Intramolecular cyclization of 4-amino-3-alkylsulfanyl-1,2,4-triazoles as a method for annelation of thiadiazine and thiadiazole rings

Article abstract of DOI:10.1134/S1070428009010199

4-Amino-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiols reacted with N-substituted isatins to give 2-oxo-3-[5-(pyridin-4-yl)-3-sulfanyl-4H-1,2,4- triazole-4-ylimino]-2,3-dihydro-1H-indoles which were treated with phenacyl bromides to obtain the corresponding

Full text of DOI:10.1134/S1070428009010199

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 1, pp. 139–145. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.A. Kolodina, A.V. Lesin, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 1, pp. 142–147.
Intramolecular Cyclization of 4-Amino-3-alkylsulfanyl-1,2,4-
triazoles as a Method for Annelation of Thiadiazine and
Thiadiazole Rings
A. A. Kolodina and A. V. Lesin
Southern Federal University, ul. Zorge 7, Rostov-on-Don, 344090 Russia
e-mail: lexandra@inbox.ru
Received February 13, 2008
Abstract—4-Amino-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiols reacted with N-substituted isatins to give
2-oxo-3-[5-(pyridin-4-yl)-3-sulfanyl-4H-1,2,4-triazole-4-ylimino]-2,3-dihydro-1H-indoles which were treated
with phenacyl bromides to obtain the corresponding S-phenacyl derivatives. The latter underwent base-cata-
lyzed intramolecular cyclization with formation of 6,7-dihydro-5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines
spiro-fused to 2-oxo-2,3-dihydro-1H-indole fragment at C3. Analogous cyclization of 2,6-di-tert-butyl-
4-[5-hetaryl-3-(2-aryl-2-oxoethylsulfanyl)-4H-1,2,4-triazole-4-ylimino]cyclohexa-2,5-dienones involved the
imino nitrogen atom to produce the corresponding 6-aroyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-hetaryl-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles.
DOI: 10.1134/S1070428009010199
We previously showed that intramolecular cycliza-
tion of S-methylene derivatives of imidazolyl imines
into 3,4-dihydro-2H-imidazo[2,1-b][1,3,4]thiadiazines
provides a new convenient method for fusion of a di-
hydrothiadiazine ring to an imidazole fragment via
formation of a new C–C bond [1]. In the present work
we examined intramolecular cyclization of S-phenacyl
derivatives of aminoazolethiols using 4-amino-5-het-
aryl-4H-1,2,4-triazole-3-thiols as examples with a view
to obtain new fused heterocycles, including spiro-fused
systems. Despite numerous publications on the synthe-
sis of fused heterocyclic systems containing a 1,2,4-tri-
azole fragment, we have found only two examples of
preparation of 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazines, namely reduction of triazolothiadi-
azines [2, 3] and reaction of arylmethylideneamino-
1,2,4-triazoles with phenacyl bromide and ethyl
bromoacetate [4, 5].
azole, but the latter rapidly underwent intramolecular
cyclization to triazolothiadiazine IV (Scheme 1).
The spirocyclic structure of compounds IV follows
from the presence in their 1H NMR spectra of two one-
proton singlets at δ 6.0–6.2 (SCH) and 7.8–8.0 ppm
(NH), whereas no two-proton singlet typical of SCH2
group was observed. Compound IVb displayed in the
1H NMR spectrum an AB quartet from protons in the
prochiral NCH2Ph methylene group at δ 4.4–5.0 ppm,
indicating formation of diastereoisomers. In addition,
some signals in the spectra of compounds IVa and IVb
were doubled at ratios of 40:60 and 50:50, respec-
tively. Thus these compounds are formed as mixtures
of diastereoisomers due to the presence in their mole-
cules of two asymmetric carbon atoms.
The structure of triazolothiadiazine derivative IVb
was unambiguously proved by X-ray analysis (Fig. 1).
The thiadiazine ring in molecule IVb is flattened
(C2S1C3N2N1 fragment); only the S1 atom considerably
deviates from the plane of the triazolothiadiazine
system. The deviations amount to 0.584 Å for C1,
0.023 Å for C2, and 0.058 Å for S1 to the same side of
the triazole ring plane, while the N1 atom deviates by
0.084 Å from the same plane to the opposite side. The
H1A and H2A atoms in the thiadiazine ring are arranged
cis with respect to each other and trans with respect to
the C1–C5 bond in the indole fragment: the torsion
By condensation of 4-amino-5-hetaryl-4H-1,2,4-tri-
azole-3-thiols Ia–Ic with N-substituted isatins and
2,6-di-tert-butyl-1,4-benzoquinone we obtained the
corresponding Schiff bases IIa, IIb, and IIIa–IIIc.
Alkylation of the sulfanyl group in II with phenacyl
bromides resulted in the formation of spiro-fused
6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadi-
azines IVa and IVb. Thus the reaction did not stop at
the stage of formation of S-phenacyl-substituted tri-
139

KOLODINA, LESIN
140
Scheme 1.
