Facile synthesis of [1,2,4]triazino[4,3-b][1,2,4,5]tetrazepin derivatives by a one-pot reactions using 4-amino-3-hydrazinyl-6-methyl-1,2,4-triazin-5(4H)-one

Article abstract of DOI:10.1016/j.cclet.2010.07.006

4-Amino-3-mercapto-6-methyl-1,2,4-triazin-5(4. H)-one 1 converted to 4-amino-6-methy-3-(methylthio)-1,2,4-triazin-5(4. H)-one by methylation with methyl iodide. Controlled hydrazination of the resulting compound afforded 4-amino-3-hydrazinyl-6-methyl-1,2,4-triazin-5(4. H)-one 2 as a building block, to the synthesis of some novel derivatives of [1,2,4]triazino [4,3,. b][1,2,4,5]tetrazepine 3-6, by the reaction with 3-chloropentane-2,4-dione, chloro acetonitrile, 1,3-dichloroacetone, and methyl bromoacetate. This general synthetic procedure can be extended to the preparation of wide variety of tetrazepines using 1,2-bielectrophiles derivatives.

Full text of DOI:10.1016/j.cclet.2010.07.006

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1419–1422
www.elsevier.com/locate/cclet
Facile synthesis of [1,2,4]triazino[4,3-b][1,2,4,5]tetrazepin
derivatives by a one-pot reactions using 4-amino-3-
hydrazinyl-6-methyl-1,2,4-triazin-5(4H)-one
a,*
Hooshang Vahedi , Ghadir Rajabzadeh , Fahimeh Farvandi
b
a
a
Department of Chemistry, Payame Noor University (PNU), Mashhad, Iran
b
Khorasan Research Institute for Food Science and Technology, Iran
Received 12 April 2010
Abstract
-Amino-3-mercapto-6-methyl-1,2,4-triazin-5(4H)-one 1 converted to 4-amino-6-methy-3-(methylthio)-1,2,4-triazin-5(4H)-
one by methylation with methyl iodide. Controlled hydrazination of the resulting compound afforded 4-amino-3-hydrazinyl-6-
4
methyl-1,2,4-triazin-5(4H)-one 2 as a building block, to the synthesis of some novel derivatives of [1,2,4]triazino
[
4,3,b][1,2,4,5]tetrazepine 3–6, by the reaction with 3-chloropentane-2,4-dione, chloro acetonitrile, 1,3-dichloroacetone, and
methyl bromoacetate. This general synthetic procedure can be extended to the preparation of wide variety of tetrazepines using 1,2-
bielectrophiles derivatives.
#
2010 Hooshang Vahedi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 4-Amino-3-hydrazinyl-6-methyl-1,2,4-triazin-5(4H)-one; [1,2,4]Triazino [4,3,b][1,2,4,5]tetrazepine; 3-Chloropentane-2,4-dione;
Chloro acetonitrile; 1,3-Dichloroacetone; Methyl bromoacetate
Tetrazepinones are a novel class of antiproliferative agents that are more potent than their clinical counterparts in
tumour cells expressing the DNA repair enzyme O6-alkylguanine transferase (AGT) [1–3]. The multistep synthesis of
tetrazepiones derivatives has been reported [4,5]. These compounds have antiproliferative and apoptotic effects
against K562, K562-R (imatinib mesilate resistant) [4]. Literature provides only a few examples of tetrazepinone ring
fused to a heterocyclic nucleus [6,7] and therefore it was decided to synthesize new derivatives of this class of
heterocycles.
In the present work we have performed a one-pot synthesis of some novel derivatives of [1,2,4]triazino
4,3,b][1,2,4,5]tetrazepine 3–6 by the reaction of 4-amino-3-hydrazinyl-6-methyl-1,2,4-triazin-5(4H)-one 2 serving
[
as a starting material. The reason for using 2 as a building block is that it is excellent binucleophilic reagent which can
react with a wide variety of 1,2-bielectrophiles.
