α-Functionalisation of Ketones Through Metal-Free Electrophilic Activation

Article abstract of DOI:10.1002/anie.202006398

Triflic anhydride mediated activation of acetophenones leads to highly electrophilic intermediates that can undergo a variety of transformations when treated with nucleophiles. This electrophilic ketone activation gives access to α-arylated and α-oxyamina

Full text of DOI:10.1002/anie.202006398

Angewandte
Communications
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How to cite:
International Edition: doi.org/10.1002/anie.202006398
German Edition: doi.org/10.1002/ange.202006398
Ketone Activation
a-Functionalisation of Ketones Through Metal-Free Electrophilic
Activation
Wojciech Zawodny, Christopher J. Teskey, Magdalena Mishevska, Martin Vçlkl, Boris Maryasin,
Leticia Gonzꢀlez, and Nuno Maulide*
Abstract: Triflic anhydride mediated activation of acetophe-
nones leads to highly electrophilic intermediates that can
undergo a variety of transformations when treated with
nucleophiles. This electrophilic ketone activation gives access
to a-arylated and a-oxyaminated acetophenones under metal-
free conditions in moderate to excellent yields and enables
extension to the synthesis of arylated morpholines via gener-
ation of vinylsulfonium salts. Computational investigations
confirmed the transient existence of intermediates derived from
vinyl triflates and the role of the oxygen atoms at the para
position of aromatic ring in facilitating their stabilisation.
the reaction of the vinyl triflate intermediate A with the aryl
sulfoxides (Scheme 1b).
Our group has a long-standing interest in the chemo-
selective triflic-anhydride-mediated activation of amides,
stemming from the pioneering early work of Ghosez[9] and
more recent reports by Charette,[10] Movassaghi,[11] Huang
and others.[12] Upon treatment of an amide with triflic
anhydride and a base, a highly electrophilic keteniminium
intermediate B is generated (Scheme 1c). B can undergo
a variety of transformations with nucleophilic species, includ-
ing aryl sulfoxides, leading to a-arylation via a [3,3]-sigma-
tropic rearrangement,[13] or TEMPO to furnish a-oxyami-
nated amides following an umpolung event (Scheme 1c).[14]
We hypothesized whether putative analogues of the pivotal
keteniminium could be generated when the lone pair of the
nitrogen atom of the amide functionality is replaced with
another strong electron-donor, such as electron-rich aromatic
rings, leading us to propose para-methoxy-substituted aceto-
phenones. The highly reactive analogous intermediate C
might reside in equilibrium with the vinyl triflate A’
(Scheme 1c). Although the formation of vinyl triflates from
the corresponding acetophenones is well-established,[15] and
F
unctionalisation of carbonyl compounds at the a-position is
of central importance in synthetic organic chemistry. The a-
arylation of carbonyl compounds has gained particular
attention due to the interesting pharmacological and biolog-
ical properties exhibited by such scaffolds.[1a–b] The advent of
transition-metal-catalysed coupling reactions (involving
mainly Pd, Ni and Cu) of aryl halides with carbonyl-derived
enolates has facilitated access to them (Scheme 1a).[1c–f]
Transition-metal-free approaches to a-arylation involve ap-
plications of stoichiometric processes involving enolate
anions and electrophilic aromatic derivatives of iodine,[2]
sulfur,[3]or benzyne.[4] Methodologies proceeding via N-alkox-
yenamines[5] or enolonium equivalents[6] have also been
developed.
Radical nucleophilic aromatic substitution (SRN1) also
enables a-arylation of ketones.[7] Alternatively, a formal
metal-free a-arylation of carbonyl compounds can be ach-
ieved by using aryl sulfoxides (Scheme 1b).[8] With aryl-
substituted acetylenes, the method requires somewhat forcing
conditions (high temperatures and solvent-free) to facilitate
[*] Dr. W. Zawodny, Dr. C. J. Teskey, M. Mishevska, M. Vçlkl,
Dr. B. Maryasin, Prof. Dr. N. Maulide
Institute of Organic Chemistry, University of Vienna
Wꢀhringer Strasse 38, 1090 Vienna (Austria)
E-mail: nuno.maulide@univie.ac.at
Homepage: http://maulide.univie.ac.at
Dr. B. Maryasin, Prof. Dr. L. Gonzꢁlez
Institute of Theoretical Chemistry, University of Vienna
Wꢀhringer Strasse 17, 1090 Vienna (Austria)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.202006398.
ꢂ 2020 The Authors. 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 reproduc-
tion in any medium, provided the original work is properly cited.
