Formation of oxopyridine ring from two cyanoacetanilide molecules via preliminary transformation of one of them into ethoxymethylidene derivative

Article abstract of DOI:10.1134/S1070428011100162

Cyanoacetanilides reacted with their ethoxymethylidene derivatives to produce two regioisomeric products from the same linear intermediate, the isomer ratio depending on the substituents in the aromatic rings of the initial cyanoacetanilides. Pleiades Pub

Full text of DOI:10.1134/S1070428011100162

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 10, pp. 1540–1543. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © V.D. Dyachenko, V.P. Tkacheva, N.Yu. Gorobets, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 10,
pp. 1512–1515.
Formation of Oxopyridine Ring from Two Cyanoacetanilide
Molecules via Preliminary Transformation of One of Them
into Ethoxymethylidene Derivative
V. D. Dyachenkoa, V. P. Tkachevaa, and N. Yu. Gorobetsb
a Taras Shevchenko Lugansk National University, ul. Oboronnaya 2, Lugansk, 91011 Ukraine
e-mail: dvd_lug@online.lg.ua
b Institute of Single Crystals, National Academy of Sciences of Ukraine, Kharkov, Ukraine
Received February 24, 2011
Abstract—Cyanoacetanilides reacted with their ethoxymethylidene derivatives to produce two regioisomeric
products from the same linear intermediate, the isomer ratio depending on the substituents in the aromatic rings
of the initial cyanoacetanilides.
DOI: 10.1134/S1070428011100162
Studies on mechanisms of chemical reactions con-
stitute an important field of synthetic organic chem-
istry. We were interested in nucleophilic vinylic sub-
stitution in ethoxymethylidene derivatives of nitriles
having an activated methylene group [1]. We previ-
ously studied reactions of diethyl ethoxymethylidene-
malonate with cyanoacetanilides, which afforded
2-amino-5-cyano-6-oxo-N,1-diaryl-1,6-dihydropyri-
dine-3-carboxamides as the major products [2]. The
same compounds were synthesized via an alternative
route, by reaction of ethoxymethylidene derivatives of
CH acids with cyanoacetanilides having similar sub-
stituents in the aryl rings. When the reaction was
carried out in the presence of 0.5 equiv of a base, we
succeeded in isolating intermediate SNVin product.
Heating of the latter in the presence of excess base
gave the expected cyclic structure.
isomer mixtures IIIa/IVa. This means that the isomer
ratio is determined by the structure of linear inter-
mediate product rather than of initial compounds.
Presumably, conjugation of lone electron pair on the
chlorine atom with the benzene ring weakens conjuga-
tion of the latter with lone electron pair on the nitrogen
atom which becomes more accessible for subsequent
cyclization; as a result, compound IIIa is formed as the
major product. Here, it does not matter whether the
substituent is present in the aromatic ring of cyano-
acetanilide I or ethoxymethylidene derivative II; in
both cases the isomer ratio IIIa:IVa depends on the
nucleophilicities of the nitrogen atoms in linear inter-
mediate A.
The results of analogous condensations of cyano-
acetanilides with ethoxymethylidene derivatives
having o-methoxy- and p-chlorophenyl substituents
(Scheme 1) confirmed our assumption that the SNVin
reaction is governed exclusively by the substituent
nature. The ratio of isomers IIIb and IVb was 91:9 (a)
and 83:17 (b). Obviously, the effect of the chlorine
atom is the same as above.
In the present work we tried to elucidate the effect
of substituents in the aromatic rings of initial cyano-
acetanilides on the direction of intramolecular cycliza-
tion of linear intermediate A. For this purpose we
performed a series of reactions with compounds I and
II having different substituents in the benzene rings
(Scheme 1). As expected, these reactions led to the
formation of two regioisomers III and IV at different
ratios.
In the reaction of o-methoxy-substituted cyanoacet-
anilide Ia with o-ethyl-substituted ethoxymethylidene
derivative IIa we succeeded in isolating intermediate
linear condensation product V (Scheme 2). The NH
signals in the 1H NMR spectrum of V were observed at
δ 8.22 ppm, whereas the cyclic structures were charac-
terized by NH chemical shifts δ of 9.45–9.67 ppm. The
The ratio of isomers IIIa and IVa obtained accord-
ing to paths a and b was ~70:30% (Scheme 1). It was
1
estimated by analysis of the H NMR spectra of crude
1540

