Deaminative chlorination of aminoheterocycles

Abstract

Selective modification of heteroatom-containing aromatic structures is in high demand as it permits rapid evaluation of molecular complexity in advanced intermediates. Inspired by the selectivity of deaminases in nature, herein we present a simple methodology that enables the NH2 groups in aminoheterocycles to be conceived as masked modification handles. With the aid of a simple pyrylium reagent and a cheap chloride source, C(sp2)‒NH2 can be converted into C(sp2)‒Cl bonds. The method is characterized by its wide functional group tolerance and substrate scope, allowing the modification of >20 different classes of heteroaromatic motifs (five- and six-membered heterocycles), bearing numerous sensitive motifs. The facile conversion of NH2 into Cl in a late-stage fashion enables practitioners to apply Sandmeyer- and Vilsmeier-type transforms without the burden of explosive and unsafe diazonium salts, stoichiometric transition metals or highly oxidizing and unselective chlorinating agents.

Direct Deaminative Functionalization

“…With few exceptions, transformations of amines into other functional groups rely on preactivation strategies, thus requiring a minimum of two distinct transformations to accomplish one desired interconversion (Figure A). The classical example of this is conversion of the amino group to a diazonium ion, , with more recent protocols employing Katrizky-type pyridinium salts − or electron-rich imines. , A rare instance of a direct deaminative functionalization was recently reported by Cornella, , in which in situ formation of a pyridinium ion allows deaminative functionalization via an S N Ar mechanism for electron-poor (hetero)­aromatics. The rarity of one-step amine diversification processes is a stark reminder of the inadequacies in this area of synthetic chemistry.…”

Mechanochemical Conversion of Aromatic Amines to Aryl Trifluoromethyl Ethers

“…Inspired by the recent successful development of a deaminative chlorination protocol for aminoheterocycles that used Pyry-BF 4 , 54 we envisioned that a similar method could be used to introduce the trifluoromethoxy group. In the current paper, we present a new methodology that enables the efficient installation of the OCF 3 functionality onto aromatic substrates through the conversion of the NH 2 group using a readily available and commercialized pyrylium tetrafluoroborate reagent (Pyry-BF 4 ).…”

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

“…When pyridinium salt 2 was mixed with various hydroxide sources, irreversible Zincke‐type unproductive ring‐opening products were always dominant [28] . Exploring alternative oxygen sources did not lead to any improvement towards formation of 3 (KOAc, TMSOK, others).…”

“…In this context, our group has reported the use of a cheap and bench-stable salt, namely pyrylium tetrafluoroborate 1, to convert À NH 2 groups from heterocyclic scaffolds in a highly chemoselective fashion through S N Ar reactions. [25][26][27][28] Yet, direct hydroxylation always eluded our efforts due to incompatibility of the nucleophilic hydroxyl source.…”