Effect of hydrochloric acid on the reductive amination of 1-(3-nitropyridin-2-yl)pyridinium salts

Full text of DOI:10.1134/S1070428007070287

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 7, pp. 1098–1100. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © R.S. Begunov, G.A. Ryzvanovich, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 7, pp. 1103–1104.
SHORT
COMMUNICATIONS
Effect of Hydrochloric Acid on the Reductive Amination
of 1-(3-Nitropyridin-2-yl)pyridinium Salts
R. S. Begunov and G. A. Ryzvanovich
Demidov Yaroslavl State University, ul. Sovetskaya 14, Yaroslavl, 150000, Russia
e-mail: begunov@bio.uniyar.ac.ru
Received December 10, 2006; revised May 14, 2007
DOI: 10.1134/S1070428007070287
We previously reported on the reductive amination
of pyridinium salts, which led to the formation of fused
systems with a bridgehead nitrogen atom, benzo[4,5]-
imidazo[1,2-a]pyridines III and pyrido[3′,2′:4,5]-
imidazo[1,2-a]pyridines IV [1–3]. However, unlike
N-arylpyridinium salts I, 1-(3-nitropyridin-2-yl)pyri-
dinium chlorides II did not always undergo cyclization
under the reduction conditions [3]. The main differ-
ence between structures I and II is that the latter
contain a nitrogen atom capable of taking up a proton.
Therefore, it may be presumed that the reduction of
compounds IIa–IIc with a solution of SnCl2·2H2O in
hydrochloric acid involves formation of the corre-
sponding hydrochloride via protonation of the nitrogen
atom. As a result, nucleophilicity of the amino group
formed by reduction of the nitro group is weakened,
and the cyclization is hindered. With a view to verify
the above assumption we examined the effect of hy-
drochloric acid concentration on the reductive amina-
tion process (see table).
acid gave in all cases the corresponding cyclization
products IVa–IVc. Raising the concentration of HCl in
the reaction mixture led to appearance of amino deriv-
atives V in addition to pyrido[3′,2′:4,5]imidazo[1,2-a]-
pyridines IV. Taking into account that the concentra-
tion of unprotonated pyridine sharply decreases as
the concentration of electrophile (proton in our case)
increases [4], the assumption implying formation of
chlorides V due to protonation of the pyridine nitrogen
atom seems to be quite reasonable.
Thus the concentration of hydrochloric acid is
a factor affecting the reductive amination of 1-(3-nitro-
pyridin-2-yl)pyridinium chlorides II. By varying the
concentration of HCl in the reaction mixture, the proc-
ess can be forced to yield either 1-(3-aminopyridin-2-
yl)pyridinium chlorides V or cyclization products IV.
The structure of the isolated compounds was con-
1
firmed by the analytical data and H NMR and mass
spectra.
We found that the reductive amination of salts II
with a solution of SnCl2 ·2H2O in 2% hydrochloric
Pyrido[3′,2′:4,5]imidazo[1,2-a]pyridines IVa–
IVc (general procedure). A solution of 0.03 mol of
R1
N
R3
X = CH
R1
N
SnCl2 ·2H2O
HCl
R2
X
III
N
R3 Cl–
R1
R1
N
R2
O2N
I, IIa–IIc
N
N
Cl–
+
N
X = N
N
R2
H2N
Va–Vc
R2
IVa–IVc
I, III, R1 = R2 = H, R3 = CF3, COOH, NO2, NH2, CN; II, IV, V, R1 = R2 = H (a), R1 = H, R2 = Me (b), R1 = R2 = Me (c).
1098

