One-pot synthesis of 3,4-dihydropyridin-2-ones via tandem reaction of Blaise reaction intermediate and acrylic ester

Article abstract of DOI:10.1002/aoc.3399

An efficient method for the synthesis 3,4-dihydropyridin-2-ones has been developed via tandem one-pot Michael-type addition and cyclization of the Blaise reaction intermediate and acrylic ester. A series of readily available nitriles, bromoacetic esters and acrylic esters have been employed to examine the scope of substrates for this method.

Full text of DOI:10.1002/aoc.3399

Full paper
Received: 16 July 2015
Revised: 25 August 2015
Accepted: 1 October 2015
Published online in Wiley Online Library: 2 November 2015
(wileyonlinelibrary.com) DOI 10.1002/aoc.3399
One-pot synthesis of 3,4-dihydropyridin-2-ones
via tandem reaction of Blaise reaction
intermediate and acrylic ester
Tuanjie Meng, Lantao Liu*, Huiyi Jia, Lifeng Ren, Cuilan Feng, Xiaojuan Wang
and Wenxian Zhao*
An efficient method for the synthesis 3,4-dihydropyridin-2-ones has been developed via tandem one-pot Michael-type addition
and cyclization of the Blaise reaction intermediate and acrylic ester. A series of readily available nitriles, bromoacetic esters and
acrylic esters have been employed to examine the scope of substrates for this method. Copyright © 2015 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web site.
Keywords: zinc; 3,4-dihydropyridin-2-ones; Blaise reaction; one-pot synthesis
and nitroolefins[22] in a tandem manner, which has provided access to
a variety of nitrogen-containing heterocyclic compounds. Inspired by
Introduction
3,4-Dihydropyridin-2-ones are embedded as prominent sub-
structures in numerous bioactive compounds exhibiting various ac-
tivities such as antibacterial,[1] antifungal[2] and antitumor,[3] also
serving as kinase inhibitors.[4] Moreover, the dihydropyridinone
skeleton has often been used in natural product synthesis.[5] The
usefulness of 3,4-dihydropyridin-2-one derivatives has made their
quick and efficient synthesis the subject of much research.
the works mentioned above, we report a tandem one-pot method
for the synthesis of 3,4-dihydropyridin-2-one compounds through
the sequential reaction of nitriles with Reformatsky reagents (the Blasie
reaction) and α,β-unsaturated carboxylic esters.
Results and discussion
So far, many methods have been developed. Among them, the
aza-annulation of enamines and α,β-unsaturated carboxylic acid
derivatives is the most commonly used method.[6] Furthermore,
3,4-dihydropyridin-2-one derivatives have been synthesized by in-
termolecular cyclization of 1-azadienes[7] with ketenes[8] or carbox-
ylic acid derivatives.[9] In addition, aza Diels–Alder reactions
between Brassard’s diene and imines are also useful methods for
their rapid synthesis.[10] Recently, multicomponent reactions have
been applied as more step- and atom-economic pathways for their
synthesis, which include the three-component reaction of alde-
hydes, cyanoacetamides and 1,3-dicarbonyl compounds devel-
oped by Lin and co-workers[11] and Das and co-workers,[12] four-
component reaction of aromatic aldehydes, 1,3-diketones, aryl
amines and dimethyl acetylenedicarboxylate reported by Yan and
co-workers[13] as well as four-component reaction of phosphonates,
nitriles, aldehydes and isocyanoacetates reported by the Orru
group.[14] Although high yields can be obtained, the methods men-
tioned above either utilize substrates that are not readily available
or require harsh reaction conditions. Thus, the search for a simple
protocol for the construction of 3,4-dihydropyridin-2-one skeletons
from readily available substrates is worth investigation.
The reaction of Blaise reaction intermediate Aaa, which is formed
from the reaction of benzonitrile (1a) with a Reformatsky reagent
generated in situ from ethyl bromoacetate (2a; 1.5 equiv.) and zinc
powder (2.0 equiv.) in tetrahydrofuran (THF), and ethyl acrylate (3a;
2.0 equiv.) was investigated for the synthesis of the 3,4-
dihydropyridin-2-one 4aaa as well as for optimization of reaction
conditions (Table 1). No desired product is observed when the reac-
tion is performed under non-catalytic conditions (Table 1, entry 1).
