Cascade reactions for constructing heterocycles containing a pyrimidino-pyrazino-pyrimidine core using 1,2,4-triazole scaffolds

Article abstract of DOI:10.1016/j.tetlet.2019.151089

The regioselective cyclocondensation of aminoethyl-1,2,4-triazoles and glyoxal provides pentacyclic heterocycles in which two 7,8-dihydro-5H-6λ²-[1,2,4]triazolo[1,5-c]pyrimidine systems are connected through CH(OH) bridges generating a central piperazine-2,5-diol ring. The structure of the new compounds was elucidated based on ¹H, ¹³C and ¹⁵N NMR spectroscopic methods. The molecular structure of the parent compound generated from aminoethyl-1,2,4-triazole was established by single crystal X-ray diffraction.

Full text of DOI:10.1016/j.tetlet.2019.151089

Tetrahedron Letters 60 (2019) 151089
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cascade reactions for constructing heterocycles containing a
pyrimidino-pyrazino-pyrimidine core using 1,2,4-triazole scaffolds
Dmytro M. Khomenko a,d, , Roman O. Doroshchuk a,d, Ilona V. Raspertova a, Jesús García López b,
⇑
Fernando López Ortiz b, Sergiu Shova c, Oleg A. Iegorov d, Rostyslav D. Lampeka a
a Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska St. 64, Kyiv 01601, Ukraine
b Área de Química Orgánica, Research Centre CIAIMBITAL, Universidad de Almería, Ctra. Sacramento s/n, 04120 Almería, Spain
c Institute of Chemistry, Academy of Sciences of Moldova, Academiei Str. 3, Chisinãu 2028, Republic of Moldova
d Enamine Ltd, Vul. Oleksandra Matrosova 23, Kyiv 01103, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselective cyclocondensation of aminoethyl-1,2,4-triazoles and glyoxal provides pentacyclic
heterocycles in which two 7,8-dihydro-5H-6k2-[1,2,4]triazolo[1,5-c]pyrimidine systems are connected
through CH(OH) bridges generating a central piperazine-2,5-diol ring. The structure of the new com-
pounds was elucidated based on 1H, 13C and 15N NMR spectroscopic methods. The molecular structure
of the parent compound generated from aminoethyl-1,2,4-triazole was established by single crystal
X-ray diffraction.
Received 15 June 2019
Revised 23 August 2019
Accepted 28 August 2019
Available online 28 August 2019
Keywords:
1,2,4-Triazole
Cyclization
Ó 2019 Elsevier Ltd. All rights reserved.
Pyrazine
Conformationally rigid
Introduction
vide the rigid cis-fused products due to a stabilizing double anome-
ric effect [9]. The condensation of glyoxal with benzylamine is the
The chemistry of polycyclic systems containing saturated hete-
rocyclic moieties is one of the most important and flourishing areas
in synthetic organic chemistry [1,2]. This is due to the presence of
sp3-hybridized atoms in saturated compounds which make possi-
ble the construction of small molecules with semi-rigid frame-
works and therefore the introduction of functional groups
responsible for molecular recognition into specific positions of
the heterocyclic skeleton. This strategy has been called stereo-
chemical diversity oriented restriction [3]. The driving force for
this approach is the ‘‘lock and key” model [4]. Recently, we have
reported the synthesis of mixed unsaturated-saturated condensed
heterocycles of the hexahydropyrazino[2,3-e]pyrazine family
through the reaction between 3-aminomethyl-1,2,4-triazoles and
glyoxal [5]. The dialdehyde glyoxal is a widely used constituent
for the preparation of saturated heterocycles. For example, the con-
densation with linear polyamines, o-aminophenol or aminoethanol
leads to pyrazino-pyrazines [6], 2,20-bioxazolidines [7] or oxazino-
oxazines [8], respectively. Typically, these bicyclic compounds pro-
key step in the preparation of the nitroamine explosive
2,4,6,8,10,12-hexanitrohexaazaisowurtzitane (HNIW), also known
as CL-20 [10].
Although aminoalkyl-1,2,4-triazoles and their analogues are
attractive polyfunctional systems, their synthetic applications
remain largely unexplored. Only a few examples of their reactivity
towards carbonyl compounds have been reported [11]. They have
been used as building blocks for the construction of peptidomimet-
ics via acylation of the primary amino group [12], whereas the con-
densation with aromatic aldehydes and ketones gives rise to
[1,2,4]triazolo[1,5-c]pyrimidines in moderate to high yield [13].
Interestingly, 3-amino-5-aminoethyl-4H-1,2,4-triazoles undergo
cyclocondensation with 1,3-dicarbonyl reagents in the presence
of HCl exclusively through the 2-amino group affording 2-ami-
noalkyl-1,2,4-triazolo[1,5-a]pyrimidine hydrochlorides [14].
As part of our work on the chemistry of aminoalkyl-1,2,4-tria-
zoles, we report herein the synthesis of three new pentacyclic
‘‘pyrazino-pyrimidines” from aminoethyl-1,2,4-triazoles. Com-
pared with the analogous reaction of aminomethyl-1,2,4-triazoles
[5], the increase of the alkyl chain length connecting the heterocy-
cle and the amino group led to the formation of a completely dif-
ferent heterocyclic system.
⇑
Corresponding author at: Department of Chemistry, Kyiv National Taras
