Alkoxy base-mediated selective synthesis and new rearrangements of 1,2,4-triazolodipyrimidinones

Article abstract of DOI:10.1016/j.tetlet.2017.01.030

A versatile approach for the synthesis of [1,2,4]triazolodipyrimidinones with various annulations of the triazole and pyrimidine rings was developed. The isomeric triazolodipyrimidinones were obtained by the stepwise condensation of partially hydrogenated

Full text of DOI:10.1016/j.tetlet.2017.01.030

Accepted Manuscript
Alkoxy base-mediated selective synthesis and new rearrangements of 1,2,4-tri-
azolodipyrimidinones
Dmitry A. Pyatakov, Alexander V. Astakhov, Andrey N. Sokolov, Artem N.
Fakhrutdinov, Andrew N. Fitch, Victor B. Rybakov, Vladimir V. Chernyshev,
Victor M. Chernyshev
PII:
S0040-4039(17)30052-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.030
TETL 48533
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 November 2016
22 December 2016
10 January 2017
Please cite this article as: Pyatakov, D.A., Astakhov, A.V., Sokolov, A.N., Fakhrutdinov, A.N., Fitch, A.N.,
Rybakov, V.B., Chernyshev, V.V., Chernyshev, V.M., Alkoxy base-mediated selective synthesis and new
rearrangements of 1,2,4-triazolodipyrimidinones, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.01.030
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Alkoxy base-mediated selective synthesis and
new rearrangements of 1,2,4-
Leave this area blank for abstract info.
triazolodipyrimidinones
Dmitry A. Pyatakov,a Alexander V. Astakhov,a Andrey N. Sokolov,a Artem N. Fakhrutdinov,b Andrew N.
Fitch,c Victor B. Rybakov,d,e Vladimir V. Chernyshevd,e and Victor M. Chernysheva
Fonts or abstract dimensions should not be changed or altered.

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Alkoxy base-mediated selective synthesis and new rearrangements of 1,2,4-
triazolodipyrimidinones
Dmitry A. Pyatakov,a Alexander V. Astakhov,a Andrey N. Sokolov,a Artem N. Fakhrutdinov,b Andrew N.
Fitch,c Victor B. Rybakov,d,e Vladimir V. Chernyshevd,e and Victor M. Chernysheva,∗
a Platov South-Russian State Polytechnic University (NPI), Prosveschenya 132, 346428 Novocherkassk, Russia.
b Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russia.
c European Synchrotron Radiation Facility, B. P. 220, F-38043 Grenoble Cedex, France.
d M. V. Lomonosov Moscow State University, Leninskie Gory 1-3, Moscow, 119991, Russia
e A.N. Frumkin Institute of Physical Chemistry and Electrochemistry RAS, Leninsky prospect 31, Moscow 119071, Russia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A versatile approach for the synthesis of [1,2,4]triazolodipyrimidinones with various annulations
of the triazole and pyrimidine rings was developed. The isomeric triazolodipyrimidinones were
obtained by the stepwise condensation of partially hydrogenated [1,2,4]triazolo[1,5-a]pyrimidin-
2-amines with β-ketoesters or diethyl ethoxymethylenemalonate, alkoxy base-mediated
cyclization of the enamines, and subsequent cascade rearrangement of the 10-oxo-
[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidines.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
nitrogen heterocycles
fused-ring systems
rearrangement
1,2,4-triazolo[1,5-a]pyrimidine
cascade reactions
———
∗Corresponding author. e-mail: chern13@yandex.ru.

2
Tetrahedron Letters
1. Introduction
features and new rearrangements of the obtained polycondensed
heterocycles are also discussed.
[1,2,4]Triazolo[1,5-a]pyrimidines are purine analogs that
exhibit beneficial biological properties and are widely applied in
2. Results and discussion
agrochemistry
and
medicine.1
For
example,
the
Partially hydrogenated 2-aminosubstituted triazolopyrimidines
1a-c18b and 2a-d as well as aromatic aminotriazolopyrimidine 318c
were used as substrates with various degrees of saturation of the
pyrimidine ring. Commercially available β-ketoesters 4a-c and
triazolopyrimidine sulfonamide herbicides flumetsulam and
metosulam have been employed in agriculture for approximately
twenty years,1c,2 and in the last decade, a new fungicide
ametoctradin (Initium®)1c,d and herbicide pyroxsulam2b,3 have
seen agricultural applications in many countries. Trapidil
(Rocornal®), which is a coronary vasodilator and anti-platelet
agent, has been used in medicine since the 1960s.1a,b,4
Furthermore, derivatives of [1,2,4]triazolo[1,5-a]pyrimidine
exhibit anticancer,5 antiparasitic,6 antibacterial,7 antiviral
(including anti-HIV and anti-HCV),8 anti-inflammatory,9
hypoglycemic,10 anticonvulsant,11 microtubule-stabilizing CNS,12
hypnotic,13 and cannabinoid CB2 antagonistic14 activities.
diethyl ethoxymethylenemalonate
5
were applied as 1,3-
biselectrophilic reagents (Fig. 1).
