Reversed-polarity synthesis of diaryl ketones via palladium-catalyzed cross-coupling of acylsilanes

Article abstract of DOI:10.1021/ja2064318

Acylsilanes serve as acyl anion equivalents in a palladium-catalyzed cross-coupling reaction with aryl bromides to give unsymmetrical diaryl ketones. Water plays a unique and crucial activating role in these reactions. High-throughput experimentation techniques provided successful reaction conditions initially involving phosphites as ligands. Ultimately, 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane was identified as giving a longer-lived catalyst with higher turnover numbers. Its use, in conjunction with a palladacycle precatalyst, led to optimal reaction rates and yields. Scope and limitations of this novel method are presented along with initial mechanistic insight.

Full text of DOI:10.1021/ja2064318

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Reversed-Polarity Synthesis of Diaryl Ketones via Palladium-Catalyzed
Cross-Coupling of Acylsilanes
Jason R. Schmink† and Shane W. Krska*,§
†Penn/Merck Laboratory for High-Throughput Experimentation, Roy and Diana Vagelos Laboratories, Department of Chemistry,
University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States
§Department of Process Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, United States
S Supporting Information
b
ABSTRACT: Acylsilanes serve as acyl anion equivalents in
a palladium-catalyzed cross-coupling reaction with aryl
bromides to give unsymmetrical diaryl ketones. Water plays
a unique and crucial activating role in these reactions. High-
throughput experimentation techniques provided success-
ful reaction conditions initially involving phosphites as
ligands. Ultimately, 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-
6-phosphaadamantane was identified as giving a longer-
lived catalyst with higher turnover numbers. Its use, in
conjunction with a palladacycle precatalyst, led to optimal
Figure 1. Cross-coupling approaches to ketone synthesis.
reaction rates and yields. Scope and limitations of this novel
method are presented along with initial mechanistic insight.
alladium-catalyzed cross-coupling reactions possess tremen-
P
dous versatility and functional group compatibility, and are
one of the most powerful tools for CÀC bond formation.1
Accordingly, Pd catalysis has been used extensively in the
formation of aryl aryl, alkyl aryl, and alkyl alkyl ketones.
Numerous reports describe the formation of ketones by coupling
activated carboxylic acid derivatives with various transmetalating
reagents2 (Figure 1A) or via carbonylative coupling of an aryl
halide with an organometallic species3 (Figure 1B).
Although these approaches have been thoroughly examined, a
third, polarity-reversed disconnection strategy has received limi-
ted attention. To date, only a handful of reports have described
the cross-coupling of acyl anion equivalents with appropriate
electrophiles to generate ketones (Figure 1C).
The majority of these protocols have involved the direct
arylation of aldehydes or activated derivatives such as imines or
hydrazones with aryl halides4 or organometallic species,5 or have
utilized vinyl ethers or metalated analogues thereof which reveal
the alkyl aryl ketone upon acidic hydrolysis of the reaction
product.6 Taken together, these reports cover a limited synthetic
scope with a patchwork of diverse reagents and conditions. If
general conditions could be identified, this reversed-polarity
approach would provide a useful alternative to the traditional
methods, and would prove especially valuable for medicinal
chemists for late-stage introduction of versatile ketone moieties
into complex scaffolds for diversity-oriented synthetic strategies.
The use of organometallic acyl compounds potentially offers
a general solution to the polarity-reversed synthesis of ketones,
although their use in cross-coupling chemistry has been ex-
plored only to a limited degree. Reports have described the
cross-coupling of acylstannanes,7 -silanes,8 and -zirconocenes9
with allylic halides and esters, affording β,γ-unsaturated ketones
Figure 2. Examples of cross-coupling of acyl organometallics (Cp =
η5-cyclopentadienyl anion).
(Figure 2A). Two of these reports also gave one example each of
low-yielding cross-coupling of acylstannane or -zirconocene
reagents with halobenzenes to give ketones (Figure 2B).7a,9a
Acyltin and -zirconocene reagents also couple with acyl chlorides,
giving unsymmetrical α,α-diketones (Figure 2C).7a,9a,10 Finally,
carbamoylsilanes11 and -stannanes12 under Pd catalysis effect the
direct carbamoylation of aryl, vinyl, benzyl, and allyl halides to
give the corresponding amides (Figure 2D).
