Efficient Synthesis and Some Transformations of 1-Hydrazinyl-5,6,7,8-tetrahydroisoquinolines Involving Rearrangement of the Pyridine Ring

Article abstract of DOI:10.1134/S1070428019090148

—A procedure was developed for the synthesis of 1-hydrazinyl-3-arylamino-5,6,7,8-tetrahydroisoquinoline- 4-carbonitriles via recyclization of the pyridine ring in 3-amino-2-aryl-1-sulfanylidene-1,2,5,6,7,8- hexahydroisoquinoline-4-carbonitriles by the act

Full text of DOI:10.1134/S1070428019090148

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 9, pp. 1351–1362. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 9, pp. 1440–1452.
Efficient Synthesis and Some Transformations
of 1-Hydrazinyl-5,6,7,8-tetrahydroisoquinolines Involving
Rearrangement of the Pyridine Ring
E. G. Paronikyana, Sh. Sh. Dashyana,* S. S. Mamyana, R. A. Tamazyana, and A. G. Ayvazyana
a Scientific Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, Yerevan, Armenia
*e-mail: Shdashyan@gmail.com
Received March 20, 2019; revised May 14, 2019; accepted May 30, 2019
Abstract—A procedure was developed for the synthesis of 1-hydrazinyl-3-arylamino-5,6,7,8-tetrahydroiso-
quinoline-4-carbonitriles via recyclization of the pyridine ring in 3-amino-2-aryl-1-sulfanylidene-1,2,5,6,7,8-
hexahydroisoquinoline-4-carbonitriles by the action of hydrazine hydrate. The recyclization products were
converted to new heterocyclic systems, 7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]isoquinolines and 1-(3,5-di-
methyl-1H-pyrazol-1-yl)-5,6,7,8-tetrahydroisoquinolines, by reactions with triethyl orthoformate and acetyl-
acetone, respectively. Treatment of 1-hydrazinyl-3-arylamino-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles
with sodium azide in acetic acid gave 1-azido-3-arylamino-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles, and
azide–tetrazole isomerism of the latter was studied. The state of the azide–tetrazole equilibrium was found to
depend on the solvent polarity and substituent nature in the arylamino group. The structure of 5-(2-methoxy-
anilino)-7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]isoquinoline-6-carbonitrile was confirmed by X-ray analysis,
and intermolecular hydrogen bonds were detected in its crystal structure. The synthesized compounds were
evaluated for antimicrobial activity.
Keywords: 5,6,7,8-tetrahydroisoquinoline, triazolo[3,4-a]pyridines, 1-(pyrazol-1-yl)tetrahydroisoquinolines,
azide–tetrazole tautomerism, rearrangement, antimicrobial activity.
DOI: 10.1134/S1070428019090148
Increased interest in partially hydrogenated isoqui-
noline derivatives is related to the presence of an iso-
quinoline fragment in molecules of many alkaloids, as
well as to the possibility of obtaining new biologically
active compounds based thereon. Synthetic 1,2,3,4-
and 5,6,7,8-tetrahydroisoquinoline derivatives were
reported to exhibit antitumor, antimicrobial, antihyper-
tensive, and neurotropic activities [1–5].
Syntheses of triazolopyridines and triazoloiso-
quinolines have been reported [6–8]. However,
7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]isoquinoline
derivatives have been poorly studied. We have found
only two publications on the synthesis and biological
activity of triazoloisoquinolines obtained from
5,6,7,8-tetrahydroisoquinoline derivatives [9, 10].
pyridines. The goal of the present work was to syn-
thesize 1-hydrazinyl-5,6,7,8-tetrahydroisoquinolines
2a–2h. Unlike the rearrangement reported in [11],
compounds 2a–2h were obtained via recyclization of
the pyridine ring in 3-amino-2-aryl-1-sulfanylidene-
1,2,5,6,7,8-hexahydroisoquinoline-4-carbonitriles
1a–1h by the action of hydrazine hydrate which is
a strong nucleophile; we thus succeeded in reducing
the number of steps. Initial hexahydroisoquinoline-
thiones 1a–1h were prepared by reactions of cyclo-
hexylidenemalononitrile with substituted phenyl iso-
thiocyanates (Scheme 1). Compounds 2a–2h were
subjected to further transformations, which led to the
formation of new heterocyclic systems. The synthe-
sized compounds were evaluated for antimicrobial
activity.
We previously described [11] recyclization of pyri-
dine ring by the action of amines. Initially, we syn-
thesized the corresponding pyridinium salts, and the
latter were converted to 6,8-diaminopyrano[3,4-c]-
The reaction of 1a–1h with hydrazine hydrate
involved opening of the pyridine ring and subsequent
recyclization accompanied by evolution of hydrogen
1351

PARONIKYAN et al.
1352
Scheme 1.
CN
CN
ArNCS, DMF
Et3N, 50°C, 1 h
NH2
Ar
CN
71–79%
N
S
1a–1h
Ar = Ph (a), 2-MeC6H4 (b), 3-MeC6H4 (c), 4-MeC6H4 (d), 2-MeOC6H4 (e), 3-MeOC6H4 (f), 4-MeOC6H4 (g), 4-ClC6H4 (h).
sulfide to afford 1-hydrazinyl derivatives 2a–2h
(Scheme 2). The mechanism of this rearrangement is
likely to be similar to that proposed in [11]. Hydrazine
molecule adds to the C1 carbon atom, leading to
cleavage of the C1–N2 bond. Rotation of the
ArNH–C3–NH2 fragment in the intermediate thus
formed is followed by pyridine ring closure with
elimination of hydrogen sulfide.
[1,2,4]triazolo[3,4-a]isoquinolines 3a–3h (Scheme 3).
The IR spectra of 3a–3h showed NH and C≡N
stretching bands in the regions 3250–3335 and 2208–
1
2216 cm–1, respectively. In the H NMR spectra of
3a–3h, the 3-H proton resonated at δ 8.27–9.15 ppm,
and the NH proton signal was observed at δ 9.32–
9.77 ppm. The C3 carbon signal of 3a–3h was located
at δC 133.6–140.0 ppm in the 13C NMR spectra.
The X-ray diffraction study of a single crystal of 3b
confirmed the assigned structure. The cyclohexene
ring in molecule 3b has a clearly defined half-chair
conformation where the C1, C4, C5, and C13 atoms lie
in one plane [the maximum deviation of atoms from
the mean-square plane is 0.0601(2) Å] and the C2 atom
deviates from that plane by 0.7866(2) Å (Fig. 1).
Analysis of the anisotropic thermal vibration ellipsoids
and difference Fourier maps revealed statistical disor-
dering of the C2 and C3 atoms by two positions whose
populations were estimated at 38 and 62%. Molecules
3b in crystal are linked through N16–H16···N8 inter-
molecular hydrogen bonds [N16···N8 2.919(4) Å] to
form infinite chains along the [0 1 0] crystallographic
direction (Fig. 2). These chains interact with each other
mainly through van der Waals forces.
According to the data of [12], compound 2a was
synthesized by heating isoquinolinethione 1a in hydra-
zine hydrate under reflux [12]. We used dimethyl
sulfoxide as solvent and thus succeeded in improving
the yield and shortening the reaction time.
The IR spectra of 2a–2h showed absorption bands
due to NH and NH2 groups in the region 3150–
3315 cm–1, and the C≡N stretching band was observed
1
at 2205–2209 cm–1. In the H NMR spectra of 2a–2h,
protons of the primary amino group resonated at
δ 3.23–4.20 ppm, and signals at δ 7.15–7.75 and 7.69–
8.21 ppm were assigned to protons of the NH groups
linked to C3 and C1, respectively.
The reaction of hydrazinylisoquinolines 2a–2h with
triethyl orthoformate afforded 7,8,9,10-tetrahydro-
Scheme 2.
CN
CN
CN
N2H4·H2O
DMSO, ∆, 8 h
NH2
Ar
NH2
Ar
NH2
NHAr
1a–1h
N
N
H
H
S
NH
S
NH
NHNH2
–S
NH2
NH2
CN
CN
CN
NHAr
NHAr
NHAr
–H2S
NH2
NHNH2
N
N
H
HS
NH
S
NHNH2
NH2
2a–2h (76–81%)
Ar = Ph (a), 2-MeC6H4 (b), 3-MeC6H4 (c), 4-MeC6H4 (d), 2-MeOC6H4 (e), 3-MeOC6H4 (f), 4-MeOC6H4 (g), 4-ClC6H4 (h).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

EFFICIENT SYNTHESIS AND SOME TRANSFORMATIONS OF 1-HYDRAZINYL-...
1353
Scheme 3.
