Asymmetric Reductive Dicarbofunctionalization of Alkenes via Nickel Catalysis

Article abstract of DOI:10.1055/s-0040-1707900

Alkenes are an appealing functional group that can be transformed into a variety of structures. Transition-metal catalyzed dicarbofunctionalization of alkenes can efficiently afford products with complex substitution patterns from simple substrates. Under reductive conditions, this transformation can be achieved while avoiding stoichiometric organometallic reagents. Asymmetric difunctionalization of alkenes has been underdeveloped, in spite of its potential synthetic utility. Herein, we present a summary of our efforts to control enantioselectivity for alkene diarylation with a nickel catalyst. This reaction is useful for preparing triarylethanes. The selectivity is enhanced by an N -oxyl radical additive.

Full text of DOI:10.1055/s-0040-1707900

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
Imprimatur:
2020, 31, A–E
synpacts
A
Date, Signature
st-2020-p0237-sp.fm
en
7/16/20
Synlett
D. Anthony, T. Diao
Synpacts
Asymmetric Reductive Dicarbofunctionalization of Alkenes via
Nickel Catalysis
David Anthony
Tianning Diao*
O
O
Et
N
N
Et
Ar2
Ni
Department of Chemistry, New York University,
Me
Me
Br
Br
(10 mol%)
100 Washington Square E, New York, NY
0003, USA
Ar2
Ar1
+
Ar2
Br
1
Ar1
6 examples, 70–95% ee
diao@nyu.edu
(
10 mol%), Zn (2 equiv)
N
2
O
Received: 22.04.2020
Accepted after revision: 20.05.2020
Published online:
DOI: 10.1055/s-0040-1707900; Art ID: st-2020-p0237-sp
Abstract Alkenes are an appealing functional group that can be trans-
formed into a variety of structures. Transition-metal catalyzed dicarbo-
functionalization of alkenes can efficiently afford products with com-
plex substitution patterns from simple substrates. Under reductive
conditions, this transformation can be achieved while avoiding stoichio-
metric organometallic reagents. Asymmetric difunctionalization of
alkenes has been underdeveloped, in spite of its potential synthetic util-
ity. Herein, we present a summary of our efforts to control enantiose-
lectivity for alkene diarylation with a nickel catalyst. This reaction is use-
ful for preparing triarylethanes. The selectivity is enhanced by an N-oxyl
radical additive.
David Anthony (left) obtained his Bachelor’s degree in chemistry
from Cornell University in 2014. As an undergraduate student, he per-
formed research in organic synthesis under the supervision of Dr. Chad
A. Lewis. In 2015, he began his graduate studies at New York University
under the supervision of Prof. Tianning Diao. His research focuses on
the development of novel chemical methods catalyzed by transition
metals.
Key words asymmetric catalysis, nickel catalysis, alkene difunctional-
ization, reductive coupling, triarylethanes
Tianning Diao (right) received her Ph.D. in chemistry from the Univer-
sity of Wisconsin–Madison in 2012 under the supervision of Prof. Shan-
non Stahl. She conducted her postdoctoral research with Prof. Paul
Chirik at Princeton University. In 2014, she joined the faculty of NYU,
where she is currently an Assistant Professor of Chemistry.
Introduction
Dicarbofunctionalization of alkenes represents a com-
pelling approach to efficiently access substituted, saturated
molecular scaffolds from simple, abundant starting materi-
1
als. Traditional methods to difunctionalize ,-unsaturated
carbonyl compounds have been achieved through a two-
step process, in which a nucleophile undergoes conjugate
addition with an activated alkene, the resulting enolate is
have been reported, but the scope has been restricted to di-
6
7
ene substrates or intramolecular reactions. Nickel cata-
lysts have expanded the scope of nucleophiles and electro-
2
then trapped with an electrophile (Scheme 1A). This strat-
8
egy is limited to activated alkenes in conjugation with a
carbonyl group, and functional groups must be compatible
with the highly reactive organometallic nucleophiles.
