Nickel-Catalyzed Asymmetric Hydroarylation of Vinylarenes: Direct Enantioselective Synthesis of Chiral 1,1-Diarylethanes

Article abstract of DOI:10.1021/acs.joc.0c02556

The enantioselective hydroarylation of vinylarenes catalyzed by a chiral, non-racemic nickel catalyst is presented as a facile method to generate chiral 1,1-diarylethanes. These reactions proceed via formation of a chiral, non-racemic nickel benzyl intermediate. Transmetalation with arylboron nucleophiles and subsequent reductive elimination enable the formation of a variety of chiral 1,1-diarylethanes. The 1,1-diarylethane products from reactions of arylboronic acids containing electron-donating substituents are formed with typically greater than 90% ee, while the 1,1-diarylethanes generated from reactions of arylboronic acids containing electron-withdrawing groups are generated with typically less than 80% ee. These results are consistent with the rate of transmetalation with an arylboron nucleophile playing a key role in the enantioselectivity of these hydroarylation reactions. This mechanistic insight has led to the development of reactions of neo-pentylglycolate esters of arylboronic acids with vinylarenes that occur with higher enantioselectivities based on increased rates of transmetalation.

Full text of DOI:10.1021/acs.joc.0c02556

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Nickel-Catalyzed Asymmetric Hydroarylation of Vinylarenes: Direct
Enantioselective Synthesis of Chiral 1,1-Diarylethanes
Hai N. Tran, Russell W. Burgett, and Levi M. Stanley*
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ABSTRACT: The enantioselective hydroarylation of vinylarenes
catalyzed by a chiral, non-racemic nickel catalyst is presented as a
facile method to generate chiral 1,1-diarylethanes. These reactions
proceed via formation of a chiral, non-racemic nickel benzyl
intermediate. Transmetalation with arylboron nucleophiles and
subsequent reductive elimination enable the formation of a variety
of chiral 1,1-diarylethanes. The 1,1-diarylethane products from
reactions of arylboronic acids containing electron-donating
substituents are formed with typically greater than 90% ee, while
the 1,1-diarylethanes generated from reactions of arylboronic acids
containing electron-withdrawing groups are generated with
typically less than 80% ee. These results are consistent with the rate of transmetalation with an arylboron nucleophile playing a
key role in the enantioselectivity of these hydroarylation reactions. This mechanistic insight has led to the development of reactions
of neo-pentylglycolate esters of arylboronic acids with vinylarenes that occur with higher enantioselectivities based on increased rates
of transmetalation.
substrates with functional groups capable of directing the
activation of an ortho C−H bond. Recently, catalytic,
enantioselective hydroarylations of vinylarenes have been
reported, which do not require directed activation of an
arene C−H bond. Unlike direct hydroarylations that rely on
generation of a metal hydride by activation of an arene C−H
bond, these hydroarylation reactions occur via generation of a
metal hydride intermediate from an additional reagent, such as
a protic solvent or a silane.5,6 In 2016, Buchwald and co-
workers reported enantioselective formal hydroarylations of
vinylarenes with aryl bromides that occur in the presence of
cooperative palladium and copper catalysts (Scheme 1b).6a
This approach to vinylarene hydroarylation generates 1,1-
diarylethanes with high enantioselectivities. Unfortunately,
these reactions rely on costly phosphine ligands for the
palladium and copper catalysts and require a silane to form the
key copper hydride intermediate. The ability to perform
catalytic, enantioselective hydroarylations with earth-abundant
metal catalysts containing cheap chiral ligands7 and to
eliminate the need for silanes as the hydride source has the
1. INTRODUCTION
Chiral 1,1-diarylethanes comprise a structural motif that has
been widely studied due to the biological activity of these
compounds and their potential as pharmaceuticals (Figure 1).1
Figure 1. Typical examples of 1,1-diarylethanes.
While numerous enantioselective syntheses have been reported
to generate chiral, non-racemic 1,1-diarylethanes over the past
decades,2−4,6 catalytic and enantioselective formal hydro-
arylations of vinylarenes have emerged as simple and direct
methods to form 1,1-diarylethanes from simple starting
materials.4,6
Received: November 10, 2020
Published: February 12, 2021
An attractive approach to catalytic, enantioselective hydro-
arylations of vinylarenes involves activation of an aryl C−H
bond (Scheme 1a).4 Generally, these reactions require arene
https://dx.doi.org/10.1021/acs.joc.0c02556
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Scheme 1. Direct Enantioselective Hydroarylation of Vinylarenes
potential to render these reactions even more attractive to the
synthetic chemistry community.
Inspired by Zhou and co-workers’ early study on hydro-
arylation of vinylarenes, we sought to develop an enantiose-
lective nickel-catalyzed hydroarylation of vinylarenes. During
our early efforts, Mei and co-workers reported enantioselective
hydroarylation of styrenes in the presence of a nickel complex
of a modified PhBOX ligand (Scheme 1d, top).6c Sub-
sequently, Zhou and co-workers reported the nickel-catalyzed
enantioselective hydroarylation of styrenes using a spiro-
aminophosphine ligand (Scheme 1d, bottom).6d We now
report catalytic, enantioselective hydroarylations of vinylarenes
in the presence of a nickel complex of the trans-Ph2BOX ligand
(Scheme 1e). These reactions occur with high enantioselec-
tivity with as low as 2.5 mol % nickel precatalyst and 0.5 mol %
of a readily accessible chiral bisoxazoline ligand. The
hydroarylation reactions encompass arylboronic acids and
arylboronate esters as nucleophiles and, in many cases, do not
require column chromatography to purify the 1,1-diarylethane
products. In addition, we have gained data that suggest that the
rate of transmetalation can significantly impact the enantiose-
lectivity of the reaction.
In 2011, Sigman and co-workers reported the first
enantioselective hydroarylations of vinylarenes with arylboron
nucleophiles to generate 1,1-diarylethanes in modest yields and
enantioselectivities (Scheme 1c).6b These reactions occur in
the presence of a palladium catalyst and a readily accessible
bisoxazoline ligand (iPrBOX) and leverage iPrOH as the
hydride source to form the key palladium hydride
intermediate. Although only three examples were reported,
this study provided the platform for recent advances in
catalytic, enantioselective hydroarylation of vinylarenes. In
2018, Zhou and co-workers reported the first achiral Ni-
catalyzed hydroarylations of styrenes and 1,3-dienes, employ-
ing MeOH as a formal hydride source and organoboron
compounds as aryl nucleophiles to generate the racemic 1,1-
diarylethanes in good to high yields.5d This study showed that
a combination of a cheap, earth-abundant nickel catalyst and
MeOH enables highly efficient hydroarylations of vinylarenes.
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a
Table 1. Reaction Optimization
b
c
entry
ligand
X
yield (%)
ee (%)
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
L1
L7
L7
L7
L1
10
99
31
70
47
6
64
77
99
96
96 (93)
88
72
80
82
81
70
67
77
88
85
55
86
92
92
87
85
80
88
10
10
10
10
10
10
10
5
2.5
1
5
2.5
1
d
8
9
e
10
11
12
13
14
29
87
f
15
2.5
a
b
1
Reaction condition: 1a (0.25 mmol), 2a (0.5 mmol), Ni(cod)2 (5 mol %), and tBuOLi (0.25 mmol). Yields were determined by H NMR
c
spectroscopy of the crude reaction mixture using dibromomethane as an internal standard. Enantioselectivities were determined by chiral HPLC.
d
e
f
Without tBuOLi. Isolated yield. 0.25 mmol EtOLi used instead of tBuOLi.
Ni(cod)2 and 2.5 mol % L1. In the most closely related
study,6c the use of EtOLi as a base in the hydroarylation
reaction led to the highest enantioselectivities, but the use of
EtOLi as a base in our model reaction led to a slightly lower
yield and enantioselectivity (entry 15).
2. RESULTS AND DISCUSSION
Initially, the reaction of styrene 1a and 4-methoxyphenylbor-
onic acid 2a in the presence of MeOH as a hydride source was
evaluated to identify suitable reaction conditions.5d Reactions
promoted by Ni(0) complexes of a variety of chiral
bisoxazoline (BOX) ligands were studied to identify active
and enantioselective catalysts (Table 1, entries 1−7). We
found that the nickel complex of trans-Ph2BOX ligand L1
provided the best combination of catalytic activity and
enantioselectivity, furnishing the 1,1-diarylethane 3aa in 99%
yield with 82% ee (entry 1). The presence of a base is critical
to achieve high enantioselectivities. When the model reaction
was run in the absence of a base, the reaction formed 1,1-
diarylethane 3aa with significantly lower enantioselectivity
(55% ee, compare entry 8 with entry 1). Notably, we found
that the loading of ligand L1 could be reduced to 1 mol %
without lowering the yield or enantioselectivity of the reaction
(entries 9−11). In fact, reducing the ligand loading in the
reaction led to improved enantioselectivities. The ability to
decrease the loading of ligand L1 without detriment to the
yield or enantioselectivity led us to reevaluate the Ni(0)
complex of L7, which has previously been reported by Mei and
co-workers (entries 12−14). Lowering the loading of ligand L7
in our model reaction does not significantly impact the
enantioselectivity of the reaction (compare entry 7 with entries
12−14), but the results clearly show the catalyst generated
from Ni(cod)2 and L7 is less active than the corresponding
nickel complex of L1. We chose to continue our studies by
conducting reactions with the catalyst generated from 5 mol %
With reaction conditions identified that lead to high yields
and enantioselectivities in our model reaction, we sought to
establish the scope of the reaction by evaluating a variety of
arylboronic acids (Scheme 2). At this stage, we found that the
yield of the reaction is significantly impacted by the identity of
the arylboronic acid. In many cases, the catalyst rapidly
decomposes when the solid catalyst precursors are exposed to
the solid arylboronic acid, especially in the presence of acidic
arylboronic acids such as 4-fluorophenylboronic acid and 4-
trifluoromethylphenylboronic acid.8 To mitigate this issue, we
performed these reactions by adding a stock solution of an
arylboronic acid in MeOH to a mixture of the Ni(0)
precatalyst, ligand L1, tBuOLi, and the vinylarene substrate.
