Controlled synthesis of 2-acetyl-6-carbethoxypyridine and 2,6-diacetylpyridine from 2,6-dimethylpyridine

Article abstract of DOI:10.1080/00397910500186995

The controlled syntheses of mono- and bis-acetylpyridine from the same starting material (2,6-dimethylpyridine) are reported, including the asymmetrical compound 2-acetyl-6-carbethoxypyridine, which has not before been reported. The influences of the amount of catalyst EtONa and the reaction conditions to the final products are also explored. A modification of the reported preparation for the 2,6-dipicolinic acid, 2,6-dicarbethoxypyridine and 2,6-diacetylpyridine with higher purity and improved yields is provided here, and the physical and spectral properties of these products are identical to those reported in the literature. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500186995

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Controlled Synthesis of
2‐Acetyl‐6‐carbethoxypyridine
and 2,6‐Diacetylpyridine from
2,6‐Dimethylpyridine
Biyun Su a , Jianshe Zhao a , Yong Cui b , Yongqing
Liang a & Wenhua Sun b
a Shaanxi Key Laboratory of Physico‐Inorganic
Chemistry, Department of Chemistry, Northwest
University, Xi'an, China
b State Key Laboratory of Engineering Plastics
and the Center for Molecular Science, Institute of
Chemistry, Chinese Academy of Sciences, Beijing,
China
Version of record first published: 18 Aug 2006.
To cite this article: Biyun Su , Jianshe Zhao , Yong Cui , Yongqing Liang &
Wenhua Sun (2005): Controlled Synthesis of 2‐Acetyl‐6‐carbethoxypyridine and
2,6‐Diacetylpyridine from 2,6‐Dimethylpyridine, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:17,
2317-2324
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Synthetic Communicationsw, 35: 2317–2324, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500186995
Controlled Synthesis of 2-Acetyl-6-
carbethoxypyridine and 2,6-
Diacetylpyridine from 2,6-Dimethylpyridine
Biyun Su and Jianshe Zhao
Shaanxi Key Laboratory of Physico-Inorganic Chemistry, Department
of Chemistry, Northwest University, Xi’an, China
Yong Cui
State Key Laboratory of Engineering Plastics and the Center
for Molecular Science, Institute of Chemistry, Chinese Academy
of Sciences, Beijing, China
Yongqing Liang
Shaanxi Key Laboratory of Physico-Inorganic Chemistry, Department
of Chemistry, Northwest University, Xi’an, China
Wenhua Sun
State Key Laboratory of Engineering Plastics and the Center
for Molecular Science, Institute of Chemistry, Chinese Academy
of Sciences, Beijing, China
Abstract: The controlled syntheses of mono- and bis-acetylpyridine from the same
starting material (2,6-dimethylpyridine) are reported, including the asymmetrical
compound 2-acetyl-6-carbethoxypyridine, which has not before been reported. The
influences of the amount of catalyst EtONa and the reaction conditions to the
final products are also explored. A modification of the reported preparation for
the 2,6-dipicolinic acid, 2,6-dicarbethoxypyridine and 2,6-diacetylpyridine with
Received in Japan December 9, 2004
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
2317

2318
B. Su et al.
higher purity and improved yields is provided here, and the physical and spectral
properties of these products are identical to those reported in the literature.
Keywords: Controlled synthesis, EtONa, mono- and bis-acetylpyridine, reaction
conditions
INTRODUCTION
Since late transition-metal catalyst systems containing bis(imino)pyridine
ligands have been proven to be significant ethylene polymerization and oligo-
merization catalysts by the groups of Brookhart[1] and Gibson[2] in 1998, a
considerable amount of effort has been dedicated to this field.[3] As a
precursor of bis(imino)pyridyl ligand (Scheme 1), 2,6-diacetylpyridine
requires an efficient and general synthetic route. Moreover, designing and
developing new analogues of 2,6-diacetylpyridine are urgent and significant
work in the field of ethylene polymerization catalysis.
RESULTS AND DISCUSSION
During the course of our research, we have designed and synthesized 2-acetyl-
6-carbethoxypyridine under the reaction conditions slightly different from that
of 2,6-diacetylpyridine. We report here the efficient synthesis methods for
2-acetyl-6-carbethoxypyridine and 2,6-diacetylpyridine starting from rela-
tively inexpensive 2,6-dimethylpyridine (Scheme 2). At the same time, we
have explored the optimum amount of the catalyst, EtONa, to form the
desired product from which we can synthesize mono- and bis-acetylpyridine.
2,6-Dimethylpyridine (1) is commercially available. It is converted to 2,6-
dipiclinic acid (2) by a modified procedure with better yield than that
reported by Singer and McElvain.[4,5] (Singer and McElvain[4] reported a
mp of 227–2288C for this compound. The difference may have been due to
the presence of traces of moisture and H2SO4, which appear to lower the
mp markedly.) Esterification of 2 is done according to a method slightly
different than that previously reported,[4,6] obtaining 2,6-dicarbethoxypyridine
(3), which is purified by a simplified method. Compound 3 is dissolved in
Scheme 1.

