C-H-Functionalization of 1,2,4-triazines: Oxidation and elimination pathways of aromatization of σh-adducts

Article abstract of DOI:10.1007/s11172-014-0603-x

An approach to the synthesis of 1,2,4-triazine thienyl and furyl derivatives through the reaction of aromatic nucleophilic substitution of hydrogen was suggested. Oxidation and cine-elimination pathways of aromatization of the intermediate σ^H-a

Full text of DOI:10.1007/s11172-014-0603-x

Russian Chemical Bulletin, International Edition, Vol. 63, No. 6, pp. 1359—1363, June, 2014
1359
C—HꢀFunctionalization of 1,2,4ꢀtriazines:
oxidation and elimination pathways of aromatization of  ꢀadducts*
H
M. V. Berezin,a G. L. Rusinov,a,b and V. N. Charushina,b
aI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
2
0 ul. S. Kovalevskoi, 620219 Ekaterinburg, Russian Federation.
Fax: +7 (343) 362 3432. Eꢀmail: berezin@ios.uran.ru
b
Ural Federal University named after the First President of Russia B. N. Yeltsin,
9 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343) 369 3058. Eꢀmail: charushin@ios.uran.ru
1
An approach to the synthesis of 1,2,4ꢀtriazine thienyl and furyl derivatives through the
reaction of aromatic nucleophilic substitution of hydrogen was suggested. Oxidation and
H
cineꢀelimination pathways of aromatization of the intermediate  ꢀadducts were considered.
Key words: 1,2,4ꢀtriazines, aromatic nucleophilic substitution of hydrogen, thiophenes,
furans.
1
1
,2,4ꢀTriazines are one of the most important class of
ble only in strongly acidic solutions ( H NMR spectroꢀ
scopic data). Attempted isolation of these adducts in the
free state failed, but acylation appeared to be one of the
nitrogenꢀcontaining heterocycles widely used in medicine,
agrichemistry and as ligands for a number of metals.
Triazine derivatives are also known to be used as dyes.6
1
—5
23
successful pathways for their stabilization. Another route
Triazine derivatives are of huge value in therapy of
malaria, epilepsy, cancer, and a number of other diseasꢀ
for modification of 1,2,4ꢀtrizine adducts is their oxidaꢀ
tion. In a number of cases the adducts can be oxidized by
atmospheric oxygen, other cases require oxidants such as
DDQ, lead tetraacetate, or potassium hexacyanoferrate.
The purpose of the present work is studies of the reacꢀ
tion of 3ꢀsubstituted 1,2,4ꢀtriazines with furans and
thiophenes. We have chosen readily available 3ꢀmethylꢀ
thioꢀ1,2,4ꢀtriazine (1) and 3ꢀaminoꢀ1,2,4ꢀtriazine (2) as
the starting compounds.
7
—12
es.
Besides, triazines are convenient synthetic blocks for
the preparation of a wide range of heterocyclic compounds,
in particular, pyridine derivatives, by the Diels—Alder reꢀ
action.1
2—14
This shows that 1,2,4ꢀtriazine derivatives are
of very much interest.
Synthesis of 1,2,4ꢀtriazine functional derivatives is
based on two principally different approaches. In the first
case, functional substituents are introduced into the heteroꢀ
cycle in the step of formation of cyclic system by condenꢀ
sation reaction.1 Second approach consists in functionꢀ
alization of heterocyclic system through the transformaꢀ
The reaction of triazines 1 and 2 with a number of
thiophenes in the presence of the oxidation mixture
K (Fe(CN) )—KOH gave good yields of the products of
,15
3
6
substitution of the hydrogen atom at atom C(5) of the
triazine ring (Scheme 1).