The scope of the enantioselective hydroarylation reaction
with respect to arylboronic acids is illustrated in Scheme 2.
Reactions of styrene 1a or 4-methoxystyrene 1e with an array
of substituted arylboronic acids generate 1,1-diarylethanes in
good-to-high yields (57−93%) with good-to-excellent enantio-
selectivities (72−92%). The scope of these hydroarylation
reactions encompasses a variety of para-, meta-, ortho-, and
disubstituted arylboronic acids. Notably, arylboronic acids
containing fluorides, chlorides, alcohols, esters, ketones, and
acetals are suitable substrates for the nickel-catalyzed hydro-
arylation reaction. Reactions of arylboronic acids containing
electron-donating substituents generally occur with high
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a
mol % L1. Generally, the hydroarylations of vinylarenes with
arylboronic acid pinacol esters occur with lower enantiose-
lectivities than the analogous reactions of arylboronic acids.
However, the increased stability of the boronate esters enables
formal hydroheteroarylations of vinylarenes. For instance, the
reaction of furan-3-boronic acid pinacol ester 2u with styrene
1a furnished 3au in 57% yield, while the reaction of furan-3-
boronic acid with styrene did not occur to form the
hydroheteroarylation product.
Scheme 2. Arylboronic Acid Substrate Scope
The scope of the enantioselective hydroarylation reaction
with respect to vinylarene substrates is shown in Scheme 4.
a
Scheme 4. Alkene Substrate Scope
a
Reaction condition: 1a/1e (0.25 mmol), 2a-p (0.5 mmol), Ni(cod)2
(0.0125 mmol), L1 (0.0063 mmol), tBuOLi (0.25 mmol), and
MeOH (1 mL). Isolated yields. Enantioselectivities were determined
by chiral HPLC.
enantioselectivities. However, lower enantioselectivities are
observed for 1,1-diarylethanes derived from reactions of
arylboronic acids with electron-withdrawing substituents.
Reactions of vinylarenes with several arylboronic acid
pinacol esters also occur to generate 1,1-diarylethanes in
good-to-high yields (Scheme 3). These hydroarylation
reactions occur in the highest yields and enantioselectivities
when the catalyst is generated from 5 mol % Ni(cod)2 and 5
a
Scheme 3. Arylboronic Acid Pinacol Ester Substrate Scope
a
Reaction condition: 1a-m (0.25 mmol), 2a/2g (0.5 mmol),
Ni(cod)2 (0.0125 mmol), L1 (0.0063 mmol), tBuOLi (0.25 mmol),
and MeOH (1 mL). Isolated yields. Enantioselectivities were
b
determined by chiral HPLC. 2.5 mol % Ni(cod)2 and 0.5 mol %
c
d
L1 were used. 1 mol % L1 was used. 10 mol % Ni(cod)2 and 5 mol
% L1 were used.
Reactions of 4-substituted styrenes containing either electron-
donating groups (1b, 1e) or electron-withdrawing groups (1d,
1f) furnished the corresponding 1,1-diarylethanes in good-to-
high yields (84−93%) and good-to-high enantioselectivities
(84−94% ee). The loadings of Ni(cod)2 and ligand L1 can be
reduced to as low as 2.5 and 0.5 mol %, respectively, without
significantly impacting the yield or enantioselectivity of the
reaction. Notably, 4-aminostyrene 1c is a suitable substrate for
the alkene hydroarylation reaction and leads to the formation
of 1,1-diarylethane 3ca in 68% yield and 92% ee. Reactions of
2-methylstyrene 1h produced the corresponding hydro-
arylation product with lower yield and enantioselectivity.
Polysubstituted styrenes 1i-1j and 2-vinylnaphthalene 1k react
to form 1,1-diarylethanes 3ia-3ka in good-to-high yields (61−
a
Reaction condition: 1a/1b/1e (0.25 mmol), 2q-u (0.5 mmol),
Ni(cod)2 (0.0125 mmol), L1 (0.0125 mmol), tBuOLi (0.25 mmol),
and MeOH (1 mL). Isolated yields. Enantioselectivities were
determined by chiral HPLC.
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92%) with excellent enantioselectivities (93−96% ee). Addi-
tionally, the hydroarylation of 3-vinylindole 1l formed the
corresponding hydroarylation product in 27% yield with 70%
ee. Reactions of α- or β-substituted styrenes (e.g., α-
methylstyrene or indalin) and unactivated alkenes (e.g., 1-
octene) did not occur under our reaction conditions.
The synthetic utility of the enantioselective hydroarylation
reaction was demonstrated in the syntheses of biologically
active 1,1-diarylethanes (Scheme 5). The reaction of 3,4,5-
arylboron nucleophile, and reductive elimination are proposed
to be involved in the catalytic cycle. More recently,
computational studies of hydroarylations of this type catalyzed
by nickel complexes of phosphine and aminophosphine ligands
have shown concerted hydronickelation of the vinylarene to be
the more kinetically favorable step to initiate the formal
hydroarylation reactions.10a,b After concerted hydronickelation,
transmetalation with an arylboron nucleophile and reductive
elimination are calculated to form the 1,1-diarylethane product.
These computational studies point to either concerted
hydronickelation or transmetalation with an arylboron reagent
as the turnover-limiting step. In a related study, Liu and Engle
showed that concerted hydronickelation is energetically
favorable in hydroarylations of carboxylic acids catalyzed by
a nickel complex of a pyridine−oxazoline ligand.10c
Scheme 5. Synthetic Utility and Scalability
These computational studies add insights into the
mechanism of the formal hydroarylation reaction and provide
a model for facial selectivity during the concerted hydro-
nickelation step. However, these studies do not address the fact
that the identity of the arylboron nucleophile significantly
impacts the enantioselectivity of the reaction. The enantiose-
lectivity of the hydroarylation reaction is significantly higher
when the reaction is run in the presence of tBuOLi versus the
absence of tBuOLi (Table 1, compare entries 1 and 8). In
addition, reactions of arylboronic acids containing electron-
donating substituents occur with higher enantioselectivity than
the reactions of arylboronic acids containing electron-with-
drawing substituents. Furthermore, reactions of arylboronate
pinacol esters generally occur with lower enantioselectivity
than the reactions of the corresponding arylboronic acids
(compare Schemes 2 and 3). These observations are consistent
with the data reported by Mei and co-workers and suggest that
the rate of transmetalation plays a key role in determining the
enantioselectivity of the hydroarylation reaction. We hypothe-
size that the benzylic nickel species can undergo isomerization
via interconversion between the η1- and η3-nickel benzyl
complexes (Scheme 7).11 In reactions of electron-rich
arylboronic acids, the rate of transmetalation is likely faster
than the rate of isomerization of the nickel benzyl species and
the enantioselectivity of the migratory insertion or concerted
hydrometalation is primarily responsible for the ratio of
enantiomers isolated from the reaction. However, trans-
metalation in the absence of a base,12 or with electron-
deficient arylboronic acids13 and arylboronate pinacol esters,14
is likely significantly slower, and the rates of transmetalation
and isomerization of the benzylic nickel intermediates may
become competitive. If the rates of transmetalation and
isomerization are competitive, transmetalation with diastereo-
meric nickel complexes and subsequent reductive elimination
can lead to lower enantioselectivities.
trimethoxystyrene 1j with 4-methoxyphenylboronic acid 2a
formed the anti-viral 1,1-diarylethane 3ja in 80% yield and 93%
ee. The reaction of 2-vinylnaphthalene 1k with 3,4,5-
trimethoxyphenylboronic acid 2v generated the tubulin
polymerization inhibitor 3kv in 70% yield and 93% ee.
These enantioselective hydroarylation reactions represent a
straightforward synthetic approach to the valuable 1,1-
diarylethane pharmacophore.9 Furthermore, these hydro-
arylation reactions scale readily to the gram scale. The gram-
scale reaction of 4-methylstyrene 1b (8.5 mmol) with 4-
methoxyphenylboronic acid 2a (17 mmol) occurs to form 3ba
in 99% yield with 95% ee in the presence of a catalyst
generated from 2.5 mol % Ni(cod)2 and 1 mol % L1. Notably,
a simple filtration through a short plug of silica enables
isolation of pure 3ba without column chromatography.
The catalytic cycle for Ni-catalyzed hydroarylation of this
type was originally proposed by Zhou and co-workers5d and
supported by studies from Mei and co-workers (Scheme 6).6c
These studies propose oxidative addition of the alcohol O−H
bond across the nickel catalyst. Subsequent migratory insertion
of a vinylarene into the nickel-hydride, transmetalation with an
The ability to perform these formal hydroarylation reactions
with arylboron nucleophiles and reaction conditions that lead
to high rates of transmetalation should result in high
enantioselectivities for the 1,1-diarylethane products. Recently,
Denmark and co-workers illustrated that the use of potassium
trimethylsilanoate (TMSOK) enabled rapid transmetalation of
neo-pentylglycolate esters of arylboronic acids in palladium-
catalyzed Suzuki−Miyaura coupling reactions.13 Several neo-
pentylglycolate esters of arylboronic acids were tested in our
hydroarylation reaction (Table 2, entry 3). Although the yields
of corresponding products were slightly lower than the
reactions of arylboronic acids, the enantioselectivities of
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Scheme 6. Proposed Mechanism
Scheme 7. Isomerization of Benzylic Nickel Species
3. CONCLUSIONS
We have developed the enantioselective hydroarylation of
vinylarenes catalyzed by a nickel catalyst prepared in situ from
Ni(cod)2 and trans-Ph2BOX ligand L1 to generate chiral 1,1-
diarylethanes. These reactions proceed under mild reaction
conditions and occur with as low as 2.5 mol % of the nickel
precatalyst and 0.5 mol % of the chiral, non-racemic
bisoxazoline ligand. Furthermore, the majority of the 1,1-
diarylethane products were isolated in high purity without
column chromatography. High enantioselectivities can be
achieved by ensuring that the rate of transmetalation of
arylboron nucleophiles is fast relative to the rate of
isomerization of the key benzylic nickel intermediate. Studies
to expand the reach of enantioselective, nickel-catalyzed alkene
hydroarylation beyond vinylarenes are ongoing in our
laboratory.
