Cascade cyclization of glycine derivatives with β-ketoesters for polysubstituted 1,4-dihydropyridines by visible light photoredox catalysis

Article abstract of DOI:10.1016/j.tet.2020.131353

Visible light photocatalytic cascade cyclization reaction between glycine derivatives and β-ketoesters using Ir (ppy)₃ as a catalyst and dicumyl peroxide (DCP) as an oxidant was described. A series of N-aryl glycine esters proceeded the cyclization smoothly with β-ketoesters at room temperature, affording the desired 1,4-dihydropyridines (1,4-DHPs) in satisfactory yields. A possible mechanism for the cascade cyclization reaction by visible light photoredox catalysis was also proposed. This protocol not only provides an efficient and convenient approach to synthetize various 1,4-dihydropyridines, but also has potential utilities for the construction of bioactive molecules.

Full text of DOI:10.1016/j.tet.2020.131353

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Cascade cyclization of glycine derivatives with β-ketoesters for polysubstituted 1,4-
dihydropyridines by visible light photoredox catalysis
Xiao Zhu, Zhi-Qiang Zhu, Dong Guo, Shan Liu, Jiu-Jian Ji, Juan Tang, En Yuan,
Zong-Bo Xie, Zhang-Gao Le
PII:
S0040-4020(20)30508-1
https://doi.org/10.1016/j.tet.2020.131353
TET 131353
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 March 2020
Revised Date: 4 June 2020
Accepted Date: 22 June 2020
Please cite this article as: Zhu X, Zhu Z-Q, Guo D, Liu S, Ji J-J, Tang J, Yuan E, Xie Z-B, Le Z-G,
Cascade cyclization of glycine derivatives with β-ketoesters for polysubstituted 1,4-dihydropyridines by
visible light photoredox catalysis, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131353.
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Visible light photocatalytic cascade cyclization reaction
between glycine derivatives and β-ketoesters using Ir(ppy)3
Cascade cyclization of glycine derivatives
with β-ketoesters for polysubstituted 1,4-
dihydropyridines by visible light photoredox
catalysis
Xiao Zhu,b Zhi-Qiang Zhu,a,b,* Dong Guo,b Shan Liu,b Jiu-Jian Ji,b Juan Tang,c En Yuan,d Zong-Bo Xieb and
Zhang-Gao Leb,*
a Jiangxi Province Key Laboratory of Polymer Micro/Nano Manufacturing and Devices, Nanchang, 330013, P. R. China
b School of Chemistry, Biology and Material Science, East China University of Technology, Nanchang, 330013, P. R. China
c
Ministry of Education Key Laboratory of Functional Small Organic Molecule, Department of Chemistry and chemical engineering, Jiangxi Normal
University, Nanchang, 330022, P. R. China
d
College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, P. R. China

Tetrahedron
journal homepage: www.elsevier.com
Cascade cyclization of glycine derivatives with β-ketoesters for polysubstituted 1,4-
dihydropyridines by visible light photoredox catalysis
Xiao Zhu,b Zhi-Qiang Zhu,a,b, Dong Guo,b Shan Liu,a Jiu-Jian Ji,b Juan Tang,c En Yuan,d Zong-Bo Xieb
and Zhang-Gao Lea,b,
a Jiangxi Province Key Laboratory of Polymer Micro/Nano Manufacturing and Devices, Nanchang, 330013, P. R. China
b School of Chemistry, Biology and Material Science, East China University of Technology, Nanchang, 330013, P. R. China
c
Ministry of Education Key Laboratory of Functional Small Organic Molecule, Department of Chemistry and chemical engineering, Jiangxi Normal University,
Nanchang, 330022, P. R. China
d
College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, P. R. China
ABSTRACT
ARTICLE INFO
Visible light photocatalytic cascade cyclization reaction between glycine derivatives and β-
ketoesters using Ir(ppy)3 as a catalyst and dicumyl peroxide (DCP) as an oxidant was described.
A series of N-aryl glycine esters proceeded the cyclization smoothly with β-ketoesters at room
temperature, affording the desired 1,4-dihydropyridines (1,4-DHPs) in satisfactory yields. A
possible mechanism for the cascade cyclization reaction by visible light photoredox catalysis
was also proposed. This protocol not only provides an efficient and convenient approach to
synthetize various 1,4-dihydropyridines, but also has potential utilities for the construction of
bioactive molecules.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Glycine
β-Ketoesters
2009 Elsevier Ltd. All rights reserved
.
