Two novel microwave-promoted reactions between ethyl 6-acetylpyridine-2- carboxylate and aromatic amine/aliphatic amine

Article abstract of DOI:10.1080/00397910601131056

The unsymmetric precursor ethyl 6-acetylpyridine-2-carboxylate (3) was synthesized from 2,6-dipiclinic acid (1). On the basis of this precursor, two distinctively different types of compounds were prepared by microwave irradiation under solvent-free condi

Full text of DOI:10.1080/00397910601131056

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Two Novel Microwave‐Promoted
Reactions between Ethyl
6‐Acetylpyridine‐2‐carboxylate and Aromatic
Amine/Aliphatic Amine
Biyun Su a , Jianshe Zhao a & Peng Zhao a
a Shaanxi Key Laboratory of Physico‐inorganic Chemistry, Department of
Chemistry , Northwest University , Xi'an, China
Published online: 10 Mar 2007.
To cite this article: Biyun Su , Jianshe Zhao & Peng Zhao (2007) Two Novel Microwave‐Promoted
Reactions between Ethyl 6‐Acetylpyridine‐2‐carboxylate and Aromatic Amine/Aliphatic Amine, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:5,
839-848, DOI: 10.1080/00397910601131056
To link to this article: http://dx.doi.org/10.1080/00397910601131056
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Synthetic Communicationsw, 37: 839–848, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601131056
Two Novel Microwave-Promoted Reactions
between Ethyl 6-Acetylpyridine-2-
carboxylate and Aromatic
Amine/Aliphatic Amine
Biyun Su, Jianshe Zhao, and Peng Zhao
Shaanxi Key Laboratory of Physico-inorganic Chemistry, Department of
Chemistry, Northwest University, Xi’an, China
Abstract: The unsymmetric precursor ethyl 6-acetylpyridine-2-carboxylate (3) was
synthesized from 2,6-dipiclinic acid (1). On the basis of this precursor, two distinc-
tively different types of compounds were prepared by microwave irradiation under
solvent-free conditions. One type was mono(imino)pyridine compounds (4a–4f), origi-
nating from the Schiff base condensation between a series of aromatic amines and the
precursor 3; another type was 6-acetylpyridine-2-carboxamide compounds (5a–5c),
which were the products of amidation reactions between a series of aliphatic amines
and the same precursor 3.
Keywords: amidation reaction, ethyl 6-acetylpyridine-2-carboxylate, microwave
irradiation, reaction mechanism, Schiff base condensation
In modern chemistry industry, organometallic catalysts play great roles in the
olefin polymerization process. Since significant late transition-metal catalyst
systems incorporating bis(imino)pyridyl ligands have been reported indepen-
dently by the groups of small[1] and Britovsek,[2] there has been considerable
sustained interest in designing and developing the analogous catalysts based
on this type of Schiff base ligands.[3] In this article, an unsymmetric
compound ethyl 6-acetylpyridine-2-carboxylate (3) (Scheme 1) is used as
Received in Japan February 15, 2006
Address correspondence to Jianshe Zhao, Shaanxi Key Laboratory of Physico-
inorganic Chemistry, Department of Chemistry, Northwest University, Xi’an
710069, China. E-mail: jszhao@nwu.edu.cn
839

840
B. Su, J. Zhao, and P. Zhao
Scheme 1. Synthesis of the precursor ethyl 6-acetylpyridine-2-carboxylate (3).
1) EtOH, oil-water seperator, using H2SO4 and benzene to remove water.
precursor for a series of new mono(imino)pyridyl compounds 4a–4f
(Scheme 2), which are straightforward modifications to one of the imine
groups in bis(imino)pyridine, and are efficiently prepared by microwave
irradiation. According to our initial research,[4] transition-metal catalysts
bearing these new mono(imino)pyridyl ligands indicate considerable activities
for the ethylene polymerization and oligomerization.
Considering the great difference in nucleophilic ability and steric effect
existing between the small aliphatic amine molecule and big aromatic amine
molecule, we also have employed a series of aliphatic amines to react with
the same precursor ethyl 6-acetylpyridine-2-carboxylate (3) to explore a new
reaction and different framework. Under the same microwave irradiation
condition, exceptional 6-acetylpyridine-2-carboxamide compounds (5a–5c)
(Scheme 3) are obtained. This result suggests that different types of
reactant—aliphatic amine and aromatic amine—react with the same precursor
3 but may result in different types of reactions and products. That is, aliphatic
amine leads to amidation whereas aromatic amine leads to Schiff base conden-
sation. It is interesting to study the mechanism of these two novel reactions.
RESULTS AND DISCUSSION
Synthetic Methods for 4a–4f, 5a–5c
Generally, preparation of Schiff base is often catalyzed with acid and by
refluxing the mixture of aldehyde (or ketone) and amine in an organic
medium.[5] However, attempts to preparing mono(imino)pyridines 4a–4f by
Scheme 2. Synthesis of mono(imino)pyridines (4a–4f).

