Nickel-Catalyzed, Regio- and Enantioselective Benzylic Alkenylation of Olefins with Alkenyl Bromide

Article abstract of DOI:10.1002/anie.202012614

A NiH-catalyzed migratory hydroalkenylation reaction of olefins with alkenyl bromides has been developed, affording benzylic alkenylation products with high yields and excellent chemoselectivity. The mild conditions of the reaction preclude olefinic products from undergoing further isomerization or subsequent alkenylation. Catalytic enantioselective hydroalkenylation of styrenes was achieved by using a chiral bisoxazoline ligand.

Full text of DOI:10.1002/anie.202012614

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Accepted Article
Title: Nickel-Catalyzed, Regio- and Enantioselective Benzylic
Alkenylation of Olefins with Alkenyl Bromide
Authors: Jiandong Liu, Hegui Gong, and Shaolin Zhu
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Nickel-Catalyzed, Regio- and Enantioselective Benzylic
Alkenylation of Olefins with Alkenyl Bromide
Jiandong Liu,[a] Hegui Gong,*[a] and Shaolin Zhu*[b]
[a]
[b]
J. Liu, Prof. H. Gong
School of Materials Science and Engineering, Center for Supramolecular Chemistry and Catalysis, Department of Chemistry, Shanghai University,
Shanghai, 200444, (China)
E-mail: hegui_gong@shu.edu.cn
Prof. S. Zhu
State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center
(ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, (China)
E-mail: shaolinzhu@nju.edu.cn
Supporting information for this article is given via a link at the end of the document.
Abstract: A NiH-catalyzed migratory hydroalkenylation reaction of
process involving olefins with significantly different reactivities
and 2) a alkenylation coupling process involving alkylnickel
olefins with alkenyl bromides has been developed, affording benzylic
alkenylation products with high yields and excellent chemoselectivity. intermediates with significantly different reactivities.
The mild conditions of the reaction preclude olefinic products from
undergoing further isomerization or subsequent alkenylation.
a
Remote C(sp3)–H functionalization via reductive NiH strategy
Catalytic enantioselective hydroalkenylation of styrenes was
achieved using a chiral bisoxazoline ligand.
R'
R
ArX, Alkyl-X,
ArNO2, RSH
R'
R
()n
NiIH
+
()n
FG
remote or
proximal olefin
electrophile
or precursor
migratory
hydrofunctionalization
A synergistic combination of a transition metal hydride[1,2]
catalyzed alkene isomerization with transition metal-catalyzed
cross-coupling enables migratory hydrofunctionalization.[3-8] The
reaction uses easily available olefinic starting materials and is an
attractive strategy for achieving formal C(sp3)-H functionalization
selectively at remote positions[9]. Owing to the low-cost and easy
access to multiple oxidation states, and the well-developed
cross-coupling chemistry,[10,11] it has recently been demonstrated
that remote hydrofunctionalization of alkenes catalyzed by nickel
hydride[2] can enable a range of functionalization reactions.[7,8]
These include arylation, alkylation, thiolation, and amination at a
distal or proximal C(sp3)-H position (Figure 1a). In reductive
processes,[7] selective functionalization depends upon the
hypothesis that one of the alkylnickel intermediates generated
by hydrometalation of an olefin, followed by chain-walking can
be selectively captured by a cross-coupling partner. We recently
questioned whether this general strategy could be expanded to
remote alkenylation when a classic cross-coupling partner, a
alkenyl bromide[12] is used (Figure 1b). We report the successful
execution of this migratory hydroalkenylation strategy and
demonstrate that by employing a chiral bisoxazoline ligand,
enantioselective hydroalkenylation process can also be
achieved.