N
N
N
N
N
N
S
N
N
O
N
HN
N
N
BrCH2C(O)Ar
COAr
O
SH
SH
+
O
O
N
N
N
N
N
NH2
R'
R'
R'
Ia
IIa, IIb
IVa, IVb
O
Bu-t
Bu-t
O
O
Ar
HS
S
O
O
t-Bu
Bu-t
N
N
N
R
N
BrCH2C(O)Ar
+
N
N
R
SH
N
N
N
t-Bu
N
t-Bu
N
NH2
Ia–Ic
R
IIIa–IIIc
Va–Vf
Ar
Bu-t
R
HO
Bu-t
HO
N
EtONa
N
S
O
N
t-Bu
N
N
R
N
S
N
Ar
t-Bu
N
O
VIa–VIf
I, III, R = pyridin-4-yl (a), pyridin-3-yl (b), 2-furyl (c); II, R′ = Me (a), PhCH2 (b); IV, Ar = Ph, R′ = Me (a); Ar = 4-BrC6H4,
R′ = PhCH2 (b); V, VI, R = pyridin-4-yl, Ar = 4-BrC6H4 (a), Ph (b); R = pyridin-3-yl, Ar = 4-BrC6H4 (c), Ph (d), 3-O2NC6H4 (e);
R = 2-furyl, Ar = 4-BrC6H4 (f).
angles H2AC2C1C5 and H1AN1C1C5 are 171.3(1) and
109.2(3)°, respectively. The C2–H2A and C1–C5 bonds
are axial, while C2–C13 and C1–C11 are equatorial. The
indole fragment is almost orthogonal to the triazolo-
thiadiazine plane, and the dihedral angle between the
C2S1C3N2N1 and C1C5N6C6C11 planes is 79.80°. The
pyridine ring is turned with respect to the triazole ring
through an angle of 5°: the torsion angles C17C16C4N2
and C15C16C4N3 are 5.1(4) and 4.5(4)°, respectively.
The aromatic rings in the N-benzyl and para-bromo-
benzoyl fragments are almost coplanar (the dihedral
angle between the corresponding planes is 10.30°) but
are located at opposite sides with respect to the indole
ring system which is orthogonal to the phenyl rings:
the corresponding dihedral angles are 79.27 (benzyl)
and 83.99° (para-bromobenzoyl).
Cahn–Ingold–Prelog. Monoclinic crystal lattice of
compound IVb consists of a racemic mixture of (S,S)-
and (R,R)-diastereoisomers. Molecules IVb with the
same configuration in crystal give rise to zigzag chains
through intermolecular NH···N hydrogen bonds (d =
2.844 Å) between their thiadiazine and triazole frag-
ments (Fig. 2).
In the reactions of quinone imines III with phen-
acyl bromides we isolated only compounds Va–Vf
which underwent intramolecular ring closure by the
action of sodium ethoxide in ethanol. However, unlike
Schiff bases derived from isatins, the products had the
structure of 5,6-dihydro[1,2,4]triazolo[3,4-b][1,3,4]-
1
thiadiazoles VI (Scheme 2). The H NMR spectra of
compounds VIa–VIf lacked two-proton singlet typical
of SCH2 methylene protons in initial quinone imines
V, while signals from CH and OH protons appeared. In
addition, two protons in the phenol fragment gave
Both asymmetric C1 and C2 atoms in the molecule
shown in Fig. 1 have S configuration according to
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 1 2009

INTRAMOLECULAR CYCLIZATION OF 4-AMINO-3-ALKYLSULFANYL-1,2,4-TRIAZOLES
141
a two-proton singlet at δ 6.9–7.5 ppm, and protons in
the tert-butyl groups resonated as a 18H-singlet at
δ 1.3–1.4 ppm.
C28
C29
C30
Br1
C9
C25
C13
O2
C8
C7
C27
C10
Presumably, closure of thiadiazole ring in com-
pounds V is favored by facile enolization of the phen-
acyl fragment due to enhanced acidity of the methyl-
ene group, and the subsequent intramolecular attack by
the electrophilic CH carbon atom on the imino nitro-
gen atom is followed by aromatization of the quinone
imine fragment.
C26
C11
C6
N6
H24
C2
C1
C12
C19
C20
S1
C5
O1
C24
N1
N2
C4
C21
C3
N4
C23
C22
To conclude, it should be noted that intramolecular
cyclization of phenacylsulfanyl derivatives of N-tri-
azolyl imines makes it possible to obtain spirocyclic
dihydrotriazolothiadiazines that are inaccessible by
other methods via formation of new C–C bond at the
last heterocyclization stage. Analogous C–C bonding
in the final stage of heterocyclization of quinone imine
derivatives V is hampered by facile aromatization of
the quinone imine fragment, which leads to the forma-
tion of dihydrotriazolothiadiazoles VI.
