Azo-coupling of pyrazole-3(5)-diazonium chlorides with cyanothioacetamide: A convenient synthesis of pyrazolo[5,1-c][1,2,4]triazine-3-carbothioamides

Article abstract of DOI:10.1016/j.tetlet.2014.01.010

Cyanothioacetamide reacts with pyrazole-3(5)-diazonium chlorides to afford pyrazolo[5,1-c][1,2,4]triazine-3-carbothioamides 5. The latter can be oxidized with H₂O₂ to give either pyrazolo[5,1-c][1,2,4]triazine-3- carboxamides or 1,2,4-thiadiazole derivatives, depending on the reaction conditions. The Hantzsch-type reaction of thioamides 5 with α-bromo ketones leads to 3-(thiazol-2-yl)pyrazolo[5,1-c][1,2,4]triazines.

Full text of DOI:10.1016/j.tetlet.2014.01.010

Accepted Manuscript
Azo-coupling of pyrazole-3(5)-diazonium chlorides with cyanothioacetamide:
a convenient synthesis of pyrazolo[5,1-c][1,2,4]triazine-3-carbothioamides
Irina V. Ledenyova, Vitaly V. Didenko, Victor V. Dotsenko, Khidmet S.
Shikhaliev
PII:
S0040-4039(14)00015-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.010
TETL 44041
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 October 2013
10 November 2013
2 January 2014
Please cite this article as: Ledenyova, I.V., Didenko, V.V., Dotsenko, V.V., Shikhaliev, K.S., Azo-coupling of
pyrazole-3(5)-diazonium chlorides with cyanothioacetamide: a convenient synthesis of pyrazolo[5,1-c]
[1,2,4]triazine-3-carbothioamides, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.01.010
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Graphical Abstract
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Azo-coupling of pyrazole-3(5)-diazonium
chlorides with cyanothioacetamide: a
convenient synthesis of pyrazolo[5,1-
c][1,2,4]triazine-3-carbothioamides
Irina V. Ledenyova, Vitaly V. Didenko, Victor V. Dotsenko,
Khidmet S. Shikhaliev

Azo-coupling of pyrazole-3(5)-diazonium chlorides with
cyanothioacetamide: a convenient synthesis of pyrazolo[5,1-
c][1,2,4]triazine-3-carbothioamides
Irina V. Ledenyovaa,*, Vitaly V. Didenkoa, Victor V. Dotsenko,b
Khidmet S. Shikhalieva
aVoronezh State University, 1 Universitetskaya pl., 394006 Voronezh, Russia
bChemEx Lab, Vladimir Dal’ East Ukrainian National University, 20A Molodezhny
kv., 91034 Lugansk, Ukraine
ABSTRACT
Cyanothioacetamide reacts with pyrazole-3(5)-diazonium chlorides to afford
pyrazolo[5,1-c][1,2,4]triazine-3-carbothioamides 5. The latter can be oxidized with
H2O2 to give either pyrazolo[5,1-c][1,2,4]triazine-3-carboxamides or 1,2,4-thiadiazole
derivatives, depending on the reaction conditions. The Hantzsch-type reaction of
thioamides 5 with α-bromo ketones leads to 3-(thiazol-2-yl)pyrazolo[5,1-
c][1,2,4]triazines.
Keywords:
Azo-coupling
Cyanothioacetamide
Hantzsch thiazole synthesis
Heterocyclization
Pyrazole-3(5)-diazonium salts
Pyrazolo[5,1-c][1,2,4]triazines
Oxidation of thioamides
* Corresponding author. E-mail: irairachem@yandex.ru

