Directed palladium(II)-catalyzed intermolecular anti-markovnikov hydroarylation of unactivated alkenes with (hetero)arylsilanes

Article abstract of DOI:10.1021/acs.orglett.0c03416

We describe herein a regioselective palladium(II)catalyzed intermolecular hydroarylation of unactivated aliphatic alkenes with electronically and sterically diverse (hetero)arylsilanes under redox-neutral conditions. A removable bidentate 8-amino-quinoline auxiliary was readily employed to dictate the regioselectivity, prevent β-hydride elimination, and facilitate protodepalladation. This silicon-based protocol features a broad substrate scope with excellent functional group compatibility and enables an expeditious route to a variety of γ-aryl butyric acid derivatives in good yields with exclusive anti-Markovnikov selectivity.

Full text of DOI:10.1021/acs.orglett.0c03416

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Letter
Directed Palladium(II)-Catalyzed Intermolecular Anti-Markovnikov
Hydroarylation of Unactivated Alkenes with (Hetero)arylsilanes
Ming-Zhu Lu,* Haiqing Luo, Zhengsong Hu, Changdong Shao, Yuhe Kan, and Teck-Peng Loh*
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ABSTRACT: We describe herein a regioselective palladium(II)-
catalyzed intermolecular hydroarylation of unactivated aliphatic
alkenes with electronically and sterically diverse (hetero)arylsilanes
under redox-neutral conditions. A removable bidentate 8-amino-
quinoline auxiliary was readily employed to dictate the
regioselectivity, prevent β-hydride elimination, and facilitate
protodepalladation. This silicon-based protocol features a broad
substrate scope with excellent functional group compatibility and
enables an expeditious route to a variety of γ-aryl butyric acid derivatives in good yields with exclusive anti-Markovnikov selectivity.
Scheme 1. Intermolecular Hydroarylation of Alkenes with
Organosilicon Reagents
lkene starting materials are versatile building blocks and
abundant chemical feedstocks readily available in bulk
A
quantities from petrochemical and renewable resources.
Accordingly, the development of transition-metal-catalyzed
functionalizations of alkenes is of great interest in modern
organic synthesis.1 Particularly, the intermolecular hydro-
functionalization reaction of alkenes with widely used organo-
metallic reagents offers an attractive synthetic strategy to
construct diverse carbon skeletons in the rapid synthesis of
complex organic molecules.2,3 Among the various organo-
metallic reagents that can be engaged in hydrofunctionaliza-
tions, user-friendly organosilicon reagents have attracted
substantial attention, because of their conspicuous advantages,
including ready availability, environmental benignity, low
toxicity, high stability, tunable reactivity, and excellent
functional group compatibility.4,5 A variety of synthetically
useful hydroarylation reactions of alkenes with organosilicon
reagents enabled by different transition metals have been
successfully reported over the past few decades.6 Despite the
remarkable advances, these well-established processes are
typically restricted to nucleophilic conjugate addition of
arylsilanes to activated or electronically biased alkenes, such
as α,β-unsaturated carbonyl compounds and related Michael
acceptors (Scheme 1a). In sharp contrast, the catalytic
intermolecular hydroarylation of unactivated alkene substrates
still remains hitherto elusive. General and pratical strategies are
highly desirable to address this issue.
The intermolecular hydrofunctionalization of unactivated
aliphatic alkenes suffers from significant challenges involving
the regioselectivity issue of the carbopalladation and the
formation of undesired alkene products by facile β-hydride
elimination. Tremendous efforts have been devoted to the
discovery and development of innovative strategies to realize
various hydrofunctionalizations of electronically unbiased
aliphatic alkenes in recent years.7 In this regard, Engle et al.
