Interaction of alkyl 5,6-dialkyl-2-amino-3-cyano-4-pyridinecarboxylates with O-nucleophiles. Synthesis of 6,7-dialkyl-4-amino-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1,3-diones

Article abstract of DOI:10.1023/B:COHC.0000008263.05381.67

The reaction of alkyl 5,6-dialkyl-2-amino-3-cyano-4-pyridinecarboxylates with certain O-nucleophiles was investigated, as a result of which 6,7-dialkyl-4-amino-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1,3-diones were synthesized.

Full text of DOI:10.1023/B:COHC.0000008263.05381.67

Chemistry of Heterocyclic Compounds, Vol. 39, No. 9, 2003
INTERACTION OF ALKYL 5,6-DIALKYL-
2
-AMINO-3-CYANO-4-PYRIDINECARBOXYLATES
WITH O-NUCLEOPHILES. SYNTHESIS OF
,7-DIALKYL-4-AMINO-2,3-DIHYDRO-1H-
6
PYRROLO[3,4-c]PYRIDINE-1,3-DIONES
A. N. Vasiliev, Ya. S. Kayukov, A. N. Lyshchikov, O. E. Nasakin, and O. V. Kayukova
The reaction of alkyl 5,6-dialkyl-2-amino-3-cyano-4-pyridinecarboxylates with certain O-nucleophiles
was investigated, as a result of which 6,7-dialkyl-4-amino-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1,3-
diones were synthesized.
Keywords: amide, aminopyridines, enamines, isonicotinic acid, imide, nitriles, nucleophiles, pyridines,
hydrolysis.
Previously we reported the preparation of alkyl 5,6-dialkyl-2-amino-3-cyano-4-pyridinecarboxylates
a-d [1]. The presence in these compounds of various functional groups opens broad possibilities for modifying
1
them. The hydrolysis of pyridines 1a-d has been investigated by us under various conditions. It was found that
the hydrolysis does not occur in dilute mineral acid even on extended boiling, which is evidently linked with
steric hindrance caused by substituents ortho to the ester and nitrile groups. However by the action of
concentrated sulfuric acid with subsequent neutralization with saturated sodium carbonate solution (conditions
for carrying out hydrolysis by a Aac1 mechanism [2]) the hydrolysis takes place even on light heating and leads
to the formation of 6,7-dialkyl-4-amino-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1,3-diones 2a-d in practically
quantitative yield (Table 1). The structure of compounds 2a-d was demonstrated by data of IR, mass, and NMR
spectroscopy. In the IR spectra of pyrrolo[3,4-c]pyridines 2a-d (Table 2) absorption bands were present at
-
1
3
450-3460 cm belonging to the stretching vibrations of the NH bond in the amide fragment. Absorption bands
-1
at 1705-1738 and 1686-1696 cm correspond to vibrations of the carbonyl group and the deformation vibrations
of the amino group respectively, but the stretching vibrations of the amino group are displayed as a medium
-1
intensity bands at 3180-3315 cm . It appears hydroxyl ion is less susceptible to the influence of steric
hindrance, as a result of which the hydrolysis of compounds 1a-d proceeds even at normal temperatures in the
presence of sodium hydroxide.
Initially only the ester group is subject to hydrolysis and leads to the formation of sodium 5,6-dialkyl-2-
amino-3-cyano-4-pyridinecarboxylates 3a-d which may be isolated by the careful evaporation of a solution of
equimolar amounts of reactants.
_
_________________________________________________________________________________________
Chuvash State University, Cheboksary 428015, Russia; e-mail: caesar7@mail.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1348-1353, September, 2003. Original article submitted
May 10, 2001.
1
182
0009-3122/03/3909-1182$25.00©2003 Plenum Publishing Corporation

