Multicomponent domino cyclization-oxidative aromatization on a bifunctional Pd/C/K-10 catalyst: An environmentally benign approach toward the synthesis of pyridines

Article abstract of DOI:10.1055/s-0028-1083177

A one-pot synthesis of substituted pyridines via a domino cyclization-oxidative aromatization (dehydrogenation) approach is described. The process is based on the use of a new bifunctional noble metal-solid acid catalyst, Pd/C/K-10 montmorillonite and mic

Full text of DOI:10.1055/s-0028-1083177

PAPER
3423
Multicomponent Domino Cyclization–Oxidative Aromatization on a
Bifunctional Pd/C/K-10 Catalyst: An Environmentally Benign Approach
toward the Synthesis of Pyridines
An
E
nvironmental
m
ly Benign Approach
a
T
oward th
r
e
Synthesis of
DPyridines e Paolis, Jonathan Baffoe, Shainaz M. Landge, Béla Török*
Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd. Boston, MA 02125, USA
Fax +1(617)2876030; E-mail: bela.torok@umb.edu
Received 23 May 2008; revised 14 July 2008
lems.7 The application of solid acid catalysis to replace the
traditional mineral acids, such as sulfuric acid, is a rapidly
growing field in organic syntheses. Solid acid catalysts,
including clays, zeolites, metal oxides, and acidic ion-
Abstract: A one-pot synthesis of substituted pyridines via a domi-
no cyclization–oxidative aromatization (dehydrogenation) ap-
proach is described. The process is based on the use of a new
bifunctional noble metal–solid acid catalyst, Pd/C/K-10 montmoril-
lonite and microwave irradiation. The cyclization readily takes exchange resins, have been widely used to develop clean
and environmentally benign synthetic processes.8 Simi-
place on the strong solid acid while palladium dehydrogenates the
dihydropyridine intermediates to the desired products.
larly, supported transition-metal catalysts became widely
Key words: Pd/C/K-10 montmorillonite, solid acid, microwave ir-
radiation, bifunctional catalysis, green chemistry, pyridines
used in hydrogenation–dehydrogenation (reduction–oxi-
dation) processes.9 Usually these materials are excellent
catalysts for microwave-assisted organic synthesis
(MAOS).10 The application of solid catalysts under micro-
Nitrogen-containing heterocycles have attracted exten- wave irradiation carries another advantage: these reac-
sive attention due to their numerous applications in phar- tions can be carried out under solvent-free conditions.
maceutical and synthetic chemistry.1 Heterocyclic
Ideally, pyridines should be synthesized in one step, via
moieties are an important part of many biologically active
an approach that conforms to current environmental regu-
compounds.2 Pyridine derivatives are particularly valu-
lations and safety expectations. This goal appears reason-
able for their wide range of biological activity. They are
able if the cyclization and oxidation are performed in a
used to modulate hypertension, and angina pectoris, they
two-step/one-pot approach by using a unique combination
act as Ca2+-channel blockers, and they are also known as
of noble metal and solid acid catalysis. We have already
vasodilator, bronchodilator, antiatherosclerotic, antitu-
illustrated the essential advantages of such catalytic sys-
mor, geroprotective, heptaprotective, and antidiabetic
tems in several reactions, such as a chemoselective hydro-
agents.3 Due to their importance, several methods have
genation of a,b-unsaturated aldehydes, a green alternative
been developed for the synthesis of pyridines.4 The pre-
to the Clemmensen or Wolff–Kishner reduction, and the
cursor compounds to the synthesis of pyridines are often
one-step synthesis of pyrazoles.11
1,4-dihydropyridines, which can be synthesized by the
well-known Hantzsch synthesis.5 The traditional cycliza-
tion of a b-keto ester, an aldehyde and an ammonium salt,
however, results in 1,4-dihydropyridines and an addition-
al oxidation step is required to complete the preparation of
aromatic products. Many efficient oxidative aromatiza-
tion processes have been reported, including both stoichi-
ometric and catalytic methods.6 Although these processes
afford the target compounds effectively, in most cases
they do not conform to recent environmental and safety
standards. The use of traditional liquid acids for the cy-
clization, and stoichiometric amounts of oxidation agents
for the oxidative aromatization, produces significant
quantities of waste, the reactions occur in two separate
steps with less than ideal atom economy and the reagents
and catalysts are corrosive and hazardous. The introduc-
tion of heterogeneous catalysis into synthetic processes is
one of the most efficient ways to attack the above prob-
Herein, we describe an environmentally benign, one-pot,
domino approach to the synthesis of substituted pyridines
using a bifunctional (metal/acid) heterogeneous catalyst
and microwave irradiation. In this way, one can introduce
a wide variety of R groups into the 4-position of the prod-
uct pyridine molecule.