1
,15
tion of substituents in the triazine ring,
including apꢀ
plication of crossꢀcoupling reactions.1
6—18
It was found that the product of the addition of
thiophene to the triazine ring is formed in the first step
of the reaction. The composition of the reaction mixꢀ
tures was analyzed by GLCꢀMS (Table 1). In a number
The problem of nucleophilic substitution of hydrogen
in 1,2,4ꢀtriazines was considered in a number of papers
and monographs.1
9—25
For example, a number of Cꢀnuꢀ
H
cleophiles were reported to be successfully introduced in
of cases,  ꢀadducts turned out to be so stable that they
2
2,23
24
H
the 1,2,4ꢀtriazine ring,
in particular, alkylphenols
were isolated in the free form. Stability of  ꢀadducts
and crownꢀethers.25 Thus, the dissolution of 1,2,4ꢀtriazines
in trifluoroacetic or acetic acid results to the formation of
protic NHꢀtriazinium salts, which at room temperature
easily react with 2,6ꢀdimethylphenol and resorcinol. This
reaction leads to a reverse formation of C(6)ꢀadducts staꢀ
depends on the character of substituent in the thioꢀ
phene ring. The larger is the donor effect of such a substitꢀ
uent (for example, phenyl), the more stable is the addiꢀ
tion product and, therefore, the higher is the yield of
the adduct. Conversely, in the case of thienylꢀ2ꢀcarbꢀ
aldehyde we isolated neither the corresponding adduct
nor the product of nucleophilic aromatic substitution
of hydrogen.
2
3
*
Dedicated to Academician of the Russian Academy of Sciences
O. N. Chupakhin on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1359—1363, June, 2014.
066ꢀ5285/14/6306ꢀ1359 © 2014 Springer Science+Business Media, Inc.
1

1
360
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
Berezin et al.
Scheme 1
R = SMe (1a, 3, 5), NH (1b, 4, 6); R´ = H (a), Br (b), Ph (c),
(d)
2
Scheme 2
The second step consists in the aromatization of the
adducts. In this case, the oxidant can be applied to both
the reaction mixture (without isolation of the intermediꢀ
ate compound) and to the individual dihydrotriazine (if it
is stable). The structures of synthesized compounds were
confirmed by a combination of spectroscopic methods, as
well as by Xꢀray diffraction studies using product 5d as an
example (Fig. 1).
Compounds 3a and 7 have different resistance to oxiꢀ
dants. Compound 7 appears to be comparatively stable to
such oxidants as atmospheric oxygen, 2,3ꢀdichloroꢀ5,6ꢀ
dicyanoꢀ1,4ꢀbenzoquinone (DDQ), and K [Fe(CN) ].
3
6
N(3)
H(5A)
N(2)
H(1B)
H(8A)
C(8)
C(5)
C(7)
H(1C)
C(1)
The reaction of triazine 1 with a 10ꢀfold excess of
thiophene (Scheme 2, pathway II) gives adduct 7, howevꢀ
er, the GLCꢀMS data show that the same reaction with
C(2)
C(6)
H(1A)
H(9A)
N(1)
1
.5—2ꢀfold excess of thiophene leads to the formation of
S(1)
C(9)
only monoadduct 3a (Scheme 2, pathway I).
S(2)
H(12A)
H(4AA)
C(11)
C(10)
H(3AA) C(4A)
S(3D)
H(12D)
C(12A)
S(3B)
C(3)
Table 1. Composition of the reaction mixtures in
the reaction of 3ꢀmethylthioꢀ1,2,4ꢀtriazine with
thiophene and furan
C(12)
C(3A)
S(3A)
H(12C)
S(3C)
C(11A)
C12)
C(4)
H(4A)
H(3A)
H(12B)
Ratio
triazine/nucleophile
Composition of mixture
(%)
C(12C)
C(10A)
S(2A)
S(1A)
H(1AA)
C(1A)
N(1A)
C(9A) C(7A)
1
1
1
1
1
1
а : 2а, 1 : 10
а : 2а*, 1 : 10
а : 2а, 1 : 2
а : 9*, 1 : 2
а : 9*, 1 : 10
2 : 2a*, 1 : 2
3a (3), 7 (80)
8 (8), 7 (65)
3a (73), 5a (17)
10 (40), 11 (58)
11 (100)
H(9AA)
C(8A)
H(8AA)
C(6A)
C(5A)
C(2A)
H(1AB) H(1AB)
N(2A)
6a (84), 13 (13)
H(5AA)
N(3A)
*
K (Fe(CN) )/KOH.
Fig. 1. Geometry of compound 5d in crystal.
3
6

C—HꢀFunctionalization of 1,2,4 ꢀtriazines
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
1361
Scheme 3
For example, analysis of the reaction mixture of 7 and
Scheme 4
K (Fe(CN) —KOH showed the presence of only 8% of
3
6
partially oxidized product 8. At the same time, comꢀ
pound 3a quite readily undergoes aromatization to 5ꢀthieꢀ
nylꢀsubstituted triazine 5a.
