6-Nitro-4,7-dihydroazolo [1,5- a ]pyrimidines: an alternative mechanism of formation and studies of alkylation
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6-Nitro-4,7-dihydroazolo[1,5-a]pyrimidines: an alternative mechanism of formation and studies of alkylation Daniil N. Lyapustin1*, Evgeny N. Ulomsky1, Vladimir L. Rusinov1 1
Ural Federal University named after the first President of Russia B. N. Yeltsin, 19 Mira St., Yekaterinburg 620002, Russia; е-mail: [email protected] Submitted May 8, 2020 Accepted June 1, 2020
Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(11), 1465–1472
Y
N NH X
+
NH2 R
NO2
Ph +
N
O
rt
Y
N N
O
H2SO4 i-PrOH
O
120°C autoclave R = H, Me X = N, CCO2Et; Y = CH, CSMe
Ph NO2
AcOH
heating Ph N H 4 examples up to 51% R1 = OH, O
Y
NO2
N N X
X
O
O
R1
R
AcOH
N
R
N H
MeI K2CO3 R2
Y
NO2
N N X
R N H 2 examples 39% and 51%
MeI K2CO3
Y
N N
NO2
X
R N Me 5 examples up to 73% R2 = Ph, H
The mechanism of a multicomponent reaction between aminoazoles, 1-morpholino-2-nitroalkenes, and benzaldehyde was studied in acidic medium. Performing the reaction in acetic acid led to the formation of 6-nitro-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidines, which subsequently underwent a rearrangement. Reaction conditions were proposed for a multicomponent synthesis with trioxane, and the alkylation reactions of 4,7-dihydroazolo[1,5-a]pyrimidine nitro derivatives were optimized. Keywords: azolo[1,5-a]pyrimidines, 4,7-dihydroazolo[1,5-a]pyrimidines, nitro compounds, nitro synthon, alkylation, exo cleavage, multicomponent reaction, reaction mechanism.
Compounds belonging to the azolo[1,5-a]pyrimidine series have found applications in various areas of organic synthesis. Even during the last year, a large number of studies have focused on the biological activity of such compounds,1 their photophysical properties,2 and metal complexes.3 No less interesting and promising from medicinal chemistry point of view are molecular structures containing a dihydropyrimidine ring4 (Fig. 1). 6-Nitroazolo[1,5-a]pyrimidines represent little studied examples of similar heterocycles. Nepali with coworkers published a review article last year,5 which was devoted to nitro compounds used as drug molecules, in order to demonstrate the unique biological action mechanisms of the nitro group. The remarkable properties of 6-nitroazolo[1,5-a]pyrimidines include not only biological activity against viruses,6 potential for the treatment of sepsis7 and diabetes mellitus,8 but also their synthetic applications as scaffolds for the design of heteroannulated purines.9 Despite the large number of reported approaches to the synthesis of azolo[1,5-a]pyrimidines, only a few examples 0009-3122/20/56(11)-1465©2020 Springer Science+Business Media, LLC
are known for the preparation of 6-nitro-4,7-dihydro derivatives.10 Therefore, the development of methods for the preparation of such synthetically interesting and potentially biologically active compounds should be regarded as an important direction of research. In addition,
Figure 1. Biologically active azolo[1,5-a]pyrimidines.
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Chemistry of Heterocyclic Compounds 2020, 56(11), 1465–1472
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