Synthesis of 5-substituted 1,3-dimethylpyrazolo[4,3-e][1,2,4]triazines

Article abstract of DOI:10.1007/s00706-006-0583-0

A novel method for the synthesis of a new series of 5-substituted 1,3-dimethyl pyrazolo[4,3-e][1,2,4]triazines is described. The new synthetic strategy is based on the classical Bischler 1,2,4-benzotriazine synthesis. This approach involves the preparatio

Full text of DOI:10.1007/s00706-006-0583-0

Monatshefte fu¨r Chemie 138, 157–160 (2007)
DOI 10.1007/s00706-006-0583-0
Printed in The Netherlands
Synthesis of 5-Substituted 1,3-Dimethylpyrazolo[4,3-e][1,2,4]triazines
Kayed A. Abu Safieh1, Ahmad M. Abu Mahthieh1, Mustafa M. El-Abadelah2,
Mikdad T. Ayoub1, and Wolfgang Voelter3;ꢀ
1
Chemistry Department, Faculty of Science, The Hashemite University, Zarqa, Jordan
2
Chemistry Department, Faculty of Science, University of Jordan, Amman, Jordan
3
¨ ¨
¨ ¨ ¨
Interfakultares Institut fur Biochemie, Universitat Tubingen, Tubingen, Germany
Received July 12, 2006; accepted July 25, 2006; published online January 17, 2007
# Springer-Verlag 2007
Summary. A novel method for the synthesis of a new series
pyrazolo[4,3-e][1,2,4]triazines involve intramolecu-
of 5-substituted 1,3-dimethyl pyrazolo[4,3-e][1,2,4]triazines is
described. The new synthetic strategy is based on the classical
Bischler 1,2,4-benzotriazine synthesis. This approach involves
the preparation of 5-hydrazinopyrazole from 5-chloro-1,3-di-
methyl-4-nitropyrazole followed by acylation and nitro group
reduction to form the corresponding 4-amino-3-(acylhydrazi-
no)pyrazoles. Intramolecular oxidative cyclization of the latter
derivatives, using polyphosphoric acid, produced the respec-
tive target pyrazolotriazines.
lar cyclization of the respective hydrazones using
phosphorous oxychloride or ethanolic HCl [8, 9]. In
literature, the reported procedures illustrate that the
pyrazole ring was constructed onto the 1,2,4-triazine
nucleus. To the best of our knowledge, the only re-
port concerned with construction of a triazine skele-
ton onto pyrazole was reported by Youssef et al. [10].
Herein, we report a new approach for the construction
of the 1,2,4-triazine nucleus on a pyrazole derivative
based on the classical Bischler 1,2,4-benzotriazine
synthesis (Scheme 1) [11].
Keywords. Pyrazolotriazines; Bischler reaction; Oxidative
cyclisation.
Introduction
The pyrazolo-1,2,4-triazines have received consid-
erable attention due to their pharmacological appli-
cations as antiviral [1], antitumor [2], antifungal [3],
analgesic, anti-inflammatory, and antipyretic agents
[4]. Thepyrazolo[4,3-e][1,2,4]triazineskeletonisalso
found in many natural products such as pseudoiodin-
ine [5] and nostocine A [6]. The latter systems inhib-
it the growth of Gram-positive and Gram-negative
bacteria with somewhat weaker action against fungi
[7, 9] as well as antitumor activity [6, 8]. The most
widely used routes to synthesize 1,3,5-trisubstituted
ꢀ
tuebingen.de
Corresponding author. E-mail: wolfgang.voelter@uni-
Scheme 1

158
K. A. Abu Safieh et al.
with reference to TMS as internal standard. Coupling constants
are given in Hz. Electron impact mass spectra (MS-EI) were
measured on a Varian MAT-112S spectrometer at 70 eV
and at an ion source temperature of 200ꢂC. Microanalyses
were performed at the Microanalytical Laboratory of the
Hashemite University, Zarqa-Jordan, and the results were
found to be in good agreement (ꢃ0.4%) with the calculated
values.
