Synthesis of functionalized 1H-pyrazolo[4,3-e][1,2,4]triazines and their fused derivatives via Ipso-substitution of methylsulfonyl group with O-, N-, S- and C-nucleophiles

Article abstract of DOI:10.3987/com-04-10108

Ipso-substitution reaction of 3-methyl-5-methylsulfonyl-1-phenyl-1H- pyrazolo[4,3-e][1,2,4]triazine (4) with a range of C-, N-, O- and S-nucleophiles afforded the corresponding substitution products (5a-m) in high yields. The reaction of 5-hydrazino compo

Full text of DOI:10.3987/com-04-10108

HETEROCYCLES, Vol. 63, No. 8, 2004, pp. 1829 - 1838
Received, 26th April, 2004, Accepted, 10th June, 2004, Published online, 11th June, 2004
SYNTHESIS OF FUNCTIONALIZED 1H-PYRAZOLO[4,3-e]-
[1,2,4]TRIAZINES AND THEIR FUSED DERIVATIVES VIA
IPSO-SUBSTITUTION OF METHYLSULFONYL GROUP
WITH O-, N-, S- AND C-NUCLEOPHILES1
Mariusz Mojzych and Andrzej Rykowski *
Department of Chemistry, University of Podlasie, ul. 3-go Maja 54, 08-110 Siedlce,
Poland, E-mail: rykowski@ap.siedlce.pl
Abstract–Ipso-substitution reaction of 3-methyl-5-methylsulfonyl-1-phenyl-
1H-pyrazolo[4,3-e][1,2,4]triazine (4) with a range of C-, N-, O- and
S-nucleophiles afforded the corresponding substitution products (5a-m) in high
yields. The reaction of 5-hydrazino compound (5m) with carboxylic acids furnished
1H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-b][1,2,4]triazines (8a) and (8b).
A variety of naturally occurring bicyclic heteroaromatic compounds are well known for their wide range
of biological activity.2 It has been reported that O- and N-alkyl derivatives of 1H-pyrazolo[4,3-
e][1,2,4]triazine such as pseudoiodinine and nostocine A, isolated from the cultural fluids of
Pseudomonas fluorescent and Nostoc spongiaeforme, exhibit an interesting combination of biological
activity.3-5 In addition to cytostatic effects they inhibit the growth of Gram-positive and Gram-negative
bacteria with a somewhat weaker action against fungi.5 Despite the potential usefulness of such
compounds, simple methods for the introduction of a range substituents into this heterocyclic ring system
have not been developed and for this reason new advances in this subject continue to be of interest.
Previous published synthetic approaches toward making 3,5-disubstituted 1H-pyrazolo[4,3-
e][1,2,4]triazine have utilized the condensation of either 5-arylidene- or 5-benzoyl-3-phenyl-1,2,4-triazin-
6-ones with hydrazine or phenylhydrazines.6,7 The methods have been effectively applied only in the
synthesis of phenyl and substituted phenyl derivatives and are inefficient for generation of analogues with
varying C-5 substituents. Recently, we have reported a new approach to 1H-pyrazolo[4,3-
e][1,2,4]triazines (2) by one-pot reaction between 5-acyl-1,2,4-triazines (1) and various hydrazine
derivatives under acidic conditions.8,9 The reaction most probably proceeds via the corresponding

hydrazone (A), followed by acid-promoted ring closure, involving the bicyclic intermediate (B), that by
an air oxidation gives 2 (see Scheme 1).
R2
R2
H
N
R2
H
N
H
+
N
N
N
N
H
N
N
N
R2 -NH-NH2. HCl
N
N
N
[O]
N
N
N
N
O
N
X
N
X
X
X
R1
R1
R1
R1
1
A
B
2
R1=CH3, C2H5, C3H7
R2 =H, alkyl, phenyl or substituted phenyl
X= SCH3, Ph
Scheme 1
This method seems to be general and allows to introduce the substituents into pyrazole and triazine rings
in the first step. Moreover, the presence of good leaving group at C-5 in 2 should provide a rapid
derivatization of this heterocyclic core via nucleophilic displacement. Since alkylsulfanyl substituents
bound to the 1,2,4-triazine ring are very reactive and readily exchangeable by a number of heteroatom
nucleophiles10 we have applied this route to the synthesis of C-5 functionalized 1H-pyrazolo[4,3-
e][1,2,4]triazine derivatives.