Cascade cyclization
1,4-Dihydropyridines
Photocatalysis
efficient methods for the preparation of potentially useful organic
molecules through C-H functionalization under mild conditions
is still highly desired.
1. Introduction
Oxidative C-H functionalization has emerged in recent years
as a powerful technique to construct complex molecules from
simple starting materials in organic synthesis [1]. Among them,
much attention has been attracted to the visible light photoredox-
mediated C-H functionalization from the chemists due to its
inherent characteristics of environmental benignity, sustainability
and ease to handle [2]. Glycine is the simplest and readily
available natural amino acids. Direct oxidative α-C-H
functionalization of glycine via visible light photoredox catalysis
provides a reliable and attractive strategy to afford structurally
diverse α-amino acid derivatives [3]. In 2015, Wu et al revealed a
cross-coupling hydrogen evolution reaction of glycine derivatives
with β-keto esters by the synergistic catalysis of Ru(bpy)3(PF6)2
and Co(dmgH)2pyCl under visible light irradiation [3a]. In 2016,
Xiao’s group reported a visible-light-initiated photocatalytic
crossing-coupling reaction of glycine derivatives with aryl
ketones and aldehyde to 1,2-amino alcohols [3b]. Although much
progress has been achieved, the development of simple and
As an important class of nitrogen-containing heterocycles, 1,4-
dihydropyridines (1,4-DHPs) are widely prevalent in a great
number of natural products, biologically active molecules and
pharmaceuticals [4-5]. In particularly, 1,4-DHPs possess a broad
range of biological properties such as anticonvulsant activity [6],
antitumor [7], antitubercular [8], anti-inflammatory [9], etc.
Several commercially available drugs like amlodipine,
nicardipine, felodipine, nifedipine and nimodipine contain 1,4-
DHP moiety in their core structure. Owing to these intriguing
characteristics and utilization, considerable research efforts have
been devoted to access various 1,4-dihydropyridine derivatives
by synthetic and medicinal chemists over the years [5]. Cascade
reaction, which can generate more chemical bonds in a one set of
fixed conditions and one-pot process during the reaction, has
been extensively applied to the construction of various bioactive
molecules, natural products and functional materials [10]. In
2014, Jia et al disclosed a radical cation salt-prompted C-H
oxidation/C-N bond cleavage to access a variety of 1,4-
Corresponding author. Tel/Fax: (+86) 0791-83896550; e-mail: zhuzq@ecut.edu.cn, zhgle@ecut.edu.cn.

2
Tetrahedron
Table 1 Optimization of the reaction conditionsa
Table 2 Cascade cyclization of glycine esters 1a-l with β-
ketoesters 2a-e by visible light photoredox catalysisa,b
entry
photocatalyst
Acr+-Mes-ClO4
oxidant
solvent
yield(%)b
-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19d
20e
air
air
air
air
air
air
K2S2O8
O2
TBHP
TBPB
DTBP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
40
51
60
Methylene blue
Ir(ppy)3
Ru(bpy3)Cl2•6H2O
Eosin Y
Rose Bengal
Ir(ppy)3
N.P.c
N.P.c
trace
27
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
--
47
trace
57
65
68
31
32
34
30
DCE
THF
DMSO
PhCl
xylene
toluene
toluene
47
67
trace
Ir(ppy)3
N.P.c
a Reaction conditions: 1a (0.2 mmol), 2a (0.44 mmol), catalyst (1 mol %),
oxidant (2 equiv.), solvent (2 mL) at room temperature under irradiation of 18
W blue LED light for 12 hrs.
b Isolated yield based on 1a.
c N.P. = No product.
d In the absence of a catalyst.
e The reaction was carried out in dark.
dihydropyridines with TMSCl as an additive [11a]. In 2016, our
group developed an aerobic oxidative coupling/ cyclization of
glycine derivatives with 1,3-dicarbonyl compounds to afford
various 1,4-dihydropyridines by copper catalysis [11b]. In view
of the biological importance of 1,4-dihydropyridines, and as our
ongoing efforts on C-H functionalization reactions [12], we
herein present a simple and efficient cascade cyclization reaction
of glycine esters with β-ketoesters to synthetize polysubstituted
1,4-dihydropyridines using visible light photoredox catalysis at
room temperature.
