Chiral Ferrocenyl N,N Ligands with Intramolecular Hydrogen Bonds for Highly Enantioselective Allylic Alkylations

Article abstract of DOI:10.1002/cctc.201701461

Several new ferrocene-derived bidentate N ligands, which contain multiple chiral factors, have been designed and synthesized by a rational combination of oxazoline and pyridine. Their catalytic performances were investigated preliminarily in Pd-catalyzed

Full text of DOI:10.1002/cctc.201701461

Accepted Article
Title: Ferrocenyl chiral N, N-ligands with intramolecular hydrogen bond
for highly enantioselective allylic alkylations
Authors: Lin Yao, Huifang Nie, Dongxu Zhang, Libin Wang, Yuhao
Zhang, Weiping Chen, Zhenhua Li, Xueying Liu, and
Shengyong Zhang
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To be cited as: ChemCatChem 10.1002/cctc.201701461
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ChemCatChem
10.1002/cctc.201701461
FULL PAPER
Ferrocenyl chiral N, N-ligands with intramolecular hydrogen bond
for highly enantioselective allylic alkylations
[
a],‡
[a],‡
[a]
[a]
[a]
[a]
Lin Yao,
Huifang Nie,
Dongxu Zhang, Libin Wang, Yuhao Zhang, Weiping Chen, Zhenhua
[
b],
[a],
[a],
Li, * Xueying Liu * and Shengyong Zhang
*
Abstract: Several novel ferrocene-derived bidentate nitrogen
ligands, which were incorporated with multi-chiral factors, have been
designed and synthesized by rational combination of oxazoline and
pyridine. Their catalytic performances were preliminarily investigated
in palladium-catalyzed asymmetric allylic alkylation, and excellent
reactivities and enantioselectivities (up to 99% yield and 98% ee)
were realized using the ligand with matched chirality. DFT
calculations illustrated that an intramolecular hydrogen bond formed
between the hydroxyl group and the oxazoline fragment of the ligand
contributed to the optimal conformation of the ligand-Pd-allyl
complex.
However, in our review of the literature, we are surprised to find
that although the ferrocene-derived ligands are quite prosperous
in modern organic synthesis, ferrocene-based N, N-bidentate
[
10]
ligands are rather limited.
Our group has recently been
focused on the development of ferrocene-based chiral ligands
[
4d-f,8b,11]
and their application in asymmetric catalysis,
with
ferrocenyl diphosphanes ChenPhos and TriFer served as
[
4e-f]
representative examples.
As part of our continuing interest in
this regard, we herein report a novel type of ferrocenyl N, N-
ligands (Figure 1) with rational incorporation of oxazoline and
pyridine, which feature in: i) multi-chiral elements; ii) easily
tunable of steric and electronic factors; iii) a free hydroxyl group
incorporated as a possible secondary interaction group; iv)
concise and modular synthetic steps. To the best of our
knowledge, this constitutes the first example of ferrocene-based
N, N-bidentate ligands bearing both oxazoline and pyridine. The
catalytic performance of these ferrocenyl N, N-ligands was
preliminarily evaluated in palladium catalyzed asymmetric allylic
alkylation substitutions and obvious matched-mismatched
effects were observed. Excellent results (99% yield, 98% ee)
have been achieved with the chiral matched ligands.
Introduction
Development of readily available and highly efficient ligands has
[
1]
long been the focus for asymmetric catalysis. Aimed to meet
the desire of preparing more intricate molecules in modern fine
chemistry, ligand design has become more sophisticated. In
addition of basic consideration of electronic and steric
adjustment, the rational combination of two privileged chiral
backbones, smart incorporation of multi-chiral sources in one
molecule and the concept of cooperative catalysis are now the
ongoing research focus in new ligand design, and have
contributed to the emergence of various excellent ligands in the
[
2]
Fe
field.
