Synthesis of Purine Analogues: Photocatalyst-Free Visible-Light-Enhanced Annulation Approach to Pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines

Abstract

A new photocatalyst-free visible-light-enhanced strategy for the synthesis of pyrazolo­[1,5-a]­[1,3,5]­triazine-2,4-diamines via the formation of electron donor–acceptor (EDA) complexes is reported. The in situ generated pyrazolthiourea intermediates from 1H-pyrazol-3-amines and isothiocyanates undergo formal [4 + 2] annulation with 1,1,3,3-tetramethylguanidines (TMG) to deliver the corresponding products involved in three C–N bond formations in a one-pot protocol. The formation of EDA complex from pyrazolthiourea and TMG is confirmed by UV–vis spectroscopy and 1H NMR experiments. Moreover, this mild reaction proceeds in the absence of any external transition metals, oxidants, bases, and ligands. This efficient methodology for the synthesis of purine analogues pyrazolo­[1,5-a]­[1,3,5]­triazine-2,4-diamines provides potential synthetic applications in the field of drug research and development.

Open-Air Dual-Diamination of Aromatic Aldehydes: Direct Synthesis of Azolo-Fused 1,3,5-Triazines Facilitated by Ammonium Iodide

“…In comparison, the more sterically hindered ortho-methylbenzal-Scheme 1. Some Pharmacologically Active Pyrazolo [1,5a][1,3,5]triazines and Methods for the Synthesis of Azolo [1,3,5] dehyde and ortho-fluorobenzaldehyde were also efficiently transformed into 3o and 3p in 72% and 56% yields, respectively. Disubstituted benzaldehydes performed well, which gave the multisubstituted 2,4-diphenylpyrazolo[1,5a][1,3,5]triazines 3x−3y in good yields.…”

“…In 2018, the Ellman group established a Rh­(III)-catalyzed C–H amidation strategy for the synthesis of a variety of azolo­[1,3,5]­triazines from dioxazolones and N -azolo imines, which were readily prepared by a simple condensation of aminoazoles with widely available aromatic aldehydes (Scheme b) . Recently, Guo et al realized a visible-light-enhanced annulation to deliver pyrazolo­[1,5- a ]­[1,3,5]­triazine-2,4-diamines, and this one-pot procedure avoided separation and purifications of the pyrazolylthiourea intermediates from isothiocyanates and 3-aminopyrazoles (Scheme c) . Bekircan and co-workers developed a metal-free approach to fused heterocyclic 1,3,5-triazines from N -acyl imidates and 3-aminoazoles .…”

“…4 Recently, Guo et al realized a visible-light-enhanced annulation to deliver pyrazolo [1,5-a][1,3,5]triazine-2,4-diamines, and this one-pot procedure avoided separation and purifications of the pyrazolylthiourea intermediates from isothiocyanates and 3-aminopyrazoles (Scheme 1c). 5 Bekircan and co-workers developed a metal-free approach to fused heterocyclic 1,3,5-triazines from N-acyl imidates and 3aminoazoles. 13 Obviously, there is a persistent need to explore a straightforward and practical approach to pyrazolo[1, 5a][1,3,5]triazines from readily available building blocks.…”

“…13 Obviously, there is a persistent need to explore a straightforward and practical approach to pyrazolo[1, 5a][1,3,5]triazines from readily available building blocks. Herein, we report a reagent-free [3 + 1 + 1 + 1] heteroannulation reaction for the direct synthesis of 2,4diarylsubstituted azolo [1,3,5]triazines by simply heating the aromatic aldehydes and 3-aminoazoles with ammonium iodide in the presence of only air.…”

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A new and practical protocol for the synthesis of medicinally privileged azolo [1,3,5]triazines by simply heating under air has been presented. The in situ generated N-azolo amidines from commercially available aromatic aldehydes and 3aminoazoles with ammonium iodide undergo the second diamination to accomplish the [3 + 1 + 1 + 1] heteroannulation reaction.

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