Intramolecular cyclization of N-propargylic β-enaminones catalyzed by silver

Article abstract of DOI:10.1016/j.tetlet.2012.11.086

The efficient synthesis of 1,2-dihydropyridine from the intramolecular cyclization reaction of N-propargylic β-enaminones [R²C(O) CHC(R¹)(N(R)CH₂CCH), where R = Pr, Bn, Ph, 4-Me-C ₆H₄, R¹ = Me, Et, Pr, R² = CF ₃, CO₂Et] using AgNO₃ as a catalyst (12 h at 25 °C) is reported. The products were obtained at good yields (70-90%). In particular, when the reaction of N-propargylic β-enaminone with R = Me was performed over a 24 h period, the intramolecular cyclization resulted in the formation of a pyrrole with 80% yield.

Full text of DOI:10.1016/j.tetlet.2012.11.086

Tetrahedron Letters 54 (2013) 847–849
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular cyclization of N-propargylic b-enaminones catalyzed by silver
Marcos A. P. Martins a, , Marcelo Rossatto b, Clarissa P. Frizzo a, Elisandra Scapin a, Lilian Buriol a,
⇑
Nilo Zanatta a, Helio G. Bonacorso a
a Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
b Rua Erechim, 860 Planalto, Instituto Federal Farroupilha, Campus Panambi, 98280-000 Panambi, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The efficient synthesis of 1,2-dihydropyridine from the intramolecular cyclization reaction of N-propar-
gylic b-enaminones [R2C(O)CH@C(R1)(N(R)CH2C„CH), where R = Pr, Bn, Ph, 4-Me-C6H4, R1 = Me, Et, Pr,
R2 = CF3, CO2Et] using AgNO3 as a catalyst (12 h at 25 °C) is reported. The products were obtained at good
yields (70–90%). In particular, when the reaction of N-propargylic b-enaminone with R = Me was per-
formed over a 24 h period, the intramolecular cyclization resulted in the formation of a pyrrole with
80% yield.
Received 26 October 2012
Revised 20 November 2012
Accepted 21 November 2012
Available online 3 December 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
N-Propargylic b-enaminones
Intramolecular cyclization
Pyrrole
1,2-Dihydropyridine
Pyridine
The reactivity associated with the conjugated systems O@C–
C@C–N (OR) makes b-enaminones1,2 and b-alkoxyvinyl ketones3,4
valuable reagents with many applications in organic synthesis. A
variety of intra-5 and intermolecular6 reactions have been per-
formed taking advantage of their electronic properties. In particu-
lar, N-propargylic b-enaminones can be a potential precursor to
intramolecular cyclocondensation when activated by transition
metal catalysis.7 From the literature,8–13 it is known that various
metals such as silver, gold, and platinum form a positive ion which
has a high affinity for C„C triple bonds. The ion forms a triple bond
that is electrophilic enough to be attacked by various nucleophilic
It is important to note that in all of these works the N-propargy-
lic b-enaminones studied were not substituted with trifluoro-
methyl groups.
Over the years, our research group has developed strategies for
the synthesis of heterocycles, especially trifluoromethylated ones,
since the presence of halogen in organic molecules gives the mol-
ecules interesting properties.14 Our methodology uses the trifluo-
romethyl b-alkoxyvinyl ketones4 and b-enaminones15 (CCC Block)
as 1,3-dieletrophile in cyclizations [3 + 2] or [3 + 3], [3 + 4] type
in order to form halogenated heterocycles. We recently published
the synthesis of novel N-propargylic b-enaminones in one step
from the reaction of b-alkoxyvinyltrifluoromethyl[carboxyethyl
ketones and propargyl amines.16 Thus, considering the importance
of developing new methods for the synthesis of heterocycles, we
present herein a reactivity study of N-propargylic b-enaminones
trifluoromethylated in intramolecular cyclizations for the synthe-
sis of 1,2-dihydropyridines using silver nitrate as the catalyst.
We began our study by investigating the reaction of trifluorom-
ethylated N-propargylic b-enaminones (1a) and silver nitrate as
the catalyst (10 mol %), in the presence of chloroform. The mixture
was stirred for 12 h at 25 °C in a nitrogen atmosphere and in the
absence of light.
carbon species such as the
a
-carbon of enamines,7 resulting in the
formation of a heterocycle.11
There are important works in the literature where the reactivity
of N-propargylic b-enaminones in the presence of metal catalyst is
investigated.7,12,13 In some cases, 1,2-dihydropyridines are
formed7,12 and in other situations, pyrroles are isolated.7,13 The for-
mation of pyrroles or 1,2-dihydropyridines appears to be related to
substituent at the frame of N-propargylic b-enaminones and to
reaction conditions, including catalyst. Cacchi et al.7 for example,
obtained a pyrrole when using Cs2CO3 at room temperature,
whereas a pyridine was formed when using CuBr and heating the
mixture.
The product isolated was a 1,2-dihydropyridine 3a at 80%
yield (Scheme 1). To support this result, N-propargylic b-enami-
nones 1b were also tested. The product obtained was also 1,2-
dihydropyridine 3b, but at 70% yield (Scheme 3). Other reaction
conditions (variations in time 6–24 h and temperature 25–60 °C)
were tested; however, they were unsuccessful for the synthesis
⇑
Corresponding author. Tel./fax: +55 55 3220 8756.
E-mail address: mmartins@base.ufsm.br (M.A.P. Martins).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.086

