Efficient iron-catalyzed synthesis of polysubstituted 1,2-dihydropyridine derivatives

Article abstract of DOI:10.1134/S1070363215090212

A simple ligand-free cyclization of propargylic alcohols with enaminones has been developed by using FeBr3 as catalyst. This reaction provides an easy and convenient method to synthesize polysubstituted 1,2-dihydropyridine derivatives.

Full text of DOI:10.1134/S1070363215090212

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 9, pp. 2163–2166. © Pleiades Publishing, Ltd., 2015.
Efficient Iron-Catalyzed Synthesis
of Polysubstituted 1,2-Dihydropyridine Derivatives1
Yi-Wen Liua,b, Yi-Bi Xiea,b, De-Jiang Lia, and Long Wanga
a College of Materials and Chemical Engineering, China Three Gorges University, Hubei Yichang, 443002 PR China
b College of Biology and Pharmacy, China Three Gorges University, Hubei Yichang, 443002 PR China
e-mail: wanglongchem@163.com
Received June 18, 2015
Abstract—A simple ligand-free cyclization of propargylic alcohols with enaminones has been developed by
using FeBr3 as catalyst. This reaction provides an easy and convenient method to synthesize polysubstituted
1,2-dihydropyridine derivatives.
Keywords: iron(III) bromide, ligand-free, dihydropyridine, cyclization, catalysis
DOI: 10.1134/S1070363215090212
1,2-Dihydropyridine and 1,4-dihydropyridine
derivatives are important substructures of many
biologically active compounds, including natural
products and pharmaceuticals [1–6]. Compared to 1,4-
dihydropyridine derivatives [7–12], the synthesis of
1,2-dihydropyridines is more difficult [13, 14]. In
2012, Ohmura and Suginome have described an
efficient method for dearomatization of pyridines to
prepare 1,2-dihydropyridines through rhodium-catalyzed
hydroboration [15]. Later, Li and coworkers reported
BF3·Et2O-catalyzed reaction of enaminones with
propargylic alcohols to synthesize 1,4-dihydropyri-
dines with moderate to good yields [16]. In 2014, Wan
and Liu developed tunable three-component reactions
of enals, electron deficient alkynes, and primary
amines for selective synthesis of 1,2-dihydropyridines
[17]. Recently, Tejedor and García-Tellado found a
practical metal-free protocol for the synthesis of 1,2-
dihydropyridines from propargyl vinyl ethers and
primary amines [18].
At the beginning, copper(I) iodide was selected to
catalyze the reaction between propargyl alcohol (1a)
and (Z)-1-phenyl-3-(phenylamino)prop-2-en-1-one
(2a). However, no reaction occurred. When Cu(OAc)2
Table 1. Synthesis of phenyl(1,4,6,6-tetraphenyl-1,6-dihyd-
ropyridin-3-yl)methanone (3a) from 1,1,3-triphenylprop2-
yn-1-ol (1a) and 1-phenyl-3-(phenylamino)prop-2-en-1-one
(2a) in different solvents in the presence of different
catalystsa
Run no.
Catalyst
Solvent
Yield of 3a,b %
1
CuI
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Benzene
DCE
<5
8
2
CuCl
Cu(OAc)2
FeCl2
FeCl3
FeBr3
FeBr3
FeBr3
FeBr3
FeBr3
–
3
12
62
68
78
67
73
41
<5
<5
4
5
6
Although there is some progress in this area [13–
19], the above reactions usually require harsh
conditions (high temperature) and expensive starting
materials and catalyst. Herein, we report a simple
ligand-free cyclization of propargylic alcohols with
enaminones using FeBr3 as catalyst. This reaction
provides an easy and convenient method to synthesize
polysubstituted 1,2-dihydropyridine derivatives
(Scheme 1).
7
8
9
THF
10
11
DMF
Toluene
a
Conditions: 1a, 0.5 mmol; 2a, 0.55 mmol; catalyst, 10 mol %;
solvent, 2 mL; 90°C. 6 h.
Isolated yield based on 1a.
b
1 The text was submitted by the authors in English.
2163