CN
NHAr
N
N
MeC(O)CH2C(O)Me
EtOH, ∆, 10 h
N
82–88%
Me
CN
NHAr
Me
HC(OEt)3, ∆, 8 h
2a–2h
4a–4h
N
81–90%
CN
N
3a–3h
N
(1) NaNO2, AcOH, 0–5°C
(2) 20–22°C, 12 h
NHAr
80–92%
N
N3
5a–5h
Ar = Ph (a), 2-MeC6H4 (b), 3-MeC6H4 (c), 4-MeC6H4 (d), 2-MeOC6H4 (e), 3-MeOC6H4 (f), 4-MeOC6H4 (g), 4-ClC6H4 (h).
By reacting 1-hydrazinyl-5,6,7,8-tetrahydroisoqui-
nolines 2a–2h with acetylacetone we obtained
1-(3,5-dimethyl-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-
isoquinolines 4a–4h (Scheme 3). The 1H NMR spectra
of 4a–4h showed a signal at δ 5.23–5.91 ppm due to
4-H proton of the pyrazole ring, and the NH signal was
located δ 7.85–8.90 ppm.
tem give rise to equilibrium in solution between
isomeric tetrazole and azide structures [13–16].
The azide–tetrazole equilibrium of compounds
5a–5g in solution (Scheme 4) was studied by 1H NMR.
Fused tetrazole ring is a stronger electron acceptor
than azido group; therefore, protons of the tetrazole
tautomer resonated in a weaker field than those of the
corresponding azido tautomer. The fractions of the
azide and tetrazole forms of 5a–5h were estimated
from the intensities of the NH and CH2 proton signals.
Treatment of hydrazines 2a–2h with sodium nitrite
in acetic acid at 0–5°C gave azido derivatives 5a–5h
(Scheme 3). The IR spectra of 5a–5h characteristically
displayed strong absorption bands in the region 2129–
2137 cm–1 due to the azido group. The stability of the
azido group in crystalline compounds 5a–5h may be
rationalized by electron-withdrawing effect of the
cyano group, as well as by steric effect of the aryl-
amino group in the 3-position, which hampers ring
closure with participation of the pyridine nitrogen
atom to form a tetrazole ring.
Compounds 5a–5h in CDCl3 exist exclusively as
azido tautomers, whereas equilibrium between the
N8
C9
N7
N10
C11
C6
N16
C4
C5
C18
It is known that unsubstituted tetrazolo[1,5-a]pyri-
dine in the crystalline state has cyclic structure which
retains in polar and nonpolar solvents. Introduction of
electron-withdrawing substituents into the cyclic sys-
C19
C12
C17
C22
C13
C14
C3
O23
C1
N15
C2
Scheme 4.
C20
C24
C21
CN
CN
NHAr
NHAr
Fig. 1. Structure of the molecule of 5-(2-methylanilino)-
7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]isoquinoline-6-car-
bonitrile (3b) according to the X-ray diffraction data. Non-
hydrogen atoms are shown as anisotropic thermal vibration
ellipsoids with a probability of 50%.
N
N
N
N
N3
N
A
5a–5h
T
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

PARONIKYAN et al.
going to DMSO-d6, the fraction of tetrazole tautomer
1354
0
increased to 35–78%. The presence of an electron-
withdrawing chlorine atom in the benzene ring consid-
erably reduced the fraction of tautomer T in com-
parison to the unsubstituted analog (R = H). By con-
trast, electron-donating groups (R = Me, MeO) in the
benzene ring shifted the equilibrium toward the tetra-
zole tautomer. The position of the NH signal of both
tautomers insignificantly depended on the substituent
in the benzene ring (Table 2), but it strongly changed
upon variation of the solvent.
N8ii
c
a
b
N16i
H16i
N8
It is known that tetrahydroisoquinoline derivatives
exhibit pronounced antimicrobial activity [1, 5]. There-
fore, all compounds synthesized in this work were
evaluated for antimicrobial activity against gram-
positive (Staphylococcus aureus 209p) and gram-
negative bacteria (Sh. Flexneri 6858, E. coli 0-55) by
the agar diffusion method [17]. Triazolo[3,4-a]isoqui-
nolines 3a–3h showed weak activity against all
bacterial strains tested (d = 10–15 mm). Pyrazole
derivatives 4a–4h were equally active only against
gram-negative bacteria. Azido derivatives 5a–5h
displayed a moderate antimicrobial activity against all
test cultures (d = 16–20 mm). All compounds were
inferior to furazolidone (d = 24–25 mm) [18].
N16
H16
N8i
N16i
H16i
Fig. 2. Infinite chain formed by molecules 3b in crystal
through intermolecular hydrogen bonds along the [010] crys-
tallographic direction; symmetry operations: i: –x, 0.5 + y,
0.5 – z; ii: –x, –0.5 + y, 0.5 – z. Hydrogen bonds are shown
with dashed lines.
In summary, an efficient procedure has been
developed for the synthesis of 1-hydrazinyl-5,6,7,8-
tetrahydroisoquinolines by recyclization of the pyri-
dine ring in 3-amino-1,2,5,6,7,8-hexahydroisoquino-
line-1-thiones. The synthesized compounds have been
used to obtain new heterocyclic systems containing
a tetrahydroisoquinoline fragment. Study of the azide–
tetrazole tautomerism of 1-azido-5,6,7,8-tetrahydroiso-
quinolines in solution has shown that increase of the
solvent polarity leads to increase of the fraction of the
azide (A) and tetrazole (T) structures was observed in
solutions in DMSO-d6 and DMSO-d6–CCl4 (1:3). The
tautomer ratio depended on the solvent polarity and
substituent on C3 (Table 1). The fraction of tautomer T
in DMSO-d6–CCl4 (1 : 3) varied from 7 to 35%,
depending on the substituent in the aniline fragment. In
Table 1. Fractions (%) of azide (A) and tetrazole (T) tautomers of 3-(arylamino)-1-azido-5,6,7,8-tetrahydroisoquinoline-4-
carbonitriles 5a–5h in different solvents at 30°C
CDCl3
DMSO-d6–CCl4, 1:3
DMSO-d6
Compound
no.
Ar
A
T
A
T
A
T
5a
5b
5c
5d
5e
5f
Ph
100
100
100
100
100
100
100
100
–
–
–
–
–
–
–
–
87
65
88
85
89
90
92
93
13
35
12
15
11
10
08
07
55
22
44
50
42
59
64
65
45
78
56
50
58
41
36
35
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-ClC6H4
5g
5h
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

EFFICIENT SYNTHESIS AND SOME TRANSFORMATIONS OF 1-HYDRAZINYL-...
1355
Table 2. Chemical shifts (δ, ppm) of the NH protons of the azide and tetrazole (A/T) tautomers of 5a–5h in different solvents
Compound
CDCl3
DMSO-d6–CCl4, 1:3
DMSO-d6
no.
5a
5b
5c
5d
5e
5f
6.92/–
6.78/–
6.83/–
6.86/–
7.79/–
6.93/–
6.78/–
6.90/–
8.61/10.55
7.97/10.33
8.42/10.44
8.42/10.41
7.80/10.21
8.53/10.47
8.67/10.54
8.85/10.60
9.00/10.51
8.54/10.34
8.90/10.44
8.88/10.43
7.99/10.31
8.96/10.48
8.83/10.36
9.18/10.58
5g
5h
tetrazole form. The tautomer ratio also depends on the
substituent in the benzene ring of the arylamino group
on C3. Some of the synthesized compounds showed
a moderate antimicrobial activity.
6.21 br.s (2H, NH2), 7.10–7.15 m (2H, Harom), 7.46–
7.52 m (1H, Harom), 7.55–7.63 m (2H, Harom). 13C NMR
spectrum (DMSO-d6), δC, ppm: 21.2, 22.4, 28.3, 28.5,
78.6, 115.6, 126.5, 127.9, 128.8, 130.0, 138.7, 144.4,
153.2, 181.9. Found, %: C 68.22; H 5.40; N 14.84;
S 11.47. C16H15N3S. Calculated, %: C 68.30; H 5.37;
N 14.93; S 11.40.