b
Expanding this migratory coupling to challenging migratory hydroalkenylation
Ar
R
+
NiIH
()n
Br
Ar
()n
R
alkenyl bromide
benzylic olefination
alkene
selective
hydrometalation
NiIH
RE
H
Ni
chain-walking
selective
Br
Ar
Ni
Ni
Ar
R
R
()n
Ar
()n+1
OA
()n
R
alkylnickel species
selective-coupling
selective insertion
c
Potential challenges
n selective hydrometalation towards different olefins
×
√
×
+
Ar
R
()n
Br
Ar
()n
R
w/o further isomerization
or alkenylation
n selective coupling towards different alkylnickel intermediates
Ni Ni
Ni
()n
Ar
R
Ar
()n
R
()n
Ar
R
Figure 1. Ligated nickel-hydride catalyzed migratory hydroalkenylation. FG =
As shown in Figure 1c, there are many potential challenges
to this process. First, the alkene, the alkenyl halide and the
migratory alkenylation product must all contain C=C double
bonds and all could potentially undergo a chain-walking or
alkenylation process with nickel hydrides. Second, isomeric
mixtures of products may often be obtained due to the similar
reactivity of different alkylnickel species. Third, it is possible that
alkenyl bromides could be reduced by NiH. Consequently, a
synthetically useful transformation requires 1) a hydrometalation
functional group.
We initiated our investigation by exploring the migratory
hydroalkenylation of 4-phenyl-1-butene (1a) with p-(2-
bromo)alkenyl anisole (2a) (Table 1). After extensive
examination of nickel catalysts, hydride sources, bases and
solvents, the desired migratory hydroalkenylation product (3a)
was produced in 86% isolated yield at -10 °C with excellent
1
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10.1002/anie.202012614
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regioselectivity. The regioisomeric ratio (rr) or the proportion of
benzylic product versus all other isomers was 95:5 (Table 1,
entry 1). Using other nickel sources, such as NiCl2·dmbpy
(dmbpy = 6,6'-dimethyl-2,2'-bipyridine), led to diminished yields
and regioselectivity (entry 2). With other ligands such as 4,4'-di-
tert-butyl-2,2'-bipyridine (dtbpy) no desired alkenylation product
was produced (entry 3). Reduction of catalyst loading to 10
mol% led to incomplete conversion (entry 4). Evaluation of
hydride sources revealed that a borane dimethyl sulfide complex
N
N
N
N
tBu
tBu
dmbpy
dtbpy
[a] Yields determined by crude 1H NMR using 2,5-dimethylfuran as the internal
standard. The yield in parentheses is the isolated yield. [b] Regioselectivity (rr)
determined by GC and GCMS analysis. HBpin = pinacolborane, DMA = N,N-
dimethylacetamide, PMP = p-methoxyphenyl.
was
comparably
effective
(entry
5)
whereas
Under the optimal reaction conditions, a fairly broad scope
of alkenes and alkenyl bromides are suitable substrates (Table
2). As shown in Table 2a, both monosubstituted terminal
alkenes (3a–3f) and less sterically hindered internal alkenes (3g,
3h) undergo this migratory hydroalkenylation chemoselectively,
producing the benzylic alkenylation products. In general,
electron-donating substituents (3b) on the remote aryl ring
showed higher rr than those with electron-withdrawing ones (3c),
and terminal alkenes with a shorter alkyl chain (3d) showed
higher rr than those with a longer alkyl chain (3e). Heterocycles
such as thiophene (3f) are also compatible. Both the β-
unsubstituted styrene (3o) and styrenes with different primary
alkyl groups substituted at the β-position (3i–3n) are well
tolerated. In contrast, styrenes with sterically hindered
substituent at either α- or β-position are unsuitable substrates
under current conditions (1p–1r).
polymethylhydrosiloxane (PMHS) offered only trace amounts of
desired product (entry 6). Replacement of LiOMe by CsF led to
diminished yield (entry 7). THF was shown to be an unsuitable
solvent (entry 8). Conducting the reaction at 0 oC (entry 9) led to
somewhat lower yield, whereas at -20 °C a comparable yield
could be obtained (entry 10). Use of only 1 equiv of the alkene
(1a) also gave inferior results (entry 11). In contrast, low yield
and moderate rr was observed under our previous reaction
conditions[7e] (entry 12).
Table 1: Variation of reaction parameters.