Among the numerous ligands with various skeletons that have
been developed during the past decades, ferrocene-based
ligands, especially those with planar chirality, are among the
most versatile ligand architectures in modern asymmetric
R3
OR
2
O
O
∗
Fe
N
N
∗
N
N
∗
R1
Linker
[
3]
R1
transformations. The majority of the ligands developed in this
[
3b,4]
[3j]
family are diphosphanes
and P, N-bidentate ligands with
[
5]
[6]
phosphane oxazolines
and amino phosphanes
act as
[
3i,7]
Figure 1. Design of ferrocene-oxazoline-pyridine (FOP) ligand
excellent examples. Besides, some P, C-bidentate ligands
[
3h-i,8]
and P, S-bidentate ligands
have also been developed. On
Results and Discussion
the other hand, chiral bidentate nitrogen-donor ligands, such as
Bisoxazoline and Pybox, have been playing a vital role in
asymmetric catalytic reactions not only for their capacity to bind
a wide variety of transition metals, but also their concise and
Preparation of ferrocene-oxazoline-pyridine (FOP) ligand
New ferrocenyl N, N-ligands were easily accessible from the
readily available ferrocene-oxazolines 1 (Scheme 1). Thus,
using oxazoline as the chiral ortho-directing group that was
firstly described simultaneously by the groups of Richards,
[
9]
modular preparation from readily available starting materials.
[
[
a]
b]
L. Yao, H.-F. Nie, D.-X. Zhang, L.-B. Wang, Y.-H. Zhang, Dr. W.-P.
Chen. Dr. X.-Y. Liu, Prof. S.-Y. Zhang
12
Uemura, and Sammakia, TMS group was introduced with high
diastereoselectivities to afford intermediate 2. Then, 2-
pyridinecarboxaldehyde was added after the lithiation of 2 to
Department of Medicinal Chemistry
School of Pharmacy, Fourth Military Medical University
1
69 Changle West Road, Xi'an, 710032, PR China
afford
S,R,S
chromatography. The TMS group could be removed with KO Bu
a
mixture of two diastereoisomers (S,S,S
p
)-3 and
E-mail: syzhang@fmmu.edu.cn; xyliu0427@163.com
Z.-H. Li
(
p
)-4, which were easily separated by column
t
Department of Chemistry, Shanghai Key Laboratory of Molecular
Catalysis and Innovative Materials, Fudan University, 220 Handan
Road, Shanghai, 200433, PR China
[
13]
in DMSO. Using this method, we further synthesized ligands
-6 in high isolated yields. In all, we have synthesized four
5
E-mail: lizhenhua@fudan.edu.cn
series of ligands (3-6) via variation of the substitute on oxazoline
‡
L. Yao & H.-F. Nie contributed equally to this work
fragment.
Supporting information for this article is given via a link at the end of
the document.
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ChemCatChem
10.1002/cctc.201701461
FULL PAPER
1
TMS
O
OHC
(S,S,R
)-7 and (S,R,R
)-8, which can only be analyzed in
H
p
p
O
1
) nBuLi
1) nBuLi
2)
N
NMR spectra, but could not be detected clearly by TLC. Thus,
TBSCl was added to silylate the hydroxyl group, and the two
diastereoisomers with protection group were successfully
separated by column chromatography. The titled ligands
Fe
N
Fe
N
2) TMSCl
R
1
R
1
1
2
TMS
O
TMS
O
OH
N
OH
+
Fe
N
Fe
(S,S,R
p p
)-7 and (S,R,R )-8 were obtained by removing the
N
N
R
1
R
1
protecting group. The configuration of the ligands was fully
4
[15]
3
p
characterized with single-crystal X-ray structure of (S,R,R )-8.
5
0%~53% yield
41%~45% yield
i
t
i
t
(
S,S,Sp)-3a, R1=Pr (S,S,Sp)-3b, R1= Bu
S,S,Sp)-3c, R1=Ph (S,S,Sp)-3d, R1=Bn
(S,R,Sp)-4a, R1=Pr (S,R,Sp)-4b, R1= Bu
(S,R,Sp)-4c, R1=Ph (S,R,Sp)-4d, R1=Bn
(
DMSO/
KO Bu
DMSO/
KO Bu
t
t
OH
OH
O
O
Fe
N
N
Fe
N
N
R
1
R
1
5
6
30%~37% yield
43%~46% yield
i
t
(S,R,S )-6a, R =iPr (S,R,S )-6b, R =tBu
(
(
S,S,Sp)-5a, R1=Pr (S,S,Sp)-5b, R1= Bu
S,S,Sp)-5c, R1=Ph (S,S,Sp)-5d, R1=Bn
p
1
p
1
(S,R,Sp)-6c, R1=Ph (S,R,Sp)-6d, R1=Bn
Scheme 1. Synthetic route of (S)-planar FOP ligand.
