The hofmann loffler reaction also referred to as hofmann loffler freytag reaction, loffler freytag reaction, loffler hofmann reaction, as well as lofflers method is an organic reaction in which a cyclic amine 2 pyrrolidine or, in some cases, piperidine is generated by thermal or photochemical decomposition of nhalogenated amine 1 in the presence of a strong acid. Files are available under licenses specified on their description page. Advanced free radical reactions for organic synthesis 1st. Role of substituents in the hofmannlofflerfreytag reaction. The hofmann loffler freytag hlf reaction and related transformations the hlf reaction can be considered as the very first example of a directed sp 3 ch insertion. Catalytic alkylation of remote ch bonds enabled by proton.
The hofmannlofflerfreytag hlf reaction can be successfully used to synthesize saturated heterocyclic nitrogencontaining naturederived. In this study the ratedetermining hydrogen atom transfer hat step in nicotine synthesis has been analyzed using quantum chemical methods. Electrophotocatalytic diamination of vicinal ch bonds. Wawzonek, who studied cyclization reactions of various nhalogenated amines. Many experimental evidences support the radical mechanism of this reaction, such as the initiation of the reaction by either photo. The latter process, a subset of the wellknown hofmannlofflerfreytag hlf reaction, relies on a favorable. Hofmann loffler reaction the hofmann loffler reaction also referred to as hofmann loffler freytag reaction, loffler freytag reaction, loffler hofmann reaction, as well as lofflers method is an organic reaction in which a cyclic amine 2 pyrrolidine or, in some cases, piperidine is generated by thermal or photochemical decomposition of nhalogenated amine 1 in the presence. Loffler manifold with amidyl radicals as the sole mediators to induce selective 1,5. Chemoselective intramolecular functionalization of methyl. The hofmann loffler freytag hlf reaction can be successfully used to synthesize saturated heterocyclic nitrogencontaining naturederived pharmaceuticals such as nicotine and its derivatives. Jul 26, 2016 the hofmannloffler reaction also referred to as hofmannlofflerfreytag reaction, or hlf reaction is an organic transformation in which a cyclic amine pyrrolidine or, in some cases, piperidine is generated by thermal or photochemical decomposition of nhalogenated amine in the presence of a strong acid typically concentrated sulfuric acid or concentrated tfa. Franklandduppa reaction freund reaction freytag see hofmann loffler freytag reaction friedelcrafts reaction friedlaender synthesis fries rearrangement fritsch see pomeranzfritsch reaction fritschbuttenbergwiechell rearrangement fujimotobelleau reaction gabriel isoquinoline synthesis gabriel ethylenimine method. Hofmannloffler reaction reaction mechanism mechanistic. Review reactions of carbon radicals generated by 1,5.
Accordingly, the selective, sulfamate esterguided chlorination of remote csp3h bonds has been developed. Zerner zindo 1991 martin gouterman chicago, 1959 john h. H directed reaction was derived from the radicalbased mechanism of the hofmann loffler freytag reaction. Chiral piperidines from acyclic amines via enantioselective, radical. Seaborg discovery of elements 94 1940, 95 1944, 96 1944, 97 1949, 98 1950. Add a oneline explanation of what this file represents. Inorganic chemistry organic chemistry hydrogen atom radical cation reaction formation these keywords were added by machine and not by the authors. Physical properties of aziridine h h n h h o h h h 109. Jan 01, 1981 the similarity and apparent sitespecificity of the initial steps of the slow on the mass spectrometer time scale intramolecular reactions of amine cation radicals in the gasphase and in solution suggests that the hofmann lfler freytag reaction is another condensedphase reaction that has a mass spectrometric counterpart. This ch alkylation represents a catalytic variant of the hofmann loffler freytag reaction, using simple, unfunctionalized amides to direct the formation of new cc bonds. However, reaction of nchloroisoquinuclidine with silver ions has the character of a heterolytic. Nov 02, 2012 one such example is the hofmann loffler freytag reaction, which provides a method for the synthesis of pyrrolidines from nhalogenated amines.
Targeted derivatization of medicines via novel c h. Unlike other books on name reactions in organic chemistry, name reactions, a collection of detailed reaction mechanisms and synthetic applications focuses on the reaction mechanisms. Accordingly, a variety of ch amination reactions have been devised, ranging from classic transformations such as the hofmann loffler freytag reaction to modern methods that involve transition metal or photoredox catalysis 2, 3. Rearrangement and hydrogen abstraction reactions of amine. Aug 01, 2012 this page was last edited on 21 april 2014, at 22. Radical transpositions from a carbon to a carbon atom involving a 1,5hydrogen transfer 5. An iodinecatalyzed hofmannloffler reaction request pdf.
Niodosuccinimidepromoted hofmannloffler reactions of. Given the prevalence of amides in pharmaceuticals and natural products, we anticipate that this method will simplify the synthesis and structural elaboration of amine. Electrophotocatalytic diamination of vicinal ch bonds science. Mechanism, references and reaction samples of the hofmannlofflerfreytag reaction. The book usefully provides experimental details for the most important reactions as well as numerous references to the original literature. Facile synthesis of tertiary aliphatic amine containing. Cyclization of nhalogenated amines the hofmannloffler reaction. Curtius was born into a scholarly family at duisburg, and entered heidelberg university to study music and science. Interrupted hofmannlofflerfreytag reaction entailing enantioselective cc formation. The reaction is effected by warming a solution of the halogenated amine in strong acid e.