12 mol% NiBr2·dmbpy
1.5 equiv HBpin
PMP
PMP
+
Br
Ph
1.5 equiv LiOMe
DMA (0.075 M)
–10 oC, 12 h
Ph
migratory hydroalkenylation
2a (0.15 mmol)
alkenyl bromide
3a
1a (1.3 equiv)
alkene
As shown in Table 2b, a wide range of β-aryl-substituted
(E)-alkenyl bromides bearing electron-rich (4d, 4e) or electron-
poor substituents (4f-4i) on the arene afford the desired product
smoothly. Good migratory coupling results were also observed
Entry
1
Variation from standard conditions
none
Yield [%][a]
rr[b]
87 (86)
36
95:5
87:13
–
2
NiCl2⋅dmbpy, instead of NiBr2⋅dmbpy
NiBr2⋅dtbpy, instead of NiBr2⋅dmbpy
10 mol% NiBr2⋅dmbpy
(CH3)2S⋅BH3, instead of HBpin
PMHS, instead of HBpin
CsF, instead of LiOMe
THF, instead of DMA
0 oC
3
0
for
β-heteroaromatic-substituted
(E)-alkenyl
bromides,
94:6
97:3
ND
4
72
5
80
containing for example a furan (4j), thiophene (4k), pyridine (4l)
or indole (4m). β-alkyl-substituted (E)-alkenyl bromides (4n–4q),
such as those containing a structurally complex fructose (4p) or
galactose derivative (4q) were also shown to be viable substrate
and β-phenoxy-substituted (E)-alkenyl bromide (4r) was also
proved to be compatible. However, a slight decrease in the
regioselectivity was observed when 1,3-dienyl bromide (4s) was
used as the substrate. Notably, α-alkyl substituted alkenyl
bromides (4t, 4u) are also competent coupling partners.
6
trace
33
0
7
8
93:7
–
9
74
84
93:7
96:4
95:5
86:14
10
11
12
–20 oC
1.0 equiv 1a
58
42
previous reaction conditions[7e]
2
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Table 2: Nickel hydride-catalyzed migratory hydroalkenylation of alkenes with alkenyl bromides.[a,b]
12 mol% NiBr2·dmbpy
1.5 equiv HBpin
n Migratory hydroalkenylation
Ar
R
+
()n
n Chemo- & regioselective
n Highly functional group tolerance
n Mild & robust conditions
Br
1.5 equiv LiOMe
DMA (0.075 M)
–10 oC, 12 h
R
Ar
()n-1
3 & 4
migratory hydroalkenylation
(a) alkene scope
PMP
1 (1.3 equiv)
2
alkene
alkenyl bromide
PMP
PMP
PMP
Ph
PMP
Ph
Ph
MeO
CF3
Ph
()3
S
3a 86% yield, 95:5 rr
3b 84% yield, 95:5 rr
3c 86% yield, 92:8 rr
3d 87% yield, >99:1 rr
3e 60% yield, 90:10 rr
3f 61% yield, 94:6 rr
PMP
PMP
PMP
PMP
PMP
PMP
Ph
Ph
Ph
CO2Et
N
MeO2C
3k 71% yield, >99:1 rr
from 1h (1.3/1 E/Z)
3h 87% yield, 99:1 rr
from 1i (1.2/1 E/Z)
3i 83% yield, >99:1 rr
from (E)-1j
3j 38% yield, >99:1 rr
3g 81% yield, 99:1 rr
3l 85% yield, >99:1 rr
unsuccessful substrates
PMP
Ph
O
Ph
PMP
AcO
AcO
Ph
OAc
OAc
3m 90% yield, >99:1 rr
3n 92% yield
3o 91% yield, >99:1 rr
1p (trace)
1q (0% yield)
1r (0% yield)
(b) alkenyl bromide scope (4-phenyl-1-butene used)
OMe
NMe2
Bpin
OMe
Ph
Ph
Ph
Ph
Ph
Ph
PMP
nPr
OMe
nPr
nPr
nPr
nPr
4b 82% yield, 95:5 rr
4c 79% yield, 94:6 rr
4d 85% yield, 97:3 rr
4e 68% yield, 98:2 rr
4f 84% yield, 95:5 rr
4g 82% yield, 95:5 rr
R
OMe
O
X
PMP
Bn
PMP
Ph
Ph
Ph
Ph
N
O
nPr
NBoc
nPr
nPr
nPr
nPr
nPr
4h R = CO2Me, 72% yield, 95:5 rr 4j X = O, 73% yield, 94:6 rr
4i R = SO2Me, 75% yield, 96:4 rr 4k X = S, 77% yield, 95:5 rr 4l 70% yield, 95:5 rr
1:1 dr
4o 80% yield, 96:4 rr
4m 71% yield, 96:4 rr
4n 75% yield, 95:5 rr
O
O
O
O
O
Ph
OPh
PMP
Ph
O
PMP
nPr
PMP
nPr
O
Ph
nPr
nPr
Ph
O
nPr
O
O
nPr
fructose derivative, 1:1 dr
galactose derivative, 1:1 dr
4p 86% yield, 98:2 rr
4q 84% yield, 95:5 rr
4r 86% yield, 98:2 rr
4s 60% yield, 92:8 rr
4t 86% yield, 96:4 rr
4u 67% yield, >99:1 rr
[a] Yield under each product refers to isolated yield of purified product (0.15 mmol scale, average of two runs). [b] rr determined by GC and GCMS analysis.
