The Hofmann-Loffler-Freytag Reaction

The thennal or photolytic decompositions of N-halogenated amines in acid (H2SO4 or CF3CO2H) solutions followed by basification of the reaction mixture to produce pyrrolidines or in some cases piperidine derivatives are known as the Hofinann-Ldffler-Freytag(HLF) reactions. For example, N-chlorobutylamine 23 gives N-butylpyrrolidine 24 [17]. 

When an N-halogenated amine contains two 6 carbons, the abstraction of hydrogen atom preferably takes place from secondary and tertiary 8-carbons. For example, N-chloro N-butyl N-pentyl amine 25 gives only l-n-butyl-2-methylpyrrolidine 26. 1-Amylpyrrolidine 27 is not detected. 

Loffler reported the synthesis of alkaloid nicotine 30 using this reaction [20]. 

This reaction has been used extensively for introduction of functionality in different classes of nitrogen heterocycles. For example, this reaction has been used in the synthesis of alkaloid, N-methylgranatinine 31 from N-chloro-N-methylcyclooctylamine 32 [21] and in a key step in the synthesis of steroidal alkaloid, dihydroconessine 33 [22]. 

The HLF reactions have been applied in the synthesis of different classes of organic compounds using usual acidic medium. The following examples [23-28] are illustrative  

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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... 

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. 

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

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.

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 Hofmann-Loffler-Freytag reaction involves a 1,5-hydrogen transfer to a nitrogen atom. This reaction has been reviewed [61-63], and a recent update is available [35] (see also Chapter 5.1, Volume 2). Its mechanism has been investigated [64], and the formation of an aminium radical has been postulated (Scheme 12). The strong... 

Transformations arising by photoinduced nitrogen-chlorine bond homolysis have again been observed. The Hofmann-Loffler-Freytag reaction of A-chloro-L-amino-acids, for example, affords 5-chlorinated intermediates which can be cyclized to L-prolines, and the yV-chloroamine (195) is converted on irradiation... 

A compound with 2,6-diaza-adamantane structure (diradical 106) was described for the first time in 1969 by Rassat. The Hofmann-Loffler-Freytag reaction of the bi-... 

A modification of the Hofmann-Loffler-Freytag reaction that avoids the harshly acidic conditions described above has been developed. The A-iodo compound is generated by reaction with iodine and iodobenzene diacetate. Warming or irradiating the reaction mixture promotes the formation of the lutrogen-centred radical and hence subsequent remote hydrogen atom abstraction. The reaction is particularly effective with carboxylic amides, sulfonamides or phosphoramidates, as illustrated in the transannular cyclization to give the indolizidine 20 and in the formation of the bicyclic produet 21 (4.21,4.22). ... 

Other references related to the Hofmann-Loffler-Freytag reaction are cited in the... 

The best known intramolecular free radical reactions probably are the 1,5-hydrogen abstractions by alkoxyl or aminium radicals used in selective functionalization. The first, known as the Barton reaction, has been reviewed, " as has the second one, the Hofmann-Loffler-Freytag reaction. Synthetic uses and mechanistic aspects of intramolecular homolytic aromatic substitution have also been reviewed recently. " ... 

On the other hand, if the halogen is y to a fully alkylated nitrogen and on a fully alkylated carbon, thermal decomposition (Scheme 10.17) can intrude (the Hofmann-Loffler-Freytag reaction) with (after hydrolysis) formation of a ketone and an alkene. 

Expanding on the Hofmann-Loffler-Freytag reaction (see Section 2.2.3), the Baran group developed a conversion of an alcohol into an A -bromocarbamate 7, irradiation of which, in the presence of silver carbonate, selectively functionalizes the most substituted C—H bond beta to the alcohol, ultimately generating a 1,3-diol 8 after cyclization and subsequent hydrolysis. ... 

Azabicyclo[3,2,l]octanes and 2-azabicycIo[3,3,l]nonanes have been prepared by the intramolecular cyclization of A -chloroamines with trifluoroacetic acid. This interesting variation of the Hofmann-Loffler-Freytag reaction is regioselective the dioxolanes react in an open chain form, and the reactions take a different course when the starting materials are photolysed (Scheme 108). ... 

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