We hypothesize that a Lewis acid catalyzes this addition and the se-
quential cyclization reaction. Screening of various Lewis acid cata-
lysts reveals that the catalyst plays a significant role in this
reaction. Only a trace amount of the desired product 4aaa is ob-
tained when zinc bromide is used as a catalyst (Table 1, entry 2). Bo-
ron trifluoride–diethyl ether complex is found to be the best of all
catalysts tested (Table 1, entries 7–11). Further reducing the catalyst
loading from 30 to 25 mol% results in a decrease in product yield
from 81 to 63% (Table 1, entries 7 and 8). The effect of temperature
on the reaction was studied. No desired product can be observed
*
Correspondence to: Lantao Liu or Wenxian Zhao, Key Laboratory of New Organic
Materials Synthesis, College of Chemistry and Chemical Engineering, Shangqiu
Normal University, Shangqiu 476000, PR China.
The Blaise reaction is a classic reaction for the zinc-mediated trans-
formation of nitriles and ethyl bromoacetate into the corresponding
β-keto esters. In recent years, the Blaise reaction intermediates, zinc-
bound β-amino-α,β-unsaturated esters, have been trapped with suit-
able partners such as acetic anhydride,[15] alkynes,[16] 1,3-enynes,[17]
propiolates,[18] halogenated hydrocarbons,[19] nitriles,[20] isocyanates[21]
E-mail: liult05@iccas.ac.cn or zhwx2595126@163.com
Key Laboratory of New Organic Materials Synthesis, College of Chemistry and
Chemical Engineering, Shangqiu Normal University, Shangqiu 476000, PR China
Appl. Organometal. Chem. 2016, 30, 47–50
Copyright © 2015 John Wiley & Sons, Ltd.

T. Meng et al.
Table 1. Optimization of conditions for the one-pot synthesis of 3,4-
and R4 in products 4aad–4aaj are trans, which has been confirmed
using X-ray crystallographic analysis.[23] Substituents on arylidene
malonates influence the yields. Generally, arylidene malonates with
electron-donating groups give poorer yields than those with
electron-withdrawing groups (Table 2, entries 21 and 25). Due to
the steric hindrance of the substituents on the aryl groups, ortho-
substituted arylidene malonates provide products in poorer yields
than para- and meta-substituted ones (Table 2, entries 21–23).
Alkylidene malonates such as diethylethylidene malonate and
diethylmethylidene malonate do not give the desired products.
A possible reaction mechanism that accounts for the formation
of products 4 is shown in Scheme 1. The first step involves a
Michael-type addition of the Blaise reaction intermediate Aaa to
3a to form an intermediate B,[22] followed by tautomerization and
proton transfer to give intermediate C. Then, intermediate C un-
dergoes tautomerization to give the enamine intermediate D,
which liberates 4aaa and BrZnOEt after classic intramolecular nu-
cleophilic cyclization and elimination reaction.
dihydropyridin-2-one via the Blaise reactiona
Entry
Catalyst (mol%)
Solvent
THF
T (°C)b
Yield (%)c
1
—
80
80
0
Trace
52
40
23
14
81
63
52
81
35
0
2
ZnBr2 (30)
THF
3
FeCl3 (30)
THF
80
4
AlCl3 (30)
THF
80
5
Cu(OTf)2 (30)
In(OTf)2 (30)
BF3ÁOEt2 (30)
BF3ÁOEt2 (25)
BF3ÁOEt2 (20)
BF3ÁOEt2 (35)
BF3ÁOEt2 (30)
BF3ÁOEt2 (30)
BF3ÁOEt2 (30)
BF3 OEt2 (30)
THF
80
6
THF
80
7
THF
80
8
THF
80
9
THF
80
10
11
12
13
14
THF
80
THF
60
THF
r.t.
