Highly Enantioselective Cross-Electrophile Aryl-Alkenylation of Unactivated Alkenes

Article abstract of DOI:10.1021/jacs.9b03863

Enantioselective cross-electrophile reactions remain a challenging subject in metal catalysis, and with respect to data, studies have mainly focused on stereoconvergent reactions of racemic alkyl electrophiles. Here, we report an enantioselective cross-el

Full text of DOI:10.1021/jacs.9b03863

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Article
Highly Enantioselective Cross-Electrophile
Aryl-Alkenylation of Unactivated Alkenes
Zhi-Xiong Tian, Jin-Bao Qiao, Guang-Li Xu, Xiaobo Pang, Liangliang Qi, Wei-Yuan Ma, Zhen-
Zhen Zhao, Jicheng Duan, Yun-Fei Du, Peifeng Su, Xue-Yuan Liu, and Xing-Zhong Shu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b03863 • Publication Date (Web): 19 Apr 2019
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Highly Enantioselective Cross-Electrophile Aryl-Alkenylation of
Unactivated Alkenes
Zhi-Xiong Tian,† Jin-Bao Qiao,† Guang-Li Xu, Xiaobo Pang, Liangliang Qi, Wei-Yuan Ma, Zhen-
Zhen Zhao, Jicheng Duan, Yun-Fei Du, Peifeng Su, Xue-Yuan Liu, Xing-Zhong Shu*
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State Key Laboratory of Applied Organic Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, 222 South Tianshui Road, Lanzhou, 730000, China.
KEYWORDS. Asymmetric Catalysis, Cross-Electrophile Reaction, Difunctionalization, Alkenes, Nickel
ABSTRACT: Enantioselective cross-electrophile reactions remain challenging subject in metal catalysis, and, to data,
studies have mainly focused on stereoconvergent reactions of racemic alkyl electrophiles. Here, we report an
enantioselective cross-electrophile aryl-alkenylation reaction of unactivated alkenes. This method provides access to a
number of biologically important chiral molecules such as dihydrobenzofurans, indolines and indanes. The incorporated
alkenyl group is suitable for further reactions that can lead to an increase in molecular diversity and complexity. The
reaction proceeds under mild conditions at room temperature, and easily accessible chiral pyrox ligand is used to afford
products with high enantioselectivity. The synthetic utility of this method is demonstrated by enabling the modification
of complex molecules such as peptides, indometacin and steroids.
1. INTRODUCTION
chemo-, regio-, and stereoselectivity challenges
encountered in this process,1d the potential of this
strategy remains largely unexplored,5 although there have
been several reports in recent years on racemic reactions.4
Scheme 1. Strategies for enantioselective cross-
electrophile reactions
In contrast, dicarbofunctionalization of alkenes has
recently received considerable attention.6 Among various
studies, the cyclization/cross-coupling reaction is
particularly attractive, because it provides facile access to
a wide range of cyclic frameworks that constitute key
moieties of many bioactive natural products and
pharmaceuticals.7 Progress in this field has led to
Scheme 2. Enantioselective dicarbofunctionalization
of unactivated alkenes
The cross-electrophile reaction has recently emerged as a
powerful tool with which to forge C–C bonds. The
approach has high step economy, excellent functional
group compatibility, and allows unique selectivity that is
orthogonal to conventional electrophile-nucleophile
reactions.1 Despite formidable advances, highly
enantioselective catalytic variants of these processes are
rare.2 Most progress has been achieved on
stereoconvergent cross-electrophile reactions, which have
enabled efficient access to enantioenriched compounds
from racemic secondary alkyl electrophiles (Scheme 1a).3
Alternatively, the cross-electrophile difunctionalizaton of
alkene can afford chiral molecules with rapid increase in
molecular diversity and complexity by constructing two
vicinal C–C bonds in
Unfortunately, partly because of the comprehensive
a
single step (Scheme 1b).4
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Table 1. Optimization of the reaction conditionsa
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numerous important synthetic methods, including a few
enantioselective reactions.5, 8 For instance, Fu and Brown
demonstrated highly enantioselective aryl-alkylation8a and
diarylation reactions8b of unactivated alkenes (Scheme 2a).
Very recently, Correia reported an aryl-carbonylation
reaction of unactivated alkenes that proceeds with good
enantioselectivity (Scheme 2b).8e Despite these advances,
to our knowledge, there have been no studies on highly
enantioselective carbo-alkenylation reactions. Such a
reaction would be especially important to increase
molecular complexity,6e,f because the incorporated alkenyl
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entry
1
change of conditions
none
yield
(%)
ee (%)
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(77)b
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group can be transformed into
a
wide range of
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Ni(cod)2 instead of NiI2
NiCl2 instead of NiI2
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95
91
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-
functionalities. We envisioned that a cross-electrophile
strategy could provide access to a complementary scope
of synthetically useful products.
