Nickel-Catalyzed Asymmetric Reductive Diarylation of Vinylarenes

Article abstract of DOI:10.1002/anie.201900228

A nickel-catalyzed asymmetric diarylation reaction of vinylarenes enables the preparation of chiral α,α,β-triarylated ethane scaffolds, which exist in a number of biologically active molecules. The use of reducing conditions with aryl bromides as coupling partners obviates the need for stoichiometric organometallic reagents and tolerates a broad range of functional groups. The application of an N-oxyl radical as a ligand to a nickel catalyst represents a novel approach to facilitate nickel-catalyzed cross-coupling reactions.

Full text of DOI:10.1002/anie.201900228

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Accepted Article
Title: Ni-Catalyzed Asymmetric Reductive Diarylation of Vinylarenes
Authors: David Anthony, Qiao Lin, Judith Baudet, and Tianning Diao
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900228
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10.1002/anie.201900228
Angewandte Chemie International Edition
COMMUNICATION
Nickel-Catalyzed Asymmetric Reductive Diarylation of
Vinylarenes
David Anthony, Qiao Lin, Judith Baudet, and Tianning Diao*[a]
Abstract:
A Ni-catalyzed asymmetric diarylation reaction of
vinylarenes represents a compelling method for preparing chiral
a,a,b-triarylated ethane scaffolds, which exist in a number of
biologically active molecules. The use of reducing conditions with
aryl bromides as coupling partners avoids stoichiometric
organometallic reagents and tolerates a broad range of functional
groups. The application of an N-oxyl radical as a ligand to Ni
catalysts represents a novel approach to facilitate Ni-catalyzed
cross-coupling reactions.
An Asymmetric Diarylation Strategy (this work)
Ph
[Ni]
Ph
+ PhBr
AcO
1
HO2C
O
2
tested as an estrogen receptor ligand
Cross-coupling
OH
Hydrogenation
Ph
Ar
+ PhZnI
Ph
Ph
+ H2
F
Ar
(±)
Alkenes are versatile functional groups that enjoy some of the
most successful asymmetric catalytic transformations, such as
NH
Ph
hydrogenation[1]
and
dihydroxylation.[2]
O
Ph
Hydrocarbofunctionalization[3] and 1,2-dicarbofunctionalization of
alkenes[4],[5] have emerged as compelling approaches to rapidly
increase molecular complexity by forming vicinal di-substitution
patterns and tertiary carbon centers. Asymmetric alkene 1,2-
dicarbofunctionalization would enable efficient construction of
H2N
N
MeO
inhibitor of PDE 4A
H
4
3
F
inhibitor of α-thrombin
new
C–C
bonds
while
simultaneously
introducing
Scheme 1. Strategies for Preparing Chiral a,a,b-Triarylated Ethane and
stereocenters,[6] but this strategy has been restricted to a
handful of precedents, with the scope limited to intramolecular[7]
and diene substrates.[8] Liu and others have reported
intermolecular, asymmetric trifluoromethylation and cyanation of
vinylarenes,[9] but intermolecular, asymmetric diarylation has not
been developed before.
Relevant Target Molecules.
Our development of this asymmetric diarylation capitalizes
on the hypothesis that Ni catalysts can create new modes of
stereo-control for alkene functionalization via radical addition
(Scheme 2).[18] The first irreversible enantio-differentiating step
would determine the enantioselectivity.[19] In traditional
asymmetric alkene functionalization reactions, such as the Pd-
catalyzed asymmetric Heck reaction, the enantio-determining
step is either alkene coordination (step i) or migratory insertion
(step ii).[20] Ni catalysts can initiate radical formation from alkyl[21]
or aryl halides,[22] and the resulting organic radicals could add to
alkenes.[23] Through this pathway, carbofunctionalization would
be expected to have different enantio-determining steps, such
as radical capture by Ni (step v) or reductive elimination (step
vi).[24]
The a,a,b-triarylated ethane motif is present in a number of
important pharmaceutical compounds and biologically active
molecules.[10] Examples include carboxylic acid 2, a molecule
tested as a bone-selective estrogen receptor ligand,[11] indole
derivative 3, an inhibitor of human a-thrombin,[12] and 4, an
inhibitor of phosphodiesterase 4 (PDE 4A) (Scheme 1).[13] While
many biological studies are performed with racemic samples,
access to enantioenriched compounds would facilitate the
assessment of their efficacy. These molecules could be
synthesized
by
asymmetric
hydrogenation[14]
or
stereospecific[15]/stereoconvergent[16] cross-coupling, but these
methods would require preparation of the substrates in multiple
steps. We report an asymmetric diarylation of vinylarenes, as an
alternative to access chiral a,a,b-triarylated ethane structures
from readily available vinylarenes. This method could be used to
rapidly build a library of triarylated molecules for drug discovery.
