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

Abstract

Imidazo[1,5-a]pyridines were efficiently prepared via the cyclization of 2-picolylamines with nitroalkanes electrophilically activated in the presence of phosphorous acid in polyphosphoric acid (PPA) medium.

Electrophilically Activated Nitroalkanes in Synthesis of 3,4-Dihydroquinozalines

“…These phosphorylated nitronates tend to react with various carbon-based nucleophiles, for instance electron-rich arenes, allowing for Friedel-Crafts-type C-H functionalization reactions, often with subsequent accompanying rearrangements [21][22][23][24]. 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] It occurred to us that a similar strategy can be applied for the straightforward preparation of 3,4-dihydroquinazolines as well.…”

“…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] It occurred to us that a similar strategy can be applied for the straightforward preparation of 3,4-dihydroquinazolines as well. In reaction with bis-nucleophilic 2-(aminomethyl) anilines (1), the phosphorylated nitronate species 5 would, after elimination of orthophosphoric acid entity, afford an amidinium intermediate 7 (Scheme 3).…”

“…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-1 H -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 ).…”

Recent synthetic methodologies for imidazo[1,5-a]pyridines and related heterocycles

“…Recently, Rubin et al developed 34 a method to efficiently synthesize imidazo[1,5- a ]pyridines 80 and 81 via the cyclization of 2-picolylamines with nitroalkanes electrophilically activated in the presence of phosphorous acid in a polyphosphoric acid (PPA) medium. Although most reactions proceeded smoothly, the reaction with α-nitrotoluene was more sluggish and 3-phenyl imidazo[1,5- a ]pyridine was obtained in a low yield (Scheme 18).…”

Does electrophilic activation of nitroalkanes in polyphosphoric acid involve formation of nitrile oxides?

“…Over the last decade, our group has been instrumental in the development of multistep cascade transformations triggered by initial electrophilic activation of nitroalkanes in the presence of polyphosphoric acid (PPA). [13][14][15][16][17] Proposed mechanistic rationales for all these processes involve formation of a phosphorylated nitronate species as a key electrophilic intermediate. Herein, we wish to disclose our recent studies proving that formation of nitrile oxide species is also possible under the same conditions.…”