Strategy for the Synthesis of pyrazolo[5,1-d][1,2,5]triazepinones, a new heterocyclic system

Article abstract of DOI:10.1134/S1070428016090128

A preparative procedure has been developed for the synthesis of 4-oxo-7-phenyl-5,8-dihydro-4H-pyrazolo[ 5,1-d][1,2,5]triazepine-2-carbohydrazide, the first representative of a new heterocyclic system, by recyclization of methyl 4-oxo-6-phenyl-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate with hydrazine hydrate.

Full text of DOI:10.1134/S1070428016090128

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 9, pp. 1322–1325. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © A.O. Kharaneko, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52, No. 9, pp. 1334–1337.
Strategy for the Synthesis of Pyrazolo[5,1-d][1,2,5]triazepinones,
a New Heterocyclic System
A. O. Kharaneko
Litvinenko Institute of Physical Organic and Coal Chemistry, ul. R. Lyuksemburg 70, Donetsk, 83114 Ukraine
e-mail: antonhar08@rambler.ru
Received June 7, 2016
Abstract—A preparative procedure has been developed for the synthesis of 4-oxo-7-phenyl-5,8-dihydro-4H-
pyrazolo[5,1-d][1,2,5]triazepine-2-carbohydrazide, the first representative of a new heterocyclic system, by
recyclization of methyl 4-oxo-6-phenyl-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate with hydrazine hydrate.
DOI: 10.1134/S1070428016090128
Seven-membered nitrogen heterocycles and their
hetero-fused derivatives are structural fragments of
many biologically active compounds and modern
medicinal agents. Among these, 1,4- and 2,3-benzodi-
azepines are very important. Drugs based thereon are
used for the treatment of anxieties, epilepsy, malignant
glioma, lateral amyotrophic sclerosis, and Parkinson’s
and Alzheimer’s diseases; they exhibit anticonvulsant
activity and may be used as minor tranquilizers [1–6].
Benzotriazepines and benzotriazepinones possess
various biological activities; in particular, they act as
antagonists of cholecystokinin receptor (CCK2) and
parathyroid peptide-related hormone receptor
(PTH1R); psychotropic compounds of these series are
characterized by a lower number of side effects than
benzodiazepine derivatives [6, 7].
Hetero-fused 1,2,5-triazepines with a bridgehead
nitrogen atom can be used as neurotropic agents [7].
Pyrazolo[1,2-a][1,2,5]triazepine derivatives affect cen-
tral nervous system [8] and exhibit pesticidal and
herbicidal activities [7]. However, such compounds
remain so far difficultly accessible because of the lack
of a general method of their synthesis.
While initiating studies on the synthesis of pyrazolo-
[5,1-d][1,2,5]triazepines from accessible reagents,
I have found no published data on this fused hetero-
cyclic system. The strategy for building up pyrazolo-
[5,1-d][1,2,5]triazepine skeleton was developed on the
basis of known methodology for diazepine ring fusion
to benzene ring or other heterocycle. 2,3-Benzodiaz-
epinones and their heterocyclic analogs were success-
fully synthesized previously by reactions of 1,5-di-
Scheme 1.
O
O
Me
OH
OH
KMnO4
+
O
N
N
N
Me
Me
N
N
H
N
H
H
HO
1
2
O
OMe
O
PhC(O)CH2Br
Na2CO3
OMe
O
MeOH, HCl
N
1
N
O
N
MeO
Ph
N
H
MeO
O
3
4
1322

