 ºC (ethyl acetate/hexane). H NMR (300 MHz, CDCl )
δ
: 7.42ꢀ7.50 (m, 3H), 7.57
3
3
3
3
(dd,
J
HH = 8.5 Hz,
J
HH = 4.1 Hz, 1H), 7.68ꢀ7.74 (m, 4H), 8.00 (s, 1H), 8.22 (d,
J
HH = 8.5 Hz, 2H),
3
4
3
4
13
1
8
.41 (dd, JHH = 8.5 Hz, JHH = 1.7 Hz, 1H), 8.91 (dd, JHH = 4.1 Hz, JHH = 1.7 Hz, 1H) ppm; C { H}
1
3
NMR (75 MHz, CDCl
3
)
δ
: 122.3, 124.5 (q, JCF = 270.1 Hz), 124.9, 126.1 (q, JCF = 4.5 Hz), 128.2,
2
1
28.6, 129.2, 130.7, 131.6 (q,
JCF = 32.5 Hz), 137.1, 138.1, 141.6, 142.5, 144.7, 149.7, 151.2, 156.3
19
+
ppm; F NMR (282 MHz, CDCl
3 13 2 3
) δ: ꢀ 63.0 ppm. HRMS (EI): calculated for C21H N F [M]
350.1031; found 350.1037.
2
-(4-Nitrophenyl)-4-phenyl-1,5-naphthyridine (5c). The general procedure was followed using imine
3
c prepared in situ and phenylacetylene 4a (7 mmol, 0.768 mL) and the reaction mixture was stirred at
refluxing chloroform for 48 h. Compound 5c (0.817 g, 50 %)was obtained as a yellow solid; mp 178ꢀ
1
179 ºC (ethyl acetate/hexane). H NMR (300 MHz, CDCl
3
)
δ
: 7.56ꢀ7.86 (m, 6H), 8.16 (s, 1H), 8.34ꢀ8.57
: 122.2, 124.2, 124.9, 128.6, 129.2,
30.6, 136.7, 138.1, 141.5, , 144.9, 148.7, 149,8, 151.6, 155.1 ppm. HRMS (EI): calculated for
13
1
(
3
m, 5H), 9.06 (s, 1H) ppm; C { H} NMR (75 MHz, CDCl ) δ
1
+
C
20 13 3 2
H N O [M] 327.1008; found 327.1013.
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4-(4-Methoxyphenyl)-2-(4-(trifluoromethyl)phenyl)-1,5-naphthyridine (5d). The general procedure
was followed using imine 3b prepared in situ and 4ꢀmethoxyphenylacetylene 4b (7 mmol, 0.908 mL)
and the reaction mixture was stirred at refluxing chloroform for 36 h. Compound 5d (1.140 g, 60 %)
1
was obtained as a white solid; mp 165ꢀ166 ºC (ethyl acetate/hexane). H NMR (300 MHz, CDCl )
δ:
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
3.91 (s, 3H), 7.09ꢀ7.13 (m, 2H), 7.66 (dd,
JHH = 8.5 Hz, JHH = 4.3 Hz, 1H), 7.69ꢀ7.77 (m, 4H), 8.10 (s,
3
3
4
3
1
H), 8.31 (d, JHH = 8.5 Hz, 2H), 8.49 (dd, JHH = 8.5 Hz, JHH = 1.8 Hz, 1H), 9.01 (dd, JHH = 4.3 Hz,
4
13
1
1
J
3 CF
HH = 1.8 Hz, 1H, Harom) ppm; C { H} NMR (75 MHz, CDCl ) δ: 55.6, 114.2, 121.8, 124.5 (q, J =
3
2
2
74.5 Hz), 124.7, 126.0 (q,
J
CF = 4.1 Hz), 128.1, 129.2, 131.6 (q,
J
CF = 33.5 Hz), 132.1, 138.1, 141.7,
19
3
142.6, 144.7, 149.2, 151.0, 156.3, 160.6 ppm; F NMR (282 MHz, CDCl ) δ: ꢀ 63.1 ppm. HRMS (EI):
+
calculated for C H F N O [M] 380.1136; found 380.1138.