Scheme 2. Synthesis of (R)-planar FOP ligand.
1
13
All the above ligands were characterized with H NMR, C NMR
and HRMS. Besides, we fortunately obtained the single-crystal
Catalytic asymmetric allylic alkylation
[
14]
p p
X-ray structure of (S,R,S )-4a and (S,R,S )-4c (Figure 2),
The asymmetric allylic alkylation has been well established and
which have contributed to the determination of the absolute
[
16]
i
the research of the reaction pathways is quite mature. Thus,
it’s a good template that could be used to evaluate and explore
the catalytic performance and stereochemistry of the newly
developed ligands. Taking 9a as the allylating reagent and 10a
as the nucleophile, we firstly tested various Pd sources with
configuration of Pr- and Ph-substituted ligands 3a-6a and 3c-6c.
1
By analysis of the H NMR spectra of the diastereomers
(
S,S,S
p
)-3a and (S,R,S
p
)-4a, (S,S,S
p p
)-3c and (S,R,S )-4c
respectively, we found that the δ
H
of the hydrogen in the benzyl
position of pyridine group is around 5.80 ppm of the (R)-
(
S,S,S
p
)-3a as catalyst in the model reaction. Encouragingly,
as the metal precursor, the reaction
configuration of hydroxyl-attached carbon, while in the
when using [Pd(allyl)Cl]
2
diastereomer of (S)-configuration, the corresponding
δ
H
is
around 5.95 ppm. The configuration of Bu- and Bn-substituted
ligands 3b-6b and 3d-6d was determined by comparing the δ in
t
went smoothly to afford the product with full conversion and up
to 96% ee in DCM (Table 1, entry 1). We then carried out
solvent screening for further optimization of the reaction
conditions. With aprotic solvents, such as THF and toluene, the
product could be obtained with high enantioselectivity, albeit with
moderate isolated yield (entry 6 and 7). Polar solvents, such as
H
1
H NMR spectra of the hydrogen in the benzyl position of
pyridine group.
CH
3
CN and MeOH could not even catalyze the reaction (entries
8
and 10), which might indicate the role of the hydroxyl on the
ligand in the catalytic reaction. The result of solvents screening
indicated DCM as the best choice, and was chosen in the
catalyst system.
Table 1. Screening of Pd sources and solvents in asymmetric allylic
[
a]
alkylation.
O
O
OAc
MeO
OMe
O
O
p
Pd/(S,S,S )-3a complex (5 mol%)
*
+
MeO
OMe
BSA/LiOAc, solvent
r.t., 10 h
9
a
10a
11aa
p p
Figure 2. X-ray single-crystal structure of (S,R,S )-4a and (S,R,S )-4c
[
b]
[c,d]
Entry
Pd source
[Pd(C )Cl]
Solvent
Yield [%]
Ee [%]
96 (S)
96 (S)
95 (S)
With the aid of the privileged ferrocene skeleton, we have also
prepared two kinds of (R)-planar FOP ligands to testify the role
of the planar chirality of this kind of ligands in their catalytic
performance. Following the procedure shown in scheme 2, 2-
pyridinecarboxaldehyde was directly introduced to ferrocene-
oxazolines 1a to afford a mixture of two diastereoisomers
1
2
3
3
H
5
2
DCM
DCM
DCM
99
82
66
Pd
Pd
2
2
(dba)
(dba)
3
3
.CHCl
3
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ChemCatChem
10.1002/cctc.201701461
FULL PAPER
4
5
6
7
8
9
1
Pd(OAc)
PdCl
2
DCM
Trace
NR
30
ND
5
(S,R,S
(S,S,S
p
)-4c
56
82
36
99
25
99
20
85
76
90
35
53
96 (S)
98 (S)
78 (S)
98 (S)
77 (S)
98 (S)
78 (S)
94 (S)
95 (S)
98 (S)
33 (S)
85 (R)
2
DCM