Received: October 13, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03416
© XXXX American Chemical Society
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A

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Letter
a b
,
first reported an unprecedented chelation-assisted strategy that
elegantly employs a removable bidentate 8-aminoquinoline
auxiliary to dictate regioselective carbopalladation, stabilize the
putative alkylpalladium(II) intermediate, and facilitate sub-
sequent protodepalladation to afford hydrofunctionalized
products.8,9 A series of regioselective hydrofunctionalization10
and 1,2-difunctionalization11 reactions of unbiased aliphatic
alkenes with a broad range of nucleophiles have been
successively accomplished using this strategy.12 To fully realize
the feasibility of unactivated alkene hydroarylation with readily
available organosilicon reagents, we envisioned that such a
reaction may potentially be achieved through the judicious use
of the proximal auxiliary-directed strategy to enable regiose-
lective syn-1,2-migratory insertion of the Pd−aryl moiety into
C−C π-bonds to form the chelation-stabilized five-membered
palladacycle species, which would effectively suppress the
competing β-hydride elimination, thus allowing the putative
alkylpalladium(II) intermediate to be intercepted by a proton
source to afford the hydrofunctionalized product (Scheme 1b).
Inspired by recent work on alkene hydrofunctionalization
reactions and with our continuous efforts in silicon-based
cross-coupling reactions,13 we describe herein a general
procedure for the palladium(II)-catalyzed chelation-assisted
intermolecular anti-Markovnikov hydroarylation reaction of
unactivated 3-butenoic acid derivatives with sterically and
electronically diverse (hetero)arylsilanes under redox-neutral
conditions. This silicon-based protocol is compatible with both
terminal and internal unactivated aliphatic alkenes, providing a
straightforward access to a wide range of synthetically valuable
γ-aryl butyric acid derivatives that are important skeletons
frequently encountered in numerous pharmaceutically relevant
molecules (see Scheme 1).14
Table 1. Optimization of Reaction Conditions
entry
catalyst
additive
solvent
yield
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OTFA)2
Pd(OAc)2
Pd(OAc)2
AgF
NaF
KF
CsF
ZnF2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
13
<5
<5
<5
0
c
TBAF
0
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
56
65
73
48
67
82
58
67
73
toluene
dioxane
MeCN
acetone
THF
10
11
12
13
14
15
THF
THF
THF
d
e
a
Reaction conditions: [Pd] catalyst (0.02 mmol, 10 mol %), 1a (0.2
mmol), trimethoxyphenylsilane 2a (0.4 mmol, 2.0 equiv), additive
(0.4 mmol, 2.0 equiv), H2O (2.0 mmol, 10 equiv), solvent (2.0 mL),
at 100 °C for 24 h. Isolated yields. TBAF (1.0 mol/L in THF). At
b
c
d
e
80 °C. Pd(OAc)2 (5 mol %).
We commenced the investigation by using 3-butenoic acid
derivative 1a bearing Daugulis’s 8-aminoquinoline directing
group as the model substrate and trimethoxyphenylsilane 2a as
the coupling partner to evaluate the feasibility of the proposed
hydroarylation reaction (see Table 1). During initial screening,
we were pleased to observe the formation of the desired anti-
Markovnikov hydroarylation product 3a in 13% yield by using
10 mol % of Pd(OAc)2 as the catalyst, 2.0 equiv of AgF as the
silane activator, and 10 equiv of water as the proton source at
100 °C in 1,2-dichloroethane (DCE) for 24 h (Table 1, entry
1). Other fluorides such as NaF, KF, CsF, ZnF2, or TBAF were
ineffective in activating the C−Si bond in this reaction (Table
1, entries 2−6), and copper(II) fluoride was found to be the
best choice to afford 3a in 56% yield (Table 1, entry 7).
Subsequently, through extensive screening of various solvents,
we identified tetrahydrofuran (THF) to be the most effective
solvent to generate the product 3a in 82% yield (Table 1, entry
12). In addition, palladium(II) trifluoroacetate proved to be
reactive for this transformation, albeit in moderate yield (Table
1, entry 13). Further evaluation demonstrated that lowering
the temperature to 80 °C or decreasing the catalyst loading to
5 mol % resulted in a reduced yield (Table 1, entries 14 and
15). Finally, alkene substrates bearing other bidentate
auxiliaries either afforded a trace amount of product or failed
to give any desired product.
