New heterocyclic systems based on 1-hydrazino- 5,6,7,8-tetrahydro[2,7] naphthyridine: 7,8,9,10-tetra- hydro[1,2,4]triazolo[3,4-a]- and 7,8,9,10-tetra- hydro[1,2,4]triazolo[5,1-a][2,7]naphthyridines s. n. sirakanyan

Article abstract of DOI:10.1007/s10593-012-1017-z

Methods have been developed for the synthesis of new substituted 7,8,9,10-tetrahydro[1,2,4]triazolo-[3,4-a][2,7]naphthyridines from 3-chloro-1-hydrazino-7-methyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-4- carbonitrile. It was shown that on heating in an amine (ethanolamine, pyrrolidine, 2-hydroxy-propylamine), they undergo a Dimroth rearrangement at the triazole fragment, being converted into 7,8,9,10-tetrahydro[1,2,4]triazolo[5,1- a][2,7]naphthyridine derivatives.

Full text of DOI:10.1007/s10593-012-1017-z

Chemistry of Heterocyclic Compounds, Vol. 48, No. 3, June, 2012 (Russian Original Vol. 48, No. 3, March, 2012)
NEW HETEROCYCLIC SYSTEMS BASED ON 1-HYDRAZINO-
5,6,7,8-TETRAHYDRO[2,7]NAPHTHYRIDINE: 7,8,9,10-TETRA-
HYDRO[1,2,4]TRIAZOLO[3,4-a]- AND 7,8,9,10-TETRA-
HYDRO[1,2,4]TRIAZOLO[5,1-a][2,7]NAPHTHYRIDINES
S. N. Sirakanyan1*, N. G. Avetisyan1, and A. S. Noravyan1
Methods have been developed for the synthesis of new substituted 7,8,9,10-tetrahydro[1,2,4]triazolo-
[3,4-a][2,7]naphthyridines from 3-chloro-1-hydrazino-7-methyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-
4-carbonitrile. It was shown that on heating in an amine (ethanolamine, pyrrolidine, 2-hydroxy-
propylamine), they undergo a Dimroth rearrangement at the triazole fragment, being converted into
7,8,9,10-tetrahydro[1,2,4]triazolo[5,1-a][2,7]naphthyridine derivatives.
Keywords: 5,6,7,8-tetrahydro[2,7]naphthyridines, 7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a][2,7]naphthyri-
dines, 7,8,9,10-tetrahydro[1,2,4]triazolo[5,1-a][2,7]naphthyridines, nucleophilic substitution, Dimroth
rearrangement.
The enhanced interest towards 1,2,4-triazoles and 2,7-naphthyridines is caused by a wide spectrum of
their biological activity [1-3]. In the present work, the synthesis of compounds combining said heterocycles as
their structural fragments, is described. The desired products were obtained from the 1,3-dichloro-7-methyl-
5,6,7,8-tetrahydro[2,7]naphthyridine-4-carbonitrile (1) synthesized by us previously [4]. The difference in
reactivity of the chlorine atoms at 0-25oC in dichloro compound 1 enabled to obtain 1-hydrazino-substituted
compound 2 in 82% yield upon treating compound 1 with hydrazine. The interaction of compound 2 with
triethyl orthoformate led to product 3 which is a representative of a new heterocyclic system of 7,8,9,10-tetra-
hydro[1,2,4]triazolo[3,4-a][2,7]naphthyridine. Compound 3 on refluxing in methanol for 2 h with amines 4a-p
was converted into the corresponding amino derivatives 5a-p (with 75-93% yield). Mention must be made of
the significant increase in reactivity of the second chlorine atom in cyclization product 3 in comparison with its
reactivity in 3-chloro-5,6,7,8-tetrahydro[2,7]naphthyridines (including also compound 2), in which substitution
by amine occurs only on extended (no less than 10 h) refluxing in butanol [4].
Attempts to rearrange compound 3 with recyclization of the piperidine ring, similarly to the
rearrangement of 1,3-diamino-5,6,7,8-tetrahydro[2,7]naphthyridines carried out by us previously [4], were not
successful, but it was discovered that under the conditions described in place of the f ormation of compounds 7a,b,
_______
*To whom correspondence should be addressed, e-mail: shnnr@mail.ru.
1The Scientific Technological Center of Organic and Pharmaceutical Chemistry of National Academy of
Sciences of the Republic of Armenia, A. L. Mnjoyan Institute of Fine Organic Chemistry, 26 Azatutyan Ave.,
Yerevan 0014, Armenia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 500-505, March, 2012. Original
article submitted February 13, 2011. Revision submitted June 5, 2011.
470
0009-3122/12/4803-0470©2012 Springer Science+Business Media, Inc.