The common intermediate, 3-methyl-5-methylsulfanyl-1-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine (3) has
been readily prepared using literature procedure8 from easily available 5-acetyl-3-methylsulfanyl-1,2,4-
triazine11 and phenylhydrazine hydrochloride. In the initial experiment 3 has been subjected to reaction
with sodium methoxide in boiling methyl alcohol. Contrary to expectation compound (3) appeared to be
unreactive and attempts to perform nucleophilic substitution of methylsulfanyl group afforded only
unreactive starting material. In searching for more effective nucleofugal group, we have explored the
substitution reaction between sodium methoxide and 3-methyl-5-methylsulfonyl-1-phenyl-1H-
pyrazolo[4,3-e][1,2,4]triazine (4), easily available by oxidation of 3 with potassium manganate(VII)
under phase transfer catalytic conditions. When instead of 3, compound (4) is used, and the same
reaction conditions were applied as mentioned above, 3-methoxy derivative (5b) is formed in 90% yield
within 30 min (Scheme 2, Table 1). Sodium hydroxide and sodium ethoxide react efficiently with 4
giving directly 5-substituted products (5a) and (5c). A similar behavior was observed with alkoxides
bearing an acetylene unit at the terminal position. These nucleophiles give functionalized
pyrazolotriazines (5d) and (5e) with dienophilic side chain tethered to C-5 (Table 1, Entries 4 and 5).
Also nucleophilic substitution of methylsulphinate by phenoxy group leading to 5f occurs readily in
reaction of 4 with sodium o-cyanophenoxide in DMF (Table 1, Entry 6). When 1,2,4-triazines bearing
side chain containing an alkyne or a cyano functionality are employed thermal cycloadditions, the

bicyclic or polycyclic pyridines are formed after expulsion of nitrogen.2 Application of this
intramolecular Diels-Alder reaction for compounds (5d-e) should provide a direct route to furo[2,3-
b]pyrazolo[3,4-e]pyridine (6d) and pirano[2,3-b]pyrazolo[3,4-e]pyridine (6e), which could otherwise
hardly be prepared by other methods. However, all attempts to transform compounds (5d-e) into 6d-e fail
because of low reactivity of the fused 1,2,4-triazine unit in 1H-pyrazolo[4,3-e][1,2,4]triazine ring system.
Ph
Ph
Ph
CH3O _
N
N
N
N
N
N
N
N
KMnO4
SCH3
N
N
N
Nu
SO2CH3
N
N
N
no reaction
N
Nu
H3C
H3C
H3C
5 a-m
3
4
N
Ph
Ph
Ph
N
N
N
( )n
N
N
N
N
( )n
( )n
N
T
- N2
N
N
N
O
O
O
N
CH3
H3C
H3C
5' d-e
5d-e
n = 1, 2
6d-e
Scheme 2
Table 1. Yields and reaction times of compounds (5a-m).
Entry
5
a
b
c
d
e
f
Nu
OH
Reaction times Yield [%]
1
2
3
4
5
6
10 min
30 min
1 h
90
90
88
74
75
84
OCH3
OC2H5
OCH2CH2C≡CH
2 h
OCH2CH2CH2C≡CH
2 h
NC
3 h
O
7
8
g
h
i
S-Ph
10 min
3 h
97
90
83
73
89
99
76
CH(COOC2H5)2
NH2
9
1 h
10
11
12
13
j
NH-Ph
17 h
4.5 h
1 h
k
l
NH-CH2-Ph
NH-CH2CH2CH2CH3
H2N-NH2
m
3 h

The ability of the 5-methylsulfonyl group in compound (4) to undergo the displacement reactions
mentioned above, has been successfully employed for the synthesis of sulfur, carbon and nitrogen
analogues of 1H-pyrazolo[4,3-e][1,2,4]triazine. Reactions of 4 with sodium thiophenoxide and ethyl
malonate carbanion in THF afford the corresponding substitution products (5g) and (5h) in good yield.
o
The reaction of 4 with liquid ammonia at –33 C gives desired 5-amino-3-methyl-1-phenyl-1H-
pyrazolo[4,3-e][1,2,4]triazine (5i) quantitatively. Interesting, treatment of 4 with ethanolic ammonia at
o
-18 C afforded 5i in low yield , whereas 5-ethoxy derivative (5c) was obtained as a main product.