The mercaptan 1 was methylated on sulfur by methyl iodide before reacting with hydrazine hydrate to give the
1
1
compound 2 which was characterized by H NMR, IR and mass spectroscopy. In the H NMR spectrum it exhibits
*
Corresponding author.
E-mail addresses: h_vahedi@pnu.ac.ir, hooshangvahedi@yahoo.co.uk (H. Vahedi).
1001-8417/$ – see front matter # 2010 Hooshang Vahedi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.07.006

[(Scheme_1)TD$FIG]
1
420
H. Vahedi et al. / Chinese Chemical Letters 21 (2010) 1419–1422
Scheme 1.
singlets at d 11.59 (NH), 6.19 (N–NH ), 5.71 (NH of hydrazine) and a singlet at d 1.98 indicating the methyl group. IR
2
2
À1
À1
À1
spectrum showed absorption bands in the regions of 3254 cm and 3321 cm (NH ), 3346 cm (NH), and
2
À1
1
684 cm (C O), respectively.
The treatment of 2 with 3-chloropentane-2,4-dione in refluxing with acetonitrile in the presence of a catalytic
amount of solid acid, prepared by boiling silica gel and sulphuric acid in acetone as reported [9], afforded 8-acetyl-
3
,7-dimethyl-[1,2,4]triazino[4,3-b][1,2,4,5]tetrazepin-4(1H,6H,9H)-one 3 (Scheme 1). IR spectrum of compound
À1 À1 À1
showed absorption bands at 1384 cm (CH ), 3203 cm (NH) and 1680 cm (C O). H NMR spectrum of
3
1
3
compound 3 confirmed singlet signals at d 2.1, 2.2 and 2.3 for methyl groups and signals at d 7.6, 8.1 and 8.6 for
three different type of NH which was exchanged for deuterium in D O. When compound 2 was allowed to react
2
with chloro acetonitrile in the presence of sodium bromide it gave 7-imino-3-methyl-6,7,8,9-tetrahydro-
[
1,2,4]triazino[4,3-b][1,2,4,5]tetrazepin-4(1H)-one 4 (Scheme 1). The structure of compound 4 was elucidated by
À1
À1
its spectral data. IR spectrum showed absorption bands in the regions of 1689 cm (CO), 3205 cm (NH),
À1 À1 À1
431 cm (CH ), 1379 cm (CH ), and 1618 cm (C N). H NMR spectrum appeared signals at d 2.1 and 2.2
2 3
1
1
for methyl and methylene, respectively and signals at d 5.9, 7.3, 8.3 and 12.5 for NH groups which disappeared on
exchanging with D O. Moreover, when compound 2 was allowed to react with 1,3-dichloroacetone in refluxing
with acetonitrile, it yielded 7-(chloromethyl)-3-methyl-8,9-dihydro-[1,2,4]triazino[4,3-b][1,2,4,5]tetrazepin-
2
4
absorption bands at 1691 cm (CO), 1625 cm (C N), 1429 cm (CH2), 3149 cm (NH) and 746 cm (C–
(1H)-one 5 (Scheme 1). The structure of compound 5 was confirmed by spectral data. IR spectrum confirmed
À1
À1
À1
À1
À1
1
Cl). H NMR spectrum verified signals at d 2.1, 2.3 for the methyl and methylene, respectively and signals at
d 7.8 and 12.2 for two different types of NH groups which proton–deuterium exchange occurred when D O was
2
used.
Finally, the reaction of 2 with methyl bromoacetate in the presence of triethylamine yielded 3-methyl-8,9-dihydro-
1,2,4]triazino[4,3-b][1,2,4,5]tetrazepine-4,7(1H,6H)-dione 6. IR spectrum of compound 6 showed absorption bands
[
at 1629 cm and 1706 cm (C O), 1442 cm (CH ) and 1382 cm (CH ). H NMR confirmed signals at d 2.1 and
À1
À1
À1
À1
1
2
3
2
disappeared on exchanging with D O.
