Diversity Oriented Synthesis of Polycyclic Heterocycles through the Condensation of 2-Amino[1,2,4]triazolo[1,5-a]pyrimidines with 1,3-Diketones

Article abstract of DOI:10.1021/acs.joc.5b01908

The acid-catalyzed condensation between 2-aminosubstituted [1,2,4]triazolo[1,5-a]pyrimidines and their analogues with various saturation of the pyrimidine ring and 1,3-diketones or 1,1,3,3-tetramethoxypropane was evaluated as a new approach for the synthesis of diversely substituted polycyclic derivatives of triazolopyrimidine. The reaction of 4,5,6,7-tetrahydro- or aromatic aminotriazolopyrimidines results in selective formation of the corresponding [1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidin-5-ium salts, and the condensation of substrates containing the 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine fragment is accompanied by a cascade rearrangement with unusual recyclization of the dihydropyrimidine ring to yield partially hydrogenated [1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidin-5-ium or pyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium salts. The proposed methodology exhibits a wide scope, providing rapid access to polycondensed derivatives of the [1,2,4]triazolo[1,5-a]pyrimidine scaffold. DFT calculations of the Gibbs free energies of possible isomers were performed to rationalize the experimentally observed reactivity and selectivity.

Full text of DOI:10.1021/acs.joc.5b01908

Article
pubs.acs.org/joc
Diversity Oriented Synthesis of Polycyclic Heterocycles through the
Condensation of 2‑Amino[1,2,4]triazolo[1,5‑a]pyrimidines with 1,3-
Diketones
†
†
†
†
Dmitry A. Pyatakov, Andrey N. Sokolov, Alexander V. Astakhov, Andrey Yu. Chernenko,
‡
§
§,∥
,†
Artem N. Fakhrutdinov, Victor B. Rybakov, Vladimir V. Chernyshev, and Victor M. Chernyshev*
†
Platov South-Russian State Polytechnic University (NPI), Prosveschenya 132, 346428 Novocherkassk, Russian Federation
‡
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russian Federation
M. V. Lomonosov Moscow State University, Leninskie Gory 1-3, Moscow, 119991, Russian Federation
§
∥
A. N. Frumkin Institute of Physical Chemistry and Electrochemistry RAS, Leninsky prospect 31, Moscow 119071, Russian
Federation
*
S Supporting Information
ABSTRACT: The acid-catalyzed condensation between 2-aminosubstituted [1,2,4]triazolo[1,5-a]pyrimidines and their
analogues with various saturation of the pyrimidine ring and 1,3-diketones or 1,1,3,3-tetramethoxypropane was evaluated as a
new approach for the synthesis of diversely substituted polycyclic derivatives of triazolopyrimidine. The reaction of 4,5,6,7-
tetrahydro- or aromatic aminotriazolopyrimidines results in selective formation of the corresponding [1,2,4]triazolo[1,5-a:4,3-
a′]dipyrimidin-5-ium salts, and the condensation of substrates containing the 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine
fragment is accompanied by a cascade rearrangement with unusual recyclization of the dihydropyrimidine ring to yield partially
hydrogenated [1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidin-5-ium or pyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium salts.
The proposed methodology exhibits a wide scope, providing rapid access to polycondensed derivatives of the [1,2,4]triazolo[1,5-
a]pyrimidine scaffold. DFT calculations of the Gibbs free energies of possible isomers were performed to rationalize the
experimentally observed reactivity and selectivity.
7
8
9
INTRODUCTION
inflammatory, hypoglycemic, microtubule-stabilizing CNS,
■
10
11
hypnotic, and other types of activities ).
1
,2,4-Triazolo[1,5-a]pyrimidines are purine analogues that are
1,2
Over the past years, in medicinal chemistry, polycyclic
molecules containing the [1,2,4]triazolo[1,5-a]pyrimidine frag-
ment annulated with different carbo- and heterocycles have
become of interest because these compounds possess
important in agricultural chemistry and medicine. Triazolo-
pyrimidine sulfonamide herbicides (e.g., Flumetsulam and
Metosulam) have been employed in agriculture for approx-
2
a,b
imately 20 years,
Ametoctradin (Initium) ) and herbicide (Pyroxsulam )
have received approval for agricultural applications. Since the
960s, Trapidil, which is a coronary vasodilator, has been used
and in the past decade, a new fungicide
3a,d,e,7,12
2c,d 2e
anticancer and anti-inflammatory activities.
In most of
(
these polycyclic molecules, the triazolopyrimidine fragment is
annulated with other cycles at one of the edges of the
pyrimidine hexagon. One of the most important approaches for
the synthesis of these compounds is based on the reactions of
partially hydrogenated triazolopyrimidines with electrophilic
1
1
a
in medicine, and most recently, a new drug to treat hepatitis
1c
C (Filibuvir) passed stage II clinical trials. Compounds
containing the [1,2,4]triazolo[1,5-a]pyrimidine core exhibit
biological activity in a variety of therapeutic domains (i.e.,
3
4a
4b,c
anticancer, antimalarial and anti-Leishmania,
antibacteri-
Received: August 16, 2015
5
6
6d,e
1c,6f
al, antiviral, including anti-HIV
and anti-HCV,
anti-
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01908
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Scheme 1
Figure 1. Structures of starting compounds 1, 3−6.
1
0,12
and bielectrophilic reagents.
However, the potential for
amenable to both aromatization by various oxidizing
13a,15
16
annulation of new cycles from the side of the triazole fragment
agents
and reduction by sodium borohydride to afford
remains unexplored.
compounds 2 and 3 (Scheme 1).
Recently, we have demonstrated the synthesis of polycyclic
compounds by annulating new cycles to the triazole moiety of
In the current article, we describe the diversity oriented
synthesis of multisubstituted polycondensed heterocycles by
reactions of 2-amino-[1,2,4]triazolo[1,5-a]pyrimidines and
analogues (1−3) with 1,3-diketones and 1,1,3,3-tetramethox-
ypropane. The proposed strategy allows for modulation of no
less than five substituents in the resulting polycyclic systems
with different annulation of the triazole and pyrimidine rings
starting from readily available diaminotriazole 4 and carbonyl
and dicarbonyl compounds.
2-amino-[1,2,4]triazolo[1,5-a]pyrimidines with various satura-
tion of the pyrimidine ring by reactions with 3-chloropropanoyl
11
chloride and α-bromoketones. In these reactions, amino-
triazolopyrimidines act as N,N′-binucleophilic synthons,
resulting in the formation of a new ring through annulation
reactions of the 2-NH and N-3 atom. On the basis of these
2
results, we hypothesized that cyclocondensation of 2-amino-
[
1,2,4]triazolo[1,5-a]pyrimidines and their analogues (1−3)
RESULTS AND DISCUSSION
with 1,3-dicarbonyl compounds may allow for the synthesis of
various substituted polycondensed heterocycles. Compounds 1
can be obtained readily from the condensation of diamino-
triazole 4 with α,ß-unsaturated carbonyls or can be obtained
from three-component reactions between triazole 4, methylene-
■
Partially hydrogenated 2-aminosubstituted triazolopyrimidines
1
3
14c
16
1a, 1b, 2a−c, triazoloquinazolines 5a−d, and aromatic
13
15
triazolopyrimidines 3a,b were used as substrates containing
the 2-amino-[1,2,4]triazolo[1,5-a]pyrimidine fragment with
various saturations of the pyrimidine ring (Figure 1). Previously
undescribed aminotriazoloquinazolines 5c,e were obtained by
14
active carbonyl compounds, and aldehydes. Compounds 1 are
especially useful because the dihydropyrimidine motif is
B
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three-component condensation of diaminotriazole 4 with
The derivatives of tetrahydrotriazolopyrimidine (compounds
7a−d) with a short period of heating in acetonitrile or ethanol
in the presence of a small excess of perchloric acid afforded
tricyclic compounds 8a−c,h (Method A, Table 2). In addition,
compounds 8 and 9 are more effectively obtained by one-pot
heating of amines 2a−c and 3a,b with diketones 6a−c,g and
substituted benzaldehydes and 5,5-dimethylcyclohexane-1,3-
14a
dione similar to compounds 5a,b,d,f (Scheme 1).
1,3-
Diketones 6a−g and 1,1,3,3-tetramethoxypropane 6h (as
equivalent of 1,3-dialdehyde) were applied as 1,3-dicarbonyls
(
Figure 1).
Heating of compounds 1b, 2a−c, and 5a with diketones 6a,f
HClO in ethanol or acetic acid (Methods B and C, Table 2).
4
in acetonitrile, ethanol, or acetic acid afforded the correspond-
ing enaminoketones 7 (Table 1). The best yields of compounds
Under these conditions, even poorly reactive dibenzoylmethane
6g and low nucleophilic amines 3a,b are involved in
condensation. Presumably, enaminoketones 7 formed by the
Table 1. Synthesis of Compounds 7a−f
acid-catalyzed condensation of diketones at the NH group are
intermediates in the one-pot process.
2
The reaction of aminotriazolopyrimidine 1a with diketone 6a
afforded a complex mixture of products from which only
aromatic compound 9a was isolated in 35% yield (Scheme 2).
Apparently, compound 9a results from the oxidative aromatiza-
tion of intermediate 10. However, an alternative route through
an initial oxidative aromatization of compound 1a to
compound 3a cannot be ruled out. The tendency to oxidative
aromatization was also observed for the products of the
reactions of compound 1a with 3-chloropropanoyl chloride and
11
α-bromoketones. It is important to note that compounds
1
7
9
a,b,e have been previously described. However, their
1
structures were determined based on indirect data from H
NMR spectra.
The condensation of enaminoketones 7e,f, in which the
dihydropyrimidine fragment contains a carbonyl group in
position 6 of the triazolopyrimidine core, proceeds in a different
manner. These compounds in the presence of perchloric acid
when heated under reflux in acetonitrile (compound 7e) or
acetic acid (compound 7f) afford compounds 11a,b (Scheme
3
). The reaction includes recyclization of the dihydropyr-
imidine ring. Analogous products were obtained for one-pot
heating of amines 1b and 5a−e with diketones 6a−g and
tetramethoxypropane 6h in the presence of mineral acids (see
below). Interestingly, according to the NMR spectra, a mixture
of regioisomers, which presumably differ from each other by
the positions of the methyl and phenyl groups on the aromatic
pyrimidine ring, was formed during cyclization of compound 7f.
Compound 11b, which apparently resulted from isomerization
of starting enaminoketone 7f through reversible hydrolysis and
intermediate formation of diketone 6f and amine 5a, followed
by acid-catalyzed condensation at the benzoyl group of the
diketone (Scheme 3), was isolated as a major product from the
mixture by crystallization.
The disclosed reaction between compounds 1b, 5, and 6 that
resulted in the formation of compounds 11 may have a high
preparative value for the synthesis of polycyclic compounds
because the starting materials are readily available. Therefore,
we optimized the preparative conditions using the reaction
between compounds 5a and 6a as an example (Table 3).
First, we investigated the reaction in the presence of a 1
7
a−f were obtained when the reagents were heated in AcOH at
90 °C. At higher temperatures, sufficient tarring of the reaction
mixtures was observed. However, at lower temperatures, the
reaction time was too long. Notably, the reaction of amines 2b
and 5a with unsymmetrical diketone 6f progressed selectively at
the acetyl group of 6f, affording compounds 7d,f. Dibenzoyl-
methane 6g is unreactive under these conditions, which was
most likely due to the low electrophilicity of the carbonyl
groups conjugated with the benzene rings. In addition, under
the studied conditions, we were unable to obtain enaminoke-
tones from amine 1a and aromatic amines 3a,b. Intensive
tarring and formation of a complex mixture of products
occurred with amine 1a due to instability of the dihydropyr-
imidine cycle. However, only starting compounds were isolated
from the reaction mixtures after heating of amines 3a,b with
diketone 6a, which is most likely due to the decreased
nucleophilicity of the NH group in compounds 3 resulting
molar equiv of HClO in various solvents heated under reflux
2
4
from the electron-withdrawing influence of the aromatic
pyrimidine ring.
with a 30% molar excess of diketone 6. In ethanol, the reaction
proceeds relatively slowly, resulting in a moderate yield of
product 11c (entry 1), which is contaminated by perchlorate
Compounds 7a−f failed to cyclize under fusion or heating
under reflux in acetic acid or DMF. Only gradual decom-
position and sufficient tarring were observed under these
conditions. Compounds 7a−f underwent cyclization in the
presence of strong mineral acids, which catalyze this reaction.
However, the direction of the reaction depends on the
saturation of the pyrimidine cycle in the starting compounds
1
from the starting aminoheterocycle based on the H NMR
spectra. In refluxing acetic acid, the reaction proceeds rapidly
(entry 1). However, the resulting product contains unidentified
impurities. Analogous impurities were detected in the product
obtained from synthesis in neat 2,4-pentanedione (entry 3).
Sufficient yields of the pure product (11c) were obtained in
refluxing acetonitrile (entry 4) and especially in acetic acid at 90
(7).
C
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Table 2. Synthesis of Compounds 8a−h and 9a−e
a
See the Experimental Section for details.
Scheme 2
to the low solubility of the hydrobromide of the starting
aminoheterocycle in the reaction mixture (entry 10). For
H SO , the yield of sulfate 11d (entry 11) was slightly lower
2
4
than that of perchlorate 1c (entry 6). An increase in the
amount of HClO (entries 12, 13) did not increase the yield of
4
11c. Therefore, the reaction conditions of entry 6 appeared to
be the best for preparative one-pot synthesis.
With good reaction conditions in hand, the substrate scope
of this reaction was investigated (Table 4).
°
C (entry 6). Therefore, we performed additional experiments
in acetic acid at 90 °C with varied reaction times, reagent ratios,
and strong acids as catalysts. Under the studied conditions,
variations in the reaction time (entry 7) and the 5a:6a molar
ratio (entries 8, 9) did not increase the yield. In the presence of
a 40% aqueous solution of HBr, only a trace yield of the desired
product was detected by NMR in the resulting precipitate due
It is important to note that our attempt to prepare polycyclic
compounds 11 using a general approach similar to the synthesis
18
of dihydroazolopyrimidines based on a three-component
condensation of aminoheterocycles with aldehydes and 1,3-
dicarbonyl compounds was unsuccessful. The heating of
aminotriazolopyrimidine 3c, benzaldehyde, and 5,5-dimethyl-
D
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Scheme 3
Table 3. Optimization of Reaction Conditions for the One-Pot Synthesis of Compounds 11
entry
solvent
temperature (°C)
time (h)
6a (equiv)
HX (equiv)
product
isolated yield (%)
1
2
3
4
5
6
7
8
9
EtOH
AcOH
neat
reflux
reflux
90
1
0.5
1
1.3
1.3
5
HClO (1.05)
11c
11c
11c
11c
11c
11c
11c
11c
11c
57
71
4
HClO (1.05)
4
HClO (1.05)
67
4
MeCN
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
reflux
50
1
1.3
1.3
1.3
1.3
1.1
2
HClO (1.05)
63
4
1
HClO (1.05)
59
4
90
1
3
HClO (1.05)
78
75
4
90
HClO (1.05)
4
90
1
HClO (1.05)
72
4
90
1
HClO (1.05)
63
4
1
1
1
1
0
1
2
3
90
1
1.3
1.3
1.3
1.3
HBr (1.05)
trace
68
90
1
H SO (1.05)
11d
11c
11c
2
4
90
1
HClO (1.3)
75
4
90
1
HClO (1.5)
70
4
cyclohexane-1,3-dione 12 in acetic acid in the presence of
stage of the reaction, compounds 1b and 5 react with
HClO afforded a mixture of the perchlorate of starting amine
dicarbonyls 6 at the NH and N-3 atom of the triazolopyr-
4
2
1
3 and xanthenedione 14 (Scheme 4). Therefore, the acid-
imidine core to form intermediates 15 as the kinetic products
(Scheme 5) because all of the other studied substrates (3, 4)
react at the same nucleophilic centers. Although the direct
formation of intermediates 16 cannot be excluded from
consideration, it is important to note that compounds 1b and
catalyzed condensation of compounds 1b or 5 with 1,3-
dicarbonyls is the only one-pot method available for the
synthesis of polycyclic derivatives 11 containing both aromatic
and dihydrogenated pyrimidine cycles annulated with a triazole
ring in one molecule (Table 4).
11
5 may react with other bielectrophiles only at N-3 and NH2.
