Copper-Catalyzed Aerobic Cascade Oxidative Coupling/Cyclization for the Construction of 1,4-Dihydropyridine Derivatives

Article abstract of DOI:10.1021/acs.joc.6b01736

An efficient copper-catalyzed cascade cyclization reaction for the preparation of polysubstituted 1,4-dihydropyridines between N-arylglycine esters and 1,3-dicarbonyl compounds using molecular oxygen as the terminal oxidant has been described. Various N-arylglycine esters 1 and 1,3-dicarbonyl compounds 2 were able to undergo the cascade reaction smoothly to afford the desired products 3 in satisfactory yields. The cascade reaction has the advantages of good functional group tolerance and mild reaction conditions. A possible mechanism has also been proposed on the basis of control experiments.

Full text of DOI:10.1021/acs.joc.6b01736

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Note
Copper-Catalyzed Aerobic Cascade Oxidative Coupling/
Cyclization for the Construction of 1,4-Dihydropyridine Derivatives
Zhi-Qiang Zhu, Zong-Bo Xie, and Zhang-Gao Le
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01736 • Publication Date (Web): 12 Sep 2016
Downloaded from http://pubs.acs.org on September 16, 2016
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Copper-Catalyzed Aerobic Cascade Oxidative Coupling/Cyclization for
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the Construction of 1,4-Dihydropyridine Derivatives
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ZhiꢀQiang Zhu,*,†,‡ ZongꢀBo Xie,†,‡ and ZhangꢀGao Le*,†,‡
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†Jiangxi 2011 Joint Center for the Innovative Mass Spectrometry and Instrumentation, East China University of Technology,
Nanchang 330013, P. R. China
‡School of Chemistry, Biology and Material Science, East China University of Technology, Nanchang 330013, P. R. China
ABSTRACT: An efficient copperꢀcatalyzed cascade cyclization reaction for the preparation of polysubstituted
1,4ꢀdihydropyridines between Nꢀaryl glycine esters and 1,3ꢀdicarbonyl compounds using molecular oxygen as the terminal oxidant
has been described. Various Nꢀaryl glycine esters 1 and 1,3ꢀdicarbonyl compounds 2 were able to undergo the cascade reaction
smoothly to afford desired products 3 in satisfactory yields. The cascade reaction has the advantages of good functional group
tolerance and mild reaction conditions. A possible mechanism has also been proposed based on control experiments.
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A cascade reaction can form two or more chemical bonds in a oneꢀpot
process without the need to isolate intermediates and change reaction
conditions during the reaction. This kind of reaction can decrease resource
consumption and environmental impact dramatically, and has been widely used
for the synthesis of natural products and pharmaceuticals etc.1 In recent years,
the direct oxidative crossꢀcoupling reactions between two CꢀH centers has
emerged as an attractive synthetic strategy for the construction of CꢀC bonds
because this type of reaction avoids prefunctionalization of both substrates
efficiently and is more environmentally friendly.2 Among them, there have
been remarkable and instructive advances on the direct coupling of αꢀC(sp3)ꢀH
bond of glycine derivatives with various nucleophiles.3ꢀ4 For example, in 2008,
Li and coworkers reported a novel copper saltꢀmediated direct oxidative
crossꢀcoupling reaction of αꢀamino acid derivatives with malonates.3a In 2010,
Huang et al. developed an efficient oxidative crossꢀcoupling reaction of
αꢀsubstituted glycine esters with ketones by the synergistic catalysis of copper
salt and pyrrolidine.3b In 2011, Wang’s group demonstrated an asymmetric
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oxidative crossꢀcoupling reaction between
Nꢀaryl αꢀamino acid esters and
αꢀsubstituted βꢀketoesters under the catalysis of a chiral copper complex.3c In
2013, Wu and coworkers revealed a dual catalytic oxidative crossꢀcoupling
reaction of
Nꢀaryl glycine derivatives with βꢀketoesters to give desired
αꢀalkylated products by the combination of photocatalysis and transition metal
catalysis.3d Despite an appealing synthetic strategy, the design and development
of novel cascade reactions involving direct oxidative C(sp3)ꢀH bond
transformations is still a challenge.