2164
YI-WEN LIU et al.
Scheme 1.
O
R2
OH
Ar1
O
NHAr2
FeBr3, toluene, 90°C
R1
Ph
+
R1
Ph
Ar1
N
Ar2
R2
1a–1c
2a–2g
3a–3j
1, R1 = R2 = Ph (a), R1 = Me, R2 = Ph (b), R1 = Ph, R2 = H (c); 2, Ar1 = Ar2 = Ph (a), Ar1 = Ph, Ar2 = 4-MeOC6H4 (b), Ar1 =
Ph, Ar2 = 4-ClC6H4 (c), Ar1 = Ph, Ar2 = 3-ClC6H4 (d), Ar1 = 4-ClC6H4, Ar2 = Ph (e), Ar1 = Ar2 = 4-ClC6H4 (f), Ar1 = Ph,
Ar2 = 4-BrC6H4 (g); for R1, R2, Ar1, Ar2 in 3, see Table 2.
Scheme 2.
O
Ph
OH
Ph
FeBr3
Ph
·
Ph
Ph
–FeBr3OH–
NHPh
Ph
Ph
1a
2a
A
O
Ph
Ph
O
Ph
Ph
O
Ph
Ph
NHPh
Ph
·
Ph
·
NHPh
–H+
Ph
Ph
N
Ph
Ph
Ph
B
3a
C
was used as catalyst, the desired product was obtained
in 12% yield (Table 1, run no. 3). The yield of 3a was
improved to 62% when the catalyst was changed to
FeCl2 (Table 1, run no. 4). Encouraged by this result,
different catalysts were tested in this reaction. The
results revealed that FeBr3 was the best catalyst (Table
1, run no. 6). Next, the effect of the solvent was also
checked for get higher yield of the product. Solvent
experiments showed that toluene was superior to other
solvents. Thus, the best reaction conditions were found
(Table 1, run no. 6). It should be noted that the reaction
could not happen without iron catalyst (Table 1,
run no. 11).
In addition, a possible reaction mechanism for the
iron-catalyzed cyclization of propargylic alcohols with
enaminones was proposed based on the earlier work
[16]. Initially, propargylic alcohol 1a reacts with FeBr3
to form intermediate A which takes up enaminone 2a
to produce intermediate B. Isomerization of the latter
gives intermediate C which undergoes intramolecular
cyclization to final product 3a (Scheme 2).
In summary, a simple and convenient ligand-free
procedure has been developed for the synthesis of
polysubstituted 1,2-dihydropyridine derivatives via
cyclization of propargylic alcohols with enaminones in
the presence of FeBr3 as catalyst. A probable reaction
mechanism has also been proposed. Further
investigation on the scope of this reaction is now in
progress.
With the optimal conditions in hands, the scope of
iron-catalyzed cyclization of propargylic alcohols with
enaminones was also examined. Generally, this
reactions work well, and the desired products were
isolated in moderate to good yields. Electron-donating
group in the aromatic ring gave a higher yield than
electron-withdrawing group (Table 2; run nos. 3, 4).
The best result (yield 82%) was achieved with
enaminone IIb having a 4-methoxyphenyl group on
the nitrogen.
EXPERIMENTAL
All solvents were dried and purified by known
procedures and were distilled under nitrogen over
appropriate drying agents prior to use. The products
were isolated by column chromatography on silica gel
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 9 2015

