Enantioselective Reductive Divinylation of Unactivated Alkenes by Nickel-Catalyzed Cyclization Coupling Reaction

Article abstract of DOI:10.1021/jacs.1c05670

Catalytic asymmetric dicarbofunctionalization of tethered alkenes has emerged as a promising tool for producing chiral cyclic molecules; however, it typically relies on aryl-tethered alkenes to form benzene-fused compounds. Herein, we report an enantioselective cross-electrophile divinylation reaction of nonaromatic substrates, 2-bromo-1,6-dienes. The approach thus offers a route to new chiral cyclic architectures, which are key structural motifs found in various biologically active compounds. The reaction proceeds under mild conditions, and the use of chiral t-Bu-pmrox and 3,5-difluoro-pyrox ligands resulted in the formation of divinylated products with high chemo-, regio-, and enantioselectivity. The method is applicable for the incorporation of chiral hetero- and carbocycles into complex molecules.

Full text of DOI:10.1021/jacs.1c05670

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Enantioselective Reductive Divinylation of Unactivated Alkenes by
Nickel-Catalyzed Cyclization Coupling Reaction
Jin-Bao Qiao,† Ya-Qian Zhang,† Qi-Wei Yao, Zhen-Zhen Zhao, Xuejing Peng, and Xing-Zhong Shu*
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ABSTRACT: Catalytic asymmetric dicarbofunctionalization of tethered alkenes has emerged as a promising tool for producing
chiral cyclic molecules; however, it typically relies on aryl-tethered alkenes to form benzene-fused compounds. Herein, we report an
enantioselective cross-electrophile divinylation reaction of nonaromatic substrates, 2-bromo-1,6-dienes. The approach thus offers a
route to new chiral cyclic architectures, which are key structural motifs found in various biologically active compounds. The reaction
proceeds under mild conditions, and the use of chiral t-Bu-pmrox and 3,5-difluoro-pyrox ligands resulted in the formation of
divinylated products with high chemo-, regio-, and enantioselectivity. The method is applicable for the incorporation of chiral
hetero- and carbocycles into complex molecules.
substrates4,6 to unactivated alkenes,5,7 and from nucleophile−
symmetric difunctionalization of alkenes catalyzed by
electrophile reactions4,5 to cross-electrophile couplings.6,7 In
Atransition metals has been recognized as a powerful tool
for the construction of chiral molecules.1 Particularly,
short contrast, the reactions of nonaromatic substrates remain
elusive, and the major advances have been limited to
carbamoyl-tethered alkenes for producing chiral pyrrolidinone
(Scheme 1b).8 The development of new tethered alkenes for
asymmetric dicarbofunctionalizations is essential for improving
the structural diversity of chiral cyclic compounds.
dicarbofunctionalization of tethered alkenes offers efficient
access to enantioenriched carbo- and heterocyclic com-
pounds.2 The majority of reports have focused on the
reactions of aryl-tethered alkenes, in which the rigid aromatic
ring is incorporated to improve the selectivity (Scheme 1a).
Over the past few years, studies along these lines have
progressed significantly, with the scope expanded from single-
molecule to two-component reactions,3 from activated
3-Methylene five-membered rings (e.g., pyrrolidine, tetrahy-
drofuran, and cyclopentane) are key structural motifs of
numerous biologically active compounds.9 Among various
approaches for their synthesis, the cyclization of 2-(pseudo)-
halo-1,6-dienes is of great interest.10 These methods have
found broad applications in the total synthesis of various
natural products.9 Despite formidable advances, asymmetric
variants of these processes are rare. The most reliable methods
depend on pre-generation of chiral 2-(pseudo)halo-1,6-dienes,
which undergo diastereoselective cyclization to afford chiral
cyclic derivatives.11 There are also a few reports demonstrating
the stereoselective cyclization of olefinic organolithium
compounds by using stoichiometric amounts of chiral
ligands.12 Alternatively, catalytic enantioselective cyclization
and C−C coupling of 2-(pseudo)halo-1,6-dienes would
provide an approach to this class of molecules with improved
molecular diversity, but it remains to be disclosed.
