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

Abstract

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.

Intramolecular Redox‐Triggered CH Functionalization

“…[20,21] Importantly, if the aromatic substituent bears a paramethoxy substituent (such as in substrates 5 o-s and 6 o), smooth cleavage of the aromatic residue can be achieved under mild conditions, [22] thus providing suitably functionalized, synthetically useful amines 7 a-f in high yields (Scheme 5). [23] Finally, the synthetic utility of the method outlined herein is showcased in the context of the total synthesis of the natural product (AE)-indolizidine 167B. [24] As depicted in Scheme 6, alkylation of pyrrolidine 8 with 2-fluoro-4-methoxybenzaldehyde 9, followed by sequential treatment with 20 mol % of Sc(OTf) 3 and the Grignard reagent 10 afforded the anisidine intermediate 11, [25] with an overall yield of 43 % for the three steps.…”

C‐H‐Funktionalisierung durch eine intramolekulare Redox‐Strategie

“…[*] Dr. [23] Abschließend konnten wir den präparativen Nutzen der hier beschriebenen Methode an einer Totalsynthese des Naturstoffs (AE)-Indolizidin 167B demonstrieren. Generell sollte in unsymmetrisch substituierten Hydriddonoren die Übertragung bevorzugt zum am besten stabilisierten Karbokation ablaufen.…”

A facile and stereoselective synthesis of the C-2 epimer of (+)-deacetylanisomycin

“…13f To further confirm the stereochemistry at the newly formed stereogenic centre the cyclised product 13 was converted into dimethoxy compound 14, whose 1 H NMR spectra were in agreement with the reported values. 15 Compound 13 was subjected to hydrogenation in the presence of Pd/C, which resulted in the formation of 2a. The specific rotation of the C-2 epimer of (+)-deacetylanisomycin 2a was ½a 25 D ¼ þ18 (c 0.8, MeOH), {lit 12d ½a 25 D ¼ þ20 (c 1, MeOH)}.…”