Synthesis and structure of 5-indolyl-6-thienyl-1,2,4-triazines

Article abstract of DOI:10.1007/s11178-005-0258-z

Acylation of indole and 2,5-dimethylthiophene with 2-(3-indolyl)-2- oxoacetyl chloride afforded the corresponding diketones. 1-(2,5-Dimethyl-3- thienyl)-2-(3-indolyl)ethanedione reacted with thiosemicarbazide under atmosperic and elevated pressure to give 6-(2,5-dimethyl-3-thienyl)-5-(3- indolyl)-2,3-dihydro-1,2,4-triazine-3-thione whose structure was studied in detail by the X-ray diffraction method. Reactions of 6-(2,5-dimethyl-3-thienyl)- 5-(3-indolyl)-2,3-dihydro-1,2,4-triazine-3-thione with amines and hydrazine resulted in formation of fused triazolo- and tetrazolotriazines.

Full text of DOI:10.1007/s11178-005-0258-z

Russian Journal of Organic Chemistry, Vol. 41, No. 6, 2005, pp. 875–883. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 6, 2005,
pp. 895–902.
Original Russian Text Copyright © 2005 by Krayushkin, Yarovenko, Sedishev, Zavarzin, Vorontsova, Starikova.
Dedicated to Full Member of the Russian Academy of Sciences
V.I. Minkin on his Jubilee
Synthesis and Structure of 5-Indolyl-6-thienyl-1,2,4-triazines
M. M. Krayushkin1, V. N. Yarovenko1, I. P. Sedishev1, I. V. Zavarzin1,
L. G. Vorontsova1, and Z. A. Starikova2
1 Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences,
Leninskii pr. 47, Moscow, 119991 Russia
e-mail: mkray@ioc.ac.ru
2 Nesmeyanov Institute of Organometallic Compounds, Russian Academy of Sciences, Moscow, Russia
Received October 18, 2004
Abstract—Acylation of indole and 2,5-dimethylthiophene with 2-(3-indolyl)-2-oxoacetyl chloride afforded the
corresponding diketones. 1-(2,5-Dimethyl-3-thienyl)-2-(3-indolyl)ethanedione reacted with thiosemicarbazide
under atmosperic and elevated pressure to give 6-(2,5-dimethyl-3-thienyl)-5-(3-indolyl)-2,3-dihydro-1,2,4-
triazine-3-thione whose structure was studied in detail by the X-ray diffraction method. Reactions of 6-(2,5-
dimethyl-3-thienyl)-5-(3-indolyl)-2,3-dihydro-1,2,4-triazine-3-thione with amines and hydrazine resulted in
formation of fused triazolo- and tetrazolotriazines.
Bisindolylethenes A attract interest as photochrom-
ic compounds [1]; in addition, they exhibit a broad
spectrum of biological activity [2, 3]. Most frequently,
the bridging group in these compounds is a maleic an-
hydride or maleimide fragment. It is known that struc-
tural variations of the bridging group in bisindolyl-
ethenes strongly affect their activity [3]. Another
promising approach to building up new biologically
active derivatives implies synthesis of bishetaryl-
ethenes in which the ring in the bridge is connected not
only to indole group but also to a different heterocyclic
[4] or aromatic substituent [5].
diketones VIIa and VIIb are formed in good yields by
reaction of 2-(3-indolyl)-2-oxoacetyl chloride (VI) [7]
with indole or 2,5-dimethylthiophene, respectively, in
a mixture of heptane with dichloroetane in the pres-
ence of aluminum chloride (Scheme 2). According to
published data, chloride VI reacts with aromatic and
heteroaromatic compounds in a mixture of dichloro-
ethane and nitromethane in the presence of AlCl3 [8].
However, the yields did not exceed 60%. Using the
acylation of 2,5-dimethylthiophene as an example, we
showed in [9] that reduction of the polarity of the
medium decreases the energy of solvation of the corre-
sponding transition complexes and thus increases the
yield of the target product and suppresses side reac-
tions [9]. In fact, by replacing nitromethane by less
polar heptane we succeeded in obtaining diketones
VIIa and VIIb in higher yields. Furthermore, the
procedure proposed by us seems to be more convenient
from the preparative viewpoint, as compared to the
In the present work we applied both approaches and
synthesized unsymmetrical compounds containing in-
dole and thiophene fragments bridged through a 1,2,4-
triazine heteroring. We previously described synthesis
of 1,2,4-triazines III–V from accessible diketone II [6]
which was prepared by oxidation of the corresponding
hydroxy ketone I (Scheme 1). We have found that
R1
R2
hν
R1
R2
hν1
X
X
R3 R4
X
X
R3 R4
A
X = NH, NR.
