Addition elimination imino ether

Imino-ethers can adopt theoretically the four conformations 179-182. In addition to the primary electronic effect, conformer 179 possesses two secondary electronic effects, conformers 180 and 181 only one whereas con-former 182 has none. Conformer 179 has a strong steric interaction between the two R groups and must be eliminated. Imino-ethers must therefore exist either in conformation 180 and 181. Meese, Walter, and Berger (40) have shown that the most stable conformation is 180. In some compounds where there is an important steric effect between the R1 and the RN group, conformation 181 is also observed. It was also found that in a polar solvent (CHjOH), there is a mixture of a major (180) and a minor (181) conformer. 

The low structural specificity in the local anesthetic sell cs is perhaps best illustrated by phenacalne (91), a local an-I -.lhetic that lacks not only the traditional ester or amide func-I ion but the basic aliphatic nitrogen as well. First prepared at I lie turn of the century, a more recent synthesis starts by con-ili iusation of p-ethoxyaniline with ethyl orthoacetate to afford I he imino ether (90), Reaction of that intermediate with a sec-I liil mole of the aniline results in a net displacement of ethanol, iiobably by an addition-elimination scheme. There is thus ob-I.lined the amidine, 91, phenacalne. 

The pharmacological versatility of this general substitution strategy is further illustrated by diazonium coupling of 14 with 2-nitrobenzenediazonium chloride to produce biarylal-dehyde 18. Formation of the oxime with hydroxylamine is followed by dehydration to the nitrile. Reaction with anhydrous methanolic hydrogen chloride leads to imino ether and addition-elimination of ammonia leads to the antidepressant amid-ine, nitrafudam (20). ... 

The addition of dry HCl to a mixture of a nitrile and an alcohol in the absence of water leads to the hydrochloride salt of an imino ester (imino esters are also called imidates and imino ethers). This reaction is called the Pinner synthesisThe salt can be converted to the free imino ester by treatment with a weak base such as sodium bicarbonate, or it can be hydrolyzed with water and an acid catalyst to the corresponding carboxylic ester. If the latter is desired, water may be present from the beginning, in which case aqueous HCl can be used and the need for gaseous HCl is eliminated. Imino esters can also be prepared from nitriles with basic catalysts. ... 

The preparation of the A -desmethyl analogue, amoxapine (39-7), illustrates an alternate approach in which the oxygen ether linkage is formed last. Reaction of the imidazolide (39-2) from 2,4-dichlorobenzoic acid (39-1) and carbonyldiimidazole with ort/zo-aminophenol (39-3) gives the benzamide (39-4). This is then converted to its imino chloride (39-5) with the ubiquitous phosphorus oxychloride. Treatment of the product with piperazine leads to the amidine (39-6), probably by an addition-elimination sequence. Copper catalyzed displacement of chlorine by phenoxide closes the ring there is thus obtained amoxapine (39-7) [40]. 

---