α-Carbonyl Cations in Sulfoxide-Driven Oxidative Cyclizations

Article abstract of DOI:10.1002/anie.201705964

The selective, metal-free generation of α-carbonyl cations from simple internal alkynes was accomplished by the addition of a sulfoxide to a densely substituted vinyl cation. The high reactivity of the α-carbonyl cations was found to efficiently induce hydrogen and even carbon shift reactions with unusual selecivities. Complex compounds with highly congested tertiary and all-carbon-substituted quartenary carbon centers can thus be accessed in a single step from simple precursors. Mechanistic analysis strongly supports the intermediacy of the title compounds and provides a simple predictive scheme for the migratory aptitude of different substituents.

Full text of DOI:10.1002/anie.201705964

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Title: α-Carbonyl Cations in Sulfoxide-Driven, Oxidative Cyclizations
Authors: Tobias Stopka, Meike Niggemann, and Nuno Maulide
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-Carbonyl Cations in Sulfoxide-Driven, Oxidative Cyclizations
Tobias Stopka,[a] Meike Niggemann*[a] and Nuno Maulide*[b]
Abstract: A selective, metal-free generation of -carbonyl
cations from simple internal alkynes was accomplished by
addition of a sulfoxide to a congested vinyl cation. The high
reactivity of the thus generated α-carbonyl cations was found to
efficiently induce hydrogen- and even carbon shift reactions with
unusual selecivities. Thereby, complex and highly congested
tertiary and quartenary, all-carbon-substituted centers are
accessed in a single step from simple precursors. Mechanistic
analysis strongly supports the intermediacy of the title species
and provides a simple predictive scheme for the migratory
aptitude of different substituents.
reactions[14a,16] using large excesses of the nucleophilic coupling
partner.
One avenue offering synthetically useful in-situ formation of
analogous intermediates has recently been demonstrated in the
realm of Au-catalyzed reactions.[17,18] Therein, alkynes were
transiently converted into -oxo metal carbenoids – or Au-
stabilized -carbonyl cations
–
by treatment of the Au+-
coordinated alkyne moiety with sulfoxides[19] or N-oxides.[20]
(Scheme 1a). Most of the reported studies focus on N-oxides as
oxidants as they proved a reliable source of -oxo gold
carbenoids for diverse transformations; Sulfoxide-based
procedures were sidelined, as the reaction mechanism of
untethered sulfoxides was found to be dominated by 3,3-
sigmatropic rearrangements prior to the formation of the
carbenoid.[21]
The chemistry of carbonyl compounds remains of fundamental
interest for the organic chemistry community.[1] The natural
polarity of these molecules - electrophilicity at the carbonyl
carbon and nucleophilicity at the α-carbon
- led to the
development of what is arguably one of the most fundamental
pillars of modern organic chemistry. Polarity reversal - or
Umpolung[2] - of the α-carbonyl carbon substantially broadens
the range of potential disconnections.[3] This can be achieved
most prominently through the use of α-halo carbonyls,[4] but also
via oxyallyl cations,[5] ,-epoxy ketones,[6] enehydrazones[7] and
oxygenated enamines.[8] Furthermore, oxidized enolates[9] and
nitroso-type electrophiles[10] can be used for formal Umpolung
processes. However, reactions that proceed via genuine polarity
reversal, involving a fully developed positive charge at an α-
carbonyl carbon, are still scarcely studied. This is certainly due
to the high reactivity of such species – the cation being
destabilized by the electron withdrawing carbonyl group – which
renders them both difficult to generate and (once eventually
made) difficult to control. Nevertheless, their existence as
reactive intermediates was proven unequivocally in physical
organic chemistry studies.[11] It should be emphasized though,
that the focus of these studies lay merely on the characterization
of a limited number of mechanistic probes. Until now, the
generation of α-carbonyl cations heavily relies on ketones
bearing a leaving group (LG) in the α-position. Cleavage of this
leaving group was achieved in the presence of stoichiometric
amounts of silver salts (LG= -I, -Br, -Cl),[12] an excess of strong
Scheme 1. Alkynes as α-carbonyl cation equivalents.
In previous studies we demonstrated efficient formation of vinyl
cations via -activation of alkynes by simple carbocations[22] as
well as the feasibility of the nucleophilic interception of vinyl
cations by sulfoxides followed by sigmatropic rearrangement.[23]
Combining our expertise we thus assumed that, as shown in
Scheme 2, the addition of a sulfoxide to an in-situ generated
vinyl cation II would lead to III, ideally poised for [3,3]-
sigmatropic rearrangement leading to highly substituted arylated
ketone 4.
acids (LG= -OH),[13] or Lewis acids (LG = -OH, -OTs,
-
OP(O)(OMe)2.[14] Furthermore, mostly stabilized α-carbonyl
cations (R’= Aryl) are accessible. The few scattered protocols
making use of α-carbonyl cations for synthetic applications, that
have been reported following the initial studies, are limited to
inter- and intramolecular Friedel-Crafts,[12c,13,14b,15] or Ritter
[a]
[b]
Dr. T. Stopka, Prof. Dr. M. Niggemann
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: niggemann@oc.rwth-aachen.de
Homepage: http://www.oc.rwth-aachen.de
Prof. Dr. N. Maulide
Scheme 2. Sulfoxide-mediated, unexpected oxidative rearrangement.