1,4ꢀdihydropyridines represents one of the most important heterocycles in
biologically active and naturally occurring molecules.5ꢀ6 Over the past few
years, much attention has been attracted on the
1,4ꢀdihydropyridines with biological activity.6 For example,
1,4ꢀdihydropyridines were prepared as Pꢀglycoproteinꢀmediated
Nꢀsubstituted
Nꢀacyloxy
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MDRꢀreversing agents,6a
Nꢀaryl substituted 1,4ꢀdihydropyridines were
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demonstrated to act as sirtuin activators and inhibitors,6b and
1ꢀphenylꢀ4ꢀglycosylꢀ1,4ꢀdihydropyridines were synthesized as potent
antileishmanial agents.6c Although a number of methods have been developed
for the preparation of 1,4ꢀdihydropyridines, most of them are mainly confined
to the Hantzsch synthesis as well as some modified approaches.7ꢀ8 Recently, Jia
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and
coworkers
reported
a
radical
cation
salt,
TBPA+•
[tris(4ꢀbromophenyl)aminium
hexachloroantimꢀonate]ꢀcatalyzed
cascade
reaction between glycine derivatives and βꢀketoesters for the construction of
1,4ꢀdihydropyridines under aerobic conditions.9 However, the precusor of the
real catalyst TBPA+• is rather expensive, and TMSCl was used as an additive to
accelerate the enolization of βꢀketoesters in the reaction system. Herein, we
wish to present a more economical, efficient, and greener approach to
polysubstituted 1,4ꢀdihydropyridines through the cascade reactions of
Nꢀaryl
glycine esters with 1,3ꢀdicarbonyl compounds by using cheap and nontoxic
copper salt as a sole catalyst, and molecular oxygen as an environmentally
benign oxidant.
Initially,
used as model substrates to explore and optimize the cascade reaction. When
FeCl2 (10 mol %) was used as catalyst, the reaction of
ꢀ4ꢀmethylphenylglycine ester 1a with ethyl acetoacetate 2a occurred under an
Nꢀ4ꢀmethylphenylglycine ester 1a and ethyl acetoacetate 2a were
a
N
oxygen atmosphere in CH3CN at 60 oC, giving the desired product 3aa in 31%
yield (entry 1, Table 1). Encourage by this result, other transitionꢀmetal salts
were probed as catalysts in the reaction. Among various transitionꢀmetal
catalysts, Cu(OTf)2 was proved to be the best for the yield of 3aa (compare
entries 1ꢀ9 with entry 10, Table 1; also see Supporting Information (SI)). No
reaction occurred in the absence of a transitionꢀmetal catalyst (entry 11, Table
1). Then, a series of oxidants were investigated in the reaction, it was found that
lower yields or no formation of 3aa were observed (compare entries 12ꢀ13 with
entry 10, Table 1; also see SI). For further screening of different solvents, the
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experiment demonstrated that toluene was the best to the yield of 3aa as
compared to CH3CN, THF, DCE, EtOH, DMF, and DMSO (compare entries 10,
14ꢀ18 with entry 19, Table 1). The effect of temperature on the reaction was
also tested. The experiment results indicated that lowering temperature to 40 oC
or raising temperature to 80 oC was not beneficial to the yield of 3aa (compare
entry 20 with entry 19, Table 1).
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Table 1. Optimization of the reaction conditionsa
entry
1
catalyst
FeCl2
oxidant
O2
solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
yield(%)
31
2
FeCl3
O2
53
3
InCl3
O2
22
4
Sc(OTf)3
Yb(OTf)3
Cu(OAc)2
CuSO4
O2
36
5
O2
52
6
O2
12
7
O2
38
8
CuCl2
O2
58
9
CuO
O2
57
10
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19
20c
Cu(OTf)2
ꢀꢀ
O2
61
O2
ꢀꢀ
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
DTBP
DCP
O2
42
55
23
O2
DCE
30
O2
EtOH
47
O2
DMF
46
O2
DMSO
Toluene
Toluene
43
O2
70
O2
63(67)d
a Reaction conditions: 1a (0.2 mmol), 2a (0.44 mmol), catalyst (10 mol %), solvent (1 mL) at 60 C under O2 (1
atm) or oxidant (2 equiv) for 12 h. b Isolated yield based on 1a. c At 80 oC. d At 40 oC for 36 h.
o
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After screening the reaction conditions, it can be concluded that the
optimized reaction should be performed in the presence of 10 mol % Cu(OTf)2
at 60 oC in toluene using molecular oxygen as an oxidant. Under the optimized
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conditions, a range of
it was found that various
cascade reaction smoothly with ethyl acetoacetate 2a to afford desired products
3aa ja in the yields of 46ꢀ72% (Table 2). The experimental results indicated
N
ꢀaryl glycine esters
1
were investigated in the reaction,
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Nꢀaryl glycine esters 1a
ꢀj
were able to undergo the
ꢀ
Table 2. Scope of the cascade reactiona,b
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that this cascade reaction is not very sensitive to the groups connected with
carbonyl groups, such as ethyl, methyl, isopropyl, tertꢀbutyl, and benzyl ester 1.