EXPERIMENTAL
The IR spectra were recorded on a Nicolet Avatar
330 FT-IR spectrometer from samples dispersed in
3-Amino-2-(2-methylphenyl)-1-sulfanylidene-
1,2,5,6,7,8-hexahydroisoquinoline-4-carbonitrile
(1b). Yield 2.243 g (74%), mp 243–245°C. IR spec-
trum, ν, cm–1: 3451, 3308, 3211 (NH2), 2205 (CN),
1
mineral oil. The H and 13C NMR spectra were re-
corded on a Varian Mercury 300 VX instrument at 300
and 75.462 MHz, respectively, using tetramethylsilane
1
1
as internal standard. Signals in the H and 13C NMR
1623 (C=C), 1237 (C=S). H NMR spectrum
(DMSO-d6), δ, ppm: 1.75–1.83 m (4H, 6-H, 7-H),
2.06 s (3H, CH3), 2.53–2.59 m (2H, 8-H), 2.66–2.73 m
(2H, 5-H), 6.21 br.s (2H, NH2), 6.99–7.04 m (1H,
Harom), 7.37–7.41 m (3H, Harom). 13C NMR spectrum
(DMSO-d6), δC, ppm: 16.7, 21.2, 22.3, 28.2, 28.4,
78.3, 115.5, 126.3, 127.5, 127.6, 129.0, 131.5, 134.9,
137.4, 144.3, 152.7, 180.8. Found, %: C 69.21; H 5.74;
N 14.08; S 10.77. C17H17N3S. Calculated, %: C 69.12;
H 5.80; N 14.22; S 10.77.
spectra were assigned with the aid of DEPT, NOESY
(mixing time 1 s), and HMQC experiments. The
elemental analyses were obtained on a Euro EA 3000
elemental analyzer. The melting points were measured
on a Boetius hot stage. The crystallographic data for
compound 3b were deposited to the Cambridge
Crystallographic Data Centre (CCDC no. 1574713).
The structure of 3b was determined by the direct
method and was refined using SHELXTL software
package [19].
3-Amino-2-(3-methylphenyl)-1-sulfanylidene-
1,2,5,6,7,8-hexahydroisoquinoline-4-carbonitrile
(1c). Yield 2.273 g (75%), mp 239–241°C. IR spec-
trum, ν, cm–1: 3445, 3317, 3215 (NH2), 2206 (CN),
Compounds 1a–1h (general procedure). Triethyl-
amine, 1 mL, was added dropwise with stirring to a so-
lution of 1.5 g (10 mmol) of cyclohexylidenemalono-
nitrile and 10 mmol of substituted phenyl isothiocy-
anate in 2 mL of DMF. The mixture was stirred for 1 h
at 50°C, cooled to room temperature, and diluted with
4 mL of methanol. The precipitate was filtered off,
washed with water, and recrystallized from nitro-
methane.
1
1627 (C=C), 1238 (C=S). H NMR spectrum
(DMSO-d6), δ, ppm: 1.72–1.83 m (4H, 6-H, 7-H),
2.45 s (3H, CH3), 2.52–2.58 m (2H, 8-H), 2.64–2.72 m
(2H, 5-H), 6.20 br.s (2H, NH2), 6.89–6.94 m (2H,
Harom), 7.29 d (1H, Harom, J = 7.6 Hz), 7.31 t (1H, Harom
,
13
J = 7.6 Hz). C NMR spectrum (DMSO-d6), δC, ppm:
20.8, 21.2, 22.4, 28.2, 28.4, 78.4, 115.6, 124.8, 126.3,
128.2, 129.5, 129.7, 138.5, 139.6, 144.2, 153.1, 181.8.
Found, %: C 69.35; H 5.76; N 14.28; S 10.74.
C17H17N3S. Calculated, %: C 69.12; H 5.80; N 14.22;
S 10.85.
3-Amino-2-phenyl-1-sulfanylidene-1,2,5,6,7,8-
hexahydroisoquinoline-4-carbonitrile (1a) [12].
1
Yield 2.252 g (78%), mp 270–271°C. H NMR spec-
trum (DMSO-d6), δ, ppm: 1.75–1.81 m (4H, 6-H, 7-H),
2.52–2.58 m (2H, 8-H), 2.67–2.73 m (2H, 5-H),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

PARONIKYAN et al.
1356
2.52–2.57 m (2H, 8-H), 2.65–2.70 m (2H, 5-H), 3.89 s
(3H, OCH3), 6.27 br.s (2H, NH2), 6.98–7.03 m (2H,
arom), 7.06–7.10 m (2H, Harom). 13C NMR spectrum
(DMSO-d6), δC, ppm: 21.2, 22.4, 28.2, 28.4, 54.8,
78.4, 115.2, 115.7, 126.2, 128.9, 131.1, 144.3, 153.6,
159.3, 182.4. Found, %: C 65.51; H 5.56; N 13.41;
S 10.18. C17H17N3OS. Calculated, %: C 65.57; H 5.50;
N 13.49; S 10.30.
3-Amino-2-(4-methylphenyl)-1-sulfanylidene-
1,2,5,6,7,8-hexahydroisoquinoline-4-carbonitrile
(1d). Yield 2.182 g (72%), mp 247–249°C. IR spec-
trum, ν, cm–1: 3392, 3306, 3214 (NH2), 2205 (CN),
H
1
1619 (C=C), 1237 (C=S). H NMR spectrum
(DMSO-d6), δ, ppm: 1.74–1.82 m (4H, 6-H, 7-H),
2.47 s (3H, CH3), 2.52–2.57 m (2H, 8-H), 2.66–2.71 m
(2H, 5-H), 6.20 br.s (2H, NH2), 6.97–7.02 m (2H,
Harom), 7.35–7.39 m (2H, Harom). 13C NMR spectrum
(DMSO-d6), δC, ppm: 20.8, 21.2, 22.4, 28.2, 28.5,
78.5, 115.6, 126.3, 127.5, 130.6, 136.0, 138.2, 144.3,
153.3, 182.0. Found, %: C 69.02; H 5.74; N 14.36;
S 10.91. C17H17N3S. Calculated, %: C 69.12; H 5.80;
N 14.22; S 10.85.
3-Amino-2-(4-chlorophenyl)-1-sulfanylidene-
1,2,5,6,7,8-hexahydroisoquinoline-4-carbonitrile
(1h). Yield 2.560 g (79%), mp 256–258°C. IR spec-
trum, ν, cm–1: 3465, 3327, 3212 (NH2), 2206 (CN),
1
1624 (C=C), 1238 (C=S). H NMR spectrum
(DMSO-d6), δ, ppm: 1.71–1.83 m (4H, 6-H, 7-H),
2.51–2.57 m (2H, 8-H), 2.65–2.73 m (2H, 5-H),
6.54 br.s (2H, NH2), 7.07–7.14 m (2H, Harom), 7.52–
7.58 m (2H, Harom). 13C NMR spectrum (DMSO-d6),
δC, ppm: 21.2, 22.4, 28.3, 28.4, 78.6, 115.6, 126.1,
129.8, 130.2, 133.9, 137.4, 144.8, 153.3, 181.8. Found,
%: C 65.91; H 4.54; N 13.18; S 10.23. C16H14ClN3S.
Calculated, %: C 60.85; H 4.47; N 13.31; S 10.15.
3-Amino-2-(2-methoxyphenyl)-1-sulfanylidene-
1,2,5,6,7,8-hexahydroisoquinoline-4-carbonitrile
(1e). Yield 2.268 g (71%), mp 296–297°C. IR spec-
trum, ν, cm–1: 3454, 3310, 3219 (NH2), 2209 (CN),
1
1628 (C=C), 1239 (C=S). H NMR spectrum
(DMSO-d6), δ, ppm: 1.74–1.82 m (4H, 6-H, 7-H),
2.52–2.58 m (2H, 8-H), 2.66–2.71 m (2H, 5-H), 3.81 s
(3H, OCH3), 6.24 br.s (2H, NH2), 7.02 d.d (1H, Harom
,
Compounds 2a–2h (general procedure). A mixture
of 10 mmol of compound 1a–1h and 10 mL of
hydrazine hydrate in 5 mL of DMSO was refluxed for
8 h. The mixture was cooled to room temperature, and
the precipitate was filtered off, washed with water,
dried, and recrystallized from dioxane.
J = 7.8, 1.8 Hz), 7.11 d.d.d (1Harom, J = 7.8, 7.3,
1.1 Hz), 7.16 d.d (1H, Harom, J = 8.4, 1.1 Hz),
13
7.46 d.d.d (1H, Harom, J = 8.4, 7.3, 1.8 Hz). C NMR
spectrum (DMSO-d6), δC, ppm: 21.2, 22.4, 28.2, 28.5,
55.3, 78.1, 113.0, 115.8, 121.3, 126.0, 126.7, 128.9,
130.4, 144.2, 153.2, 153.8, 181.7. Found, %: C 65.48;
H 5.57; N 13.34; S 10.37. C17H17N3OS. Calculated, %:
C 65.57; H 5.50; N 13.49; S 10.30.