It is reasonable to consider some key peculiarities of the
synthesis of compounds 11. In contrast to compound 1a and
other 4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidines unsubsti-
tuted in position 6 of the triazolopyrimidine core, compounds
Intermediates 15 contain both the dihydro[1,2,4]triazolo[1,5-
a]pyrimidine and aromatic [1,2,4]triazolo[4,3-a]pyrimidine
fragments. [1,2,4]Triazolo[4,3-a]pyrimidines are prone to
Dimroth rearrangement into [1,2,4]triazolo[1,5-a]pyrimidines,
1
a,19
1
b and 5 are resistant to oxidative aromatization in the
which are typically more thermodynamically stable.
reactions with dicarbonyls 6. However, in these reactions, in
Apparently, intermediates 15 reversibly rearrange into inter-
mediates 16. We were able to isolate one of the intermediates
(compound 16n) in 52% yield by performing the reaction of
compounds 5a and 6h at 20 °C for a short period of time
(Scheme 6). Compound 16n can be easily rearranged into
compound 11n by heating at 90 °C in an acetic acid solution
(Scheme 6). Compounds 16 are thermodynamically unstable
1
1
contrast to reactions with other bielectrophiles, the
dihydrotriazolopyrimidine core undergoes a rearrangement
that involves recyclization of the dihydropyrimidine ring
(Scheme 5). It is also important to note that the formation
of compounds 11, most probably, involves two rearrangements
that occur in a cascade fashion (Scheme 5). During the first
E
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Table 4. Scope of the One-Pot Procedure for the Preparation of Polycyclic Compounds 11
Scheme 4
due to electronic factors (two neighboring “pyrrole” nitrogen
dihydropyrimidine ring. However, this rearrangement has an
inverse direction for the majority of [1,2,4]triazolopyrimidines
and can be characterized as a retro-Dimroth rearrangement.
1
1,20
atoms)
and steric repulsions between R and Ar (Scheme
19c
5). These factors promote Dimroth-type recyclization of the
F
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Scheme 5
9, 11, and 15−18 (see the Supporting Information). For the
reactions of tetrahydrotriazolopyrimidines, only the equilibrium
between possible isomeric products 8 and 17 was considered
because recyclization of the tetrahydropyrimidine ring was not
observed under the studied conditions. Analogously, only the
equilibrium between isomers 9 and 18 was studied for the
reactions of amines 3 because both pyrimidine cycles in
products 9 are aromatic. Therefore, consideration of a
rearrangement analogous to the rearrangement leading to 11
was pointless.
Several tautomers are possible for each isomer of compounds
8
, 11, and 15−17 (see the Supporting Information). Therefore,
the most stable tautomeric forms (A) shown in Scheme 7 were
determined after geometry optimization and calculation of the
The general direction of the cascade reaction is determined by
the gain in energy from the formation of the more stable
aromatic [1,2,4]triazolo[1,5-a]pyrimidine fragment in mole-
cules 11. It is important to note that this reaction is the first
reported example of a Dimroth rearrangement of the
dihydro[1,2,4]triazolo[1,5-a]pyrimidine fragment into a
dihydro[1,2,4]triazolo[4,3-a]pyrimidine fragment. In addition,
the rearrangement cascade shown in the Scheme 5 is quite
unusual because it includes Dimroth rearrangements of both
azine rings annulated with one azole cycle. All of the nitrogen
atoms of the triazole ring participate in the translocations of the
nitrogen atoms in the pyrimidine rings, and the triazole ring
does not undergo recyclization. Detailed study of energy
profiles for this cascade rearrangement, which may help to
clarify the mechanism, will be published elsewhere.
The following questions arise: What is the reason for these
differences in the direction of the reactions for the formation of
polycyclic compounds 8, 9, and 11 from the saturation of the
pyrimidine ring in starting compounds 1−3 and 5, and are
similar rearrangements possible for compounds 8 and 9?
To answer these questions, we performed computational
analysis to determine the relative thermodynamic stability of
various isomers of polycyclic compounds that could be
theoretically expected as products of reactions between 2-
amino[1,2,4]triazolo[1,5-a]pyrimidines 1−3, 5, and 1,3-dicar-
bonyls.
2
98
Gibbs free energy (ΔG ) for each tautomer (see the
Supporting Information). The calculations of the relative
298
Gibbs free energies (ΔG ) of the isomers in the studied
equilibriums (Scheme 7) were based on the assumption that
only the most stable tautomers were present in the equilibrium
mixtures. The equilibrium compositions of the mixtures of
isomers were computed from standard Gibbs free energy
functions through the following relationship: ΔG = −RT ln K,
where ΔG is the difference between the Gibbs free energy for a
given isomer and that calculated for the lowest energy and K is
the equilibrium constant for these species.
298
The values of ΔG and the relative concentrations of the
isomers in aqueous solutions are shown in the Scheme 7. In
vacuum and DMSO solutions (see the Supporting Informa-
tion), these parameters did not fundamentally change.
21
As shown in Scheme 7, molecules 11-A and 9 are
substantially more stable isomers in the corresponding
equilibriums. Therefore, the so-called thermodynamic products
were obtained in the reactions of compounds 1, 3 with
dicarbonyls 6. The experimentally observed rearrangement of
kinetic product 16n into thermodynamic product 11n is in
good agreement with this conclusion.
Apparently, the formation of isomers 8-A and 17-A can be
expected in cyclocondensations of compounds 2 with
dicarbonyls 6. Although the model cations 17-A are slightly
more stable than 8-A in the case of R = H, the presence of
bulky substituents in the real molecules shifts the equilibrium to
the side of isomers 8-A, as it is seen in the case of R = Ph
(Scheme 7). It is important to note that we were unable to
obtain isomers 17-A or detect them in the uncrystallized
products. Kinetic products 8 were formed under the studied
reaction conditions. Our attempts to perform rearrangement of
compounds 8 into 17 were futile. Only the starting compound
was isolated from the reaction mixture after heating perchlorate
8b in absolute refluxing ethanol or dry acetonitrile. Prolonged
heating of 8b in 95% ethanol or DMF was accompanied by
solvolysis, affording perchlorate 19 (Scheme 8). Attempts to
rearrange compounds 8 in alkaline medium were also
unsuccessful. Compounds 8b,e,g in an ethanol solution
Quantum chemical calculations were performed using the
22
Gaussian 09 suite of computational programs at the DFT
23
B3LYP/6-311++G(2d,2p) level. The solvent effects were
modeled by the integral equation formalism version of the
polarizable continuum model (IEF-PCM) developed by
2
4
Tomasi. The character of the stationary points on the
potential energy surface (local minimum) was confirmed by
calculation of the Hessian matrix at the same level of theory
within the harmonic approximation. All optimized geometries
had only real frequencies. The computed energetic parameters
and atomic coordinates of all of the species are provided in the
Supporting Information.
We considered the thermodynamic stability of possible
products of cyclocondensation on examples of model cations 8,
Scheme 6
G
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Scheme 7. Hypothetic Equilibriums, Calculated Relative Gibbs Free Energies (ΔG298, kcal/mol), and Equilibrium Compositions
(x, %) of Model Molecules of Isomeric Cations of Polycyclic Compounds in Aqueous Solution
Scheme 8
Scheme 9
containing KOH at room temperature yielded free bases 20a−
c, and only solvolysis product 2b was isolated after heating
under reflux (Scheme 8). Compounds 20a−c formed initial
perchlorates 8b,e,g after treatment with perchloric acid in
acetonitrile (Scheme 8).
Mesoionic free bases 21a−c were also successfully prepared
by treating perchlorates 11a,c,i with an aqueous solution of
sodium acetate (Scheme 9). The starting perchlorates can be
readily obtained by the action of perchloric acid on bases 21 in
acetonitrile (Scheme 9). Compounds 21 are stable in a
crystalline state. However, in solution, these compounds
decomposed within a few days to form complex mixtures of
dark brown products.
Compounds 9 did not change when treated with aqueous
solutions containing sodium acetate at room temperature.
However, in ethanol solutions containing KOH, these
compounds decomposed to yield complex mixtures of dark
red products.
The structures of the synthesized compounds were
established by HRMS and NMR spectroscopic data including
1
13
H− C heteronuclear correlation HSQC and HMBC spectra
for the majority of compounds, NOESY spectrum for 8a, and
H
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X-ray diffraction studies of 8h, 11b,c,p, 9a, 16n, and 20a (for
details, see the Supporting Information).
[1′,2′:1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium salts with re-
versed annulation of the aromatic and hydrogenated pyrimidine
rings. The proposed methodology for the synthesis of
polycyclic derivatives of triazolopyrimidine is based on the
application of readily available starting compounds and
demonstrates a broad substrate scope and high efficiency.
Some NMR spectral peculiarities and key correlation
schemes in the HMBC and NOESY spectra used for the
assignment of structures 8, 9, 11, and 16n are shown in Figure
2
. In the 13C NMR spectra of compounds 8, the signals
EXPERIMENTAL SECTION
■
General Information. Melting points were determined in open
capillary tubes in a Thiele apparatus and are uncorrected. IR spectra
were recorded using a single reflection diamond ATR system as a
1
sampling accessory. H NMR spectra were acquired at 500 MHz and
13
1
C { H} NMR spectra were acquired at 125 MHz in DMSO-d using
6
TMS as an internal standard. Mass spectra were recorded in the form
of m/z (intensity relative to base 100) using electron impact ionization
(
70 eV). High-resolution mass spectra (HRMS) were obtained on a
TOF MS instrument using electrospray ionization (ESI) in positive
ion mode (interface capillary voltage − 4500 V).
1
3a
14b
16
15
26
14a
Starting compounds 1a, 1b, 2a−c, 3a,b, 3c, and 5a,b,d
were prepared by known methods. All other chemicals are
commercially available.
2
-Amino-9-(4-bromophenyl)-6,6-dimethyl-5,6,7,9-
tetrahydro[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one (5c). A
magnetically stirred mixture of 3,5-diamino-1,2,4-triazole (1.0 g, 10.0
mmol), 4-bromobenzaldehyde (1.85 g, 10.0 mmol), 5,5-dimethylcy-
clohexane-1,3-dione (1.4 g, 10.0 mmol), and DMF (3 mL) was
refluxed for 30 min, then diluted with ethanol (15 mL) and cooled to
Figure 2. NMR spectral characteristics (chemical shifts, δ, ppm) of
2
0 °C. The precipitate formed was collected by filtration, recrystallized
compounds 8, 9e, 11n,o,s, and 16n in DMSO-d and key correlations
6
from DMF/EtOH (1:5), and dried at 120 °C to give 5c. Yield 2.1 g
in the NOESY and HMBC spectra.
−
1
(
3
55%) of colorless crystals, mp > 300 °C. IR (cm ): 3461, 3302,
181, 2955, 2818, 1661, 1645, 1598, 1570, 1515, 1459, 1411, 1365,
1
corresponding to the carbon atoms of the triazole cycle were
observed in the 143−147 ppm region, which is very close to the
structurally analogous 3-amino-2-benzyl-[1,2,4]triazolo[4,3-a]-
1336, 1253, 1012, 826, 751. H NMR (500 MHz, DMSO-d ): δ 0.95
6
(s, 3H, CH
), 1.03 (s, 3H, CH
), 2.05 (d, J = 16.2 Hz, 1H, 7-CH ),
2
3
3
2
.20 (d, J = 16.2 Hz, 1H, 7-CH ), 2.45−2.54 (m, 2H, 5-CH ), 5.20 (br
2
2
25
s, 2H, NH ), 5.90 (s, 1H, H-9), 7.11−7.12 (m, 2H, Ar), 7.46−7.47 (m,
pyrimidin-2-ium salts. The signals corresponding to the
2
13
2
2
1
H, Ar), 10.79 (br s, 1H, NH). C NMR (125 MHz, DMSO-d ): δ
6
triazole carbons of compound 16n are shifted downfield to
6.9, 28.4, 32.1, 49.8, 56.6, 105.3, 120.5, 129.1, 131.0, 141.5, 145.6,
150−152 ppm, and in isomers 11, these signals were observed
50.3, 162.1, 192.9 (signals of 3 carbons are overlapped). HRMS (ESI-
in the 141−149 ppm region. It is important to note that the
signal corresponding to H-7 (7.08 ppm) in the spectrum of
compound 16n is shifted downfield by ∼0.5 ppm relative to the
analogous signals of H-10 or H-12 (6.5−6.6 ppm) in isomers
+
TOF) m/z: [M + H] Calcd for C H BrN O 388.0767; Found
17
19
5
3
88.0753.
2-Amino-6,6-dimethyl-9-(2-methoxyphenyl)-5,6,7,9-
tetrahydro[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one (5e).
Compound 5e was synthesized according to the procedure for
preparation of compound 5c using 2-methoxybenzaldehyde (1.36 g,
1
1.
1
0.0 mmol). Yield 1.7 g (50%) of colorless crystals, mp 259−260 °C.
CONCLUSION
■
−1
IR (cm ): 3459, 3417, 3293, 3185, 3126, 2951, 2881, 2830, 1659,
1
NMR (500 MHz, DMSO-d ): δ 0.91 (s, 3H, CH ), 1.02 (s, 3H, CH ),
1.95 (d, J = 16.2 Hz, 1H, 7-CH ), 2.17 (d, J = 16.2 Hz, 1H, 7-CH ),
2.38 (d, J = 16.8 Hz, 1H, 5-CH ), 2.49−2.53 (m, 1H, 5-CH ), 3.66 (s,
3H, CH
In summary, we have developed a new methodology for the
preparation of diversely substituted polycyclic derivatives of
triazolopyrimidine based on acid-catalyzed cyclocondensation
between 2-aminosubstituted [1,2,4]triazolo[1,5-a]pyrimidines
with a pyrimidine ring with various saturation and 1,3-
dicarbonyls. The orientation of the pyrimidine rings in the
resulting polycondensed heterocycles depends on the satu-
ration of the pyrimidine cycle in the starting aminotriazolopyr-
imidines. 4,5,6,7-Tetrahydro- and aromatic aminotriazolopyr-
1
640, 1596, 1569, 1513, 1466, 1366, 1245, 1116, 1035, 861, 742. H
6
3
3
2
2
2
2
O), 5.07 (br s, 2H, NH
H, Ar), 7.14−7.17 (m, 2H, Ar), 10.63 (br s, 1H, NH). C NMR
), 6.10 (s, 1H, H-9), 6.81−6.89 (m,
3
2
1
3
2
(125 MHz, DMSO-d ): δ 26.2, 28.8, 32.0, 39.6, 49.9, 53.8, 55.5, 105.1,
6
1
11.3, 119.8, 128.7, 129.5, 129.6, 146.0, 150.4, 157.2, 161.6, 192.6.
+
HRMS (ESI-TOF) m/z: [M + H] Calcd for C H N O 340.1768;
18
22
5
2
Found 340.1764.
imidines react with dicarbonyls at the 2-NH and N-3 to
2
General Procedure for the Synthesis of Compounds 7a−d. A
magnetically stirred mixture of the appropriate amine 1b, 2a−c (2
mmol), diketone 6a,f (4 mmol), and AcOH (1 mL) was heated at 90
°C for 4 h, then cooled to room temperature and diluted with ethanol
(5 mL). The solid precipitate was collected by filtration and
recrystallized from an appropriate solvent.
selectively yield the corresponding [1,2,4]triazolo[1,5-a:4,3-
a′]dipyrimidin-5-ium salts. 2-Aminosubstituted dihydrotriazo-
lopyrimidine with no substituent in position 6 undergoes
oxidative aromatization of the dihydropyrimidine ring. Cyclo-
condensation between stable-to-oxidation derivatives of 4,7-
dihydro-[1,2,4]triazolo[1,5-a]pyrimidines, which contain a
carbonyl group as a substituent in position 6 of the
triazolopyrimidine system, and 1,3-dicarbonyls is accompanied
by a cascade rearrangement with unusual recyclization of the
dihydropyrimidine ring to afford partially hydrogenated
4
-[(5-Methyl-7-phenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]-
pyrimidin-2-yl)amino]pent-3-en-2-one (7a). Yield 0.261 g (42%) of
colorless crystals, mp 188−189 °C (from DMF/EtOH 1:3). IR
−1
(cm ): 3232, 2967, 2927, 2927, 1620, 1601, 1579, 1544, 1457, 1381,
1
1
362, 1424, 1288 1031, 992, 759. H NMR (500 MHz, DMSO-d ): δ
6
1.14 (d, J = 4.6 Hz, 3H, 5-CH ), 1.67−1.73 (m, 1H, 6-CH ), 1.95 (s,
3H, CH CO), 2.13 (s, 3H, CH ), 2.27−2.29 (m, 1H, 6-CH ), 3.59 (m,
3
2
[
1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidin-5-ium and pyrimido-
3
3
2
I
DOI: 10.1021/acs.joc.5b01908
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
7
H, H-5), 5.15 (s, 1H, H-7), 5.17 (s, 1H, H-3 of pent-3-en-2-one),
.15−7.33 (m, 6H, Ph + NH), 12.39 (s, 1H, NH). C NMR (125
59.3, 97.7, 99.4, 126.8, 127.8, 128.3, 141.6 (carbons of Ph), 146.1+,
146.2, 155.9, 156.9, 164.9, 196.5. HRMS (ESI-TOF) m/z: [M + Na]
Calcd for C H N O Na 404.1693; Found 404.1687.
13
MHz, DMSO-d ): δ 20.5 (5-CH ), 20.7 (CH ), 29.1 (CH CO), 40.9
6
3
3
3
20 23
5
3
(
(
(
C-6), 45.3 (C-5), 58.2 (C-7), 98.6 (C-3 of pent-3-en-2-one), 126.8
2C), 127.5, 128.3 (2C), 140.3 (carbons of Ph), 154.46 (C-3a), 154.54
6,6-Dimethyl-2-{[4-oxo-4-phenylbut-2-en-2-yl]amino}-9-phenyl-
5,6,7,9-tetrahydro[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one (7f).