Institute of Organic Chemistry, University of Vienna
Währinger Straße 38, 1090 Vienna (Austria)
E-Mail: nuno.maulide@univie.ac.at
Homepage: http://maulide.univie.ac.at
Supporting information for this article is given via a link at the end of
the document.
Much to our surprise, the very first experiments with benzylic
alcohol 1a and diphenylsulfoxide, under the influence of catalytic
amounts of a Brønsted acid promoter, led instead to two new
products assigned as the olefins 2a/3a in a >7:1 ratio.
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Table 1. Substrate scope: H-shift.[a]
Intrigued by this unusual result, and suspecting the intermediacy
of an -carbonyl cation, we carried out a series of control
experiments. Brominated compound 5 was reacted with an
excess of silver salt, an experiment known to generate -
carbonyl cations[12c] (Scheme 3a). This led to
a product
distribution very similar to our model reaction in Scheme 2.
[a] Reactions were performed at 80°C for 10 min with 1 (0.25 mmol, 1.0
equiv), Ph2SO (1.00 mmol, 4.0 equiv) and HOTf (0.05 mmol, 20 mol %) in
MeNO2 (2.5 mL). Yields refer to the isolated compounds. [b] Conjugated
double bond isomer (see SI for more information).
formation. However to enable these reactions, substituents
inside the chain that arrange a favorable conformation might
have a positive effect. For example, a phenyl-bridged substrate
gave access to an interesting phenanthrene derivative in
excellent yield (entry 6k).
Scheme 3. Control experiments probing the intermediacy of an α-carbonyl
cation A.
Reaction of deuterium-labeled compound 1a-D lends strong
Table 2. Substrate scope: C-shift.[a]
support to
a
1,2-hydrogen shift (Wagner-Meerwein-type
rearrangement) for the formation of 2a with 3a being the result of
the direct deprotonation of A (Scheme 3b). Mechanisms in
which cyclization and oxidation occur independently were ruled
out via the unproductive subjection of 7 and 8 to the reaction
conditions. Hence, hypothetical oxidation of alcohol 1, followed
by hydrolysis of the alkyne to a ketone and subsequent aldol
condensation (Scheme 3c), as well as hypothetical interception
of vinyl cation IIa by H2O and a sulfoxide-mediated oxidation
(Scheme 3d) do not provide access to ketone 2a. In addition,
Ph2S was regularly recovered from the reaction mixture.
With strong evidence for the intermediacy of a -carbonyl cation,
the influence of substitution patterns on reactivity was
subsequently investigated (Table 1).
A range of alkynols
smoothly reacted with Ph2SO providing access to -oxo cations
and the oxidative cyclization products in good to excellent yields.
Electron-rich as well as –withdrawing substituents R2 were well
tolerated (2b-d). Also, heterocycles could be introduced (2e).
Next, the influence of different substituents R1 was investigated.
Interestingly, even alcohol 1f with an aliphatic cyclopropyl moiety
gave 6f in excellent 89% yield. A sterically demanding naphthyl
group did not impede the reaction sequence (2g). With electron-
rich alcohols, an isomerization of product 2 was observed, while
[a] Reactions were performed at 80°C for 10 min with 1 (0.25 mmol, 1.0
equiv), Ph2SO (1.00 mmol, 4.0 equiv) and HOTf (0.05 mmol, 20 mol %) in
MeNO2 (2.5 mL). Yields refer to the isolated compounds.
At this juncture we were eager to investigate the possibility of
1,2-carbon shifts by employing tertiary alcohol substrates. In the
event, (Table 2) this led to an efficient synthesis of highly
congested, quarternary all-carbon substituted α-carbonyl
compounds. Starting from simple substrates 1l-q, different
aliphatic as well as aromatic groups were efficiently incorporated
at the quarternary α-carbonyl position (Table 2). Electronically
retaining moderate to good overall yield (entries 2h-j).[24]
A
starting material with an additional CH2-unit also reacted to the
desired cyclohexenyl product (entry 2j). Here an increased yield
can be explained by the more challenging 6-membered ring
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10.1002/anie.201705964
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different substituents such as a phenyl group, a heterocycle or a
methyl group were readily shifted. Interestingly, albeit yields
remained satisfactory, the carbon shift was rather indiscriminate,
when it came to the differentiation between two substituents.
