Enantioselective synthesis of axially chiral vinyl arenes through palladium-catalyzed C-H olefination

Article abstract of DOI:10.1039/C8CC05555F

A palladium-catalyzed ketoxime-chelation-assisted enantioselective C-H olefination of 2-arylcyclohex-2-enone oxime ether with a wide range of olefins as coupling partners was developed. Employing ketoxime ether as an efficient directing group, a variety of axially chiral vinyl arenes was synthesized by Pd(ii)-catalyzed C-H functionalization with excellent enantioselectivities (96 → 99% ee) under mild conditions.

Full text of DOI:10.1039/C8CC05555F

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Enantioselective synthesis of axially chiral vinyl arenes through
palladium-catalyzed C-H olefination
Received 00th January 20xx,
Qiao-Ying Sun, Wei-Yang Ma, Ke-Fang Yang, Jian Cao, Zhan-Jiang Zheng, Zheng Xu, Yu-Ming Cui*
and Li-Wen Xu*
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
important atropisomeric compounds of this type have
A
palladium-catalyzed
ketoxime-chelation-assisted
only recently been achieved. Gu and co-workers
enantioselective C-H olefination of 2-arylcyclohex-2-enone oxime
ether with a wide range of olefins as coupling partners was
developed. Employing ketoxime ether as an efficient directing
group, a variety of axially chiral vinyl arenes was synthesized by
developed an efficient palladium-catalyzed asymmetric
synthesis of axially chiral vinyl arenes from aryl
bromides and hydrozones, representing a pioneering
example for the atroposelective catalytic synthesis of
axially chiral styrene-type derivatives (Scheme 1).6
Based on their earlier success in this area, the same
group also disclosed an alternative approach to axially
chiral compounds from 2-iodo-3-methylcyclohex-2-
enones and aryl boronic acids which served as a class of
platform molecules for the synthesis of biary
atropisomers.7 A catalytic enantioselective synthesis of
axially chiral vinyl arenes was reported by Smith et al.
through a quinidine-derived ammonium salt catalyzed
atroposelective O-alkylation.8 Likewise, the utility of
these atropisomeric enolates was further demonstrated
by oxidation to BINOL derivatives. In recent
contributions, Tan and co-workers used the chiral
secondary amine catalyzed Michael reactions of
substituted diones/ketoneesters/malononitrile to
Pd(II)-catalyzed
C-H
functionalization
with
excellent
enantioselectivities (96->99% ee) under mild conditions.
Axially chiral compounds are widespread in numerous
biologically active natural products and have found a
plethora of applications in asymmetric catalysis,1
material science,2 and medicinal chemisrty.3 Due to the
fundamental importance of axially chiral scaffolds
exemplified by 1,1’-bi-2-naphthol (BINOL), diverse
synthetic methods4 have been developed, especially in a
catalytic manner. However, in sharp contrast to the
divergent strategies toward axially chiral biarys, the
catalytic atroposelective construction of vinyl arenes
bearing a chiral axis about the sp2-sp2 single bond in
styrene structure remains a formidable task. The main
challenges in this area are the difficulties to install fairly
large substituents to prevent rotation about the styryl
sp2-sp2 single bond and to develop efficient chiral
catalytic systems to control the enantioselectivity. Thus
accordingly, it is not surprising that optical resolution of
racemates or separation of diastereomers has been the
approaches to them traditionally employed.5
Scheme 1. Strategies in atroposelective synthesis of axially chiral vinyl arenes.