The electronꢀdonating groups on Nꢀbenzene rings of glycine esters 1aꢀc seem to be
more beneficial to the cascade reaction as compared to the electronꢀwithdrawing
groups on Nꢀbenzene rings of glycine esters. Then, various 1,3ꢀdicarbonyl
compounds 2 were examined in the cascade reaction with Nꢀaryl glycine esters 1b.
As shown in Table 2, a series of βꢀcarbonyl esters 2aꢀd were able to undergo the
cascade reaction smoothly to give the corresponding products 3baꢀ3bd in
satisfactory yields. The 1,3ꢀdiketone compound 2e was also suitable to this
transformation, which gave desired product 3be in good yield. The experimental
results also indicated that the steric hindrance of 1,3ꢀdicarbonyl compounds 2 had
significant impact on the reaction yields. When 1ꢀphenylbutaneꢀ1,3ꢀdione 2f,
which has a bulky phenyl group at αꢀposition was employed instead of ethyl
acetoacetate 2a, low yield of desired product 3bf was obtained. When
1,3ꢀdiphenylpropaneꢀ1,3ꢀdione was used instead of ethyl acetoacetate, no expected
product was observed.
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For further examining the generality of this protocol, three component cascade
cyclization reactions were probed for the synthesis of unsymmetrical
1,4ꢀdihydropyridines (Table 3). The experiment results demonstrated that a series
of Nꢀaryl glycine esters 1a-b,g were able to perform the cascade cyclization
reactions smoothly with acetoacetate esters 2a and acetylacetone 2e to afford
desired products 3aae, 3bae and 3gae in moderate yields under optimized
conditions. The experiment also demonstrated that a series of βꢀcarbonyl esters
2aꢀd were able to perform the cascade cyclization reactions smoothly with Nꢀaryl
glycine esters 1b and acetylacetone 2e to provide desired products 3baeꢀ3bde in
moderate yields. It seems that the cascade cyclization reaction is sensitive to steric
hindrance of the groups connected with carbonyl groups, such as ethyl, methyl,
isopropyl, and tertꢀbutyl esters 2.
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Table 3. Synthesis of unsymmetrical 1,4ꢀdihydropyridinesa,b
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To gain insight into this cascade cyclization reaction, we carried out several
control experiments on the mechanistic pathway (Scheme 1). Firstly, when a
radical inhibitor, 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol (BHT) was added to the
standard reaction conditions, the yield of the desired product 3aa decreased
dramatically from 70% to 25% [Eq. (1)]. This result suggests that free radical
intermediate might be involved in this cascade cyclization reaction. Secondly,
intermediate 4 was obtained in 47% yield from the oxidative crossꢀcoupling
reaction of 1a and 2a under room temperature after a relatively short reaction time
[Eq. (2)]. Moreover, we found that the isolated intermediate 4 was able to undergo
cyclization reaction with 2a successfully to provide desired product 3aa in good
yield [Eq. (3)]. The experiment results indicate that the oxidative crossꢀcoupling
product 4 is the key intermediate of this copperꢀcatalyzed cascade cyclization.
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Scheme 1. Control experiments
Based on the experiment results and previous literature,3ꢀ4,10 a plausible mechanism
for the cascade reaction is depicted in Scheme 2. Initially, iminium intermediate A
and copper (I) were generated form the oxidation of glycine ester 1 by two moleculars
of Cu(OTf)2.4d,f Immediately, copper (I) can be oxidized to copper (II) for catalytic
recycle by molecular oxygen.10 In the presence of Cu(OTf)2 as a Lewis acid, the
electrophilic addition of iminium intermediate A to the Lewis acidꢀbonded
nucleophile B gives intermediate 4.3cꢀd Subsequently, the second 1,3ꢀdicarbonyl
compound 2 reacts with intermediate 4 to provide intermediate C. Finally,
intermediate C undergoes condensation reaction with aryl amine and loss of water to
afford desired polysubstituted 1,4ꢀdihydropyridines 4.
1/2 O2
H2O
Cu
H
O
O
O
2CuOTf
2TfOH
ArHN
O
OR1
R2
2Cu(OTf)2
R2
O
O
B
ArHN
ArN
OR1
OR1
1
4
A
O
COR2
O
O
OR1
O
O
CO2R1
O
R2
R2
R2
N
ArNH2
- 2H2O
COR2
2
Ar
- ArNH2
O O
3
C
Scheme 2. Plausible mechanism.