FORMATION OF OXOPYRIDINE RING FROM TWO CYANOACETANILIDE MOLECULES
1541
Scheme 1.
OEt
H
H
N
N
CN
CN
CN
a
b
X
Y
+
+
O
O
O
O
X(Y)
Y(X)
EtONa (1 equiv)
EtOH
I
II
O
O
OEt
CN
N
N
H
H
H
H
N
CN
CN
N
Y
X
A
I
II
O
O
Y
X
CN
CN
O
N
N
H
H
H2N
N
O
H2N
N
+
X
Y
IIIa, IIIb
IVa, IVb
III, IV, X = 4-Cl, Y = H (a), 2-MeO (b).
Path
X
Y
Products (ratio, %)
a
4-Cl
4-Cl
4-Cl
4-Cl
H
IIIa, IVa (71 : 29)
IIIb, IVb (91 : 9)
IIIa, IVa (68 : 32)
IIIb, IVb (83 : 17)
2-OMe
H
b
2-OMe
IR spectrum of V contained absorption bands at 2210
and 2190 cm–1 due to stretching vibrations of the
cyano groups [3], and the carbonyl stretching vibration
bands were observed at 1635 cm–1, which is typical of
such compounds [3].
holic sodium ethoxide gave a mixture of isomers IIIc
and IVc at a ratio of 92:8.
Thus we presumed that only one linear intermediate
product is formed, which gives rise to two isomeric
cyclic structures.
1
The structure of V can be represented as anion gen-
erated as a result of elimination of proton and distribu-
tion of the negative charge over all functional groups.
The COSY spectrum of V showed coupling between
protons in the ethyl group and CH proton. This indi-
cates that the cyano group is neighboring to the amide
nitrogen atom linked to the o-methoxyphenyl substit-
uent. Such spatial orientation of the substituents in
molecule V implies preferential formation of cyclic
structure IIIc with o-methoxyphenyl group on the
nitrogen atom in the pyridine ring. The formation of
isomer IVc requires an alternative structure of linear
intermediate V, where the cyano group appears in the
vicinity of the anilide fragment with o-ethylphenyl
substituent. In fact, heating of compound V in alco-
Linear structure can be detected by H NMR spec-
troscopy only when both initial compounds contain
a substituent in the ortho position of the benzene
ring. Intermediate product could not be isolated in
reactions with unsubstituted or para-substituted deriv-
atives. The reaction gives two isomeric pyridinones
with different positions of substituted aryl groups, and
their ratio depends on the substituent nature. Reactions
with ortho-substituted compounds are also affected
by steric factor which is likely to slightly hamper
cyclization of linear intermediate, so that the latter can
be isolated in some cases. We ought to refrain from
estimating the effect of ortho substituents because of
the lack of definite relations in the formation of final
products.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 10 2011