1070-4280/05/4106-0875 © 2005 Pleiades Publishing, Inc.

KRAYUSHKIN et al.
876
Scheme 1.
O
OH
O
O
Me
Me
Me
Me
S
S
S
S
Me Me
Me Me
II
I
N
N
SR
N
R'
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
Me
S
S
S
S
S
S
Me Me
Me Me
Me Me
III
IV
V
Scheme 2.
COCOCl
COCOHet
HetH, AlCl3
N
N
H
H
VI
VIIa, VIIb
VII, Het = 2,5-dimethyl-3-thienyl (a), 3-indolyl (b).
S
NH
O
OH
N
N
NaBH4
H2NC(S)NHNH2
VIIa
Me
Me
N
S
N
S
Me
VIIIa
Me
IX
H
H
HO
OH
NaBH4
VIIb
N
N
H
H
VIIIb
tarring. No triazinethione was formed from diketone
synthesis of diketone VIIb via reaction of chloride VI
with magnesium derivative of indole [3, 7].
VIIb even at elevated pressure (up to 1000 MPa).
Diketone VIIa was more reactive than bisindolyl
derivative VIIb; however, it was much less reactive
than dithienylethanedione II. Below are given the
yields of compound IX in the reaction of diketone
VIIa with thiosemicarbazide at 75°C, depending on
the pressure and reaction time (according to the
1H NMR data).
Diketones II, VIIa, and VIIb are characterized by
considerably different reactivities. For instance, we
failed to obtain the corresponding 1,2,4-triazinethione
from symmetric diketone VIIb. When the reaction was
performed under the conditions described for the syn-
thesis of II and III, the initial diketone was recovered
from the reaction mixture, while more severe condi-
tions (elevated temperature, the use of acids as solvent
or of thiosemicarbazide hydrochloride) resulted in
The yield of triazinethione IX in the reaction of
VIIa with thiosemicarbazide under atmospheric pres-
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SYNTHESIS AND STRUCTURE OF 5-INDOLYL-6-THIENYL-1,2,4-TRIAZINES
S1
877
sure (6 h) was only 46% (run no. 2), whereas anal-
ogous bisthienyl derivative III was formed almost
quantitatively under the same conditions [6]. We
succeeded in considerably raising the yield of IX by
increasing the reaction time (run no. 3). It is known
that in some cases high pressure favors formation of
heterocyclic compounds [10–12]. In our case, carrying
out the reaction under high pressure allowed us to
shorten the reaction time and increase the product
yield (run nos. 4–6). Such effect of high pressure on
the formation of triazinethiones was not reported
previously.
N2
C3
N1
C6
N4
C5
C4"
C3a
C4'
C5'
C3'
C2'
C3"
C5"
C6"
C2"
C7a
C16
C17
N1"
C7"
S2
Run no.
Pressure, MPa
Time, h
Yield, %
Fig. 1. Structure and conformation of the molecule of 6-(2,5-
dimethyl-3-thienyl)-5-(3-indolyl)-2,3-dihydro-1,2,4-triazine-
3-thione (IX).
1
2
3
4
5
6
0000.0.1
0000.0.1
0000.0.1
0500
02
06
48
02
02
06
30
46
86
60
78
94
1000
O1a
1000
We were the first to synthesize triazines having
vicinal indolyl and thienyl substituents. Therefore, it
was reasonable to determine the steric structure and
geometric parameters of molecule IX by X-ray anal-
ysis and compare the obtained data with those avail-
able from the Cambridge Crystallographic Data Center
(CCDC) [13], namely for 3,4-bis(3-indolyl)-1H-pyr-
role-2,5-dione [5] and dithienylethenes [14] which
include structural fragments of IX.
S2a
N1"a
N4a
N1a
O1d
N2a
Compound IX crystallized from a mixture of
methanol with acetone as solvate with the composition
C17H14N4S2·MeOH (IXa). The structure of molecule
IX is shown in Fig. 1. The triazine, indole, and thio-
phene rings are planar within ±0.05, ±0.005, and
±0.008 Å, respectively. The dihedral angles between
their planes are as follows: 55.8° between the triazine
and thiophene rings, 18.96° between the triazine and
indole rings, and 59.88° between the thiophene and
indole rings. These parameters are typical of dithienyl-
ethenes with such heterocyclic bridging fragments as
maleic anhydride and maleimide [15].