Two Novel Microwave-Promoted Reactions
841
Scheme 3. Synthesis of 6-acetylpyridine-2-carboxamides (5a–5c).
catalytic condensation of 3 with the corresponding substituted aniline in
refluxing ethanol and in the presence of acetic acid[5,6] affords very low
yield (about 10–15%) even after undergoing a long refluxing period (up to
12 h) and leads to many by-products. Compared with this synthetic
procedure, microwave-assisted condensation[7–9] seems to be much better
in terms of improved reaction rate, simple workup procedure, and formation
of cleaner products in preparing 4a–4f.
We also have applied microwave irradiation to reaction of precursor 3
and the aliphatic amine to prepare 5a–5c. It appears to be successful. In
addition, this amidation reaction seems to occur more easily, and the
reaction period is not so long (5–10 min) as compared with the Schiff base
condensation reaction.
Reaction Mechanisms of Aromatic Amine and Aliphatic Amine with 3
Theoretically, there are two unique reactive sites in the unsymmetric precursor
ethyl 6-acetylpyridine-2-carboxylate (3): the carbethoxy group in 2-position
of pyridine ring and the acetyl group in 6-position. Amine may react with
the carbethoxy to result in amidation or attack the acetyl group to engender
Schiff base condensation. According to our experiments, the aromatic
amine will first attack the acetyl group to result in Schiff base compound
mono(imino)pyridines 4a–4f; the amidation reaction does not easily happen
for the aromatic amine. In contrast, aliphatic amine will lead to the
amidation result 6-acetylpyridine-2-carboxamides 5a–5c but not the Schiff
base product.
This significant result indicates that different types of amines may
greatly influence reaction kinds and cause various products because of their
difference in nucleophilic ability and steric effect. The possible reasons can
be detailed as the following: owing to the stronger nucleophilic ability of

842
B. Su, J. Zhao, and P. Zhao
the aliphatic amine compared with the aromatic amine, and the greater steric
effect of –OEt group, which can easily drop out from the precursor 3 in
addition-elimination, the reaction, when the aliphatic amine reacts with 3, it
first attacks the carbon atom of carbethoxy group to result in an amidation
product. In the case of the aromatic amine, because of its weaker nucleophilic
ability and greater steric effect, it first attacks the acetyl group to result in
Schiff base condensation. Without the aid of the basic catalyst (strongly
nucleophilic reagent), the amidation reactions hardly happens to the
aromatic amine.
In summary, assisted by microwaves, two different types of new
compounds [mono(imino)pyridines 4a–4f and 6-acetylpyridine-2-carboxa-
mides 5a–5c] are synthesized from the same precursor (ethyl 6-acetylpyri-
dine-2-carboxylate) with aromatic amines and aliphatic amines respectively.
The synthetic method has been studied, and the mechanisms of the two
reactions also have been explored.
EXPERIMENTAL
C, H, and N analyses were performed by a HP-MOD 1106 microanalyzer.
IR spectra were carried out with a Perkin-Elemer FTIR 2000 spectrometer.
1H NMR spectra were recorded on Inova-400 NMR spectrometer using
TMS as internal standard. Mass spectra were determined with a Kratos AEI
MS-50 instrument using the electron impact (EI) method. The microwave-
assisted condensation was carried out in a domestic oven, Midea PJ 21B-A
800 W (21L). Melting points determined with a melting apparatus were uncor-
rected. 2,6-Dipiclinic acid, 2,6-dimethylaniline, 2,4,6-trimethylaniline,
2,6-diethylaniline, 2,6-difluoroaniline, 2,6-dichloroaniline, and 2,6-dibromoa-
niline were purchased from the Albemarle Co. (USA).
Preparation of the Precursor Ethyl 6-Acetylpyridine-2-carboxylate (3)
Initially, esterification of 2,6-dipiclinic acid (1) was done by a modified
procedure with better yield (84%) than that reported,[10] resulting in 2,6-dicar-
bethoxypyridine (2), which was purified by a simplified method. The dry 2
was dissolved in freshly distilled EtOAc, then treated with dry EtONa
powder and excess of concentrated HCl to afford ethyl 6-acetylpyridine-2-car-
1
boxylate (3) with yield of 28.0%. Mp 50.0–51.58C. H NMR (400 MHz,
CDCl3): d 8.27 (d, 1H, Py-Hm), 8.20 (d, 1H, Py-Hm), 7.99 (t, 1H, Py-Hp),
4.49 (m, 2H, CH2), 2.81 [s, 3H, O55C(CH3)], 1.47 [t, 3H, CH2(CH3)]. IR
(KBr) nC55O 1726 cm21, 1706 cm21, nC–O–C 1156 cm21. MS (EI): m/z 193
(Mþ). Anal. calcd. for C10H11NO3: C, 62.17; H, 5.74; N, 7.25. Found: C,
62.51; H, 5.76; N, 7.30.