Results and Discussion
5-Chloro-1,3-dimethyl-4-nitro-1H-pyrazole (1) is
utilized as synthon in the preparation of the target
compounds. Hydrazinolysis of 1, using hydrazine
hydrate and ethanol at reflux, yielded the corre-
sponding 5-hydrazino derivative 2 in an SN Ar addi-
tion-elimination reaction. Acylation of 2 with the
appropriate acyl chloride in dry THF furnished the
respective acid hydrazides 3a–3e. The nitro group of
the latter compounds was reduced chemically (using
hydrazine hydrate and Raney nickel) into their re-
spective 4-amino analogs 4a–4e, which were rela-
tively unstable intermediates (Scheme 1). Of these,
4b was characterized whilst the others were not puri-
fied, but were used directly (as crude products) for
the final cyclization step. Intramolecular oxidative
cyclodehydration of 4a–4e into the corresponding
targeted bicycles was accomplished using polyphos-
phoric acid (PPA).
5-Hydrazino-1,3-dimethyl-4-nitro-1H-pyrazole
(2, C5H9N5O2)
To a solution of 0.88 g 1 (5 mmol) in 30 cm3 absolute etha-
nol, was added dropwise hydrazine hydrate (85%, 8 cm3,
160 mmol). The resulting yellow solution was stirred for
15 min at ambient temperature, then refluxed (H2O bath)
for 2 h. The solvent was then removed under vacuum, and
the residual solid product was recrystallized from ethanol to
afford yellow crystals of 2. Yield 0.59g (69%); mp 179–
1
180ꢂC (Ref. [12] 175–176ꢂC); H NMR (300MHz, CDCl3):
ꢁ ¼ 2.39 (s, C(3)-CH3), 3.92 (br s, C(5)-NH2), 3.95 (s, N(1)-
CH3), 8.07 (br s, C(5)-NH) ppm; 13C NMR (75 MHz, CDCl3):
ꢁ ¼ 14.4 (C(3)-CH3), 39.3 (N(1)-CH3), 118.1 (C-3), 145.0
(C-4), 147.6 (C-5); IR: ꢀꢀ¼ 3339 (NH), 1664 (C¼N), 1582,
1367 (NO2) cmꢁ1
.
The structures of the new compounds 3a–3e, 4b,
and 5a–5e were supported by elemental analysis, IR,
MS, and NMR spectral data. Thus, the mass spectra
displayed the correct molecular ions [Mþ] suggest-
ed from their molecular formulae. Those of 5a–5e
are dominated by fragment ions corresponding to
[M ꢁ 28] and [M ꢁ 43] due to successive loss of N2
and methyl radical. The IR spectra of 5a–5e showed
strong bands in the range of ꢀꢀ¼ 1510–1560 cmꢁ1
corresponding to C¼N stretching, but lack those
bands around 1660 cmꢁ1 attributed to the hydrazide
General Procedure for the Synthesis of N0-(1,3-Dimethyl-
4-nitro-1H-pyrazol-5-yl) acid hydrazides 3a–3e
To a cooled (0ꢂC) solution of 0.17 g 2 (1mmol) in 30cm3 dry
THF was added dropwise 1.5 mmol of the appropriate acid
chloride. The reaction mixture was further stirred at 0ꢂC for
1.5 h and stirring was continued at ambient temperature for
overnight. The solvent was then removed under vacuum and
the residual solid product was collected by suction filtration,
washed with petroleum ether (bp 40–60ꢂC, 2ꢄ10 cm3) and
dried to give the respective products 3a–3e.
1
C¼O present in 4. H and 13C signal assignments
N0-(1,3-Dimethyl-4-nitro-1H-pyrazol-5-yl)benzohydrazide
(3a, C12H13N5O3)
are based on DEPT and 2D (COSY, HMQC, and
HMBC) experiments.
Yield 95%; mp 230ꢂC (dec); 1H NMR (300MHz, DMSO-d6):
ꢁ ¼ 2.30 (s, C(3)-CH3), 3.60 (s, N(1)-CH3), 7.53 (m, H-30 þ H-
40 þ H-50), 7.85 (m, H-20 þ H-60), 8.97 (br s, C(5)-NH), 10.93
(br s, HN-C¼O) ppm; 13C NMR (75 MHz, DMSO-d6):
ꢁ ¼ 14.5 (C(3)-CH3), 38.2 (N(1)-CH3), 118.7 (C-3), 128.0
(C-20 þ C-60), 129.2 (C-30 þ C-50), 132.0 (C-10), 132.8 (C-40),
144.0 (C-4), 147.0 (C-5), 167.2 (C¼O) ppm; IR: ꢀꢀ¼ 3254
1
The H NMR spectrum of 5b lacks the signals
corresponding to C(5)-NH, C(4)-NH2 and C(5)-
NHCO protons present in its precursor 4b. Likewise,
the 13C NMR spectrum of 5b lacks the signal around
ꢁ ¼ 170 ppm present in the spectrum of 4b, assigned
to the carbon of the CONH group.
