Piperidine, exhaustive methylation

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. 

The above example was selected because the penta-1,4-diene cannot isomerize to a more conjugated isomer however, in many other examples this is not the case and, for example, a Hofmann exhaustive methylation reaction upon piperidine itself eventually leads to penta-2,4-diene (Scheme 2.33). 

Assuming isomerism occurs to give the mosl stable (most conjugated and most highly substituted) dienes during the reactions, the two piperidines would undergo Hofmann exhaustive methyl-ation and subsequent ozonolysis as shown below. The diflerent orientation patterns are then reflected in the constitutions of the aldehydes and ketones that are formed. 

In analogy to piperidines, some 3-piperideines were subjected to the Hofmann exhaustive methylation. 5-Dimethylamino-l,3-pentadiene... 

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... 

Exhaustive methylation at the piperidine nitrogen followed by a Hofmann degradation of the resulting quaternary ammonium hydroxide ... 

The action of bromine and alkali on amides to form amines containing an atom of carbon less, was discovered by Hofmann. Another Hofmann reaction , now called exhaustive methylation , was applied to convert piperidine into an unsaturated hydrocarbon piperylene, CgHg. (The simplest case, the decomposition by heat of tetraethylammonium hydroxide (C2H5)4N0H = (C2Hs)3N + C2H4 + H2O, he discovered in 1851 see p. 440.)... 

The exhaustive methylation of sparteine was reinvestigated by Karrer, Shibata, Wettstein and Jacubowitz. At each stage they reduced the unsaturated product formed and so ended up with a pentadecane, CijHgj (b.p. 2427729 mm., 0-7740, n ° 1-43351). The object of this work was to compare this substance with the pentadecanes theoretically derivable by exhaustive methylation from bases represented by formulae (I) to (IV), which are based on the assumption that sparteine is derived from lupinine by the addition of a piperidine ring, the lupinine formula being that of Karrer, Canal, Zohner and Widmer. ... 

The Hofmann exhaustive N-methylation procedure, often used in classical structure determinations of alkaloids containing the piperidine nucleus, depends upon the formation of quaternary methyl salts. 

---