Gu's report:
Y
R1
R3
R2
R4
R3
R4
Pd/P ligand
+
R1
R2
cross coupling
Although tremendous efforts were devoted to
exploiting asymmetric reactions for the synthesis of
axially chiral vinyl arenes, catalytic construction of the
X
This work:
OMe
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of
Education, Hangzhou Normal University, Hangzhou 311121, P. R. China. Fax: (+86)-
571-28865135; phone: (+86)-571-28865135; e-mail: ym_cui@hznu.edu.cn or
liwenxu@hznu.edu.cn
OMe
R1
R2
N
H
Pd/MPAA
R1
R2
N
R3
+
R3
C-H activation
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
easily available catalyst
high atom economy
excellent ee
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alkynals as a powerful and straightforward synthetic amino acids have strong influence on the reactivity and
route toward styrene derivatives.9 Recently, this enantioselectivity (Table S1, entries 10-16). Variation of
methodology has also been extended to preparation of the oxidant using either benzoquinone or catalytic
axially chiral sulfone-containing styrenes via the amount of AgOAc under O2 instead of 3 equiv of
quinine-derived
addition to
thiourea-catalyzed
vinylidene o-quinone
nucleophilic AgOAc led to very poor results (Table S1, entries 17
methide and 18). The reaction gave best results (71% yield and
intermediate.10 Despite the impressive progress in 97% ee) in the presence of Pd(OAc)2 and mono
construction of axially chiral styrene-type skeletons, the protected amino acid15 (MPAA) Ac-L-Ala-OH (L8) in
development of new versatile methods using easily methanol at 40 oC using AgOAc as the oxidant.
available catalytic systems to obtain synthetically
valuable atropisomeric vinyl arenes is in great demand.
Having identified the optimal reaction conditions, we
next investigated the substrate scope. Firstly, we tested
Over the past decades, developing enantioselective C- the generality of this novel method regarding different
H
bond functionalization process has attracted substituted olefins with 1a as a coupling partner
considerable attention in terms of its atom economy (Scheme 2). We were pleased to find that various
and step economy, and great progress has been olefins such as methyl, butyl, n-butyl, and t-butyl
witnessed in this field.11 Since the pioneering report12 acrylates, vinyl ketone, phenyl vinyl sulfone, and
concerning rhodium-catalyzed atroposelective C-H alkenylphosphate are compatible with the reaction
alkylation of biaryls, the asymmetric synthesis of conditions and the corresponding axially chiral products
atropisomeric biaryls via transition metal-catalyzed C-H were afforded in satisfactory yields and excellent
bond activation was successfully realized by several enantioselectivities. Moreover, the reactions of acrolein
groups in this context.13 Nevertheless, catalytic with a highly reactive aldehyde groups under oxidative
construction of axially chiral vinyl arenes through conditions gave 3f in high level of chiral induction,
enantioselective C-H functionalization has not been albeit with much lower isolated yield. In addition, the
reported, which may be rationalized when considering reactions of several para-substituted styrene decorated
the fact that: (1) many C-H bond activation reactions by various electron-withdrawing (F, Cl, Br) and
require harsh conditions, making matched chiral electron-donating group (OMe) proceeded smoothly to
catalytic systems are extremely rare, (2) vinylarenes furnish the desired products in 49-74% yields with 96-
have relatively lower rotation energy compared with the 97% ee. The absolute configuration of 3j was S as
rigid biaryls.
confirmed by X-ray crystallography16 and those of the
On the basis of Gu’s findings that axially chiral 2-aryl other products were assigned by analogy.
cyclohex-2-enones are valuable intermediates for
Scheme 2. Scope of olefins
synthesis of biaryl atropisomers,7 we envisioned that
atropisomeric vinyl arenes of this type might be
accessed under transition metal catalysis if a suitable
directing group was installed to facilitate C-H activation.
It is well known that the oxime ether is one of the most
efficient directing groups14 which can not only be
prepared from ketones but also be removed readily. It
would be highly desirable if the ketoxime directing
group in such axially chiral motifs can act as a good
binding site to finely tune the properties of metal and
the resulted complex is a suitable catalyst for further
asymmetric catalytic transformations, which will
undoubtedly expand the scope of their synthetic
applications. To the best of our knowledge, so far, no
related examples about transition metal-catalyzed
enantioselective C-H functionalization using ketoxime
as directing groups have appeared. Herein, we report a
novel and straightfoward route toward the synthesis of
axially chiral vinyl arenes by Pd(II)-catalyzed C-H
enantioselective olefination in moderate to good yields
and excellent enantioselectivities, thus providing a
conceptually different pathway to the atropisomers of
this class.