Transition metal catalysis has allowed for one-step di-
functionalization of alkenes using a nucleophile and an
philes to include alkyl groups, but asymmetric reactions
have been restricted to intramolecular examples.9
Reductive coupling reactions have recently emerged to
eschew stoichiometric nucleophiles and thus expand the
substrate scope to include moieties sensitive to organome-
1a
10
electrophile (Scheme 1B). This redox-neutral strategy has
employed palladium catalysts and aryl or vinyl nucleop-
hiles and electrophiles to achieve the regioselective difunc-
tallic nucleophiles. Nevado developed a Ni-catalyzed re-
ductive dicarbofunctionalization of alkenes using alkyl and
aryl iodides in combination with tetrakis(dimethylami-
3
4
11
tionalization of vinylarenes, dienes, and, using a directing
no)ethylene (TDAE) as a reductant (Scheme 1C). In this re-
5
group, unactivated alkenes. A few asymmetric variants
action, Ni mediates the formation of an alkyl radical, which
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
D. Anthony, T. Diao
Synpacts
(
A) Traditional difunctionalization of activated alkenes
R2
R3
enylethane in good yield, so these conditions were used as a
basis from which an asymmetric reaction could be evolved
(Equation 1). Polar, aprotic solvents such as N,N-dimethy-
lacetamide (DMA) or dimethylpropyleneurea (DMPU) were
necessary in order to achieve high yields of the desired di-
functionalization products. Heterogeneous reductants such
as manganese and magnesium offered some diarylation
product, while zinc powder gave the highest yield. Among
various classes of chiral ligands, biOxazoline (biOx) ligands,
commonly used in nickel catalysis,16 proved to be the most
effective for achieving high yield and enantioselectivity.
O
O
M
OM
X
R1
R2
R1
R1
R2
R3
M = Mg, Cu
(
B) Transition-metal-catalyzed alkene difunctionalization
TM catalyst
R3
R1
+
R2
+
R3
M
X
R2
R1
M = Zn, B, Sn
X = Br, I, OTf
(
C) Nevado's reductive alkene dicarbofunctionalization
Ni], ligand
Ar
R2
[
R3
R4
AcO
+
Ar
R2
I
AcO
Me2N
Me2N
NMe2
NMe2
R3
R4
racemic
+
iPr
iPr
iPr
iPr
I
[Ni]2 (5 mol%)
Zn (2 equiv)
N
N
Ph
Ni
(
D) Asymmetric reductive alkene dicarbofunctionalization (this work)
Ph
+
PhBr
Ph
DMA
50 °C, 16 h
Ph
65% yield
Br
Br
[Ni], chiral ligand, Zn
Ar2
1 equiv
4 equiv
Ar1
+
Ar2 Br
[Ni]
Ar2
Ar1
[Ni]2
Scheme 1 Strategies for difunctionalization of alkenes
Equation 1 Racemic diarylation of styrene with bromobenzene
is added to the alkene. Combination of the radical and Ni
forms a Ni-alkyl intermediate, which undergoes reductive
elimination to afford the product. While the C(sp ) electro-
phile is restricted to tertiary alkyl iodides, this method is
notable for its mild conditions.
We observed a marked decrease in enantioselectivity
from 38% to only 2% when the styrene substrate was dis-
tilled prior to use rather than used directly from its com-
mercial bottle (Table 1, entries 1 and 2). Due to their pro-
pensity for auto-polymerization, styrenes are typically sta-
bilized with radical inhibitors such as 2,6-di-tert-butyl-4-
methylphenol (BHT). We speculated that the presence of
such an additive, or the stabilized O-radical resultant from
3
This example highlights the radical reactivity of nickel
compared to its Group 10 congener palladium, which favors
12
two-electron pathways. The access to radical intermedi-
ates by nickel catalysts provides new opportunities for con-
trolling enantioselectivity. In particular, for palladium-cata-
lyzed arylation of alkenes, the enantioselectivity is dictated
by either the alkene coordination or migratory insertion
Table 1 Optimization of Reaction Conditionsa
Br
(
dme)NiBr2
Ph
O
N
O
N
13
iPr-biOx, Zn
step (Scheme 2, steps i and ii), while for a nickel-mediated
pathway involving single-electron redox chemistry, radical
capture by nickel (v) or reductive elimination (vi) could be
Ph
+
additive
AcO
DMPU, 25 °C
HO
iPr-biOx
14
enantio-determining. We applied the radical properties of
nickel catalysts to develop an intermolecular asymmetric
difunctionalization of alkenes (Scheme 1D).
Yield (%)b
ee (%)c
Entry
Additive (mol%)
1d
2
3
4
5
6
7
none
73
61
62
44
72
1
38
2
none
Pd-catalyzed alkene arylation
BHT (10%)
14
49
26
–
O
O
O
(iii)
O
(
i)
(ii)
[Pd(Ph)]+
Ph
Ph
+
TEMPO (10%)
TEMPO (5%)
TEMPO (20%)
ABNO (10 mol%)
ABNO (8 mol%)
[
Pd(Ph)]+
–
[Pd(H)]+
Pd]+
[
Ni-catalyzed alkene difunctionalization
[
Ni]R2
(v)
R1
(iv)
[
Ni]R2
(vi)
R2
R2
57
90
76
91
+
R1
R2
R2
R1
– [Ni]
R1
R2
X
8e
[Ni]
[Ni]X
a
Reaction conditions: 4-acetoxystyrene (0.2 mmol), bromobenzene (0.8
(10 mol%), iPr-biOx (13 mol%), Zn (0.4 mmol), DMPU
0.2 mL). Reaction was performed for 16 h, then ester was hydrolyzed with
aqueous NaOH prior to purification.
