2
Tetrahedron Letters
we have developed effective methods for the synthesis of 1,2,4-
simple filtration.14 An attempt to substitute triethyl orthoformate
with DMF-DMA in the microwave reaction was not successful
and resulted in a mixture containing 16% of 3a, as determined by
HPLC. However, triethyl orthoformate could be replaced by
trimethyl orthoformate without substantial change in the yield of
3a (72%).
triazolo[1,5-a][1,3,5]triazines with 7-amino-,1,9d 5,7-diamino-,9j
and 2,5,7-triamino-9h substitution types. The synthesis of
substituted 2,7-diamino-1,2,4-triazolo[1,5-a][1,3,5]triazines can
be achieved using a previously reported method,9d as was
demonstrated by the preparation of 7-amino-2-phenylamino-
1,2,4-triazolo[1,5-a][1,3,5]triazine (3a). Condensation of 5-
To study the substrate scope, a series of 3,5-diamino-1,2,4-
triazoles (1) were subjected to the reaction with triethyl
orthoformate and cyanamide under the optimized conditions
(Table 1). The presence of electron-donating and electron-
withdrawing groups on the phenyl ring was well tolerated and
afforded products 3b-h in good yields (70-75%). Moreover, the
reaction was also successful for the preparation of 7-amino-1,2,4-
triazolo[1,5-a][1,3,5]triazines with phenylalkylamino substituents
at position 2 of the heterocyclic ring (3i,j). Overall, the reaction
demonstrated high selectivity. No products of side reactions at
the substituted amino group of the triazoles 1 were isolated.
Morpholine- and methylthio-substituted products 3k and 3l were
synthesized via this method from the corresponding triazoles 1k
and 1l without any complications.
amino-3-phenylamino-1,2,4-triazole
(1a)
with
N,N-
dimethylformamide dimethyl acetal (DMF-DMA) followed by
the base-catalyzed reaction of the resulting product 2a with
cyanamide successfully afforded 3a (Scheme 1). Other methods
for the annelation of aminotriazine rings to give 1,2,4-
triazolo[1,5-a][1,3,5]triazines involve various combinations of
stepwise sequential reactions of 5-amino-1,2,4-triazoles, triethyl
orthoformate and cyanamide or their synthetic equivalents.9d,10
Considering the fact that the outcome of all these reactions was
independent of the reagent introduction order, we assumed that
the synthesis of 2,7-diamino-1,2,4-triazolo[1,5-a][1,3,5]triazines
could be carried out using these reagents in a one-pot, three-
component process.
One-pot multicomponent reactions play an important role in
medicinal chemistry providing diverse small drug-like molecules
in a single step.11 Multicomponent syntheses have been exploited
for the preparation of many heterocyclic scaffolds. In general, the
multicomponent approach relies on channeling all pre-
equilibrated reactions into a convergent manner leading to
exclusive formation of the desired products. This challenge
required careful selection of the reagents and reaction conditions.
Using 5-amino-1,2,4-triazoles in multicomponent reactions as a
1,3-binucleophilic reagent has been well documented;12 triethyl
orthoformate has also been applied for various multicomponent
heterocyclic syntheses.13 Therefore we expected that these
reagents would be suitable for the preparation of 2,7-diamino-
1,2,4-triazolo[1,5-a][1,3,5]triazines in a multicomponent fashion.
In this Letter, we report a new, one-pot, multicomponent method
for the synthesis of 2-amino-substituted 7-amino-1,2,4-
triazolo[1,5-a][1,3,5]triazines (3).
Similar to the stepwise sequential aminotriazine annelation,
our one-pot procedure was regioselective, with triazine ring
closure at N-1 of the aminotriazoles 1 and introduction of the
amino group at position 7. Theoretically possible side products of
the cyclization at N-4 of 1 as well as a regioisomer with the
amino group at position 5 were not isolated.
Structure assignments were made on the basis of spectral
analysis15 and by comparison with isomeric [4,3-a]-fused
structures,16 as well as known 3a, and related 7-amino-,1,9d 5,7-
diamino-9j and 2,5,7-triamino-9h substituted 1,2,4-triazolo[1,5-
a][1,3,5]triazines. Similar to the observations for these structures,
the lone pair of electrons on the 7-amino group of 3 were highly
delocalized over the π-electron system of the 1,2,4-triazolo[1,5-
a][1,3,5]triazine skeleton. This led to an increased rotational
barrier at the 7-amino group, which was coplanar with the
heterocyclic ring. As a result, the signals of the 7-amino group in
1
the H NMR spectra were split and shifted downfield (7.86-8.38
For the preparation of the starting 3,5-diamino-1,2,4-triazoles
(1), we employed a previously reported method9h using the
reaction of dimethyl N-cyanodithiocarbonimidate (4) with
different amines, followed by treatment of N-substituted N′-
cyano-S-methylisothioureas 5 with hydrazine in ethanol (Scheme
2). The reaction of 4 with hydrazine afforded triazole 6, which
was also used as a substrate for our three-component reaction.
1
ppm and 8.51-9.01 ppm). In the H NMR spectra, the triazine
ring proton gave a signal at 8.11-8.29 ppm. The characteristic
signals of the 1,2,4-triazolo[1,5-a][1,3,5]triazine core in the 13C
NMR spectra of 3 appeared at 150.0-150.6 ppm (C-7), 155.8-
157.4 ppm (C-3a), 157.9-159.1 ppm (C-5) and 161.6-166.6 ppm
(C-2).
In conclusion, we have developed a new, efficient, one-pot,
three-component method for the synthesis of 2-amino-substituted
7-amino-1,2,4-triazolo[1,5-a][1,3,5]triazines (3) from 3,5-
diamino-1,2,4-triazoles (1), cyanamide and triethyl orthoformate.
The reaction was enabled by heating under microwave
irradiation. Advantages of the reported method for the
construction of drug-like molecules with a 5-azapurine core
include the use of easily available reagents, short reaction times
and operational simplicity.
We started optimization of the conditions for our planned
multicomponent reaction by attempting the preparation of already
known9d
7-amino-2-phenylamino-1,
2,4-triazolo[1,5-
a][1,3,5]triazine (3a) as a model case. Our attempt to carry out
the reaction of 1a, triethyl orthoformate and cyanamide by
heating in methanol overnight resulted in the formation of a
complex mixture of compounds with only 6% of the desired
product 3a, as identified by HPLC analysis. Exploring the
reaction further, we were pleased to find that heating (150 °C, 20
min) in methanol under microwave irradiation resulted in
.
formation of 3a, which could be easily isolated in 75% yield by
Scheme 2. Reagents and conditions: (i) R1R2NH (1 equiv), MeOH,
reflux, 3 h; (ii) N2H4 (1.1 equiv), EtOH, reflux, 3 h; (iii) N2H4 (1.1
equiv), MeOH, 40 °C, 5 h.
Scheme 1. Reagents and conditions: (i) DMF-DMA (1.5 equiv),
toluene, reflux, 10 min; (ii) NCNH2 (2 equiv), MeONa (2 equiv),
MeOH, reflux, 24 h.
Kalinina, Svetlana A.