Primary aliphatic and aromatic amines are also excellent reagents for this nucleophilic substitution
reaction giving good yields of products, regardless of the kind of the amine used (Scheme 2, Table 1,
Entries 9-11). Similarly, the treatment of 4 with anhydrous hydrazine in teterahydrofuran provides 5-
hydrazino-3-methyl-1-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine (5m) exclusively. Oxidation of the latter
with yellow mercury(II) oxide results in replacement of 5-hydrazino group by hydrogen, giving 3-methyl-
1-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine (7), respectively. Bearing in mind that functionalization of
monocyclic 1,2,4-triazines can be achieved in a more direct way by nucleophilic substitution of hydrogen
we have attempted to apply this methodology to the synthesis of C-5 substituted pyrazolotriazines.
Among many variants of this process, the most general appears to be vicarious nucleophilic substitution of
hydrogen when carbanions with a good leaving group attached to the carbanionic center are employed
as nucleophiles.12,13,14 This reaction enables the preparation of a wide variety of the C-3 and C-5
substituted 1,2,4-triazines.15 However, pyrazolotriazine derivative (7) is resistant to nucleophilic
substitution of hydrogen, when reacting with chloromethyl phenylsulfone or N,N-
dimethyl(chloromethane)sulfonamide in dry DMSO in the presence of powdered potassium hydroxide
(Scheme 3).
R1
Ph
N
N
N
N
N
N
N
H3C
Ph
Ph
8a R1 =H
N
N
N
N
N
R1COOH
NH-NH2
N
Cl
SO2R
HgO
N
N
8b R1 =CH3
N
no reaction
N
KOH / DMSO / 20oC
H
H3C
H3C
R=Ph, N(CH )
3 2
Ph
7
5m
N
N
N
N
N
N
H3C
N
R1
9a R1 =H
9b R1 =CH3
Scheme 3

The potential of 5-hydrazino compound (5m) for synthesis of more elaborate ring systems is illustrated
by reaction of 5m with carboxylic acids (see Scheme 3). Thus treatment of hydrazino compound (5m)
with formic or acetic acid furnished 1H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-b][1,2,4]triazines (8a) and (8b)
respectively, the derivatives of a new heteroaromatic ring system (Scheme 3). Theoretically, another
direction of ring closure toward the N-4 atom may be assume in which case the angularly arranged 1H-
pyrazolo[4,3-e]-1,2,4-triazolo[3,4-c][1,2,4]triazines (9a) and (9b) would form. NOE difference
spectroscopy provides an unambiguous assignment for linear structure for 8b. It was found that
irradiation of the protons of the methyl group in pyrazole ring in 8b (2.65 ppm) did not lead to Nuclear
Overhauser Enhancement for the signal of protons of the methyl group in 1,2,4-triazole ring (2.17 ppm).
Lack of such interactions confirms the linear structure for compounds (8a) and (8b).
In summary, we have prepared several functionalised 1H-pyrazolo[4,3-e][1,2,4]triazines (5a-m) by
nucleophilic substitution of 4 bearing sulfonyl group at C-5 with O-, N-, S- and C-nucleophiles. The ease
and efficiency of this one-pot approach makes it attractive for the preparation of other 1H-pyrazolo[4,3-
e][1,2,4]triazine analogues and their condensed derivatives.