Our hypothesis is that the solid acid catalyzes the cycliza-
tion to produce 1,4-dihydropyridine, which immediately
undergoes oxidative aromatization (dehydrogenation) on
the added metal and results in the formation of the aromat-
ic product. The approach, essentially, is an environmen-
tally friendly pyridine synthesis, a unique combination of
the Hantzsch synthesis and the subsequent oxidation step.
A schematic depiction of the process is shown in
Scheme 1.
To verify our hypothesis, the cyclization of ethyl aceto-
acetate, benzaldehyde and ammonium acetate was inves-
tigated under widely varied experimental conditions. It
included testing of catalysts, activation methods, and re-
action temperatures. K-10 montmorillonite was the solid
acid catalyst of choice based on our recent studies.12 This
SYNTHESIS 2008, No. 21, pp 3423–3428
x
x.
x
x
.
2
0
0
8
Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083177; Art ID: M02308SS
© Georg Thieme Verlag Stuttgart · New York

3424
O. De Paolis et al.
PAPER
R
N
general procedure (see experimental). The results are
summarized in Table 1.
R
EtO2C
CO2Et
EtO2C
CO2Et
O
The data show that formation of the aromatic product was
strongly catalyst- and temperature-dependent. Catalysts
with Al2O3 and C-supports (entries 1,2,7,8 and 9) only af-
forded the product in low yield; an analysis of the product
mixture revealed that these catalysts were not able to cat-
alyze the cyclization efficiently. On the other hand, K-10
montmorillonite was only able to yield the 1,4-dihydropy-
ridine in the absence of metal – aromatization did not oc-
cur on the solid acid itself (entry 6). For comparison, two
commonly used liquid acids, such as triflic acid and acetic
acid, were also tested in the presence of Pd/C (entries 10
and 11). The results were inferior to those obtained with
the K-10 catalyzed process (entries 3–5 and 12). A com-
parison of microwave irradiation and conductive heating
resulted in the expected results: although the traditional
heating gave slightly higher yields, the reaction time re-
quired was 20 times longer.
O
O
Pd
MW
+
NH4
R
EtO2C
CO2Et
–
– H2
X
K-10
MW
N
H
Scheme 1 Microwave-assisted cyclization-oxidative aromatization
for the synthesis of pyridines by bifunctional Pd/C/K-10 catalyst
Table 1 Effect of Catalyst, Activation Method and Temperature on
the Microwave-Assisted (MW) Synthesis of Pyridines by Pd/C/K-10
Catalysta
Ph
O
O
EtO2C
CO2Et
catalyst
∆
+
NH4OAc
CO2Et
+
2
Ph
H
N
Entry Catalyst
Methodb T (°C) Time (h) Yield (%)c
We further optimized the reaction using Pd/C/K-10 cata-
lyst under the microwave conditions and found 130 °C to
be the optimum temperature. The aromatization did not
occur efficiently at lower temperatures and higher temper-
atures resulted in significant product decomposition.
1
2
Pt/Al2O3/K-10
Pd/Al2O3/K-10
Pd/C/K-10
Pd/C/K-10
Pd/C/K-10
K-10
MW
MW
MW
MW
MW
MW
MW
MW
MW
CH
130
130
110
130
150
130
130
130
130
130
110
140
100
150
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.0
1.0
15
20
22
78
31
0
3
4
Based on the above data, the scope of the reaction was ex-
tended using several substituted benzaldehydes. It ap-
peared that varying aldehyde structure required a fine-
tuning of the reaction time and sometimes temperature.