Two Novel Microwave-Promoted Reactions
843
General Procedure for the Synthesis of Mono(imino)pyridines 4a–4f
The microwave-assisted condensation of ethyl 6-acetylpyridine-2-carboxylate
(3) and aromatic amine was performed in a domestic oven, Midea PJ 21B-A
800 W (21 L). Compound 3 (3 mmol) and excess of substituted aniline (about
6 mmol) were mixed in an Erlenmeyer flask. The mixture was irradiated
several times during the period of 10 min (to avoid burst temperature) on
the “M-High or High” setting (616 or 800 W), using thin-layer chromato-
graphy (TLC) to monitor the progress of reaction. After an optimized
reaction time, the obtained mixture was subjected to column chromatography
to give the desired product. The power, reaction time, yield, melting point, and
elute solvents used to purify products of 4a–4f are reported in Table 1.
Spectral data of 4a–4f are listed below.
Data
2-Carbethoxy-6-f1-[(2,6-dimethylphenyl)imino]ethylgpyridine (4a)
1H NMR (400 MHz, CDCl3): d 8.57 (d, 1H, Py-Hm), 8.19 (d, 1H, Py-Hm),
7.94 (t, 1H, Py-Hp), 7.06 (d, 2H, Ar-Hm), 6.95 (t, 1H, Ar-Hp), 4.50 (m, 2H,
CH2), 2.26 [s, 3H, N55C(Me)], 2.02 (s, 6H, Ar-Me), 1.46 [t, 3H,
CH2(CH3)]. IR (KBr): nC55O 1741 cm21, nC55N 1644 cm21, nC–O–C
1141 cm21. Anal. calcd. for C18H20N2O2: C, 72.95; H, 6.80; N, 9.45.
Found: C, 73.04; H, 6.81; N, 9.26.
2-Carbethoxy-6-f1-[(2,4,6-trimethylphenyl)imino]ethylgpyridine (4b)
1H NMR (400 MHz, CDCl3): d 8.56 (d, 1H, Py-Hm), 8.19 (d, 1H, Py-Hm),
7.94 (t, 1H, Py-Hp), 6.90 (s, 2H, Ar-Hm), 4.88 (m, 2H, CH2), 2.26 [d, 3H,
N55C(Me)], 2.06 (s, 6H, Ar-Me), 1.47 [t, 3H, CH2(CH3)]. IR (KBr): nC55O
1716 cm21, nC55N 1643 cm21, nC–O–C 1137 cm21. Anal. calcd. for
C19H22N2O2: C, 73.52; H, 7.14; N, 9.03. Found: C, 73.31; H, 7.12; N, 8.94.
2-Carbethoxy-6-f1-[(2,6-diethylphenyl)imino]ethylgpyridine (4c)
1H NMR (400 MHz, CDCl3): d 8.48 (d, 1H, Py-Hm), 8.11 (d, 1H, Py-Hm),
7.87 (t, 1H, Py-Hp), 7.30 (d, 2H, Ar-Hm), 6.99 (t, 1H, Ar-Hp), 4.43 (m, 2H,
COOCH2), 2.28 [m, 4H, (CH2)CH3], 2.20 [s, 3H, N55C(Me)], 1.39 [t, 3H,
COOCH2(CH3)], 1.05 [t, 6H, CH2(CH3)]. IR (KBr): nC55O 1742 cm21, nC55N
1640 cm21, nC–O–C 1166 cm21. Anal. calcd. for C20H24N2O2: C, 74.04; H,
7.46; N, 8.64. Found: C, 74.18; H, 7.70; N, 8.17.