Yield 0.707 g (78%) of colorless crystals, mp 232−233 °C (from
C-2), 157.6 (C-4 of pent-3-en-2-one), 195.8 (CO). MS (EI, 70 eV),
+
−1
m/z (%): 311 (38) [M] , 268 (39), 192 (78), 164 (89), 150 (24), 131
DMF/EtOH 1:3). IR (cm ): 3028, 2955, 2865, 2792, 2732, 2682,
(
(
3
28), 125 (15), 115 (12), 104 (16), 91 (28), 77 (19), 69 (27), 43
1620 (shoulder), 1582, 1546, 1515, 1445, 1315, 1282, 1149, 1059, 836,
+
1
100). HRMS (ESI-TOF) m/z: [M + H] Calcd for C H N O
752. H NMR (500 MHz, DMSO-d
6
): δ 0.97 (s, 3H, 6-CH
3
), 1.04 s,
17
22
5
12.1819; Found 312.1819.
-[(5,7-Diphenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]-
pyrimidin-2-yl)amino]pent-3-en-2-one (7b). Yield 0.537 g (72%) of
3H, 6-CH
3
), 2.10 (d, J = 16.7 Hz, 1H, H-7), 2.22 (d, J = 16.7 Hz, 1H,
4
H-7), 2.53−2.54 (m, 2H, H-5), 6.10 (s, 1H, CH), 6.12 (s, 1H, H-9),
7.21−7.52 (m, 8H, Ph), 7.89−7.90 (m, 2H, Ph), 11.14 (s, 1H, NH),
−1
13
colorless crystals, mp 161−162 °C (from acetonitrile). IR (cm ):
3
1
13.18 (s, 1H, NH). C NMR (125 MHz, DMSO-d ): δ 21.9, 27.5,
6
251, 3031, 1620 (shoulder), 1603, 1579, 1550, 1514, 1496, 1427,
29.0, 32.8, 40.8, 50.5, 58.3, 96.3, 106.6, 127.5, 127.7, 128.4, 128.9,
129.0, 132.2, 139.4, 141.8 (carbons of 2Ph), 147.0, 150.6, 156.4, 160.4,
1
355, 1284, 1199, 1028, 920, 837, 751. H NMR (500 MHz, DMSO-
+
d ): δ 1.97 (s, 3H, CH CO), 2.03−2.10 (m, 1H, 6-CH ), 2.16 (s, 3H,
188.9, 193.6. HRMS (ESI-TOF) m/z: [M + Na] Calcd for
6
3
2
CH ), 2.41−2.43 (m, 1H, 6-CH ), 4.69−4.71 (m, 1H, H-5), 5.20 (s,
C H N O Na 476.2057; Found 476.2052.
3
2
27 27
5
2
1
1
H, H-3 of pent-3-en-2-one), 5.34−5.35 (m, 1H, H-7), 7.23−7.44 (m,
General Procedure for the Synthesis of Compounds 8a−f,
9a−e. Method A. A magnetically stirred mixture of the appropriate
0H, 2Ph), 7.57 (br s, 1H, NH), 12.44 (s, 1H, NH). 13C NMR (125
MHz, DMSO-d ): δ 20.7, 29.0, 42.0, 53.5, 58.3, 98.6, 118.4, 126.4
enamine 7a−d (1 mmol), a 70% aqueous solution of HClO (0.152 g,
4
6
(
(
(
(
2C), 126.9 (2C), 127.5, 128.2 (2C), 128.3 (2C), 139.8, 141.3
1.05 mmol), and acetonitrile (4 mL) was refluxed for 1 h. The
precipitate formed after cooling to 20 °C was collected by filtration
and recrystallized from acetonitrile/EtOH (1:3).
carbons of 2Ph), 154.6, 154.8, 157.5, 195.9. MS (EI, 70 eV), m/z
+
%): 373 (22) [M] , 330 (26), 254 (50), 226 (74), 212 (13), 193
14), 115 (46), 104 (42), 91 (29), 77 (35), 43 (100). HRMS (ESI-
Method B. A magnetically stirred mixture of the appropriate
compound 2a−c (1 mmol), diketone 6a−c,g (1.3 mmol), a 70%
+
TOF) m/z: [M + H] Calcd for C H N O 374.1975; Found
22
24
5
3
74.1970.
-{[7-(4-Methoxyphenyl)-5-phenyl-4,5,6,7-tetrahydro[1,2,4]-
triazolo[1,5-a]pyrimidin-2-yl]amino}pent-3-en-2-one (7c). Yield
.492 g (61%) of colorless crystals, mp 166−167 °C (from
aqueous solution of HClO (0.152 g, 1.05 mmol), and ethanol (4 mL)
4
4
was refluxed for 2 h. The precipitate formed after cooling to 20 °C was
collected by filtration and recrystallized from acetonitrile/EtOH (1:3).
Method C. A magnetically stirred mixture of the appropriate
compound 2b, 3a,b (1 mmol), diketone 6a,b,g or 1,1,3,3-
tetramethoxypropane 6h (1.3 mmol), a 70% aqueous solution of
0
−1
acetonitrile). IR (cm ): 3239, 2951, 2835, 1605, 1579, 1551, 1512,
1
1
430, 1351, 1280, 1247, 1202, 1173, 1030, 826, 772. H NMR (500
MHz, DMSO-d ): δ 1.96 (s, 3H, CH CO), 2.03−2.09 (m, 1H, 6-
HClO (0.152 g, 1.05 mmol), and AcOH (0.5 mL for the synthesis of
6
3
4
CH ), 2.16 (s, 3H, CH ), 2.35−2.37 (m, 1H, 6-CH ), 3.72 (s, 3H,
9a−e, 1.0 mL for the preparation of 8g) was refluxed for 2 h (or 5 min
for compound 9e) and then diluted with ethanol (3 mL). The
precipitate formed after cooling to room temperature was collected by
filtration and recrystallized from acetonitrile (compounds 9a−e) or
DMF/EtOH 1:3 (compounds 8g).
2
3
2
CH O), 4.67−4.69 (m, 1H, H-5), 5.19 (s, 1H, H-3 of pent-3-en-2-
3
one), 5.26−5.27 (m, 1H, H-7), 6.86−6.87 (m, 2H, Ar), 7.16−7.43 (m,
7
H, Ar), 7.52 (br s, 1H, NH), 12.43 (s, 1H, NH). 13C NMR (125
MHz, DMSO-d ): δ 20.7 (CH ), 29.1 (CH CO), 42.1 (C-6), 53.7 (C-
6
3
3
5
1
), 55.0 (CH O), 58.0 (C-7), 98.6 (C-3 of pent-3-en-2-one), 113.6,
26.5, 127.5, 128.2, 128.3, 131.6, 141.5 (carbons of aromatic), 154.5
Method D. A magnetically stirred mixture of compound 1a (1
mmol), diketone 6a (1.3 mmol), a 70% aqueous solution of HClO4
(0.152 g, 1.05 mmol), and AcOH (1.0 mL) was heated at 90 °C for 2
h and then diluted with ethanol (3 mL). The precipitate of compound
9a formed after cooling to room temperature was collected by
filtration and recrystallized from DMF/EtOH (1:3).
3
(
C-3a), 154.7 (C-2), 157.6 (C-4 of pent-3-en-2-one), 158.7
(
CH OC ), 195.8 (CO). MS (EI, 70 eV), m/z (%): 403 (19)
3
Ar
+
[
M] , 360 (11), 254 (58), 252 (23), 226 (95), 223 (33), 145 (10), 134
(
(
30), 131 (19), 121 (15), 115 (29), 106 (20), 104 (21), 91 (32), 77
28), 43 (100). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
Method E. A mixture of compound 20a−c (1 mmol), a 70%
C H N O 404.2081; Found 404.2078.
aqueous solution of HClO (0.152 g, 1.05 mmol), and EtOH (5 mL)
2
3
26
5
2
4
3
-[(5,7-Diphenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]-
was stirred at 20 °C for 20 min. The precipitated perchlorate 8b,e,g
was collected by filtration, washed with EtOH, and dried at 80 °C to
give.
pyrimidin-2-yl)amino]-1-phenylbut-2-en-1-one (7d). Yield 0.652 g
(
(
75%) of yellowish crystals, mp 185−186 °C (from acetonitrile). IR
cm ): 3214, 3062, 3033, 2973, 2914, 1591, 1582, 1536, 1469, 1418,
313, 1289, 1275, 1222, 1027, 747. H NMR (500 MHz, DMSO-d ):
−1
2,8,10-Trimethyl-4-phenyl-1,2,3,4-tetrahydro[1,2,4]triazolo[1,5-
a:4,3-a′]dipyrimidin-5-ium Perchlorate (8a). Yield 0.768 g (65%,
Method A), 0.685 g (58%, Method B) of colorless crystals, mp 194−
1
1
6
δ 2.07−2.14 (m, 1H, 6-CH ), 2.35 (s, 3H, CH ), 2.43−2.46 (m, 1H, 6-
2
3
−
1
CH ), 4.73−4.75 (m, 1H, H-5), 5.36−5.39 (m, 1H, H-7), 6.06 (s, 1H,
195 °C. IR (cm ): 3369, 3081, 1647, 1582, 1549, 1496, 1457, 1376,
2
1
H-2 of 1-phenylbut-2-en-1-one), 7.26−7.53 (m, 13H, Ar), 7.65 (br s,
1338, 1228, 1079, 1033, 730. H NMR (500 MHz, DMSO-d ): δ 1.37
6
13
1
H, NH), 7.90−7.92 (m, 2H, Ar), 13.15 (s, 1H, NH). C NMR (125
(d, 3H, J = 6.2 Hz, 2-CH ), 2.04−2.08 (m, 1H, H-3), 2.43 (s, 3H, 8-
3
MHz, DMSO-d ): δ 21.1 (CH ), 41.9 (C-6), 53.4 (C-5), 58.3 (C-7),
CH ), 2.54−2.56 (m, 1H, H-3), 2.84 (s, 3H, 10-CH ), 3.91−3.95 (m,
6
3
3
3
9
1
4.7 (C-2 of 1-phenylbut-2-en-1-one), 126.3, 126.8, 127.4, 128.1,
28.2, 131.2, 138.7, 139.6, 141.2 (carbons of 3Ph, signals are partially
1H, H-2), 5.56−5.59 (m, 1H, H-4), 6.83 (s, 1H, H-9), 7.35−7.43 (m,
5H, Ph), 8.33 (br s, 1H, NH). 13C NMR (125 MHz, DMSO-d ): δ
6
overlapped), 154.3 (C-3a), 154.8 (C-2), 160.1 (C-3 of 1-phenylbut-2-
en-1-one), 187.5 (CO). HRMS (ESI-TOF) m/z: [M + H] Calcd for
17.7 (10-CH ), 19.9 (2-CH ), 24.9 (8-CH ), 37.6 (C-3), 47.2 (C-2),
60.3 (C-4), 111.5 (C-9), 127.7, 128.43, 128.47, 137.5 (carbons of Ph),
3
3
3
+
C H N O 436.2132; Found 436.2122.
143.8 (C-11a), 145.4 (C-10), 147.2 (C-6a), 169.8 (C-8). MS (EI, 70
2
7
26
5
+
+
Ethyl 5-Methyl-2-{[4-oxopent-2-en-2-yl]amino}-7-phenyl-4,7-
dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (7e). Yield
.225 g (59%) of colorless crystals, mp 232−233 °C (from DMF/
eV), m/z (%): 294 (7) [M − ClO ] , 293 (30) [M − HClO ] , 278
4
4
(43), 189 (20), 174 (59), 148 (34), 107 (40), 104 (34), 91 (27), 77
0
(34), 67 (100), 51 (33), 44 (49). HRMS (ESI-TOF) m/z: [M −
−1
+
EtOH 1:3). IR (cm ): 3231, 3106, 3061, 2974, 2887, 1697, 1617,
ClO ] Calcd for C H N 294.1713; Found 294.1713.
4
17 20
5
1
1
552, 1531, 1453, 1379, 1288, 1252, 1169, 1077, 838, 774. H NMR
8,10-Dimethyl-2,4-diphenyl-1,2,3,4-tetrahydro[1,2,4]triazolo[1,5-
a:4,3-a′]dipyrimidin-5-ium Perchlorate (8b). Yield 0.971 g (71%,
Method A), 0.834 g (61%, Method B), 1.272 g (93%, Method E) of
(
500 MHz, DMSO-d ): δ 1.03 (t, J = 7.1 Hz, 3H, OCH CH ), 1.98 (s,
6
2
3
3
2
1
H, CH CO), 2.19 (s, 3H, 5-CH ), 2.39 (s, 3H, CH ), 3.93−3.96 (m,
3
3
3
−1
H, OCH CH ), 5.26 (s, 1H, H-3 of 4-oxopent-2-ene group), 6.14 (s,
colorless crystals, mp 221−222 °C. IR (cm ): 3307, 3079, 3041,
2
3
H, H-7), 7.21−7.33 (m, 5H, Ph), 10.80 (s, 1H, NH), 12.51 (s, 1H,
2952, 1643, 1582, 1547, 1455, 1323, 1224, 1203, 1079, 1021, 764, 723.
13
1
NH). C NMR (125 MHz, DMSO-d ): δ 13.7, 18.2, 20.7, 29.1, 59.0,
H NMR (500 MHz, DMSO-d ): δ 2.33−2.39 (m, 1H, H-3), 2.47 (s,
6
6
J
DOI: 10.1021/acs.joc.5b01908
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
3
1
8
H, CH ), 2.67−2.69 (m, 1H, H-3), 2.87 (s, 3H, CH ), 5.03−5.05 (m,
1244, 1093, 1081, 752. H NMR (500 MHz, DMSO-d ): δ 2.34−2.42
3
3
6
H, H-2), 5.72−5.74 (m, 1H, H-4), 6.88 (s, 1H, H-9), 7.35−7.43 (m,
(m, 1H, H-3), 2.65−2.68 (m, 1H, H-3), 4.82−4.85 (m, 1H, H-2),
5.71−5.74 (m, 1H, H-4), 7.27−7.65 (m, 16H, Ar), 7.80 (s, 1H, H-9),
7.92 (br s, 1H, NH), 7.97−8.05 (m, 2H, Ar), 8.31−8.32 (m, 2H, Ar).
13
H, Ar), 7.54−7.55 (m, 2H, Ar), 9.10 (br s, 1H, NH). C NMR (125
MHz, DMSO-d ): δ 17.7 (10-CH ), 25.0 (8-CH ), 39.2 (C-3), 54.6
6
3
3
13
(
C-2), 60.3 (C-4), 111.6 (C-9), 126.5, 127.9, 128.0, 128.4, 128.5,
C NMR (125 MHz, DMSO-d ): δ 40.2, 55.6, 61.2, 110.6, 126.8,
6
1
1
28.6, 136.7, 139.9 (carbons of 2Ph), 144.2 (C-11a), 145.4 (C-10),
128.5, 128.6, 128.7, 128.8, 129.05, 129.08, 129.3, 129.7, 130.7, 132.5,
133.4, 135.2, 137.4, 140.5 (carbons of 4Ph, signals of two carbon
atoms of benzene rings are overlapped), 144.3, 147.0, 148.0, 163.9.
47.2 (C-6a), 169.9 (C-8). MS (EI, 70 eV), m/z (%): 356 (5) [M −
+
+
ClO ] , 355 (21) [M − HClO ] , 250 (100), 107 (12), 104 (19), 77
4
4
+
+
(
12), 67 (28), 44 (55). HRMS (ESI-TOF) m/z: [M − ClO ] Calcd
HRMS (ESI-TOF) m/z: [M − ClO ] Calcd for C H N 480.2183;
4
4
32 26
5
for C H N 356.1870; Found 356.1873.
Found 480.2177.
22
22
5
4
-(4-Methoxyphenyl)-8,10-dimethyl-2-phenyl-1,2,3,4-tetrahydro-
1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidin-5-ium Perchlorate (8c). Yield
.005 g (69%, Method A), 0.860 g (59%, Method B) of colorless
8-Methyl-2,4,10-triphenyl-1,2,3,4-tetrahydro[1,2,4]triazolo[1,5-
[
1
a:4,3-a′]dipyrimidin-5-ium Perchlorate (8h). Yield 0.326 g (63%,
−1
Method A) of yellow crystals, mp 245−246 °C. IR (cm ): 3224, 3068,
−1
crystals, mp 173−174 °C. IR (cm ): 3607, 3529, 3253, 3000, 1646,
578, 1514, 1457, 1321, 1246, 1176, 1081, 1019, 837, 770. H NMR
1643, 1629, 1580, 1536, 1475, 1458, 1331, 1072, 1018, 1001, 761, 749,
1
1
1
720. H NMR (500 MHz, DMSO-d ): δ 2.37−2.44 (m, 1H, H-3), 2.61
6
(
500 MHz, DMSO-d ): δ 2.33−2.39 (m, 1H, H-3), 2.46 (s, 3H, CH ),
(s, 3H, CH ), 2.68−2.71 (m, 1H, H-3), 4.86−4.88 (m, 1H, H-2),
6
3
3
2
5
6
.61−2.64 (m, 1H, H-3), 2.87 (s, 3H, CH ), 3.75 (s, 3H, CH O),
5.74−5.75 (m, 1H, H-4), 7.19 (s, 1H, H-9), 7.32−7.53 (m, 10H, Ar),
7.65−7.70 (m, 3H, Ar), 7.86 (br s, 1H, NH),7.90−8.02 (m, 2H, Ar).