OH
MeO
R1
O-
O
O-
O
OMe
CN
NH2
R1
R2
R1
CN
CN
OH–
–
MeOH
N
NH2
R2
N
R2
N
OMe
3
a–d
1
a–d
HCl
OH
H
O
O
N
R1
R1
O
to
CN
CH N
2 2
1
a–d
R2
N
NH2
R2
N
NH2
4
a,b,d
2
a–d
1
2
1
2
1
2
1
2
2
-4 a R +R = (CH
2
)
4
, b R +R = (CH
2
)
3
, d R = H, R = Me; 2, 3 c R = R = Me
The structure of salts 3a-d was presumed from the data of IR spectroscopy and elemental analysis. The
IR spectra of compounds 3a-d (Table 2) are characterized by the presence of high intensity absorption band for
-
1
-1
the conjugated cyano group at 2210-2230 cm . The intense absorption bands at 3315-3500 cm belong to the
asymmetric and symmetric stretching vibrations of the amino group, but the absorption bands at 1580-1605 and
-1
1
620-1640 cm belong to the vibrations of the carboxylate ion and the deformation vibrations of the amino
group respectively. In addition it was found that on careful neutralization of solutions of salts 3a,b,d 5,6-dialkyl-
2
-amino-3-cyanoisonicotinic acids 4a,b,d were formed. The structure of acids 4a,b,d was assumed from the
data of IR and NMR spectroscopy and elemental analysis. In the IR spectra (Table 2) of compounds 4a,b,d
TABLE 1. Characteristics of Compounds 2a-d, 3a-d, and 4a,b,d
Found, %
Com-
pound
Empirical
formula
——————
Calculated, %
mp, °C
Yield, %
С
H
N
2
2
2
2
3
3
3
3
4
4
4
а
b
c
C
C
C
C
C
C
C
C
C
C
C
11
10
H
H
9
11
N
3
O
2
60.85
5.05
5.07
19.36
19.35
223
235
269
235
295
296
240
260
250
290
160
99
98
96
98
84
92
79
96
87
84
78
6
0.83
9
N
3
O
2
59.14
4.44
20.70
5
9.11
4.43
20.69
9
H
N
3
3
O
2
56.53
4.72
4.71
22.01
21.99
5
6.54
d
а
b
c
8
H
7
N
O
2
54.25
3.93
23.72
5
4.23
3.92
23.71
11
10
H
10
N
3
NaO
2
55.21
4.22
4.21
17.58
17.57
5
5.23
53.35
3.34
H
8
N
3
NaO
2
3.57
18.65
5
3.58
18.66
9
H
8
N
3
3
NaO
2
2
50.69
3.77
3.78
19.69
19.71
5
0.71
d
а
b
d
8
H
6
H
H
N
NaO
48.24
3.05
21.11
4
8.25
3.04
21.10
11
10
11
N
3
O
2
60.82
5.05
5.07
19.37
19.35
6
0.83
9
N
3
O
2
59.13
4.41
20.71
5
9.11
4.43
20.69
8
H
7
N
3
O
2
54.20
3.95
3.92
23.74
23.71
5
4.23
1
183

-1
highly intense absorption band was present at 2223-2242 cm , indicating the presence in the obtained
-1
compounds of a conjugated cyano group. The absorption bands at 1683-1692 and 1650-1670 cm correspond to
the vibrations of the carbonyl group and the deformation vibrations of the amino group respectively. Stretching
-1
vibrations characteristic of the amino group are displayed at 3320-3390 cm . The structures of acids 4a,b,d
were also confirmed by conversion of them to the initial esters 1a-d by the action of diazomethane.
Compounds 3 and 4 were unstable in solution and on heating or on extended storage cyclize
intramolecularly to pyrrolo[3,4-c]pyridine-1,3-diones 2a-d.
Reaction with bifunctional compounds such as formamide is widely known for compounds having an
o-enaminonitrile fragment, leading to the formation of the corresponding pyrido[2,3-b]pyrimidine derivatives
[
3]. Unexpectedly we found that the products of the reaction of pyridines 1 with formamide were pyrrolo[3,4-c]-
pyridines 2. Pyrrolo[3,4-c]pyridines 2 are also formed on reaction of pyridines 1 with homologs of formamide.
We assumed the following scheme for this reaction process:
O
OMe
CN
O
OMe
NH
O
R C
NH2
O
C
R
NH
N
NH2
N
NH2
1
a
OMe
HO
O
N
N
O
C
R
OH
2
a
NH –RCN
–
MeOH
N
NH2
N
NH2
R = H, Me
According to this scheme the amides act as O-nucleophiles which initially probably add to the cyano
group. An intramolecular cyclization then occurs with subsequent elimination of a molecule of methanol and a
molecule of the corresponding nitrile. In support of the scheme described above for the interaction of pyridines
1
with amides is the fact that the acetonitrile eliminated was identified by GLC from the reaction mixture in the
case of acetamide.
TABLE 2. IR Spectra of Compounds 2a-d, 3a-d, and 4a,b,d
IR spectrum, cm-1
Compound
ν
NH
δ
NH
ν
C=O
[RCO
2
]–
ν
C≡N
2
2
а
3455, 3307, 3185
3455, 3311, 3182
3460, 3310, 3180
3450, 3315, 3190
3300, 3450
1686
1696
1685
1686
1620
1630
1640
1620
1660
1670
1650
1705, 1726
1720, 1738
1705, 1727
1702, 1720
—
—
—
—
—
1595
1590
1580
1605
—
—
—
—
b
2
c
2
3
3
d
а
b
—
2230
2225
2225
2210
2235
2223
2242
3315, 3445
—
3
c
3315, 3420
3500, 3460
3372, 3320
3390, 3320
3335, 3360
—
—
1683
1692
3d
4а
4b
4d
—
—
1690
1
184

