Alkyl 2-amino-5,6-dialkyl-3-cyanopyridine-4-carboxylates in reactions with electrophilic reagents

Article abstract of DOI:10.1134/S1070428007100223

In reaction of alkyl 2-amino-5,6-dialkyl-3-cyanopyridine-4-carboxylates with isocyanates formed unstable ureas, and with nitrous acid at 60-70°C alkyl 5,6-dialkyl-2-oxo-1,2-dihydro-4-pyidinecarboxylates were obtained. It was shown for the latter that their reactions with organic acids and amides occurred at the cyano group, and the alkaline hydrolysis involved the ester group.

Full text of DOI:10.1134/S1070428007100223

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 10, pp. 1537−1544. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © A.N. Vasil’ev, A.N. Lyshchikov, O.E. Nasakin, S.A. Paramonov, Ya.S. Kayukov, 2007, published in Zhurnal Organicheskoi
Khimii, 2007, Vol. 43, No. 10, pp. 1541−1548.
Alkyl 2-amino-5,6-dialkyl-3-cyanopyridine-4-carboxylates
in Reactions with Electrophilic Reagents
A. N. Vasil’ev, A. N. Lyshchikov, O. E. Nasakin, S. A. Paramonov, and Ya. S. Kayukov
I.N. Ul\yanov Chuvash State University, Cheboksary, 428015 Russia
e-mail: caesar7@mail.ru
Received October 7, 2006
Abstract—In reaction of alkyl 2-amino-5,6-dialkyl-3-cyanopyridine-4-carboxylates with isocyanates formed
unstable ureas, and with nitrous acid at 60–70°C alkyl 5,6-dialkyl-2-oxo-1,2-dihydro-4-pyidinecarboxylates were
obtained. It was shown for the latter that their reactions with organic acids and amides occurred at the cyano
group, and the alkaline hydrolysis involved the ester group.
DOI: 10.1134/S1070428007100223
Nowadays a special attention is attracted to com-
pounds containing the structural skeleton of the known
pharmaceuticals; at the same time the presence of reactive
functional groups is favorable for their further application
to the synthesis of biologically active compounds.
Formerly synthesized alkyl 2-amino-5,6-dialkyl-3-cyano-
pyridine-4-carboxylates Ia–Ii are promising in this
respect [1, 2]. We investigated their reactions with N-, O-
nucleophiles and the reduction; as a result pyrrolo[3,4-c]-
pyridines and furo[3,4-c]-pyridines were obtained. In the
study of the properties of the enaminonitrile fragment of
pyridines Ia–Ii the reactivity of the functional groups
combined in the structure should be taken into consider-
ation also as separate agents. Amino group in the
molecules of pyridines Ia–Ii possesses low basicity due
to the presence of strong electron-withdrawing groups.
We used as reagents m-chlorophenyl isocyanate,
phenyl isocyanate, and ethyl isocyanate. It was found
that this reaction occurred only in the presence of Lewis
acids (aluminum chloride and zinc chloride) leading to
the formation of 3-cyano-2-(3-R-ureido)-5,6-dialkyl-
pyridine-4-carboxylates IIa–IIl. The substances obtained
were fine needle light-red crystals stable at room
temperature.
Scheme 1.
Me
O
O
R3
N
R1
R2
CN
+
C
O
N
NH2
It is known that compounds containing in the structure
an ortho-enaminonitrile fragment are capable to enter
into electrophilic reactions at the amino group with
bifunctional compounds and CH-acids (acetylacetone,
ethyl acetoacetate, ethyl cyanoacetate, formamide, and
formic acid), suggesting the possibility to synthesise
therefrom new fused heterocycles. Amino group in
pyridine I as show experimental data does not react by
the classic scheme due to its low nucleophilicity.
Therefore the reaction of pyridines I with active
compounds like isocyanates is complicated. Notwith-
standing the low nucleophilicity of the amino group we
still succeeded in performing this reaction and syn-
thesizing the corresponding ureas IIa–IIl (Scheme 1).
_
Iа Id
Me
O
O
R1
R2
CN
ZnCl2, dioxane
R3
HN
N
N
O
H
_
IIа IIl
R3 = Et, R1,R2 = (CH2)4 (a), (CH2)3 (b), Me (c), R1 = H,
R2 = Me, (d); R3 = Ph, R1,R2 = (CH2)4 (e), (CH2)3 (f),
Me (g), R1 = H, R2 = Me (h), R3 = 3-Cl-C6H4, R1,R2 =
(CH2)4 (i), (CH2)3 (j), Me (k), R1 = H, R2 = Me (l).
1537

VASIL’EV et al.
1538
The structures of compounds IIa–IIl were suggested
the observed temperature mode of this reaction is the
formation not of diazopyridines A but alkyl 5,6-dialkyl-
2-oxo-1,2-dihydropyridine-4-carboxylates IIIa–IIIi
(Scheme 2). The obtained esters IIIa–IIIi are dark-
yellow crystalline substances stable in air and strongly
fluorescent even in highly diluted solutions.
based on 1H NMR, mass, and IR spectra. The IR spectra
confirm that the ester and cyano groups remained intact
as show strong bands of the stretching vibrations in the
regions 1734–1703 and 2245–2233 cm–1 respectively.
The medium absorption bands in the region 3405–3175
and 1629–1579 cm–1 were assigned to the stretching and
bending vibrations of amino groups.
