Nickel-catalyzed asymmetric intramolecular reductive heck reaction of unactivated alkenes

Article abstract of DOI:10.1021/acs.orglett.9b02577

An asymmetric Ni-catalyzed intramolecular reductive Heck reaction of unactivated alkenes tethered to aryl bromides has been accomplished, providing a variety of benzene-fused cyclic compounds bearing a quaternary stereogenic center in good to excellent yi

Full text of DOI:10.1021/acs.orglett.9b02577

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Asymmetric Intramolecular Reductive Heck
Reaction of Unactivated Alkenes
Feiyan Yang,† Youxiang Jin,† and Chuan Wang*
Hefei National Laboratory for Physical Science at the Microscale, Department of Chemistry, Center for Excellence in Molecular
Synthesis, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. China
S
* Supporting Information
ABSTRACT: An asymmetric Ni-catalyzed intramolecular reductive
Heck reaction of unactivated alkenes tethered to aryl bromides has
been accomplished, providing a variety of benzene-fused cyclic
compounds bearing a quaternary stereogenic center in good to
excellent yields and high enantioselectivities. A mechanism has been
proposed, which involves the enantiodetermining migratory insertion
and the following protonation with water or alcoholic solvents as the
proton source.
eductive Heck reactions, in which migratory insertion of a
carbometal species into a C−C double bond is followed
interest in Ni-catalyzed reductive electrophilic functionaliza-
tions of olefins,13,16 we envisage a Ni-catalyzed asymmetric
intramolecular reductive Heck reaction of unactivated 1,1-
disubstituted alkenes with tethered aryl bromides with the
assistance of a stoichiometric amount of metal as a reductant,
to afford an array of enantioenriched benzene-fused cyclic
compounds bearing a quaternary stereocenter via a migratory
insertion/protonation cascade (Scheme 1). Notably, asym-
metric construction of quaternary stereogenic centers is highly
challenging due to the steric congestion imposed by four
attached carbon atoms.17
R
by protonation or coupling with a hydride, enable the cross-
coupling between aryl or alkenyl (pseudo)halides and alkenes,
while avoiding the use of organometallics, which suffer from
low functionality tolerance (Grignard reagents, organo-
lithiums), toxicity (organotins),1 or pyrophoricity (diorgano-
zincs).2 Therefore, reductive Heck reactions have emerged as a
powerful tool for construction of saturated C−C bonds in the
synthesis of natural products,3 since its Pd- and Ni-catalyzed
versions were discovered by Cacchi and Umani-Ronchi in the
1980s, respectively.4 Significant advances have also been
achieved in the asymmetric reductive Heck reaction using
chiral Pd-catalysts.5 Elegant work in this field include
hydroarylation or hydroalkenylation of norbornene,5a−c α,β-
unsaturated ketones5d−f and amides,5g 2-substituted indoles,5h,i
1,1-disubstituted and 1,1,2-trisubstituted alkenes,5j−l and
cyclopentenes.5m Furthermore, numerous examples of highly
enantioselective hydrocarbonation with aryl or alkyl halides as
precursors proceeding in a nonreductive-Heck reaction
pathway have also been reported.6
Scheme 1. Ni-Catalyzed Enantioselective Intramolecular
Reductive Heck Reaction of Unactivated Alkenes with
Tethered Aryl Bromides
In comparison to the noble metal palladium, nickel is a more
desirable catalyst in the viewpoint of abundance and cost.
Although nickel has been reported as an efficient catalyst for
Heck reaction,7 reductive Heck reaction,4b,7a,8 and reductive-
Heck-like hydrocarbonation,6c,d,9 the Ni-catalyzed enantiose-
lective variant of reductive Heck reaction is very scarce. To the
best of our knowledge, only Zhou and his co-workers
described a Ni-catalyzed asymmetric reductive Heck reaction
of aryl chlorides to the electron-rich C−C double bond of the
indole ring.10
Recently, significant progress has been achieved in the field
of asymmetric functionalizations of tethered alkenes including
Heck reaction,7j reductive Heck reaction,5 carbohalogena-
tion,11 diarylation,12 arylalkylation,13 and arylalkenylation,14 in
which intramolecular arylmetalation is engaged as an
enantiodetermining step.15 As a continuation of our ongoing
For optimization of the reaction conditions, we used the aryl
bromide 1a tethering a 1,1-disubstituted olefinic unit as the
standard substrate and water as the proton source (Table 1).
