Halocyclization of 3-allylthio-5H-[1,2,4]triazino[5,6-b]indole

Article abstract of DOI:10.1007/s10593-010-0599-6

The synthesis of 3-allylthio-5H-[1,2,4]triazino[5,6-b]indole has been carried out by the reaction of 3-mercapto-5H-[1,2,4]triazino[5,6-b]indole with allyl bromide in the NaOH-H₂O-DMSO system and in a one-pot synthesis from isatin-β-thiosemicarbazide. Halocyclization of allylthio-5H-[1,2,4]- triazino[5,6-b]indole synthesized the 3-halomethyl-3,10-dihydro-2H-[1,3] thiazolo[3',2':2,3][1,2,4]-triazino[5,6-b]indolium halides.

Full text of DOI:10.1007/s10593-010-0599-6

Chemistry of Heterocyclic Compounds, Vol. 46, No. 7, 2010
HALOCYCLIZATION OF 3-ALLYLTHIO-
5H-[1,2,4]TRIAZINO[5,6-b]INDOLE
D. G. Kim1* and A. V. Zhuravlyova1
The synthesis of 3-allylthio-5H-[1,2,4]triazino[5,6-b]indole has been carried out by the reaction of
3-mercapto-5H-[1,2,4]triazino[5,6-b]indole with allyl bromide in the NaOH–H2O–DMSO system and in
a one-pot synthesis from isatin-β-thiosemicarbazide. Halocyclization of allylthio-5H-[1,2,4]-
triazino[5,6-b]indole synthesized the 3-halomethyl-3,10-dihydro-2H-[1,3]thiazolo[3',2':2,3][1,2,4]-
triazino[5,6-b]indolium halides.
Keywords:
3-allylthio-5H-[1,2,4]triazino[5,6-b]indole,
3-halomethyl-3,10-dihydro-2H-[1,3]thiazolo-
[3',2':2,3][1,2,4]triazino[5,6-b]indolium halides, phase-transfer catalysis, one-pot synthesis.
Derivatives of [1,2,4]triazino[5,6-b]indoles possess high biological activity and a wide spectrum of
antifungal [1, 2] and antihypoxic activity [3], they are used in prophylaxis and treatment of an extensive index of
viruses and have for a long time attracted attention in connection with the search for new antimicrobial and
anticancer agents [4].
In the literature [3, 5] there is information on the synthesis of 3-allylthio-5H-[1,2,4]triazino[5,6-b]indole
(1, yield 45%) by the alkylation of 3-mercapto-5H-[1,2,4]triazino[5,6-b]indole (2) with an allyl halide in
aqueous NaOH solution. However only the UV spectral data were cited in these papers.
In the present work we have synthesized compound 1 in high yield (87%) by the reaction of compound
2 with allyl bromide in a mixture of NaOH–H2O–DMSO. Compound 1 was also obtained by a one-pot synthesis
from isatin-β-thiosemicarbazone (3) in water without isolating compound 2. The essence of this method is that
compound 3 is boiled in aqueous alkali (cyclization with formation of compound 2) and then allyl bromide and
triethylbenzylammonium chloride (TEBAC) as phase-transfer catalyst are added to the reaction mixture.
We have found that 3-bromomethyl-3,10-dihydro-2H-[1,3]thiazolo[3',2':2,3][1,2,4]triazino[5,6-b]-
indolium bromide (4a) was formed on reaction of compound 1 with bromine in DMF.
3-Iodomethyl-3,10-dihydro-2H-[1,3]thiazolo[3',2':2,3][1,2,4]triazino[5,6-b]indolium triiodide was formed
by the interaction of compound 1 with iodine in chloroform, and was converted to the monoiodide 4b by
treatment with NaI in acetone. Halocyclization of 3-allylthio-5-phenyl-1,2,4-triazine also occurs with formation
of the dihydrothiazolo[3,2-b][1,2,4]triazinium system [6].
_______
* To whom correspondence should be addressed, e-mail: kim_dg48@mail.ru.
1South Urals State University, Chelyabinsk 454080, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, 1107-1109, July, 2010. Original
article submitted December 19, 2009.
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0009-3122/10/4607-0896©2010 Springer Science+Business Media, Inc.

