Palladium-Catalyzed Direct β-C?H Arylation of Ketones with Arylboronic Acids in Water

Article abstract of DOI:10.1002/adsc.201700277

A palladium-catalyzed direct β-C?H arylation of ketones was developed under mild conditions in water, featuring commercially available arylboronic acids as nucleophilic aryl sources and o-iodoxybenzoic acid as the oxidant. The method provides a concise route to access β-arylated ketones. Preliminary studies indicated that direct asymmetric β-C?H arylation of ketones could be achieved by this strategy. (Figure presented.).

Full text of DOI:10.1002/adsc.201700277

Title: Palladium-catalyzed direct β-C-H arylation of ketones with
arylboronic acids in water
Authors: Xiaoyun Hu, Xiaobo Yang, and Xijie Dai
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10.1002/adsc.201700277
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Direct β-C-H Arylation of Ketones with
Arylboronic Acids in Water
Xiaoyun Hu,a,b Xiaobo Yang,a Xi-Jie Daia and Chao-Jun Li*a
a
Department of Chemistry and FQRNT Centre for Green Chemistry and Catalysis, McGill University, Montreal, QC
H3A 0B8, Canada. email: cj.li@mcgill.ca
College of Chemistry and Materials, South-Central University for Nationalities, Wuhan, 430074, PR China
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: A palladium-catalyzed direct β-C-H arylation of
ketones was developed under mild conditions in water,
featuring commercially available arylboronic acids as
nucleophilic aryl sources and o-iodoxybenzoic acid as the
oxidant. The method provides a concise route to access β-
arylated ketones. Preliminary studies indicated that direct
asymmetric β-C-H arylation of ketones could be achieved
by this strategy.
Keywords: β-C-H arylation; arylboronic acids; o-
iodoxybenzoic acid; β-arylated ketones; palladium
Functionalization of carbonyl compounds to form
new C-C bonds is of vital importance in organic
synthesis.[1] While carbonyl groups and their α-
Scheme 1. Direct β-C-H arylation of ketones.
hydrogens are prone to functionalization due to their
intrinsic electrophilicity and acidity, the direct β-
functionalization of carbonyl compounds remains a
challenging academic pursuit. Past decades have
diaryliodonium salts from aryl iodides or arylboronic
although additional steps are required to synthesize
acids.[10]
witnessed increasing synthetic efforts to address this
challenge.[2] The β-C-H arylation of carbonyl
derivatives, such as amides,[3] ester,[4] carboxylic
acid[5] and 1,3-dicarbonyl compounds,[6] has been
successfully developed. In contrast, little progress has
been made in the direct β-C-H arylation of ketones
until very recently. Classified by the mechanistic
profile, the development in this direction includes the
photo-initiated single electron transfer (SET) process,
Palladium(II) catalyst serves two purposes in the
previous catalytic β-C-H arylation protocols: (1) to
catalyze ketone dehydrogenation, and (2) to generate
aryl nucleophiles from electrophilic aryl species by
oxidative addition. The use of electrophilic aryl
sources demands heating and the presence of the
oxidant in these routes, likely due to the involvement
of Pd(0)/Pd(II) cycle. To achieve direct β-C-H
arylation of ketones under milder conditions, we
envisioned an alternative oxidation/conjugate
addition process without the involvement of
Pd(0)/Pd(II) cycle, whereby nucleophilic aryl
reagents replace the electrophilic aryl precursors.
Among known nucleophilic reagents, commercially
available arylboronic acids have been widely used
due to their commercial availability and stability to
heat, air and water, as well as the ease of handling
and compatibility with a wide range of functional
groups.[11] Herein we report a novel direct β-C-H
arylation of ketones under very mild conditions in
and
the
transition
metal-catalyzed
oxidation/conjugate addition sequence. The former
method utilizes electron-deficient aryl cyanides as the
aryl source (Scheme 1a).[7] In the latter case,
electrophilic aryl iodides are employed in a
palladium-catalyzed β-C-H arylation of ketones via a
successive dehydrogenative oxidation and conjugate
addition at elevated temperature (Scheme 1b-1).[8] To
avoid the stoichiometric silver-based oxidant and air-
sensitive P(i-Pr)3 ligand, hypervalent diaryliodonium
salts were proven effective alternatives as both the
oxidant and the aryl source (Scheme 1b-2),[9]
1
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10.1002/adsc.201700277
Advanced Synthesis & Catalysis
aqueous solution,[12] in which readily available o-
iodoxybenzoic acid (IBX)[13] is used as the oxidant
and arylboronic acids as nucleophilic reagents.
this reaction, providing 3a in 78% yield. The survey