6
p
)-3d
[Pd(C
[Pd(C
[Pd(C
[Pd(C
[Pd(C
3
3
3
H
H
H
H
H
5
5
5
)Cl]
)Cl]
)Cl]
)Cl]
)Cl]
2
2
2
THF
91 (S)
94 (S)
7
(S,R,S )-4d
p
p
p
Toluene
46
8
(S,S,S )-5a
CH
3
CN
NR
87
9
(S,R,S )-6a
3
3
5
5
2
2
DCE
96 (S)
10
11
(S,S,S )-5b
p
0
MeOH
NR
(S,R,S )-6b
p
1
1
1
1
1
1
2
3
4
5
6
7
(S,S,S
p
)-5c
[
a] All the reactions were performed with 9a (0.8 mmol), 10a (2.40 mmol), Pd
source (5 mol%), (S,S,S )-3a (7.5 mol%), LiOAc (0.06 mmol) and BSA (2.4
mmol) in solvent at r.t. [b] Yield of isolated product. [c] Determined by chiral
HPLC analysis on a chiral stationary phase. [d] Absolute configuration of the
p
(S,R,S
p
)-6c
[
8b]
(S,S,S
(S,R,S
(S,S,R
p
)-5d
major product was determined by comparing with known data.
p
)-6d
)-7
Then, we systematically evaluated the performance of ligands 3-
p
8
in the reaction under optimized conditions. While adduct of
9% yield and 98% ee was obtained using (S,S,S )-3a as the
)-4a could
9
p
(S,R,R
p
)-8
Trace
ND
ligand(Table 1, entry 1), its diastereoisomer (S,R,S
p
only afford trace amount of the allylic alkylation product (Table 2,
entry 1). For the ligands with various substituents on oxazoline
fragment, an obvious match-mismatch effect was observed. In
all cases, ligands 3a-d and 5a-d with (S)-configuration of
hydroxyl-attached carbon performed better than their
corresponding diastereoisomers 4a-d and 6a-d (Table 2). When
[
a] Reactions were performed with 9a (0.8 mmol), 10a (2.40 mmol),
[Pd(C )Cl] (5 mol%), ligand (0.75 mol%), LiOAc (0.06 mmol) and BSA
2.4 mmol) in solvent at r.t. [b] Yield of isolated product. [c] Determined by
3
H
5
2
(
chiral HPLC analysis on a chiral stationary phase. [d] Absolute configuration
of the major product was determined by comparing with known data.
[8b]
(
S,S,R
the allylic alkylation adduct was obtained in 53% yield and 85%
ee as (R)-configuration, while its diastereoisomer (S,R,R )-8
could only afford trace amount of the product (Table 2, entries
6 and 17). These results indicated that both the planar chirality
p
)-7 was employed as ligand under optimized conditions,
Encouraged by the excellent results obtained above, we further
examined the scope of this catalytic system. As shown in Table
3, a wide range of nucleophiles could be successfully allylated in
high yields and excellent ee values. For allylating agents with
either electron withdrawing or electron donating groups, high
reactivities and enantioselectivities were both observed (Table 3,
entries 1-14). We have also tried using cyclohex-2-en-1-yl
acetate 9d and 1-phenylallyl acetate 9e as the allylating agents,
unfortunately, only trace amount of adduct was obtained with 9d,
while with 9e as the allylating agent, the starting material
disappeared to afford only linear adduct.
p
1
and the central chirality strongly influence the activities and
enantioselectivities.
Among ligands with chiral matched configuration, ligand
(
p
S,S,S )-5a stood out in terms of both activity and
enantioselectivity (Table 2, entry 8). In addition, the comparison
of the catalytic efficiency of ligands 3a-d and 5a-d showed that
the TMS group slightly decreased the enantioselectivities.
p
Table 3. Asymmetric allylic alkylation reaction catalyzed by Pd/(S,S,S )-5a
[
a]
complex.
