Ceric ammonium nitrate oxidation of N-(p-methoxybenzyl)lactams: competing formation of N-(hydroxymethyl)δ-lactams

Krishna Annadi,Andrew G H Wee

doi:10.3998/ark.5550190.p008.840

Abstract

The ceric ammonium nitrate mediated oxidative deprotection of N-(p-methoxybenzyl) δ-lactams leads to the formation of an unexpected N-(hydroxymethyl) δ-lactam along with the Ndeprotected δ-lactam. In comparison, N-(p-methoxybenzyl) γ-lactams are completely deprotected under the same reaction conditions. Further studies indicated that addition of an aqueous solution of ceric ammonium nitrate to an acetonitrile solution of N-(p-methoxybenzyl) δ-lactams in the presence of 2-amino-2-methyl-1-propanol as an additive promoted N-deprotection. Ceric ammonium nitrate oxidation of N-(α,α-dideuterio-p-methoxybenzyl)-6-allyl-δ-lactam (8), revealed that the methylene unit of the N-(hydroxymethyl) group is derived from the benzylic methylene unit of the N-protecting group. A plausible reaction pathway for the formation of the N-(hydroxymethyl) δ-lactams from an N-acyliminium ion intermediate is proposed.

Highlights

We found that (a) δ-lactams have a higher tendency to give the N-(hydroxymethyl) derivative whereas γ-lactams undergo efficient and complete deprotection, (b) the ratio of the Ndeprotected to N-(hydroxymethyl) δ-lactams is sensitive to the substrate structure and the reaction conditions employed, and (c) the p-methoxybenzyl methylene unit is the source of the methylene moiety of the N-(hydroxymethyl) group
ceric ammonium nitrate (CAN) oxidation of N-PMB δ-lactam 1 As mentioned above, our studies began with the deprotection of N-PMB δ-lactam 1 (Scheme 1) following literature procedure, which entailed the addition of solid CAN7,33 (4.1 equiv, final concentration = 0.25 M) to a solution of 1 in 3:1 v/v MeCN/H2O.34
Whereas N-PMB γ-lactams were deprotected cleanly, the deprotection of δ-lactams always led to the formation of a mixture of the N-deprotected and N-(hydroxymethyl) δ-lactams

Summary

Introduction

The p-methoxybenzyl (PMB) group is often used for the N-protection[1] of amides, lactams and aza-heterocycles in the synthesis of natural[2,3,4,5,6,7,8,9,10,11,12] and non-natural products[13,14,15,16,17,18,19,20,21,22,23] because of its ease of removal. To the best of our knowledge, the formation of N-(hydroxymethyl) lactams during CAN mediated N-PMB deprotection has not been documented before Intrigued by this observation, we conducted a more detailed study of the CAN oxidation of N-PMB lactams and we report our findings here. The findings reported in this study will be helpful where CAN oxidation method is used for the deprotection of N-PMB δ-lactams

Methods

Results

Conclusion