Shevchenko University, Volodymyrska St. 64, Kyiv 01601, Ukraine.
E-mail addresses: dkhomenko@ukr.net (D.M. Khomenko), flortiz@ual.es (F. López
Ortiz).
https://doi.org/10.1016/j.tetlet.2019.151089
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
D.M. Khomenko et al. / Tetrahedron Letters 60 (2019) 151089
group in an equatorial position of the six-membered ring and
Results and discussion
eclipsed with the NH linkage. This arrangement is stabilized by
an intramolecular Oꢀ ꢀ ꢀHAN hydrogen bond and would be retained
in the reaction with a second molecule of IIa through the formation
of an intermolecular Oꢀ ꢀ ꢀHAN hydrogen bonding leading to 7.
Alternatively, the successive addition of two molecules of II to
one molecule of glyoxal would afford intermediate III, which is sta-
bilized as the cyclic bis-hemiacetal 8. The presence of small
amounts of other stereoisomers below the detection level of 1H
NMR spectra (600 MHz, cryoprobe), could not be discarded due
to the extremely low solubility of compounds 7 and 8.
The synthesis of the new heterocyclic system was based on the
use 3-aminoethyl-1,2,4-triazoles 6 as building blocks. These pre-
cursors were readily accessible starting from commercially avail-
able Boc-b-alanine 1 following a slightly modified procedure
previously reported for the preparation of aminomethyl-1,2,4-tria-
zoles (Scheme 1) [5]. Thus, transformation of the carboxylic group
of 1 into a 1,2,4-triazole moiety was achieved through the forma-
tion of ethyl ester 2 followed by conversion into hydrazide 3 and
subsequent cyclization by reaction with the corresponding ethyl
imidate hydrochloride 4. Finally, N-Boc deprotection using HCl in
EtOH-H2O at reflux afforded the required 3-aminoethyl-1,2,4-tria-
zoles 6a-d as hydrochlorides. Treating 6a-d with glyoxal in a
water-ethanol solution (1:1 molar ratio) in the presence of Et3N
afforded pyrazino-pyrimidines 7a-d in high yields as a single
stereoisomer. Compounds 7a,c,d were obtained with a purity
higher than 97% (determined by 1H NMR) by simple filtration of
the crude reaction mixture. However, 7b was isolated as a mixture
with by-product 8 in a 70:30 ratio. The extremely low solubility of
this mixture in all common solvents made its purification by
recrystallization or chromatographic methods impossible.
Attempts to improve the yield of 7b using different reaction condi-
tions (time, temperature, and stoichiometry) were unsuccessful.
The formation of the title compounds can be explained by a
mechanism of cascade reactions (Scheme 2) involving condensa-
tion of aminotriazole 6 with one carbonyl group of glyoxal to give
Compound 7a, which crystalizes in the P21/c space group of the
monoclinic system with two co-crystallized water molecules, was
characterized using single-crystal X-ray diffraction analysis [15–
17]. The structure is shown in Fig. 1 and the bond distances and
angles are summarized in Table S1. Compound 7a contains an
inversion center. The primed atoms are symmetry related by inver-
sion to the unprimed atoms. The central hexahydropyrazine ring
has a chair conformation, while the tetrahydropyrimidine rings
have a twist-conformation. The deviation of N(1) from the mean
plane of atoms C(5)N(2)C(4)C(3)C(2) is ꢁ0.26 Å. Two hydroxy
groups are in the trans-position relative to each other and have
an axial orientation to the central ring (torsion angle C(5)N(1)C
(1)O(1) ꢁ59,15(14)°).
In the crystal, compound 7a and solvate molecules interact
through numerous OAHꢀ ꢀ ꢀN and OAHꢀ ꢀ ꢀO intermolecular hydro-
gen bonds (Table S2) to form a three-dimensional supramolecular
network, as shown in Fig. S2.
azomethine intermediate
I which would undergo cyclization
The formation of compounds 7 was further supported by MS
spectrometry and NMR spectroscopy. Although the solubility of
these compounds in deuterated solvents was very low, 1H, 13C
and 15N NMR spectra could be acquired for all of them. The NMR
spectra show only half the expected number of signals which
was in agreement with a structure of Ci symmetry. Using com-
pound 7a as a reference for structural analysis, the OH signal
(H11) at d 5.75 ppm was established by the lack of correlation in
the 1H,13C HSQC spectrum. Protons H6, H100 (Fig. 1, overlapped
through intramolecular attack of the NH group of the 1,2,4-triazole
to the C@N moiety furnishing tetrahydro-[1,2,4]triazolo[1,5-c]
pyrimidine-5-carbaldehyde derivative II. Subsequent double hemi-
aminal formation via stepwise intermolecular-intramolecular
addition processes between the amino and formyl groups of two
molecules of II would provide product 7.
The stereoselective formation of 7 via intermediate II is sup-
ported by computations at the M06-2X/6-31G(d) level of theory
(Fig. S16). The conformer of minimum energy IIa has the carbonyl
Scheme 1. Reagents and conditions: (I) ethyl chloroformate, CH2Cl2, 0 °C, 1 h; DMAP, room temp., 12 h. (II) N2H4, EtOH, reflux, 10 h. (III) NEt3, EtOH, reflux, 12 h. (IV) HCl, EtOH-
H2O, reflux, 12 h. (V) Glyoxal, NEt3, EtOH-H2O, room temp., 12 h.