Pyrazolo[5,1-c][1,2,4]triazines are known to exhibit a broad range of biological
activity.1-5 Due to their structural similarities to nucleic bases, pyrazolo[5,1-
c][1,2,4]triazines may act as metabolites and may therefore be useful as antiviral and
antitumor agents.1 Pyrazolotriazines were reported to have remarkable cytotoxic
activity against colon, breast and lung carcinoma cells.6 Some derivatives showed
selective cytotoxicity under hypoxic and normoxic conditions.7 According to the
patent data,8 certain polysubstituted pyrazolo[5,1-c][1,2,4]triazines inhibit selectively
B-Raf kinase activity, and are useful for treating disorders mediated by B-Raf kinase.
The most concise approach to the synthesis of pyrazolo[5,1-c][1,2,4]triazine
scaffolds is based on the azo-coupling of pyrazole-3(5)-diazonium salts 1 with active
methylene/methine compounds, followed by intramolecular cyclization of the
hydrazone intermediates 2 (Scheme 1).1,9,10
Scheme 1. General approach to the synthesis of pyrazolo[5,1-c][1,2,4]triazines
A number of 4-aminopyrazolo[5,1-c][1,2,4]triazines were obtained by reactions
of diazonium salts 1 with active methylene nitriles such as malononitrile,11-27 2-
(cyanomethyl)thiazoles,28,29
cyanoacetate,11,17,20,21,26,30,31 α-cyanoketones,30,32-35 2-(cyanomethyl)thiadiazoles,36,37
cyanoacetamides,38-42 nitroacetonitrile,43,44 cyanomethylphosphonates,45
2-
2-(cyanomethyl)benzoxazole,19
ethyl
(cyanomethyl)pyridine,46 2-(cyanomethyl)benzimidazole,47,48 etc. In continuation of
our studies on the azo-coupling reactions,49-52 we report herein the results of the azo-
couplings of 2-cyanothioacetamide (3) with diazonium salts 1. 2-Cyanothioacetamide
(3) and its derivatives are widely used for the synthesis of S,N-heterocyclic
compounds (see previous reviews53-59 and some recent examples60-63). 2-
Cyanothioacetamide can be easily prepared by passing hydrogen sulfide through a
malononitrile solution in the presence of a catalytic amount of base.64,65

It was found that salts 1 readily react with 2-cyanothioacetamide (3) under mild
conditions to give brightly colored compounds which are presumed to be hydrazones
4. These hydrazones are quite unstable and undergo fast intramolecular cyclization
when purified by column chromatography or recrystallization, or even under
moderate heating while trying to determine melting points. The preparative scale
heterocyclization was performed by heating hydrazones 4 in DMF which led to the
expected pyrazolo[5,1-c][1,2,4]triazine-3-carbothioamides 5 in moderate yields
(Scheme 2).
Scheme 2. Synthesis of thioamides 5.
The structures of thioamides 5 were elucidated on the basis of IR, 1H NMR, 13C
13
1
NMR, 2D NOESY and C APT NMR spectra. The H NMR spectra of products 5
showed the presence of four one-proton signals at δ 9.30-10.92 and the absence of a
pyrazole NH signal at low field. The 2D NOESY NMR spectrum of 5b displayed
cross peaks between the C(S)NH2 protons (δ 9.73 and 10.03) and the NH2 protons (δ
9.40 and 10.80); due to C=S…H–N hydrogen bonding, the signal of one of the NH2
protons was shifted downfield by 1.4 ppm compared to the non-hydrogen bonded
proton.
When thioamides 5a,b were treated with α-halo ketones in hot DMF, the
Hantzsch-type thiazoles 6a-e were obtained in high yields (Scheme 3, Table 1).
Therefore pyrazolo[5,1-c][1,2,4]triazine-3-carbothioamides 5 serve as useful synthons
for the preparation of polyheterocyclic ensembles due to the neighboring NH2 and
C(S)NH2 groups.
First, we decided to study the oxidation ability of compounds 5 under various
reaction conditions. In general, oxidation of thioamides is very unpredictable and can
take several different courses.66-68 Depending on the structures of both the oxidant and
the substrate, as well as on the reaction conditions, the oxidation process may lead to

