Hofmann-Ldffler-Freytag reaction

When formation of either the five- or six-membered ring was possible for N-chloroamine 37, only the five-membered ring was conducive under the Hofmann-Ldffler-Freytag reaction conditions, forming exclusively 6-ethyl-6-aza-bicyclo[3.2.1]-octane (38). No 2-ethyl-2-aza-bicyclo[2.2.2]-octane (39) was observed. On the other hand, 2-methyl-2-aza-bicyclo[2,2.2]octan-6-one (41) was installed by UV irradiation of a solution of A -chloroamine 40 in TFA. Ironically, when the ketone functionality on 40 was protected as its ethylene ketal group, the resultant steric interactions completely prohibited the classic Hofmann-Loffler-Freytag reaction. 

Hydrogen abstraction is the key factor in the intramolecular radical functionalization step of the Hofmann-Ldffler-Freytag reaction (Scheme 32) [335]. 

Hofmann-Ldffler-Freytag reaction Formation of cyclic amines from N-halogenated amines via an intramolecular 1,5-hydrogen atom transfer to a nitrogen radical. 208... 

N-halo amine amine Hofmann-Ldffler-Freytag reaction... 

For instance, L-leucine is converted into cis- and tra i-4-methyl-L-proline in good yield (Eq. 12.1) [65]. Rassat applied the Hofmann-Ldffler-Freytag reaction for the key step of the synthesis of 1,3,5,7-tetramethyl-2,6-diazaadamantane-2,6-dioxide (Eq. 12.2) [66]. 

Suarez developed neutral conditions for the Hofmann-Ldffler-Freytag reaction using a similar approach to the hypoiodite reaction described in Section 3.6.2.2. In this procedure, A -iodoamides are generated in situ by reaction of the corresponding amine derivative with iodine in the presence of lead tetraacetate or DIB as oxidizing agent. Nitroamines (Z = NO2) [67], phosphoramidates [Z = PO(OR)2 and PO(OEt)2] [68] and cyanamides (Z = CN) [69] have been used (Scheme 13, Eq. 13.1). A typical example is presented in Eq. (13.2). 

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