EFFICIENT IRON-CATALYZED SYNTHESIS
2165
Table 2. Synthesis of dihydropyridines 3a–3j from propargylic alcohols 1a–1c and enaminones 2a–2g in the presence of
a
FeBr3
Run no.
01
Initial reactants
R1
Ph
R2
Ph
Ar1
Ph
Ar2
Product
Yield,b %
78
1a, 2a
Ph
Ph
3a
02
03
04
05
06
07
08
09
10
1b, 2a
1b, 2b
1b, 2c
1b, 2d
1b, 2e
1b, 2f
1b, 2g
1a, 2c
1c, 2d
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
Ph
3b
3c
3d
3e
3f
76
82
77
75
68
71
73
69
<5
Ph
4-MeOC6H4
4-ClC6H4
3-ClC6H4
Ph
Ph
Ph
4-ClC6H4
4-ClC6H4
Ph
4-ClC6H4
4-BrC6H4
4-ClC6H4
3-ClC6H4
3g
3h
3i
Ph
Ph
Ph
3j
a
Conditions: 1a, 0.5 mmol; 2a, 0.55 mmol; FeBr3, 10 mol %; toluene, 2 mL; 90°C. 6 h.
Isolated yield based on 1.
b
(200–300 or 100–200 mesh) using ethyl acetate and
petroleum ether as eluents. The progress of reactions
and the purity of products were routinely monitored by
TLC using SiO2 plates, and spots were visualized
d (2H, J = 7.2 Hz), 7.42–7.12 m (12H), 6.81–6.62 m
(4H), 5.17 s (1H), 3.73 s (3H), 1.78 s (3H).
[1-(4-Chlorophenyl)-6-methyl-4,6-diphenyl-1,6-
dihydropyridin-3-yl](phenyl)methanone (3d). 1H
NMR spectrum, δ, ppm: 7.67 d (2H, J = 4.8 Hz), 7.53
d (2H, J = 6.6 Hz), 7.42–7.25 m (7H), 7.24–7.06 m
(7H), 6.79 d (2H, J = 7.8 Hz), 5.19 s (1H), 1.82 s (3H).
1
under UV light. The H NMR spectra were recorded
on a Bruker Avance III 600 (600 MHz) spectrometer
using CDCl3 as a solvent and tetramethylsilane as
reference.
[1-(2-Chlorophenyl)-6-methyl-4,6-diphenyl-1,6-
dihydropyridin-3-yl](phenyl)methanone (3e). 1H
NMR spectrum, δ, ppm: 7.68 d (2H, J = 7.8 Hz), 7.54
d (2H, J = 6.0 Hz), 7.43–7.28 m (7H), 7.24–7.06 m
(7H), 6.90 s (1H), 6.75 d (1H, J = 6.6 Hz), 5.21 s (1H),
1.84 s (3H).
Phenyl(1,4,6,6-tetraphenyl-1,6-dihydropyridin-
3-yl)methanone (3a). Iron(III) bromide (10 mol %)
was added at room temperature to a mixture of
propargylic alcohol 1a (0.50 mmol) and enaminone 2a
(0.55 mmol) in toluene (2 mL), and the mixture was
stirred for 6 h at 90°C. When the reaction was
complete, the solvent was distilled off, and the residue
was purified by column chromatography on silica gel
using ethyl acetate–petroleum ether (1 : 10, by
(4-Chlorophenyl)(6-methyl-1,4,6-triphenyl-1,6-
1
dihydropyridin-3-yl)methanone (3f). H NMR spec-
trum, δ, ppm: 7.58 d (2H, J = 8.4 Hz), 7.54 d (2H, J =
7.2 Hz), 7.44–7.13 m (14H), 6.92–6.83 m (2H), 5.19 s
(1H), 1.82 s (3H).
1
volume) as eluent. H NMR spectrum, δ, ppm: 7.67 s
(1H), 7.47–7.38 m (5H), 7.34–6.90 m (20H), 5.63 s
(1H).
(4-Chlorophenyl)[1-(4-chlorophenyl)-6-methyl-
4,6-diphenyl-1,6-dihydropyridin-3-yl]methanone
(6-Methyl-1,4,6-triphenyl-1,6-dihydropyridin-3-
1
1
(3g). H NMR spectrum, δ, ppm: 7.70–7.45 m (4H),
yl)(phenyl)methanone (3b). H NMR spectrum, δ,
7.44–6.98 m (13H), 6.88–6.71 m (2H), 5.19 s (1H),
1.82 s (3H).
ppm: 7.68 d (2H, J = 5.4 Hz), 7.54 d (2H, J = 6.0 Hz),
7.43–7.10 m (15H), 6.94–6.80 m (2H), 5.19 s (1H),
1.82 s (3H).
[6-Methyl-1-(4-methylphenyl)-4,6-diphenyl-1,6-
dihydropyridin-3-yl](phenyl)methanone (3h). 1H
NMR spectrum, δ, ppm: 7.67 d (2H, J = 7.8 Hz), 7.54
d (2H, J = 7.2 Hz), 7.43 t (2H, J = 7.2 Hz), 7.38–7.30
[1-(4-Methoxyphenyl)-6-methyl-4,6-diphenyl-
1,6-dihydropyridin-3-yl](phenyl)methanone (3c). 1H
NMR spectrum, δ, ppm: 7.66 d (2H, J = 6.6 Hz), 7.54
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 9 2015

2166
YI-WEN LIU et al.
6. Barbe, G. and Charette, A.B., J. Am. Chem. Soc., 2008,
m (6H), 7.24–7.20 m (3H), 7.11 s (1H), 6.97 d (2H, J =
8.4 Hz), 6.74 d (2H, J = 7.2 Hz), 5.18 s (1H), 2.26 s
(3H), 1.80 s (3H).
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[1-(4-Chlorophenyl)-4,6,6-triphenyl-1,6-
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(20H), 7.00 d (2H, J = 8.4 Hz), 6.91 d (2H, J =
8.4 Hz), 5.65 s (1H).
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We gratefully acknowledge financial support of this
work by the National Natural Science Foundation of
China (no. 31100080) and Natural Science Foundation
of Hubei (no. 2011CDB186).
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