Thus, the reaction was optimized for each substrate to en-
sure the highest yield. Representative examples are shown
in Table 2.
5
6
7
Pd/C
51
7
8
Pt/Al2O3
As the data show, the corresponding 4-aryl substituted py-
ridines were obtained in good to excellent yields. The only
exception was 2-naphthylaldehyde, where only a moder-
ate yield was obtained due to decomposition of the alde-
hyde. It appeared that the electronic or steric effects of the
substituents of the reactant benzaldehyde in the para-
position had no significant effect on the yield of the prod-
ucts. However, using ortho-substituted aldehydes, an in-
teresting change in product selectivity was observed. The
reactions were carried out with o-bromobenzaldehyde and
o-tolualdehyde. The reaction yielded the aromatic product
in high overall yields (88% and 82% yields, respectively)
very similar to those obtained with their para-substituted
counterparts. The selectivity, however, completely
changed; in both cases the major product was found to be
the unsymmetric pyridine [e.g. diethyl 4-(2¢-bromophe-
nyl)-2,5-dimethylpyridine-3,6-dicarboxylate], with ex-
cellent selectivities (90:10 for o-bromobenzaldehyde, and
55:45 for o-tolualdehyde).
9
Pd/Al2O3
20
50
10
88
11
20
10
11
12
13
14
Pd/C/TfOH
Pd/C/HOAc
Pd/C/K-10
Pd/C/K-10
Pd/Al2O3/K-10
14
CH
24
29
28
24
CH
CH
CH
a Reagents and conditions: keto ester (2 mmol), benzaldehyde (1
mmol), NH4OAc (1 mmol), (toluene, pressure tube for CH).
b Microwave heating (MW), conventional heating (CH).
c Determined by GC.
catalyst is a well-known, commercially available, strong
solid acid with high surface area. It is active under micro-
wave conditions and is very robust and stable. Its physical
characterization, activity and performance and wide ap-
plicability in synthetic reactions have been a topic of
many reviews.13 Besides K-10, Al2O3 and C-supported
catalysts were also tested in the current study in order to
identify the role of the solid acid in the transformation. Pt
and Pd were selected as metals.11,14 Reactions were car-
ried out in a CEM Discover microwave reactor and, for
comparison, in a pressure vessel under conventional heat-
ing. The microwave reactions were carried out using a
To further extend the applicability of the procedure, we
submitted a variety of aliphatic aldehydes to the devel-
oped experimental conditions. The results are summa-
rized in Table 3.
As the data indicate, aliphatic aldehydes readily undergo
both the cyclization and the subsequent dehydrogenation
reactions to afford the corresponding substituted py-
Synthesis 2008, No. 21, 3423–3428 © Thieme Stuttgart · New York

PAPER
Environmentally Benign Approach toward the Synthesis of Pyridines
3425
The mechanism of the reaction involves two major steps
as depicted on Scheme 1. The first step, the Hantzsch cy-
clization, follows the well-known mechanism. The dehy-
drogenation step occurs on the surface of the metal, most
likely as a concerted reaction. The presence of the acidic
surface, however, appears to be advantageous in the dehy-
drogenation process as well, likely due to anchoring the
intermediate via its basic nitrogen.
Table 2 Microwave-Assisted, One-Pot Synthesis of Pyridines by
Pd/C/K-10 Catalyst from Ethyl Acetoacetate, Ammonium Acetate
and Substituted Benzaldehydesa
Ar
10%
Pd/C/K-10
O
EtO2C
CO2Et
O
+
NH4OAc
+
CO2Et
2
Ar
H
MW,
130 °C
N
Entry
Ar
Ph
Time (min)
90
Yield (%)b
As a last step in our investigation, we have attempted to
recycle our catalyst under the general reaction conditions
in order evaluate its lifetime and reusability. We have cho-
sen hexanal with the keto ester and ammonium acetate as
a probe for these experiments. The reaction was carried
out as described above, and the product was isolated.
Then the catalyst was simply washed with acetone and
dichloromethane and air-dried. The dry catalyst was then
used to prepare the second reaction mixture. This process
was repeated several times. Even under these simple con-
ditions the catalyst appeared to be recyclable, although
moderate deactivation (about 10%) was observed after
each run.