DMF instead of DMF/THF
THF instead of DMF/THF
Zn instead of Mn
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12
Herein, we report a nickel-catalyzed enantioselective
trace
cross-electrophile
aryl-alkenylation
reaction
of
unactivated alkene (Scheme 2c). This reaction proceeds
under mild conditions at room temperature, and the use
of easily accessible chiral pyrox ligand affords products
containing an enantioenriched quaternary stereocenter9
with high chemo-, regio-, and stereoselectivity. The
reaction represents one of rare examples of cross-
electrophile reactions that use equimolar amounts of
coupling fragments.1 Moreover, this method is amenable
to the functionalization of complex molecules.
2. RESULTS AND DISCUSSION
2.1 Reaction Optimization. We began our
investigation by exploring the reaction of alkene 1a with
alkenyl triflate 2a (Table 1). As expected, our initial
studies revealed that the selectivity for 3a is challenged by
a number of side reactions, such as the direct coupling of
Ar–I with alkenyl triflate, the protonation and
homocoupling of 1a, 2a, or cyclized intermediate. Further
studies established that performing the reaction at room
temperature with chiral 5-CF3-Pyrox-tBu(L1)10 as ligand
gave the best result, affording 3a with 77% isolated yield
and 98% ee (entry 1).11 A comparable result was observed
when Ni(cod)2 was used, whereas the reaction with NiCl2
afforded 3a with low yield and decreased ee (entries 2 and
3). The use of THF as cosolvent inhibited the
homocoupling of cyclized intermediate (entries 1 vs. 4).
The reaction in THF is less effective, affording alkenyl
dimer from 2a and leaving most of 1a intact (entry 5).
Traces of 3a were observed when Zn was used instead of
Mn (entry 6). The investigation of ligands revealed that
the 5-CF3-Pyrox ligands were more effective at promoting
this cyclization/cross-coupling process (L1–L14). We
noted that (S,S)-Bn-Box (L10) and (S,S)-Ph-Box (L11), the
ligands used by Correia, Weix and Reisman,2, 8e performed
poorly under our conditions. The reaction with (S,Sp)-iPr-
Phosferrox L14, a ligand that is used in reductive
diarylation of activated alkene,5 did not give any desired
product.
a1a (0.1 mmol) and 2a (0.1 mmol) were used. The yields
were determined by GC analysis with dodecane as an internal
standard. bIsolated yield.
2.2
Reactions
for
With
the
Synthesis
optimized
of
Dihydrobenzofurans.
reaction
conditions in hand, we evaluated the scope of the
reaction with respect to alkenyl triflates (Table 2). Cyclic
alkenyl triflates ranging from five- to eight-membered
rings coupled efficiently to give enantioenriched products
with moderate to good yields and 97–99% ee (3b–g).
Incorporation of the functionalized alkenyl group is
important to increase molecular diversity. In this respect,
the reaction of 1a with carbonyl derivative affords 3h with
82% yield and 98% ee. Nonaromatic heterocycles are
prevalent in a wide range of pharmaceuticals, but
incorporation of them through C–C bond formation
represents
a
challenge.12 Under our conditions,
dihydrobenzofurans hybridized with 3,6-dihydro-2H-
pyran (3i), 3,6-dihydro-2H-thiopyran (3j), and 3-
piperideine (3k, 3l) were produced with high
enantioselectivity. The reactions of indenyl and 3,4-
dihydro-1-naphthyl triflates performed well (3m, 3n). The
reactions of 1a with 1-substituted alkenyl triflates afforded
functionalized products with moderate to good yields and
high ee (3o–q). Unfortunately, the reaction with 2-
substituted alkenyl triflate did not give any desired
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product (3r). The use of 1,2-disubstituted alkenyl triflate
Table 3. Scope of the reaction with respect to alkenea
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(E:Z = 2.8:1) gave a product with a ratio of E/Z = 2.5:1,
indicating the alkene geometry might be retained in this
process (3s). When a fully substituted alkenyl triflate was
employed, product 3t was obtained with 43% yield and
more than 99% ee. While the reaction of 1a with Ph–OTf
gave no desired product, the use of Ph–I afforded 3u with
70% yield and 98% ee.