the formation of amides, thioamide S-oxides, 1,2,4-thiadiazoles, disulfides,
benzothiazoles, α-oxothioamides, 1,2-dithiolium salts, 1,2,4-dithiazoles, 1,2,3-
thiadiazolium salts, etc.68 However, the oxidation of 3-aminoprop-2-enethioamides
and related compounds with neighboring NHR and C=S moieties is known to be one
of the most convenient methods for the construction of an isothiazole unit.69-72 It was
expected that the oxidation of 4-aminopyrazolotriazine-3-carbothioamides 5 would
give isothiazolo[5,4-e]pyrazolo[5,1-c][1,2,4]triazines 7. Surprisingly, only 4-
aminopyrazolo[5,1-c][1,2,4]triazin-3-carboxamide (8) was isolated in almost
quantitative yield when thioamide 5b was gently heated to 50 °C in the presence of
aqueous H2O2 for 30 minutes (Scheme 3). A plausible mechanism for the formation of
amide 8 includes oxidation of a sulfenate fragment followed by hydrolysis73 (Scheme
4). On the other hand, on changing the conditions, the reaction of thioamide 5b with
hydrogen peroxide proceeded via a different route to give 3,3'-(1,2,4-thiadiazole-3,5-
diyl)bis(pyrazolo[5,1-c][1,2,4]triazine) (9) as the major oxidation product.
Scheme 3. The reactions of thioamides 5a,b
Table 1. Compounds 5a,b, 6a-e, 8 and 9.
Compound
R
Ar
Yield (%)
M.p. (°C)
277-279
257-259
>300
5a
5b
6a
6b
6c
6d
6e
8
H
–
50
54
66
75
78
80
72
93
55
Me
Me
H
–
Ph
Ph
>300
H
4-ClC6H4
>300
H
4-MeC6H4
>300
Me
Me
Me
4-BrC6H4
276-278
228-230
>300
–
–
9
Scheme 4. A mechanistic pathway for the synthesis of carboxamide 8.

To summarize, a novel azo-coupling method has been developed. Using this
approach, 4-aminopyrazolo[5,1-c][1,2,4]triazin-3-carbothioamides were generated as
convenient building blocks for the construction of heterocyclic ensembles with
potential bioactivity.
Preparation of 4-amino-8-phenylpyrazolo[5,1-c][1,2,4]triazine-3-carbothioamides
5a,b. A suspension of the corresponding 3(5)-aminopyrazole74 (0.03 mol) in H2O (30
mL) was treated with HCl (9.0 mL, d = 1.19 g/mL) and then cooled to 0 °C. To the
resulting solution was added crystalline NaNO2 (2.07 g, 0.03 mol) portionwise over a
period of 15 min under vigorous stirring. Once the addition was complete, the
obtained cold (0–5 °C) solution of pyrazolediazonium chloride 1a,b was added
dropwise to a solution of 2-cyanothioacetamide (3) (3.0 g, 0.03 mol) and excess
NaOAc (30 g, 0.37 mol) in AcOH (30 mL). The mixture was stirred at ambient
temperature for 1 h and the obtained solid orange hydrazone 4 was collected by
filtration and washed with H2O, and then heated in DMF (30 mL) for 20 min. The
solution was allowed to cool and the resulting canary-yellow crystalline products
were filtered off, washed with i-PrOH and dried to give pyrazolotriazines 5a,b.
Compounds 5a,b were purified by recrystallization from appropriate solvents.
4-Amino-7-methyl-8-phenylpyrazolo[5,1-c][1,2,4]triazine-3-carbothioamide
(5b).
Yield 54%, yellow crystals, mp 257-259 °C (DMF); νmax (KBr): 3462, 3447, 3319,
3294 (N–H); 1H NMR (500 MHz, DMSO-d6): δ 2.64 (3H, s, CH3), 7.35-7.37 (1H, m,
Ph), 7.49-7.52 (2H, m, Ph), 7.86 (2H, d, 3J = 8.0 Hz, Ph), 9.40 (1H, s, NH2), 9.73 (1H,
s, CSNH2), 10.03 (1H, s, CSNH2), 10.80 (1H, s, NH2); 13C NMR (126 MHz, DMSO-
d6): 14.2 (Me), 110.5 (C-3), 121.7 (C-8), 126.9 (C-4 Ph), 128.6 (C-3, C-5 Ph), 128.7
(C-2, C-6 Ph), 130.8 (C-1 Ph), 141.5 (C-4), 145.8 (C-7), 153.5 (C-8a), 190.4 (C=S);
13C APT NMR (126 MHz, DMSO-d6): 14.2* (CH3), 110.5 (C-3), 121.7 (C-8), 126.9*
(C-4 Ph), 128.5* (C-3, C-5 Ph), 128.7* (C-2, C-6 Ph), 130.8 (C-1 Ph), 141.5 (C-4),