3-Anilino-1-hydrazinyl-5,6,7,8-tetrahydroisoqui-
noline-4-carbonitrile (2a) [12]. Yield 2.207 g (79%),
mp 238–239°C. IR spectrum, ν, cm–1: 3440, 3320,
1
3-Amino-2-(3-methoxyphenyl)-1-sulfanylidene-
1,2,5,6,7,8-hexahydroisoquinoline-4-carbonitrile
(1f). Yield 2.396 g (75%), mp 218–220°C. IR spec-
trum, ν, cm–1: 3451, 3308, 3215 (NH2), 2208 (CN),
3234 (NH, NH2), 2206 (CN), 1611 (C=C). H NMR
spectrum (DMSO-d6–CCl4, 1:3), δ, ppm: 1.74–1.83 m
(4H, 6-H, 7-H), 2.22–2.29 m (2H, 8-H), 2.64–2.70 m
(2H, 5-H), 4.27 br.s (2H, NH2), 6.87–6.93 m (1H,
1
1621 (C=C), 1234 (C=S). H NMR spectrum
H
H
arom), 7.18–7.24 m (2H, Harom), 7.58–7.63 m (2H,
arom), 7.76 br.s (1H, NH), 7.92 br.s (1H, NH).
(DMSO-d6), δ, ppm: 1.73–1.83 m (4H, 6-H, 7-H),
2.52–2.58 m (2H, 8-H), 2.64–2.71 m (2H, 5-H), 3.84 s
(3H, OCH3), 6.31 br.s (2H, NH2), 6.66–6.71 m (2H,
Harom), 6.99–7.04 m (1H, Harom), 7.44–7.51 m (1H,
13C NMR spectrum (DMSO-d6–CCl4, 1:3), δC, ppm:
21.4, 21.5, 21.7, 27.6, 79.3, 106.6, 117.1, 120.1, 121.0,
127.6, 140.1, 147.2, 154.5, 157.7. Found, %: C 68.87;
H 6.08; N 25.19. C16H17N5. Calculated, %: C 68.79;
H 6.13; N 25.07.
13
Harom). C NMR spectrum (DMSO-d6), δC, ppm: 21.2,
22.4, 28.2, 28.4, 54.8, 78.5, 113.4, 114.8, 115.6, 119.6,
126.2, 130.6, 139.5, 144.3, 153.2, 160.7, 181.7. Found,
%: C 65.68; H 5.44; N 13.57; S 10.22. C17H17N3OS.
Calculated, %: C 65.57; H 5.50; N 13.49; S 10.30.
1-Hydrazinyl-3-(2-methylanilino)-5,6,7,8-tetra-
hydroisoquinoline-4-carbonitrile (2b). Yield 2.392 g
(81%), mp 182–183°C. IR spectrum, ν, cm–1: 3445,
3318, 3231 (NH, NH2), 2205 (CN), 1617 (C=C).
1H NMR spectrum (DMSO-d6–CCl4, 1:3), δ, ppm:
1.73–1.83 m (4H, 6-H, 7-H), 2.20–2.27 m (2H, 8-H),
2.30 s (3H, CH3), 2.64–2.69 m (2H, 5-H), 4.00 br.s
(2H, NH2), 6.94 d.d.d (1H, Harom, J = 8.4, 7.8, 1.1 Hz),
7.09–7.17 m (3H, NH, Harom), 7.69 br.s (1H, NH),
3-Amino-2-(4-methoxyphenyl)-1-sulfanylidene-
1,2,5,6,7,8-hexahydroisoquinoline-4-carbonitrile
(1g). Yield 2.332 g (73%), mp 252–254°C. IR spec-
trum, ν, cm–1: 3455, 3312, 3223 (NH2), 2209 (CN),
1
1631 (C=C), 1236 (C=S). H NMR spectrum
(DMSO-d6), δ, ppm: 1.73–1.82 m (4H, 6-H, 7-H),
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EFFICIENT SYNTHESIS AND SOME TRANSFORMATIONS OF 1-HYDRAZINYL-...
1357
7.77 d (1H, Harom, J = 7.8 Hz). 13C NMR spectrum
(DMSO-d6–CCl4, 1:3), δC, ppm: 17.6, 21.3, 21.4, 21.7,
27.6, 78.3, 106.0, 117.3, 122.8, 123.0, 125.4, 129.4,
129.5, 137.9, 146.8, 155.2, 157.8. Found, %: C 69.74;
H 6.49; N 23.82. C17H19N5. Calculated, %: C 69.60;
H 6.53; N 23.87.
1-Hydrazinyl-3-(3-methoxyanilino)-5,6,7,8-tetra-
hydroisoquinoline-4-carbonitrile (2f). Yield 2.475 g
(80%), mp 193–194°C. IR spectrum, ν, cm–1: 3445,
3315, 3216 (NH, NH2), 2208 (CN), 1629 (C=C).
1H NMR spectrum (DMSO-d6–CCl4, 1:3), δ, ppm:
1.74–1.83 m (4H, 6-H, 7-H), 2.23–2.28 m (2H, 8-H),
2.64–2.69 m (2H, 5-H), 3.76 s (3H, OCH3), 4.18 br.s
(2H, NH2), 6.44 d.d.d (1H, Harom, J = 8.0, 2.6, 1.1 Hz),
1-Hydrazinyl-3-(3-methylanilino)-5,6,7,8-tetra-
hydroisoquinoline-4-carbonitrile (2c). Yield 2.304 g
(78%), mp 204–205°C. IR spectrum, ν, cm–1: 3440,
3325, 3218 (NH, NH2), 2208 (CN), 1626 (C=C).
1H NMR spectrum (DMSO-d6–CCl4, 1:3), δ, ppm:
1.74–1.82 m (4H, 6-H, 7-H), 2.23–2.28 m (2H, 8-H),
2.32 s (3H, CH3), 2.64–2.69 m (2H, 5-H), 4.18 br.s
(2H, NH2), 6.71 br.d (1H, Harom, J = 7.5 Hz), 7.09 d.d
(1H, Harom, J = 8.8, 7.5 Hz), 7.39–7.44 m (2H, Harom),
7.75 br.s (1H, NH), 7.76 br.s (1H, NH). 13C NMR
spectrum (DMSO-d6–CCl4, 1:3), δC, ppm: 21.0, 21.4,
21.5, 21.7, 27.6, 79.1, 106.4, 117.2, 120.6, 121.9,
127.5, 136.8, 140.0, 147.1, 154.5, 157.8. Found, %:
C 69.68; H 6.57; N 23.79. C17H19N5. Calculated, %:
C 69.60; H 6.53; N 23.87.
7.08 t (1H, Harom, J = 8.0 Hz), 7.15 d.d.d (1H, Harom
,
J = 8.0, 1.8, 1.1 Hz), 7.34 d.d (1H, Harom, J = 2.6,
1.8 Hz), 7.77 br.s (1H, NH), 7.90 br.s (1H, NH).
13C NMR spectrum (DMSO-d6–CCl4, 1:3), δC, ppm:
21.4, 21.5, 21.7, 27.6, 54.4, 79.3, 105.3, 106.6, 107.1,
112.2, 117.1, 128.2, 141.4, 147.1, 154.4, 157.7, 159.2.
Found, %: C 66.08; H 6.24; N 22.58. C17H19N5O.
Calculated, %: C 66.00; H 6.19; N 22.64.
1-Hydrazinyl-3-(4-methoxyanilino)-5,6,7,8-tetra-
hydroisoquinoline-4-carbonitrile (2g). Yield 2.444 g
(79%), mp 193–194°C. IR spectrum, ν, cm–1: 3444,
3311, 3215 (NH, NH2), 2206 (CN), 1627 (C=C).
1H NMR spectrum (DMSO-d6–CCl4, 1:3), δ, ppm:
1.73–1.83 m (4H, 6-H, 7-H), 2.23–2.28 (2H, 8-H),
2.63–2.69 m (2H, 5-H), 3.23 br.s (2H, NH2), 3.77 s
(3H, OCH3), 6.75–6.81 m (2H, Harom), 7.45–7.50 m
(2H, Harom), 7.76 br.s (1H, NH), 7.80 br.s (1H, NH).
13C NMR spectrum (DMSO-d6–CCl4, 1:3), δC, ppm:
21.4, 21.5, 21.7, 27.6, 54.6, 78.8, 106.0, 112.9, 117.2,
122.3, 132.0, 147.4, 154.4, 154.8, 157.4. Found, %:
C 66.12; H 6.15; N 22.71. C17H19N5O. Calculated, %:
C 66.00; H 6.19; N 22.64.
1-Hydrazinyl-3-(4-methylanilino)-5,6,7,8-tetra-
hydroisoquinoline-4-carbonitrile (2d). Yield 2.245 g
(76%), mp 219–220°C. IR spectrum, ν, cm–1: 3437,
3309, 3200 (NH, NH2), 2205 (CN), 1631 (C=C).