C17
C16
N3
C18
N5
C15
C14
Fig. 1. Structure of the molecule of 1-benzyl-7′-(4-bromo-
benzoyl)-3′-(pyridin-4-yl)-5′,7′-dihydrospiro[indole-3,6′-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin]-2(1H)-one (IVb) ac-
cording to the X-ray diffraction data.
EXPERIMENTAL
1
The H NMR spectra were measured at 25°C on
Varian Unity-300 (300 MHz) and Bruker DPX-250
(250 MHz) spectrometers using tetramethylsilane as
internal reference. The mass spectra were recorded on
a Finnigan MAT INCOS-50 mass spectrometer.
A 0.25×0.35×0.40-mm single crystal of compound
IVb suitable for X-ray analysis was obtained by crys-
tallization from acetonitrile. The X-ray diffraction data
(an experimental set of 22445 reflections) were ac-
quired at 120 K on a Bruker SMART 1000 CCD dif-
fractometer (graphite monochromator, λMoKα irradia-
tion, 2θmax = 58°). Averaging of equivalent reflections
gave 7641 independent reflections with Rint = 0.0444,
which were used in the structure solution and refine-
ment. Colorless needles, C32H24BrN7O2S, M 650.55,
monoclinic crystals. Unit cell parameters (120 K): a =
14.3376(18), b = 7.7669(10), c = 26.417(3) Å; β =
101.086(3); V = 2886.9(6) Å3; space group P2(1)/c;
Z = 4; dcalc = 1.497 g/cm3; µ = 15.4 cm–1. The structure
was solved by the direct method; all non-hydrogen
atoms were localized by difference syntheses of elec-
tron density, and their positions were refined by F2hkl in
anisotropic approximation. The positions of hydrogen
atoms were determined from the geometry considera-
tions and were involved in the refinement procedure
using the riding model, U(H) = nU(C), where U(C) is
the equivalent temperature factor of the corresponding
carbon atom; n = 1.2 and 1.5 for sp2- and sp3-carbon
Fig. 2. A fragment of intermolecular hydrogen bond chain in
the crystalline structure of 1-benzyl-7′-(4-bromobenzoyl)-3′-
(pyridin-4-yl)-5′,7′-dihydrospiro[indole-3,6′-[1,2,4]triazolo-
[3,4-b][1,3,4]thiadiazin]-2(1H)-one (IVb) according to the
X-ray diffraction data.
atoms, respectively. The final divergence factors were
R1 = 0.0532 [for 4587 reflections with I > 2σ(I)] and
wR2 = 0.1386 (for all 7641 independent reflections);
goodness of fit 0.991; 388 refined parameters. All cal-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 1 2009

KOLODINA, LESIN
142
culations were performed using SHELXTL PLUS 5
software package [6]. The complete set of crystallo-
graphic data for compound IVb was deposited to the
Cambridge Crystallographic Data Centre (entry
no. CCDC 677672).
mixture was cooled, diluted with water, and neutral-
ized to pH 7.0–7.5 with dilute hydrochloric acid, and
the precipitate was filtered off and recrystallized from
benzene–hexane (1:1).
2,6-Di-tert-butyl-4-[5-(pyridin-4-yl)-3-sulfanyl-
4H-1,2,4-triazole-4-ylimino]cyclohexa-2,5-dienone
(IIIa). Yield 4.345 g (55%), orange crystals,
Initial 4-amino-5-hetaryl-4H-1,2,4-triazole-3-thiols
were synthesized according to the procedure described
previously [7].
1
mp 234°C. H NMR spectrum (acetone-d6), δ, ppm:
1.25 s and 1.38 s (9H each, t-Bu), 7.18 d and 7.26 d
(1H each, 3-H, 5-H, J = 2.63 Hz), 7.85 d and 8.74 d
(2H each, pyridine, J = 6.13 Hz). Mass spectrum, m/z
(Irel, %): 395 (55.0) [M]+, 338 (100), 294 (5.1), 250
(3.2), 218 (65.0), 202 (22.9), 178 (24.2), 105 (22.6),
77 (22.3). Found, %: C 63.83; H 6.35; N 17.80.
C21H25N5OS. Calculated, %: C 63.79; H 6.33; N 17.72.
M 395.53.
3-[5-(Pyridin-4-yl)-3-sulfanyl-4H-1,2,4-triazole-
4-ylimino]-2,3-dihydro-1H-indol-2-ones IIa and
IIb (general procedure). A mixture of 20 mmol of
aminotriazole Ia, 20 mmol of the corresponding
N-substituted isatin, and 20 ml of glacial acetic acid
was heated for 4 h under reflux. The mixture was
cooled and diluted with water, and the precipitate was
filtered off and recrystallized from ethanol.
2,6-Di-tert-butyl-4-[5-(pyridin-3-yl)-3-sulfanyl-
4H-1,2,4-triazole-4-ylimino]cyclohexa-2,5-dienone
(IIIb). Yield 4.976 g (63%), red crystals, mp 224°C.
