Regioselective and regiospecific reactions of ethyl ortho- (dimethylaminovinylazoloazinylcarboxylates with hydrazine

Article abstract of DOI:10.1134/S1070363210040225

Selectivity of reactions of ethyl 4-[(E)-2(dimethylamino)vinyl]pyrazolo[5, 1-c]-[1,2,4]triazino-3-ylcarboxylates and ethyl 7-[(E)-2-(dimethylamino)vinyl] [1,2,4]triazolo[1,5]pyrimidine-6-ylcarboxylates with hydrazine in various solvents was studied. The formation of a pyridone cycle proceeds regiospecifically in dimethyl formamide or dimethyl acetamide. A regioselective cyclization resulting in fused 1,2-diazepines occurs in acetic or propionic acid. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S1070363210040225

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 4, pp. 814–817. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © V.V. Didenko, A.Yu. Potapov, I.V. Ledeneva, Kh.S. Shikhaliev, O.V. Konyushko, 2010, published in Zhurnal Obshchei Khimii, 2010,
Vol. 80, No. 4, pp. 653–656.
Regioselective and Regiospecific Reactions
of Ethyl ortho-(Dimethylaminovinylazoloazinylcarboxylates
with Hydrazine
V. V. Didenkoa, A. Yu. Potapova, I. V. Ledenevaa, Kh. S. Shikhalieva, and O. V. Konyushkob
a Voronezh State University, Universitetskaya pl. 1, Voronezh, 394006 Russia
e-mail: chocd261@chem.vsu.ru
b Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia
Received June 12, 2009
Abstract―Selectivity of reactions of ethyl 4-[(E)-2(dimethylamino)vinyl]pyrazolo[5,1-c]-[1,2,4]triazino-3-
ylcarboxylates and ethyl 7-[(E)-2-(dimethylamino)vinyl][1,2,4]triazolo[1,5]pyrimidine-6-ylcarboxylates with
hydrazine in various solvents was studied. The formation of a pyridone cycle proceeds regiospecifically in
dimethyl formamide or dimethyl acetamide. A regioselective cyclization resulting in fused 1,2-diazepines
occurs in acetic or propionic acid.
DOI: 10.1134/S1070363210040225
Boiling of enamines Ia–Ic with hydrazine in DMF
or dimethyl acetamide leads exclusively to derivatives
of 7-aminopyrazolo[5,1-c]pyrido[4,3-e][1,2,4]triazino-
6(7H)-one (IIа) and 7-aminopyrido[3,4-e][1,2,4]-
triazolo[1,5-a]pyrimidin-6(7H)-one (IIb, IIc) through
the stage of the formation of presumed intermediate A
Derivatives of pyrazolo[5,1-c][1,2,4]triazine and
[1,2,4]triazolo[1,5]pyrimidine are of great interest for
researchers. Being isosteres of biogenic purine bases,
these compounds exhibit a wide spectrum of
pharmacological activity and are applied as pesticides,
antineoplastic and antiviral drugs [1–4]. Preparatively
accessible methods of the synthesis of azoloazines
make it possible to obtain compounds with versatile
substituents in both fragments [5–10]. In this con-
nection further modification of the specified systems
with the purpose of obtaining new polyheterocycles
and studying their biological activity is actual.
1
[14]. In the H NMR spectra of the obtained com-
pounds signals of vinyl protons in the region of 7.50
and 9.50 ppm and also signals of two methyl groups at
the nitrogen atom disappear. Instead of them doublets
of aromatic pyridine protons (δ 7.05–7.10 and 8.20–
8.30 ppm) and a singlet of the N-amino group are
observed.
The application of acetic or propionic acid as a
solvent in essence changes the cyclization direction.
Analysis of the mixture of reaction products has shown
that compounds IIа–IIc are present as minor products
(5–10%). Previously unknown 8H-pyrazolo[5',1':3,4]-
[1,2,4]triazino[6,5-d][1,2]diazepine (IIIа) and 8H-[1,2,4]-
triazolo[5',1':2,3]pyrimido[5,4-d][1,2]diazepines (IIIb,
IIIc) were isolated as dominating compounds, which
can also exist in the corresponding 4H tautomeric
It is known that the CH3 group in a vicinal position
to the nodal nitrogen atom of pyrazolo[5,1-c][1,2,4]-
triazines and also of pyrazolo- and symm-triazolo[1,5]-
pyrimidines undergoes the aminomethyleneation upon
short-term heating with dimethylacetal in DMF.
Enamines having an ester group in the ortho-position
are capable to close the pyridine cycle on interacting
with primary amines [11–13]. To continue our inves-
tigations [12, 13], we have studied special features of
the reactions of the third cycle fusion with participa-
tion of ethyl ortho-(dimethylaminovinyl)azoloazinyl-
carboxylates and hydrazine in protic (AcOH and
propionic acid) and aprotic (DMF and dimethylacet-
amide) solvents.
1
forms IVа–IVc. In the H NMR spectra of the
obtained substances there are doublets of CH protons
of a seven-membered cycle in the region of 6.88–7.00
and 7.70–7.78 ppm, and also broadened signals of two
“acid” protons at 13.15–13.40 and 14.12–14.20 ppm
belonging to the OH and NH groups.
814