S1a
S1
O1c
N2
N1
N4
N1"
S2
The bond lengths in the triazine ring indicate the
absence of a common conjugation system. Electron
density delocalization is observed only in the C6–N1–
N2–C3–N4–C5 fragment; the bond lengths therein cor-
respond to C–N and N–N bonds with an order of 1.5:
1.312, 1.349, 1.340, 1.353, and 1.333 Å, respectively.
On the other hand, the C5–C6 bond (1.446 Å) is
O1b
Fig. 2. Intermolecular hydrogen bonds in the crystalline
structure of 6-(2,5-dimethyl-3-thienyl)-5-(3-indolyl)-2,3-di-
hydro-1,2,4-triazine-3-thione–methanol solvate (IXa).
a typical single Csp
2
–Csp bond [16]. This strongly
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

KRAYUSHKIN et al.
878
differentiates electronic structure of the bridge in
molecule IX from that in dihetarylethenes with fixed
double C5=C6 bond [14].
be influenced by intermolecular hydrogen bond be-
tween the pyrrole NH atom and oxygen atom of the
solvate methanol molecule (Fig. 2). According to the
crystallo-graphic criteria [19], this hydrogen bond is
referred to as strong; its parameters are as follows:
O1b···N1'' 2.820 Å, O1b···H–N1'' 1.98 Å, ∠O1b···H–N1''
171°. It is quite probable that electron density redistri-
bution in the indole fragment changes the electronic
state of the C2'' atom. As a result, the hydrogen atom on
C2'' becomes more labile, and anomalously short intra-
molecular C2'–C2'' contact (3.183 Å) is observed.
Some specific features were also found in the
indole fragment. First of all, the C2''–C3'' (1.384 Å)
and N1''–C7a bonds (1.378 Å) are appreciably longer
than the corresponding bonds in unsubstituted indole
(1.345 and 1.365 Å, respectively) [17]. This suggests
reorganization of the electronic system in the indole
fragment, which is induced by the triazine π-electron
system. Taking into account that the angle between the
indole and triazine ring planes is only ~19°, such effect
is quite admissible. An analogous effect on the indole
ring (i.e., bond lengths therein) is produced by the car-
bonyl group in position 3 of, e.g., 1H-indole-3-carbal-
dehyde, where the corresponding bond lengths are
1.389 and 1.382 Å, respectively [18]. On the other
hand, the electronic system of the indole fragment may
In addition, there are two weak intermolecular
hydrogen bonds in the crystalline structure of solvate
IXa. Molecules IX in crystal are related through
a symmetry center, and they form dimers via inter-
molecular hydrogen bonding between the thione sulfur
atom of one molecule and NH hydrogen atom in the
triazine ring of the other molecule. These hydrogen
Scheme 3.
N
R
N
N
N
N
RCOOH
H2N NH
N
Me
N
H
S
Me
N
N
N2H4, MeOH
XIa–XIc
IX
N
Me
N
N
N
H
S
Me
N
N
N
X
HNO2
Me
N
H
S
Me
XII
XI, R = Me (a), 2-thienyl (b), 3-indolylmethyl (c).
X
N
N
X
NH
N
N
IX
Me
N
S
Me
H
XIIIa–XIIId
XIII, X = bond (a), O (b), NMe (c), CH2 (d).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

SYNTHESIS AND STRUCTURE OF 5-INDOLYL-6-THIENYL-1,2,4-TRIAZINES
879
bonds are characterized by the following parameters:
S1 ···N2a 3.248 Å, S1 ···H–N2a 2.40 Å, ∠S1 ···H–N2a
155°. A weak intermolecular hydrogen bond is also
formed between the thione sulfur atom and hydroxy
proton of the solvate methanol molecule: S1 ···O1c
3.289 Å, S1···H–O1c 2.32 Å, ∠S1···H–O1c 161°. Thus
the triazine and indole fragments in molecule IX are
involved in various intramolecular hydrogen bonds,
which is quite untypical of dithienylethenes [14].
triazine (XII). Also, triazinethione IX smoothly
reacted with amines, yielding 3-aminotriazines XIIIa–
XIIId (Scheme 3).
Thus the results of our study showed that 2-(3-in-
dolyl)-1-(2,5-dimethyl-3-thienyl)ethanedione can be
used as starting compound for the synthesis of 1,2-di-
hetarylethenes in which the indole and thiophene rings
are linked through various 1,2,4-triazine-containing
bridges.