Ar
Ar
Ph
COOEt
N
N
N
N
N
N
N
N
H N
2
H N
2
H N
2
N
N
N
H
R
N
H
1a-c
2a-d
3
In recent years, polycyclic molecules containing the
[1,2,4]triazolo[1,5-a]pyrimidine fragment annulated with
different carbo- and heterocycles have received considerable
attention in view of their pronounced anticancer and anti-
inflammatory activities.5a,b,9,15 Commonly applied approaches for
the synthesis of these compounds are based on various
O
O
O
O
O
O
O
O
OEt
OEt
OEt
EtO
OEt
Cl
4c
OEt
4a
4b
5
1a: Ar = R = Ph;
1b: Ar = Ph, R = Me;
1c: Ar = 4-MeOC H , R = Ph;
2a: Ar = Ph;
2b: Ar = 3-MeO-C H ;
6
4
electrophilic
triazolopyrimidines at the electron-rich C6 atom and a substituent
in position
or 7.13,15b,c,16 However, the potential of
reactions
of
partially
hydrogenated
2c: Ar = 3-Cl-C H ;
6 4
6
4
2d: Ar = 3-Br-C H
6
4.
Figure 1. Starting compounds.
5
triazolopyrimidines as N-nucleophilic synthons for the annulation
of new rings from the side of the triazole fragment remains
poorly studied.
Recently, we demonstrated the possibility of annulating new
rings to the triazole moiety of partially hydrogenated
aminotriazolopyrimidines (Scheme 1).17 The proposed strategy
was based on the reactions between readily available 2-
aminosubstituted [1,2,4]triazolo[1,5-a]pyrimidines I-III with
various degrees of saturation of the pyrimidine ring,16a,18 and 1,2-
or 1,3-biselectrophilic reagents.
Compounds 2a-d were obtained using a two-step procedure
including condensation of acetoacetic ester with benzaldehydes
in the presence of the AcOH-piperidine catalytic system to give
intermediate enones 6a-d,20 followed by the one-pot
condensation of 6 with diaminotriazole 7 in DMF to give
compounds 2a-d in 71-83% yield (Scheme 2).
R1
R1
7
R1
1
N
R2
R3
R2
R3
R2
R3
N
N
[H]
[O]
N
N
N
N
N
2
6
3
H2
N
H2
N
H2N
4
N
N
H
N
H
5
N
III
3a
I
II
biselectrophile
Cl O4
R1
R1
R1
R4
X
R2
R3
R2
R3
R2
R3
R5
R6
N
N
N
N
N
N
N
N
N
N
N
N
N
HN
R2
N
Scheme 2. Synthesis of starting compounds 2a-d.
N
R6
N
N
N
N
O
R4
R3
R4
R1
R5
IV
V
VI
VII
Attempts to perform the condensation of partially
hydrogenated aminotriazolopyrimidines 1a and 2 or aromatic 3
with β-ketoesters 4a-c in ethanol, THF, or acetonitrile,
analogously to the previously described procedures for the
O
O
O
O
biselectrophile:
R4
R6
,
,
Br
Cl
Cl
R4
R5
Scheme 1. Synthesis of polycondensed heterocycles IV-VI from
aminotriazolopyrimidines I-III and various biselectrophiles.
preparation
of
enaminoesters
of
1-substituted
3,5-
diamino[1,2,4]triazoles,19c,e were unsuccessful due to insufficient
solubility of the aminotriazolopyrimidines. Heating compound 2a
with ketoester 4a in DMF at 90 °C afforded a complex mixture
from which enaminoester 8d was isolated in 63% yield (Scheme
3). At higher temperatures, significant tarring of the reaction
mixtures was observed. However, at lower temperatures, the
reaction time was too long. In contrast to ketoesters 4a-c, the
condensation of diethyl ethoxymethylenemalonate 5 with amines
1a-c, 2a, b, d, 3 in DMF at 90 °C afforded well-crystallized
enaminoesters 8a-c, e-h in 69-82% yield (Scheme 3).
β-Ketoesters and alkoxymethylenemalonates are useful
biselectrophilic reagents for the synthesis of various types of
heterocycles, especially pyrimidine derivatives.1a,19 However,
potential reactions between aminotriazolopyrimidines I-III and
β-ketoesters or alkoxymethylenemalonates have not yet been
investigated.
In the current article, we describe a new approach for the
preparation of multi-substituted polycondensed heterocycles with
various annulations of the triazole and pyrimidine rings via the
reactions between aminotriazolopyrimidines I-III and β-
ketoesters or diethyl ethoxymethylenemalonate. The structural

3
present in partially hydrogenated triazolopyrimidines 1 and 2
(ESI, Scheme S01).