EFFECT OF HYDROCHLORIC ACID ON THE REDUCTIVE AMINATION
1099
Effect of HCl concentration on the yield of reduction prod-
ucts IV and V
SnCl2 ·2H2O in 15 ml of 2% hydrochloric acid was
added under stirring to a mixture of 0.01 mol of
1-(3-nitropyridin-2-yl)pyridinium chloride IIa–IIc in
20 ml of ethanol. After10 min, the mixture was ad-
justed to pH 7–8 by adding 25% aqueous ammonia and
extracted with several portions of chloroform (total of
150 ml). The products were isolated by removal of the
solvent from the extract.
Yield, %
Concentration
of HCl, %
IVa
Va IVb Vb IVc
Vc
02
03
06
12
90
91
88
49
00
00
06
37
85
82
16
00
00
00
63
84
79
11
00
00
00
83
89
88
Pyrido[3′,2′:4,5]imidazo[1,2-a]pyridine (IVa).
Yield 90%, mp 120–122°C; published data [5]:
1
mp 130°C. H NMR spectrum, δ, ppm: 7.08 t (1H,
8-H, J = 9.5 Hz), 7.59 m (1H, 3-H), 7.65–7.75 m (2H,
6-H, 7-H), 8.24 d (1H, 4-H, J = 10.0 Hz), 8.51 d (1H,
2-H, J = 7.0 Hz), 8.95 d (1H, 9-H, J = 8.5 Hz). Mass
spectrum, m/z (Irel, %): 169 (100) [M]+, 142 (7), 78
(28), 51 (12). Found, %: C 70.81; H 4.17; N 25.02.
C10H7N3. Calculated, %: C 71.09; H 4.24; N 24.89.
M 169.18.
1-(3-Aminopyridin-2-yl)pyridinium chloride
(Va). Yield 37%, mp 182–185°C. H NMR spectrum,
1
δ, ppm: 6.05 s (2H, NH2), 7.44–7.50 m (2H, 4′-H,
5′-H), 7.86 d.d (1H, 6′-H, J = 7.5, 1.5 Hz), 8.35 t (2H,
3-H, 5-H, J = 8.5 Hz), 8.81 t (1H, 4-H, J = 9.0 Hz),
9.31 d (2H, 2-H, 6-H, J = 8.0 Hz). Mass spectrum, m/z
(Irel, %): 172 (28) [M]+, 169 (100), 142 (11), 119 (19),
78 (65), 64 (18), 51 (38), 39 (41), 36 (42). Found, %:
C 57.91; H 5.03; Cl 17.17; N 20.15. C10H10ClN3.
Calculated, %: C 57.83; H 4.82; Cl 17.11; N 20.24.
M 172.21.
6-Methylpyrido[3′,2′:4,5]imidazo[1,2-a]pyridine
(IVb). Yield 85%, mp 111–113°C; published data [5]:
1
mp 117°C. H NMR spectrum, δ, ppm: 2.61 s (3H,
CH3), 6.83 t (1H, 8-H, J = 9.5 Hz), 7.30–7.45 m (2H,
3-H, 7-H), 8.20 d (1H, 4-H, J = 10.0 Hz), 8.42 d
(1H, 2-H, J = 7.0 Hz), 8.59 d.d (1H, 9-H, J = 8.0,
1.5 Hz). Mass spectrum, m/z (Irel, %): 183 (100) [M]+,
169 (8), 157 (26), 78 (31), 51 (10). Found, %: C 71.79;
H 5.16; N 23.31. C11H9N3. Calculated, %: C 72.10;
H 4.97; N 23.09. M 183.21.
1-(3-Aminopyridin-2-yl)-3-methylpyridinium
1
chloride (Vb). Yield 84%, mp 161–164°C. H NMR
spectrum, δ, ppm: 2.55 s (3H, CH3), 6.05 s (2H, NH2),
7.44–7.50 m (2H, 4′-H, 5′-H), 7.85 d.d (1H, 6′-H, J =
8.0, 1.5 Hz), 8.23 m (1H, 5-H), 8.65 d.d (1H, 4-H, J =
8.5, 2.0 Hz), 9.09 d (1H, 6-H, J = 8.0 Hz), 9.19 d (1H,
2-H, J = 1.5 Hz). Mass spectrum, m/z (Irel, %): 186
(42) [M]+, 183 (100), 170 (28), 120 (23), 92 (25), 78
(13), 65 (19), 39 (29). Found, %: C 59.62; H 5.33;
Cl 16.27; N 18.79. C11H12ClN3. Calculated, %: C 59.59;
H 5.42; Cl 16.03; N 18.96. M 186.24.
6,8-Dimethylpyrido[3′,2′:4,5]imidazo[1,2-a]pyr-
1
idine (IVc). Yield 79%, mp 95–97°C. H NMR spec-
trum, δ, ppm: 2.39 s (3H, 8-CH3), 2.59 s (3H, 6-CH3),
7.55 m (1H, 3-H), 7.64 d (1H, 7-H, J = 1.0 Hz),
8.24 d.d (1H, 4-H, J = 10.0, 1.5 Hz), 8.46 d.d (1H,
2-H, J = 8.0, 1.0 Hz), 8.61 d (1H, 9-H, J = 1.5 Hz).
Mass spectrum, m/z (Irel, %): 197 (100) [M]+, 182 (30),
169 (7), 155 (5), 77 (16), 51 (12), 39 (20). Found, %:
C 72.93; H 5.39; N 21.24. C12H11N3. Calculated, %:
C 73.11; H 5.62; N 21.36. M 197.24.
1-(3-Aminopyridin-2-yl)-3,5-dimethylpyridinium
1
chloride (Vc). Yield 88%, mp 204–206°C. H NMR
spectrum, δ, ppm: 2.51 s (6H, CH3), 6.05 s (2H, NH2),
7.44–7.50 m (2H, 4′-H, 5′-H), 7.85 d (1H, 6′-H, J =
6.5 Hz), 8.50 s (1H, 4-H), 9.05 s (2H, 2-H, 6-H). Mass
spectrum, m/z (Irel, %): 200 (50) [M]+, 198 (100), 184
(34), 120 (39), 108 (17), 77 (10), 36 (26). Found, %:
C 61.09; H 6.01; Cl 15.13; N 18.01. C12H14ClN3.
Calculated, %: C 61.15; H 5.95; Cl 15.07; N 17.83.
M 200.26.
1-(3-Aminopyridin-2-yl)pyridinium chlorides
Va–Vc (general procedure). A solution of 0.03 mol of
SnCl2 ·2H2O in 15 ml of 12% hydrochloric acid was
added under stirring to a mixture of 0.01 mol of
1-(3-nitropyridin-2-yl)pyridinium chloride IIa–IIc in
20 ml of ethanol. After 10 min, the mixture was ad-
justed to pH 7–8 by adding 25% aqueous ammonia and
extracted with several portions of chloroform (total of
200 ml). The solvent was distilled off, and compounds
IVa and Va were separated by treatment with boiling
hexane where the latter is insoluble.
1
The H NMR spectra were recorded on a Bruker
DRX-500 spectrometer (500 MHz) from solutions in
DMSO-d6 using tetramethylsilane as internal refer-
ence. The mass spectra were obtained on an MKh-
1310 instrument. The elemental compositions were
determined on a CHN-1 analyzer.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 7 2007

BEGUNOV, RYZVANOVICH
3. Begunov, R.S., Ryzvanovich, G.A., and Nozdrache-
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 7 2007