3
3
.02−5.03 (m, 1H, H-2), 5.67−5.68 (m, 1H, H-4), 6.87 (s, 1H, H-9),
13
13
.93−6.94 (m, 2H, Ar), 7.32−7.56 (m, 7H, Ar), 9.06 (s, 1H, NH).
C
C NMR (125 MHz, DMSO-d ): δ 25.0 (CH ), 39.5 (C-3), 54.7 (C-
6
3
NMR (125 MHz, DMSO-d ): δ 17.7 (10-CH ), 25.0 (8-CH ), 39.2
2), 60.4 (C-4), 113.8 (C-9), 126.1, 127.8, 128.27, 128.31, 128.4, 129.6,
131.7, 136.7, 139.7(carbons of 3Ph, signals of three carbon atoms of
6
3
3
(
C-3), 54.7 (C-2), 55.2 (CH O), 60.0 (C-4), 111.6 (C-9), 113.8,
26.5, 128.1, 128.5, 128.6, 129.4, 140.0 (carbons of aromatic), 144.0
C-11a), 145.3 (C-10), 147.1 (C-6a), 159.4 (CH OC ), 169.8 (C-8).
MS (EI, 70 eV), m/z (%): 385 (1) [M − HClO ] , 250 (100), 134
94), 119 (43), 107 (27), 103 (10), 91 (65), 89 (19), 77 (26), 67 (66),
5 (40), 51 (26), 44 (66). HRMS (ESI-TOF) m/z: [M − ClO ]
Calcd for C H N O 386.1975; Found 386.1974.
3
1
benzene rings are overlapped), 143.5 (C-11a), 144.5 (C-10), 146.9 (C-
+
(
6a), 169.2 (C-8). HRMS (ESI-TOF) m/z: [M − ClO ] Calcd for
3
Ar
4
+
4
C H N 418.2026; Found 418.2019.
27 24
5
(
6
8,10-Dimethyl-2,4-diphenyl[1,2,4]triazolo[1,5-a:4,3-a′]-
dipyrimidin-5-ium Perchlorate (9a). Yield 0.257 g (57%, Method C),
0.068 g (35%, Method D) of yellowish crystals, mp 285−286 °C. IR
+
4
23
24
5
−1
8
,9,10-Trimethyl-2,4-diphenyl-1,2,3,4-tetrahydro[1,2,4]triazolo-
(cm ): 3075, 3005, 1636, 1597, 1561, 1500, 1445, 1382, 1244, 1091,
1
[
1,5-a:4,3-a′]dipyrimidin-5-ium Perchlorate (8d). Yield 0.305 g (65%,
1078, 769, 725. H NMR (500 MHz, DMSO-d ): δ 2.77 (s, 3H, CH ),
6
3
−1
Method B) of colorless crystals, mp 203−204 °C. IR (cm ): 3629,
3.31 (s, 3H, CH ), 7.54 (s, 1H, H-9), 7.71−7.84 (m, 6H, Ar), 8.36−
3
1
13
3
536, 3297, 1638, 1577, 1540, 1459, 1323, 1200, 1088, 1020, 755. H
8.37 (m, 2H, Ar), 8.61−8.62 (m, 2H, Ar), 9.01 (s, 1H, H-3). C NMR
(125 MHz, DMSO-d ): δ 18.6 (CH ), 25.8 (CH ), 113.6 (C-3), 114.0
NMR (500 MHz, DMSO-d ): δ 2.22 (s, 3H, 9-CH ), 2.35−2.37 (m,
6
3
6
3
3
1
1
7
H, H-3), 2.51 (s, 3H, 8-CH ), 2.65−2.67 (m, 1H, H-3), 2.86 (s, 3H,
(C-9), 127.7, 128.8, 129.0, 129.6, 130.4, 133.1, 133.5, 133.8 (carbons
of 2Ph), 143.3 (C-11a), 148.2 (C-8 or C-10), 149.3 (C-2 or C-4),
151.8 (C-6a), 162.1 (C-2 or C-4), 175.3 (C-8 or C-10). HRMS (ESI-
3
0-CH ), 5.01−5.02 (m, 1H, H-2), 5.71−5.72 (m, 1H, H-4), 7.37−
3
13
.54 (m, 10H, Ar), 9.07 (br s, 1H, NH). C NMR (125 MHz,
+
DMSO-d ): δ 13.1 (9-CH ), 14.8 (10-CH ), 24.9 (8-CH ), 39.2 (C-
), 54.6 (C-2), 60.4 (C-4), 117.7 (C-9), 126.5, 127.9, 128.0, 128.4,
28.5, 128.6, 136.9, 140.0 (carbons of 2Ph), 140.8 (C-10), 144.1 (C-
1a), 146.0 (C-6a), 170.7 (C-8). HRMS (ESI-TOF) m/z: [M −
ClO ] Calcd for C H N 370.2026; Found 370.2019.
TOF) m/z: [M − ClO ] Calcd for C H N 352.1557; Found
6
3
3
3
4
22 18
5
3
1
1
352.1553.
2,4,8,10-Tetraphenyl[1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidin-5-
ium Perchlorate (9b). Yield 0.374 g (65%, Method C) of yellow
+
−1
crystals, mp > 300 °C. IR (cm ): 3065, 1627, 1596, 1562, 1504, 1492,
4
23 24
5
1
9
-Chloro-8,10-dimethyl-2,4-diphenyl-1,2,3,4-tetrahydro[1,2,4]-
1367, 1356, 1309, 1238, 1086, 762. H NMR (500 MHz, DMSO-d
6
):
triazolo[1,5-a:4,3-a′]dipyrimidin-5-ium Perchlorate (8e). Yield 0.299
δ 7.59−7.61 (m, 2H, Ar), 7.70−7.75 (m, 3H, Ar), 7.80−7.95 (m, 7H,
g (61%, Method B), 0.441 g (90%, Method E) of yellowish crystals, mp
Ar), 8.07−8.08 (m, 2H, Ar), 8.11−8.13 (m, 2H, Ar), 8.43−8.44 (m,
−1
13
2
1
01−202 °C. IR (cm ): 3299, 2939, 1642, 1632, 1570, 1539, 1460,
326, 1280, 1084, 1056, 1033, 763, 737. H NMR (500 MHz, DMSO-
3H, Ar + H-9), 8.63−8.64 (m, 2H, Ar), 9.01 (s, 1H, H-3). C NMR
1
(125 MHz, DMSO-d ): δ 111.9 (C-9), 114.2 (C-3), 128.3, 129.0,
6
d ): δ 2.33−2.40 (m, 1H, H-3), 2.61 (s, 3H, 8-CH ), 2.69−2.72 (m,
129.2, 129.58, 129.63, 129.7, 129.8, 130.0, 130.3, 131.0, 132.2, 133.7,
134.08, 134.12, 134.6, 134.8 (carbons of benzene rings), 143.1 (C-
11a), 149.6 (C-8 or C-10), 149.9 (C-2 or C-4), 153.1 (C-6a), 161.9
6
3
1
H, H-3), 3.00 (s, 3H, 10-CH ), 5.04−5.06 (m, 1H, H-2), 5.76−5.79
3
(
1
m, 1H, H-4), 7.36−7.45 (m, 8H, Ar), 7.53−7.55 (m, 2H, Ar), 9.36 (s,
H, NH). 13C NMR (125 MHz, DMSO-d ): δ 15.7 (10-CH ), 24.8
(C-2 or C-4), 168.8(C-8 or C-10). HRMS (ESI-TOF) m/z: [M −
6
3
+
(
8-CH ), 38.9 (C-3), 54.6 (C-2), 60.6 (C-4), 118.3 (C-9), 126.5,
ClO
4
] Calcd for C32
H
22
N
5
476.1870; Found 476.1861.
3
1
1
27.8, 128.1, 128.4, 128.59, 128.63, 136.5, 139.6 (carbons of 2Ph),
8,10-Dimethyl-2-(4-methylphenyl)-4-phenyl[1,2,4]triazolo[1,5-
a:4,3-a′]dipyrimidin-5-ium Perchlorate (9c). Yield 0.302 g (67%,
42.4 (C-10), 144.3 (C-11a), 145.0 (C-6a), 167.2 (C-8). HRMS (ESI-
−1
+
Method C) of cream-colored crystals, mp > 300 °C. IR (cm ): 3082,
TOF) m/z: [M − ClO ] Calcd for C H ClN 390.1480; Found
4
22 21
5
1
637, 1603, 1570, 1488, 1447, 1382, 1349, 1255, 1075, 829, 771, 723.
3
90.1470.
,8,9,10-Tetramethyl-4-phenyl-1,2,3,4-tetrahydro[1,2,4]triazolo-
1,5-a:4,3-a′]dipyrimidin-5-ium Perchlorate (8f). Yield 0.293 g (72%,
1
H NMR (500 MHz, DMSO-d ): δ 2.50 (s, 3H, CH ), 2.80 (s, 3H,
2
6
3
[
CH ), 3.33 (s, 3H, CH ), 7.55−7.56 (m, 3H, Ar + H-9), 7.82−7.86
3
3
−1
Method B) of colorless crystals, mp 233−234 °C. IR (cm ): 3297,
(m, 3H, Ar), 8.38−8.39 (m, 2H, Ar), 8.54−8.55 (m, 2H, Ar), 8.99 (s,
1H, H-3). 13C NMR (125 MHz, DMSO-d
): δ 19.2, 21.7, 26.4, 113.7,
2
7
2
990, 2941, 1633, 1576, 1537, 1486, 1400, 1331, 1302, 1240, 1081,
56, 714. H NMR (500 MHz, DMSO-d ): δ 1.32 (d, J = 6.2 Hz, 3H,
6
1
114.5, 128.3, 129.3, 129.5, 130.8, 131.0, 131.7, 133.6, 143.8, 144.9,
6
-CH ), 1.94−2.02 (m, 1H, H-3), 2.16 (s, 3H, CH ), 2.44 (s, 3H,
148.7, 149.7, 152.3, 162.7, 175.7. HRMS (ESI-TOF) m/z: [M −
3
3
+
CH ), 2.48−2.51 (m, 1H, H-3), 2.77 (s, 3H, CH ), 3.82−3.88 (m, 1H,
ClO
4
] Calcd for C23
H
20
N
5
366.1713; Found 366.1712.
3
3
H-2), 5.51−5.54 (m, 1H, H-4), 7.32−7.34 (m, 5H, Ph), 8.26 (s, 1H,
8,9,10-Trimethyl-2-(4-methylphenyl)-4-phenyl[1,2,4]triazolo[1,5-
NH). 13C NMR (125 MHz, DMSO-d ): δ 13.7, 15.3, 20.5, 25.4, 38.2,
a:4,3-a′]dipyrimidin-5-ium Perchlorate (9d). Yield 0.336 g (70%,
6
−1
Method C) of yellow crystals, mp 281−282 °C. IR (cm ): 3067, 1638,
4
1
7.7, 60.9, 118.1, 128.2, 128.9, 129.0, 138.2 (carbons of Ph), 141.3,
+
1
603, 1568, 1519, 1487, 1368, 1381, 1213, 1079, 1014, 829, 767, 748.
44.3, 146.7, 171.2. HRMS (ESI-TOF) m/z: [M − ClO ] Calcd for
4
1
H NMR (500 MHz, DMSO-d ): δ 2.50 (s, 3H, CH ), 2.51 (s, 3H,
C H N 308.1870; Found 308.1876.
6
3
1
8
22
5
2
,4,8,10-Tetraphenyl-1,2,3,4-tetrahydro[1,2,4]triazolo[1,5-a:4,3-
CH
3
), 2.84 (s, 3H, CH
3
), 3.39 (s, 3H, CH
3
), 7.55−7.56 (m, 2H, Ar),
a′]dipyrimidin-5-ium Perchlorate (8g). Yield 0.457 g (79%, Method
7.82−7.85 (m, 3H, Ar), 8.37−8.38 (m, 2H, Ar), 8.51−8.53 (m, 2H,
C), 0.550 g (95%, Method E) of yellow crystals, mp 273−274 °C. IR
cm ): 3408, 3067, 3030, 2897, 1653, 1631, 1576, 1526, 1478, 1398,
Ar), 8.96 (s 1H, H-3). 13C NMR (125 MHz, DMSO-d ): δ 13.9, 16.0,
6
−1
(
21.7, 26.1, 113.5, 121.4, 128.4, 129.2, 129.5, 130.8, 130.9, 131.8, 133.5,
K
DOI: 10.1021/acs.joc.5b01908
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
43.7, 144.65, 144.70, 149.5, 151.0, 162.1, 176.2. HRMS (ESI-TOF)
(s, 3H, 9-CH ), 1.09 (s, 3H, 9-CH ), 2.19 (d, J = 16.3 Hz, 1H, 10-
3
3
+
m/z: [M − ClO ] Calcd for C H N 380.1870; Found 380.1869.
CH ), 2.30 (d, J = 16.3 Hz, 1H, 10-CH ), 2.64−2.70 (m, 2H, 8-CH ),
4
24 22
5
2
2
2
2
,4-Diphenyl[1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidin-5-ium Per-
2.66 (s, 3H, CH ), 2.75 (s, 3H, CH ), 6.47 (s, 1H, H-12), 7.28−7.37
3
3
chlorate (9e). Yield 0.258 g (61%, Method C) of cream-colored
crystals, mp 268−269 °C. IR (cm ): 3098, 3075, 1635, 1600, 1558,
(m, 3H, Ar), 7.46−7.48 (m, 2H Ar), 7.70 (s, 1H, H-3), 12.32 (br s,
−1
13
1H, NH). C NMR (125 MHz, DMSO-d ): δ 16.1 (CH ), 24.5
6
3
1
1
7
2
527, 1369, 1250, 1079, 926, 768. H NMR (500 MHz, DMSO-d ): δ
(CH ), 26.9 (9-CH ), 28.0 (9-CH ), 32.4 (C-9), 39.7 (C-8), 49.6 (C-
6
3 3 3
.76−7.84 (m, 7H, Ar + H-9), 8.40−8.42 (m, 2H, Ar), 8.72−8.74 (m,
10), 54.7 (C-12), 107.1 (C-11a), 116.1 (C-3), 127.8, 128.4, 128.7,
137.9 (carbons of Ph), 144.0 (C-6a or C-13a), 147.6 (C-6a or C-13a),
149.0 (C-7a), 150.4 (C-4), 168.7 (C-2), 192.8 (CO). HRMS (ESI-
H, Ar), 9.08 (s, 1H, H-3), 9.43 (br s, 1H, H-8), 9.88−9.89 (m, 1H,
13
H-10). C NMR (125 MHz, DMSO-d ): δ 113.0 (C-9), 114.0 (C-3),
6
+
1
1
27.3, 128.8, 128.9, 129.4, 130.3, 133.1, 133.4, 133.6 (carbons of 2Ph),
34.0 (C-10), 142.0 (C-11a), 149.5 (C-2 or C-4), 150.9 (C-6a), 162.9+
TOF) m/z: [M − ClO ] Calcd for C H N O 374.1975; Found
4
22 24
5
374.1975.
(
C-2 or C-4), 165.7 (C-8). HRMS (ESI-TOF) m/z: [M − ClO4]
2,4,9,9-Tetramethyl-11-oxo-12-phenyl-7,8,9,10,11,12-hexahydro-
pyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium Hydrogen
Sulfate (11d). Yield 0.273 g (68%, Method B) of colorless crystals, mp
Calcd for C H N 324.1244; Found 324.1245.
20
14
5
General Procedure for the Synthesis of Compounds 11a−t.
Method A. A magnetically stirred mixture of the appropriate
enaminoketone 7e,f (1 mmol), a 70% aqueous solution of HClO4
−
1
2
1
75−276 °C (from i-PrOH). IR (cm ): 3055, 2935, 2739, 1666,
1
648, 1594, 1445, 1382, 1341, 1224, 1156, 1041, 881, 739. H NMR
(
2
500 MHz, DMSO-d ): δ 1.01 (s, 3H, 9-CH ), 1.09 (s, 3H, 9-CH ),
(
1
0.152 g, 1.05 mmol), and acetonitrile (4 mL, for the preparation of
1a) or AcOH (1 mL for the preparation of 11b) was refluxed for 1 h.
6 3 3
.16−2.32 (m, 2H, 10-CH ), 2.65 (s, 3H, CH ), 2.70−2.72 (m, 2H, 8-
2
3
CH ), 2.75(s, 3H, CH ), 6.47 (s, 1H, H-12), 7.27−7.37 (m, 3H, Ar),
The precipitate formed after cooling to 20 °C was collected by
filtration and recrystallized from acetonitrile/EtOH (1:3).