Scheme 3. Synthesis of enaminoesters 8a-h.
The cyclization of enaminoesters 8 was investigated under a
variety of reaction conditions (ESI, Table S01). The cyclization
failed upon heating compounds 8 in acidic and neutral
conditions, or in the presence of KOH: complex mixtures were
obtained from which only aminotriazolopyrimidines 1-3 were
separated after neutralization and crystallization. However, we
observed that heating compounds 8 in the presence of sodium
ethoxide in absolute ethanol and subsequent neutralization
resulted in formation of the corresponding 10-oxo-
[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidines 9 or 10 (Scheme 4).
The highest yields of compounds 9 and 10 were observed upon
heating compounds 8 with sodium ethoxide in absolute ethanol
(8:EtONa = 1:3) at reflux for 0.5 h. Based on the optimized
conditions (ESI, Table S01), the selective cyclization of
enaminoesters 8a-g into the 10-oxo-[1,2,4]triazolo[1,5-a:4,3-
a']dipyrimidines 9a-c and 10a-d was performed in good yields
(Scheme 4, Method A). Intermediate sodium salts 11a,b were
also isolated from the reaction mixtures. Compounds 11a,b
afforded the corresponding neutral triazolodipyrimidines 10a,b in
the presence of acetic acid in ethanol (Scheme 4, Method B).
Scheme 4. Synthesis of compounds 9-11.
Compounds 10e-h were obtained by a one-pot procedure
(Scheme 4, Method C) via heating the aminotriazolopyrimidines
2a,c,d with ketoesters 4a-c in DMF at 90 °C, subsequent solvent
evaporation, and cyclization of the resulting enaminoesters in a
solution of EtONa in ethanol at reflux with subsequent
acidification of the formed sodium salt.
Apparently, the cyclization is initiated by the formation of
delocalized nucleophilic anions owing to proton abstraction from
one of the NH groups of compounds 8 in the presence of the
ethoxide anion (Scheme 5, see additional discussion of DFT
calculations in the ESI).
Scheme 5. Ethoxide-catalyzed cyclization of enaminoesters 8.
Compounds 9 and 10 contain two differently annulated
triazolopyrimidine frameworks (Fig. 2). The first framework,
denoted further as [1,5-a], is
hydrogenated [1,2,4]triazolo[1,5-a]pyrimidine fragment. The
second framework, denoted further as [4,3-a], is
[1,2,4]triazolo[4,3-a]pyrimidine fragment, which, in great
measure, is aromatic (the aromatic resonance structure is shown
in Fig. 2). It is known that aromatic [1,2,4]triazolo[4,3-
a]pyrimidines are prone to the Dimroth rearrangement to give
[1,2,4]triazolo[1,5-a]pyrimidines, which are typically more
thermodynamically stable.1a,21 Additionally, we recently observed
an unusual rearrangement of dihydro-[1,2,4]triazolo[1,5-a:4,3-
a
nonaromatic partially
Additionally, under the studied conditions, we were unable to
cyclize compound 8h which contained the aromatic
triazolopyrimidinium bicyclic ring system. Application of
stronger (tert-BuOK in DMF) or milder (K2CO3 in EtOH, or
Et3N in acetonitrile) bases afforded no triazolodipyrimidines and
only the starting compound 8h and amine 3, the product of
solvolysis, were isolated from the reaction mixtures. Apparently,
the hypothetical isomeric triazolodipyrimidine, which can be
formed from the cyclization of 8h, is unstable in the presence of
nucleophilic bases. The triazolodipyrimidines, that can form from
enaminoester 8h, contain no ionizable NH group, which is
a
a']dipyrimidinium
[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidinium
Compounds VI, which can be considered as isoelectronic
salts
(VI)
into
7,10-dihydro-
salts (VII).

4
Tetrahedron Letters
2
R
Ar
OEt
analogues of compounds 10, are proposed but not isolated
intermediates in the acid-catalyzed condensation of compounds 2
with 1,3-diketones.17c The last rearrangement includes
recyclization of the pyrimidine rings in both the [4,3-a] and [1,5-
a] frameworks. Taking into consideration the literature data, the
abilities of compounds 9 and 10 to undergo rearrangements and
the synthetic potential of the presumed reactions, these were
studied both experimentally and by DFT calculations.