100
100
Conclusions
Toluened
1,4-Dioxaned
36
76
We have developed an efficient one-pot protocol for the synthesis
of 3,4-dihydropyridin-2-ones based on BF3-catalyzed tandem
Michael-type addition and cyclization between Blaise reaction in-
termediates and acrylic esters. Considering the ready availability
of the starting materials, the one-pot operation and the mild condi-
tions, the present protocol could be a useful method for the synthe-
sis of 3,4-dihydropyridin-2-ones. Further investigations of the
mechanism and synthetic applications of the reaction presented
here are in progress.
aGeneral conditions: benzonitrile (1.0 equiv.), ethyl bromoacetate (1.5
equiv.), zinc (2.0 equiv.), ethyl acrylate (2.0 equiv.), 8 h (after adding
ethyl acrylate).
bOil bath temperature.
cIsolated yields.
dAfter removing THF, toluene or 1,4-dioxane was added.
when the reaction is performed at room temperature, but the
β-keto ester is mostly obtained (Table 1, entry 12). The reaction pro-
ceeds sluggishly at 60°C and is not completed even after 24 h
(Table 1, entry 11). An examination of the importance of the sol-
vents in this reaction reveals that THF is better than toluene and
1,4-dioxane (Table 1, entries 13 and 14).
Experimental
General
All the tandem reactions were performed under an argon atmo-
sphere using oven-dried Schlenk flasks. The chemicals were pur-
chased from Alfa Aesar and Acros Chemicals. All solvents and
materials were pre-dried, redistilled or recrystallized before use.
1H NMR (400 MHz) and 13C NMR (101 MHz) spectra were recorded
using a Bruker Avance 400 spectrometer with CDCl3 as the sol-
vent. Chemical shifts were measured in ppm by assigning
With the optimized reaction conditions in hand, the scope and
limitation of this reaction were then explored. We were pleased to
find that intermediates A, formed from 2a and aryl nitriles having
various substituents on the aryl moiety, can react with 3a to afford
the corresponding 3,4-dihydropyridin-2-ones 4aaa–4kaa in mod-
erate to good yields (Table 2, entries 1, 4–13). In particular, the inter-
mediate A derived from 4-(trifluoromethyl)benzonitrile affords 3,4-
dihydropyridin-2-one 4kaa in a good yield of 83% (Table 2, entry
13). However, pyridine nitriles do not afford at all the corresponding
3,4-dihydropyridin-2-ones. Aliphatic nitriles can also be trans-
formed to the corresponding desired products in moderate yields
via the tandem reaction of the Blaise reaction intermediate with
3a (Table 2, entries 14–17). Methyl 2-bromoacetate (2b) and tert-
butyl 2-bromoacetate (2c) react smoothly to give the correspond-
ing 3,4-dihydropyridin-2-ones in good yields (Table 2, entries 18
and 19). Acrylic esters 3b and 3c give the desired product 4aaa in
80 and 55% yields, respectively (Table 2, entries 2 and 3). These re-
sults suggest that the tandem reaction is sensitive to the steric hin-
drance of the acrylic esters 3. In order to further expand the scope
of the substrates 3, ethyl cinnamate was added to the formed Blaise
reaction intermediate Aaa, but no desired product is obtained. To
increase the reactivity of the substrates 3, more electron-deficient
alkenes, arylidene malonates, were used. To our delight, various
arylidene malonates can react smoothly with intermediate Aaa in
the presence of boron trifluoride, affording the corresponding
products in moderate to good yields (Table 2, entries 20–26). R3
1
tetramethylsilane resonance in the H NMR spectra as 0.00 ppm
and CDCl3 resonance in the 13C NMR spectra as 77.0 ppm. All cou-
pling constants (J values) were measured in hertz. Column chro-
matography was performed on silica gel 200–300 mesh. Melting
points were measured using a WC-1 microscopic apparatus and
were uncorrected. Fourier transform infrared spectra were re-
corded using KBr pellets in the range 400–4000 cmÀ1 with a Nico-
let 5DX spectrometer. Mass spectra were obtained with an Agilent
LC-MSD-Trap-XCT instrument. Arylidene malonates 3d–3j were
prepared using published procedures.[24]
General procedure for synthesis of 3,4-Dihydropyridin-2-ones
To a stirred suspension of commercial zinc dust (10 mmol, 0.65 g) in
THF (2.0 ml) was added 1,2-dibromoethane (10 mol%) and the reac-
tion mixture was heated to 65°C until the solvent began to reflux.