22
15
3
2
4
-(4-Methoxyphenyl)-2-(4-nitrophenyl)-1,5-naphthyridine (5e). The general procedure was followed
using imine 3c prepared in situ and 4ꢀmethoxyphenylacetylene 4b (7 mmol, 0.908 mL) and the reaction
mixture was stirred at refluxing chloroform for 18 h. Compound 5e (1.071 g, 60 %) was obtained as a
1
white solid; mp 134ꢀ135 ºC (ethyl acetate/hexane). H NMR (400 MHz, CDCl
3
)
δ: 3.92 (s, 3H), 7.11 (d,
3
3
3
3
JHH = 8.7 Hz, 2H),7.70 (dd, JHH = 8.5 Hz, JHH = 4.0 Hz, 1H), 7.83 (d, JHH = 8.7 Hz, 2H), 8.13 (s,
3
4
3
4
1H), 8.40 (s, 4H), 8.52 (dd, JHH = 8.5 Hz, JHH = 2.0 Hz, 1H), 9.54 (dd, JHH = 4.0 Hz, JHH = 2.0 Hz,
13
1
1
3
H) ppm; C { H} NMR (75 MHz, CDCl ) δ: 55.6, 114.2, 121.8, 124.3, 124.9, 128.6, 129,0, 132.2,
1
38.2, 143.3, 144.7, 145.1, 149.4, 151.4, 151.5, 155.2, 160.7 ppm. HRMS (EI): calculated for
+
C
21
H
15
N
3
O
3
[M] 357.1112; found 357.1117.
2
,4-bis(4-(Trifluoromethyl)phenyl)-1,5-naphthyridine (5f). The general procedure was followed using
imine 3b prepared in situ and 4ꢀtrifluoromethylphenylacetylene 4c (7 mmol, 1.190 g) and the reaction
mixture was stirred at refluxing chloroform for 36 h. Compound 5f (1.251 g, 60 %) was obtained as a
1
3
white solid; mp 191ꢀ192 ºC (ethyl acetate/hexane). H NMR (300 MHz, CDCl )
δ
: 7.73 (dd, JHH = 8.5
3
3
3
3
Hz,
J
HH = 4.1 Hz, 1H), 7.75ꢀ7.85 (m, 4H), 7.95 (d,
J
HH = 8.0 Hz, 2H), 8.13 (s, 1H), 8.34 (d,
J
HH = 8.6
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Hz, 2H), 8.56 (dd, JHH = 8.5 Hz, JHH = 1.7 Hz, 1H), 9.02 (dd, JHH = 4.1 Hz, JHH = 1.7 Hz, 1H) ppm;
1
3
1
3
3
3
C { H} NMR (75 MHz, CDCl ) δ: 122.2, 122.4 (q, JCF = 272.8 Hz), 122.8 (q, JCF = 272.3 Hz),
1
25.1, 125.5, 126.1, 128.1, 131.1ꢀ132.4 (m), 138.2, 140.6, 141.1, 142.1, 144.6, 148.2, 151.5, 156.4 ppm;
1
9
+
F NMR (282 MHz, CDCl
3 12 6 2
) δ: ꢀ 63.1, ꢀ 63.6 ppm. HRMS (EI): calculated for C22H F N [M]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
418.0905; found 418.0908.
3
-(2-Oxo-2-phenylethyl)-2-(pyridin-3-yl)isoindolin-1-one (6). The general procedure was followed
using imine 3d prepared in situ and phenylacetylene 4a (7 mmol, 0.768 mL) and the reaction mixture
was stirred at refluxing chloroform for 48 h. Compound 6 (0.984 g, 60 %).was obtained as a white solid;
1
2
3
mp 152ꢀ153 ºC (ethyl acetate/hexane). H NMR (400 MHz, CDCl )
δ
: 3.25 (dd, JHH = 17.4 Hz, JHH
=
3
2
3
3
3
9
.4 Hz, 1H), 3.50 (dd,
J
HH = 17.4 Hz,
J
HH = 2.8 Hz, 1H), 6.0 (dd,
J
HH =9.4 Hz,
J
HH = 2.8 Hz, 1H),
4
7
.33ꢀ7.42 (m, 3H), 7.47ꢀ7.55 (m, 4H), 7.81ꢀ7.84 (m, 2H), 7.89ꢀ7.91 (m, 1H), 8.09 (ddd, JHH = 1.5 Hz,
4
3
3
4
J
HH = 2.7 Hz,
J
HH = 9.3 Hz, 1H, Harom), 8.42 (dd,
J
HH = 4.8 Hz,
J
HH = 1.5 Hz, 1H, Harom), 8.85 (d,
: 41.8, 56.3, 123.3, 123.9, 124.3,
4
13
1
JHH = 2.7 Hz, 1H, Harom) ppm; C { H} NMR (100 MHz, CDCl )
δ
3
1
28.1, 128.8, 129.0, 130.1, 131.1, 132.9, 133.6, 134.0, 136.1, 143.8, 145.2, 146.3, 167.2, 197.1 ppm.
