Hofmann elimination exhaustive methylation

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. 

Pyridine (and quinoline) which in so many respects are aromatic and comparable to benzene, lose this character completely on hydrogenation to piperidine (and hydroquinoline), which are entirely of the same nature as secondary aliphatic amines. The completely hydrogenated heterocyclic bases undergo degradation reactions which have become important particularly in the investigation of the constitution of alkaloids. A. W. Hofmann s method of opening rings by means of exhaustive methylation may be illustrated with piperidine. By thermal decomposition of the quaternary ammonium base a C—N-link-age is broken and at the same time water is eliminated. 

Problem 18.30 Deduce the structures of the following amines from the products obtained from exhaustive methylation and Hofmann elimination, (a) C,H jN (A) reacts with 1 mol of CH,I and eventually yields propene. (6) CjHjjN (B) reacts with 2 mol of CHjI and gives ethene and a 3° amine. The latter reacts with 1 mol of CH,I and eventually gives propene. 

Problem 18.31 Outline the reactions and reagents used to establish the structure of 4-methylpyridine by exhaustive methylation and Hofmann elimination. ... 

Problem 18.58 An optically active amine is subjected to exhaustive methylation and Hofmann elimination. The alkene obtained is ozonized and hydrolyzed to give an equimolar mixture of formaldehyde and butanal. What is the amine ... 

An alternative bimolecular elimination process involves the thermal decomposition in an atmosphere of nitrogen of a quaternary ammonium hydroxide (Hofmann exhaustive methylation procedure). 

Hofmann elimination of exhaustively methylated butan-2-amine. The most stable conformation of the C2—C3 bond has no proton on C3 in an anti relationship to the leaving group. Along the Cl —C2 bond, however, any staggered conformation has an anti relationship between a proton and the leaving group. Abstraction of a proton from Cl gives the Hofmann product. 

The full account has appeared " of the synthesis of the A °-marine steroid (284). In addition the isolation and synthesis of the related 3iS-hydroxy-A -compound (285) " and the lla-hydroxy-3-oxo-A -compound (286) were reported. In the synthesis of (286) the 17/3-ethenyl group was constructed through exhaustive methylation of the 20-amino-compound followed by Hofmann elimination. Epimerization of pregnenolone at C-17 led to the synthesis of a number of 20-methyl-17a-pregnanes. Syntheses have been reported for the four isomeric 3,ll-diamino-5a-pregnanes, and the 6,19-dimethoxy-3,5-cyclopregnan-20-one (287) was synthesized in model experiments aimed at a strophanthidin synthesis. ... 

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%). ... 

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 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. 

In 1851, A.W. Hofmann discovered that when trimethylpropylammonium hydroxide is heated, it decomposes to form a tertiary amine (trimethylamine), an olefin (propene), and water. Widespread use of this transformation did not occur until 1881, when Hofmann applied this method to the study of the structure of piperidines and nitrogen-containing natural products (e.g., alkaloids). " The pyrolytic degradation of quaternary ammonium hydroxides to give a tertiary amine, an olefin and water is known as the Hofmann elimination. The process involves three steps 1) exhaustive methylation of the primary, secondary or tertiary amine with excess methyl iodide to yield the... 

An example of a reaction that shows this latter regiochemistry is the Hofmann exhaustive methylation, which is sometimes called, rather ambiguously, the Hofmann degradation (this is a term best avoided, because it is sometimes also used to describe the Hofmann rearrangement). In this reaction, an amine is methylated with methyl iodide until the quaternary ammonium iodide is formed. This is then treated with moist silver oxide to convert the iodide to the hydroxide. Write out the final elimination step that occurs on heating. 

When we looked at anti-E2 bimolecular eliminations, we saw that the Hofmann exhaustive methylation followed that pathway. There are occasions, however, when it proceeds via different route. Normally, the hydroxide anion removes the (P-hydrogen, which then initiates the E2 mechanism. If, however, the quaternary ammonium derivative is so highly hindered that this is not possible, then the hydroxide anion removes a proton from one of the methyl... 

The compound was quite obviously an amine due to its basic character. Von Braun degradation (NMe - NCN) and Hofmann degradation (sequential methylation -elimination) implied a cyclic tertiary amine. Further exhaustive Hofmann degradation led to an unusual net elimination of both trimethylamine and ethylene. (This reaction was driven by aromatization of the C-ring after elimination of the Q5-C16-N17 ethylamine bridge). 

The Hofmann elimination reaction was used by early organic chemists as the last step of a process known as a Hofmaim degradation—a method used to identify amines. In a Hofmann degradation, an amine is exhaustively methylated with methyl iodide, treated with silver oxide to convert the quaternary ammonium iodide to a quaternary ammonium hydroxide, and then heated to allow it to undergo a Hofmann elimination. Once the alkene is identified, working backwards gives the stmcture of the amine. 

A second exhaustive methylation and Hofmann degradation eliminates the nitrogen of a-methyltropidine as trimethylamine. These last two reactions demonstrate that the tertiary nitrogen of tropidine (and hence of tropine)... 

Exhaustive methylation of a-methyltropidine followed by a Hofmann degradation eliminates the nitrogen as trimethylamine and the low boiling cycloheptatriene (tropilidene) was isolated in good yield (22,121). Tropane may be converted through the intermediate methyltropane to A -cyclo-heptadiene (hydrotropilidene) by a similar process. In the conversion of methyltropane methohydroxide to cycloheptadiene (139), 20% of the methyltropane is reformed by the loss of methanol, a side reaction which occurs in most Hofmann degradations to a greater or lesser extent. Cycloheptatriene and cycloheptadiene have been reduced to cycloheptane (194) which in turn has been oxidized (nitric acid) to pimelic acid. 

Finally, as foreshadowed in Chapter 7 (Scheme 7.24 ft, the Hofmann elimination) and Chapter 8, Part I, Section F, A. W. Hofmann (1818-1895) pointed out that elimination from ammonium ions yielded the least highly substituted alkene rather than the most highly substituted alkenes (the Saytzeff elimination). Thus, as shown in Scheme 10.47, when 2-aminobutane is exhaustively methylated with iodomethane (ICH3) and treated with base, there is more ehmination to yield 1-butene (about 60%) than when, for example, the same elimination reaction is effected on 2-bromobutane (about 20%). It has been argued that this result comes about because the base is closely associated with the positively charged ion and the hindered environment favors loss of the proton from the primary carbon. 

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