D.M. Khomenko et al. / Tetrahedron Letters 60 (2019) 151089
3
Scheme 2. Suggested reaction mechanism for the formation of 7 and 8.
tive configuration of C12/C120 was tentatively assigned based on
the absence of NOEs between H12/H120and nearby protons.
Compounds 7 are the first examples of polyazacycloalkanes
containing
a
dodecahydropyrimido[10,20:4,5]pyrazino[1,2-a]
pyrimidine central core, i.e. a linear arrangement or perhydroan-
thracene-like skeleton. It has been reported that the condensation
of pyridoxamine with glyoxal furnished five-membered ring
adducts containing a piperazine-oxazine central system built up
by reaction between the amino and phenolic groups of two pyri-
doxamine with two molecules of glyoxal [19]. Similar geometrical
constraints (the Oꢀ ꢀ ꢀN distance in pyridoxamine is very close to the
Naminꢀ ꢀ ꢀNtrz distance in 3-aminoethyl-1,2,4-triazole) and the acid-
ity of the triazolic and phenolic protons would explain why the
reactions of 3-aminoethyl-1,2,4-triazole and pyridoxamine with
glyoxal proceed in a similar manner. We have previously observed
similar behavior between 3-aminomethyl-1,2,4-triazole and o-
aminophenol [5]. On the other hand, the analogous perhy-
drophenanthrene-like or angular bis-aminals (dodecahydropyrim-
ido[20,10:3,4]pyrazino[1,2-a]pyrimidine) have been prepared by the
condensation of glyoxal with linear polyamines [6a,20]. These
multidonor systems were used as ligands in coordination
chemistry [21]. It is also interesting to note that compound 8
obtained as a by-product in the synthesis of 7b contains an
unprecedented [7,70-bioxazolo[3,4-a][1,2,4]triazolo[1,5-c]pyrim-
idine] structure. The compounds reported herein contain a number
of donor atoms of different natures arranged in a rigid heterocyclic
core that could be useful for constructing MOF systems, among
other applications. We are currently exploring methodologies to
achieve that goal.
Fig. 1. X-ray molecular structure of 7a with atom labeling and thermal ellipsoids at
50% probability. Symmetry code: ꢁx, 1 ꢁ y, 1 ꢁ z.
at d 5.11 ppm) and H11 give rise to an ABX spin system. The corre-
lations observed in the 1H,15N HMQC spectrum support the
formation of the piperazine-2,5-diol substructure. Thus, protons
H9 (d 2.89 ppm) and H6/H10 (d 5.11 ppm) correlate with nitrogen
atom N7 (d 55.7 ppm, Fig. 2a). Additionally, H9 shows a second cor-
relation with N2 at d 208.6 ppm. Finally, N1 (d 279.6 ppm) and N4
(d 224 ppm) were identified through their correlations with H5.
The 15N chemical shifts of N1, N2 and N4 are in the expected range
for 1,2,4-triazoles [18].
A similar NMR study allowed the structure of compound 8 to be
determined (Fig. 2). A distinctive feature of 8 is the autocorrelation
observed in the HMBC spectrum between H12 and C120. The rela-
Fig. 2. (a) Correlations observed in the 1H,15N HMQC spectrum (blue arrows) of 7a measured in DMSO d6 and optimized for a coupling constant of 10 Hz, 1024 scans per
increment. Numbering scheme is included. (b) Structure of compound 8 showing key correlations observed in the HMBC spectrum (blue arrows) and the NOE detected
between H6 and H10 (red arrow).

4
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graphic details and copies of spectral data of all new compounds)
to this article can be found online at https://doi.org/10.1016/j.tet-
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