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In conclusion, we have developed a novel and facile copperꢀcatalyzed cascade
reaction between Nꢀaryl glycine esters and 1,3ꢀdicarbonyl compounds for the efficient
synthesis of polysubstituted 1,4ꢀdihydropyridine derivatives by using molecular
oxygen as the terminal oxidant. Various Nꢀaryl glycine esters 1 and 1,3ꢀdicarbonyl
compounds 2 were able to perform the cascade reaction smoothly to give desired
products 3 in satisfactory yields. A possible mechanism has also been proposed based
on control experiments. This synthetic method has the advantages of good functional
group tolerance, simple operation and mild reaction conditions. The cascade
cyclization reaction may have potential to be used for the synthesis of natural
products and biologically active molecules.
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EXPERIMENTAL SECTION
General procedure for synthesis of 1,4-dihydropyridines 3aa-3bf. To a solution
of
Nꢀaryl glycine esters
1
(0.2 mmol) in toluene (1 mL) was added
1,3ꢀdicarbonyl compounds
2
(0.44 mmol) and Cu(OTf)2 (7.4 mg, 0.02 mmol).
o
The reaction mixture was stirred at 60 C under oxygen atmosphere for 12ꢀ18
hrs. After the reaction was finished, the resulting mixture was concentrated
under vacuum and the residue was subjected to column chromatography (silica
gel, 15:1 petroleum ether/ethyl acetate as an eluent) to afford the corresponding
products
3.
Triethyl
1,4-dihydro-2,6-dimethyl-1-p-tolylpyridine-3,4,5-tricarboxylate
(3aa):8f Yield 70% (58.1 mg); yellow oil; 1H NMR (400 MHz, CDCl3), δ (ppm): 7.21
(d, J = 8.0 Hz, 2H), 7.04 (dd, J = 6.8 Hz, J = 2.0 Hz, 2H), 4.87 (s, 1H), 4.27ꢀ4.11 (m,
6H), 2.39 (s, 3H), 2.05 (s, 6H), 1.30 (t, J = 7.0 Hz, 6H), 1.25 (t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3), δ (ppm): 173.9, 167.6, 149.0, 138. 7, 137.5, 130.1, 130.0,
101.0, 60.6, 60.1, 40.1, 21.2, 18.2, 14.3, 14.2; MS (EI) m/z 415 (M)+, 342(100), 314,
286, 91.
Triethyl 1,4-dihydro-1-(4-methoxyphenyl)-2,6-dimethylpyridine-3,4,5-tricarb-
o
oxylate (3ba): Yield 72% (62.1 mg); yellowish solid; mp 106ꢀ107 C (lit.8f
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108.2ꢀ109.5 oC); 1H NMR (400 MHz, CDCl3), δ (ppm): 7.09 (d, J = 9.2 Hz, 2H), 6.92
(d, J = 8.8 Hz, 2H), 4.87 (s, 1H), 4.27ꢀ4.11 (m, 6H), 3.84 (s, 3H), 2.06 (s, 6H), 1.30 (t,
J = 7.0 Hz, 6H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3), δ (ppm):
173.9, 167.5, 159.4, 149.3, 132.8, 131.3, 114.4, 101.1, 60.6, 60.1, 55.5, 40.1, 18.2,
14.3, 14.2; MS (EI) m/z 431 (M)+, 358(100), 330, 302, 77.
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Triethyl 1,4-dihydro-2,6-dimethyl-1-m-tolylpyridine-3,4,5-tricarboxylate (3ca):
Yield 58% (48.2 mg); yellow oil; 1H NMR (400 MHz, CDCl3), δ (ppm): 7.32ꢀ7.27 (m,
1H), 7.20 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 6.0 Hz, 2H), 4.87 (s,1H), 4.27ꢀ4.12 (m, 6H),
2.37 (s, 3H), 2.05 (s, 6H), 1.30 (t, J = 7.0 Hz, 6H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3), δ (ppm): 173.9, 167.6, 148.8, 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; HRMS (EIꢀTOF) m/z calcd for
C23H29NO6 415.1995, found 415.1982.
Triethyl
1,4-dihydro-2,6-dimethyl-1-phenylpyridine-3,4,5-tricarboxylate
1
(3da):8f Yield 55% (44.1 mg); yellow oil; H NMR (400 MHz, CDCl3), δ (ppm):
7.45ꢀ7.38 (m, 3H), 7.19 (d, J = 6.4 Hz, 2H), 4.88 (s, 1H), 4.27ꢀ4.12 (m, 6H), 4.14 (m,
13
2H), 2.05 (s, 6H), 1.30 (t, J = 7.0 Hz, 6H), 1.26 (t, J = 7.2 Hz, 3H); C NMR (100
MHz, CDCl3) ), δ (ppm): 173.8, 167.5, 148.8, 140.2, 130.5, 129.4, 128.7, 101.2, 60.6,
60.1, 40.1, 18.2, 14.3, 14.2; MS (EI) m/z 401 (M)+, 328(100), 300, 272, 77.