1H NMR spectrum (DMSO-d6–CCl4, 1:3), δ, ppm:
1.73–1.82 m (4H, 6-H, 7-H), 2.21–2.28 m (2H, 8-H),
2.30 s (3H, CH3), 2.63–2.68 m (2H, 5-H), 4.13 br.s
(2H, NH2), 6.99–7.05 m (2H, Harom), 7.43–7.48 m (2H,
Harom), 7.70 br.s (1H, NH), 7.77 br.s (1H, NH).
13C NMR spectrum (DMSO-d6–CCl4, 1:3), δC, ppm:
20.3, 21.4, 21.5, 21.7, 27.6, 78.7, 106.2, 117.3, 120.5,
128.2, 130.1, 137.5, 147.1, 154.7, 157.8. Found, %:
C 69.54; H 6.51; N 23.92. C17H19N5. Calculated, %:
C 69.60; H 6.53; N 23.87.
3-(4-Chloroanilino)-1-hydrazinyl-5,6,7,8-tetra-
hydroisoquinoline-4-carbonitrile (2h). Yield 2.486 g
(78%), mp 218–219°C. IR spectrum, ν, cm–1: 3439,
3317, 3220 (NH, NH2), 2209 (CN), 1630 (C=C).
1H NMR spectrum (DMSO-d6–CCl4, 1:3), δ, ppm:
1.72–1.83 m (4H, 6-H, 7-H), 2.22–2.30 m (2H, 8-H),
2.63–2.70 m (2H, 5-H), 4.14 br.s (2H, NH2), 7.15–
7.20 m (2H, Harom), 7.61–7.67 m (2H, Harom), 7.75 br.s
(1H, NH), 8.21 br.s (1H, NH). 13C NMR spectrum
(DMSO-d6–CCl4, 1:3), δC, ppm: 21.4, 21.5, 21.7, 27.6,
79.5, 106.9, 117.0, 121.5, 125.2, 127.4, 139.1, 147.3,
154.2, 157.7. Found, %: C 61.29; H 5.17; N 22.28.
C16H16ClN5. Calculated, %: C 61.24; H 5.14; N 22.32.
1-Hydrazinyl-3-(2-methoxyanilino)-5,6,7,8-tetra-
hydroisoquinoline-4-carbonitrile (2e). Yield 2.382 g
(77%), mp 233–234°C. IR spectrum, ν, cm–1: 3443,
3312, 3218 (NH, NH2), 2206 (CN), 1630 (C=C).
1H NMR spectrum (DMSO-d6–CCl4, 1:3), δ, ppm:
1.74–1.84 m (4H, 6-H, 7-H), 2.24–2.29 m (2H, 8-H),
2.65–2.70 m (2H, 5-H), 3.96 s (3H, OCH3), 4.20 br.s
(2H, NH2), 6.86–6.94 m (3H, Harom), 7.51 br.s (1H,
NH), 7.72 br.s (1H, NH), 8.45–8.50 m (1H, Harom).
13C NMR spectrum (DMSO-d6–CCl4, 1:3), δC, ppm:
21.3, 21.5, 21.7, 27.5, 55.4, 79.0, 106.1, 109.5, 117.0,
118.5, 120.2, 120.7, 129.1, 146.7, 147.4, 154.2, 158.2.
Found, %: C 65.94; H 6.23; N 22.69. C17H19N5O.
Calculated, %: C 66.00; H 6.19; N 22.64.
Compounds 3a–3h (general procedure). A mixture
of 5 mmol of compound 2a–2h and 40 mL of triethyl
orthoformate was refluxed for 8 h. The mixture was
cooled, and the precipitate was filtered off, washed
with ethanol, dried, and recrystallized from ethanol–
chloroform (1:1).
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PARONIKYAN et al.
1358
134.8, 138.8, 142.4, 150.7, 153.1. Found, %: C 71.21;
5-Anilino-7,8,9,10-tetrahydro[1,2,4]triazolo-
H 5.68; N 23.17. C18H17N5. Calculated, %: C 71.27;
H 5.65; N 23.09.
[3,4-a]isoquinoline-6-carbonitrile (3a). Yield 1.258 g
(87%), mp 288–290°C. IR spectrum, ν, cm–1: 3400
(NH), 2207 (CN), 1615 (C=C). H NMR spectrum
1
5-(2-Methoxyanilino)-7,8,9,10-tetrahydro[1,2,4]-
triazolo[3,4-a]isoquinoline-6-carbonitrile (3e). Yield
1.373 g (86%), mp 263–264°C. IR spectrum, ν, cm–1:
(DMSO-d6–CCl4, 1:3), δ, ppm: 1.85–1.98 m (4H, 8-H,
9-H), 2.71–2.78 m (2H, 10-H), 2.89–2.97 m (2H, 7-H),
7.01–7.14 m (3H, Harom), 7.29-7.37 m (2H, Harom),
1
3405 (NH), 2208 (CN), 1608 (C=C). H NMR spec-
13
8.93 s (1H, 3-H), 9.68 br.s (1H, NH). C NMR spec-
trum (DMSO-d6–CCl4, 1:3), δ, ppm: 1.82–1.94 m (4H,
8-H, 9-H), 2.64–2.70 m (2H, 10-H), 2.88–2.93 m (2H,
7-H), 3.84 s (3H, OCH3), 6.95 t.d (1H, Harom, J = 7.7,
1.3 Hz), 7.03 d.d (1H, Harom, J = 8.3, 1.3 Hz), 7.15 d.d
(1H, Harom, J = 7.7, 1.6 Hz), 7.24 d.d.d (1H, Harom, J =
8.3, 7.7, 1.6 Hz), 9.15 s (1H, 3-H), 9.34 br.s (1H, NH).
13C NMR spectrum (DMSO-d6–CCl4, 1:3), δC, ppm:
20.9, 21.8, 22.8, 26.8, 55.1, 81.1, 111.4, 113.3, 113.9,
120.2, 125.1, 126.0, 126.8, 133.6, 134.6, 140.5, 148.4,
153.2. Found, %: C 67.78; H 5.34; N 21.81.
C18H17N5O. Calculated, %: C 67.70; H 5.37; N 21.93.
trum (DMSO-d6–CCl4, 1:3), δC: 20.9, 21.7, 22.9, 26.8,
85.4, 114.0, 115.8, 120.4, 123.5, 128.7, 134.0, 134.3,
138.8, 139.4, 148.6. Found, %: C 70.65; H 5.19;
N 24.14. C17H15N5. Calculated, %: C 70.57; H 5.23;
N 24.21.
5-(2-Methylanilino)-7,8,9,10-tetrahydro[1,2,4]-
triazolo[3,4-a]isoquinoline-6-carbonitrile (3b). Yield
1.229 g (81%), mp 193–195°C. IR spectrum, ν, cm–1:
1
3401 (NH), 2207 (CN), 1612 (C=C). H NMR spec-
trum (DMSO-d6–CCl4, 1:3), δ, ppm: 1.81–1.93 m (4H,
8-H, 9-H), 2.29 s (3H, CH3), 2.68–2.73 m (2H, 10-H),
2.84–2.89 m (2H, 7-H), 7.19–7.28 m (4H, Harom),
5-(3-Methoxyanilino)-7,8,9,10-tetrahydro[1,2,4]-
triazolo[3,4-a]isoquinoline-6-carbonitrile (3f). Yield
1.389 g (87%), mp 268–269°C. IR spectrum, ν, cm–1:
13
8.29 s (1H, 3-H), 9.32 br.s (1H, NH). C NMR spec-
1
trum (DMSO-d6–CCl4, 1:3), δC, ppm: 17.5, 21.0, 21.8,
22.9, 27.2, 78.3, 112.7, 113.1, 125.8, 127.3, 127.6,
130.0, 135.3, 135.7, 139.0, 143.1, 150.5, 153.1. Found,
%: C 71.35; H 5.61; N 22.98. C18H17N5. Calculated, %:
C 71.27; H 5.65; N 23.09.
3395 (NH), 2207 (CN), 1612 (C=C). H NMR spec-
trum (DMSO-d6–CCl4, 1:3), δ, ppm: 1.85–1.98 m (4H,
8-H, 9-H), 2.73–2.79 m (2H, 10-H), 2.89–2.97 m (2H,
7-H), 3.79 s (3H, OCH3), 6.53–6.67 m (3H, Harom),
7.20 t (1H, Harom, J = 8.1 Hz), 8.89 s (1H, 3-H),
9.67 br.s (1H, NH). 13C NMR spectrum (DMSO-d6–
CCl4, 1:3), δC, ppm: 20.8, 21.7, 22.9, 26.8, 54.6,
86.1, 106.1, 109.0, 112.2, 114.0, 116.1, 129.4, 134.0,
134.3, 139.1, 140.0, 148.6, 159.8. Found, %: C 67.81;
H 5.31; N 21.84. C18H17N5O. Calculated, %: C 67.70;
H 5.37; N 21.93.
