Loffler-Freytag reaction

Hofmann rearrangement, 7, 34 Hofmann-Loffler-Freytag reaction, 4, 91 Holomycin... 

The Hofmann-Loffler-Freytag reaction represents formation of pyrrolidines or piperidines by thermal or photochemical decomposition of protonated A -haloamines in the presence of strong acid such as sulfuric acid or trifluoroacetic acid. " The Hofmann-Loffler-Freytag reaction may also be carried out in milder conditions, for example, PhI(OAc)2,12, hv as shown in section 2.3.4. 

In 1878, Hofmann reported that treatment of D-l-bromo-2-propylpiperidine (3) with hot sulfuric acid gave rise to a tertiary amine 4, D-octahydroindolizine. In the ensuing decade, Loffler and Freytag extended the reaction to simple secondary amines and found it to be a general way to synthesize pyrrolidines as exemplified by transformation of N-bromo-A-methyl-2-butylaminylpyridine 5 to nicotine (6). The Hofmann-Loffler-Freytag reaction is sometimes referred to as Loffler s method, Hofmann-Loffler reaction, Loffler-Hofmann reaction, as well as Loffler-Freytag reaction. 

Another variation of the Hofmann-Loffler-Freytag reaction involves sulfonamides in place of A-chloroamines. For instance, in the presence of NaaSaOg and CuCb, butylsulfonamide (17) was transformed to 4-chlorobutylsulfonamide (18) and 3-chlorobutylsulfonamide (18) in the absence of an acid. ... 

The Suarez modification of the Hofmann-Loffler-Freytag reaction was review by... 

Not surprising, the most prevalent synthetic utility is the assembly of the pyrrolidine ring. N-Chloroamine 27 was obtained by treatment of N-methyl-2-cyclopentylethylamine (26) with N-chlorosuccinimide. Under classic Hofmann-Loffler-Freytag reaction conditions, 27 was rearranged either thermally or by UV irradiation in sulfuric acid to bicyclic amine... 

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. 

In conclusion, the Hofmann-Loffler-Freytag reaction tends to give moderate and sometimes poor yields for the preparation pyrrolidines under the classic conditions. Nonetheless, the utility of this reaction to functionalize molecules via the aminyl radical mechanism plays an unique role in the tool box for the organic chemist, enabling transformations not easily achievable using other means. Furthermore, milder conditions and better yields can be achieved by taking advantages of the newer developments such as the Suarez modification. 

Prior to 1958, the only well known examples of functionalization at non activated carbon atoms, in a predictable and specific manner, were those where the Hoffmann-Loffler-Freytag reaction was used. 

Electrophilic radical cyclizations of alkenyl aminium cation radicals have shown synthetic utility. Hofmann-Loffler-Freytag reactions do not compete with 5-exo cyclizations (75BSF1429). The homolytic cyclization of Af-chloroalkenylamines under acidic or Lewis acidic conditions has been studied primarily by Surzur and Stella, and the chemistry of these precursors for electrophilic aminyl radical generation has been reviewed [83AG(E)337]. Radical chain reactions can be initiated by heat, UV photol-... 

HYDROGEN-ATOM ABSTRACTION BY NITROGEN-CENTERED RADICALS THE HOFMANN-LOFFLER-FREYTAG REACTION... 

Fig. 26 Titanium-initiated Hofmann-Loffler-Freytag reactions...

An early version was the Hofmann-Loffler-Freytag reaction (Scheme 1). Irradiation of a chloramine in acid leads to formation of the aminium radical, which can abstract a hydrogen to generate a caibon radical. Then the resulting carbon radical abstracts chlorine from another protonated chloramine, producing a chlorinated carbon and regenerating the chain-carrying radical. On treatment with base, the product... 

Scheme 32. Successful preparation of pentacycle 29 [336] via the Hofmann-Loffler Freytag reaction.

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