Syntheses of Mono- and Bis-acetylpyridine
2319
Scheme 2. 3) EtOH oil-water separator, using H2SO4 and benzol to remove water.
The reaction conditions to prepare 4 and 5 are slightly different.
freshly distilled EtOAc, and then treated with dry EtONa powder and excess
of concentrated HCl to afford the final products 2-acetyl-6-carbethoxypyridine
(4) or 2,6-diacetylpyridine (5). The molar ratio between EtONa and intermedi-
ate 3 is a decisive factor.
To ascertain the role of EtONa in the synthesis of 2-acetyl-6-carbethoxy-
pyridine and 2,6-diacetylpyridine, we have designed a series of experiments
in which the molar ratio of EtONa to 3 and other reaction conditions are
regularly changed (Table 1). The results show that the desired reaction
hardly takes place because small traces of EtOH or H2O exist in EtONa
powder (see Table 1, a). Thus, EtONa used in the next four experiments
has been dried in vacuum at least for 6 h. When molar ratio of reactant 3 to
catalyst EtONa is used as described in Ref. 7, products 4 and 5 are both
obtained (this is different from the results reported in Ref. 7; see Table 1,
b). As a solvent that is also one of the reactants, EtOAc is excessive in this
reaction. The yield of the reaction has not been significantly improved when
Table 1. Influence of molar ratio between EtONa and 3 to the products and the yields
Reactants
Products, yield (g, %)
Run
3 (g, mol)
EtONa (g, mol)
EtOAc (mL)
4
5
a
11.17 (0.05)
11.17 (0.05)
11.17 (0.05)
11.17 (0.05)
11.17 (0.05)
6.20 (0.09)
6.20 (0.09)
6.20 (0.09)
4.08 (0.06)
15.64 (0.23)
20
20
40
40
40
Trace
2.69 (27.8)
2.71 (28.0)
4.35 (45.0)
—
Trace
1.48 (18.1)
1.55 (18.9)
—
b[7]
c
d
e[8]
4.80 (58.8)
a. Residual humidity and EtOH has not been eliminated completely in this
experiment.
b, e. Molar ratios among reactants are in accordance with data reported in Refs.[7,8]
respectively.
,

2320
B. Su et al.
a large excess of EtOAc (twice that in b) is used (see Table 1, c). Therefore,
quantity of EtONa seems to be the decisive factor to the final products and
yields. By reducing the molar ratio (EtONa : 3) to about 1 : 1, only 4 is
obtained (see Table 1, d). When the molar ratio of EtONa to 3 is increased
nearly to 5 : 1, the final separated product is only 5 (see Table 1, e). Consider-
ing these results, we find that quality and quantity of EtONa in the reaction are
key elements for final products and yields. This accords with the conclusion
illustrated in Scheme 3. Compound 4 can be obtained when the molar ratio
of EtONa to 3 is controlled between 1.2 and 1.5, and 5 can be obtained
between 4.5 and 5.0.
Comparing our results of experiment b (Table 1) with that of reported in
literature,[7] we have found there are some problems in literature.[7]
1. Our experiment shows that the final product reported in literature[7] is not
only the 2,6-diacetylpyridine, but the mixture of 2-acetyl-6-carbethoxy-
pyridine in major and 2,6-diacetylpyridine in minor amounts. This
mixture has been separated by column chromatography and proved by
1H NMR, MS, IR, and elemental analysis respectively.
2. The melting point (44–468C) of 2,6-diacetylpyridine reported in this lit-
erature[7] is not comparable to other literature[8,9] (mp 79–808C) and
commercial-grade specification[10] (mp 808C). Through exploration, we
have found the melting point reported in literature[7] is an eutectic point
of 2-acetyl-6-carbethoxypyridine and 2,6-diacetylpyridine (see Fig. 1).
Melting point of 2,6-diacetylpyridine is determined to be 79–808C
after separation from the mixture and it is comparable to the literature[8,9]
and commercial-grade specification.[10]
Scheme 3. Mechanism of the reaction to prepare 2-acetyl-6-carbethoxypyridine.