a Reaction conditions: 1 (0.2 mmol), 2 (0.44 mmol), Ir(ppy)3 (1 mol %), DCP
(2 equiv.), toluene (2 mL) at room temperature under irradiation of 18 W blue
LED light for 12 hrs.
b Isolated yield based on 1.
c For 36 hrs.
was obtained in xylene (entry 18, Table 1). In the absence of a
photocatalyst, only a trace amount of product 3aa was detected
(entry 19, Table 1). When the reaction was performed in dark, no
desired product 3aa was observed (entry 20, Table 1). The result
suggested that both visible light and photocatalyst were crucial to
this transformation. After exploring different parameters, we
defined the cascade cyclization reaction of N-4-
methylphenylglycine ethyl ester 1a and ethyl acetoacetate 2a in
the presence of 1 mol % of Ir(ppy)3, DCP (2 equiv.) in toluene (2
mL) at room temperature under irradiation of 18 W blue LED
light as the standard conditions.
With the preliminary optimized reaction conditions in hand, a
range of N-aryl glycine esters 1 and β-ketoesters 2a were
examined. As shown in Table 2, a large array of N-aryl glycine
esters 1a-k underwent the cascade cyclization readily with ethyl
acetoacetate 2a, affording the corresponding products 3aa-la in
satisfactory yields. For example, N-arylglycine ethyl ester 1a-g
bearing either electron-donating or electron-withdrawing groups
on the N-benzene rings performed the reaction well with ethyl
acetoacetate 2a, producing the corresponding products 3aa-ha in
41-68% yields. It was observed that the reactivity of the electron-
donating substituents was superior to that of the electron-
withdrawing substituents on the the para-position of the benzene
rings of N-arylglycine esters. Notably, the synthetically valuable
2. Results and discussion
Our investigation began with the model reaction of N-4-
methylphenylglycine ethyl ester 1a and ethyl acetoacetate 2a in
-
the presence of 1 mol % Acr+-Mes-ClO4 (9-Mesityl-10-
methylacridinium Perchlorate) in toluene under irradiation of 18
W blue LED light at room temperature. To our delight, the
desired cyclization product 3aa was isolated with a yield of 40%
(entry 1, Table 1). Encouraged by this result, a variety of
common photocatalysts such as Ir(ppy)3, methylene blue,
Ru(bpy3)Cl2•6H2O, eosin Y and rose bengal were explored to
improve the reaction efficiency (entries 2-6, Table 1). Screening
results revealed that Ir(ppy)3 showed the best catalytic efficiency,
resulting the desired product 3aa with a yield of 60%. Next, a
series of oxidants including K2S2O8, O2, tert-butyl hydroperoxide
(TBHP), tert-butyl peroxybenzoate (TBPB), di-tert-butyl
peroxide (DTBP) and dicumyl peroxyide (DCP) were tested, and
DCP was the best choice, leading to the product 3aa in 68% yield
(compare entries 3, 7-11 with 12, Table 1). Among various
solvents screened, toluene was the most effective reaction
medium than others such as DCE, THF, PhCl and DMSO
(compare entries 13-18 with 12, Table 1). A similar yield of 3aa

halogen groups, like fluoro and chloro were well tolerated with
the current conditions. Besides, N-arylglycine esters 1i-l
possessing a number of different ester groups, such as methyl,
isopropyl, tert-butyl and benzyl esters, were also compatible with
the standard conditions, providing the desired products 3ia-3la in
moderate to good yields. On the other hand, a diverse range of β-
ketoesters were investigated with N-arylglycine ester 1a or 1b
under the standard conditions. The experimental results revealed
that β-ketoesters 2b-e including methyl, isopropyl and isobutyl
acetoacetate proceeded the cascade cyclization reaction readily
with N-arylglycine ester 1a or 1b, affording the corresponding
products 3ab-3ad, 3bb-be in good yields. Unfortunately, when
acetylacetone was used instead of 2a with 1a under the standard
reaction conditions, only a trace amount of the desired product
was observed.
nucleophilic attack on the iminium ion B by an ethyl acetoacetate
2a affords intermediate C, which further reacts with another ethyl
acetoacetate 2a, and followed by dehydration to provide
intermediate D. Immediately, intermediate
D
via the
rearrangement, elimination to afford intermediate F [14b].