O
7
Ar
OEt
8
N
N
N
O
6
1
R
4
DMF, 90 °C
5
N
N
10
9
N
O
3
N
Method A
1
R
N
H
10a
N
2
N
H
2
R
O
10a-f
13
O
O
6
1
R
4
5
Ph
OEt
N
N
6a
3
NH
N
AcOH, 90 °C
DMF, 90 °C
1
N
O
7
2
R
N
10a
N
11a
N
8
B
hod
Met
10
N
N
9
Ar
H
OEt
H
Ar
(74%)
O
13a
14a-f
N
N
O
O
O
N
N
non-aromatic
EtOOC
EtOOC
N
N
N
N
N
N
aromatic
[4,3-a] framwork
N
N
[1,5-a] framework
N
H
NH
NH
NH
N
N
N
N
Me
Me
Me
O
9,10
Ph
Ph
COOEt
COOEt
COOEt
14c
Br
Figure 2. Aromatic and non-aromatic [1,2,4]triazolopyrimidine frameworks
in compounds 9,10.
14a
14b
72% (A), 87% (B)
72% (A)
69% (A)
O
O
O
EtOOC
N
N
N
N
N
N
N
Prolonged heating a solution of compound 9a in ethanol at
reflux in the presence of sodium ethoxide was accompanied by
solvolysis to amine 1a. Heating 9a in acetic acid or DMF at 90-
100 °C, even in the presence of catalytic perchloric or sulfuric
acids, resulted in the formation of complex mixtures. At
temperatures higher than 110 °C, significant tarring was
observed. According to the 1H NMR spectra, these mixtures
contained the starting compound 9a and a new product (ESI, Fig.
S12). The NMR signals of the new product were similar to those
of compound 9a; therefore we proposed the formation of
isomeric triazolodipyrimidine 12 (15-20% relative to the starting
compound 9a), which probably results from Dimroth
recyclization of the pyrimidinone ring (Scheme 6). Prolonging
the reaction time did not change the ratio between the signal
intensities of compound 9a and plausible isomer 12.
Unfortunately, we were unable to separate this product from the
reaction mixtures.
NH
NH
NH
N
N
N
N
N
Me
Me
COOEt
COOEt
COOEt
MeO
Br
Cl
14d
14e
80% (A)
14f
71% (A)
65% (A)
Scheme 7. Cascade rearrangement of compounds 10a-g.
Thus, compounds 10 undergo a cascade rearrangement that is
similar to the recently disclosed rearrangement of non-isolable
1,4-dihydro-[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidinium salts VI
via the acid-catalyzed cyclization of enaminoketones derived
from the compounds II and 1,3-diketones.17c However, in the
reaction described herein, all three types of isomeric products
were in hand. In the first stage of the rearrangement, the aromatic
[4,3-a] triazolopyrimidine framework of compounds 10
undergoes a Dimroth rearrangement to the thermodynamically
more stable aromatic [1,5-a] framework to give intermediate
molecule 13. Compounds 13 are not quite thermodynamically
stable due to electronic factors (two neighboring “pyrrole”
nitrogen atoms)17c and steric repulsion between the oxygen atom
and Ar (Scheme 7). Therefore, in the second stage, intermediates
13 undergo the retro-Dimroth17c recyclization of the nonaromatic
dihydropyrimidine ring to give the thermodynamically more
stable products 14.
Scheme 6. Plausible rearrangement of compound 9a.
When heated in DMF at 90-100 °C compounds 10a-f undergo
a cascade rearrangement, forming triazolodipyrimidines 14a-f
(Scheme 7). In one case, we also succeeded in obtaining
intermediate product 13. Heating compound 10a in acetic acid at
85-90 °C resulted in formation of compound 13a, which
crystallized from the reaction mixture due to its low solubility.
Compound 13a also underwent rearrangement to compound 14a
in DMF at 90-100 °C (Scheme 7). Upon heating in DMF or
AcOH at 90-100 °C, compound 10g afforded a mixture of
sparingly soluble isomers that could not be separated by
crystallization. Compound 10h (R1 = Cl) decomposed upon
heating in DMF or AcOH to give a complex reaction mixture.
The comparatively low stability of the analogous chloro-
substituted triazolopyrimidinones was previously observed.19c
Attempts to recrystallize compounds 10 or 13a from hot
solutions in various solvents resulted in the formation of
admixtures of isomerized products in the crystallized samples.
However, compounds 10 may be recrystallized from a solution of
sodium ethoxide in ethanol by careful neutralization with acetic
acid. Compound 13a in DMSO or DMF completely rearranges
into 14a within a few days even at room temperature.
Considering the reactions described above, it can be
concluded that compounds 9 and 10, formed from the base-
mediated cyclization of enaminoesters 8, are so-called “kinetic
products”, which are apparently stabilized by deprotonation in
the strong alkaline solution of sodium ethoxide to form salts such
as compound 11. The neutral forms of compounds 9 and 10 are
less stable and can easily isomerize in solution. The
tetrahydropyrimidine ring in compounds 9 is quite resistant, and
therefore only a reversible Dimroth-type recyclization of the
aromatic [4,3-a] to the [1,5-a] triazolopyrimidine fragment may
be proposed from the experimental data. However, the
dihydropyrimidine ring of compounds 10 is sufficiently mobile,
therefore the cascade recyclization of both pyrimidine rings is
observed.