on reaction solvents showed that the reaction can
proceed in neat water (entry 5), but the addition of a
small amount of DMSO is favorable for forming 3a
in high yield (entry 6). Other palladium and rhodium
catalysts were also tested (entries 7-10), and
Pd(bpy)Cl2 showed the best catalytic performance.
Additionally, the effect of additives, such as
pyrrolidine and L-proline, was also examined (entries
11-14). The absence of TFA or the addition of
pyrrolidine led to low yield of 3a and the formation
of 10-15% the Heck-type product 4a. Furthermore, it
was observed that deboronation of 2a occurred under
the above conditions. Since there are two competing
reactions for 2a―nucleophilic addition and
deboronation, this reaction was subjected to milder
reaction conditions. To our delight, the reaction can
To test our hypothesis, cyclohexanone 1a and
phenylboronic acid 2a were used in the model study
(Table 1). The choice of oxidant is very crucial for
the success of this tandem oxidative transformation.
It has to satisfy the following criteria: (a) be
compatible with the conditions of conjugate addition
reaction, (b) be able to selectively oxidize
cyclohexanone 1a in the presence of oxidative-
coupling prone phenylboronic acid 2a, and (c) be able
to prevent the over-oxidation of 1a. Examination of
oxidants was initially conducted in the presence of
Pd(II) complex bound to 2,2’-bipyridine (bpy) in
water at 75 oC. Various common oxidants such as O2,
H2O2, tBuOOH and oxone failed to afford the desired
β-arylated product (entries 1-4). When O2 was used
o
proceed much better at room temperature (ca. 23 C)
as an oxidant, most of 2a was converted into biphenyl. and afforded 3a in 87% yield in a prolonged reaction
IBX was found to be the preferred oxidant to promote
time (entry 14).
Table 1. Optimization of the reaction conditions[a].
Entry[a] Oxidant
Catalyst
Additive
Yield of 3a (%)[b]
4a (%)[b]
1[c]
2
O2
Pd(bpy)Cl2
Pd(bpy)Cl2
Pd(bpy)Cl2
Pd(bpy)Cl2
Pd(bpy)Cl2
Pd(bpy)Cl2
Pd(OAc)2/bpy
Pd(OAc)2
-
-
-
H2O2
tBuOOH
oxone
IBX
IBX
IBX
IBX
IBX
IBX
IBX
IBX
IBX
IBX
-
-
-
3
-
-
-
4
-
-
-
5[d]
6
TFA
66
78
51
34
55
-
trace
trace
-
TFA/DMSO
TFA/DMSO
TFA/DMSO
TFA/DMSO
NaHCO3/DMSO
DMSO
7
8
trace
trace
-
9
Pd(4,4′-(OMe)2bpy)Cl2
[RhCl(cod)]2
Pd(bpy)Cl2
Pd(bpy)Cl2
Pd(bpy)Cl2
Pd(bpy)Cl2
10
11
12[e]
13[e]
14[e]
42
trace
31
87
10
L-proline/DMSO
Pyrrolidine/DMSO
TFA/DMSO
-
15
trace
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), oxidant (1.5 equiv), catalyst (5 mol%), TFA (1.0 equiv) and DMSO
[b]
1
(10 equiv) in 1.0 mL H2O under atmospheric conditions for 16 h. Yields were determined by H-NMR spectroscopy
using trimethoxybenzene as the internal standard. Biphenyl was obtained. 6 equiv TFA was used. Reactions were
carried out at r.t. for 72 h. TFA=trifluoroacetic acid.
[c]
[d]
[e]
With the optimized reaction conditions in hand, the
scope of arylboronic acids was explored (Table 2). In
general, arylboronic acids bearing electron-donating
or electron-withdrawing groups all reacted efficiently
with 1a. Various electron-rich arylboronic acids such
as phenyl-, 4-tolyl-, 4-methoxylphenyl, 3-
methoxylphenyl, 4-tert-butylphenyl and 2-
naphthylboronic acids proceeded smoothly at room
temperature to give the desired product in good to
excellent yields (3a-3f). 4-Bromophenylboronic acid
2
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10.1002/adsc.201700277
Advanced Synthesis & Catalysis
Table 2. Scope of arylboronic acids[a].
Table 3. Scope of ketones[a,b]
.
[a] Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), IBX
(1.5 equiv), Pd(bpy)Cl2 (5 mol%), TFA (1.0 equiv) and
DMSO (10 equiv) in H2O (1.0 mL) under atmospheric
conditions for 72 h. [b] The d.r. values were determined by
[a]
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), IBX
o
GC analysis. [c] Reactions were carried out at 75 C for 16
(1.5 equiv), Pd(bpy)Cl2 (5 mol%), TFA (1.0 equiv) and
DMSO (10 equiv) in H2O (1.0 mL) under atmospheric
conditions for 72 h. [b]50 oC, 24 h. [c] 2.0 equiv 2, 75 oC, 16
h.
h.
group at C4-position gave the trans products with
excellent diastereoselectivity (> 20:1) (3u-3w), albeit
in low yields. Linear as well as five- and seven-
membered ring cyclic ketones were also successfully
arylated with arylboronic acids (3x-3ab).
This method was applied to synthesize β-
substituted cyclopentadecanone, the main component
of musk.[14] As illustrated in Scheme 2, with this
direct β-C-H arylation method, ketone 5 was obtained
in a single step from cyclopentadecanone, while five
steps were generally required previously for
preparing β-substituted cyclopentadecanone from the
same ketones.[15]
Our attempt to carry out an enantioselective β-C-H
arylation of ketones based on this strategy was