REGIOSELECTIVE AND REGIOSPECIFIC REACTIONS
H2N
815
H2N
N
N
HN
а
b
N2H4·H2O
CO2Et
CO2Et
CO2Et
N N
X
N
N
Y
Y
Y
N
N
N
R
H
B
Iа−Ic
А
а
b
DMF
AcOH
H
NH2
O
N
N
N
N
Y
N
OH
OH
N
N
N
Y
Y
N
N
N
H
IIа−IIc
IIIа−IIIc
IVа−IVc
I–IV, R = Me, X = C–Ph, Y = N (а); R = H (b); R = CF3 (c); X = N, Y = CH (b, c).
medium the cyclization occurs regiospecifically along
path a with the participation of the second amino
group of enhydrazine A and with the fusion into a less
stressed pyridine ring. The path b implemented in the
medium of carboxylic acids involves a regioselective
cyclocondensation with the participation of the free
amino group of intermediate B and the closure of a
seven-membered cycle. The reaction of enamines Iа–
Ic with hydrazine hydrate in АсОН or propionic acid
can be considered as a new method of the synthesis of
fused 1,2-diazepines, as thus far such transformations
were not described in the literature [15].
The NOESY experiment has allowed us to
determine strictly that tricyclic diazepines exist in
DMSO-d6 in the tautomeric form IVа–IVc. Correla-
tion peaks between the NH proton of the triazine cycle
(δ 14.11 ppm) and ortho-protons of the phenyl group
(7.52 ppm) are observed in the two-dimensional
spectrum of compound IVa. Furthermore the NH
proton gives intensive cross-peaks with the hydroxy
1
group at 13.15/14.11 ppm. The 2D H NMR spectrum
of compound IVb also points to the presence of the
lactim hydrogen atom (13.30 ppm) interacting with
protons of the pyrimidine CH (8.47 ppm) and NH
groups (14.15 ppm).
EXPERIMENTAL
N
N
Monitoring of the individuality of reagents and
products and qualitative analysis of reaction mixtures
were carried out by the TLC on Merk Silufol UV-254
plates with chloroform and ethyl acetate as eluents.
OH
N
N
N
N
N
N
1
OH
H
The Н NMR spectra were recorded on a Bruker AM-
N
N
CH
300 spectrometer (300 MHz) at 20°С in DMSO-d6,
internal reference TMS. The 2D 1Н NMR spectra were
HC
CH
N
H
obtained on
a
Bruker DRX-500 spectrometer
IVb
IVа
(500 MHz) in similar conditions. Mass spectra were
recorded on an LKB-9000 instrument with direct
sample injection in an ionic source; energy of ionizing
electrons 70 eV. The elemental analysis was carried
out on a Carlo Erba NA 1500 analyzer.
Thus our experimental data testify that the direction
of the heterocyclization reaction of ethyl ortho-(di-
methylaminovinyl)azoloazinylcarboxylates with hyd-
razine depends on the solvent nature. In an aprotic
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