Scheme 2 Mechanisms of palladium- and nickel-catalyzed asymmetric
alkene functionalization
mmol), (dme)NiBr
(
2
b
1
Yields were determined by H NMR analysis with mesitylene as internal
standard.
Reaction Development
c
Enantiomeric excess was determined by HPLC with a chiral column after
column chromatography purification.
We began our investigation by developing conditions for
racemic diarylation of styrene using bromobenzene. A di-
meric nickel(I) catalyst has been previously shown to en-
d
4-Acetoxystyrene was used directly from commercial bottle without dis-
tillation.
e
Reaction performed with (dme)NiBr (10 mol%), sec-Bu-biOx (20 mol%),
2
15
and DMPU/THF (0.1 mL each) at 10 °C.
able the carbofunctionalization of styrene to 1,1,2-triph-
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
Synlett
D. Anthony, T. Diao
Synpacts
quenching of a radical by BHT, could be responsible for this
discrepancy. While the use of BHT did not result in higher
enantioselectivity (entry 3), the addition of (2,2,6,6-te-
tramethylpiperidin-1-yl)oxyl (TEMPO) had a dramatic ef-
fect, raising the enantiomeric excess to 49% (entry 4). Fur-
thermore, equimolar TEMPO loading with respect to nickel
was paramount in order to achieve optimal results, with
lower loading engendering worse enantioselectivity (entry
(
dme)NiBr2
O
N
O
N
R1
sec-Bu-biOx
R2
+
R2
Et
Et
N
ABNO, Zn
DMPU/THF, 10 °C
R1
O
R2 Br
sec-Bu-biOx
ABNO
X
O
Ph
57% yielda
91% ee
X = Cl
O
Ph
X
BPin 76% yielda
O
=
HO
55% ee
O
0% yielda
Ph
9
= OMe
5), while higher loading shut down the reaction (entry 6).
0% yielda
89% ee
7
9
1% ee
HO
70% yield
83% ee
These observations led us to evaluate various accessible
N-oxyl radicals. The enantioselectivity exhibits a strong
MeN
7
8% yield
correlation with the percent buried volume (%Vbur), a com-
Ph
X = NMe2
91% ee
Me
Ph
Ph
17
putationally derived steric descriptor, of the N-oxyl radi-
cal. Less bulky N-oxyl additives gave higher enantioselec-
tivities (Figure 1). 9-Azabicyclo[3.3.1]nonane N-oxyl (AB-
NO) delivered the difunctionalized product with the
highest enantiomeric excess (Table 1, entry 7). Enantiose-
lectivity was further improved by modifying the substitu-
ent on the biOx ligand, lowering the reaction temperature,
and using a mixture of DMPU and tetrahydrofuran (THF) as
the solvent (entry 8).
N
Ph
73% yieldb
79% ee
=
CF3
N
Ph
Ts
X
= CO2Me
36% yieldb
91% ee
53% yieldb
83% ee
7
0% yield
83% ee
OMe
MeO
Ph
Ph
Ph
Ph
+
Ph
Ph
OMe
OMe
7% yieldb
1
HO
OMe
2% yield
76% yielda
2% ee
70% ee
exclusively trans
57% yield
9
94% ee
Scheme 3 Selected asymmetric diarylation substrate scope. Reagents
and conditions: alkene (0.2 mmol), aryl bromide (0.8 mmol), (dme)Ni-
Br (10 mol%), sec-Bu-biOx (20 mol%), ABNO (8 mol%), Zn (0.4 mmol),
2
DMPU/THF (0.1 mL each). Reactions were performed for 16 h. Yields
1
a
were measured by H NMR analysis with an internal standard. Product
b
was hydrolyzed with aqueous NaOH prior to isolation. 20 mol%
(
dme)NiBr , 40 mol% sec-Bu-biOx, and 16 mol% ABNO were used.
2
presence of excess N-oxyl radical with respect to nickel in-
hibited the reaction, mostly likely via interference of radical
intermediates. Finally, no evident linear correlation was
found between the observed enantiomeric ratio and the
electronic effect of vinylarenes, suggesting that the enan-
tio-determining step perhaps involves radicals.