Scheme 1. Dicarbofunctionalization of Tethered Alkenes
Catalyzed by Transition Metals
Herein, we report a nickel-catalyzed enantioselective
cyclization-vinylation reaction of 2-bromo-1,6-dienes and
thus establish a new method for the synthesis of chiral 3-
methylene five-membered hetero- and carbocycles (Scheme
Received: June 1, 2021
Published: August 12, 2021
https://doi.org/10.1021/jacs.1c05670
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1c). This work represents the first asymmetric divinylation
reaction of alkenes. High chemo-, regio-, and enantioselectivity
was generally obtained by using chiral t-Bu-pmrox (L12)13 and
3,5-difluoro-pyrox ligands L3−L5,14 which have not previously
been realized in the field of alkene functionalization.
significant amount of cyclized protonation byproduct 12 (see
below) (entry 5). The MnBr2 formed in situ may account for
the decreased yield and enantioselectivity (see Table S3). No
reaction was observed in the absence of a nickel catalyst or
reductant (entry 6).
Cross-electrophile coupling has recently emerged as a
promising tool for forging the C−C bonds.15 Our group has
an ongoing interest in developing new and unconventional
coupling partners for this type of chemistry.16 Very recently,
we reported a nickel-catalyzed enantioselective cross-electro-
phile aryl-vinylation reaction of unactivated alkenes.7a We
wondered whether nonaromatic tethered substrate could be
involved and afford new chiral cyclic architectures. We then
focused on the reaction of 2-bromo-1,6-diene 1a with vinyl
bromide 2a (Table 1, also see Table S1 for details). After
The choice of ligand had a substantial effect on the reaction
(Table 1). The 5-CF3-pyrox ligands, which are highly effective
for enantioselective cross-electrophile aryl-vinylation reactions
of alkenes,6b,7a gave 3a in low yield and moderate ee (L1 and
L2). In the case of reaction with L1, the protonation of
cyclized intermediate was determined as the major side
reaction. Further studies in the field of pyrox ligands revealed
that 3,5-difluoro-pyrox ligands14 could be used to improve the
yield and enantioselectivity (L3−L5), and indeed, the use of
L5 gave 3a in 62% yield and 86% ee. While chiral ligands,
including (S,S)-Bn-biOx (L6),17 (S,S)-iBu-biOx (L7),1j,m
(S,S)-Ph-box (L8),18 (S)-Ph-Phox (L9),6c and (S,Sp)-iPr-
Phosferrox (L10),6a,d proved highly effective for asymmetric
cross-electrophile difunctionalization of alkenes and cross-
coupling reactions, they failed to give any desired product. The
reaction of (S,S)-Ph-PyBox (L11) gave 3a in 9% yield and 5%
ee. Finally, we found that pmrox ligands L12−L16 were
effective for this reaction, and the use of t-Bu-pmrox (L12)
gave the best result.13
The sulfonate groups had little effect on the reaction. In
general, the reactions of fluorinated aryl sulfonates gave slightly
higher enantioselectivity than those of electron-rich derivatives
(1b−e). However, the enantioselectivity decreased slightly
when the more electron-poor CF3 group was used (1f).
Mesylated substrate 1g gave the desired product in 88% yield
and 84% ee. N-Benzyl diene 1h did not give any desired
product, and most of staring materials were recovered.
With the optimal reaction conditions in hand, we studied the
scope of the reaction for vinyl electrophiles (Table 2). Styrenyl
bromides, bearing either electron-rich or -poor groups, coupled
with 1a efficiently to afford 3i−p in moderate to high yields
and 88−95% ee. Substituents at the para-, meta-, or ortho-
positions of the aryl group were tolerated (3i−k). The absolute
configuration of 3k was determined by X-ray analysis, and that
of all other products was assigned accordingly.19 Function-
alities, including silyl ether (3l), aryl fluoride (3m), chloride
(3n), and trifluoromethyl and ester groups (3o and 3p), were
tolerated. The reactions of heteroaryl and polyaryl substrates
afforded the divinylation products 3q−t in good yields and
high ee. The reaction of dienyl bromide afforded triene 3u in
68% yield and 93% ee. cis-β-Bromostyrene gave 3v in 54%
yield with partial retention of alkene stereochemistry but a
decreased ee value. Trisubstituted vinyl bromide also worked
and gave 3w in 87% ee. However, when α-bromostyrene was
employed, the reaction resulted in recovery of 1a and 2q (3x).
