Reduction of imidazo[4,5-c]pyridine and [1,2,3]triazolo[4,5-c]pyridine derivatives to spinaceamines and 2-azaspinaceamines

Article abstract of DOI:10.1023/A:1016350629395

Reduction of 1-substituted [1,2,3]triazolo[4,5-c]pyridines with nickel-aluminum alloy in aqueous alkali gave 2-azaspinaceamines. Reduction of imidazo[4,5-c]pyridine and [1,2,3]triazolo[4,5-c]pyridine derivatives with formic acid in the presence of triethy

Full text of DOI:10.1023/A:1016350629395

Russian Journal of Organic Chemistry, Vol. 38, No. 3, 2002, pp. 419 423. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 3, 2002,
pp. 440 444.
Original Russian Text Copyright
2002 by Yutilov, Smolyar, Astashkina.
Reduction of Imidazo[4,5-c]pyridine
and [1,2,3]Triazolo[4,5-c]pyridine Derivatives to Spinaceamines
and 2-Azaspinaceamines
Yu. M. Yutilov, N. N. Smolyar, and N. V. Astashkina
Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine,
ul. R. Luxemburg 70, Donetsk, 83114 Ukraine
Received March 6, 2001
Abstract Reduction of 1-substituted [1,2,3]triazolo[4,5-c]pyridines with nickel aluminum alloy in aqueous
alkali gave 2-azaspinaceamines. Reduction of imidazo[4,5-c]pyridine and [1,2,3]triazolo[4,5-c]pyridine
derivatives with formic acid in the presence of triethylamine resulted in formation of 5-formylspinaceamines
and 2-azaspinaceamines. The 5-formyl group in the latter can be removed by acid hydrolysis. Unsubstituted
2-azaspinaceamine, an aza analog of natural spinaceamine, was synthesized for the first time.
Development of new methods for synthesizing of
spinaceamine (Ia) [1] and 2-azaspinaceamine deriva-
tives [2] (4,5,6,7-tetrahydroimidazo[4,5-c]pyridines
and 4,5,6,7-tetrahydro[1,2,3]triazolo[4,5-c]pyridines,
respectively), made it possible to vary over a wide
range the substitution pattern in both imidazole (tri-
azole) and partially saturated pyridine rings. In such
a way various derivatives of spinaceamine and 2-aza-
spinaceamine were obtained, some of which exhibited
analgetic, spasmolythic, psychosedative, myorelaxant,
hypotensive, and antihypoxic activity [3 6]. However,
to be especially interesting. Therefore, we made
an attempt to fill the above synthetic gap via direct
reduction of imidazo[4,5-c]pyridine and [1,2,3]tri-
azolo[4,5-c]pyridine derivatives.
It is known [7] that pyridine and isoquinoline
derivatives react with nickel aluminum alloy in
aqueous alkali to give products of reduction of the
pyridine ring. Under analogous conditions, the reduc-
tion of 1-substituted [1,2,3]triazolo[4,5-c]pyridines
Ia Ic afforded the corresponding tetrahydro deriva-
tives IIa IIc in 80 91% yield (Scheme 1, Table 1).
these procedures do not ensure preparation of spinace- The products were individual compounds, as followed
amines and 2-azaspinaceamines having no substituent
on the nitrogen atom in the imidazole or triazole ring.
Pharmacological properties of such compounds seem
from the data of thin-layer chromatography and
elemental analysis. They are low-melting substances,
readily soluble in various organic solvents. Some
Scheme 1.
X = N, R = H, R = Me (a), Et (b), CH2Ph (c), Ph (d); R = R = Et (e); X = CH, R = H, R = Me (f), Ph (g); X = CMe, R = H,
R = Me (h); X = CPh, R = Me, R = H (i); R = R = H, X = N (j), CH (k), CMe (l), CPh (m).
1070-4280/02/3803-0419$27.00 2002 MAIK Nauka/Interperiodica

420
YUTILOV et al.
Table 1. Yields, melting points, and elemental analyses of spinaceamine and 2-azaspinaceamine derivatives IIa IIm,
IIId IIIf, and IIIj IIIm
Found, %
H
Calculated, %
H
Comp. Yield,
mp C (solvent)
Formula
no.