Triethyl 1-([1,1'-biphenyl]-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,4,5-tricar-
o
1
boxylate (3ea): Yield 52% (49.6 mg); light yellow solid; mp 108ꢀ109 C; H NMR
(400 MHz, CDCl3), δ (ppm): 7.45 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 7.6 Hz, 2H), 7.47 (t,
J = 7.6 Hz, 2H), 7.39 (t, J = 7.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 4.89 (s, 1H),
4.28ꢀ4.14 (m, 6H), 2.11 (s, 6H), 1.31 (t, J = 7.2 Hz, 6H), 1.27 (t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3), δ (ppm): 173.3, 167.0, 148.3, 141.2, 139.3, 138.9, 130.3,
128.4, 127.5, 127.4, 126.6, 100.9, 60.1, 59.6, 39.7, 17.8, 13.8, 13.7; HRMS (EIꢀTOF)
m/z calcd for C28H31NO6 477.2151, found 477.2149.
Triethyl 1-(4-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,4,5-tricarbox-
ylate (3fa):8f Yield 46% (40.0 mg); yellow oil; 1H NMR (400 MHz, CDCl3), δ (ppm):
7.41 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 4.85 (s, 1H), 4.27ꢀ4.11 (m, 6H),
13
2.04 (s, 3H), 1.30 (t, J = 7.0 Hz, 6H), 1.25 (t, J = 7.2 Hz, 3H); C NMR (100 MHz,
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CDCl3), δ (ppm): 173.8, 167.3, 148.3, 138.8, 134.7, 131.8, 129. 7, 101.8, 60.7, 60.2,
40.1, 18.20, 14.3, 14.2; MS (EI) m/z 435 (M)+, 362(100), 334, 306, 77.
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3,5-Diethyl 4-methyl 1,4-dihydro-2,6-dimethyl-1-p-tolylpyridine-3,4,5-tricarb-
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oxylate (3ga):8d Yield 71% (56.9 mg); yellow oil; H NMR (400 MHz, CDCl3), δ
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(ppm): 7.22 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 4.90 (s, 3H), 4.27ꢀ4.17 (m,
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4H), 3.69 (s, 3H), 2.39 (s, 3H), 2.05 (s, 6H), 1.29 (t, J = 7.2 Hz, 6H); C NMR (100
MHz, CDCl3), δ (ppm): 174.4, 167.5, 149.2, 138.7, 137.4, 130.1, 130.0, 100.9, 60.2,
52.0, 40.0, 21.2, 18.2, 14.3; HRMS (EIꢀTOF) m/z calcd for C22H27NO6 401.1838,
found 401.1833.
3,5-Diethyl 4-isopropyl 1,4-dihydro-2,6-dimethyl-1-p-tolylpyridine-3,4,5-tricar-
1
boxylate (3ha): Yield 62% (53.2 mg); yellow oil; H NMR (400 MHz, CDCl3), δ
(ppm): 7.22 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 5.02ꢀ4.95 (m, 1H), 4.82 (s,
1H), 4.28ꢀ4.14 (m, 4H), 2.39 (s, 3H), 2.04 (s, 6H), 1.30 (t, J = 7.0 Hz, 6H), 1.22 (d, J
= 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3), δ (ppm): 173.4, 167.6, 148.9, 138.6,
137.6, 130.1, 130.0, 101.1, 67.8, 60.0, 40.3, 21.8, 21.1, 18.2, 14.4; HRMS (EIꢀTOF)
m/z calcd for C24H31NO6 429.2151, found 429.2155.
4-tert-Butyl 3,5-diethyl 1,4-dihydro-2,6-dimethyl-1-p-tolylpyridine-3,4,5-trica-
1
rbxylate (3ia):8d Yield 60% (53.2 mg); yellow oil; H NMR (400 MHz, CDCl3), δ
(ppm): 7.21 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 4.77 (s, 1H), 4.25ꢀ4.17 (m,
13
4H), 2.39 (s, 3H), 2.04 (s, 6H), 1.43 (s, 9H), 1.31 (t, J = 7.0 Hz, 6H); C NMR (100
MHz, CDCl3), δ (ppm): 172.8, 167.7, 148.4, 138.6, 137.6, 130.1, 130.0, 101.5, 80.1,
60.0, 40.9, 28.0, 21.1, 18.1, 14.4; HRMS (EIꢀTOF) m/z calcd for C25H33NO6 443.2308,
found 443.2313.