Ultimately, the following intramolecular Micheal addition and
loss of water in F generates the desired product 3aa.
3. Conclusions
In summary, we have achieved a simple and convenient
visible-light-induced photocatalytic cascade cyclization reaction
of glycine derivatives with β-ketoesters using dicumyl peroxide
(DCP) as an oxidant. A wide range of N-aryl glycine esters
proceed the cascade cyclization readily with various β-ketoesters
to
provide
the
corresponding
polysubstituted
1,4-
dihydropyridines in satisfactory yields. A possible mechanism for
the cascade cyclization by visible light photoredox catalysis is
also proposed. The synthetic protocol features good functional
group tolerance, mild conditions and simple operation, and has
potential to be used to synthetize natural products as well as
biologically active molecules.
4. Experimental section
4.1. General information
Scheme 1 Control experiments
Unless otherwise indicated, all reagents were purchased from
commercial distributors and used without further purification. 1H
NMR and 13C NMR were recorded at 400 MHz and 100 MHz,
respectively, using tetramethylsilane as an internal reference.
High-resolution mass spectra (HRMS) were measured on a
quadrupole time-of-flight (Q-TOF) mass spectrometer instrument
with an electrospray ionization (ESI) source. Melting points were
uncorrected. Flash column chromatography was performed over
silica gel 200-300 mesh. Thin-layer chromatography (TLC) was
carried out with silica gel GF254 plates. N-Aryl glycine esters 1
were prepared according to the previous reported protocols [11].
To elucidate the underlying reaction mechanism, we
examined the conversion of the oxidative coupling of 1a with
ethyl acetoacetate 2a under the standard conditions after 1 h. As
expected, coupling intermediate C was detected by the ESI mass
spectrometry analysis, albeit with a low isolated yield. Moreover,
when the reaction of intermediate C and 2a was dealt under
standard condition at room temperature, the desired product 3aa
was obtained in 87% yield (Scheme 1). On the basis of the
experimental results and reported literatures [11,13], a tentative
mechanism for the cascade cyclization reaction is proposed, as
depicted in Scheme 2. Firstly, upon irradiation with visible-light,
photocatalyst IrIII(ppy)3 can readily accept a photon to generate
the photoexcited state *IrIII(ppy)3, which acts as a strong
reductant to reduce DCP via single electron transfer (SET) to
form IrIV(ppy)3 [3b,13]. At the same time, DCP undergoes a
cleavage to afford an alkoxy radical and an alkoxy anion.
Subsequently, glycine ester 1a gives a single electron to
IrIV(ppy)3 to produce the radical cation A, and regenerates the
ground-state photocatalyst. Next, alkoxy radical abstracts a
hydrogen atom from A, giving rise to the iminium ion B. Then,
4.2. General procedure for the cascade cyclization of glycine
derivatives with β-ketoesters
To a solution of glycine derivatives
1 (0.2 mmol), β-keto
esters (0.44 mmol) in toluene (2 mL) was added Ir(ppy)3
2
(0.002 mmol, 1.31 mg) and DCP (0.4 mmol, 108.15 mg).
Then, the reaction mixture was stirred at room temperature
under irradiation of 18 W blue LED light. After the reaction
was completed, the resulting mixture was concentrated
under vacuum and the residue was subjected to column
chromatography (silica gel, petroleum ether/ethyl acetate as
an eluent) to afford the corresponding coupling products
3aa
.
4.2.1. Triethyl 1,4-dihydro-2,6-dimethyl-1-p-tolyl-pyridine-3,4,5-
tricarboxylate (3aa) [11b]
1
Yellow oil (56.5 mg
,
68%); H NMR (400 MHz, CDCl3): δ
7.20 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 7.9 Hz, 2H), 4.85 (s, 1H),
4.23-4.14 (m, 6H), 2.38 (s, 3H), 2.03 (s, 6H), 1.28 (t, J = 7.2 Hz,
6H), 1.25 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
173.9, 167.6, 149.0, 138.7, 137.5, 130.1, 130.0, 101.0, 60.6, 60.1,
40.1, 21.1, 18.2, 14.3, 14.2.