EXPERIMENTAL
Melting points were determined on Boetius melting point apparatus and are uncorrected. IR spectra were
measured with a Magna IR-760 spectrophotometer. The 1H-NMR spectra were recorded in
deuteriochloroform (CDCl3) on a Varian Gemini 200 MHz spectrometer. Chemical shifts are expressed in
ppm with reference to TMS as an internal standard. Coupling constants are given in hertz (Hz). MS
spectra were measured on AMD 604 spectrometer [electron impact (EI)] and API 350 [electrospray
ionization (ESI)]. Elemental analyses were recorded on Perkin-Elmer 2400-CHN analyser and the results
for the indicated elements were within 0.3 % of the calculated values.
3-Methyl-5-methylsulfonyl-1-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine (4)
To a solution of 3 (257 mg, 1 mmol) in 20 mL of benzene were added water (30 mL), potassium
manganate(VII) (474 mg, 3 mmol), catalytic amounts of tetrabutylammonium bromide (65 mg, 0.2
mmol) and 1,5 mL of acetic acid. The reaction mixture was stirred at rt for 1 h. A saturated solution of
Na2S2O5 in water was added to the mixture until the purple color disappeared. The organic layer was
separated and water phase was extracted with benzene (3x10 mL). The combined extracts were dried
over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography
(silica gel and chloroform as eluent) and recrystallized from ethanol to give 257 mg (89%) of 4.
o
1
mp 141 C; H-NMR (CDCl3) δ: 2.87 (s, 3H), 3.60 (s, 3H), 7.40-7.49 (m, 1H), 7.56-7.67 (m, 2H), 8.33-

8.39 (m, 2H); IR (KBr) cm-1: 1600, 1350, 1120, 820, 780, 700; MS (m/z, %): 289 (22) [M+], 141 (50),
104 (40), 77 (100); Anal. Calcd for C12H11N5O2S: C, 49.82; H, 3.80; N, 24.22. Found: C, 49.86; H,
3.82; N, 24.14.
5-Hydroxy-3-methyl-1-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine (5a)
A solution of sulfone (4) (145 mg, 0.5 mmol) and KOH (31 mg, 0.55 mmol) in ethanol-water 4:1 (20 mL)
was refluxed for 10 min. After that time the mixture was acidified with acetic acid. The red precipitate
1
that formed was filtered off to give 102 mg (90%) of 5a. mp 235-237 oC; H-NMR (CD3COOD) δ: 2.58
(s, 3H), 7.26-7.34 (m, 1H), 7.48-7.52 (m, 2H), 8.01-8.06 (m, 2H); HRMS (ESI, m/z) 228.0881, Calcd for
C11H10N5O (M+H) 228.0880.
The hygroscopic nature of the compound led to variability in the microanalytical data.
5-Methoxy-3-methyl-1-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine (5b) and 5-ethoxy-3-methyl-1-
phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine (5c)
Compound (4) (289 mg, 1 mmol) was added to a solution of metal sodium (26 mg, 1.1 mmol) in dry
appropriate alcohol-methanol or ethanol (20 mL). The mixture was heated at reflux (for the reaction time
see Table 1). The solvent was evaporated under reduced pressure and the residue was chromatographed
on silica gel and eluted with chloroform. Evaporation of the solvent afforded 5b or 5c.
5b mp121-122 oC (recrystallized from ethanol); 1H-NMR (CDCl3) δ: 2.70 (s,3H), 4,27 (s, 3H), 7.29-7.38
(m, 1H), 7.50-7.60 (m, 2H), 8.31-8.38 (m, 2H); IR (KBr) cm-1: 1600, 1510, 1120, 1030,780;
MS (m/z, %): 241 (45) [M+], 213 (14), 129 (48), 104 (25), 95 (25), 77 (100); Anal. Calcd for C12H11N5O:
C, 59.75; H, 4.56; N, 29.04. Found: C, 59.59; H, 4.55; N, 28.96.
5c mp 104-105 oC (recrystallized from ethanol); 1H-NMR (CDCl3) δ: 1.57 (t, 3H, J=7.0 Hz), 2.69 (s, 3H),
4.70 (q, 2H, J=7 Hz), 7.29-7.38 (m, 1H), 7.50-7.60 (m, 2H), 8.30-8.37 (m, 2H); IR (KBr) cm-1: 1600,
1130, 1070, 780; MS (EI, m/z, %): 255 (45) [M+], 227 (13), 199 (18), 129 (16), 104 (36), 77 (100); Anal.