(NH), 1659 (C¼O), 1577, 1357 (NO2) cmꢁ1
.
N0-(1,3-Dimethyl-4-nitro-1H-pyrazol-5-yl)-
4-methylbenzohydrazide (3b, C13H15N5O3)
Experimental
Yield 93%; mp 221ꢂC (dec); 1H NMR (300MHz, DMSO-d6):
ꢁ ¼ 2.29 (s, C(40)-CH3), 2.36 (s, C(3)-CH3), 3.58 (s, N(1)-
CH3), 7.29 (d, J ¼ 7.8 Hz, H-30 þ H-50), 7.76 (d, J ¼ 7.8 Hz,
H-20 þ H-60), 8.94 (br s, C(5)-NH), 10.84 (br s, HN–C¼O)
ppm; 13C NMR (75 MHz, DMSO-d6): ꢁ ¼ 14.5 (C(3)-CH3),
21.5 (C(40)-CH3), 38.2 (N(1)-CH3), 118.7 (C-3), 128.0 (C-
20 þ C-60), 129.1 (C-10), 129.7 (C-30 þ C-50), 143.0 (C-40),
144.0 (C-4), 147.1 (C-5), 167.0 (HN–C¼O) ppm; IR:
5-Chloro-1,3-dimethyl-4-nitropyrazole (1) was purchased
from Maybridge CombiChem (UK) and the acyl chlorides
employed in this study were purchased from Acros. Melting
points were determined on a SMP2 Stuart melting point
apparatus. IR spectra were measured as KBr discs with a
Nicolet-MAGNA-IR-560 spectrophotometer. 1H and 13C NMR
spectra were recorded in CDCl3 or DMSO-d6 on a Bruker
DPX-300 instrument. Chemical shifts are expressed in ppm
ꢁ1
ꢀ
ꢀ ¼ 3272 (NH), 1669 (C¼O), 1577, 1352 (NO2) cm
.

5-Substituted 1,3-Dimethylpyrazolo[4,3-e][1,2,4]triazines
159
N0-(1,3-Dimethyl-4-nitro-1H-pyrazol-5-yl) acetohydrazide
(3c, C7H11N5O3)
The following compounds of this series 4a and 4c–4e were
prepared by adopting the same procedure and experimental
conditions described above for 4b:
Yield 85%; mp 235ꢂC (dec); 1H NMR (300 MHz, DMSO-d6):
ꢁ ¼ 1.86 (s, O¼C–CH3), 2.26 (s, C(3)-CH3), 3.58 (s, N(1)-
N0-(4-Amino-1,3-dimethyl-1H-pyrazol-5-yl)benzohydrazide
(4a, C12H15N5O)
CH3), 8.66 (br s, C(5)-NH), 10.36 (br s, HN–C¼O) ppm; 13
C
NMR (75 MHz, DMSO-d6): ꢁ ¼ 14.5 (C(3)-CH3), 20.5 (C(4)-
CH3), 38.1 (N(1)-CH3), 118.5 (C-3), 143.9 (C-4), 146.9 (C-5),
170.1 (HN–C¼O) ppm; IR: ꢀꢀ¼ 3276 (NH), 1667 (C¼O),
N0-(4-Amino-1,3-dimethyl-1H-pyrazol-5-yl)acetohydrazide
(4c, C7H13N5O)
N0-(4-Amino-1,3-dimethyl-1H-pyrazol-5-yl)-2-thienohydrazide
(4d, C10H13N5OS)
1582, 1357 (NO2) cmꢁ1
.
N0-(4-Amino-1,3-dimethyl-1H-pyrazol-5-yl)-2-furohydrazide
(4e, C10H13N5O2)
N0-(1,3-Dimethyl-4-nitro-1H-pyrazol-5-yl)-2-
thienohydrazide (3d, C10H11N5O3S)
However, these compounds were directly used as crude
products, without characterization, for the synthesis of the
respective target compounds 5a–5e.