STRATEGY FOR THE SYNTHESIS OF PYRAZOLO[5,1-d][1,2,5]TRIAZEPINONES
1323
Scheme 2.
O
O
NHNH2
N2H4·H2O
N2H4·H2O
O
HN
N
4
O
N
N
N
N
NHNH2
H2NNH
Ph
Ph
5
O
O
O
O
HN
PPA
N2H4·H2O
O
4
N
N
N
N
OMe
N
NHNH2
Ph
Ph
6
7
ketones or 2-aroyl(acetyl)phenylacetic acids and their
esters with hydrazine [9–11]. Therefore, dimethyl 1-(2-
oxo-2-phenylethyl)-1H-pyrazole-3,5-dicarboxylate (4)
was selected as probable precursor to pyrazolo[5,1-d]-
[1,2,5]triazepine.
2,5-Dihydro-5H-2,3-benzodiazepin-1-one [13] and
pyrrolo[3,4-d][1,2]diazepinone derivatives [9] were
synthesized previously in preparative yields by reac-
tions of 3-(3,4-dimethoxyphenyl)-1H-isochromen-1-
one and pyrano[3,4-c]pyrrol-4(2H)-one with hydrazine
hydrate. Taking these results into account, compound 6
was used as starting material for the synthesis of
pyrazole fused to triazepine. In fact, pyrazolooxazine 6
reacted with hydrazine hydrate in isopropyl alcohol
under reflux to give 57% of 4-oxo-7-phenyl-5,8-di-
hydro-4H-pyrazolo[5,1-d][1,2,5]triazepine-2-carbohy-
drazide (7) (Scheme 2). A probable reaction mecha-
nism is shown in Scheme 3. The triazepinone ring is
formed via expansion of the lactone ring (without
opening) with hydrazine, followed by elimination of
water molecule.
The oxidation of 3,5-dimethylpyrazole with potas-
sium permanganate gave a mixture of 1H-pyrazol-3,5-
dicarboxylic acid (1) [12] and 5-methyl-1H-pyrazole-
3-carboxylic acid (2) (Scheme 1). Acids 1 and 2 were
separated by precipitation from aqueous solution at
different pH values. Esterification of 1 with methanol,
followed by alkylation of dimethyl 1H-pyrazole-3,5-
dicarboxylate (3) with phenacyl bromide afforded di-
methyl 1-(2-oxo-2-phenylethyl)-1H-pyrazole-3,5-di-
carboxylate (4).
It was expected that heating of 4 in hydrazine
hydrate would give rise to 4-oxo-7-phenyl-5,8-dihy-
dro-4H-pyrazolo[5,1-d][1,2,5]triazepine-2-carbohydra-
zide. However, the only isolated product was 1-(2-phe-
nylethyl)-1H-pyrazole-3,5-dicarbohydrazide (5, yield
10%; Scheme 2). Further accumulation of compound 5
was observed when the filtrate obtained after separa-
tion of 5 was heated under reflux. Obviously, the
Wolff–Kishner reduction of the ketone carbonyl group
in 4 occurred under milder conditions than those typi-
cal of such reactions. Heating of 4 in polyphosphoric
acid (PPA) led to the formation of methyl 4-oxo-6-
phenyl-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylate
(6) (Scheme 2).
Taking into account accessibility of the initial
reactants and good yield, the proposed procedure for
the synthesis of 4-oxo-7-phenyl-5,8-dihydro-4H-pyra-
zolo[5,1-d][1,2,5]triazepine-2-carbohydrazide by reac-
tion of methyl 4-oxo-6-phenyl-4H-pyrazolo[5,1-c]-
[1,4]oxazine-2-carboxylate with hydrazine hydrate
may be recommended for preparative purposes.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Bruker Avance spectrometer at 400 and 100 MHz,
respectively, using DMSO-d6 as solvent and tetra-
Scheme 3.
O
O
O
O
NH
NH
OH
NH
N
N2H4·H2O
O
O
NH2
NH
Ph
–H2O
N
N
N
N
N
N
N
N
Ph
Ph
Ph
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 9 2016