a Dimroth rearrangement of the triazole ring occurred, which is highly characteristic for such compounds [5]. Thus,
refluxing the tetrahydrotriazolo[3,4-a][2,7]naphthyridine 3 in an excess of amine 4a,g,i led to the formation of the
corresponding products 6a-c, representing a new heterocyclic system, the 7,8,9,10-tetrahydro[1,2,4]-tria-zolo[5,1-
a][2,7]naphthyridines.
CN
CN
N2H4 ·H2O
Cl
Cl
HC(OEt)3
MeOH
N
N
N
N
0–25°C

Me
Me
HN
Cl
NH2
1
2
R1
N
CN
CN
NHR1R2
4a–p
Cl
R2
N
N
N
N
MeOH
Me
Me

N
N
N
N
5a–p
3
Me
N
1
CN
R
O
H
N
4a,g,i
(excess)
4g
(excess)
N
R2
4g,i
R2
5b,f
3

N
N

Me
N
N
N
N
6a,c (from 3)
N
6b (from 3 and 5f)
6d (from 5b)
7a,b
4, 5 a R1 + R2 = –(CH2)4–, b R1 + R2 = –(CH2)5–, c R1 + R2 = –(CH2)2CH(CH2Ph)(CH2)2–,
d R1 + R2 = –(CH2)2N(CH2CH2OH)(CH2)2–, e R1 + R2 = –(CH2)2O(CH2)2–, f–p R1 = H;
f R2 = CH2CH2CHMe2, g R2 = CH2CH2OH, h R2 = 2-methoxyethyl, i R2 = CH2CH(OH)Me,
j R2 = CH2Ph, k R2 = 4-4-pyridylmethyl, l R2 = 2-furylmethyl, m R2 = 2-morpholinoethyl,
n R2 = (CH2)3OH, o R2 = CH2CH2Ph, p R2 = CH2CH2(3,4-(MeO)2C6H3); 6 a R1 + R2 = –(CH2)4–,
b,c R1 = H, d R1 + R2 = – (CH2)5–; 6b, 7a R2 = CH2CH2OH, 6c, 7b R2 = CH2CH(OH)Me
An analogous rearrangement also took place on refluxing amino derivatives 5b,f in ethanolamine (4g),
but in the case of the (isopentyl)amino-substituted carbonitrile 5f reamination also occurred involving the
solvent, and the sole product 6b in 77% yield was formed.
1
In the H NMR spectra of products 6a-d, the signal of the CH proton of the triazole ring was shifted
towards high field by 0.7-1.2 ppm in comparison with the analogous signal of the isomeric compounds 5a,g,i,b
while the remaining signals differed insignificantly. This confirmed the formation of a 7,8,9,10-tetrahydro-
[1,2,4]triazolo[5,1-a][2,7]naphthyridine system. In the case of formation of structure 7 the differences in the
spectra of these compounds would be more substantial by far.
Thus, in the course of investigations, derivatives have been obtained of two new heterocyclic systems
containing in their structure 1,2,4-triazole and 2,7-naphthyridine rings as fragments, that opens new possibilities
in the synthesis of heterocyclic compounds. In addition, the broad spectrum of biological activity of analogous
derivatives predetermines the expediency of investigating this promising class of condensed compounds for the
creation of new pharmacologically active substances.
471

