Nickel-Catalyzed Asymmetric Reductive Arylalkylation of Unactivated Alkenes

Article abstract of DOI:10.1002/anie.201901067

Reported is an asymmetric reductive dicarbofunctionalization of unactivated alkenes. Under the catalysis of a Ni/BOX system, various aryl bromides, incorporating a pendant olefinic unit, were successfully reacted with an array of primary alkyl bromides in the presence of Zn as a reductant, furnishing a series of benzene-fused cyclic compounds bearing a quaternary stereocenter in high enantioselectivities. Notably, this reaction avoids the use of pregenerated organometallics and demonstrates high tolerance of sensitive functionalities. The preliminary mechanistic investigations reveal that this Ni-catalyzed reaction proceeds as a cascade consisting of migratory insertion and cross-coupling with a nickel(I)-mediated intramolecular 5-exo cyclization as the enantiodetermining step.

Full text of DOI:10.1002/anie.201901067

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Accepted Article
Title: Ni-Catalyzed Asymmetric Reductive Arylalkylation of Unactivated
Alkenes
Authors: Youxiang Jin and Chuan Wang
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Ni-Catalyzed Asymmetric Reductive Arylalkylation of Unactivated
Alkenes
[a]
[a]
Youxiang Jin , and Chuan Wang*
Dedication ((optional))
Abstract: In this protocol we developed an asymmetric reductive
dicarbofunctionalization of unactivated alkenes. Under the catalysis of
Ni-BOX system, various aryl bromides incorporating a pendant
olefinic unit were successfully reacted with an array of primary alkyl
bromides in the presence of Zn as reductant, furnishing a series of
benzene-fused cyclic compounds bearing a quaternary stereocenter
in high enantioselectivities. Notably, this reaction avoids of the use of
pre-generated organometallics and demonstrates high tolerance of
sensitive functionalities. The preliminary mechanistic investigations
reveal that this Ni-catalyzed reaction proceeds as a cascade
consisting of migratory insertion and cross-coupling with a Ni-(I)-
mediated intramolecular 5-exo cyclization as the enantio-determining
step.
incorporation of two carbo-moieties directly from aryl or alkyl
halides in assistance of a reducing agent and thus eliminates the
additional step of preparation of sensitive organometallics as well
as the related issue of functional group compatibility. Despite
rapid progresses in this area, the asymmetric version of reductive
dicarbofunctionalization of unactivated olefins remains still
elusive.[5,6] Very recently, our group reported a racemic version of
Ni-catalyzed reductive arylalkylation of unactivated alkenes
tethered to aryl bromides.[ In this context, we report a significant
advance of our method to have identified a chiral ligand in the
highly enantioselective variant, enabling the efficient synthesis of
various benzene-fused cyclic compounds with the construction of
a challenging quaternary stereogenic center[ (Scheme 1B).
4i]
7]
Asymmetric difunctionalizations of unactivated alkenes are
among the most important reactions in organic synthesis, as
diverse optically active compounds can be accessed in one single
step using simple olefins as precursors. Transition-metal catalysis
has proven to be a powerful tool for dicarbofunctionalizations of
unactivated alkenes including diarylation, dialkylation as well as
arylalkylation, and tremendous advances have been achieved
recently using both redox-neutral[1-3] and reductive strategies .
However, asymmetric versions of these reactions are still rare. In
the field of diarylation, Sigman et al. developed a Pd-catalyzed
enantioselective diphenylation of 1,3-dienes,[3c] while Brown and
his co-worker reported a Cu-promoted asymmetric diarylation of
pendant olefins tethered on aryl boronates.[2d] Recently, Liu et al.
achieved Cu-catalyzed enantioselective dicarbofuntionalizations
[4]
of styrenes involving the installation of
a CF
3
-moeity.[3d,j]
Furthermore, Fu et al. accomplished an enantioselective variant
of two-component arylalkylation.[2b] In this Ni-catalyzed reaction,
arylboranes incorporating a terminal olefinic unit were reacted
with unactivated alkyl halides, affording various benzofurans and
indanes in high enantioselectivities (Scheme 1A). However, all
the aforementioned asymmetric dicarbofunctionalizations of
unactivated olefins require the use of pre-generated
organometallics as coupling partners, which is less desirable in
the viewpoint of both step-economy and functionality tolerance.