In the IR spectra of compounds IIIa–IIIi the presence
of strong absorption bands in the region 1707–1724 and
2232–2243 cm–1 indicated the presence in the molecules
of a carbonyl and a conjugated cyano groups. The
medium bands in the region 3460–3147 and 1625–1587
cm–1 evidenced the presence of the stretching and
bending vibrations of the NH bond, and the absorption
bands in the region 1669–1630 cm–-1 were assigned to
the vibrations of the amide carbonyl.
An important proof of the presence of two NH groups
in the urea fragment is the appearance of singlets in the
1H NMR spectrum in the region 7.79–9.92 ppm. The
methoxy group gives rise to a singlet at 4.00–3.96 ppm.
The presence of Lewis acids did not cause intramolecular
cyclization into pyrrolo[3,4-c]pyridines like in reactions
with formamide or other bifunctional compounds. This
fact is due to the total absence of water in the system.
However the prolonged heating led to the formation of
insignificant amounts of the mentioned pyrrolo[3,4-c]-
pyridines, and in some cases these substances formed in
a quantitative yield. The governing factor here is the
synthesis conditions and the stability of ureas obtained.
1
In the H NMR spectra of compounds IIIa–IIIi
singlets appeared at 10.13–13.92 ppm characteristic of
NH groups of a pyridone ring. Mass spectra of pyridones
IIIa–IIIi contain molecular ions peaks of low intensity
and also strong peaks of fragment ions [M – CH3]+, [M
– OCH3]+ whose formation is due to the presence of
ester groups in the molecules.
Compounds IIa–IIl are of low stability, and in acid
medium or in the presence of small quantity of aluminum
oxide the urea fragment suffers decomposition, and form
initial pyridines I. A similar pattern is followed by TLC.
The mass spectra of synthesized ureas IIa–IIl are
characterized by molecular ions of various intensity
apparently due to the nature of the used isocyanate.
The spectral data suggest with a high probability that
the reaction proceeds by the assumed Scheme 2. The
primary formation of a diazo group by diazotization of
the amino group in acid medium does not differ from the
synthesis of similar known aromatic diazo structures
except for the modified conditions of the process. Further
the diazo product apparently suffers hydrolysis in the
water medium at the formed diazo group resulting in its
replacement and introduction of a hydroxy group into
the pyridine ring; the product readily isomerizes into
more stable pyridones IIIa–IIIi.
A characteristic feature of aromatic amines is
diazotization commonly performed by treating with
nitrous acid at low temperature [3–7].
A distinctive feature of this reaction with compounds
Ia–Ii is its uncommon conditions. Diazotization of the
amino group in pyridines Ia–Ii occurred only at elevated
temperature (60–70°C). However the stability of diazon-
ium salts decreases with rising temperature. Apparently
We continuously attempted to find favorable
conditions and methods for introducing diazo group.
Neither of the procedures used gave a positive result.
Scheme 2.
R1
O
R1
O
R1
O
O
O
O
R2
R3
CN
R2
R3
CN
H2O,
_N2
R2
R3
CN
O
NaNO2, HCl
+
N
NH2
N
N
Cl_
N
N
H
_
_
IIIа IIIi
А
Iа Ii
R1 = Me, R2,R3= (CH2)4 (a), (CH2)3 (b), Me (c); R1 = R3 = Me, R2 = H (d); R1 = HOCH2CH2, R2,R3 = (CH2)4 (e), (CH2)3
(f), Me (g), R2 = H, R3 = Me (h); R1 = Et, R2,R3 = (CH2)4 (i).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

ALKYL 2-AMINO-5,6-DIALKYL-3-CYANOPYRIDINE-4-CARBOXYLATES
1539
Thus the above reaction is, firstly, a preparative method
of synthesis for pyridones IIIa–IIIi, and secondly, an
illustrative example of diazotization proceeding at high
temperature demonstrating the versatility of classic
reactions.
cyanopyridones III like pyridines I occurred in acid
medium evidently by AaC1 mechanism. The distinctive
feature of the process is that it easyly proceeded with
quantitative yield even at low temperature.
1H NMR spectroscopy revealed that pyrrolo[3,4-c]-
pyridine-1,3,4(2H,5H)-trione IVa in DMSO underwent
equilibrium tautomeric transformation of the amide form
into imidol one IVa’, and the content of the latter
according to 1H NMR was 25%.
The presence in the structure of pyridones IIIa–IIIi
like in that of pyridines Ia–Ii of several reactive sites,
such as ester and cyano groups, makes it possible to study
their reactions with N- and O-nucleophiles. The
hydrolysis of pyridones IIIa–IIIi with mineral acids
occurred along the pattern analogous to the reaction of
pyridines I involving directly the ester and cyano group
and providing 6,7-dialkyl-1H-pyrrolo[3,4-c]pyridine-
1,3,4(2H,5H)-triones IVa–IVd in virtually quantitative
yields (Scheme 3).
Inasmuch as compounds III underwent the acid
hydrolysis by the same scheme as pyridines I [2] we
additionally compared their reactions with organic acids,
amides, and alkali. 6,7-Dialkyl-1H-pyrrolo[3,4-c]-
pyridine-1,3,4(2H,5H)-trione (IVa) was also obtained by
reactions of pyridone IIIa with organic acids and the
corresponding amides. The pattern of trione IVa
formation (Scheme 4) evidently does not differ from
the analogous reaction of pyridine I with these reagents.
Organic acids and their amides also behave as O-
nucleophiles with respect to the carbon of the cyano
group of pyridone IIIa. The used reagents were formic
and butyric acids, formamide, and acetamide. This
approach is distinguished by milder reaction conditions.