4-Benzyl 3,5-diethyl 1,4-dihydro-2,6-dimethyl-1-p-tolylpyridine-3,4,5-tricarbo-
o
1
xylate (3ja): Yield 66% (63.0 mg); yellowish solid; mp 116ꢀ118 C; H NMR (400
MHz, CDCl3), δ (ppm): 7.33ꢀ7.27 (m, 5H), 7.15 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 7.6
Hz, 2H), 5.14 (s, 2H), 5.00 (s, 1H), 4.21ꢀ4.15 (m, 4H), 2.37 (s, 3H), 2.04 (s, 6H), 1.24
(t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3), δ (ppm): 173.4, 167.4, 149.3, 138.6,
137.3, 136.5, 130.1, 130.0, 128.3, 127.9, 127.8, 100.8, 80.1, 66.3, 60.2, 40.0, 21.1,
18.2, 14.3; HRMS (EIꢀTOF) m/z calcd for C28H31NO6 477.2151, found 477.2140.
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4-Ethyl 3,5-dimethyl 1,4-dihydro-1-(4-methoxyphenyl)-2,6-dimethylpyridine-
o
3,4,5-tricarboxylate (3bb): Yield 73% (58.9 mg); yellowish solid; mp 101ꢀ102 C
(lit.8f 101.6ꢀ103.1 oC); 1H NMR (400 MHz, CDCl3), δ (ppm): 7.08 (d, J = 8.8 Hz, 2H),
6.93 (d, J = 8.8 Hz, 2H), 4.87 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.76 (s,
3H), 3.75 (s, 3H), 2.07 (s, 6H), 1.25 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3),
δ (ppm): 173.6, 167.9, 159.5, 149.7, 132.6, 131.2, 114.5, 100.7, 60.7, 55.5, 51.4, 39.9,
18.2, 14.2; MS (EI) m/z 403 (M)+, 344, 330(100), 212, 77.
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4-Ethyl 3,5-diisopropyl 1,4-dihydro-1-(4-methoxyphenyl)-2,6-dimethylpyridine
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-3,4,5-tricarboxylate (3bc):8f Yield 59% (54.2 mg); yellow oil; H NMR (400 MHz,
CDCl3), δ (ppm): 7.09 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 5.11ꢀ5.05 (m, 2H),
4.85 (s,1H), 4.14 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 2.04 (s, 6H), 1.29ꢀ1.26 (m, 15H);
13C NMR (100 MHz, CDCl3), δ (ppm): 174.0, 167.1, 159.4, 148.9, 132.9, 131.4,
114.4, 101.5, 67.4, 60.6, 55.5, 40.2, 22.0, 21.9, 18.1, 14.3; MS (EI) m/z 459 (M)+,
386(100), 302, 212, 77.
3,5-Di-tert-butyl 4-ethyl 1,4-dihydro-1-(4-methoxyphenyl)-2,6-dimethylpyridi-
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ne-3,4,5-tricarboxylate (3bd):8f Yield 53% (51.5 mg); yellow oil; H NMR (400
MHz, CDCl3), δ (ppm): 7.08 (dd, J = 6.8 Hz, J = 2.0 Hz, 2H), 6.90 (dd, J = 6.8 Hz, J
= 2.0 Hz, 2H), 4.79 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 2.01 (s, 6H), 1.50
(s, 18H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3), δ (ppm): 174.2, 166.9,
159.3, 148.3, 133.0, 131.5, 114.3, 102.4, 79.9, 60.5, 55.5, 40.9, 28.2, 18.0, 14.4; MS
(EI) m/z 487 (M)+, 414(100), 358, 303, 212.
Ethyl 3,5-diacetyl-1,4-dihydro-1-(4-methoxyphenyl)-2,6-dimethylpyridine-4-
carboxylate (3be):8f Yield 65% (48.3 mg); yellow oil; 1H NMR (400 MHz, CDCl3), δ
(ppm): 7.08 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 4.74 (s,1H), 4.16 (q, J = 7.2
13
Hz, 2H), 3.85 (s, 3H), 2.42 (s, 6H), 2.03 (s, 6H), 1.26 (t, J = 7.2 Hz, 3H); C NMR
(100 MHz, CDCl3), δ (ppm): 197.9, 173.0, 159.6, 148.5, 132.3, 131.1, 114.6, 110.3,
61.1, 55.5, 41.0, 30.2, 18.9, 14.2; MS (EI) m/z 371 (M)+, 299(100), 240, 212, 77.