Table 2. Comparison of Yields and Enantioselectivities of
Products Generated from Different Arylboron Nucleophiles
4. EXPERIMENTAL SECTION
4.1. General Information and Method. Unless otherwise
noted, all reactions were conducted under an inert atmosphere in a
nitrogen-filled dry box or by standard Schlenk techniques. All
glassware used for reactions were dried at 140 °C in an oven
overnight.
The majority of hydroarylation products were isolated in high
purities without column chromatography. If further purification was
required, flash column chromatography was performed on SiliFlash
P60 silica gel (40−63 μm, 60 Å) using hexanes/ethyl acetate or
hexanes/diethyl ether mixtures as eluents. Reaction products were
visualized on thin-layer chromatography by UV light.
HRMS analysis was performed at the Iowa State University
Chemical Instrumentation Facility on an Agilent 6540 QTOF
spectrometer (ESI) or Agilent 7250 GC/Q-TOF (EI). NMR spectra
were acquired on Varian MR-400 at the Iowa State University
Chemical Instrumentation Facility. Chemical shifts are reported in
parts per million relative to a residual solvent peak (CDCl3 = 7.26
ppm for 1H and 77.16 ppm for 13C). Coupling constants are reported
in hertz. HPLC analyses were carried out on a Water Alliance HPLC
system with an e2695 Separations Module and a 2489 (UV/vis) dual
a
b
c
X = 2.5, Y = 1, tBuOLi as base. X = 5, Y = 1, tBuOLi as base. X =
d
e
2.5, Y = 0.5, TMSOK as base. Isolated yields. Enantioselectivities
were determined by chiral HPLC.
products derived from electron-deficient nucleophiles were
improved (Table 2).
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wavelength detector. Optical rotations were measured on an Atago
AP-300 automatic polarimeter.
mmol, 5 equiv) was added to the mixture. Next, a solution of
cyclohexane-1,1-dicarbonyl chloride28 (5 mmol, 1 equiv) in DCM (10
mL) was added dropwise to the flask. The ice bath was removed, and
the resulting mixture was stirred overnight at room temperature. The
reaction mixture was washed with 1 N HCl and then saturated
aqueous NaHCO3. The organic layer was dried over Na2SO4, and the
organic layer was concentrated in vacuo. The resultant bis-amide
residue was directly used for the next step without purification.
To a solution of the bis-amide (1 mmol) in DCM (20 mL) were
added 4-(dimethylamino)pyridine (5 mmol, 5 equiv) and triethyl-
amine (5 mmol, 5 equiv). Then, a solution of p-toluenesulfonyl
chloride (2.5 equiv) in DCM (12 mL) was added at room
temperature. The resulting mixture was stirred at room temperature
for 3 days. Upon completion of the reaction, the solution was washed
with saturated aqueous NH4Cl and then saturated aqueous NaHCO3.
The resulting organic layer was concentrated in vacuo and purified by
silica gel column chromatography (hexane/EtOAc = 80:20) to afford
4.2. Materials. All chemicals obtained from commercial sources
were used directly without further purification. Bis(1,5-
cyclooctadiene)nickel(0) was purchased from Strem Chemicals.
Thionyl chloride was purchased from Sigma-Aldrich. Dimethylma-
lonic acid was purchased from Oakwood. (1R,2S)-2-Amino-1,2-
diphenylethanol, (S)-(+)-2-phenylglycinol, and TMSOK were
purchased from AK Scientific. Anhydrous methanol was purchased
from Sigma-Aldrich.
The following boron compounds were purchased from AK
Scientific: 4-methoxylphenylboronic acid; 4-methylphenylboronic
acid; phenylboronic acid; 4-fluorophenylboronic acid; 3-methoxyphe-
nylboronic acid; 3-fluorophenylboronic acid; 4-methoxycarbonylphe-
nylboronic acid; 4-acetylphenylboronic acid; 4-phenylboronic acid
pinacol ester; and furan-3-boronic acid pinacol ester. The following
arylboronic acid were purchased from Frontier: 4-chlorophenylbor-
onic acid; 4-(trifluoromethyl)phenylboronic acid; 2-methoxyphenyl-
boronic acid; and 3-methoxyphenylboronic acid. The following boron
compounds were purchased from Combi-Blocks: 2-methylphenylbor-
onic acid; 3-hydroxyphenylboronic acid; 2-naphthaleneboronic acid;
3,4-(methylenedioxy)phenylboronic acid; 2-fluoro-4-methoxyphenyl-
boronic acid; 4-methoxyphenylboronic acid pinacol ester; 4-
methylphenylboronic acid pinacol ester; and 4-(trifluoromethyl)-
phenylboronic acid pinacol ester. 2-Biphenylboronic acid was
obtained from Oakwood. Neopentylglycol esters were synthesized
according to a reported literature procedure.15
1
the desired BOX ligand L6 (0.38 g, 72%) as a white solid. H NMR
(400 MHz, CDCl3): δ 7.33−7.29 (m, 20H), 5.30 (d, J = 7.8 Hz, 2H),
5.16 (d, J = 7.9 Hz, 2H), 2.43−2.39 (m, 4H), 1.83−1.79 (m, 4H),
1.65−1.59 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 168.6,
142.1, 140.4, 128.9, 128.8, 128.4, 127.7, 126.8, 126.0, 89.4, 78.8, 44.3,
+
32.7, 25.4, 22.9. HRMS (ESI): calcd for C36H35N2O2 ([M + H]+),
527.2693; found: 527.2738.
4.3.3. Ligand L7. Ligand L7 was synthesized using an analogous
procedure to that for the synthesis of ligand L6 with (S)-(+)-2-
phenylglycinol used in place of (1R,2S)-2-amino-1,2-diphenylethanol.
The crude product was purified by silica gel column chromatography
(hexane/EtOAc = 80:20) to afford the desired BOX ligand L7 (0.29
Styrene and 4-fluorostyrene were purchased from Sigma-Aldrich. 4-
Methoxystyrene, 4-methylstyrene, and 2-methylstyrene were pur-
chased from Alfa Aesar. The following vinylarenes were synthesized
by Wittig reactions according to a reported literature procedure:16 4-
trifluoromethylstyrene; 3-methoxystyrene; 3,4-dimethoxystyrene;
3,4,5-trimethoxystyrene; and 2-vinylnaphthalene. 3-Vinylindole was
prepared according to a previous report.17 Characterization for data of
4-trifluoromethylstyrene,18 3-methoxystyrene,19 3,4-dimethoxystyr-
ene,20 3,4,5-trimethoxystyrene,21 2-vinylnaphthalene,22 and 3-vinyl-
indole17 were in accordance with the reported data.
1
g, 78%) as a white solid. H NMR (400 MHz, CDCl3): δ 7.33−7.23
(m, 10H), 5.26 (dd, J = 10.2, 7.8 Hz, 2H), 4.65 (dd, J = 10.2, 8.4 Hz,
2H), 4.12 (t, J = 8.3 Hz, 2H), 2.27−2.16 (m, 4H), 1.71−1.65 (m,
4H), 1.54−1.50 (m, 2H). The NMR spectrum was in accordance with
the reported data.29
4.4. General Procedure for Ni-Catalyzed Hydroarylation of
Vinylarenes with Arylboronic Acids. In a nitrogen-filled glovebox,
an oven-dried 1-dram vial was charged with an appropriate
arylboronic acid 2 (0.5 mmol) and MeOH (1 mL). The resulting
mixture was gently stirred at room temperature until it was clear and
was used immediately.
4.3. Ligand Synthesis. Ligands L2,23 L3,24 L4,25 and L526 were
synthesized according to reported literature procedures.
4.3.1. Ligand L1. A mixture of dimethylmalonic acid (5.0 mmol) in
SOCl2 (20 mL) was refluxed in an oil bath for 5 h. After cooling to
room temperature, the solvent was removed under reduced pressure
to afford the corresponding crude acid chloride, which was directly
used for the next step without further purification.
In a second oven-dried 1-dram vial, Ni(cod)2 (0.0125 mmol),
ligand L1 (0.0063 mmol), tBuOLi (0.25 mmol), and styrene 1a or 4-
methoxystyrene 1e (0.25 mmol) were sequentially added. Then, the
vial was charged with the as-prepared solution of the arylboronic acid
in MeOH from the first vial, sealed, and taken out of the glovebox.
The reaction mixture was stirred at 50 °C in an aluminum reaction
block (for 1-dram vials) for 3 h. Upon completion, the reaction was
cooled to room temperature and was diluted with 20 mL of DCM.
The solvent was removed under vacuum. The resulting residue was
redissolved with DCM, filtered through a short plug of silica gel
eluting with DCM, and concentrated under vacuum. Unless otherwise
stated, the hydroarylation products were isolated in high purity after
concentration under vacuum. The racemic products were synthesized
either by the same procedure with racemic ligand L7 or by a
previously reported procedure.5d The absolute configuration of the
chiral product 3aa was assigned by comparison to the optical rotation
reported in the literature.6c Absolute configurations of additional 1,1-
diarylethanes were assigned based on the sense of absolute
configuration observed for compound 3aa.
(1R,2S)-2-Amino-1,2-diphenylethanol (10 mmol, 2 equiv) was
dissolved in DCM (20 mL) under nitrogen. The solution was cooled
to 0 °C using an ice bath, and triethylamine (25 mmol, 5 equiv) was
added to the mixture. Next, a solution of crude dimethylmalonyl
dichloride in DCM (10 mL) was added dropwise to the flask. The ice
bath was removed, and the resulting mixture was stirred overnight at
room temperature. The reaction mixture was washed with 1 N HCl
and then saturated aqueous NaHCO3. The organic layer was dried
over Na2SO4 and concentrated in vacuo. The resultant bis-amide
residue was directly used for the final step without further purification.