1H NMR spectrum (CDCl3), δ, ppm: 1.22 s and 1.31 s
(9H each, t-Bu), 6.79 d and 7.11 d (1H each, 3-H, 5-H,
J = 2.71 Hz), 7.43 d.d (1H, pyridine, J = 4.84,
8.07 Hz), 8.18 d (1H, pyridine, J = 8.20 Hz), 8.73 d
(1H, pyridine, J = 4.84 Hz), 9.07 s (1H, pyridine),
11.42 br.s (1H, SH). Mass spectrum, m/z (Irel, %): 395
(10.3) [M]+, 338 (26.9), 294 (2.1), 250 (2.3), 218
(27.0), 202 (9.3), 193 (100), 178 (26.2), 105 (57.5),
78 (43.6). Found, %: C 63.91; H 6.44; N 17.79.
C21H25N5OS. Calculated, %: C 63.79; H 6.33; N 17.72.
M 395.53.
1-Methyl-3-[5-(pyridin-4-yl)-3-sulfanyl-4H-1,2,4-
triazole-4-ylimino]-2,3-dihydro-1H-indol-2-one
(IIa). Yield 2.352 g (35%), orange crystals, mp 230°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 3.08 s (3H,
CH3), 6.85 d (1H, Harom, J = 7.77 Hz), 7.02 t (1H,
H
arom, J = 7.45 Hz), 7.56 t (1H, Harom, J = 7.45 Hz),
7.81–7.86 m (3H, 1Harom, 2H, pyridine), 8.73 d (2H,
pyridine, J = 4.53 Hz), 14.51 s (1H, SH). Mass spec-
trum, m/z (Irel, %): 336 (60.0) [M]+, 308 (100), 232
(10.1), 193 (13.4), 178 (20.0), 160 (37.8), 131 (76.7),
104 (99.0), 77 (95.0). Found, %: C 57.36; H 3.42;
N 25.13. C16H12N6OS. Calculated, %: C 57.13; H 3.60;
N 24.98. M 336.38.
1-Benzyl-3-[5-(pyridin-4-yl)-3-sulfanyl-4H-1,2,4-
triazole-4-ylimino]-2,3-dihydro-1H-indol-2-one
(IIb). Yield 3.131 g (38%), orange crystals, mp 234°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 4.72 d and
5.03 d (1H each, NCH2, J = 15.86 Hz), 6.9 d (1H,
2,6-Di-tert-butyl-4-[5-(furan-2-yl)-3-sulfanyl-4H-
1,2,4-triazole-4-ylimino]cyclohexa-2,5-dienone
(IIIc). Yield 5.143 g (67%), yellow crystals, mp 197°C.
1H NMR spectrum (CDCl3), δ, ppm: 1.21 s and 1.33 s
(9H each, t-Bu), 6.55 m (1H, furan), 6.76 d (1H, 3-H,
J = 2.68 Hz), 6.97 d (1H, furan, J = 3.60 Hz), 7.18 d
(1H, 5-H, J = 2.66 Hz), 7.61 s (1H, furan), 11.56 br.s
(1H, SH). Mass spectrum, m/z (Irel, %): 384 (15.1)
[M]+, 369 (6.1), 327 (25.0), 263 (2.2), 218 (24.9), 202
(11.8), 167 (18.0), 93 (32.6), 41 (100). Found, %:
C 62.62; H 6.48; N 14.37. C20H24N4O2S. Calculated,
%: C 62.50; H 6.25; N 14.58. M 384.50.
Harom, J = 7.44 Hz), 7.02 m (1H, Harom), 7.18 t (1H,
Harom, J = 7.44 Hz), 7.33–7.43 m (5H, Ph), 7.58 m (1H,
Harom), 7.89 d (2H, pyridine, J = 6.15 Hz), 8.76 d (2H,
pyridine, J = 6.15 Hz), 14.51 s (1H, SH). Mass spec-
trum, m/z (Irel, %): 412 (0.9) [M]+, 384 (1.6), 321 (0.7),
193 (100), 178 (2.1), 162 (6.3), 122 (13.2), 105 (32.5),
78 (39.2). Found, %: C 63.93; H 3.75; N 20.80.
C22H16N6OS. Calculated, %: C 64.06; H 3.91; N 20.37.
M 412.48.
Triazolo[3,4-b][1,3,4]thiadiazines IVa and IVb
(general procedure). Compound IIa or IIb, 5 mmol,
and phenacyl or 4-bromophenacyl bromide, 5 mmol,
were added to a solution of 5 mmol of sodium hydrox-
ide in 10 ml of alcohol. The mixture was heated to the
boiling point, cooled, and diluted with 50 ml of water,
and the precipitate was filtered off and recrystallized
from acetonitrile.