To support the assumed scheme we identified in the
reaction mixtures by GLC arising acetonitrile and methyl
butyrate in reactions with acetamide and butyric acid
respectively.
Compounds IVa–IVd are yellow fine crystalline
substances sparingly soluble in most organic solvents
save hot DMSO. Their structure was assumed based on
spectral data. In the IR spectra of compounds obtained
two strong absorption bands are present in the region
1717–1702 cm–1 originating from the stretching
vibrations of the carbonyl group in the imide moiety.
The absorption bands in the region 3340–3110 and 1640–
1630 cm–1 correspond to the stretching and bending
vibrations of the amino group. The additional most
informative signals in the region 1685–1670 and 1587–
1530 cm–1 are the absorption bands “amide I” and “amide
II”. The 1H NMR data indicate the presence of two NH
groups giving rise to two informative downfield singlets
at 10.80–10.87 and 12.30–12.57 ppm respectively.
The presence of an ester fragment in pyridones III
structure, like in pyridines I suggested to test their reac-
tion with alkali. The experiments showed that pyridones
III readily reacted with alkali solutions to give solutions
of isonicotinic acids salts B. A specific feature of the
reaction was unsuccessful attempt to isolate pyridine-4-
carboxylic acid sodium salt B. The attempts to isolate
the salt in the individual state, like in hydrolysis of
pyridines I in alkali [2], resulted in intramolecular
Identification of compounds IVa–IVd suggested a
scheme assuming that the hydrolysis of 4-pyridine-
carboxylates derivatives started at the cyano group
located in the ortho-position with respect to the
akoxycarbonyl moiety. We presume that this route is
preferable because of more favorable stabilization by
cyclization involving the ester group. Hydrolysis of
Scheme 3.
R1
O
H
H
O
O
O
N
+
NH
N
R2
R3
R2
R3
R2
R3
O
O
H2SO4
NaHCO3, H2O
_
IIIа IIIh
R1OH, (NH4)2SO4
N
O
N
OH
N
O
H
H
_
IVа
IVа IVd
R2,R3 = (CH2)4 (a), (CH2)3 (b), Me (c), R2 = H, R3 = CH3 (d).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

VASIL’EV et al.
1540
Scheme 4.
CH3
O
CH3
O
H3C
OH
O
R
C
O
O
O
N
NH
R
C
R
C
NH
CN
O
O
NH2
O
NH
N
N
O
N
O
H
H
H
IIIa
O
N
OH
_RCN,
IVa
_ CH3OH
N
O
H
H3C
OH
CH3
O
R
O
O
O
N
NH
O
C
C
R
C
O
O
OH
O
R
N
O
N
H
O
H
CH3
O
O
O
O
R
R
N
N
N
C
O
OH
OH
O
O
CH3OH
_ CH3OH
IVa
O
N
O
N
O
N
O
_ R
C
H
H
H
OCH3
R = H, Me, Pr.
region 3382–3227 and 1630–1617 cm–1 the stretching
and bending vibrations of NH bonds are observed.
heterocyclization with a simultaneous formation of
an imide ring. At the same time a cautious neutralization
of the salts solutions with diluted acids till pH 4 (against
Congo Red) permitted a synthesis of the corresponding
acids Va and Vd that we isolated and identified.
1H NMR spectra give the best confirmation of the
suggested structures by observation in the downfield
region of acid hydroxy group signal at 12.20–12.75 ppm.
The resonance at 9.20 ppm belongs to the NH group of
the pyridone ring, but in the spectrum of compound Vd
this peak does not appear or is of low intensity. The
solutions of 2-oxoisonicotinic acids V and their salts are
unstable and at heating or at long storage in the presence
of moisture traces they undergo intramolecular
cyclization into pyrrolo[3,4-c]pyridine-1,3,4-triones
IVa–IVd.
The structure of 5,6-dialkyl-2-oxo-1,2-dihydro-4-
pyridine carboxylic acids Va–Vd was derived from the
IR and 1H NMR spectra, the composition was confirmed
by elemental analysis. In the IR spectra the characteristic
strong bands in the region 2241–2235cm–1 indicate the
presence of a conjugated cyano group, and the absorption
in the region 1710–1707 cm–1 corresponds to the
stretching vibrations of the carbonyl group. Absorption
bands “amide I “ and “amide II” appear in the region
1679–1680 and 1555–1541 cm–1 respectively, and in the
Thus pyridones III that we synthesized are similar in
reactivity to pyridines I in reactions with O-nucleophiles
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

ALKYL 2-AMINO-5,6-DIALKYL-3-CYANOPYRIDINE-4-CARBOXYLATES
1541
zinc chloride. The mixture was boiled at exclusion of air
moisture till disappearance of the initial pyridine. The
mixture was cooled to –5°C for 5 h, the separated
colorless precipitate was quickly filtered off, washed with
5 ml of anhydrous ethyl ether, and dried in a vacuum
desiccator.
OH
O
O_
1OR
R2
O_
R2
R3
CN
O
OH _
CN
_R1OH
_
IIIа IIId
R3
N
H
O
N
H
Methyl 5,6-dialkyl-3-cyano-2-(3-phenylureido)-
pyridine-4-carboxylates IIe–IIh were similarly
prepared from 1 mmol of pyridine Ia–Id and 1.2 g (0.01
mol) of phenyl isocyanate.