Internal vinyl triflates are more readily available than bromide
derivatives. Their reactions afforded the target products with a
scope that is complementary to those of vinyl bromides. Cyclic
vinyl triflates, including five-, six-, and eight-membered rings,
were coupled well; the reactions delivered 3y−ab in high
enantioselectivity. Acyclic vinyl triflates also worked. For
example, the reactions of gem-substituted substrates afforded
3ac−ad in moderate yields with good to high enantioselectiv-
ity.
a
Table 1. Optimization of the Reaction Conditions
entry
change of conditions
none
Ni(cod)2 instead of NiBr2
NiCl2 instead of NiBr2
NiI2 instead of NiBr2
Mn instead of Zn
yield (%)
ee (%)
b
1
2
3
4
5
6
84 (78)
92
88
87
86
60
62
70
72
32
0
no Ni or Zn
a
1a (0.1 mmol) and 2a (0.15 mmol) were used; reactions proceeded
for 24 h. The yields were determined by GC analysis with dodecane as
b
internal standard. 1a (0.2 mmol) was used; the isolated yield is
given.
numerous trials, we determined that the combination of NiBr2,
t-Bu-pmrox L12, and Zn in DMA at −5 °C gave the best
result; the reaction afforded 3a in 78% isolated yield and 92%
ee (entry 1). The reactions also worked in the presence of
other nickel sources but resulted in decreased yields and
slightly lower ee values (entries 2−4). Unlike previous
observations with aryl-vinylation reactions,7a the use of Mn
instead of Zn gave 3a in low yield, and the reaction afforded a
In comparison to aryl-tethered alkenes, the chemo- and
enantioselectivity of cross-electrophile divinylation of non-
aromatic substrate is much more difficult to control. This
agrees with the fact that due to the inherent similarity in the
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a
a
Table 2. Reactions of Vinyl Electrophiles
Table 3. Reactions of N-Tethered Bromodienes
a
Bromodienes 1 (0.2 mmol) and vinyl electrophiles (0.3 mmol) were
used. Dienyl bromide 2n was used for 3af−an, 3ar, and 3as; styrenyl
bromide 2a was used for 3ao, 3ap, and 3at. 1H-Inden-2-yl triflate 2r
was used for 3aq. Reactions proceeded for 48 h; isolated yields are
b
given. Tethered terminal vinyl iodide 1w was used.
TBS-protected alcohol afforded 3al in 87% yield and 90% ee.
However, when a styrene component was employed, the
reaction afforded 3am in low yield with most of the starting
material being recovered. The reaction of monosubstituted
alkene afforded the desired product 3an in moderate yield and
with high enantioselectivity. The substrate scope of vinyl
coupling partners could be expanded from dienyl to styrenyl
bromides (3ao and 3ap) and vinyl triflate (3aq). Tethered
internal vinyl bromide (3ar) or alkene (3as) did not give the
desired product, with most of starting materials being
recovered. Terminal iodide gives no six-membered cycle 3at
but does give a large amount of vinyl−H and vinyl−vinyl
byproducts.