Similarly, the reaction of 3ꢀmethylthiotriazine 1a with
a 10ꢀfold excess of furan (9) in the presence of an oxidant
leads to the formation of only disubstitution product 11,
but the intermediate monoadduct were not even detected
in the reaction mixture. In turn, in the reaction with a twoꢀ
fold excess of furan under oxidation conditions, a mixture
of compounds 10 and 11 is formed, in which case comꢀ
pound 10 was isolated and characterized (Scheme 3).
Attempted introduction of halogen atom at position
C(6) of the 1,2,4ꢀtriazine ring in order to increase synꢀ
thetic potential of obtained thiophene and furan derivaꢀ
tives of 3ꢀmethylthiotriazine failed. However, brominaꢀ
tion of 3ꢀaminoꢀ1,2,4ꢀtriazine proceeds rather smoothly,
giving rise to 3ꢀaminoꢀ6ꢀbromotriazine in good yield.
tives with thiophene and furan derivatives. New monoꢀ and
dithienyl or furyl derivatives of 3ꢀsubstituted 1,2,4ꢀtriazines
were obtained.
3
ꢀAminoꢀ6ꢀbromoꢀ1,2,4ꢀtriazine (12) was found to
react with thiophenes under acidꢀcatalyzed conditions with
subsequent oxidation by K [Fe(CN) ]—KOH to the cineꢀ
3
6
substitution products 6 (Scheme 4). GLCꢀMS analysis of
the reaction mixture in the case of the reaction of comꢀ
pound 12 with thiophene in the step of addition of the
latter to 3ꢀaminoꢀ6ꢀbromoꢀ1,2,4ꢀtriazine (12) showed the
absence of the molecular peak corresponding to the exꢀ
Experimental
Solvents and reactants were dried and purified according to
2
6
the procedures taken from the literature.
1H NMR spectra were recorded on a Bruker DRXꢀ400 specꢀ
H
pected  ꢀadduct. Analysis of the same reaction mixture
trometer (400 MHz), using SiMe as an internal standard. Eleꢀ
4
after completion of the reaction showed that formation of
compound 6a (84%) is the main reaction result, whereas
the product of oxidative substitution of hydrogen 13 was
formed only in 13% yield. These data allowed us to suggest
that in the case of 6ꢀbromoꢀ1,2,4ꢀtriazine, aromatization
follows mainly elimination cineꢀmechanism with the loss
of the halogen atom. In fact, the reaction can be carried
out without oxidant, but with addition of a base (morphoꢀ
line) to the reaction mixture, which results in the formaꢀ
tion of the only product 6a.
mental analysis was performed on a Perkin Elmer PEꢀ2400 autoꢀ
mated analyzer. Melting points were determined on combined
Boetius heating stages and were not corrected. Flashꢀchromaꢀ
tography was performed using Lancaster 0.040—0.063 mm silica
gel (230—400 mesh).
Reaction progress and purity of products were monitored by
TLC on Sorbfil plates, visualizing under UV light or in I vapors.
2
Xꢀray diffraction study was carried out on a Xcaliburꢀ3 Xꢀray
diffractometer with a CCDꢀdetector according to the standard
procedure: (MoꢀK), graphite monochromator, ꢀscan techꢀ
nique. The structures of all the compounds were solved by direct
method using the SHELXSꢀ97 program and refined using the
SHELXLꢀ97 program in anisotropic (isotropic for hydrogen
In conclusion, in the work we showed a possibility of
a direct C—Hꢀfunctionalization of 1,2,4ꢀtriazine derivaꢀ

1
362
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
Berezin et al.
atoms) approximation. No correction for absorption was made.
The results of Xꢀray diffraction study of compound 5d were
deposited with the Cambridge Structural Database (CCDC
Na SO , and concentrated. An oily residue was separated on
2
4
silica gel (eluent CHCl —EtOH (8 : 2)). The products were adꢀ
3
ditionally purified by recrystallization from proper solvents.
Compounds 3, 5, and 6 were obtained by both methods A and B.
3ꢀMethylsulfanylꢀ5ꢀ(thiophenꢀ2ꢀyl)ꢀ4,5ꢀdihydroꢀ1,2,4ꢀtriꢀ
azine (3a). The product was obtained by methods A and В.