Assessing the range of potential organometallic acyl anion
equivalents, we decided to focus our attention on silicon. The use
of silicon as competent metaloid in transition metal-catalyzed
Received: July 11, 2011
Published: November 09, 2011
r
2011 American Chemical Society
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Figure 3. Initial HTE screening lead and reaction impurity profile.
cross-coupling has been widely demonstrated,13 and acylsilanes
are stable, isolable compounds with a high functional group
tolerance. Furthermore, acylsilanes do not have the toxicity
problems associated with tin and are more accessible and easily
handled than the corresponding acylzirconocenes.14 Indeed,
there has been a recent renaissance in the use of acylsilanes as acyl
anion equivalents in addition reactions to active electrophiles
such as aldehydes,15 ketones,16 Michael acceptors,17 imines,17d,18
and nitrones19 catalyzed by Lewis bases such as fluoride, cyanide,
N-heterocyclic carbenes (NHCs), or metallophosphites. Herein
we report the successful development of a Pd-catalyzed cross-
coupling between arylacylsilanes and aryl bromides to afford the
corresponding unsymmetrical diaryl ketones.20
To begin our investigations, we utilized a high-throughput
experimentation (HTE)21 platform to assess a wide range of
conditions (Figure 3). The initial screen sought to cross-couple
4-bromoanisole 1 with phenyl trimethylsilyl ketone 2. In general,
the reaction performed best in ethereal solvents (THF, 2-MeTHF,
1,4-dioxane); [(allyl)PdCl]2 was found to be the best Pd source,
and both K3PO4 and Cs2CO3 were found to be capable bases,
although all others screened show little or no desired reactivity.
With respect to ligand, though a few bulky, electron-rich phos-
phine ligands showed some desired reactivity,22 all gave significant
amounts of the desbromination of 1 (Figure 3, SP1). Phosphites
such as triethylphosphite gave the highest levels of desired
product.23 Although reactions with phosphite ligand tended not
to form desbromination byproduct SP1, other byproducts were
observed, including decarbonylated biphenyl SP2, symmetric
biphenyl SP3, and benzaldehyde SP4 arising from the hydrolysis
of acylsilane. Surprisingly, the most crucial component for the
success of the reaction was found to be water. Of all other potential
activators screened—including alcohols, tertiary amines, pyridines,
NHCs, and numerous fluoride sources—none showed any desired
product formation. Currently, the desired reaction only proceeds in
the presence of water.13c Intrigued, we sought to probe this reaction
in more detail to gain some insight into its dynamics.
Figure 4. Comparison of reactivity using conditions A (red) vs B (blue).
range of phosphite analogues.25 Only P(Oi-Pr)3 showed modest
overall improvement (assay yield of 52%), and still with significant
side-product formation. Similarly, all attempts to dose additional
ligand or additional Pd/ligand complex over time proved unpro-
ductive, and impeded rather than augmented product formation.
Confronted with the conflicting roles of water in enabling the
desired catalytic cycle though ultimately deactivating the catalyst,
we returned to the screening platform in search of a ligand that was
tolerant of water, yet mimicked the activity of the phosphite ligands.
Gratifyingly, this second screen of 72 phosphine ligands returned
the bulky 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaada-
mantane ligand (PA-PPh; Figure 4, L1)26 that performed nearly on
par (38% yield by assay at 100 °C) with the phosphite ligands.
Additionally, this new system showed desired reactivity at lower
temperatures (80 °C, 57% yield by assay), raising the prospect that
side product formation could be attenuated at lower temperatures
while maintaining reasonable reaction times.
Recently, the design27 of aminobiphenyl palladacycle compounds
and their subsequent exploitation as a platform to generate active
Pd(0)Àligand complexes under mild conditions28 has shown some
promise in terms of increased reactivity at lower temperatures,
prompting us to explore their use in this system. Here too,
substituting the aminobiphenyl palladacycle precatalyst PC1 in place
of the in situ combination of [(allyl)PdCl]2 and free ligand L1 led to
a significant increase in catalytic activity at 80 °C (Figure 4).29 This
increased reactivity ultimately allowed the reaction temperature to be
lowered to 60 °C and provided a cleaner reaction profile. Final
optimization led to a general set of conditions: 2% of PC1, 6 equiv of
H2O, 2.5 equiv of K3PO4, and 1.5 equiv of the acylsilane in
2-MeTHF for 18À20 h at 60 °C. Using these conditions, product
3a was isolated in 78% yield after column chromatography.
These optimized reaction conditions were applied to various aryl
bromides and arylacylsilanes, providing moderate to good yields for
the synthesis of a range of unsymmetrical benzophenones (Table 1).