2,6-Di-tert-butyl-4-(5-hetaryl-3-sulfanyl-4H-
1,2,4-triazole-4-ylimino)cyclohexa-2,5-dienones
IIIa–IIIc (general procedure). Aminotriazole Ia–Ic,
20 mmol, was dissolved in a solution of 20 mmol of
sodium hydroxide in 50 ml of methanol, 20 mmol of
2,6-di-tert-butyl-1,4-benzoquinone was added, and the
mixture was heated for 30–60 min under reflux. The
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INTRAMOLECULAR CYCLIZATION OF 4-AMINO-3-ALKYLSULFANYL-1,2,4-TRIAZOLES
143
t-Bu), 4.90 s (2H, SCH2), 6.45 d and 7.13 d (1H, 3-H,
5-H, J = 2.71 Hz), 7.63 d (2H, Harom, J = 8.59 Hz),
7′-Benzoyl-1-methyl-3′-(pyridin-4-yl)-5′,7′-di-
hydrospiro[indole-3,6′-[1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazin]-2(1H)-one (IVa). Yield 0.272 g (12%),
7.69 d (2H, pyridine, J = 6.14 Hz), 7.87 d (2H, Harom
,
1
J = 8.60 Hz), 8.69 d (2H, pyridine, J = 6.13 Hz).
Found, %: C 58.84; H 5.11; N 11.71. C29H30BrN5O2S.
Calculated, %: C 58.78; H 5.07; N 11.82.
colorless crystals, mp 211°C. H NMR spectrum
(DMSO-d6), δ, ppm: 2.82 s (1.8H) and 3.09 s (1.2H)
(CH3), 5.98 s (0.6H) and 6.11 s (0.4H) (7′-H), 6.85 d
(0.4H, Harom, J = 8.02 Hz), 6.96–7.14 m (1.2H, Harom),
7.3–7.45 m (5H, Harom), 7.57 m (1.6H, Harom), 7.72 t
(0.4H, Harom, J = 6.87 Hz), 7.84 d (2H, pyridine, J =
5.72 Hz), 7.95 m (1.4H, NH, Harom), 8.65 d (2H, pyri-
dine, J = 5.72 Hz). Mass spectrum, m/z (Irel, %): 454
(0.16) [M]+, 308 (2.6), 277 (8.2), 173 (8.7), 160 (6.6),
131 (17.1), 105 (100), 77 (96.0). Found, %: C 63.62;
H 3.48; N 19.07. C24H18N6O2S. Calculated, %:
C 63.42; H 3.99; N 18.49. M 454.51.
2,6-Di-tert-butyl-4-[3-(2-oxo-2-phenylethylsul-
fanyl)-5-(pyridin-4-yl)-4H-1,2,4-triazol-4-ylimino]-
cyclohexa-2,5-dien-1-one (Vb). Yield 1.197 g (78%),
1
yellow crystals, mp 186°C. H NMR spectrum (ace-
tone-d6), δ, ppm: 1.20 s and 1.35 s (9H each, t-Bu),
5.05 s (2H, SCH2), 6.82 d and 7.31 d (1H each, 3-H,
5-H, J = 2.69 Hz), 7.58 t (2H, Ph, J = 7.12 Hz), 7.71 t
(1H, Ph, J = 7.27 Hz), 7.78 d (2H, pyridine, J =
6.19 Hz), 8.11 d (2H, Ph, J = 7.02 Hz), 8.69 d (2H,
pyridine, J = 6.16 Hz). Mass spectrum, m/z (Irel, %):
513 (7.0) [M]+, 471 (67.5), 456 (17.5), 380 (6.7), 338
(20.0), 232 (29.6), 202 (19.8), 176 (17.6), 105 (100),
77 (51.1). Found, %: C 67.99; H 5.91; N 13.77.
C29H31N5O2S. Calculated, %: C 67.84; H 6.04;
N 13.65. M 513.67.
1-Benzyl-7′-(4-bromobenzoyl)-3′-(pyridin-4-yl)-
5′,7′-dihydrospiro[indole-3,6′-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazin]-2(1H)-one (IVb). Yield 0.344 g
1
(11%), colorless crystals, mp 214°C. H NMR spec-
trum (DMSO-d6), δ, ppm: 4.39 d and 4.83 d (0.5H
each, NCH2, J = 15.82 Hz), 4.75 d and 4.93 d (0.5H,
NCH2, J = 15.89 Hz), 6.05 s and 6.22 s (0.5H each,
7′-H), 6.82 d (0.5H, Harom, J = 7.91 Hz), 6.94–7.12 m
(4H, Harom), 7.15–7.34 m (4H, Harom), 7.37 d (1H,
Harom, J = 8.57 Hz), 7.45 d (0.5H, Harom, J = 7.32 Hz),
7.62 d (1H, Harom, J = 8.49 Hz), 7.78–7.86 m (3H, NH,
4-{3-[2-(4-Bromophenyl)-2-oxoethylsulfanyl]-
5-(pyridin-3-yl)-4H-1,2,4-triazol-4-ylimino}-2,6-di-
tert-butylcyclohexa-2,5-dien-1-one (Vc). Yield 1.434 g
1
(81%), yellow crystals, mp 194°C. H NMR spectrum
(CDCl3), δ, ppm: 1.09 s and 1.29 s (9H each, t-Bu),
4.86 s (2H, SCH2), 6.49 d and 7.10 d (1H each, 3-H,
5-H, J = 2.73 Hz), 7.36 d.d (1H, pyridine, J = 4.84,
8.15 Hz), 7.61 d and 7.86 d (2H each, Harom, J =
8.58 Hz), 8.13 d (1H, pyridine, J = 7.99 Hz), 8.61 d
(1H, pyridine, J = 4.87 Hz), 8.94 s (1H, pyridine).
