A Novel Bisoxazoline-Imidazolium Salt in Ytterbium-Catalyzed Asymmetric Reduction of Ketone

Article abstract of DOI:10.1002/ejoc.202000816

Chiral N-heterocyclic carbene (NHC), a privileged ligand for transition metals, has had a profound impact on organometallic chemistry. The monodentate and bidentate chiral carbenes have been developed significantly, while the tridentate ones have been less exploited. Herein, we designed and synthesized a new bisoxazoline-imidazolium salt as a carbene precursor, which owns three chelating sites and two kinds of chiral information centers. A preliminary investigation on the asymmetric ketone reduction was also studied.

Full text of DOI:10.1002/ejoc.202000816

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: A Novel Bisoxazoline-Imidazolium Salt in Ytterbium-Catalyzed
Asymmetric Reduction of Ketone
Authors: Yujie Zhai, Wenhao Xu, Dong Wang, Purui Zheng, Xiaoming
Zhao, and Tao XU
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000816
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01/2020

10.1002/ejoc.202000816
European Journal of Organic Chemistry
COMMUNICATION
A Novel Bisoxazoline-Imidazolium Salt in Ytterbium-Catalyzed
Asymmetric Reduction of Ketone
Yujie Zhai,[a] Wenhao Xu,[a] Dong Wang,[a] Purui Zheng,[a] Xiaoming Zhao,* [a] and Tao XU *[a]
Dedication ((optional))
Abstract: Chiral N-heterocyclic carbene (NHC), a privileged ligand for
transition metals, has had a profound impact on organometallic
chemistry. The monodentate and bidentate chiral carbenes have been
developed significantly, while the tridentate ones have been less
exploited. Herein, we designed and synthesized a new bisoxazoline-
imidazolium salt as a carbene precursor, which owns three chelating
sites and two kinds of chiral information centers. A preliminary
investigation on the asymmetric ketone reduction was also studied.
the skeleton with the chiral backbone and another two auxiliary
groups, which could possibly strengthen the efficiency through the
superimposed effect of the couple of chiral centers.
The preparation of the enantiopure molecules is of high demand
in pharmaceutical, organic synthesis, and material science.1
Although many special structures can be obtained from natural
products, it remains a huge requirement that promotes chemists
to take efforts to explore new enantioselective catalytic
methodologies utilizing chiral catalysis or ligands. Since the
pioneering work of Tschugajeff on the pure form of diamino
carbene complex2 and Arduengo on the isolated free N-
Heterocyclic carbene (NHC) compound3, NHCs have been widely
used as promising ligands4 in organometallic chemistry and
excellent organocatalysts5 in novel methodologies development.
Among them, the chiral carbenes have importantly made
tremendous growth in the application on the asymmetric
reactions.6
Chiral NHC complexes were prepared over dozens of years
before the resurgence of being the privileged ligand for the
transition metals in the late last century.7 Meanwhile, a large
amount of new chiral carbenes were designed and studied on
their functions (Scheme 1).8 For the monodentate NHC, the chiral
element usually locates on the ligand backbone (type A)9 or the
N-substituents (type B)10. To efficiently convey chiral information
to the catalytic active site, the sterically bulky N-substituents are
often necessary to impede the rotation of the C-Metal bond. The
design of bidentate chiral carbenes could better block this internal
rotation with another coordination group. The bis(NHCs) skeleton
with a chiral linker (type C)11 were reported. Unfortunately, the
efficiency in transition metal-catalyzed reactions remains
somewhat limited. The more successful bidentate chiral carbenes
are type D12 and type E13 where a chiral (or an achiral) backbone
with an achiral (or a chiral) chelating site (including N, O, P et. al)
in the N-substituents. However, to the best of our knowledge, the
tridentate chiral carbenes are still less developed14, especially on
Scheme 1. The types of chiral carbenes.
The oxazoline framework is one of the most popular classes
