Nickel-catalyzed asymmetric reductive cross-coupling between vinyl and benzyl electrophiles

Article abstract of DOI:10.1021/ja508067c

A Ni-catalyzed asymmetric reductive cross-coupling between vinyl bromides and benzyl chlorides has been developed. This method provides direct access to enantioenriched products bearing aryl-substituted tertiary allylic stereogenic centers from simple, stable starting materials. A broad substrate scope is achieved under mild reaction conditions that preclude the pregeneration of organometallic reagents and the regioselectivity issues commonly associated with asymmetric allylic arylation.

Full text of DOI:10.1021/ja508067c

Communication
pubs.acs.org/JACS
Nickel-Catalyzed Asymmetric Reductive Cross-Coupling Between
Vinyl and Benzyl Electrophiles
Alan H. Cherney and Sarah E. Reisman*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: A Ni-catalyzed asymmetric reductive cross-
coupling between vinyl bromides and benzyl chlorides has
been developed. This method provides direct access to
enantioenriched products bearing aryl-substituted tertiary
allylic stereogenic centers from simple, stable starting
materials. A broad substrate scope is achieved under mild
reaction conditions that preclude the pregeneration of
organometallic reagents and the regioselectivity issues
commonly associated with asymmetric allylic arylation.
i-catalyzed reductive cross-coupling reactions have
Nrecently emerged as direct methods for carbon−carbon
bond formation between two organic electrophiles.1 In these
reactions, Mn0 or Zn0 are typically employed as stoichiometric
reductants to turn over a Ni catalyst. Improvements in ligand
structure and mechanistic understanding have enabled the cross-
coupling between a range of C(sp3) and C(sp2) electrophiles
bearing a variety of functional groups.2−4 The ability to employ
bench stable and readily available organic halides, without the
need to pregenerate a reactive organometallic reagent, endows
these reductive cross-coupling reactions with a practical
advantage over many conventional cross-coupling procedures.
In addition, several studies have demonstrated that sec-alkyl
electrophiles are competent reaction partners, providing racemic
products bearing stereogenic centers.2a,b,d,e,h,3a,5 The utility of
Figure 1. Catalytic asymmetric synthesis of alkenes bearing aryl-
substituted allylic stereogenic centers.
such transformations would be greatly improved if rendered
enantioselective, providing direct access to enantioenriched
chiral products from racemic starting materials.6
bearing allylic stereogenic centers are prepared in good yields
Alkenes bearing stereogenic, aryl-substituted tertiary allylic
centers are synthetically useful compounds that can be
challenging to prepare using conventional asymmetric allylic
substitution reactions (Figure 1a).7,8 Significant progress toward
the catalytic enantioselective arylation of allylic electrophiles has
been made to selectively form branched over linear mono-
substituted products.9 Stereospecific and regioselective arylation
of allylic electrophiles to form disubstituted products has also
been disclosed for a series of organometallic reagents.10
However, catalysts that simultaneously induce high regio- and
enantioselection in the arylation of acyclic, unsymmetrical α,γ-
disubstituted allylic electrophiles have not been developed.11 We
envisioned that a Ni-catalyzed asymmetric reductive cross-
coupling could provide a mild and selective alternative approach
to such products. Here, we report a highly enantioselective Ni-
catalyzed reductive cross-coupling between vinyl bromides and
benzyl chlorides (Figure 1b).12,13 A variety of alkenyl products
with high enantiomeric excess under mild conditions.
Our investigations commenced with the coupling of an
equimolar mixture of vinyl bromide 1a and benzyl chloride 2a
using NiCl2(dme) (10 mol %), a chiral ligand (11 mol %), Mn0 as
the stoichiometric reductant, and DMA as solvent. Several
isopropylidene-linked bis(oxazoline) ligands delivered product
3a in moderate yield and enantioselectivity but favored
formation of butane-2,3-diyldibenzene (4), arising from
homocoupling of 2a (Table 1, entries 1−3).14 In all cases, 4
was observed as a 1:1 mixture of the meso and rac diastereomers.
