Loffler

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

Loffler-Freitag reaction, 4, 471 Indolizidine, 3-butyl-5-methyl-occurrence, 4, 477... 

LL-Z1220, 7, 192 Local anaesthetics, 1, 178 Loffler-Freitag reaction... 

Unpublished data of General Chemicals Division, Allied Chemical Company. Used by permission, c = critical temperature. No material in SI units appears in the 1993 ASHRAE Handbook—Fundamentals (SI ed.). Tables and a chart to 50 ata, 200 C are given by Mathias, H. and H. J. Loffler, Techn. Univ. Berhn rept., 1966 (42 pp.). A chart to 1500 psia, 500 F was given by Mears, W. H., E. Rosenthal, et al.,y, Chem. Eng. Data, 11, 3 (1966) 338-. l43. 

The Coniceines, CgH jN. Six of these products have been obtained in various ways from the two conhydrines. Their chief characteristics are tabulated below. oL-Coniceine is perhaps the least well-defined of the six it is one component of the mixture resulting from the action of hydrochloric acid on conhydrine, and is described by Loffler (1904) as stereoisomeric with e-coniceine (II). 

P-Coniceine is the chief product of the action of phosphoric oxide on conhydrine and was shown by Loffler and collaborators to be 2-propenylpiperidine, CjHgNH. CH CH. CHg. 

S-Coniceine (2-piperolidine), is prepared by the action of sulphuric acid on bromoconiine. It has a multiplicity of names. Itw, s first characterised by Lellmann, who assigned to it formula (III) and was synthesised by Loffler and Kaim who distilled piperidylpropionic acid to obtain piperolid-2-one (IV) and reduced this to 2-piperolidine (III) which proved... 

Constitution. Pelletierine behaves as a secondary amine and the oxygen atom of the alkaloid is present in the form of an aldehyde group, since the base yields an oxime, convertible by the action of phosphorus pentachloride into a nitrile, b.p. 104-6°/13 mm., which is hydrolysed by caustic potash in alcohol to an acid, the ethyl ester of which is Loffler and Kaim s ethyl -2-piperidylpropionate. Pelletierine is not directly oxidisable to this acid. It also yields a liquid hydrazone, b.p. 130°/20 ram., which with sodium in alcohol at 136-70° reduces to dZ-eoniine. These reactions are explained by the following formulas, in which pelletierine is represented as -2-piperidylpropionaldehyde. 

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... 

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. 

En route to the total synthesis of cinchona alkaloid meroquinene, a Hoffmann-La Roehe group took advantage of the Hofmann-Loffler-Freytag reaetion to funetionalize the ethyl side ehain in piperidine 49 to give ehloroethylpiperidine 51 via the intermediaey of protonated aminyl radieal 50. °... 

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. 

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