Table 1. Experimental data for the mono(imino)pyridines 4a–4f and 6-acetylpyridine-2-carboxamides 5a–5c
Product
Amine
Power (W)
616
Time (min)
Yield (%)a
62.5
Mpb
Elute solvents (V/V)
4a
10 þ 10 þ 10
58–59
Petroleum ether/EtOAc ¼ 2/1
4b
616
10 þ 10
74.1
75–76
Petroleum ether/EtOAc ¼ 3/2
4c
800
616
10 þ 10 þ 10
25.3
44.0
84–86
—
Dichloromethane/n-hexane ¼ 2/1
Petroleum ether/EtOAc ¼ 6/1
4d
10

4e
4f
616
616
10 þ 5
28.4
67.8
—
—
Petroleum ether/EtOAc ¼ 5/2
Petroleum ether/EtOAc ¼ 3/1
10
5a
5b
5c
CH3NH2
616
616
616
5 þ 5
5 þ 5
5
68.0
45.0
72.5
98–100
61–63
HCCl3/CH3COCH3/EtOEt ¼ 9/1/1
Petroleum ether/EtOAc/HCCl3 ¼ 1/1/1
EtOH/petroleum ether/HCCl3 ¼ 2/1/1
CH3CH2NH2
NH2CH2CH2NH2
188–190
aYield refers to isolated yield.
bCompounds 4d, 4e, 4f are liquid in room temperature, so the melting point columns are blank.

846
B. Su, J. Zhao, and P. Zhao
2-Carbethoxy-6-f1-[(2,6-difluorophenyl)imino]ethylgpyridine (4d)
1H NMR (400 MHz, CDCl3): d 8.51 (d, 1H, Py-Hm), 8.18 (d, 1H, Py-Hm),
7.90 (t, 1H, Py-Hp), 7.22 (d, 2H, Ar-Hm), 6.98 (t, 1H, Ar-Hp), 4.45 (q, 2H,
COOCH2), 2.25 [s, 3H, N55C(CH3)], 1.40 [t, 3H, COOCH2(CH3)], IR
(KBr): nC55O 1725 cm21, nC55N 1646 cm21, nC–O–C 1168 cm21. Anal.
calcd. for C16H14F2N2O2: C, 63.15; H, 4.64; N, 9.21. Found: C, 63.21; H,
4.46; N, 9.35.
2-Carbethoxy-6-f1-[(2,6-dichlorophenyl)imino]ethylgpyridine (4e)
1H NMR (400 MHz, CDCl3): d 8.56 (d, 1H, Py-Hm), 8.21 (d, 1H, Py-Hm),
7.95 (t, 1H, Py-Hp), 7.32 (d, 2H, Ar-Hm), 7.05 (t, 1H, Ar-Hp), 4.46 (q, 2H,
COOCH2), 2.31 [s, 3H, N55C(CH3)], 1.43 [t, 3H, COOCH2(CH3)], IR
(KBr): nC55O 1724 cm21, nC55N 1649 cm21, nC–O–C 1158 cm21. Anal.
calcd. for C16H14Cl2N2O2: C, 56.99; H, 4.18; N, 8.31. Found: C, 56.63; H,
4.42; N, 7.98.
2-Carbethoxy-6-f1-[(2,6-dibromophenyl)imino]ethylgpyridine (4f)
1H NMR (400 MHz, CDCl3): d 8.58 (d, 1H, Py-Hm), 8.20 (d, 1H, Py-Hm),
7.88 (t, 1H, Py-Hp), 7.36 (d, 2H, Ar-Hm), 6.94 (t, 1H, Ar-Hp), 4.41 (q, 2H,
COOCH2), 2.18 [s, 3H, N55C(CH3)], 1.45 [t, 3H, COOCH2(CH3)], IR
(KBr): nC55O 1729 cm21, nC55N 1658 cm21, nC–O–C 1152 cm21. Anal.
calcd. for C16H14Br2N2O2: C, 45.10; H, 3.31; N, 6.57. Found: C, 45.35; H,
3.41; N, 6.92.
General Procedure for the Synthesis of 6-Acetylpyridine-2-
carboxamides 5a–5c
The microwave-assisted condensation of ethyl 6-acetylpyridine-2-carboxylate
(3) and aliphatic amine was performed in a domestic oven, Midea PJ 21B-A
800 W (21 L). Compound 3 (0.4 mmol) and excess of aliphatic amine
(about 1.0 mmol) were mixed in an Erlenmeyer flask. The mixture was irra-
diated several times during the period of 5 min (to avoid burst temperature)
on the “M-High” setting (616 W), using TLC to monitor the progress of the
reaction. After an optimized reaction time, the obtained mixture was
subjected to column chromatography to afford the desired product. The
power, reaction time, yield, melting point, and elute solvents used to purify
products of 5a–5c are reported in Table 1. Spectral data of 5a–5c are listed
below.

