Neber rearrangements

The Neber rearrangement of oxime sulfonates has been considered to proceed via a nitrene pathway or an anion pathway. If the latter mechanism is operative, the use of a certain chiral base might result in the discrimination of two enantiotropic a-protons to furnish optically active a-amino ketones. Verification of this hypothesis was provided by realizing the asymmetric Neber rearrangement of simple oxime sulfonate 83, 

Entry R Reaction time (h) Yield (%) anti/syn ee (%) (anti) 

The catalyhc asymmetric epoxidahon of electron-deficient olefins, parhcularly a,P-unsaturated ketones, has been the subject of numerous inveshgations, and a 

Chiral monoaza-15-crown-5 derived from D-glucose 92 was shown to be another good catalyst in the asymmetric epoxidation of chalcones with tert-butylhydroper-oxide as the oxidant, with the highest enantioselectivity (94% ee) being reported by Bako (entry 4, Table 11.8) [71]. The tetracyclic C2-symmetric guanidiurn salt 93, which was prepared from (SJ-malic acid by Murphy, also showed excellent enantioselection in the asymmetric epoxidation of chalcone (entry 5) [72]. 

We designed a new and highly efficient chiral N-spiro-type quaternary ammonium salt 73 with dual functions for the asymmetric epoxidation of various enone substrates (entries 5-9, Table 11.8) [73]. The exceedingly high asymmetric induction was ascribable to the molecular recognition ability of the catalyst toward enone substrates by virtue of the appropriately aligned hydroxy functionality, as well as the 

The Neber rearrangement is the transition of an oxime / -toluenesulfonate into an amino ketone under the influence of an alkoxide, e.g.  

A methylene group adjacent to the oxime group is essential for occurrence of the Neber rearrangement. In oximes of unsymmetrical ketones it is the 

The scope of this rearrangement has been expanded by observations of Baumgarten and his colleagues, who found that JV,iV-dichloro amines give amino ketones under the influence of sodium methoxide JV-chloro imides are formed as intermediates and are analogous to the oxime toluenesulfonates. The following scheme illustrates these reactions 60 

A ketoxime tosylate 1 can be converted into an a-amino ketone 2 via the Neber rearrangement by treatment with a base—e.g. using an ethoxide or pyridine. Substituent R is usually aryl, but may as well be alkyl or H substituent R can be alkyl or aryl, but not H. 

The following mechanism is generally accepted, since azirine 3, that has been identified as intermediate, can be isolated  

The ketoxime derivatives, required as starting materials, can be prepared from the appropriate aromatic, aliphatic or heterocyclic ketone. Aldoximes (where R is H) do not undergo the rearrangement reaction, but rather an elimination of toluenesulfonic acid to yield a nitrile. With ketoxime tosylates a Beckmann rearrangement may be observed as a side-reaction. 

Unlike the Beckmann rearrangement, the outcome of the Neber rearrangement does not depend on the configuration of the starting oxime derivative E- as well as Z-oxime yield the same product. If the starting oxime derivative contains two different a-methylene groups, the reaction pathway is not determined by the configuration of the oxime, but rather by the relative acidity of the a-methylene protons the more acidic proton is abstracted preferentially.  

An a-amino ketone, obtained by the Neber rearrangement, can be further converted into an oxime tosylate, and then subjected to the Neber conditions a ,a -diamino ketones can be prepared by this route. 

The net conversion of a ketone into an a-aminoketone via the oxime is known as the Neber rearrangement. 

The reaction begins with conversion of the carbonyl compound (1) to the oxime (2), which is then treated with base to form the 2/f-azirine (3). Subsequent hydrolysis under acidic conditions generates the a aminoketone 

During the course of investigating the Beckmann rearrangement, Neber observed unexpected reactivity of some tosyloximes. When he treated oxime 6 with sodium ethoxide he obtained pyrazine 7, clearly not the result of a Beckmann rearrangement. Furthermore, he learned that by treating 6 with potassium ethoxide followed by acetic acid, the product obtained was aminoacetal 5. Similarly, treatment of 9 with ethanolic ammonia provided pyrazine 10, whereas treatment with potassium ethoxide followed by acid gave the a-aminoketone 8, which could be converted to 10 via treatment with 