DYACHENKO et al.
1542
Scheme 2.
Me
N
OEt
O
O
OMe
Et
H
H
N
N
N
CN
CN
EtONa
Na+
H
+
O
O
N
Et
N
H
O
N
Ia
IIa
V
O
O
CN
CN
N
N
H
H
Et
OMe
H2N
N
O
H2N
O
+
OMe
Et
IIIc
IVc
To conclude, cyano(ethoxymethylidene)acetanilides
II act as three-carbon synthons in the formation pyri-
dine ring. The position of differently substituted aryl
groups in the resulting compounds depends on the
substituent nature. The cyclization to pyridin-2-one is
facilitated by increase in nucleophilicity of the anilide
nitrogen atom.
(a solid separated from the solution). The mixture was
left to stand for 2 h, the precipitate was filtered off and
washed with ethanol and hexane, and H NMR spec-
1
trum of the crude product was recorded. The isomer
ratio was calculated from the intensities of 4-H and
NH signals. Isomer IIIa or IIIb was isolated by
recrystallization of the crude product from acetone–
ethanol (4:1).
1
EXPERIMENTAL
Isomer mixture IIIa/IVa. H NMR spectrum, δ,
ppm: 7.11 t (major), 7.34 t (major), 7.39–7.42 m
(minor) (3H, C6H5, J = 7.3 Hz); 7.43 d (major), 7.58–
7.59 m (major), 7.65 d (minor), 7.67 d (major) (4H,
4-ClC6H4, J = 8.5 Hz); 7.57–7.58 m (minor), 7.61 d
(major) (2H, C6H5, J = 7.9 Hz); 8.69 s (minor), 8.70 s
(major) (1H, 4-H); 9.93 br.s (major), 10.02 br.s (minor)
(1H, NH).
The melting points were determined on a Kofler hot
stage. The IR spectrum of compound V (in mineral oil)
1
was recorded on an IKS-29 spectrometer. The H and
13C NMR spectra were measured on a Bruker Avance
DRX-500 spectrometer from solutions in DMSO-d6
using tetramethylsilane as internal reference. The mass
spectrum of V was obtained on a Hewlett–Packard HP
5890/5972 GC/MS system (HP-5MS column; electron
impact, 70 eV). The progress of reactions and the
purity of products were monitored by thin-layer chro-
matography on Silufol UV-254 plates using acetone–
hexane (3:5) as eluent; spots were developed by treat-
ment with iodine vapor or under UV light.
2-Amino-1-(4-chlorophenyl)-5-cyano-6-oxo-N-
phenyl-1,6-dihydropyridine-3-carboxamide (IIIa).
Yield 68–72%, colorless plates, mp 278–280°C (from
1
acetone–EtOH, 4:1). H NMR spectrum, δ, ppm: 7.11 t
(1H, C6H5, J = 7.3 Hz), 7.34 t (2H, C6H5, J = 7.3 Hz),
7.43 d (2H, C6H4, J = 8.5 Hz), 7.61 d (2H, C6H5, J =
7.9 Hz), 7.67 d (2H, C6H4, J = 8.5 Hz), 8.70 s (1H,
4-H), 9.93 br.s (1H, NH); signals from the NH2 group
were not observed, presumably because of fast ex-
change. 13C NMR spectrum, δC, ppm: 30.64, 84.93,
93.40, 117.73, 120.93, 123.77, 128.54, 130.47, 130.77,
132.93, 134.56, 138.50, 146.28, 157.23, 159.55,
164.84. Found, %: C 62.41; H 3.42; N 15.11.
C19H13ClN4O2. Calculated, %: C 62.56; H 3.59;
N 15.36.
2-Amino-N,1-diaryl-5-cyano-6-oxo-1,6-dihydro-
pyridine-3-carboxamides IIIa, IIIb, IVa, and IVb
(general procedure). Metallic sodium, 0.23 g
(10 mmol), was dissolved in 20 ml of anhydrous
ethanol, 10 mmol of the corresponding cyanoacet-
anilide I added, and the mixture was stirred for 5 min
(it became homogeneous). Compound II, 10 mmol,
was then added, and the mixture was stirred for 10 min
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 10 2011

