Reactions of 4-oxobenz[1,3-e]oxazinium perchlorates with α-aminoazoles

Article abstract of DOI:10.1134/S1070428013020188

Reactions of 4-oxo benz[1,3-e]oxazinium perchlorates with 1-R ¹-3-R²-5-aminopyrazoles lead to the formation of derivatives of pyrazolo[3,4-d]pyrimidine and pyrazolo[1,5-a]1,3,5]triazine series, and with 3-amino-1,2,4-triazole, to [1,2,4]triazolo[1,5-a][1,3,5] triazines.

Full text of DOI:10.1134/S1070428013020188

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 2, pp. 288−293. © Pleiades Publishing, Ltd., 2013.
Original English Text © L.L. Zamigailo, O.N. Petrova, M.G. Shirobokova, V.V. Lipson, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 2,
pp. 295−299.
Reactions of 4-Oxobenz[1,3-е]oxazinium Perchlorates
with α-Aminoazoles
L. L. Zamigailoa, O. N. Petrovaa, M. G. Shirobokovaa, and V. V. Lipsona–c
aSSI “Institute for Single Crystals” National Academy of Sciences of Ukraine, Kharkov, 61001 Ukraine
е-mail: lipson@ukr.net
bSI “V. Ya. Danilevsky Institute for Endocrine Pathology Problems” National Academy of Medical Sciences of Ukraine,
Kharkov, Ukraine
cKarazin Kharkov National University, Kharkov, Ukraine
Received July 7, 2012
Abstract—Reactions of 4-oxobenz[1,3-e]oxazinium perchlorates with 1-R1-3-R2-5-aminopyrazoles lead to the
formation of derivatives of pyrazolo[3,4-d]pyrimidine and pyrazolo[1,5-a]1,3,5]triazine series, and with 3-amino-
1,2,4-triazole, to [1,2,4]triazolo[1,5-a][1,3,5]triazines.
DOI: 10.1134/S1070428013020188
Cyclocondensations of carbonyl 1,3-bielectrophiles
with α-aminoazoles containing an amidine or guanidine
fragments are widely known procedures of the synthesis
of azoloazine systems. The set of bielectrophiles tested
up till now in these reactions is numerous and includes
dicarbocylic acids chlorides and anhydrides [1], keto-
and unsaturated acids and also their derivatives [2–9],
1,3-diketones [1–5], α,β-unsaturated ketones [10–13],
Mannich bases hydrochlorides [10, 11, 13], cycloalka-
nones alkyl(aryl)methylidene derivatives [11, 13], Mel-
drum’s acids [14], barbituric acids derivatives [15], and
their synthetic precursors. Notwithstanding the extensive
research the interest to such transformations does not
weaken, and the search for new building blocks is go-
ing on. In this connection the most discussed problems
are still the regiodirection of the reaction due to the
nonequivalence of the reaction sites in the molecules of
aminoazoles and 1,3-bielectrophiles, the selectivity of
the formation processes of azoloazine systems, and the
degree of saturation of the azine ring in these systems. The
Scheme 1.
R
N
O
NH2
NH
OH
N
PhNHNH2
AcOH
H2SO4
NH
OH
N
N
H2N
NH2
2
+
N
MeONa_MeOH
O
ClO4
R
_
N
R
Ph
II
I
IV
.
AcOH
NH2OH HCl
R
OH
N
N
O
III
R = CH3, C6H5, CH=CC6H5, (CH2)3Cl.
288