.3 for methyl and methylene, respectively and signals at d 5.7, 7.3 and 11.3 for three type of NH groups which
2
All melting points were measured in a BUCHI 530 melting point apparatus. The IR spectra were recorded on an FT-
IR-8400 Shimadzu spectrometer. The NMR spectra were recorded on a Brucker AC-100 spectrometer using
tetramethylsilane as an internal standard. High resolution Mass Spectra were recorded on a Shimadzu GT-17A
spectrometer. 4-Amino-3-mercapto-6-methyl-1,2,4-triazin-5(4H)-one was synthesized according to a procedure
reported in the literature [8].
4-Amino-3-hydrazinyl-6-methyl-1,2,4-triazin-5(4H)-one 2: 4-Amino-3-mercapto-6-methyl-1,2,4-triazin-5(4H)-
one (5.8 g, 0.03 mol) was added to a solution of sodium hydroxide (1.57 g, 0.3 mol) in methanol (40 mL), stirred

H. Vahedi et al. / Chinese Chemical Letters 21 (2010) 1419–1422
1421
for 5 min before adding excess amount of methyl iodide (6.8 mL). The mixture was stirred for 4 h at room
temperature. The precipitate was filtered off and crystallized in water to give colourless crystals of 4-amino-6-methyl-
3-methylthio-1,2,4-triazin-5(4H)-one (86%). mp 165 8C. To a solution of 4-amino-6-methyl-3-methylthio-1,2,4-
triazin-5(4H)-one (2.0 g, 0.032) in n-butanol (30 mL) was added hydrazine hydrate (3.2 mL, 80%) during two steps.
The mixture was refluxed for 8 h, cooled to room temperature to give crystals which was filtered off and recrystallized
1
in n-butanol (47%), mp 263 8C; H NMR (DMSO-d ): d 1.98 (s, 3H, CH ), 5.71 (s, 2H, NH ), 6.19 (s, 2H, NH ), 11.59
6
3
2
2
À1
1H, NH); FT-IR(KBr disc) n (cm ): 1684 (C O), 3254 (NH ), 3321 (NH ), 3346 (NH); m/z: 158 (10, M+2), 156(27,
2 2
(
+
M ), 140 (34), 124 (6), 114 (18), 105 (100), 98 (3), 89 (27), 72 (28), 56 (52), 41 (62), 27 (96), 17 (90).
-Acetyl-3,7-dimethyl-[1,2,4]triazino[4,3-b][1,2,4,5]tetrazepin-4(1H,6H,9H)-one 3: 4-Amino-3-hydrazinyl-6-
8
methyl-1,2,4-triazin-5(4H)-one (0.7 g, 4.5 mmol) and 3-chloropentane-2,4-dione (0,7 mL, 5.2 mmol) was
dissolved in acetonitrile followed by adding solid acid (0.07 g). The mixture was refluxed for 6 h, cooled to
room temperature to give a precipitate which was filtered off and recrystalized from ethanol to yield brown
1
crystals (57%), mp 237 8C; H NMR (DMSO-d ): d 2.1 (s, 3H, CH ), 2.2 (s, 3H, CH ), 2.3 (s, 3H, CH ), 7.6 (1H,
6
3
3
3
À1
NH), 8.1 (1H, NH), 8.6 (1H, NH); FT-IR (KBr disc) n (cm ): 1650 (C O), 1584 (C O), 3203(NH), 1384 (CH3);
+
m/z: 236 (3, M ), 225 (4), 211 (5), 197 (5), 183 (7), 169 (8), 155 (10), 141 (13), 127 (18), 113 (23), 99 (30), 85
(
93), 71 (100), 57 (100).
