Hofmann-Loffler reaction

The Hofmann-Loffler Reaction has been used most frequently with secondary amines, but can be applied to primary amines as well. ... 

Hecogenin p-toluenesulfonylhydrazone, 402 Hofmann-Loffler reaction, 257 Homoallylic rearrangements, 379 A-homo-5a-cholestan-3-one, 356, 358, 362 A-homo-5a-cholestan-4-one, 359, 360, 368 A-homo-choIest-4a-en-3-one, 366 A-homo-estra-1(10), 2,4a-triene-4,17-dione, 367,370... 

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. 

This mechanism is similar to that of the Hofmann-Loffler reaction (18-40). 

This reaction takes place only when the methyl group is in a favorable steric position.The mechanism is similar to that of the Hofmann-Loffler reaction. ... 

One example of this type of reaction is the photolytically initiated decomposition of N-chloroamines in acidic solution, which is known as the Hofmann-Loffler reaction,208 The initial products are d-chloroamines, but these are usually converted to pyrrolidines by intramolecular nucleophilic substitution. 

Steps similar to the Hofmann-Loffler reaction are also involved in cyclization of N-alkylmethanesulfonamides by oxidation with Na2S204 in the presence of cupric ion.210... 

Many synthetic methods have been reported for the pyrrolidine alkaloids, including procedures based on the Hofmann-Loffler reaction 132,412), the metal hydride reduction of pyrrolines 413,414), the a-alkylation of N-nitro-sopyrrolidine 412,415), the catalytic hydrogenation of pyrroles 133), the reductive amination of 1,4-diketones 25,138), the direct alkylation of 1-methoxy-carbonyl-3-pyrroline 416), the versatile synthesis from the Lukes-Sorm dilac-... 

M.E. Wolff, Chem. Rev. 63, 55-64 (1963) . .Cyclisation of N-Halogenated Amines (The Hofmann-Loffler Reaction)". 

It is sometimes possible to combine a radical reaction with a heterolytic process to achieve a synthetically useful result, as in the Hofmann-Loffler reaction (Scheme 16).200... 

The venom of the fire ant, Solenopsis punctaticeps, contains several 2,5-dialkyl-pyrrolidines and -pyrrolines their structures have been settled by combined g.c-m.s., and confirmed by syntheses employing the Hofmann-Loffler reaction on the corresponding primary amines.7 A new synthesis of 2,5-dialkyl-pyrrolidines via lithiated iV-nitrosopyrrolidine and two stages of alkylation, followed by removal of the nitroso-group, should be applicable to the synthesis of the venom components. The major products are trans in stereochemistry.8... 

Certain 2,5-dialkyl-pyrrolidines, which are trail pheromones of the pharaoh ant (Monomorium pharaonis L.), have been synthesized by application of the Hofmann-Loffler reaction to 5-aminotridecane and 7-aminopentadecane. The same type of compound results from Seebach alkylation of TV-nitrosopyrrolidines.4... 

In a study of the Hofmann-Loffler reaction, the jV-chloro-amine (8a) was irradiated in trifluoroacetic acid solution and underwent photolysis to yield the pyrrolidine (9a) together with the 205-isomer (9b) in a ratio 8 1. The starting amine (8b) was prepared by hydrogenation of (8c), followed by von Braun demethylation and hydrolysis of the JV-cyano-amine (8d) which was so formed. The n.m.r. spectrum of (8b) and of related amines in the presence of lanthanide shift reagents was discussed.10... 

In the Hofmann-Loffler reaction an A-alkyl-A-haloamine is heated under acidic conditions to give the/V-alkyl-pyrrolidine or A-alkyl-piperidine product. A related process is the Barton reaction, in which a methyl group that is 5 to a hydroxyl group is oxidised into an aldehyde. 

Cyclisation of M-halogenated amines. (The Hofmann-Loffler reaction) , Wolff, M. E., Chem. Rev., 1963, 63, 55. 

The oldest synthetic reaction which involves //-centered radical intermediates is the so-called Hofmann-Loffler reaction [21]. When //-haloalkylamines 8 are heated or photolyzed in strongly acidic solution, pyrrolidines 12 are isolated upon basic workup (Scheme 2). Ferrous salts can also promote the reaction [22]. 

In contrast, aminyl radicals complexed to metal ions, such as neutral aminyl radicals, do not undergo Hofmann-Loffler reaction. The Hofmann-Loffler reaction is unable to compete with intramolecular aromatic amination, with intramolecular addition to olefins, and with intermolecular addition to dienes [7],... 

The Hofmann-Loffler reaction, namely, cyclization of iV-halo derivatives of secondary aliphatic amines,406 is a method of intramolecular amination ... 

Coleman and Goheen409 found it better to use iV-chloro amines rather than the A-bromo compounds for synthesis of pyrrolidines and in this way achieved yields of around 75% of substituted pyrrolidines. The method has also proved valuable for synthesis of bicyclic tertiary amines.410"412 Schmitz413 applied it to N,N-dibromo derivatives of primary amines from iV,JV-dibromo-l-propylbutylamine he obtained pyrrolizidine in 35% yield,414 the best yields being obtained here, as in other cases,412 415 416 when the reaction is carried out with irradiation in ultraviolet light. Recently ring closure was also achieved with JV-monochloro derivatives of primary amines 417 pyrrolidine (70%) was obtained from butylamine, 2-methylpyrrolidine (80%) from pentylamine, and 2-propylpyrrolidine (50% and 70%, respectively) from heptylamine or 1-pro-pylbutylamine.417 The mechanism of the Hofmann-Loffler reaction has been discussed by Wawzonek and Culbertson.416... 

Indoles are obtained by specific cyclizations (Fischer synthesis, Reissert synthesis, Batcho-Leimgruber synthesis, Nenitzescu synthesis), as are carbazoles from biphenylene or diphenyl-amines and pyrrolidines (Hofmann-Loffler reaction). 

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