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Hydroxylations
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Redox-Neutral Selenium-Catalysed Isomerisation of para-Hydroxamic
Acids into para-Aminophenols
Hsiang-Yu Chuang, Manuel Schupp, Ricardo Meyrelles, Boris Maryasin,* and Nuno Maulide*
Abstract: A selenium-catalysed para-hydroxylation of N-aryl-
hydroxamic acids is reported. Mechanistically, the reaction
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comprises an N O bond cleavage and consecutive selenium-
induced [2,3]-rearrangement to deliver para-hydroxyaniline
derivatives. The mechanism is studied through both 18O-
crossover experiments as well as quantum chemical calcula-
tions. This redox-neutral transformation provides an uncon-
ventional synthetic approach to para-aminophenols.
T
he para-aminophenol motif, epitomized by the century-old
analgesic paracetamol, is an important structural feature in
pharmaceuticals and materials. Numerous methods for the
preparation of para-aminophenols have been reported ever
since Eugen Bamberger discovered the first practical syn-
thesis employing the rearrangement of N-arylhydroxylamine
in aqueous sulfuric acid (Scheme 1a).[1] This process presum-
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ably involves the heterolytic cleavage of the N O bond and
subsequent intermolecular addition of water to a nitrenium
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intermediate. Besides strong Brønsted acids, these N O bond
cleavage/rearrangement events have also been triggered by
Lewis acids,[2] thermal activation[3] or transition metals.[4]
Pioneering work using Lewis acid-mediated ortho-migration
of a methoxy group was reported by Kikugawa (Sche-
me 1b).[2] Later, the same group disclosed the PBu3/CCl4-
induced ortho-migration of the hydroxyl group in N-acyl-N-
phenylhydroxylamines (Scheme 1c); minor amounts of the
para-isomer were also observed.[5] Ngai described the elegant
ortho-trifluoromethoxylation of aniline through a thermal
rearrangement process (Scheme 1d).[3] Recently, Terada
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Scheme 1. Approaches to N O bond cleavage/oxygen-migration reac-
tions and work presented herein.
reported an in-depth study of the elegant cobalt-catalysed
[1,3]-migration of alkoxycarbonyloxyl groups (Scheme 1e).[5]
Interestingly, the large majority of these N O bond cleavage
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processes lead to the formation of new C O bonds with ortho-
[*] Dr. H.-Y. Chuang, M. Schupp, R. Meyrelles, Dr. B. Maryasin,
Prof. Dr. N. Maulide
selectivity. The few approaches achieving para-hydroxylation
either require relatively harsh conditions or produce a mixture
of ortho- and para-regioisomers.[5,6] To the best of our
knowledge, a mild and practical method for regioselective
para-hydroxylation still has not emerged.[7]
University of Vienna, Institute of Organic Chemistry
Wꢀhringer Strasse 38, 1090 Vienna (Austria)
E-mail: nuno.maulide@univie.ac.at
Selenium is an essential oligoelement, perhaps best
known for its occurrence in selenocysteine.[8–10] Within
organic synthesis, organoselenium reagents have also
M. Schupp, Prof. Dr. N. Maulide
CeMM—Research Center for Molecular Medicine of the Austrian
Academy of Sciences
Lazarettgasse 14, AKH BT 25.3, 1090 Vienna (Austria)
emerged as unique catalysts for oxidation,[11] reduction,[12]
[13–15]
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C C/C X bond formation and rearrangements.
The
R. Meyrelles, Dr. B. Maryasin
University of Vienna, Institute of Theoretical Chemistry
Wꢀhringer Straße 17, 1090 Vienna (Austria)
E-mail: boris.maryasin@univie.ac.at
heavier selenium shows distinct properties when compared
to the other chalcogens.[16] Herein we present a new selenium-
catalysed, redox-neutral para-selective hydroxylation starting
from hydroxamic acids via consecutive [2,3]-rearrangements
to form para-aminophenols (Scheme 1 f).
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
In initial efforts, we treated hydroxamic acid 1 with one
equivalent of PhSeBr. Gratifyingly, the para-aminophenol 2
was obtained in 72% isolated yield (Table 1, entry 1).
Encouraged by this early result, we realized that reducing
the loading of phenylselenyl bromide to 10 mol% still
ꢁ 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.
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
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