Quaternary ammonium salts exhaustive methylation

Apart from the reactions of diazonium salts, a number of other reactions are known in which the C-N bond is broken. The best known of these is the Hofmann elimination of quaternary ammonium hydroxides (Scheme 2.37). An amine is converted by methylation with methyl iodide to the quaternary ammonium salt ( exhaustive methylation ). The iodide, on treatment with moist silver oxide, forms the quaternary ammonium hydroxide which undergoes a bimolecular elimination to form an alkene. The bimolecular elimination of onium salts yields the least alkylated alkene. This substitution pattern is determined by the ease with which a hydrogen atom can be attacked by the base. 

Quaternary ammonium salts. Exhaustive methylation. Hofmann elimination... 

The preparation of an alkene 3 from an amine 1 by application of a /3-elimination reaction is an important method in organic chemistry. A common procedure is the Hofmann elimination where the amine is first converted into a quaternary ammonium salt by exhaustive methylation. Another route for the conversion of amines to alkenes is offered by the Cope elimination. 

An amino group can be converted to a good leaving group by exhaustive methyla-tion, which converts it to a quaternary ammonium salt that can leave as a neutral amine. Exhaustive methylation is usually accomplished using methyl iodide. 

Thermal decomposition of quaternary ammonium salts and bases is most valuable in structural investigations of amines, particularly heterocyclic secondary amines (Hofmann exhaustive methylation). The course of the elimination (A or B) is determined by the nature of the four alkyl groups on the nitrogen atom. The reaction has found little use in the synthesis of pure olefins. The yields are low even when three of the alkyl groups are methyl radicals. Carbon-skeleton rearrangement does not occur. Thus, the only olefin obtained by pyrolysis of pinacolyltri-methylammonium hydroxide, (CHj),CCH(CHj)N(CHj)j OH, is /-butylethylene (50%). ... 

The formation of quaternary ammonium salts, followed by an elimination of the kind just described, is very useful in the determination of the structures of certain complicated nitrogen-containing compounds. The compound, which may be a primary, secondary, or tertiary amine, is converted into the quaternary ammonium hydroxide by treatment with excess methyl iodide and silver oxide. The number of methyl groups taken up by nitrogen depends upon the class of the amine a primary amine will take up three methyl groups, a secondary amine will take up two, and a tertiary amine only one. This process is known as exhaustive methylation of amines. 

The total synthesis of the cembranoid diterpene (+)-crassin acetate methyl ether was accomplished by W.G. Dauben et al. In the final stages of the total synthesis, the sensitive a-methylene group was introduced onto the six-membered lactone by using the Eschenmoser methenylation procedure. The lactone was deprotonated with LDA and then treated with Eschenmoser s salt. In the second step, the dimethylamino group was exhaustively methylated and the quaternary ammonium salt underwent a smooth Hofmann elimination upon deprotonation with DBU. 

The enantioselective formal total synthesis of 4-demethoxydaunomycin was accomplished in the laboratory of M. Shibasaki. The key intermediate was prepared from an enantiomerically enriched frans- 3-amino alcohol, which was first exhaustively methylated to the corresponding quaternary ammonium salt. This salt was then treated with excess n-BuLi to afford the desired allylic alcohol in moderate yield. 

Quaternary ammonium salts are obtained by exhaustive methylation of aliphatic tertiary amines. 

In exhaustive methylation, an amine will react with CH3I to form the quaternary ammonium salt (RN(CH3)tl ) / with 1 , 2 and 3 amines incorporating three, two and one methyl groups respectively. Looking at the data ... 

Methyl iodide reacts so readily with nucleophiles that primary amines are completely converted to quaternary ammonium salts by a process called exhaustive fflethylation. 

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