B
O
OH
CN
Methyl 5,6-dialkyl-3-cyano-2-[3'-(3''-chloro-
phenyl)ureido]pyridine-4-carboxylates IIi–IIl were
similarly prepared from 1 mmol of pyridine Ia–Id and
1.5 g (0.01 mol) m -chlorophenyl isocyanate.
R2
R3
, H O
Δ
2
_
IVa IVd
N
O
H
Methyl 5,6-tetramethylene-3-cyano-2-(3-ethyl-
ureido)pyridine-4-carboxylate (IIa). Yield 54%, mp
112°C. IR spectrum, ν, cm–1: 3305, 3292, 3185 (NH,
NH2), 1734 (C=O), 2242 (C≡N). 1H NMR spectrum, δ,
_
Vа Vd
R2,R3 = (CH2)4 (a), (CH2)3 (b), Me (c), R2 = H, R3 = Me
(d).
ppm: 1.07 t (3H, CH3CH2), 1.87 m
(4H,
and suffer hydrolysis with acids and alkali with the direct
participation of cyano or ester groups.
CH2CH2CH2CH2), 2.87 t (2H, CH2CH2), 2.97 t (2H,
CH2CH2), 3.18 q (2H, CH2CH3), 4.00 s (3H, CH3),
7.79 s (1H, NH), 8.15 s (1H, NH). Mass spectrum, m/z
(Irel, %): 302 (88) [M]+, 258 (71), 244 (29), 231 (86),
216 (69), 116 (55), 101 (15), 71 (17), 56 (22), 44 (100).
Found, %: C 59.69; H 6.17; N 18.47. C15H18N4O3.
Calculated, %: C 59.59; H 6.00; N 18.53. M 302.33.
EXPERIMENTAL
The monitoring of reactions progress and checking
the purity of substances obtained was performed by TLC
on Silufol UV-254 plates, development under UV
irradiation (365 nm) or in iodine vapor. IR spectra were
recorded on a spectrophotometer UR-20 from thin films
(or mulls in mineral oil). 1H NMR spectra were registered
from solutions in DMSO-d6 on spectrometers Bruker
WM-250, BrukerAM-300, Bruker DRX-500 at operating
frequencies 250.13, 300.13, and 500.13 M Hz respec-
tively (internal refeence TMS). Mass spectra of high
and low resolution were taken on a Finnigan MAT
INCOS-50 instrument at the ionization energy 70 eV.
GLC analyses were carried out on a chromatograph
LKhM-6MD equipped with katharometer, column
3000×3 mm, stationary phase SP-2100 (or XΕ-60), 5%
on the carrier Chromaton N-AW-DMCS, grains 0.250–
0.315 μm, oven temperature 115–120°C, carrier gas
helium, flow rate 40 ml/min, detector current 140 μA,
sensitivity 10, sample volume 0.5 μl, rate of the recorder
chart 240 mm/h.
Methyl 5,6-trimethylene-3-cyano-2-(3-ethyl-
ureido)-pyridine-4-carboxylate (IIb). Yield 57%, mp
158°C. IR spectrum, ν, cm–1: 3306, 3292, 3187 (NH,
NH2), 1716 (C=O), 2237 (C≡N). Found, %: C 58.35;
H 5.39; N 19.51. C14H16N4O3. Calculated, %: C 58.32;
H 5.59; N 19.43.
Methyl 5,6-dimethyl-3-cyano-2-(3-ethylureido)-
pyridine-4-carboxylate (IIc). Yield 34%, mp 147°C. IR
spectrum, ν, cm–1: 3405, 3356, 3276, 3190 (NH, NH2),
1
1728 (C=O), 2245 (C≡N). H NMR spectrum, δ, ppm:
1.12 t (3H, CH3CH2), 2.39 s (3H, CH3), 2.60 s (3H, CH3),
3.20 q (2H, CH2CH3), 4.01 s (3H, CH3), 7.62 s (1H, NH),
8.71 s (1H, NH). Found, %: C 56.54; H 5.68; N 20.23.
C13H16N4O3. Calculated, %: C 56.51; H 5.84; N 20.28.
Methyl 6-methyl-3-cyano-2-(3-ethylureido)-
pyridine-4-carboxylate (IId). Yield 45%, mp 163°C.
IR spectrum, ν, cm–1: 3370, 3250, 3187 (NH, NH2), 1717
1
Methyl 5,6-dialkyl-3-cyano-2-(3-ethylureido)-
pyridine-4-carboxylates IIa–IId. To a solution of
1 mmol of pyridine Ia–Id in 5 ml of anhydrous dioxane
at exclusion of air moisture was added 0.71 g (0.01 mol)
of ethyl isocyanate and 0.0136 g (0.1 mmol) of anhydrous
(C=O), 2230 (C≡N). H NMR spectrum, δ, ppm: 1.17 t
(3H, CH3CH2), 2.59 t (3H, CH3), 3.25 q (2H, CH2CH3),
3.97 s (3H, CH3), 7.47 s (1H, CH), 7.98 C (1H, NH),
8.52 s (1H, NH). Mass spectrum, m/z (Irel, %): 262 (2)
[M]+, 217 (3), 191 (100), 160 (24), 133 (26), 91 (19), 64
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

VASIL’EV et al.
1542
(8), 42 (20). Found, %: C 55.01; H 5.24; N 21.47.
C12H14N4O3. Calculated, %: C 54.96; H 5.38; N 21.36.
M 262.27.
