A revisit to the Hantzsch reaction: Unexpected products beyond 1,4-dihydropyridines

Article abstract of DOI:10.1039/b906358g

A novel green and efficient one-pot three-component synthesis of 2-aryl-pyridines in good to excellent yields has been reported. The methodology initially involved the formation of 1,2-dihydropyridine intermediates via reaction of a variety of aromatic al

Full text of DOI:10.1039/b906358g

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www.rsc.org/greenchem | Green Chemistry
A revisit to the Hantzsch reaction: Unexpected products beyond
1,4-dihydropyridines†
Li Shen, Song Cao,* Jingjing Wu, Jian Zhang, Hui Li, Nianjin Liu and Xuhong Qian*
Received 1st April 2009, Accepted 12th June 2009
First published as an Advance Article on the web 8th July 2009
DOI: 10.1039/b906358g
A novel green and efficient one-pot three-component synthesis of 2-aryl-pyridines in good to
excellent yields has been reported. The methodology initially involved the formation of
1,2-dihydropyridine intermediates via reaction of a variety of aromatic aldehydes with ethyl
(methyl) acetoacetate and ammonium acetate, which were the same starting materials as the
Hantzsch reaction, under solvent-, catalyst- and heat-free (at room temperature) conditions,
followed by air oxidation for 72 hours. In this paper, we also systematically reinvestigated the
classic Hantzsch reaction under different reaction conditions, analyzed the main products as well
as byproducts, corrected some mistakes in the literature and elucidated the reaction mechanism.
Our group has devoted much effort over the years to multi-
Introduction
component reactions under solvent-free conditions.10 Although
care needs to be taken as the solvent is often the heat sink that ab-
sorbs the heat from exothermic reactions, for reactions without
a strong exotherm, solvent-free conditions offer environmental
advantages and will be safe and efficient. Recently, we have
surprisingly found that the unsymmetric 2-arylpyridine 3 could
be obtained as a major product by the one-pot multicomponent
reaction of benzaldehyde, ethyl acetoacetate and ammonium
acetate under solvent-free, heat-free, catalyst-free and oxidant-
free conditions, whereas only trace amounts of classic Hantsch
products were detected (Scheme 1).
There is always something new on the old topic of the Hantzsch
reaction since Arthur Hantzsch first reported it in 1882.1 This is
mainly due to the fact that it offers an efficient way to prepare
the 1,4-dihydropyridines (1,4-DHPs) which exhibit significant
biological activities in the treatment of cardiovascular disease
as calcium channel blockers. More than twelve commercial,
clinically important drugs such as Amlodipine, Nifedipin,
Nimodipin, Felodipine, Isradipine, and Nicardipine containing
the 1,4-dihydropyridine parent nucleus have been manufactured
and used worldwide.2 Up till now, numerous literature citations
exist relating to various attempts to improve the Hantzsch
reaction using alternative catalysts and greener methods.3
Almost all of the new methodologies of organic synthesis, for
instance, microwave-assisted synthesis,4 the promotion of solar
thermal energy5 and ultrasound irradiation,6 the replacement
of the organic solvents by ionic liquids or water7 and the use
of a variety of metal halides or triflates as Lewis catalysts8
have been employed for the synthesis of 1,4-DHPs. However,
most of the research has been focused on the modification and
optimization of the Hantzsch reaction to maximize reaction
conversion, minimize reaction time and offer high purity
1,4-DHPs. At the same time, the oxidative aromatization of
1,4-DHPs to corresponding pyridines has also been extensively
studied. A plethora of oxidants including air, catalyzed by RuCl3
or Pd/C have been applied in the aromatization reactions.9 All
of these studies seem to indicate that the reaction conditions,
products and mechanism of the Hantzsch reaction have been
well understood.
Scheme 1 Synthesis of 2-arylpyridine 3a–n under mild reaction
conditions.
2-Arylpyridines have received significant attention in the fields
of biologically active molecules and supramolecular coordina-
tion chemistry.11 One of the most commonly used methods
for the synthesis of 2-arylpyridines is based on the metal-
catalyzed cross-coupling reactions of aryl- or pyridylhalide.
However, one has to introduce functional groups after the cross-
coupling because of the low compatibility of the organometallic
intermediates with many substituents.12 Thus, there is still a need
for a straightforward and “green” approach to 2-arylpyridines.
