Metal‐free Synthesis of Aryl Amines: Beyond Nucleophilic Aromatic Substitution

Abstract

A mild and metal‐free approach to C−N coupling is described that employs diaryliodonium salt electrophiles and secondary aliphatic amine nucleophiles. This reaction results in direct ipso‐substitution of the iodonium moiety and unsymmetrical aryl(TMP)iodonium salts are primarily employed. Moreover, arene substituents and substitution patterns that currently pose a challenge to classical metal‐free methods are accommodated and the alicyclic amine nucleophiles used here are unprecedented in other contemporary metal‐free C−N coupling reactions.

Regiospecific N‐Arylation of Aliphatic Amines under Mild and Metal‐Free Reaction Conditions

“…Arylation of secondary,c yclic amines was expected to be more facile than primary amines,a ss uch amines were previously the only suitable substrates. [17] Indeed, cyclic amines proved highly reactive under our standard reaction conditions without excess reagents (Scheme 3a). Piperidines, morpholine,and thiomorpholine provided the products 5a-d in good to excellent yields with 2a.While N-phenylpiperazine proved less suitable (5e), pyrrolidine and tetrahydroisoquinoline were efficiently arylated, delivering 5f and 5g,r espectively,i ne xcellent yields.T he preferential arylation of secondary,c yclic amines over primary was illustrated by acompetition experiment that delivered 5cand 3ain 4:1ratio (see Scheme S5 in the Supporting Information).…”

“…[20] Indeed, 2e and 2f could both be employed under our reaction conditions,albeit with moderate results (entries 9and 10). To the contrary,only decomposition was observed when 1a was reacted with 2f using Stuarts recently reported procedure for cyclic amines, [17] illustrating the large difference between these protocols.…”

“…[16] In 2016, Stuart and co-workers reported the first synthetically useful, intermolecular arylation of amines with diaryliodonium salts (Scheme 1b). [17] In this pioneering paper,arange of electron-deficient aryl groups could be transferred using excess amounts of cyclic,s econdary amines in halogenated solvent. Thel imited substrate scope and environmental aspects of this procedure inspired us to initiate an investigation towards ag eneral methodology.H erein we present the efficient arylation of primary amines,a sw ell as acyclica nd cyclic secondary amines.T he reactions are high-yielding without excess reagents,a nd tolerate diaryliodonium salts with both electron-withdrawing (EWG) and electron-donating (EDG) substituents (Scheme 1c).…”

“…Thes ubstrate scope was investigated under the reaction conditions in entry 5o fT able 1, that is,w ithout excess substrate or reagents.T oour satisfaction, avariety of primary amines,c yclic and acyclics econdary amines,p roved suitable for the transformation. As previous protocols were incompatible with primary amines, [16,17] the scope investigation was focused on this substrate class.N itrophenylation of primary amines with 2a could be performed within 4hours,a s depicted in Scheme 2a.A mines with various hydrocarbon chains were efficiently monoarylated to provide the arylamines 3a-e in 79-91 %y ield. Cycloalkyl substituents were also tolerated, with improved reactivity for larger ring sizes (3f-h).…”

Quantitative Assessment of the Lewis Acidity of Diaryliodonium Salts

“…A thorough search of the relevant literature yielded only one study that made use of diaryliodonium salts as Lewis acid catalyst to promote a reaction, 24 which emphasizes the lack of knowledge in this area. Although a few reports proposed that diaryliodonium salts act as Lewis acids prior to oxidation processes, 25,26 hypervalent iodine reagents are greatly underexploited in this context. There is a current gap of knowledge on how diaryliodonium salts compare to common Lewis acids.…”