Initially, a series of chiral ligands were examined for this
reaction. When BINAP L1, Trost-ligand L2, PyBOX L3, and
BOX L4 were employed as the ligand, only a trace amount of
the desired product 2a was formed (entries 1−4). In contrast,
in the case of BOX L5, PyrOX L6 and L7 the reductive Heck
reaction occurred, albeit in low yields (entries 5−7).
Importantly, moderate to excellent enantiomeric excesses
Received: July 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02577
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
After establishing the optimal reaction conditions, we started
to evaluate the substrate spectrum of this Ni-catalyzed reaction
(Scheme 2). First, permutation of the geminal substituent of
Table 1. Metals, Ligands, Solvents, and Reductants
Screening for the Ni-Catalyzed Enantioselective Reductive
a
Heck Reaction
a−c 20
,
Scheme 2. Evaluation of the Substrate Scope
b
c
entry
metal
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
Ni(acac)2
Ni(dme)Br2
Ni(BF4)2·6H2O
Ni(BF4)2·6H2O
Ni(BF4)2·6H2O
Ni(BF4)2·6H2O
Ni(BF4)2·6H2O
Ni(BF4)2·6H2O
Ni(BF4)2·6H2O
Ni(BF4)2·6H2O
Ni(BF4)2·6H2O
ligand
solvent
yield (%)
ee (%)
d
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
trace
trace
trace
trace
20
10
25
0
30
51
54
trace
50
98
71
98
90
82
n.d.
d
n.d.
d
n.d.
d
n.d.
92
60
94
−
9
90
94
92
10
11
12
13
14
d
THF
n.d.
MeOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
94
94
88
94
94
94
e
15
f
16
f g
17 ,
f h
18 ,
a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of the aryl bromide 1a using 1.5 equiv of H2O, 15 mol % Ni-salt,
15 mol % ligand, and 3 equiv of Zn at 55 °C in 0.5 mL of solvent for
b
10 h under a N2 atmosphere (Set-up in glovebox). Yields of the
c
isolated product after flash chromatography. Determined by HPLC-
d
e
analysis on chiral stationary phase. Not determined. Mn was used as
f
reductant instead of Zn. Reaction was performed without H2O.
Reaction was performed with 10 mol % catalyst loading. Reaction
g
h
a
was performed with 5 mol % catalyst loading.
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of the aryl bromides 1 using 15 mol % Ni(BF4)2·6H2O, 15 mol
% ligand L7, and 3 equiv of Zn at 55 °C in 0.5 mL of i-PrOH for 10 h
could be achieved in these cases. Encouraged by this result, we
then surveyed various Ni-salts as catalysts (entries 8−10), and
the best outcome in terms of both efficiency and selectivity was
obtained in the case of Ni(BF4)2·6H2O (entry 10). Next, a
brief solvent screening was undertaken (entries 11−14) and it
turned out that the yield of the reductive Heck reaction could
be improved to an excellent level when isopropanol was used
as solvent (entry 14). Replacing Zn by Mn as the reducing
agent resulted in a decreased yield and enantioselectivity
(entry 15). Notably, the reductive Heck reaction still
proceeded smoothly in the absence of additional water,
affording the product with the same efficiency and
enantiocontrol (entry 16). Finally, reducing the catalyst
loading to 5 or 10 mol % led to diminished yields (entries
17 and 18).
b
under a N2 atmosphere (Set-up in glovebox). Yields of the isolated
c
products after flash chromatography. All enantiomeric excesses were
d
determined by HPLC-analysis on chiral stationary phase. Reaction
e
performed on a scale of 5 mmol. The iodo analogue of 1b or 1g was
used instead.