The
asymmetric
version
of
nickel-catalyzed
pinacol ester (8e) remained intact. Alkenylferrocene (8j) could
hydroalkenylation was next explored using optically active
also undergo the reaction, providing access to highly
ligands (Table 3). Systematic evaluation of various chiral ligands, enantioenriched ferrocene derivatives. Heterocycles such as
showed that both high enantiomeric excess and yields were
observed with a chiral nickel-bis(oxazoline) catalyst 5[12a,c] for a
range of styrenes[13,14] with alkenyl bromides. As shown in Table
3a, styrenes with a variety of substituents on the aromatic ring,
both electron-rich (8b, 8c) and electron-deficient (8d-8i),
underwent this enantioselective hydroalkenylation smoothly with
high levels of enantiocontrol. Ortho-substituted styrenes (8h, 8i)
were also suitable substrates. Notably, this catalyst system
couples an alkenyl bromide in the presence of an aryl halide with
high selectivity (8f-8i). Under these exceptionally mild reaction
conditions, even a sensitive functional group like a boronic acid
furan (8k), thiophene (8l), benzofuran (8m), benzothiophene
(8n), and pyridine (8o) were also competent coupling partners.
The scope of the alkenyl bromide component was explored
(Table 3b), and a range of structurally diverse β-aryl substituted
(E)-alkenyl bromides bearing electron-rich (9b) or electron-poor
(9c-9g) substituents on the arene as well as β-heteroaryl
substituted (E)-alkenyl bromides (9h-9k) were shown to
participate in the reaction. In addition, 1,3-dienyl bromide (9l)
reacted smoothly, and β-alkyl substituted (E)-alkenyl bromides
(9m-9o) were also suitable substrates but with slightly reduced
ee.
3
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Table 3: Nickel hydride-catalyzed asymmetric hydroalkenylation of styrenes with alkenyl bromides.[a]
10 mol% cat 5
O
O
2.5 equiv HSi(OEt)3
Ar
+
Br
Ar
N
N
2.0 equiv CsF
DMA/THF (2:5, 0.21 M)
0 oC, 14 h
Ni
6
7 (1.3 equiv)
alkenyl bromide
8 & 9 (enantioenriched)
asymmetric hydroalkenylation
Br
Br
styrene
catalyst 5
(a) alkene scope
R
MeO
CF3
Bpin
F
PMP
PMP
PMP
PMP
PMP
PMP
Cl
8a R = H, 96% yield, 96% ee
8b R = Me, 93% yield, 93% ee
8c 94% yield, 93% ee
8d 95% yield, 94% ee
8e 85% yield, 97% ee
8f 76% yield, 93% ee
8g 87% yield, 95% ee
Cl
PMP
PMP
Ph
PMP
PMP
S
PMP
N
PMP
Fe
O
X
R
8h R = Cl, 80% yield, 94% ee
8i R = Br, 66% yield, 93% ee
8m X = O, 68% yield, 93% ee
8n X = S, 76% yield, 94% ee
8j 80% yield, 88% ee
8k 52% yield, 87% ee
8l 72% yield, 90% ee
8o 60% yield, 93% ee
(b) alkenyl bromide scope
F
OMe
OMe
R
SO2Me
S
Ph
PMP
PMP
Ph
PMP
Ph
OMe
F
9e R = CF3, 70% yield, 94% ee
9b 86% yield, 96% ee
9c 89% yield, 96% ee
9d 91% yield, 92% ee 9f R = Bpin, 90% yield, 95% ee 9g 74% yield, 96% ee
9h 50% yield, 96% ee
OMe
O
PMP
Ph
PMP
R
PMP
PMP
PMP
O
PMP
N
NBoc
N
9m[b] R = Ph, 63% yield, 88% ee
9l 55% yield, 93% ee 9n[b] R = PMP, 66% yield, 91% ee 9o[b] 76% yield, 94:6 dr
9i 81% yield, 92% ee
9j 61% yield, 86% ee
9k 83% yield, 92% ee
[a] Yield under each product refers to isolated yield of purified product (0.15 mmol scale, average of two runs), >99:1 regioisomeric ratio (rr) unless otherwise
noted, enantioselectivities were determined by chiral HPLC analysis; the absolute configuration was assigned by chemical correlation or by analogy. [b] at 10 oC,
DMA/NMP (2:8, 0.15 M) used.
