EXPLORATORY SYNTHETIC STUDIES OF THE ALPHA-METHOXYLATION OF AMIDES VIA CUPROUS ION-PROMOTED DECOMPOSITION OF O-DIAZOBENZAMIDES

A convenient nonelectrochemical amide oxidation method has been develo ped. The process involves a cuprous ion-promoted decomposition of o-di azobenzamides like 4, generated in situ from the corresponding o-amino benzamides, to give N-acyliminium ion intermediate 9 via a 1,5-H-atom transfer, followed by metal-catalyzed oxidation of the resulting alpha -amidyl radical. The transformation produces alpha-methoxybenzamides 1 5 in good yields. An attempt was made to apply this oxidation method t o a total synthesis of the alkaloid (-)-anisomycin (16). Scalemic o-am inobenzamide pyrrolidine derivatives 18a/18b underwent oxidation to gi ve a-methoxylated amide substrates 19a/ 19b, respectively, in good yie lds. However, alkylation of the N-acyliminium intermediate 20 with (p- methoxybenzyl)magnesium chloride gave the undesired anti-compounds 22a /22b as the major products. The amide oxidation exhibits good regiosel ectivity with many unsymmetrical 2-substituted piperidine and pyrrolid ine systems. In general, it appears that the larger the C-2 substituen t, the greater the methylene/methine H-atom abstraction ratio. A mecha nistic rationale for this selectivity is suggested based upon amide ro tamer populations. An extension of this methodology can be used to con duct two sequential amide oxidations using readily prepared 2-amino-6- nitrobenzamides such as 68 and 69.