Syntheses of Mono- and Bis-acetylpyridine
2321
Figure 1. Melting-point composition diagram of binary system comp. 4 and comp. 5.
We assume the mechanism (see Scheme 3) of the reaction to prepare 4
might be the following: Ethoxide ion abstracts (step 1) a hydrogen ion from
the a-carbon of the ethyl acetate to form carbanion I. The powerfully nucleo-
philic carbanion I attacks (step 2) one of the carbonyl carbon of 2,6-carbethoxy-
pyridine to displace ethoxide ion and yields the keto ester. Then, keto ester
reacts with ethoxide ion to form ethyl alcohol and the salt of keto ester,
which is essential to the success of the reaction; of the various equilibria
involved in the reaction, only this step is favorable to the product we
desired. Because step 1 and 2 are equilibrium reactions, it is necessary to
use an excess of the EtONa or else to remove the product EtOH from the
reaction mixture to shift the equilibrium to the right. Acidic hydrolysis of II
(step 3) is promoted by removal of CO2 produced in reaction through
heating, and the final product 4 is afforded. During the experiment, we have
detected production of CO2 using suspension of Ca(OH)2, which also
confirms the mechanism.
In summary, we have realized the controlled synthesis of mono- and bis-
acetylpyridine from the same starting material 2,6-dimethylpyridine and
modified the reported synthesis procedures of 2, 3, and 5. It is noteworthy
to mention here that, to the best of our knowledge, the preparation of
2-acetyl-6-carbethoxypyridine (4) has not been reported. The frame of this
new asymmetrical compound is a straightforward modification of the structure
of 2,6-diacetylpyridine, which may lead to a series of new monoiminopyridine
ligands, according to our initial research. The transition-metal compounds
bearing these ligands as the catalysts for ethylene polymerization would be
quite a significant subject to study.

2322
B. Su et al.
EXPERIMENTAL
Infrared spectra were obtained as KBr pellets on a Perkin-Elmer FTIR 2000
spectrometer. 1H NMR spectra were recorded on a Bruker spectrometer
DMS-300 with TMS as the internal standard. EI-Mass spectra were
measured on a Kratos AEI MS-50 instrument. Elemental analyses were
carried out on a HP-MOD 1106 microanalyzer. Melting points were taken
on a XT-4 melting-point apparatus and are uncorrected. 2,6-dimethylpyridine
was purchased from Aldrich Chemical Company. Silica gel 60 F254 (Merck)
was used for TLC. EtOH and EtOAc were dried and purified by the
standard purification procedures and used as freshly distilled.
Preparation of 2,6-Dipicolinic Acid (2)
In a 2-L, three-necked flask fitted with a reflux condenser, 16.7 g (0.156 mol) of
2,6-dimethylpyridine (1) was added to a solution of potassium permanganate
(53.3 g, 0.34 mol) in 750 mL of water. After refluxing for about 1.5 h until
the color of potassium permanganate had nearly disappeared, another 53.3-g
portion of potassium permanganate was added through one branch of the
three-necked flask and washed with 150 mL of water. The heating was
continued until the purple color was dissolved again (2–2.5 h). The mixture
was cooled to room temperature, and manganese dioxide was filtered and
washed with 30 mL of hot water. The filtrate was collected and concentrated
to about 200 mL, then filtered to remove the residual manganese dioxide,
and acidified with slightly excess of concentrated H2SO4 (98%, 18.7 mL).
The solution was allowed to stand under room temperature for about 6 h to
afford white crystals of dipicolinic acid, which were collected by filtration
and dried in vacuum. The filtrate was acidified with H2SO4 again and cooled
to 08C; 10% of product can be recovered and thus the yield was improved to
70% (18.24 g). Mp 250–2518C (lit.[4] 64%, mp 227–2288C; lit.[5] mp 2508C).
Preparation of 2,6-Dicarbethoxypyridine (3)
Dipicolinic acid (33.4 g, 0.2 mol) was refluxed with 400 mL of absolute
ethanol for a 24-h period using 8 mL of concentrated H2SO4 and 20 mL of
benzol. The water was removed by an oil–water separator. After excess of
ethanol was distilled, 100 mL of water was added and the residual acid was
neutralized to pH ¼ 6.5–7.0 with Na2CO3 powder. The resulting mixture
was abstracted with CHCl3 (5 ꢀ 50 mL). The combined organic phase was
dried over anhydrous Na2SO4, evaporated under reduced pressure, and dried
in vacuum; white crystals were obtained in good yield (37.02 g, 83%) (lit.[6]
60%) and high purity (mp 41.0–41.58C) (lit.[6] 41–428C).