Table 2. Catalytic efficiencies of the FOP ligands in asymmetric allylic
[
a]
alkylation.
O
O
O
O
R2
MeO
2
C
CO
2
Me
OAc
Ar
OAc
3 5 2 p
[Pd(C H )Cl] /(S,S,S )-5a (5 mol%)
R
1
R
1
∗
+
R1
R1
[
Pd(C3H5)Cl]2/L (5 mol%)
Ar
*
+
MeO
2
C
CO
2
Me
R2
10
BSA/LiOAc, DCM, r.t., 8 h
Ar
Ar
BSA, LiOAc
9
11
DCM, r.t., 8 h
9
a
10a
11aa
9
9
a: Ar=Ph
b: Ar=4-ClPh
c: Ar=4-OMePh
10a: CH
10b: CH
2
(CO
2
Me)
2
10d: CH
10e: CH
2
(CO
2
CH
2
C
6
H
5
)
2
2
(CO
2
Et)
2
3
CH(CO
2
Me)
2
[
b]
[c]
Entry
Ligand
Yield [%]
Trace
70
Ee [%]
ND
i
9
10c: CH
2
(CO
2
Pr)
2
10f: CH
3
2 2
CH(CO Et)
1
2
3
4
(S,R,S
p
)-4a
OAc
OAc
(S,S,S
(S,R,S
(S,S,S
p
)-3b
97 (S)
ND
9
e
9
d
p
)-4b
Trace
80
Allylating
agents
Yield [%]
[c]
Entry
NuH
Product
[b]
Ee [%]
p
)-3c
93 (S)
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FULL PAPER
single structure of the complex, we tried to analyze it by means
1
2
3
4
5
6
7
8
9
9a
9a
9a
9a
9a
9a
10a
10b
10c
10d
10e
10f
11aa
11ab
11ac
11ad
11ae
11af
99
99
85
80
99
99
99
99
99
99
99
98 (S)
98 (S)
98 (S)
98 (S)
96 (S)
98 (S)
98 (S)
98 (S)
98 (S)
98 (S)
97 (S)
of density functional theory (DFT) calculations with the ωB97-
[
17]
XD functional.
During our process to optimize the
conformation, we surprisingly found that an intramolecular
hydrogen bond between the hydroxyl group and the oxazoline
frangment of the ligand was formed in the optimized
conformation (Figure 3). This is rather interesting since in many
reported asymmetric allylic alkylation versions, the free hydroxyl
group of the ligand could either direct the attack of the
[
18]
[19]
nucleophile or coordinate with the central metal, such as Pd
to affect the reaction results. While in our case, the free hydroxyl
group forms an intramolecular hydrogen bond, which may cause
the change of the ligand’s conformation to reach the best
catalytic performance. This is much like some active
macromolecules, such as antibody or enzyme in the biological
activities. Along this line of thought, we tried to collect more
detailed evidence through analysis of the key parameters of the
Pd-C bond in the ligand-Pd-allyl complex based on the above-
optimized conformation. Since the (R)- and (S)-adducts is
produced by attack of the nucleophile with two different carbons
9b
9b
9b
9b
10a
10b
10c
10d
10a
11ba
11bb
11bc
11bd
11ca
1
0
1
1
9c
9c
9c
9c
9d
9e
1
1
1
1
1
2
3
4
5
6
10b
10c
10d
10a
10a
11cb
11cc
11cd
11da
11ea
99
83
97 (S)
95 (S)
98 (S)
ND
1 2
(C or C in Figure 3) of the ligand-Pd-allyl complex following
with the break of the corresponding Pd-C bond. Therefore, the
difficulty of the Pd-C bond breakage should be indicative of the
stereoselectivity of the product. We computed the bond order
and bond length of the Pd-C bond in several complexes; the
results were tabulated in Table 4. For some complexes, both the
endo and exo configurations exist simultaneously as they have
similar energy, their ratios at 298.15 K computed according to
their Gibbs free energy differences were listed. As showed in the
76
Trace
-
[
a] The reaction was performaed with 9 (0.8 mmol), NuH 10 (2.4 mmol),
Pd(C )Cl] (5 mol%), (S,S,S )-5a (7.5 mol%), LiOAc (0.06mmol) and BSA
2.4 mmol) in DCM at r.t. for 10 h. [b] Yield of isolated product. [c] Determined
by chiral HPLC analysis on a chiral stationary phase. [d] Absolute configuration
[
(
3
H
5
2
p
p
table, with Pd/(S,S,S )-5a complex as catalyst, the bond order of
the breaking Pd-C bond for producing the (S)-adduct is smaller
than that for producing the (R)-adduct, and the bond length of
the breaking Pd-C bond for producing the (S)-adduct is longer
than that for producing the (R)-adduct, thus affording the (S)-
[
8b]
of the major product was determined by comparing with known data.