C6H5), 7.30 d.d (1H, C6H5), 7.70 d (1H, C6H5), 9.12 s
(1H, NH), 9.79 s (1H, NH). Found, %: C 58.47; H 4.19;
N 9.49. C18H15ClN4O3. Calculated, %: C 58.31; H 4.08;
N 9.56.
Methyl 5,6-tetramethylene-2-(3-phenylureido)-3-
cyanopyridine-4-carboxylate (IIe). Yield 36%, mp
181°C. IR spectrum, ν, cm–1: 3323, 3282, 3193 (NH,
Methyl 5,6-dimethyl-2-[3-(3-chlorophenyl)]-3-
cyanopyridine-4-carboxylate (IIk). Yield 41%, mp
140°C. IR spectrum, ν, cm–1: 3382, 3248, 3175 (NH,
NH2), 1720 (C=O), 2235 (C≡N). 1H NMR spectrum, δ,
ppm: 2.23 s (3H, CH3), 2.59 s (3H, CH3), 4.00 s (3H,
CH3), 7.00 d (1H, C6H5), 7.29 d.d (1H, C6H5), 7.70 d
(1H, C6H5), 9.29 s (1H, NH), 9.83 s (1H, NH). Found,
%: C 56.73; H 4.17; N 9.75. C17H15ClN4O3. Calculated,
%: C 56.91; H 4.21; N 9.88.
1
NH2), 1716 (C=O), 2237 (C≡N). H NMR spectrum, δ,
ppm: 1.80 m (2H, CH2CH2CH2CH2), 1.87 m (2H,
CH2CH2CH2CH2), 2.70 t (2H, CH2CH2), 2.93 t (2H,
CH2CH2), 3.96 s (3H, CH3), 7.25 m (5H, C6H5), 9.18 s
(1H, NH), 9.18 s (1H, NH). Found, %: C 65.01; H 5.27;
N 15.86. C19H18N4O3. Calculated, %: C 65.13; H 5.18;
N 15.99.
Methyl 6-methyl-2-[3-(3-chlorophenyl)]-3-
cyanopyridine-4-carboxylate (IIl). Yield 52%, mp
138°C. IR spectrum, ν, cm–1: 3337, 3285 (NH, NH2),
1703 (C=O), 2234 (C≡N). 1H NMR spectrum, δ, ppm:
2.63 t (3H, CH3), 3.95 s (3H, CH3), 7.00 s (1H, CH),
7.07 s (1H, C6H5), 7.29 d.d (1H, C6H5), 7.70 d (1H,
C6H5), 9.11 s (1H, NH), 10.11 s (1H, NH). Mass spec-
trum: m/z (Irel, %): 344(11) [M]+, 217(14), 191(100),
186(23), 160(27), 153(36), 133(23), 127(46), 99(38),
63(31), 42(23). Found, %: C 55.87; H 3.77; N 10.14.
C16H13ClN4O3. Calculated, %: C 55.74; H 3.80; N 10.28.
M 344.76.
Methyl 5,6-trimethylene-2-(3-phenylureido)-3-
cyanopyridine-4-carboxylate (IIf). Yield 41%, mp
192°C. IR spectrum, ν, cm–1: 3379, 3253, 3185 (NH,
NH2), 1713 (C=O), 2241 (C≡N). Found, %: C 64.58; H
4.62; N 16.74. C18H16N4O3. Calculated, %: C 64.28; H
4.79; N 16.66.
Methyl 5,6-dimethylene-2-(3-phenylureido)-3-
cyanopyridine-4-carboxylate (IIg). Yield 47%, mp
161°C. IR spectrum, ν, cm–1: 3323, 3285, 3195 (NH,
NH2), 1717 (C=O), 2233 (C≡N). 1H NMR spectrum, δ,
ppm: 2.21 s (3H, CH3), 2.59 s (3H, CH3), 3.99 s (3H,
CH3), 6.95 m (5H, C6H5), 9.21 s (1H, NH), 9.51 s (1H,
NH). Found, %: C 62.77; H 4.81; N 17.38. C17H16N4O3.
Calculated, %: C 62.95; H 4.97; N 17.27.
Alkyl 5,6-dialkyl-2-oxo-1,2-dihydropyridine-4-
carboxylates IIIa–IIIi. A dispersion of 1 mmol of
pyridine Ia–Ii in 50 ml of 10% water solution of sodium
nitrite was heated to 65°C, and gradually was added
dropwise 5% HCl. The diazotization process was
monitored by test with iodine-starch test paper. The
completion of the reaction was determined by TLC. On
the completion of the reaction the mixture was cooled to
0°C. The precipitated yellow crystals of the product were
filtered off, washed with 3 ml of 2-propanol, recrystalliz-
ed from DMF, and dried in a vacuum desiccator.
Methyl 6-methyl-2-(3-phenylureido)-3-cyano-
pyridine-4-carboxylate (IIh). Yield 32%, mp 176°C.
IR spectrum, ν, cm–1: 3365, 3249, 3185 (NH, NH2), 1714
(C=O), 2235 (C≡N). Found, %: C 61.85; H 4.71; N 18.17.
C16H14N4O3. Calculated, %: C 61.93; H 4.55; N 18.06.