2
3
1
3
7
.46−7.47 (m, 2H, Ar), 7.73 (s, 1H), 12.34 (br s, 1H, NH). C NMR
(125 MHz, DMSO-d ): δ 16.2, 24.5, 26.9, 28.1, 32.4, 42.2, 49.6, 54.7,
Method B. A magnetically stirred mixture of the appropriate amine
b, 5a−e (1 mmol), diketone 6a−g or tetramethoxypropane 6h (1.3
6
1
1
07.1, 116.2, 127.8, 128.5, 128.7, 138.1, 144.0, 147.6, 149.2, 150.4,
1
+
68.7, 192.9. HRMS (ESI-TOF) m/z: [M − HSO ] Calcd for
mmol), a 70% aqueous solution of HClO (0.152 g, 1.05 mmol, for the
preparation of compounds 11a−c,e−s) or concentrated H SO (0.11
g, 1.05 mmol, for the preparation of 11d,t), and AcOH (0.5 mL) was
heated at 90 °C for 1 h and then diluted with ethanol (2 mL). The
precipitate formed after cooling to room temperature was collected by
filtration and recrystallized.
4
4
C H N O 374.1975; Found 374.1970.
22 24
5
2
4
1
2-(4-Methoxyphenyl)-2,4,9,9-tetramethyl-11-oxo-
7
,8,9,10,11,12-hexahydropyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]-
quinazolin-5-ium Perchlorate (11e). Yield 0.287 g (67%, Method B)
of yellowish crystals, mp 246−247 °C (from i-PrOH). IR (cm ):
207, 2960, 2872, 1665, 1591, 1513, 1440, 1380, 1243, 1092, 1048,
−1
3
1
Method C. A mixture of compound 21a−c (1 mmol), a 70%
1
022, 849, 762. H NMR (500 MHz, DMSO-d ): δ 1.03 (s, 3H, 9-
6
aqueous solution of HClO (0.152 g, 1.05 mmol), and EtOH (5 mL)
was stirred at 20 °C for 20 min. The precipitate formed was collected
by filtration, washed with EtOH, and dried at 80 °C.
4
CH ), 1.09 (s, 3H, 9-CH ), 2.19 (d, J = 16.2 Hz, 1H, 10-CH ), 2.30
3
3
2
(
d, J = 16.2 Hz, 1H, 10-CH ), 2.67 (s, 3H, CH ), 2.68−2.70 (m, 2H,
2
3
8
6
1
-CH ), 2.74 (s, 3H, CH ), 3.71 (s, 3H, CH O), 6.43 (s, 1H, H-12),
2 3 3
9
-(Ethoxycarbonyl)-2,4,8-trimethyl-10-phenyl-7,10-dihydro-
1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidin-5-ium Perchlorate (11a).
Yield 0.276 g (70%, Method A), 0.264 g (67%, Method B), 0.362 g
92%, Method C) of colorless crystals, mp 226−227 °C (from EtOH).
.88−6.90 (m, 2H, Ar), 7.38−7.40 (m, 2H, Ar), 7.69 (s, 1H, H-3),
[
13
2.29 (br s, 1H, NH). C NMR (125 MHz, DMSO-d ): δ 16.1
6
(
4
CH ), 24.5 (CH ), 26.9 (CH ), 28.1 (CH ), 32.4 (C-9), 39.7 (C-8),
9.7 (C-10), 54.2 (C-12), 55.1 (CH O), 107.2 (C-11a), 113.8 (carbon
3
3 3 3 3
(
−
1
IR (cm ): 3234, 3173, 3082, 2980, 1707, 1666, 1640, 1599, 1531,
1
δ 1.08 (t, 3H, CH CH ), 2.53 (s, 3H, CH ), 2.65 (s, 3H, CH ), 2.72
of benzene ring), 116.0 (C-3), 129.2, 130.2 (carbons of benzene ring),
44.0 (C-6a or C-13a), 147.6 (C-6a or C-13a), 148.8 (C-7a), 150.3
C-4), 159.4 (CH O-C ), 168.6 (C-2), 192.9 (CO). HRMS (ESI-
1
441, 1378, 1270, 1249, 1073, 762. H NMR (500 MHz, DMSO-d ):
6
1
2
3
3
3
(
3
Ar
(
7
1
s, 3H, CH ), 3.99−4.05 (m, 2H, CH CH ), 6.52 (s, 1H, H-10),
+
3
2
3
TOF) m/z: [M − ClO ] Calcd for C H N O 404.2081; Found
4
4
23 26
5
2
.30−7.38 (m, 3H, Ar), 7.47−7.49 (m, 2H, Ar), 7.67 (s, 1H, H-3),
04.2076.
1.97 (br s, 1H, NH). 13C NMR (125 MHz, DMSO-d ): δ 13.7
6
2
-(4-Bromophenyl)-2,4,9,9-tetramethyl-11-oxo-7,8,9,10,11,12-
(
(
(
CH CH ), 16.1 (CH ), 18.1 (CH ), 24.4 (8-CH ), 56.0 (C-10), 60.1
CH CH ), 99.9 (C-9), 116.0 (C-3), 127.9, 128.5, 128.9, 138.2
carbons of Ph), 143.5 (C-6a or C-13a), 144.9 (C-8), 147.5 (C-6a or
2 3 3 3 3
hexahydropyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium
2
3
Perchlorate (11f). Yield 0.386 g (80%, Method B) of yellowish crystals,
mp 202−203 °C (from EtOH). IR (cm ): 3209, 3146, 3085, 2962,
2877, 1666, 1597, 1441, 1382, 1273, 1246, 1089, 1010, 841, 764. H
−
1
1
C-13a), 150.3 (C-4), 163.8 (CO), 168.4 (C-2). HRMS (ESI-TOF) m/
z: [M − ClO ] Calcd for C H N O 364.1768; Found 364.1769.
+
4
20 22
5
2
NMR (500 MHz, DMSO-d ): δ 1.02 (s, 3H, 9-CH ), 1.09 (s, 3H, 9-
6
3
4
,9,9-Trimethyl-11-oxo-2,12-diphenyl-7,8,9,10,11,12-hexahydro-
CH ), 2.19 (d, J = 16.1 Hz, 1H, 10-CH ), 2.29 (d, J = 16.1 Hz, 1H, 10-
3
2
pyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium Perchlo-
CH ), 2.65−2.69 (m, 5H, 8-CH + CH ), 2.75 (s, 3H, CH ), 6.45 (s,
2
2
3
3
rate (11b). Yield 0.466 g (49%, Method A), 0.441 g (45%, Method
1
1
1
H, H-12), 7.43−7.45 (m, 2H, Ar), 7.54−7.56 (m, 2H, Ar), 7.70 (s,
−1
B) of colorless crystals, mp > 300 °C (from acetonitrile). IR (cm ):
3
1
13
H, H-3), 12.38 (br s, 1H, NH). C NMR (125 MHz, DMSO-d ): δ
6
275, 3202, 3143, 3089, 3011, 2967, 2934, 2875, 1671, 1639, 1604,
6.1 (CH ), 24.5 (CH ), 27.0 (CH ), 28.0 (CH ), 32.4 (C-9), 39.5
3
3
3
3
1
375, 1330, 1254, 1109, 1038, 928, 756. H NMR (500 MHz, DMSO-
(C-8), 49.6 (C-10), 54.3 (C-12), 106.6 (C-11a), 116.1 (C-3), 122.0,
d ): δ 1.06 (s, 3H, 9-CH ), 1.12 (s, 3H, 9-CH ), 2.21 (d, J = 16.4 Hz,
6
3
3
130.3, 131.3, 137.2 (carbons of benzene ring), 144.0 (C-6a or C-13a),
147.5 (C-6a or C-13a), 149.4 (C-7a), 150.3 (C-4), 168.7 (C-2), 192.9
1
8
H, 10-CH ), 2.32 (d, J = 16.4 Hz, 1H, 10-CH ), 2.69−2.77 (m, 2H,
2
2
+
-CH ), 2.84 (s, 3H, 4-CH ), 6.60 (s, 1H, H-12), 7.28−7.31 (m, 1H,
2
3
(CO). HRMS (ESI-TOF) m/z: [M − ClO ] Calcd for C H BrN O
4
22 23
5
Ar), 7.38−7.41 (m, 2H, Ar), 7.61−7.69 (m, 5H, Ar), 8.31−8.32 (m,
H, Ar), 8.45 (s, 1H, H-3), 12.42 (br s, 1H, NH). 13C NMR (125
MHz, DMSO-d ): δ 17.1 (4-CH ), 27.5 (9-CH ), 28.6 (9-CH ), 32.9
4
52.1080; Found 452.1057.
2
1
2-(2,4-Dichlorophenyl)-2,4,9,9-tetramethyl-11-oxo-
6
3
3
3
7,8,9,10,11,12-hexahydropyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]-
quinazolin-5-ium Perchlorate (11g). Yield 0.374 g (79%, Method B)
of yellowish crystals, mp 279−280 °C (from AcOH/benzene 1:4). IR
(
C-9), 40.2 (C-8), 50.2 (C-10), 55.6 (C-12), 107.6 (C-11a), 112.4 (C-
3
2
1
), 128.6, 128.8, 129.0, 129.3, 130.1, 133.7, 134.3, 138.6 (carbons of
Ph), 145.0 (C-6a or C-13a), 148.4 (C-6a or C-13a), 149.6 (C-7a),
52.1 (C-4), 162.6 (C-2), 193.5 (CO). HRMS (ESI-TOF) m/z: [M −
−1
(cm ): 3140, 3091, 2959, 1658, 1641, 1592, 1526, 1443, 1377, 1343,
1
1274, 1116, 1076, 866, 767. H NMR (500 MHz, DMSO-d
(s, 3H, 9-CH ), 1.07 (s, 3H, 9-CH ), 2.13 (d, J = 16.2 Hz, 1H, 10-
CH ), 2.27 (d, J = 16.2 Hz, 1H, 10-CH ), 2.58 (s, 3H, CH ), 2.61−
2.68 (m, 2H, 8-CH ), 2.74 (s, 3H, CH
): δ 1.01
6
+
ClO ] Calcd for C H N O 436.2132; Found 436.2130.
3
3
4
27 26
5
2
,4,9,9-Tetramethyl-11-oxo-12-phenyl-7,8,9,10,11,12-hexahydro-
2
2
3
pyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium Perchlo-
2
3
), 6.73 (s, 1H, H-12), 7.40−
rate (11c). Yield 0.303 g (78%, Method B), 0.389 g (95%, Method
7.42 (m, 1H, Ar), 7.51−7.64 (m, 2H, Ar), 7.69 (s, 1H, H-3), 12.44 (br
s, 1H, NH). C NMR (125 MHz, DMSO-d ): δ 16.7 (CH ), 25.2
−1
13
C) of colorless crystals, mp 268−269 °C (from EtOH). IR (cm ):
3
1
6
3
143, 3084, 3025, 2963, 1670, 1658, 1607, 1437, 1380, 1335, 1247,
(CH ), 27.5 (CH ), 28.7 (CH ), 32.9 (C-9), 40.3 (C-8), 50.3 (C-10),
3 3 3
1
116, 1077, 1050, 1026, 929. H NMR (500 MHz, DMSO-d ): δ 1.01
53.5 (C-12), 106.4 (C-11a), 116.9 (C-3), 128.1, 129.5, 134.6, 134.74,
6
L
DOI: 10.1021/acs.joc.5b01908
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
1
34.78 (carbons of benzene ring, signals are partially overlapped),
44.7 (C-6a or C-13a), 148.1 (C-6a or C-13a), 150.2 (C-7a), 150.9
Perchlorate (11l). Yield 0.233 g (54%, Method B) of colorless crystals,
−
1
mp 186−187 °C (from EtOH). IR (cm ): 3199, 3142, 3080, 3030,
(
C-4), 169.4 (C-2), 193.6 (CO). HRMS (ESI-TOF) m/z: [M −
2958, 2872, 1663, 1636, 1593, 1450, 1378, 1337, 1255, 1095, 1052,
+
1
ClO ] Calcd for C H Cl N O 442.1196; Found 442.1180.
928, 840. H NMR (500 MHz, DMSO-d ): δ 0.94 (t, J = 6.9 Hz, 3H,
4
22 22
2
5
6
2
,3,4,9,9-Pentamethyl-11-oxo-12-phenyl-7,8,9,10,11,12-
(CH ) CH ), 1.03 (s, 3H, 9-CH ), 1.10 (s, 3H, 9-CH ), 1.40−1.51
2
3
3
3
3
hexahydropyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium
(
m, 4H, CH (CH ) CH ), 2.19 (d, J = 16.3 Hz, 1H, 10-CH ), 2.31 (d,
2 2 2 3 2
Perchlorate (11h). Yield 0.351 g (82%, Method B) of colorless crystals,
mp 269−270 °C (from EtOH). IR (cm ): 3204, 3149, 3089, 3028,
962, 2873, 1669, 1632, 1598, 1447, 1373, 1335, 1245, 1116, 1050,
J = 16.3 Hz, 1H, 10-CH ), 2.66−2.74 (m, 5H, CH + 8-CH ), 2.77−
2
3
2
−
1
2
.81 (m, 5H, CH + CH (CH ) CH ), 6.47 (s, 1H, H-12), 7.28−7.38
3
2
2
2
3
2
1
13
(m, 3H, Ar), 7.48−7.50 (m, 2H, Ar), 12.31 (br s, 1H, NH). C NMR
1
037, 1003, 931, 740. H NMR (500 MHz, DMSO-d ): δ 1.02 (s, 3H,
6
(125 MHz, DMSO-d ): δ 13.3 ((CH ) CH ), 13.5 (CH ), 21.8
6
2
3
3
3
CH ), 1.10 (s, 3H, CH ), 2.20 (d, J = 16.4 Hz, 1H, 10-CH ), 2.31 (d, J
3
3
2
(
(
CH ), 23.3 (CH ), 26.7 (9-CH ), 26.8 (CH ), 27.9 (9-CH ), 30.0
2 3 3 2 3
=
+
16.4 Hz, 1H, 10-CH ), 2.37 (s, 3H, CH ), 2.65−2.70 (m, 5H, 8-CH
2
3
2
CH ), 32.2 (C-9), 39.5 (C-8, overlapped by DMSO signal), 49.5 (C-
2
CH ), 2.78 (s, 3H, CH ), 6.48 (s, 3H, H-12), 7.28−7.37 (m, 3H,
3
3
1
1
0), 54.4 (C-12), 106.9 (C-11a), 127.3 (C-3), 127.7, 128.3, 128.5,
37.9 (carbons of benzene ring), 141.8(C-6a or C-13a), 147.2(C-6a or
13
Ar), 7.48 (d, J = 7.4 Hz, 2H, Ar), 12.30 (br s, 1H, NH). C NMR
(
(
1
125 MHz, DMSO-d ): δ 13.5 (CH ), 13.7 (CH ), 24.0 (CH ), 26.7
CH ), 27.9 (CH ), 32.2 (C-9), 39.7 (C-8), 49.5 (C-10), 54.4 (C-12),
06.8 (C-11a), 123.5 (C-3), 127.6, 128.3, 128.5, 137.9 (carbons of
Ph), 141.7 (C-6a or C-13a), 147.1 (C-6a or C-13a), 147.7 (C-4),
48.9 (C-7a), 167.7 (C-2), 192.7 (CO). HRMS (ESI-TOF) m/z: [M
6
3
3
3
C-13a), 148.1 (C-7a), 148.9(C-4), 167.3 (C-2), 192.7 (CO). HRMS
3
3
+
(
ESI-TOF) m/z: [M − ClO4] Calcd for C H N O 430.2601;
26
32
5
Found 430.2598.
9
,9-Dimethyl-11-oxo-2,4,12-triphenyl-7,8,9,10,11,12-hexahydro-
1
−
pyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium Perchlo-
+
ClO ] Calcd for C H N O 388.2132; Found 388.2128.
