Exploratory Synthetic Studies of the α-Methoxylation of Amides via Cuprous Ion-Promoted Decomposition of o-Diazobenzamides

A convenient nonelectrochemical amide oxidation method has been developed. The process involves a cuprous ion-promoted decomposition of o- diazobenzamides like 4, generated in situ from the corresponding o -aminobenzamides, to give N -acyliminium ion intermediate 9 via a 1,5- H -atom transfer, followed by metal-catalyzed oxidation of the resulting α-amidyl radical. The transformation produces α-methoxybenzamides 15 in good yields. An attempt was made to apply this oxidation method to a total synthesis of the alkaloid (−)-anisomycin ( 16 ). Scalemic o- aminobenzamide pyrrolidine derivatives 18a / 18b underwent oxidation to give α-methoxylated amide substrates 19a / 19b, respectively, in good yields. 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 regioselectivity with many unsymmetrical 2-substituted piperidine and pyrrolidine systems. In general, it appears that the larger the C -2 substituent, the greater the methylene/methine H -atom abstraction ratio. A mechanistic rationale for this selectivity is suggested based upon amide rotamer populations. An extension of this methodology can be used to conduct two sequential amide oxidations using readily prepared 2-amino-6-nitrobenzamides such as 68 and 69 .