Methyl 5,6-tetramethylene-2-[3-(3-chlorophenyl)]-
3-cyanopyridine-4-carboxylate (IIi). Yield 43%, mp
260°C. IR spectrum, ν, cm–1: 3385, 3307, 3187 (NH,
NH2), 1721 (C=O), 2240 (C≡N). 1H NMR spectrum, δ,
ppm: 1.85 m (4H, CH2CH2CH2CH2), 2.73 t (2H,
CH2CH2), 2.96 t (2H, CH2CH2), 3.97 s (3H, CH3), 7.03
d (1H, C6H5), 7.30 d.d (1H, C6H5), 7.70 s (1H, CH), 9.28
s (1H, NH), 9.92 s (1H, NH). Found, %: C 59.53; H
4.56; N 9.11. C19H17ClN4O3. Calculated, %: C 59.30; H
4.45; N 9.21.
Methyl 2-oxo-5,6-tetramethylene-3-cyano-1,2-
dihydropyridine-4-carboxylate (IIIa). Yield 43%, mp
200°C. IR spectrum, ν, cm–1: 3460, 3307, 3205, 3155
1
(NH, NH2), 1724 (C=O), 2232 (C≡N). H NMR spec-
trum, δ, ppm: 1.71 m (4H, CH2CH2CH2CH2), 2.34 t
(2H, CH2CH2), 2.64 t (2H, CH2CH2), 3.92 s (3H, CH3),
12.65 s (1H, NH). Mass spectrum, m/z (Irel, %): 232 (27)
[M]+, 217 (100), 201 (20), 200 (27), 199 (89), 71 (30),
70 (26), 69 (42), 60 (34). Found, %: C 62.13; H 5.17; N
12.11. C12H12N2O3. Calculated, %: C 62.06; H 5.21; N
12.06. M 232.24.
Methyl 5,6-trimethylene-2-[3-(3-chlorophenyl)]-3-
cyanopyridine-4-carboxylate (IIj). Yield 39%, mp
215°C. IR spectrum, ν, cm–1: 3382, 3264, 3178 (NH,
NH2), 1716 (C=O), 2234 (C≡N). 1H NMR spectrum, δ,
ppm: 2.16 m (2H, CH2CH2CH2), 2.93 t (2H, CH2CH2),
3.58 t (2H, CH2CH2), 4.05 s (3H, CH3), 7.03 d (1H,
Methyl 2-oxo-5,6-trimethylene-3-cyano-1,2-
dihydropyridine-4-carboxylate (IIIb). Yield 68%, mp
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

ALKYL 2-AMINO-5,6-DIALKYL-3-CYANOPYRIDINE-4-CARBOXYLATES
1543
215°C. IR spectrum, ν, cm–1: 3535, 3385, 3290 (NH,
207°C. IR spectrum, ν, cm–1: 3442, 3356, 3274, 3156
(NH, NH2), 1707 (C=O), 2232 (C≡N). Mass spectrum,
m/z (Irel, %): 222 (9) [M]+, 192 (19), 179 (13), 162 (69),
134 (100), 105 (12), 92 (13), 78 (10), 64 (15), 42 (39).
Found, %: C 54.13; H 4.43; N 12.76. C10H10N2O4.
Calculated, %: C 54.05; H 4.54; N 12.61. M 222.20.
1
NH2), 1723 (C=O), 2235 (C≡N). H NMR spectrum, δ,
ppm: 2.11 m (4H, CH2CH2CH2), 2.81 t (2H, CH2CH2),
2.86 t (2H, CH2CH2), 3.93 s (3H, CH3), 13.09 s (1H,
NH). Found, %: C 60.59; H 4.65; N 12.76. C11H10N2O3.
Calculated, %: C 60.55; H 4.62; N 12.84.
Methyl 5,6-dimethyl-2-oxo-3-cyano-1,2-dihydro-
pyridine-4-carboxylate (IIIc). Yield 47%, mp 220°C.
IR spectrum, ν, cm–1: 3457, 3316, 3167 (NH, NH2), 1720
Ethyl 2-oxo-5,6-tetramethylene-3-cyano-1,2-
dihydropyridine-4-carboxylate (IIIi). Yield 65%, mp
193°C. IR spectrum, ν, cm–1: 3435, 3305, 3250, 3147
1
1
(C=O), 2232 (C≡N). H NMR spectrum, δ, ppm: 1.95 t
(NH, NH2), 1713 (C=O), 2232 (C≡N). H NMR
(3H, CH3), 2.31 t (3H, CH3), 3.97 s (3H, CH3), 12.80 s
(1H, NH). Found, %: C 58.24; H 4.91; N 13.53.
C10H10N2O3. Calculated, %: C 58.25; H 4.89; N 13.59.
spectrum, δ, ppm: 1.35 t (3H, CH3CH2), 1.71 m (4H,
CH2CH2CH2CH2), 2.35 t (2H, CH2CH2), 2.63 t (2H,
CH2CH2), 4.40 q (2H, CH2CH3), 12.62 s (1H, NH).
Found, %: C 63.43; H 5.75; N 11.31. C13H14N2O3.
Calculated, %: C 63.40; H 5.73; N 11.38.
Methyl 6-methyl-2-oxo-3-cyano-1,2-dihydro-
pyridine-4-carboxylate (IIId). Yield 38%, mp 240°C.
IR spectrum, ν, cm–1: 3365, 3310, 3150 (NH, NH2), 1722
(C=O), 2233 (C≡N). 1H NMR spectrum, δ, ppm: 2.34 t
(3H, CH3), 6.50 s (1H, CH), 13.92 s (1H, NH). Found,
%: C 56.22; H 4.21; N 14.58. C9H8N2O3. Calculated, %:
C 56.25; H 4.20; N 14.58.
