Synthesis of pyridines by cyclocondensation of acetyl and benzoyl pyruvates with enamines

Article abstract of DOI:10.1007/s10593-011-0659-6

4-Ethoxycarbonylpyridines containing acetyl, benzoyl, cyclopropanoyl, and nitro groups at position 3 have been synthesized by the reaction of acetyl and benzoyl pyruvates with various enamines.

Full text of DOI:10.1007/s10593-011-0659-6

Chemistry of Heterocyclic Compounds, Vol. 46, No. 10, 2011
SYNTHESIS OF PYRIDINES BY CYCLOCONDENSATION
OF ACETYL AND BENZOYL PYRUVATES WITH ENAMINES
G. P. Sagitullina1**, A. K. Garkushenko1, M. A. Dushek1,
N. V. Poendaev1, and R. S. Sagitullin1*
4-Ethoxycarbonylpyridines containing acetyl, benzoyl, cyclopropanoyl, and nitro groups at position 3
have been synthesized by the reaction of acetyl and benzoyl pyruvates with various enamines.
Keywords: enamines, pyridines with acceptor substituents, one-pot synthesis.
The most valuable method for the synthesis pyridines with acceptor substituents in positions 3 and 5 of
the nucleus is the Hantzsch synthesis [1, 2]. In one variant of the Hantzsch synthesis for the preparation of
pyridines condensation of ethyl ethoxymethyleneacetoacetate (or other products of the reaction of β-dicarbonyl
compounds with ethyl orthoformate) with enamines of β-dicarbonyl compounds is used [3]. We have previously
successfully used a one-pot variant of this synthesis using methylene-activated nitroacetone and
nitroacetophenone [4, 5].
In a development of this work we have investigated the possibility of using a one-pot synthesis of
pyridines 8 and 9 by a triple-component of acetyl and benzoyl pyruvates. However it appears that esters 1 and 2
did not react under mild conditions with ethyl orthoformate to form ethoxymethylene derivatives and
consequently pyridines 8 and 9 were not formed. Under these conditions another variant of the Hantzsch
synthesis – the Guareschi-Thorpe reaction – led to the formation of pyridines 5-7 in preparative yields [6-9].
The spectral data for the previously undescribed pyridines 5-7 are given in Tables 1 and 2.
CO2Et
CO2Et
O
X
X
COMe
Me
HC(OEt)3, AcOH
30°C, N2, 72 h
AcOH, N2
30°C, 72 h
O
R
+
1
1
R
N
R
H2N
R
R
O
EtO2C
N
3a-e, 4a,e
1, 2
5a,e, 6a-e, 7a,e
8, 9
1, 8 R = Me, 2, 9 R = Ph; 3 R1 = Me, 4 R1 = Ph; 5 R = R1 = Me, 6 R = Ph, R1 = Me,
O
7 R = Me, R1 = Ph; 3–7 a X = CN, b X = COMe, c X = COPh, d X =
, e X = NO2
_______
* Deceased.
** To whom correspondence should be addressed, e-mail: Sagitullina@orgchem.univer.omsk.su.
1F. M. Dostoevsky Omsk State University, Omsk 644077, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, 1546-1550, October 2010. Original
article submitted December 28, 2009.
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0009-3122/11/4610-1250©2011 Springer Science+Business Media, Inc.