4 23 26 5
rate (11m). Yield 0.438 g (84%, Method B) of yellow crystals, mp
87−288 °C (from acetonitrile). IR (cm ): 3060, 2948, 2695, 1684,
628, 1577, 1543, 1491, 1378, 1365, 1277, 1252, 1071, 844, 751. H
1
2-(2,4-Dichlorophenyl)-2,3,4,9,9-pentamethyl-11-oxo-
,8,9,10,11,12-hexahydropyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]-
quinazolin-5-ium Perchlorate (11i). Yield 0.417 g (85%, Method B),
.442 g (90%, Method C) of yellowish crystals, mp 208−209 °C (from
−1
2
1
7
1
NMR (500 MHz, DMSO-d ): δ 1.08 (s, 3H, CH ), 1.13 (s, 3H, CH ),
6
3
3
0
−1
2.23 (d, J = 16.5 Hz, 1H, 10-CH
2
), 2.35 (d, J = 16.5 Hz, 1H, 10-CH
),
2
EtOH). IR (cm ): 2956, 2869, 1666, 1589, 1452, 1379, 1340, 1274,
100, 1051, 857, 757. H NMR (500 MHz, DMSO-d ): δ 1.01 (s, 3H,
-CH ), 1.08 (s, 3H, 9-CH ), 2.13 (d, J = 16.2 Hz, 1H, 10-CH ), 2.27
d, J = 16.2 Hz, 1H, 10-CH ), 2.33 (s, 3H, CH ), 2.58 (s, 3H, CH ),
1
2.69−2.77 (m, 2H, 8-CH
2
), 6.67 (s, 1H, H-12), 7.33−7.35 (m, 1H,
1
9
(
2
6
Ar), 7.43−7.46 (m, 2H, Ar), 7.68−7.81 (m, 8H, Ar), 8.21−8.23 (m,
3
3
2
2
H, Ar), 8.50−8.52 (m, 2H, Ar), 8.63 (s, 1H, H-3), 12.48 (br s, 1H,
2 3 3
13
NH). C NMR (125 MHz, DMSO-d ): δ 27.5, 28.6, 33.0, (signal of
6
.61−2.68 (m, 2H, 8-CH ), 2.76 (s, 3H, CH ), 6.73 (s, 1H, H-12),
2
3
C-8 is overlapped by DMSO signal), 50.2, 55.7, 107.6, 111.8, 128.3,
128.9, 129.0, 129.3, 130.0, 130.8, 133.4, 133.8, 134.4, 138.6 (signals of
7
.40 (d, J = 7.2 Hz, 1H, Ar), 7.48−7.64 (m, 2H, Ar), 12.39 (s, 1H,
13
NH). C NMR (125 MHz, DMSO-d ): δ 14.3 (CH ), 14.5 (CH ),
6
3
3
carbons of benzene rings are partially overlapped), 145.8, 148.4, 149.7,
2
(
1
4.8 (CH ), 27.5 (9-CH ), 28.7 (9-CH ), 32.9 (C-9), 40.2 (C-8), 50.3
3 3 3
+
1
50.0, 163.3, 193.5. HRMS (ESI-TOF) m/z: [M − ClO ] Calcd for
4
C-10), 53.2 (C-12), 106.4 (C-11a), 124.5 (C-3), 128.1, 129.5, 134.6,
34.8, 134.9 (carbons of benzene ring, signals are partially over-
lapped), 142.6 (C-6a or C-13a), 147.8 (C-6a or C-13a), 148.5 (C-4),
50.3 (C-7a), 168.6 (C-2), 193.6 (CO). HRMS (ESI-TOF) m/z: [M
C H N O 498.2288; Found 498.2284.
32
28
5
9
,9-Dimethyl-11-oxo-12-phenyl-7,8,9,10,11,12-hexahydro-
pyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium Perchlo-
1
−
rate (11n). Yield 0.282 g (74%, Method B) of colorless crystals, mp
94−195 °C (from acetonitrile). IR (cm ): 3211, 3094, 2961, 2873,
671, 1634, 1590, 1403, 1335, 1249, 1121, 1038, 920, 813, 767. H
+
ClO ] Calcd for C H Cl N O 456.1352; Found 456.1329.
−1
4
23 24
2
5
1
1
3
-Chloro-2,4,9,9-tetramethyl-11-oxo-12-phenyl-7,8,9,10,11,12-
1
hexahydropyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium
NMR (500 MHz, DMSO-d ): δ 1.03 (s, 3H, 9-CH ), 1.11 (s, 3H, 9-
Perchlorate (11j). Yield 0.340 g (77%, Method B) of colorless crystals,
6
3
−1
CH ), 2.20 (d, J = 16.4 Hz, 1H, 10-CH ), 2.31 (d, J = 16.4 Hz, 1H, 10-
mp 213-214 °C (from i-PrOH). IR (cm ): 3214, 3150, 3082, 2961,
878, 1662, 1590, 1452, 1379, 1246, 1104, 1059, 1018, 805, 760, 720.
H NMR (500 MHz, DMSO-d ): δ 1.03 (s, 3H, 9-CH ), 1.10 (s, 3H,
3
2
CH ), 2.68−2.77 (m, 2H, 8-CH ), 6.54 (s, 1H, H-12), 7.29−7.38 (m,
2
2
2
1
3H, Ar), 7.50−7.52 (m, 2H, Ar), 7.88−7.90 (m, 1H, Ar), 9.11−9.12
6
3
1
3
(
(
(
m, 1H, Ar), 9.69−9.70 (m, 1H, Ar), 12.42 (br s, 1H, NH). C NMR
9
1
6
1
-CH ), 2.20 (d, J = 16.2 Hz, 1H, 10-CH ), 2.31 (d, J = 16.2 Hz, 1H,
3
2
125 MHz, DMSO-d ): δ 27.4 (9-CH ), 28.6 (9-CH ), 32.9 (C-9),
signal of C-8 is overlapped by DMSO signal), 50.2 (C-10), 55.7 (C-
0-CH ), 2.67−2.76 (m, 5H, CH + 8-CH ), 2.87 (s, 3H, 4-CH ),
6
3
3
2
3
2
3
.51 (s, 1H, H-12), 7.29−7.38 (m, 3H, Ph), 7.48−7.50 (m, 2H, Ph),
2.48 (br s, 1H, NH). 1 C NMR (125 MHz, DMSO-d ): δ 15.0
3
12), 107.7 (C-11a), 116.8 (C-3), 128.6, 129.0, 129.3, 138.4 (carbons of
6
Ph), 140.4 (C-4), 145.1 (C-13a), 149.0 (C-6a), 149.4 (C-7a), 158.9
(
CH ), 24.2 (CH ), 26.9 (9-CH ), 28.1 (9-CH ), 32.4 (C-9), 39.5 (C-
), 49.6 (C-10), 55.0 (C-12), 107.1 (C-11a), 123.3 (C-3), 127.9,
28.5, 128.8, 137.7 (carbons of benzene ring), 142.0 (C-6a or C-13a),
3 3 3 3
+
(
C-2), 193.5 (CO). HRMS (ESI-TOF) m/z: [M − ClO ] Calcd for
8
1
1
(
4
4
C H N O 346.1662; Found 346.1666.
20 20
5
1
2-(4-Methoxyphenyl)-9,9-dimethyl-11-oxo-7,8,9,10,11,12-
48.1 (C-6a or C-13a), 148.8 (C-7a), 148.9 (C-4), 165.7 (C-2), 192.9
+
hexahydropyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium
CO). HRMS (ESI-TOF) m/z: [M − ClO ] Calcd for C H ClN O
4
22 23
5
Perchlorate (11o). Yield 0.392 g (70%, Method B) of colorless crystals,
mp 201−202 °C (from AcOH/EtOAc 1:4). IR (cm ): 3261, 3206,
159, 3082, 3032, 2954, 1669, 1633, 1585, 1512, 1404, 1244, 1104,
08.1586; Found 408.1579.
-Chloro-12-(2-methoxyphenyl)-2,4,9,9-tetramethyl-11-oxo-
−1
3
3
1
7
,8,9,10,11,12-hexahydropyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]-
1
171, 808, 764. H NMR (500 MHz, DMSO-d ): δ 1.03 (s, 3H, 9-
quinazolin-5-ium Perchlorate (11k). Yield 0.315 g (69%, Method B)
of colorless crystals, mp 269−270 °C (from DMF/EtOH 1:3). IR
6
CH ), 1.09 (s, 3H, 9-CH ), 2.18 (d, J = 16.3 Hz, 1H, 10-CH ), 2.29
3
3
2
−1
(
d, J = 16.3 Hz, 1H, 10-CH ), 2.65−2.74 (m, 2H, 8-CH ), 3.70 (s, 3H,
3
(
1
(
cm ): 3233, 2956, 2842, 1671, 1637, 1592, 1496, 1453, 1378, 1336,
2
2
1
CH O), 6.48 (s, 1H, H-12), 6.88 (d, J = 7.3 Hz, 2H, Ar), 7.41 (d, J =
268, 1110, 1060, 1026, 755. H NMR (500 MHz, DMSO-d ): δ 0.92
s, 3H, 9-CH ), 1.07 (s, 3H, 9-CH ), 2.09 (d, J = 16.4 Hz, 1H, 10-
6
7.3 Hz, 2H, Ar), 7.85−7.87 (m, 1H, Ar), 9.09−9.10 (m, 1H, Ar),
3
3
13
CH ), 2.29 (d, J = 16.4 Hz, 1H, 10-CH ), 2.51−2.54 (m, 1H, 8-CH ),
9.65−9.66 (m, 1H, Ar), 12.34 (br s, 1H, NH). C NMR (125 MHz,
2
2
2
2
.67 (s, 3H, CH ), 2.69−2.72 (m, 1H, 8-CH ), 2.85 (s, 3H, CH ), 3.67
DMSO-d
49.7 (C-10), 54.7 (C-12), 55.1 (CH
116.2 (C-3), 129.5, 130.0, 139.9 (carbons of benzene ring), 144.6 (C-
13a), 148.5 (C-6a), 148.6 (C-7a), 158.3 (C-2), 159.4 (CH O-CAr),
Calcd for
): δ 26.9 (9-CH
6
), 28.1 (9-CH
3
3
), 32.4 (C-9), 39.5 (C-8),
3
2
3
(
(
(
s, 3H, CH O), 6.52 (s, 1H, H-12), 6.95−6.96 (m, 2H, Ar), 7.25−7.28
3
O), 107.3 (C-11a), 113.8 (C Ar),
3
13
m, 1H, Ar), 7.54−7.56 (m, 1H, Ar), 12.37 (br s, 1H, NH). C NMR
125 MHz, DMSO-d ): δ 15.1, 24.2, 25.9, 28.5, 32.2, (signal of C-8 is
3
6
+
overlapped by DMSO signal), 49.1, 53.6, 55.4, 105.5, 111.6, 119.8,
23.2, 124.4, 130.4, 131.6, 142.0, 148.6, 148.9, 149.0, 157.4, 165.5,
193.0 (CO). HRMS (ESI-TOF) m/z: [M − ClO
376.1768; Found 376.1761.
9-(Ethoxycarbonyl)-2,3,4,8-tetramethyl-10-phenyl-7,10-dihydro-
]
4
1
1
C H N O
21 22 5 2
+
92.8. HRMS (ESI-TOF) m/z: [M − ClO ] Calcd for
4
C H ClN O 438.1691; Found 438.1685.
[1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidin-5-ium Perchlorate (11p).
2
3
3
25
5
2
-Butyl-2,4,9,9-tetramethyl-11-oxo-12-phenyl-7,8,9,10,11,12-
Yield 0.382 g (90%, Method B) of colorless crystals, mp 228−229
−1
hexahydropyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium
°C (from i-PrOH). IR (cm ): 3216, 3169, 3099, 3033, 2986, 1721,
M
DOI: 10.1021/acs.joc.5b01908
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
+
1
672, 1635, 1598, 1535, 1386, 1247, 1109, 1075, 1055, 1003, 758. H
149.4, 167.9, 193.0. HRMS (ESI-TOF) m/z: [M − HSO ] Calcd for
4
NMR (500 MHz, DMSO-d ): δ 1.10 (t, J = 7.0 Hz, 3H, CH CH ),
C H BrN O 466.1237; Found 466.1216.
6
2
3
23 25
5
2
3
.37 (s, 3H, CH ), 2.55 (s, 3H, 8-CH ), 2.67 (s, 3H, CH ), 2.77 (s,
Reaction of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-
amine (3c), Dimedone (12), and Benzaldehyde. A magnetically
stirred mixture of amine 3c (0.326 g, 2 mmol), compound 12 (0.308 g,
3
3
3
H, CH ), 4.03−4.06 (m, 2H, CH ), 6.55 (s, 1H, H-10), 7.31−7.40
3
2
13
(
m, 3H, Ar), 7.51−7.52 (m, 2H, Ar), 12.0 (br s, 1H, NH). C NMR
2
.2 mmol), benzaldehyde (0.233 g, 2.2 mmol), a 70% aqueous solution
(
125 MHz, DMSO-d ): δ 13.5 (CH ), 13.6 (OCH CH ), 13.8 (CH ),
6
3
2
3
3
of HClO (0.302 g, 2.1 mmol), and AcOH (1.0 mL) was heated at 90
1
1
1
8.0 (CH ), 23.9(CH ), 55.7 (C-10), 59.9 (OCH CH ), 99.7 (C-9),
4
3
3
2
3
°
C for 1 h, then diluted with ethanol (5 mL) and cooled to 40 °C. The
23.4 (C-3), 127.7, 128.4, 128.7, 138.2 (carbons of Ph), 141.3 (C-
precipitate formed was collected by filtration and washed with ethanol
to give 3,3,6,6-tetramethyl-9-phenyl-3,4,5,6,7,9-hexahydro-1H-xanthene-
1a), 144.8 (C-8), 147.0 (C-6a), 147.7 (C-4), 163.7 (COOEt), 167.5
+
(
3
C-2). HRMS (ESI-TOF) m/z: [M − ClO ] Calcd for C H N O
4
21 24
5
2
1
2
1
,8(2H)-dione (14). Yield 0.392 g (73%) of colorless crystals, mp
78.1925; Found 378.1921.
-Chloro-9-(ethoxycarbonyl)-2,4,8-trimethyl-10-phenyl-7,10-
27
−1
01−203 °C (lit. 202−204 °C). IR (cm ): 2959, 2915, 2871, 1679,
3
1
625, 1360, 1198, 1140, 1002, 699. H NMR (500 MHz, DMSO-d ):
dihydro[1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidin-5-ium Perchlorate
6
(
2
11q). Yield 0.353 g (81%, Method B) of colorless crystals, mp 236−
δ 0.91 (s, 6H, 2CH ), 1.04 (s, 6H, 2CH ), 2.08 (d, J = 16.2 Hz, 2H,
3
3
−
1
CH ), 2.27 (d, J = 16.2 Hz, 2H, CH ), 2.51−2.60 (m, 4H, CH ), 4.53
37 °C (from i-PrOH). IR (cm ): 3148, 3080, 1701, 1663, 1587,
2
2
2
1
(
(
s, 1H, CH), 7.08−7.24 (m, 5H, Ph). MS (EI, 70 eV), m/z (%): 350
1
530, 1369, 1265, 1111, 1062, 1026, 1004, 757. H NMR (500 MHz,
+
71) [M] , 273 (100), 265 (11), 217 (15), 161 (10), 133 (4), 77 (6).
DMSO-d ): δ 1.09 (t, J = 7.1 Hz, 3H, OCH CH ), 2.55 (s, 3H, 8-
6
2
3
The solution after separation of 14 was evaporated to a volume of
CH ), 2.76 (s, 3H, CH ), 2.85 (s, 3H, CH ), 4.02−4.05 (m, 2H,
3
3
3
∼
2 mL and cooled to 20 °C. The precipitate formed was collected by
OCH CH ), 6.57 (s, 1H, H-10), 7.33−7.40 (m, 3H, Ph), 7.51−7.52
2
3
13
filtration and recrystallized from EtOH to give 5,7-dimethyl-[1,2,4]-
triazolo[1,5-a]pyrimidin-2-amine perchlorate (13). Yield 0.368 g (70%)
(
m, 2H, Ph), 12.16 (br s, 1H, NH). C NMR (125 MHz, DMSO-d ):
6
δ 13.7 (OCH CH ), 15.1 (CH ), 18.2 (CH ), 24.1 (8-CH ), 56.3 (C-
2
3
3
3
3
−1
of colorless crystals, mp 256−258 °C. IR (cm ): 3333, 3148, 3002,
1
1
1
0), 60.2 (OCH CH ), 100.2 (C-9), 123.3 (C-3), 128.0, 128.6, 129.0,
38.0 (carbons of Ph), 141.7 (C-11a), 144.8 (C-8), 147.9 (C-6a),
48.7 (C-4), 163.8 (CO), 165.5 (C-2). HRMS (ESI-TOF) m/z: [M −
2 3
1
2
764, 1654, 1563, 1538, 1421, 1360, 1204, 1116, 1028, 775. H NMR
(
500 MHz, DMSO-d ): δ 2.45 (s, 3H, CH ), 2.56 (s, 3H, CH ), 6.25
6
3
3
13
+
(br s, 2H, NH ), 6.84 (s, 1H, H-6). C NMR (125 MHz, DMSO-d ):
2
6
ClO ] Calcd for C H ClN O 398.1378; Found 398.1371.