145.8 (C-7), 153.5 (C-8a), 190.4 (C=O). *Negative peaks. Anal. Calcd for C13H12N6S:
C, 54.91; H, 4.25; N, 29.56. Found C, 54.85; H, 4.37; N, 29.50.
Preparation
of
4-amino-3-(4-arylthiazol-2-yl)-8-phenylpyrazolo[5,1-c][1,2,4]-
triazines 6a-e. A solution of pyrazolotriazine-3-carbothioamide 5a,b (5 mmol) and
the corresponding α-bromo ketone (5 mmol) in DMF (5 mL) was refluxed for 10 min.
Upon cooling to room temperature, the solid deposit was separated by filtration and
washed with i-PrOH. Analytically pure products were obtained by recrystallization
from N,N-dimethylacetamide (DMA).
4-Amino-7-methyl-8-phenyl-3-(4-phenylthiazol-2-yl)pyrazolo[5,1-c][1,2,4]triazine
(6а). Yield 66%, yellow crystals, mp >300 °C (from DMA); νmax (KBr): 3294, 3136
1
(NH2), 1636 (C=N); H NMR (400 MHz, DMSO-d6): δ 2.67 (3H, s, CH3), 7.40-7.42
(2H, m, Ph), 7.50-7.54 (4H, m, Ph), 7.88 (2H, d, 3J = 6.8 Hz, Ph), 8.02 (2H, d, 3J =7.0
Hz, Ph), 8.16 (1H, s, H-5 thiazolyl), 9.23 (1H, br s, NH2), 9.50 (1H, br s, NH2); 1H
NMR (500 MHz, TFA-d): δ 2.55 (3H, s, CH3), 7.25-7.47 (8H, m, 2 Ph), 7.65-7.72
13
(3H, m, Ph, thiazolyl H-5); C NMR (126 MHz, TFA-d): 13.8 (CH3), 110.6 (C-3),
116.7 (C-8), 118.4 (thiazolyl C-5), 125.5 (C-Ar), 128.0 (C-Ar), 128.1 (CH Ph),
131.06 (CH Ph), 131.12 (CH Ph), 131.4 (CH Ph), 131.7 (CH Ph), 132.0 (CH Ph),
134.4 (C-Ar), 138.9 (C-Ar), 144.1 (C-7), 159.2 (thiazolyl C-1), 163.2 (C-8a); MS (EI,
70 eV): m/z (%): 384 [M]+ (39), 209 (5), 200 (13), 187 (27), 172 (11), 156 (22), 142
(55), 134 (100), 130 (13), 115 (60), 102 (46), 89 (53), 77 (28), 63 (14), 51 (17), 42
(26), 29 (5). Anal. Calcd for C21H16N6S: C, 65.61; H, 4.19; N, 21.86. Found C, 65.70;
H, 4.12; N, 21.81.
Preparation
of
4-amino-7-methyl-8-phenylpyrazolo[5,1-c][1,2,4]triazine-3-
carboxamide (8). A solution of thioamide 5b (1.42 g, 0.005 mol) in aqueous H2O2
(30%, 10 mL) was heated at 50 °C for 30 min. After cooling to room temperature, the

