Nitrogen Beckmann rearrangement

Another important reaction involving migration to electron-deficient nitrogen is the Beckmann rearrangement, in which oximes are converted to amides.282... 

This, on treatment with sulfuric acid, then undergoes the Beckmann rearrangement to caprolactam. The nitrosyl chloride is made by reacting nitrosyl sulfuric acid (made from oxides of nitrogen and sulfuric acid) with hydrogen chloride gas ... 

The oxime nitrogen can also participate in cycloamination reactions to give pyrroles. Thus, treatment of oxime esters such as 185 with Pd(Ph3P)4 readily affords 186 [129]. The pentafluorophenyl group is necessary for good results otherwise a Beckmann rearrangement can unfavorably enter the picture. The oxime stereochemistry makes no difference on the outcome of the reaction. In addition to 186, pyrroles 187 and 188 were also prepared in this study (among others) [129]. 

Due to its Lewis acidic properties, the use of chloral (trichloroacetaldehyde) in the Beckmann rearrangement was investigated . When a variety of ketoximes is admixed with chloral hydrate and the mixture is heated at low pressure in nitrogen atmosphere, the Beckmann rearrangement afforded the corresponding amides in excellent yields (73-98%). The transformation occurs under neutral, relatively mild and solvent-free conditions. 

A simplified mechanism for the Beckmann rearrangements and important related reactions is shown hi Scheme 9. Summarizing the mechanism section, the key step of the reaction is the migration of an a-carbon group to the electronically deficient nitrogen atom of the oxime. A nitrilium ion in some cases or an imidate in others are key intermediates in the reaction. Their destiny determines the course of the transformation. Basically, three different pathways may be possible and can be synthetically exploited ... 

By this strategy, anilines 299 can be obtained from aromatics ketones 300 (equation 104). The Beckmann rearrangement/hydrolysis sequence is able to replace an acyl group by an amine and has been used in aromatic synthesis to attach directly nitrogen atoms to aromatic rings, providing an alternative strategy to the classical nitration/reduction sequence. 

Imidates, or even nitrogen compounds produced from imidates by the addition of nucleophiles, may be obtained from oximes by a Beckmann rearrangement-addition process. 

Expansions of oximes of B-ring steroid systems are much less common. Recently, during the synthesis of a 6-aza-pregnane derivative 387, the introduction of the nitrogen was made using the Beckmann rearrangement reaction (equation 156). 

Novel 2,6-diazabicyclo[3.2.v]alkan 3-ones (424, n = 1 to 3) were synthesized by the same authors using the Beckmann rearrangement. The insertion of the nitrogen occurred next to the bridgehead atom (equation 179). 

The asymmetric synthesis of (+)-Codeine 432 devised by White and colleagues included a Beckmann rearrangement to introduce the nitrogen atom in the carbocyclic structure (equation 182). Even though two isomeric lactams 430 and 431 were obtained as a result of the rearrangement, the preferential migration of the bridgehead carbon atom produced 430 as the predominant isomer. The synthesis of the non-natural enantiomer of Codeine was completed after oxidation, olefin formation and reduction. 

Recently, racemic 2-azabicyclo[3.2.2]nonanes 437 were synthesized to be tested as /3-glycoside inhibitors (equation 185). Once again the Beckmann rearrangement was selected as the method to introduce selectively the nitrogen atom into the carbocyclic structure. 

Phenethyl ketone oximes have been cyclized by a Beckmann rearrangement to isoquinolines 477 (equation 205), but quinoline derivatives 478 can also be obtained as a result of a formal displacement at the nitrogen atom of the oxime (equation 206). 

Reactions which insert an O or NH group next to a carbonyl can be used to form heterocycles (Scheme 23). The Schmidt reaction or the Beckmann rearrangement can accomplish this for nitrogen, the Baeyer-Villiger oxidation does it for oxygen. For example, cyclohexanone is converted in this way into 2-azepinone and into 2-oxepinone cycloheptanone yields the corresponding eight-membered heterocycles. 

It should be noted that amines may be formed by hydrolysis of amides arising from the intramolecular Beckmann rearrangement of ketoximes (p. 1047) this rearrangement is a further example of the migration of a nucleophilic carbon species from a carbon to an electron-deficient nitrogen. 

The mechanism for this reaction, shown in Figure 22.6, proceeds via an allowed [1,2] sigmatropic rearrangement to an electron-deficient nitrogen. Another example of the Beckmann rearrangement is provided in the following equation ... 

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