Exploratory synthetic studies of the α-methoxylation of amides via cuprous ion-promoted decomposition of o-diazobenzamides

Gyoonhee Han, Matthew G. LaPorte, Mathias C. McIntosh, Steven M. Weinreb, Masood Parvez

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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.

Original languageEnglish (US)
Pages (from-to)9483-9493
Number of pages11
JournalJournal of Organic Chemistry
Issue number26
StatePublished - Dec 27 1996

All Science Journal Classification (ASJC) codes

  • Organic Chemistry


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