FORMATION OF OXOPYRIDINE RING FROM TWO CYANOACETANILIDE MOLECULES
1543
1
Isomer mixture IIIb/IVb. H NMR spectrum, δ,
ppm: 3.72 s (major), 3.73 s (min) (3H, MeO); 6.83–
6.88 m, 6.95–7.00 m (1H, Harom); 6.92–6.49 m (major),
7.10–7.11 m (minor) (2H, Harom); 7.23 d (major),
7.28 d (minor), 7.45–7.48 m (minor), 7.62 d (major)
(4H, ClC6H4, J = 8.5 Hz); 8.11 s (minor), 8.13 s
(major) (1H, 4-H); 8.51 d (major), 8.52 d (minor) (1H,
7.21 t (1H, MeOC6H4, J = 7.6 Hz), 7.28 d (1H,
MeOC6H4, J = 7.7 Hz), 7.44 m (2H, Harom), 7.54 d
(2H, Harom, J = 6.5 Hz), 8.74 s (1H, 4-H), 9.46 br.s
(1H, NH); signals from the NH2 group were not ob-
served, presumably because of fast exchange. 13C NMR
spectrum, δC, ppm: 13.63, 23.06, 55.60, 84.98, 93.16,
111.62, 117.68, 120.03, 125.95, 126.41, 127.98,
128.02, 128.72, 129.88, 130.23, 132.18, 140.93,
146.38, 152.80, 156.89, 159.29, 164.85. Found, %:
C 67.92; H 5.01; N 14.33. C22H20N4O3. Calculated, %:
C 68.03; H 5.19; N 14.42.
(E)-2,4-Dicyano-N1-(2-ethylphenyl)-N5-(2-me-
thoxyphenyl)pent-2-enediamide (V). Yield 60%,
yellow powder, mp 237–238°C (first from acetone and
then from acetone–EtOH, 4:1). IR spectrum, ν, cm–1:
3470, 3420 (NH); 2210, 2190 (C≡N); 1635 (C=O).
1H NMR spectrum, δ, ppm: 1.16 t (3H, CH2CH3, J =
7.3 Hz), 2.57 q (2H, CH2CH3, J = 7.3 Hz), 3.86 s (3H,
H
arom, J = 7.7 Hz); 13.33 br.s (major), 13.84 br.s
(minor) (1H, NH).
2-Amino-1-(4-chlorophenyl)-5-cyano-N-(2-me-
thoxyphenyl)-6-oxo-1,6-dihydropyridine-3-carbox-
amide (IIIb). Yield 83–91%, white powder, mp 262–
1
264°C (from acetone–EtOH, 4:1). H NMR spectrum,
δ, ppm: 3.72 s (3H, MeO), 6.83 t (1H, Harom, J =
8.5 Hz), 6.92–6.94 m (2H, Harom), 7.23 d (2H, ClC6H4,
J = 8.5 Hz), 7.62 d (2H, ClC6H4, J = 8.5 Hz), 8.13 s
(1H, 4-H), 8.51 d (1H, Harom, J = 7.7 Hz), 13.33 br.s
(1H, NH); signals from the NH2 group were not ob-
served, presumably because of fast exchange. Found,
%: C 60.72; H 3.77; N 14.02. C20H15ClN4O3. Calculat-
ed, %: C 60.84; H 3.83; N 14.19.
MeO), 6.89 t (1H, Harom, J = 7.6 Hz), 7.96 t (1H, Harom
J = 6.9 Hz), 7.04 d (2H, Harom, J = 7.8 Hz), 7.15 t (1H,
arom, J = 7.3 Hz), 7.19 d (1H, Harom, J = 7.4 Hz),
,
H
7.71 d (1H, Harom, J = 9.3 Hz), 8.06 s (1H, 4-H),
Compounds IIIc, IVc, and V. Compound V was
synthesized according to the procedure described
above for IIIa/IVa and IIIb/IVb. Recrystallization of
the crude product from acetone–ethanol (4:1) gave
compound V. Heating of the latter in ethanolic sodium
ethoxide [0.23 g (10 mmol) of metallic sodium was
dissolved in 20 ml of anhydrous ethanol] gave isomer
mixture IIIc/IVc.
8.22 br.s and 8.24 br.s (1H each, NH), 8.27 d (1H,
H
arom, J = 7.9 Hz). 13C NMR spectrum, δC, ppm: 14.31,
24.37, 56.51, 73.84, 75.45, 111.07, 118.88, 120.46,
121.07, 122.81, 124.07, 124.63, 126.48, 128.80,
129.03, 135.96, 137.28, 148.00, 164.03, 164.67. Mass
spectrum: m/z 388.4 (Irel 100%) [M]+. Found, %:
C 67.92; H 5.01; N 14.33. C22H20N4O3. Calculated, %:
C 68.03; H 5.19; N 14.42. M 388.424.
1
Isomer mixture IIIc/IVc. H NMR spectrum, δ,
ppm: 1.12 t (major), 1.15 t (minor) (3H, CH2CH3, J =
7.5 Hz); 2.28–2.37 m (2H, CH2CH3); 3.79 s (minor),
3.84 s (major) (3H, MeO); 6.95 t (major), 7.15 t
(minor) (1H, MeOC6H4, J = 7.5 Hz); 7.10 d (major),
7.31 d (minor) (1H, Harom, J = 7.3 Hz); 7.21 t (major),
7.25 m (minor) (1H, MeOC6H4, J = 7.6 Hz); 7.28 d
(major), 7.32–7.33 m (minor) (1H, MeOC6H4, J =
7.7 Hz); 7.43–7.47 m (2H, Harom); 7.51–7.58 m (2H,
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δ, ppm: 1.12 t (3H, CH2CH3, J = 7.5 Hz), 2.33 q (2H,
CH2CH3, J = 7.5 Hz), 3.84 s (3H, MeO), 6.95 t (1H,
MeOC6H4, J = 7.5 Hz), 7.10 d (1H, Harom, J = 7.3 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 10 2011