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\begin{document}

\title{Design and Synthesis of {[}2.2{]}Paracyclophane-based Oxazole-Pyrimidine
Ligands and Application in Nickel-Catalyzed 1,2-Reduction of
\selectlanguage{greek}α,β-\selectlanguage{english}Unsaturated Ketones\selectlanguage{english}}



\author[1]{Juan Wang}%
\author[2]{Qing-Xian Xie}%
\author[1]{Xiang  Li }%
\author[2]{Chang-Bin Yu}%
\author[2]{Yong-Gui Zhou}%
\affil[1]{Dalian University of Technology}%
\affil[2]{Chinese Academy of Sciences Dalian Institute of Chemical Physics}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\selectlanguage{english}
\begin{abstract}
The {[}2.2{]}paracyclophane-derived oxazole-pyrimidine ligands with
planar chirality (PYMCOX) were designed, synthesized and successfully
applied in nickel-catalyzed asymmetric 1,2-reduction of \selectlanguage{greek}α,β-\selectlanguage{english}unsaturated
ketones, affording the chiral allylic alcohols with up to 99\% yield and
99\% ee. Meanwhile, this reduction reaction could be conducted on
gram-scale without loss of activity and enantioselectivity, and the
chiral ligand could be conveniently recovered with high yield.%
\end{abstract}%



\sloppy


\textbf{Cite this paper:}\emph{Chin. J. Chem.} \textbf{2023} , \emph{41}
, XXX---XXX. \textbf{DOI: 10.1002/cjoc.202300XXX}

Synthesis of Planar-Chiral {[}2.2{]}Paracyclophane-based
Oxzole-Pyrimidine Ligands and Application in Nickel-Catalyzed
1,2-Reduction of \selectlanguage{greek}α,β-\selectlanguage{english}Unsaturated Ketones

Juan Wang,\emph{\textsuperscript{a}} Qing-Xian
Xie,\emph{\textsuperscript{b}} Xiang
Li,\emph{\textsuperscript{a}}Chang-Bin Yu,*\textsuperscript{,\emph{b}}
and Yong-Gui Zhou*\textsuperscript{,\emph{a,b}}

\textsuperscript{a}School of Chemistry, Dalian University of Technology,
2 Linggong Road, Dalian 116024, P. R. China.\textsuperscript{b}State Key
Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China.\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Keywords}\tabularnewline
\midrule
\endhead
Oxzole-Pyrimidine Ligands \textbar{} Planar Chirality \textbar{}
Nickel-Catalyzed Hydroboration \textbar{}\selectlanguage{greek}α,β-\selectlanguage{english}Unsaturated
Ketones\tabularnewline
\textbf{Comprehensive Summary}\tabularnewline
The {[}2.2{]}paracyclophane-derived oxazole-pyrimidine ligands with
planar chirality (PYMCOX) were designed, synthesized and successfully
applied in nickel-catalyzed asymmetric 1,2-reduction of \selectlanguage{greek}α,β-\selectlanguage{english}unsaturated
ketones, affording the chiral allylic alcohols with up to 99\% yield and
99\% ee. Meanwhile, this reduction reaction could be conducted on
gram-scale without loss of activity and enantioselectivity, and the
chiral ligand could be conveniently recovered with high
yield.\tabularnewline
\bottomrule
\end{longtable}