Yield 82%; mp 170ꢂC (dec); 1H NMR (300 MHz, DMSO-d6):
ꢁ ¼ 2.28 (s, C(3)-CH3) 3.60 (s, N(1)-CH3), 7.17 (dd, J ¼ 4.1,
5.3 Hz, H-40), 7.84 (d, J ¼ 5.3 Hz, H-30), 7.92 (d, J ¼ 4.1 Hz,
H-50), 9.00 (br s, C(5)-NH), 11.08 (br s, HN–C¼O) ppm; 13C
NMR (DMSO-d6): ꢁ ¼ 14.5 (C(3)-CH3), 38.3 (N(1)-CH3),
118.7 (C-3), 128.9 (C-40), 130.2 (C-50), 132.9 (C-30), 136.4
(C-20), 144.0 (C-4), 146.9 (C-5), 162.1 (HN–C¼O) ppm; IR:
ꢀꢀ¼ 3233 (NH), 1651 (C¼O), 1572, 1357 (NO2) cm1.
General Procedure for the Synthesis of 5-Substituted 1,3-
Dimethylpyrazolo[4,3-e][1,2,4]triazines 5a–5e
A stirred suspension of substituted N0-(4-amino-1,3-dimethyl-
1H-pyrazol-5-yl) acid hydrazides 4a–4e in 15cm3 PPA was
heated in an oil bath at 140ꢂC for 1 h. The reaction mix-
ture was then slowly poured with stirring onto crushed ice
(50 cm3). Sodium hydrogen carbonate was added until the
solution was basic, then the mixture was extracted with CHCl3
(3ꢄ75 cm3). The combined organic extracts were dried
(anhydrous Na2CO3) and the solvent was concentrated under
reduced pressure to give the respective title products 5a–5e
which were further purified on silica gel TLC plates using
CHCl3:MeOH (98:2, v:v) as the developing solvent mixture.
N0-(1,3-Dimethyl-4-nitro-1H-pyrazol-5-yl)-2-furohydrazide
(3e, C10H11N5O4)
Yield 95%; mp 175ꢂC (dec); 1H NMR (300 MHz, DMSO-d6):
ꢁ ¼ 2.28 (s, C(3)-CH3), 3.57 (s, N(1)-CH3), 6.65 (br , H-40),
7.26 (br d, J ¼ 3.1Hz, H-30), 7.91 (br d, J ¼ 2.8 Hz, H-50), 8.96
(br s, N(1)H), 10.86 (br s, HN¼C¼O) ppm; 13C NMR
(75 MHz, DMSO-d6): ꢁ ¼ 14.5 (C(3)-CH3), 38.2 (N(1)-CH3),
112.6 (C-40), 116.0 (C-30), 118.6 (C-3), 144.0 (C-4), 145.8 (C-
5), 146.8 (C-50), 146.9 (C-20), 158.6 (HN–C¼O) ppm; IR:
1,3-Dimethyl-5-phenyl-1H-pyrazolo[4,3-e][1,2,4]triazine
(5a, C12H11N5)
ꢀꢀ¼ 3235 (NH), 1654 (C¼O), 1579, 1357 (NO2) cmꢁ1
.
Yield 24%; mp 122–123ꢂC; 1H NMR (300MHz, CDCl3):
ꢁ ¼ 2.71 (s, C(3)-CH3), 4.29 (s, N(1)-CH3), 7.54 (m, H-30 þ
H-40 þ H-50), 8.60 (dd, J ¼ 7.6, 2.0 Hz, H-20 þ H-60) ppm; 13C
NMR (75 MHz, CDCl3): ꢁ ¼ 11.1 (C(3)-CH3), 34.8 (N(1)-
CH3), 128.1 (C-20 þ C-60), 128.9 (C-30 þ C-50), 130.7 (C-40),
136.0 (C-3), 142.3 (C-3a), 147.6 (C-7a), 159.1 (C-5) ppm; IR:
ꢀꢀ¼ 1511 (C¼N) cmꢁ1; MS-EI: m=z (%) ¼ 225 (25) [Mþ],
197 (100), 182 (39),156 (66), 141 (56).
