Site-Selective Copper-Catalyzed Amination and Azidation of Arenes and Heteroarenes via Deprotonative Zincation

Abstract

Arene amination is achieved by site-selective C–H zincation followed by copper-catalyzed coupling with O-benzoylhydroxylamines under mild conditions. Key to this success is ortho-zincation mediated by lithium amido diethylzincate base that is effective for a wide range of arenes, including non-activated arenes bearing simple functionalities such as fluoride, chloride, ester, amide, ether, nitrile, and trifluoromethyl groups as well as heteroarenes including indole, thiophene, pyridine and isoquinoline. An analogous C–H azidation is also accomplished using azidoiodinane for direct introduction of a useful azide group onto a broad scope of arenes and heteroarenes. These new transformations offer rapid access to valuable, diverse chemical space of aminoarenes. Their broad applications in organic synthesis and drug discovery are demonstrated in the synthesis of novel analogs of natural product (–)-nicotine and antidepressant sertraline by late-stage amination and azidation reactions.

Metal‐ and Base‐Free Room‐Temperature Amination of Organoboronic Acids with N‐Alkyl Hydroxylamines

“…[13] Nevertheless, as pointed out by the authors,a ryl boronic acids containing N-acyl or carbonyl groups,orthose with unprotected Natoms (e.g.,i ndoles) or Satoms,a re not suitable substrates.M oreover, this reaction gives primary anilines as the products,and thus cannot be used to build up molecular complexity.M ost recently,t he conversion of BAsi nto diaryl amines was reported. [3b] In continuation of our interest in developing novel methods for the synthesis of amines, [14] we herein report am ild transformation (Scheme 1c, 8 + 11!12)t hat converts BAsi nto secondary amines at ambient temperature (28 8 8C) and in the absence of added metal or base.O ur method employs readily available N-alkyl hydroxylamines 11 as the electrophilic nitrogen source.R emarkably,w hile the parent hydroxylamine (9)has been used as an oxygen-transfer agent that converts aryl boronic acid derivatives into phenols (8 + 9!10), [15] we establish in this work that N-alkyl hydroxylamine 11 is an effective reagent for the amination of BAs (8) in the presence of as toichiometric amount of trichloroacetonitrile (CCl 3 CN). This process was adopted for the amination of both aryl and alkyl boronic acids.M oreover,t he amination of alkyl boronic acids was found to be stereoretentive.T his method tolerates ar emarkable range of functional groups,i ncluding amides,k etones,e sters,u nprotected alcohols,a nd carboxylic acids.T he reaction is operationally simple,a nd can be performed open to air.T he generality of this method was demonstrated by its application in the preparation of products containing peptide side chains or carbohydrate motifs.…”

“…[7] Notably,r eactions converting BAsi nto amines are unconventional in that the Catom in the resulting CÀNb ond could be viewed as an ucleophile. [8] With recent developments,m ethods in this category have become important alternatives to produce amines.H owever,t he aforementioned reactions also require the participation of transition metals.…”

Metal‐ and Base‐Free Room‐Temperature Amination of Organoboronic Acids with N‐Alkyl Hydroxylamines

“…[12] However,t he high basicity of this reagent limits the variety of compatible functional groups.T he groups of Kürti and Falck reported the elegant use of O- (2,4-dinitrophenyl)hydroxylaminea sa na minating agent for aryl boronic acids under mild conditions. [3b] In continuation of our interest in developing novel methods for the synthesis of amines, [14] we herein report am ild transformation (Scheme 1c, 8 + 11!12)t hat converts BAsi nto secondary amines at ambient temperature (28 8 8C) and in the absence of added metal or base.O ur method employs readily available N-alkyl hydroxylamines 11 as the electrophilic nitrogen source.R emarkably,w hile the parent hydroxylamine (9)has been used as an oxygen-transfer agent that converts aryl boronic acid derivatives into phenols (8 + 9!10), [15] we establish in this work that N-alkyl hydroxylamine 11 is an effective reagent for the amination of BAs (8) in the presence of as toichiometric amount of trichloroacetonitrile (CCl 3 CN). [3b] In continuation of our interest in developing novel methods for the synthesis of amines, [14] we herein report am ild transformation (Scheme 1c, 8 + 11!12)t hat converts BAsi nto secondary amines at ambient temperature (28 8 8C) and in the absence of added metal or base.O ur method employs readily available N-alkyl hydroxylamines 11 as the electrophilic nitrogen source.R emarkably,w hile the parent hydroxylamine (9)has been used as an oxygen-transfer agent that converts aryl boronic acid derivatives into phenols (8 + 9!10), [15] we establish in this work that N-alkyl hydroxylamine 11 is an effective reagent for the amination of BAs (8) in the presence of as toichiometric amount of trichloroacetonitrile (CCl 3 CN).…”

“…Additionally,t he groups of Lei, Liebeskind, Lalic, and others have reported on the amination of BAswith N-chloro amides or N-alkyl hydroxylamine derivatives in the presence of copper-o rr hodiumbased catalysts (Scheme 1a, 1 + 3!4). [8] With recent developments,m ethods in this category have become important alternatives to produce amines.H owever,t he aforementioned reactions also require the participation of transition metals. [8] With recent developments,m ethods in this category have become important alternatives to produce amines.H owever,t he aforementioned reactions also require the participation of transition metals.…”

Recent Applications of the Zhdankin Reagent in Organic Synthesis

“…The latter methodology allows the generation of radicals under particularly mild conditions. The Zhdankin reagent is frequently employed in tandem with a metal catalyst such as copper [7][8][9][10][11][12] or iron. [13,14] This article highlights some notable applications of molecule 3 that have appeared since 2016.…”