5-(3-Methylanilino)-7,8,9,10-tetrahydro[1,2,4]-
triazolo[3,4-a]isoquinoline-6-carbonitrile (3c). Yield
1.289 g (85%), mp 257–258°C. IR spectrum, ν, cm–1:
1
3393 (NH), 2205 (CN), 1610 (C=C). H NMR spec-
trum (DMSO-d6–CCl4, 1:3), δ, ppm: 1.85–1.98 m (4H,
8-H, 9-H), 2.36 s (3H, CH3), 2.72–2.78 m (2H, 10-H),
2.91–2.97 m (2H, 7-H), 6.79–6.85 m (2H, Harom),
6.91 br.d (1H, Harom, J = 7.6 Hz), 7.20 t (1H, Harom, J =
7.6 Hz), 8.88 s (1H, 3-H), 9.61 br.s (1H, NH).
13C NMR spectrum (DMSO-d6–CCl4, 1:3), δC, ppm:
20.8, 20.9, 21.7, 22.9, 26.8, 85.3, 114.0, 115.6, 117.5,
120.9, 124.3, 128.5, 133.9, 134.3, 138.1, 138.6, 139.3,
148.6. Found, %: C 71.32; H 5.69; N 23.15. C18H17N5.
Calculated, %: C 71.27; H 5.65; N 23.09.
5-(4-Methoxyanilino)-7,8,9,10-tetrahydro[1,2,4]-
triazolo[3,4-a]isoquinoline-6-carbonitrile (3g). Yield
1.437 g (90%), mp 214–216°C. IR spectrum, ν, cm–1:
1
3402 (NH), 2208 (CN), 1609 (C=C). H NMR spec-
trum (DMSO-d6–CCl4, 1:3), δ, ppm: 1.83–1.94 m (4H,
8-H, 9-H), 2.64–2.70 m (2H, 10-H), 2.86–2.91 m (2H,
7-H), 3.82 s (3H, OCH3), 6.87–6.97 m (2H, Harom),
7.07–7.12 m (2H, Harom), 9.07 s (1H, 3-H), 9.52 br.s
(1H, NH). 13C NMR spectrum (DMSO-d6–CCl4, 1:3),
δC, ppm: 20.9, 21.8, 22.7, 26.8, 54.8, 81.0, 113.5,
113.9, 114.1, 124.7, 130.7, 133.6, 134.8, 140.9, 148.5,
156.9. Found, %: C 67.77; H 5.43; N 22.05.
C18H17N5O. Calculated, %: C 67.70; H 5.37; N 21.93.
5-(4-Methylanilino)-7,8,9,10-tetrahydro[1,2,4]-
triazolo[3,4-a]isoquinoline-6-carbonitrile (3d). Yield
1.335 g (88%), mp 242–244°C. IR spectrum, ν, cm–1:
1
3386 (NH), 2206 (CN), 1605 (C=C). H NMR spec-
trum (DMSO-d6–CCl4, 1:3), δ, ppm: 1.82–1.95 m (4H,
8-H, 9-H), 2.39 s (3H, CH3), 2.73–2.79 m (2H, 10-H),
2.85–2.92 m (2H, 7-H), 7.09–7.16 m (4H, Harom),
5-(4-Chloroanilino)-7,8,9,10-tetrahydro[1,2,4]-
triazolo[3,4-a]isoquinoline-6-carbonitrile (3h). Yield
1.408 g (87%), mp 227–229°C. IR spectrum, ν, cm–1:
13
8.27 s (1H, 3-H), 9.48 br.s (1H, NH). C NMR spec-
1
trum (DMSO-d6–CCl4, 1:3), δC, ppm: 20.5, 21.0, 21.8,
3296 (NH), 2216 (CN), 1618 (C=C). H NMR spec-
23.0, 27.2, 80.6, 113.6, 113.7, 123.8, 128.7, 134.2,
trum (DMSO-d6–CCl4, 1:3), δ, ppm: 1.83–1.98 m (4H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

EFFICIENT SYNTHESIS AND SOME TRANSFORMATIONS OF 1-HYDRAZINYL-...
1359
8-H, 9-H), 2.70–2.78 m (2H, 10-H), 2.89–2.98 m (2H,
7-H), 7.00–7.08 m (2H, Harom), 7.28–7.34 m (2H,
H
spectrum (DMSO-d6–CCl4, 1:3), δC, ppm: 20.8, 21.7,
22.9, 26.8, 85.9, 114.0, 116.2, 121.5, 127.8, 128.6,
134.0, 134.3, 137.8, 139.1, 148.6. Found, %: C 63.15;
H 4.31; N 21.70. C17H14ClN5. Calculated, %: C 63.06;
H 4.36; N 21.63.
CCl4, 1:3), δ, ppm: 1.68–1.76 m (2H, 7-H), 1.83–
1.92 m (2H, 6-H), 2.19 s (3H, CH3), 2.21 s (3H, CH3),
2.30 s (3H, CH3), 2.57–2.64 m (2H, 8-H), 2.90–2.97 m
(2H, 5-H), 5.86 s (1H, 4′-H), 6.78 d (1H, Harom, J =
arom), 8.99 s (1H, 3-H), 9.77 br.s (1H, NH). 13C NMR
7.5 Hz), 7.06–7.12 m (2H, Harom), 7.27 d.d (1H, Harom
,
13
J = 2.6, 1.9 Hz), 8.54 s (1H, NH). C NMR spectrum
(DMSO-d6–CCl4, 1:3), δC, ppm: 11.7, 13.1, 20.9, 21.1,
21.8, 24.5, 28.4, 92.0, 106.2, 106.3, 114.7, 118.5,
118.6, 121.9, 123.2, 127.5, 136.8, 139.2, 139.9, 147.5,
150.7, 153.3, 154.3. Found, %: C 73.87; H 6.45;
N 19.67. C22H23N5. Calculated, %: C 73.92; H 6.49;
N 19.59.
Compounds 4a–4h (general procedure). A mixture
of 2 mmol of compound 2a–2h and 0.40 g (4 mmol) of
pentane-2,4-dione in 15 mL of anhydrous ethanol was
refluxed for 10 h. The mixture was cooled, and the
precipitate was filtered off, washed with ethanol, dried,
and recrystallized from ethanol.
1-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-(4-methyl-
anilino)-5,6,7,8-tetrahydroisoquinoline-4-carbo-
nitrile (4d). Yield 629.1 mg (88%), mp 229–230°C. IR
spectrum, ν, cm–1: 3403 (NH), 3128 (C–H), 2209
3-Anilino-1-(3,5-dimethyl-1H-pyrazol-1-yl)-
5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (4a).
Yield 576.9 mg (84%), mp 206–207°C. IR spectrum,
ν, cm–1: 3405 (NH), 3126 (C–H), 2210 (CN), 1627
1
(CN), 1627 (C=C). H NMR spectrum (DMSO-d6–
CCl4, 1:3), δ, ppm: 1.67–1.75 m (2H, 7-H), 1.83–
1.91 m (2H, 6-H), 2.16 d (3H, CH3, J = 0.6 Hz), 2.18 s
(3H, CH3), 2.30 s (3H, CH3), 2.56–2.61 m (2H, 8-H),
2.90–2.96 m (2H, 5-H), 5.85 br.s (1H, 4′-H), 6.99–
7.04 m (2H, Harom), 7.30–7.35 m (2H, Harom), 8.56 m
(1H, NH). 13C NMR spectrum (DMSO-d6–CCl4, 1:3),
δC, ppm: 11.8, 13.1, 20.3, 21.2, 21.8, 24.4, 28.4,
91.6, 106.2, 114.8, 118.3, 121.7, 128.2, 131.4, 136.6,
139.9, 147.5, 150.7, 153.5, 154.2. Found, %: C 73.98;
H 6.46; N 19.55. C22H23N5. Calculated, %: C 73.92;
H 6.49; N 19.59.
1
(C=C). H NMR spectrum (DMSO-d6–CCl4, 1:3), δ,
ppm: 1.67–1.76 m (2H, 7-H), 1.83–1.92 m (2H, 6-H),
2.17 d (3H, CH3, J = 0.6 Hz), 2.19 s (3H, CH3), 2.57–
2.62 m (2H, 8-H), 2.92–2.97 m (2H, 5-H), 5.85 br.s
(1H, =CH), 6.93–6.99 m (1H, Harom), 7.18–7.25 m (2H,
H
arom), 7.44–7.49 m (2H, Harom), 8.65 br.s (1H, NH).
