Vinyl Cation Stabilization by Silicon Enables a Formal Metal-Free α-Arylation of Alkyl Ketones

Article abstract of DOI:10.1002/anie.201909381

The ability of silicon to stabilize vinyl cationic species leads to a redox arylation of alkynes whereby the stringent limitations of reactivity and regioselectivity of alkyl-substituted alkynes are lifted. This allows the synthesis of a range of α-silyl-

Full text of DOI:10.1002/anie.201909381

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International Edition: DOI: 10.1002/anie.201909381
German Edition: DOI: 10.1002/ange.201909381
Sigmatropic Rearrangement
Vinyl Cation Stabilization by Silicon Enables a Formal Metal-Free a-
Arylation of Alkyl Ketones
Amandine Pons+, Jean Michalland+, Wojciech Zawodny+, Yong Chen, Veronica Tona, and
Nuno Maulide*
Abstract: The ability of silicon to stabilize vinyl cationic
species leads to a redox arylation of alkynes whereby the
stringent limitations of reactivity and regioselectivity of alkyl-
substituted alkynes are lifted. This allows the synthesis of
a range of a-silyl-a’-arylketones under mild conditions in good
to excellent yields and with high functional group tolerance,
whereby the silicon moiety in the final products can either be
removed for a formal acetone monoarylation transform, or
capitalized upon for subsequent electrophilic substitutions at
either side of the carbonyl group.
R
edox-neutral strategies for the a-functionalization of
carbonyl compounds through sigmatropic rearrangements
À
have become a powerful tool for the formation of C C bonds.
Recently, our group used this approach for the synthesis of
enantioenriched 1,4-dicarbonyl arrays from vinyl sulfoxides
and ynamides (Scheme 1a).[1] Similarly, a formal metal-free
a-arylation of carbonyl compounds can be achieved by using
aryl sulfoxides (Scheme 1a).[2] However, those methods
mandate the presence of heteroatoms[2a–d] or aryl rings[2e–f] in
the alkyne reactants as a crucial feature for stabilization of the
vinyl cation intermediate A (Scheme 1a). Even with aryl-
substituted acetylenes, the method requires somewhat forcing
conditions (high temperatures and solvent-free conditions)
and is not efficient for alkyl-substituted acetylenes. Indeed
(Scheme 1b), while phenylacetylene affords arylated prod-
ucts in excess of 90% yield, the non-aromatic counterpart
cyclohexylacetylene B provides a disappointing 32% yield of
product. In the case of unsymmetrical dialkyl-substituted
internal alkynes, this poor reactivity is compounded by
a complete lack of regioselectivity, a consequence of unse-
lective protonation.
In addition, the application of this methodology to the
synthesis of acetone-derived arylation products would require
[*] Dr. A. Pons,[+] J. Michalland,[+] Dr. W. Zawodny,[+] Dr. Y. Chen,
Dr. V. Tona, 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
[+] 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:
https://doi.org/10.1002/anie.201909381.
Scheme 1. a) Redox-neutral a-functionalization of carbonyl com-
pounds, b) limitations of reactivity and selectivity, and c) novel
approach presented herein.
ꢁ 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. 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.
the use of propyne—a gas at ambient pressure—as a starting
material, adding yet another layer of complexity to an already
convoluted problem. The direct mono-a-arylation of simple
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ketones such as acetone remains a challenge even for
palladium-catalyzed procedures, often requiring the use of
acetone as a solvent in order to avoid polyarylation.[3]
To address these issues, we envisioned to use the known
ability of silicon to stabilize a b-positive charge[4] as a tool to
solve the problems of reactivity and selectivity upon forma-
tion of vinyl cationic species. Herein, we show how silicon not
only activates the alkyne partner but decisively guides
regioselectivity for internal, dialkyl-substituted alkynes
while offering a simple protodesilylation path to the formal
a-arylation of acetone (and other simple ketones) (Sche-
me 1c).[5]
We first investigated the reaction between terminal
propargyl silane 1a and different sulfoxides in the presence
of a Brønsted acid, exploring a range of solvents (for full
optimization details, see the Supporting Information). From
the outset, high reactivity at room temperature was observed,
in sharp contrast to the sluggishness of aliphatic alkynes
described in Scheme 1b. Pleasingly, the use of bis(trifluor-
omethane)sulfonimide as acid and either dichloromethane or
nitromethane allowed the productive union of 1a and
diphenyl sulfoxide to deliver the corresponding a-silyl-a’-
arylketone 2a in a high 84% isolated yield, along with small
amounts (< 5%) of protodesilylated product. The reaction
could be readily scaled up to a 10 mmol scale to afford 2.5 g of
a-silyl ketone.
A screening of sulfoxides, depicted in
Scheme 2, revealed that a diversity of substituents were
tolerated at the para-position, such as the electron-donating
methyl, methoxy, and phenyl groups (2b–d), halogens (2e–g),
and an electron-withdrawing nitrile moiety (2h). A tricyclic
sulfoxide derived from dibenzothiophene reacted promptly to
afford compound 2i. When bis(meta,para-dimethylphenyl)
sulfoxide was used, the corresponding compound 2j was
isolated with a high yield but as a 1:1 mixture of regioisomers.
Aryl alkyl sulfoxides were also suitable partners in the
reaction, as shown by the formation of compounds 2k–o.
Importantly, and as hinted by the occasional observation of
minute amounts of protodesilylated material, a simple HCl
