A Direct approach to a 6-hetarylamino[1,2,4]triazolo[4,3-b][1,2,4,5] tetrazine library

Article abstract of DOI:10.1021/ol403308h

The synthesis of 6-hetarylamino[1,2,4]triazolo[4,3-b]-[1,2,4,5]tetrazines is reported. The functionalized secondary amines were constructed via a K ₂CO₃-mediated SNAr reaction of weakly basic hetarylamines with 3-(3,5-dimethylpyrazol-1-yl)[1,2,4]triazolo[4,3-b]-[1,2,4,5]tetrazines, which allowed displacement 3,5-dimethylpyrazolyl leaving group. Significantly, the reaction exhibited a broad substrate scope and proceeded in good yields.

Full text of DOI:10.1021/ol403308h

Letter
pubs.acs.org/OrgLett
A Direct Approach to a
6‑Hetarylamino[1,2,4]triazolo[4,3‑b][1,2,4,5]tetrazine Library
Nadezhda V. Palysaeva,† Katerina P. Kumpan,†,⊥ Marina I. Struchkova,† Igor L. Dalinger,†
Aleksandr V. Kormanov,† Nataly S. Aleksandrova,† Victor M. Chernyshev,‡ Dmitrii F. Pyreu,§
Kyrill Yu. Suponitsky,∥ and Aleksei B. Sheremetev*,†
†N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991, RussianFederation
‡South-Russia State Technical University, Novocherkassk 346428, Russian Federation
§Ivanovo State University, Ivanovo 153025, Russian Federation
∥A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow 119991,Russian Federation
S
* Supporting Information
ABSTRACT: The synthesis of 6-hetarylamino[1,2,4]triazolo[4,3-b]-
[1,2,4,5]tetrazines is reported. The functionalized secondary amines
were constructed via a K2CO3-mediated SNAr reaction of weakly basic
hetarylamines with 3-(3,5-dimethylpyrazol-1-yl)[1,2,4]triazolo[4,3-b]-
[1,2,4,5]tetrazines, which allowed displacement 3,5-dimethylpyrazolyl
leaving group. Significantly, the reaction exhibited a broad substrate
scope and proceeded in good yields.
Because of importance of the secondary [1,2,4]triazolo[4,3-
b][1,2,4,5]tetrazinamines, a straightforward protocol to prepare
them using mild conditions and more readily available reagents
would thus offer a valuable tool for the synthesis of these high-
nitrogen molecules.
We recently reported an efficient procedure for the SNAr
reactions of 3,6-bis(3,5-dimethylpyrazol-1-yl)-s-tetrazine 1 with
weakly basic hetarylamines on heating in MeCN in the
presence of K2CO3 or Cs2CO3.16 This methodology allows
an efficient access to 3-hetarylamino-6-(3,5-dimethylpyrazol-1-
yl)-s-tetrazines, as the result of a displacement 3,5-dimethylpyr-
azolyl group. Similar reaction with a related fused tetrazine has
never been reported in the literature. However, this strategy
would be of even greater appeal if it was applicable to the fused
tetrazine derivatives, allowing the synthesis of corresponding
secondary biheterocyclic amines.
The main concern in applying this strategy on 3-(3,5-
dimethylpyrazol-1-yl)[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines 2
was the known instability of the bicyclic core under basic
conditions. However, it was interesting to discover that under
the same reaction conditions as developed for compound 1,
using K2CO3 as a base in MeCN at reflux, triazolotetrazine 2
underwent efficient couplings with 3-amino-4-R-furazans 3a−v
(Scheme 1).
In a typical procedure, solid K2CO3 was added in one portion
to a suspension of the triazolotetrazine 2 and a furazanamine in
boiling acetonitrile. The solution became dark red, and after the
disappearance of starting reagents the desired product was
isolated by an aqueous acidic17 workup, subsequently washed,
[1,2,4]Triazolo[4,3-b][1,2,4,5]tetrazines are molecules of wide
interest and importance due to their utilization in synthetic
chemistry1 and as key scaffolds in energetic materials.2 Some
derivatives of the bicycle also possess a wide spectrum of the
biological activities with antihemostatic,3 antimicrobial,4 and
antitumor properties,5 as inhibitors of a Bcl-2 protein,6 and as
antibacterial serine-threonine protein kinases.7 On the other
hand, in recent years, interest in secondary s-tetrazinamines
with respect to their unique potential in high energetic
materials8 and pharmaceutical applications9 has been followed
by development of the new and useful methods for their
synthesis. Typically, these compounds are synthesized by the
nucleophilic aromatic substitution (SNAr) reaction of s-
tetrazines bearing a leaving group with amines; 3,5-
dimethylpyrazolyl moiety has been used in place of a halogen
as a leaving group in many reactions.10 However, the reported
successful SNAr reactions at s-tetrazine ring are limited to some
highly basic primary amines; even at elevated temperatures,
anilines bearing electron-withdrawing groups remained un-
reactive.11 No previous nucleophilic replacement of a leaving
group of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines with a primary
amine has been documented. Moreover, the electrophilic
bicyclic heterocyclic system was usually destroyed by O-,12
N-,13 and C-nucleophiles.1
We recently reported an approach to s-tetrazines and
[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazins bearing 3-R-furazan-4-
ylamino substituents via the copper catalyzed cross-coupling
of the corresponding tetrazinylamines with iodofurazans (3-
iodo-1,2,5-oxadiazoles).14 However, moderate yields (42−58%)
and the application of hardly accessible iodofurazans15 limit the
scope of this reaction
Received: November 15, 2013
© XXXX American Chemical Society
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Letter
It is important to note that the reaction of the diamine
derivative using an identical protocol resulted in selective
monohetarylation in good yields (e.g., compound 4p, Scheme
1). Two-fold coupling of triazolotetrazine 2a (2.2 equiv) with
4,4′-diaminoazofurazan 3p at a more prolonged time provided
the bis-product 4s in 89% yield (Scheme 1). In order to further
extend the utility of the cyclization protocol, several mono- and
bis-secondary diamines were prepared from primary diamines
in good to excellent yields (see the Supporting Information).