of chiral ligands due to its many outstanding features including
easy preparation, air stability, excellent enantioinduction, and so
on.15 Incorporating an oxazoline unit to the NHC has been proved
to be a promising way to exploit the new type of chiral ligands
(Scheme 2a). In 1996, Herrmann reported this type of ligand and
synthesized the first chiral carbene transition metal complexes by
using rhodium.16 Gade and Bellemin-Laponnaz designed an
imidazolium salt with a direct link between the NHC and the
oxazoline in 2005.17 Besides, Burgess and co-workers, by
changing the chiral center to the methylene linker, devolved a
novel chiral NHC in 2001 and a family of iridium complexes were
synthesized.18 These complexes were successfully applied in
many asymmetric reactions.19 Meanwhile, the Pfaltz group also
prepared a similar imidazolium salt but with a shorter linking
carbon chain.20 To introducing the planar chirality, in 2003 and
2005, the Bolm group described two new types of oxazoline-
NHCs with chiral paracyclophane and 1,2-substituted ferrocene
scaffold.21 In 2009, Kuang and co-workers also produced a chiral
ferrocene-oxazoline-NHC in which the NHC was connected
directly with the ferrocene, and probably more rigid than Bolm’s
ligand.22 Importantly, in 2002, the Glorius group demonstrated a
novel imidazolium salt which can be readily prepared from
bioxazoline and oxazolineimine.23 Application of the ligand in the
intramolecular α–arylation gave excellent enantioselectivities.24
[a]
P. Zheng, Y. Zhai, Prof. Dr. X. Zhao, Prof. Dr. T. XU
Shanghai Key Laboratory of Chemical Assessment and
Sustainability, School of Chemical Science and Engineering, Tongji
University
1239 Siping Road, Shanghai, 200092, P. R. of China
E-mail: taoxu@tongji.edu.cn; xmzhao08@mail.tongji.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.202000816
European Journal of Organic Chemistry
COMMUNICATION
N-bromosuccinimide (NBS) provided the best result while N-
iodosuccinimide (NIS) gave the product with a bit lower yield, and
N-chlorosuccinimide (NCS) didn’t work. The extremely dilute
DCM solvent was also vital for this transformation. THF or MeCN
was proven to be not feasible.
Table 1. The optimization of oxidation conditions.a
Entry
Oxidant
Solvent
1a(%)b
1
2
3
4
5
NCS (X=Cl)
NBS (X=Br)
NIS (X=I)
DCM
DCM
DCM
THF
trace
89
83
NBS (X=Br)
NBS (X=Br)
35
MeCN
trace
[a] Reaction conditions: 5a (0.1 mmol), oxidant (0.1 mmol), solvent (20 mL), 0
oC to room temperature. [b] Isolated yield.
Scheme 2. The chiral carbenes with oxazoline unit.
Under these conditions, the oxidation process with different
substituted oxazoline and their diastereoisomers were tested.
They can give the corresponding products in 83-93% yields
(Table 2). From this table, it apparently shows several attractive
features of this kind of carbene salts: 1) they can be conveniently
obtained with our method by using the commercially available
enantiopure diamine and amino alcohols; 2) the enantiomers and
diastereoisomers significantly enrich the diversity of the ligands
through simply cross combination of the configurations of the two
chiral sources; 3) the steric properties can be fine-tuned by
variation of the substituents at the oxazoline rings; 4) changing
the electron density of diphenyl groups at the imidazoline provides
a potential to adjust the electronic effect of the carbene in the
further modification.
Although several types of oxazoline-NHCs have been
reported, there is still much room for the development of novel
chiral oxazoline carbenes. For example, the C2-symmetry
concept25, which is very popular in ligand design, has not been
adequately introduced into this kind of NHC (F). Considering the
nitrogen site is a very promising chelating group, we envisioned a
motif like type F’ deserves to be studied (Scheme 2b). To
incorporating another chiral skeleton, the new chiral tridentate
oxazoline-NHC as ligand 1 was proposed. Herein, we reported
the synthesis of this novel NHC precursor salt and the preliminary
application in asymmetric ketone reduction.
Table 2. The scopes of the bisoxazoline-imidazolium salts.a