Mass spectrum, m/z (Irel, %): 591 (0.6) [M]+, 552 (2.8),
494 (5.1), 492 (5.1), 232 (58.0), 218 (22.3), 202 (27.9),
185 (97.0), 183 (100). Found, %: C 58.88; H 5.16;
N 11.92. C29H30BrN5O2S. Calculated, %: C 58.78;
H 5.07; N 11.82. M 592.56.
H
H
arom), 7.9 d (1H, Harom, J = 8.64 Hz), 8.04 d (1H,
arom, J = 2.05 Hz), 8.59 d (1H, Harom, J = 6.01 Hz),
8.65 d (1H, Harom, J = 5.93 Hz). Mass spectrum, m/z
(Irel, %): 236 (36.5), 208 (19.3), 185 (19.5), 183 (19.5),
157 (7.3), 155 (7.3), 145 (34.2), 117 (13.5), 91 (100).
Found, %: C 60.62; H 3.48; N 14.37. C30H21BrN6O2S.
Calculated, %: C 59.12; H 3.47; N 13.79.
2,6-Di-tert-butyl-4-[5-hetaryl-3-(2-aryl-2-oxo-
ethylsulfanyl)-4H-1,2,4-triazol-4-ylimino]cyclo-
hexa-2,5-dienones Va–Vf (general procedure). Com-
pound IIIa–IIIc, 3 mmol, was added to a solution of
3 mmol of sodium hydroxide in 10 ml of methanol,
the mixture was stirred until it turned homogeneous,
3 mmol of the phenacyl bromide or 4-bromophenacyl
bromide was added, and the mixture was stirred for
15 min on slight heating and evaporated. The residue
was treated with 50 ml of water, and the precipitate
was filtered off and recrystallized from benzene–
hexane (1:3).
2,6-Di-tert-butyl-4-[3-(2-oxo-2-phenylethylsul-
fanyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-ylimino]-
cyclohexa-2,5-dien-1-one (Vd). Yield 1.250 g (81%),
yellow crystals, mp 88°C. 1H NMR spectrum (CDCl3),
δ, ppm: 1.12 s and 1.31 s (9H, t-Bu), 4.95 s (2H,
SCH2), 6.50 d and 7.12 d (1H, 3-H, 5-H, J = 2.69 Hz),
7.39 d.d (1H, pyridine, J = 4.84, 8.13 Hz), 7.48 t (2H,
Ph, J = 7.21 Hz), 7.60 t (1H, Ph, J = 7.26 Hz), 8.02 d
(2H, Ph, J = 7.27 Hz), 8.16 d.d (1H, pyridine, J = 8.12,
3.57 Hz), 8.64 d.d (1H, pyridine, J = 4.72, 1.31 Hz),
8.94 d (1H, pyridine, J = 1.31 Hz). Mass spectrum, m/z
(Irel, %): 513 (4.0) [M]+, 471 (7.9), 414 (15.2), 336
(2.5), 232 (42.3), 218 (14.9), 202 (22.0), 176 (31.4),
105 (100). Found, %: C 68.18; H 5.66; N 12.94.
4-{3-[2-(4-Bromophenyl)-2-oxoethylsulfanyl]-
5-(pyridin-4-yl)-4H-1,2,4-triazol-4-ylimino}-2,6-di-
tert-butylcyclohexa-2,5-dien-1-one (Va). Yield 1.456 g
(82%), yellow crystals, mp 207–208°C. 1H NMR spec-
trum (CDCl3), δ, ppm: 1.11 s and 1.33 s (9H each,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 1 2009

KOLODINA, LESIN
144
C29H31N5O2S. Calculated, %: C 67.81; H 6.08;
N 13.63. M 513.67.
5-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(pyri-
din-4-yl)-5,6-dihydro[1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazol-6-yl(phenyl)methanone (VIb). Yield
0.470 g (46%), light yellow crystals, mp 232°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.35 s (18H,
t-Bu), 6.79 s (1H, 6-H), 7.44 s (2H, 2′-H, 6′-H), 7.85 d
(2H, pyridine, J = 4.89 Hz), 7.92 m (3H, Ph), 8.71 m
(2H, Ph), 8.74 d (2H, pyridine, J = 5.08 Hz), 13.91 s
(1H, OH). Mass spectrum, m/z (Irel, %): 513 (0.7)
[M]+, 336 (6.3), 282 (3.8), 216 (11.2), 178 (13.8), 105
(100), 77 (74.9). Found, %: C 68.03; H 6.21; N 13.82.