quench allowed direct access to product 3a—the elusive
product of redox arylation of propyne and corresponding to
a formal metal-free a-arylation of acetone (Scheme 2,
bottom).
Eager to obtain more mechanistic insights, we performed
some competition experiments. Using a 1:1 mixture of p-
chloro- and p-methyl-arylated sulfoxides, a strong (77:23)
preference for the most electron-rich sulfoxide was observed
Scheme 2. a) Scope of sulfoxide partners and b) in situ desilylation. [a] Reaction was performed in dichloromethane. [b] Reaction was performed
in nitromethane. [c] Reaction was performed on 5 mmol scale. [d] Reaction was performed on 10 mmol scale.
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Scheme 3. Competition experiments. X=TIPS or H.
(Scheme 3a), akin to the intramolecular case where a sulfox-
ide carrying both groups was used (Scheme 3b). These results
are consistent with the selectivity previously observed for this
type of rearrangement.[2e]
Figure 1. Kinetic experiments (top: kinetic plot; bottom: Hammett
plot; for details, see the Supporting Information).
Unexpectedly, we observed a marked influence of the
substitution pattern of the sulfoxide on the kinetics of the
reaction. As shown in Figure 1, when an electron-rich
sulfoxide such as bis(p-methoxyphenyl) sulfoxide was used,
the reaction was much slower than in the case of an electron-
poor counterpart (such as for example, the p-fluoro deriva-
tive). We measured the initial rate of the reaction for several
substituents and a Hammett plot showed a good correlation.
These observations suggest that the Brønsted basicity of the
sulfoxide plays an important role in the reaction (Figure 1).
Therefore, it is reasonable to suggest that triflimide first
protonates the sulfoxide, which in turn protonates the
propargyl silane with a rate that depends on its substitution.
We then turned our attention to the use of internal
alkynes in the reaction (Scheme 4). Although the reactions
were slower than in the unsubstituted case, the use of
a propargyl silane derived from 2-hexyne led to the corre-
sponding branched product 4a with complete regioselectivity.
The reaction also proceeded smoothly in the presence of
a secondary alkyl substituent (4b,c). Acetoxy- (4d), bromide-
(4e), and phthalimide- (4 f) containing substrates are toler-
ated (Scheme 4). Propargyl silanes bearing substituents a- to
the silicon rearranged into 1,3-dienes under the reaction
conditions.[6]
Scheme 4. Scope of substituted propargylsilane partners. [a] d.r.=1:1;
[b] 8 h reaction time.
Finally, having two methylene groups adjacent to the
carbonyl group in 2a, we set out to direct substitution at either
side of the molecule with by using different sets of reagents.
We hypothesized that the obtained a-silyl-a’-arylketones
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might be amenable nucleophiles for a Mukaiyama aldol-type
coupling.[7,8] Among other strategies, fluoride sources have
been reported to activate the silyl group and generate
a nucleophilic enolate.[9] In our case, the use of tetramethy-
lammonium fluoride triggered an aldol reaction in the
presence of benzaldehyde, leading to product 5 in 46%
yield (Scheme 5). We also managed to alkylate the benzylic
position using NaHMDS as a base and MeI as an electrophile
to give 6. Finally, the arylsulfanyl moiety can be easily
removed under mild conditions while preserving the triiso-
propylsilyl group to give 7.[2a]
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Scheme 5. Mukaiyama-type reaction of 2a. TMAF=tetramethylammo-
nium fluoride.
In summary, we have shown that the ability of silicon to
stabilize vinyl cationic species leads to a redox arylation
whereby the limitations of reactivity and regioselectivity of
alkyl-substituted alkynes are lifted. A range of a-silyl-a’-
arylketones were obtained under mild conditions in good to
excellent yields and high functional group tolerance. In situ
protodesilylation affords the products of a formal acetone
monoarylation while Mukaiyama-type aldol reaction and
alkylation of the benzylic position showcase the utility of
silicon incorporation in the adducts. Kinetic analysis suggests
that an unusual sulfoxide-mediated protonation is operative.
Acknowledgements
Financial support by the ERC (CoG FLATOUT 682002) and
the FWF (P 30226 and M 2407) is gratefully acknowledged.
We are grateful to the University of Vienna for continued
support of our research programs. Technical assistance by S.
Senoner (U. Vienna) is acknowledged.
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Conflict of interest
The authors declare no conflict of interest.
[9] R. Noyori, K. Yokoyama, J. Sakata, I. Kuwajima, E. Nakamura,
M. Shimizu, J. Am. Chem. Soc. 1977, 99, 1265 – 1267.
Keywords: a-arylation · sigmatropic rearrangement ·
silicon b-effect · vinyl cations
Manuscript received: July 25, 2019
Version of record online: && &&, &&&&
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Communications
Sigmatropic Rearrangement
A. Pons, J. Michalland, W. Zawodny,
Y. Chen, V. Tona,
N. Maulide*
&&&& — &&&&
Vinyl Cation Stabilization by Silicon
Enables a Formal Metal-Free a-Arylation
of Alkyl Ketones
I can Si clearly now: The ability of silicon
to stabilize vinyl cationic species enables
a redox arylation of alkynes whereby the
poor reactivity and regioselectivity of
alkyl-substituted alkynes are lifted. This
enables the synthesis of a range of a-silyl-
a’-arylketones under mild conditions in
good to excellent yields. The silicon
moiety of the products can either be
À
removed or harnessed for additional C C
bond formation.
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