A competition experiment was conducted to compare the
relative reactivities of different types of C=C bond (Scheme 1a).
a
Competition experiment: terminal alkene vs internal alkene
The hydroalkenylation protocol described here exhibited
excellent chemoselectivity when equal amounts of three olefins
were present. In general, the steric effect is the dominant factor
and the observed order is monosubstituted alkene (1a) > internal
alkene (1i) > sterically hindered internal alkene (1s), which is
consistent with the excellent chemoselectivity observed in the
model reaction. Moreover, crossover experiment using a 1:1
mixture of deuterium-labeled alkene (1a-d2) and undeuterated
alkene (1t) was carried out (Scheme 1b). No H/D scrambled
crossover products were obtained which indicates that chain-
walking proceeds without dissociation of NiH from olefin.
2a
PMP
PMP
Et
1a
1i
Ph
Ph
(1.0 equiv)
+
+
3s
standard
conditions
Ph nPr
3a
72% yield, 94:6 rr 12% yield, >99:1 rr
Ph
trace
1s
PMP
(1.3 equiv each)
Ph
3i
the reactivities of various olefins:
terminal olefin (1a) > internal olefin (1i) > sterically hindered internal olefin (1s)
b
Crossover experiment: no intermolecular H/D scrambled crossover products
D
PMP
Ph
PMP
2a
1a-d2
(1.3 equiv)
MeO
D
(2.0 equiv)
+
MeO
MeO
(0.30 D)
standard
conditions
Ph
(1.50 D)
3t
(0.20 D)
MeO
1t (1.3 equiv)
(no D incorporation)
3a-d2
Scheme 1. Competition experiment: terminal alkene vs internal alkene.
In conclusion, we have realized a nickel-catalyzed reductive
alkenylation of remote and proximal olefins with benzylic
selectivity. Excellent regio- and chemoselectivity were observed
for a broad scope of alkenes and alkenyl bromides as starting
materials. Critical to the success of the reaction is the highly
selective hydrometalation and alkenylation. Alkenylation only
takes place at benzylic position and the olefinic products are left
intact with no further isomerization or subsequent alkenylation.
4
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Catalytic enantioselective hydroalkenylation of styrenes was
also observed when a chiral bisoxazoline ligand was used. The
development of
a migratory asymmetric version of this
transformation and detailed mechanistic studies are currently in
progress in our laboratory.
Acknowledgements
Support was provided by NSFC (21871173, 21572140).
Keywords: alkenes • asymmetric catalysis • isomerization •
nickel • alkenylation
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[13] For β-substituted styrenes, no desired product was obtained.
[14] For vinylarenes with moderate yields (8k, 9h, 9l), the major by-products
were the reduction of the corresponding vinylarenes.
5
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10.1002/anie.202012614
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Ar
R
NiIH
+
()n
Br
Ar
()n
R
alkenyl bromide
migratory hydroalkenylation
alkene
n Chemoselective n Regioselective n Enantioselective n Mild & broad scope
A nickel hydride-catalyzed highly selective migratory hydroalkenylation proceeds through competitive hydrometalation and oxidative
addition. Employing a chiral bisoxazoline ligand, a catalytic enantioselective hydroalkenylation of styrenes was observed. The mild
conditions of the reaction produced the benzylic alkenylation products exclusively, leaving the olefinic product intact.
6
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