Compared with ones of triazolotetrazine 2a, the 1H, 13C and
15N NMR spectra of products 4a−v displayed the disappear-
ance of dimethylpyrazol moiety signals, and the appearance of
signal characteristic of furazanic C-NH atom at δ ca. 154 ppm
Scheme 1. Synthesis of Selected N-([1,2,4]Triazolo[4,3-
b][1,2,4,5]tetrazin-3-yl)-4-R-furazan-3-amines
a
in 13C NMR and signal for NH group at δ ca. −295 ppm in 15
N
NMR. The spectral data of compounds 4a,b,i,k−n are also
consistent with those reported previously.14,18
It was next sought to extend the reaction scope to include
triazolotetrazines bearing a substituent at the 3-position of the
triazole ring. Both trifluoromethyl (2b) and 3-methylfurazan-4-
yl derivatives (2c)13 underwent coupling reactions efficiently
when the standard procedure was used: K2CO3 in boiling
MeCN (Scheme 2). Unfortunately, in the presence of the
Scheme 2. Synthesis of Selected 3-Substituted Secondary
a
[1,2,4]Triazolo[4,3-b][1,2,4,5]tetrazinamines
a
Reaction conditions: (i) triazolotetrazine 2a (0.5 mmol), furazan-
amine 3a−v (0.6 mmol), K2CO3 (0.6 mmol), MeCN (10 mL), reflux;
(ii) aqueous HCl to pH 1. Isolated yields are for an average of at least
two runs. A full list of products is given in the Supporting Information.
b
Time at which TLC (CCl4/MeCN, 3:1) indicated complete
c
disappearance of the starting reagents. In this case: triazolotetrazine
a
2a (1 mmol), diamine 3o−q,u,v (0.5 mmol), K2CO3 (0.6 mmol),
MeCN (10 mL), reflux.
Reaction conditions: (i) triazolotetrazine 2b or 2c (0.5 mmol),
furazanamine 3g,k,l,n,p,q (0.6 mmol), K2CO3 (0.6 mmol), MeCN (10
mL), reflux; (ii) aqueous HCl to pH 1. Isolated yields are for an
average of at least two runs. A full list of products is given in the
b
Supporting Information. Time at which TLC (CHCl3/MeCN, 3:1)
and dried. To our delight, a range of electron-donating and
electron-withdrawing groups at the furazan ring are well
tolerated, and the desired secondary amines 4 were formed in
good to excellent yields. Our experiments clearly demonstrate
that more electron-deficient furazanamines 3 show shorter
reaction time. Thus, in the case of 3-amino-4-nitrofurazan 3j
the reaction was completed in less than 1 h, while for 3,4-
diaminofurazan 3k it took over 3 h to react completely.
Notably, in cases if the triazolotetrazine 2a was combined with
3-aminofurazan-4-carboxylic acid 3w (not shown), the
disappearance of the starting reagents resulted in an inseparable
mixture from which the desired product 4w could not be
isolated.
indicated complete disappearance of the starting reagents.
amino group at the triazole ring of the bicycle, reactions of
triazolotetrazine 2d (R = NH2, not shown) with aminofurazans
substituted by both electron-withdrawing (e.g., nitro) and
electron-donating groups (e.g., methoxy) failed; the disappear-
ance of the starting 6-(3,5-dimethyl-1H-pyrazol-1-yl)[1,2,4]-
triazolo[4,3-b][1,2,4,5]tetrazin-3-amine 2d resulted in a
complicated mixture.