To a solution of the bis-amide (1 mmol, 1 equiv) in DCM (20 mL)
were added 4-(dimethylamino)pyridine (5 mmol, 5 equiv) and
triethylamine (5 mmol, 5 equiv). Then, a solution of p-toluenesulfonyl
chloride (2.5 mmol, 2.5 equiv) in DCM (12 mL) was added at room
temperature. The resulting mixture was stirred at room temperature
for 3 days. Upon completion of the reaction, the solution was washed
with NH4Cl and then NaHCO3. The resulting organic layer was
concentrated under reduced pressure and purified by silica gel column
chromatography (hexane/EtOAc = 80:20) to afford the desired BOX
ligand L1 (0.40 g, 82%) as a white solid. 1H NMR (400 MHz,
CDCl3): δ 7.34−7.27 (m, 10H), 5.33 (d, J = 7.6 Hz, 2H), 5.12 (d, J =
7.6 Hz, 2H), 1.90 (s, 6H). The NMR spectrum was in accordance
with the reported data.27
4.4.1. (R)-1-Methoxy-4-(1-phenylethyl)benzene (3aa).6c Prepared
according to the general procedure from styrene 1a (26.0 mg, 0.25
mmol) and 4-methoxyphenylboronic acid 2a (76.0 mg, 0.5 mmol).
3aa was isolated in high purity without further purification as a
colorless oil in 93% yield (49.4 mg, 0.22 mmol). The enantiomeric
excess was determined by HPLC analysis (220 nm, 25 °C) tR 18.0
min (minor); tR 19.4 min (major) [CHIRALCEL OJ-H (0.46 cm ×
25 cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0
1
4.3.2. Ligand L6. (1R,2S)-2-Amino-1,2-diphenylethanol (10 mmol,
2 equiv) was dissolved in DCM (20 mL) under nitrogen. The
solution was cooled to 0 °C using an ice bath, and triethylamine (25
mL/min] to be 92% ee. [α]2D4 = −1.49° (c 0.74, CHCl3). H NMR
(400 MHz, CDCl3): δ 7.31−7.28 (m, 2H), 7.25−7.15 (m, 5H), 6.85
(d, J = 8.7 Hz, 2H), 4.13 (d, J = 7.2 Hz, 1H), 3.80 (s, 3H), 1.64 (d, J =
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7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 157.8, 146.8,
138.6, 128.5, 128.3, 127.5, 125.9, 113.1, 55.2, 43.9, 22.1.
mg, 0.25 mmol) and phenylboronic acid 2g (61.0 mg, 0.5 mmol). 3eg
was isolated in high purity without further purification as a colorless
oil in 87% yield (46.2 mg, 0.22 mmol). The enantiomeric excess was
determined by HPLC analysis (220 nm, 25 °C) tR 17.6 min (major);
tR 19.0 min (minor) [CHIRALCEL OJ-H (0.46 cm × 25 cm) (from
Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be
87% ee. [α]2D4 = +1.55° (c 0.58, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 7.31−7.28 (m, 2H), 7.25−7.15 (m, 5H), 6.85 (d, J = 8.7
Hz, 2H), 4.13 (d, J = 7.2 Hz, 1H), 3.80 (s, 3H), 1.64 (d, J = 7.2 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 157.8, 146.8, 138.6, 128.5,
128.3, 127.5, 125.9, 113.1, 55.2, 43.9, 22.1.
4.4.2. (R)-1-Methyl-4-(1-phenylethyl)benzene (3ab).3d Prepared
according to the general procedure from styrene 1a (26.0 mg, 0.25
mmol) and 4-methylphenylboronic acid 2b (68.0 mg, 0.5 mmol). 3ab
was isolated in high purity without further purification as a colorless
oil in 93% yield (49.3 mg, 0.23 mmol). The enantiomeric excess was
determined by HPLC analysis (220 nm, 25 °C) tR 11.5 min (minor);
tR 12.6 min (major) [CHIRALCEL OJ-H (0.46 cm × 25 cm) (from
Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be
88% ee. [α]2D4 = −1.60° (c 0.6, CHCl3). 1H NMR (400 MHz,
CHCl3): δ 7.34−7.30 (m, 2H), 7.28−7.26 (m, 2H), 7.24−7.19 (m,
1H), 7.18−7.13 (m, 4H), 4.17 (q, J = 7.2 Hz, 1H), 2.36 (s, 3H), 1.67
(d, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 146.6,
143.4, 135.5, 129.1, 128.4, 127.6, 127.5, 126.0, 44.4, 22.0, 21.0.
4.4.3. (R)-1-Fluoro-4-(1-phenylethyl)benzene (3ac).3e Prepared
according to the general procedure from styrene 1a (26.0 mg, 0.25
mmol) and 4-fluorophenylboronic acid 2c (70.0 mg, 0.5 mmol). 3ac
was isolated in high purity without further purification as a colorless
oil in 93% yield (46.6 mg, 0.23 mmol). The enantiomeric excess was
determined by HPLC analysis (220 nm, 25 °C) tR 8.7 min (minor); tR
10.3 min (major) [CHIRALCEL OJ-H (0.46 cm × 25 cm) (from
Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be
72% ee. [α]2D4 = −1.30° (c 0.74, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 7.32−7.28 (m, 2H), 7.22−7.16 (m, 5H), 6.98 (t, J = 8.7
Hz, 2H), 4.15 (q, J = 7.2 Hz, 1H), 1.64 (d, J = 7.2 Hz, 3H). 13C{1H}
4.4.8. (S)-1-Methoxy-4-(1-(4-(trifluoromethyl)phenyl)ethyl)-
benzene (3eh).2c Prepared according to the general procedure from
4-methoxystyrene 1e (33.5 mg, 0.25 mmol) and 4-(trifluoromethyl)-
phenylboronic acid 2h (95.0 mg, 0.5 mmol). 3eh was isolated in high
purity without further purification as a colorless oil in 85% yield (59.6
mg, 0.21 mmol). The enantiomeric excess was determined by HPLC
analysis (220 nm, 25 °C) tR 7.0 min (major); tR 9.7 min (minor)
[CHIRALCEL OJ-H (0.46 cm × 25 cm) (from Daicel Chemical Ind.,
Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be 79% ee. [α]D24
=
+1.74° (c 0.54, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.55 (d, J =
8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.87
(d, J = 8.7 Hz, 2H), 4.18 (d, J = 7.2 Hz, 1H), 3.80 (s, 3H), 1.65 (d, J =
7.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 158.1, 150.9,
137.4, 128.5, 128.3 (d, C−F, 2JC−F = 32.3 Hz), 127.9, 125.3 (q, C−F,
3JC−F = 3.8 Hz), 124.3 (d, C−F, 1JC−F = 272.7 Hz), 113.9, 55.2, 43.9,
21.8. 19F NMR (376 MHz, CDCl3): δ −62.3.
1
NMR (101 MHz, CDCl3): δ 161.3 (d, C−F, JC−F = 243.9 Hz),
4
3
4.4.9. (R)-1-Methoxyl-3-(1-phenylethyl)benzene (3ai).31 Prepared
according to the general procedure from styrene 1a (26.0 mg, 0.25
mmol) and 3-methoxyphenylboronic acid 2i (76.0 mg, 0.5 mmol). 3ai
was isolated in high purity without further purification as a colorless
oil in 82% yield (43.5 mg, 0.20 mmol). The enantiomeric excess was
determined by HPLC analysis (220 nm, 25 °C) tR 7.2 min (minor); tR
7.7 min (major) [CHIRALCEL OD-H (0.46 cm × 25 cm) (from
Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be
77% ee. [α]2D4 = −1.21° (c 0.76, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 7.33−7.30 (m, 2H), 7.27−7.19 (m, 4H), 6.86 (d, J = 8.0
Hz, 1H), 6.82 (t, J = 2.4 Hz, 1H), 6.76 (dd, J = 8.2, 2.6 Hz, 1H), 4.16
(q, J = 7.2 Hz, 1H), 3.80 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3): δ 159.6, 148.1, 146.2, 129.3, 128.4, 127.6,
126.1, 120.1, 113.8, 111.0, 55.1, 44.8, 21.8.
146.2, 142.0 (d, C−F, JC−F = 3.4 Hz), 129.0 (d, C−F, JC−F = 7.7
Hz), 128.4, 127.5, 126.2, 115.1 (d, C−F, 2JC−F = 21.1 Hz), 44.0, 22.0.
19F NMR (376 MHz, CDCl3): δ −117.5.
4.4.4. (R)-1-Chloro-4-(1-phenylethyl)benzene (3ad).3d Prepared
according to the general procedure from styrene 1a (26.0 mg, 0.25
mmol) and 4-chlorophenylboronic acid 2d (78.2 mg, 0.5 mmol). 3ad
was isolated in high purity without further purification as a colorless
oil in 57% yield (30.9 mg, 0.14 mmol). The enantiomeric excess was
determined by HPLC analysis (220 nm, 25 °C) tR 7.7 min (minor); tR
8.4 min (major) [CHIRALCEL OJ-H (0.46 cm × 25 cm) (from
Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be
77% ee. [α]2D4 = −1.5° (c 0.64, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 7.33−7.16 (m, 9H), 4.15 (q, J = 7.2 Hz, 1H), 1.64 (d, J =
7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 145.8, 144.9,
131.8, 129.0, 128.5, 128.5, 127.5, 126.3, 44.2, 21.8.
