Direct Synthesis of Mono-α-arylated Ketones from Alcohols and Olefins via Ni-Catalyzed Oxidative Cross-Coupling

Article abstract of DOI:10.1021/acs.orglett.0c02340

Controlled synthesis of α-monoarylated ketones is significant yet challenging due to the site-selectivity issues and nonproductive overarylation reactions. Herein, we reported the direct synthesis of α-arylated ketones enabled by Ni-catalyzed dehydrogenative cross-coupling reaction cascade between alcohols and olefins. The use of readily available and cost-effective alcohols and olefins provides a straightforward access to monoarylated ketones in good yields with exclusive selectivity without using any advanced synthetic intermediates.

Full text of DOI:10.1021/acs.orglett.0c02340

pubs.acs.org/OrgLett
Letter
Direct Synthesis of Mono-α-arylated Ketones from Alcohols and
Olefins via Ni-Catalyzed Oxidative Cross-Coupling
Peng-Fei Yang and Wei Shu*
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ABSTRACT: Controlled synthesis of α-monoarylated ketones is significant yet challenging due to the site-selectivity issues and
nonproductive overarylation reactions. Herein, we reported the direct synthesis of α-arylated ketones enabled by Ni-catalyzed
dehydrogenative cross-coupling reaction cascade between alcohols and olefins. The use of readily available and cost-effective alcohols
and olefins provides a straightforward access to monoarylated ketones in good yields with exclusive selectivity without using any
advanced synthetic intermediates.
with high atom and step economy.9 This ideal process involves
etones are ubiquitous in natural products, drugs, and
Kfunctional materials and serve as key intermediates in the a metal-catalyzed insertion of a C−H bond to form an acyl-
synthesis of C−C bonds and other functional groups.1 Ketones
metal-hydride intermediate and a following addition across
olefins and reductive elimination to form the desired ketones.
In 1972, the Sakai group reported the first example of metal-
mediated intramolecular hydroacylation of olefins by using a
stoichiometric amount of a rhodium complex to afford
cyclopentanones.10 Over the past decades, significant advances
on metal-catalyzed intra- and intermolecular hydroacylation of
olefins have been made.11 However, an intermolecular version
of hydroacylations requires additional coordinating/directing
groups on aldehydes or olefins to facilitate the addition process
due to the competitive decarbonylation reaction of the acyl-
metal-hydride intermediate.12
Additionally, most current hydroacylation protocols heavily
rely on precious metals such as rhodium, which significantly
limits the opportunity for broad application of this strategy.13
Moreover, existing protocols for hydroacylation basically could
be applied to strained olefins, electronically biased olefins, or
terminal aliphatic olefins.14 Regioselective intermolecular
hydroacylation of styrenes remains a formidable challenge,
thus not being able to afford formal α-arylation of ketones. In
2016, the Zhou group reported the first nickel-catalyzed
intermolecular hydroacylation reaction of styrenes with simple
aldehydes to afford α-arylated ketones via ligand-to-ligand
are most often synthesized by the addition of an organo-
metallic reagent to an aldehydes or acid derivatives, followed
by oxidation.1a,2,3 Furthermore, site-selective and controlled
synthesis of mono-α-arylated ketones is attractive yet
challenging due to the competitive site-selectivity issues and
unproductive diarylation processes.4 Over the past decades,
selective synthesis of mono-α-aryl ketones has received much
attention. Buchwald,5 Hartwig,6 and Miura7 intensively
developed the catalytic conditions for selective direct
monoarylation from ketones. These methods suffer from the
limited scope of ketones with specific substitution patterns or
preformed ketone enolates (Scheme 1a).8 On the other hand,
transition-metal-catalyzed hydroacylation of olefins is a
potential and straightforward alternative for ketone synthesis
Scheme 1. Challenges and Strategies for Mono-α-arylated
Ketone Synthesis