4.2.2. Triethyl 1,4-dihydro-1-(4-methoxyphenyl)-2,6-dimethyl-
pyridine-3,4,5-tricarboxylate (3ba) [14a]
Yellow solid (57.8 mg, 67%); mp 107.3-108.2 °C (lit. 108.2-
1
109.5°C); H NMR (400 MHz, CDCl3): δ 7.07 (d, J = 8.8 Hz,
2H), 6.90 (d, J = 8.8 Hz, 2H), 4.84 (s, 1H), 4.23-4.09 (m, 6H),
3.81 (s, 3H), 2.04 (s, 6H), 1.29 (t, J = 7.2 Hz, 6H), 1.24 (t, J = 7.2
Scheme 2 Possible mechanism

4
Tetrahedron
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 173.9, 167.5, 159.4,
4.2.10. 3,5-Diethyl 4-isopropyl 1,4-dihydro-2,6-dimethyl-1-p-
149.3, 132.7, 131.3, 114.4, 101.1, 60.6, 60.1, 55.5, 40.1, 18.2,
14.3, 14.2.
tolyl-pyridine-3,4,5-tricarboxylate (3ja) [11b]
Yellow oil (39.5 mg, 46%); H NMR (400 MHz, CDCl3): δ
1
7.20 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 5.00-4.93 (m,
1H), 4.80 (s, 1H), 4.26-4.12 (m, 4H), 2.38 (s, 3H), 2.03 (s, 6H),
1.32 (t, J = 7.0 Hz, 6H), 1.20 (d, J = 6.4 Hz, 6H); 13C NMR (100
MHz, CDCl3): δ 173.4, 167.6, 148.9, 138.6, 137.6, 130.1, 130.0,
101.1, 67.8, 60.1, 40.3, 21.8, 21.1, 18.2, 14.4.
4.2.3. Triethyl 1,4-dihydro-2,6-dimethyl-1-m-tolylpyridine-3,4,5-
tricarboxylate (3ca) [11b]
Yellow oil (44.8 mg, 54%); H NMR (400 MHz, CDCl3): δ
1
7.31-7.27 (m, 1H), 7.18 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 6.0 Hz,
2H), 4.85 (s, 1H), 4.25-4.10 (m, 6H), 2.35 (s, 3H), 2.03 (s, 6H),
1.28 (t, J = 7.0 Hz, 6H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 173.9, 167.6, 148.9, 140.1, 139.6, 130.9, 129.4,
129.0, 127.5, 101.0, 60.6, 60.1, 40.1, 21.2, 18.2, 14.3, 14.2.
4.2.11. 4-tert-Butyl 3,5-diethyl 1,4-dihydro-2,6-dimethyl-1-p-
tolyl-pyridine-3,4,5-tricarbxylate (3ka) [11b]
1
Yellow oil (38.1 mg, 43%); H NMR (400 MHz, CDCl3): δ
7.20 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 4.76 (s, 1H),
4.23-4.15 (m, 4H), 2.37 (s, 3H), 2.02 (s, 6H), 1.42 (s, 9H), 1.29
(t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 172.8, 167.7,
148.4, 138.6, 137.6, 130.1, 130.0, 101.5, 80.2, 60.0, 40.9, 28.0,
21.1, 18.1, 14.4.
4.2.4. Triethyl 1,4-dihydro-2,6-dimethyl-1-o-tolylpyridine-3,4,5-
tricarboxylate (3da)
Yellow oil (44.0 mg, 53%); H NMR (400 MHz, CDCl3) δ
1
7.31 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 6.2
Hz, 2H), 4.87 (s, 1H), 4.24-4.14 (m, 6H), 2.37 (s, 3H), 2.05 (s,
6H), 1.32-1.24 (m, 9H). 13C NMR (100 MHz, CDCl3): δ 173.7,
167.4, 148.9, 138.5, 137.3, 130.0, 129.8, 100.9, 60.5, 60.0, 40.0,
21.0, 18.1, 14.2, 14.1. HRMS (ESI) calcd for C23H30NO6 (M+H)+
416.2068, found 416.2064.