Two minutes later it was cooled to room temperature and
trimethylchlorosilane (10 mol%) was added. After stirring for 15
min at room temperature, nitrile (5.0 mmol), THF (2 ml) and
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Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2016, 30, 47–50

Synthesis of 3, 4-dihydropyridin-2-ones via Blaise reaction
Table 2. One-pot synthesis of 3,4-dihydropyridin-2-ones from acrylic estersa
Entry
Nitrile 1
R = Ph (1a)
Bromoacetic ester 2
Acrylic ester 3
Product 4
4aaa
Yield (%)b
1
R1 = Et (2a)
R2 = Et, R3 = H, R4 = H (3a)
81
80
55
75
69
79
75
78
79
65
71
63
83
62
53
44
41
76
70
76
56
64
45
68
80
61
2
1a
2a
R2 = Me, R3 = H, R4 = H (3b)
3
1a
R = 3-MePh (1b)
R = 2-MePh (1c)
R = 4-ClPh (1d)
R = 2-ClPh (1e)
R = 3-FPh (1f)
R = 4-FPh (1g)
R = 2-FPh (1h)
Piperonylonitrile (1i)
Cinnamonitrile (1j)
R = 4-F3CPh (1k)
R = 4-ClPhCH2 (1l)
R = 2-ClPhCH2 (1m)
R = Et (1n)
R = Me (1o)
1a
2a
R2 = t-Bu, R3 = H, R4 = H (3c)
4
2a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
4baa
4caa
4daa
4eaa
4faa
4gaa
4haa
4iaa
5
2a
6
2a
7
2a
8
2a
9
2a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
2a
2a
2a
4jaa
2a
4kaa
4laa
2a
2a
4maa
4naa
4oaa
4aba
4aca
4aad
4aae
4aaf
4aag
4aah
4aai
2a
2a
R1 = Me (2b)
1a
R1 = t-Bu (2c)
1a
2a
2a
2a
2a
2a
2a
2a
R
2 = Et, R3 = Ph, R4 = CO2Et (3d)
1a
R2 = Et, R3 = 4-MeOPh, R4 = CO2Et (3e)
R2 = Et, R3 = 3-MeOPh, R4 = CO2Et (3f)
R2 = Et, R3 = 2-MeOPh, R4 = CO2Et (3g)
R2 = Et, R3 = 2-ClPh, R4 = CO2Et (3h)
R2 = Et, R3 = 4-ClPh, R4 = CO2Et (3i)
R2 = Et, R3 = 4-MePh, R4 = CO2Et (3j)
1a
1a
1a
1a
1a
4aaj
aGeneral conditions: nitrile (5.0 mmol), bromoacetic ester (7.5 mmol), zinc (10 mmol, 0.65 g), BF3ÁOEt2 (30 mol%), acrylic ester (10 mmol), 8 h (after adding
ethyl acrylate), 80°C (oil bath temperature).
bIsolated yields after flash column chromatography.
over by anhydrous MgSO4 and evaporated under vacuum. The de-
sired 3,4-dihydropyridin-2-ones were obtained after purification by
flash chromatography on silica gel with petroleum ether–ethyl ace-
tate as the eluent.
Acknowledgments
This research was supported by the National Natural Science Foun-
dation of China (U1204204, 21202095, 21172139), the Science and
Technology Key Project of Henan Province (142102210635) and the
Program for Science and Technology Innovation Talents in Univer-
sities of Henan Province (14HASTIT016). We thank Dr Z. Y. Li (SQNC)
for his help with X-ray single-crystal analysis.
Scheme 1. Proposed mechanism.
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Supporting Information
Additional supporting information may be found in the online
version of this article at the publisher’s web site.
wileyonlinelibrary.com/journal/aoc
Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2016, 30, 47–50