Received: July 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02340
© XXXX American Chemical Society
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hydrogen transfer (LLHT) in the presence of a phosphine
ligand.15 Unfortunately, this protocol is not applicable to the
reaction of alcohols with olefins. Due to the instability and high
cost of aldehydes, the discovery of more cost-effective and
user-benign equivalents as the aldehyde surrogate would be of
synthetic interest in organic synthesis. Aliphatic alcohols are
bulk chemicals in industrial production and serve as important
precursors for the construction of value-added target molecules
in organic synthesis.16 Moreover, the use of alcohols instead of
aldehydes to access mono-α-arylated ketones would be
mechanistically interesting and challenging. First, nickel
needs to play a twofold role with one ligand in dehydrogen-
ation of alcohols to produce aldehydes17 as well as formal
regioselective hydroacylation of olefins with aldehydes. Second,
a unified reaction condition has to be identified which is
applicable to Ni-catalyzed transfer hydrogenation of alcohols
with olefins, and regioselective hydroacylation of olefins in a
sequential and controlled manner. Third, it would be of
interest to understand whether the aldehyde intermediate is
stoichiometrically or catalytically formed during the reaction
course. Thus, we envisioned accessing formal mono-α-arylated
ketones using alcohols as a more readily available, cost-
effective, and challenging surrogate for aldehydes. Herein, we
report the formal synthesis of mono-α-arylated ketones via a
Ni-catalyzed oxidative cross-coupling of alcohols with olefins.
The use of alcohols as latent carbonyl precursor allows for the
α-arylation of ketones from inexpensive starting materials in a
site-selective and controlled manner, circumventing the use of
unstable and expensive aldehydes as a carbonyl source.
We set out to explore the reaction conditions using 3-
phenylpropan-1-ol 1a and styrene 2a as substrates. After
extensive condition evaluation, we defined the optimal
conditions as the use of Ni(COD)2 (10 mol %), IAd·HCl
(10 mol %), and potassium tert-butoxide (15 mol %) in the
mixture of toluene and dioxane (1:1) at 110 °C, coupling the
alcohol with styrene to give α-phenyl ketone 3a in 85%
isolated yield (Table 1, entry 1). Due to the stoichiometric
consumption of styrene by serving as a hydrogen acceptor, 3
equiv of 2a were used. The ligand is crucial for this
regioselective oxidative hydroacylation reaction, replacing the
IAd·HCl with other NHC ligands, such as IMes·HCl, IPr·HCl,
and ICy·HCl, giving inferior results, with partial starting
material 1a recovered (Table 1, entries 2−5). A catalytic
amount of strong base is required for this transformation. The
use of sodium tert-butoxide or lithium tert-butoxide in lieu of
potassium tert-butoxide could catalyze the reaction, giving 3a
in 74% and 40% yields, respectively (Table 1, entries 6 and 7).
The use of a weaker base, such as cesium carbonate, led to
formation of a trace amount of the desired product 3a (Table
1, entry 8). Investigation of the solvent effect revealed that the
reaction proceeded in toluene, dixoane, or diglyme, albeit in
lower efficiency (Table 1, entries 9−12). Both a transition
metal and anchoring ligand are essential to the reaction, as no
reaction occurred in the absence of nickel or ligand (Table 1,
entry 13).18
Table 1. Conditions Evaluation for α-Monoarylated
Ketones
a
b
Entry
Variation from “standard conditions”
Yield (%)
c
1
none
89 (85)
d
2
3
4
5
6
7
8
9
10
11
12
13
IMes·HCl instead of IAd·HCl
SIMes·HCl instead of IAd·HCl
IPr·HCl instead of IAd·HCl
ICy·HCl instead of IAd·HCl
NaOtBu instead of KOtBu
LiOtBu instead of KOtBu
Cs2CO3 instead of KOtBu
toluene
dioxane
diglyme
DMA
no nickel or ligand
5 (85)
3 (60)
0 (95)
0 (92)
74
40 (35)
trace (88)
55
84
61
6 (51)
NR
d
d
d
d
d
d
a
The reaction was conducted using 0.2 mmol of 1a and 0.6 mmol of
b
2a under indicated conditions for 10 h, NR = No reaction. Yields
were determined by GC using dodecane as internal standard.
c
d
Isolated yield after flash chromatography. Recovery of 1a.
