Nitroalkanes as electrophiles: synthesis of triazole-fused heterocycles with neuroblastoma differentiation activity

Abstract

We discovered a reaction of nitroalkanes with 2-hydrazinylquinolines, 2-hydrazinylpyridines and bis-2,4-dihydrazinylpyrimidines in polyphosphoric acid (PPA) affording 1,2,4-triazolo[4,3-a]quinolines, 1,2,4-triazolo[4,3-a]pyridines and bis[1,2,4]triazolo[4,3-a:4',3'-c]pyrimidines, respectively. The reaction expands the scope of heterocyclic annulations involving...

Electrophilically Activated Nitroalkanes in Synthesis of 3,4-Dihydroquinozalines

“…Furthermore, it was found that nitrogen-based nucleophiles (6), such as aliphatic amines [25][26][27], anilines [28][29][30][31], or hydrazines [32,33], can be utilized instead of water in a process mechanistically related to the classical Nef reaction [34][35][36]. Employing strategically placed second nucleophilic functionality (carbon or heteroatom-based), the resulting amidinium species (7) can be transformed into a variety of heterocyclic compounds, such as benzoxazoles (8) [23,28] or benzimidazoles (9) [28], perimidines (10) [29], 6,7-dihydro-1H-cyclopenta[gh]perimidines (11) [31], 1,3,4-oxa-di-azoles (12) [32,33], imidazolines (13) [25], 3,4-dihydro-iso-quinolines (14) [27], imidazo [1,5-a]pyridines (15) [26], and [1,2,4]triazolo [4,3-a]pyridines (16) [37] (Scheme 2). Scheme 2.…”

Electrophilically Activated Nitroalkanes in Double Annulation of [1,2,4]Triazolo[4,3-a]quinolines and 1,3,4-Oxadiazole Rings

“…These entities readily react with amines B to afford amidinium intermediates C , which can be used for the highly efficient assembly of imidazoles or oxazoles ( D ) [ 20 , 21 ], as well as imidazolines [ 22 ] and other nitrogen-based heterocycles [ 23 , 24 ]. Furthermore, the reaction with 2-hydrazinylpyridines H enacts formation of the corresponding (hydrazineyl)alkaniminium species I , which was found to undergo intramolecular cyclocondensations to obtain 1,2,4-triazolo[4,3- a ]pyridines ( J ) ( Scheme 1 ) [ 2 ]. Similarly, a mechanistically related reaction with acylhydrazides E proved useful for cyclization toward 1,3,4-oxadiazoles G .…”

“…There is significant emphasis on the role of [1,2,4]triazolo[4,3- a ]quinolines in modern-day drug discovery and medicinal chemistry. This privileged scaffold was utilized in the design of potent and selective aldosterone synthase inhibitors with antihypertensive activity [ 1 ], as well as prospective antitumor [ 2 , 3 ], anticonvulsant [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ], anti-inflammatory [ 11 , 12 ], and antimicrobial [ 13 , 14 ] agents. It was also found that an introduction of a heterocyclic substituent at C-5 could allow for the preparation of chimeric scaffolds with improved biological activities.…”

“…This strategy was employed in the development of cytotoxic and antiviral agents [ 15 ], as well as analgesic and anti-inflammatory drug candidates [ 16 ]. Recently, we described the preparation of novel antitumor agents with in vitro differentiation activity against neuroblastoma cancer cell lines [ 2 ]. These compounds were assembled via an unusual annulation reaction between electrophilically activated nitroalkanes [ 17 ] and 2-hydrazinylquinolines.…”

Synthesis of imidazo[1,5-a]pyridines via cyclocondensation of 2-(aminomethyl)pyridines with electrophilically activated nitroalkanes

“…We have also shown that a nucleophilic attack on the phosphorylated nitronate species 2 can be carried out with the participation of N-acylhydrazides or thiosemicarbazides to afford the 1,3,4oxadiazoles 9 [45] and the 1,3,4-thiadiazoles 10 [46], respectively (Scheme 1). Finally, it was found that the reaction of 2-hydrazinylpyridine with electrophilically activated nitroalkanes provides the corresponding triazolopyridines 11 (Scheme 1) [47]. These results prompted the desire to implement this general scheme in order to access highly important imidazo [1,5a]pyridines.…”