A colorless powder. The yield was 58% (A), m.p. 143—144 C.
Found (%): C, 45.60; H, 4.45; N, 20.04. Calculated (%): C,
9
93541). These materials are available free of charge and
can be requested at: wwwwww.ccdc.cam.ac.uk/data_request/
cif.ccdc.cam.ac.uk/data_request/cif.
3
ꢀMethylsulfanylꢀ1,2,4ꢀtriazine (1a). Triazine 1a was obꢀ
2
7
tained according to the known procedure as a yellow powder.
The yield was 92%, m.p. 31—33 C. Found (%): C, 38.07;
H, 3.80; N, 33.00. C H N S. Calculated (%): C, 37.80; H, 3.94;
1
45.47; H, 4.29; N, 19.89. C H N S . H NMR (DMSOꢀd ),
8
9
3
2
6
: 10.83 (br.s, 1 H, NH); 7.40—7.43 (m, 1 H, C(6)H); 7.24—7.26
(m, 1 H, thiophene); 6.86—7.04 (m, 2 H, thiophene); 5.03. (s, 1 H,
4
5
3
1
N, 33.07. H NMR (DMSOꢀd ), : 8.65 (d, 1 H, triazine,
6
J = 2.3 Hz); 8.32 (d, 1 H, triazine, J =2.3 Hz); 2.27 (s, 3 H, S—CH3).
C(5)H); 2.36 (s, 3 H, S—CH ).
3
3
ꢀAminoꢀ1,2,4ꢀtriazine (1b). Triazine 1b was obtained acꢀ
3ꢀMethylsulfanylꢀ(5ꢀthiophenꢀ2ꢀyl)ꢀ1,2,4ꢀtriazine (5a). The
product was obtained by methods A and В and isolated by recrysꢀ
tallization from ethanol as a light yellow powder. The yield was
65% (A), m.p. 98—100 C. Found (%): C, 45.74; H, 3.12; N, 20.03.
2
8
cording to the known procedure as a yellow powder. The yield
was 90%, m.p. 174—176 C. Found (%): C, 37.80; H, 4.00;
N, 58.50. C H N . Calculated (%): C, 37.50; H, 4.20; N, 58.31.
3
4
4
1
1
H NMR (DMSOꢀd ), : 8.55 (d, 1 H, triazine, J = 2.28 Hz);
C H N S . Calculated (%): C, 45.91; H, 3.37; N, 20.08. H NMR
6
8
7
3 2
8
.21 (d, 1 H, triazine, J = 2.28 Hz); 7.19 (br.s, 2 H, NH ).
(DMSOꢀd ), : 9.71 (s, 1 H, C(6)H); 8.33 (dd, 1 H, thiophene,
2
6
3
ꢀAminoꢀ6ꢀbromoꢀ1,2,4ꢀtriazine (12). Triazine 12 was obꢀ
J = 1.04 Hz, J = 3.84 Hz); 8.06 (dd, 1 H, thiophene, J = 1.04 Hz,
1
2
1
2
9
tained according to the known procedure as a yellow powder.
The yield was 58%, m.p. >300 C. Found (%): C, 19.93; H, 1.70;
N, 31.83. C H N Br. Calculated (%): C, 20.59; H, 1.73; N, 32.02.
H NMR (DMSOꢀd ), : 8.40 (s, 1 H, triazine); 7.47 (br.s, 2 H, NH ).
Synthesis of  ꢀadducts of 5ꢀhetarylꢀ3ꢀRꢀ1,2,4ꢀtriazines
general procedure). The starting triazine (1 mmol) was dissolved in
a mixture of trifluoroacetic acid and chloroform (dichloromethꢀ
ane) (2 mL, 1 : 1), then thiophene or furan (1.1 mmol) was added.
The mixture obtained was refluxed for 1.5 h (method A) or
stirred for 24 h at room temperature (method В).
J = 4.92 Hz); 7.35 (dd, 1 H, thiophene, J = 3.84 Hz, J = 4.92 Hz);
2
1
2
2.69 (s, 3 H, S—CH ).
3
3ꢀAminoꢀ5ꢀ(thiophenꢀ2ꢀyl)ꢀ1,2,4ꢀtriazine (6a). The product
was obtained by methods A and В and isolated by recrystallizaꢀ
tion from ethanol as a light yellow powder. The yield was 70%
(A), m.p. 120—121 C. Found (%): C, 47.34; H, 3.12; N, 31.15.