4,4,4-trifluorobutan-1-ol are good substrates, delivering corre-
sponding arylated ketones 3d−3f in 43%−81% yields, while
methanol is not efficient enough to produce a corresponding
α-arylated aldehyde. β-Branched alcohol could be also
tolerated in the reaction, furnishing β′-branched-α-aryl ketone
product 3g in 74% yield. Tetrahydrogeraniol could be
converted to corresponding α-monoarylated ketone 3h in
81% yield. Heterocycles, such as pyridine and piperidine,
derived alcohols could be transformed into α-monoarylated
ketones 3i and 3j in 55% and 82% yields, respectively. Notably,
α-branched alcohols could be converted into desired product,
giving α,α′-arylated or α-arylated-α′-alkylation ketones in good
to excellent yields (3k−3o). Moreover, benzyl alcohols are
good substrates in this reaction, delivering α-arylated aromatic
ketones (3p and 3q) in synthetic useful yields. Unfortunately,
benzylic alcohols with para-NO2, NH2, CO2Me, CO2H, CHO,
CN, or vinyl are not good substrates under the reaction
conditions. Next, we tested different aromatic alkenes to
determine the variation of aromatic substitutions. para-, meta-,
and ortho-Substituted styrenes with electron-donating or
-withdrawing substitution patterns could couple with different
alcohols to afford different aryl substituted α-monoarylated
ketones in good yields (4a−4i). Notably, vinylpyridine is also
compatible under the reaction conditions, affording mono-α-
pyridinyl ketone 4j in moderate yield. Internal styrene could be
applied to the reaction, affording mono-α-arylation of ketones
with other alkyl substitutions, albeit with moderate efficiency
(4k). Norbornene could be coupled with styrene to give
corresponding ketone 4l in 74% yield with 4:1 dr. Ethylene
could not be successfully incorporated in the reaction,
probably due to poor mixing efficiency of two phases. To
further demonstrate the scope of this methodology, natural
product derived alcohols are tested. Primary alcohols based on
β-pinene and lithocholic acid could be successfully coupled
with styrene, furnishing mono-α-arylated ketones with complex
structural scaffold 4m and 4n in 80% and 91% yields,
respectively. Interestingly, β-citronellol and geraniol could
With the optimized conditions in hand, we turned to
examine the scope of this formal mono-α-arylation of ketones
via Ni-catalyzed oxidative cross-coupling of alcohols with
olefins. The results are summarized in Scheme 2. First, the
scope of primary alcohols is investigated. Phenyl tethered
alcohols with different alkyl chains are compatible under the
reaction conditions, giving corresponding α-arylation of
ketones 3a−3c in good yields. 1-Pentanol, ethanol, and
B
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a
Scheme 2. Scope for Synthesis of α-Monoarylated Ketones in Terms of Alcohols and Olefins
a
b
The reaction was set up on 0.2 mmol scale. For detail reaction conditions, see Table 1, entry 1. The reaction was carried out using IMes·HCl (10
c
mol %) as ligand. The reaction was carried out at 130 °C using IMes·HCl (10 mol %) as ligand.
react with styrene to deliver the identical product 4o under the
reaction conditions in 78% and 70% yields, respectively.