\section*{}

{\label{section}}

Background and Originality Content

The remarkable modification ability of \selectlanguage{greek}\emph{α} -\selectlanguage{english}chiral allylic alcohols
has attracted extensive attentions of researchers, and has demonstrated
fascinating functionalities in the field of natural product synthesis as
well as polymer and material science.\textsuperscript{{[}1{]}} As one of
the most direct and efficient strategies, asymmetric 1,2-reduction of
readily available \selectlanguage{greek}α,β-\selectlanguage{english}unsaturated ketones was adopt by many researchers
to synthesize \selectlanguage{greek}α-\selectlanguage{english}chiral allylic alcohols with various chiral catalyst
systems, such as
Ru,\textsuperscript{{[}2{]}}Ir,\textsuperscript{{[}3{]}}
Cu,\textsuperscript{{[}4{]}}etc.\textsuperscript{{[}5{]}} However, there
were relatively few reports involving fertile metallic nickel. In 2017,
Zhu's group reported the first nickel-catalyzed chemoselective
1,2-reduction of \selectlanguage{greek}α,β-\selectlanguage{english}unsaturated ketones with oxazoline-pyrimidine
ligand with central chirality, affording the allylic alcohols with
excellent reactivity and enantioselectivity.\textsuperscript{{[}6{]}}
Until now, there were no other type ligands applied in this catalytic
system. Therefore, it is extremely attractive to exploit a novel type of
chiral ligands to achieve nickel-catalyzed enantioseletive 1,2-reduction
of \selectlanguage{greek}α,β-\selectlanguage{english}unsaturated ketones with high enantioselectivity.

In recent years, planar-chiral ligands have been widely applied as a
class of unique and significant ligands in asymmetric catalysis.
Planar-chiral ligands mainly include ferrocenes, metal carbonyl-
complexes, paracyclophane units, etc.\textsuperscript{{[}7{]}} Among
them, the skeleton of {[}2.2{]}paracyclophane has the advantages of
stable properties, rigid structure and large steric
hindrance.\textsuperscript{{[}8{]}} Considering the characteristics of
this skeleton, our group has been committed to design and synthesis of
various kinds of {[}2.2{]}paracyclophane-derived ligands with planar
chirality, such as chiral oxzole-pyridine ligands and tridentate PNO
ligands.\textsuperscript{{[}9{]}} Inspired by the excellent performance
of the {[}2.2{]}paracyclophane skeleton, a series of {[}2.2{]}
paracyclophane-derived oxazole-pyrimidine ligands containing planar
chirality (abbreviated as PYMCOX) were designed, synthesized, and
successfully applied in nickel-catalyzed asymmetric 1,2-reduction of
\selectlanguage{greek}α,β-\selectlanguage{english}unsaturated ketones with up to 99\% yield and 99\% ee. Furthermore,
the reduction could be conducted at gram-scale without loss of activity,
and the oxazole-pyrimidine ligand could be also recovered by flash
column chromatography.

\textbf{Scheme 1} Metal-catalyzed asymmetric 1,2-reduction of
\selectlanguage{greek}α,β-\selectlanguage{english}unsaturated ketones

Results and Discussion

At the beginning, the paracyclophane-derived chiral \emph{N,N} -ligands
PYMCOX (\emph{R} \textsubscript{p})-\textbf{L1-10} were synthesized from
the known {[}2,2{]}paracyclophane-derived chiral aminophenol (\emph{R}
\textsubscript{p})-\textbf{1} through two approaches according to the
known similar procedures (see Supporting Information). Method A:
2-cyanopyrimidines \textbf{2} under- went the nucleophilic addition with
methanol to give the intermediates methyl ester of imino-pyrimidine acid
derivatives.\textsuperscript{{[}10{]}} Then, the intermediates underwent
the condensation reaction with paracyclophane-derived aminophenol
(\emph{R} \textsubscript{p})-\textbf{1} to afford the chiral PYMCOX
ligands (\emph{R} \textsubscript{p})-\textbf{L1-9} . Method B:
2-cyanopyrimidine \textbf{2} underwent the hydrolysis to give the
carboxylic acid \textbf{3} .\textsuperscript{{[}11{]}} Then, two step
condensation/cyclization reactions between chiral aminophenol (\emph{R}
\textsubscript{p})-\textbf{1} and carboxylic acid \textbf{3}were
conducted to provide the chiral PYMCOX ligand (\emph{R}
\textsubscript{p})-\textbf{L10} .\textsuperscript{{[}12{]}}