+
HRMS (EI): calculated for C H N O [M] 328.1212; found 328.1215.
21 16
2
2
Synthesis of tetrahydroisoindolonaphthyridinones 11 and 12. General procedure.
Styrene 9 (7.5 mmol, 0.862 ml) or indene 10 (7.5 mmol, 0.868 ml) and BF ·Et O (10 mmol, 1.230 ml)
3
2
were added to a solution of the previously prepared aldimine 3d (5 mmol) in CHCl (10 ml). The
3
1
mixture was stirred at the appropriate temperature until TLC and H NMR spectroscopy indicated the
disappearance of imine 3d. The reaction mixture was washed with 2M aqueous solution of NaOH (20
ml) and water (20 ml), extracted with dichloromethane (20 ml), and dried over anhydrous MgSO4. The
removal of the solvent under vacuum afforded an oil or solid that was purified by silica gel flash column
chromatography using a gradient elution of 10ꢀ60% ethyl acetate in hexane to afford the desired
products 11 or 12.
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2
2
2
2
2
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3
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5
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5
5
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5-Phenyl-6,6a-dihydroisoindolo[2,1-a][1,5]naphthyridin-11(5H)-one (11). The general procedure was
followed using styrene 9, and the reaction mixture was stirred at chloroform reflux for 24 h. Compound
1
1
1 (1.248 g, 80 %) was obtained as a white solid; mp 242ꢀ243 ºC (ethyl acetate/hexane). H NMR (400
2
3
3
2
MHz, CDCl3) δ: 1.95 (ddd, JHH = 12.4 Hz, JHH = 12.4 Hz, JHH = 12.4 Hz, 1H), 2.95 (ddd, JHH = 12.4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
3
3
2
Hz,
J
HH = 6.3 Hz,
J
HH = 2.5 Hz, 1H), 4.53 (dd,
J
HH = 12.4 Hz,
J
HH = 6.3 Hz, 1H), 4.98 (dd,
J
HH
=
=
3
3
1
2.4 Hz, JHH = 2.5 Hz, 1H), 7.12ꢀ7.15 (m, 2H), 7.21ꢀ7.34 (m, 4H), 7.50ꢀ7.64 (m, 3H), 7.96 (d, JHH
3
4
3
4
7
.6 Hz, 1H), 8.33 (dd,
JHH = 4.6 Hz,
J
HH = 1.6 Hz, 1H), 8.89 (dd,
J
HH = 8.3 Hz,
J
HH = 1.6 Hz, 1H),
1
3
1
ppm; C { H} NMR (100 MHz, CDCl ) δ: 38.4, 47.3, 58.5, 122.1, 122.3, 124.4, 126.9, 127.4, 128.6,
3
16 2
128.9, 129.0, 132.1, 132.7, 133.5, 143.9, 144.0, 145.2, 148.9, 166.6 ppm. (EI): calculated for C21H N O
+
[
M] 312.1263; found 312.1265.