To probe the mechanism of this reaction, we carried out the
reaction using 3-phenylpropan-1,1-d2-1-ol (1a-d2) and 4-tert-
butylstyrene under standard conditions. The desired α-
monoarylated ketone 5 was obtained in 89% yield with
deuterium scrambling observed (eq 1). When aldehyde 6 was
submitted to the standard conditions instead of parent alcohol
1a, 27% of ester 7 was observed with trace amount of 4d (eq
2). This indicates that a stoichiometric amount of aldehyde is
not compatible in the reaction, which may lead to fast
dimerization to give ester byproduct under the reaction
conditions. If secondary alcohol 8 was used in the reaction
with 4-tert-butylstyrene, olefin hydrogenation product 10 was
formed in 63% yield based on conversion along with forming
an equal amount of ketone 9 (eq 3), suggesting the transfer
hydrogenation process of alcohol to olefin. Moreover, the
reaction of 1a with styrene was conducted with anhydrous
copper sulfate (1 equiv) under otherwise identical to standard
conditions. Desired ketone 3a was formed in 70% yield
without formation of bimolecular condensation product 11 via
dehydration or copper sulfate hydrate (eq 4).
C
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To further understand the reaction mechanism, we
conducted the reaction of 1a with 4-tert-butylstyrene to
monitor the kinetic behavior of this reaction (Figure 1).
In summary, the Ni-catalyzed direct oxidative cross-coupling
of alcohols with olefins is described for the first time, affording
a variety of mono-α-arylated ketones in good yields. The
judicious selection of NHC ligand along with reaction
conditions enables the selective and sequential dehydrogen-
ation and assembly of alcohols onto olefins. Nickel plays an
essential twofold catalytic role in this reaction with one ligand.
This operationally simple protocol features the use of readily
available and cost-effective starting materials, allowing for the
straightforward access of monoarylated ketones with broad
functional group tolerance.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02340.
General procedures for the synthesis of α-monoarylated
ketones from alcohols and olefins, conditions optimiza-
tion, characterization of new compounds, mechanistic
experiments, and copies of NMR spectra (PDF)
Figure 1. Reaction profile of 1a with 4-tert-butylstyrene.
Desired ketone 4d was formed from the beginning of the
reaction and increased along the reaction time. Aldehyde could
be observed throughout the reaction course, albeit in low
concentration (<5%). These results further prove aldehyde is
the intermediate formed catalytically during the reaction
course.
AUTHOR INFORMATION
Corresponding Author
■
Wei Shu − Shenzhen Grubbs Institute and Department of
Chemistry and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen 518055, Guangdong, P. R. China; orcid.org/
0000-0003-0890-2634; Email: shuw@sustech.edu.cn
Based on the results and literature precedence, a work
proposal for the transformation is depicted in Figure 2. Nickel
Author
Peng-Fei Yang − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, Guangdong, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02340
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge NSFC (21971101 and 21801126), Guang-
dong Basic and Applied Basic Research Foundation
(2019A1515011976), Guangdong Provincial Key Laboratory
of Catalysis (No. 2020B121201002), Thousand Talents
Program for Young Scholars, and Shenzhen Nobel Prize
Scientists Laboratory Project (C17783101) for financial
support. We acknowledge the assistance of SUSTech Core
Research Facilities. We thank Wen-Bo Hu (SUSTech) for
reproducing the results of 3c, 4b, and 4e.
Figure 2. Proposed mechanism for the reaction.
plays a twofold role in two catalytic cycles. One cycle is for the
oxidative dehydrogenation of alcohols to aldehydes, the other
cycle is for regioselective hydroacylation of aldehydes with
olefins. First, nickel(0) inserts into O−H bond to give Ni(II)
intermediate A, which could undergo hydrometalation onto 2
to give intermediate B. This alkyoxylnickel intermediate
undergoes site-selective β-H elimination to give aldehydes
D17 and nickel(II) intermediate C. C could undergo reductive
elimination to regenerate Ni(0) species by excursion of alkane.
Then, Ni(0) could initiate the second catalytic cycle. In the
presence of alkene and aldehydes, nickel(0) coordinates with
an aldehyde and an alkene to form intermediate E, which could
undergo site-selective ligand-to-ligand hydrogen transfer
(LLHT) to furnish ketone intermediate F.15 F could form
the final α-arylated ketones and regenerate nickel(0) via
reductive elimination.
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(18) For more details on conditions optimization, see Supporting
Information.
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