Palladium-catalyzed acetylation of arenes

Article abstract of DOI:10.1021/ol403570z

A simple method for the preparation of aryl methyl ketones is reported. The transformation involves the Pd-catalyzed coupling of an acyl anion equivalent, acetyltrimethylsilane, with aryl bromides to afford the corresponding acetylated arenes in synthetically useful yields. The methodology is tolerant of heterocycles and provides a new method for arene functionalization.

Full text of DOI:10.1021/ol403570z

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Acetylation of Arenes
Stephen D. Ramgren and Neil K. Garg*
Department of Chemistry and Biochemistry University of California, Los Angeles, California 90095-1569, United States
S
* Supporting Information
ABSTRACT: A simple method for the preparation of aryl methyl
ketones is reported. The transformation involves the Pd-catalyzed
coupling of an acyl anion equivalent, acetyltrimethylsilane, with aryl
bromides to afford the corresponding acetylated arenes in
synthetically useful yields. The methodology is tolerant of
heterocycles and provides a new method for arene functionaliza-
tion.
alladium-catalyzed cross-couplings remain indispensable
hydrolysis,8 and cross-coupling of α-alkoxyvinyl metal reagents
with ensuing hydrolysis.9,10 The most commonly used of these
cross-couplings is highlighted in Figure 1. Stannane 1 can be
coupled to aryl electrophiles to give ketone products 2 after
hydrolysis of the intermediate coupling adduct.5,10
We envisioned an alternative approach that would employ
commercially available acetyltrimethylsilane (3).11 Acyl silanes,
which are stable acyl anion precursors,12 exhibit umpolung
reactivity of typical carbonyl moieties and have seen limited use
in Pd-catalyzed cross-couplings.13,14 For instance, Schmink and
Krska employed arylsilylketones for the synthesis of biaryl
ketones,14 whereas others have studied the reaction of acyl
silanes with allylic and benzylic substrates.15 Herein, we
demonstrate that acylsilane 3 readily undergoes Pd-catalyzed
cross-coupling with a variety of aryl and hetaryl bromides to
efficiently deliver aryl and hetaryl methyl ketones.
P
tools for the assembly of carbon−carbon (C−C) bonds.1
Whereas most C−C bond-forming methodologies allow for
aryl−aryl or aryl−alkene couplings to proceed, fewer methods
are available to introduce aryl-carbonyl linkages from standard
electrophilic cross-coupling partners (Figure 1). Catalytic
We began our study by exploring the cross-coupling between
acylsilane 3 and p-substituted toluene electrophiles.16,17 An
extensive survey of reaction parameters (e.g., palladium
complexes, ligands, solvents, bases, temperature, additives,
substrates) led to the identification of reaction conditions
that facilitated the desired acetylation. Although yields were
modest using p-iodotoluene as the substrate (Table 1, entry 1),
treatment of p-bromotoluene with acetyltrimethylsilane (3) in
the presence of catalytic Pd(PPh3)4 and CsF, in 1,2-dichloro-
ethane at 75 °C for 6 h, afforded the desired acylated arene 4 in
79% yield (entry 2). The use of the corresponding triflate also
gave 4 in good yield (entry 3). With promising optimized
conditions in hand, we tested additional bromide and triflate
substrates. In the case of naphthyl derivatives, coupling took
place to deliver ketone 5 (entries 4 and 5). The corresponding
coupling of p-bromomethoxybenzene proceeded smoothly
(entry 6), whereas lower yields of 6 were obtained for the
coupling of the corresponding triflate (entry 7). As the aryl
bromides generally performed best, we elected to focus our
subsequent efforts on their cross-coupling with acylsilane 3.
Figure 1. Known couplings and our approach to aryl and hetaryl
methyl ketones 2.
couplings of aryl electrophiles to generate aryl carbonyl
derivatives typically involve the use of CO or CO2,2 which
can be undesirable because of safety and practical consid-
erations.3
Aryl methyl ketones are an integral class of carbonyl
derivatives, which serve as versatile synthetic building blocks.
Not only do aryl methyl ketones participate as precursors to
heterocycles, fragrances, and resins,4 they have also been used
as intermediates in the syntheses of a variety of drug
candidates.5 Several cross-coupling approaches to aryl methyl
ketones have been reported, including carbonylative cross-
couplings,6,7 Heck reactions of enol ethers with subsequent
Received: December 10, 2013
© XXXX American Chemical Society
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Letter
a
Table 1. Initial Survey of the Reaction Scope
Figure 2. Scope of acetylation using aryl bromide coupling partners.
Conditions: Pd(PPh3)4 (5 mol %), substrate (1 equiv), 3 (2 equiv),