A strong difference in the reactivity of the carbonyl
groups in diketone VIIa favors formation of only one
isomer of triazinethione IX. The X-ray diffraction data
unambiguously show that nucleophilic attack by thio-
semicarbazide is directed exclusively at the “thienyl”
carbonyl group. Neither excess thiosemicarbazide nor
high pressure conditions affect the regioselectivity of
the process.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
AM-300 spectrometer in DMSO-d6. The mass spectra
(electron impact, 70 eV) were obtained on a Kratos
instrument with direct sample admission into the ion
source. The melting points were determined on
a Boetius melting point apparatus and were not cor-
rected. The progress of reactions was monitored by
TLC on Silufol UV-254 plates using petroleum ether–
ethyl acetate (1:2) as eluent. Silica gel from Acros
(CAS-7631-86-9, 0.060–0.200 mm) was used for
column chromatography.
The carbonyl groups in diketone VIIa behave
differently in reactions with reducing agents. We
succeeded in effecting regioselective reduction of one
carbonyl group in VIIa by the action of NaBH4 in
alcohol. The product was compound VIIIa containing
an acyloin fragment. This compound is an analog of
I which (as shown previously) attracts considerable
interest from the viewpoint of design of various hetero-
cyclic bridging fragments in bishetarylethenes [20, 21].
According to the 1H NMR data, the reduction involves
the carbonyl group neighboring to the thiophene ring.
The indole proton signals in the spectrum of VIIIa
appear at the same positions as in the spectrum of
initial diketone VIIa, while the singlet from 4-H in
the thiophene ring shifts appreciably upfield. It should
be noted that the formation of a hydroxy ketone moiety
was observed previously only in the electrochemical
reduction of diketone VIIb [3] and that attempts to
accomplish selective reduction of only one carbonyl
group in the same diketone by the action of both
NaBH4 and other reducing agents (effective in the
reduction of benzil to benzoin [22, 23]) resulted in
formation of diol VIIIb.
Dichloroethane was heated for 3 h over P2O5 under
reflux and distilled. Heptane and alcohols were used
without additional purification. Diethyl ether and tetra-
hydrofuran were dried over metallic sodium. 2-(3-In-
dolyl)-2-oxoacetyl chloride (VI) was synthesized by
the procedure described in [7]. High-pressure reactions
were carried out in Teflon ampules using a setup
described in [25].
X-Ray diffraction study of 6-(2,5-dimethyl-3-
thienyl)-5-(3-indolyl)-2,3-dihydro-1,2,4-triazine-3-
thione–methanol solvate (IXa). Light yellow mono-
clinic crystals, C17H14N4S2·MeOH, with the following
unit cell parameters: a = 7.724(1), b = 17.636(3), c =
13.594(2) Å; β = 92.88(4)°; V = 1849.3(5) Å3; ρcalc
=
1.331 g/cm3; space group P21/c; Z = 4. The unit cell
parameters and intensities of 5367 independent reflec-
tions were measured on a Bruker SMART-1000
diffractometer (MoKα, graphite monochromator, φ-ω
scanning in the range 1.89 ≥ θ ≤ 30.11°). The structure
was solved by the direct method which localized all
non-hydrogen atoms and was refined using 3453 re-
flections with I > 2σ(I) by the full-matrix least-squares
procedure for non-hydrogen atoms. The positions of
hydrogen atoms were determined by the difference
synthesis of electron density and were refined by the
least-squares procedure in isotropic approximation.
The reactivity of the thioxo group in the triazine
ring of IX its typical of thiones. Compound IX reacts
with hydrazine to afford the corresponding hydrazino
derivative X. By analogy with published data [24, 6],
reactions of X with carboxylic acids led to formation
of 3-substituted 6-(2,5-dimethyl-3-thienyl)-7-(3-in-
dolyl)[1,2,4]triazolo[4,3-b][1,2,4]triazines XIa–XIc,
and nitrosation of this compound gave 7-(2,5-di-
methyl-3-thienyl)-6-(3-indolyl)tetrazolo[1,5-b][1,2,4]-
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KRAYUSHKIN et al.
880
1
The final divergence factors were R1 = 0.062 and
wR2 = 0.174 (R1 = 0.084, wR2 = 0.192 for all independ-
ent reflections). The calculations were performed using
Bruker SMART [26], SHELXL-97, and Bruker
SHELXTL software [27]. The coordinates and thermal
parameters of atoms were deposited to the Cambridge
Crystallographic Data Center (entry no. 251952).
crystals, mp 203–206°C. H NMR spectrum, δ, ppm:
2.32 s (3H, CH3), 2.47 s (3H, CH3), 5.30 br.s (1H,
OH), 5.62 d (1H, CH), 6.56 s (1H, thiophene), 7.16 m
(2H, indole), 7.43 m (1H, indole), 8.14 d (1H, indole),
8.23 m (1H, indole), 11.76 br.s (1H, NH). Mass spec-
trum, m/z (Irel, %): 285 (8) [M]+, 145 (16), 144 (100),
140 (11), 139 (36), 116 (28), 89 (20), 67 (21), 59 (13),
43 (8). Found, %: C 67.12; H 5.24; N 4.90; S 11.25.