Calcd for C13H13N5O: C, 61.17; H, 5.09; N, 27.45. Found: C, 61.28; H, 5.06; N, 27.25.
5-(3-Butynyloxy)-3methyl-1-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine (5d) and 5-(4-petynyloxy)-3-
methyl-1-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine (5e)
To a suspension of sodium hydride (45 mg, 1.1 mmol, 60 % suspension in paraffin oil) in dry
tetrahydrofuran (20 mL) was added appropriate unsaturated alcohol (1.1 mmol) and then 289 mg (1
mmol) of 4 at once. The mixture was heated at reflux for 2 h. The solvent was evaporated under reduced
pressure and the crude product was purified by column chromatography packing with silica gel and using
chloroform as eluent.

5d mp 134-135oC (recrystallized from ethanol); 1H-NMR (CDCl3) δ: 2.07 (t, 1H, J=2.6 Hz), 2.70 (s, 3H),
2.83-2.91 (m, 2H, J=2.7 Hz, J=7.0 Hz), 4.75 (t, 2H, J=7.0 Hz), 7.30-7.39 (m, 1H), 7.50-7.61 (m, 2H),
8.30-8.37 (m, 2H); IR (KBr) cm-1: 3280 (C≡C), 2936, 1600, 1130, 1100, 780; MS (m/z, %): 279 (1) [M+];
251 (100), 223 (4), 209 (7), 181 (14), 154 (5), 77 (50); Anal. Calcd for C15H13N5O: C, 64.51; H, 4.65; N,
25.08. Found: C, 64.29; H, 4.78; N, 24.96.
5e mp 99-100 oC (recrystallized from ethanol); 1H-NMR (CDCl3) δ: 1.99 (t, 1H, J=2.6 Hz), 2.11-2.25 (m,
2H), 2.48-2.56 (td, 2H, J=2.6 Hz, J=6.6 Hz), 4.74 (t, 2H, J=6.1 Hz), 7.31-7.39 (m, 1H), 7.52-7.60 (m,
2H), 8.32-8.37 (m, 2H); IR (KBr) cm-1: 3250 (C≡C), 2930, 1600, 1330, 1130, 1070, 700; MS (m/z, %):
293 (5) [M+], 265 (38), 236 (6), 188 (10), 130 (16), 77 (100); Anal. Calcd for C16H15N5O: C, 65.52; H,
5.12; N, 23.89. Found: C, 65.32; H, 5.32; N, 23.99.
5-(2-Cyanophenoxy)-3-methyl-1-phenyl-1H-pirazolo[4,3-e][1,2,4]triazine (5f)
To a solution of sulfone (4) (289 mg, 1 mmol) in dry DMF (10 mL) sodium 2-cyanophenolate (155 mg,
o
1.1 mmol) was added. The resulting solution was stirred at 120 C for 1.5 h, then was poured into
ice/water (100 mL). The precipitate solid of 5f was collected by filtration and washed with water. The
crude product was purified on column chromatography (silica gel, chloroform) to yield 259 mg (79%) of
o
1
yellow solid. mp 183 C (recrystallized from ethanol); H-NMR (CDCl3) δ: 2.71 (s, 3H), 7.31-7.46 (m,
3H), 7.50-7.60 (m, 2H), 7.68-7.81 (m, 2H), 8.29-8.36 (m, 2H); IR (KBr) cm-1: 2980, 2230 (C≡N), 1600,
1300, 1150, 750; MS (m/z, %): 328 (37) [M+]; 299 (11), 259 (6), 223 (7), 196 (11), 77 (100); Anal. Calcd
for C18H12N6O: C, 65.85; H, 3.65; N, 25.60. Found: C, 65.57; H, 3.83; N, 25.68.