Ethyl 3,5-dibenzoyl-1-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-4-
carboxylate (3bf):8f Yield 23% (22.8 mg); yellow oil; 1H NMR (400 MHz, CDCl3), δ
(ppm): 7.81 (d, J = 6.8 Hz, 4H), 7.50ꢀ7.47 (m, 2H), 7.41 (t, J = 7.4 Hz, 4H), 7.17 (d, J
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= 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.65 (s, 1H), 4.06 (q, J = 7.2 Hz, 2H), 3.83 (s,
13
3H), 1.65 (s, 6H), 1.13 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3), δ (ppm):
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197.1, 172.7, 159.5, 145.4, 139.8, 132.5, 131.9, 131.2, 128.8, 128.5, 114.5, 109.3,
61.1, 55.5, 44.0, 19.7, 14.0; MS (EI) m/z 495 (M)+, 422(100), 362, 105, 77.
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General procedure for the synthesis of unsymmetrical 1,4-dihydropyridines 3.
To a solution of Nꢀaryl glycine esters 1 (0.2 mmol) in toluene (1 mL) was added
1,3ꢀdicarbonyl compounds 2 (0.22 mmol), acetylacetone 2e (22 mg, 0.22 mmol) and
o
Cu(OTf)2 (7.4 mg, 0.02 mmol). The reaction mixture was stirred at 60 C under
oxygen atmosphere for 12 hrs. After the reaction was finished, the resulting mixture
was concentrated under vacuum and the residue was subjected to column
chromatography (silica gel, 10:1 petroleum ether/ethyl acetate as an eluent) to afford
the corresponding products 3.
Diethyl 5-acetyl-1,4-dihydro-2,6-dimethyl-1-p-tolylpyridine-3,4-dicarboxylate
(3aae): Yield 52% (40.1 mg); yellow oil; 1H NMR (400 MHz, CDCl3), δ (ppm): 7.22
(d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 4.79 (s, 1H), 4.27ꢀ4.13 (m, 4H), 2.43 (s,
3H), 2.40 (s, 3H), 2.09 (s, 3H), 1.98 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H), 1.26 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3), δ (ppm): 198.9, 173.3, 167.3, 149.5, 147.9,
138.8, 137.3, 130.0, 129.9, 109.3, 101.0, 60.9, 60.2, 40.9, 29.8, 21.2, 18.7, 18.2, 14.4,
14.2; HRMS (EIꢀTOF) m/z calcd for C22H27NO5 385.1889, found 385.1896.
Diethyl 5-acetyl-1,4-dihydro-1-(4-methoxyphenyl)-2,6-dimethylpyridine-3,4-di-
carboxylate (3bae):8f Yield 54% (43.3 mg); yellow oil; 1H NMR (400 MHz, CDCl3),
δ (ppm): 7.07 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.79 (s, 1H), 4.24ꢀ4.12 (m,
4H), 3.84 (s, 3H), 2.42 (s, 3H), 2.09 (s, 3H), 1.99 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H),
1.26 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3), δ (ppm): 198.9, 173.3, 167.2,
159.5, 149.7, 148.1, 132.5, 131.2, 114.5, 109.4, 101.1, 60.9, 60.3, 55.5, 40.8, 29.8,
18.7, 18.2, 14.4, 14.2; MS (EI) m/z 401 (M)+, 328(100), 300, 212, 77.
Ethyl
4,5-diacetyl-1,4-dihydro-2,6-dimethyl-1-p-tolylpyridine-3-carboxylate
(3gae): Yield 53% (39.3 mg); yellow oil; 1H NMR (400 MHz, CDCl3), δ (ppm): 7.23
(d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 4.83 (s, 1H), 4.24ꢀ4.21 (m, 2H), 3.71 (s,
3H), 2.42 (s, 3H), 2.40 (s, 3H), 2.09 (s, 3H), 1.99 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H); 13C
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NMR (100 MHz, CDCl3), δ (ppm): 198.8, 173.8, 167.2, 149.6, 148.0, 138.9, 137.2,
130.0, 129.9, 109.2, 100.9, 60.3, 52.2, 40.7, 29.9, 21.6, 18.8, 18.2, 14.4; HRMS
(EIꢀTOF) m/z calcd for C21H25NO5 371.1733, found 371.1737.