the terminal olefinic unit was carried out. In the case of a linear
primary alkyl chain as a substituent, all the reactions proceeded
smoothly, furnishing the products 2a−j in good to excellent
yields and enantiomeric excesses. Good compatibility of
functional moieties including carboxylate, tosylate, silyl ether,
and sulfonamide was observed. When the geminal substituent
is a bulkier secondary alkyl group, the reactions still provided
the desired products 2k and 2l in moderately good yields and
B
DOI: 10.1021/acs.orglett.9b02577
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
excellent enantioselectivities. Moreover, the aryl-substituted
alkenes turned out to be successful substrates for this reductive
Heck reaction, affording the corresponding products 2m−s
with high enantiocontrol. Subsequently, we investigated the
substrate scope further by varying the substitution of the
tethered aryl bromides. In this case, both electron-donating
and electron-withdrawing groups were well tolerated and the
corresponding products 2t−w were obtained in excellent
enantioselectivities. Furthermore, this method was also
applicable for the synthesis of the dihydrobenzofurans 2x−aa
and the indoline 2ab. Although the yields were relatively low,
the level of asymmetric induction remained high. Of note is
that compound 2aa is a selective CB2 receptor antagonist.18
Unfortunately, the reaction yielding tetrahydroisoquinoline 2ac
as the product resulted in low enantioselectivity. To our
gratification, the alkene 1ad containing a deuterated methylene
moiety was also successfully employed as a precursor,
furnishing the product 2ad with a CD2H group in good
yield and excellent enantioselectivity. In addition, a 5-mmol-
scale reaction using 1a as substrate was conducted, affording
the product 2a in a similar yield. Tethered aryl iodides were
also employed as the substrates, and the corresponding
reactions proceeded in lower yields in comparison to these
using the bromides (2b and 2g). In these cases a significant
amount of deiodination product was observed. Remarkably,
most of the products mentioned above are inaccessible (2j−w
and 2y−ac) or difficult to prepare (2a−h) through our
previously reported Ni-catalyzed reductive arylalkylation,13
enabling this reductive Heck reaction to be a complementary
method for synthesis of benzene-fused cyclic compounds.
Unsuccessful substrates for this Ni-catalyzed reaction include
1,2-disubstituted and 1,1,2-trisubstituted alkenes, α-thienyl-
substituted terminal olefin, 1-bromo-2-(2-methyleneheptyl)-
benzene, and the ones with a substituent ortho to bromide.19
Some derivatizations based on the conversion of the indane
scaffold were carried out in order to achieve some other
benzene-fused cyclic compounds (Scheme 3). First, Ru-
To gain some insight into the migratory insertion step, a
number of stoichiometric reactions using the olefin 1ae as the
substrate were conducted (Table 2). In our previously
a b
,
Table 2. Stoichiometric Reactions
entry condition 1ae (%) 2ae (%) 2ae-1 (%) 2ae-2 (%) 2ae-3 (%)
1
2
3
4
5
A
B
C
D
E
20
9
0
0
0
5
60
68
48
94
1
21
20
0
56
0
0
16
0
17
10
12
35
0
6
a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of the aryl bromide 1ae using 1 equiv of Ni-salt and 1 equiv of
b
ligand under a N2 atmosphere (Set-up in glovebox). GC-yields using
n-dodecane as an internal standard.
reported Ni-catalyzed reductive arylalkylation reaction,13 we
disclosed that Ni(II) species, generated through oxidative
addition of aryl bromides to Ni(0), undergoes preferentially 6-
endo cyclization (entry 1). In contrast, under the conditions of
this reductive Heck reaction, the stoichiometric reaction using
Ni(COD)2 provided the 5-exo ring closure product 2ae as the
major product, while the formation of 2ae-2 was not observed
(entry 2). A similar product profile was obtained when
performing the stoichiometric reaction in the presence of Zn
(entry 3). The generation of 2ae-2 and the dimer 2ae-3 was
obviously benefited in the case of the chiral BOX L5 as ligand,
which was the one used in the previous arylalkylation reaction
(entry 4). These results indicate that both ligand and solvent
could have significant influence on the migratory insertion
step. In addition, the stoichiometric reaction involving the
Ni(II)-salt in the presence of Zn afforded 2ae in an excellent
yield with a slight amount of debromination product 2ae-1
(entry 5). In conclusion, the results aforementioned support a
Ni(II)-mediated cyclization process with Zn as the terminal
reductant.
