Metal-Free Synthesis of N-Aryl-Substituted Azacycles from Cyclic Ethers Using POCl₃

Abstract

A facile method for the synthesis of N-aryl-substituted azacycles from arylamines and cyclic ethers has been developed. In this study, arylamines were treated with cyclic ethers in the presence of POCl3 and DBU to provide five- and six-membered azacycles. Using this method, various azacycloalkanes, isoindolines, and tetrahydroisoquinolines were prepared in high yields. This synthetic method offers an efficient approach to the production of azacycles from cyclic ethers.

Facile titanium(IV) chloride and TBD‐mediated synthesis of N‐aryl‐substituted azacycles from arylhydrazines

“…One the other hand, arylhydrazines are also one of the popular moieties in organic synthesis; thus, reactions of arylhydrazines could provide alternative useful approaches to prepare azacycles during multistep reactions. Particularly, reaction using the previously reported methods that readily produced azacycles from amines 14d,14e,15,18a could not provide successful results for the synthesis of azacycles from amines: reaction of phenylhydrazine in the presence of AlMe 3 did not afford the target azacyles, reaction of phenylhydrazine in the presence of TiCl 4 gave the target azacyles with 9%, reaction of phenylhydrazine in the presence of BF 3 ∙ OEt 2 did not yield the target azacyles, and reaction of phenylhydrazine in the presence of POCl 3 /DBU afforded the target azacyles with 53%. It suggested that reaction of arylhydrazine is more difficult than reaction of anilines, and that novel reaction method using TiCl 4 and TBD is more efficient to prepare the target azacycles.…”

“…B(C 6 F 5 ) 3 was used as a nonmetal catalyst for the preparation of N ‐substituted azacycles from arylamines and cyclic ethers in the presence of p ‐TsOH as a co‐catalyst 17 . In addition, reactions of arylamines and cyclic ethers in the presence of POCl 3 and DBU have been carried out to produce N ‐substituted azacycles 18 …”

Recent Advances in Synthetic Routes to Azacycles

“…In 2019, Kim and co-workers discovered a non-metal synthetic method for azacycles through a phosphoramidate intermediate [ 90 ]. Reactions between arylamines and cyclic ethers were carried out in the presence of POCl 3 and DBU in xylene at 110 °C ( Scheme 29 ).…”

Construction of N-Aryl-Substituted Pyrrolidines by Successive Reductive Amination of Diketones via Transfer Hydrogenation

“…Additionally, the hydrogenation of N -heteroaromatics was employed as well for the construction of N -aryl-substituted pyrrolidines [ 24 , 25 , 26 ]. It is worth noting that other methods, including cross-coupling of aryl halides [ 27 ], reduction in tertiary amides [ 28 ] and lactams [ 29 , 30 ], intramolecular C-N coupling [ 31 ] or C-N amination [ 32 ], reactions of cyclic ether compounds with primary arylamines [ 33 , 34 , 35 , 36 , 37 ] or arylhydrazines [ 38 ], Mitsunobu cyclodehydration reaction [ 39 ], Prins cyclization [ 40 , 41 ], aminomercuration demercuration [ 42 ], as well as intramolecular carbonyl olefination of amides [ 43 ], were established to furnish N -aryl-substituted pyrrolidines. Furthermore, chiral-substituted pyrrolidines could be delivered via copper-catalyzed asymmetric 1,3-diploar cycloaddition [ 44 ].…”