C16H15NO2S. Calculated, %: C 67.34; H 5.30; N 4.91;
S 11.23. M 285.37.
General procedure for the synthesis of diketones
VIIa and VIIb. Chloride VI, 4.16 g (20 mmol), was
added in portions over a period of 3–5 min to a sus-
pension of 12.0 g (90 mmol) of AlCl3 in a mixture of
20 ml of dichloroethane and 10 ml of heptane under
stirring at 18–20°C. A solution of 33 mmol of indole or
2,5-dimethylthiophene in 20 ml of dichloroethane was
then added dropwise under stirring, and the mixture
was stirred until the reaction was complete (TLC). The
mixture was poured into 100 ml of an ice–water mix-
ture, and the product was extracted into ethyl acetate
(3×100 ml). The extract was dried over Na2SO4 and
evaporated under reduced pressure, and the residue
was recrystallized from alcohol.
1,2-Bis(3-indolyl)ethane-1,2-diol (VIIIb). Sodium
tetrahydridoborate was added in 15–20 mg portions to
a solution of 145 mg (0.5 mmol) of diketone VIIb in
10 ml of methanol, and the mixture was heated for 3–
5 min under reflux until the initial compound disap-
peared (TLC, Rf 0.35). Total of 75 mg (2 mmol) of
NaBH4 was added. The mixture was diluted with water
and extracted with ethyl acetate (3×50 ml). The extract
was dried over Na2SO4, the solvent was distilled off
under reduced pressure, and the residue was recrystal-
lized from methanol. Yield 118 mg (81%), colorless
1
crystals, mp 210–212°C. H NMR spectrum, δ, ppm:
1-(2,5-Dimethyl-3-thienyl)-2-(3-indolyl)ethane-
dione (VIIa). Reaction time 4 h, yield 4.27 g (75%),
yellow crystals, mp 149–151°C (from MeOH).
1H NMR spectrum, δ, ppm: 2.35 s (3H, CH3), 2.67 s
(3H, CH3), 6.98 s (1H, thiophene), 7.30 m (2H,
indole), 7.54 m (1H, indole), 8.15 m (2H, indole),
12.36 br.s (1H, NH). Mass spectrum, m/z (Irel, %): 283
(12) [M]+, 145 (28), 144 (100), 140 (9), 139 (43), 116
(31), 89 (30), 67 (18), 59 (23), 43 (13). Found, %:
C 66.94; H 4.53; N 5.02; S 11.18. C16H13NO2S. Cal-
culated, %: C 67.92; H 4.62; N 4.95; S 11.32. M 283.33.
4.73 br.s (2H, OH), 5.14 s (2H, CH), 6.98 m (4H,
indole), 7.17 s (2H, indole), 7.34 d (2H, indole), 7.59 d
(2H, indole), 10.76 br.s (2H, NH). Mass spectrum, m/z
(Irel, %): 274 (22) [M – H2O]+, 243 (18), 144 (100),
130 (42), 116 (39), 88 (34), 57 (23), 43 (52). No
molecular ion was detected in the mass spectrum.
Found, %: C 74.02; H 5.50; N 9.52. C18H16N2O2. Cal-
culated, %: C 73.95; H 5.52; N 9.58. M 292.34.
6-(2,5-Dimethyl-3-thienyl)-5-(3-indolyl)-2,3-di-
hydro-1,2,4-triazine-3-thione (IX). A mixture of
850 mg (3 mmol) of dione VIIa and 460 mg (5 mmol)
of thiosemicarbazide in 5 ml of ethanol was heated for
30 min under reflux. Potassium carbonate, 450 mg
(4 mmol), was then added, and the mixture was heated
for 48 h under reflux, diluted with 5 ml of water, and
acidified with 5 ml of acetic acid. The precipitate was
filtered off, washed with a small amount of methanol,
and dried. Yield 738 mg (74%), yellow crystals,
1,2-Bis(3-indolyl)ethanedione (VIIb). Reaction
time 2 h, yield 4.23 g (73%), brownish crystals,
mp 275–280°C (from MeOH); published data [7]:
1
mp 279–280°C. H NMR spectrum, δ, ppm: 7.32 m
(4H), 7.57 m (2H), 8.28 m (2H), 12.26 br.s (2H, NH).