REACTIONS OF 4-OXOBENZ[1,3-Е]OXAZINIUM PERCHLORATES
289
and 3-methyl-5-amino-1Н-pyrazole (Vа) in alcoholic
medium in the presence of sodium methylate within 2.5 h
pyrazolotriazine VI was obtained. Its composition was
confirmed by the mass spectrum and elemental analysis,
and its structure, by IR and 1Н NMR spectra. The 1Н NMR
spectrum contained signals from protons of the ortho-
disubstituted benzene ring, singlets from the protons of
two methyl groups, a singlet of the methine proton of the
pyrazole ring, and a broadened downfield singlet of the
ОН group. The signal of the СН proton of the pyrazole
ring (δ 6.62ppm) indicates the formation of a triazine and
not a pyrimidine system. The lack of signals from NH and
СН groups of the azine ring confirms the heteroaromatic
character of the formed compound.
practical importance of the fused heterocycles obtained
by the mentioned reactions consists in their prospects to
be tested as pharmacological objects.
Among the mentioned bielectrophiles giving fused
heterocyclic systems in the reactions with α-aminoazoles
the 4-oxo-1,3-benzoxazinium perchlorates were not
named. The existing information concerns only reactions
of salts I with hydrazines, hydroxylamine, and guanidine
(Scheme 1) resulting in nonfused hydroxyaryl-substituted
azoles II, III or azines IV [16, 17].
The azolopyrimidines and –triazines, expected prod-
ucts in the reactions of compounds I with α-aminoazoles
are interesting as agrochemical agents and are attractive
for pharmacology as substances of presumably wide range
of actions [18–21].
The choice of the structure VI was done basing on
the NOE experiment: at the irradiation of the protons of
the methyl group of the pyrazole fragment a response
was observed from the protons of the methyl group of
the triazine ring.
The goal of this study was establishing the direction
of the reaction between 4-oxobenz[1,3-e]oxazinium
perchloratesIа,Iband1-R1-3-R2-5-aminopyrazolesVа–Vd,
3-amino-1,2,4-triazole (ХI), and 2-aminobenzimidazole
(ХVI) under diverse experimental conditions.
In the presence of a substituent at the endocyclic
nitrogen atom of the aminopyrazole molecule the forma-
tion of the triazine derivative is impossible. Therefore
we brought into the reaction with 4-oxobenzoxazinium
perchlorate (Ib) 1,3-dimethyl- (Vb) and 3-methyl-1-
phenyl-5-amino-1Н-pyrazole (Vc) (Scheme 3). The
reaction was carried out by boiling equimolar amounts of
the initial compounds in DMF for 1.5–2 h. We obtained
pyrazolopyrimidines Хb–Xd; their composition was also
confirmed by mass spectra and elemental analyses. The
absence in the 1Н NMR spectra of compounds Хb–Xd of
the singlet belonging to the СН group of the pyrazole ring
The structure of 3-methyl-5-amino-1Н-pyrazole
(Vа) contains four nucleophilic sites. Therefore in the
reactions with benzoxazinium perchlorate Ia the forma-
tion of versatile structures is expectable, among them
also of mixtures, where the most probable would be
pyrazolotriazine VI, VII and pyrazolopyrimidine VIII,
IХ systems (Scheme 2). They, in turn, may be distin-
guished by the position of the substituents in the azine
ring because of the nonequivalence of the reaction sites
in the 4-oxobenzoxazinium molecule.
Actually at boiling equimolar quantities of salt Ia
Scheme 2.
CH3
OH
N
N
N
OH
N
H3C
N
N
N
H3C
O
CH3
N
VII
CH3
CH3ONa_CH3OH
VI
NH
+
N
+
O
H2N
HN
N
H
N
CH3
ClO4_
HN
N
H3C
H3C
N
Va
Ia
N
OH
N
CH3
H3C
N
OH
IX
VIII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 2 2013