6,7-Dialkyl-1H-pyrrolo[3,4-c]pyridine-1,3,4-
(2H,5H)triones IVa–IVd. A solution of 1 mmol of
pyridone IIIa–IIIh was heated at 150°C for 1 min in
2 ml of concn. H2SO4. On cooling to room temperature
the reaction mixture was neutralized with concn.
NaHCO3 toward litmus. Yellow precipitate was filtered
off, washed with 5 ml of 2 propanol, recrystallized from
DMF, and dried in a vacuum desiccator.
2-Hydroxyethyl 2-oxo-5,6-tetramethylene-3-
cyano-1,2-dihydropyridine-4-carboxylate (IIIe). Yield
58%, mp 262°C. IR spectrum, ν, cm–1: 3437, 3352, 3185
(NH, NH2), 1713 (C=O), 2243 (C≡N). Mass spectrum,
m/z (Irel, %): 262 (25) [M]+, 217 (100), 200 (86), 172
(84), 145 (20), 118 (18), 104 (22), 91 (28), 77 (28), 41
(27). Found, %: C 59.49; H 5.39; N.65. C13H14N2O4.
Calculated, %: C 59.54; H 5.38; N 10.68. M 262.
6,7-Tetramethylene-1H-pyrrolo[3,4-c]pyridine-
1,3,4(2H,5H)trione (IVa). Yield 84%, mp 260°C. IR
spectrum, ν, cm–1: 3340, 3280 (NH, NH2), 1717, 1705
1
(C=O). H NMR spectrum, δ, ppm: 1.75 m (4H,
CH2CH2CH2CH2), 2.51 t (2H, CH2CH2), 2.92 t (2H,
CH2CH2), 6.37 s 1H, OH), 10.80 s (1H, NH), 12.30 s
(1H, NH). Found, %: C 60.41; H 4.63; N 12.85.
C11H10N2O3. Calculated, %: C 60.55; H 4.62; N 12.84.
2-Hydroxyethyl 2-oxo-5,6-trimethylene-3-cyano-
1,2-dihydropyridine-4-carboxylate (IIIe). Yield 63%,
mp 258°C. IR spectrum, ν, cm–1: 3437, 3350, 3180 (NH,
NH2), 1713 (C=O), 2244 (C≡N). Found, %: C 58.16;
H 4.84; N 11.33. C12H12N2O4. Calculated, %: C 58.06;
H 4.87; N 11.29.
6,7-Trimethylene-1H-pyrrolo[3,4-c]pyridine-
1,3,4(2H,5H)trione (IVb). Yield 95%, mp 271°C. IR
spectrum, ν, cm–1: 3221, 3157 (NH, NH2), 1709, 1702
(C=O). Found, %: C 58.60; H 3.97; N 13.69. C10H8N2O3.
Calculated, %: C58.82; H 3.95; N 13.72.
2-Hydroxyethyl 5,6-dimethyl-2-oxo-3-cyano-1,2-
dihydropyridine-4-carboxylate (IIIg). Yield 70%, mp
230°C. IR spectrum, ν, cm–1: 3480, 3365, 3170 (NH,
NH2), 1726 (C=O), 2237 (C≡N). 1H NMR spectrum, δ,
ppm: 1.62 t (3H, CH3), 2.18 t (3H, CH3), 2.57 t (2H,
CH2CH2OH), 1.47 m (2H, CH2CH2OH), 3.71 s (1H,
OH), 10.13 s (1H, NH). Mass spectrum, m/z (Irel, %):236
(3) [M]+, 235 (8), 234 (16), 216 (7), 197 (23), 159 (100),
131 (42), 118 (30), 114 (29), 104 (42), 90 (54), 77 (36),
73 (40). Found, %: C 55.56; H 5.22; N 11.78.
C11H12N2O4. Calculated, %: C 55.93; H 5.12; N 11.86.
M 236.23.
6,7-Dimethyl-1H-pyrrolo[3,4-c]pyridine-
1,3,4(2H,5H)trione (IVc). Yield 83%, mp 262°C. IR
spectrum, ν, cm–1: 3220, 3150 (NH, NH2), 1710, 1702
1
(C=O). H NMR spectrum, δ, ppm: 2.30 s (3H, CH3),
2.37 s (3H, CH3), 10.83 s (1H, NH), 12.50 s (1H, NH).
Found, %: C 56.40; H 4.15; N 14.60. C9H8N2O3.
Calculated,%: C 56.25; H 4.20; N 14.58.
6-Methyl-1H-pyrrolo[3,4-c]pyridine-1,3,4-
(2H,5H)trione (IVd). Yield ) 87%, mp 259°C. IR
spectrum, ν, cm–1: 3285,3110 (NH, NH2), 1717, 1705
1
2-Hydroxyethyl 6-methyl-2-oxo-3-cyano-1,2-
dihydropyridine-4-carboxylate (IIIh). Yield 37%, mp
(C=O). H NMR spectrum, δ, ppm: 2.50 s (3H, CH3),
6.40 s (1H, CH), 10.87 s (1H, NH), 12.57 s (1H, NH).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

VASIL’EV et al.
1544
Found, %: C 53.97; H 3.46; N 15.62. C8H6N2O3.
Calculated,%: C 53.94; H 3.39; N 15.73.
IR spectrum, ν, cm–1: 3376, 3227 (NH, NH2), 1710
1
(C=O), 2241 (C≡N). H NMR spectrum, δ, ppm: 1.73
m (4H, CH2CH2CH2CH2), 2.34 t (2H, CH2CH2), 2.62 t
(2H, CH2CH2), 9.20 s (1H, NH), 12.20 s (1H, OH).