solid was filtered off, washed with H2O and dried to give 8. Yield 1.25 g (93%),
yellow crystals, mp 228-230 °C (from i-PrOH); νmax (KBr): 3334 (N-H), 3483 (N-H),
1627 (C=N), 1500 (N=N); 1H NMR (500 MHz, DMSO-d6): δ 2.65 (3H, s, CH3), 7.37
(1H, t, 3J = 7.0 Hz, Ph), 7.50-7.53 (2H, m, Ph), 7.69 (1H, br s, NH2), 7.86 (2H, d, 3J =
7.3 Hz, Ph), 8.36 (1H, s, NH2), 9.09 (1H, s, NH2), 9.22 (1H, s, NH2); MS (EI, 70 eV):
m/z (%): 268 [M]+ (100), 251 (7), 156 (20), 142 (15), 128 (14), 115 (75), 103 (6); 89
(13), 77 (10), 68 (10), 44 (38), 39 (10). Anal. Calcd for C13H12N6O: C, 58.20; H, 4.51;
N, 31.33. Found C, 58.31; H, 4.44; N, 31.25.
Preparation
of
3,3'-(1,2,4-thiadiazole-3,5-diyl)bis(4-amino-7-methyl-8-
phenylpyrazolo[5,1-c][1,2,4]triazine) (9). A mixture of thioamide 5b (1.42 g, 0.005
mol), aqueous H2O2 (30%, 1.0 mL) in DMF (15 mL) was stirred at room temperature
for 4 h in the presence of a catalytic amount of i-Pr3N. The solid deposit obtained was
collected by filtration, washed with i-PrOH and recrystallized from DMF to give
thiadiazole 9. Yield 55%, yellow crystals, mp >300 °C (DMF); νmax (KBr): 3439,
1
3412, 3294 (NH2), 1624 (C=N); H NMR (TFA-d, 500 MHz): δ 2.57 (3H, s, CH3),
2.60 (3H, s, CH3), 7.48-7.60 (10H, m, 2Ph); The signals of the NH2 protons are not
13
observed due to H–D exchange. C NMR (126 MHz, TFA-d): 13.93, 13.95 (2 CH3),
112.1, 112.9 (C-3, C-3'), 122.6, 122.8 (C-8, C-8'), 127.6, 127.9 (C-4, C-4'), 131.1,
131.2 (C-3, C-5 Ph), 131.78, 131.82 (C-2, C-6 Ph), 132.2, 132.3 (C-4 Ph), 138.5,
139.1 (C-1 Ph), 143.8, 145.3 (C-7, C-7'), 164.2, 164.7 (C-8a, C-8a'), 168.2
(thiadiazole C-3), 184.6 (thiadiazole C-5); MS (EI, 70 eV): m/z (%): 531 [M-1]+ (53),
251 (23), 157 (24), 142 (55), 115 (65), 89 (10), 77 (14), 36 (40). Anal. Calcd for
C26H20N12S: C, 58.64; H, 3.79; N, 31.56. Found C, 58.72; H, 3.74; N, 31.63.
Acknowledgments
This research was supported by the Ministry of Education and Science of the Russian
Federation (grants No. 3.1930.2011 and No. 02.G25.31.0007).

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Supplementary Data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/..

Scheme 1. General approach to the synthesis of pyrazolo[5,1-c][1,2,4]triazines
Scheme 2. Synthesis of thioamides 5.
R
N
S
N
NH
NH2S
Ph
Cl
NH2
Ph
R
DMF
N
3
N
NH2
NH
N
N
R
N
N
N
N
N
AcONa
N
H
Ph
S
NH2
1a,b
5a,b
1, 5 a R = H
b R = Me
4
Scheme 3. The reactions of thioamides 5a,b
Me
N
Ph
N
NH2
N
N
CONH2
8
aq. H2O2
Ar
N
40-50 °C, 30 min
S
N
NH2
CSNH2
S
aq. H2O2
H2N
H2N
ArC(O)CH2Br
DMF, reflux
N
N
N
N
N
N
N
N
N
N
N
R
N
Ph
Me
Ph
Ph
Me
5a,b
aq. H2O2
DMF, i-Pr3N, r.t., 4 h
7
6a-e
N
NH2
N
S
N
N
N
N
NH2
Ph
Me
Me
N
N
N
N
Ph
9
Scheme 4. A mechanistic pathway for the synthesis of amide 8.
O
O
O
O
S
S
NH2
+
O2S
H2O2
H2O
H2O2
H
H2O2
H2N
N
H2N
N
H2O2
N
NH2
5b
H2N
8
N
N
H
N
N
- H2SO4
N
N
N