Selective Functionalization of Aminoheterocycles by a Pyrylium Salt

Abstract

The functionalization of aminoheterocycles by using a pyrylium tetrafluoroborate reagent (Pyry‐BF4) is presented. This reagent efficiently condenses with a great variety of heterocyclic amines and primes the C−N bond for nucleophilic aromatic substitution. More than 60 examples for the formation of C−O, C−N, C−S, or C−SO2R bonds are disclosed herein. In contrast to C−N activation through diazotization and polyalkylation, this method is characterized by its mild conditions and impressive functional‐group tolerance. In addition to small‐molecule derivatization, Pyry‐BF4 allows the introduction of functional groups in a late‐stage fashion to furnish highly functionalized structures.

Mechanistic Approach Toward the C4‐Selective Amination of Pyridines via Nucleophilic Substitution of Hydrogen

“…The obtained 4‐halopyridine products ( 24 – 27 ) can be further diversified through conventional halogen substitution reactions. Analogously, reactions of heteroaryl pyridinium salts with thiols ( 28 – 30 ), benzenesulfinate ( 31 and 32 ), and phenol ( 33 ) [24a] proceeded smoothly in moderate to good yields. The merger of pyridination and aniline substitution reactions [24a] was also feasible ( 34 – 36 ), providing a direct route to arylamination.…”

“…Analogously, reactions of heteroaryl pyridinium salts with thiols ( 28 – 30 ), benzenesulfinate ( 31 and 32 ), and phenol ( 33 ) [24a] proceeded smoothly in moderate to good yields. The merger of pyridination and aniline substitution reactions [24a] was also feasible ( 34 – 36 ), providing a direct route to arylamination. Furthermore, a Smiles‐type rearrangement occurred upon addition of 2,2,2‐trifluoroacetophenone and lithium bis(trimethylsilyl)amide to forge C−O and C−C bonds, affording an α‐tertiary ether ( 37 ) [25] …”

Internal Atom Exchange in Oxazole Rings: A Blueprint for Azole Scaffold Evaluation

“…4 In particular, we have been interested in the replacement of N atoms in complex molecules through deaminative strategies, thus considering NH 2 groups as linchpin sites for modification. 4a c d Inspired by natural deaminases and imine-ketone condensations, we have recently disclosed a methodology that permits the replacement of NH 2 with OH groups in heterocyclic amines (Scheme 1 A). 5 Despite the potential of this technique, the N-to-O exchange occurs at the peripheral atoms , thus leaving the heterocycle intact.…”

Bio‐Inspired Deaminative Hydroxylation of Aminoheterocycles and Electron‐Deficient Anilines

“…Whereas alkyl pyridinium are ideal partners to generate alkyl radicals, [21–24] this reactivity remains challenging when translating it to the (hetero)aromatic amines, and polar reactivity still dominates. In this context, our group has reported the use of a cheap and bench‐stable salt, namely pyrylium tetrafluoroborate 1 , to convert −NH 2 groups from heterocyclic scaffolds in a highly chemoselective fashion through S N Ar reactions [25–28] . Yet, direct hydroxylation always eluded our efforts due to incompatibility of the nucleophilic hydroxyl source.…”