Stereochemistry and mechanistic considerations
p
adduct. Pd/(S,R,S )-6a complex has two conformations, one
Starting from the original design of the ligand, we firstly explored
the role of the hydroxyl group of the ligands in their catalytic
leads to the (S)-adduct, while another leads to the (R)-adduct.
Also, the bond orders of the Pd-C bonds of both two
conformations for producing the (S)-adduct are greater than
performances. A control experiment employing ligand (S,S,S
p
)-
1
2, which is the alkylated derivative of (R,S,S )-5a, in
p
those of the Pd/(S,S,S
ligand is more enentioselective and reactive than (S,R,S
The catalytic efficiencies with ligands (S,S,R )-7, (S,R,R )-8 and
S,S,S )-12 can be explained similarly. Based on the above
p
)-5a complex. That’s why (S,S,S
p
)-5a as
benchmark reaction was carried out. As illustrated in Scheme 3,
when the OH group of the ligand was methylated, the catalytic
efficiency of the ligand has dramatically decreased. There’s no
doubt that the hydroxyl group plays a very important role in this
catalysis.
p
)-6a.
p
p
(
p
experiment results and DFT calculations, we reasoned that the
formation of the above-mentioned intramolecular hydrogen bond
makes the conformation change of the ligand-Pd-allyl complex
and contributes to the breakage of the Pd-C2 bond, thus
affording the (S)-adduct with highest enantioselectivity.
OR
O
Fe
N
N
(
(
S,S,S
S,S,S
p
)-5a, R=H, 99% yield, 98% ee
)-12, R=Me, 46% yield, 36% ee
Table 4. Some calculated key parameters of the Pd-C bond in some ligand-
[
a]
Pd-allyl complexes.
p
Complex
Ratio
Bond order
Bond length
(Å)
Figure 3. Control experiment result.
(
298K)
To get more insights into the source of the high
enantioselectivity, we set out to study the characteristics of the
ligand-Pd-allyl complex. While we failed to obtain the X-ray
R
S
R
S
(
S,S,S
p
)-5a_Pd_9a_allyl_exo
100%
0.515
0.402
2.121
2.278
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ChemCatChem
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FULL PAPER
(
S,S,S
p
)-5a (0.06 mmol) and [Pd(C
3
H
5
)Cl]
2
(0.04 mmol, 5 mol%) were
(
(
(
(
(
(
S,R,S
S,R,S
S,S,R
p
p
p
)-6a_Pd_9a_allyl_endo
)-6a_Pd_9a_allyl_exo
)-7_Pd_9a_allyl_exo
41%
59%
0.481
0.478
0.507
0.482
0.498
0.502
0.473
0.485
0.465
0.476
0.470
0.469
2.133
2.157
2.168
2.134
2.135
2.175
2.168
placed in a 10 mL Schlenk tube under a nitrogen atmosphere, and 2 mL
2.138 of dry CH
Cl was added. The reaction mixture was allowed to stir for 1 h
at room temperature to form the active catalyst. Then, allylic acetate 9
0.8 mmol) dissolved in 1 mL CH Cl was added, followed by malonate
0 (2.4 mmol), LiOAc (0.06mmol) and BSA (2.4 mmol). The resulting
mixture was stirred at room temperature for 10 h and then was diluted
2
2
100%
89%
2.168
2.160
(
2
2
1
S,R,R
S,R,R
p
)-8_Pd_9a_allyl_exo
)-8_Pd_9a_allyl_endo
11%
2.153 with Et O and washed with saturated NH Cl (aq). The organic layers
p
2
4
were dried over Na
2
SO
4
and filtered, and the solvents were evaporated.