In this paper, we would like to report a new efficient and green
method to synthesize 2-arylpyridine derivatives.
Shanghai Key Laboratory of Chemical Biology, Center of Fluorine
Chemical Technology, School of Pharmacy, East China University of
Science and Technology, Shanghai, China. E-mail: scao@ecust.edu.cn,
xhqian@ecust.edu.cn; Fax: +86 (21)64252603
† Electronic supplementary information (ESI) available: Spectra of the
pyridine derivatives. See DOI: 10.1039/b906358g
Due to some contradictory results and the wrong interpreta-
tion of the product structure published over the years and even
recently,13–15 it is timely for chemists to present a comprehensive
research study on the Hantzsch reaction. This motivates us to
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Scheme 2 Model reaction for the synthesis of 2-arylpyridines.
Table 2 Effects of the solvents on the reaction under catalyst-free
experimentally reexamine the title reaction thoroughly in the
second section of this paper.
conditions in an air atmosphere at 20 ◦
C
Entry
Solvent
Ratioa
Yieldb
Results and discussion
1
2
3
4
5
6
7
8
CH3OH
THF
EtOH
CH2Cl2
CH3CN
DMSO
AcOH
None
4a:5a = 57:43
4a:5a = 60:40
4a:5a = 62:38
4a:5a = 59:41
4a:5a = 69:31
4a:5a = 26:74
3a:5a = 90:10
3a:5a = 94:6
40.2
55.5
55.7
37.2
35.7
43.2
70.7
93.5
As part of our drug discovery efforts, we recently were required
to prepare a number of 1,4-DHPs. According to the literature
procedure,15 the reaction of benzaldehyde, ethyl acetoacetate and
◦
ammonium acetate was performed at 80 C under solvent-free
conditions. However, in contrast to the results of the previous
report, the reaction did not afford the desired 1,4-DHP product
in highyield (5a, 1.5 h, 93%), instead, 1,2-DHP (4a)was obtained
as the main product with a small amount of other isomers
(1H NMR analysis indicated a mixture of two isomers in a 3:1
ratio).16 Much to our surprise, the aromatic oxidative product,
unsymmetric 2-arylpyridine 3a, was obtained by prolonging
the reaction time to 12 h (Scheme 2). Encouraged by this
result, benzaldehyde, ethyl acetoacetate and ammonium acetate
(1:2.4:1.2) were selected as representative reactants for further
optimization of the reaction conditions.
For our initial studies, the effects of the temperature on
the reaction were examined under solvent-free, catalyst-free
conditions in an air atmosphere with different reaction times.
The ratio of two products (3a and 5a) was strongly dependent
on the temperature. A mixture of 3a and 5a was formed in the
ratio of 42:58 at 120 ◦C, whereas at 20 ◦C the final ratio of the
two products was 94:6, which indicated that the formation of
the desired product, 2-arylpyridine 3a, was highly favored by
a decrease in reaction temperature. The results are shown in
Table 1.
a Yields and ratios were based on GC analysis. b Yields in Entry 1–6
referred to 4a and in Entry 7–8 referred to 3a.
Table 3 Effect of catalyst on the product selectivity under solvent-free
conditions in an air atmosphere at 20 ◦
C
Entry
Catalysta
Ratiob
Time (h)
Yieldc
1
2
3
4
None
3a:5a = 94:6
3a:5a = 89:11
3a:5a = 90:10
3a:5a = 94:6
72
72
72
72
93.5
88.3
87.2
78.6
Piperidine
Yb(PFO)3
InCl3·4H2O
a 10 mol% of catalysts were used. b Yields and ratios were based on GC
analysis. c Yields referred to the desired product 3a.
products were observed even after prolonged reaction time.
Finally, to our delight, the best results (3a as the only major
product) were obtained when the reaction was conducted in the
absence of solvent at 20 ◦C.
Usually, catalyst plays an important role in the synthesis
of 1,4-DHPs.17 Accordingly, piperidine, Yb(PFO)3 (ytterbium
perfluorooctanoate) and InCl3·4H2O were selected to investigate
the effect of catalysts on ratio of products under solvent-free
conditions at 20 ◦C (Table 3). However, the results indicated little
influence of catalyst on ratio of product. The classical Hantzsch
product 1,4-DHP 5a was produced as a minor product.
