Meerwein-Wagner rearrangements

Wagner-Meerwein rearrangement and related reactions 1. Wagner-Meerwein rearrangement3b 

Wagner-Meerwein rearrangements comprise reorganization of the carbon skeleton in eliminations that lead to olefins, in additions to multiple bonds, and in nucleophilic substitutions. Their common characteristic is that after or during formation of an electron deficiency on a carbon atom an alkyl or aryl group moves to that site from a neighboring carbon atom. The electron deficiency can occur as follows  

After a substituent has moved from a neighboring carbon atom to the site of the electron deficiency, the rearranged cation becomes stabilized by addition of an anion or loss of a proton, e.g.  

Formally there has been an interchange of positions between alkyl and halogen or hydroxyl groups. 

The steric course at the carbon atom from which the leaving group departs is between the extremes of complete Walden inversion and complete racemiza-tion the same is true for the carbon atom from which the migrating group departs but the migrating group always retains its configuration.139 

The research team of G. Prater investigated the acid catalyzed rearrangement of p-monocyclofamesol for the synthesis of tricyclic ketones with sesquiterpene skeleton. The substrate p-monocyclofamesol, prepared from dihydro-P-ionone in two steps, was exposed to concentrated formic acid, which resulted in the formation of a mixture of three different formates. 

The Wagner-Meerwein rearrangement was one of the key steps in the total synthesis of (+)-quadrone by A.B. Smith and co-workers. The propellane substrate was treated with 40% sulfuric acid, which resulted in the [1,2]-alkyl shift of the initially formed cyclobutylcarbinyl system. 

Skeletal rearrangements of carbenium ion species 2, that involve nucleophilic 1,2-migrations of alkyl groups, are called Wagner-Meerwein rearrangements 

In an initial step the carbenium ion species 2 has to be generated, for example by protonation of an alcohol 1 at the hydroxyl oxygen under acidic conditions and subsequent loss of water. The carbenium ion 2 can further react in various ways to give a more stable product—e.g. by addition of a nucleophile, or by loss of a proton from an adjacent carbon center the latter pathway results in the formation of an alkene 3. 

In the case of an appropriate substrate structure, the carbenium ion species can undergo a 1,2-alkyl shift, thus generating a different carbenium ion—e.g. 4. The driving force for such an alkyl migration is the formation of a more stable carbenium ion, which in turn may undergo further rearrangement or react to a final product by one of the pathways mentioned above—e.g. by loss of a proton to yield an alkene 3  

Named Organic Reactions, Second Edition T. Laue and A. Plagens 2005 John Wiley Sons, Ltd ISBNs 0-470-01040-1 (HB) 0-470-01041-X (PB) 

Of synthetic importance is the Wagner-Meerwein rearrangement especially in the chemistry of terpenes and related compounds. For example isoborneol 5 can be dehydrated and rearranged under acidic conditions to yield camphene 6  

In 1899, Wagner published The Strueture of Camphene, in which he challenged the accepted structure of the bicyclic monoterpene camphene that had been proposed by his contemporaries. He stipulated that the acid-catalyzed dehydration of bomeol (1) resulted from a skeletal rearrangement to give camphene (2), a structure unique from its precursor. 

What followed were decades of investigation to determine the mechanism through which such a rearrangement would occur. Notably, the work of Meerwein and van Emster demonstrated the presence of a cationic intermediate that preceded the 1,2-alkyl migration. Through his studies of equilibrium isomerism of bomyl chloride, camphene hydrochloride (3), and isobomyl chloride (6), Meerwein established that the rearrangement mechanism relied on ionization, and exhibited a heavily solvent-dependant kinetic profile. These studies, which laid the foundation for modem 

While only an ancillary topic in this discussion, the nonclassical ion controversy, extensively reviewed elsewhere,has a foundation in the historical context of the Wagner-Meerwein rearrangement. After completing a solvolytic study of structurally similar exo- and e cto-2-norbomyl brosylates, Winstein and Trifan suggested that the reaction s cationic intermediate was instead a o-delocalized, symmetrically bridged norbomyl ion 9. This concept deviated from the accepted classical cation structure proposed by Meerwein as the equilibrium between 7 and 8, where the positive charge was considered to be localized on a single atom. 

This intermediate was postulated as a result of several facts regarding the acetolysis of 2-norbomyl arenesulfonates. First, the exo-isomer reacts more rapidly than the corresponding e t/o-isomer, presumably from heightened levels of anchimeric assistance. Regardless of which isomer endolexo) is utilized as the reactant, the exo-acetate is produced exclusively. Finally, optically active exo-starting materials react to give complete 

A major opponent of this nonclassical ion intermediate was Brown,who published dissenting views throughout the latter half of the twentieth century. He insisted on the existence of a rapid equilibrium between the two classical carbocation forms facilitated via Wagner-Meerwein rearrangement. Exo- and endo-T tQ ratios were attributed to steric effects, as strain caused e (3to-isomers to exhibit more hindrance to ionization. Finally, Brown criticized the bridged intermediate model for not providing sufficient electrons for all bonds.  

Acid-catalyzed alkyl group migration of alcohols to give more substituted olefins. 

Cerda-Garcia-Rojas, C. M. Flores-Sandoval, C. A. Roman, L. U. Hernandez, J. D. Joseph-Nathan, P. Tetrahedron 2002, 58, 1061. 