The use of an aryl bromide as the coupling partner under
reducing conditions eschews the need for pre-generating air-
sensitive organometallic coupling reagents,[17] and thus enables
a broad scope with good functional group compatibility.
- Heck reaction: alkene coordination or migratory insertion
O
- [PdH]+
O
Ph
O
(i)
O
(ii)
Ph
[Pd–Ph]+
+
[(Ph)Pd]+
(iii)
[Pd]+
- Ni-catalyzed alkene functionalization: radical capture or
reductive elimination
[Ni] [Ni] X
R2
R2
[Ni]R2
- [Ni]
R1
[Ni]
R2
R1
R2
R2
+ R2–X
[a]
David Anthony, Qiao Lin, Judith Baudet, and Tianning Diao
Chemistry Department
(iv)
R1
(vi)
(v)
R1
New York University
100 Washington Square East, New York, NY 10003
E-mail: diao@nyu.edu
Scheme 2. Enantio-determining Steps for Alkene Carbofunctionalization.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201900228
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COMMUNICATION
Our catalyst development employed para-acetoxystyrene 1
as the model substrate and PhBr as the electrophile coupling
partner (Table 1). Initial optimization concluded that the use of
10 mol% Ni(DME)Br2 as the catalyst and Zn powder as the
reductant resulted in conversion of 1 to the desired diphenylation
product, which upon hydrolysis gave 5, an appealing precursor
10
11
12
13
14
iPr-pybox
iBu-biOx
iBu-biOx
iBu-biOx
iBu-biOx
DMPU
25
10
10
10
10
5
-
DMPU
38
74
90
28
90
90
91
91
DMPU/THF (3:1)
DMPU/THF (1:1)
DMPU/THF (1:3)
to
2.
Replacing
Zn
with
Mg
and
TDAE
with
(tetrakis(dimethylamino)ethylene) both gave product
5
modest ee (Table S1). When PhZnCl was subjected to the
conditions in place of PhBr, the reactions failed to afford any
alkene arylation product (Scheme S1). These results rule out
organo-zinc reagents as intermediates, suggesting that zinc
merely serves as a reductant.
O
N
O
N
O
O
O
N
N
N
N
iBu
iBu
iPr
Ph
Ph
iPr-pyrox
iBu-biOx
Ph-box
Bi-oxazoline (biOx) ligands have been extensively utilized in
25]
recent Ni-catalyzed asymmetric coupling reactions,[16,
and
[a] Reaction conditions: [1 (0.2 mmol)] = 1 M, [PhBr] = 4 M. Yields determined
by 1H NMR spectroscopy using mesitylene as an internal standard. Ee
determined by HPLC.
proved to be effective with ABNO as an additive, whose role will
be discussed below in Table 2 (Table 1, entries 1-7). The
substituents on the biOx ligand, surprisingly, have only a minor
effect on the ee, except for tBu-biOx and Ph-biOx, which
resulted in significantly lower yields and no enantioselectivity
(entries 4-5). This observation could be attributed to the bulky
substituents that prevent coordination, evident from the different
reaction color. Other common N-ligands frequently used in
asymmetric Ni catalysis, such as bis-oxazoline (box), pyridine-
bisoxazoline (pybox), and pyridine-oxazoline (pyrox) resulted in
low conversion (entries 8-10). Lowering the temperature led to
slightly higher ee, albeit with a lower yield (entry 11). The low
yield could result from inefficient mixing, due to high viscosity of
N,N’-dimethylpropyleneurea (DMPU) at low temperatures. A
mixture of DMPU and THF in a 1:1 ratio ameliorated this
viscosity issue, improving the yield to 90% with an ee of 91%
(entry 13).