\textbf{Scheme 2} The synthesis of chiral PYMCOX ligands

With the chiral PYMCOX ligands in hand, we began our investigation with
(\emph{E} )-4-phenylbut-3-en-2-one (\textbf{4a} ) as model substrate.
Ni(COD)\textsubscript{2} (2.0 mol \%) and PYMCOX \textbf{L1} (2.4 mol
\%) were employed in the presence of 1.2 equivalent of pinacolborane
(HBpin), 1.5 equivalent of 1,4-diazobicyclo{[}2.2.2{]}octane (DABCO) and
toluene at -25 \selectlanguage{ngerman}°C for 1 hour. To our delight, the chemoselective
reduction underwent smoothly to afford the desired allylic
alcohol\textbf{5a} (entry 1, 92\% yield, 97\% ee), and the product of
1,4-reduction was not detected. The other parameters were summarized as
follows: (a) Ni precursors such as nickel triflate and nickel acetate
were completely inefficient (entries 2, 3). (b) The base is of utmost
importance, in which DABCO was optimum. Others like DBU and DIPEA, the
target product was obtained with lower yield or enantioselectivity
(entries 4, 5). (c) While the reductant HBpin was a competent hydrogen
source, both catcholborane (CB) and
Ph\textsubscript{2}SiH\textsubscript{2} were ineffective (entries 6, 7).
(d) The activity and enantio- selectivity were also affected by the
changes in solvents. It was found that the solvents like dichloromethane
(DCM), ethyl acetate (EA) and diethyl ether were superior to polar
aprotic and protic alternatives (entries 8-11). Encouraged by these
results, compared with different chiral ligands ((\emph{R}
\textsubscript{p})-\textbf{L1} to (\emph{R}
\textsubscript{p})-\textbf{L10} ), the oxazole-pyrimidine
ligand\textbf{L2} bearing 4-methylpyrimidine motif povided the highest
99\% of yield and 98\% of enantioselectivity.

\textbf{Table 1} Optimization of reaction
parameters.\emph{\textsuperscript{a}}\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
Entry & {[}Ni{]} & Base & {[}H{]} source & Solvent & \textbf{L} & Yield
of \textbf{5a} (\%)\emph{\textsuperscript{b}} & ee of \textbf{5a}
(\%)\emph{\textsuperscript{c}}\tabularnewline
\midrule
\endhead
1 & Ni(COD)\textsubscript{2} & DABCO & HBpin & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L1} & 92 & 97\tabularnewline
2 & Ni(OTf)\textsubscript{2} & DABCO & HBpin & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L1} & \textless{}5 &
-\tabularnewline
3 & Ni(OAc)\textsubscript{2} & DABCO & HBpin & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L1} & \textless{}5 &
-\tabularnewline
4 & Ni(COD)\textsubscript{2} & DBU & HBpin & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L1} & 40 & 15\tabularnewline
5 & Ni(COD)\textsubscript{2} & DIPEA & HBpin & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L1} & 93 & 92\tabularnewline
6 & Ni(COD)\textsubscript{2} & DABCO & CB & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L1} & \textless{}5 &
-\tabularnewline
7 & Ni(COD)\textsubscript{2} & DABCO &
Ph\textsubscript{2}SiH\textsubscript{2} & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L1} & \textless{}5 &
-\tabularnewline
8 & Ni(COD)\textsubscript{2} & DABCO & HBpin & Et\textsubscript{2}O &
(\emph{R}\textsubscript{P})-\textbf{L1} & 99 & 95\tabularnewline
9 & Ni(COD)\textsubscript{2} & DABCO & HBpin & DCM &
(\emph{R}\textsubscript{P})-\textbf{L1} & 97 & 94\tabularnewline
10 & Ni(COD)\textsubscript{2} & DABCO & HBpin & EA &
(\emph{R}\textsubscript{P})-\textbf{L1} & 92 & 97\tabularnewline
11 & Ni(COD)\textsubscript{2} & DABCO & HBpin &
\emph{\textsuperscript{i}}PrOH & (\emph{R}\textsubscript{P})-\textbf{L1}
& \textless{}5 & -\tabularnewline
12 & Ni(COD)\textsubscript{2} & DABCO & HBpin & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L2} & 99 & 98\tabularnewline
13 & Ni(COD)\textsubscript{2} & DABCO & HBpin & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L3} & 99 & 96\tabularnewline
14 & Ni(COD)\textsubscript{2} & DABCO & HBpin & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L4} & 99 & 97\tabularnewline
15 & Ni(COD)\textsubscript{2} & DABCO & HBpin & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L5} & 96 & 96\tabularnewline
16 & Ni(COD)\textsubscript{2} & DABCO & HBpin & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L6} & 91 & 7\tabularnewline
17 & Ni(COD)\textsubscript{2} & DABCO & HBpin & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L7} & 89 & 82\tabularnewline
18 & Ni(COD)\textsubscript{2} & DABCO & HBpin & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L8} & 98 & 98\tabularnewline
19 & Ni(COD)\textsubscript{2} & DABCO & HBpin & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L9} & \textless{}5 &
-\tabularnewline
20 & Ni(COD)\textsubscript{2} & DABCO & HBpin & Toluene &
(\emph{R}\textsubscript{P})-\textbf{L10} & 87 & 95\tabularnewline
\bottomrule
\end{longtable}

