Iron-Catalyzed Intermolecular Amination of Benzylic C(sp³)–H Bonds

Abstract

A catalytic system for intermolecular benzylic C(sp 3 )−H amination is developed utilizing 1,2,3,4-tetrazole as a nitrene precursor via iron catalysis. This method enables direct installation of 2-aminopyridine into the benzylic and heterobenzylic position. The method selectively aminates 2°benzylic C(sp 3 )−H bond over the 3°and 1°benzylic C(sp 3 )−H bonds. Experimental studies reveal that the C(sp 3 )−H amination undergoes via the formation of a benzylic radical intermediate. This study reports the discovery of new method for 2-pyridine substituted benzylamine synthesis using inexpensive, biocompatible base metal catalysis that should have wide application in the context of medicinal chemistry and drug discovery.

The Recent Advances in Iron‐Catalyzed C(sp3)−H Functionalization

“…In 2022, Bhuddhadeb et al developed a highly efficient strategy for intermolecular amination of a wide range of substrates containing benzylic C(sp 3 )À H bonds 163 with various tetrazole 164 units utilizing inexpensive iron-porphyrin catalyst 165 via radical denitrogenation pathway (Scheme 42). [64] This protocol features many advantages such as readily available substrates, inexpensive and biocompatible base-metal catalyst, and mild conditions that override the conventional strategy. Next, they performed optimization from ethyl benzene and tetrazole with diethylamide substituent at the C-6 position as starting substrates.…”

Recent Advances in Nonprecious Metal Catalysis

“…More recently, the Chattopadhyay group has explored the use of 1,2,3,4-tetrazoles in Fecatalyzed annulations, intramolecular C(sp 3 )−H amination, and ring expansion, as well as other precious metal-catalyzed transformations. 18 This type of tetrazole (Scheme 4) is known to equilibrate between a closed and an open form, making it able to engage with the catalyst, leading to the metal−nitrene active species. Increased reactivity is observed for heterocycles bearing electron-withdrawing substituents in the C6 position, known to favor the open form at low temperatures (<100 °C).…”

“…Common nitrene sources include organoazides, N -oxy reagents, and iminoiodinanes. More recently, the Chattopadhyay group has explored the use of 1,2,3,4-tetrazoles in Fe-catalyzed annulations, intramolecular C­(sp 3 )–H amination, and ring expansion, as well as other precious metal-catalyzed transformations . This type of tetrazole (Scheme ) is known to equilibrate between a closed and an open form, making it able to engage with the catalyst, leading to the metal–nitrene active species.…”

Iron‐Catalyzed Intermolecular C−H Amination Assisted by an Isolated Iron‐Imido Radical Intermediate

“…[23,24] Iron catalysts have been successfully used in a variety of intramolecular CÀ H amination reactions to produce cyclic products. [25][26][27][28][29][30][31][32] However, iron-catalyzed intermolecular CÀ H amination reactions, are rare [33][34][35][36][37] and have drawbacks including long reaction times, high temperatures, high catalyst loadings, limited scope of nitrene precursors, and require additional oxidants. Other advances in this area have come from photocatalysis, [38] microwave radiation, [39] and enzyme catalysis.…”