CsF (4 equiv), trimethoxybenzene (0.1 equiv), 6 h. The yield of the
product was determined by 1H NMR analysis of crude reaction
mixtures using trimethoxybenzene as an internal standard. For 7,
Pd(PPh3)4 (10 mol %) was used.
a
Conditions: Pd(PPh3)4 (5 mol %), substrate (1 equiv), acylsilane 3
b
(2 equiv), CsF (4 equiv), trimethoxybenzene (0.1 equiv), 6 h. Yield
of product was determined by H NMR analysis of crude reaction
1
mixtures using trimethoxybenzene as an internal standard.
As shown in Figure 2, the methodology is tolerant of a
variety of functional groups on bromoaromatic substrates.
Electron-deficient substrates containing ester or ketone func-
tional groups underwent the desired coupling to give ketone-
containing products 7−9. Additionally, trifluoromethyl and
chloride bearing substrates were successfully employed, as
demonstrated by the formation of coupled products 10 and 11,
respectively. We also examined substrates bearing amine and
methoxy substituents and found that products 12−14 could be
obtained without event. Although the formation of 14
demonstrates that ortho substituents are tolerated, we further
validated this notion by coupling o-bromotoluene to give 15 in
56% yield. Additional products obtained include 16−18, which
show that the m-methyl group is tolerated, in addition to vinyl
and acetal functional groups. It should be noted that several of
the compounds obtained would likely be challenging to
synthesize through standard Friedel−Crafts acylation chemistry
(e.g., 9, 10, and 13).18
Figure 3. Scope of acetylation using hetaryl bromide coupling
partners. Conditions: Pd(PPh3)4 (5 mol %), substrate (1 equiv), 3 (2
equiv), CsF (4 equiv), trimethoxybenzene (0.1 equiv), 6 h. The yield
of the product was determined by 1H NMR analysis of crude reaction
mixtures using trimethoxybenzene as an internal standard. For 19, 20,
and 24, Pd(PPh3)4 (10 mol %) was used.
We also examined a variety of heterocyclic substrates, which
proved to be excellent cross-coupling partners (Figure 3).
Pyridine19 and quinoline substrates were tolerated, as judged by
the formation of ketones 19 and 20. Indoles and aza-derivatives
B
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Letter
could also be employed in this methodology to afford 21−23.
We also tested O- and S-containing heterocycles and found that
products 24−26 were formed in good to excellent yields.
To further probe the scope and utility of the acetylation
methodology, estrone derivatives 27 and 29 were independ-
ently subjected to the coupling conditions (Figure 4). We were
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Figure 4. Acetylation of estrone derivatives 27 and 29.
delighted to find that the acetylation proceeded in both cases to
furnish 28 in 58% and 90% isolated yields, respectively. The
ability to access 28 demonstrates that the acetylation
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the derivatization of biologically relevant compounds.
In summary, we have developed an efficient and simple
method for the synthesis of aryl methyl ketones. The
transformation relies on the Pd-catalyzed coupling of aryl
bromides with the commercially available reagent acetyltrime-
thylsilane (3) to furnish the desired cross-coupled products in
good or excellent yields. The methodology is tolerant of a
variety of functional groups, in addition to N-, O-, and S-
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useful for arene functionalization in the complex settings
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ASSOCIATED CONTENT
* Supporting Information
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Experimental details and compound characterization data. This
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: neilgarg@chem.ucla.edu.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Liana Hie (UCLA) for helpful discussions. The
authors are grateful to Boehringer Ingelheim, DuPont, Eli Lilly,
Amgen, AstraZeneca, Roche, Bristol-Myers Squibb, the Camille
and Henry Dreyfus Foundation, the A. P. Sloan Foundation,
the S. T. Li Foundation, and the University of California, Los
Angeles for financial support. S.D.R. thanks the Foote Family
and the UCLA Graduate Division’s Dissertation Year Fellow-
ship Program for support of his graduate studies. These studies
were supported by shared instrumentation grants from the NSF
(CHE-1048804) and the National Center for Research
Resources (S10RR025631).
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heterocyclic substrates, it should be noted that exposure of 2-
chloropyridine to our optimal reaction conditions delivered the
corresponding methyl ketone product, albeit in a modest 23% yield.
D
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