Probably pyridines 1 interact with organic acids by an analogous scheme. Since it is possible to carry
out these reactions in the complete absence of water (such as with butyric acid in a medium of butyric
anhydride), it was assumed that carboxylic acids also react as O-nucleophiles. We therefore propose the
following scheme:
OMe
O
NH
O
O C R
O
R C
OH
1
a
N
O
NH2
OMe
N
HO
N
O
NH2
N
O C R
O
C
O
R
+MeOH
–MeOH
N
O
N
NH2
O
N
OMe
OH
NH2
O
R
2
a
OH
–RCOOMe
R = C
N
N
NH2
3
H
7
After adding the carboxylic acid at the cyano group and subsequent intramolecular cyclization with
formation of the pyrrole ring, fission of the ester group occurs with ejection of a molecule of acid as the methyl
ester.
Confirmation of this mechanism may be the fact that on using butyric acid methyl butyrate was isolated
and identified by GLC among the reaction products.
EXPERIMENTAL
A check on the progress of reactions and the purity of the synthesized substances was effected by TLC
on Silufol UV-254 plates, visualizing with UV light and iodine vapor. The IR spectra were obtained in thin
films (of nujol suspensions) with a UR-20 instrument. The NMR spectra were recorded on Bruker WM-250
(
250 MHz) and AM-300 (300 MHz) instruments, solvent was DMSO-d , internal standard was HMDS. The
6
high and low resolution mass spectra were obtained on a Varian MAT-212 instrument with an ionization energy
of 70 eV. Chromatographic investigations were carried out on a LXhM 8MD chromatograph, thermal
conductivity detector, the column (3000 × 3 mm) was packed with chromaton N-AW-DMCS, granule size
0
.250-0.315, liquid phase 5% XE-60, column temperature was 120°C, carrier gas helium at 40 ml/min, detector
current 140 µA, sensitivity 30, sample volume 1 µl, tape speed 240 mm/h.
Sodium 5,6-Dialkyl-2-amino-3-cyano-4-pyridinecarboxylates (3a-d). Pyridine 1a-d (0.01 mol) was
dissolved in a mixture of NaOH (0.4 g, 0.01 mol) and water (1 ml) at 60°C. A portion of the solvent was then
carefully evaporated from the obtained solution on a water bath. The mixture was cooled to room temperature,
and the obtained suspension was filtered off. The solid was washed with 2-propanol (2 ml), then with diethyl
ether (5 ml). The product was dried in a vacuum desiccator over P
2
O to constant weight. Mass spectrum of
5
compound 3d, m/z (Irel, %): 177 (9), 45 (100), 44 (32) (3 available fragment ions are given).
1
185