\emph{\textsuperscript{a}} Reaction conditions: \textbf{4a} (0.2 mmol),
{[}Ni{]} (2.0 mol\%), \textbf{L} (2.4 mol\%), {[}H{]} source (1.2
equiv.), base (1.5 equiv.), solvent (2.0 mL), -25 \textsuperscript{o}C,
0.8 - 4.0 h. \emph{\textsuperscript{b}} Isolated
yield.\emph{\textsuperscript{c}} Determined by HPLC with chiral column.
Et\textsubscript{2}O: ethyl ether, DCM: dichloromethane, EA: ethyl
acetate, \emph{\textsuperscript{i}} PrOH: isopropanol, CB:
catecholborane, DBU: 1,8-diazabicyclo{[}5.4.0{]}undec-7-ene,
DIPEA:\emph{N} ,\emph{N} -diisopropylethylamine.

With the optimum conditions in hand, the substrate scope of this
methodology was examined. Firstly, the aryl ring in \selectlanguage{greek}α,β-\selectlanguage{english}unsaturated
ketones with different functional groups including \emph{ortho}
-,\emph{meta} - and \emph{para} -substitutions could be reacted well to
afford the target products in high yields and excellent enantiomeric
excesses (\textbf{5a-5l} ). The \emph{ortho} -substituents were methyl
(\textbf{5b} : 99\% yield, 99\% ee), methoxyl (\textbf{5c} : 96\% yield,
99\% ee) and cyano (\textbf{5d} : 99\% yield, 96\% ee). The\emph{meta}
-substituents were methyl (\textbf{5e} : 99\% yield, 98\% ee) and
halogen (\textbf{5f} , \textbf{5g} , \textbf{5h} : 91-99\% yield,
97-98\% ee). The \emph{para} -substituents were methyl (\textbf{5i} :
97\% yield, 97\% ee), halogen (\textbf{5j} : 96\% yield, 98\% ee
and\textbf{5k} : 99\% yield, 98\% ee) and phenyl (\textbf{5l} : 99\%
yield, 98\% ee). When the naphthyl was employed as substituent group,
excellent yield and enantiomeric excess (\textbf{5m} : 99\% yield, 98\%
ee) were observed. Secondly, \selectlanguage{greek}α\selectlanguage{english}'-substituents, such as ethyl (\textbf{5n}
: 99\% yield, 98\% ee) and \emph{n} -propyl (\textbf{5o} : 99\% yield,
94\% ee), were also suitable for this reductive reaction in high yields
and enantiomeric excesses under the standard conditions. But when
\selectlanguage{greek}α\selectlanguage{english}'-substituent was changed to isopropyl (\textbf{5p} ), the enantiomeric
excess decreased to moderate 65\% ee.