General Procedure for the Synthesis of N0-(4-Amino-1,3-
dimethyl-1H-pyrazol-5-yl) Acid Hydrazides 4a–4e
Exemplified by 4b
N0-(4-Amino-1,3-dimethyl-1H-pyrazol-5-yl)-4-
methylbenzohydrazide (4b, C13H17N5O)
A solution of hydrazine hydrate (85%, 20 cm3, 0.41 mol)
was added dropwise to a solution of 0.58 g 3b (2 mmol) in
25 cm3 methanol and 0.8 g of Raney nickel catalyst at room
temperature. After addition of 10 cm3 hydrazine hydrate,
another 0.4 g of Raney nickel were added, then the rest of
hydrazine hydrate was added dropwise. The reaction mix-
ture was refluxed for 1 h, cooled and the catalyst removed by
filtration. The filtrate was concentrated under reduced pres-
sure, and the residue was recrystallized from chloroform-
petroleum ether to give 0.15 g (29%) 4b. Mp 149–150ꢂC;
1H NMR (300 MHz, CDCl3): ꢁ ¼ 2.07 (s, C(40)-CH3),
2.35(s, C(3)-CH3), 3.66(s, N(1)-CH3), 7.17 (d, J ¼ 7.4 Hz,
H-30 þ H50), 7.61 (d, J ¼ 7.4 Hz, H-20 þ H-60), 3.24 (br s,
C(5)-NH þ C(4)-NH2), 8.52 (s, NH–C¼O) ppm; 13C NMR
(75 MHz, DMSO-d6): ꢁ ¼ 11.3 (C(3)-CH3), 21.6 (C(40)-
CH3), 34.9 (N(1)-CH3), 119.1 (C-3), 127.1 (C-20 þ C-60),
129.0 (C-10), 129.5 (C-30 þ C-50), 133.0 (C-40), 137.1(C-4),
143.0 (C-5), 168.6 (NH–C¼O) ppm; IR: ꢀꢀ¼ 3375 (NH),
1,3-Dimethyl-5-(4-methylphenyl)-1H-pyrazolo[4,3-e]
[1,2,4]triazine (5b, C13H13N5)
Yield 21%; mp 152–153ꢂC; 1H NMR (300MHz, CDCl3):
ꢁ ¼ 2.43 (s, C(40)-CH3), 2.70 (s, C(3)-CH3), 4.28 (s, N(1)-
CH3), 7.34 (d, J ¼ 8.1 Hz, H-30 þ H-50), 8.49 (d, J ¼ 8.1 Hz,
H-20 þ H-60) ppm; 13C NMR (75 MHz, CDCl3): ꢁ ¼ 11.1
(C(3)-CH3), 21.5 (C(1)-CH3), 34.7 (N(1)-CH3) 128.0 (C-
20 þ C-60), 129.6 (C-30 þ C-50), 133.3 (C-10), 135.0 (C-3),
141.4 (C-40), 142.1(C-3a), 147.6 (C-7a), 159.2 (C-5) ppm;
IR: ꢀꢀ¼ 1511 (C¼N) cmꢁ1; MS-EI: m=z (%) ¼ 239 (21)
[Mþ], 211 (100), 196 (66), 170 (27), 155 (36).
1,3,5-Trimethyl-1H-pyrazolo[4,3-e][1,2,4]triazine
(5c, C7H9N5)
Yield 20%; mp 83–84ꢂC; 1H NMR (300 MHz, CDCl3):
ꢁ ¼ 2.63 (s, C(3)-CH3), 3.04 (s, C(5)-CH3), 4.24 (s, N(1)-
CH3) ppm; 13C NMR (75 MHz, CDCl3): ꢁ ¼ 11.0 (C(3)-CH3),
1636 (C¼O) cmꢁ1
.

160
K. A. Abu Safieh et al.: 5-Substituted 1,3-Dimethylpyrazolo[4,3-e][1,2,4]triazines
23.6 (C(5)-CH3), 34.7 (N(1)-CH3), 134.6 (C-3), 141.1 (C-3a),
147.6 (C-7a), 161.3 (C-5) ppm; IR: ꢀꢀ¼ 1557 (C¼N) cmꢁ1
Bu¨ro des Bundesministeriums fu¨r Bildung und Forschung
(Bonn, Germany) for financial support.