During catalyst optimization, we noticed that the N-oxyl
radical additive exerts
a
significant effect on the
enantioselectivity (Table 2). Examining a number of N-oxyl
radical derivatives, we used multivariate analysis[26] to
deconvolute parameters that contribute to affecting the ee.
Several parameters were computed to describe the electronic
and steric effects of various N-oxyl radicals, including SOMO
energy (ESOMO), redox potential, IR stretching frequency of the
corresponding R2N+=O (uN+=O), polarizability, and buried
volume (%Vbur) (Table S2). In particular, %Vbur is obtained by
submitting the structures of (bipyridine)Ni(N-oxyl) after geometry
optimization to SambVca 2.0.[27] When we applied linear
regression modeling to relate the enantioselectivity (expressed
as DDG‡) and the computed parameters, %Vbur exhibits a
dominant effect, providing a linear correlation with an R2 value of
0.8 when plotted directly against DDG‡ (Figure S3). The most
sterically unhindered N-oxyl additives, ABNO and AZADO, gave
the greatest ee. A stronger correlation (R2 = 0.96) was obtained
when ESOMO and uN+=O were included along with %Vbur as
descriptors (Figure S4). Examining the stoichiometry of
Ni:ABNO revealed that it is critical to apply a Ni:ABNO ratio of
1:1–1:0.8 to obtain high yield and ee, as a slight excess of
ABNO led to complete inhibition of the diarylation reaction. While
characterizing the precise nature of the observed N-oxyl effect
needs further investigation, the required 1:1 ratio of Ni:ABNO is
consistent with it serving as a ligand.[28]
Table 1. Catalyst Optimization: Effect of ligands and solvents. [a]
(1) Ni(DME)Br2 (10 mol%)
Ph
ligand (20 mol%)
Ph
ABNO (8 mol%)
AcO
Zn (2 equiv.), solvent, T, 16 h
1
HO
5
+
(2) NaOH, MeOH/H2O
PhBr
Entry Ligand
Solvent
T (ºC) Yield (%) ee (%)
Table 2. Catalyst Optimization: Effect of an N-oxyl Additive. [a]
1
2
3
4
5
6
7
8
9
iPr-biOx
DMPU
DMPU
DMPU
DMPU
DMPU
DMPU
DMPU
DMPU
DMPU
25
25
25
25
25
25
25
25
25
52
69
41
28
25
64
52
0
83
89
87
0
iBu-biOx
Cy-biOx
Ph
Ni(DME)Br2 (10 mol%)
(S)-iBu-biOx (20 mol%)
Ph
Additive (8 mol%)
Zn (2 equiv.), 16 h
DMPU:THF = 1:1, 10 ºC
AcO
1
tBu-biOx
Ph-biOx
HO
5
PhBr
+
0
Additive
none
Yield (%) ee (%) Additive
Yield (%)
63
2-Me-AZADO 71
AZADO 76
ee (%)
60
4-hept-biOx
indane-biOx
Ph-box
73
64
-
78
60
26
21
29
tBu NO
2
TEMPO
57
4-oxo-TEMPO 50
89
iPr-pyrox
30
28
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10.1002/anie.201900228
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COMMUNICATION
4-OAc-TEMPO 64
4-OH-TEMPO 82
33
46
ABNO
90
91
Aryl Bromide Scope
NO
39
54
Ar1
=
[a] Reaction conditions: [1 (0.2 mmol)] = 1 M, [PhBr] = 4 M. Crude reaction
mixtures were treated with aqueous NaOH to saponify the acetate. Yields
determined by 1H NMR using mesitylene as an internal standard. Ee
determined by HPLC.
AcO
Ar2
=
X = CF3
8
X = H 5
X = F 6
X = Cl 7
90% yield
(80 ± 11)%[d,e]
91% ee
60% yield[e] 57% yield[e] 44% yield[e]
90% ee 91% ee 86% ee
With the optimized conditions, we explored the scope of
asymmetric diarylation (Table 3). The enantioselectivity of the
reactions, in general, appeared to be insensitive to the electronic
nature of the electrophile component. The low ee of 10 may be
attributed to an interaction of Ni with the boronic ester. The
reaction conditions are compatible with a number of functional
groups, including fluoride, chloride, ester, amine, and indole
moieties. When bromobenzene was used as the electrophile
and the vinylarene component was varied, a wide variety of
electron-rich and electron-deficient vinylarenes underwent
diphenylation to give a,a,b-triarylethane products (19-30).