Aryl chlorides were tolerated (3d, 3e), as were heterocycles (3h, 3p,
3s, 3t, 3v, 3w, 3y). As the system became more sterically demand-
ing in the series 1-bromonaphthalene (3f), 2-bromoanisole (3c),
Kinetic studies showed that the reaction exhibited a significant
induction period when using 2.5% [(allyl)PdCl]2 and 10%
P(OEt)3, i.e., 1:2 Pd:L stoichiometry.22 However, upon moving
to a 1:1 Pd:L ratio the reaction initiated immediately, suggesting
that the active catalyst might be an L1Pd complex.24 In both cases
the desired reaction stalled after about 3 h at ∼40% yield. These
observations suggested the phosphite ligand was undergoing
hydrolysis under the reaction conditions, thus truncating the
useful catalyst lifetime and hampering desired product yield.
Hoping to attenuate the rate of ligand hydrolysis, we screened a
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COMMUNICATION
Table 1. Substrate Scope with Isolated Product Yields
Figure 5. Hammett plot with negative slope (F) indicating positive
charge buildup on rate-determining step.
Figure 6. Putative mechanism.
the rate-determining step.31 Next, on the basis of our observa-
tions of the crucial role of water as an activator and because
fluoride ion provided no desired product, we propose anion
metathesis and formation of the palladium hydroxo intermediate
III in our putative mechanism. It should be noted that recent
work by both Jutand and Hartwig as well as early work by
Miyaura32 similarly suggests an intermediate palladium hydroxo
complex that then undergoes transmetalation in the SuzukiÀ
Miyaura reaction under certain conditions. After transmetalation
to IV, reductive elimination yields the title benzophenone and
regenerates the PdL1 catalyst I. It is reasonable to speculate that
the buildup of positive charge indicated by the Hammett study
could manifest itself in the transitions states of any one of the
remaining three steps, i.e., ii, iii, or iv. As such, at this time no
reasonable speculation can be made as to which subsequent step
after oxidative insertion is the rate-determining step.33
In conclusion, we have disclosed an effective new strategy for
the polarity-reversed synthesis of diaryl ketones via a Pd-cata-
lyzed cross-coupling between aryl halides and arylacylsilanes. Use
of HTE techniques and in-depth investigations revealed the
crucial role water played in enabling this reaction and identified
the bulky phosphaadamantyl ligandÀpalladacycle precatalyst
PC1 combination which gave enhanced reactivity and yield.
Continued mechanistic studies and methodology extension are
underway and will be reported in due course.
a Isolated as inseparable 92:8 mixture with hydrolyzed acylsilane
(aldehyde). b Reaction time = 3 d, isolated as inseparable 95:5 mixture
with the dimerized acylsilane (1,2-diketone). c Reaction time = 2 d, 80
°C. d Reaction temp = 67 °C. e Reaction temp = 67 °C; time = 91 h.
2-bromotoluene (3g), and 2,6-dimethylbromobenzene (3r), reaction
times had to be extended to fully consume the aryl bromide (e.g., 3r, 3
days), though eventually each was isolated in modest to good yield.
Although electron-withdrawing groups were tolerated as part of
the aryl bromide (3m), the attempted coupling between 3-(tri-
fluoromethyl)phenyl trimethylsilyl ketone and 4-bromoanisole pro-
vided none of the desired benzophenone, presumably due to the
attenuated nucleophilicity and decreased hydrolytic stability of the
former. Similarly, substrates with strongly Lewis basic sites inhibited
the reaction, and heterocycles with acidic sites (e.g., pyrazoles) rapidly
decomposed the acylsilanes. However, protection of the nitrogen
allowed these substrates to engage in the desired coupling (3v, 3w,
3y). Our initial attempts to cross-couple alkanoylsilanes have been
met with some success and will be reported in due course.22
Preliminary mechanistic studies indicate these reactions ex-
hibit overall first-order kinetics across a range of electronically
diverse aryl bromides. The results of a small Hammett study
(Figure 5) suggest the buildup of positive charge during the rate-
determining step (F = À0.53).30 Though exhaustive mechanistic
studies are yet to be completed, our initial qualitative and
quantitative observations allow us to propose a putative reaction
mechanism for this transformation (Figure 6).
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and ana-
b
lytical data. This material is available free of charge via the
We speculate that traditional oxidative insertion of mono-
ligated Pd(0) complex I into bromoanisole 2 leads to Pd(II) aryl
bromide complex II. Because it is widely believed that electron-
withdrawing groups facilitate the oxidative insertion step in Pd-
catalyzed cross-coupling reactions, and given the results of the
Hammett study, we believe oxidative insertion is unlikely to be
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
shane_krska@merck.com
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’ ACKNOWLEDGMENT
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The authors dedicate this Communication to Prof. Dietmar
Seyferth. J.R.S. acknowledges the National Science Foundation
for support (NSF-GOALI 0848460). Dr. Matthew T. Tudge
(Merck & Co.) is thanked for assistance in the synthesis of PC1.
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