After the preliminary investigations, our efforts were directed
towards the evaluation of the solvent in the synthesis of
2-arylpyridine using the same substrates after stirring for 72 h
in an air atmosphere under optimized temperature conditions
(Table 2). Only acetic acid afforded a good yield (70.7%) of the
expected product 3a, whereas a mixture of 1,4- and 1,2-DHPs
was obtained in other solvents (Entry 1–6) and no oxidative
Under these optimized reaction conditions, the generality
and scope of this new one-pot three-component protocol was
then explored. A range of structurally diverse aldehydes, ethyl
(methyl) acetoacetate and ammonium acetate were subjected
under solvent-free, catalyst-free conditions in an air atmo-
sphere at 20 ◦C to produce the corresponding 2-arylpyridine
derivatives (Table 4). Substituted benzaldehydes afforded high
to excellent yield of 2-arylpyridine derivatives irrespective of
electronic effects. Pyridine aldehydes also worked well with
this protocol (Compounds 3g and 3j). However, when furan
aldehyde, thiophene aldehyde and aliphatic aldehydes were used
as substrates, the main products obtained by this new method
were the classical 1,4-DHPs, few desired products were observed.
Table 1 Effect of the reaction temperature on the ratio of the products
under solvent-free, catalyst-free conditions in an air atmosphere
Entry
Temperature (◦C)
Time (h)a
Ratiob
Yieldc
1
2
3
4
5
120
80
65
50
20
7
12
14
24
72
3a:5a = 42:58
3a:5a = 69:31
3a:5a = 72:28
3a:5a = 77:23
3a:5a = 94:6
40.5
67.4
70.2
76.6
93.5
a The reaction time was monitored by TLC and similar results were
obtained by prolonging the reaction time. b Yields and ratios were based
on GC analysis. c Yields referred to the desired product 3a.
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Table 4 Synthesis of 2-arylpyridines 3a–n under solvent-free, catalyst-
free conditions in an air atmosphere at 20 ◦
Conclusions
C
In summary, we have developed a novel, efficient and envi-
ronmentally friendly one-pot three-component method for the
synthesis of the 2-arylpyridines in air at room temperature.
The methodology does not require the use of any organic
solvent, catalyst and additional oxidant, thus eminently meeting
green chemistry objectives. To minimize misunderstandings and
confusions with earlier publications, this paper also introduced
the details of experimental research of the classical and improved
Hantzsch reaction. Our aim is to provide an intuitional picture
for describing this chemical reaction. These studies will be
important for the understanding of the process. However, these
efforts do not mean that everything is known, and there is still a
lot to learn about this fascinating and useful reaction.
Comp.
R1
R2
Yielda
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
C6H5
C2H5
C2H5
C2H5
CH3
C2H5
CH3
C2H5
CH3
CH3
CH3
C2H5
CH3
C2H5
CH3
93.5
75.4
82.5
90.2
79.3
80.8
69.0
87.1
68.2
81.8
82.5
84.1
82.3
85.9
4-NO2C6H4
4-CH3C6H4
C6H5
4-BrC6H4
4-CNC6H4
3-Pyridinyl
4-OCF3C6H4
4-OCH3C6H4
3-(6-ClPyridinyl)
3-BrC6H4
4-CH3C6H4
4-FC6H4
4-ClC6H4
a Yields were based on GC analysis.
Experimental
Materials and methods
After the successful synthesis of a series of 2-arylpyridines
under these new reaction conditions, we next turned our atten-
tion to present comprehensive results from the experimental
research on the reactivity and selectivity of the Hantzsch
reaction. In order to verify the results of the literature, some
important reported procedures were repeated and several pa-
rameters, including solvent, catalyst (piperidine), temperature
and reaction time were reexamined. The detailed results are
summarized in Scheme 3. Generally speaking, low temperature
and solventless reaction conditions were favorable for forming
1,2-DHP (C). Once the intermediate 1,2-DHP was formed, the
oxidation product 2-arylpyridine was generated easily in situ
by air oxidation after stirring for a prolonged period (72 h) at
20 ◦C in high yield. The reaction was also performed under
an argon atmosphere and gave mixtures of 1,4-DHP (A) and
1,2-DHP(C) (32:68), no 2-arylpyridine was detected. This result
further verified that the air played a key role in the oxidation of
1,2-DHPs. The acetic acid was a unique solvent for this reaction.
