Synthesis of polyheterocyclic compounds derived from 6-amino- 4-aryl-2-r-4h-furo[2,3-b]pyran-5-carbonitriles

Article abstract of DOI:10.1007/s10593-010-0450-0

Syntheses were developed for 4-aryl-6-ethoxy-2-R-furo[2,3-b]pyridine-5- carbonitriles and ethyl esters of 5-amino-4-aryl-7-methyl-2-R-1,9-dioxa-8- azacyclopenta[b]naphthalene-6-carboxylic acids based on the reaction of 6-amino-4-aryl-2-R-4H-furo[2,3-b]pyr

Full text of DOI:10.1007/s10593-010-0450-0

Chemistry of Heterocyclic Compounds, Vol. 45, No. 12, 2009
SYNTHESIS OF POLYHETEROCYCLIC
COMPOUNDS DERIVED FROM 6-AMINO-
4-ARYL-2-R-4H-FURO[2,3-b]PYRAN-
5-CARBONITRILES
T. V. Anis'kova1*, V. V. Chadina2, and A. Yu. Yegorova1
Syntheses were developed for 4-aryl-6-ethoxy-2-R-furo[2,3-b]pyridine-5-carbonitriles and ethyl esters
of 5-amino-4-aryl-7-methyl-2-R-1,9-dioxa-8-azacyclopenta[b]naphthalene-6-carboxylic acids based on
the reaction of 6-amino-4-aryl-2-R-4H-furo[2,3-b]pyran-5-carbonitriles with ethyl acetoacetate and
nucleophilic recyclization. The mechanisms of these reactions are considered.
Keywords:
6-amino-4-aryl-2-R-4H-furo[2,3-b]pyran-5-carbonitriles,
4-aryl-6-ethoxy-2-R-furo-
[2,3-b]pyridine-5-carbonitriles, ethyl acetoacetate, ethyl esters of 5-amino-4-aryl-7-methyl-2-R-4H-1,9-
dioxa-8-aza-cyclopenta[b]naphthalene-6-carboxylic acids, recyclization.
6-Amino-4-aryl-2-R-4H-furo[2,3-b]pyran-5-carbonitriles 1-3 are an important class of heterocyclic
compounds, which hold considerable interest in light of their various chemical transformations and practical
applications [1]. These bifunctional compounds, containing vicinal nitrile and amino groups, are promising
starting materials for obtaining previously not readily available fused heterocyclic systems. The synthesis of
carbonitriles 1-3 employs the base-catalyzed Michael condensation of 5-aryl-3-arylmethylene-3H-furan-2-ones
with malononitrile [2].
The reaction of carbonitriles 1-3 with a C-nucleophile, namely, ethyl acetoacetate, upon heating in
ethanol at reflux in the presence of catalytic amounts of triethylamine gives ethyl esters of 5-amino-4-aryl-
7-methyl-2-R-4H-1,9-dioxa-8-azacyclopenta[b]naphthalene-6-carboxylic acids 4-6.
Ar
Ar
NH2
EtO
Me
Et3N
CN
O
O
CO2Et
Me
+
R
R
O
O
NH2
O
O
N
1–3
4–6
1, 4 R = Ph; 2, 5 R = 4-MeC6H4, 3, 6 R = 4-MeOC6H4; 1–6 Ar = 2-ClC6H4
_______
* To whom correspondence should be addressed, e-mail: aniskovatv@mail.ru.
1N. G. Chernyshevskii Saratov State University, Saratov 410012, Russia.
2Engels Technological Institute, Branch of Saratov State Technical University, Engels 413100, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1812-1816, December, 2009.
Original article submitted March 22, 2009.
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0009-3122/09/4512-1460©2009 Springer Science+Business Media, Inc.