Scheme 3. Derivatizations of the Reductive Heck Reaction
a
Product 2a
Regarding the source of the upcoming hydrogen we
hypothesized two reaction pathways: (A) protonation of the
Ni(II) species 6; (B) radical H-abstraction of the intermediate
7 from the solvent molecules, which is generated through
homolyptic Ni−C bond cleavage of 6 (Scheme 4). A series of
deuterium labeling experiments were carried out to shed light
on the origin of the introduced hydrogen in the reductive Heck
product (Table 3). First, the reactions conducted in d8-
isopropanol or d4-methanol with Ni(BF4)2·6H2O as catalyst
provided the cyclization product with a significant amount of
incorporated deuterium (entries 1 and 2). In contrast, when
CD3OH was used as solvent, no trace of deuterium was
detected in the reductive Heck product (entry 3). These
results rule out the radical hydrogen abstraction from the C−D
a
(a) RuCl3 (0.16 mol%), PhI (5 mol%), oxone, MeCN/H2O (1:1),
rt, 10 h; (b) mCPBA, pTsOH·H2O, DCE, 60 °C, 5 h; (c) NH2OH·
HCl, NaOAc·3H2O, MeOH, reflux,1 h; (d) PCl5, THF, reflux, 1.5 h.
catalyzed benzylic oxidation of the indane 2a provided an
indanone 3 in an excellent yield.21 Subsequently, a
dihydrocoumarin 4 was synthesized with good efficiency
starting from the indanone 3 by means of mCPBA-mediated
Baeyer−Villiger oxidation. Furthermore, upon treatment with a
hydroxyl amine the indanone 3 was readily transferred into an
oxime, from which a dihydroquinolinone 5 was obtained
through a PCl5-mediated Beckmann rearrangement.
C
DOI: 10.1021/acs.orglett.9b02577
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
bromides 1, affording Ni(II) complex II. In the next step, the
enantiodetermining intramolecular migratory insertion leads to
the formation of a cyclic Ni(II) intermediate III. Alternatively,
the absolute configuration might be controlled by the energies
of the oxidative addition transition states.7j The subsequent
protonation provides the reductive Heck product 2 and the
Ni(II) species IV. Finally, the Ni(0) species I was regenerated
through Zn-mediated reduction for the next catalytic cycle.
In summary, we developed an asymmetric Ni-catalyzed
intramolecular reductive Heck reaction of unactivated alkenes,
offering an efficient entry to a variety of benzene-fused cyclic
compounds bearing a quaternary stereogenic center in a highly
enantioselective manner. Preliminary mechanistic studies
suggest a mechanism involving the enantiodetermining
migratory insertion and the following protonation with water
or alcoholic solvents as the proton source.
Scheme 4. Possible Pathways for the Installation of
Hydrogen
a b
,
Table 3. Deuterium-Labeling Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
b
entry
Ni-salt
solvent
yield (%)
% D
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02577.
1
2
3
Ni(BF4)2·6H2O
Ni(BF4)2·6H2O
Ni(BF4)2·6H2O
Ni(dme)Br2
d8-isopropanol
CD3OD
CD3OH
DMA
isopropanol
98
70
50
29
90
78
87
0
86
0
c
Representative experimental procedures and necessary
characterization data for all new compounds (PDF)
4
c
5
Ni(BF4)2·6H2O
a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of the aryl bromide 1a using 15 mol % Ni-salt, 15 mol % ligand
AUTHOR INFORMATION
■
b
L7, and 3 equiv of Zn at 55 °C in 0.5 mL of solvent for 10 h. Yields
Corresponding Author
*E-mail: chuanw@ustc.edu.cn.
ORCID
c
of the isolated products after flash chromatography. Reaction
performed with 5 equiv of D2O.
Chuan Wang: 0000-0002-9219-1785
Author Contributions
bond of the solvent and indicate that the proton in the reaction
mixture serves as the source of the upcoming hydrogen atom
in the product. To exclude the influence of the water contained
in Ni(BF4)2·6H2O, we performed the reaction using Ni(dme)-
Br2 as catalyst in DMA with 5 equiv of D2O (entry 4). In this
case the product was formed with 86% deuterium incorpo-
ration. In contrast, the reaction facilitated in isopropanol with
Ni(BF4)2·6H2O as catalyst and 5 equiv of D2O did not yield a
trace of deuterated product (entry 5). These results suggest
that both water and alcoholic solvents might act as the proton
source for this reductive Heck reaction.
†F.Y. and Y.J. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by National Natural Science
Foundation of China (Grant No. 21772183), the Fundamental
Research Funds for the Central Universities
(WK2060190086), “1000-Youth Talents Plan” start-up fund-
ing, and the University of Science and Technology of China.
On the basis of the control experiments, we proposed the
following reaction mechanism (Scheme 5). Initially, Ni(0)
species I is generated under the reaction conditions, which
subsequently undergoes the oxidative addition with the aryl
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