The O-tethered 2-bromo-1,6-dienes coupled well with
various vinyl bromides, and high enantioselectivity was
achieved when 3,5-difluoro-pyrox L5 was employed (Table
4). Bromostyrenes, bearing electron-neutral, -rich, and -poor
substituents, were tolerated (3au−ay). The reactions of
heteroaryl substituted vinyl bromide afforded bis-heterocycle
compounds 3az and 3ba in 95 and 94% ee, respectively. The
reactions of vinyl triflate and dienyl bromide afforded 3bb and
3bc in 90 and 92% ee, respectively. Monosubstituted alkene
substrate gave 3bd in 94% ee. The C-tethered 2-bromo-1,6-
a
Reaction conditions are as shown in Table 1, entry 1. 1a (0.2 mmol)
b
and 2 (0.3 mmol) were used; the isolated yields are given. Z-
Bromostyrene was used; 3v (Z/E = 8:1) was obtained. Reaction at
room temperature.
c
reactivity of the two coupling partners reaction involving two
vinyl electrophiles remains a significant challenge in cross-
coupling arena.20 Indeed, when the methyl group was replaced
with a more sterically hindered C6H13 substituent, the
cyclization of 2-bromo-1,6-dienes was partially blocked; the
reaction afforded 3af in 53% yield and 84% ee, along with 21%
yield of cross vinyl−vinyl coupling byproduct. The selectivity
for the cyclization product could be improved by using AgBF4
as an additive, and rescreening of the reaction conditions
resulted in the formation of 3af with 72% yield and 91% ee
(see Table S2). Under these conditions, various pyrrolidines
that contain an enantioenriched quaternary stereocenter were
produced in high enantioselectivity (Table 3). The more
sterically hindered isobutyl substituent was tolerated (3ah).
The reactions were compatible with acid-, base-, and
nucleophile-sensitive functionalities, such as acetal (3ai),
alcohol (3aj), and alkyl chloride (3ak). The reaction of
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a
Table 4. Reactions of O-/C-Tethered Bromodienes
Scheme 2. Catalytic Functionalization of Complex
Molecules
a
a
Reaction conditions are as shown in Table 1, entry 1. 1a (0.2 mmol)
and vinyl triflates (0.24 mmol) were used; isolated yields are given.
b
c
Ligand L3 was used. Ligand L4 was used.
Scheme 3. Derivatization of Product 3a
a
Reaction conditions are as shown in Table 1, entry 1. Bromodienes 1
(0.2 mmol) and vinyl bromide 2 (0.3 mmol) were used; the isolated
yields are given. Ligand L5 and 4 Å MS (40 mg) were used for O-
tethered substrates; ligand L2 was used for C-tethered substrates.
b
c
d
Vinyl triflate 2r was used. Reaction at 0 °C. Reaction at −10 °C.
e
Reaction at −18 °C.
a
3a (0.2 mmol) and Mg turning (6.0 mmol) in MeOH (3.0 mL) was
b
ultrasonicated for 3 h. 3a (0.2 mmol) and Pd/C (15 mg, 10% w/w)
in DCM (0.5 mL). 3a (0.2 mmol) and m-CPBA (0.3 mmol) in
CHCl3 (6.0 mL) at room temperature (rt). 3a (0.2 mmol), Et3N·
3HF (0.3 mmol), and NBS (0.3 mmol) in DCM (3.0 mL) at rt; the
c
diene also worked well; the reactions afforded 3be−bh in
moderate to high yields with high enantioselectivity obtained
in the presence of ligand L2. However, the reaction of 2-
bromohepta-1,6-diene only afforded cyclized-protonation
product (3bi), indicating the coordinating tether may have
positive impact on the selectivity for the cross-product.
The modification of biologically active compounds offers a
promising approach to altering their pharmacological profiles.
This method allows for the incorporation of chiral five-
membered ring structures into complex molecules (Scheme 2).
For example, vinyl triflates derived from indometacin (4),
lithocholic acid (5), testosterone (6), and adapalene (7) could
undergo divinylation reactions with 1a, and chiral pyrrolidine-
containing complex molecules were obtained with high
enantioselectivity.
The derivatization of formed product is shown in Scheme 3,
which offers opportunities for increasing molecular diversity.