Found, %: C 60.34; H4.56; N 12.87. C11H10N2O3.
Calculated, %: C 60.55; H 4.62; N 12.84.
6,7-Tetramethylene-1H-pyrrolo[3,4-c]pyridine-
1,3,4(2H,5H)trione (IVa). a. A dispersion of 0.232 g (1
mmol) of pyridone IIIa in 2 ml of formamide was sealed
in an ampule and heated for 12 h at 130°C. On completion
of the reaction the cooled ampule was carefully opened,
and the reaction mixture was diluted with 2 ml of 1,4-
dioxane. The yellow precipitate was filtered off, washed
with 2 ml of 1,4-dioxane, recrystallized from DMF, and
dried in a vacuum desiccator. Yield 0.166 g (76%), mp
260°C. Found, %: C 60.41; H 4.63; N 12.85. C11H10N2O3.
Calculated, %: C 60.55; H 4.62; N 12.84.
2-Oxo-5,6-trimethylene-3-cyano-1,2-dihydro-
pyridine-4-carboxylic acid (Vb). Yield 57%, mp
239°C. IR spectrum, ν, cm–1: 3378, 3225 (NH, NH2),
1708 (C=O), 2240 (C≡N). Found, %: C 58.68; H 3.93;
N 13.67. C10H8N2O3. Calculated, %: C 58.82; H 3.95;
N 13.72.
5,6-Dimethyl-2-oxo-3-cyano-1,2-dihydropyridine-
4-carboxylic acid (Vc). Yield 43%, mp 196°C. IR
spectrum, ν, cm–1: 3380, 3227 (NH, NH2), 1710 (C=O),
2237 (C≡N). Found, %: C 56.39; H 4.27; N 14.64.
C9H8N2O3. Calculated, %: C56.25; H 4.20; N 14.58.
b. Under conditions similar to procedure a by reaction
of 0.232 g (1 mmol) of pyridone IIIa with 0.0886 g
(0.0015 mol) of acetamide we obtained 0.142 g (65%)
of trione IVa. To prove acetonitrile formation in the
reaction a fraction boiling within 76–85°C was taken
from the filtrate, and the presence of acetonitrile in the
fraction was confirmed by GLC.
6-Methyl-2-oxo-3-cyano-1,2-dihydropyridine-4-
carboxylic acid (Vd). Yield 34%, mp 185°C. IR
spectrum, ν, cm–1: 3382, 3286 (NH, NH2), 1707 (C=O),
c. Under conditions similar to procedure a we
obtained 0.105 g (48%) of pyrrolo[3,4-c]pyridine (IVa)
from 0.231 (0.001 mol) of pyridone IIIa and a mixture
of 2 ml of butyric acid and 0.5 ml of butyric anhydride.
To prove methyl butyrate formation in the reaction a
fraction boiling within 95-110°C was taken from the
filtrate, and the presence of methyl butyrate in the fraction
was confirmed by GLC.
1
2235 (C≡N). H NMR spectrum, δ, ppm: 2.32 s (3H,
CH3), 6.49 s (1H, CH), 12.75 s (1H, OH). Found, %:
C 53.99; H 3.46; N 15.55. C8H6N2O3. Calculated, %:
C 53.94; H 3.39; N 15.73.
REFERENCES
1. Vasil’ev, A.N., Kayukov, Ya.S., Lyshchikov, A.N., Nasa-
kin, O.E., Nesterov, V.N., Kayukova, O.V., and
Pul’kherovskaya, O.V., Khim. Geterotsikl. Soedin., 2001,
p. 338.
2. Vasil’ev, A.N., Kayukov, Ya.S., Lyshchikov, A.N., Nasa-
kin, O.E., and Kayukova, O.V., Khim. Geterotsikl. Soedin.,
2003, p. 1348.
3. Hawes, E.M. and Wibberley, D.G., J. Chem. Soc., 1966,
p. 315.
4. Junek, H., Monath. Chem., 1963, p. 890.
5. Graboyes, H., Jaffe, G.E., Pachter, I.J., Rosenbloom, J.P.,
Villani, A.J., Wilson, J.W., and Weinstock, J., J. Med.
Chem., 1968, p. 568.
d. Under conditions similar to procedure a we
obtained 0.168 g (77%) of pyrrolo[3,4-c]pyridine (IVa)
from 0.231 g (0.001 mol) of pyridone IIIa and freshly
distilled formic acid.
5,6-Dimethyl-2-oxo-3-cyano-1,2-dihydropyridine-
4-carboxylic acids Va–Vd. In a mixture of 0.4 g (0.001
mol) of NaOH and 1 ml of water was dissolved at slight
heating 0.001 mol of pyridone IIIa–IIIh. To the solution
obtained was added dropwise 5% solution of
hydrochloric acid till pH 4 against Congo Red. Some
time later the reaction mixture get turbid. The colorless
precipitate obtained was filtered off, washed with 3 ml
of water, and recrystallized from water; the product was
dried in a vacuum desiccator till constant weight.
6. Hussei, Abdel and Halleem, Mostafa, Afinidad, 1999,
vol. 56, no. 484, p. 377.
7. Mokrushin, V.S., Pospelova, T.A., and Shafran, Yu.M.,
Khim. Geterotsikl. Soedin., 1995, p. 267.
2-Oxo-5,6-tetramethylene-3-cyano-1,2-dihydro-
pyridine-4-carboxylic acid (Va). Yield 46%, mp 243°C.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007