3
3
4
1
6
H
2
(
1
C H N S. Calculated (%): C, 47.18; H, 3.39; N, 31.44. H NMR
7
6
4
(DMSOꢀd ), : 9.61 (s, 1 H, C(6)H); 8.53 (dd, 1 H, thiophene,
6
J = 1.00 Hz, J = 3.80 Hz); 8.16 (dd, 1 H, thiophene, J = 1.00 Hz,
1
2
1
J = 4.85 Hz); 7.45 (br.s, 2 H, NH ), 7.27 (dd, 1 H, thiophene,
2
2
Then, the reaction mixture was concentrated, an oily reꢀ
sidue was neutralized with saturated aqueous sodium bicarbonꢀ
ate. A precipitate formed was filtered off. The products were
additionally purified by recrystallization from proper solvents.
Synthesis of 5ꢀhetarylꢀ3ꢀRꢀ1,2,4ꢀtriazines (general proceꢀ
dure). The starting triazine (1 mmol) was dissolved in a mixture
of trifluoroacetic acid and chloroform (dichloromethane) (2 mL,
J = 3.80 Hz, J = 4.85 Hz).
1
2
5ꢀ(5ꢀBromothiophenꢀ2ꢀyl)ꢀ3ꢀmethylsulfanylꢀ1,2,4ꢀtriazine
(5b). The product was obtained by methods A and В and isolated
by recrystallization from ethanol as yellow crystals. The yield
was 78% (A), m.p. 144—146 C. Found (%): C, 33.45; H, 2.30;
N, 14.25. C H N S Br. Calculated (%): C, 33.34; H, 2.10;
8
6
3 2
1
N, 14.58. H NMR (CDCl ), : 9.12 (s, 1 H, C(6)H); 7.64 (d, 1 H,
3
1
: 1), then thiophene or furan (1.1 mmol) was added.
thiophene, J = 4.0 Hz); 7.19 (d, 1 H, thiophene, J = 4.0 Hz);
The mixture obtained was refluxed for 1.5 h (method A) or
2.67 (s, 3 H, S—CH ).
3
stirred for 24 h at room temperature (method В).
3ꢀAminoꢀ5ꢀ(5ꢀbromothiophenꢀ2ꢀyl)ꢀ1,2,4ꢀtriazine (6b). The
product was obtained by methods A and В and isolated by recrysꢀ
tallization from acetonitrile as a colorless powder. The yield was
88% (A), m.p. >300 C. Found (%): C, 32.58; H, 2.10; N, 24.49.
Then, the reaction mixture was neutralized with saturated
aqueous sodium bicarbonate. A mixture of KOH (3 mmol) and
K (Fe(CN) (3 mmol) in water (5 mL) was added to the twoꢀphase
3
6
1
system, which was stirred for 5 h. The organic phase was separatꢀ
ed, the aqueous phase was additionally washed with chloroform
C H N SBr. Calculated (%): C, 32.70; H, 1.96; N, 21.79. H NMR
7
5
4
(DMSOꢀd ), : 9.16 (s, 1 H, triazine); 8.01 (d, 1 H, thiophene J =
6
(
3×5 mL). The combined organic phase was washed with water,
= 4.0 Hz); 7.43 (d, 1 H, thiophene J = 4.0 Hz); 7.28 (br.s, 2 H, NH2).
3ꢀMethylsulfanylꢀ5ꢀ(5ꢀphenylthiophenꢀ2ꢀyl)ꢀ1,2,4ꢀtriazine
(5c). The product was obtained by methods A and В and isolated
by recrystallization from ethanol as a yellow powder. The yield
was 69% (A), m.p. 138—139 C. Found (%): C, 88.30; H, 4.02;
N, 14.57. C H N S . Calculated (%): C, 58.92; H, 3.89; N, 14.72.
dried with Na SO , and concentrated. An oily residue was separatꢀ
ed on silica gel (eluent CHCl —EtOH (8 : 2)). The products
were additionally purified by recrystallization from proper solvents.
