Hydrative Aminoxylation of Ynamides: One Reaction, Two Mechanisms

Article abstract of DOI:10.1002/chem.201706063

Organic synthesis boasts a wide array of reactions involving either radical species or ionic intermediates. The combination of radical and polar species, however, has not been explored to a comparable extent. Herein we present the hydrative aminoxylation

Full text of DOI:10.1002/chem.201706063

A Journal of
Accepted Article
Title: Hydrative Aminoxylation of Ynamides: One Reaction, Two
Mechanisms
Authors: Alexandre Pinto, Daniel Kaiser, Boris Maryasin, Giovanni Di
Mauro, Leticia Gonzalez, and Nuno Maulide
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Hydrative Aminoxylation of Ynamides: One Reaction, Two
Mechanisms
Alexandre Pinto,[a]† Daniel Kaiser,[a]† Boris Maryasin,[a,b]† Giovanni Di Mauro,[a] Leticia González,[b] and
Nuno Maulide*[a]
Abstract: Organic synthesis boasts a wide array of reactions
involving either radical species or ionic intermediates. The
combination of radical and polar species, however, has not been
explored to a comparable extent. Herein we present the hydrative
aminoxylation of ynamides, a reaction which can proceed by either a
polar-radical crossover mechanism or through a rare cationic
activation. Common to both processes is the versatility of the
persistent radical TEMPO and its oxidised TEMPO+ oxoammonium
derivative. The unique mechanisms of these processes are elucidated
experimentally and by in-depth DFT-calculations.
compounds,12
a task which it achieves via its oxidised
oxoammonium counterpart TEMPO+. Curiously, the chemistry of
oxoammonium salts is not much developed beyond this
synthetically useful reactivity manifold (Scheme 1b).13
Introduction
The chemistry of free radicals has shaped organic chemistry for
over a hundred years and during this time has produced several
ground-breaking innovations.1 Once thought uncontrollable due
to high reactivity and barely predictable behaviour, the last
decades have brought a deeper understanding of the role of free
radicals in organic reactions,2 and have placed them at the
forefront of some major developments in organic synthesis.
These range from free radical chain reactions,3 all the way to
photoredox catalysis.4 In contrast to transient radicals generated
in situ, persistent radicals exhibit much greater lifetimes and
therefore stability.5 The triphenylmethyl radical, the first described
member of this family,6 is perhaps the most well-known carbon-
centered radical, while the oxygen-centered persistent nitroxyl
radical (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) has itself
also gained widespread attention since its discovery in 1959.7
TEMPO (alongside other nitroxyl radicals) has found extensive
application in hydrogen-abstraction reactions,8 as well as in
combination with organometallic reagents for C–O, C–N and also
C–C coupling reactions,7c,d and in nitroxide-mediated living free-
radical polymerization (NMP)7a,9 (Scheme 1a). Additionally, its
longevity allows TEMPO to be used as a trapping agent or radical
scavenger in radical carbon–carbon bond forming reactions.7c,10
Similarly, TEMPO itself has been employed in the aminoxylation
of enolate derivatives, affording α-oxidized carbonyl products.11 It
is, however, arguably most famous for its ability to oxidize primary
and secondary alcohols to the corresponding carbonyl
Scheme 1. (a) Reactivity patterns of TEMPO, (b) TEMPO+ and (c) our hydrative
aminoxylation.
Herein we report the TEMPO-mediated hydrative aminoxylation
of ynamides (Scheme 1c), an unusual reaction that can proceed
by either a polar-radical crossover mechanism or a cationic
hydrative pathway and which showcases the unique versatility of
the chemistries of persistent radicals and keteniminium ions, as
well as a detailed mechanistic and computational study of the
process.
Results and Discussion
Following our recent report on the reaction of TEMPO with
activated amides,14 our initial efforts focused on the combination
of ynamides15 with TEMPO under the action of a Brønsted acid
(Scheme 2). We eventually found that it was possible to intercept
an acid-preactivated ynamide 1a with TEMPO under mild
[a]
A. Pinto[+], D. Kaiser[+], Dr. B. Maryasin[+],G. Di Mauro, Prof. Dr. N.
Maulide
Institute of Organic Chemistry
University of Vienna
conditions. This enabled the preparation of
a hydrative
Währinger Strasse 38, 1090 Vienna, Austria
E-mail: nuno.maulide@univie.ac.at
Dr. B. Maryasin[+], Prof. Dr. L. González
Institute of Theoretical Chemistry
University of Vienna
oxyamination product 2a in 80% isolated yield.16 Further
modification of the conditions, including the premixing of ynamide
and TEMPO, as well as the use of fewer equivalents of TEMPO,
led to no improvement in yield (details of optimization
experiments are compiled in the Supporting Information). The
strict requirement for 2.2 equivalents of TEMPO in order to obtain
high yields of product would prove to have significant mechanistic
implications (vide infra).