4.4.10. (R)-3-(1-Phenylethyl)phenol (3aj).9a Prepared according to
the general procedure from styrene 1a (26.0 mg, 0.25 mmol) and 3-
hydroxyphenylboronic acid 2j (69.0 mg, 0.5 mmol). 3aj was isolated
in high purity without further purification as a colorless oil in 85%
yield (42.1 mg, 0.21 mmol). The enantiomeric excess was determined
by HPLC analysis (220 nm, 25 °C) tR 28.4 min (major); tR 38.4 min
(minor) [CHIRALCEL OJ-H (0.46 cm × 25 cm) (from Daicel
Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be 86%
ee. [α]2D4 = −1.11° (c 0.54, CHCl3). 1H NMR (400 MHz, CDCl3): δ
7.36−7.29 (m, 2H), 7.26−7.15 (m, 4H), 6.84 (d, J = 7.6 Hz, 1H),
6.69−6.65 (m, 2H), 4.79 (s, 1H), 4.12 (q, J = 7.2 Hz, 1H), 1.64 (d, J
= 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 155.4, 148.4,
146.1, 129.6, 128.4, 127.6, 126.1, 120.2, 114.6, 113.0, 44.6, 21.7.
4.4.11. (R)-1-Methoxy-2-(1-phenylethyl)benzene (3ak).32 Pre-
pared according to the general procedure from styrene 1a (26.0
mg, 0.25 mmol) and 2-methoxyphenylboronic acid 2g (76.0 mg, 0.5
mmol). 3ak was isolated in high purity without further purification as
a colorless oil in 83% yield (44.1 mg, 0.21 mmol). The enantiomeric
excess was determined by HPLC analysis (220 nm, 25 °C) tR 9.0 min
(major); tR 14.1 min (minor) [CHIRALCEL OJ-H (0.46 cm × 25
cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0
4.4.5. Methyl (R)-4-(1-Phenylethyl)benzoate (3ae).6c Prepared
according to the general procedure from styrene 1a (26.0 mg, 0.25
mmol) and 4-(methoxycarbonyl)phenyl)boronic acid 2e (90.0 mg,
0.5 mmol). 3ae was isolated in high purity without further purification
as a colorless oil in 86% yield (52.9 mg, 0.22 mmol). The
enantiomeric excess was determined by HPLC analysis (220 nm, 25
°C) tR 6.0 min (major); tR 6.8 min (minor) [CHIRALCEL AS-H
(0.46 cm × 25 cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH,
90:10, 1.0 mL/min] to be 74% ee. [α]2D4 = −0.82° (c 0.78, CHCl3).
1H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 8.3 Hz, 2H), 7.33−7.29
(m, 4H), 7.23−7.20 (m, 3H), 4.22 (q, J = 7.2 Hz, 1H), 3.91 (s, 3H),
1.67 (d, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 167.0,
151.7, 145.4, 129.8, 128.5, 128.0, 127.7, 127.6, 126.3, 52.0, 44.8, 21.6.
4.4.6. (R)-1-(4-(1-Phenylethyl)phenyl)ethan-1-one (3af).30 Pre-
pared according to the general procedure from styrene 1a (26.0 mg,
0.25 mmol) and 4-acetylphenylboronic acid 2f (82.0 mg, 0.5 mmol).
3af was isolated in high purity without further purification as a
colorless oil in 82% yield (45.9 mg, 0.20 mmol). The enantiomeric
excess was determined by HPLC analysis (220 nm, 25 °C) tR 10.9
min (minor); tR 11.4 min (major) [CHIRALCEL AS-H (0.46 cm ×
25 cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH, 98:2, 1.0
mL/min] to be 92% ee. [α]2D4 = −1.45° (c 0.62, CHCl3). H NMR
1
mL/min] to be 74% ee. [α]2D4 = −1.1° (c 0.86, CHCl3). H NMR
(400 MHz, CDCl3): δ 7.35−7.30 (m, 4H), 7.26−7.19 (m, 3H), 6.97
(td, J = 7.5, 1.2 Hz, 1H), 6.90 (dd, J = 8.1 Hz, 1.2 Hz, 1H), 4.65 (q, J
= 7.3 Hz, 1H), 3.82 (s, 3H), 1.65 (d, J = 7.3 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3): δ 156.9, 146.4, 134.9, 128.1, 127.8, 127.7, 127.1,
125.7, 120.6, 110.6, 55.4, 37.4, 21.0.
1
(400 MHz, CDCl3): δ 7.89 (d, J = 8.4 Hz, 2H), 7.34−7.29 (m, 4H),
7.23−7.19 (m, 3H), 4.22 (q, J = 7.2 Hz, 1H), 2.58 (s, 3H), 1.67 (d, J
= 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 197.8, 152.0,
145.3, 135.2, 128.6, 128.5, 127.8, 127.6, 126.4, 44.8, 26.6, 21.6.
4.4.7. (S)-1-Methoxy-4-(1-phenylethyl)benzene (3eg).6a Prepared
according to the general procedure from 4-methoxystyrene 1e (33.5
4.4.12. (R)-1-Methyl-2-(1-phenylethyl)benzene (3al).32 Prepared
according to the general procedure from styrene 1a (26.0 mg, 0.25
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1
mmol) and 2-methylphenylboronic acid 2l (68.0 mg, 0.5 mmol). 3al
was isolated in high purity without further purification as a colorless
oil in 85% yield (41.7 mg, 0.21 mmol). The enantiomeric excess was
determined by HPLC analysis (220 nm, 25 °C) tR 10.5 min (major);
tR 14.7 min (minor) [CHIRALCEL OJ-H (0.46 cm × 25 cm) (from
Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be
87% ee. [α]2D4 = −1.20° (c 0.78, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 7.35−7.29 (m, 3H), 7.28−7.25 (m, 1H), 7.24−7.18 (m,
5H), 4.38 (q, J = 7.2 Hz, 1H), 2.29 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 146.3, 144.0, 136.1, 130.4,
128.4, 127.7, 126.7, 126.1, 126.1, 125.9, 41.0, 22.2, 19.8.
MHz, CDCl3): δ 161.0 (d, C−F, JC−F = 245.3 Hz), 159.2 (d, C−F,
3JC−F = 11.0 Hz), 145.5, 128.8 (d, C−F, 3JC−F = 7.0 Hz), 128.4, 127.4,
2
4
126.1, 125.2 (d, C−F, JC−F = 19.8 Hz), 109.6 (d, C−F, JC‑F = 3.0
Hz), 101.6 (d, C−F, JC−F = 28.4 Hz), 55.5, 37.1, 20.9. 19F NMR
2
(376 MHz, CDCl3): δ −115.7.
4.4.17. (R)-1-Methoxy-4-(1-(p-tolyl)ethyl)benzene (3ba).35 Pre-
pared according to the general procedure from 4-methylstyrene 1b
(29.5 mg, 0.25 mmol) and 4-methoxyphenylboronic acid 2a (76.0 mg,
0.5 mmol), with 0.0025 mmol L1 used. 3ba was isolated in high
purity without further purification as a colorless oil in 91% yield (51.5
mg, 0.23 mmol). The enantiomeric excess was determined by HPLC
analysis (220 nm, 25 °C) tR 18.8 min (minor); tR 21.4 min (major)
[CHIRALCEL OJ-H (0.46 cm × 25 cm) (from Daicel Chemical Ind.,
4.4.13. (R)-2-(1-Phenylethyl)-1,1′-biphenyl (3am). Prepared ac-
cording to the general procedure from styrene 1a (26.0 mg, 0.25
mmol) and 2-biphenylboronic acid 2m (99.0 mg, 0.5 mmol). The
crude reaction mixture was purified by flash column chromatography
(hexane/EtOAc = 90:10) to give 3am as a colorless oil in 75% yield
(48.4 mg, 0.19 mmol). The enantiomeric excess was determined by
HPLC analysis (220 nm, 25 °C) tR 6.3 min (minor); tR 8.3 min
(major) [CHIRALCEL OJ-H (0.46 cm × 25 cm) (from Daicel
Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be 84%
ee. [α]2D4 = −0.87° (c 0.90, CHCl3). 1H NMR (400 MHz, CDCl3): δ
7.47−7.38 (m, 5H), 7.34−7.28 (m, 6H), 7.23−7.19 (m, 1H), 7.17−
7.14 (m, 2H), 4.39 (q, J = 7.2 Hz, 1H), 1.63 (d, J = 7.2 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 146.6, 144.1, 141.9, 141.8,
130.1, 129.4, 128.2, 128.1, 127.7, 127.6, 127.6, 126.9, 125.8, 125.8,
Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be 94% ee. [α]D24
=
1
−1.45° (c 0.66, CHCl3). H NMR (400 MHz, CDCl3): δ 7.18−7.11
(m, 6H), 6.86 (d, J = 8.7 Hz, 2H), 4.11 (q, J = 7.2 Hz, 1H), 3.81 (s,
3H), 2.35 (d, J = 1.2 Hz, 3H), 1.64 (d, J = 7.2 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3): δ 157.8, 143.8, 138.8, 135.4, 129.0, 128.5,
127.4, 113.7, 55.2, 43.6, 22.2, 21.0.
4.4.18. (R)-4-(1-(4-Methoxyphenyl)ethyl)aniline (3ca).36 Prepared
according to the general procedure from 4-vinylaniline 1d (29.8 mg,
0.25 mmol) and 4-methoxyphenylboronic acid 2a (76.0 mg, 0.5
mmol). 3ca was isolated in high purity without further purification as
1
a white solid in 68% yield (38.6 mg, 0.17 mmol). H NMR (400
MHz, CDCl3): δ 7.13 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H),
6.83 (d, J = 8.7 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 4.02 (q, J = 7.2 Hz,
1H), 3.78 (s, 5H), 1.58 (d, J = 7.2 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 157.7, 143.8, 139.2, 137.3, 128.4, 128.3, 115.4,
113.6, 55.2, 43.1, 22.2. Next, 3ca (15.00 mg, 0.066 mmol, 1 equiv),
benzoyl chloride (13.86 mg, 0.099 mmol, 1.5 equiv), triethylamine
(33.33 mg, 0.33 mmol, 5 equiv), and DCM (2 mL) were combined in
a 1-dram vial under air and stirred overnight at room temperature.