C18H12N2O2. Mass spectrum, m/z (Irel, %): 288 (13)
[M]+, 144 (100), 117 (13), 116 (38), 89 (40), 63 (13),
57 (9), 43 (10). Calculated: M 288.30.
1
mp 248–251°C (from MeOH). H NMR spectrum, δ,
ppm: 2.25 s (3H, CH3), 2.48 s (3H, CH3), 6.70 s (1H,
thiophene), 6.92 d (1H, indole), 7.26 m (2H, indole),
7.45 m (1H, indole), 8.73 m (1H, indole), 11.96 s
(1H, NH), 14.30 s (1H, NHCS). Mass spectrum, m/z
(Irel, %) : 338 (100) [M]+, 305 (16), 280 (36), 251 (91),
236 (28), 218 (17), 142 (23), 126 (18), 117 (12), 97
(13), 77 (13), 59 (45), 43 (29). Found, %: C 59.84;
H 4.13; N 16.12; S 18.61. C17H14N4S2. Calculated, %:
C 60.33; H 4.17; N 16.55; S 18.95. M 338.42.
2-(2,5-Dimethyl-3-thienyl)-1-(3-indolyl)-2-hy-
droxyethanone (VIIIa). Sodium tetrahydridoborate
was added in 5–10 mg portions to a solution of 60 mg
(0.5 mmol) of diketone VIIa in 20 ml of methanol
under stirring at 18–20°C until the initial compound
disappeared (TLC, Rf 0.6). Total of about 30 mg of
NaBH4 was added. The mixture was diluted with
water, and the precipitate was filtered off and washed
with dilute methanol. Yield 58 mg (93%), colorless
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SYNTHESIS AND STRUCTURE OF 5-INDOLYL-6-THIENYL-1,2,4-TRIAZINES
881
indole), 7.26 m (2H, indole, thiophene), 7.47 m (1H,
indole), 7.73 m (2H, thiophene), 8.07 d (1H, indole)
8.72 m (1H, indole), 11.90 br.s (1H, NH). Mass spec-
trum, m/z (Irel, %): 428 (23) [M]+, 292 (8), 251 (9), 155
(15), 154 (100), 136 (28), 128 (84), 111 (96), 81 (25),
71 (23), 59 (44), 57 (49), 45 (53). Found, %: C 61.58;
H 3.69; N 19.50; S 15.01. C22H16N6S2. Calculated, %:
C 61.66; H 3.76; N 19.61; S 14.97. M 428.55.
6-(2,5-Dimethyl-3-thienyl)-5-(3-indolyl)-1,2,4-
triazin-3-ylhydrazine (X). A solution of 150 mg
(0.45 mmol) of thione IX in a mixture of 1 ml of
methanol and 1 ml of hydrazine hydrate was heated
for 6 h under reflux. The mixture was cooled, and the
precipitate was filtered off, washed with water and
dilute methanol, and dried. Yield 125 mg (84%),
yellowish crystals, mp 126–129°C (from MeOH).
1H NMR spectrum, δ, ppm: 2.18 s (3H, CH3), 2.48 s
(3H, CH3), 3.60 br.s (2H, NH2), 6.63 s (1H, thiophene),
6.70 d (1H, indole), 7.16 m (2H, indole), 7.39 m (1H,
indole), 8.40 br.s (1H, NHNH2), 8.78 m (1H, indole),
12.00 br.s (1H, NH). Mass spectrum, m/z (Irel, %): 336
(4) [M]+, 321 (20), 306 (90), 273 (15), 251 (55), 236
(24), 190 (12), 142 (24), 111 (37), 67 (33), 59 (100),
43 (63). Found, %: C 60.40; H 4.65; N 25.03; S 9.41.
C17H16N6S. Calculated, %: C 60.70; H 4.79; N 24.98;
S 9.53. M 336.35 .