Scheme 1. (a) Previous approaches to a-arylation of ketones. (b)
Hydrative a-arylation of acetylenes. (c) Amide activation and ketone
activation.
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Scheme 2. a) Scope of a-arylation of ketones and b) telescoped synthesis of a-aryl-a-alkyl ketones; a 0.2 mmol scale; b 7.0 mmol scale; DTBMP
ꢀ2,6-di-tert-butyl-4-methyl-pyridine.
they can be often purified by chromatography and isolated,
the reactivity of such species with electron-donating groups at
the para-position is scarcely reported due to their decreased
stability.[16]
Herein, we report, to the best of our knowledge, the first
example of electrophilic ketone activation and subsequent
metal-free a-arylation and oxyamination.
We first set out to attempt a-arylation of ketones by using
4-methoxyacetophenone and diphenyl sulfoxide as model
substrates (Scheme 2a, for full optimization details, see the
SI), investigating a range of conditions. Initially, standard
procedures used for amide activation (Tf2O, 2-I-pyr in DCE at
08C for 15 min, then addition of the sulfoxide) gave the target
a-arylated product 2a in a moderate yield. Pleasingly,
stoichiometric amounts of a bulky, non-nucleophilic base
(2,6-di-tert-butyl-4-methylpyridine, DTBMP) led to an
increase in yield and even allowed us to scale up the reaction
to 7 mmol (60% yield). On the other hand, the use of an
excess of the base afforded the corresponding phenylacety-
lene. As alluded to previously, attempted isolation of the
intermediate enol triflate failed due to decomposition.
With the optimized conditions in hand, we investigated
the scope of the methodology by screening various sulfoxides
with the model substrate 4-methoxyacetophenone (Sche-
me 2a). A variety of substituents was tolerated at the para-
position of the aryl sulfoxides, including the electron-donating
methyl, phenyl and methoxy groups (2b–d), as well as
halogens (2e–g). Additionally, an aryl alkyl sulfoxide could
also be employed, affording 2h. We then moved on to
investigate the scope of 4-methoxyacetophenone derivatives
and how the substitution pattern on the aromatic ring affects
the duration of the ketone activation, the completion of which
is indicated by intensely purple colour of the reaction mixture.
With halogens at the 3-position of the aromatic ring, the
activation time prior to the addition of sulfoxide had to be
extended to 120 min. Nevertheless, the corresponding prod-
ucts were obtained in excellent yields (2i–k). Lastly, we
explored substrates where the activating oxygen atom in the
para-position of the aromatic rings is incorporated within
a ring. Six- and five-membered cyclic substrates proved more
reactive than the model substrate 4-methoxyacetophenone,
necessitating activation for shorter time to give products 2l,m.
Encouraged by the development of this procedure for the
metal-free a-arylation of 4-methoxyacetophenone and its
derivatives, we aimed to extend this one pot procedure to
cases where there is no strongly electron-donating group in
2
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the para position of the ketoneꢀs aromatic ring (Scheme 2a).
gave the best yields for products 10a–c. The six-membered
As expected, longer reaction times were needed for activation
under conditions akin to those applied to para-oxygen
activated substrates.[15a,b,17]
3-Methoxyacetophenone (4a,b), 4-fluoroacetophenone
(4c–e), 4-chloroacetophenone (4 f,g) and acetophenone
(4h–j) gave good yields with diphenyl sulfoxide as well as
its para-substituted analogues carrying methyl- or chloro-
substituents.
ring substrate gave 10d in a similar yield, while the more
reactive 10e,f worked less well.
The highly reactive intermediates generated by ketone
activation can be captured by other nucleophiles than aryl
sulfoxides or TEMPO (Scheme 3b). For instance, addition of
tetrahydrothiophene allows the obtention of vinylsulfonium
triflate 11. After isolation by aqueous work-up without
further purification, and following Aggarwalꢀs methodol-
ogy,[19] 11 was treated with N-tosyl-aminoethanol 12 under
basic conditions to obtain morpholine 13.
Following our findings and the observation that aceto-
phenones with electron donating para-substitution are acti-
vated much more easily than their unsubstituted counterparts,
we studied this electrophilic ketone activation computation-
ally. Figure 1 shows the computed reaction profile for the
conversion of the initial intermediate A into the ketenimi-
nium analogue C via the vinyl triflate B. Three systems are
presented for comparison: the system I derived from para-
methoxy-acetophenone, II—from the dihydrofuran-substi-
tuted acetophenone and III—from unsubstituted acetophe-
none.