To corroborate the above conclusions concerning the observed
rearrangements, we performed a computational evaluation of the
relative thermodynamic stability of the various isomers that could
be expected from the isomerizations of compounds 9 and 10. The
thermodynamic stability of the possible isomers, including
anions, or the model molecules 9, 10, 12-14 was considered
(Scheme 8 and ESI for details).

5
Calculations of the relative Gibbs free energies (ΔG298) for the
isomers in the studied equilibriums (Scheme 8) were based on the
assumption that only the most stable tautomers were present in
the equilibrium mixtures. According to the calculations,
tautomers A were the predominant forms of molecules 9-14 in
both polar and nonpolar media. Notably, the intramolecular
hydrogen bond, which is present in tautomers 9A and 10A
(Scheme 8) according to X-ray analyses and DFT calculations, is
too weak to be responsible for such stabilization of the polar
mesoionic forms of compounds 9 and 10 (ESI, Figure S01).22
enhancement of the aromaticity of the triazole and pyrimidinone
rings in the polycyclic molecules (ESI, Table S17).
Another question that needed to be addressed was why the
alkoxy base-mediated cyclization of enaminoesters 8a-g resulted
in the selective formation of compounds 9 and 10 without further
rearrangement. Apparently, the formation of compounds 9 and 10
from enaminoesters 8 in the EtONa/EtOH media proceeds
selectively, in the first instance, owing to the higher rate of
intramolecular acylation at the N3 atom than at the N1 atom. It
was previously shown that the N3 atom of partially hydrogenated
2-amino-[1,2,4]triazolo[1,5-a]pyrimidines and the analogous
atom of 1-substituted 3-amino-1,2,4-triazoles was more
nucleophilic towards hard electrophiles.23 Calculations of the
molecular electrostatic potential (MESP) predict
a higher
nucleophilicity for N3 (ESI, Fig. S02 and S03). Another reason,
apparently, is the enhanced resistance of anions 9an and 10an
(Scheme 5) towards recyclization. The above described
rearrangements of compounds 9 and 10 more probably proceed
through an ANRORC (Addition Nucleophile Ring-Opening Ring
Closure) mechanism, which is typical for the Dimroth-type
recyclizations of azoloazines.21 In the ANRORC mechanism, the
addition of a nucleophile (nucleophilic catalyst or solvent
molecule) is a key stage for the rearrangement. However,
molecules 9 and 10, only formed during the cyclization of
enaminoesters 8, are rapidly deprotonated to form anions 9an and
10an in the strongly alkaline EtONa/EtOH media (Scheme 5).
These delocalized anions should be significantly less
electrophilic than the neutral molecules 9 and 10, therefore,
addition of the nucleophile is unfavored. For example, the
resistance of anion 10an towards isomerization is demonstrated
by the recrystallization of salts 11a,b without appreciable
decomposition from boiling DMF.
Scheme 8. Hypothetic equilibriums, calculated relative Gibbs free energies
(ΔG298, kcal/mol), and equilibrium compositions (x, %) of model molecules
of polycyclic compounds 9, 10, 12-14 in aqueous solution.
As shown in Scheme 8, both isomers 9 and 12 can be
expected in the cyclocondensations of enaminoesters 8a-c under
“thermodynamic control”. Although isomer 12A is slightly more
stable than 9A in the case of R = H, the presence of bulky
substituents in the actual molecules can shift the equilibrium
towards isomers 9, as is seen in the case of R = Ph (Scheme 8).
Therefore, the assumption for the formation of small amounts of
isomer 12 upon prolonged heating of compound 9a in DMF or
AcOH agrees well with the calculations. The deprotonation of
molecules 9 and 12 does not significantly affect the relative
stability of the corresponding anions (ESI, Table S15).
The structures of the synthesized compounds 2, 8-11, 13, and
14 were established by HRMS and NMR spectroscopic data,
1
including H-13C HMBC spectra for selected compounds, and X-
ray diffraction studies of 9a, 11b, 13a, and 14a (see ESI for
details).24
3. Conclusions
In summary, we have demonstrated that the condensation of
partially hydrogenated 2-aminosubstituted [1,2,4]triazolo[1,5-
a]pyrimidines with 1,3-dicarbonyl compounds can serve as a
versatile methodology for the preparation of substituted
[1,2,4]triazolodipyrimidines with various annulations of the
triazole and pyrimidine rings. The conditions for the selective
synthesis of isomeric triazolodipyrimidinones from partially
Molecule 14A is a substantially more stable (> 6 kcal/mol)
isomer in the equilibriums between molecules 10A, 13A and
14A, while isomer 13A is only ~1 kcal/mol more stable than
isomer 10A. Hence, in solution, compounds 10 should reversibly
isomerize into 13, while the subsequent rearrangement of 13 into
14 should be, in practice, irreversible. In analogy to compounds 9
and 12, the deprotonation of molecules 10, 13 and 14 does not
substantially change the thermodynamic stability of the
corresponding anions (ESI, Table S16). Therefore, compounds
10 and 13 are the so-called “kinetic products”, while compounds
14 are the “thermodynamic products”. The experimentally
observed rearrangements of compounds 10 and 13a into
compounds 14 agree well with this conclusion. The isolation of
compound 13a was possible owing to its low solubility in acetic
acid and the resulting precipitation from solution during the first
stage of the rearrangement of compound 10a.