At 20 ◦C, the 1,2-DHP and its oxide (D) were favored, whereas in
the refluxing HOAc, a higher percentage of Hantzsch 1,4-DHP
was observed, and unexpectedly a small amount of the oxidative
product of 1,4-DHP (B) was also detected.
All chemicals were purchased commercially and used without
further purification. Melting points were measured in an open
capillary using Bu¨chi melting point B540 apparatus and were
1
uncorrected. H NMR and 13C NMR spectra were recorded
on a Bruker AM-400 spectrometer (400 MHz and 100 MHz,
respectively) using TMS as internal standard. Gas chromatog-
raphy (GC) was recorded on a HP 6890 Plus GC instrument
and high-resolution mass spectra (HRMS) were recorded under
electron impact conditions using a MicroMass GCT CA 055
instrument.
General procedure for the synthesis of substituted pyridines
A 10 mL round-bottomed flask was charged with aldehyde
(1 mmol), 1,3-dicarbonyl compound (2.4 mmol) and◦ammonium
acetate (1.2 mmol). The mixture was stirred at 20 C until the
reaction was completed (monitored by TLC). The reaction mix-
ture was treated with brine solution, extracted with ethyl acetate
and dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure to leave the crude product which was
purified by chromatography over silica gel.
In order to explain the formation of the different products,
1,4-DHPs and 2-arylpyridines (3), a mechanism is suggested in
Scheme 4. The so-callled “twin-reactions” use almost similar
types of two-step mechanisms. The initial step is the same in
two reaction conditions. At this stage, the reaction involves a
Knoevenagel condensation of the 1,3-dicarbonyl compound
with the aldehyde to give an a,b-unsaturated carbonyl com-
pound 7 and a condensation of ammonia with another equiva-
lent of the 1,3-dicarbonyl compound to afford an enamine 6.18
The rate determining step is the Michael addition of the enamine
to the a,b-unsaturated carbonyl compound. However, unlike
the previously known mechanism of the Hantzsch reaction, the
enamine intermediate prefers to attack on the carbon atom of
Spectroscopic data for compounds 3a–n
Diethyl 2-phenyl-4,6-dimethylpyridine-3,5-dicarboxylate (3a).
Yield 82% (isolated yield and the same below); colorless oil; dH
(400 MHz, CDCl3): 7.59–7.57 (2H, m, PhH), 7.45–7.42 (3H, m,
PhH), 4.48 (2H, q, J = 7.2 Hz, 3-CO2CH2CH3), 4.12 (2H, q,
J = 7.2 Hz, 5-CO2CH2CH3), 2.64 (3H, s, 6-CH3), 2.38 (3H, s, 4-
CH3), 1.44 (3H, t, J = 7.2 Hz, 3-CO2CH2CH3), 1.00 (3H, t, J =
7.2 Hz, 5-CO2CH2CH3); dC (100 MHz, CDCl3): 168.2 (C=O),
168.1 (C=O), 156.3 (C-6), 155.1 (C-2), 142.7 (C-4), 139.6 (Ph-
C), 128.7 (Ph-C), 128.4 (Ph-C), 128.2 (Ph-C), 128.1 (C-3), 127.2
(C-5), 61.5 (–OCH2CH3), 61.4 (–OCH2CH3), 23.0 (6-CH3), 16.7
(4-CH3), 14.1 (–OCH2CH3), 13.5 (–OCH2CH3); HRMS: calc.
for C19H21NO4 (M+): 327.1471, found: 327.1472.
=
the C O double bond (carbon b of 7) instead of the carbon
=
atom of the C C double bond (carbon a of 7). Subsequently,
the intermediate 9 undergoes an intramolecular addition of the
amino to the carbon–carbon double bond to afford the 1,2-
dihydropyridine 4, which can be further oxidized to the desired
pyridines 3 in air.
Diethyl 2-(4-nitrophenyl)-4,6-dimethylpyridine-3,5-dicarboxy-
late (3b). Yield 60%; colorless crystal; mp: 47.1–48.5 ◦C; dH
(400 MHz, CDCl3): 8.27–8.23 (2H, m, PhH), 7.75–7.72 (2H, m,
PhH), 4.45 (2H, q, J = 7.2 Hz, 3-CO2CH2CH3), 4.13 (2H, q,
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Scheme 3 A survey of the reaction of benzaldehyde with ethyl acetoacetate and ammonium acetate under different reaction conditions.