4.2.12. 4-Benzyl 3,5-diethyl 1,4-dihydro-2,6-dimethyl-1-p-tolyl-
pyridine- 3,4,5-tricarboxylate (3la) [11b]
Yellow solid (49.6 mg, 52%); mp 116-118 °C (lit. 116-
118 °C); 1H NMR (400 MHz, CDCl3): δ 7.34-7.30 (m, 5H), 7.15
(d, J = 8.0 Hz, 2H), 6.87 (d, J = 7.7 Hz, 2H), 5.13 (s, 2H), 4.97
(s, 1H), 4.18-4.13 (m, 4H), 2.37 (s, 3H), 2.03 (s, 6H), 1.23 (t, J =
7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 173.2, 166.3, 158.5,
148.0, 132.0, 130.5, 113.5, 66.5, 59.7, 54.6, 39.3, 21.2, 21.0,
17.3, 13.4.
4.2.5. Triethyl 1,4-dihydro-2,6-dimethyl-1-phenylpyridine-3,4,5-
tricarboxylate (3ea) [11b]
Yellow oil (44.9 mg, 56%); H NMR (400 MHz, CDCl3): δ
1
7.43-7.39 (m, 3H), 7.19 (dd, J = 7.8, 2 Hz, 2H), 4.87 (s, 1H),
4.28-4.11 (m, 6H), 2.04 (s, 6H), 1.32-1.23 (m, 9H).
13C NMR
(100 MHz, CDCl3): δ 173.9, 167.5, 148.8, 140.2, 130.5, 129.4,
128.7, 101.2, 60.7, 60.2, 40.1, 18.2, 14.3, 14.2.
4.2.13. Ethyl 3,5-diacetyl-1,4-dihydro-1-(4-methphenyl)-2,6-
dimethylpyridine-4-carboxylate (3ab) [14b]
Yellow oil (48.8 mg, 63%); 1H NMR (400 MHz, CDCl3): δ
7.19 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 4.83 (s, 1H),
4.10 (q, J = 7.1 Hz, 2H), 3.70 (d, J = 8.1 Hz, 6H), 2.35 (s, 3H),
2.02 (s, 6H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 173.6, 167.9, 149.4, 138.8, 137.4, 130.0, 129.7, 100.6,
60.7, 51.4, 39.9, 29.7, 21.1, 18.17, 14.2.
4.2.6. Triethyl 1-([1,1'-biphenyl]-4-yl)-2,6-dimethyl-1,4-dihydro-
pyridine-3,4,5-tricarboxylate (3fa) [11b]
Yellow solid (50.6 mg, 53%); mp 108.7-109 °C (lit. 108-
109°C); 1H NMR (400 MHz, CDCl3): δ 7.31 (d, J = 7.6 Hz, 2H),
7.11 (d, J = 7.6 Hz, 2H), 7.10 (t, J = 7.6 Hz, 2H), 6.91 (t, J = 7.0
Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 4.55 (s, 1H), 3.95-3.81 (m, 6H),
1.76 (s, 6H), 0.98 (t, J = 7.2 Hz, 6H), 0.91 (t, J = 7.0 Hz, 3H) 13C
NMR (100 MHz, CDCl3): δ 173.9, 167.5, 148.8, 141.6, 139.7,
139.3, 130.8, 129.0, 128.0, 127.9, 127.2, 101.4, 60.7, 60.2, 40.2,
18.3, 14.3, 14.2.
4.2.14. 4-Ethyl 3,5-diisopropyl 1,4-dihydro-1-(4-methphenyl)-
2,6-dimethylpyridine-3,4,5-tricarboxylate (3ac)
1
Yellow oil (64.7 mg, 73%); H NMR (400 MHz, CDCl3): δ
7.02 (d, J = 8.2 Hz, 2H), 6.83 (d, J = 7.6 Hz, 2H), 4.66 (dt, J =
12.4, 6.2 Hz, 2H), 4.45 (s, 1H), 3.75 (q, J = 7.1 Hz, 2H), 2.06 (s,
3H), 1.65 (s, 6H), 0.93 (m, 12H), 0.86 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 173.2 166.3, 147.8, 137.8, 136.8,
129.4, 129.1, 112.4, 66.5, 59.7, 39.5, 21.1, 20.3, 17.3, 13.5;
HRMS (ESI) calcd for C25H34NO6 (M+H)+ 444.2381, found
444.2377.