Name Reactions, 4lh ed., DOI 10.1007/978-3-642-01053-8 264, Springer-Verlag Berlin Heidelberg 2009 

Mullins, R. J. Grote, A. L. Wagner-Meerwein rearrangement. In Name Reactions for Homologations-Part II Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 373-394. (Review). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 283, Springer International Publishing Switzerland 2014 

Wagner, G. J. Russ. Phys. Chem. Soc. 1899, 31, 690. Wagner first observed this rearrangement in 1899 and German ehemist Hans Meerwein unveiled the mechanism in 1914. 

Garcia Martinez, A. Teso Vilar, E. Garcia Fraile, A. Martinez-Ruiz, P. Tetrahedron 2003, 59, 1565. 

Conversion of azoxy compounds to p-hydroxy azo compounds upon treatment with acid. 

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Oxabicyclo[2.2.1 ]heptyl 2-cation Wagner-Meerwein rearrangement, 1, 418... 

A mechanism for formation of the first product by Wagner-Meerwein rearrangement has been proposed. ... 

Dehydration to olefins, which sometimes accompanies the reaction of alcohols with DAST [95, 108], is seldom as extensive as with a-fluoroamines (FAR and 1,1,2,3,3,3 hexafluoropropyldiethylamine) but occurs in a few cases to the exclusion of fluonnation, thus, 9a-fluoro-11-hydroxysteroids give 9a fluoro-A -steroids [127, 128] Dehydration accompanied by Wagner-Meerwein rearrangement occurs during the fluonnation of testosterone [129] Intermolecular dehydration to form ethers in addition to fluorides is observed in the reaction of benzhydryl alcohols [104] (Table 6)... 

From 5 the formation of alkene 2 is possible through loss of a proton. However, carbenium ions can easily undergo a Wagner-Meerwein rearrangement, and the corresponding rearrangement products may be thus obtained. In case of the Bamford-Stevens reaction under protic conditions, the yield of non-rearranged olefins may be low, which is why this reaction is applied only if other methods (e.g. dehydration of alcohols under acidic conditions) are not practicable. 

Except for terpene chemistry, the Wagner-Meerwein rearrangement is of limited synthetic importance. It is rather found as an undesired side-reaction with other reactions, for example in the synthesis of alkenes by elimination reactions. 

Diazomethanc undergoes addition of xanthylium perchlorate to afford dibenz[6,/]oxepin (4).193 The formation of this product can be rationalized by a carbenium ion that undergoes a Wagner Meerwein rearrangement. 

The formation of the isocorrolecarbaldehyde 5 may be best explained if one invokes 1,2-diol 4 as an intermediate of the McMurry coupling which would then react in a titanium(IV) chloride induced Wagner-Meerwein rearrangement to yield the isocorrole 5 as a minor product during... 

Addition of bromine to 1 in chloroform solution at 10°C led in high yield to the formation of the exo-5-a/ih -7-dibromide 2. No other products were isolated. The formation of this rearranged product can be explained in terms of Wagner-Meerwein rearrangement where migration of the aryl group is involved (eqn. 1). 

Wagner-Meerwein rearrangements were first discovered in the bicyclic terpenes. 

It was mentioned above that even alkanes undergo Wagner-Meerwein rearrangements if treated with Lewis acids and a small amount of initiator. An interesting application of this reaction is the conversion of tricyclic molecules to adamantane and its derivatives. It has been found that all tricyclic alkanes containing 10 carbons are converted to adamantane by treatment with a Lewis acid such as AICI3. If the substrate contains more than 10 carbons, alkyl-substituted adamantanes are produced. The lUPAC name for these reactions is Schleyer adamantization. Two examples are... 

Wagner-Meerwein rearrangements to give cyclic products... 

One of the most characteristic properties of carbonium ions is their great tendency to undergo rearrangements. These rearrangements include 1,2-alkyl shifts, hydride shifts, cyclopropylcarbinyl rearrangements, Wagner-Meerwein rearrangements, and others. 

Hogeveen, H., and van Kruchten, E. M. G. A. Wagner-Meerwein Rearrangements in Long-lived Polymethyl Substituted Bicyclo[3.2.0]heptadienyl Cations. 80, 89-124 (1979). 

Cram, D. Studies in Stereochemistry. I. The Stereospecific Wagner-Meerwein Rearrangement of the Isomers of 3-Phenyl-2-butanol. J. Amer. chem. Soc. 71, 3863 (1949). 

An elimination/double Wagner-Meerwein rearrangement process has recently been developed by Langer and coworkers [39]. Treatment of compound 1-136, obtained by reaction of 1-134 and 1-135, with trifluoroacetic acid (TFA) led to the cationic species 1-137, which then underwent a twofold Wagner-Meerwein rearrangement to give the bicydic compound 1-139 via 1-138 (Scheme 1.34). 

Scheme 1.34. Domino elimination/double Wagner-Meerwein rearrangement reaction.

Reactions. Part. I. The Mechanism of the Wagner-Meerwein Rearrangement. Exchange of Radioactive Chlorine and of Deuterium between Camphene Hydrochloride and Hydrogen Chloride. J. chem. Soc. [London] 1939, 1188. 

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