H
N
N
N
N
N
N
S
SNa
SH
NaOH
HCl
CH2
N
N
NH2
O
N
N
N
H
H
H
2
3
CH2
Br
Hal
CH2
–
+
N
N
N
Hal
Br
S
N
Hal2
S
N
Me
N
N
H
N
H
N
N
4a,b
1
S
N
Na2CO3
Hal = I
N
5
I
CH2
N
N
N
N
N
S
S
N
N
N
5b
5a
4 a Hal = Br, b Hal = I
In the 1H NMR spectra of compounds 4a,b, in contrast to that of compound 1, the signals of the protons of
the SCH2 group are nonequivalent and form two sets of multiplets in the regions 3.60-3.90 and 4.10-4.40 ppm.
3-Methyl[1,3]thiazolo[3',2':2,3][1,2,4]triazino[5,6-b]indole (5) was formed on addition of aqueous
Na2CO3 solution to the iodide 4b. Evidently the reaction proceeds with the intermediate formation of
compounds 5a and 5b. We had previously prepared compound 5 from 3-propargylthio-5H-[1,2,4]triazino-
1
[5,6-b]indole [7]. The H NMR spectra and melting points of compound 5 prepared by the different methods
were identical. Mixed melting points showed no depression.
EXPERIMENTAL
1H NMR spectra of DMSO-d6 solutions with TMS as internal standard were recorded on a Bruker DRX-
400 (400 MHz) instrument. Mass spectra were measured on a Hewlett Packard GC/MS-IBM instrument with a
HP-5890 gas chromatograph series II, an HP-5972 mass-selective detector, EI ionization, and an ionization
energy of 70eV.
3-Allylthio-5H-[1,2,4]triazino[5,6-b]indole (1). A. NaOH (0.160 g, 4 mmol) in water (3 ml) and allyl
bromide (0.490 g, 4 mmol) were added to a solution of compound 2 (0.810 g, 4 mmol) in DMSO (10 ml) and the
mixture was stirred for 2 h. The yellow precipitate was filtered off and dried. Yield 0.844 g (87%); mp 250°C
(DMF) (mp 280°C [5]). 1H NMR spectrum, δ, ppm (J, Hz): 3.97 (2H, d, J = 6.81, SCH2); 5.17 (1H, dd, J = 10.0,
J = 1.7, =CH2); 5.41 (1H, dd, J = 1.7, J = 17.0, =CH2); 6.05 (1H, m, CH=); 7.43, 7.58, 7.67, 8.31 (4H, m, H Ar).
Mass spectrum, m/z (Irel, %): 242 [M]+ (17), 227 [M-5]+ (100), 209 [M-33]+ (33), 146 [M – 93]+ (83).
B. Isatin-β-thiosemicarbazide (1.700 g, 7.7 mmol) in 0.1 N NaOH (40 ml) was boiled for 3 h, allyl
bromide (0.64 ml, 7.7 mmol) and TEBAC (10 mg) were then added and the mixture was stirred at room
temperature. The yellow precipitate was filtered off, washed with water, and dried. Yield 0.467 g (25%).
897

3-Bromomethyl-3,10-dihydro-2H-[1,3]thiazolo[3',2':2,3][1,2,4]triazino[5,6-b]indolium Bromide (4a).
A solution of bromine (0.052 ml, 1 mmol) in DMF (5 ml) was added to a solution of compound 1 (0.121 g,
0.5 mmol) in DMF (5 ml). After 48 h the yellow precipitate was filtered off. Yield 0.094 g (47%); mp 298°C
(dec.). 1H NMR spectrum, δ, ppm: 3.86 (1H, m, SCH2); 4.20 (2H, m, CH2Br); 4.29 (1H, m, SCH2); 5.78 (1H, m,
H-3); 7.62, 7.77, 7.92, 8.32 (4H, m, H Ar). Found, %: C 35.61; H 2.51; Br 39.91; N 13.93. C12H10Br2N4S.
Calculated, %: C 35.84; H 2.51; Br 39.74; N 13.93.
3-Iodomethyl-3,10-dihydro-2H-[1,3]thiazolo[3',2':2,3][1,2,4]triazino[5,6-b]indolium Iodide (4b). A
solution of iodine (0.127g, 0.5 mmol) in chloroform (5 ml) was added to a solution of compound 1 (0.121 g,
0.5 mmol) in chloroform (5 ml). After 48 h the chloroform was evaporated, the residue was dissolved in acetone,
and NaI (50 mg) was added. After 24 h the precipitate was filtered off and dried. Yield 0.82 g (33%); mp 168°C
1
(dec.). H NMR spectrum, δ, ppm: 3.72 (1H, m, SCH2); 3.91 (2H, m, CH2); 4.17 (1H, m, SCH2); 5,46 (1H, m,
H-3); 7.59, 7.75, 7.89, 8.31 (4H, m, H Ar). Found, %: C 29.05; H 2.01; I 51.48; N 11.10. C12H10I2N4S.
Calculated, %: C 29.05; H 2.03; I 51.16; N 11.29.
3-Methyl[1,3]thiazolo[3',2':2,3][1,2,4]triazino[5,6-b]indole (5). Na2CO3 (20 mg, 0.240 mmol) in water
(3 ml) was added to a solution of compound 4b (0.070 g, 0.14 mmol) in DMF (5 ml). Needle-like crystals were
filtered off after 48 h. Yield 0.015 g (50%); mp 139°C (mp 140°C [7]). 1H NMR spectrum, δ, ppm: 2.64 (3H, s,
CH3); 7.47 (1H, s, SCH=); 7.33, 7.69, 8.23 (4H, m, H Ar).
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