α-Arylation of Carbonyl Compounds through Oxidative C?C Bond Activation

Article abstract of DOI:10.1002/anie.201904899

A synthetically useful approach for the direct α-arylation of carbonyl compounds through a novel oxidative C?C bond activation is reported. This mechanistically unusual process relies on a 1,2-aryl shift and results in all-carbon quaternary centers. The transformation displays broad functional-group tolerance and can in principle also be applied as an asymmetric variant.

Full text of DOI:10.1002/anie.201904899

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Title: a-Arylation of Carbonyl Compounds by Oxidative C−C Bond
Activation
Authors: Jing Li, Adriano Bauer, Giovanni Di Mauro, and Nuno Maulide
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10.1002/anie.201904899
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-Arylation of Carbonyl Compounds by Oxidative C−C Bond
Activation
Jing Li, Adriano Bauer, Giovanni Di Mauro and Nuno Maulide*
Abstract: A synthetically useful approach for the direct -arylation of
carbonyl compounds via a novel oxidative C-C bond activation is
reported. This mechanistically unusual process relies on a 1,2-aryl
shift and results in all-carbon quaternary centers. The transformation
displays broad functional group tolerance and is amenable to an
asymmetric variant.
disubstituted ketone nucleophile 1, to an enolonium F [9a,b,c]. We
then hoped to funnel this intermediate selectively to the
phenonium intermediate G – ring-opening of which would
effectively constitute a novel approach for the -arylation of
carbonyl compounds and formation of a quaternary center.
Herein we report the development of this approach into a formal
metal-free -arylation by oxidative C-C bond activation.
The appendage of an aryl substituent to the -position of a
carbonyl moiety remains a transformation of central importance in
synthetic organic chemistry. The advent of powerful metal-
catalysed coupling processes paved the way for the introduction
of catalytic (involving mainly organometallic complexes of Pd and
Cu) coupling reactions uniting aryl halides (or equivalents) to
carbonyl-derived enolates.[1,2] Pre- and post-dating these
advances, useful transition-metal free -arylation processes have
involved stoichiometric reactions of enolate anions (or
equivalents) with electrophilic aromatic derivatives of Bi(V),[3]
Pb(IV),[4] I(III),[5] S(IV)[6] or benzyne.[7] Stepwise methods by initial
formation of N-alkoxyenamines[8] or enolonium equivalents
followed by nucleophilic attack have also used for -arylation of
ketones[9b,9d]
.
We have established
a
research program exploiting the
electrophilic activation of amides drawing on pioneering work from
the groups of Ghosez,[10] and more recently Charette,[11]
Movassaghi,[12] Huang and others.[13] A current focus of interest
resides in the implications of an Umpolung strategy exploiting
pyridine
N-oxide-mediated
formation
of
enolonium
equivalents[9,14] under mild conditions, enabling a series of novel
transformations for the α-functionalization of amides.[15]
During these studies, an unexpected result caught our attention
(Scheme 1b). Substrate A, bearing a phenyl group in -position
of the amide, generated trace amounts of an unexpected product
C. Our mechanistic interpretation of this result suggested that
fragmentation of the enolonium B was triggered by nucleophilic
attack of the neighboring arene to generate phenonium
intermediate D.[16] Ring-opening by weakly nucleophilic triflate
accounted for formation of the unexpected product C.
Scheme 1. Representative approaches for -functionalisation of carbonyl
compounds and a proposed arylation via C-C bond activation. PNO: pyridine-
N-oxide; Tf2O: trifluoromethanesulfonic anhydride; 2-I-Py: 2-iodo-
pyridine.
Aiming to capitalize on this serendipitous observation in a more
general context, we hypothesized that a metal-free -arylation by
skeletal reorganization could be developed (Scheme 1c). Our
mechanistic postulate involved conversion of a generic, -
A number of potential pitfalls are readily apparent in this ambitious
proposal. Most notably, 1) intermediate F has a readily available
elimination pathway accessible to generate a particularly stable
-aryl-,-unsaturated carbonyl compound 3 and 2) even if it
survives elimination, intermediate F can suffer direct attack by any
nucleophile in solution to form (in this case) undesired -
functionalized, Umpolung products 2.[9a] Aware of these possible
problems, we began our investigations on the proposed oxidative
C-C bond activation reaction with ketoester 1a, a compound with
a beneficial, sizeable enol content. Aiming to develop an
[*]
Dr. J. Li, A. Bauer, G. Di Mauro, Prof. Dr. N. Maulide
University of Vienna, Institute of Organic Chemistry
Währinger Strasse 38, 1090 Vienna, Austria
Homepage: http://maulide.univie.ac.at
E-mail: nuno.maulide@univie.ac.at
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201904899