5
,6-Dialkyl-2-amino-3-cyano-4-pyridinecarboxylic Acids (4a,b,d). Pyridine 1a,b,d (0.01 mol) was
dissolved in a mixture of NaOH (0.4 g, 0.01 mol) in water (1 ml) with gentle warming. A 5% solution of
hydrochloric acid was added dropwise to the solution obtained to pH 4 to litmus. After some time a cloudiness
was observed in the reaction mixture. A white solid crystallized out. The obtained solid was filtered off, and
washed with water (5 ml). The product was recrystallized from water, and dried in a desiccator over P
2
O to
5
1
constant weight. H NMR spectrum, δ, ppm: 4a 1.72 (4H, m, CH
2
CH
); 2.85 (2H, t, CH
); 6.83 (1H, s, CH).
,7-Dialkyl-4-amino-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1,3-diones (2a-d). Pyridine 1a-d
2
CH
2
2
CH ); 2.60 (2H, t, CH
2
); 2.70 (2H, t,
CH
2
); 6.45 (2H, s, NH
2
); 4b 2.02 (2H, m, CH
2
CH
2
CH
2
2
); 2.97 (2H, t, CH
2
); 6.50 (2H, s, NH
2
);
4
d 2.40 (3H, s, CH
3
); 6.59 (2H, s, NH
2
6
(
0.01 mol) was dissolved in concentrated sulfuric acid (2 ml) at room temperature. The solution obtained was
cooled to room temperature, then neutralized to litmus with concentrated sodium bicarbonate solution. In the
course of neutralization a yellow solid crystallized out, and was then filtered off. The solid was washed with
2
-propanol (5 ml), and recrystallized from DMF, then dried in a vacuum desiccator over P
2
O
5
to constant
);
); 6.53
); 10.85 (1H, s, NH);
1
weight. H NMR spectrum, δ, ppm: 2a 1.77 (4H, m, CH
2
CH
CH
); 2.45 (3H, s, CH
2
CH
2
CH
); 2.86 (2H, t, CH
); 6.38 (2H, s, NH
2
); 2.77 (2H, t, CH
2
); 2.90 (2H, t, CH
2
6
.53 (2H, s, NH
2
); 10.95 (1H, s, NH); 2b 2.16 (2H, m, CH
2
2
CH
2
2
); 3.00 (2H, t, CH
2
(
2H, s, NH ); 10.85 (1H, s, NH); 2c 2.43 (3H, s, CH
2
3
3
2
2
d 2.50 (3H, s, CH
3
); 5.17 (2H, s, NH ); 6.86 (1H, s, CH); 11.15 (1H, s, NH). Mass spectrum of compound 2a,
2
m/z (Irel, %): 217 (100), 202 (23), 189 (15), 161 (11), 171 (16), 118 (11), 91 (39), 63 (22), 77 (37), 44 (47) (the
molecular ion peak and nine intense peaks for fragment ions are given).
4
-Amino-6,7-tetramethylene-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1,3-dione (2a). A. Pyridine 1a
(
0.231 g, 1 mmol) was suspended in formamide (2 ml) and the suspension sealed into an ampule. The ampule
was then heated at 130°C for 12 h, then opened carefully. The contents were diluted with 1,4-dioxane (2 ml), the
yellow crystalline solid was filtered off, washed with 1,4-dioxane (2 ml), and recrystallized from DMF. The
product was dried in a vacuum desiccator over P
2
O to constant weight. Compound 2a (0.117 g, 54%) was
5
obtained; mp 223°C. Found, %: C 60.84; H 5.07; N 19.36. C11
H
11
N
3
O . Calculated, %: C 60.83; H 5.07;
2
N 19.35.
B. Under conditions analogous to method A, on interacting pyridine 1a (0.231 g, 1 mmol) with
acetamide (0.0886 g, 1.5 mmol) compound 2a (0.097 g, 45%) was obtained; mp 223°C. Found, %: C 60.82;
H 5.05; N 19.34. C11
H
11
N
3
2
O . Calculated, %: C 60.83; H 5.07; N 19.35.
To demonstrate the formation of acetonitrile in the reaction the filtrate was distilled and the fraction
with bp 76-85°C collected. The presence of acetonitrile in this mixture was demonstrated by GLC.
C. Pyridine 1a (0.231 g, 1 mmol) was suspended in freshly distilled butyric acid (2 ml). The suspension
was sealed in an ampule. The ampule was heated at 130°C for 12 h, then opened carefully. The contents of the
ampule were diluted with 2-propanol (2 ml), and the crystalline yellow solid was filtered off, then recrystallized
from DMF. The solid was washed with 2-propanol, and dried in a vacuum desiccator over P
weight. Compound 2a (0.137 g, 63%) was obtained; mp 223°C. Found, %: C 60.81; H 5.05; N 19.37.
. Calculated, %: C 60.83; H 5.07; N 19.35.
2
5
O to constant
C
11
H
11
N
3
O
2
To demonstrate the formation of methyl butyrate in the reaction the fraction of boiling point 95-110°C
was distilled from the filtrate. The presence of methyl butyrate in this mixture was demonstrated by GLC.
Interaction of 2-Amino-3-cyano-5,6-tetramethyleneisonicotinic Acid 3a with Diazomethane. Acid
3
a (0.217 g, 1 mmol) was dissolved in dioxane (20 ml). A current of diazomethane was passed through this
solution until the disappearance of the initial compound from the reaction mixture. The solvent was distilled off,
and the residue of methyl 2-amino-3-cyano-5,6-tetramethylene-4-pyridinecarboxylate 1a was filtered off. The
product was recrystallized from ethyl acetate, and dried in a vacuum desiccator over P
2
O to constant weight.
5
Compound 1a (0.215 g, 93%) was obtained; mp 195°C. Found, %: C 62.31; H 5.72; N 18.14. C11
H
11
N
3
2
O .
Calculated, %: C 62.33; H 5.66; N 18.17 [1].
1
186

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1
.
A. N. Vasiliev, Ya. S. Kayukov, O. E. Nasakin, A. N. Lyshchikov, V. N. Nesterov, O. V. Kayukova, and
O. V. Pul'kherovskaya, Khim. Geterotsikl. Soedin., 338 (2001).
2.
.
J. March, Organic Chemistry, Vol. 2 [Russian translation], Mir, Moscow (1987), p. 109.
th
3
A. Abd El-Hamid, A. Essawy, and A. M. Amer, in Abstracts of the 4 Ibn Sina Int. Symp. Pure and
Appl. Heterocycl. Chem., Cairo (1992), p. 17.
1
187