J = 7.2 Hz, 5-CO2CH2CH3), 2.59 (3H, s, 6-CH3), 2.36 (3H, s,
4-CH3), 1.40 (3H, t, J = 7.2 Hz, 3-CO2CH2CH3), 1.03 (3H,
t, J = 7.2 Hz, 5-CO2CH2CH3); dC (100 MHz, CDCl3): 167.8
(C=O), 167.7 (C=O), 155.7 (C-6), 153.8 (C-2), 148.0 (C-4),
145.8 (C-NO2), 143.4 (Ph-C), 129.6 (Ph-C), 129.4 (C-3), 127.5
(C-5), 123.5 (Ph-C), 61.9 (–OCH2CH3), 61.8 (–OCH2CH3), 23.0
(6-CH3), 16.9 (4-CH3), 14.1 (–OCH2CH3), 13.7 (–OCH2CH3);
HRMS: calc. for C19H20N2O6 (M+): 372.1321, found: 372.1308.
(3H, s, 6-CH3), 2.39 (3H, s, CH3Ph), 2.36 (3H, s, 4-CH3), 1.43
(3H, t, J = 7.2 Hz, 3-CO2CH2CH3), 1.06 (3H, t, J = 7.2 Hz,
5-CO2CH2CH3); dC (100 MHz, CDCl3): 168.6 (C=O), 168.4
(C=O), 156.4 (C-6), 155.2 (C-2), 142.7 (C-4), 138.8 (Ph-C),
136.8 (Ph-C), 129.0 (Ph-C), 128.2 (Ph-C), 128.1 (C-3), 127.1
(C-5), 61.7 (–OCH2CH3), 61.5 (–OCH2CH3), 23.1 (6-CH3), 21.3
(Ph-CH3), 16.9 (4-CH3), 14.1 (–OCH2CH3), 13.7 (–OCH2CH3);
HRMS: calc. for C20H23NO4 (M+): 341.1627, found: 341.1627.
Diethyl 2-(4-methylphenyl)-4,6-dimethylpyridine-3,5-dicarbo-
xylate (3c). Yield 73%; light-yellow crystal; mp: 49.1–50.3 ◦C;
dH (400 MHz, CDCl3) 7.49–7.47 (2H, m, PhH), 7.24 (1H, s,
PhH), 7.22 (1H, s, PhH), 4.46 (2H, q, J = 7.2 Hz, 3-
CO2CH2CH3), 4.15 (2H, q, J = 7.2 Hz, 5-CO2CH2CH3), 2.61
Dimethyl
2-phenyl-4,6-dimethylpyridine-3,5-dicarboxylate
(3d). Yield 79%; colorless crystal; mp: 85.0–86.2 ◦C; dH
(400 MHz, CDCl3): 7.61–7.57 (2H, m, PhH), 7.50–7.41 (3H, m,
PhH), 3.99 (3H, s, 3-CO2CH3), 3.65 (3H, s, 5-CO2CH3), 2.62
(3H, s, 6-CH3), 2.36 (3H, s, 4-CH3); dC (100 MHz, CDCl3):
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Scheme 4 Proposed mechanisms for the synthesis of 2-arylpyridines.
168.9 (C=O), 168.8 (C=O), 156.4 (C-6), 155.6 (C-2), 143.1
(C-4), 139.4 (Ph-C), 130.1 (Ph-C), 129.0 (Ph-C), 128.4 (Ph-C),
128.2 (C-3), 127.0 (C-5), 52.6 (–OCH3), 52.4 (–OCH3), 23.2
(6-CH3), 17.1 (4-CH3); HRMS: calc. for C17H17NO4 (M+):
299.1158, found: 299.1160.
(C-5), 123.3 (Ph-C), 61.7 (–OCH2CH3), 61.6 (–OCH2CH3), 23.0
(6-CH3), 16.8 (4-CH3), 14.1 (–OCH2CH3), 13.6 (–OCH2CH3);
HRMS: calc. for C19H20NO4Br (M+): 405.0576, found:
405.0578.