The reaction mixture was washed successively with 1 N HCl and
brine. The organic layer was separated, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure to afford the amide
derivative of 3ca as a white solid which was used directly to determine
the enantiomeric excess without further purification. The enantio-
meric excess was determined by HPLC analysis (220 nm, 25 °C) tR
27.9 min (major); tR 40.1 min (minor) [CHIRALCEL OJ-H (0.46 cm
× 25 cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10,
1.0 mL/min] to be 92% ee. [α]2D4 = −1.70° (c 0.65, CHCl3).
+
40.2, 22.4. HRMS (EI): calcd for C20H18 ([M]+), 258.1403; found,
258.1404.
4.4.14. (R)-5-(1-Phenylethyl)-1,3-benzodioxole (3an).9a Prepared
according to the general procedure from styrene 1a (26.0 mg, 0.25
mmol) and 3,4-methylenedioxyphenylboronic acid 2n (83.0 mg, 0.5
mmol). 3an was isolated in high purity without further purification as
a colorless oil in 88% yield (49.8 mg, 0.22 mmol). The enantiomeric
excess was determined by HPLC analysis (220 nm, 25 °C) tR 19.6
min (major); tR 20.9 min (minor) [CHIRALCEL OJ-H (0.46 cm ×
25 cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0
mL/min] to be 86% ee. [α]2D4 = −0.94° (c 0.68, CHCl3). H NMR
1
(400 MHz, CDCl3): δ 7.33−7.30 (m, 2H), 7.26−7.19 (m, 3H),
6.78−6.72 (m, 3H), 5.92 (s, 2H), 4.11 (q, J = 7.2 Hz, 1H), 1.63 (d, J
= 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 147.6, 146.4,
145.7, 140.5, 128.4, 127.5, 126.1, 120.4, 108.2, 108.0, 100.8, 44.5,
22.0.
4.4.15. (R)-2-(1-(4-Methoxyphenyl)ethyl)naphthalene (3eo).33
Prepared according to the general procedure from 4-methoxystyrene
1e (33.5 mg, 0.25 mmol) and 2-naphthaleneboronic acid 2o (86.0
mg, 0.5 mmol). The crude reaction mixture was purified by flash
column chromatography (hexane/EtOAc = 90:10) to give 3eo as a
colorless oil in 75% yield (49.2 mg, 0.19 mmol). The enantiomeric
excess was determined by HPLC analysis (220 nm, 25 °C) tR 23.7
min (major); tR 30.4 min (minor) [CHIRALCEL OJ-H (0.46 cm ×
25 cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0
4.4.19. (R)-1-Methoxy-4-(1-(4-(trifluoromethyl)phenyl)ethyl)-
benzene (3da).6c Prepared according to the general procedure
from 4-(trifluoromethyl)styrene 1e (43.0 mg, 0.25 mmol) and 4-
methoxyphenylboronic acid 2a (76.0 mg, 0.5 mmol). 3da was isolated
in high purity without further purification as a colorless oil in 90%
yield (63.1 mg, 0.23 mmol). The enantiomeric excess was determined
by HPLC analysis (220 nm, 25 °C) tR 7.0 min (minor); tR 9.6 min
(major) [CHIRALCEL OJ-H (0.46 cm × 25 cm) (from Daicel
Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be 93%
ee. [α]2D4 = −1.67° (c 0.72, CHCl3). 1H NMR (400 MHz, CDCl3): δ
7.55 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.4 Hz,
2H), 6.87 (d, J = 8.7 Hz, 2H), 4.18 (d, J = 7.2 Hz, 1H), 3.80 (s, 3H),
1.65 (d, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 158.1,
150.9, 137.4, 128.5, 128.3 (d, C−F, 2JC−F = 32.3 Hz), 127.8, 125.3 (q,
C−F, 3JC−F = 3.8 Hz), 124.3 (d, C−F, 1JC−F = 272.7 Hz), 113.9, 55.2,
43.8, 21.8. 19F NMR (376 MHz, CDCl3): δ −62.3.
mL/min] to be 86% ee. [α]2D4 = +1.50° (c 0.77, CHCl3). H NMR
1
(400 MHz, CDCl3): δ 7.85−7.82 (m, 2H), 7.78 (d, J = 8.5 Hz, 1H),
7.73 (s, 1H), 7.52−7.44 (m, 2H), 7.35 (dd, J = 8.5, 1.7 Hz, 1H), 7.22
(d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.32 (q, J = 7.2 Hz, 1H),
3.82 (s, 3H), 1.76 (d, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 158.0, 144.2, 138.4, 133.6, 132.1, 128.7, 128.0, 127.8,
127.6, 126.9, 126.0, 125.4, 125.2, 113.8, 55.3, 44.1, 22.0.
4.4.20. (S)-1-Fluoro-4-(1-phenylethyl)benzene (3fg).9a Prepared
according to the general procedure from 4-fluorostyrene 1f (30.5 mg,
0.25 mmol) and 4-methoxyphenylboronic acid 2a (76.0 mg, 0.5
mmol). 3fg was isolated in high purity without further purification as
a colorless oil in 90% yield (40.1 mg, 0.23 mmol). The enantiomeric
excess was determined by HPLC analysis (220 nm, 25 °C) tR 8.7 min
(major); tR 10.3 min (minor) [CHIRALCEL OJ-H (0.46 cm × 25
cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0
4.4.16. (R)-2-Fluoro-4-methoxy-1-(1-phenylethyl)benzene
(3ap).34 Prepared according to the general procedure from styrene
1a (26.0 mg, 0.25 mmol) and 3,4-methylenedioxyphenylboronic acid
2p (85.0 mg, 0.5 mmol). 3ap was isolated in high purity without
further purification as a colorless oil in 85% yield (48.9 mg, 0.21
mmol). The enantiomeric excess was determined by HPLC analysis
(220 nm, 25 °C) tR 19.8 min (major); tR 20.9 min (minor)
[CHIRALCEL OJ-H (0.46 cm × 25 cm) (from Daicel Chemical Ind.,
mL/min] to be 85% ee. [α]2D4 = +1.45° (c 0.58, CHCl3). H NMR
1
Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be 75% ee. [α]D24
=
1
(400 MHz, CDCl3): δ 7.32−7.28 (m, 2H), 7.22−7.16 (m, 5H), 6.98
−0.92° (c 0.98, CHCl3). H NMR (400 MHz, CDCl3): δ 7.34−7.26
(m, 4H), 7.24−7.19 (m, 1H), 7.13 (t, J = 8.7 Hz, 1H), 6.67 (dd, J =
8.6, 2.3 Hz, 1H), 6.61 (dd, J = 12.0, 2.5 Hz, 1H), 4.43 (q, J = 7.3 Hz,
1H), 3.79 (s, 3H), 1.64 (d, J = 7.3 Hz, 3H). 13C{1H} NMR (101
(t, J = 8.7 Hz, 2H), 4.15 (q, J = 7.2 Hz, 1H), 1.64 (d, J = 7.2 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 161.3 (d, C−F, JC−F = 243.9
1
4
3
Hz), 146.2, 142.0 (d, C−F, JC−F = 3.4 Hz), 129.0 (d, C−F, JC−F
=
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Article
2
7.7 Hz), 128.4, 127.5, 126.2, 115.1 (d, C−F, JC−F = 21.1 Hz), 44.0,
determined by HPLC analysis (220 nm, 25 °C) tR 11.8 min (minor);
tR 13.3 min (major) [CHIRALCEL OD-H (0.46 cm × 25 cm) (from
Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be
70% ee. [α]2D4 = −1.50° (c 0.52, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 7.94 (s, 1H), 7.36 (dd, J = 14.3, 8.0 Hz, 2H), 7.21 (d, J =
8.6 Hz, 2H), 7.15 (d, J = 7.2 Hz, 1H), 7.03−6.99 (m, 2H), 6.83 (d, J
= 8.7 Hz, 2H), 4.34 (q, J = 7.2 Hz, 1H), 3.78 (s, 3H), 1.69 (d, J = 7.1
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 157.7, 139.0, 136.6,
128.3, 126.9, 121.9, 121.8, 121.0, 119.8, 119.2, 113.7, 111.0, 55.2,
36.1, 22.6.
4.5. General Procedure for Ni-Catalyzed Hydroarylation of
Vinylarenes with Arylboronic Acid Pinacol Esters. In a nitrogen-
filled glovebox, an oven-dried 1-dram vial was charged with an
appropriate arylboronic acid pinacol ester 2 (0.5 mmol) and MeOH
(1 mL). The resulting mixture was gently stirred at room temperature
until it was clear and was used immediately.
22.0. 19F NMR (376 MHz, CDCl3): δ −117.5.
4.4.21. (S)-1-Methoxy-3-(1-(4-methoxyphenyl)ethyl)benzene
(3ga).6c Prepared according to the general procedure from 3-
methoxystyrene 1g (33.5 mg, 0.25 mmol) and 4-methoxyphenylbor-
onic acid 2a (76.0 mg, 0.5 mmol). 3ha was isolated in high purity
without further purification as a colorless oil in 78% yield (43.5 mg,
0.20 mmol). The enantiomeric excess was determined by HPLC
analysis (220 nm, 25 °C) tR 25.8 min (minor); tR 33.7 min (major)
[CHIRALCEL OJ-H (0.46 cm × 25 cm) (from Daicel Chemical Ind.,
Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be 93% ee. [α]D24
=
−1.83° (c 0.76, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.23 (t, J =
7.9 Hz, 1H), 7.18 (d, J = 8.7 Hz, 2H), 6.87−6.84 (m, 3H), 6.81−6.80
(m, 1H), 6.76 (dd, J = 8.1, 2.6 Hz, 1H), 4.11 (q, J = 7.2 Hz, 1H), 3.80
(d, 6H, 2× OMe), 1.64 (d, J = 7.2 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 159.6, 157.9, 148.5, 138.4, 129.3, 128.5, 120.1,
113.8, 113.7, 110.9, 55.2, 55.1, 44.0, 22.0.