KHARANEKO
1324
methylsilane as internal standard. The IR spectra were
measured in KBr on a Specord IR-75 instrument. The
melting points were determined on a Boetius hot stage
and are uncorrected.
1-(2-Phenylethyl)-1H-pyrazole-3,5-dicarbohy-
drazide (5). A mixture of 1 g (3.70 mmol) of 4 and
7 mL of hydrazine hydrate was refluxed for 2 h.
Excess hydrazine hydrate was evaporated by half, and
the residue was left to stand overnight at room tem-
perature. The precipitate was filtered off and washed
with water. Yield 0.1 g (10%), white crystals, mp 220–
221°C. IR spectrum, ν, cm–1: 3700 br (NH), 3240 br
1H-Pyrazole-3,5-dicarboxylic acid (1). 3,5-Di-
methyl-1H-pyrazole, 78.5 g (0.818 mol), was dissolved
in 700 mL of water heated to 70°C, and 517 g
(3.271 mol) of potassium permanganate was added to
the hot solution, maintaining the temperature no higher
than 90°C. The mixture was cooled to room tempera-
ture, the precipitate of MnO2 was filtered off and
washed with water, and the filtrate was acidified with
aqueous HCl to pH 2 and left overnight. The pre-
cipitate was filtered off and washed with water. Yield
41.75 g (33%), white crystals, mp 257–258°C.
1H NMR spectrum: δ 7.07 ppm, s (1H, 4-H).
1
(NH2), 1660 s (C=O), 1620 s (C=Carom). H NMR
spectrum, δ, ppm: 3.09 t (2H, CH2, J = 7.6 Hz),
4.38 br.s (4H, NH2, J = 7.6 Hz), 4.74 t (2H, CH2, J =
7.6 Hz), 7.28–7.17 m (6H, CH), 9.06 s (1H, NH),
9.83 s (1H, NH). 13C NMR spectrum, δC, ppm: 38.5
(CH2), 54.5 (CH2), 109.2, 128.3, 130.2, 130.6, 137.0,
139.8, 145.7, 160.4 (C=O), 162.4 (C=O). Found, %:
C 54.21; H 5.67; N 29.23. C13H16N6O2. Calculated, %:
C 54.16; H 5.59; N 29.15.
5-Methyl-1H-pyrazole-3-carboxylic acid (2). The
aqueous filtrate obtained after separation of diacid 1,
was neutralized to pH 5–6, and the precipitate of 2 was
filtered off and washed with water. Yield 18.1 g (18%),
Methyl 4-oxo-6-phenyl-4H-pyrazolo[5,1-c][1,4]-
oxazine-2-carboxylate (6). A mixture of 1 g
(3.31 mmol) of 4 and 6 g of polyphosphoric acid was
heated for 1 h at 140°C. The mixture was diluted with
excess methanol, and the precipitate was filtered off.
Yield 0.35 g (39%), white crystals, mp 197–198°C. IR
spectrum, ν, cm–1: 1750 s (C=O), 1695 s (C=Carom),
1
white crystals, mp 210–211°C. H NMR spectrum, δ,
ppm: 2.25 s (3H, CH3), 6.42 s (1H, 4-H).
Dimethyl 1H-pyrazole-3,5-dicarboxylate (3).
A mixture of 31.7 g (0.203 mol) of diacid 1 and
125 mL of methanol was saturated with gaseous HCl.
The mixture was refluxed for 3 h and left overnight at
room temperature. The precipitate was filtered off and
washed with methanol. Yield 23.5 g (63%), white
crystals, mp 142–143°C. IR spectrum, ν, cm–1: 3105 br
1
1250 s (C–O–C). H NMR spectrum, δ, ppm: 3.91 s
(3H, CH3), 7.47–7.59 m (4H, Harom), 7.87 d (2H, CH,
J = 6.8 Hz), 8.79 s (1H, CH). 13C NMR spectrum, δC,
ppm: 50.98 (CH3), 106.21, 109.18, 123.28, 126.75,
127.72, 128.01, 128.86, 142.50, 142.83, 151.67 (C=O),
159.55 (C=O). Found, %: C 62.19; H 3.80; N 10.41.
C14H10N2O4. Calculated, %: C 62.22; H 3.73; N 10.37.
1
(NH), 1710 s (C=O), 1240 s (C–O–C). H NMR spec-
trum, δ, ppm: 3.82 s (6H, CH3), 6.36 s (1H, 4-H),
4-Oxo-7-phenyl-5,6-dihydro-4H-pyrazolo[5,1-d]-
[1,2,5]triazepine-2-carbohydrazide (7). A mixture of
0.5 g (1.85 mmol) of 6 and 0.37 g (7.41 mmol) of
hydrazine hydrate in 5 mL of isopropyl alcohol was
refluxed for 3 h. The solution was cooled to room
temperature, and the precipitate was filtered off. Yield
0.3 g (57%), white crystals, mp 186–187°C. IR spec-
trum, ν, cm–1: 3300 br (NH), 1680 s (C=Carom).
1H NMR spectrum, δ, ppm: 5.73 s (2H, CH2), 7.08–
7.26 m (6H, CH), 7.68 d (2H, CH, J = 6.4 Hz), 9.25 s
(1H, NH), 10.04 s (1H, NH. 13C NMR spectrum, δC,
ppm: 46.31 (CH2), 108.90, 127.23, 129.10, 130.04,
137.82, 139.84, 141.51, 146.28, 160.74 (C=O), 162.18
(C=O). Found, %: C 54.87; H 4.29; N 29.55.
C13H12N6O2. Calculated, %: C 54.93; H 4.25; N 29.56.
14.43 s (1H, NH).
Dimethyl 1-(2-oxo-2-phenylethyl)-1H-pyrazole-
3,5-dicarboxylate (4). A mixture of 20.4 g (0.111 mol)
of diester 3, 33.19 g (0.167 mol) of phenacyl bromide,
and 23.5 g (0.222 mol) of sodium carbonate in 100 mL
of DMF was stirred for 13 h at 85°C. The mixture was
poured into water, and the precipitate was filtered off
and recrystallized from methanol. Yield 15.6 g (47%),
colorless crystals, mp 127–128°C. IR spectrum, ν,
cm–1: 1695 s (C=O), 1220 s (C–O–C). H NMR spec-
1
trum, δ, ppm: 3.81 s (3H, CH3), 3.87 s (3H, CH3),
6.17 s (2H, CH2), 7.31 s (1H, CH), 7.56 t (2H, CH,
J = 7.6 Hz), 7.67 t (1H, CH, J = 7.2 Hz), 8.05 d (2H,
CH, J = 7.6 Hz). 13C NMR spectrum, δC, ppm: 50.27
(CH3), 50.78 (CH3), 57.90 (CH2), 111.66, 126.65,
127.39, 132.47, 132.51, 132.77, 140.37, 157.47 (C=O),
159.62 (C=O), 190.33 (C=O). Found, %: C 59.53;
H 4.73; N 9.22. C15H14N2O5. Calculated, %: C 59.60;
H 4.67; N 9.27.
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