On the other side, the reductive strategy of
dicarbofunctionalizations of C−C double bonds allows the
Scheme 1. Redox-Neutral (A) and Reductive Strategy (B) for Asymmetric
Arylalkylation
For optimization of the reaction conditions, we used the
bromobenzene 1a incorporating a terminal olefinic unit and 4-
bromobutyl acetate (2a) as standard substrates (Table 1). Initially,
an array of chiral ligands were tested for this reaction. When chiral
phosphine ligands including DIOP L1, SEGphos L2 and PHOX
L3 were utilized, no desired reaction occurred (entries 1-3). In the
case of PyBox L4, only a trace of arylalkylated product 3a was
formed (entry 4), while the reaction employing BOX L5 failed to
deliver the target compound 3a (entry 5). In all the cases above-
mentioned, recovery of substrate 1a and formation of some by-
products 3a-1-3a-4 were observed. In contrast, the reaction using
Pyrox L6 as ligand afforded the desired product 3a in a moderate
yield and enantioselectivity (entry 6). In this case, the dimer 3a-1
was delivered as a by-product with a 42 % GC-yield. Encouraged
by this result, a series of Pyrox ligands L7-9 and structurally
related BOX ligands L10-11 were investigated for this Ni-
catalyzed reaction (entries 7-11). In the most cases, similar
[
a]
Mr. Y. Jin, Prof. Dr. C. 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 20237 (P. R. China)
E-mail: chuanw@ustc.edu.cn
Supporting information for this article is given via a link at the end of
the document.
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product profiles were obtained with the dimer 3a-1 and the
reductive Heck product 3a-2 as the major by-products. To our
delight, the facial selectivity could be elevated to an excellent level
through employing BOX L11 as ligand (entry 11). Of note is that
the corresponding dimer 3a-1 was also afforded in a high
diastereomeric ratio (dr=97:3). Next, a brief screening of Ni-salts,
temperature, solvents and reductants provided the best outcome
and it turned out that both electron-donating and –withdrawing
groups were well tolerated. Furthermore, our method is also
applicable to preparation of highly enantioenriched indolines 3n
and 3o. Unfortunately, only low enantiomeric excesses could be
achieved for synthesis of the six-membered ring products 3p and
3q. Subsequently, we continued to examine the substrate
spectrum by varying the structure of the alkyl bromides 2. In all
the cases of linear alkyl bromides, the products 3r-z were
obtained with satisfactory to good efficiency and in high to
excellent enantioselectivities. It is noteworthy that this Ni-
catalyzed reaction demonstrated high compatibility of a broad
range of functional moieties, such as alcohol (3s), acetal (3t),
boronate (3u), cyanide (3w), imide (3x) and ester (3x and 3y).