The electron-deficient hetarylamine substrate scope for this
reaction was next explored. As can be seen in Scheme 3,
pyrazoles, triazoles, tetrazoles, pyridines, pyrazines, and
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Letter
a b
,
Scheme 3. Synthesis of Selected N-([1,2,4]Triazolo[4,3-
b][1,2,4,5]tetrazin-6-yl)hetarylamines
Scheme 4. Synthesis of Selected Secondary N-Amines
a
a
Reaction conditions: (i) triazolotetrazine 2a (0.5 mmol), N-amine
19−21 (0.6 mmol), K2CO3 (0.6 mmol), MeCN (10 mL), reflux; (ii)
aqueous HCl to pH 1. Isolated yields are for an average of at least two
runs. A full list of products is given in the Supporting Information.
b
Time at which TLC (CCl4/MeCN, 3:1) indicated complete
disappearance of the starting reagents.
a
Reaction conditions: (i) triazolotetrazine 2b/2c (0.5 mmol), amine
7−12 (0.6 mmol), K2CO3 (0.6 mmol), MeCN (10 mL), reflux; (ii)
aqueous HCl to pH 1. Isolated yields are for an average of at least two
runs. A full list of products is given in the Supporting Information.
b
Time at which TLC (CCl4/MeCN, 3:1) indicated complete
disappearance of the starting reagents.
tetrazines reacted in moderate to good yields. However, when
using parent aminopyridines, no reaction was observed after 12
h at reflux. Similarly, the reaction with 2,6-diamino-3,5-
dinitropyrazine N-oxide was also unsuccessful.
Figure 1. General view of 23b in a representation of atoms by thermal
displacements ellipsoids with 50% probability.
A range of N-aminohetarenes were well tolerated. In
particular, diamine, such as 3-amino-4-(4-amino-4H-1,2,4-
triazol-3-yl)furazan, underwent this transformation in a good
yield and with excellent chemoselectivity. In this case, only
single product 23b was obtained from the reaction. As can be
seen from Scheme 4, both mono- and dinitroazoles were also
converted by this method in good yields to the corresponding
products. Notably, in the cases where the triazolotetrazine 2a
was combined with an N-amine containing activated chlorine
atom, such as 1-amino-4-chloro-3,5-dinitropyrazole (not
shown), all attempts to establish reaction conditions which
would give separable product were unsuccessful.
(23a and 23b), the molecules were nonplanar. On the contrary,
for compounds bearing C-NH-C bridge, nearly planar
molecular structures were observed (4k, 4o, and 5d). The
details of the X-ray study are given in the Supporting
Information.
In conclusion, we have developed a general and straightfor-
ward protocol for the synthesis of high nitrogen secondary
dihetarylamines from various weakly basic primary azolyl- and
azinylamines. To the best of our knowledge, the present
approach is the first combinatorial synthesis of the energetic
compound library.
The characteristic resonance by 15N NMR at ca. −256 ppm
indicated the presence of the Het(N)-NH- atom attached to
the 6-positions of the triazolotetrazine core (Scheme 4).
The structures of compounds 4k, 4o, 5d, 23a, and 23b were
confirmed by single-crystal X-ray study. In all of the molecules,
hydrogen atom was localized at the bridged nitrogen atom (see
Figure 1 for 23b as an example). In the case of products when
the NH bridge was attached to the nitrogen atom of the azole
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and copies of H and 13C, 15N, 14N,
1
19F NMR spectra corresponding to all isolated and purified
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
C
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Letter
(14) Sheremetev, A. B.; Palysaeva, N. V.; Struchkova, M. I.;
Suponitsky, K. Y.; Antipin, M. Y. Eur. J. Org. Chem. 2012, 2266.
(15) Sheremetev, A. B.; Shamshina, Yu. L.; Dmitriev, D. E.;
Lyubetskii, D. V.; Antipin, M. Y. Heteroatom Chem. 2004, 15, 199.
(16) (a) Sheremetev, A. B.; Palysaeva, N. V.; Struchkova, M. I.;
Suponitsky, K. Yu. Mendeleev Commun. 2012, 22, 302. (b) Suponitsky,
K. Yu.; Chernyshev, V. M.; Mazharova, A. G.; Palysaeva, N. V.;
Sheremetev, A. B. Acta Crystallogr. 2013, E69, o1630.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sab@ioc.ac.ru.
Present Address
⊥University of Bath, Claverton Down, Bath, BA2 7AY, UK.
Notes
(17) The synthesized secondary dihetaryl amines are strong NH-
acids. See the Supporting Information.
(18) Sheremetev, A. B.; Palysaeva, N. V.; Struchkova, M. I. Mendeleev
The authors declare no competing financial interest.
Commun. 2010, 20, 350.
ACKNOWLEDGMENTS
■
A part of this work was supported by the Russian Foundation
for Basic Research (grant nos. 12-03-31346), the Presidium of
the Russian Academy of Sciences (the program OKhNM-04),
and the Ministry of Education and Science of the Russian
Federation (The Federal Target Program ‘Research and
Educational Staff of Innovative Russia in 2012−2013’, Grant
No. 14.B37.21.0827).
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