In a second oven-dried 1-dram vial, Ni(cod)2 (0.0125 mmol),
ligand L1 (0.0125 mmol), tBuOLi (0.25 mmol), and an appropriate
vinylarene 1 (0.25 mmol) were sequentially added. Then, the vial was
charged with the as-prepared solution of the arylboronic acid pinacol
ester in MeOH from the first vial, sealed, and taken out of the
glovebox. The reaction mixture was stirred at 50 °C in an aluminum
reaction block (for 1-dram vials) for 3 h. Upon completion, the
reaction was cooled to room temperature and was diluted with 20 mL
of DCM. The solvent was removed under vacuum. The resulting
residue was redissolved with DCM, filtered through a short plug of
silica gel eluting with DCM, and concentrated under vacuum. The
crude product was purified by flash column chromatography (hexane/
Et2O = 100:1). The racemic products were synthesized either by the
same procedure with racemic ligand L7 or by a previously reported
method.5d
4.4.22. (S)-1-(1-(4-Methoxyphenyl)ethyl)-2-methylbenzene
(3ha).6c Prepared according to the general procedure from 2-
methylstyrene 1h (29.5 mg, 0.25 mmol) and 4-methoxyphenylboronic
acid 2a (76.0 mg, 0.5 mmol), with 0.025 mmol Ni(cod)2 and 0.013
mmol L1 used. 3ga was isolated in high purity without further
purification as a colorless oil in 70% yield (39.6 mg, 0.18 mmol). The
enantiomeric excess was determined by HPLC analysis (220 nm, 25
°C) tR 11.0 min (minor); tR 13.7 min (major) [CHIRALCEL OJ-H
(0.46 cm × 25 cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH,
90:10, 1.0 mL/min] to be 77% ee. [α]2D4 = −1.16° (c 0.74, CHCl3).
1H NMR (400 MHz, CDCl3): δ 7.29−7.26 (m, 1H), 7.24−7.18 (m,
1H), 7.15−7.14 (m, 2H), 7.09 (d, J = 8.9 Hz, 2H), 6.83 (d, J = 8.7
Hz, 2H), 4.30 (q, J = 7.2 Hz, 1H), 3.79 (s, 3H), 2.26 (s, 3H), 1.61 (d,
J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 157.7, 144.3,
138.4, 136.0, 130.4, 128.6, 126.6, 126.0, 126.0, 113.7, 55.2, 40.1, 22.2,
19.7.
4.5.1. (R)-1-Methoxy-4-(1-phenylethyl)benzene (3aa).6c Prepared
according to the general procedure from styrene 1a (26.0 mg, 0.25
mmol) and 4-methoxyphenylboronic acid pinacol ester 2q (117.0 mg,
0.5 mmol). 3aa was isolated as a colorless oil in 86% yield (45.6 mg,
0.22 mmol). The enantiomeric excess was determined by HPLC
analysis (220 nm, 25 °C) tR 17.7 min (minor); tR 19.1 min (major)
[CHIRALCEL OJ-H (0.46 cm × 25 cm) (from Daicel Chemical Ind.,
4.4.23. (S)-1,2-Dimethoxy-4-(1-(4-methoxyphenyl)ethyl)benzene
(3ia).37 Prepared according to the general procedure from 3,4-
dimethoxystyrene 1i (41.1 mg, 0.25 mmol) and 4-methoxyphenylbor-
onic acid 2a (76.0 mg, 0.5 mmol). 3ia was isolated in high purity
without further purification as a colorless oil in 92% yield (62.6 mg,
0.23 mmol). The enantiomeric excess was determined by HPLC
analysis (220 nm, 25 °C) tR 27.5 min (minor); tR 38.3 min (major)
[CHIRALCEL OJ-H (0.46 cm × 25 cm) (from Daicel Chemical Ind.,
Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be 76% ee. [α]D24
=
−1.40° (c 0.60, CHCl3). The NMR spectra were in agreement with
product 3aa derived from 4-methoxyphenylboronic acid 2a.
Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be 96% ee. [α]D24
=
4.5.2. (R)-1-Fluoro-4-(1-phenylethyl)benzene (3ac).3e Prepared
according to the general procedure from styrene 1a (26.0 mg, 0.25
mmol) and 4-fluorophenylboronic acid pinacol ester 2r (111.0 mg,
0.5 mmol). 3ac was isolated in high purity without further purification
as a colorless oil in 29% yield (14.5 mg, 0.073 mmol). The
enantiomeric excess was determined by HPLC analysis (220 nm, 25
°C) tR 8.5 min (minor); tR 10.1 min (major) [CHIRALCEL OJ-H
(0.46 cm × 25 cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH,
90:10, 1.0 mL/min] to be 69% ee. [α]2D4 = −1.38° (c 0.70, CHCl3).
The NMR spectra were in agreement with product 3ac derived from
4-fluorophenylboronic acid 2c.
−1.02° (c 0.88, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.14 (d, J =
8.6 Hz, 2H), 6.88−6.76 (m, 4H), 6.72 (d, J = 1.6 Hz, 1H), 4.07 (q, J
= 7.2 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.79 (s, 3H), 1.61 (d, J =
7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 157.8, 148.8,
147.2, 139.4, 138.8, 128.4, 119.2, 113.7, 111.1, 111.0, 55.9, 55.8, 55.2,
43.5, 22.3.
4.4.24. (S)-2-(1-(4-Methoxyphenyl)ethyl)naphthalene (3ka).3b
Prepared according to the general procedure from 2-vinylnaphthalene
1k (38.5 mg, 0.25 mmol) and 4-methoxyphenylboronic acid 2a (76.0
mg, 0.5 mmol). The crude reaction mixture was purified by flash
column chromatography (hexane/Et2O = 100:1) to give 3ka as a
colorless oil in 61% yield (40.0 mg, 0.15 mmol). The enantiomeric
excess was determined by HPLC analysis (220 nm, 25 °C) tR 24.5
min (minor); tR 31.2 min (major) [CHIRALCEL OJ-H (0.46 cm ×
25 cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0
4.5.3. (S)-1-Methoxy-4-(1-(4-(trifluoromethyl)phenyl)ethyl)-
benzene (3eh).2c Prepared according to the general procedure from
4-methoxystyrene 1e (33.5 mg, 0.25 mmol) and 4-(trifluoromethyl)-
phenylboronic acid pinacol ester 2s (136.0 mg, 0.5 mmol). 3eh was
isolated as a colorless oil in 75% yield (52.5 mg, 0.19 mmol). The
enantiomeric excess was determined by HPLC analysis (220 nm, 25
°C) tR 7.3 min (major); tR 10.7 min (minor) [CHIRALCEL OJ-H
(0.46 cm × 25 cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH,
90:10, 1.0 mL/min] to be 61% ee. [α]2D4 = +1.70° (c 0.70, CHCl3).
The NMR spectra were in agreement with product 3eh derived from
4-trifluoromethylphenylboronic acid 2h.
mL/min] to be 93% ee. [α]2D4 = −1.38° (c 0.64, CHCl3). H NMR
1
(400 MHz, CDCl3): δ 7.85−7.82 (m, 2H), 7.78 (d, J = 8.5 Hz, 1H),
7.73 (s, 1H), 7.52−7.44 (m, 2H), 7.35 (dd, J = 8.5, 1.7 Hz, 1H), 7.22
(d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.32 (q, J = 7.2 Hz, 1H),
3.82 (s, 3H), 1.76 (d, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 157.9, 144.2, 138.4, 133.6, 132.1, 128.7, 128.0, 127.8,
127.6, 126.9, 126.0, 125.4, 125.2, 113.8, 55.3, 44.1, 22.0.
4.5.4. (S)-1-Methyl-4-(1-phenylethyl)benzene (3bt).9a Prepared
according to the general procedure from 4-methylstyrene 1b (29.5
mg, 0.25 mmol) and phenylboronic acid pinacol ester 2t (102.0 mg,
0.5 mmol). 3bt was isolated as a colorless oil in 90% yield (44.2 mg,
0.23 mmol). The enantiomeric excess was determined by HPLC
analysis (220 nm, 25 °C) tR 11.4 min (major); tR 12.5 min (minor)
[CHIRALCEL OJ-H (0.46 cm × 25 cm) (from Daicel Chemical Ind.,
4.4.25. (S)-3-(1-(4-Methoxyphenyl)ethyl)-1H-indole (3la).2g Pre-
pared according to the general procedure from 3-vinylindole 1l (35.6
mg, 0.25 mmol) and 4-methoxyphenylboronic acid 2a (76.0 mg, 0.5
mmol). The crude reaction mixture was purified by flash column
chromatography (hexane/EtOAc = 90:10) to give 3la as a while solid
in 27% yield (40.0 mg, 0.07 mmol). The enantiomeric excess was
3845
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Article
Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be 86% ee. [α]D24
=
procedure for Ni-catalyzed hydroarylation of vinylarenes with
arylboronic acids.
1
+1.50° (c 0.76, CHCl3). H NMR (400 MHz, CHCl3): δ 7.34−7.30
(m, 2H), 7.28−7.26 (m, 2H), 7.24−7.19 (m, 1H), 7.18−7.13 (m,
4H), 4.17 (q, J = 7.2 Hz, 1H), 2.36 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 146.6, 143.4, 135.5, 129.1,
4.7.1. (S)-1,2,3-Trimethoxy-5-(1-(4-methoxyphenyl)ethyl)-
benzene (3ja).9a Prepared according to the general procedure (see
Section 4.4) from 3,4,5-trimethoxystyrene 1j (48.6 mg, 0.25 mmol)
and 4-methoxyphenylboronic acid 2a (76.0 mg, 0.5 mmol). 3ja was
isolated in high purity without further purification as a colorless oil in
80% yield (60.5 mg, 0.20 mmol). The enantiomeric excess was
determined by HPLC analysis (220 nm, 25 °C) tR 28.7 min (minor);
tR 38.2 min (major) [CHIRALCEL OJ-H (0.46 cm × 25 cm) (from
Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be
94% ee. [α]2D4 = +1.59° (c 0.58, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 7.15 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.43 (s,
2H), 4.04 (q, J = 7.2 Hz, 1H), 3.82 (s, 3H), 3.82 (s, 6H), 3.79 (s,
3H), 1.60 (d, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
157.9, 153.0, 142.5, 138.3, 136.2, 128.4, 113.7, 104.6, 60.8, 56.0, 55.2,
44.2, 22.2.