Moreover, our method was also successfully implemented in the
reaction employing structurally complex alkyl bromides as
precursors (3z and 3aa) derivatized from menthol and estrone,
respectively. In the case of bulkier (bromomethyl)cyclohexane as
reactant, the reaction also furnished the product 3ab in a
moderataly good yield and high enantioselectivity. In addition, a
in the reaction using NiBr
entry 12).[8]
2
(dme) with Zn-powder in DMA at 40︒C
(
Table 1. Ligands, Solvents, Ni-Salts and Temperature Screening[a]
5-mmol-scale reaction using the aryl bromide 1a as substrate and
ent-L11 as ligand was conducted, providing the product ent-3a in
a similar yield. One limitation of our method was observed in the
use of secondary and tertiary bromides as coupling partners,
which failed to deliver the desired products under the standard
conditions.[9]
In order to demonstrate the utility of this developed method,
some derivatizations of the arylalkylation product ent-3a were
accomplished to achieve diverse chiral scaffolds bearing a
quaternary stereogenic center (Scheme 2). First, the benzylic
position of the compound ent-3a was successfully oxidized
Entry
Ligand
L1
L2
L3
L4
L5
L6
L7
L8
Ni-salt
Yield [%][b]
0
0
0
trace
0
55
3
43
53
29
ee [%][c]
through the Ru-catalyzed oxidation, providing a chiral indanone 4
1
2
3
4
5
6
7
8
9
NiBr
NiBr
NiBr
NiBr
NiBr
2
2
2
2
2
-
-
-
in an excellent yield.[
10]
The subsequent m-CPBA-mediated
n.d.[
d]
Baeyer-Villiger oxidation led to an efficient synthesis of a chiral
chromanone 5. Furthermore, the arylalkylation product ent-3a
was reacted with tosylhydrazine and the afforded hydrazone 6
was then subjected to a Pd-catalyzed cross-coupling reaction,
furnishing a chiral indene 7 in a good yield.[11]
A series of control experiments were carried out to shed a
light on the mechanism of this Ni-catalyzed asymmetric reductive
dicarbofunctionalization. First, we performed stoichiometric
reactions between Zn and both bromide precursors under the
standard reaction conditions. After quenching with water, no
debrominated products were formed in either case.[12] These
results indicate that the reaction pathway involving organozinc
compounds is less likely.
-
NiBr
NiBr
NiBr
NiBr
NiBr
NiBr
2
2
2
2
2
2
58
n.d.
66
39
86
94
94
L9
10
11
12
L10
L11
L11
53
[
e]
64 (69[f])
2
NiBr (dme)
[
a] Unless otherwise specified, reactions were performed on a 0.2 mmol scale
of the aryl bromide 1a using 2.0 equiv 4-bromobutyl acetate (2a), 15 mol % Ni-
salt and 15 mol% ligand in 0.5 mL solvent at 55 ℃ for 10 h. [b] GC-yields.
c] Determined by HPLC-analysis on chiral stationary phase. [d] Not determined.
e] Reaction temperature: 40︒C. [f] Yield of the isolated product.
[
[
It is known that aryl Ni(II) species can undergo migratory
insertion to activated C−C double bonds.[5] We wonder whether
the same process can occur on the unactivated olefinic unit. To
With the optimum reaction conditions in hand, we started to
evaluate the substrate scope of this Ni-catalyzed asymmetric
reductive arylalkylation (Table 2). First, the influence of geminal
substitution of the pendant olefin of the aryl bromides 1 was
explored. To our delight, all the reactions using geminal
disubstituted alkenes proceeded smoothly, furnishing the
verify this, we performed the stoichiometric reaction of Ni(COD)
2
with the pendant alkene 1a and quenched it with water (Table 3,
entry 1). Surprisingly, the expected reductive Heck product 3a-2
was afforded only in a trace amount. Instead, a Heck product 3a-
4
was obtained in a moderate yield, implying that the aryl Ni(II)
corresponding products 3a-h containing
a
quaternary
intermediate generated via oxidative addition favors 6-endo
cyclization followed by β-H elimination in the case of unactivated
alkenes. Next, a similar stoichiometric reaction was performed in
stereocenter in moderate to good yields and high to excellent
enantioselectivities. When monosubstituted alkenes were used
as substrates, no desired products were delivered due to the high
tendency to undergo β-H-elimination. Next, the permutation of
substitution of on the phenyl ring (3i-m and 3x) was carried out
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Table 2. Evaluation of the Substrate Scope[a-c],[13]
[
a] Unless otherwise specified, reactions were performed on a 0.4 mmol scale of the aryl bromides 1 using 2.0 equiv alkyl bromides 2, 15 mol % NiBr
mol% ligand L11 in 1.0 mL DMA at 40 ℃ for 10 h. [b] Yields of the isolated products. [c] The ee or dr were determined by HPLC-analysis on chiral stationary phase.
d] Reaction was performed on a 5-mmol-scale of the aryl bromide 1a. [e] Reactions were performed using the enantiomer of the ligand L11. [f] Enantiopure
2
(dme) and 15
[
precursors were employed.