Two Novel Microwave-Promoted Reactions
Data
847
6-Acetyl-N-methylpyridine-2-carboxamide (5a)
1H NMR (400 MHz, CDCl3): d 8.41 (d, 1H, Py-Hm), 8.18 (d, 1H, Py-Hm),
8.03 [q, 1H, CH3(NH)], 8.00 (t, 1H, Py-Hp), 3.12 [d, 3H, NH(CH3)], 2.78
[s, 3H, C55O(CH3)]. IR (KBr) nN–H 3393 cm21, nC55O 1687 cm21, nC55O
1525 cm21. MS (EI): m/z 178 (M). Anal. calcd. for C9H10N2O2: C, 60.66;
H, 5.66; N, 15.72. Found: C, 61.28; H, 5.59; N, 15.37.
6-Acetyl-N-ethylpyridine-2-carboxamide (5b)
1H NMR (400 MHz, CDCl3): d 8.41 (d, 1H, Py-Hm), 8.18 (d, 1H, Py-Hm),
8.03 [t, 1H, CH2(NH)], 7.97 (t, 1H, Py-Hp), 3.58 [m, 2H, CH3(CH2)NH],
2.77 [s, 3H, C55O(CH3)], 1.32 [t, 3H, CH2(CH3)]. IR (KBr) nN–H
3404 cm21, nC55O 1683 cm21, nC55O 1524 cm21. MS (EI): m/z 192 (M).
Anal. calcd. for C10H12N2O2: C, 62.49; H, 6.29; N, 14.57. Found: C, 63.08;
H, 6.27; N, 14.08.
N,N0-1,2-Ethanediylbis(6-acetyl)pyridine-2-carboxamide (5c)
1H NMR (400 MHz, CDCl3): d 8.57 (d, 2H, Py-Hp), 8.38 (d, 2H, Py-Hm),
8.03 (d, 2H, Py-Hm), 8.00 [t, 2H, CH2(NH)], 3.86 [m, 4H, CH2(CH2)NH],
2.83 [s, 6H, C55O(CH3)]. IR (KBr) nN–H 3374 cm21, nC55O 1698 cm21
,
nC55O 1527 cm21. MS (EI): m/z 355 [M þ H]2. Anal. calcd. for
.
C19H22N4O4 0.25H2O: C, 60.24; H, 5.20; N, 15.61. Found: C, 60.42; H,
5.50; N, 15.53.
ACKNOWLEDGMENT
We are grateful to the Chinese Academy of Science, the Natural Science
Foundation of China (No. 20371039), National Basic Research Program
(the 973 Program, No. 2003CB214600), the Program for Changjiang
Scholars and Innovative Research Team in University, PCSIRTU
(IRT0559), the Key Laboratory Research and Establishment Program of
Shaanxi Education Section (No. 03JS006), and the Natural Science Foun-
dation of Shaanxi Education Section (No. 04JK143) for financial support.
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