4.2.7. Triethyl 1-(4-chlorophenyl)-1,4-dihydro-2,6-dimethyl-
pyridine-3,4,5-tricarboxylate (3ga) [11b]
Yellow oil (40.0 mg, 43%); 1H NMR (400 MHz, CDCl3): δ
7.43 (d, J = 8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 4.83 (s, 1H),
4.25-4.09 (m, 6H), 2.05 (s, 6H), 1.32 (t, J = 7.0 Hz, 6H), 1.27 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 173.8, 167.4,
148.4, 138.8, 134.8, 131.8, 129.7, 101.8, 60.7, 60.3, 40.1, 18.2,
14.3, 14.3.
4.2.15. 4-Ethyl 3,5-diisobutyl 1,4-dihydro-1-(4-methphenyl)-2,6-
dimethylpyridine-3,4,5-tricarboxylate (3ad)
1
Yellow oil (57.4 mg, 61%); H NMR (400 MHz, CDCl3): δ
4.2.8. Triethyl 1-(4-fluorophenyl)-1,4-dihydro-2,6-dimethyl-
7.22 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.2 Hz, 2H), 4.95 (s, 1H),
4.12 (dt, J = 7.1, 5.9 Hz, 2H), 3.92 (p, J = 4.3 Hz, 3H), 2.38 (s,
1H), 2.06 (s, 3H), 2.00 (s, 6H), 1.95 (m, 2H), 1.23 (t, J = 7.1 Hz,
3H), 0.97 (d, J = 6.7 Hz, 12H); 13C NMR (100 MHz, CDCl3): δ
173.6, 167.2, 149.2, 138.5, 137.2, 129.8, 70.5, 60.9, 39.6, 27.6,
20.9, 19.0, 17.9, 14.0; HRMS (ESI) calcd for C27H38NO6 (M+H)+
472.2694, found 472.2696.
pyridine-3,4,5-tricarboxylate (3ha) [11b]
Yellow solid (34.4 mg, 41%); mp 119.0-120.4 °C; H NMR
1
(400 MHz, CDCl3): δ 6.91 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6
Hz, 2H), 4.55 (s, 1H), 3.95-3.81 (m, 6H), 1.74 (s, 6H), 1.01 (t, J
= 7.1 Hz, 6H), 0.93 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
DMSO): δ 173.8, 167.3, 162.3 (d, JC-F = 248.3 Hz), 148.6, 136.1,
132.2 (d, JC-F = 8.1 Hz), 116.3 (d, JC-F = 22.5 Hz), 101.7, 60.7,
60.2, 40.1, 18.1, 14.3, 14.2.
4.2.16. 4-Ethyl 3,5-dimethyl 1,4-dihydro-1-(4-methoxyphenyl)-
2,6-dimethylpyridine-3,4,5-tricarboxylate (3bb) [11b]
4.2.9. 3,5-Diethyl 4-methyl 1,4-dihydro-2,6-dimethyl-1-p-tolyl-
Yellow solid (45.2 mg, 56%); mp 101-103.2 °C (lit.101-
102 °C); 1H NMR (400 MHz, CDCl3): δ 7.05 (d, J = 8.8 Hz, 2H),
6.89 (d, J = 8.9 Hz, 2H), 4.83 (s, 1H), 4.11 (q, J = 7.1 Hz, 2H),
3.81 (s,3H), 3.72 (s, 3H), 3.75 (s, 3 H), 2.04 (s, 6H), 1.21 (t, J =
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 175.3, 169.6, 161.3,
151.4, 132.9, 116.1, 102.4, 62.4, 57.2, 53.1, 41.6, 19.8, 15.9.
pyridine-3,4,5-tricarboxylate (3ia) [11b]
1
Yellow oil (48.9 mg, 61%); H NMR (400 MHz, CDCl3): δ
7.19 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 4.84 (s, 1H),
4.24-4.14 (m, 6H), 2.36 (s, 3H), 2.02 (s, 6H), 1.26 (m, 9H); 13C
NMR (100 MHz, CDCl3): δ 174.4, 167.5, 149.1, 138.7, 137.4,
130.1, 130.0, 100.9, 60.1, 51.9, 39.9, 21.1, 18.2, 14.3.