3-Methyl-1-phenyl-5-phenylosulfanyl-1H-pyrazolo[4,3-e][1,2,4]triazine (5g).
To the solution of 4 (145 mg, 0.5 mmol) in dry THF (5 mL) cooled to 0-5 oC was added thiophenol (0.1
o
mL) and sodium hydride (24 mg, 0.55 mmol, 60 %). The resulting mixture was stirred at 0-5 C for 10
min. After that time the solvent was evaporated in vacuo and the crude product was purified by column
chromatography (silica gel, chloroform) and recrystallized from ethanol to give 144 mg (90%) of 5g.
mp 142 oC (recrystallized from ethanol); 1H-NMR (CDCl3) δ: 2.65 (s, 3H), 7.33-7.37 (m, 1H), 7.46-7.57
(m, 5H), 7.71-7.76 (m, 2H), 8.29-8.34 (m, 2H); IR (KBr) cm-1: 1600, 1500, 1290, 1120, 780, 700; MS
(m/z, %): 319 (44) [M+], 290 (69), 214 (28), 188 (16), 121 (100), 77 (86); Anal. Calcd for C17H13N5S: C,
63.94; H, 4.07; N, 21.94. Found: C, 63.85; H, 4.21; N, 22.04.
2-(3-Methyl-1-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazin-5-yl)malonic acid diethyl ester (5h)
To a solution of sulfone 4 (145 mg, 0.5 mmol) in dry THF (10 mL) was added malonic diethyl ester (0.3
mL, 2 mmol) and sodium hydride (80 mg, 2 mmol, 60 %). The reaction mixture was refluxed for 3 h and

then the solvent was evaporated under reduced pressure. The resulting precipitate was chromatographed
o
1
(silica gel, chloroform) and recrystallized from ethanol to give 140 mg (76 %) of 5h. mp 140 C; H-
NMR (CDCl3) δ: 1.32 (t, 6H, J=7 Hz), 2.77 (s, 3H), 4.34 (q, 4H, J=7 Hz), 5.54 (s, 1H), 7.33-7.41 (m, 1H),
7.53-7.61 (m, 2H), 8.35-8.41 (m, 2H); HRMS (ESI) m/z, 392.1343, Calcd for C18H19N5O4Na [M+Na]
392.1329. This compound undergoes partial hydrolysis during recrystallization from ethanol what led to
variability in the microanalytical data.
5-Amino-3-methyl-1-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine (5i)
Compound (4) (289 mg, 1 mmol) was dissolved in 15 mL of dry liquid ammonia with exclusion of
moistuire. The mixture was stirred for 1 h at _33 oC and after that time ammonia was evaporated. Crude
o
1
solid was recrystallized from ethanol to give 219 mg (97 %) of 5i as yellow solid. mp 241 C; H-NMR
(CDCl3) δ: 2.70 (s, 3H), 7.27-7.50 (m, 3H, 1HAr, NH2), 7.50-7.62 (m, 2H), 8.05-8.14 (m, 2H); IR (KBr)
cm-1: 3350, 2990, 1600, 760, 700; MS (m/z, %): 226 (65) [M+]; 198 (23), 156 (5), 121 (9), 104 (65), 95
(27), 77 (100); Anal. Calcd for C11H10N6 : C, 58.40; H, 4.42; N, 37.16. Found: C, 58.25; H, 4.51; N,
36.99.
General procedure for the reaction of the sulfone (4) with amines
The sulfone (4) (289 mg, 1 mmol) was dissolved in 5 mL of anhydrous and fresh distilled amine. The
resulting solution was refluxed until the starting materials disappeared (TLC). The solvent was
evaporated to dryness and the residue was purified on silica gel and eluted with chloroform. Evaporation
of the solvent gave products (5j-5l).
