Pyrrolidines quaternization

The conversion of pyridine by thionyl chloride to 4-pyridyl-pyridinium chloride hydrochloride (65), followed by heating in DMF as solvent and reactant to afford DMAP (228) and pyridine, was the first commercial process to give DMAP (228) in ton amounts at reasonable prices. Amination of 4-pyridylpyridinium chloride hydrochloride with pyrrolidine also furnishes PPY (184) directly (cf. Section IV,H). Alternatively, the inexpensive 4-cyanopyridine (274) is quaternized by either 2-vinylpyridine-HCI or acrylamide-HCI and readily aminated with dimethyl-amine or pyrrolidine to give, after alkaline treatment, DMAP (228) or PPY (184) (cf. Section V,A). 

A rather different approach to the hydroazulenic synthesis has been adopted by Hendrickson and Boeckman. Treatment of 1-cyclopentenylcarboxalde-hyde (411) with the pyrrolidine enamine of cyclopentanone (412) yielded the thermodynamically most stable adduct (413) which, on quaternization and base-induced fragmentation, gave the acid (414) in 25% yield. Furthermore, the acid (414) has been converted into the epoxide (415) and the (5-lactone (416), both of which are potential synthetic precursors of guaiane-type sesquiterpenoids, e.g. pseudoguaianolides. 

Selective quaternization of tertiary tropane bases with different R halides leading to the R-equatorial tropanium salt has been described 2, 58, 59). By first introduction of R and subsequent methylation the methyl-equatorial epimer was formed. Evidence was furnished by using a carboxymethyl for R with a tropane base having an adjacent hydroxyl either in the pyrrolidine or in the piperidine ring. Since lactones were... 

A cationic center, preferably a basic or quaternized nitrogen, is required. In nicotine, this requirement is satisfied by the pyrrolidine nitrogen. 

Quaternizing 1-pyrroHnes (40, R = H, R = Me R = Ph, R = H) with 4-R Cf H4CH2Br (R = 4-N02, Br, CN, COOMe) gave 1-pyrrolinium salts, which were deprotonated with base to give the tertiary pyrrolidine enamines 41, ... 

Acetylcholine (7.4), important transmitter of the nervous impulse between cells, is an aliphatic quaternary amine and hence completely ionized in all circumstances. The active form of nicotine (7.26), which mimics the action of acetylcholine at several sites, must be the cation because its methiodide (quaternized on the pyrrolidine nitrogen atom) is no less active (Barlow and Hamilton, 1962). The arecoline (12.80) cation, too, has potent acetylcholinelike properties (see Section 12.6). However, in experiments made (over the pH range 6.05 to 9.36) on the guinea-pig ileum, the neutral species of arecoline was found to have only 2% of the activity of the cation (Burgen, 1965). 

Pyrrolidines and N-substituted pyrrolidines undergo reactions typical of secondary or tertiary alkylamines. They can be alkylated and quaternized NH-pyrrolidines can be acylated and nitrosated. The basicity and nucleophilicity of pyrrohdine is, however, greater than those of diethylamine (pyrrolidine pKa = 11.27, diethylamine pKa = 10.49). Because of these properties, pyrrolidine is an often used amine component for the conversion of carbonyl compounds into enamines ... 

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