Scheme 3. The synthesis route of the compound 5.
The attempt on many traditional synthesis routes was in
vain.26 After many experiments conducted, a successful route
was listed in Scheme 3. Condensation of the diamine 2 with
paraformaldehyde to afford compound 3 which was subsequently
reacting with 2 equivalent of substrate 4 to form compound 5.
Then, oxidation of 5 to imidazolium salt 1 with 5a as a model
substrate was carefully studied. It can be found that, in table 1,
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10.1002/ejoc.202000816
European Journal of Organic Chemistry
COMMUNICATION
Although the enantioselectivities were modest, some
information can be discussed and that’s helpful to understand this
kind of chiral carbenes. Compared with copper, rhodium, and
other metals, ytterbium was not a common catalyst for this
reaction but shows the highest activity here. And surprisingly, the
other catalysts didn’t give any enantiomeric excess under these
conditions. Meanwhile, according to the results, the absolute
configuration of the products should be influenced by not only the
two chiral centers but also steric properties. The configuration of
the alcohols seems to depend on the chiral center of the oxazoline
part in the use of ligand 1a-1h, yet the results with ligand 1i-1j
violated this regularity. The expected superimposed effect of the
couple of chiral centers was not obvious in this reduction reaction,
although the majority of the ligands with the same configuration
(1a, 1c, 1f) are a bit better than their isomers (1b, 1d, 1e).
In summary, a novel bisoxazoline-imidazolium salt, as a new
carbene ligand precursor, was invented. In this scaffold, following
the C2-symmetric design concept, three chelating sites were
embedded and two kinds of chiral information sources were
incorporated. Although the control on the enantioselectivity in the
ketone reduction was unsatisfactory, the prospect of this ligand
still deserves to be expected. Application of the ligand in other
asymmetric reactions is on-going in our lab.
[a] The reaction was conducted in 0.2 mmol scale under the standard conditions
in Entry 2, Table 1. [b] Isolated yields were given.
To investigate the potential of these carbene precursors, we
tested them in the asymmetric reduction of acetophenone with
HBPin as the reductant (Table 3). One mole equivalent of a base
(tBuOLi) to the salt was added to free the carbene. A screening of
metal catalysts showed Yb(OTf)3 was the best choice to give the
alcohol in 70% yield and 19% ee with 1a as the ligand. The other
catalysts, such as Cu(acac)2, [Rh(C2H4)Cl]2, Zn(OAc)2 only gave
the racemic product. Further optimization with ligands disclosed
the best enantioselectivity was recorded with carbene salt 1i,
while 38% ee was obtained.
Acknowledgements
We thank NFS of China (Grants 21801188), Shanghai Pujiang
Program, the “1000 Youth Talents Plan”, and Tongji University for
financial support.
Table 3. The asymmetric reduction of ketone with ligand 1.a
Keywords: Bisoxazoline-Imidazolium • Chiral Carbene •
Ytterbium-Catalyzed reaction • Novel Ligand
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10.1002/ejoc.202000816
European Journal of Organic Chemistry
COMMUNICATION
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COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
Key Topic: Ligand Development
Yujie Zhai, Wenhao Xu, Dong Wang,
Purui Zheng, Xiaoming Zhao*, and Tao
XU*
Page No. – Page No.
Chiral N-heterocyclic carbene has had a profound impact on organometallic
chemistry. The monodentate and bidentate chiral carbenes have been developed
significantly, while the tridentate ones have been less exploited. Herein, we designed
and synthesized a new bisoxazoline-imidazolium salt as a carbene precursor, which
owns three chelating sites and two kinds of chiral information. A preliminary
investigation on the asymmetric ketone reduction was also studied.
A
Salt
Novel Bisoxazoline-Imidazolium
in Ytterbium-Catalyzed
Asymmetric Reduction of Ketone
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