the stoichiometric reaction (Scheme 3B). After quenching with
water, the hyroarylation product 3g-1 was yielded in a similar
enantiomeric excess as compound 3g in Table 1, implying the Ni-
mediated migratory insertion is the enantio-determining step.[14]
Table 3. Stoichiometric Reactions [a],[b]
Yield 3a-1
%]
17
9
Yield 3a-2
[%]
5
61
78
Yield 3a-
3 [%]
<5
<5
<5
Yield 3a-
4 [%]
56
22
Entry
Conditions
[
1
2
3
A
B
C
Scheme 2. Derivatizations of the Arylalkylation Product ent-3a.
9
4
[a] Unless otherwise specified, reactions were performed on a 0.2 mmol scale
of the aryl bromide 1a using 100 mol % Ni-salt and 100 mol% ligand L11 in 0.5
mL DMA at 40 ℃ for 1 h. [b] GC-yields.
the presence of Zn (entry 2). In this case, reductive Heck reaction
turned out to be the major reaction. Furthermore, replacing
2 2
Ni(COD) by Ni(dme)Br in the stoichiometric reaction gave a
similar product profile, wherein only a small amount of 3a-4 was
formed (entry 3). These results suggest that the aryl Ni(II)
intermediate probably undergoes first Zn-mediated reduction to a
Ni(I) species, which performs preferentially the 5-exo cyclization
Subsequently, we assumed that the reaction between
cyclized Ni-intermediate 8 and alkyl bromides 2 would lead to the
formation of the final products. Therefore, the sequential
stoichiometric reaction by adding the alkyl bromide 2a at the
second stage was carried out (Scheme 3A). Indeed, the
arylalkylation product 3a was furnished in a moderate yield and
excellent enantioselectivity, proving that our presumed pathway
is feasible. Moreover, we employed the alkene 1g as precursor in
Scheme 3. Sequential Stoichiometric Reactions.
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It is well-known that alkyl halides can form radicals with Ni-
catalyst.15,16 Thus we conducted the reaction using the alkyl
bromide with a terminal olefinic unit (Scheme 4A). In this case, a
double cyclized product 3ac was obtained with a diastereomeric
ratio of 50:50. Relying on the result that the intramolecular
arylation process provides high enantioselectivity, we conclude
that the cyclization of the alkyl bromide must proceed with no
enantiocontrol, which is characteristic for radical-mediated ring-
closure. Next, a trisubstituted olefin containing a cyclopropyl
group was employed in the radical clock reaction, affording the
ring opening product 3ad in a moderate yield (Scheme 4B). In
contrast, the formation of unrearranged product 3ad’ was not
observed. To interpret this result, we presume that the ring
opening of cyclopropane is likely initiated by a radical, which is
generated through homolytic Ni-Alkyl bond cleavage of the Ni(I)-
species after the formation of indane ring. However, non-radical
bearing a quaternary stereocenter in highly enantioselective
manner. Remarkably, this new method is bestowed with better
step-economy and high tolerance of
a wide range of
functionalities through circumventing the use of pre-generated
organometallics. In the plausible reaction mechanism, a Ni(I)-
mediated 5-exo cyclization turns out to be the enantio-
determining step, and the following cage-bound oxidative addition
with alkyl bromides and reductive elimination provides the
dicarbofunctionalization products.
Acknowledgements
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” starting up funding, as well as by the University of
Science and Technology of China. We also thank Prof. Mingming
Ma for the measurements of CD spectra.
cyclopropane ring opening via
a migratory insertion/β-C
elimination cascade could not be rule out in this case.
Keywords: Dicarbofunctionalization • Reductive Coupling •
Asymmetric Ni-Catalysis •Unactivated Alkenes • Quaternary
Stereocenter
[
1]
2]
For a review on redox-neutral dicarbofunctionalization of unactivated
alkenes, see: S. KC, R. Giri, J. Org. Chem. 2018, 83, 3013.
[
For
selected
examples
on
two-component
redox-neutral
dicarbofunctionalization of unactivated alkenes see: a) V. B. Phapale, E.