13C NMR spectrum (DMSO-d6–CCl4, 1:3), δC, ppm:
11.8, 13.1, 21.1, 21.8, 24.4, 28.4, 92.0, 106.3, 114.7,
118.7, 121.3, 122.3, 127.6, 139.3, 140.0, 147.5, 150.6,
153.3, 154.3. Found, %: C 73.50; H 6.20; N 20.33.
C21H21N5. Calculated, %: C 73.44; H 6.16; N 20.39.
1-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-(2-methoxy-
anilino)-5,6,7,8-tetrahydroisoquinoline-4-carbo-
nitrile (4e). Yield 619.9 mg (83%), mp 190–191°C. IR
spectrum, ν, cm–1: 3399 (NH), 3126 (C–H), 2211
1-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-(2-methyl-
anilino)-5,6,7,8-tetrahydroisoquinoline-4-carbo-
nitrile (4b). Yield 586.2 mg (82%), mp 164–165°C. IR
spectrum, ν, cm–1: 3387 (NH), 3132 (C–H), 2208
1
(CN), 1625 (C=C). H NMR spectrum (DMSO-d6–
1
CCl4, 1:3), δ, ppm: 1.68–1.77 m (2H, 7-H), 1.84–
1.92 m (2H, 6-H), 2.23 s (3H, CH3), 2.24 s (3H, CH3),
2.61 t (2H, 8-H, J = 6.2 Hz), 2.96 t (2H, 5-H, J =
6.3 Hz), 3.94 s (3H, OCH3), 5.91 br.s (1H, 4′-H), 6.83–
7.00 m (3H, Harom), 7.85 s (1H, NH), 8.06 d.d (1H,
Harom, J = 8.1, 1.4 Hz). 13C NMR spectrum (DMSO-d6–
CCl4, 1:3), δC, ppm: 11.6, 13.1, 21.0, 21.7, 24.3, 28.3,
55.3, 92.1, 104.8, 106.4, 109.6, 114.4, 118.9, 119.6,
120.0, 122.4, 128.0, 139.9, 147.7, 148.5, 150.6, 152.6,
154.0. Found, %: C 70.82; H 6.24; N 18.67.
C22H23N5O. Calculated, %: C 70.76; H 6.21; N 18.75
(CN), 1625 (C=C). H NMR spectrum (DMSO-d6–
CCl4, 1:3), δ, ppm: 1.66–1.75 m (2H, 7-H), 1.82–
1.91 m (2H, 6-H), 1.95 d (3H, CH3, J = 0.6 Hz), 2.15 s
(3H, CH3), 2.23 br.s (3H, CH3), 2.60 t (2H, 8-H, J =
6.3 Hz), 2.94 t (2H, 5-H, J = 6.3 Hz), 5.77 s (1H, 4-H),
7.02–7.18 m (3H, Harom), 7.29 d.d (1H, Harom, J = 7.8,
1.5 Hz), 8.17 br.s (1H, NH). 13C NMR spectrum
(DMSO-d6–CCl4, 1:3), δC, ppm: 11.6, 13.0, 17.7, 21.2,
21.9, 24.5, 28.4, 90.5, 106.3, 114.9, 117.3, 124.8,
125.5, 126.1, 129.7, 133.4, 137.4, 140.2, 147.3, 150.9,
154.0, 154.6. Found, %: C 73.84; H 6.52; N 19.52.
C22H23N5. Calculated, %: C 73.92; H 6.49; N 19.59.
1-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-(3-methoxy-
anilino)-5,6,7,8-tetrahydroisoquinoline-4-carbo-
nitrile (4f). Yield 642.3 mg (86%), mp 170–171°C. IR
spectrum, ν, cm–1: 3406 (NH), 3129 (C–H), 2210
1-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-(3-methyl-
anilino)-5,6,7,8-tetrahydroisoquinoline-4-carbo-
nitrile (4c). Yield 600.5 mg (84%), mp 182–183°C. IR
spectrum, ν, cm–1: 3392 (NH), 3138 (C–H), 2212
1
(CN), 1628 (C=C). H NMR spectrum (DMSO-d6–
1
(CN), 1626 (C=C). H NMR spectrum (DMSO-d6–
CCl4, 1 :3), δ, ppm: 1.68–1.76 m (2H, 7-H), 1.84–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

PARONIKYAN et al.
1360
1.91 m (2H, 6-H), 2.19 s (3H, CH3), 2.21 s (3H, CH3),
2.57–2.62 m (2H, 8-H), 2.91–2.97 m (2H, 5-H), 3.77 s
(3H, OCH3), 5.87 s (1H, 4′-H), 6.48–6.53 m (1H,
Harom), 7.07–7.16 m (3H, Harom), 8.67 br.s (1H, NH).
13C NMR spectrum (DMSO-d6–CCl4, 1:3), δC, ppm:
11.8, 13.1, 21.1, 21.8, 24.4, 28.4, 54.3, 92.3, 106.2,
106.7, 107.9, 113.2, 114.6, 118.9, 128.2, 139.9, 140.5,
147.6, 150.6, 153.1, 154.4, 159.1. Found, %: C 70.69;
H 6.16; N 18.70. C22H23N5O. Calculated, %: C 70.76;
H 6.21; N 18.75.
3-Anilino-1-azido-5,6,7,8-tetrahydroisoquino-
line-4-carbonitrile (5a). Yield 2.323 g (80%),
mp 189–190°C. IR spectrum, ν, cm–1: 3324 (NH),
2210 (CN), 2136 (N3), 1615 (C=C). 1H NMR spectrum
(CDCl3), δ, ppm: 1.73–1.86 m (4H, 6-H, 7-H), 2.42–
2.48 m (2H, 8-H), 2.80–2.86 m (2H, 5-H), 6.92 br.s
(1H, NH), 7.07–7.12 m (1H, Harom), 7.31–7.39 m (2H,
Harom), 7.60–7.65 m (2H, Harom). 13C NMR spectrum
(CDCl3), δC, ppm: 21.7, 22.1, 22.9, 28.6, 88.6, 114.2,
116.2, 120.2, 123.4, 128.9, 138.8, 153.6, 154.0, 155.4.
Found, %: C 66.27; H 4.83; N 28.88. C16H16N6. Cal-
culated, %: C 66.19; H 4.86; N 28.95
1-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-(4-methoxy-
anilino)-5,6,7,8-tetrahydroisoquinoline-4-carbo-
nitrile (4g). Yield 619.9 mg (83%), mp 190–191°C.
IR spectrum, ν, cm–1: 3400 (NH), 3128 (C–H), 2208
1-Azido-3-(2-methylanilino)-5,6,7,8-tetrahydro-
isoquinoline-4-carbonitrile (5b). Yield 2.709 g
(89%), mp 146–147°C. IR spectrum, ν, cm–1: 3186
1
(CN), 1624 (C=C). H NMR spectrum (DMSO-d6–
1
(NH), 2205 (CN), 2138 (N3), 1624 (C=C). H NMR
CCl4, 1:3), δ, ppm: 1.66–1.74 m (2H, 7-H), 1.82–
1.92 m (2H, 6-H), 2.13 d (3H, CH3, J = 0.7 Hz), 2.18 s
(3H, CH3), 2.55–2.60 m (2H, 8-H), 2.90–2.95 m (2H,
5-H), 3.75 s (3H, OCH3), 5.83 br.s (1H, 4′-H), 6.74–
6.79 m (2H, Harom), 7.29–7.34 m (2H, Harom), 8.46 br.s
(1H, NH). 13C NMR spectrum (DMSO-d6–CCl4, 1:3),
δC, ppm: 11.8, 13.0, 21.2, 21.9, 24.4, 28.3, 54.5,
91.0, 106.1, 112.9, 114.8, 117.8, 123.8, 132.0, 140.0,
147.4, 150.7, 153.9, 154.1, 155.3. Found, %: C 70.84;
H 6.18; N 18.82. C22H23N5O. Calculated, %: C 70.76;
H 6.21; N 18.75.
spectrum (CDCl3), δ, ppm: 1.74–1.87 m (4H, 6-H,
7-H), 2.36 s (3H, CH3), 2.41–2.48 m (2H, 8-H), 2.80–
2.88 m (2H, 5-H), 6.78 br.s (1H, NH), 7.02–7.09 m
(1H, Harom), 7.18–7.26 m (2H, Harom), 7.95–8.00 m
(1H, Harom). 13C NMR spectrum (CDCl3), δC, ppm:
18.1, 21.9, 22.3, 23.0, 28.7, 88.6, 113.9, 116.2, 122.6,
124.4, 126.6, 129.1, 130.6, 137.0, 153.4, 154.6, 155.4.
Found, %: C 67.17; H 5.35; N 27.52. C17H16N6.