Dimethyl 2-(4-cyanophenyl)-4,6-dimethylpyridine-3,5-dicarbo-
Diethyl 2-(4-bromophenyl)-4,6-dimethylpyridine-3,5-dicarbo-
xylate (3e). Yield 70%; colorless oil; dH (400 MHz, CDCl3):
7.57 (2H, d, J = 8.8 Hz, PhH), 7.47 (2H, d, J = 8.4 Hz,
PhH), 4.47 (2H, q, J = 7.2 Hz, 3-CO2CH2CH3), 4.16 (2H, q,
J = 7.2 Hz, 5-CO2CH2CH3), 2.62 (3H, s, 6-CH3), 2.37 (3H, s,
4-CH3), 1.43 (3H, t, J = 7.2 Hz, 3-CO2CH2CH3), 1.08 (3H,
t, J = 7.2 Hz, 5-CO2CH2CH3); dC (100 MHz, CDCl3): 168.0
(C=O), 167.9 (C=O), 155.3 (C-6), 154.9 (C-2), 142.9 (C-4),
138.5 (Ph-C), 131.4 (Ph-C), 130.0 (Ph-C), 128.7 (C-3), 127.1
xylate (3f). Yield 72%; colorless crystal; mp: 112.1–112.6 ◦C;
d
H (400 MHz, CDCl3): 7.76–7.73 (2H, m, PhH), 7.71–7.69 (2H,
m, PhH), 4.00 (3H, s, 3-CO2CH3), 3.68 (3H, s, 5-CO2CH3), 2.62
(3H, s, 6-CH3), 2.37 (3H, s, 4-CH3); dC (100 MHz, CDCl3): 168.4
(C=O), 168.3 (C=O), 156.0 (C-6), 154.3 (C-2), 143.8 (C-4),
143.6 (Ph-C), 132.2 (Ph-C), 129.2 (Ph-C), 129.0 (C-3), 127.1 (C-
5), 118.5 (–CN), 112.7 (C-CN), 52.7 (–OCH3), 52.6 (–OCH3),
23.1 (6-CH3), 17.1 (4-CH3); HRMS: calc. for C18H16N2O4 (M+):
324.1110, found: 324.1112.
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Diethyl 4,6-dimethyl-2,3¢-bipyridine-3,5-dicarboxylate (3g).
Yield 58%; light-yellow oil; dH (400 MHz, CDCl3): 8.69–
8.68 (2H, m, PyH), 7.49–7.48 (2H, m, PyH), 4.46 (2H, q,
J = 7.2 Hz, 3-CO2CH2CH3), 4.14 (2H, q, J = 7.2 Hz, 5-
CO2CH2CH3), 2.61 (3H, s, 6-CH3), 2.37 (3H, s, 4-CH3), 1.42
(3H, t, J = 7.2 Hz, 3-CO2CH2CH3), 1.03 (3H, t, J = 7.2 Hz,
5-CO2CH2CH3); dC (100 MHz, CDCl3): 167.7 (C=O), 167.5
(C=O), 155.7 (C-6), 153.5 (C-6¢), 149.7 (C-2, C-2¢), 147.0 (C-
4), 143.2 (C-3¢, C-4¢), 129.5 (C-3), 127.3 (C-5), 122.8 (C-5¢),
61.8 (–OCH2CH3), 61.7 (–OCH2CH3), 23.0 (6-CH3), 16.8 (4-
CH3), 14.1 (–OCH2CH3), 13.4 (–OCH2CH3); HRMS: calc. for
C18H20N2O4 (M+): 328.1423, found: 328.1424.
(4-CH3), 14.1 (–OCH2CH3), 13.6 (–OCH2CH3); HRMS: calc.
for C19H20NO4Br (M+): 405.0576, found: 405.0575.