Unfortunately, with 4-methoxypropiophenone and
diphenyl sulfoxide, the one-pot approach did not furnish the
target compound in satisfactory yields. Monitoring the
1
activation of 4-methoxypropiophenone by H NMR showed
that the consumption of the starting material to generate the
vinyl triflate reaction intermediate A competes with the
decomposition of the latter (see the SI for details). Hence, we
hypothesized that the observed low yields may stem from the
presence of the pyridinium triflate 9 in the reaction mixture
after the generation of the reactive intermediate (Sche-
me 2b). To this end, a telescoped approach, in which we
added a non-polar solvent after the generation of vinyl
triflate, in order to precipitate 9, was developed. This protocol
increased the yields of a-aryl-a-alkyl ketones 7 to syntheti-
cally useful levels and was then applied to unactivated
acetophenones, also increasing the yields of a-aryl-a-alkyl
ketones 8 with respect to the one-pot procedure.
The first step is deprotonation by the base (2,6-dimethyl-
pyridine is used for the calculations), leading to the vinyl
triflate B via the transition state TSA-B with a small barrier of
DG°(A!B, I) = 9.8 kcalmolꢀ1. This step is highly exergonic
Inspired by previous work in our group,[14] we then sought
application of this novel ketone activation to a-oxyamination
(Scheme 3a).[18] Following removal of pyridinium triflate 9,
we substituted addition of an aryl sulfoxide for an excess of
TEMPO to yield products 10. As previously observed upon a-
arylation, 4-methoxyacetophenone and its 3-haloanalogues
(DG(A!B, I) = ꢀ30.2 kcalmolꢀ1).
2
ꢀ
In the next step, the C(sp ) O bond with the triflate
fragment is broken and the intermediate C is formed via the
transition state TSB-C. The computed barrier of the B!C step
is substantially lower for the cyclic system II: DDG° =
DG°(B!C, I)ꢀDG°(B!C, II) = 2.2 kcalmolꢀ1. This means,
in accordance with the Eyring equation, that the half-life time
(t1/2) of the step B!C for system II is approx. 40 times smaller
as compared to system I. This result agrees well with the
experimental evidence. Intermediate C is also found to be
3.1 kcalmolꢀ1 more stable for system II. In the case of system
III, intermediate C is highly destabilized (DG(B!C, III) =
28.4 kcalmolꢀ1) and undergoes a barrierless rearrangement to
the deprotonated form intermediate C’ with a distinctive
hydrogen bond, as shown in Figure 1. The intermediate C’ is
connected to the corresponding vinyl triflate B via transition
state TSB-C’ with the very high barrier of DG°(B!C’) =
27.8 kcalmolꢀ1. The latter explains the experimental obser-
vation that elevated temperatures are required for the
reaction with unsubstituted acetophenone. The second step
B!C is computed to be endergonic. However, intermediate
C undergoes additional steps leading to the final products
making the overall process thermodynamically accessible.
Our calculations show that in the case of the system III the
sigmatropic rearrangement precursor intermediate D can be
obtained directly from intermediate C’ via the transition state
TSC’-D
.
It is worth noting that calculations deny the possibility of
a concerted conversion of the intermediate A to C. The
mechanism is stepwise and requires the formation of the
intermediate B.
In summary, we have shown that the electrophilic ketone
activation enables a-arylation, -oxyamination and formation
Scheme 3. a) a-Aminoxylation of acetophenones; b) Application of
ketone activation to the synthesis of a morpholine.
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Acknowledgements
Funding of this research by the Austrian Science Fund
(P30226) and the European Research Council (ERC CoG
682002 VINCAT) is acknowledged. We are grateful to the
University of Vienna for continued support of our research
programs.
Conflict of interest
The authors declare no conflict of interest.
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Keywords: sigmatropic rearrangement · vinyl cations ·
vinyl triflate · a-arylation · a-oxyamination
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Manuscript received: May 3, 2020
Version of record online: && &&, &&&&
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Communications
Ketone Activation
W. Zawodny, C. J. Teskey, M. Mishevska,
M. Vçlkl, B. Maryasin, L. Gonzꢁlez,
N. Maulide*
&&&& — &&&&
a-Functionalisation of Ketones Through
Metal-Free Electrophilic Activation
Electrophilic ketone activation: Triflic
anhydride mediated activation of aceto-
phenones leads to highly electrophilic
intermediates undergoing various trans-
formations with nucleophiles. The meth-
odology gives access to a-arylated and a-
oxyaminated acetophenones under
metal-free conditions in moderate to
excellent yields.
6
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