Formation of unreactive chlorostyrene side products, resulting
from Ni-catalyzed halide exchange of 1a, was also observed.15
Indanyl-substituted ligand L4 improved the selectivity, permit-
ting formation of 3a in 26% yield and 70% ee (entry 4). Tuning
Received: August 6, 2014
Published: September 22, 2014
© 2014 American Chemical Society
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Communication
Table 1. Optimization of Ni-Catalyzed Asymmetric Reductive
Coupling
Table 2. Substrate Scope of Benzyl Chlorides
a
b
entry
R1
R2
pdt
yield (%)
ee (%)
1
2
3
H
4-Me
3-Me
2-Me
4-OMe
4-F
Me
3a
3b
3c
3d
3e
3f
91
82
88
44
64
81
75
59
84
80
82
68
81
60
93
94
93
85
93
89
88
90
88
97
93
94
96
94
temp
yield 4
b
yield 3a
b
ee 3a
c
a
Me
entry ligand additive
(°C)
(%)
(%)
(%)
Me
1
2
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
L6
L6
L6
−
−
−
−
−
−
20
20
20
20
20
20
20
20
20
20
0
48
33
38
35
21
20
30
26
17
13
8
50
21
25
26
33
56
39
33
67
64
93
69
0
40
57
68
70
49
87
86
73
87
91
93
89
−
c
4
Me
5
6
Me
3
Me
4
c
7
4-Cl
4-Br
4-OCF3
H
Me
Me
3g
3h
3i
5
8
6
−
TFA
c
9
Me
7
10
11
12
13
Et
3j
8
TMSCl
H
Bn
3k
3l
d
9
NaI
H
4-pentenyl
2-hydroxyethyl
2-chloroethyl
d
10
11
TBAI
H
3m
3n
d
NaI
c
14
H
e
d
12
13
NaI
0
8
a
f
d
Isolated yield, reactions conducted under N2 on 0.2 mmol scale for 6
NaI
0
0
b
c
g
d
h. Determined by SFC using a chiral stationary phase. Run with 15
mol % NiCl2(dme) and 16 mol % L6.
14
15
NaI
0
0
0
−
−
d
NaI
0
0
0
a
Reactions conducted under N2 on 0.2 mmol scale for 6 h.
trifluoromethoxide are tolerated (entries 5−9); however, in
some cases increased levels of the butane-2,3-diyldiarene product
is observed. For these substrates, improved results are achieved
with 15 mol % catalyst loading. We were pleased to find that β-
substituted benzyl chlorides react with no erosion of ee as
compared to the parent substrate 2a (entries 10−14). Alkenyl
substrate 2l, potentially capable of cyclization under radical
conditions, exclusively produced uncyclized product 3l (entry
12). A substrate bearing a free alcohol can also be coupled in high
yield and ee (entry 13).
b
c
Determined by GC vs an internal standard. Determined by SFC
d
e
using a chiral stationary phase. 0.5 equiv. Zn0 used instead of Mn0.
f
g
No Mn0. No NiCl2(dme).
the bite angle of the ligand by changing the central linker revealed
that cyclopropyl-linked ligand L6 produced 3a in 56% yield and
87% ee (entry 6).
A broad scope of styrenyl bromides undergo the cross-
coupling to furnish product 5 in good yields and enantiose-
lectivities (Table 3). Higher catalyst loadings are sometimes
necessary to mitigate formation of 4. Notably, the pinacol
boronate (5j) and free phenol (5k) functional groups are
compatible with the reaction, but substrates possessing an aryl
ester or nitrile react poorly.18 Unfortunately, trisubstituted
olefins bearing a methyl group in either the α or β position of the
styrene are slow to react (not shown).16 The reductive cross-
coupling can be extended beyond styrenyl systems; e.g., furan 5l
and diene 5m are prepared in good yield and high ee (Scheme 1).