Changing the electronic nature of the vinylarene component by
using various para-substituted styrenes seemed to have a
modest effect on enantioselectivity. However, the observed
enantiomeric ratios of products do not show a linear-free-energy
relationship with the Hammett parameters for the corresponding
para-substituents (R2 = 0.17, Figure S6). Simple disubstituted
olefins, such as a- and b-methylstyrene, gave no diarylation
product under the optimized conditions. Performing the
diphenylation of 1 on a 1.0 mmol scale furnished 5 in 71%
isolated yield and 92% ee. When the reaction was conducted on
bench using standard Schlenk techniques, 5 was formed in 66%
yield and 90% ee. The catalyst, once activated, decomposes in
air, thus the reaction requires an inert atmosphere.
X
X = CO2Me 9
X = BPin 10 X = Me 11 X = OMe 12
76% yield[b] 77% yield[b,e]
70% yield[e]
89% ee
48% yield
93% ee
55% ee
90% ee
O
O
O
O
N
Me
14
O
O
13
15
40% yield[b,e]
70% ee
78% yield[e]
69% yield[e]
Ph
90% ee
87% ee
16
70% yield
83% ee
17
18
MeO
Me
76% yield[e]
67% yield[e]
92% ee
91% ee
Vinylarene and Heterocycle Scope
Ar2 = Ph
Ar1
=
MeO
Me
Me2N
tBu
19
78% yield
91% ee
20
82% yield
82% ee
21
22
64% yield
89% ee
85% yield
77% ee
N
Subsequently, we carried out preliminary studies to probe
factors that control the enantioselectivity. We first sought to
examine the ratio of the ligand to Ni. The ee of the product
exhibits a linear correlation with the ee of the ligand (Figure
S7).[29] This observation suggests that the ligand to Ni ratio is 1:1
in the enantio-determining step, although excess ligand is
required to stabilize the Ni catalyst in solution.
MeO2C
F3C
23
24
25
26
62% yield[c,d]
68% yield
85% ee
73% yield[c]
79% ee
53% yield[c]
83% ee
76% ee
MeO
27
73% yield
83% ee
28
72% yield
82% ee
Me
Table 3. Substrate Scope of Asymmetric Diarylation of Vinylarenes. [a]
N
Ni(DME)Br2 (10 mol%)
(S)-iBu-biOx (20 mol%)
OMe
Ar2
Ts
Ar2Br
Ar1
Ar2
+
29
30
Ar1
36% yield[c]
91% ee
57% yield
94% ee
ABNO (8 mol%), Zn (2 equiv.)
DMPU:THF = 1:1, 10 ºC, 16 h
31
72% yield
88% ee
Me
[a] Reaction conditions: [vinylarene (0.2 mmol)] = 1 M, [ArBr] = 4 M. Yields
determined by 1H NMR using mesitylene as an internal standard. Ee
determined by HPLC. Absolute stereochemistry was assigned for 29 based on
X-ray crystallography, while all other products were assigned by analogy. [b]
[vinylarene] = 0.5 M. [c] With 20 mol% Ni(DME)Br2, 40 mol% iBu-biOx, and 16
mol% ABNO. [d] Isolated yield. The error bar is based on four duplicate
experiments. [e] The product was isolated as the corresponding phenol
following deacylation with aq. NaOH.
It is generally accepted that Ni-catalyzed cross-coupling
reactions proceed through radical intermediates.[31] Several
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10.1002/anie.201900228
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COMMUNICATION
observations provide evidence for the formation of radical
intermediates at the benzylic position: (1) inhibition of the
reaction by excess N-oxyl, which could be attributed to its
conjunction with a chiral Ni catalyst, enabled the formation of
dicarbofunctionalized products with high enantioselectivity. We
anticipate that this insight could inform catalyst development for
interaction with organic radicals; (2) formation of benzylic dimers, other Ni-catalyzed cross-coupling reactions.
such as 32, with several substrates (eq 1);[32] (3) selective
formation of trans-diphenylation product 33 in 70% ee with
indene (eq 2).