hydrogenated
2-aminotriazolopyrimidines
and
diethyl
ethoxymethylenemalonate or β-ketoesters were defined. The
uncatalyzed condensation between these reagents in DMF affords
the corresponding enaminoesters. Heating the enaminoesters with
sodium ethoxide in ethanol results in the selective formation of
10-oxo-[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidines, which are
stabilized by deprotonation in the alkaline media. The direction
of the alkoxy base-mediated cyclization of the enaminoesters is
determined by kinetic factors. The neutral forms of the 10-oxo-
1,4-dihydro-10H-[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidines
in
solution undergo a cascade rearrangement that includes the
recyclization of both pyrimidine rings and results in the
Taking into account the previous results,17c it can be
concluded that the described cascade rearrangement is
formation
of
7,10-dihydro-4H-[1,2,4]triazolo[1,5-a:4,3-
a
a']dipyrimidin-4-ones with reversed annulation of the aromatic
and hydrogenated pyrimidine rings. The corresponding 4,7-
characteristic reaction of dihydro-[1,2,4]triazolo[1,5-a:4,3-
a']dipyrimidines and related compounds with an aromatic [4,3-a]
framework. Presumably, the driving force of the rearrangement is
a gain in energy due to formation of the more stable aromatic
[1,5-a] framework from the less stable aromatic [4,3-a]
framework. Additionally, isomerization gives rise to
dihydro-1H-[1,2,4]triazolo[1,5-a:2,3-a']dipyrimidinone,
an
intermediate product of the rearrangement, has also been isolated
and characterized.
The described cascade rearrangement has a generic character
for 1,4-dihydro-[1,2,4]triazolo[1,5-a:4,3-a']dipyrimidines and

6
Tetrahedron Letters
12.
Cornec, A.-S.; James, M. J.; Kovalevich, J.; Trojanowski, J. Q.;
Lee, V. M. Y.; Smith Iii, A. B.; Ballatore, C.; Brunden, K. R. Bioorg. Med.
Chem. Lett. 2015, 25, 4980.
opens new possibilities for the synthesis of polycondensed
heterocycles from partially hydrogenated
aminotriazolopyrimidines and biselectrophiles.
13.
Shahhosseini, S.; Tabatabai, S. A. Biorg. Med. Chem. 2015, 23, 480.
14. Aghazadeh Tabrizi, M.; Baraldi, P. G.; Ruggiero, E.; Saponaro,
Faizi, M.; Dabirian, S.; Tajali, H.; Ahmadi, F.; Zavareh, E. R.;
Acknowledgments
G.; Baraldi, S.; Poli, G.; Tuccinardi, T.; Ravani, A.; Vincenzi, F.; Borea, P.
A.; Varani, K. Eur. J. Med. Chem. 2016, 113, 11.
This work was financially supported by the Russian Science
Foundation (grant no. 14-23-00078). The X-ray part of this
research was supported by the Russian Ministry of Science and
Education (grant no. RFMEFI61616X0069). The authors also
thank ESRF for the access to ID22 station, experiment MA-3313.
15.
(a) Mohana Roopan, S.; Sompalle, R. Synth. Commun. 2016, 46,
645; (b) Beck, H. P.; DeGraffenreid, M.; Fox, B.; Allen, J. G.; Rew, Y.;
Schneider, S.; Saiki, A. Y.; Yu, D.; Oliner, J. D.; Salyers, K.; Ye, Q.; Olson,
S. Bioorg. Med. Chem. Lett. 2011, 21, 2752; (c) 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.
Supplementary Data
16.
(a) Sedash, Y. V.; Gorobets, N. Y.; Chebanov, V. A.; Konovalova,
Supplementary data (additional discussion of some
experimental and literature data, synthetic procedures and
characterization of isolated compounds, detailed results of
quantum chemical calculations, X-Ray investigations, FTIR,
HRMS and NMR spectra) associated with this article can be
found in the online version at doi:
I. S.; Shishkin, O. V.; Desenko, S. M. RSC Advances 2012, 2, 6719; (b)
Sidorenko, D. Y.; Orlov, V. D. Ultrason. Sonochem. 2011, 18, 300; (c)
Lipson, V. V.; Desenko, S. M.; Shishkin, O. V. Mendeleev Commun. 2006,
16, 280; (d) Lipson, V. V.; Desenko, S. M.; Ignatenko, I. V.; Shishkin, O. V.;
Shishkina, S. V. Russ. Chem. Bull. 2006, 55, 345; (e) Chebanov, V. A.;
Desenko, S. M. Chem. Heterocycl. Compd. 2012, 48, 566.