Buñuel, M. García-Iglesias, D. J. Cárdenas, Angew. Chem. Int. Ed. 2007,
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5700; f) S. KC, P. Basnet, S. Thapa, B. Shrestha, R. Giri, J. Org. Chem.
2018, 83, 2920.
Scheme 4. Radical Clock Reactions.
[3]
For
selected
examples
on
three-component
redox-neutral
dicarbofunctionalization of unactivated alkenes, see: a) K. Mizutani, H.
Shinokubo, K. Oshima, Org. Lett. 2003, 5, 3959; b) J. Terao, Y. Kato, N.
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F. Wang, X. Wan, D. Wang, P. Chen, G. Liu, J. Am. Chem. Soc. 2017,
Subsequently, we utilized two trisubstituted olefins with an
E/Z ratio of 50:50 as substrates in the Ni-catalyzed arylalkylation
reaction (Scheme 5). If the homolytic Ni-carbon bond cleavage
does not exist, the products 3ae and 3af are supposed to have
similar diastereomeric ratios as their alkene precursors. Actually,
they were both furnished in complete diastereoselectivities, which
supports our assumption.
139, 2904; e) B. Shrestha, P. Basnet, R. K. Dhungana, S. KC, S. Thapa,
J. M. Sears, R. Giri, J. Am. Chem. Soc. 2017, 139, 10653; f) J. Derosa,
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K. M. Engle, Chem. Sci. 2018, 9, 5278; h) S. KC, R. K. Dhungana, B.
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[4]
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L. Kuang, X.-F. Wang, D. Anthony, T.-N. Diao, Chem. Commun. 2018,
In conclusion, we developed a Ni-catalyzed asymmetric two-
component reductive arylalkylation of unactivated alkenes
tethered to aryl bromides with primary alkyl bromides, offering an
entry to approach diverse chiral benzene-fused cyclic compounds
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54, 2558; h) J. Xiao, X.-W. Cong, G.-Z. Yang, Y.-W. Wang, Y. Peng, Org.
Lett. 2018, 20, 1651; i) Y. Jin, C. Wang, Chem. Sci. 2019, 10, 1780.
Very recently, Kong et al. reported a Ni-catalyzed reductive diarylation of
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Soc., 2018, 140, 12364.
[
5]
6]
[
During the reviewing of our manuscript a Ni-catalyzed asymmetric
reductive diarylation of styrenes was published by Diao et al.: D. Anthony,
Q. Lin, J. Baudet, T. Diao, Angew. Chem. Int. Ed. 2019, 58, 3198; Angew.
Chem. 2019, 131, 3230.
[7]
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[
8]
9]
For detailed information for the solvents, Ni-salts, temperature and
reductants screening, see: SI, Page 3.
[
The reactions using cyclohexyl bromide or tert-butyl bromide failed to
yield the desired products, while the asymmetric arylalkylation using
cyclohexyl iodide proceeded under the modified reaction conditions. For
detailed information of this reaction, see: SI, Page S12.
[
10] M. S. Yusubov, V. N. Nemykin, V. V. Zhdankin, Tetrahedron 2010, 66,
745.
5
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[
[
[
12] For detailed information for these stoichiometric reactions, see: SI Page
S15.
13] For detailed information for determination of the absolute configuration
of arylalkylated products, see: SI, Page 18.
14] For recent examples on enantioselective hydroarylation or
hydroalkylation of unactivated alkenes, see: a) Z.-M. Zhang, B. Xu, Y.
Qian, L. Wu, Y. Wu, L. Zhou, Y. Liu, J. Zhang, Angew. Chem. Int. Ed.
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e) E. Richmond, J. Moran, Synthesis 2018, 50, 499.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Youxiang Jing, Chuan Wang *
Page No. – Page No.
Ni-Catalyzed Asymmetric Reductive
Arylalkylation of Unactivated Alkenes
A Ni-catalyzed asymmetric arylalkylation of tethered unactivated alkenes has been
developed, providing an entry to benzene-fused cyclic compounds containing a
quaternary stereocenter in highly enantioselective manner.
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