Development of a Regioselective N-Methylation of (Benz)imidazoles Providing the More Sterically Hindered Isomer

Abstract

An efficient and highly regioselective N-methylation of (NH)-(benz)imidazoles furnishing the sterically more hindered, less stable, and usually minor regioisomer has been developed. The methodology involves very mild reaction conditions and tolerates a wide range of functional groups.

Carbon Chain Rupture: Base-Induced Radical C–C Bond Cleavage of Alkylbenzimidazoles

“…13 C NMR (101 MHz, CDCl 3 ):  = 144.5, 144.5, 133.2, 125.0, 122.3, 121.5, 118.3, 34.1, 18.4.The data match with literature [17]. …”

Diarylborinic Acid-Catalyzed Regioselective Ring Openings of Epoxy Alcohols with Pyrazoles, Imidazoles, Triazoles, and Other Nitrogen Heterocycles

“…However, aromatic nitrogen heterocycles present an additional selectivity challenge, because (depending on the ring system and its substitution) they may be ambident nucleophiles that can give rise to isomeric products based on the position of N-functionalization. While several protocols for selective N–C­(sp 2 ) and N–C­(sp 3 ) bond formation on azoles and related structures have been reported, − including enantioselective, catalytic transformations, achieving regioselective N-alkylation via ring opening of a sterically and electronically unbiased epoxide is beyond the scope of current synthetic technologies. Considering that our proposed mechanism for the C3-selective ring openings involves activation of both the epoxy alcohol and the nucleophile, we speculated that an organoboron catalyst could give rise to different regioselectivity for heterocycle N-alkylation than would be obtained under conventional conditions.…”

Direct, Regioselective N-Alkylation of 1,3-Azoles

“…Under conventional conditions, alkylation favors the less sterically encumbered site . In many instances, the desired reverse selectivity could be achieved through protection of the less hindered position followed by alkylation of the desired position and then deprotection. , A PGF alternative to this less efficient process would therefore be desirable.…”