Beckmann rearrangement transform

Lasubines I and II are alkaloids containing a 4-arylquinolizidine substructure that have been isolated from plants of the Lythraceae family and have attracted the attention of synthetic chemists for some time. While numerous racemic syntheses of these and related compounds have been reported, only a few enantioselective syntheses are known. Some examples of these syntheses are given below, and the strategies involved in these examples are summarized in Scheme 92. Three of these syntheses involve the creation of the quinolizidine system by formation of one bond at the a- or 7-positions, while the fourth approach is based on a ring transformation associated with a photochemical Beckmann rearrangement. 

Ozonolysis of alkene 446 in the presence of acetaldehyde afforded diketone 448 through the intermediacy of 447. Ring expansion through Beckmann rearrangement took place when bis-oxime 449 was mesylated and warmed in aqueous tetrahydrofuran (THF). The bis-lactam so formed gave piperidinediol 450 on reduction with lithium aluminium hydride, and this compound was transformed into ( )-sparteine by treatment with triphenylphosphine, CCI4, and triethylamine (Scheme 105) <20050BC1557>. 

The transformation of oximes to lactams (the Beckmann rearrangement) was one of the earliest such acid-catalyzed reactions to be reported with TS-1 (138) and TS-2 (247) catalysts. The rearrangement of cyclohexanone oxime to e-caprolactam proceeds with high selectivity in the presence of TS-1, with high catalyst stability (138,247). 

The previous referred inconveniences have prompted an increasing interest in the development of alternative, essentially neutral and more environmental-friendly catalysts to promote the rearrangement of O-unsubstituted oximes. The development of highly efficient and selective transformations and also of processes for catalyst recovery and its reuse are the aim of some of the more recent studies. Much of this work is being done in industry to improve current production processes and is the subject of new patent applications. During the last two decades environment concerns have led to the development of green, simple and cost-effective catalytic systems for the Beckmann rearrangement. 

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 ... 

Fragmentation of the intermediate or concerted formation of nitriles from the activated oxime (Scheme 9, pathway 3) this is the Beckmann fragmentation. In some circumstances this pathway becomes dominant, particularly when there are quaternary carbons adjacent to the oxime. This transformation has found particular utility in ring-cleavage processes (sometimes called abnormal or second-order Beckmann rearrangements). 

Pathway 2 of Scheme 9 corresponds to one of the most interesting developments in the Beckmann rearrangement chemistry. By trapping of the electrophilic intermediate with a nucleophile (Nu ) other than water, an imine derivative 227 is produced that may be used for further transformations. Carbon or heteroatom nucleophiles have been used to trap the nitrilium intermediate. Reducing agents promote the amine formation. More than one nucleophile may be added (for example, two different Grignard reagents can be introduced at the electrophilic carbon atom). Some of the most used transformations are condensed in Scheme 11. 

When the nucleophile is already present as a part of the starting oxime (for example, a heteroatom or a C=C double bond), intramolecular trapping of the electrophilic intermediate is possible and a new cycle is formed. This transformation is usually referred to as a Beckmann Rearrangement-Cychzation reaction. Two modes of ring closure may be possible, depending on the oxime structure (equations 111 and 112) ... 

Some other syntheses of y-lactams by the Beckmann rearrangement were also tested without great success, the nitrile being the major product of the transformation (equations 130 and 131). 

The most important route is the conversion of pyrimidines into 1,3,5-triazines. The first one-step transformation was effected by Taylor and Jefford (62JA3744) by heating the pyrimidine (179) with benzenesulfonyl chloride in pyridine (equation 106). The reaction may be considered as an example of an abnormal Beckmann rearrangement. The mechanism of the reaction of the 4-aminopyrimidine (180) is probably dependent on the nature of the 2-substituent (180, R). If R is an electron-releasing moiety, pathway B seems more likely (Scheme 109). The 4-hydroxypyrimidine (179 R = OH) behaves similarly. Many 2-cyano-1,3,5-triazines may be synthesized by this method. 

Another transformation that has received considerable interest is the Beckmann rearrangement. Traditionally, this process requires the presence of a strong acid with heating at high temperatures over extended periods of times. It therefore represents an... 

Six-membered rings can also serve as precursors to seven-membered rings by ring-transformation processes. Thus, Beckmann rearrangement of 308 selectively afforded the azepinones 309 (e.g., R=R = R2 = H, R3 = Me 50%) (Equation 45) <1998JGM198>, while reaction of 310 with azide gave the azido azepine 311 (Equation 46) <1998H(48)427>. 

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