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EXPERIMENTAL
1
IR spectra of compounds 5a,e, 6a-c, 7a,e were measured with a Simex FT-801 in CHCl3. H NMR
spectra of compounds 6a,b and 7a,e were recorded on a Bruker AC-250 (250 MHz) spectrometer with TMS as
internal standard, and 5a,e and 6c-e on a Bruker DRX-400 (400 MHz) instrument with CHCl3 as internal
standard (δC 7.26). 13C NMR spectra were recorded on a Bruker DRX-400 (100 MHz) spectrometer with CDCl3
as internal standard (δC 77.00). Elemental analyses were obtained on a Perkin-Elmer CHN analyzer Merck 60A,
60-200 μm silica gel was used for column chromatography. Monitoring of reactions and purity of the
compounds obtained was by TLC on Silufol UV-254 plates.
Ethyl 2,4-Dioxopentanoate (1) was synthesized according to [10] and Ethyl 2,4-Dioxo-4-phenyl-
butanoate (2) according to [11]. 4-Aminopent-3-en-2-one (3b), 3-Amino-1-phenyl-but-2-en-1-one (3c),
3-Amino-1-cyclo-propylbut-2-en-1-one (3d), and 3-Amino-3-phenylacrylonitrile (4a) were obtained as
described in [3, 12-14]. 1-Methyl-2-nitrovinylamine (3c) was obtained by the transamination of (1-methyl-
2-nitrovinyl)phenylamine [15-17]. 2-Nitro-1-phenylethylenamine (4e) was obtained by the transamination of
N-(2-nitro-1-phenyl-vinyl)aniline [16, 18, 19]. 3-Aminobut-2-enenitrile was obtained from Fluka.
Synthesis of Pyridines 5a,e, 6a-e, and 7a,e (General Method). A solution of ester 1 (or 2) (6 mmol)
and corresponding enamine 3a-e, 4a,e (6 mmol) in acetic acid (5 ml) was stirred for 72 h at 30°C. The reaction
mixture was diluted with water and ice and the crystals formed were filtered off.
Ethyl 3-Cyano-2,6-dimethylisonicotinate (5a). Yield 70%; mp 38-39°C (petroleum ether 40-70°C).
Found, %: C 64.56; H 5.98; N 13.87. C11H12N2O2. Calculated, %: C 64.69; H 5.92; N 13.72.
Ethyl 2,6-Dimethyl-3-nitroisonicotinate (5e). Yield 80%; mp 54-55°C (ethanol) (mp 58-59°C [20]).
Found, %: C 53.17; H 5.34; N 12.56. C10H12N2O4. Calculated, %: C 53.57; H 5.39; N 12.49.
Ethyl 3-Cyano-2-methyl-6-phenylisonicotinate (6a). Yield 75%; mp 94-95°C (ethanol). Found, %:
C 72.55; H 5.33; N 10.62; C16H14N2O2. Calculated, %: C 72.16; H 5.30; N 10.52.
Ethyl 3-Acetyl-2-methyl-6-phenylisonicotinate (6b). Yield 80%; mp 64-65°C (petroleum ether
40-70°C). Found, %: C 71.79; H 6.03; N 5.23. C17H17NO3. Calculated, %: C 72.07; H 6.05; N 4.94
Ethyl 3-Benzoyl-2-methyl-6-phenylisonicotinate (6c). Yield 72%; mp 111-112° (ethanol). Found, %:
C 76.56; H 5.62; N 4.45. C22H19NO3. Calculated, %: C 76.50;, H 5.54; N 4.06.
Ethyl 3-(Cyclopropylcarbonyl)-2-methyl-6-phenylisonicotinate (6d). Yield 60%; mp 112-113°C
(ethanol). Found, %: C 73.81; H 6.32; N 4.75. C19H19NO3. Calculated, %: C 73.77; H 6.19; N 4.53.
Ethyl 2-Methyl-3-nitro-6-phenylisonicotinate (6e). Yield 75%; mp 82-83°C (ethanol). Found, %:
C 62.57; 4.75; 9.84. C15H14N2O2. Calculated, %: C 62.93; H 4.93; N 9.79.
Ethyl 3-Cyano-6-methyl-2-phenylisonicotinate (7a). Yield 77%; mp 75-76°C (ethanol). Found, %:
C 71.92; H 5.37; N 10.61. C16H14N2O2. Calculated, %: C 72.16; H 5.30; N 10.52.
Ethyl 6-Methyl-3-nitro-2-phenylisonicotinate (7e). Yield 40%; mp 77-78°C (ethanol). Found, %:
C 62.55; H 4.82; N 9.56. C15H14N2O4. Calculated, %: C 62.93; H 4.93; N 9.79.
This work was supported by a financial subvention from the Russian Fund for Fundamental Research
(grant 07-03-000783-a).
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