[b]
[+]
Währinger Strasse 17, 1090 Vienna, Austria
These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document
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the reaction benefited from slightly elevated temperatures
(40 C). When these conditions were applied, linear (2j, k
)
and branched (2l–n) aliphatic substrates alike smoothly
underwent hydrative aminoxylation and good to excellent
yields of the corresponding products were isolated. Both for
aromatic and aliphatic substrates, poor diastereocontrol was
observed (2i and 2n, respectively). Cyclopropyl ynamide 1o
,
Scheme 2. Coupling of 1a with TEMPO following preactivation with a
Brønsted acid
.
a valuable substrate to probe radical processes (vide infra),
also underwent the reaction with minimal ring-cleavage.17
However, isolation of the corresponding product 2o required
reductive TMP-cleavage (vide infra) and TBDPS-protection,
contributing to the modest 35% yield. Various functional
groups were tolerated under the reaction conditions,
Having identified optimal reaction conditions, we were
interested in investigating the scope and functional group
tolerance of the reaction (Scheme 3).
including alkene (2p), chloride (2q), ester (2r18
phthalimide (2t) moieties.
-2s) and
From the outset, we were intrigued about the role of TEMPO in
this reaction, and carried out the mechanistic experiments
depicted in Scheme 4.19-21 For instance, we initially suspected that
TEMPO+, the oxoammonium counterpart of TEMPO, was
involved in this process. However, substituting TEMPO for
TEMPO+ in the procedure presented above yielded no traces of
product (Scheme 4a). Similar thoughts concerning a possible in
situ disproportionation of TEMPO under reaction conditions led us
to add TEMPO-H (the reduced, protonated form of TEMPO)
instead, which also did not afford any product (with or without
added TEMPO+, Scheme 4b).
Scheme 4 Mechanistic experiments.
Scheme 3. Scope of the aminoxylation reaction of ynamides with TEMPO.
Yields refer to isolated products. For details, see the Supporting
Information. a reaction performed at 40 °C
Similarly, the addition of triflic acid to TEMPO (known to
promote disproportionation)22 followed by subsequent
introduction of the ynamide into the reaction mixture afforded
only 7% NMR yield of the hydrative aminoxylation product
(Scheme 4c).
Aromatic substituents on the ynamide were well tolerated
throughout
(2a–i), affording the desired hydrative
aminoxylation products in high yields. Upon changing the
substitution to aliphatic chains (2j–t), it became evident that
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Surprisingly, however, we observed that in the absence of
triflic acid, a combination of TEMPO+ (1.00 eq) and water
(2.00 eq) is competent in providing the hydrative
aminoxylation product 2a in 62% yield (Scheme 4d). This
unexpected observation hints at the ability of TEMPO+ to
activate ynamides as a cationic O+-donor reagent.23
TEMPO in the latter set of conditions contrasts with the successful
hydrative aminoxylation observed with only 1 equivalent TEMPO+
in the aqueous procedure. Furthermore, the possibility that both
mechanisms would overlap remained open – until the isotopic
labeling experiments of Scheme 6 were carried out.
The generality of this transformation was briefly investigated
and results are compiled in Scheme 5. As can be seen, the
use of TEMPO+/water allows hydrative aminoxylation of
several ynamides in yields comparable to those of the
combined TfOH/TEMPO procedure (and with considerably
shorter reaction times) for a variety of substitution patterns.
In addition to select repeated examples from Scheme 3
(2a
,
b
,
d
,
k
,
m
,
p
,
s
,
t), ynamides containing varying alkyl and
aryl substitution (2u
–
x
) were smoothly converted to the
desired products and, pleasingly, both silyl ethers (2y) and
nitriles (2z) were tolerated under the reaction conditions.
Scheme 6. (a) Proposed mechanistic outline and isotopic labelling
validation for the TEMPO+-mediated hydrative aminoxylation of ynamides;
(b) Double incorporation of the 18O-label for the reaction with TEMPO.
As shown, when using 18O-water in conjunction with
TEMPO+, unambiguous incorporation of the label into the
carbonyl oxygen was observed (Scheme 6a). This strongly
suggests that the reaction proceeds by cationic activation of
the ynamide coupled to hydrolysis. Unexpectedly, the use of
18O-labeled TEMPO for the TfOH/TEMPO procedure led to
significant double incorporation of the label (Scheme 6b),
indicating that both oxygens inserted into the final product
originate from the persistent aminoxyl radical reagent.