1
2
75
95
70
65
95
75
75
70
65
45
4-BrC6H4
4-ClC6H4
4-FC6H4
110
90
3
4
90
5
4-O2NC6H4
4-MeC6H4
4-NCC6H4
110
90
6
7
120
110
120
110
8
3,4-di(MeO)C6H3
3,4-diClC6H3
2-Naph
9
In conclusion, a new direct approach to the synthesis of
substituted pyridine derivatives has been developed. The
application of the bifunctional solid acid/noble metal
Pd/C/K-10 catalyst resulted in the efficient synthesis of a
wide variety of substituted pyridine derivatives from sim-
ple and commercially available starting materials. The mi-
crowave-assisted process appears to be widely applicable
and affords the products in good to excellent yields, high
selectivities and in short reaction times compared to tradi-
tional heating. The solid catalyst, short reaction times and
easy product isolation make this approach an attractive,
environmentally benign alternative synthesis of the target
compounds.
10
a Reagents and conditions: keto ester (2 mmol), benzaldehyde (1
mmol), NH4OAc (1 mmol).
b Determined by GC.
Table 3 Microwave-Assisted, One-Pot Synthesis of Pyridines by
Pd/C/K-10 Catalyst from Ethyl Acetoacetate, Ammonium Acetate
and Aliphatic Aldehydesa
R
10%
Pd/C/K-10
O
EtO2C
CO2Et
O
+
NH4OAc
+
CO2Et
2
R
H
MW,
130 °C
N
Entry
R
Time (min)
Yield (%)b
All reactants, including the catalyst Pd/C/K-10 montmorillonite,
were purchased from Aldrich and used without further purification.
1H and 13C NMR spectra were obtained on a 300 MHz Varian NMR
spectrometer, in CDCl3, with TMS (CFCl3 for 19F NMR) or the re-
sidual solvent signal as reference. The mass spectrometric identifi-
cation of the products was carried out on an Agilent 6850 GC with
a 5973 MS system (EI, 70 eV) using a 30 m DB-5 type column
(J&W Scientific). Melting points were recorded on a MEL-TEMP
apparatus and are uncorrected.
1
2
3
4
5
6
7
8
9
Me
Et
90
90
80
60
45
95
95
95
90
79c
95c
n-Pr
90
n-Bu
i-Bu
110
90
n-Pent
C7H15
90
Synthesis of Substituted Pyridines; General Procedure
A mixture of ethyl acetoacetate (2.0 mmol), aldehyde (1 mmol) and
ammonium acetate (1 mmol) were dissolved in MeOH (5 mL) in a
round-bottomed flask. A mechanically premixed combination of
10% Pd/C (200 mg) and K-10 (500 mg) was added. After 10 min
stirring, the solvent was evaporated in vacuo. The dry mixture was
placed into a reaction vial and irradiated in a microwave reactor
(CEM Discover Benchmate, 130 °C). During optimization, the re-
action was monitored by TLC and GC-MS. When the reaction was
complete, MeOH (5 mL) was added to the cold mixture, stirred for
10 min and the catalyst was removed by filtration. The products
were purified by flash chromatography. All products showed satis-
factory spectral data (MS, 1H and 13C NMR). The full spectral char-
acterization of the known compounds synthesized in this study are
shown below.
110
90
CH(Me)Ph
Bn
90
a Reagents and conditions: keto ester (2 mmol), aldehyde (1 mmol),
NH4OAc (1 mmol).
b Determined by GC.
c R = H products formed due to benzyl cleavage.
ridines in high yields. It is worth mentioning that the alde-
hydes in entries 8 and 9 yielded the same product in which
R = H. This product most likely formed by Pd-catalyzed
cleavage of the benzyl group.
Synthesis 2008, No. 21, 3423–3428 © Thieme Stuttgart · New York

3426
O. De Paolis et al.
PAPER
Diethyl 2,6-Dimethyl-4-phenylpyridine-3,5-dicarboxylate
(Table 2, Entry 1)
13C NMR (75 MHz, CDCl3): d = 168.0, 155.2, 146.1, 138.2, 133.5,
128.7, 127.9, 127.0, 61.3, 22.8, 21.2, 13.5.