successful by combining a chiral diphosphine
ligand[16] with Pd(II), providing chiral 3a with
excellent enantioselectivity (up to 95% ee) (Scheme
3), although with a low conversion at this stage.
Efforts towards developing highly efficient and
enantioselective transformations are ongoing.
was also reactive in this reaction, affording the
desired product in 70% yield (3g). However, the
reaction proceeded less efficiently when 4-
chlorophenyl- and 4-fluorophenylboronic acids were
used at room temperature. By increasing the reaction
o
temperature to 50 C, the corresponding β-arylated
ketones were obtained in good yields (3h, 3i). For
arylboronic acids with electron-withdrawing or
sterically hindered groups such as 2-bromophenyl, 4-
trifluromethylphenyl, 3-trifluromethylphenyl, 4-
methoxy carboxyphenyl, 4-acetylphenyl, 4-biphenyl
and 1-naphthyl, a higher temperature was typically
o
required. By elevating the temperature to 75 C, the
desired β-C-H arylated products were also obtained in
moderate to good yields (3j-3p).
Furthermore, different ketones reacted with
phenyl-, 4-tolyl, 4-fluorophenyl, 4-acetylphenyl- and
4-tert-butylphenylboronic acids to afford the
corresponding β-arylated ketones in moderate to good
yields (Table 3). Substituents at the γ-position of
cyclohexanone caused a negative effect on the
reaction efficiency. Direct β-C-H arylation of 4-
methylcyclohexan-1-one proceeded smoothly with
electron-rich arylboronic acids at room temperature,
and with electron-withdrawing arylboronic acids at
higher temperature to afford relatively satisfying
yields (3q-3t). However, the presence of a phenyl
3
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10.1002/adsc.201700277
Advanced Synthesis & Catalysis
Scheme 2. Direct β-C-H arylation of cyclopentadecanone.
Scheme 4. A tentative mechanism for the direct β-C-H
arylation of ketones.
stability towards air and water, as well as
compatibility with a wide range of functional groups.
Additionally, the very mild conditions in aqueous
solution make this method more user-friendly and
more promising to obtain asymmetric β-C-H
arylation products.
Scheme 3. Preliminary examination of asymmetric direct
β-C-H arylation of 1a.
Experimental Section
General procedure for the direct β-C-H arylation of
To better understand this chemistry, two control
experiments were conducted (Scheme 4). The results
showed that 2-cyclohexen-1-one could also afford the
β-C-H arylated product 3a in 68% yield under the
standard reaction conditions; whereas in the absence
of Pd(bpy)Cl2, the reaction only furnished 2-
cyclohexen-1-one in 72% yield, and compound 3a
was not observed. Based on the previous report[17] on
Pd(II)-catalyzed conjugate addition and our
mechanistic studies, a tentative mechanism is
proposed for this reaction (Scheme 4). Firstly,
enolization of ketones catalyzed by acids occurred,
and the enol reacted with IBX to generate α,β-
unsaturated ketones.[13g] Then, Ar-[Pd] formed via
transmetalation of the aryl group from arylboronic
acids to the palladium reacted with the C=C bond of
α,β-unsaturated ketones to give a palladium enolate A.
Finally, protonolysis of A furnished the desired β-
arylated ketone with regeneration of the Pd catalyst.
In conclusion, we have developed a simple and
efficient protocol for direct β-C-H arylation of
ketones with arylboronic acids under mild conditions
in water. The use of commercially available
arylboronic acids as aryl source would make this
method more practical and popular due to their
ketones with aryboronic acids
In a 10 mL microwave vial were combined ketone (0.20
mmol), arylboronic acid (0.30 mmol), Pd(bpy)Cl2 (3.3 mg,
5 mol%), IBX (0.3 mmol), DMSO (2.0 mmol) and TFA
(0.20 mmol) in water (1.0 mL). The mixture was then
stirred at r.t. under atmospheric conditions for the time
specified in Table 2 and 3. The mixture was then extracted
with ethyl acetate (3 × 3 mL). Solvent was removed, and
the residue was separated by column chromatography to
give the pure sample.
Acknowledgements
We thank the CSC (China Scholarship Council) for a Visiting
Scholar fellowship (XYH) and NSERC, FQRNT, CFI, and the
Canada Research Chair (to CJL) for their support of our
research.
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Advanced Synthesis & Catalysis
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This article is protected by copyright. All rights reserved.

10.1002/adsc.201700277
Advanced Synthesis & Catalysis
COMMUNICATION
Palladium-catalyzed direct β-C-H arylation of
ketones with arylboronic acids in water
Adv. Synth. Catal. 2017, Volume, Page – Page
Xiaoyun Hu,a,b Xiaobo Yang,a Xi-Jie Daia and
Chao-Jun Li*a
7
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