4
b,14b,14c,15-Tetrahydro-10H-indeno[2,1-c]isoindolo[2,1-a][1,5]naphthyridin-10-one (12). The
general procedure was followed using indene, and the reaction mixture was stirred at room temperature
for 24 h. Compound 12 (1.377 g, 85 %) was obtained as a white solid; mp 223ꢀ224 ºC (ethyl
1
3
acetate/hexane). H NMR (300 MHz, CDCl )
δ
: 2.24ꢀ2.45 (m, 2H), 3.69ꢀ3.80 (m, 1H), 4.70 (d, JHH
=
3
3
8
.4 Hz, 1H), 5.11 (s, 1H), 6.88ꢀ6.90 (m, 1H), 7.00ꢀ7.18 (m, 3H), 7.46ꢀ7.62 (m, 3H), 7.73 (d,
J
HH = 7.4
3
3
3
Hz, 1H), 7.88 (dd, JHH = 7.4 Hz, JHH = 1.4 Hz, 1H), 8.28ꢀ8.30 (m, 1H), 8.56 (d, JHH = 8.3 Hz, 1H)
13
1
ppm; C { H} NMR (75 MHz, CDCl
3
)
δ: 31.2, 42.1, 48.4, 59.0, 121.9, 122.2, 124.5, 126.8, 127.5,
1
27.7, 128.9, 132.2, 132.7, 132.8, 141.2, 143.1, 143.8, 145.7, 149.0, 166.9 ppm. (EI): calculated for
+
C
22 16 2
H N O [M] 324.1263; found 324.1265.
Synthesis of propargylamine 15. To a solution of the previously prepared imine 3c (5 mmol, 1.250 g)
in chloroform, 4ꢀmethoxyphenylacetylene 4b (7 mmol, 0.908 ml) and diphenylphosphonic acid (10
mmol, 2.5 ml) were added and the mixture was stirred in chloroform for 24 h. The reaction mixture was
washed with 2M aqueous solution of NaOH (20 ml) and water (20 ml), extracted with dichloromethane
4
(20 ml), and dried over anhydrous MgSO . Purification by silica gel flash column chromatography using
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a gradient elution of 10ꢀ50% ethyl acetate in hexane to afford the desired products 15 as an orange oil
1
(
(
(
0.955 g, 50%). Rf: 0.54 (50:50 ethyl acetate/hexane). H NMR (300 MHz, CDCl
3
)
δ: 3.80 (s, 3H), 4.32
3
3
3
d,
d,
J
J
HH = 7.2 Hz, 1H), 5.54 (d,
HH = 9.0 Hz, 2H), 7.67 (d,
J
HH = 7.2 Hz, 1H), 6.82 (d,
HH = 8.6 Hz, 2H), 7.77 (d,
J
HH = 9.0 Hz, 2H), 7.00ꢀ7.15 (m, 2H,), 7.34
3
3
3
J
J
HH = 8.6 Hz, 2H), 8.05ꢀ8.07 (m, 1H), 8.16ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
1
8.17 (m, 1H) ppm; C { H} NMR (75 MHz, CDCl
3
)
δ
: 50.3, 55.5, 85.3, 86.5, 114.1, 118.9 120.4,
1
3
2
1
23.8, 125.9 (q, JCF = 247.1 Hz), 126.0 (q, JCF = 3.9 Hz), 127.8, 130.6 (q, JCF = 33.1 Hz), 133.4,
1
9
1
3
37.4, 140.4, 142.3, 143.3, 160.1 ppm. F NMR (282 MHz, CDCl ) δ: ꢀ 63.0 ppm. HRMS (EI):
+
calculated for C22
H
17
F
3
N
2
O [M] 382.1293; found 382.1297.
Acknowledgements Financial support from the Dirección General de Investigación del Ministerio
de Economía, Ciencia e Innovación (MICINN, Madrid DGI, CTQ2015ꢀ67871ꢀR) and by Gobierno
Vasco, Universidad del País Vasco (GV, IT 992ꢀ16; UPV) is gratefully acknowledged. Technical and
human support provided by IZOꢀSGI, SGIker (UPV/EHU, MICINN, GV/EJ, ERDF and ESF) is
gratefully acknowledged. M.G. thanks the Basque Government for a formation contract.
SUPPORTING INFORMATION AVAILABLE
1
13
Copies of H NMR and C NMR spectra of compounds 3d, 5aꢀf, 6, 11, 12 and 15 and COSY
experiment of compound 6. Xꢀray structure and crystallographic data for 5d. Study by 1DꢀNOESY of
1
13
structure for compound 11. H and C NMR study of the reaction between aldimine 3b and acetylene
4b promoted by Brönsted acid. Computational Studies: Cartesian coordinates, harmonic analysis data,
and energies for all the stationary points discussed. This material is available free of charge via the
Internet at http://pubs.acs.org.
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