A difunctionalization going through olefin
Acknowledgements
migratory insertion has been reported to form cis-products.[33]
The trans-diastereoselectivity observed here could arise from a
cis-migratory insertion, followed by reversible radical ejection
that scrambles the benzylic stereocenter as the coordination
favors the less-hindered face (step vi, Scheme 3). This proposal
serves as an experimental support for Kozlowski and Molander’s
computational study.[24] The observation of 70% ee of 33 could
rule out free phenyl radical addition to indene. In Scheme 3, we
present a plausible mechanism. Detailed mechanistic study is
underway to fully elucidate the sequence of reagent activation
and the identity of the enantio-determining step.
This work was supported by the National Science Foundation
under Award Number DMR-1420073. The NMR cryoprobe is
supported by NIH (S10 OD016343). T.D. is grateful to the Sloan
Foundation (FG-2018-10354). D.A. thanks Prof. Jim Canary for
sharing chiral HPLC columns, Dr. Giulio Volpin and Peter
Rühmann (Trauner group) for help purifying 14 and 26 using
preparatory HPLC and Lotus Separations for determining the ee
of 24.
Keywords: Diarylation • Alkenes • Nickel • Asymmetric catalysis
• ABNO
MeO
Ni(DME)Br2 (10 mol%)
iBu-biOx (20 mol%)
Ph
30
(1)
+
Ph
ABNO (8 mol%)
Zn (2 equiv.)
OMe
PhBr
[1]
[2]
[3]
[4]
a) W. S. Knowles, Angew. Chem. Int. Ed. 2002, 41, 1998-2007; b) R.
Noyori, Angew. Chem. Int. Ed. 2002, 41, 2008-2022.
+
57%
DMPU:THF = 1:1, 10 ºC
OMe
H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev. 1994,
94, 2483-2547.
32 2%
S. W. M. Crossley, C. Obradors, R. M. Martinez, R. A. Shenvi, Chem.
Rev. 2016, 116, 8912-9000.
Ph
Ni(DME)Br2 (20 mol%)
iBu-biOx (40 mol%)
a) R. K. Dhungana, S. KC, P. Basnet, R. Giri, The Chemical Record
2018, 18, 1314-1340; b) R. Giri, S. Kc, The Journal of Organic
Chemistry 2018, 83, 3013-3022.
Ph
(2)
ABNO (16 mol%)
Zn (2 equiv.)
DMPU, 25 ºC
PhBr
+
33
17% yield, 70% ee
no cis-product observed
[5]
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3149; b) W. You, M. K. Brown, J. Am. Chem. Soc. 2014, 136, 14730-
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Ph
1/2 Zn
Ph
(vii)
Ar
1/2 ZnBr2
[NiI]Br
(i)
[Ni0]
Ph
Ar
[NiIII]Br
Ph
[NiII]Br
Ph
Ar
PhBr
Ph
(ii)
(vi)
[NiII]–Ph
Br
1/2 Zn
1/2 ZnBr2
(v)
(iii)
PhBr
[NiI]
(iv)
Ph
[NiI]–Ph
Ar
Ar
Scheme 3. Proposed Mechanism.
[6]
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In summary, we developed a Ni-catalyzed asymmetric
diarylation reaction of vinylarenes. The reaction represents a
compelling method for preparing chiral a,a,b-triarylated ethane
scaffolds. The use of reducing conditions with aryl bromides as
the coupling partner avoids the use of stoichiometric
organometallic reagents and allows for tolerance of a broad
range of functional groups. During catalyst development, we
discovered that the use of an auxiliary N-oxyl ligand, in
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COMMUNICATION
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10.1002/anie.201900228
Angewandte Chemie International Edition
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A nickel catalyst with chiral bi-
oxazoline ligands in combination of
ABNO effects asymmetric 1,2-
diarylation of vinyl arenes to form
David Anthony, Qiao Lin, Judith Baudet,
and Tianning Diao*
Page No. – Page No.
a,a,b-triarylated ethane scaffolds.
Nickel-Catalyzed Asymmetric
Reductive Diarylation of Vinylarenes
This article is protected by copyright. All rights reserved.