The IR spectra of esters 4-6 display bands for stretching vibrations of the ester groups at 1735-1715 cm-1
(broad), NH2 group at 3450-3350 cm-1 (two narrow bands), and the pyridine ring at 3050-3030, 1200-1180, and
1590-1550 cm-1.
1
Characteristic signals in the H NMR spectra of esters 4-6, which confirm their structure, are the broad
signal for the amino group at 9.30-9.35 ppm, triplet for the ester methyl group protons at 1.30-1.35 ppm, quartet
for the ester methylene group protons at 4.06-4.12 ppm, and signal for the methyl group at C-7 at
2.25-2.32 ppm.
Ar
NH2
EtO
Me
CO2Et
Me
O
O
a
R
1–3
+
O
O
NH2 O
A
b
Ar
Ar
O
NH2
CN CO2Et
COMe
O
4–6
R
R
Me
N
O
O
O
N
H
H
C
B
The existence of several reaction sites in the starting compounds would lead us to expect a complex
reaction leading to several reaction products. Generation of the ethyl acetoacetate carbanion occurs under base
catalysis conditions, followed by the addition of this carbanion at the nitrile group carbon atom to give
β-aminoester A, which undergoes intramolecular heterocyclization due to attack of the carbonyl carbon atom of
ethyl acetoacetate by the enamine amino group to give the pyridine ring in esters 4-6 (pathway a). An alternative
pathway involving attack of the amino group at C-2 of the pyran ring to give pyridone structure C does not take
place under the conditions studied. We cannot exclude initial attack of the amino group in carbonitriles 1-3 at
the oxo group of ethyl acetoacetate to give aminoprotonate B, which subsequently undergoes cyclization
involving the substrate cyano group (pathway b) to give esters 4-6.
Upon the action of sodium alcoholate, furopyrans 1-3 recyclize upon heating in ethanol to give
4-aryl-6-ethoxy-2-R-furo[2,3-b]pyridine-5-carbonitriles 7-9.
The IR spectra of pyridinecarbonitriles 7-9 have bands for the stretching vibrations of the cyano group at
2215-2210 cm-1 and –C–O–C– group at 1130-1120 cm-1 but lack bands for amino and cyano groups, which
supports the formation of the indicated products.
Ar
Ar
Ar
H
CN
CN
R
CN
OEt
EtOH
1–3
R
O
R
O
OEt
N
EtONa
O
OEt
N
O
H
H2N
HO
7–9
1, 7 R = Ph; 2, 8 R = 4-MeC6H4; 3, 9 R = 4-MeOC6H4, 1–3, 7–9 Ar = 2-ClC6H4
1
The H NMR spectra of pyridinecarbonitriles 7-9, in contrast to the spectra of the starting compounds,
display a series of upfield signals at 1.42-1.47 and 4.20-4.30 ppm, while the amino group proton signal at
~9.3 ppm is lacking.
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TABLE 1. Physicochemical Characteristics of the Ethyl Esters of
5-Amino-4-aryl-7-methyl-2-R-4H-1,9-dioxa-8-azacyclopenta[b]pyridine-
5-carbonitriles 7-9
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
С
Н
N
4
5
6
7
8
9
C26H21ClN2O4
C27H23ClN2O4
C27H23ClN2O5
C22H15ClN2O2
C23H17ClN2O2
C23H17ClN2O3
68.00
67.75
67.90
68.28
65.85
66.06
70.24
70.50
70.86
71.04
68.52
68.23
4.19
4.59
5.38
4.88
4.85
4.72
4.33
4.03
4.60
4.41
4.64
4.23
6.43
6.08
6.30
5.90
5.43
5.71
7.53
7.47
7.05
7.20
7.23
6.92
136-138
153-155
164-166
161-162
157-159
168-170
64
71
69
75
68
82
TABLE 2. 1H NMR Spectra of Esters 4-6 and Carbonitriles 7-9
Chemical shifts, δ, ppm (J, Hz)
H-4 OCH2CH3 OCH2CH3 NH2
Com-
pound
Fur
