Loffler-Freytag pyrrolidine

Loffler-Freytag pyrrolidine ring closure, with prim, amines, s. 17, 565... 

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. 

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... 

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. 

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). 

Hofmann-Loffler-Freytag reaction. Formation of pyrrolidines or piperidines by thermal or photochemical decomposition of protonated /V-ha-loam ines. 

A very neat method for the synthesis of pyrrolidines does not require a difunctionalised starting material, but relies on the Hofmann-Loffler-Freytag reaction - which is a radical process - to introduce the second functional group. The six-membered size of the cyclic transition state leads selectively to a 1,4-halo-amine, and thence to pyrrolidines. 

The history of C-H amination can be traced to the earliest work of Hofmann involving the reactivity of /V-bi omoamines. chemistry later recognized by Loffler and Freytag for its potential to facilitate pyrrolidine synthesis from simple acyclic precursors [11]. The intermediacy of both haloamine and aminyl radical in this stepwise oxidation reaction is now generally accepted, as is the hyper-reactivity of... 

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