Nucleophiles saturated nitrogen heterocycles

Many saturated nitrogen heterocycles are commercially available from industrial processes, which involve, for example, nucleophilic substitution of hydroxyl groum by amino groups under conditions far from laboratory use, e.g. 

In many reactions the simple saturated nitrogen heterocycles—piperidine, pyrrolidine, piperazine, and morpholine—behave simply as secondary amines that happen to be cyclic. They do the sorts of things that other amines do, acting as nucleophiles in addition and substitution reactions. Morpholine, for example, is acylated by 3,4,5-trimethoxybenzoyl chloride to form the tranquillizer and muscle relaxant trimetozine, and N-methyl piperazine can be alkylated in an S l reaction with diphenylmethyl chloride to give the travel-sickness drug cyclizine. 

Aziridine and azetidine are stable, if volatile, members of the saturated nitrogen heterocycle family, and aziridine has some interesting chemistry of its own. Like pyrrolidine and piperidine, aziridine can be acylated by treatment with an acyl chloride, but the product is not stable. The ring opens with attack of chloride, a relatively poor nucleophile, and an open-chain secondary amide results. 

In Chapter 6 it was mentioned that certain saturated nitrogen heterocycles such as piperidine and piperazine are common components of many drugs. These groups are cyclic amines and are also subject to metabolism by MFO by the mechanism outlined above. The amine and carbonyl components that result from this process, however, remain attached to each other by the remainder of the ring. This makes it likely that they will react with each other since amines are nucleophiles and aldehydes and ketones are electrophiles. Thus there are two possible outcomes ... 

Aminals are another class of saturated heterocycles that form very readily under thermodynamic control aminals are nitrogen analogues of acetals. They are usually made by refluxing a 1,2-diamine with an aldehyde in toluene (no acid catalyst is needed because the nitrogens are very nucleophilic), and this makes a very useful way of forming a chiral derivative of an achiral aldehyde. Here is an example the diamine is made from the amino acid proline. The product has a new chiral centre, and it forms as a single diastereoisomer because the phenyl ring prefers to be on the exo face of the bicyclic system (see Chapter 33). 

In the second case, the chlorine on the heterocyclic ring is much more reactive towarc. nucleophilic substitution as the intermediate is stabilized by both nitrogen atoms and the benzer. ring is not disturbed. The saturated heterocycle (a piperazine) can be made to react once only as thr product under the reaction conditions is strictly the hydrochloride of the unreacted amino grour This is much more basic than the one that has reacted as its lone pair is conjugated with th heterocyclic ring. 

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