Synthesis of 5,6ꢀdihetarylꢀ3ꢀRꢀ1,2,4ꢀtriazines and their tetraꢀ
hydro adducts (general procedure). The starting triazine (1 mmol)
was dissolved in a mixture of trifluoroacetic acid and chloroform
2
4
3
14
11
3 2
1
H NMR (CDCl ), : 9.18 (s, 1 H, C(6)H); 7.87—7.88 (m, 1 H,
3
(
dichloromethane) (2 mL, 1 : 1), followed by addition of thiophene
phenyl); 7.68—7.70 (m, 2 H, thiophene); 7.32—7.48 (m, 4 H,
or furan (10 mmol). The reaction mixture was stirred for 24 h at
room temperature and concentrated, an oily residue was neutralꢀ
ized with saturated aqueous sodium bicarbonate. A precipitate
formed was filtered off. The products were additionally purified by
recrystallization from proper solvents. A compound obtained
was dissolved in chloroform, followed by addition of KOH (6 mmol)
and K (Fe(CN) (6 mmol) in water (10 mL). The reaction mixture
phenyl); 2.70 (s, 3 H, S—CH ).
3
3ꢀAminoꢀ5ꢀ(5ꢀphenylthiophenꢀ2ꢀyl)ꢀ1,2,4ꢀtriazine (6c). The
product was obtained by method A and isolated by recrystallization
from ethanol as a yellow powder. The yield was 65%, m.p.
163—164 C. Found (%): C, 61.55; H, 4.34; N, 22.04. C H N S.
Calculated (%): C, 61.40; H, 3.96; N, 22.03. H NMR (CDCl ), :
9.58 (s, 1 H, C(6)H); 7.67—7.68 (m, 1 H, phenyl); 7.58—7.60 (m, 2 H,
13
10
4
1
3
3
6
was stirred for 5 h. Then, the organic phase was separated, the
aqueous phase was additionally washed with chloroform (3×5 mL).
The combined organic phase was washed with water, dried with
thiophene); 7.32 (br.s, 2 H, NH ), 7.22—7.38 (m, 4 H, phenyl).
5ꢀ(2,2´ꢀBithiophenꢀ5ꢀyl)ꢀ3ꢀmethylsulfanylꢀ1,2,4ꢀtriazine
(5d). The product was obtained by method A and isolated by
2

C—HꢀFunctionalization of 1,2,4 ꢀtriazines
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
1363
recrystallization from ethanol as a brown powder. The yield was
3. X.ꢀL. Wang, H. Chao, H. Li, X.ꢀL. Hong, Y.ꢀJ. Liu, L.ꢀF.
Tan, L.ꢀN. Ji, Inorg. Biochem., 2004, 98, 1143.
4. M. J. Hudson, M. G. B. Drew, M. R. Foreman, C. Hill,
N. Huet, C. Madie, T. G. A. Youngest, Dalton Trans., 2003,
1675—1685.
7
C
8%, m.p. 122—124 C. Found (%): C, 49.60; H, 3.09; N, 14.52.
H N S . Calculated (%): C, 49.46; H, 3.11; N, 14.42.
1
2
9
3 3
1
H NMR (CDCl ), : 9.15 (s, 1 H, C(6)H); 7.80—7.81 (m, 1 H,
3
thiophene); 7.34—7.35 (m, 2 H, thiophene); 7.26—7.27 (m, 2 H,
thiophene); 2.67 (s, 3 H, S—CH ).
5. P. L. Croot, K. A. Hunter, Anal. Chime Acta, 2000, 406, 289.
6. H. Neunhoeffer, in Comprehensive Heterocyclic Chemistry II;
Eds A. R. Katritzky, C. W. Rees, E. F. V. Scriven, Pergamon
Press, Oxford, 1996, V. 6, pp. 507—573.
7. L. L. Wotring, L. B. Townsend, Cancer Res., 1989, 49, 289.
8. S. RaiꢀMali, M. Grdia, K. Pavelic, M. Mintas, Eur. J. Med.
Chem., 1999, 34, 405.
3
3
ꢀAminoꢀ5ꢀ(2,2´ꢀbithiophenꢀ5ꢀyl)ꢀ1,2,4ꢀtriazine (6d). The
product was obtained by method A and isolated by recrystallizaꢀ
tion from acetonitrile as a brown powder. The yield was 67%,
m.p. 225—226 C. Found (%): C, 50.60; H, 3.09; N, 21.47.