3-Methyl-1-phenyl-5-phenylamino-1H-pyrazolo[4,3-e][1,2,4]triazine (5j)
o
1
mp 264 C (recrystallized from ethanol); H-NMR (CDCl3) δ: 2.72 (s, 3H), 6.65 (s, 1H, NH), 7.18-7.25
(m, 1H), 7.34-7.49 (m, 3H), 7.50-7.61 (m, 2H), 7.68-7.81 (m, 2H), 8,12-8.25 (m, 2H); IR (KBr) cm-1:
3280, 2980, 1610, 1500, 1130, 770, 690; MS (m/z, %): 302 (46) [M+], 273 (23), 232 (9), 197 (18), 104
(48), 77 (100); Anal. Calcd for C17H14N6: C, 67.54; H, 4.63; N, 27.81. Found: C, 67.55; H, 4.71; N,
27.78.
5-Benzylamino-3-methyl-1-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine (5k)
o
1
mp 173 C (recrystallized from ethanol); H-NMR (CDCl3) δ: 2.67 (s, 3H), 4.83 (s, 2H), 7.26-7.32 (m,
1H), 7.32-7.40 (m, 3H), 7.40-7.48 (m, 2H), 7.41-7.48 (m, 2H), 8.03-8.12 (m, 2H); IR (KBr) cm-1: 3250,
1580, 750, 700; MS (m/z, %): 316 (67) [M+], 287 (41), 211 (23), 142 (14), 91 (100), 77 (83); Anal. Calcd
for C18H16N6: C, 68.35; H, 5.06; N, 26.58. Found: C, 68.05; H, 5.22; N, 26.62.
5-Butylamino-3-methyl-1-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine (5l)

mp 151 oC (recrystallized from ethanol); 1H-NMR (CDCl3) δ: 0.99 (t, 3H, J=7.3 Hz), 1.44-1.53 (m, 2H),
1.70-1.78 (m, 2H), 2.69 (s, 3H), 3.64 (t, 2H, J=7.1 Hz), 7.34-7.38 (m, 1H), 7.51-7.56 (m, 2H), 8.04-8.07
(m, 2H); IR (KBr) cm-1: 3250, 2970, 1580, 760,700; MS (m/z, %): 282 (78) [M+]; 253 (11), 211 (51), 184
(16), 104 (37), 77 (100); Anal. Calcd for C15H18N6: C, 63.82; H, 6.38; N, 29.78. Found: C, 63.76; H,
6.36; N, 29.74.
5-Hydrazino-3-methyl-1-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine (5m)
To the solution of 4 (289 mg, 1 mmol) in dry THF (10 mL) cooled to 0-5 oC was added 0.1 mL (3 mmol)
o
anhydrous hydrazine. The reaction was stirred at 0-5 C for 30 min and additional 3 h at rt. After that
time the solvent was evaporated in vacuo and the crude product was recrystallized from ethanol to give
215 mg (89%) of the orange solid. mp 190 oC; 1H-NMR (CDCl3) δ: 2.66 (s, 3H), 4.09 (s, 2H, NH2), 6.91
(s, 1H, NH), 7.31-7.35 (m, 1H), 7.49-7.57 (m, 2H), 8.28-8.33 (m, 2H); IR (KBr) cm-1: 3300, 1600, 750;
MS (EI, m/z, %): 241 (30) [M+], 226 (12), 198 (10), 129 (20), 104 (34), 77 (100); HRMS (ESI) m/z
242.1133, Calcd for C11H12N7 (M+H) 242.1149.
The hygroscopic nature of this compound led to variability in the microanalytical data.
3-Methyl-1-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine (7)
To the solution of compound (5m) (241 mg, 1 mmol) in dry ethanol (20 mL) yellow mercury oxide(II)
(1.08 g, 5 mmol) was added and the mixture was heated at reflux for 1 h. After that time the reaction
mixture was filtered off and the solvent was evaporated in vacuo. The crude product was purified by
o
column chromatography (silica gel, chloroform) to give 129 mg (61%) of 7. mp 95 C (recrystallized
1
from ethanol); H-NMR (CDCl3) δ: 2.80 (s, 3H), 7.33-7.41 (m, 1H), 7.54-7.62 (m, 2H), 8.36-8.41 (m,
2H), 9.82 (s, 1H); IR (KBr) cm-1: 1600, 760, 700; MS (m/z, %): 211 (42) [M+], 183 (18), 142 (100), 115
.