Moreover, the heteroaromatic substrate, like furan, could also work
smoothly to deliver the desired product in excellent enantiomeric excess
(\textbf{5q} : 76\% yield, 94\% ee). \selectlanguage{greek}β,β-\selectlanguage{english}Disubstituted enones
(\textbf{4r} and \textbf{4s} ) were successfully participated to afford
the reductive products (\textbf{5r} : 88\% yield, 74\% ee and\textbf{5s}
: 85\% yield, 58\% ee), respectively. Subsequently, we attempted to use
the (\emph{E} )-2-benzylidenecyclohexanone (\textbf{4t} ) as the
substrate to explore the substrate scope. Unfortunately, the
enantiomeric excess was unsatisfied (\textbf{5t} : 93\% yield, 26\% ee).
In addition, chalcone substrate (\textbf{4u} ) underwent 1,2-reduction
to afford the chiral alcohol in moderate yield and enantiomeric excess
after a series of ligands screening (\textbf{5u} : 76\% yield, 68\%
ee,\textbf{L9} ), and a small amount of sideproduct of 1,4-reduction
(24\% yield) was also observed. For the substrate \textbf{5v} with
strong electron-withdrawing trifluoromethyl group, 91\% yield and
moderate 74\% of enantiomeric excess were obtained. Finally, the
substrates with \selectlanguage{greek}α\selectlanguage{english}'-substituent such as methoxycarbonyl group and benzyl
were investigated, and the results were also unsatisfactory.

\textbf{Scheme 3} Substrate scope for \selectlanguage{greek}α,β-\selectlanguage{english}unsaturated ketones

\textbf{Scheme 4} Scale-up experiment

To demonstrate the practicality of this methodology, the asymmetic
reduction at the 6.84 mmol scale of \textbf{4a} was proceeded under the
standard conditions, and the reductive product \textbf{5a} was isolated
in 99\% yield and 96\% ee without loss of activity. Notably, the chiral
ligand PYMCOX (\emph{R} \textsubscript{p})-\textbf{L2} could be
recovered with 97\% isolated yield by flash silica gel column
chromatography. These results showed the potential application of
{[}2.2{]}paracyclophane-derived oxazole-pyrimidine ligands.

Conclusions

In conclusion, we have successfully designed and synthesized a series of
{[}2,2{]}paracyclophane-derived oxazole-pyrimidine ligands from the
chiral {[}2,2{]}paracyclophane-derived aminophenol, and successfully
applied them in nickel-catalyzed asymmetric 1,2-reduction of
\selectlanguage{greek}α,β-\selectlanguage{english}unsaturated ketones, affording the chiral allylic alcohols with up
to 99\% yield and 99\% ee. Meanwhile, the chiral ligand could be
conveniently recovered at gram-scale with high yield through flash
column chromatography. Highlights of this work involve a series of
easily accessible chiral ligands, inhibition of asymmetric
1,4-reduction, wide substrate scope and mild reaction condition. Further
efforts to expand other fertile metal-catalyzed asymmetric reactions are
currently under investigation in our laboratories.