816
DIDENKO et al.
Initial enamines Iа–Ic were obtained by the
procedure described earlier [12, 13].
(42%), mp 290°С with decomposition (AcOH–DMF,
2:1), yellow crystals. Н NMR spectrum, δ, ppm: 2.41
1
s (3H, Me), 6.99 d (1H, CHdiazepine, J = 2.0 Hz), 7.39 m
(1H, CHarom), 7.52 d (4H, CHarom, J = 1.5 Hz), 7.70 d
(1H, CHdiazepine, J = 2.0 Hz), 13.15 br.s (1H, OH),
14.12 br.s (1H, NH). Mass spectrum, m/z (Irel, %): 292
[M]+ (55). Found, %: C 61.58; H 4.20; N 28.69.
C15H12N6O. Calculated, %: C 61.64; H 4.14; N 28.75.
M 292.30.
Pyrazolo[5,1-c]pyrido[4,3-e][1,2,4]triazine-6(7H)-
on (IIа) and pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyr-
imidine-6(7H)-ones (IIb, IIc). A mixture of 4 mmol
of enamine Iа–Ic, 4 ml of hydrazine hydrate, and 3–
4 ml of DMF (or dimethyl acetamide) was boiled for
0.5 h. The precipitate formed on cooling was filtered
off, washed with isopropanol, and recrystallized.
4H-[1,2,4]Triazolo[5',1':2,3]pyrimidino[5,4-d][1,2]-
diazepin-6-ol (IVb). Yield 0.53 g (65%), mp 199–
201°С (AcOH–DMF, 2:1). 1Н NMR spectrum, δ, ppm:
6.90 d (1H, CHdiazepine, J = 3.0 Hz), 7.76 d (1H,
CHdiazepine, J = 3.0 Hz), 8.31 s (1Н, CHtriazole), 8.47 s
(1H, СHpyrimidine), 13.30 br.s (1H, OH), 14.15 br.s (1H,
NH). Mass spectrum, m/z (Irel, %): 202 [M]+ (40).
Found, %: C 47.60; H 2.92; N 41.49. C8H6N6O.
Calculated, %: C 47.53; H 2.99; N 41.57. M 202.17.
7-Amino-2-methyl-3-phenylpyrazolo[5,1-c]pyrido-
[4,3-e][1,2,4]triazine-6(7H)-one (IIа). Yield 0.70 g
(50%), mp 227–229°С (DMF), orange powder. 1Н NMR
spectrum, δ, ppm: 2.72 s (3H, Me), 6.20 br.s (2H,
NH2), 7.03 d (1H, СHpyridine, J = 8.0 Hz), 7.40 t (1H,
CHarom, J = 7.5 Hz), 7.52 t (2H, CHarom, J = = 7.6 Hz),
7.83 d (2H, CHarom, J = 7.6 Hz), 8.25 d (1Н, СHpyridine
,
J = 8.0 Hz). Mass spectrum, m/z (Irel, %): 292 [M]+
(100). Found, %: C 61.51; H 4.24; N 28.85.
C15H12N6O. Calculated, %: C 61.64; H 4.14; N 28.75.
M 292.30.
2-(Trifluoromethyl)-4H-[1,2,4]triazolo[5',1':2,3]-
pyrimidino[5,4-d][1,2]diazepin-6-ol (IVc). Yield
1
0.65 g (60%), mp 171–173°С (AcOH–DMF, 2:1). Н
7-Aminopyrido[3,4-e][1,2,4]triazolo[1,5-a]pyr-
imidine-6(7H)-one (IIb). Yield 0.61 g (77%), mp
274–276°С (DMF). 1Н NMR spectrum, δ, ppm: 6.25 s
(2H, NH2), 7.05 d (1H, СHpyridine, J = 7.7 Hz), 8.32 d
(1Н, СНpyridine, J = 7.7 Hz), 8.72 s (1Н, СHtriazole), 9.37
s (1Н, СНpyrimidine). Mass spectrum, m/z (Irel, %): 202
[M]+ (100). Found, %: C 47.44; H 3.11; N 41.65.
C8H6N6O. Calculated, %: C 47.53; H 2.99; N 41.57. M
202.17.
NMR spectrum, δ, ppm: 6.88 d (1H, CHdiazepine, J =
3.0 Hz), 7.78 d (1H, CHdiazepine, J = 3.0 Hz), 8.59 s (1H,
СHpyrimidine), 13.40 br.s (1H, OH), 14.20 br.s (1H, NH).
Mass spectrum, m/z (Irel, %): 270 [M]+ (26). Found, %:
C 40.17; H 1.80; N 31.03. C9H4F3N6O. Calculated, %:
C 40.01; H 1.87; N 31.11. M 270.17.
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7-Amino-2-(trifluoromethyl)pyrido[3,4-e][1,2,4]-
triazolo[1,5-a]pyrimidine-6(7H)-one (IIc). Yield
0.76 g (71%), mp 231–233°С (DMF). 1Н NMR
spectrum, δ, ppm: 6.40 s (2H, NH2), 7.12 d (1H,
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31.01. C9H4F3N6O. Calculated, %: C 40.01; H 1.87; N
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