Notably, quenching the TfOH/TEMPO reaction with
18O-labelled water did not lead to incorporation of the label
into the final product, thereby further corroborating a
difference in mechanism for the two transformations. At this
juncture, we resorted to quantum chemical calculations at
the DFT level of theory (see the SI for the computational
details) to shed more light on the intricacies of this unusual
polar-radical crossover process.
DFT Studies
As previously shown,24 the treatment of ynamide 1a with
TfOH leads to the transient formation of an E/Z-mixture of the
triflated species A-OTf, which exists in equilibrium with the
keteniminium ion
reaction mechanism for the formation of products 2a were
performed starting from (Scheme 7).
A. For this reason, calculations of the
A
Scheme 5. Scope of the electrophilic TEMPO+/H2O addition to ynamides. Yields
refer to isolated products.
Mechanistic Studies
The unusual observation that two sets of diametrically opposed
conditions lead to the same product raises significant mechanistic
questions. While the procedure involving TEMPO+/water appears
to proceed by a “conventional” cationic activation/aqueous
capture pathway (Scheme 6a), we still had no clear picture for the
intriguing polar-radical combination of the TfOH/TEMPO protocol.
In particular, the stringent requirement for 2 equivalents of
Scheme 7. Established characteristics on the reaction of ynamides with
TfOH.
At the outset of our calculations, we were mindful of the
labelling studies that effectively established the prerequisite
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for incorporation of two oxygen atoms from TEMPO in the
final product; this prerequisite was reflected in the
calculations.
The computed reaction profile is shown in Figure 1. The
starting point (intermediate A’) presents two TEMPO radicals
potential energy surface. This means that this process has a
large kinetic barrier and therefore is highly unlikely to take
place. This is consistent with the aforementioned
experimental observations (cf. Scheme 4).
and the keteniminium cation
TEMPO radicals attacks the cation
intermediate
(Pinner-type).25 The intermediates A’ and
A
. In the first step, one of the
Conclusions
A
leading to the imidate
B
B,
as well as the corresponding transition state TSA’-B are
cationic diradicals and therefore exist both in triplet and
singlet states, both of which were considered in the
calculations (shown in red and blue, Figure 1).26 Intersystem
crossing (ISC) of the triplet and the singlet states occurs on
the phase between the transition state TSA’-B and the
In conclusion, we have documented an unusual hydrative
aminoxylation of ynamides that can proceed by two different
mechanisms. Crucial to each pathway is the presence of
either the persistent aminoxyl radical TEMPO or its oxidized
oxoammonium variant TEMPO+. The first process involves
addition of a radical species to a keteniminium intermediate,
a transformation which is underrepresented in synthesis and
which was elucidated by extensive DFT calculations. The
second pathway dispenses with acidic pre-activation and
proceeds by a classical nucleophile/electrophile cooperative
process. Both processes highlight the versatility of TEMPO
as a truly chameleonic reagent in synthesis.
intermediate
B (Figure 1). The depicted resonance structure
of (a N,O-ketene acetal derivative) also accounts for the
B
stability of the cationic radical species and thereby can be
reconciled with the low amounts of the corresponding ring-
opening product detected in the case of cyclopropyl product
2o (vide supra).
Acknowledgements
Financial support of this research by the ERC (CoG 682002 to
N.M.) and the FWF (Grant P30226) is acknowledged. D.K. is a
DOC-fellow of the Austrian Academy of Sciences. A.P.
acknowledges a Grant from the Ministerio de Economía, Industria
y Competitividad (BES-2013-064292 and EEBB-I-17-11898).
Calculations were partially performed at the Vienna Scientific
Cluster (VSC). Generous continued support of our research by
the University of Vienna is gratefully acknowledged.
Keywords: ynamide • keteniminium • TEMPO • radical •
aminoxylation
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Same product, different mechanisms:
Taking advantage of the versatility of
TEMPO and its oxidised TEMPO+
oxoammonium derivative, we report the
TEMPO-mediated hydrative aminoxylation
of ynamides via the intermediacy of
keteniminium ions, an unusual reaction
that can proceed by either a polar-radical
Alexandre Pinto, Daniel Kaiser, Boris
Maryasin, Giovanni Di Mauro, Leticia
González, and Nuno Maulide*
Page No. – Page No.
Hydrative Aminoxylation of
Ynamides: One Reaction, Two
Mechanisms
crossover mechanism or
hydrative pathway.
a
cationic
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