%
C
N
C
N
IIaa
IIbb
IIc
80
91
89
94
93
92
94
91
92
93
93
90
92
88
91
90
93
92
81
95
101 103 (2-propanol)
48 50 (ethanol)
33.97 5.64 26.38 C6H10N4 2HCl
40.82 3.82 25.60 C7H12N4 C6H3N3O7
67.11 6.52 26.04 C12H14N4
34.11
40.95
67.26
65.98
42.70
40.02
52.95
42.87
54.56
30.47
36.75
40.02
52.96
63.14
5.72
3.96
6.59
6.04
7.16
6.24
5.55
6.75
5.98
5.11
5.65
6.24
5.55
5.30
4.38
6.71
2.91
3.18
3.58
3.53
26.52
25.71
26.15
27.98
22.13
20.00
15.44
18.75
14.68
28.43
21.43
20.00
15.44
24.55
22.42
25.44
25.72
22.10
21.31
18.41
94 95c (heptane)
84 85 (hexane)
IId
65.79 6.00 27.89 C11H12N4
IIea
IIfa
165 167 (2-propanol)
225 228 (methanol)
>250 (ethanol)
249 252 (methanol)
>250 (ethanol)
118 120 (ethanol)
>250 (methanol)
210 212 (ethanol)
>250 (ethanol)
153 155 (benzene)
59 60 (ethanol)
79 80 (2-propanol)
60 61 (ethanol)
200 202 (ethanol)
181 183 (2-propanol)
178 180 (2-propanol)
42.53 7.11 22.01 C9H16N4 2HCl
39.85 6.11 19.87 C7H11N3 2HCl
52.80 5.49 15.32 C12H13N3 2HCl
42.69 6.68 18.59 C18H13N3 2HCl
54.40 5.88 14.53 C13H15N3 2HCl
30.31 5.03 28.29 C5H8N4 2HCl
36.57 5.58 21.31 C6H9N3 2HCl
39.80 6.15 19.81 C7H11N3 2HCl
52.78 5.46 15.29 C12H13N3 2HCl
62.94 5.20 24.43 C12H12N4O
43.86 4.32 22.27 C10H16N4O C6H3N3O7 43.94
58.01 6.65 25.31 C8H11N3O
37.68 2.83 25.59 C6H8N4O C6H3N3O7
40.88 3.11 22.02 C7H9N3O C6H3N3O7
42.44 3.49 21.16 C8H11N3O C6H3N3O7
IIga
IIha
IIia
IIja
IIka
IIla
IIma
IIId
IIIeb
IIIf
58.17
37.80
41.06
42.65
IIIjb
IIIkb
IIIlb
IIImb
49.72 3.45 18.28 C13H13N3O C6H3N3O7 50.00
a
b
c
The melting point and analytical data are given for the corresponding dihydrochloride.
The melting point and analytical data are given for the corresponding picrate.
Published data [5]: mp 93 94 C.
products were characterized as the corresponding
dihydrochlorides (Table 1). The spectral parameters
of free bases IIa IIc and their dihydrochlorides are
collected in Table 2. Unlike initial [1,2,3]triazolo-
[4,5-c]pyridines Ia Ic, their reduction products IIa
line is reduced on heating in a boiling mixture of
formic acid with triethylamine.
The reduction of substituted [1,2,3]triazolo[4,5-c]-
pyridines Ia, Id, Ie, and Ij and imidazo[4,5-c]pyri-
dines If Ii and Ik Im was carried out as described in
[10] for isoquinoline. The yields of the resulting
5-formyl derivatives IIIa and IIId IIIm were 88
95% (Table 1). Most products were light yellow low-
melting or oily substances which were characterized
as the corresponding picrates. Free bases III are
readily soluble in alcohol, water, benzene, and chloro-
form. Their structure was confirmed by the IR and
1H NMR spectra (Table 2). In the IR spectra of III we
1
IIc show in the H NMR spectra signals from ali-
phatic protons in positions 4, 6, and 7. For example,
the spectrum of IIb contains signals at 1.31 (CH3)
and 4.26 ppm (CH2) from the N1C2H5 group and also
methylene proton signals at
4.59 (C4H2), 3.61
(C6H2), and 3.09 ppm (C7H2) (Table 2).
The proposed procedure for synthesizing 4,5,6,7-
tetrahydro[1,2,3]triazolo[4,5-c]pyridines IIa IIc is
more advantageous than the known method [8] due to
its experimental simplicity, accessibility of reagents,
and high yields and purity of the products. However,
bases Id Im are insoluble in aqueous alkali. In order
to increase their solubility, in some cases aqueous
alkali was replaced by aqueous alcoholic alkali, but
the desired results were not obtained. Therefore, we
tried to apply Lukes’ procedure [9], according to
which the pyridine fragment in quinoline or isoquino-
1
observed a strong absorption band at about 1660 cm
due to stretching vibrations of the aldehyde carbonyl
group. The 1H NMR spectra of these compounds
differ from those of initial triazolopyridines I by the
presence of signals from the methylene protons in
positions 4, 6, and 7 and from the aldehyde proton
as a doublet at 8.17 8.38 ppm, J = 10 Hz (Table 2).