Dimethyl 2-(4-methylphenyl)-4,6-dimethylpyridine-3,5-dicar-
boxylate (3l). Yield 75%; light-yellow crystal; mp: 83.6–
85.3 ◦C; dH (400 MHz, CDCl3): 7.49 (2H, d, J = 8.0 Hz, PhH),
7.24 (2H, d, J = 8.4 Hz, PhH), 3.98 (3H, s, 3-CO2CH3), 3.68
(3H, s, 5-CO2CH3), 2.63 (3H, s, 6-CH3), 2.40 (3H, s, CH3Ph),
2.35 (3H, s, 4-CH3); dC (100 MHz, CDCl3): 169.1 (C=O), 168.8
(C=O), 156.3 (C-6), 155.5 (C-2), 142.3 (C-4), 138.9 (Ph-C),
136.6 (Ph-C), 129.2 (Ph-C), 128.1 (Ph-C), 127.9 (C-3), 126.8 (C-
5), 52.5 (–OCH3), 52.4 (–OCH3), 23.2 (6-CH3), 21.3 (Ph-CH3),
17.0 (4-CH3); HRMS: calc. for C18H19NO4 (M+): 313.1314,
found: 313.1315.
Dimethyl 2-(4-trifluoromethoxyphenyl)-4,6-dimethylpyridine-
3,5-dicarboxylate (3h). Yield 76%; colorless crystal; mp: 60.4–
60.9 ◦C; dH (400 MHz, CDCl3): 7.62 (2H, d, J = 8.8 Hz, PhH),
7.28 (2H, d, J = 8.4 Hz, PhH), 3.99 (3H, s, 3-CO2CH3), 3.67
(3H, s, 5-CO2CH3), 2.61 (3H, s, 6-CH3), 2.35 (3H, s, 4-CH3);
dC (100 MHz, CDCl3): 168.6 (C=O), 168.5 (C=O), 155.7 (C-
6), 154.8 (C-2), 149.7 (C-OCF3), 143.3 (C-4), 138.1 (Ph-C),
129.8 (Ph-C), 128.5 (C-3), 126.9 (C-5), 120.7 (Ph-C), 120.4
(–OCF3), 52.5 (–OCH3), 52.3 (–OCH3), 23.0 (6-CH3), 16.9 (4-
CH3); HRMS: calc. for C18H16NO5F3 (M+): 383.0981, found:
383.0982.
Diethyl 2-(4-fluorophenyl)-4,6-dimethylpyridine-3,5-dicarbo-
xylate (3m). Yield 71%; colorless oil; dH (400 MHz, CDCl3):
7.60–7.56 (2H, m, PhH), 7.14–7.10 (2H, m, PhH), 4.47 (2H,
q, J = 7.2 Hz, 3-CO2CH2CH3), 4.15 (2H, q, J = 7.2 Hz, 5-
CO2CH2CH3), 2.63 (3H, s, 6-CH3), 2.37 (3H, s, 4-CH3), 1.43
(3H, t, J = 7.2 Hz, 3-CO2CH2CH3), 1.07 (3H, t, J = 7.2 Hz,
5-CO2CH2CH3); dC (100 MHz, CDCl3): 168.2 (C=O), 168.1
(C=O), 164.5 (C-6), 162.0 (C-F), 155.2 (C-2), 142.9 (C-4), 135.7
(Ph-C), 130.2 (Ph-C), 128.5 (C-3), 127.2 (C-5), 115.3 (Ph-C),
61.7 (–OCH2CH3), 61.5 (–OCH2CH3), 23.0 (6-CH3), 16.8 (4-
CH3), 14.1 (-OCH2CH3), 13.6 (–OCH2CH3); HRMS: calc. for
C19H20NO4F (M+): 345.1376, found: 345.1375.
Dimethyl 2-(4-methoxyphenyl)-4,6-dimethylpyridine-3,5-dicar-
boxylate (3i). Yield 59%; oil; dH (400 MHz, CDCl3): 7.57 (2H,
d, J = 8.8 Hz, PhH), 6.96 (2H, d, J = 8.4 Hz, PhH), 3.98 (3H, s,
3-CO2CH3), 3.86 (3H, s, PhOCH3), 3.70 (3H, s, 5-CO2CH3), 2.62
(3H, s, 6-CH3), 2.34 (3H, s, 4-CH3); dC (100 MHz, CDCl3): 169.2
(C=O), 168.8 (C=O), 160.3 (C-6), 155.8 (C-OCH3), 155.4 (C-2),
143.0 (C-4), 131.9 (Ph-C), 129.6 (Ph-C), 127.6 (C-3), 126.5 (C-
5), 113.9 (Ph-C), 55.3 (Ph-OCH3), 52.5 (–OCH3), 52.4 (–OCH3),
23.2 (6-CH3), 17.0 (4-CH3); HRMS: calc. for C18H19NO5 (M+):
329.1263, found: 329.1265.