It is also important to note that several intermediates in this sequence have been isolated and characterized, further bolstering the mechanistic interpretation. Neber isolated an azirine of type which has been conclusively corroborated. In fact, there are many reports which do not hydrolyse the azirine to the aminoketone, but rather isolate these moieties in good yields (vide supra). Intermediates of type 13 have been isolated, after alkoxide addition to the azirine. Furthermore, the azirine was shown to be non-isomerizing under the reaction conditions, allowing predictable application of this reaction. Finally, it was shown that when two ionizable a-centers are present, deprotonation occurs at the most acidic site.  

Trimethylhydrazonium iodides (16) can be prepared and rearranged. Finally, even oximocarbamates (17) have been reported to undergo Neber- 

Mphahlele, M. J. Phosphorus, Sulfur Silicon Relat. Elem. 1999,144-146, 351. 

aryl R = alkyl, aryl, 0-alkyl, NH2, NH-alkyl R = SO2C6H4CH3, SO2CH3 base NaOEt, KOEt 

The first step of the mechanism is the deprotonation of the O-acylated ketoxime at its a-position, which gives rise to the corresponding enolate. This enolate then can react via two possible pathways 1) a concerted anionic pathway in which the leaving group is directly displaced to give the isolable 2H-azirine or 2) a nitrene pathway that leads to the same 2/-/-azirine intermediate via nitrene Insertion. The nitrene pathway has not been disproved experimentally. 

The chemoenzymatic synthesis of a Ps adrenergic receptor agonist was developed by J.Y.L. Chung and co-workers. The key chiral 3-pyridylethanolamine intermediate was prepared via the Neber rearrangement of the ketoxime tosylate derived from 3-acetylpyridine. The oxime formation and the tosylation were carried out in a one-pot process using pyridine as the solvent. The solution of the ketoxime tosylate in ethanol was then cooled to 10 °C and potassium ethoxide was added. After the TsOK salt was removed from the reaction mixture, HCI gas was bubbled through the solution until the pH reached 2 and the 3-pyridylaminomethyl ketal was isolated as its di-HCI salt. 

The synthesis of optically active 3-amino-2/-/-azirines was carried out using a modified Neber rearrangement in the laboratory of I.P. Piskunova. The optically active amidoximes were acylated using mesyl chloride to give 0-mesyl derivatives that upon treatment with sodium methoxide afforded the desired product with high diastereoselectivity. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 175, Springer-Verlag Berlin Heidelberg 2009 

Richter, J. M. Neber rearrangement. In Name Reactions for Homologations-Part 1 Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 464-473. (Review). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 188, Springer International Publishing Switzerland 2014 

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Important synthetic paths to azirines and aziridines involve bond reorganization, or internal addition, of vinylnitrenes. Indeed, the vinylnitrene-azirine equilibrium has been demonstrated in the case of trans-2-methyl-3-phenyl-l-azirine, which at 110 °C racemizes 2000 times faster than it rearranges to 2-methylindole (80CC1252). Created in the Neber rearrangement or by decomposition of vinyl azides, the nitrene can cyclize to the p -carbon to give azirines (Scheme 4 Section 5.04.4.1). 

One of the more important approaches to 1-azirines involves a similar base-induced cycloelimination reaction of a suitably functionalized ketone derivative (route c. Scheme 1). This reaction is analogous to route (b) (Scheme 1) used for the synthesis of aziridines wherein displacement of the leaving group at nitrogen is initiated by a -carbanionic center. An example of this cycloelimination involves the Neber rearrangement of oxime tosylate esters (357 X = OTs) to 1-azirines and subsequently to a-aminoketones (358) (71AHC-(13)45). The reaction has been demonstrated to be configurationally indiscriminate both syn and anti ketoxime tosylate esters afforded the same product mixture of a-aminoketones... 

The aminoketone 1, required as starting material, can be obtained by a Neber rearrangement from a A -tosylhydrazone. Another route to a-aminoketones starts with the nitrosation of an a-methylene carbonyl compound—often in situ—to give the more stable tautomeric oxime 7, which is then reduced in a subsequent step to yield 1 ... 