C29H31N5O2S. Calculated, %: C 67.84; H 6.04;
N 13.65. M 513.67.
2,6-Di-tert-butyl-4-{3-[2-(3-nitrophenyl)-2-oxo-
ethylsulfanyl]-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl-
imino}cyclohexa-2,5-dien-1-one (Ve). Yield 1.411 g
1
(84%), yellow crystals, mp 117°C. H NMR spectrum
(CDCl3), δ, ppm: 1.12 s and 1.31 s (9H each, t-Bu),
4.92 s (2H, SCH2), 6.52 d and 7.13 d (1H, 3-H, 5-H,
J = 2.63 Hz), 7.39 d.d (1H, pyridine, J = 4.88,
8.38 Hz), 7.72 t (1H, Harom, J = 8.05 Hz), 8.16 d.d (1H,
pyridine, J = 8.02, 3.70 Hz), 8.36 d (1H, Harom, J =
7.78 Hz), 8.45 d (1H, Harom, J = 7.42 Hz), 8.64 d (1H,
pyridine, J = 4.80 Hz), 8.84 d (1H, Harom, J = 1.80 Hz),
8.94 s (1H, pyridine). Mass spectrum, m/z (Irel, %): 559
(4.1) [M]+, 459 (20), 395 (12.5), 338 (30.0), 232
(45.2), 216 (75.0), 202 (23.8), 178 (46.1), 150 (100).
Found, %: C 62.18; H 5.74; N 14.64. C29H30N6O4S.
Calculated, %: C 62.35; H 5.41; N 15.04. M 558.66.
(4-Bromophenyl){5-(3,5-di-tert-butyl-4-hydroxy-
phenyl)-3-(pyridin-3-yl)-5,6-dihydro[1,2,4]triazolo-
[3,4-b][1,3,4]thiadiazol-6-yl}methanone (VIc). Yield
0.517 g (44%), colorless crystals, mp 214–216°C.
1H NMR spectrum (CDCl3), δ, ppm: 1.35 s (18H,
t-Bu), 5.26 s (1H, 6-H), 6.90 s (2H, 2′-H, 6′-H), 7.34 m
(1H, pyridine), 7.35 d and 7.44 d (2H each, Harom, J =
8.63 Hz), 8.45 m (2H, pyridine), 9.61 s (1H, pyridine).
Mass spectrum, m/z (Irel, %): 593 (12.4) [M + 1]+, 591
(12.4) [M – 1]+, 575 (1.8), 416 (0.8), 362 (0.6), 263
(0.5), 216 (17.1), 178 (100), 105 (23.2), 78 (15.9).
Found, %: C 58.91; H 5.24; N 12.03. C29H30BrN5O2S.
Calculated, %: C 58.78; H 5.07; N 11.82. M 592.56.
4-{3-[2-(4-Bromophenyl)-2-oxoethylsulfanyl]-5-
(furan-2-yl)-4H-1,2,4-triazol-4-ylimino}-2,6-di-tert-
butylcyclohexa-2,5-dien-1-one (Vf). Yield 1.327 g
1
(76%), yellow crystals, mp 180°C. H NMR spectrum
(CDCl3), δ, ppm: 1.11 s and 1.33 s (9H each, t-Bu),
4.87 s (2H, SCH2), 6.49 d.d (1H, furan, J = 3.48,
1.77 Hz), 6.51 d (1H, 3-H, J = 2.64 Hz), 6.85 d (1H,
furan, J = 3.26 Hz), 7.14 d (1H, 5-H, J = 2.67 Hz),
7.48 s (1H, furan), 7.62 d and 7.88 d (2H each, Harom
,
5-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(pyri-
din-3-yl)-5,6-dihydro[1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazol-6-yl(phenyl)methanone (VId). Yield
J = 8.51 Hz). Mass spectrum, m/z (Irel, %): 583 (15)
[M + 1]+, 581 (14.5) [M – 1]+, 483 (22.2), 481 (21.6),
232 (41.7), 218 (22.0), 202 (35.9), 185 (87.5), 183
(100). Found, %: C 57.91; H 5.06; N 9.71.
C28H29BrN4O3S. Calculated, %: C 57.83; H 4.99;
N 9.64. M 581.54.
1
0.386 g (38%), colorless crystals, mp 192°C. H NMR
spectrum (DMSO-d6), δ, ppm: 1.31 s (18H, t-Bu),
6.75 s (1H, 6-H), 7.39 m (1H, pyridine), 7.41 s (2H,
2′-H, 6′-H), 7.55 m (3H, Ph), 8.22 m (1H, pyridine),
8.61 m (3H, Ph, pyridine), 9.06 s (1H, pyridine). Mass
spectrum, m/z (Irel, %): 513 (1.9) [M]+, 497 (0.6), 452
(1.2), 336 (4.2), 282 (77.3), 263 (38.1), 178 (76.2), 105
(100), 77 (18.4). Found, %: C 67.18; H 6.16; N 13.24.
C29H31N5O2S. Calculated, %: C 67.81; H 6.08; N 13.63.