66%, and 81%, respectively. No reaction occurred with
phenyltrimethylsilane, phenylmethoxydimethylsilane and phe-
nyldimethylsilanol as coupling partners. The reaction of several
ortho-substituted arylsilanes with 3-butenamide 1a proceeded
smoothly to generate the corresponding products 3b−3e in
high yields (69%−84%). Moreover, meta-substituted arylsi-
lanes could tolerate this hydroarylation reaction (3f−3i).
Remarkably, a variety of arylsilanes bearing both electron-
donating and electron-withdrawing functional groups at the
para-position produced the desired products in yields from
46% to 76% (3j−3u). Gratifyingly, naphthylsilanes also proven
to be favorable coupling partners to afford the products 3v and
3w in yields of 78% and 63%, respectively. Notably, a broad
range of disubstituted and trisubstituted arylsilanes reacted
well under the optimized conditions (3x−3ao), whereas
sterically congested mesityltrimethoxysilane 2ap resulted in
18% yield. Note that this silicon-based protocol is also
compatible with diverse heteroarylsilanes, enabling the
formation of products 3aq−3av in satisfactory yields (49%−
75%).
To further extend this protocol, we turned to evaluate the
generality of this hydroarylation reaction with both terminal
and internal unbiased aliphatic alkenes (Scheme 3). Generally,
a variety of α-substituted terminal alkenes were found to be
suitable substrates and underwent anti-Markovnikov hydro-
arylation reaction in good yields (4b−4d). Alkene substrates
bearing a single substituent at the β-position reacted to give
product 4e in a moderate yield (38%), revealing the obvious
steric inhibition on the reactivity of this reaction. Encourag-
ingly, this approach was very compatible with unactivated
internal alkenes; an array of simple and functionalized alkyl-
With these optimized reaction conditions established, we
proceeded to evaluate the substrate scope of this γ-selective
hydroarylation reaction. Initially, a series of phenylsilicon
reagents were investigated. As shown in Scheme 2, the use of
phenyltriethoxysilane, phenyldimethoxymethylsilane, and di-
phenyldimethoxysilane gave the product 3a in yields of 79%,
B
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Scheme 2. Directed Pd(II)-Catalyzed Hydroarylation of
Unactivated Alkene 1a with (Hetero)arylsilanes 2
Scheme 3. Directed Pd(II)-Catalyzed Hydroarylation of 3-
a b
a,
b
,
Alkenamides 1 with Trimethoxyphenylsilane 2a
a
Unless otherwise noted, the reaction conditions were as follows:
unactivated alkene 1 (0.2 mmol), trimethoxyphenylsilane 2a (0.4
mmol, 2.0 equiv), Pd(OAc)2 (0.02 mmol, 10 mol %), CuF2 (0.4
mmol, 2.0 equiv), H2O (2.0 mmol, 10 equiv), in THF (2.0 mL) at
b
c
100 °C for 24 h. Isolated yields. Trimethoxyphenylsilane 2a (3.0
equiv) was used.
To illustrate the synthetic practicality of this protocol, we
next performed a gram-scale hydroarylation reaction of 3-
butenoic acid derivative 1a with trimethoxyphenylsilane 2a.
The desired product 3a was obtained in 76% yield when the
model reaction was performed on a 5.0 mmol scale (see
Scheme 4), thus demonstrating the scalability of this strategy.