The Neber rearrangement has for example found application in natural product synthesis. 

Isolation of an Intermediate. It is sometimes possible to isolate an intermediate from a reaction mixture by stopping the reaction after a short time or by the use of very mild conditions. For example, in the Neber rearrangement (18-12)... 

Miscellaneous PTC Reactions The field of PTC is constantly expanding toward the discovery of new enantioselective transformations. Indeed, more recent applications have demonstrated the capacity of chiral quaternary ammonium salts to catalyze a number of transformations, including the Neber rearrangement (Scheme 11.19a), ° the trifluoromethylation of carbonyl compounds (Scheme 11.19b), ° the Mannich reaction (Scheme 11.19c), and the nucleophilic aromatic substitution (SnAt)... 

Both oximes (10) and their ester (11) or ether derivatives can be used in the classical Beckmann rearrangement and the reaction usually proceeds under acidic or neutral conditions (although basic conditions may also be used). In sharp contrast, only 0-oxime esters can be used as starting materials for the Neber rearrangement and basic conditions are always necessary. The Neber rearrangement is not stereospecific, as the stereochemistry of the starting material E or Z) does not influence the outcome of the reaction. In... 

The Neber rearrangement was discovered in 1926 during the investigation of the Beckmann rearrangement. It was reported that treatment of ketoxime tosylate 517 with potassium ethoxide followed by acetic and hydrochloric acid produced a-amino ketones 518 (equation 231). 

Although both the Beckmann and Neber reactions can use oxime derivatives as starting materials, O-unsubstituted oximes cannot undergo the Neber rearrangement. The latter occurs only in strongly alkaline reaction conditions while the former can also proceed in both acid and basic media. As a consequence, the Neber rearrangement will only be a possible side reaction of base-induced Beckmann rearrangements. 

The Neber rearrangement is usually performed with ketoxime tosylates but ketone trimethylhydrazonium halides (519), iV,iV-dichloro-5ec-alkyl amines (520), N-chloroimines (521) and A-chloroimidates (522) may also be precursors for the reaction. Only the Neber rearrangement of oxime derivatives will be analysed in this chapter. 

Generally, the Neber rearrangement is a base-catalysed conversion of 0-acylated ketoximes 523 (but not aldoximes) to a-amino ketones 525 via an isolable 2//-azirine intermediate 524 (equation 232). The azirine itself may be used as a valuable synthetic tooP and the Neber rearrangement is commonly used to produce it. 

Both cyclic and acyclic ketoximes may be used in this transformation and the reaction is usually performed in an alcohol solution containing equimolar quantities of alkoxide. For a successful reaction, the starting material usually contains at least an a-methylene group but the presence of only one a-hydrogen may suffice. When treated with base the 0-acylated aldoximes do not react via the Neber rearrangement and instead they undergo an E2 elimination to cyanides or isocyanides. 

The Neber rearrangement has been used as a valuable synthetic tool to introduce an a-amino group relative to a ketone and it has been used as a key step in the synthesis of a large array of heterocycles, including imidazoles, oxazoles, isoquinolines and pyrazines and has been reviewed long ago °° . ... 

Similar Neber rearrangements were used to produce 528, an intermediate for an efficient synthesis of 2-imidazol-2-yl acetates 530 (equation 234). Condensation of the a-amino ketals 528 with imidates 529, followed by cyclization in refluxing acidic dioxane, yielded 2-imidazol-2-yl acetates 530 in a one-pot reaction. 

During the total synthesis of Dragmacidin F (537) from quinic acid, Stoltz and col-leagues applied a high-yield late-stage Neber rearrangement to introduce in a completely enantioselective manner an amino group into a complex framework (equation 238). 

Asymmetric induction in the Neber rearrangement was also obtained under phase-transfer conditions with chiral quaternary ammonium bromides 544 as catalysts (equation 243). Moderate enantioselectivities (30-70% ee, 60-95% yield) were observed, but there is still an opportunity for extending the full synthetic utility of this classical rearrangement. 

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