ZAMIGAILO et al.
290
Scheme 3.
R1
O
N
N
R1
R2
Br
N N
NH
N
DMF
+
+
O
R2
Br
R3
N
NH2
CH3
ClO_4
HO
Xb_Xd
Ib
Vb_Vd
V, R1 = R2 = CH3 (b); R1 = C6H5, R2 = CH3 (c); R1 = CH3, R2 = tert-C4H9 (d); X, R1 = R2 = R3 = CH3 (b); R1 = C6H5,
R2 = R3 = CH3 (c); R1 = CH3, R2 = tert-C4H9, R3 = H (d).
indicates the formation of the pyrazolopyrimidine system.
group of the pyrazole ring.
In the reaction involving 3-tert-butyl-1-methyl-5-
amino-1Н-pyrazole (Vd) pyrazolopyrimidine Xd ob-
tained did not contain a methyl group in the pyrimidine
ring as was confirmed by the data of mass and 1Н NMR
spectra. Evidently at the opening of the oxazine ring the
acetyl fragment was replaced by a formyl moiety due to
the interaction with a DMF molecule.
2.46
CH3
N
N
N
OH
H3C
2.92
N
CH3
In keeping with the above data the direction of the
formation of the azine fragment in the compounds under
consideration corresponds to the reaction of the carbonyl
group of the 4-oxo-1,3-benzoxazinium salt with the exo-
cyclic amino group of the aminoazole, and of the electro-
philic center С2 of the oxazine ring with the carbon atom
in the position 4 of aminopyrazole or with the endocyclic
nitrogen atom in the case of the 1-unsubstituted azole ring.
N
N
2.64
H3C
N
Br
H3C
N
2.90
HO
Xb
N
CH3
Triazolotriazine system XII was obtained at prolonged
(8 h) boiling of 3-aminotriazole (XI) with perchlorate
Ib in DMF (Scheme 4). The choice of the structure XII
among four possible isomers ХII, ХIII and XIV, XV was
done basing on the chemical shift of the methine proton of
the triazole ring (δ 8.1 ppm) in the 1Н NMR spectrum. It is
known that in the presence of a substituent at the atom N3
the proton signal of the group С2Н of 1,2,4-triazoloazines
shifts downfield, to 9.0–9.5 ppm [2, 4, 22]. In the spectra
of the closest structural analogs of the compound in ques-
tion, 5,7-diaryl[1,2,4]-triazolo[2,3-а][1,3,5]triazines [23]
and 5-substituted-7-phenyl[1,2,4]triazolo[1,5-а][1,3,5]
triazines [24] the singlet of the corresponding proton is
observed in the range δ 8.84–8.33 ppm. Structure XII
was preferred to structure XIII because in all events
under our consideration the exocyclic amino group of
the aminoazole reacted with the carbonyl electrophilic
site of salts Ia, Ib.
N
4.03
tert-C4H9
N
H
8.57
Br
N
HO
H
7.55
Xd
The position of substituents in the pyrazolopyrimidine
system of compounds Хb–Xd was established with the
use of NOE method.
The irradiation of the protons of the methyl group at-
tached to the atom С3 in compound Xb gets a response
from the protons of the СН3 group of the pyrimidine ring
showing their spatial proximity. In compound Xd the
change in the resonance conditions of the ortho-protons
of the aryl substituent affects the protons of the N-methyl
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REACTIONS OF 4-OXOBENZ[1,3-Е]OXAZINIUM PERCHLORATES
291
Scheme 4.
N
N
N
N
N
N
N
N
Br Br
N
CH3
H3C
N
O
OH
XIII
HO
Br
XII
N NH
N
DMF
NH
+
+
O
N
NH2
N
N
N
CH3
ClO4_
N
N
N
N
Iб
XI
Br Br
N
CH3
H3C
N
OH
XV
HO
XIV
Scheme 5.
O
O
O
Br
Br
N
MeOH_MeONa
DMF
N
CH3
NH
XVI
H
+
+
NH2
+
O
N
H
OH
CH3
ClO_4
XVII
Ib
XVI
O
Br
N
O
NH2
+
N
N
CH3
OH
XIX
H
H
XVIII
Unlike the experiments discussed above the boiling
of perchlorate Ib with 2-aminobenzimidazole (ХVI) in
a mixture sodium methylate–methanol (Scheme 5) afford-
ed the mixture of the initial amine ХVI and N-substituted