Experimental

\textbf{Procedures for synthesis of chiral PYMCOX
ligands(\emph{R}\textsubscript{p})-L1-10}

\textbf{Method A} : \textbf{typical procedure for synthesis of PYMCOX
(\emph{R}\textsubscript{p})-L1:} A stirred solution of sodium (18.4 mg,
0.8 mmol) in methanol (16.0 mL) was cooled to 0 \textsuperscript{o}C.
After sodium was fully consumed, 2-cyanopyrimidines \textbf{2} (8.0
mmol) were added. The resulting mixture was warmed to room temperature
and stirred for 24 hours. Then, the chiral
{[}2.2{]}paracyclophane-derived aminophenol (\emph{R}
\textsubscript{p})-\textbf{L1} (1.920 g, 8.0 mmol) was added. The
mixture was stirred at 50 \textsuperscript{o}C for 24 hours. Then, the
volatiles were evaporated under the reduced pressure. The crude residue
was dissolved in dichloromethane, and water (10 mL) was added. The
aqueous phase was extracted three times with dichloromethane. The
combined organic phases were dried over anhydrous sodium sulfate,
filtered and concentrated under the reduced pressure. The crude residue
was purified by flash column chromatography on silica gel using
hexanes/ethyl acetate as eluent (20/1 - 5/1) to give the desirable
chiral PYMCOX ligand (\emph{R} \textsubscript{p})-\textbf{L1} 1.460 g
with 56\% yield.

The same method was used for the synthesis of (\emph{R}
\textsubscript{p})-\textbf{L2} -\textbf{9} . These chiral PYMCOX ligands
are solid, and could be further purified by recrystallization with
acetone and hexanes.

\textbf{Method B: the synthesis of PYMCOX
(\emph{R}\textsubscript{p})-L10:} The
4-trifluoromethyl-pyrimidine-2-carbonitrile (0.350 g, 2.0 mmol) was
dissolved in a solution of hydrogen chloride in water (6 M, 10 mL) and
heated at reflux temperature overnight. The reaction mixture was cooled
to room temperature, and concentrated under the reduced pressure.
Toluene (10 mL) was then added and the mixture was concentrated under
the reduced pressure. This process was repeated with 1,4-dioxane and
ethyl ether. Then the solids were filtered off. The filtrate was
concentrated under the reduced pressure to afford 0.410 g of
4-trifluoromethyl-pyridine-2-carboxylic acid as white solid, which was
directly used in the next step without the further purification.

The chiral aminophenol (\emph{R} \textsubscript{p})-\textbf{1} (0.240 g,
1.0 mmol) and 4-trifluoromethyl-pyridine-2-carboxylic acid (0.288 g, 1.5
mmol) were dissolved in dichloromethane (5.0 mL). Then,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC\selectlanguage{ngerman}·HCl,
0.383 g, 2.0 mmol) and 1-hydroxybenzotriazole (HOBt, 0.304 g, 2.0 mmol)
were added at 0 \textsuperscript{o}C under nitrogen gas. The mixture was
stirred at room temperature for 18 hours. Water (10 mL) was added to
quench the reaction. The aqueous phase was extracted three times with
dichloromethane. The combined organic phases were washed with brine,
dried over anhydrous sodium sulfate, filtered and concentrated under the
reduced pressure to give amide intermediate.

A solution of the above amide intermediate (0.487 g, 1.0 mmol)
and\emph{p} -toluenesulfonic acid monohydrate (0.285 g, 1.5 mmol)
in\emph{p} -xylene (10 mL) was stirred at 120 \textsuperscript{o}C (oil
bath temperature) for 24 h. After cooled to room temperature, saturated
sodium carbonate solution (10 mL) was added. The aqueous phase was
extracted three times with ethyl acetate. The combined organic phases
were washed with brine, dried over anhydrous sodium sulfate, filtered
and concentrated under the reduced pressure. The crude residue was
purified by flash column chromatography on silica gel using
hexanes/dichloromethane/ethyl acetate (15/1/1) as eluent to give the
chiral PYMCOX ligand (\emph{R} \textsubscript{p})-\textbf{L10} .

