Angewandte
Communications
Chemie
How to cite:
Synthetic Methods
Chemoselective g-Oxidation of b,g-Unsaturated Amides with TEMPO
Sebastian Heindl, Margaux Riomet+, Jꢀn Matyasovsky+, Miran Lemmerer+, Nicolas Malzer, and
Dedicated to Professor Barry M. Trost on the occasion of his 80th birthday
Abstract: A chemoselective and robust protocol for the g-
oxidation of b,g-unsaturated amides is reported. In this
method, electrophilic amide activation, in a rare application
to unsaturated amides, enables a regioselective reaction with
TEMPO resulting in the title products. Radical cyclisation
reactions and oxidation of the synthesised products highlight
the synthetic utility of the products obtained.
alkoxy or g-hydroxy-a,b-unsaturated carbonyl compounds
was developed by Tiecco, although only one amide example
was reported and an excess of ammonium persulfate as
oxidising agent was required, limiting functional group
tolerance (Scheme 1b).[20] TEMPO addition to ketenes was
previously reported, including one sole example of g-amino-
xylation, albeit in low yield.[21a] g-Hydroxylation of carbonyls,
however not selective to amides, has also been achieved under
copper catalysis.[21b] A general method for direct, chemo-
selective g-oxidation of unsaturated amides has, however, not
emerged yet. Our group has previously studied the intercep-
tion of keteniminium ions in oxidative contexts beyond the
use of N-oxides, namely involving the persistent radical
TEMPO.[22,23] Herein, we present an approach to the chemo-
selective g-oxidation of unsaturated amides—to the best of
our knowledge, a rare instance of electrophilic amide
activation as applied to unsaturated substrates—as well as
the intriguing reactivity that is unlocked when this reactivity
manifold is leveraged by single-electron processes.
We focused our attention on model b,g-unsaturated amide
1a. Even though such substrates are rare features in the
context of electrophilic amide activation, from the outset
selective g-oxidation with concomitant double-bond migra-
tion dominated the reactivity panorama. Further optimisation
(see Supporting Information for details) showed that slightly
more than two equivalents of TEMPO are required for
efficient conversion. Equally relevant appears to be the
I
t is well-documented that amides react only sluggishly with
common nucleophiles, a fact typically ascribed to the
electron-releasing effect of the nitrogen center. Activation
is therefore often necessary to promote carbonyl-type reac-
tivity in this family of compounds.[1] After early, successful
attempts at amide activation,[2] trifluoromethanesulfonic
anhydride (Tf2O) has eventually emerged as a general
activating reagent following its introduction by Ghosez et al.
in 1981.[3–5] This paved the way for further discoveries, ranging
from Movassaghiꢀs heterocycle synthesis to Huangꢀs sequen-
tial reductive alkylation or Charetteꢀs chemoselective reduc-
tion methods.[6–9] Our group has employed this activation
mode, as a platform enabling ready access to highly reactive
keteniminium ions, for the development of rearrangement-
driven transformations, including a-arylation[10,11] and a-
amination.[12] In combination with N-oxide reagents,[13] a con-
ceptually different Umpolung approach enabled the nucleo-
philic a-incorporation of halides[14] and other heteroatoms
into amides,[15] as well as the formation of lactams[16] and 1,4-
dicarbonyls.[17]
In comparison to this plethora of methods for a-function-
alisation,[10–18] accessing remote positions has remained
largely an unexplored area in amide activation. Two examples
of g-aminoxylation were reported for conjugated acyloxazo-
lidinone (imide) Ti-enolates by Romea and Urpi (Sche-
me 1a).[19] A Se-catalysed approach for the synthesis of g-
[*] S. Heindl, Dr. M. Riomet,[+] Dr. J. Matyasovsky,[+] M. Lemmerer,[+]
N. Malzer, Prof. Dr. N. Maulide
Institute of Organic Chemistry, University of Vienna
Wꢀhringer Strasse 38, 1090 Vienna (Austria)
E-mail: nuno.maulide@univie.ac.at
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
ꢁ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
Scheme 1. a,b) Strategies for g-oxidation of b,g-unsaturated amides.
c) Proposed approach and the challenge of using unsaturated amides
in electrophilic activation.
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
ꢁ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
1
These are not the final page numbers!