Mp 59–61 °C.
MS: m/z (%) = 341 (81) [M+], 296 (33), 250 (100), 223 (33), 152
(40).
1H NMR (300 MHz, CDCl3): d = 7.36 (m, 2 H), 7.25 (m, 3 H), 4.00
(q, J = 7.2 Hz, 4 H), 2.61 (s, 6 H), 0.90 (t, J = 7.2 Hz, 6 H).
Diethyl 4-(4¢-Cyanophenyl)-2,6-dimethylpyridine-3,5-dicar-
boxylate (Table 2, Entry 7)
Mp 101–103 °C.
1H NMR (300 MHz, CDCl3): d = 7.69 (d, J = 8.4 Hz, 2 H), 7.38 (d,
J = 8.4 Hz, 2 H), 4.03 (q, J = 7.2 Hz, 4 H), 2.63 (s, 6 H), 0.96 (t,
J = 7.2 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 167.9, 155.4, 146.1, 136.5, 128.4,
128.1, 128.0, 126.9, 61.3, 22.9, 13.5.
MS: m/z (%) = 327 (100) [M+], 282 (53), 252 (33), 236 (84), 210
(44), 139 (65).
Diethyl 4-(4¢-Bromophenyl)-2,6-dimethylpyridine-3,5-dicar-
boxylate (Table 2, Entry 2)
Mp 50–52 °C.
13C NMR (75 MHz, CDCl3): d = 167.1, 156.0, 144.1, 141.4, 131.7,
129.0, 126.1, 118.2, 112.3, 61.5, 23.0, 13.6.
1H NMR (300 MHz, CDCl3): d = 7.52 (d, J = 8.4 Hz, 2 H), 7.14 (d,
J = 8.4 Hz, 2 H), 4.04 (q, J = 7.2 Hz, 4 H), 2.61 (s, 6 H), 0.98 (t,
J = 7.2 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 167.5, 155.6, 144.8, 135.4, 131.2,
129.7, 126.6, 122.8, 61.5, 22.9, 13.6.
MS: m/z (%) = 405 (49) [M+], 362 (30), 316 (58), 252 (55), 139
(100).
MS: m/z (%) = 352 (75) [M+], 307 (100), 278 (28), 164 (40).
Diethyl 4-(3¢,4¢-Dimethoxy)-2,6-dimethylpyridine-3,5-dicar-
boxylate (Table 2, Entry 8)
Mp 98–100 °C.
1H NMR (300 MHz, CDCl3): d = 6.85 (m, 3 H), 4.06 (q, J = 7.2 Hz,
4 H), 3.90 (s, 3 H), 3.85 (s, 3 H), 2.59 (s, 6 H), 1.03 (t, J = 7.2 Hz,
6 H).
Diethyl 4-(4¢-Chlorophenyl)-2,6-dimethylpyridine-3,5-dicar-
boxylate (Table 2, Entry 3)
13C NMR (75 MHz, CDCl3): d = 168.1, 155.1, 149.1, 148.5, 145.5,
128.8, 127.1, 120.7, 111.3, 110.6, 61.3, 55.8, 22.8, 13.7.
Mp 67–69 °C.
MS: m/z (%) = 387 (100) [M+], 296 (60), 115 (42).
1H NMR (300 MHz, CDCl3): d = 7.36 (d, J = 8.4 Hz, 2 H), 7.20 (d,
J = 8.4 Hz, 2 H), 4.04 (q, J = 7.2 Hz, 4 H), 2.61 (s, 6 H), 0.98 (t,
J = 7.2 Hz, 6 H).
Diethyl 4-(3¢,4¢-Dichlorophenyl)-2,6-dimethylpyridine-3,5-di-
carboxylate (Table 2, Entry 9)
Mp 68–70 °C.
13C NMR (75 MHz, CDCl3): d = 167.5, 155.5, 144.8, 139.7, 131.4,
129.5, 128.3, 126.8, 61.5, 22.8, 13.6.