salicilamide ХVII.
of compounds obtained was checked by TLC on Silufol
UV-254 plates in the systems toluene–ethyl acetate,
3:1, CH2Cl2–i-PrOH, 10:1 (development in iodine va-
por). IR spectra were recorded on a spectrophotometer
Specord-M-82 from pellets with KBr, 1Н NMR spectra
were registered on a spectrometer Varian Mercury VX-
200 (solvent DMSO-d6, internal reference TMS). Mass
spectra were taken on an instrument Hewlett Packard LC/
MSD 1100, EI at 70 eV. Elemental analysis was carried
out on an analyzer LECO CHNS-900. Melting points
were measured on a Koeffler heating block.
The boiling of the initial compounds in DMF
led to the formation of a mixture of (N-acetyl)-2-
aminobenzimidazole (XVIII) and salicilamide ХIX
instead of the expected fused azoloazine system.
Therefore in the reactions with α-aminoazoles 4-oxo-
1,3-benzoxazinium perchlorates depending on the nature
of the binucleophile may act either as bielectrophilic
agents or as carriers of an acetyl residue.
4-Oxobenz[1,3-e]oxazinium perchlorates Ia, Ib were
obtained by procedure [25].
2-(4,7-Dimethylpyrazolo[1,5-a][1,3,5]triazin-2-yl)
phenol (VI). A mixture of 0.26 g (1 mmol) of 2-methyl-
4-oxo-4H-benz[1,3-e]oxazinium perchlorate (Iа) and
0.10 g (1 mmol) of 3-methyl-5-amino-1H-pyrazole (Va)
EXPERIMENTAL
The reaction progress was monitored and the purity
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ZAMIGAILO et al.
292
4-Bromo-2-(7-methyl[1,2,4]triazolo[1,5-a]
[1,3,5]-triazin-5-yl)phenol (ХII). To a solution of 0.34 g
(1 mmol) of compound Ib in 3 ml of DMF was added
0.084 g (1 mmol) of 5-amino-1H-1,2,4-triazole (ХI), and
the mixture was boiled for 8 h (TLC monitoring). The
reaction mixture was cooled, the light-brown precipitate
was filtered off and washed on the filter with methanol.
in 5 ml of a mixture sodium methylate–methanol was
boiled for 2.5 h. The reaction mixture was cooled, the
yellow precipitate was filtered off and washed on the filter
with methanol. Yield 0.7 mmol (71%), mp 156–158°С.
1Н NMR spectrum, δ, ppm: 2.46 (3Н, 4-СН3), 2.92 s (3Н,
7-СН3), 6.62 s (1Н, Н8), 7.00–6.94 m (2Н, С6Н4), 7.43 t
(1Н, С6Н4, J 8.0 Hz), 8.39 d (1Н, С6Н4, J 8.8 Hz), 12.71 s
(1Н, ОН). Mass spectrum, m/z (Irel, %): 241[M + 1]+, 240
[M]+, 223, 147, 76. Found, %: С 64.90; Н 4.97; N 23.28.
С13Н12N4О. Calculated, %: С64.99; Н 5.03; N 23.32.
1
Yield 0.6 mmol (62%), mp 234–2360С. Н NMR spec-
trum, δ, ppm: 2.56 s (3Н, 7-СН3), 6.92 d (1Н, С6Н3,
J 9.0Hz), 7.58 d.d (1Н, С6Н3, J 8.6, 2.0 Hz), 8.09 br.s
(2Н, С6Н3 + Н2), 13.68 br.s (1Н, ОН). Mass spectrum,
m/z (Irel, %): 308 (306) [M + 1]+, 307 (305) [M]+, 291
(289), 226, 173 (171), 134, 81 (79). Found, %: С 43.01;
Н 2.77; N 23.00. С11Н8BrN5О. Calculated, %: С43.16;
Н 2.63; N 22.88.
4-Bromo-2-(1,3,4-trimethyl-1H-pyrazolo[3,4-d]
pyrimidin-6-yl)phenol (Xb). A mixture of 0.34 g
(1 mmol) of 6-bromo-2-methyl-4-oxo-4H-benz[1,3-e]
oxazinium perchlorate (Ib) and 0.11g (1 mmol) of 1,3-di-
methyl-5-amino-1H-pyrazole (Vb) in 2 ml of DMF was
boiled for 1 h (TLC monitoring). The reaction mixture
was cooled, the yellow precipitate was filtered off and
washed on the filter with hexane. Yield 0.8 mmol (82%),
mp 242–2440С. IR spectrum, cm–1: 2928, 1584, 1568,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 2 2013

REACTIONS OF 4-OXOBENZ[1,3-Е]OXAZINIUM PERCHLORATES
293
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