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N ‐Acetylation as a Means to Activate Polyfluoroarylamines for Selective ortho ‐Hydrodefluorination by Zinc in Aqueous Ammonia: A Concise Route to Polyfluorobenzo Azaheterocycles
Author(s) -
Laev Sergey S.,
Gurskaya Larisa Yu.,
Selivanova Galina A.,
Beregovaya Irina V.,
Shchegoleva Lyudmila N.,
Vasil’eva Nadezhda V.,
Shakirov Makhmut M.,
Shteingarts Vitalij D.
Publication year - 2007
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200600684
Subject(s) - chemistry , moiety , regioselectivity , aqueous solution , leaving group , zinc , aniline , combinatorial chemistry , medicinal chemistry , organic chemistry , photochemistry , catalysis
N ‐Acetylation of polyfluoroarylamines is proposed as a meansto remove the amino group blocking effect of their hydrodefluorination by zinc in aqueous ammonia. With pentafluoroacetanilide, the Zn ion specific effect has been demonstrated to be responsible for ortho hydrodefluorination. This regiochemistry is accompanied by the removal of a fluorine atom from the para position, which occurs predominantly in the initial phase of the process in the absence of deliberately added zinc salt. The CuCl 2 additive has been found to accelerate the reaction and to propel it to double defluorination. Quantum chemical calculations suggest a diminished electron affinity of pentafluoroaniline, which is responsible for its inertness in relation to the hydrodefluorination reaction. The pentafluoroaniline radical anion, which essentially has a nonplanar structure, is prone to easy fragmentation to give an aminotetrafluorophenyl radical. For pentafluoroacetanilide, CVA experiments and quantum chemical calculations predict that the pentafluorophenyl moiety serves as the electron receptor and that the acetamido group is twisted out of coplanarity with the benzene ring; thus, together with the electron‐withdrawing effect of the acetyl group, the amino group blocking effect is suppressed. On this ground, the selective ortho hydrodefluorination of polyfluoroacetanilides is developed as an important protocol for the expeditious and general synthesis of polyfluorobenzo azaheterocycles via readily accessible polyfluoroarylamines from base polyfluoroarenes. Its applicability has been illustrated by preparing quinolines that possess a polyfluorinated benzene moiety by the Skraup synthesis utilizing crude polyfluoroacetanilide hydrodefluorination products as starting materials. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)