\selectlanguage{greek}\textbf{General procedure fornickel-catalyzed 1,2-reduction of
α,β-unsaturated ketones:}\selectlanguage{english} In a nitrogen-filled glovebox,
Ni(COD)\textsubscript{2} (2.2 mg, 0.008 mmol, 2.0 mol\%), (\emph{R}
\textsubscript{p})-2-(4-methylpyrimidin-2-yl){[}2.2{]}
paracyclophano{[}4,5-\emph{d} {]}oxazole (PYMCOX \textbf{L2} ) (3.3 mg,
0.0096 mmol, 2.4 mol\%), and 1,4-diazobicyclo{[}2.2.2{]}octane (DABCO,
67.8 mg, 0.6 mmol) were added to a 10 mL Schlenk tube, equipped with a
magnetic stirring bar. Then, toluene (1.6 mL) was added and the mixture
was stirred for 10 min before addition of pinacolborane (HBpin) (70 \selectlanguage{greek}μ\selectlanguage{english}L,
0.48 mmol). The reaction tube was sealed with a Teflon screw cap,
removed from glovebox and stirred for 10 min in a cooling bath at
-25\textsuperscript{o}C before the \selectlanguage{greek}α,β-\selectlanguage{english}unsaturated ketones \textbf{4}
(0.4 mmol in 0.4 mL toluene) solution was added by syringe. Then the
reaction mixture was stirred at this temperature for 1-8 h. A saturated
solution of ammonium fluoride in methanol (1.0 mL) was added, and the
mixture was removed from the cooling bath, then stirred at room
temperature for 30 min and followed by addition of water (2.0 mL) and
ethyl acetate (3.0 mL). The aqueous phase was extracted three times with
ethyl acetate. The combined organic phases were dried over anhydrous
sodium sulfate, filtered and concentrated under the reduced pressure.
The residue was purified by chromatography on silica gel using
hexanes/ethyl acetate as eluent (20/1 - 5/1) to afford the desirable
chiral product allylic alcohols \textbf{5} .

The enantiomeric excesses were determined by HPLC analysis using the
chiral column. The racemates could be prepared by the Luche or sodium
borohydride reduction at 0 \textsuperscript{o}C.

Supporting Information

The supporting information for this article is available on the WWW
under https://doi.org/10.1002/cjoc.2023xxxxx.

Acknowledgement

Financial support from National Natural Science Foundation of China
(22171260) and K. C. Wong Education Foundation of CAS (GJTD-2020-08) is
acknowledged.

References

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\item
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\end{enumerate}\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
(The following will be filled in by the editorial staff)\tabularnewline
Manuscript received: XXXX, 2023 Manuscript revised: XXXX, 2023
Manuscript accepted: XXXX, 2023 Accepted manuscript online: XXXX, 2023
Version of record online: XXXX, 2023\tabularnewline
\bottomrule
\end{longtable}

\textbf{Entry for the Table of Contents}\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\selectlanguage{greek}\textbf{Synthesis of Planar-Chiral {[}2.2{]}Paracyclophane-based
Oxazole-Pyrimidine Ligands and Application in Nickel-Catalyzed
1,2-Reduction of α,β-Unsaturated Ketones}\selectlanguage{english} Juan Wang, Qing-Xian Xie,
Xiang Li, Chang-Bin Yu,* and Yong-Gui Zhou* \emph{Chin. J.
Chem.}\textbf{2023}, \emph{41}, XXX---XXX. \textbf{DOI:
10.1002/cjoc.202300XXX}\tabularnewline
The {[}2.2{]}paracyclophane-derived oxazole-pyrimidine ligands with
planar chirality (PYMCOX) were designed, synthesized and successfully
applied in nickel-catalyzed asymmetric 1,2-reduction of \selectlanguage{greek}α,β-\selectlanguage{english}unsaturated
ketones, affording the chiral allyilic alcohols with up to 99\% yield
and 99\% ee. Meanwhile, this reduction reaction could be conducted on
gram scale without loss of activity and enantioseletivity, and the
chiral ligand could be conveniently recovered with high
yield.\tabularnewline
\bottomrule
\end{longtable}

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