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operationally simple protocol, we explored the use of
commercially available ethyl 2-benzylacetoacetate 1a and
different oxidants to mediate the proposed process. (see the SI
for a detailed optimization) After considerable experimentation,
we found that iodosobenzene (1.2 equiv.) and MsOH (2.4 equiv.)
enable reorganization of 1a to -arylation product 4a by oxidative
C-C bond activation in an excellent 81% yield (Scheme 2).
Finally, we turned our attention to nucleophiles other than
methanesulfonate (MsO-). Gratifyingly, when Pyridine·9HF was
used instead of MsOH, the -fluoride product 4o was obtained in
moderate yield.
After these promising investigations on oxidative C-C bond
activation on active methylene compounds, we turned our
attention to simple ketones. In the event, our investigations
showed that ketone-derived silyl enol ethers featuring an arene
residue in allylic position are also amenable to this transformation,
resulting in -arylated products (Scheme 3). As shown, electron-
donating groups such as 3,4-di-OMe 6d was well tolerated in the
migrating arene. Their electron-poor counterparts (cf. p-CF3
6m)[16b] afforded lower yields, likely a consequence of diminished
migratory ability. Interestingly, this approach can be employed to
convert ,-diphenyl substituted ketones to product 6n in very
good yield and as a single diastereoisomer.
Scheme 2. Scope of oxidative C-C bond activation of 2-benzyl-
substituted 1,3-dicarbonyl compounds. Reaction Conditions: [a] Reactions
conducted on 0.2 mmol scale. All yields refer to pure, isolated materials.
See SI for details. [b] Pyridine.9HF (0.1 mL) used instead of MsOH. DCM:
dichloromethane; MSOH: methanesulfonic acid. OMS: mesylate
Scheme 3. Scope of oxidative C-C bond activation of ketone-derived silyl
enol ethers. [a] Reactions conducted on 0.2 mmol scale. All yields refer to
pure, isolated materials. See SI for details. BF3•Et2O: boron trifluoride
diethyl etherate.
group.
In a preliminary effort to identify asymmetric variants of this
oxidative C-C bond formation, chiral hypervalent iodane 7[17] was
prepared and examined in the reaction of silyl enol ether 5a
(Scheme 4). Promisingly, the reaction proceeded in good yield
and an enantioselectivity of 70% ee was obtained after only 5
minutes at -78 °C.
With optimized conditions in hand, we then turned our attention to
the scope of this transformation (Scheme 2). First, we evaluated
a range of 2-benzyl-substituted 1,3-dicarbonyl compounds under
our conditions, such as ketoester 4a, ketoamide 4b, diketone 4j
or the ketonitrile 4h. The reactions proceeded smoothly, affording
the desired products in good chemical yield. Furthermore, this
transformation exhibited good tolerance to diverse aromatic
substitution (4i-4n).
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Scheme 4. Enantioselective -arylation of 5a via oxidative C-C bond
activation.
[4]
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The resulting -arylated ketones lend themselves to further
functionalization. For instance (Scheme 5), diastereoselective
reduction of 6a with LiAlH4 proceeds in quantitative yield [18]. This
results in 1,3-diol 8, a single isomeric species containing vicinal
stereocenters. Alternatively, simple treatment of 6a with NH2NH2
results in pyrazoline 9[19] in very good chemical yield.
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Scheme 5. Functionalization of oxidative C-C bond activation product
6a. See SI for details. LiAlH4: lithium aluminium hydride; NH2NH2:
hydrazine.
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In conclusion, a metal-free, stereoselective -arylation of carbonyl
compounds by oxidative C-C bond activation was developed. The
ability to use simple and easily available reagents under mild
condition is a distinctive feature of this process, which effectively
cleave and reorganize C-C bonds in simple carbonyl-containing
feedstocks.
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Generous support of our research programs by the University of
Vienna is acknowledged. We are grateful for financial support of
this research by the ERC (CoG VINCAT), the FWF (Project
P30226).
Keywords: Ketone • Arylation • Umpolung • C-C bond activation
• Enolonium
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Jing Li, Adriano Bauer, Giovanni Di Mauro and Nuno
Maulide*
Page No. – Page No.
-Arylation of Carbonyl Compounds by Oxidative
C−C Bond Activation
Oxidative activation: A synthetically useful approach for the direct -
arylation of carbonyl compounds via a novel oxidative C-C bond activation is
reported. This mechanistically unusual process relies on a 1,2-aryl shift and
results in all-carbon quaternary centers. The transformation displays broad
functional group tolerance and is amenable to an asymmetric variant.
This article is protected by copyright. All rights reserved.