4
20 21
5
2
δ 17.0, 24.5, 109.0, 145.3, 154.7, 161.8, 166.5. HRMS (ESI-TOF) m/z:
3
-Benzyl-9-(ethoxycarbonyl)-2,4,8-trimethyl-10-phenyl-7,10-
+
[
M − ClO ] Calcd for C H N 164.0931, found 164.0931.
dihydro[1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidin-5-ium Perchlorate
4
7
10
5
1
0,10-Dimethyl-8-oxo-7-phenyl-7,8,9,10,11,12-hexahydro-
(
1
11r). Yield 0.366 g (76%, Method B) of colorless crystals, mp 156−
−
1
pyrimido[1′,2′:2,3][1,2,4]triazolo[5,1-b]quinazolin-6-ium Perchlo-
57 °C (from i-PrOH). IR (cm ): 3213, 3161, 2926, 1706, 1660,
1
rate (16n). A mixture of compound 5a (1 mmol), tetramethox-
1
593, 1527, 1455, 1383, 1271, 1248, 1107, 1057, 930, 739, 703. H
ypropane 6h (1.3 mmol), a 70% aqueous solution of HClO (0.152 g,
4
NMR (500 MHz, DMSO-d ): δ 1.08 (t, J = 7.0 Hz, 3H, CH CH ),
2
OCH CH ), 4.28 (s, 2H, CH Ph), 6.55 (s, 1H, H-10), 7.13−7.14
6
2
3
1
1
.05 mmol), and AcOH (0.5 mL) was stirred at room temperature for
0 min and then diluted with acetone (3 mL). The precipitate formed
.56 (s, 6H, 2CH ), 2.79 (s, 3H, CH ), 4.02−4.04 (m, 2H,
3
3
2
3
2
was collected by filtration and dried in vacuum at room temperature.
(
7
m, 2H, Ph), 7.21−7.24 (m, 1H, Ar), 7.28−7.34 (m, 3H, Ar), 7.37−
−1
Yield 0.231 g (52%) of colorless crystals, mp 197−198 °C. IR (cm ):
13
.40 (m, 2H, Ar), 7.52−7.54 (m, 2H, Ar), 12.05 (br s, 1H, NH). C
3
1
0
9
217, 3137, 3088, 2959, 2895, 1659, 1626, 1566, 1538, 1497, 1412,
NMR (125 MHz, DMSO-d ): δ 13.8 (OCH CH ), 14.2 (CH ), 18.2
1
6
2
3
3
331, 1274, 1109, 1039, 908, 799. H NMR (500 MHz, DMSO-d ): δ
6
(
CH ), 23.8 (8-CH ), 32.5 (CH Ph), 56.0 (C-10), 60.1 (OCH CH ),
3 3 2 2 3
.99 (s, 3H, 10-CH ), 1.11 (s, 3H, 10-CH ), 2.21 (d, J = 16.2 Hz, 1H,
3
3
9
1
1
9.9 (C-9), 125.4 (C-3), 126.6, 127.9, 128.0, 128.6 (2C), 128.9, 136.8,
38.4 (carbons of 2Ph), 142.1 (C-11a), 145.1 (C-8), 147.4 (C-6a),
-CH ), 2.36 (d, J = 16.2 Hz, 1H, 9-CH ), 2.68−2.75 (m, 2H, 11-
2
2
CH ), 7.08 (s, 1H, H-7), 7.34−7.41 (m, 3H, Ar), 7.59−7.60 (m, 2H,
2
49.3 (C-4), 163.9 (COOEt), 168.1 (C-2). HRMS (ESI-TOF) m/z:
Ar), 7.74 (dd, J = 6.9, 4.6 Hz, 1H, Ar), 9.15−9.16 (m, 1H, Ar), 9.48−
+
[
M − ClO ] Calcd for C H N O 454.2238; Found 454.2230.
13
4
27 28
5
2
9.49 (m, 1H, Ar), 12.81 (br s, 1H, NH). C NMR (125 MHz,
9
-(Ethoxycarbonyl)-8-methyl-10-phenyl-7,10-dihydro[1,2,4]-
triazolo[1,5-a:4,3-a′]dipyrimidin-5-ium Perchlorate (11s). Yield
.270 g (72%, Method B) of colorless crystals, mp 259−260 °C
DMSO-d ): δ 27.2 (10-CH ), 28.5 (10-CH ), 32.9 (C-10), 39.7 (C-
6
3
3
1
1
1
1), 50.0 (C-9), 57.7 (C-7), 109.8 (C-7a), 114.0 (C-3), 128.7, 129.4,
30.1, 134.9 (carbons of benzene ring), 135.7 (C-2 or C-4), 148.7 (C-
0
−1
(
from MeCN). IR (cm ): 3166, 3099, 2976, 1708, 1670, 1629, 1594,
1a), 150.4 (C-12a), 152.2 (C-13a), 161.6 (C-2 or C-4), 193.6 (CO).
1
1
533, 1402, 1262, 1246, 1123, 1045, 1089, 767. H NMR (500 MHz,
+
HRMS (ESI-TOF) m/z: [M − ClO ] Calcd for C H N O
346.1662; Found 346.1658.
4
20 20
5
DMSO-d ): δ 1.09 (t, J = 7.0 Hz, 3H, OCH CH ) 2.55 (s, 3H, 8-
CH ), 4.01−4.04 (m, 2H, OCH CH ), 6.60 (s, 1H, H-10), 7.31−7.40
6
2
3
3
2
3
Rearrangement of Compound 16n to Compound 11n. A
magnetically stirred mixture of compound 16n (0.446 g, 1 mmol) and
AcOH (0.5 mL) was heated at 90 °C for 1 h and then diluted with
ethanol (2 mL). The precipitate formed after cooling to room
temperature was collected by filtration to yield perchlorate 11n (0.405
g, 91%).
(
(
1
m, 3H, Ph), 7.52−7.53 (m, 2H, Ph), 7.85−7.87 (m, 1H, H-3), 9.08
d, J = 3.9 Hz, 1H, H-4), 9.65 (d, J = 6.5 Hz, 1H, H-2), 12.09 (br s,
H, NH). 13C NMR (125 MHz, DMSO-d ): δ 13.7 (OCH CH ), 18.2
6 2 3
(
CH ), 56.5 (C-10), 60.2 (OCH CH ), 100.2 (C-9), 116.2 (C-3),
3
2
3
1
1
28.2, 128.6, 128.9, 138.1 (carbons of Ph), 139.8 (C-2), 144.2 (C-
1a), 144.6 (C-8), 148.4 (C-6a), 158.1 (C-4), 163.8 (COOEt). HRMS
2
-Amino-5,7-diphenyl-4,5,6,7-tetrahydro-3H-[1,2,4]triazolo[1,5-
+
(
ESI-TOF) m/z: [M − ClO4] Calcd for C H N O 336.1455;
a]pyrimidin-8-ium Perchlorate (19). A solution of compound 8b
(0.456 g, 1 mmol) in EtOH (5.0 mL) or DMF (2.0 mL) was refluxed
(or heated at 90 °C in case of DMF) for 24 h. The precipitate formed
after cooling to room temperature was collected by filtration and
recrystallized from ethanol to give compound 19 as colorless crystals.
Yield 0.265 g (68%, from EtOH), 0.202 g (52%, from DMF), mp
18
18
5
2
Found 336.1452.
1
2-(4-Bromophenyl)-2,3,4,9,9-pentamethyl-11-oxo-
7
,8,9,10,11,12-hexahydropyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]-
quinazolin-5-ium Hydrogen Sulfate (11t). Yield 0.265 g (57%,
Method B) of yellowish crystals, mp 234−235 °C (from i-PrOH). IR
−1
−
1
(
cm ): 3053, 2958, 2868, 2738, 1667, 1651, 1591, 1451, 1378, 1340,
2
03−204 °C. IR (cm ): 3447, 3363, 3184, 3090, 2970, 1656, 1458,
1
1
1
213, 1177, 1042, 894, 758. H NMR (500 MHz, DMSO-d ): δ 1.01
1074, 753, 699, 622. H NMR (500 MHz, DMSO-d ): δ 2.25−2.33
6
6
(
s, 3H, 9-CH ), 1.09 (s, 3H, 9-CH ), 2.18 (d, J = 16.2 Hz, 1H, 10-
(m, 1H, CH ), 2.46−2.55 (m, 1H, CH ), 4.86−4.90 (m, 1H, H-5),
3
3
2
2
CH ), 2.29 (d, J = 16.2 Hz, 1H, 10-CH ), 2.35 (s, 3H, CH ), 2.65 (s,
3
5.26−5.30 (m, 1H, H-7), 7.32−7.58 (m, 10H, 2Ph), 8.92 (br s, 1H,
2
2
3
H, CH ), 2.69−2.71 (m, 2H, 8-CH ), 2.77 (s, 3H, CH ), 6.44 (s, 1H,
NH) (signals of NH and NH are broadened and merged into the
3
2
3
2
background). 13C NMR (125 MHz, DMSO-d ): δ 39.8, 53.5, 58.5,
H-12), 7.44 (d, J = 8.4 Hz, 2H, Ar), 7.54 (d, J = 8.4 Hz, 2H, Ar), 12.34
6
(
br s, 1H, NH). 13C NMR (125 MHz, DMSO-d ): δ 13.7, 13.9, 24.2,
126.8, 127.7, 128.2, 128.4, 128.6, 137.6, 139.7 (signals of two aromatic
carbons are overlapped), 148.0, 150.8. Anal. Calcd for C H ClN O :
6
2
5
7.0, 28.1, 32.4, (signal of C-8 is overlapped by DMSO signal), 49.6,
4.2, 106.5, 121.9, 123.7, 130.2, 131.3, 137.4, 142.0, 147.1, 147.9,
17
18
5
4
C, 52.11; H, 4.63; N, 17.87. Found: C, 51.92; H, 4.74; N, 17.80.
N
DOI: 10.1021/acs.joc.5b01908
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
+
HRMS (ESI-TOF) m/z: [M − ClO ] Calcd for C H N 292.1557;
8), 50.3 (C-10), 55.1 (C-12), 107.1 (C-11a), 116.4 (C-3), 128.3,
129.0, 129.1, 139.0 (Ph), 144.5 (C-13a), 149.2 (C-6a), 150.5 (C-4),
4
17 18
5
Found 292.1555.
General Procedure for the Synthesis of Compounds 20a−c.
A suspension of the appropriate perchlorate 8b,e,g (1 mmol) in 5%
ethanol solution of KOH (5 mL) was stirred for 15 min and then
diluted with water (5 mL). The precipitate formed was collected by
filtration, washed with water, and recrystallized from CHCl3/
CH COOC H (1:3).
151.9 (C-7a), 168.6 (C-2), 193.1 (CO). HRMS (ESI-TOF) m/z: [M
+
+ H] Calcd for C22
H
24
N
O 374.1975; Found 374.1977.
5
9-(Ethoxycarbonyl)-2,4,8-trimethyl-10-phenyl-7,10-dihydro-
[
1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidin-5-ium-7-ide (21b). Yield
−1
0
3
1
.323 g (89%) of yellow crystals, mp 208−209 °C. IR (cm ):
210, 3173, 3074, 2979, 2941, 1707, 1667, 1639, 1596, 1531, 1439,
3
2
5
1
378, 1245, 1106, 1067, 753, 706. H NMR (500 MHz, DMSO-d ): δ
8
,10-Dimethyl-2,4-diphenyl-3,4-dihydro-2H-[1,2,4]triazolo[1,5-
6
a:4,3-a′]dipyrimidine (20a). Yield 0.263 g (74%) of orange-red
1.09 (t, J = 7.1 Hz, 3H, OCH
CH ), 2.73 (s, 3H, CH ), 4.0−4.04 (m, 2H, OCH
H-10), 7.29−7.39 (m, 3H, Ph), 7.48−7.50 (m, 2H, Ph), 7.66 (s, 1H,
H-3). 13C NMR (125 MHz, DMSO-d
): δ 13.8, 16.2, 18.9, 24.4, 56.0,
59.9, 99.3, 115.9, 127.9, 128.6, 128.8, 138.7, 143.6, 146.6, 148.2, 150.1,
64.0, 168.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C H N O 364.1768; Found 364.1762.
2
CH
3
), 2.53 (s, 3H, CH
3
), 2.65 (s, 3H,
), 6.53 (s, 1H,
3
−1
crystals, mp 206−207 °C. IR (cm ): 3057, 3029, 2962, 2873, 2837,
655, 1634, 1563, 1528, 1299, 1281, 1181, 746. H NMR (500 MHz,
3
3
2
CH
1
1
DMSO-d ): δ 1.64−1.71 (m, 1H, H-3), 2.23 (s, 3H, CH ), 2.46−2.48
6
6
3
(
=
7
2
1
m, 1H, H-3), 2.81 (s, 3H, CH ), 4.71−4.73 (m, 1H, H-2), 5.29 (dd, J
3
1
10.6, 4.6 Hz, 1H, H-4), 6.15 (s, 1H, H-9), 7.17−7.33 (m, 8H, Ar),
1
3
.45−7.46 (m, 2H, Ar). C NMR (125 MHz, DMSO-d ): δ 18.4,
20 22
5
2
6
1
2-(2,4-Dichlorophenyl)-2,3,4,9,9-pentamethyl-11-oxo-
5.2, 41.9, 56.7, 59.4, 107.5, 126.7, 126.9, 127.8, 128.0, 128.4, 128.7,
8
,10,11,12-tetrahydro-9H-pyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]-
40.8, 145.9, 147.1, 147.2, 149.1, 168.6. HRMS (ESI-TOF) m/z: [M +
+
quinazolin-5-ium-7-ide (21c). Yield 0.333 g (73%) of yellow crystals,
H] Calcd for C H N 356.1870; Found 356.1867.
22
22
5
−1
mp > 300 °C. IR (cm ): 2950, 2920, 2865, 1633, 1566, 1528, 1494,
2
,4,8,10-Tetraphenyl-3,4-dihydro-2H-[1,2,4]triazolo[1,5-a:4,3-a′]-
1
381, 1355, 1265, 1199, 1124, 1090, 851. 1H NMR (500 MHz,
dipyrimidine (20b). Yield 0.402 g (84%) of violet crystals, mp 207−
−1
DMSO-d ): δ 0.92 (s, 3H, 9-CH ), 1.00 (s, 3H, 9-CH ), 1.90 (d, J =
6 3 3
2
1
08 °C. IR (cm ): 3064, 3033, 2965, 2920, 1653, 1617, 1599, 1516,
490, 1360, 1297, 1282, 1184, 1132, 1016. H NMR (500 MHz,
1
15.9 Hz, 1H, 10-CH ), 2.10 (d, J = 15.9 Hz, 1H, 10-CH ), 2.21 (s, 3H,
2 2
CH ), 2.35−2.43 (m, 2H, 8-CH ), 2.45 (s, 3H, CH ), 2.65 (s, 3H,
3
2
3
DMSO-d ): δ 1.70−1.80 (m, 1H, H-3), 2.50−2.54 (m, 1H, H-3),
6
CH ), 6.65 (s, 1H, H-12), 7.19−7.39 (m, J = 16.0 Hz, 2H, Ar), 7.42
3
4
1
.62−4.64 (m, 1H, H-2), 5.33−5.35 (m, 1H, H-4), 7.07−7.58 (m,
7H, Ar), 7.86−7.87 (m, 2H, Ar), 8.19−8.21 (d, J = 7.0 Hz, 2H, Ar).
13
(
br s, 1H, Ar). C NMR (125 MHz, DMSO-d ): δ 14.1, 14.3, 24.3,
6
1
3
27.7, 29.8, 32.5, (signal of C-8 is overlapped by DMSO signal), 47.1,
C NMR (125 MHz, DMSO-d ): δ 41.5 (C-3), 56.2 (C-2), 59.3 (C-
6
5
1
0.9, 102.9, 122.1, 127.8, 128.9, 132.4, 133.2, 134.1, 138.6, 142.8+,
4
1
1
), 105.2 (C-9), 125.9, 126.4, 126.8, 127.39, 127.43, 127.5, 127.6,
28.2, 128.8, 129.9, 130.0, 130.5, 131.6, 135.5, 140.2, 145.1, 145.2,
46.9, 149.4, 162.1. HRMS (ESI-TOF) m/z: [M + H] Calcd for
46.2, 155.0, 163.9, 165.9, 191.0. HRMS (ESI-TOF) m/z: [M + H]
Calcd for C H Cl N O 456.1352; Found 456.1342.
+
23 24
2
5
C H N 480.2183; Found 480.2177.
3
2
26
5
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01908.
9
-Chloro-8,10-dimethyl-2,4-diphenyl-3,4-dihydro-2H-[1,2,4]-
■
*
triazolo[1,5-a:4,3-a′]dipyrimidine (20c). Yield 0.296 g (76%) of red
S
−1
crystals, mp 193−194 °C. IR (cm ): 3026, 2911, 2836, 1659, 1617,
564, 1517, 1494, 1429, 1319, 1367, 1269, 1187, 1028, 733. H NMR
1
1
(
500 MHz, DMSO-d ): δ 1.65−1.72 (m, 1H, H-3), 2.37 (s, 3H, CH ),
6
3
Crystallographic data for 8h, 9a, 11b, 11c, 11p, 16n, and
2
5
7
5
1
.51−2.53 (m, 1H, H-3), 3.03 (s, 3H, CH ), 4.72−4.74 (m, 1H, H-2),
3
20a (ZIP)
.32 (dd, J = 10.8, 4.7 Hz, 1H, H-4), 7.18−7.34 (m, 8H, H Ar), 7.45−
.46 (m, 2H, Ar). 13C NMR (125 MHz, DMSO-d ): δ 15.0, 24.7, 41.6,
B3LYP 6-311++G(2d,2p) fully optimized geometries,
given in standard XYZ format (XYZ)
Detailed results of quantum chemical calculations, copies
of NMR and IR spectra, and HRMS data (PDF)
6
6.8, 59.7, 113.8, 126.7, 126.9, 127.8, 128.0, 128.4, 128.7, 140.6, 145.0,
45.8, 146.4, 147.1, 165.3. HRMS (ESI-TOF) m/z: [M + H] Calcd
+
for C H ClN 390.1480; Found 390.1469.