Moreover, the 8-aminoquinoline directing group could be
readily removed by treatment with NaOH (10.0 equiv) in
EtOH at 130 °C, affording the free 4-(p-tolyl)butanoic acid 5a
in 94% yield. Alternatively, the directing group could also be
easily cleaved by treatment with BF3·OEt2 in EtOH to generate
the ethyl ester 5b in 87% yield. Moreover, the deprotection of
8-aminoquinoline auxiliary (AQ) using Ohshima’s Ni(tmhd)2-
catalyzed alcoholysis protocol provided methyl ester 5c in 82%
yield.15
To probe the mechanism of this process, a series of control
and deuteration experiments were performed next (see Scheme
5). No reaction occurred when N-(naphthalen-1-yl)but-3-
enamide 6a and quinolin-8-yl but-3-enoate 6b were used as the
aliphatic alkene substrates (Scheme 5a). This indicates that the
Daugulis’s bidentate 8-aminoquinoline directing group is
a
Unless otherwise noted, the reaction conditions were as follows: 1a
(0.2 mmol), (hetero)arylsilane 2 (0.4 mmol, 2.0 equiv), Pd(OAc)2
(0.02 mmol, 10 mol %), CuF2 (0.4 mmol, 2.0 equiv), H2O (2.0 mmol,
b
10 equiv), in THF (2.0 mL), stirred at 100 °C for 24 h. Isolated
yields. The corresponding aryltriethoxysilane was used. (Hetero)-
arylsilane (3.0 equiv) was used.
c
d
substituted internal aliphatic alkenes proceeded uneventfully to
furnish the corresponding hydroarylation products with
exclusive regioselectivity (4f−4q). As expected, the Z- and E-
configured internal alkenes performed similarly under the
optimized conditions (4g). In addition, internal alkenes
bearing aryl substituents at the γ-position of the amides
could also be readily converted to the corresponding
hydroarylation products 4r−4t in yields of 66%−75%.
C
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reversible in nature, and the Pd−aryl moiety undergoes 1,2-
migratory insertion into C−C π-bonds to generate a
thermodynamically favored five-membered alkylpalladium(II)
intermediate, ruling out the intermediacy of a palladium
enolate species during the catalytic cycle. Finally, when
unbiased alkene 1a was subjected to the typical conditions
using D2O in place of H2O as the deuteron source, as expected,
the deuterium incorporation (71%) occurred only at the β-
position of hydroarylation product 3a, which is in accordance
with a protodepalladation reaction mechanism (Scheme 5d).
Although the detailed mechanism of this directed Pd(II)-
catalyzed anti-Markovnikov hydroarylation reaction remains
uncertain at this stage, a plausible catalytic cycle was tentatively
proposed on the basis of preliminary observations and
literature reports (see Scheme 6).12,13 Initially, palladium(II)
Scheme 4. Large-Scale Synthesis and Deprotection
Scheme 6. Proposed Catalytic Cycle
Scheme 5. Preliminary Mechanistic Investigations
coordinates to the 8-aminoquinoline directing group, which
brings it in close proximity to the alkene moiety. Subsequent
rate-controlling transmetalation with intermediate B, the
pentavalent arylsilicate or copper−aryl species17 generated in
situ by reaction of arylsilanes with copper(II) fluoride, results
in the formation of intermediate C, which then undergoes a
syn-selective 1,2-migratory insertion into the CC bond to
form the chelation-stabilized five-membered alkylpalladium(II)
intermediate D. Because of the stability and conformational
rigidity imparted by the tethered bidentate 8-aminoquinoline
directing group, the putative palladacycle species does not
undergo β-H elimination to yield an olefin and, instead, is
further intercepted by a proton in a reversible protodepalla-
dation step to give the key product-bound palladium
intermediate E, which eventually dissociates to release the
desired hydroarylated product and regenerate the palladium-
(II) catalyst.