17.
(a) 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; (b) Chernyshev, V. M.; Pyatakov, D. A.;
Sokolov, A. N.; Astakhov, A. V.; Gladkov, E. S.; Shishkina, S. V.; Shishkin,
O. V. Tetrahedron 2014, 70, 684; (c) Pyatakov, D. A.; Sokolov, A. N.;
Astakhov, A. V.; Chernenko, A. Y.; Fakhrutdinov, A. N.; Rybakov, V. B.;
Chernyshev, V. V.; Chernyshev, V. M. J. Org. Chem. 2015, 80, 10694; (d)
Sokolov, A. N.; Mischenko, M. S.; Gladkov, E. S.; Chernyshev, V. M. Chem.
Heterocycl. Compd. 2011, 47, 249.
References and notes
1.
(a) Fischer, G. Adv. Heterocycl. Chem. 2007, 95, 143; (b)
Rodriguez-Torres, M.; Yoshida, E. M.; Marcellin, P.; Srinivasan, S.; Purohit,
V. S.; Wang, C.; Hammond, J. L. Ann. Hepatol. 2014, 13, 364; (c) Hu, M.;
Liu, X.; Dong, F.; Xu, J.; Li, S.; Xu, H.; Zheng, Y. Food Chem. 2015, 175,
395; (d) Zhu, X.; Zhang, M.; Liu, J.; Ge, J.; Yang, G. J. Agric. Food. Chem.
2015, 63, 3377; (e) Clough, J. M.; Dale, R. P.; Elsdon, B.; Hawkes, T. R.;
Hogg, B. V.; Howell, A.; Kloer, D. P.; Lecoq, K.; McLachlan, M. M. W.;
Milnes, P. J.; O'Riordan, T. J. C.; Ranasinghe, S.; Shanahan, S. E.; Sumner,
K. D.; Tayab, S. Pest Manage. Sci. 2016, 72, 2254; (f) Liu, Y.-C.; Qu, R.-Y.;
Chen, Q.; Yang, J.-F.; Cong-Wei, N.; Zhen, X.; Yang, G.-F. J. Agric. Food.
Chem. 2016, 64, 4845; (g) El Maatougui, A.; Azuaje, J.; González-Gómez,
M.; Miguez, G.; Crespo, A.; Carbajales, C.; Escalante, L.; García-Mera, X.;
Gutiérrez-de-Terán, H.; Sotelo, E. J. Med. Chem. 2016, 59, 1967.
18.
(a) Chernyshev, V. M.; Khoroshkin, D. A.; Sokolov, A. N.;
Taranushich, V. A.; Gladkov, E. S.; Shishkina, S. V.; Shishkin, O. V.;
Desenko, S. M. J. Heterocycl. Chem. 2008, 45, 1419; (b) Chernyshev, V. M.;
Sokolov, A. N.; Khoroshkin, D. A.; Taranushich, V. A. Russ. J. Org. Chem.
2008, 44, 715; (c) Chernyshev, V. M.; Sokolov, A. N.; Taranushich, V. A.
Russ. J. Appl. Chem. 2006, 79, 1134; (d) Chernyshev, V. M.; Sokolov, A. N.;
Taranushich, V. A. Russ. J. Appl. Chem. 2007, 80, 1691.
19.
(a) Sachdeva, N.; Dolzhenko, A. V.; Lim, S. J.; Ong, W. L.; Chui,
2.
(a) Sabra, F. S.; Mahmoud, M. S. Asian Journal of Agriculture
W. K. New J. Chem. 2015, 39, 4796; (b) Fizer, M.; Slivka, M. Chem.
Heterocycl. Compd. 2016, 52, 155; (c) Chernyshev, V. M.; Astakhov, A. V.;
Starikova, Z. A. Tetrahedron 2010, 66, 3301; (d) Astakhov, A. V.;
Chernyshev, V. M. Chem. Heterocycl. Compd. 2010, 46, 1144; (e) Astakhov,
A. V.; Zubatyuk, R. I.; Abagyan, R. S.; Chernyshev, V. M. Chem.
Heterocycl. Compd. 2014, 49, 1500.
and Food Sciences 2015, 3, 103; (b) Xu, J.; Zhang, J.; Dong, F.; Liu, X.; Zhu,
G.; Zheng, Y. Anal. Methods 2015, 7, 9791.
3.
Feng, Y.; Gao, Y.; Zhang, Y.; Dong, L.; Li, J. Weed Sci. 2016, 64,
695.
4.