Heating of compounds III in boiling concentrated
hydrochloric acid results in elimination of the formyl
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REDUCTION OF IMIDAZO[4,5-c]PYRIDINE AND [1,2,3]TRIAZOLO[4,5-c]PYRIDINE
421
Table 2. 1H NMR spectra of spinaceamine and 2-azaspinaceamine derivatives IIa IIm, IIIa, IIId IIIf, and IIIj IIIm
a
Chemical shifts
X
,
ppm
Comp.
no.
N1R
C4H2 or C4HR
N5CHO
C6H2
3.62 t
3.61 t
3.52 t
3.14 t
C7H2
3.09 t
3.10 t
2.81 t
2.82 t
IIa
IIb
3.92 s (3H, CH3) 4.62 t (2H, CH2)
1.31 t (3H, CH3), 4.59 t (2H, CH2)
4.26 q (2H, CH2)
5.42 s (2H, CH2), 4.58 t (2H, CH2)
7.04 s (5H, C6H5)
7.48 7.55 m (5H, 4.11 t (2H, CH2)
C6H5)
1.37 t (3H, CH3), 1.13 t (3H, CH3),
6.62 q (2H, CH2) 1.98 q (2H, CH2)
IIc
IId
IIe
3.14 3.67 m 2.99 t
IIf
3.80 s (3H, CH3) 4.65 t (2H, CH2) 8.99 s (1H, 2-H)
7.30 s (5H, C6H5) 4.80 t (2H, CH2) 8.92 s (1H, 2-H)
3.37 s (3H, CH3) 3,75 t (2H, CH2) 2.47 s (3H, 2-CH3)
3.78 s (3H, CH3) 4.67 t (2H, CH2) 7.27 s (5H, 2-C6H5)
10.12 d (1H, 1-H) 4.19 t (2H, CH2)
4.32 t (2H, CH2) 8.33 s (1H, 2-H)
4.46 t (2H, CH2) 2.36 s (3H, 2-CH3)
4.58 t (2H, CH2) 7.30 s (5H, 2-C6H5)
3.69 s (3H, CH3) 4.58 s (1H, CH),
4.71 s (1H, CH)
3.76 t
3.92 t
3.12 t
3.66 t
3.68 t
3.42 t
3.72 t
3.67 t
3.22 t
3.20 t
2.94 t
3.17 t
3.14 t
2.85 t
2.71 t
2.73 t
IIg
IIh
IIi
IIj
IIk
IIl
IIm
IIIa
8.32 db 3.72 t (1H), 2.66 2.69 m
3.89 t (1H)
IIId
IIIe
7.26 7.55 m (5H, 4.68 s (1H, CH),
8.28 db 3.72 t (1H), 2.89 2.94 m
3.90 t (1H)
C6H5)
4.82 s (1H, CH)
1.39 t (3H, CH3), 0.99 t (3H, CH3),
4.23 q (2H, CH2) 1.73 q (2H, CH2),
4.54 4.64 m (1H,
8.17 s
3.45 t
2.74 t
CH)
IIIf
IIIj
3.85 s (3H, CH3) 4.29 t (2H, CH2) 8.83 s (1H, 2-H)
4.55 s (1H, CH),
8.34 db 3.67 t
3.41 t
8.38 db 3.40 s (1H), 3.00 t
3.74 s (1H)
4.79 s (1H, CH)
IIIk
IIIl
IIIm
4.60 s (2H, CH2) 9.10 s (1H, 2-H)
4.54 s (2H, CH2) 2.38 s (3H, 2-CH3)
4.53 s (2H, CH2) 7.20 7.30 m (5H,
2-C6H5)
8.48 db 3.78 t
8.87 db 3.68 t
8.90 db 3.75 t
2.83 t
2.74 t
2.67 t
a
Solvents: CF3COOH (IIa IIc, IIf, IIg, IIk, IIl); DMSO-d6 (IIe, IIh, IIj); CDCl3 (IId, IIIa, IIId, IIIj); CD3CN (IIIe); CD3OD
(IIIk IIIm).