1H NMR (300 MHz, CDCl3): d = 7.46 (d, J = 8.4 Hz, 1 H), 7.39 (d,
J = 2.4 Hz, 1 H), 7.11 (dd, J = 1.8, 8.1 Hz, 1 H), 4.11 (q, J = 7.2 Hz,
4 H), 2.61 (s, 6 H), 1.04 (t, J = 7.2 Hz, 6 H).
MS: m/z (%) = 361 (84) [M+], 316 (55), 270 (79), 139 (100).
Diethyl 2,6-Dimethyl-4-(4¢-Fluorophenyl)pyridine-3,5-dicar-
boxylate (Table 2, Entry 4)
13C NMR (75 MHz, CDCl3): d = 167.3, 155.8, 143.4, 136.2, 132.9,
132.4, 130.1, 127.6, 126.5, 61.6, 23.0, 13.7.
Mp 87–88 °C.
MS: m/z (%) = 395 (90) [M+], 350 (96), 322 (42), 304 (82), 173
(100).
1H NMR (300 MHz, CDCl3): d = 7.25 (m, 2 H), 7.08 (m, 2 H), 4.04
(q, J = 7.2 Hz, 4 H), 2.60 (s, 6 H), 0.98 (t, J = 7.2 Hz, 6 H).
Diethyl 2,6-Dimethyl-4-(naphth-2-yl)pyridine-3,5-dicarboxy-
late (Table 2, Entry 10)
Mp 61–62 °C.
1H NMR (300 MHz, CDCl3): d = 7.83 (m, 3 H), 7.74 (s, 1 H), 7.51
(m, 2 H), 7.38 (dd, J = 1.8, 8.4 Hz, 1 H), 3.94 (q, J = 7.2 Hz, 4 H),
2.64 (s, 6 H), 0.78 (t, J = 7.2 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 167.7, 164.4, 161.1, 155.4, 130.1,
129.9, 126.9, 115.2, 61.4, 22.8, 13.6.
19F NMR (282 MHz, CDCl3): d = –111.35 (s, 1 F).
MS: m/z (%) = 345 (100) [M+], 300 (80), 272 (75), 254 (75), 157
(85), 123 (43).
13C NMR (75 MHz, CDCl3): d = 167.8, 155.4, 146.1, 133.9, 132.8,
132.6, 128.1, 127.8, 127.6, 127.3, 127.1, 126.6, 126.5, 125.8, 61.3,
22.9, 13.5.
MS: m/z (%) = 377 (63) [M+], 286 (57), 259 (54), 230 (43), 189
(100).
Diethyl 2,6-Dimethyl-4-(4¢-nitrophenyl)pyridine-3,5-dicarbox-
ylate (Table 2, Entry 5)
Mp 113–115 °C.
1H NMR (300 MHz, CDCl3): d = 8.26 (d, J = 8.7 Hz, 2 H), 7.46 (d,
J = 8.7 Hz, 2 H), 4.04 (q, J = 7.2 Hz, 4 H), 2.64 (s, 6 H), 0.98 (t,
J = 7.2 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 167.1, 156.1, 147.7, 143.8, 143.2,
129.3, 126.1, 123.1, 61.6, 23.0, 13.6.
MS: m/z (%) = 372 (37) [M+], 355 (31), 327 (100), 299 (53), 127
(45).
Diethyl 2,4,6-Trimethylpyridine-3,5-dicarboxylate (Table 3,
Entry 1)
Oil.
1H NMR (300 MHz, CDCl3): d = 4.41 (q, J = 7.2 Hz, 4 H), 2.52 (s,
6 H), 2.27 (s, 3 H), 1.39 (t, J = 7.2 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 168.3, 154.8, 141.9, 127.5, 61.5,
Diethyl 2,6-Dimethyl-4-p-tolylpyridine-3,5-dicarboxylate
(Table 2, Entry 6)
Mp 70–72 °C.
22.9, 16.9, 14.1.
MS: m/z (%) = 265 (35) [M+], 236 (27), 220 (100), 192 (23).
1H NMR (300 MHz, CDCl3): d = 7.15 (d, J = 2.4 Hz, 4 H), 4.03 (q,
J = 7.2 Hz, 4 H), 2.60 (s, 6 H), 2.36 (s, 3 H), 0.95 (t, J = 7.2 Hz,
6 H).
Diethyl 2,6-Dimethyl-4-ethylpyridine-3,5-dicarboxylate (Table
3, Entry 2)
Oil.