(1Н, s)
СH3
(3H, s)
Ar (m)
CH3
OCH3
(1H, s) (2Н, m)
(3Н, t)
(2H, s)
4
5
6
7
8
9
6.50 7.05-7.36 2.55
5.40
5.75
5.63
4.40
4.45
4.47
4.20
4.30
4.27
1.30
(J = 7.0)
9.30
—
—
—
2.15
—
(9H)
(3H, s)
6.53 7.13-7.38 2.58
1.35
(J = 6.8)
9.35
9.32
(8H)
(3H, s)
6.60 7.00-7.30 2.62
1.33
(J = 6.8)
3.45
(3H, s)
(8H)
(3H, s)
6.50 7.25-7.68
—
1.42
(J = 6.4)
—
(9Н)
6.64 7.15-7.50 2.35
1.47
(J = 6.5)
—
(8Н)
6.57 7.19-7.67
—
1.45
3.83
(8Н)
(J = 6.4)
The formation of the pyran ring in furopyrans 1-3 due to intramolecular reaction of the hydroxyl and
cyano groups is reversible [3]. Under certain conditions, the pyran ring is opened by the action of nucleophilic
reagents with subsequent cyclization and aromatization to give the pyridine ring due to attack of the amino
group nitrogen atom. Nucleophilic addition of the alcoholate anion at the α-carbon atom of the pyran ring
probably occurs initially, followed by opening of the heterocycle. Subsequent attack of the nitrogen atom at the
carbonyl carbon atom of the lactone group, cyclization, and aromatization lead to formation of the pyridine ring.
EXPERIMENTAL
The IR spectra were taken on an FSM-1201 Fourier spectrometer for KBr pellets at 400-4000 cm-1. The
1H NMR spectra were taken on a Bruker MSL-400 spectrometer at 400 MHz at 20-25°C in CDCl3 with TMS as
the internal standard. Thin-layer chromatography was carried out on Silufol UV-254 plates with 2:2:1 hexane–
ethyl acetate–chloroform and development by iodine vapor.
6-Amino-4-aryl-2-R-4H-furo[2,3-b]pyran-5-carbonitriles 1-3 were obtained by a standard method [2].
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Ethyl Esters of 5-Amino-4-aryl-7-methyl-2-R-4H-1,9-dioxa-8-azacyclopenta[b]naphthalene-
6-carboxylic Acids 4-6. Triethylamine (10 mmol) in ethanol was added to a mixture of 6-amino-4-aryl-2-R-
4H-furo[2,3-b]pyran-5-carbonitrile 1-3 (10 mmol) and ethyl acetoacetate (15 mmol). The reaction mixture was
heated at reflux for 5-8 h, poured into cold water, and neutralized by adding dilute hydrochloric acid. The
precipitated crystals were filtered off and recrystallized from hexane.
4-Aryl-6-ethoxy-2-R-[2,3-b]pyridine-5-carbonitriles 7-9. A mixture of 6-amino-4-aryl-2-R-4H-furo-
[2,3-b]pyran-5-carbonitrile 1-3 (10 mmol) and sodium alcoholate (10 mmol) in ethanol was heated for 3-4 h at
reflux, poured into cold water, and neutralized by adding dilute hydrochloric acid. The crystals precipitated was
filtered off and recrystallized from 2:1 hexane–2-propanol.
This work was carried out with the financial support of a grant from the Russian Federation President's
Fund for State Support of Young Russian Scientists MK-635.2009.3.
REFERENCES
1.
2.
G. Tacconi, G. Gatti, and G. Desimoni, J. Prakt. Chem., 322, 831 (1980).
T. V. Anis'kova, A. Yu. Yegorova, and Z. Yu. Timofeeva, in: A. F. Kriven'ko (editor), Carbonyl
Compounds in Heterocyclic Synthesis [in Russian] (2008), p. 32.
3.
F. S. Babichev, Yu. A. Sharanin, V. P. Litvinov, V. K. Promonenkov, and Yu. M. Volovenko,
Intramolecular Reactions of Nitrile and C–H, O–H, and S–H Groups [in Russian], Naukova Dumka
(1985).
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