Dimethyl 2-(4-chlorophenyl)-4,6-dimethylpyridine-3,5-dicar-
boxylate (3n). Yield 76%; light-yellow crystal; mp: 81.9–
90.2◦C; dH (400 MHz, CDCl3): 7.55 (2H, d, J = 8.4 Hz, PhH),
7.42 (2H, d, J = 8.4 Hz, PhH), 4.00 (3H, s, 3-CO2CH3), 3.69
(3H, s, 5-CO2CH3), 2.66 (3H, s, 6-CH3), 2.37 (3H, s, 4-CH3);
dC (100 MHz, CDCl3): 168.7 (C=O), 168.6 (C=O), 155.7 (C-
6), 155.0 (C-2), 143.3 (C-4), 137.9 (Ph-C), 135.2 (Ph-C), 129.6
(Ph-C), 128.7 (Ph-C), 128.4 (C-3), 126.9 (C-5), 52.6 (–OCH3),
52.5 (–OCH3), 23.1 (6-CH3), 17.1 (4-CH3); HRMS: calc. for
C17H16NO4Cl (M+): 333.0768, found: 333.0764.
Dimethyl 6¢-chloro-4,6-dimethyl-2, 3¢-bipyridine-3,5-dicarbo-
xylate (3j). Yield 73%; colorless crystal; mp: 70.1–70.4 ◦C; dH
(400 MHz, CDCl3): 8.59 (1H, d, J = 2.4 Hz, 2¢- PyH), 7.92 (1H,
dd, J = 8.4, 2.4 Hz, 4¢-PyH), 7.41(1H, d, J = 8.4 Hz, 5¢- PyH),
3.99 (3H, s, 3-CO2CH3), 3.75 (3H, s, 5-CO2CH3), 2.62 (3H, s,
6-CH3), 2.36 (3H, s, 4-CH3); dC (100 MHz, CDCl3): 168.2
(C=O), 168.1 (C=O), 156.1 (C-6), 151.8 (C-Cl), 148.9 (C-2),
143.5 (C-4), 138.5 (C-2¢), 134.1 (C-4¢), 129.0 (C-5, C-3¢), 127.1
(C-3), 123.9 (C-5¢), 52.6 (–OCH3), 52.5 (–OCH3), 23.0 (6-CH3),
17.0 (4-CH3); HRMS: calc. for C16H15N2O4Cl (M+): 334.0720,
found: 334.0718.
Acknowledgements
Financial support from the National High Technology Re-
search and Development Program of China (863 Program,
2006AA10A201), the Shanghai Foundation of Science of Tech-
nology (073919107), the Shanghai Leading Academic Discipline
Project (B507), the National Key Project for Basic Research
(973 Project, 2007BAQ03771), and the Shanghai Education
Commission are kindly acknowledged.
Diethyl 2-(3-bromophenyl)-4,6-dimethylpyridine-3,5-dicarbo-
xylate (3k). Yield 72%; light-yellow oil; dH (400 MHz, CDCl3):
7.75 (1H, t, J = 1.6 Hz, PhH), 7.56–7.54 (1H, m, PhH),
7.52–7.49 (1H, m, PhH), 7.30 (1H, t, J = 8.0 Hz, PhH),
4.47 (2H, q, J = 7.2 Hz, 3-CO2CH2CH3), 4.18 (2H, q, J =
7.2 Hz, 5-CO2CH2CH3), 2.62 (3H, s, 6-CH3), 2.37 (3H, s, 4-
CH3), 1.43 (3H, t, J = 7.2 Hz, 3-CO2CH2CH3), 1.09 (3H, t,
J = 7.2 Hz, 5-CO2CH2CH3); dC (100 MHz, CDCl3): 167.9
(C=O), 167.8 (C=O), 155.3 (C-6), 154.5 (C-2), 142.9 (C-
4), 141.5 (Ph-C), 131.7 (Ph-C), 131.3 (Ph-C), 129.8 (Ph-
C), 128.8 (Ph-C), 127.3 (C-5), 126.9 (C-3), 122.3 (Ph-C),
61.7 (–OCH2CH3), 61.6 (–OCH2CH3), 23.0 (6-CH3), 16.8
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