848
M. A. P. Martins et al. / Tetrahedron Letters 54 (2013) 847–849
dines are very sensitive to the presence of oxygen,18 1,2-dihydro-
pyridine obtained in this work showed relative stability
O
O
Me
a
i
F3C
Me
F3C
N
Bn
(5 days) in the presence of oxygen. The stability of 1,2-dihydro-
pyridines was retained even during purification in a chromatog-
raphy column, probably due to use of nitrogen atmosphere. The
collected products were either light yellow solid or light brown
oil. When left in solution for this time, 1,2-dihydropyridines un-
dergo degradation.
N
Bn
H
1a
3a
Scheme 1. Reagents and conditions: AgNO3 (10 mol %), CHCl3, 25 °C, 12 h.
When the N-propargylic b-enaminone 1h was reacted, unex-
pectedly, polysubstituted pyrrole was obtained at 50% yield. In
an attempt to increase the product yield, the mixture was stirred
for 24 h and the pyrrole was obtained at an excellent yield (80%)
(Scheme 2).17 Other reaction conditions (variations in time 6–
24 h and temperature 60 °C) were tested; however, they were
unsuccessful for the synthesis of pyrrole. The formation of pyrrole
O
O
Me
Me
F3C
Me
i
F3C
N
Pr
N
Pr
H
1i
2i
indicates an attack of the
a-carbon in the internal carbon triple
bond, as described by Cacchi et al.7 occurred. An aza-Claisen rear-
rangement13 could occur, but from the product it can be seen that a
5-exo-dig mechanism is operating. If aza-Claisen rearrangement
had occurred, the methyl group would be attached at 2-position
of pyrrole and not at 3. The conditions to the formation of this
product have been investigating in our laboratories and the results
will be published hereafter.
The identification of 1,2-dihydropyridines synthesized in this
work was done using 1H and 13C NMR, and mass spectroscopy.
The NMR and 1H spectra of the 1,2-dihydropyridines synthesized
showed the presence of a characteristic signal of 1,2-dihydropiri-
dines. From the data obtained by mass spectrometry for the com-
pounds 3a–i it was observed that all the compound showed a
molecular ion and a stable fragment ion (base peak) corresponding
to the loss of a proton for all compounds, except for 3c–d. In these
compounds, loss of proton corresponded to a peak intensity of 5%
relative to the base peak.
Scheme 2. Reagents and conditions: AgNO3 (10 mol %), CHCl3, 25 °C, 24 h, 80%.
O
O
R1
i
R2
R2
N
R
R1
N
R
3a-h
H
1a-h
R1
R2
Product
3a
Yield (%)
R
Bn
Me
Me
Et
CF3
CF3
80
70
90
87
89
80
85
75
Ph
3b
Pr
CF3
3c
Pr
Pr
CF3
3d
By analogy with other cyclizations activated by transition metal
from acetylenic compounds,7,20 we propose that the mechanism
for the formation of 1,2-dihydropyridine from 1 involves the coor-
dination of the triple bond with silver to give I, followed by cycli-
zation of a type 6-endo-dig via intramolecular nucleophilic attack
Bn
Et
CF3
3e
Ph
Me
Me
Pr
CO2Et
CF3
3f
4-Me-C6H4
4-Me-C6H4
3g
CF3
3h
of the carbonyl group’s
a carbon on the activated triple bond. Sub-
stitution of the C–H bond for the C–Ag bond of the resultant vinyl–
Ag intermediate I yields II, with concomitant regeneration of
AgNO3, as shown in Scheme 4.
Scheme 3. Reagents and conditions: AgNO3 (10 mol %), CHCl3, 12 h, 25 °C.
In summary, in this Letter we showed that when a triple bond is
activated by silver nitrate, the terminal carbon of the triple is more
reactive than internal and it undergoes nucleophilic attack by the
of 1,2-dihydropyridine. To evaluate the scope and limitations of
this reaction, we performed the reaction in accordance with
the previous optimization for other N-propargylic b-enaminones.
Fortunately, we derived a method for other N-propargylic b-
enaminones and obtained a series of 1,2-dihydropyridines at
good to excellent yields (Scheme 3).19 Reactions were also per-
carbonyl group’s
a carbon, resulting in 1,2-dihydropyridine. Thus,
we developed an efficient, highly regioselective, and inexpensive
method for the synthesis of novel 1,2-dihydropyridine trifluorom-
ethylated from the intramolecular cyclization of N-propargylic
b-enaminones using silver nitrate as the catalyst.
formed in the absence of light in
a nitrogen atmosphere.
Although it is reported in the literature that some dihydropyri-
Acknowledgments
R3
O
The authors thank the Conselho Nacional de Desenvolvimento
Científico e Tecnológico em Pesquisa (CNPq/PADCT), Fundação de
Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) for
financial support. The fellowships from CNPq, CAPES, and FAPERGS
are also acknowledged.
O
R3
R2
N
R
R2
N
R
3
AgNO3
H
1
R3
O
H
Ag
O
R3
Supplementary data
R2
N
R
R2
N
R
-
H
NO3
Supplementary data (general procedures and characterization
data (1H NMR, 13CNMR, MS and melting points) of compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.11.086.
Ag
NO3
I
II
Scheme 4.

M. A. P. Martins et al. / Tetrahedron Letters 54 (2013) 847–849
849
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P. T.; Frizzo, C. P.; Zanatta, N.; Bonacorso, H. G. Ultrason. Sonochem. 2012, 19,
227.
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