1
C H N S . Calculated (%): C, 50.75; H, 3.10; N, 21.52. H NMR
11
8
4 2
(
CDCl ), : 9.55 (s, 1 H, C(6)H); 7.68—7.71 (m, 1 H, thiophene);
3
7
7
.38—7.39 (m, 2 H, thiophene); 7.36—7.29 (m, 2 H, thiophene);
9. J. D. Morrey, D. F. Smee, R. W. Sidwell, C. Tseng, Antiviral
Res., 2002, 55, 107.
.25 (br.s, 2 H, NH ).
2
3
ꢀMethylsulfanylꢀ5,6ꢀbis(thiophenꢀ2ꢀyl)ꢀ1,4,5,6ꢀtetrahydroꢀ
10. A. P. Sharma, A. P. Ollapally, W. Jones, T. Lemon, Nucleoꢀ
sides, Nucleotides Nucleic Acids, 1992, 11, 1009.
1
,2,4ꢀtriazine (7). The product was obtained by method B and
isolated by recrystallization from ethanol as a colorless powder.
The yield was 80%, m.p. >250 °C. Found (%): C, 48.71; H, 4.41;
N, 13.98. C H N S . Calculated (%): C, 48.78; H, 4.44; N, 14.22.
11. V. L. Rusinov, I. N. Egorov, O. N. Chupakhin, E. F. Belꢀ
anov, N. I. Bormotov, O. A. Serova, Pharm. Chem. J.
(Engl. Transl.), 2012, 45, 655 [Khim. Farm. Zh., 2011, 45, 7].
12. S. A. Raw, R. J. Taylor, in Advances in Heterocyclic Chemisꢀ
try; Ed. A. R. Katritzky, Academic Press, Oxford, 2010,
V. 100, p. 75.
12
13
3 3
1
H NMR (DMSOꢀd ), : 7.40—7.41 (m, 2 H, thiophene); 7.16
6
(
(
br.s, 1 H, NH); 6.87—6.89 (m, 2 H, thiophene); 6.77—6.78
m, 2 H, thiophene), 6.31 (br.s, 1 H, NH); 4.67—4.69 (m, 1 H,
C(5)H); 4.12—4.13 (m, 1 H, C(6)H); 2.27 (s, 3 H, S—CH ).
13. D. L. Boger, S. N. Weinreb, in Hetero Diels—Alder Methodology
in Organic Synthesis, Academic Press, London, 1987, V. 47.
14. V. N. Charushin, B. van Velhuizen, H. C. van der Plas, C. H.
Stam, Tetrahedron, 1989, V. 45, p. 6499—6510.
15. C. W. Lindsley, M. E. Layton, 1,2,4ꢀTriazines, in Methods of
Molecular Transformations, Part 2, Hetarenes and Related Ring
Systems. Sixꢀmembered Hetarenes with two unlike or more
than two Heteroatoms and Fully Unsaturated LargerꢀRing
Heterocycles, Georg Thieme—Verlag, Stuttgart, 2004, p. 357.
16. S. Laphookhieo, S. Jones, S. Raw, Y.ꢀF. Sainz, R. Taylor,
Tetrahedron Lett., 2006, 47, 3865.
17. D. Branowska, O. Siuchta, Z. Karczmarzyk, W. Wysocki,
E. Wolin´ska, M. Mojzych, R. Kawecki, Tetrahedron Lett.,
2011, 52, 7054.
18. F.ꢀA. Alphonse, F. Suzenet, A. Keromnes, B. Lebret, G. Guilꢀ
laumet, Synthesis, 2004, 2893.
3
3
ꢀMethylsulfanylꢀ5ꢀ(furanꢀ2ꢀyl)ꢀ1,2,4ꢀtriazine (10). The
product was obtained by method B and isolated by recrystallizaꢀ
tion from acetonitrile as a yellow powder. The yield was 30%,
m.p. 154—155 C. Found (%): C, 49.34; H, 3.60; N, 21.58.
1
C H N OS. Calculated (%): C, 49.73; H, 3.65; N, 21.75. H NMR
8
7
3
(
DMSOꢀd ), : 9.85 (s, 1 H, triazine); 8.42—8.44 (m, 1 H,
6
furan); 8.15—8.16 (m, 1 H, furan); 7.37—7.39 (m, 1 H, furan);
.63 (s, 3 H, S—CH ).
2
3
3
ꢀMethylsulfanylꢀ5,6ꢀbis(furanꢀ2ꢀyl)ꢀ1,2,4ꢀtriazine (11).