-Imino-3-methyl-6,7,8,9-tetrahydro-[1,2,4]triazino[4,3-b][1,2,4,5]tetrazepin-4(1H)-one 4: 4-Amino-3-hydra-
7
zinyl-6-methyl-1,2,4-triazin-5(4H)-one (0.34 g, 2.16 mmol) was dissolved in acetonitrile (5 mL) and a few drops
of acetone. Chloro acetonitrile (0.4 mL, 6.35 mmol) and sodium bromide (0.22 g, 2.12 mmol) was added and the
mixture was refluxed for 8 h. After concentrating of the mixture by evaporating some of the solvents the product was
precipitated out which was filtered off and recrystalized from n-butanol to give a yellow crystals (53%), mp (200–
1
2
02 8C); H NMR (DMSO-d ): d 2.1 (s, 3H, CH ), 2.2 (s, 2H, CH ), 5.9 (1H, NH), 7.3 (1H, NH), 8.3 (1H, NH), 12.5
6
3
2
À1 À1
broad, 1H, NH); FT-IR(KBr disc) n (cm ): 1689.5 (C O), 3205.5 (NH), 1431 (CH ), 1379 (CH ), 1618 cm
3 2
(
(
+
C N); m/z: 195 (6, M ), 181 (7), 167 (6), 156 (3), 141 (11), 127 (7), 113 (13), 96 (14), 85 (39), 71 (57), 57 (100).
-(Chloromethyl)-3-methyl-8,9-dihydro-[1,2,4]triazino[4,3-b][1,2,4,5]tetrazepin-4(1H)-one 5: 4-Amino-3-hydra-
zinyl-6-methyl-1,2,4-triazin-5(4H)-one (0.5 g, 3.2 mmol) and 1,3-dichloroacetone (0.42 g, 3.35 mmol) in acetonitrile
10 mL) and solid acid (0.05 g) was refluxed for 5 h, cooled to room temperature, filtered off the precipitate and
7
(
1
recrystalized in ethanol to give brown crystals (48%), mp (250–252 8C); H NMR (DMSO-d ): d 2.1 (s, 3H, CH ), 2.3
6
3
À1
s, 2H, CH NH), 4.0 (s, 2H, CH Cl), 7.8 (1H, NH), 12.2 (1H, NH); FT-IR (KBr disc) n (cm ): 1691 (C O), 1625
2 2
(
(
(
+
C N), 3149(NH), 1380 (CH ), 1429 (CH ), 746.1 (C–Cl); m/z: 228 (6, M ), 211 (5), 196 (7), 181 (7), 169 (25), 156
3
2
66), 140 (86), 127 (18), 112 (48), 97 (36), 82 (100), 69 (95), 57 (100).
-Methyl-8,9-dihydro-[1,2,4]triazino[4,3-b][1,2,4,5]tetrazepine-4,7(1H,6H)-dione 6: 4-Amino-3-hydrazinyl-6-
methyl-1,2,4-triazin-5(4H)-one (0.7 g, 4.5 mmol) and methyl bromoacetate (0,55 mL, 3.85 mmol) in acetonitrile
20 mL) and containing 5 drops of triethylamine was refluxed for 7 h. After cooling the mixture of the reaction to room
temperature the product was precipitated out which was crystallized in methanol to give a yellow crystals (37%), mp
3
(
1
2
FT-IR(KBr disc) n (cm ):1629 (C O), 1706 (C O), 3217 (NH), 1442 (CH ), 1382 (CH ); m/z: 196 (7, M ), 181 (9),
60–262 8C; H NMR (DMSO-d ): d 2.1 (s, 3H, CH ), 2.3 (s, 2H, CH ), 5.7 (1H, NH), 7.3 (1H, NH), 11.3 (1H, NH);
6
3
2
À1
+
2
3
1
67 (5), 152 (6), 141 (33), 127 (11), 112 (13), 98 (7), 82 (40), 69 (49), 57 (100).
In summery facile synthesis of [1,2,4]triazino[4,3-b][1,2,4,5]tetrazepin derivatives by a one-pot reactions was
investigated. This general synthesis can be extended to the preparation of wide variety of tetrazepines using 1,2-
bielectrophiles derivatives.
Acknowledgments
Financial support of Payame Noor University and Department of Chemistry, Khorasan Science and Technology
Park (KSTP), Iran is sincerely acknowledged.
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