This finding is consistent with the computational mechanistic
analysis discussed below.
of Gǂ = 8 kcal/mol the S-O bond is easily cleaved and -
carbonyl cation A is formed upon departure of diphenyl sulfide.
As mentioned above, the addition of sulfoxides to vinyl cations
or Au+-activated alkynes is dominated by a subsequent [3,3]-
sigmatropic rearrangement resulting in the formation of
thioethers.[21,23] The deviation from this pathway can be ascribed
to the very low activation barrier for the hydride shift (TS:Ab-B)
of only Gǂ = 2.5 kcal/mol. The respective barrier for the [3,3]-
sigmatropic rearrangement is ~ 10 kcal/mol higher (TS:A’-4a-H+),
with a value for Gǂ = 12.4 kcal/mol.
The preference for the hydride shift over direct deprotonation of
A was analysed next. As known from fundamental studies[11,12b]
and mechanistic analyses of the gold stabilized counter-
part[19b,20c,21b] the -carbonyl cation is indeed a non-classical
cation. In barrierless processes it changes conformation to allow
an interaction of a free electron pair of the carbonyl oxygen with
the empty p-orbital, an extreme form of this stabilization resulting
in the two vinyl epoxide renditions Aa and Ab. From Aa an ipso-
Friedel Crafts attack easily leads to the phenonium ion Ac, the
energetic minimum of the non-classical cation.
Scheme 4. α-Keto cation mediated synthesis of bicycles.
After this initial reactivity
screen, we sought to apply
this
oxidative
cyclization
towards the synthesis of more
complex structures (Scheme
3). The use of cyclopentanol 9
smoothly resulted in the ring-
expanded bicyclic enone 10.
Conversely,
substituted cyclopentanol 11
yielded selectively the
the
phenyl-
diquinane 12 (Scheme 3b).
Here, a carbon shift in the α-
keto
generate
[3.3.1]
cation
A-II
bridged bicylic
system by ring-
would
a
expansion, so that elimination
is precluded by the Bredt rule
(Ph migration is energetically
unfavourable, see below).
Therefore,
the
otherwise
unfavourable direct deproto-
nation of A-II becomes
predominant.
With the aim of providing a
predictive model, DFT-based
computational analysis was
undertaken. As shown in
Figure 1. Profile for the formation, rearrangement and deprotonation of -carbonyl cation A, calculated for the reaction of
ionized 1a with Ph2SO. Free energy values (G in kcal/mol; M06-2X/6-31+G(d,p)) relative to the separated reactants.
Figure
1 ionized 1a first
stabilizes as a cyclic cation-
The high reactivity of the -carbonyl cation strongly disfavours
-complex Ia’. This complex is then further stabilized by
interacting with the lone pairs of a sulfoxide’s oxygen atom,
which results in immediate cyclisation yielding sulfoxide
stabilized vinyl cation IIa. A cyclization of Ia’ without the
assistance of SOPh2 is ~ 6 kcal/mol higher in energy. From IIa, a
quasi-concerted addition of the sulfoxide ensues. With a barrier
intermolecular over intramolecular reaction pathways. Hence,
deprotonation is assisted by a carbonyl oxygen lone pair. For the
cleavage of Ha a transition state was located from Ac (TS:Ac-Ha),
thus completing a Ph-shift, albeit with a high activation barrier of
17.2 kcal/mol. Starting from Aa and Ab, two transition states
(TS: Aa-Hb/Ab-Hb) were located for the deprotonation of Hb.
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cyclizations driven by sulfoxide interception of a vinyl cation.
This reaction involves the transient formation of a highly reactive
-carbonyl cation under moderate temperatures. DFT
computations clarify the fate of the cation as a function of
substitution pattern and available pathways while providing a
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We thank D. Rice (RWTH Aachen) for skilful laboratory assistance, and C.
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support of this research by the ERC (VINCAT CoG 682002 to N.M.), the
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Keywords: alpha-carbonyl cation • vinyl cation • sulfoxide •
oxidative cyclization • rearrangement
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.
Entry for the Table of Contents
COMMUNICATION
Tobias Stopka, Meike Niggemann* and
Nuno Maulide*
Page No. – Page No.
-Carbonyl Cations in Sulfoxide-
Driven, Oxidative Cyclizations
Combining forces to generate -carbonyl cations from vinyl cations in an acid-
catalysed procedure. Highly reactive, they induce hydrogen and carbon shift
reactions with unusual selectivities. Mechanistic analysis confirmed their
intermediacy and provides a prediction scheme for the migratory aptitude of
different substituents.
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