To further explore the scope of this transformation,
We evaluated the coupling reaction of 3-methyl-2-
naphthylcyclohex-2-enone oxime ether 1a with ethyl
acrylate 2a to optimize the reaction conditions (Table
S1) by screening temperature, solvents, ligands, and
oxidants. The substituents and protecting groups of the
we then evaluated the use of various oxime ethers as
substrates (Scheme 3). All the substrates were subjected
to the C-H olefination with ethyl acrylate 2a and the
corresponding alkenylated products were produced in
moderate
yields
(35-72%)
and
excellent
2 | J. Name., 2012, 00, 1-3
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enantioselectivities (96->99% ee), but except 3y and 3z
which displayed no axial chirality probably due to the
lower rotation energy relative to those of others. The
naphthyl group in 1a could be replaced by the
differently substituted phenyl groups without affecting
the chemical yields and enantioselectivities, in spite of
the electronic properties of substituents in aromatic
rings. For example, compounds bearing electron-
donating groups such as methoxyl and hydroxyl or
electron-withdrawing group such as chloro in ortho-
position to chiral axis were converted into the
corresponding products in good yields of up to 72% as
well as excellent enantioselectivities of >99% ee (3o-u).
The resulting axially chiral vinylarenes are useful
synthetic intermediates because these reactive groups
are suitable for further selective transformations.
Notably, the sterically hindered substrate containing a
fluoro atom ortho to the olefination position was tested
in this reaction and the desired compound 3o was
successfully obtained in 56% yield with 98% ee. As
expected, 2-naphthyl-3-phenylcyclohex-2-enone oxime
ether also reacted well with phenyl vinyl sulfone and
alkenylphosphate, generating products 3w and 3x with
synthetically
useful
yields
and
excellent
enantioselectivities.
Scheme 4. Scale-up preparation, derivatization, and further application of
products.
It should be noted that the reaction could be
performed on a large scale with consistent efficiency, as
exemplified by the synthesis of 3a using the standard
substrates 1a and 2a under similar conditions (Scheme 4,
eq 1). To further demonstrate the utility of this
enantioselective olefination protocol, derivatizations of
the formed products were attempted. To be noted, one
of the two double bonds in 3a could be selectively
reduced under hydrogen atmosphere in the presence of
Pd/C catalyst to afford 4 in 55% yield (Scheme 4, eq 2).
A new axially chiral phosphinite compound 5 derived
from 3t was obtained in one step (Scheme 4, eq 3). A
preliminary examination of 5 in a palladium-catalyzed
the asymmetric allylation reaction between (E)-1,3-
diphenylallyl acetate 6 and dimethyl malonate disclosed
that this type of P,N-ligand is efficient, providing 7 in
moderate yield and enantioselectivity (Scheme 4, eq 4).
In addition, the oxime ether directing group was
removed readily to release the parent ketone 8 (Scheme
4, eq 5).
In conclusion, we have developed a novel palladium-
catalyzed ketoxime-chelation-assisted enantioselective
olefination reaction of arenes C-H bonds. This strategy
features simple catalytic system, good functional group
compatibility, and gram-scale preparation, providing a
practical access to axially chiral vinyl arenes with good
Scheme 3. Scope of oxime ethers.
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available starting materials under mild conditions.
Furthermore, the resulting olefination products with the
unique structures exhibited diverse synthetic
applications, further enhancing the utility of the current
method. Further studies on the other atroposelective
olefination and the mechanism of this process are
ongoing.
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Conflicts of interest
There are no conflicts to declare.
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A palladium-catalyzed ketoxime-chelation-assisted C-H olefination was developed to
afford axially chiral vinyl arenes with excellent enantioselectivities.