J4,5 = 10 Hz.
b
group with formation of 5-unsubstituted tetrahydro
derivatives II in 80 94% yield (Table 1). Compounds
IIg IIi can also be obtained without isolation of
5-formyl derivatives by reduction of Ig Ii with formic
acid and subsequent hydrolysis with concentrated
hydrochloric acid. The structure of products IIg IIi
or methine protons in positions 4, 6, and 7. The
chemical shifts are well consistent with those reported
in [5] for 2-azaspinaceamines.
We were the first to synthesize unsubstituted 2-aza-
spinaceamine (IIj) (which is a 2-aza analog of natural
spinaceamine [11]) by reduction of 1H-[1,2,3]triazolo-
[4,5-c]pyridine (Ij) with formic acid. Spinaceamine
was obtained in 93% yield by reduction of 1H-imid-
azo[4,5-c]pyridine (Ij) with formic acid. Starting
1
was proved by the H NMR and IR spectra (Table 2).
1
Their H NMR spectra contain signals from protons of
alkyl or aryl groups on N1 and C4 and from methylene
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 3 2002

422
YUTILOV et al.
from 2-methyl- and 2-phenylimidazo[4,5-c]pyridines
Il and Im we synthesized 2-methyl- and 2-phenyl-
spinaceamines IIl and IIm.
under reflux and was then evaporated to dryness. The
residue was recrystallized from alcohol to obtain
colorless dihydrochloride of IId, IIf, or IIg (Table 1).
5-Formylspinaceamines and 5-formyl-2-aza-
spinaceamines IIIa and IIId IIIg. To a solution of
10 mmol of base Ia or Id Ij in 80 mmol of 99%
formic acid we added in portions 20 mmol of triethyl-
amine on cooling. The mixture was heated for 10 h at
100 C, cooled, diluted with 20 ml of distilled water,
neutralized with sodium carbonate, and evaporated
to dryness. The residue was extracted with isopropyl
alcohol, and the solvent was distilled off from the
extract to obtain light yellow bases III which were
converted into the corresponding picrates (compounds
IIId and IIIf) by heating with an equimolar amount
of picric acid in alcohol for 3 5 min (Table 1).
Base IIIa, 5 mmol, was dissoloved in 10 ml of
benzene or isopropyl alcohol, and 2 ml of a saturated
solution of hydrogen chloride in isopropyl alcohol
was added on cooling (8 10 C). The precipitate was
filtered off and dried in a desiccator over calcium
chloride at room temperature (Table 1).
EXPERIMENTAL
1
The H NMR spectra were recorded on a Tesla BS-
467C spectrometer (80 MHz) in CF3COOH and on
a Varian Gemini-200 instrument (200 MHz) in CDCl3,
DMSO-d6, or CD3CN; HMDS was used as internal
reference. The IR spectra were measured on a UR-20
spectrophotometer in mineral oil. The purity of the
products was checked by TLC on Silufol UV-254
plates with alcohol as eluent; spots were visualized
by UV light or iodine vapor.
Initial [1,2,3]triazolo[4,5-c]pyridines Ia Id and
Ij were synthesized by the procedure reported in
[12, 13]; compound Ie was obtained as described in
[14]. Imidazo[4,5-c]pyridines If Ii and Ik Im were
prepared according to [15 21].
1-Alkyl-4,5,6,7-tetrahydro[1,2,3]triazolo[4,5-c]-
pyridines IIa IIc. a. To a solution of 10 mmol of
1-alkyl[1,2,3]triazolo[4,5-c]pyridine Ia Ic in 32 ml of
0.5 M aqueous KOH (or NaOH) we added in portons
3.9 g of a 1:1 nickel aluminum alloy under vigorous
stirring at room temperature. After 20 24 h, an addi-
tional 3.2 g of Raney nickel was added under the
same conditions. The mixture was stirred for 4 5 h
and filtered, and the filtrate was treated with chloro-
form. The organic phase was separated and dried
over anhydrous sodium sulfate, and the solvent was
distilled off. The residue was purified by recrystal-
lization from heptane (or hexane). The corresponding
picrate was prepared from equimolar amounts of the
free base and picric acid, which were heated for
a short time in ethanol (Table 1).
Compound IIa, 5 mmol, was dissolved in 10 ml
of alcohol, and either gaseous hydrogen chloride was
passed through the solution or 2 ml of concentrated
hydrochloric acid was added. The mixture was then
evaporated to dryness, and the residue was recrystal-
lized from alcohol or reprecipitated with acetone from
a solution in propanol (Table 1).
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