8
9
We then studied the substrate scope of the reaction
with respect to aryl iodide-tethered alkenes (Table 3).
Substrates with electron-donating, electron-withdrawing,
or sterically hindered substituents at the aromatic ring
were tolerated (3v–3ae). Furthermore, the reaction could
be scaled up to gram-scale, and afforded 3w with 72%
yield and 97% ee. The absolute configuration of 3z was
determined by X-ray analysis, and that of all other
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Table 2. Scope of alkenyl triflatesa
a1 (0.2 mmol) and 2 (0.2 mmol) were used. Isolated yields.
c
bAlkene 1e (1.8 equiv), Ni catalyst (15%) was used. Reaction
in DMF. dReaction at 60 oC. eAlkene 1r (1.8 equiv) was used.
products was assigned accordingly.13 The reactions of
substrates bearing a substituent at the ortho-position of
iodide only gave trace of 3aa and 3ad with most of aryl
iodides protonated. In contrast, the reactions of
substrates bearing a substituent at the para- or meta-
position of the iodide afforded the cyclization-coupling
products with moderate yields and high enantioselectivity
(3x, 3ab, 3ac, 3ae). This substitution influence is
consistent with the previous reports.5,8a-b,e The presence of
t
a Bu group, alkyl long chain, or functionalized alkyl
group at the quaternary carbon center was tolerated (3af–
3ai). The reaction was effective for the synthesis of six-
membered O-heterocycle (3aj), but was failed to produce
seven-membered ring product (3ak). Optically active 2,3-
dihydrobenzofurans exhibit interesting biological activity,
and they have potential use as CB2 receptor agonists.14
Our method provides facile access to this type of
analogue (3al). At the current stage, the reactions of
monosubstituted, 1,2-disubstituted or trisubstituted
a1a (0.2 mmol) and 2 (0.2 mmol) were used. Isolated yields.
c
bReactions in DMF. Alkene 1a (2.0 equiv) was used, reaction
d
e
in THF. Alkene 1a (3.0 equiv) was used. Alkenyl triflate 2r
(Z/E = 7:1) was used. fAlkenyl triflate 2s (E/Z = 2.8:1) was used.
g4-(tert-butyl)-2-iodo-1-((2-methylallyl)oxy)benzene 1b was
used.
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alkenes were unsuccessful (1s–1w). In these cases, the
reactions typically afforded the direct aryl-alkenyl
coupling products.
Table 5. The reactions of C-tethered alkenes with
alkenyl triflatesa
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3
2.3 Reactions for the Synthesis of Indolines. 3,3-
Disubstituted indolines are ubiquitous structural motifs
in many biologically active compounds and natural
products, and their synthesis has attracted intense
attention.15 While a number of cyclization approaches to
enantioenriched 2-oxindoles have been reported, the
asymmetric synthesis of 3,3-disubstituted indolines has
been less developed.5,7b We therefore studied the
possibility of constructing these valuable targets through
the cross-electrophile method. Under slightly modified
standard conditions,16 a number of N-tether alkenes were
cyclized and coupled with alkenyl triflates selectively
(Table 4). The reactions of substrate 1x with cyclohexenyl-,
tetrahydropyridinyl, functionalized cycloalkenyl, and
indenyl triflates afforded the desired products in
synthetically useful yields and good to high
enantioselectivity (3am–3ap). The enantioselectivity was
improved when the N-Ac-protected substrate was used
instead of the N-Boc-protected one (3am, 3aq). In some
cases, the use of modified ligand L8 was required to
achieve high ee values (3an, 3ap, and 3aq). The use of
electron-rich aryl iodides significantly improved the
reaction efficiency, affording the products with good to
high yields (3ar–3at). The reaction of 4-chloro-aryl
substrate gave 3au with 58% yield and 96% ee.
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a1 (0.2 mmol) and 2 (0.2 mmol) were used. Isolated yields.
bReaction in DMF/THF (1:1). cL8 was used.
dihydronaphthalene were produced with moderate to
good yields and usually high enantioselectivity (3av–3ay).
While inferior results were obtained when a methyl
substituted aryl iodide was employed (3az, 3ba), the use
of more electron-rich substrate afforded the products
with moderate yields and 94% ee (3bb, 3bc).
Unfortunately, at present, the reaction of tethered aryl
iodide bearing an electron-withdrawing group was
inefficient, and only gave trace of 3bd with most of aryl
iodide protonated.