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2,6-dimethylpyridine-3,4,5-tricarboxylate (3bc) [11b]
1
Yellow oil (57.9 mg, 63%); H NMR (400 MHz, CDCl3): δ
7.07 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 5.09-5.02 (m,
2H), 4.82 (s, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 2.02 (s,
6H), 1.27-1.23 (m, 15H); 13C NMR (100 MHz, CDCl3): δ 173.2,
166.3, 158.5, 148.0 , 132.0, 130.5, 113.5, 66.5, 59.7, 54.6, 39.3,
21.1 (d, J = 13.8 Hz), 17.3, 13.4.
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4.2.18. 3,5-Diisobutyl 4-ethyl 1,4-dihydro-1-(4-meth-oxyphenyl)-
2,6-dimethylpyridine-3,4,5-tricarboxylate (3bd)
1
Yellow oil (62.4 mg, 64%); H NMR (400 MHz, CDCl3): δ
7.26 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.94 (s, 1H),
4.23-4.11 (m, 2H), 4.26-3.81 (m, 4H), 3.72 (s, 3H), 2.06 (s, 6H),
1.98-1.95 (m, 2H), 1.27-1.23 (m, 3H), 1.23 (d, J = 6.7 Hz, 12H);
13C NMR (100 MHz, CDCl3): δ 172.9, 166.5, 158.5, 148.8,
131.8, 130.4, 113.5, 100.0, 69.5, 59.7, 54.5, 38.9, 26.9, 18.3,
17.0, 13.3; HRMS (ESI) calcd for C27H38NO7 (M+H)+ 488.2643,
found 488.2644.
4.2.19.
3,5-Di-tert-butyl
4-ethyl
1,4-dihydro-1-(4-meth-
oxyphenyl)-2,6-dimethylpyridine-3,4,5-tricarboxylate (3be) [11b]
1
Yellow oil (67.2 mg, 69%); H NMR (400 MHz, CDCl3): δ
7.08 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 4.78 (s, 1H),
4.16-4.11 (m, 2H), 3.87 (s, 3H), 2.0 (s, 6H), 1.50 (t, J = 7.1 Hz,
18H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
171.7, 164.5, 156.9, 145.9, 130.6, 129.0, 111.9, 100.0, 77.5, 58.1,
53.0, 38.4, 25.8, 15.6, 12.0.
4.2.20. Diethyl 2-acetyl-3-(p-tolylamino)succinate (C) [14a]
1
Yellow oil (15.4 mg, 24%); H NMR (400 MHz, CDCl3) δ
6.99 (d, J = 7.2 Hz, 2H), 6.63 (dd, J = 8.4, 3.6 Hz, 2H), 4.70-4.68
(m, 1H), 4.39 (brs, 1H), 4.52-4.09 (m, 5H), 2.32 (s, 1.5H), 2.27
(s, 1.5H), 2.23 (s, 3H), 1.32-1.18 (m, 6H); 13C NMR (100 MHz,
CDCl3): δ 201.2, 171.5, 171.4, 167.9, 167.8, 144.2, 143.9, 129.8,
129.7, 128.4, 114.4, 114.3, 61.8, 61.7, 61.6, 61.1, 60.8, 57.3, 56.7,
30.0, 29.8, 20.4, 14.0, 13.9; MS (ESI) m/z: [M+H]+ 322, [M+Na]+
344.
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Acknowledgments
We thank the National Natural Science Foundation of China
(11765002 and 21966003), the Natural Science Foundation of
Jiangxi Province (20181BAB203019), the Postdoctoral
Science Foundation of Jiangxi Province (2019KY41), the
Opening Project of Jiangxi Province Key Laboratory of Polymer
Micro/Nano Manufacturing and Devices, and the Innovation
Fund Designated for Graduate Students of Jiangxi Province
(YC2019-S274) for financial supports.
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Supplementary date
Supplementary date associated with this article can be found at
http://dx.doi.org/10.1016/j.tet.
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Highlights
• Visible light photocatalytic cascade cyclization reaction at room temperature.
• A wide range of N-aryl glycine esters proceed the cascade cyclization well with
various β-ketoesters to afford diverse polysubstituted 1,4-dihydropyridines.
• A possible mechanism for the cascade cyclization reaction by visible light
photoredox catalysis was also proposed on the basis of control experiments.
• The synthetic protocol features good functional group tolerance, mild conditions and
simple operation.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: