Synthesis and chemical conversions of 2-chloro-3-cyano-4-methylamino-5-nitropyridine

Article abstract of DOI:10.1023/A:1023962726390

5-Cyano-6-(β-dimethylamino)vinyl-1-methyl-4-pyrimidinone was synthesized by the interaction of α-cyano-β-(N-methylamino)crotonamide with N,N-dimethylformamide diethylacetal. Recyclization of the product in alkaline medium leads to 3-cyano-4-methylamino-2-pyridone. Nitration of the latter and transformation of the nitropyridone by boiling in POCl₃ gave 2-chloro-3-cyano-4-methylamino-5-nitropyridine. This is a key compound for various transformations including the synthesis of derivatives of dipyrido[1,2-a:3,2-e]pyrimidine, thieno[2,3-b]pyridine, and (2-pyridylamino)polyene derivatives.

Full text of DOI:10.1023/A:1023962726390

Chemistry of Heterocyclic Compounds, Vol. 39, No. 3, 2003
SYNTHESIS AND CHEMICAL
CONVERSIONS OF 2-CHLORO-3-CYANO-
4-METHYLAMINO-5-NITROPYRIDINE
E. S. Krichevsky, L. M. Alekseeva, and V. G. Granik
5-Cyano-6-(β-dimethylamino)vinyl-1-methyl-4-pyrimidinone was synthesized by the interaction of
α-cyano-β-(N-methylamino)crotonamide with N,N-dimethylformamide diethylacetal. Recyclization of
the product in alkaline medium leads to 3-cyano-4-methylamino-2-pyridone. Nitration of the latter and
transformation of the nitropyridone by boiling in POCl3 gave 2-chloro-3-cyano-4-methylamino-5-
nitropyridine. This is a key compound for various transformations including the synthesis of derivatives
of dipyrido[1,2-a:3,2-e]pyrimidine, thieno[2,3-b]pyridine, and (2-pyridylamino)polyene derivatives.
Keywords: nitropyridine, 2-pyridone, 4-pyrimidinone, Torp–Ziegler reaction
Previously we developed a general approach to the synthesis of derivatives of 4-amino-3-cyano-2-
pyridone based on the cyclization of enamino amides under the action of amideacetals into derivatives of
4-pyrimidone and recyclization of the latter in alkaline media [1-3]. Recently it was established on investigating
the properties and conversions of 2-chloro-3-cyano-5-nitropyridine that this compound reacts smoothly with
pyridine with the formation of a pyridylpyridinium salt, which is a promising starting material for the synthesis
of various pyridine derivatives, including condensed pyridines [4].
The aim of the present work was to combine these two approaches, to synthesize derivatives of 3-cyano-
5-nitro-2-pyridone containing an additional electron-donating functional substituent (substituted amino group) at
position 4 of the pyridine ring, and to study the transformations of a key compound, 2-chloro-3-cyano-4-
methylamino-5-nitropyridine (1), into various pyridine derivatives. In the first stage of the investigation the
possibility was studied of synthesizing 3-cyano-4-isopropylamino-2-pyridone (2), starting from α-cyano-β-
isopropylaminocrotonamide (4), itself obtained by the transamination of the tertiary enamino amide 3 [5] with
isopropylamine. Interaction of compound 4 with DMF diethylacetal (5) occurs smoothly, but in this case
introduction of the β-dimethylaminovinyl fragment into position 6 of the 4-pyrimidinone ring was unsuccessful.
Probably steric difficulties arising from the presence of the bulky isopropyl group in position 1 impede attack of
acetal 5 at the 6-CH3 group. Condensation of acetal under the usual and under more forcing conditions does not
occur. As a result 5-cyano-1-isopropyl-6-methyl-1,4-dihydro-4-pyrimidinone (6) is formed which is incapable of
recyclizing into the desired pyridone 2 (Scheme 1).
As a consequence of this the previously described amide of α-cyano-β-(N-methylamino)crotonic acid
(7) [6] was selected for subsequent work. Compound 7 was transformed into 3-cyano-4-methylamino-2-
pyridone (10) through 5-cyano-1,6-dimethyl-1,4-dihydro-4-pyrimidinone (8) and 5-cyano-6-(N,N-
dimethylaminovinyl)-1-methyl-1,4-dihydro-4-pyrimidinone (9) by the usual method. Compound 10 was
__________________________________________________________________________________________
NIOPIK State Scientific Center of the Russian Federation, Moscow 103787; e-mail:
makar-cl@ropnet.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 371-378, March,
2003. Original article submitted May 26, 2000.
328
0009-3122/03/3903-0328$25.00©2003 Plenum Publishing Corporation

Scheme 1
CN
CH2
Me
CN
Me2CHNH2
Me
+
Me2NC(OEt)2
CONH2
Me2N
CONH2
3
Me
Me2NCH(OEt)2
CN
Me
Me2HC
CN
5
N
CONH2
Me2CHNH
N
6
O
4
NMe2
NHCHMe2
CN
Me2HC
N
CN
O
N
N
H
O
N
2
subjected to nitration at position 5 and the nitro derivative 11 obtained was converted by boiling in phosphorus
oxychloride into 2-chloro-3-cyano-4-methylamino-5-nitropyridine (1), which is the main key intermediate for
the subsequent syntheses.
NMe2
Me
_
Me
CN
Me
OH
5
Me
CN
O
5
CN
O
MeNH2
N
N
3
CONH2
MeNH
N
N
7
9
8
NHMe
NHMe
CN
NHMe
HNO3
(H2SO4)
CN
O2N
O2N
CN
N
H
N
Cl
O
N
H
11
O
10
1
It turned out that in compound 1, in spite of the presence at position 4 of a strong electron-donating
substituent, the chlorine atom at position 2 was fairly reactive and may easily be replaced by various groups
under nucleophilic attack. The interaction of chloropyridine 1 with 2-aminopyridine takes place in the same
direction as for 2-chloro-3-cyano-5-nitropyridine [4], with the formation of 5-imino-4-methylamino-3-
nitrodipyrido-[1,2-a:3,2-c]pyrimidine (12).
The reaction of compound 1 with pyridine also proceeds extremely smoothly. In this case the pyridyl-2-
pyridinium salt 13 is formed, which according to the previously well-founded scheme of [4] reacts with
piperidine with the formation of the 2-amino derivative 14, giving with alkali the pyridylaminodiene 15, and
with malono-dinitrile the pyridylaminotriene 16. The ability of the pyridinium fragment to be replaced on
interaction with nucleophilic reagents is also confirmed by the reaction of salt 13 with thioglycolic ester with
the formation of 3-cyano-2-ethoxycarbonylmethylthio-4-methylamino-5-nitropyridine (17). Under the action of
329

sodium ethylate the latter smoothly undergoes Torp–Ziegler cyclization [7] with the formation of 3-amino-2-
1
ethoxycarbonyl-4-methylamino-5-nitrothieno[2,3-b]pyrimidine (18). Signals were observed in the H NMR
spectrum of compound 12 in DMSO-d6 at 2.94 (3H, s, NHCH3); 7.22-9.39 (4H, m, arom. H); 8.66 (1H, s, 2-H);
8.81 ppm (1H, br. s, NH); in the spectrum of compound 15 at 3.30 (3H, d, NHCH3); 6.04 (1H, q, J1 = 8.6,
J2 = 14.7 Hz, δ-H); 6.55 (1H, q, J1 = 11.3, J2 = 13.2 Hz, β-H); 7.48 (1H, q, J1 = 14.7, J2 = 11.3 Hz, γ-H); 8.00
(1H, d, J = 13.2 Hz, α-H); 8.93 (1H, s, 6-H); 9.03 (1H, q, J = 6.4 Hz, NHCH3); 9.43 (1H, d, J = 8.6 Hz, CHO);
10.41 ppm (1H, br. s, 2-NH); in the spectrum of triene 16 at 3.30 (NHCH3 coinciding with the signal of water in
DMSO-d6); 6.58 (2H, m, β-, δ-H); 7.44 (1H, q, J1 = 12, J2 = 14 Hz, γ-H); 7.96 (1H, d, J = 12 Hz, ε-H); 8.14 (1H,
d, J = 13.2 Hz, α-H); 8.95 (1H, s, 6-H); 9.06 (1H, q, J = 6 Hz, NHCH3); 10.56 ppm (1H, br. s, NH).
MeNH
NH
O2N
N
NH2
N
1
N
N
12
N
NHMe
CN
NHMe
CN
O2N
O2N
HN
+
_
N
NH2
N
N
-
Cl
14
13
_
CH2(CN)2
OH
NHMe
NHMe
CN
CN
O2N
O2N
γ
α
γ
α
ε
CHO
CN
CN
N
N
H
N
N
H
β
β
δ
δ
15
16
NHMe
NHMe
CN
NH2
O2N
O2N
HSCH2COOEt
EtONa
COOEt
13
S
N
18
N
17
SCH2COOEt
Me
CH(OMe)3, Ac2O
N
N
N
S
O2N
COOEt
19
330

TABLE 1. Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp*, °С
Yield, %
C
H
N
1*2
4
C7H5ClN4O2
39.2
39.5
2.4
2.3
26.7
26.3
32-134
166-167
279-273
199-200
189-191
232-234
274-276
302-305
>360
70
87
85
95
79
76
85
41
84
94
72
92
60
68
63
84
C8H13N3O
C9H11N3O
C6H9N3O
57.5
8.0
25.1
57.5
7.8
25.1
61.3
61.0
6.5
6.3
24.1
23.7
6
52.0
6.4
30.0
7
51.8
6.5
30.2
C7H7N3O
56.1
56.4
4.9
4.7
28.3
28.2
8
C10H12N4O
C7H7N3O
59.1
6.0
28.0
9
58.8
5.4
27.4
56.2
56.4
4.8
4.8
28.2
28.2
10
11
12
13*3
14
15
16
17*4
18*5
19
C7H6N4O3
C12H10N6O2
C12H10ClN5O2
C7H7N5O2
C12H11N5O3
C15H11N7O2
C11H12N4O4S
C11H12N4O4S
C10H12N6O2
43.2
3.3
28.8
43.3
3.3
28.9
53.0
53.3
3.7
3.7
31.1
31.1
49.5
3.8
24.1
202-204
320-322
225-227
>360
49.4
3.5
24.0
43.8
43.5
3.7
3.7
36.3
36.9
52.8
2.4
26.7
52.7
2.3
26.5
56.1
56.1
3.4
3.5
30.5
30.5
44.4
4.4
19.2
122-124
163-165
238-240
44.6
4.1
18.9
44.5
44.6
4.4
4.1
19.0
18.9
48.7
4.9
34.1
48.4
4.9
33.9
_______
* Solvents for crystallization: EtOH (compounds 1, 7-10, 13, 15, 17),
i-PrOH (4, 6, 18), AcOH (11), water–DMF (14), MeCN (19).
*2 Found, %: Cl 16.9. Calculated, %: Cl 16.7.
*3 Found, %: Cl 12.0. Calculated, %: Cl 12.2.
*4 Found, %: S 10.9. Calculated, %: S 10.8.