Table 4. The reactions of N-tethered alkenes with
alkenyl triflatesa
2.5 Application. To further demonstrate the synthetic
utility of this method, we investigated its potential in the
functionalization of molecules derived from complex
biologically active compounds (Scheme 3). Substrates
derived from peptides, which have always been
problematic in transition-metal catalysis,18 are tolerated
under our conditions, and enantioenriched 2,3-
dihydrobenzofuran was incorporated with 78% yield and
97% de (4). Indometacin is a prescription medication
used to reduce fever, pain, and stiffness from
Scheme 3. Catalytic functionalization of complex
moleculesa
a1 (0.2 mmol) and 2 (0.2 mmol) were used. Isolated yields.
bL8 was used.
2.4 Reactions for the Synthesis of Indanes. Indanes
are substructures present in a large number of naturally
occurring products and pharmaceutical compounds.17 The
potential of this method for the synthesis of these unique
structures was then evaluated (Table 5). Under our
conditions, enantioenriched indanes hybridized with
functionalized cyclohexene, 3-piperideine, indene, and
aSee conditions in Table 1, entry 1, but 1a (1.8 equiv) was
used. b1a (3.0 equiv) was used.
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inflammation.19 The reactions of indometacin derivatives
with 1a gave enantioenriched products 5 and 6 with
excellent enantioselectivity. The reactions of triflated
steroids also proceeded well (7, 8).
Scheme 5. Proposed mechanism
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2.6 Mechanistic Investigation and Proposed
Mechanism. Alkenyl–OTf was reported to be more
reactive than Ar–I toward oxidative addition to Pd(0).20
To establish whether the reaction starts with the
activation of alkenyl–OTf or Ar–I in our reaction, a
number of control experiments were conducted. The
reaction of 9 with 2a gave no cross-product, along with 17%
of alkenyl dimer 10, suggesting that an intermolecular
migratory insertion of unactivated alkene into the
alkenyl–Ni bond is not favored under our conditions
(Scheme 4a). In the absence of Mn, the reaction of 1a and
2a with Ni(0) (0.5 equiv) afforded dimer 11 with 21% yield,
leaving alkenyl–OTf intact (Scheme 4b). Moreover, the
reaction of 1n with 2e gave the desired product 3ah and
protonated byproduct 13 with the same enantioselectivity
(Scheme 4c). These results support the reaction pathway
that involves activation of Ar–I with Ni(0), intramolecular
migratory insertion, and reductive coupling with alkenyl–
OTf.
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3. CONCLUSION
In summary, we have developed the first catalytic
asymmetric aryl-alkenylation reaction of unactivated
alkenes by using a cross-electrophile method. This
reaction proceeds under mild conditions at room
temperature using equimolar amounts of coupling
fragments, and easily accessible chiral pyrox ligand was
used to obtain products with enantioselectivity up to
more than 99% ee. The synthetic utility of this method
has been demonstrated by enabling the modification of
biologically active complex molecules such as peptides,
indomethacin, and steroids. This method showcases the
potential of using cross-electrophile strategies to access
complex chiral structures, wherein the incorporated
alkene group will be useful to further increase molecular
complexity. Further expansion of the scope of the
Scheme 4. Mechanistic investigation
asymmetric
cross-electrophile
difunctionalization
reaction is ongoing in our laboratory.
ASSOCIATED CONTENT
Supporting Information
General information, experimental procedures, new
compound characterization, crystallographic data (CIF),
spectroscopic data, HPLC chromatograms and NMR spectra
are provided in the Supporting Information. This material is
available free of charge on the ACS Publication website.
aStandard conditions, but Ni(cod)2 (0.5 equiv) and L1 (0.7
b
equiv) were used and no Mn. Standard conditions, but NiI2
(0.5 equiv), L1 (0.7 equiv), and MeOH (1.0 equiv) were used.
Although a detailed mechanism for this reaction is yet
to be established, based on the above results and reported
work, we tentatively suggest the catalytic cycle shown in
Scheme 5. The reaction of Ar–I with Ni(0) might give
intermediate A, which undergoes an enantioselective
migratory insertion process to afford complex B.
Reduction of B with Mn, followed by oxidative addition
with 2a and reductive elimination, would afford the cross-
product 3a.21
AUTHOR INFORMATION
Corresponding Author
shuxingzh@lzu.edu.cn
Author Contributions
† These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of
China for their financial support (21772072, 21502078).
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(5) During the preparation of this work, Kong et al. reported a
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Total Synthesis of Indoline Alkaloids:
A Cyclopropanation
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(13) CCDC 1890459(3u) contains the supplementary
crystallographic data for this paper.
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