Hofmann-Loffler-Freytag Reaction Remote Functionalization

HOFMANN-LOFFLER-FREYTAG REACTION (REMOTE FUNCTIONALIZATION) 

Suarez and co-workers prepared chiral 7-oxa-2-azabicyclo[3.2.1]octane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems derived from carbohydrates via an intramolecular hydrogen abstraction reaction promoted by A/-centered radicals. The A/-centered radicals were obtained under mild conditions (Suarez modification) from phenyl and benzyl amidophosphates and alkyl and benzyl carbamate derivatives of aminoalditols by treatment with PIDA/I2 or PhlO/l2. The initial A/-radical undergoes a 1,5-hydrogen abstraction to form an alkyl radical, which is oxidized to the corresponding stabilized carbocation (oxocarbenium ion) under the reaction conditions. The overall transformation may be considered as an intramolecular N-glycosidation reaction. 

The Su rez modification of the HLF reaction was the basis of the new synthetic method developed by H. Togo et al. The authors prepared A/-alkyl-1,2-benzisothiazoline-3-one-1,1-dioxides (A/-alkylsaccharins) from A/-alkyl(o-methyl)-arenesulfonamides using (diacetoxyiodo)arenes in the presence of iodine via sulfonamidyl radicals. The transformations did not work in the dark, indicating the radical nature of the reaction. The yields varied from moderate to excellent and the nature of the aromatic substituents on both the substrate and the (diacetoxyiodo)arenes were important. It should be noted that the oxygen atom at the C3 position most likely arises from the hydrolysis of a C3 diiodo intermediate (not isolated). 

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The Hofmann-Loffler-Freytag (HLF) reaction is the oldest known reaction that involves aminium cation radicals (Scheme 14) (50JA2118 60JA1657). This reaction is a remote functionalization reaction where an N-chloro- or N-bromo-amine 46 is converted to a 8-haloamine 49 via the intermediate aminium cation radical 47. Pyrrolidine products are obtained by cyclization of the 8-haloamines under basic conditions. A comprehensive survey of the synthetic utility of this reaction has been reported by Wolff (63CRV55). 

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