*5 Found, %: S 11.2. Calculated, %: S 10.8
TABLE 2. 1H NMR Spectra of Some of the Synthesized Compounds
Compound
Chemical shifts, δ, ppm. (J, Hz)
1.41 (6H, d, J = 7.2, СН(СН3)2); 2.54 (3Н, s, 6-СН3); 4.50 (1Н, m, СН(СНз)2);
8.68 (1Н, s, 2-Н)
6
2.48 (3H, s, 6-СН3); 3.59 (3Н, s, 1-СН3); 8.42 (1Н, s, 2-Н)
8
10
2.83 (3H, s, NHCH3); 5.84 (1Н, d, J = 7.2, 5-Н); 7.36 (1H, d, 6-Н);
7.24 (1Н, br. s, NHCH3); 11.02 (1H, br. s, NH)
3.30 (3H, d, J = 6.4, NHCH3); 8.74 (1Н, s, 6-Н); 8.80 (1Н, q, NHCH3);
11
17
18
12.5 (1H, br. s, 1-NH)
1.19 (3H, t, J = 7.2, СН2СН3); 3.34 (3H, d, J = 6.4, NHCH3); 4.12 (2Н, q, СН2СН3);
4.14 (2Н, s, SCH2); 8.94 (1H, s, 6-H); 8.96 (1H, q, NHCH3)
1.28 (3H, t, J = 7.2, СН2СН3); 2.92 (3Н, s, NHCH3); 4.27 (2Н, q, СН2СН3);
6.99 (2Н, br. s, NH2); 8.02 (1Н, br. s, NH); 8.83 (1H, s, 6-Н)
331

The main tendencies linked with substitution or opening of the pyridine ring are therefore unchanged in
comparison with those observed in [4], in spite of the presence of an additional electron-donating group in
position 4.
Summing up the data obtained, it is possible using compound 13 as an example, to refine the probable
reasons for the phenomena observed.
NHMe
_
CN
O2N
RS
H
SR
_
..
13
N
N
–RS
(A)
_
_
RS
–RS
NHMe
CN
NHMe
CN
O2N
O2N
+
SR
N
N
N
+
_
N
17
SR
(B)
(R = CH2COOEt)
The rate of attack of anion at the α-position of the pyridinium ring is greater due to the wholenumbered
positive charge and the more stable neutral molecule (A) compared with the zwitter-ion (B). However the
stabilization of (A) is hindered (the medium is alkaline and protonation is slowed), while (B) is stabilized
irreversibly with the splitting away of a pyridine molecule. A different picture is observed on treating the
pyridinium salt with anions containing an atom of hydrogen [–OH or HC–(CN)2].
NHMe
NHMe
O2N
CN
_
CN
O2N
OH
γ
α
H
_
CHO
13
..
OH
N
N
H
– OH
N
N
δ
β
15
(C)
_
_
OH
– OH
NHMe
NHMe
CN
OH
O2N
O2N
CN
+
N
N
N
+
N
H
O
(C1)
11
In this case intermediate C is characterized by a rapid and irreversible prototropic shift of the OH [or
HC(CN)2] group proton to the pyridinium ring nitrogen accompanied by opening of the ring. This type of
stabilization proved to be the most effective, but the other, similar to that observed on obtaining compound 17
(C1 pyridone), does not take place in practice.
332

In conclusion we note that the presence in position 4 of an additional functional group, a methylamino
group, opens new possibilities for various heterocyclizations. One of them was effected in the present work.
Heating bicyclic compound 18 with ethyl orthoformate leads to the formation of a pyrimidine ring involving the
1
3-NH2 and 4-NHMe groups. The thienopyrimidine derivative 19 was obtained as a result. H NMR spectrum
(DMSO-d6), δ, ppm: 1.32 (3H, t) and 4.31 (2H, q) from the COOEt group; 3.39 (3H, s, N-CH3); 8.07 (1H, s,
4-H); 8.86 (1H, s, 7-H).
The data of elemental analysis and NMR spectra of the substances obtained are given in Tables 1 and 2.
EXPERIMENTAL
1
The IR spectra for nujol suspensions were recorded on a Perkin–Elmer 457 instrument. The H NMR
spectra were obtained on a Varian Unity 400 (400 MHz) spectrometer, solvent was DMSO-d6. The mass spectra
were recorded on a MAT 112 instrument with direct insertion of samples into the ion source. The purity of
substances and the reaction times were checked by TLC on Silufol UV 254 plates in the system methanol–
benzene, 2:8, visualizing in UV light.