The sulfonyl group could be removed, and the reaction
afforded 8 in 82% yield. The two alkenes are differentiated
synthetically. For example, hydrogenation and epoxidation
reactions of compound 3a selectively afforded 9 and 10 in 68
and 78% yields, respectively, leaving the exo-methylene group
available for further derivatization. The tandem deprotection
and cyclization reaction afforded polycyclic compound 11 in
76% yield as a single isomer.
d
absolute stereochemistry of 11 was not assigned.
equiv) and 2a (4.0 equiv) showed that 40% yield of cyclized
protonation product 8 was formed from 1a, and most vinyl
bromide 2a was recovered (Scheme 4a, entry 1). This result
suggests a reaction pathway involving 2-bromo-1,6-dienes first
react with nickel to form complex B (see below) and then
undergo C−C coupling with vinyl bromides. This reaction
pathway is supported further by the following findings: (1)
When above mixture was treated with Zn (2.4 mmol) instead
of H2O and stirred for another 24 h, protonation byproduct 12
was significantly decreased with 3a being isolated in 65% yield
(Scheme 4a, entry 2). (2) In the presence of MeOH (3.0
equiv), the reaction of 1j and 2n afforded target product 3ag
and protonation byproduct 13 with the same enantioselectivity
(Scheme 4b).
On the basis of the above results and on reported
work,6a,7a,21 we tentatively suggest the catalytic cycle shown
in Scheme 5. The reaction of 1 with Ni(0) affords complex A,
which undergoes an enantioselective migratory insertion
process to afford complex B.6a,7a Reduction of complex B
gives a Ni(I) species, which undergoes oxidative addition with
2, followed by reductive elimination to afford desired product
3.21 The bidentate coordination of dienes to nickel may favor
Mechanistic studies on this process are summarized in
Scheme 4. The stoichiometric reaction of Ni(0) with 1a (4.0
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Scheme 4. Mechanistic Investigation
General information, experimental procedures, new
compound characterization, spectroscopic data, HPLC
chromatograms and NMR spectra (PDF)
Accession Codes
CCDC 2001088 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Xing-Zhong Shu − State Key Laboratory of Applied Organic
Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, China;
orcid.org/0000-0002-0961-1508; Email: shuxingzh@
lzu.edu.cn
a
Reaction conditions are as shown in Table 1, entry 1, but Ni(cod)2
(0.2 mmol, 1.0 equiv), L12 (2.0 equiv), 1a (4.0 equiv), and 2a (4.0
equiv) were used. Zn (2.4 mmol) was added after 24 h in entry 2;
isolated yields are with respect to the amount of Ni in entry 1 and 1a
in entry 2. Reaction conditions are as shown in Table 3, but NiBr2
(1.0 equiv), L12 (2.0 equiv) and MeOH (3.0 equiv) were used.
Authors
b
Jin-Bao Qiao − State Key Laboratory of Applied Organic
Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, China
Ya-Qian Zhang − State Key Laboratory of Applied Organic
Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, China
Qi-Wei Yao − State Key Laboratory of Applied Organic
Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, China
Zhen-Zhen Zhao − State Key Laboratory of Applied Organic
Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, China
Xuejing Peng − State Key Laboratory of Applied Organic
Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, China
Scheme 5. Proposed Mechanism
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05670
Author Contributions
†J.-B.Q. and Y.-Q.Z. authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
this process, which may allow Ni(0) to first undergo oxidative
addition reaction with 2-bromo-1,6-dienes. Moreover, the
coordination of tether to nickel may stabilize complex B and
thus contribute to the success of the reaction.22
In summary, we have reported a nickel-catalyzed cross-
electrophile cyclization-vinylation reaction of 2-bromo-1,6-
dienes with vinyl bromides. This work represents the first
asymmetric divinylation reaction of alkenes and demonstrates
the use of a new nonaromatic tethered alkene for
enantioselective difunctionalization reactions. The approach
thus offers a route to new chiral cyclic architectures that are
otherwise difficult to form. Further expansion of the scope of
the asymmetric cross-electrophile difunctionalization of 2-
bromo-1,6-dienes is ongoing in our laboratory.
■
We thank the National Natural Science Foundation of China
for their financial support (21772072 and 22071084). We are
grateful to Prof. Xue-Yuan Liu (Lanzhou University) for
helpful discussion.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05670.
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