M 513.67.
1,2,4-Triazolo[3,4-b][1,3,4]thiadiazoles VIa–VIf
(general procedure). Compound Va–Vf, 2 mmol, was
added to 10 ml of a solution of excess sodium ethoxide
in ethanol on cooling with an ice bath. The mixture
was kept for 15 min, diluted with 50 ml of water, and
neutralized with dilute acetic acid to pH 7.0–7.5. The
precipitate was filtered off and recrystallized from
benzene–hexane (3:1).
5-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(pyri-
din-3-yl)-5,6-dihydro[1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazol-6-yl(3-nitrophenyl)methanone (VIe).
Yield 0.400 g (36%), colorless crystals, mp 195°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.34 s (18H,
t-Bu), 6.81 s (1H, 6-H), 7.42 m (1H, pyridine), 7.45 s
(2H, 2′-H, 6′-H), 7.79 m (1H, Harom), 8.26–8.41 m (2H,
(4-Bromophenyl){5-(3,5-di-tert-butyl-4-hydroxy-
phenyl)-3-(pyridin-4-yl)-5,6-dihydro[1,2,4]triazolo-
[3,4-b][1,3,4]thiadiazol-6-yl}methanone (VIa). Yield
0.600 g (51%), light yellow crystals, mp 154°C.
1H NMR spectrum (CDCl3), δ, ppm: 1.40 s (18H,
t-Bu), 5.31 s (1H, 6-H), 6.89 s (2H, 2′-H, 6′-H), 7.35 d
and 7.51 d (2H each, Harom, J = 8.53 Hz), 7.90 d and
8.51 d (2H each, pyridine, J = 4.80 Hz). Found, %:
C 58.91; H 5.24; N 12.11. C29H30BrN5O2S. Calculated,
%: C 58.78; H 5.07; N 11.82.
Harom, pyridine), 8.63 m (2H, Harom, pyridine), 9.12 m
(2H, Harom, pyridine). Mass spectrum, m/z (Irel, %): 540
(0.5), 525 (0.8), 493 (1.2), 446 (1.1), 370 (1.8), 325
(2.2), 248 (4.3), 216 (7.5), 178 (27.3), 150 (72.4), 104
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INTRAMOLECULAR CYCLIZATION OF 4-AMINO-3-ALKYLSULFANYL-1,2,4-TRIAZOLES
145
(100), 76 (91.1). Found, %: C 62.88; H 5.84; N 15.67.
C29H30N6O4S. Calculated, %: C 62.35; H 5.41; N 15.04.
REFERENCES
1. Kolodina, A.A., Gaponenko, N.I., and Lesin, A.V., Chem.
Heterocycl. Compd. (Engl. Transl.), 2007, vol. 43, no. 9,
p. 1202.
(4-Bromophenyl){5-(3,5-di-tert-butyl-4-hydroxy-
phenyl)-3-(furan-2-yl)-5,6-dihydro[1,2,4]triazolo-
[3,4-b][1,3,4]thiadiazol-6-yl}methanone (VIf). Yield
2. George, T., Tahilramani, R., and Dabholkar, D.A., Indian
J. Chem., 1969, vol. 7, p. 957.
1
0.546 g (47%), colorless crystals, mp 151°C. H NMR
spectrum (CDCl3), δ, ppm: 1.35 s (18H, t-Bu), 5.29 s
(1H, 6-H), 6.87 s (2H, 2′-H, 6′-H), 7.37 m (4H, Harom),
7.90 d (1H, furan, J = 5.90 Hz), 8.33 m (1H, furan),
8.60 d (1H, furan, J = 5.74 Hz). Mass spectrum, m/z
(Irel, %): 397 (0.7), 216 (8.0), 185 (94.2), 183 (100),
167 (23.1), 157 (25.0), 155 (25.0), 109 (16.1), 76 (23.3).
Found, %: C 58.04; H 5.11; N 9.81. C28H29BrN4O3S.
Calculated, %: C 57.83; H 4.99; N 9.64.
3. Pascal, J.C. and Pinhas, H., FRG Patent no. 2818395,
1978; Chem. Abstr., 1979, vol. 90, no. 152246.
4. Molina, P., Alajarín, M., de Veg, M.J.P., de la Concepción
Foces-Foces, M., Cano, F.H., Claramunt, R.M., and
Elguero, J., J. Chem. Soc., Perkin Trans. 1, 1987, p. 1853.
5. Ibrahim, Y.A., Elwahy, A.H.M., and El-Fiky, A.E.M.,
Heteroatom Chem., 1994, vol. 5, p. 321.
6. Sheldrick, G.M., SHELXTL v 5.10, Structure Determina-
tion Software Suite, Madison WI, USA: Bruker AXS,
1998.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 05-03-32534). The authors thank Z.A. Starikova
for performing X-ray analysis.
7. Reid, J.R. and Heindel, N.D., J. Heterocycl. Chem., 1976,
vol. 13, p. 925.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 1 2009