Figure 1 Steric effect of N-oxyl additives on enantioselectivity
With optimized conditions in hand, we explored the
18
substrate scope of this reaction (Scheme 3). Electron-do-
nating and -withdrawing substituents had little effect on
the enantioselectivity, although higher catalyst loadings
were required to obtain good yields for electron-poor viny-
larene substrates. Disubstituted alkenes were not well-tol-
erated, with 1,1-disubstituted vinylarenes showing no reac-
tivity, although diarylation of indene gave a 17% yield of the
trans-difunctionalized product.
(
A)
PhBr (4 equiv)
dme)NiBr2 (10 mol%)
sec-Bu-biOx (20 mol%)
MeO
(
Ph
Ph
Ph
+
ABNO (8 mol%)
Zn (2 equiv)
DMPU/THF, 10 °C, 16 h
OMe
Ph
OMe
OMe
% yield
57% yield
2
(
B)
PhBr (4 equiv)
dme)NiBr2 (20 mol%)
sec-Bu-biOx (40 mol%)
(
Ph
Ph
Mechanistic Investigation
+
We gained insight into the mechanism by considering
several observations. First, formation of a dimer at the ben-
zylic position suggests the presence of a benzylic radical
ABNO (16 mol%)
Zn (2 equiv)
DMPU, 25 °C, 16 h
Ph
Ph
1
7% yield
70% ee
not observed
(
Scheme 4A). Second, the diarylation of indene resulted
solely in the formation of the trans-diarylation product
Scheme 4B). One would expect a syn-addition from a typi-
(
C)
[NiIII]Ph
Ph
[Ni ]Ph
II
[NiIII]Ph – [NiI]
Ph
Ph
(
Ph
Ph
cal migratory insertion, so the observed product diastereo-
mer suggests the formation of a radical that combines with
nickel on its less-hindered face (Scheme 4C). Third, the
Scheme 4 Mechanistic experiments and proposed origin of trans-dias-
tereoselectivity
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
Synlett
D. Anthony, T. Diao
Synpacts
We performed control experiments to investigate the
possible in situ generation of an organozinc reagent, which
could afford the difunctionalized alkene as in redox-neutral
strategies. When phenylzinc chloride was used in place of
bromobenzene in the absence of zinc powder, no diaryla-
tion product was observed. This experiment suggests that
direct oxidative addition of zinc to the aryl bromide does
not enable the reaction.
Funding Information
This work was supported by the National Science Foundation (CHE-
654483) and the National Institutes of Health■■ok?■■ (NIH) (R01
1
GM127778). D.A. is supported by the Margaret and Herman Sokol Fel-
lowship. T.D. is a recipient of the Alfred P. Sloan Research Fellowship
(FG-2018-10354) and the Camille and Henry Dreyfus Founda-
tion■■OK?■■ (Camille-Dreyfus Teacher-Scholar Award TC-19-019).
N
ati
o
n
a
lS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
(C
H
E-1
6
5
4
4
8
3)Nati
o
n
a
lInstitutesof
H
e
a
l
th (R
0
1
G
M
1
2
7
7
7
8)A
l
f
re
d
P
.
S
l
o
a
n
F
o
u
n
d
ati
o
n
(FG-2
0
1
8-1
0
3
5
4)C
a
m
i
l
e-Dreyfus
T
e
a
c
h
er-S
c
h
o
l
ar
A
w
ard (TC-19-0
1
9)
A mechanistic hypothesis consistent with our findings
is presented in Scheme 5. Oxidative addition and reduction
of a nickel(I) bromide species to the aryl bromide electro-
Acknowledgment
19
phile results in an arylnickel(I) species. This intermediate
undergoes migratory insertion with the alkene substrate.
Oxidative addition of another molecule of aryl bromide to
the arylnickel(I) makes a nickel(III) species. This open-shell
intermediate can eject a stabilized benzylic radical, which
accounts for our observations of both the benzylic dimer
byproduct and the trans-diastereoselectivity with indene.
This reversible radical ejection is consistent with computa-
tional work performed by Kozlowski and co-work-
We would like to thank Dr. Chunhua Hu for X-ray crystallographic
analysis and Prof. Jim Canary for sharing chiral HPLC columns.
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Future Outlook
We have developed the first intermolecular asymmetric
diarylation of vinylarenes using a chiral biOx-nickel cata-
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auxiliary N-oxyl radical ligand, although the precise role of
this radical remains obscure. However, we have shown that
the radical mechanistic pathways available to nickel can be
harnessed to elicit control over reaction outcomes in a dif-
ferent way than palladium commonly operates. We antici-
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additive could provide insight for the development of
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©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

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©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E