The product was obtained by method B and isolated by recrystalꢀ
lization from ethanol as a yellow powder. The yield was 53%,
m.p. 170—171 C. Found (%): C, 55.34; H, 3.25; N, 16.18.
C H N O S. Calculated (%): C, 55.59; H, 3.50; N, 16.21.
1
2
9
3
2
1
H NMR (DMSOꢀd ), : 8.06 (dd, 1 H, furan, J = 0.68 Hz,
6
1
J = 1.68 Hz); 7.96 (dd, 1 H, furan, J = 0.76 Hz, J = 1.76 Hz);
2
1
2
7
.05 (dd, 1 H, furan, J = 0.76 Hz, J = 3.4 Hz); 6.89 (dd, 1 H,
19. O. N. Chupakhin, V. N. Charushin, H. C. van der Plas,
Nucleophilic Aromatic substitution of Hydrogen., Acad. Press,
New York—San Diego, 1994, 367 p.
1
2
furan, J = 0.68 Hz, J = 3.64 Hz); 6.75—6.78 (m, 2 H, furan);
2
1
2
.69 (s, 3 H, S—CH ).
3
2
0. V. N. Charushin, S. G. Alexeev, O. N. Chupakhin, H.C. van
der Plas, Adv. Heterocycl. Chem., Academic Press, New
York—San Diego, 1989, V. 46, pp. 74—142.
1. O. N. Chupakhin, S. G. Alexeev, B. Rudakov, V. N. Charꢀ
ushin, Heterocycles., 1992, 33, 931.
This work was financially supported by the Russian
Academy of Sciences (Programs UrO RAN 12ꢀPꢀ3ꢀ1014,
2ꢀTꢀ3ꢀ1025, 12ꢀTꢀ3ꢀ1031, and 13ꢀ3ꢀ019ꢀUMA), the
Council on Grants at the President of the Russian Federation
Program of State Support for Leading Scientific Schools
of the Russian Federation, Grant NShꢀ5505.2012.3), the
Russian Foundation for Basic Research (Project Nos 13ꢀ
3ꢀ96049ꢀr_ural_a, 13ꢀ03ꢀ90606ꢀArm_a, and 14ꢀ03ꢀ
1040ꢀmol_a), as well as the Ministry of Education and
Science of the Russian Federation (Agreement No. 8430)
and the Sverdlovsk Region Government.
1
2
(
22. V. L. Rusinov, G. V. Zyryanov, T. L. Pilicheva, O. N. Chupaꢀ
khin, H. Neunhoeffer, J. Heterocyclic Chem., 1997, 34, 1013.
3. O. N. Chupakhin, V. L. Rusinov, D. G. Beresnev, H. Neunꢀ
hoeffer, J. Heterocyclic Chem., 1997, 34, 573.
4. V. L. Rusinov, D. G. Beresnev, N. A. Itsikson, O. N. Chupaꢀ
khin, Heterocycles, 2001, 12, 2349.
5. N. A. Itsikson, D. G. Beresnev, G. L. Rusinov, O. N. Chuꢀ
pakhin, ARKIVOC, 2004, 12, 6.
6. L. F. Tietze, T. Eicher, Reaktionen und Sythrsen im orgaꢀ
nischꢀchemischen Praktikum und Forschungslaboratorium,
Georg Thieme Verlag Stuttgart, New York, 1991.
2
2
2
2
0
3
References
1
2
. V. N. Charushin, V. L. Rusinov, O. N. Chupakhin, 1,2,4ꢀ
Triazines and their Benzo Derivatives, in Comprehensive
Heterocyclic Chemistry, 3rd ed., Eds A. R. Katritzky, R. Tayꢀ
lor, Elsevier, 2008, V. 9, Ch. 2, p. 95—196.
. A. N. Vzorov, D. Bhattacharyya, L. G. Marzili, R. W. Comꢀ
pans, Antiviral Res., 2005, 65, 57.
2
2
2
7. W. W. Paulder, TehꢀKuei Chen, J. Heterocycl. Chem., 1970, 7, 767.
8. WO2009143211 Pct Int. Appl.; Chem. Abstrs, 2009, 152, 12394.
9. WO 2011018454 Pct. Int. Appl; Chem. Abstrs, 2011, 154, 199497.
Received March 31, 2014;
in revised form April 30, 2014