α-Cyano-β-isopropylaminocrotonic Acid Amide (4). A mixture of amide 3 (7.7 g, 50 mmol),
isopropylamine (13 ml, 150 mmol), and methanol (50 ml) was boiled for 2 h. The reaction mixture was cooled,
the solid filtered off, and compound 4 was obtained.
5-Cyano-1-isopropyl-6-methyl-1,4-dihydro-4-pyrimidinone (6). A mixture of compound 4 (3.34 g,
20 mmol) and acetal 5 (10 ml) in DMF (15 ml) was boiled for 8 h. The DMF was evaporated in vacuum, a 5%
solution of sodium hydroxide (130 ml) was added to the residue, the mixture boiled for 1 h, cooled, and
acidified with hydrochloric acid to pH 6-7. The precipitate of compound 6 was filtered off, washed with water,
and dried.
α-Cyano-β-(N-methylamino)crotonic Acid Amide (7). A mixture of compound 3 (7.3 g, 47 mmol)
and a 33% solution of methylamine in alcohol (90 ml) was stored for 24 h at 20°C. The precipitate was filtered
off, washed with alcohol, dried, and compound 7 was obtained. The same compound was obtained previously in
[6].
5-Cyano-1,6-dimethyl-1,4-dihydro-4-pyrimidinone (8). A solution of compound 7 (1.4 g, 10 mmol)
and compound 5 (8 ml) in isopropyl alcohol (10 ml) was boiled for 8 h. The mixture was cooled, the solid
filtered off, and washed with alcohol.
5-Cyano-6-(N,N-dimethylaminovinyl)-1-methyl-1,4-dihydro-4-pyrimidinone (9). A mixture of
compound 8 (2.8 g, 20 mmol) and compound 5 (18.3 ml, 100 mmol) was boiled for 6 h. The mixture was
cooled, filtered, and the solid was washed with alcohol.
3-Cyano-4-methylamino-2-pyridone (10). Compound 9 (4.08 g, 20 mmol) was boiled with 5%
aqueous sodium hydroxide solution (130 ml) for 1 h. The mixture was cooled, acidified with hydrochloric acid
to pH 6-7, the precipitate of pyridone 10 was filtered off, washed with water, and dried.
2-Cyano-4-methylamino-5-nitro-1,2-dihydro-2-pyridone (11). Compound 10 (7.5 g, 50 mmol) was
stirred in conc. H2SO4 (40 ml) at 20°C, after which the reaction mixture was cooled to 0-2°C and nitric acid
(d 1.5) (9 ml) was added dropwise at the same temperature. The mixture was stirred for 2 h at 0-2°C then for 1 h
at 20°C. The reaction mixture was poured onto ice (250 g), and left for 1 h. The solid was filtered off, washed
with ice water, and dried.
2-Chloro-3-cyano-4-methylamino-5-nitropyridine (1). A mixture of compound 11 (2.5 g, 38 mmol),
triethylamine hydrochloride (3.9 g, 28 mmol), and phosphorus oxychloride (20 ml) was boiled for 3 h. The
excess of phosphorus oxychloride was evaporated in vacuum. The residue was treated with ice (100 g) and
made alkaline with sodium hydroxide solution to pH 7. The precipitate of compound 1 was filtered off, washed
with water, and dried.
333

a
c
5-Imino-4-methylamino-3-nitrodipyrimido[1,2- :3,2- ]pyrimidine (12).
2-Aminopyridine (1.44 g,
16 mmol) was added to a solution of compound 1 (2.34 g, 11 mmol) in acetonitrile (35 ml). The reaction
mixture was stirred for 4 h at 20°C, the precipitate of compound 12 was filtered off, and washed with cold
acetonitrile.