6-(2,5-Dimethyl-3-thienyl)-7-(3-indolyl)-3-
(3-indolylmethyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine
(XIc). Yield 76 mg (77%), yellow crystals, mp >350°C
(from MeOH). 1H NMR spectrum, δ, ppm: 2.22 s (3H,
CH3), 2.48 s (3H, CH3), 4.55 s (2H, CH2), 6.74 m (2H,
thiophene, indole), 7.00 m (2H, indole), 7.24 m (3H,
indole), 7.35 d (1H, indole), 7.46 m (1H, indole),
7.62 d (1H, indole), 8.69 m (1H, indole), 10.87 br.s
(1H, NH), 11.82 br.s (1H, NH). Mass spectrum, m/z
(Irel, %): 475 (64) [M]+, 337 (7),196 (13), 156 (49), 154
(100), 142 (29), 130 (59), 101 (16), 91 (26), 77 (40),
59 (55), 43 (47). Found, %: C 68.00; H 4.39; N 20.41;
S 6.57. C27H21N7S. Calculated, %: C 68.19; H 4.45;
N 20.62; S 6.74. M 475.58.
6-(2,5-Dimethyl-3-thienyl)-7-(3-indolyl)-3-
methyl[1,2,4]triazolo[4,3-b][1,2,4]triazine (XIa).
A mixture of 100 mg (0.3 mmol) of hydrazine X and
2 ml of acetic acid was heated for 6 h under reflux.
The mixture was cooled, and the precipitate was fil-
tered off, washed with water and methanol, and dried.
Yield 97 mg (95%), yellow crystals, mp >350°C (from
7-(2,5-Dimethyl-3-thienyl)-6-(3-indolyl)tetrazolo-
[1,5-b][1,2,4]triazine (XII). Compound X, 70 mg
(0.2 mmol), was dissolved in 2 ml of 5% hydrochloric
acid, and a solution of 15 mg (0.2 mmol) of sodium
nitrite was added. The precipitate was filtered off,
washed with water, and recrystallized from methanol.
Yield 62 mg (77%), yellow crystals, mp 260°C
1
MeOH). H NMR spectrum, δ, ppm: 2.12 s (3H,
3-CH3), 2.28 s (3H, CH3), 2.48 s (3H, CH3), 6.63 m
(2H, thiophene, indole), 7.37 m (2H, indole), 7.47 m
(1H, indole), 8.68 m (1H, indole), 12.00 br.s (1H, NH).
Mass spectrum, m/z (Irel, %): 360 (100) [M]+, 345 (34),
290 (8), 258 (14), 154 (83), 127 (68), 117 (10), 100
(18), 91 (17), 77 (34), 71 (21), 59 (76), 45 (50), 43
(53). Found, %: C 62.71; H 4.42; N 22.85; S 8.83.
C19H16N6S. Calculated, %: C 63.31; H 4.48; N 23.31;
S 8.89. M 360.44.
1
(decomp.). H NMR spectrum, δ, ppm: 2.32 s (3H,
CH3), 2.48 s (3H, CH3), 6.80 s (1H, thiophene), 6.87 d
(1H, indole), 7.32 m (2H, indole), 7.52 m (1H, indole),
8.69 m (1H, indole), 12.25 br.s (1H, NH). Mass spec-
trum, m/z (Irel, %): 347 (18) [M]+, 321 (47), 291 (45),
263 (83), 250 (100), 238 (36), 223 (26), 117 (16), 91
(18), 84 (80), 66 (96), 59 (37), 43 (33). Found, %:
C 53.34; H 4.53; N 23.08; S 15.05. C17H13N7S. Calcu-
lated, %: C 53.63; H 4.50; N 23.04; S 15.07. M 347.40.
Triazolotriazines XIb and XIc (general proce-
dure). A mixture of 70 mg (0.2 mmol) of hydrazine
derivative X and 0.5 mmol of 2-thiophenecarboxylic
acid or (3-indolyl)acetic acid was heated until it
melted, kept for 6 h at 100–120°C, and cooled. Excess
acid was removed by washing in succession with
a solution of potassium hydrogen carbonate and water.
The melt was then washed with methanol, and the
precipitate was filtered off, washed with methanol,
and dried.
3-Aminotriazines XIIIa–XIIId (general proce-
dure). A mixture of 70 mg (0.2 mmol) of thione IX and
2 ml of the corresponding amine was heated for 6 h at
the boiling point. The mixture was cooled and treated
with water, and the precipitate was filtered off and
washed with water and methanol, and dried.
6-(2,5-Dimethyl-3-thienyl)-7-(3-indolyl)-3-
(2-thienyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine (XIb).
Yield 56 mg (63%), brownish crystals, mp >350°C
(from MeOH). H NMR spectrum, δ, ppm: 2.32 s
(3H, CH3), 2.48 s (3H, CH3), 6.80 m (2H, thiophene,
6-(2,5-Dimethyl-3-thienyl)-5-(3-indolyl)-3-(1-pyr-
rolidinyl)-1,2,4-triazine (XIIIa). Yield 61 mg (78%),
yellowish crystals, mp 284–287°C (from MeOH).