Nonconjugated vinyl bromides are also suitable reaction partners
(5n−p), as are cyclic benzylic halides (3o and 3p). A limitation of
the existing methodology is that Z-vinyl bromides react slowly
and undergo isomerization to deliver the E-alkene product in low
yield (not shown).16
A series of experiments were conducted to provide insight
about the reaction mechanism. The reaction proceeds cleanly in
the presence of the radical inhibitor 2,6-bis(1,1-dimethylethyl)-
4-methylphenol (BHT, as high as 50 mol %).19 In addition,
radical clock substrate 6 was found to couple in good yield,
without detection of any cyclized product or isomerization of the
olefin geometry (Scheme 2a). Taken together, these two results
appear inconsistent with a radical chain mechanism and suggest
that if oxidative addition of 6 occurs by a stepwise mechanism,
radical recombination is rapid and precludes cyclization.20,21 The
The reaction was further optimized through systematic study
of several parameters. Whereas the enantioselectivity was
maintained in other polar solvents, increased homocoupling to
give 4 was observed; use of ethereal solvents resulted in lower
enantioselection.16 Trifluoroacetic acid (TFA) and trimethylsilyl
chloride (TMSCl), additives known to activate the Mn0 surface,
failed to increase reaction efficiency (entries 7 and 8). In contrast,
iodide sources, such as NaI or TBAI, improved the yield of 3a and
decreased the yield of 4 (entries 9−10). NaI is known to enhance
reactivity in reductive cross-couplings, possibly through
acceleration of electron transfer between Mn and Ni or through
in situ formation of organo-iodide electrophiles.17 Lowering the
reaction temperature to 0 °C produced 3a in 93% yield and 93%
ee (entry 11). A series of control experiments confirmed that
product was not formed in the absence of Mn0, NiII precatalyst,
or ligand; significant decomposition of vinyl bromide 1a was also
detected in the absence of ligand (entries 13−15).
With optimized conditions in hand, we investigated the scope
of the C(sp3) coupling partner. A variety of benzyl chlorides can
be coupled in high yield and high enantioselectivity (Table 2).
Whereas meta and para substitution is well-tolerated, ortho
substituents result in lower yield and ee (entry 2−4). Functional
groups such as methoxide, fluoride, chloride, bromide, and
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Journal of the American Chemical Society
Communication
required to fully elucidate the reaction mechanism and the
origin of enantioinduction.23
Table 3. Substrate Scope of Styrenyl Bromides
In conclusion, a highly enantioselective reductive cross-
coupling between vinyl bromides and benzyl chlorides has
been developed. The reaction occurs under mild conditions and
is tolerant of a variety of functional groups, providing products in
good yields and high enantioselectivities. This work provides
further evidence of the feasibility of developing a broad range of
asymmetric reductive cross-coupling reactions, an endeavor that
is currently ongoing in our laboratory.
a
b
entry
R
pdt
yield (%)
ee (%)
1
2
4-Me-C6H4
4-F-C6H4
5a
5b
5c
5d
5e
5f
83
74
66
49
81
82
55
76
73
59
86
96
94
95
94
94
96
95
96
95
94
93
c
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
3
4-Cl-C6H4
■
c
4
4-CF3-C6H4
4-OCF3-C6H4
4-OTBS-C6H4
4-NMe2-C6H4
2,3-diMe-C6H3
3,4-diMeO-C6H3
4-Bpin-C6H4
4-OH-C6H4
S
c
5
c
6
c
7
5g
5h
5i
c
8
AUTHOR INFORMATION
Corresponding Author
reisman@caltech.edu
■
c
9
c
10
5j
11
5k
Notes
a
Isolated yield, reactions conducted under N2 on 0.2 mmol scale for 6
h. Determined by SFC using a chiral stationary phase. Run with 15
mol % NiCl2(dme) and 16 mol % L6.
The authors declare no competing financial interest.
b
c
ACKNOWLEDGMENTS
■
We thank Prof. Brian Stoltz, Dr. Scott Virgil, and the Caltech
Center for Catalysis and Chemical Synthesis for access to
analytical equipment. Fellowship support was provided by the
National Science Foundation (Graduate Research Fellowship,
A.H.C., grant no. DGE-1144469) and the ACS Division of
Organic Chemistry (A.H.C., sponsored by Amgen). S.E.R. is a
fellow of the Alfred P. Sloan Foundation, a Camille Dreyfus
Teacher-Scholar, and an American Cancer Society Research
Scholar. Financial support from NIH (GM111805-01), Amgen,
Novartis, DuPont, and Eli Lilly is gratefully acknowledged.
Scheme 1. Further Investigation of Reaction Scope
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Journal of the American Chemical Society
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