22
21
5
5
,7-Diphenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-2-
amine (2b). A suspension of compound 8b (0.456 g, 1 mmol) in 5%
ethanol solution of KOH (5 mL) was refluxed for 24 h. The precipitate
formed after cooling to room temperature was collected by filtration
and washed with ethanol to give amine 2b. Yield 0.279 g (87%), mp
AUTHOR INFORMATION
Corresponding Author
*E-mail: chern13@yandex.ru.
Notes
■
16
1
2
79−280 °C (lit. mp 279−280 °C). H NMR (500 MHz, DMSO-
d ): δ 1.99 (m, 1H, 6-CH ), 2.33 (m, 1H,6-CH ), 4.60 (m, 1H, H-5),
6
2
2
The authors declare no competing financial interest.
4
8
5
.85 (2H, NH ), 5.12 (m, 1H, H-7), 7.03 (s, 1H, NH), 7.18−7.37 (m,
2
H, Ar.), 7.42 (m, 2H, Ar). Anal. Calcd for C H N : C, 70.08; H,
17
17
5
ACKNOWLEDGMENTS
.88; N, 24.04. Found: C, 70.15; H, 5.90; N, 23.94. HRMS (ESI-TOF)
■
+
m/z: [M + H] Calcd for C H N 292.1557; Found 292.1555.
This work was financially supported by the Russian Science
Foundation (grant no. 14-23-00078). The authors also thank
the Shared Research Center “Nanotechnologies” of the Platov
South-Russian State Polytechnic University for IR analytical
services and the MSU Development Program for the X-ray
diffractometer purchase.
17
18
5
Spectral characteristics and physical properties of the compound
obtained are identical to the authentic sample of 2b.
General Procedure for the Synthesis of Compounds 21a−c.
A suspension of the appropriate perchlorate 11a,c,i in a saturated
aqueous solution of CH COONa (5 mL) was stirred for 15 min. The
3
precipitate formed was collected by filtration, washed with water, and
recrystallized from EtOH/H O (1:3).
2
REFERENCES
2
,4,9,9-Tetramethyl-11-oxo-12-phenyl-8,10,11,12-tetrahydro-9H-
■
pyrimido[1′,2′:1,5][1,2,4]triazolo[3,4-b]quinazolin-5-ium-7-ide
(1) (a) Fischer, G. Adv. Heterocycl. Chem. 2007, 95, 143. (b) Guan,
A.; Liu, Ch.; Yang, X.; Dekeyser, M. Chem. Rev. 2014, 114, 7079.
(c) Rodríguez-Torres, M.; Yoshida, E. M.; Marcellin, P.; Srinivasan, S.;
Purohit, V. S.; Wang, C.; Hammond, J. L. Ann. Hepatol. 2014, 13, 364.
(2) (a) Submitted by the Terminology Committee: Bhowmik, P. C.;
Bussan, A. J.; Griffin, J. L.; Hazen, J. L.; Miller, T. W.; Reddy, K. N.;
Salisbury, C. D.; Tranel, P. J.; Vencill, W. K.; Wright, T. R. Common
and Chemical Names of Herbicides Approved by the Weed Science
Society of America. Weed Sci. 2000, 48, 786. (b) Sabra, F. S.;
(
21a). Yield 0.313 g (85%) of yellow crystals, mp > 300 °C. IR
cm ): 3272, 3145, 3076, 3025, 2964, 2870, 1670, 1658, 1608, 1436,
−1
(
1
1
381, 1336, 1247, 1118, 1050, 930, 741. H NMR (500 MHz, DMSO-
d ): δ 0.94 (s, 3H, 9-CH ), 1.02 (s, 3H, 9-CH ), 2.10 (d, J = 16.1, 1H,
6
3
3
1
+
0-CH ), 2.21 (d, J = 16.1, 1H, 10-CH ), 2.54−2.63 (m, 5H, 10-CH
2
2
2
CH ), 2.67 (s, 3H, CH ), 6.40 (s, 1H, H-12), 7.21−7.39 (m, 5H,
3
3
13
Ph), 7.59 (s, 1H, H-3). C NMR (125 MHz, DMSO-d ): δ 16.7
6
(
CH ), 25.0 (CH ), 27.5 (9-CH ), 28.7 (9-CH ), 32.9 (C-9), 41.0 (C-
3 3 3 3
O
DOI: 10.1021/acs.joc.5b01908
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Mahmoud, M. S. Asian J. Agric Food Sci. 2015, 3, 103. (c) Hu, M.; Liu,
X.; Dong, F.; Xu, J.; Li, S.; Xu, H.; Zheng, Y. Food Chem. 2015, 175,
A. Y.; Yu, D.; Oliner, J. D.; Salyers, K.; Ye, Q.; Olson, S. Bioorg. Med.
Chem. Lett. 2011, 21, 2752.
(13) (a) Desenko, S. M.; Kolos, N. N.; Tueni, M.; Orlov, V. D. Chem.
́
Heterocycl. Compd. 1990, 26, 782. (b) Lipson, V. V.; Desenko, S. M.;
Orlov, V. D.; Shishkin, O. V.; Shirobokova, M. G.; Chernenko, V. N.;
Zinov'eva, L. I. Chem. Heterocycl. Compd. 2000, 36, 1329.
(c) Chebanov, V. A.; Desenko, S. M.; Gurley, T. W. Azaheterocycles
Based on α,ß-Unsaturated Carbonyls; Springer: Berlin, 2008; pp 61−
3
95. (d) Zhu, X.; Zhang, M.; Liu, J.; Ge, J.; Yang, G. J. Agric. Food
Chem. 2015, 63, 3377. (e) deBoer, G. J.; Thornburgh, S.; Gilbert, J.;
Gast, R. E. Pest Manage. Sci. 2011, 67, 279.
(
3) (a) Yu, B.; Shi, X.-J.; Zheng, Y.-F.; Fang, Y.; Zhang, E.; Yu, D.-Q.;
Liu, H.-M. Eur. J. Med. Chem. 2013, 69, 323. (b) Vidler, L. R.;
Filippakopoulos, P.; Fedorov, O.; Picaud, S.; Martin, S.; Tomsett, M.;
Woodward, H.; Brown, N.; Knapp, S.; Hoelder, S. J. Med. Chem. 2013,
1
(
47.
14) (a) Lipson, V. V.; Desenko, S. M.; Borodina, V. V.; Shirobokova,
M. G.; Musatov, V. I. Russ. J. Org. Chem. 2005, 41, 114.
b) Chernyshev, V. M.; Sokolov, A. N.; Taranushich, V. A. Russ. J.
5
6, 8073. (c) Łakomska, I.; Hoffmann, K.; Wojtczak, A.; Sitkowski, J.;
Maj, E.; Wietrzyk, J. J. Inorg. Biochem. 2014, 141, 188. (d) Li, Q.;
Chen, Y.-M.; Hu, Y.-G.; Luo, X.; Ko, J. K. Sh.; Cheung, C. W. Res.
Chem. Intermed. 2015, DOI: 10.1007/s11164-015-2064-8. (e) Hassan,
G. S.; El-Sherbeny, M. A.; El-Ashmawy, M. B.; Bayomi, S. M.;
Maarouf, A. R.; Badria, F. A. Arabian J. Chem. 2013, DOI: 10.1016/
j.arabjc.2013.04.002.
(
Appl. Chem. 2007, 80, 1691. (c) Sedash, Yu. V.; Gorobets, N. Yu.;
Chebanov, V. A.; Konovalova, I. S.; Shishkin, O. V.; Desenko, S. M.
RSC Adv. 2012, 2, 6719.
(
15) Chernyshev, V. M.; Sokolov, A. N.; Taranushich, V. A. Russ. J.
Appl. Chem. 2006, 79, 1134.
16) Chernyshev, V. M.; Sokolov, A. N.; Khoroshkin, D. A.;
Taranushich, V. A. Russ. J. Org. Chem. 2008, 44, 715.
17) (a) Chuiguk, V. A.; Glukhova, T. I. Ukr. Khim. Zh. 1980, 46,
35. (Chem. Abstr. 1981, 94, 65605). (b) Chuiguk, V. A. Chem.
Heterocycl. Compd. 1983, 19, 1.
18) (a) Chebanov, V. A.; Gura, K. A.; Desenko, S. M. Top.
(
4) (a) Deng, X.; Kokkonda, S.; El Mazouni, F.; White, J.; Burrows, J.
(
N.; Kaminsky, W.; Charman, S. A.; Matthews, D.; Rathod, P. K.;
Phillips, M. A. J. Med. Chem. 2014, 57, 5381. (b) Da Silva, E. R.;
Boechat, N.; Pinheiro, L. C. S.; Bastos, M. M.; Costa, C. C. P.;
Bartholomeu, J. C.; da Costa, T. H. Chem. Biol. Drug Des. 2015,
(
8
DOI: 10.1111/cbdd.12566. (c) Caballero, A. B.; Rodríguez-Dieg
́
uez,
, M.; Salas, J. M.; Huertas, O.; Ramírez-Macías, I.; Olmo, F.;
Marín, C.; Chaves-Lemaur, G.; Gutierrez-Sanchez, R.; Sanchez-
Moreno, M. Eur. J. Med. Chem. 2014, 85, 526.
5) (a) Luo, Y.; Zhang, Sh.; Liu, Z.-J.; Chen, W.; Fu, J.; Zeng, Q.-F.;
Zhu, H.-L. Eur. J. Med. Chem. 2013, 64, 54. (b) Wang, H.; Lee, M.;
Peng, Z.; Blazquez, B.; Lastochkin, E.; Kumarasiri, M.; Bouley, R.;
Chang, M.; Mobashery, Sh. J. Med. Chem. 2015, 58, 4194.
6) (a) Khalymbadzha, I. A.; Shestakova, T. S.; Subbotina, J. O.;
(
́
A.; Quiros
́
Heterocycl. Chem. 2010, 23, 41. (b) Chebanov, V. A.; Desenko, S. M.
Chem. Heterocycl. Compd. 2012, 48, 566.
́
́
(19) (a) El Ashry, E. S. H.; Nadeem, S.; Shah, M. R.; El Kilany, Y.
(
Adv. Heterocycl. Chem. 2010, 101, 161. (b) Salgado, A.; Varela, C.;
Collazo, A. M. G.; García, F.; Pevarello, P.; Alkorta, I.; Elguero, J. J.
Mol. Struct. 2011, 987, 13. (c) Shaban, M. A. E.; Morgaan, A. E. A. Adv.
Heterocycl. Chem. 1999, 73, 131−176. (d) Golubushina, G. M.;
Poshtaruk, G. N.; Chuiguk, V. A. Chem. Heterocycl. Compd. 1974, 10,
́
(
Eltsov, O. S.; Musikhina, A. A.; Rusinov, V. L.; Chupakhin, O. N.;
Karpenko, I. L.; Jasko, M. V.; Kukhanova, M. K.; Deev, S. L.
Tetrahedron 2014, 70, 1298. (b) Lepri, S.; Nannetti, G.; Muratore, G.;
Cruciani, G.; Ruzziconi, R.; Mercorelli, B.; Palu, G.; Loregian, A.;
̀
Goracci, L. J. Med. Chem. 2014, 57, 4337. (c) Massari, S.; Nannetti, G.;
4
(
91.
20) (a) Anders, E.; Wermann, K.; Wiedel, B.; Vanden Eynde, J.-J. V.
Lieb. Ann./Recueil 1997, 1997, 745. (b) Karpinska, G.; Dobrowolski, J.
Cz. J. Mol. Struct.: THEOCHEM 2008, 853, 7.
21) (a) Jindal, G.; Kisan, H. K.; Sunoj, R. B. ACS Catal. 2015, 5,
́
(
Desantis, J.; Muratore, G.; Sabatini, S.; Manfroni, G.; Mercorelli, B.;
480. (b) Thiel, W. Angew. Chem., Int. Ed. 2014, 53, 8605. (c) Li, D.;
Wang, Y.; Han, K. Coord. Chem. Rev. 2012, 256, 1137. (d) Li, D.;
Huang, X.; Han, K.; Zhan, Ch.-G. J. Am. Chem. Soc. 2011, 133, 7416.
(22) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E., Jr.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.;
Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi,
J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J.
B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.
E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador,
P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,
Revision A.02; Gaussian, Inc.: Wallingford, CT, 2009.
̀
Cecchetti, V.; Palu, G.; Cruciani, G.; Loregian, A.; Goracci, L.;
Tabarrini, O. J. Med. Chem. 2015, 58, 3830. (d) Wang, L.; Tian, Y.;
Chen, W.; Liu, H.; Zhan, P.; Li, D.; Liu, H.; De Clercq, E.;
Pannecouque, C.; Liu, X. Eur. J. Med. Chem. 2014, 85, 293. (e) Huang,
B.; Li, C.; Chen, W.; Liu, T.; Yu, M.; Fu, L.; Sun, Y.; Liu, H.; De
Clercq, E.; Pannecouque, C.; Balzarini, J.; Zhan, P.; Liu, X. Eur. J. Med.
Chem. 2015, 92, 754. (f) Singer, R. A.; Ragan, J. A.; Bowles, P.;
Chisowa, E.; Conway, B. G.; Cordi, E. M.; Leeman, K. R.; Letendre, L.
J.; Sieser, J. E.; Sluggett, G. W.; Stanchina, C. L.; Strohmeyer, H.;
Blunt, J.; Taylor, S.; Byrne, C.; Lynch, D.; Mullane, S.; O’Sullivan, M.
M.; Whelan, M. Org. Process Res. Dev. 2014, 18, 26.
(
7) (a) Ashour, H. M.; Shaaban, O. G.; Rizk, O. H.; El-Ashmawy, I.
M. Eur. J. Med. Chem. 2013, 62, 341.
8) Brigance, R. P.; Meng, W.; Fura, A.; Harrity, Th.; Wang, A.;
Zahler, R.; Kirby, M. S.; Hamann, L. G. Bioorg. Med. Chem. Lett. 2010,
0, 4395.
9) Cornec, A.-S.; James, M. J.; Kovalevich, J.; Trojanowski, J. Q.;
(
2
(
Lee, V. M.-Y.; Smith, A. B., III; Ballatore, C.; Brunden, K. R. Bioorg.
Med. Chem. Lett. 2015, DOI: 10.1016/j.bmcl.2015.03.002.
(
23) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.;
Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter Mater. Phys. 1988,
7, 785.
24) (a) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105,
999. (b) Bachrach, S. M. Computational Organic Chemistry; Wiley:
Hoboken, NJ, 2014; p 607.
25) Astakhov, A. V.; Chernyshev, V. M. Chem. Heterocycl. Compd.
012, 48, 1417.
26) Bishop, B. C.; Marley, H.; Preston, P. N.; Wright, S. H. B. J.
Chem. Soc., Perkin Trans. 1 1999, 1527.
27) Al-Omran, F.; Mohareb, R. M.; El-Khair, A. A. Med. Chem. Res.
014, 23, 1623.
(
10) Faizi, M.; Dabirian, S.; Tajali, H.; Ahmadi, F.; Zavareh, E. R.;
Shahhosseini, S.; Tabatabai, S. A. Bioorg. Med. Chem. 2015, 23, 480.
11) (a) Chernyshev, V. M.; Pyatakov, D. A.; Sokolov, A. N.;
3
(
2
(
Astakhov, A. V.; Gladkov, E. S.; Shishkina, S. V.; Shishkin, O. V.
Tetrahedron 2014, 70, 684. (b) Chernyshev, V. M.; Pyatakov, D. A.;
Astakhov, A. V.; Sokolov, A. N.; Fakhrutdinov, A. N.; Rybakov, V. B.;
Chernyshev, V. V. Tetrahedron 2015, 71, 6259.
(
2
(
(
12) (a) Allen, J. G.; Bourbeau, M. P.; Wohlhieter, G. E.; Bartberger,
M. D.; Michelsen, K.; Hungate, R.; Gadwood, R. C.; Gaston, R. D.;
Evans, B.; Mann, L. W.; Matison, M. E.; Schneider, S.; Huang, X.; Yu,
D.; Andrews, P. S.; Reichelt, A.; Long, A. M.; Yakowec, P.; Yang, E. Y.;
Lee, T. A.; Oliner, J. D. J. Med. Chem. 2009, 52, 7044. (b) Beck, H. P.;
DeGraffenreid, M.; Fox, B.; Allen, J. G.; Rew, Y.; Schneider, S.; Saiki,
(
2
P
DOI: 10.1021/acs.joc.5b01908
J. Org. Chem. XXXX, XXX, XXX−XXX