3.4.5-Trimethoxybenzoyl chloride Trimetozine

Problem 21.11 i Write the mechanism of the reaction just shown between 3,4,5-trimethoxybenzoyl chloride and morpholine to form trimetozine. Use curved arrows to show the electron flow in each step. 

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. 

Since HCl is formed during the reaction, 2 equivalents of the amine must be used. One equivalent reacts with the acid chloride, and 1 equivalent reacts with the HC] by-product to form an aniinonium chloride salt. If however, the amine component is valuable, amide synthesis is often carried out using 1 equivalent of the amine plus 1 equivalent of an inexpensiv base such as NaOH. For example, the sedative trimetozine is prepa industrially by reaction of 3,4,5-trimethoxybenzoyl chloride with the aniij morpholine in the presence of 1 equivalent of NaOH. 

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