Calculated, %: C 67.09; H 5.30; N 27.61.
1-Azido-3-(3-methylanilino)-5,6,7,8-tetrahydro-
isoquinoline-4-carbonitrile (5c). Yield 2.648 g (87%),
mp 157–158°C. IR spectrum, ν, cm–1: 3019 (NH),
2208 (CN), 2132 (N3), 1634 (C=C). 1H NMR spectrum
(CDCl3), δ, ppm: 1.74–1.87 m (4H, 6-H, 7-H), 2.38 s
(3H, CH3), 2.43–2.48 m (2H, 8-H), 2.81–2.87 m (2H,
5-H), 6.83 br.s (1H, NH), 6.90 br.d (1H, Harom, J =
8.1 Hz), 6.90 d.d (1H, Harom, J = 8.1, 7.9 Hz), 7.33 br.d
(1H, Harom, J = 7.9 Hz), 7.60 br.s (1H, Harom). 13C NMR
spectrum (CDCl3), δC, ppm: 20.9, 21.2, 21.5, 22.2,
27.8, 88.7, 112.7, 114.9, 117.6, 121.1, 122.8, 127.3,
136.7, 138.9, 153.0, 153.6, 153.8. Found, %: C 67.02;
H 5.26; N 27.67. C17H16N6. Calculated, %: C 67.09;
H 5.30; N 27.61.
3-(4-Chloroanilino)-1-(3,5-dimethyl-1H-pyrazol-
1-yl)-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile
(4h). Yield 642.4 mg (85%), mp 210–211°C. IR spec-
trum, ν, cm–1: 3395 (NH), 3118 (C–H), 2214 (CN),
1
1628 (C=C). H NMR spectrum (DMSO-d6–CCl4,
1:3), δ, ppm: 1.67–1.77 m (2H, 7-H), 1.83-1.92 m
(2H, 6-H), 2.17 br.s (3H, CH3), 2.19 s (3H, CH3),
2.57–2.63 m (2H, 8-H), 2.91–2.97 m (2H, 5-H), 5.87 s
(1H, 4′-H), 7.15–7.21 m (2H, Harom), 7.47–7.53 m (2H,
Harom), 8.90 br.s (1H, NH). 13C NMR spectrum
(DMSO-d6–CCl4, 1:3), δC, ppm: 11.8, 13.1, 21.1, 21.7,
24.4, 28.4, 92.3, 106.3, 114.6, 119.2, 122.5, 126.5,
127.5, 138.2, 139.9, 147.6, 150.5, 152.9, 154.5. Found,
%: C 66.87; H 5.30; N 18.47. C21H20ClN5. Calculated,
%: C 66.75; H 5.33; N 18.53.
1-Azido-3-(4-methylanilino)-5,6,7,8-tetrahydro-
isoquinoline-4-carbonitrile (5d). Yield 2.739 mg
(90%), mp 175–176°C. IR spectrum, ν, cm–1: 3341
1
Compounds 5a–5h (general procedure). A solution
of 1.4 g (20 mmol) of sodium nitrite in 10 mL of water
was added dropwise with stirring to a mixture of
10 mmol of compound 2a–2h and 50 mL of glacial
acetic acid, cooled to 0°C. The mixture was stirred for
12 h at room temperature, and the precipitate was
filtered off, washed with water, and recrystallized from
ethanol–methylene chloride (1:3).
(NH), 2209 (CN), 2137 (N3), 1614 (C=C). H NMR
spectrum (CDCl3), δ, ppm: 1.74–1.85 m (4H, 6-H,
7-H), 2.35 s (3H, CH3), 2.41–2.47 m (2H, 8-H), 2.80–
2.86 m (2H, 5-H), 6.86 br.s (1H, NH), 7.12–7.16 m
13
(2H, Harom), 7.46–7.51 m (2H, Harom). C NMR spec-
trum (CDCl3), δC, ppm: 20.9, 21.8, 22.2, 23.0, 28.6,
88.4, 96.3, 113.4, 116.1, 120.5, 129.4, 133.0, 136.3,
153.5, 154.2, 155.4. Found, %: C 67.15; H 5.34;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

EFFICIENT SYNTHESIS AND SOME TRANSFORMATIONS OF 1-HYDRAZINYL-...
1361
N 27.53. C17H16N6. Calculated, %: C 67.09; H 5.30;
N 27.61.
ppm: 21.8, 22.2, 23.0, 28.7, 88.9, 114.6, 115.9, 121.5,
128.6, 129.0, 137.4, 153.7, 153.8, 155.4. Found, %:
C 59.26; H 4.29; N 25.79. C16H13ClN6. Calculated, %:
C 59.17; H 4.03; N 25.88.
1-Azido-3-(2-methoxyanilino)-5,6,7,8-tetrahy-
droisoquinoline-4-carbonitrile (5e). Yield 2.755 g
(86%), mp 173–174°C. IR spectrum, ν, cm–1: 3393
1
FUNDING
(NH), 2201 (CN), 2134 (N3), 1612 (C=C). H NMR
spectrum (CDCl3), δ, ppm: 1.74–1.87 m (4H, 6-H,
7-H), 2.43–2.49 m (2H, 8-H), 2.81–2.89 m (2H, 5-H),
3.97 s (3H, OCH3), 6.89–7.03 m (3H, Harom), 7.79 br.s
(1H, NH), 8.46–8.51 m (1H, Harom). 13C NMR spec-
trum (CDCl3), δC, ppm: 21.8, 22.2, 23.0, 28.6, 56.0,
89.5, 110.0, 113.8, 115.9, 119.2, 120.8, 122.5, 128.9,
148.2, 153.5, 153.9, 155.4. Found, %: C 63.68; H 5.08;
N 26.16. C17H16N6O. Calculated, %: C 63.74; H 5.03;
N 26.23.
This study was performed in part under financial
support by the State Science Committee of the
Ministry of Education and Science of Armenia in the
framework of research project no. 18T-1D066.
CONFLICT OF INTERESTS
The authors declare the absence of conflict of
interests.
1-Azido-3-(3-methoxyanilino)-5,6,7,8-tetrahy-
droisoquinoline-4-carbonitrile (5f). Yield 2.595 g
(81%), mp 166–167°C. IR spectrum, ν, cm–1: 3363
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(NH), 2208 (CN), 2129 (N3), 1618 (C=C). H NMR
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7-H), 2.42–2.48 m (2H, 8-H), 2.79–2.85 m (2H, 5-H),
3.85 s (3H, OCH3), 6.63 d.d.d (1H, Harom, J = 8.1, 2.5,
0.7 Hz), 6.93 br.s (1H, NH), 7.05 d.d.d (1H, Harom, J =
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89.0, 105.6, 109.6, 112.3, 114.3, 116.0, 129.6, 140.1,
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(89%), mp 151–152°C. IR spectrum, ν, cm–1: 3385
1
(NH), 2205 (CN), 2131 (N3), 1610 (C=C). H NMR
5. Faidallah, H.M., Rostom, Sh.A.F., Asiri, A.M.,
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spectrum (CDCl3), δ, ppm: 1.73–1.85 m (4H, 6-H,
7-H), 2.40–2.46 m (2H, 8-H), 2.79–2.85 m (2H, 5-H),
3.82 s (3H, OCH3), 6.78 br.s (1H, NH), 6.85–6.91 m
13
(2H, Harom), 7.45–7.50 m (2H, Harom). C NMR spec-
6. Schmidt, M.A. and Qian, X., Tetrahedron Lett., 2013,
trum (CDCl3), δC, ppm: 21.8, 23.0, 28.7, 55.6, 89.0,
111.4, 113.1, 124.5, 127.3, 130.0, 132.6, 148.8, 153.7,
154.2, 155.4. Found, %: C 63.65; H 5.11; N 26.13.
C17H16N6O. Calculated, %: C 63.74; H 5.03; N 26.23.
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1-Azido-3-(4-chloroanilino)-5,6,7,8-tetrahydro-
isoquinoline-4-carbonitrile (5h). Yield 2.988 g
(92%), mp 195–196°C. IR spectrum, ν, cm–1: 3321
8. Burbiel, J.C., Ghattas, W., Kuppers, P., Kose, M.,
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cmdc.201600255
1
(NH), 2208 (CN), 2134 (N3), 1606 (C=C). H NMR
spectrum (CDCl3), δ, ppm: 1.73–1.87 m (4H, 6-H,
7-H), 2.41–2.48 m (2H, 8-H), 2.81–2.87 m (2H, 5-H),
6.90 br.s (1H, NH), 7.28–7.34 m (2H, Harom), 7.55–
7.60 m (2H, Harom). 13C NMR spectrum (CDCl3), δC,
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