(46), 77 (64), 51 (90); Anal. Calcd for C11H9N5 0.25 H2O: C, 61.25; H, 4.40; N, 32.48. Found: C, 61.52;
H, 4.39; N, 32.70.
7-Methyl-1-phenyl-1H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-b][1,2,4]triazine (8a) and 3,7-dimethyl-5-
phenyl-1H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-b][1,2,4]triazine (8b)
Compound (5m) (120 mg, 0.5 mmol) was treated with appropriate carboxylic acid (2 mL) and heated at
100 oC for 1 h. The reaction mixture was poured into ice/water (50 mL) and the precipitated solids (8a) or
(8b) were collected by filtration and washed with water. The crude products were purified by column
chromatography using chloroform-ethanol mixture 30:1 as eluent.
8a Yield 92 %. mp 180 oC (recrystallized from ethanol); 1H-NMR (CDCl3) δ: 2.80 (s, 3H), 7.31-7.39 (m,
1H), 7.52-7.60 (m, 2H), 8.09-8.14 (m, 2H), 9.35 (s, 1H); MS (m/z, %): 251 (100) [M+], 155 (12, 103 (72),

77(44); Anal. Calcd for C12H9N7: C, 57.37; H, 3.58; N, 39.04. Found: C, 57.30; H, 3.60; N, 39.05.
o
8b Yield 89 %. mp 205 C (recrystallized from ethanol); 1H-NMR (CDCl3) δ: 2.17 (s, 3H), 2.65 (s, 3H),
7.32-7.36 (m, 1H), 7.49-7.57 (m, 2H), 8.27-8.31 (2H); MS (m/z, %): 265 (4) [M+], 241 (41), 226 (11),
.
197 (12), 129 (18), 104 (25), 94 (12), 77 (100); Anal. Calcd for C13H11N7 H2O: C, 55.12; H, 4.59; N,
34.62. Found: C, 55.13; H, 4.62; N, 34.45.
REFERENCES
1. Part 25 in a series “1,2,4-Triazines in Organic Synthesis”. For Part 24, see D. Branowska,
Tetrahedron, 2004, in print.
2. H. Neunhoeffer, in Comprehensive Heterocyclic Chemistry, Vol. 6, ed. by A. R. Katritzky and C. V.
Ress, Pergamon Press, Oxford, 1996, pp. 507-573.
3. H. J. Linder and G. Schaden, Chem. Ber., 1972, 105, 1949.
4. K. Hirata, H. Nakagami, J. Takashina, T. Mahmud, M. Kobayashi, Y. In, T. Ishida, and K. Miyamoto,
Heterocycles, 1996, 43, 1513.
5. V. V. Smirnov, E. A. Kiprianowa, A. D. Garagulya, S. E. Esipov, and S. A. Dovjenko, FEMS
Microbiology Lett., 1997, 153, 357.
6. K. Nalepa and J. Slouka, Pharmazie, 1984, 39, 504.
7. M. Z. A. Badr, M. M. Aly, Z. H. Khalil, and A. A. Attalla, Ind. J. Chem., 1982, 21B, 115.
8. A. Rykowski, M. Mariusz, and Z. Karczmarzyk, Heterocycles, 2000, 53, 2175.
9. M. Mojzych and A. Rykowski, Polish J. Chem., 2003, 77, 1797.
10. V. N. Charushin, S. G. Alexeev, O. N. Chupakhin, and H. C. van der Plas, Adv. Heterocycl. Chem.,
1989, 46, 73.
11. A. Rykowski and T. Lipińska, Synt. Comm., 1996, 26, 4409.
12. V. N. Charushin, O. N. Chupakhin, and H. C. van der Plas “Nucleophilic Substitution of Hydrogen”,
Academic Press, 1994.
13. M. Mąkosza and K. Wojciechowski, Heterocycles, 2001, 54, 445.
14. M. Mąkosza and K. Wojciechowski, Chem. Rev., 2004, 104, 2631.
15. A. Rykowski and M. Mąkosza, Liebigs Ann. Chem., 1988, 627.