In summary, we have developed a palladium(II)-catalyzed
intermolecular hydroarylation reaction of both terminal and
internal unactivated 3-butenoic acid derivatives with a variety
of readily available (hetero)arylsilanes by utilizing a removable
8-aminoquinoline directing group to control the regioselectiv-
ity, stabilize the alkylpalladium(II) intermediate, and prevent
β-hydride elimination. Copper(II) fluoride was readily used as
the efficacious sliane activator with water as the proton source
in this transformation. This redox-neutral strategy features a
broad substrate scope, accommodates a wide range of
indispensable for this reaction. Subsequently, we conducted an
intermolecular competition experiment between arylsilanes 2l
and 2s to delineate the electronic preference of this strategy
(Scheme 5b), and the ratio of the corresponding products
clearly demonstrates that electron-deficient 4-CF3-substituted
arylsilane 2s is inherently more favorable and preferentially
converted to the product (3l/3s = 1/3.47), which is consistent
with Lewis base coordination to Si during the transmetalation
step.16 To probe the reversibility of this reaction, product 3a
was treated with the addition of arylsilane 2s (2.0 equiv) under
the standard conditions (Scheme 5c), and no aryl exchange
product 3s was detected after 24 h, supporting the notion that
the transmetalation and/or migratory insertion steps are
irreversible. Furthermore, the H/D scrambling experiment of
product 3a was performed next, and 62% deuterium
incorporation was detected exclusively at the β-position of
the amide with no H/D exchange observed at the α- and γ-
positions, revealing that the protodepalladation step should be
D
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synthetically useful functional groups, and affords a series of
structurally diverse γ-arylated alkyl carboxylic acid derivatives
in good yields with excellent anti-Markovnikov selectivity.
ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03416.
Experimental procedures and spectral data for all new
compounds (1H NMR, 13C NMR, HRMS) (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Ming-Zhu Lu − Jiangsu Key Laboratory for Chemistry of Low-
Dimensional Materials, School of Chemistry and Chemical
Engineering, Huaiyin Normal University, Huaian 223300,
China; orcid.org/0000-0002-6333-0803; Email: mzlu@
hytc.edu.cn
(4) Hiyama, T.; Oestreich, M. Organosilicon Chemistry: Novel
Approaches and Reactions; Wiley−VCH: Weinheim, Germany, 2019.
(5) For selected reviews on Hiyama cross-coupling, see: (a) Den-
mark, S. E.; Liu, J. H.-C. Silicon-Based Cross-Coupling Reactions in
the Total Synthesis of Natural Products. Angew. Chem., Int. Ed. 2010,
49, 2978−2986. (b) Nakao, Y.; Hiyama, T. Silicon-Based Cross-
Coupling Reaction: an Environmentally Benign Version. Chem. Soc.
Rev. 2011, 40, 4893−4901. (c) Sore, H. F.; Galloway, W. R. J. D.;
Spring, D. R. Palladium-Catalysed Cross-Coupling of Organosilicon
Reagents. Chem. Soc. Rev. 2012, 41, 1845−1866. (d) Komiyama, T.;
Minami, Y.; Hiyama, T. Recent Advances in Transition-Metal-
Catalyzed Synthetic Transformations of Organosilicon Reagents. ACS
Catal. 2017, 7, 631−651.
Teck-Peng Loh − Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371;
orcid.org/0000-0002-2936-337X; Email: teckpeng@
ntu.edu.sg
Authors
Haiqing Luo − Department of Chemistry & Chemical
Engineering, Gannan Normal University, Ganzhou 341000,
China
Zhengsong Hu − Jiangsu Key Laboratory for Chemistry of Low-
Dimensional Materials, School of Chemistry and Chemical
Engineering, Huaiyin Normal University, Huaian 223300,
China
Changdong Shao − Jiangsu Key Laboratory for Chemistry of
Low-Dimensional Materials, School of Chemistry and Chemical
Engineering, Huaiyin Normal University, Huaian 223300,
China
Yuhe Kan − Jiangsu Key Laboratory for Chemistry of Low-
Dimensional Materials, School of Chemistry and Chemical
Engineering, Huaiyin Normal University, Huaian 223300,
China; orcid.org/0000-0002-2082-6796
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledged the finanical support
from the Natural Science Foundation of Jiangsu Province
(Nos. BK20181066 and 18KJD150002), the National Natural
Science Foundation of China (No. 21762002), and the
“Innovation and Entrepreneurship Talents Plan” of Jiangsu
Province.
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