1-(3-Cyano-4-methylamino-5-nitro-2-pyridyl)pyridinium Chloride (13). A mixture of compound 1
(12 g, 10 mmol) and pyridine (3.8 g, 47 mmol) in acetonitrile (40 ml) was stirred for 3.5 h at 20°C. The
precipitate of salt 13 was filtered off, and washed with cold acetonitrile.
3-Cyano-2-ethoxycarbonylmethylthio-4-methylamino-5-nitropyridine (17). Thioglycolic acid ethyl
ester (0.9 ml, 7.5 mmol) and sodium acetate (0.6 g, 7.5 mmol) were added to a solution of salt 13 (1.6 g,
5.5 mmol) in methanol (70 ml). The reaction mixture was stirred for 1 h at 20°C, the precipitate of compound 17
was filtered off, washed with cold methanol, and with water, and dried.
b
Sodium ethylate
3-Amino-2-ethoxycarbonyl-4-methylamino-5-nitrothieno[2,3- ]pyridine (18).
(0.06 g Na in 10 ml absolute alcohol) was added dropwise with stirring to a suspension of compound 17 (0.6 g,
2 mmol) in absolute alcohol (40 ml), and the mixture was heated to form a solution. The mixture was then
cooled, the precipitate of 18 was filtered off, and washed with alcohol.
2-Amino-3-cyano-4-methylamino-5-nitropyridine (14). Piperidine (12.7 ml, 126 mmol) was added to
a solution of salt 13 (2.5 g, 86 mmol) in water (25 ml). The mixture was boiled for 5 min, cooled, acetone
(10 ml) was added, the mixture was filtered, the precipitate of compound 14 was washed with water, and dried.
6-(3-Cyano-4-methylamino-5-nitro-2-pyridyl)amino -1,1-dicyanohexatriene (16). Malonodinitrile
(0.2 g, 2.8 mmol) and triethylamine (0.28 g, 2.8 mmol) were added to a solution of salt 13 (0.75 g, 2.6 mmol) in
methanol (50 ml). The reaction mixture was stirred for 1 h at 20°C, the precipitate of 16 was filtered off, and
washed with cold methanol.
4-(3-Cyano-4-methylamino-5-nitro-2-pyridyl)amino-1-formylbutadiene (15). A solution of salt 13
(1.5 g, 5 mmol) was stirred with sodium hydroxide (0.2 g, 5 mmol) in water (5 ml) for 2 h at 20°C. The
precipitated solid was filtered off, washed with water, dried and butadiene 15 was obtained.
2-Ethoxycarbonyl-5-methyl-6-nitro-1,5-dihydro-1-thia-3,5,8-triaza-acenaphthene (19). A mixture
of compound 18 (1 g, 3.4 mmol), ethyl orthoformate (1.06 g, 10 mmol), and acetic anhydride (10 ml) was boiled
for 3.5 h, then cooled. The precipitate was filtered off, washed with water to pH 6-7, dried, and tricyclic
compound 19 was obtained.
REFERENCES
1.
2.
3.
4.
V. G. Granik, E. O. Sochneva, and N. P. Solov'eva, Khim. Geterotsikl. Soedin., 416 (1980).
V. G. Granik, A. M. Zhidkova, and R. A. Dubinskii, Khim. Geterotsikl. Soedin., 269 (1981).
V. G. Granik, A. M. Zhidkova, and R. A. Dubinskii, Khim. Geterotsikl. Soedin., 518 (1982).
M. Yu. Yakovlev, A. V. Kadushkin, N. P. Solov'eva, O. S. Anisimova, and V. G. Granik, Tetrahedron,
54, 5775 (1998).
5.
6.
L. V. Ershov, S. S. Kiselev, and V. G. Granik, Khim. Geterotsikl. Soedin., 538 (1984).
S. A. Ryndina, A. V. Kadushkin, N. P. Solov'eva, and V. G. Granik, Khim. Geterotsikl. Soedin., 1643
(2000).
7.
V. G. Granik, A. V. Kadushkin, and U. Liebscher, Adv. Heterocycl. Chem., 72, 79 (1998).
334