Synthesis 2008, No. 21, 3423–3428 © Thieme Stuttgart · New York

PAPER
Environmentally Benign Approach toward the Synthesis of Pyridines
3427
1H NMR (300 MHz, CDCl3): d = 4.41 (q, J = 7.2 Hz, 4 H), 2.62 (q,
J = 7.5 Hz, 2 H), 2.51 (s, 6 H), 1.39 (t, J = 7.2 Hz, 6 H), 1.19 (t,
J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 168.5, 155.0, 147.6, 127.0, 61.5,
24.7, 22.9, 15.1, 14.1.
1H NMR (300 MHz, CDCl3): d = 8.68 (s, 1 H), 4.40 (q, J = 7.2 Hz,
4 H), 2.85 (s, 6 H), 1.42 (t, J = 7.2 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 165.9, 162.2, 140.8, 122.9, 61.3,
24.9, 14.2.
MS: m/z (%) = 251 (36) [M+], 206 (100), 178 (51).
MS: m/z (%) = 279 (10) [M+], 250 (100), 234 (53), 222 (81).
Acknowledgment
Diethyl 2,6-Dimethyl-4-propylpyridine-3,5-dicarboxylate
(Table 3, Entry 3)
Oil.
1H NMR (300 MHz, CDCl3): d = 4.41 (q, J = 7.2 Hz, 4 H), 2.55 (t,
J = 8.1 Hz, 2 H), 2.51 (s, 6 H), 1.57 (m, 2 H), 1.39 (t, J = 7.2 Hz,
6 H), 0.93 (t, J = 7.2 Hz, 3 H).
The financial support provided by University of Massachusetts
Boston and ACS PRF is gratefully acknowledged.
References
13C NMR (75 MHz, CDCl3): d = 168.5, 154.9, 146.3, 127.2, 61.5,
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Diethyl 4-Butyl-2,6-dimethylpyridine-3,5-dicarboxylate (Table
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32.9, 31.1, 23.0, 22.8, 14.1, 13.6.
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Diethyl 2,6-Dimethyl-4-isobutylpyridine-3,5-dicarboxylate
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Oil.
1H NMR (300 MHz, CDCl3): d = 4.40 (q, J = 7.2 Hz, 4 H), 2.61 (d,
J = 7.5 Hz, 2 H), 2.52 (s, 6 H), 1.81 (m, 1 H), 1.39 (t, J = 7.2 Hz,
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13C NMR (75 MHz, CDCl3): d = 168.6, 154.9, 145.7, 127.5, 61.5,
39.2, 29.5, 23.0, 22.5, 14.1.
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Diethyl 2,6-Dimethyl-4-pentylpyridine-3,5-dicarboxylate
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Oil.
1H NMR (300 MHz, CDCl3): d = 4.41 (q, J = 7.2 Hz, 4 H), 2.56 (t,
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6 H), 1.32 (m, 4 H), 0.89 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 168.5, 154.9, 146.5, 127.1, 61.5,
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Diethyl 2,6-Dimethyl-4-heptylpyridine-3,5-dicarboxylate
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Oil.
1H NMR (300 MHz, CDCl3): d = 4.41 (q, J = 7.2 Hz, 4 H), 2.56 (t,
J = 8.1 Hz, 2 H), 2.51 (s, 6 H), 1.52 (m, 2 H), 1.39 (t, J = 7.2 Hz,
6 H), 1.26 (m, 8 H), 0.87 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 168.5, 154.9, 146.5, 127.1, 61.5,
31.6, 31.4, 30.8, 29.9, 28.8, 22.9, 22.5, 14.1, 14.0.
MS: m/z (%) = 349 (5) [M+], 320 (85), 304 (100), 192 (30).
Diethyl 2,6-Dimethylpyridine-3,5-dicarboxylate (Table 3,
Entries 8 and 9)
Mp 70–71 °C.
Synthesis 2008, No. 21, 3423–3428 © Thieme Stuttgart · New York

3428
O. De Paolis et al.
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