1H NMR spectrum, δ, ppm: 2.10 t (4H, CH2CH2),
2.14 s (3H, CH3), 2.48 s (3H, CH3), 3.76 t (4H, CH2N),
1
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KRAYUSHKIN et al.
882
6.64 s (1H, thiophene), 6.83 d (1H, indole), 7.16 m
(2H, indole), 7.43 m (1H, indole), 8.58 m (1H, indole),
11.57 br.s (1H, NH). Mass spectrum, m/z (Irel, %): 375
(64) [M]+, 252 (18), 251 (100), 236 (15), 191 (18), 189
(16), 142 (25), 96 (8), 55 (8). Found, %: C 66.94;
H 5.61; N 18.52; S 8.59. C21H21N5S. Calculated, %:
C 67.17; H 5.64; N 18.65; S 8.54. M 375.49.
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6-(2,5-Dimethyl-3-thienyl)-5-(3-indolyl)-3-mor-
pholino-1,2,4-triazine (XIIIb). Yield 57 mg (70%),
yellowish crystals, mp 220–224°C (from MeOH).
1H NMR spectrum, δ, ppm: 2.16 s (3H, CH3), 2.47 s
(3H, CH3), 3.82 t (4H, CH2N), 3.93 t (4H, CH2O),
6.63 s (1H, thiophene), 6.84 d (1H, indole), 7.18 m
(2H, indole), 7.43 m (1H, indole), 8.40 m (1H, indole),
11.70 br.s (1H, NH). Mass spectrum, m/z (Irel, %): 391
(83) [M]+, 334 (12), 252 (22), 251 (98), 250 (27), 139
(22), 111 (9), 100 (17), 91 (24), 86 (18), 69 (16), 59
(80), 43 (100). Found, %: C 64.04; H 5.41; N 17.14;
S 8.20. C21H21N5OS. Calculated, %: C 64.43; H 5.41;
N 17.89; S 8.19. M 391.49.
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6-(2,5-Dimethyl-3-thienyl)-5-(3-indolyl)-3-(4-
methyl-1-piperazinyl)-1,2,4-triazine (XIIIc). Yield
56 mg (67%), yellowish crystals, mp 218–220°C (from
MeOH). 1H NMR spectrum, δ, ppm: 2.14 s (3H, CH3),
2.27 s (3H, NCH3), 2.47 s (3H, CH3), 2.53 t (4H, CH2),
3.94 t (4H, CH2 ), 6.62 s (1H, thiophene), 6.83 d (1H,
indole), 7.18 m (2H, indole), 7.42 m (1H, indole),
8.42 m (1H, indole), 11.68 br.s (1H, NH). Mass spec-
trum, m/z (Irel, %): 404 (30) [M]+, 335 (27), 334 (98),
322 (15), 251 (40), 236 (13), 143 (25), 100 (30), 91
(26), 83 (42), 71 (57), 70 (100), 59 (70), 57 (60), 43
(32). Found, %: C 65.06; H 5.91; N 20.70; S 7.88.
C22H24N6S. Calculated, %: C 65.32; H 5.98; N 20.77;
S 7.93. M 404.54.
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14. Krayushkin, M.M., Vorontsova, L.G., and Uzhi-
6-(2,5-Dimethyl-3-thienyl)-5-(3-indolyl)-3-piper-
idino-1,2,4-triazine (XIIId). Yield 57 mg (71%),
yellowish crystals, mp 244–246°C (from MeOH).
1H NMR spectrum, δ, ppm: 1.72 m (6H, CH2), 2.16 s
(3H, CH3), 2.47 s (3H, CH3), 3.96 m (4N, NCH2),
6.62 s (1H, thiophene), 6.84 d (1H, indole), 7.16 m
(2H, indole), 8.40 m (1H, indole), 11.62 br.s (1H, NH).
Mass spectrum, m/z (Irel, %): 389 (67) [M]+, 252 (15),
251 (100), 236 (8), 165 (5), 142 (8), 110 (6), 84 (15),
69 (6), 59 (12), 55 (14), 43 (9). Found, %: C 66.99;
H 5.85; N 17.91; S 8.11. C22H23N5S. Calculated, %:
C 67.84; H 5.95; N 17.98; S 8.23. M 389.52.
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SYNTHESIS AND STRUCTURE OF 5-INDOLYL-6-THIENYL-1,2,4-TRIAZINES
883
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