;
MS-EI: m=z (%) ¼ 163 (30) [Mþ], 135 (58), 120 (22), 94
(100), 79 (43).
References
1,3-Dimethyl-5-(2-thienyl)-1H-pyrazolo[4,3-e]
[1] Manfredini S, Bazzanini R, Baraldi PG, Guarneri M,
Simoni D, Marongiu ME, Pani A, La Colla P,
Tramontano E (1992) J Med Chem 35: 917
[2] Arden GM, Grant DJW, Partridge MW (1970) Biochem
Pharmacol 19: 71
[3] Tewari AK, Mishara L, Verma HN (2002) Indian J Chem
41B: 664
[4] Mavel S, Rubat C, Coudert P, Privat AM, Couquelet J,
Tronche P, Bastide P (1993) Arzneimettel-Forschung
43: 464
[1,2,4]triazine (5d, C10H9N5S)
Yield 32%; mp 138–140ꢂC; 1H NMR (300MHz, CDCl3):
ꢁ ¼ 2.66 (s, C(3)-CH3), 4.24 (s, N(1)-CH3), 7.19 (dd, J ¼ 3.7,
5.0 Hz, H-40), 7.49 (d, J ¼ 5.0 Hz, H-30), 8.13 (d, J ¼ 3.7 Hz,
H-50) ppm; 13C NMR (75 MHz, CDCl3): ꢁ ¼ 11.1 (C(3)-CH3),
34.8 (N(1)-CH3), 128.4 (C-40), 128.7 (C-30), 129.7 (C-50),
134.5 (C-3), 140.7 (C-20), 141.9 (C-3a), 147.2 (C-7a), 156.7
(C-5) ppm; IR: ꢀꢀ¼ 1511 (C¼N) cmꢁ1; MS-EI: m=z (%) ¼
231 (58) [Mþ], 203 (70), 188 (100), 162 (33), 147 (48).
[5] Lindner HJ, Schaden G (1972) Chem Ber 105: 1949
[6] Hirata K, Nakagami H, Takashina J, Mahmud T,
Kobayashi M, In Y, Ishida T, Miyamoto K (1996)
Heterocycles 43: 1513
l,3-Dimethyl-5-(2-furyl)-1H-pyrazolo[4,3-e][1,2,4]triazine
(5e, C10H9N5O)
Yield 26%; mp 143–145ꢂC; 1H NMR (300MHz, CDCl3):
ꢁ ¼ 2.70 (s, C(3)-CH3), 4.34 (s, N(1)-CH3), 6.62 (dd, J ¼ 3.0,
3.4 Hz, H-40), 7.51 (d, J ¼ 3.4 Hz, H-30), 7.69 (br d, J ¼ 3.0 Hz,
H-50) ppm; 13C-NMR (75 MHz, CDCl3): ꢁ ¼ 11.2 (C(3)-CH3),
34.8 (N(1)-CH3), 112.4 (C-40), 113.4 (C-30), 134.8 (C-3),
142.1 (C-3a), 145.3 (C-50), 147.0 (C-7a), 150.7 (C-20), 156.6
(C-5) ppm; IR: ꢀꢀ¼ 1521 (C¼N) cmꢁ1; MS-EI: m=z (%) ¼ 215
(100) [Mþ], 187 (5), 172 (4), 146 (7), 131 (4).
[7] Mojzych M, Rykowski A (2004) Heterocycles 63: 1829
´
´
[8] Nalepa K, Guky T (2001) Acta Univ Palacki Olomuc
Fac Rer Nat Chemica 40: 49
[9] Rykowski A, Mojzych M, Karczmazyk Z (2000)
Heterocycles 53: 2175; Mojzych M, Rykowski A,
Wierzchowski J (2005) Molecules 10: 1298
[10] Youssef MSK, Hassan KM, Atta FM, Abbady MS
(1984) J Heterocycl Chem 21: 1565
[11] Abramovitch RA, Schofield K (1955) J Chem Soc
2326
Acknowledgements
We are grateful to the Deanship of Scientific Research of the
Hashemite University (Zarqa, Jordan) and to Internationales
[12] Baryshnenkova LI, Perevalov VP, Polyakov VA (1997)
Chemistry of Heterocyclic Compounds 33(9): 1113