As a way of generalizing this protocol to medicines, it has been sought to exclude the harsh halogenation typically required for the sequential 1,5hydrogen shift and cyclization. Sep 15, 2010 the synthesis of pyrrolidine or piperidine derivatives by thermal or photochemical decomposition of the protonated aliphatic n. In 1949, wawzonek and thelan reported that a solution of nchloronmethylcyclooctylamine 7 in. It covers over 320 classical as well as contemporary name reactions. The synthesis of pyrrolidine or piperidine derivatives by thermal or photochemical decomposition of the protonated aliphatic n. Although powerful, these transformations typically require oxidative nprefunctionalization of the amide starting materials to achieve efficient amidyl generation. Early works on ch amination hofmann loffler freytag reaction hofmann, 1885 loffler and freytag, 1909 radical mechanism 2 hofmann, a. The mechanism of the hofmann loffler freytag reaction was first investigated by s. Moreover, in the reactions, the amine or amide compounds need to be converted to the. All structured data from the file and property namespaces is available under the creative commons cc0 license. Despite the power and scope of these advances, the vast majority of such methods result in the transformation of.
The hofmann loffler reaction also referred to as hofmann loffler freytag reaction is an organic reaction in which a cyclic amine pyrrolidine or, in some cases, piperidine is generated by thermal or photochemical decomposition of nhalogenated amine in the presence of a strong acid typically concentrated sulfuric acid or concentrated. Preface 4cc acetoacetic ester condensation acyloin. Niodosuccinimide is the only required promoter for this transformation, which is conveniently initiated by visible light. An iodinemediated hofmann loffler freytag reaction of sulfoximines leading to dihydroisothiazole oxides. Stereoselective synthesis of nalkylaziridines from n. Hofmannlofflerfreytag reaction anthony crasto organic. Recently, the application of hofmannlofflerfreytag hlf type 1,5hydrogen atom transfer. Hofmannlofflerfreytag reaction radical chemistry youtube. Using substrate geometry to dictate the site of ch. Large number of new reagents, reactions and rearrangements these are. Feb 15, 2019 the hofmann loffler freytag hlf reaction is a prototypical example of radicalbased remote functionalization of unactivated csp 3h bond. The overall transformation provides pyrrolidines under. Schematic representation of the hofmannlofflerfreytag reaction.
Coppercatalyzed remote c sp 3 h azidation and oxidative. One such example is the hofmann loffler freytag reaction, which provides a method for the synthesis of pyrrolidines from nhalogenated amines. Hofmann rule 1851, benzidine rearrangement 1863, hofmann elimination 1881, hofmann martius rearrangement 1871, hofmann loffler freytag reaction 18831909 floryhuggins theory 1942. Study documents, essay examples, research papers, course.
H2so4 or cf3cooh, or by irradiation of the acid solution with ultraviolet light. Advanced free radical reactions for organic synthesis. Request pdf hofmannlofflerfreytag reaction formation of pyrrolidines or piperidines by thermal or photochemical decomposition of protonated nhaloamines. The hofmannlofflerfreytag reaction proceeds via an intramolecular hydrogen atom transfer to a nitrogencentered radical and is an example of a remote. Hofmann loffler freytag reaction the baran lab has now introduced a hlf variation allowing for the synthesis of a 1,3diol from the corresponding monool doi illustrated here with the conversion of menthol to isopulegol hydrate. N h cl hn ior fei h n h n h h n h h cl basic workup n neale, r. Protonated aminyl radicals hofmannlofflerfreytag reaction. Multiple halogenation events of up to four innate c. Visiblelight promoted regioselective amination and alkylation of. Richter nitrogen centered radicals 33104 group meeting selected transformations. Reactions of chloramines with ag0 and agi states canadian. Baylishillman reaction, bucherer reaction, coreyposner and whitesideshouse synthesis, coreysuggs oxidation, dessmartin reagent, dienonephenol rearrangement, friedlander synthesis, hallerbauer reaction, heck reaction, hofmann loeffler. Jul 18, 2018 the hofmann loffler freytag reaction, discovered more than a century ago, uses in situ generated bromo amines for remote radical c.
For more on barton mccombie deoxygenation radical abstraction reactions this video, i discussed about a. For more on barton mccombie deoxygenation radical abstraction reactions s. New methods for the synthesis of sulfamate esters have facilitated access to these valuable functional motifs, thereby allowing their use in hofmann loffler freytag reactions. Although the reaction was first reported in 1883, its mechanistic details were not fully understood until late 1950s. Advances in selectivity of the suzukimiyaura and hofmann. This process is experimental and the keywords may be updated as the learning algorithm improves. Conditions for an attractive and productive protocol for the positionselective intramolecular ch amination of aliphatic groups hofmann loffler reaction are reported employing sulfonimides as nitrogen sources. In this study the ratedetermining hydrogen atom transfer hat step in nicotine synthesis has been analyz. Hofmann loffler freytag hofmann loffler freytag reaction,hlf, hofmann loffler hofmann loffler reaction. Recently, the application of hofmann loffler freytag hlftype 1,5hydrogen atom transfer 1, in csp 3 h functionalization reactions received much attention due to their unique. Radicalmediated methyl iodination and subsequent oxidative deiodination are the key steps in this functionalization, where iodine chemistry has a pivotal role on the formation of the cn bond. A manual for csirugc national eligibility test for lectureship and jrfnamed reactions hofmann lofforfreytage reaction.
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