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4-Ethyl 3-methyl 5-acetyl-1,4-dihydro-1-(4-methoxyphenyl)-2,6-dimethylpyri-
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dine-3,4-dicarboxylate (3bbe):8f Yield 55% (42.6 mg); yellow oil; H NMR (400
MHz, CDCl3), δ (ppm): 7.07 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.78 (s,
1H), 4.16 (qd, J = 7.6 Hz, J = 2.4 Hz, 2H), 3.84 (s, 3H), 3.76 (s, 3H), 2.43 (s, 3H),
2.10 (s, 3H), 1.99 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3), δ
(ppm): 198.9, 173.2, 167.7, 159.5, 150.2, 148.0, 132.5, 131.2, 114.5, 109.5, 100.6,
61.0, 55.5, 51.6, 40.8, 29.9, 21.6, 18.7, 18.2, 14.2; MS (EI) m/z 387 (M)+, 330,
314(100), 212, 77.
4-Ethyl 3-isopropyl 5-acetyl-1,4-dihydro-1-(4-methoxyphenyl)-2,6-dimethylpy-
1
ridine-3,4-dicarboxylate (3bce):9 Yield 47% (39.8 mg); yellow oil; H NMR (400
MHz, CDCl3), δ (ppm): 7.07 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.13ꢀ5.06
(m, 1H), 4.78 (s, 1H), 4.15 (qd, J = 6.8 Hz, J = 2.8 Hz, 2H), 3.84 (s, 3H), 2.42 (s, 3H),
2.08 (s, 3H), 1.99 (s, 3H), 1.30ꢀ1.24 (m, 9H); 13C NMR (100 MHz, CDCl3), δ (ppm):
198.9, 173.4, 166.8, 159.5, 149.3, 148.2, 132.6, 131.2, 114.5, 109.3, 101.6, 67.6, 60.9,
55.5, 40.9, 29.8, 22.0, 21.9, 18.7, 18.1, 14.3; MS (EI) m/z 415 (M)+, 342(100), 300,
212, 77.
3-tert-Butyl 4-ethyl 5-acetyl-1,4-dihydro-1-(4-methoxyphenyl)-2,6-dimethylpy-
1
ridine-3,4-dicarboxylate (3bde):9 Yield 45% (38.6 mg); yellow oil; H NMR (400
MHz, CDCl3), δ (ppm): 7.07 (dd, J = 6.8 Hz, J = 2.0 Hz, 2H), 6.92 (dd, J = 6.8 Hz, J
= 2.0 Hz, 2H), 4.74 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 2.41 (s, 3H), 2.05
(s, 3H), 1.99 (s, 3H), 1.51 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3), δ (ppm): 198.8, 173.4, 166.6, 159.4, 148.5, 148.4, 132.6, 131.3, 114.4, 109.1,
102.9, 80.4, 60.8, 55.5, 41.2, 29.8, 28.3, 18.7, 18.1, 14.3; MS (EI) m/z 429 (M)+, 356,
300(100), 212, 77.
Diethyl 2-acetyl-3-(p-tolylamino)succinate (4): Light yellow oil, dr = 1:1.
Mixture of two diastereomers: 1H NMR (400 MHz, CDCl3), δ (ppm): 6.99 (d, J = 6.8
Hz, 2H), 6.64ꢀ6.61 (m, 2H), 4.71ꢀ4.67 (m, 1H), 4.40ꢀ4.37 (m, 1H), 4.27ꢀ4.13 (m, 4H),
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4.11 (d, J = 5.6 Hz, 0.5H), 4.07 (d, J = 6.0 Hz, 0.5H), 2.32 (s, 1.5H), 2.27 (s, 1.5H),
2.23 (s, 3H), 1.30ꢀ1.18 (m, 6H); 13C NMR (100 MHz, CDCl3), δ (ppm): 202.2, 201.3,
171.5, 171.4, 168.0, 167.9, 144.2, 143.9, 129.8, 129.8, 128.4, 114.4, 114.2, 61.9, 61.9,
61.8, 61.7, 61.0, 60.8, 57.3, 56.7, 30.0, 29.9, 20.4, 14.0, 14.0; MS (EI) m/z 321 (M)+,
206, 192, 160(100), 91.
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: zhuzq@ecit.cn; zhgle@ecit.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial supports from the National Natural Science Foundation of China (21602027, 21262002 and 21465002)
and the Program for Changjiang Scholars and Innovative Research Team in University (IRT13054) are gratefully
acknowledged.
ASSOCIATED CONTENT
Supporting Information. Optimization of reaction conditions and spectra of H NMR, 13C NMR and HRMS for
1
products. This material is available free of charge via the internet at http://pubs.acs.org.).
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