Syntheses of Mono- and Bis-acetylpyridine
2323
Preparation of 2-Acetyl-6-carbethoxypyridine (4)
Sodium (2.10 g, 0.09 mol) was dissolved in 60 mL of pure and dry ethanol,
then excess of ethanol was removed, and the obtained white powder was
dried in vacuum for 3 h. 2,6-Dicarbethoxypyridine (11.17 g, 0.05 mol) in
40 mL of freshly distilled EtOAc was added dropwise to the dry EtONa
powder with stirring to afford a yellow mixture, which was refluxed for 12 h
and allowed to stand overnight. Excess (33 mL) of concentrated HCl was
added dropwise with stirring to the resulting mixture and refluxed for a
period of 7–8 h to complete the reaction. After water was added to dissolve
the NaCl formed in the reaction, the mixture turned to an orange solution
(100 mL). The aqueous phase was shaken with CHCl3 (4 ꢀ 25 mL). The
combined extracts were washed with 5% aqueous Na2CO3 and the aqueous
phase was extracted by CHCl3 (3 ꢀ 10 mL) again. The combined organic
phase was dried over anhydrous Na2SO4 and filtered, and the solvent was
evaporated under reduced pressure. The obtained mixture was separated by
column chromatography (silica-gel, petroleum ether–EtOAc ¼ 4 : 1). First
eluted was 2,6-diacetylpyridine (yield: 1.55 g, 18.98%). Second eluted was
1
2-acetyl-6-carbethoxypyridine (yield: 2.71 g, 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 1725.98 cm21, 1705.83 cm21, nC22O22C
1155.74 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.
Preparation of 2,6-Diacetylpyridine (5)
The procedure was the same as that of compound 4. The key difference was the
purity, dryness of EtONa, and the molar ratio of EtONa to the compound 3.
Sodium (5.3 g, 0.23 mol) was dissolved in 130 mL of pure and dry ethanol. The
obtained EtONa powder was dried in vacuum at least for 6 h to get rid of
ethanol completely. 2,6-Dicarbethoxypyridine (11.17 g, 0.05 mol) in 40 mL of
freshly distilled EtOAc was added. The final product 5 was purified by column
chromatography and recrystallized from ethanol. Yield: 4.8 g, 58.8%; mp
1
79.0–80.08C (lit.[8] yield: 61.3%, mp 798C; lit.[9] mp 78–808C). H NMR
(400 MHz, CDCl3): d 8.22 (d, 2H, Py-Hm), 8.01 (t, 1H, Py-Hp), 2.81 [s, 6H,
O55C (CH3)]. IR (KBr) nC55O 1704.83 cm21. MS (EI): m/z 163(Mþ). Anal.
calcd. for C9H9NO2: C, 66.25; H, 5.56; N, 8.58. Found: C, 66.24; H, 5.53; N, 8.73.
ACKNOWLEDGMENT
We are grateful to the Chinese Academy of Science, the Natural Science
Foundation of China (No. 20371039), National Basic Research Program

2324
B. Su et al.
(the 973 Program, No. 2003CB214600), the Key Laboratory Research and
Establishment Program of Shaanxi Education Section (No. 03JS006), and
the Natural Science Foundation of Shaanxi Education Section (No.
04JK143) for financial support.
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