S,S,S
p
)-12_Pd_9a_allyl_exo
100%
2.157
The residue was purified by flash column chromatrography to afford the
[
17] allylic alkylation adduct 11, the enantioselectivity of which was
[
a] All the DFT calculations were performed with the ωB97-XD functional
[20]
determined by chiral HPLC analysis on a chiral stationary phase.
implemented in the Gaussian 09 software package.
Computational details
[
17]
All the DFT calculations were performed with the ωB97-XD functional
[
20]
Pd
implemented in the Gaussian 09 software package.
The basis set
H
N
O
O
N
used was a combined basis set in which the SDD pseudo potential was
used for Fe and Pd, the 6-31+G(d,p) basis set was used for the C, H, O
and N atoms that directly coordinating with the Pd atom, and the 6-31G
basis set was used for the rest atoms. A pruned (99,590) integration grid
was used in all the DFT calculations. Harmonic vibrational frequency
computations were performed to provide zero-point energy (ZPE) and
thermodynamic corrections and to ensure no imaginary frequencies for a
minima.
Fe
!
(S,S,Sp)-5a_Pd_9a_allyl_exo
Nu
(R)-adduct
(S)-adduct
C
1
C
2
Pd
Acknowledgements
H
N
O
O
N
We thank the National Natural Science Foundation of China (No.
Fe
2
1172262, 21573044), Key Research and Development
Program of Shaanxi Province (2017KW-047) and 2015
Collaborative Innovation Program of Shaanxi Province (2015XT-
Nucleophic attack of the Pd-allyl complex
5
6) for financial support. We thank Dr. Zhenhua Li from Fudan
Figure 4. The calculated optimized conformation and the proposed transition
state
University for support of DFT calculations.
Keywords: asymmetric catalysis • ferrocene • bidentate
nitrogen-donor ligands • alkylation • intramolecular hydrogen
bond
Conclusions
In conclusion, a series of novel bidentate nitrogen ligands
derived from the previleged ferrocene skeleton have been
developed. These ligands feature in multi-chiral elements, easily
tunable of steric and electronic factors and concise synthetic
steps. Our pilot study of the developed ligands in Pd-catalyzed
asymmetric allylic alkylation substitutions revealed their potential
in asymmetric catalysis. The rigidity originating from the
ferrocene skeleton and the structural variability brought by the
oxazoline fragment cooperates to provide a relatively fixed chiral
cavity. Besides, the hydroxyl group of the ligands contributes to
the formation of the optimized conformation via the formation of
a kind of rare intramolecular hydrogen bond within the ligand,
which plays a key role in this catalysis. We are currently
focusing on the exploration of these ligands in other asymmetric
transformations.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
[
a],‡
[a],‡
Lin Yao,
Huifang Nie,
Dongxu
[
a]
[a]
[a]
Zhang, Libin Wang, Yuhao Zhang,
[
a]
[b],
Weiping Chen, Zhenhua Li, * Xueying
OH
O
[
a],
[a],
N
(
Fe
Liu * and Shengyong Zhang
*
Nu
N
p
S,S,S )-5a
O
O
Pd
N
O
O
R2
H
OAc
Ar
O
O
[
Pd(C
3
H
5
)Cl]
2
/(S,S,S )-5a (5 mol%)
p
R1
R1
N
+
R1
R1
*
Ar
Ferrocenyl chiral N, N-ligands with
intramolecular hydrogen bond for
highly enantioselective allylic
alkylations
R2
BSA/LiOAc, DCM, r.t., 10 h
Ar
Ar
Fe
up to 99% yield, 98% ee
Intramolecular hydrogen bond makes sense: A series of novel chiral ferrocenyl N,N-
ligands have been designed and synthesized. Their application in Pd-catalyzed
allylic alkylations showed a great potential of the developed ligands in asymmetric
catalysis (up to 99% yield, 98% ee), DFT calculations indicated the intramolecular
hydrogen bond formed within the ligand plays a vital role in this catalysis.
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