TABLE 1. Physicochemical Characteristics of the Synthesized Compounds
2, 3, 5a-p, 6a-d
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, °C
Yield, %
C
H
N
C10H12ClN5
50.41
50.53
53.42
53.34
63.84
63.81
64.75
64.84
71.62
71.48
59.75
59.81
60.27
60.39
64.29
64.40
57.28
57.34
58.68
58.73
58.68
58.73
67.85
67.91
63.86
63.93
62.25
62.33
59.69
59.81
58.65
58.73
5.14
5.09
4.15
4.07
6.31
6.43
6.71
6.80
6.71
6.78
6.73
6.79
6.11
6.08
7.35
7.43
5.85
5.92
6.27
6.34
6.26
6.34
5.58
5.70
5.28
5.37
5.14
5.23
6.75
6.79
6.29
6.34
29.35
29.46
28.35
28.28
29.68
29.76
28.42
28.36
21.68
21.74
28.65
28.72
28.22
28.17
28.24
28.16
30.75
30.86
29.29
29.35
29.26
29.35
26.34
26.40
30.64
30.70
27.21
27.26
28.68
28.72
29.28
29.35
233-235
230-232
210-212
225-227
212-214
224-226
246-248
159-161
207-209
147-149
175-178
244-247
230-232
221-223
208-210
166-168
242-244
218-220
202-204
197-199
165-167
221-223
82
85
78
81
75
82
84
87
85
80
87
85
75
84
91
84
93
89
81
85
77
74
2
C11H10ClN5
C15H18N6
3
5a
5b
5c
5d
5e
5f
C16H20N6
C23H26N6
C17H23N7O
C15H18N6O
C16H22N6
C13H16N6O
C14H18N6O
C14H18N6O
C18H18N6
5g
5h
5i
5j
C17H17N7
5k
5l
C16H16N6O
C17H23N7O
C14H18N6O
C19H20N6
5m
5n
5o
5p
6a
6b
6c
6d
68.60
68.65
64.15
64.27
63.78
63.81
57.28
57.34
58.66
58.73
64.72
64.84
6.13
6.06
6.20
6.16
6.32
6.43
5.85
5.92
6.28
6.34
6.75
6.80
25.22
25.28
21.35
21.41
29.64
29.76
30.75
30.86
29.29
29.35
28.33
28.36
C21H24N6O2
C15H18N6
C13H16N6O
C14H18N6O
C16H20N6
EXPERIMENTAL
1
The IR spectra were recorded on a UR-20 spectrometer in nujol. The H NMR spectra of the
synthesized compounds were recorded on a Varian Mercury-300 VX instrument (at 300 MHz) in DMSO-d6,
internal standard was TMS. A check on the progress of reactions and the purity of the obtained compounds was
performed by TLC on Silufol UV-254 plates. Physicochemical characteristics of the synthesized compounds are
shown in Table 1 and 1H NMR spectral data are given in Table 2.
3-Chloro-1-hydrazino-7-methyl-5,6,7,8-tetrahydro[2,7]naphthyridine-4-carbonitrile (2). Hydrazi-
ne hydrate (5.00 g, 0.10 mol) was added with stirring to a solution of dichloro compound 1 (2.42 g, 0.01 mol) in
abs. MeOH (100 ml) cooled to 0-5oC. The reaction mixture was stirred for 8 h, gradually increasing the
472

473

474

temperature to 20-25oC. The precipitated crystals of product 2 were filtered off, washed with water, dried, and
1
recrystallized from DMF. IR spectrum, , cm-1: 3660, 3220 (NHNH2), 2220 (CN). H NMR spectrum, δ, ppm
3
3
5
(J, Hz): 2.40 (3H, s, CH3); 2.60 (2H, t, J = 5.7, 6-CH2); 2.79 (2H, tt, J = 5.7, J = 1.6, 5-CH2); 3.13 (2H, t,
5J = 1.6, 8-CH2); 4.25 (2H, m, NH2); 8.38 (1H, s, NH).
5-Chloro-9-methyl-7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a][2,7]naphthyridine-6-carbonitrile (3).
A mixture of compound 2 (2.38 g, 0.01 mol) and triethyl orthoformate (50 ml) was refluxed for 10 h, the excess
of ester was distilled off to dryness, and hexane (25 ml) was added to the residue. The resulting crystals were
filtered off, washed with hexane, dried, and recrystallized from CHCl3. IR spectrum, , cm-1: 2220 (CN).
5-(R1,R2-Amino)-9-methyl-7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a][2,7]naphthyridine-6-carbo-
nitriles 5a-p (General Method). A mixture of chloro compound 3 (2.48 g, 0.010 mol) and the corresponding
amine 4a-p (0.022 mol) in abs. MeOH (50 ml) was refluxed for 2 h. The MeOH was distilled off to dryness,
water (50 ml) was added to the residue, the separated crystals of product 5 were filtered off, washed with water,
dried, and recrystallized from EtOH.
5-(R1,R2-Amino)-9-methyl-7,8,9,10-tetrahydro[1,2,4]triazolo[5,1-a][2,7]naphthyridine-6-carbo-
nitriles 6a-d (General Method). A mixture of chloro compound 3 (2.48 g, 0.01 mol) or 5b,f (0.01 mol) and the
corresponding amine 4a,g,i (0.10 mol) was refluxed for 3 h. After cooling, water (50 ml) was added, the
separated crystals of product 6a-d were filtered off, washed with water, dried, and recrystallized from EtOH.
The identity of both samples of product 6b, obtained from compounds 3 and 5f by refluxing with amine 4g, was
demonstrated by 1H NMR spectroscopy.
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