128.4, 127.6, 127.5, 126.0, 44.4, 22.0, 21.0.
4.5.5. (R)-3-(1-Phenylethyl)furan (3au). Prepared according to the
general procedure from styrene 1b (26.0 mg, 0.25 mmol) and furan-3-
boronic acid pinacol ester 2u (97.0 mg, 0.5 mmol). 3au was isolated
as a colorless oil in 57% yield (24.5 mg, 0.14 mmol). The
enantiomeric excess was determined by HPLC analysis (220 nm, 25
°C) tR 13.9 min (major); tR 15.9 min (minor) [CHIRALCEL OJ-H
(0.46 cm × 25 cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH,
95:5, 1.0 mL/min] to be 71% ee. [α]2D4 = −1.30 (c 0.76, CHCl3). 1H
NMR (400 MHz, CHCl3) 7.35 (t, J = 1.7 Hz, 1H), 7.33−7.29 (m,
2H), 7.24−7.19 (m, 4H), 6.22−6.21 (m, 1H), 3.97 (q, J = 6.9 Hz,
1H), 1.56 (d, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
146.0, 142.9, 138.8, 130.3, 128.4, 127.3, 126.2, 110.5, 36.4, 22.0.
HRMS (EI): calcd for C12H12O+ ([M]+), 172.0883; found, 172.0881.
4.6. General Procedure for Ni-Catalyzed Hydroarylation of
Vinylarenes with Arylboronic Acid Neopentylglycol Esters. In
an oven-dried 1-dram vial, Ni(cod)2 (0.0125 mmol), ligand L1
(0.0063 mmol), TMSOK (0.25 mmol), arylboronic acid neo-
pentylglycol ester 2, an appropriate vinylarene 1 (0.25 mmol), and
MeOH (0.5 mL) were sequentially added. Then, the vial was sealed
and taken out of the glovebox. The reaction mixture was stirred at 50
°C in an aluminum reaction block (for 1-dram vials) for 3 h. Upon
completion, the reaction was cooled to room temperature and was
diluted with 20 mL of DCM. The solvent was removed under
vacuum. The resulting residue was redissolved with DCM, filtered
through a short plug of silica gel eluting with DCM, and concentrated
under vacuum. The crude product was purified by flash column
chromatography (hexane/Et2O = 100:1). The racemic products were
synthesized either by the same procedure with racemic ligand L7 or
by a previously reported method.5d
4.7.2. (R)-2-(1-(3,4,5-Trimethoxyphenyl)ethyl)naphthalene
(3kv).9d Prepared according to the general procedure (see Section
4.4) from 2-vinylnaphthalene 1k (48.6 mg, 0.25 mmol) and 3,4,5-
trimethoxyphenylboronic acid 2v (106.0 mg, 0.5 mmol). The crude
reaction mixture was purified by flash column chromatography
(hexane/Et2O = 100:1) to give 3kv as a colorless oil in 70% yield
(56.42 mg, 0.18 mmol). The enantiomeric excess was determined by
HPLC analysis (220 nm, 25 °C) tR 10.7 min (minor); tR 11.3 min
(major) [CHIRALCEL OD-H (0.46 cm × 25 cm) (from Daicel
Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be 93%
ee. [α]2D4 = +1.80° (c 0.54, CHCl3). H NMR (400 MHz, CDCl3): δ
1
7.83−7.79 (m, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.49−7.42
(m, 2H), 7.33 (dd, J = 8.5, 1.8 Hz, 1H), 6.48 (s, 2H), 4.26 (q, J = 7.2
Hz, 1H), 3.84 (s, 3H), 3.81 (s, 6H), 1.73 (d, J = 7.2 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 153.1, 143.6, 141.9, 136.3,
133.5, 132.1, 128.0, 127.7, 127.6, 126.7, 126.0, 125.4, 125.2, 104.9,
60.8, 56.1, 45.1, 21.9.
4.8. Gram-Scale Reaction. In a nitrogen-filled glovebox, an oven-
dried 20 mL scintillation vial was charged with 4-methoxyphenylbor-
onic acid 2a (2.58 g, 17 mmol) and MeOH (10 mL). The resulting
mixture was gently stirred at room temperature until it was clear.
Next, tBuOLi (0.680 g, 8.5 mmol), 4-methylstyrene 1b (1.00 g, 8.5
mmol), ligand L1 (41.31 g, 0.085 mmol), and Ni(cod)2 (58.65 g,
0.212 mmol) were sequentially added. Then, the vial was sealed and
gently stirred for 2 min at room temperature before being taken out of
the glovebox. The reaction mixture was stirred at 50 °C in an
aluminum reaction block (for 20 mL scintillation vials) for 10 h.
Upon completion, the reaction was cooled to room temperature and
was diluted with 20 mL of DCM. The solvent was removed under
vacuum. The resulting residue was redissolved with hexane/DCM =
70:30, filtered through a short plug of silica gel eluting with hexane/
DCM = 70:30, and concentrated under vacuum to obtain 1.90 g of 4b
(99% yield, 95% ee) as a clear liquid. The product was isolated in high
purity without column chromatography. The enantiomeric excess was
determined by HPLC analysis (220 nm, 25 °C) tR 18.4 min (minor);
tR 20.9 min (major) [CHIRALCEL OJ-H (0.46 cm × 25 cm) (from
Daicel Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be
95% ee. [α]2D4 = −1.45° (c 0.76, CHCl3). The NMR spectra were in
agreement with product 3ba derived from the small-scale reaction.
4.6.1. (R)-1-Methoxy-4-(1-phenylethyl)benzene (3aa).6c Prepared
according to the general procedure from styrene 1a (26.0 mg, 0.25
mmol) and 4-methoxyphenylboronic acid neopentylglycol ester 2w
(110.0 mg, 0.5 mmol). 3aa was isolated as a colorless oil in 93% yield
(45.6 mg, 0.22 mmol). The enantiomeric excess was determined by
HPLC analysis (220 nm, 25 °C) tR 17.6 min (minor); tR 18.8 min
(major) [CHIRALCEL OJ-H (0.46 cm × 25 cm) (from Daicel
Chemical Ind., Ltd.) hexane/iPrOH, 90:10, 1.0 mL/min] to be 88%
ee. [α]2D4 = −1.42° (c 0.62, CHCl3). The NMR spectra were in
agreement with product 3aa derived from 4-methoxyphenylboronic
acid 2a.
4.6.2. (R)-1-Fluoro-4-(1-phenylethyl)benzene (3ac).3e Prepared
according to the general procedure from styrene 1a (26.0 mg, 0.25
mmol) and 4-fluorophenylboronic acid neopentylglycol ester 2x
(104.0 mg, 0.5 mmol). 3ac was isolated in high purity without further
purification as a colorless oil in 63% yield (31.5 mg, 0.16 mmol). The
enantiomeric excess was determined by HPLC analysis (220 nm, 25
°C) tR 8.9 min (minor); tR 10.5 min (major) [CHIRALCEL OJ-H
(0.46 cm × 25 cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH,
90:10, 1.0 mL/min] to be 88% ee. [α]2D4 = −1.38° (c 0.70, CHCl3).
The NMR spectra were in agreement with product 3ac derived from
4-fluorophenylboronic acid 2c.
4.6.3. (S)-1-Methoxy-4-(1-(4-(trifluoromethyl)phenyl)ethyl)-
benzene (3eh).2c Prepared according to the general procedure from
4-methoxystyrene 1e (33.5 mg, 0.25 mmol) and 4-(trifluoromethyl)-
phenylboronic acid neopentylglycol ester 2y (129.0 mg, 0.5 mmol).
3eh was isolated as a colorless oil in 79% yield (55.4 mg, 0.20 mmol).
The enantiomeric excess was determined by HPLC analysis (220 nm,
25 °C) tR 7.3 min (major); tR 10.1 min (minor) [CHIRALCEL OJ-H
(0.46 cm × 25 cm) (from Daicel Chemical Ind., Ltd.) hexane/iPrOH,
90:10, 1.0 mL/min] to be 83% ee. [α]2D4 = +1.74° (c 0.54, CHCl3).
The NMR spectra were in agreement with product 3eh derived from
4-trifluoromethylphenylboronic acid 2h.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02556.
■
sı
NMR spectra and HPLC traces (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Levi M. Stanley − Department of Chemistry, Iowa State
University, Ames, Iowa 50011, United States; orcid.org/
0000-0001-8804-1146; Email: lstanley@iastate.edu
4.7. Synthetic Utility. The anti-viral agent 3ja and the tubulin
polymerization inhibitor 3kv were synthesized following the general
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J. Org. Chem. 2021, 86, 3836−3849

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pubs.acs.org/joc
Article
Kozlowski, M. C. Nickel-Catalyzed Cross-Coupling of Photoredox-
Generated Radicals: Uncovering a General Manifold for Stereo-
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2015, 137, 4896−4899. (b) Zhou, Q.; Srinivas, H. D.; Dasgupta, S.;
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Iterative Suzuki−Miyaura Cross-Couplings. J. Am. Chem. Soc. 2017,
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Organoboronic Esters with Retention of Configuration. J. Am. Chem.
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Authors
Hai N. Tran − Department of Chemistry, Iowa State
University, Ames, Iowa 50011, United States
Russell W. Burgett − Department of Chemistry, Iowa State
University, Ames, Iowa 50011, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02556
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Science Foundation-CHE (grant no.
1955529) for supporting this work.
■
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