Kim, S.-D.; Kim, H.-N.; Lee, J.-H.; Jin, W. J.; Hwang, S. J.; Kim,
H.-H.; Ha, H.; Lee, Z. H. Biochem. Pharmacol. 2013, 86, 782.
5. (a) Yu, B.; Shi, X.-J.; Zheng, Y.-F.; Fang, Y.; Zhang, E.; Yu, D.-
20.
21.
Correa, W. H.; Scott, J. L. Green Chem. 2001, 3, 296.
(a) El Ashry, E. S. H.; Nadeem, S.; Shah, M. R.; Kilany, Y. E.
Q.; Liu, H.-M. Eur. J. Med. Chem. 2013, 69, 323; (b) Li, Q.; Chen, Y.-M.;
Hu, Y.-G.; Luo, X.; Ko, J. K. S.; Cheung, C. W. Res. Chem. Intermed. 2015,
42, 939; (c) Łakomska, I.; Stefańczak, K.; Fandzloch, M.; Sitkowski, J.; Filip-
Psurska, B.; Wojtczak, A. Polyhedron 2016, 109, 33; (d) Fandzloch, M.;
Wojtczak, A.; Wiśniewska, J.; Stefańczak, K.; Salas, J. M.; Łakomska, I.
Inorg. Chim. Acta 2016, 443, 170.
Adv. Heterocycl. Chem. 2010, 101, 161; (b) Salgado, A.; Varela, C.; García
Collazo, A. M.; García, F.; Pevarello, P.; Alkorta, I.; Elguero, J. J. Mol.
Struct. 2011, 987, 13.
22.
Astakhov, A. V.; Chernyshev, V. M. Chem. Heterocycl. Compd.
2014, 50, 319.
23.
(a) Astakhov, A. V.; Sokolov, A. N.; Pyatakov, D. A.; Shishkina,
6.
(a) da Silva, E. R.; Boechat, N.; Pinheiro, L. C. S.; Bastos, M. M.;
S. V.; Shishkin, O. V.; Chernyshev, V. M. Chem. Heterocycl. Compd. 2015,
51, 1039; (b) Chernyshev, V. M.; Vlasova, A. G.; Astakhov, A. V.;
Shishkina, S. V.; Shishkin, O. V. J. Org. Chem. 2015, 80, 375.
24. Final atomic coordinates, geometrical parameters and crystallographic
data have been deposited at the Cambridge Crystallographic Data Centre
(CCDC), deposition numbers CCDC: 1483881 (compound 9a), 1483883
(compound 11b), 1483885 (compound 13a), and 1483886 (compound 14a).
Costa, C. C. P.; Bartholomeu, J. C.; da Costa, T. H. Chem. Biol. Drug Des.
2015, 86, 969; (b) Kokkonda, S.; Deng, X.; White, K. L.; Coteron, J. M.;
Marco, M.; de las Heras, L.; White, J.; El Mazouni, F.; Tomchick, D. R.;
Manjalanagara, K.; Rudra, K. R.; Chen, G.; Morizzi, J.; Ryan, E.; Kaminsky,
W.; Leroy, D.; Martínez-Martínez, M. S.; Jimenez-Diaz, M. B.; Bazaga, S.
F.; Angulo-Barturen, I.; Waterson, D.; Burrows, J. N.; Matthews, D.;
Charman, S. A.; Phillips, M. A.; Rathod, P. K. J. Med. Chem. 2016, 59, 5416.
These
data
can
be
obtained
free
of
charge
via
7.
Wang, H.; Lee, M.; Peng, Z.; Blázquez, B.; Lastochkin, E.;
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: (0044) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk).
Kumarasiri, M.; Bouley, R.; Chang, M.; Mobashery, S. J. Med. Chem. 2015,
58, 4194.
8.
(a) Massari, S.; Nannetti, G.; Desantis, J.; Muratore, G.; Sabatini,
S.; Manfroni, G.; Mercorelli, B.; Cecchetti, V.; Palù, G.; Cruciani, G.;
Loregian, A.; Goracci, L.; Tabarrini, O. J. Med. Chem. 2015, 58, 3830; (b)
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; (c) Wang, H.; Guo, C.; Chen, B.-Z.; Ji, M. Antiviral
Res. 2015, 113, 79.
9.
Ashour, H. M.; Shaaban, O. G.; Rizk, O. H.; El-Ashmawy, I. M.
Eur. J. Med. Chem. 2013, 62, 341.
10.
Gomha, S. M.; Eldebss, T. M. A.; Badrey, M. G.; Abdulla, M. M.;
Mayhoub, A. S. Chem. Biol. Drug Des. 2015, 86, 1292.
11.
Ayati, A.; Emami, S.; Foroumadi, A. Eur. J. Med. Chem. 2016,
109, 380.

Highlights
Selective base-mediated cyclization of enaminoesters into triazolodipyrimidinones
A new cascade rearrangement of the triazolodipyrimidinones
An experimental and DFT study