A New Phosphine-Amine-Oxazoline Ligand for Ru-Catalyzed Asymmetric Hydrogenation of N-Phosphinylimines

Article abstract of DOI:10.1002/cjoc.201800343

A series of chiral phosphine-amine-oxazoline (PAO) ligands with an NH moiety were synthesized and applied to the ruthenium-catalyzed asymmetric hydrogenation of N-phosphinylimines. The ligand bearing phenyl groups at the phosphorus moiety and isopropyl at the oxazoline moiety exhibits good activity and excellent enantioselectivity (up to 99% ee). This catalytic system provides an efficient and mild approach to access enantioriched amines.

Full text of DOI:10.1002/cjoc.201800343

A New Phosphine-Amine-Oxazoline Ligand for Ru-Catalyzed Asymmetric
†
Hydrogenation of N-Phosphinylimines
‡
‡
Xiaochen Ma, Lin Qiao, Guixia Liu,* Zheng Huang*
ABSTRACT A series of chiral phosphine-amine-oxazoline (PAO) ligands with an NH moiety were synthesized and applied to the ruthenium-catalyzed
asymmetric hydrogenation of N-phosphinylimines. The ligand bearing phenyl groups at the phosphorus moiety and isopropyl at the oxazoline moiety
exhibits good activity and excellent enantioselectivity (up to 99% ee). This catalytic system provides an efficient and mild approach to access
enantioriched amines.
KEYWORDS amines, chiral ligand, hydrogenation, imines, ruthenium
Introduction
The asymmetric synthesis of chiral amines is of great
significance in organic chemistry due to the prevalence of amine
enantioselectivity (<70% ee). Later, the scope and the
enantioselectivity were improved by using a combination of
palladium salt and (S)-SegPhos, as reported by the Zhou group.
Despite of these advances, it is still desired to develop mild,
general, and efficient catalytic systems for asymmetric
[5]
[
1]
units in bioactive molecules and chiral auxiliaries. Among
various approaches for the synthesis of chiral amines, the
asymmetric hydrogenation of imines using molecular hydrogen as
the reducing agent presents one of the most efficient and
atom-economical methods. However, important challenges
remain in this transformation: poor enantioselecitvity for imines
containing the mixture of E and Z isomers, the instability of some
imines prepared from ketones, and the inhibitory effect of the
amine products on the metal catalysts. To overcome these issues,
stable and readily available N-phosphinylimines have been used
as substrates in asymmetric hydrogenations. The phosphinyl
group can potentially serve as a second anchoring group, thus
enhancing the reactivity of the imines, and can be removed easily
hydrogenation of N-phosphinylimines, especially by using less
[6b]
expensive metals.
Given its rich chemistry in catalytic
[7]
hydrogenation reactions
platinum-group metals, it is surprising that, up to date,
ruthenium-catalyzed asymmetric hydrogenation of
N-phosphinylimines has not be reported yet.
and low-cost relative to other
[
2]
Ligand design has been continuously playing a central role in
developing more efficient catalytic systems for asymmetric
[8]
hydrogenations. Seminal work by Noyori and others revealed
the key cooperative effect of
transition-metal-catalyzed hydrogenation reactions.
a
NH moiety in the
[9,10]
On the
other hand, while a myriad of transition-metal catalytic systems
employ chiral bidentate ligands, several groups including our
[
3]
under acidic conditions.
[
11]
laboratory
showed that group 8 metal complexes of chiral
Scheme
1
Catalytic systems for asymmetric hydrogenation of
tridentate ligands hold promise in asymmetric organic
N-phosphinylimines
[12]
transformations.
On the basis of these precedents, we are
interested in developing NH-containing chiral tridentate ligands,
which may provide deep concave chiral environments and
potentially enhance the thermal stability of the resultant metal
complexes due to the chelating effects. Here we report the
synthesis of a novel class of chiral phosphine-amine-oxazoline
(
PAO) ligands and their applications to Ru-catalyzed asymmetric
hydrogenation of N-phosphinylimines (Scheme 1).
Results and Discussion
The
procedure
for
the
synthesis
of
chiral
phosphine-amine-oxazoline (PAO) ligands is depicted in Scheme 2.
The key building blocks, chiral amino oxazoline 1 with various
substituents in the oxazoline ring and a tBu substituent attached
to the chiral carbon center  to the amino group, were prepared
Extensive studies have been conducted on the hydrogenation
of N-aryl/N-alkyl imines and N-tosylimines, but examples of
asymmetric hydrogenation of N-phosphinylimines are relatively
[
13]
according to previously reported procedues. The condensation
of 1 with phosphinobenzaldehyde containing either a PPh or
2
[
4-6]
PtBu2 group yielded the corresponding imine, which was
submitted to further reduction without purification. Upon
treatment with NaBH4, the crude imine product was reduced to
the desired PAO ligand in useful yields. The chirality of the ligands,
originated from chiral -amino acids, could be fine-tuned. Given
the ease of preparation and modularity, a variety of PNN type of
tridentate chiral ligands with varying steric and electronic
rare (Scheme 1).
Pioneering work by Blaser and co-workers
employed the Rh complexes of the chiral ferrocenyldiphosphine
ligands for asymmetric hydrogenation of N-phosphinylimines with
[
4]
up to 99% ee. However, the reaction scope was not well
illustrated (five substrates were shown) and some
para-substituted aryl methyl N-phosphinylimines gave moderate
a
State Key laboratory of Organometallic Chemistry, Center for Excellence in
*E-mail: guixia@sioc.ac.cn; huangzh@sioc.ac.cn
†
Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Rd,
Shanghai 200032, China
Dedicated to Professor Xiyan Lu on the occasion of his 90th birthday
‡
These two authors contributed equally
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been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
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properties can be readily obtained.
and 15 mol% of ligand 3a, in combination with 10 mol% of base
gave the best results (88% yield, 98% ee, entry 12). Decreasing the
amount of ligand or the base led to diminished yields (entries 11
Scheme 2 Synthesis of chiral phosphine-amine-oxazoline (PAO) ligands
a
Table 1 Optimization of Reaction Conditions
Using the complex generated in situ from transition metals
and chiral ligands as the precatalyst in asymmetric catalysis is a
convenient approach for catalyst screening, which obviates the
need for the synthesis of chiral metal complexes. Thus, the
application of chiral PAO ligands was tested in the hydrogenation
of N-diphenylphosphinylimine 4a with the catalyst derived from
RuCl
KOtBu as the activator.
room temperature under 50 atm of H
2 3 3
(PPh ) and ligands in the presence of catalytic amount of
[14]
All the reactions were conducted at
and the results are
a
Reaction conditions: 4a (0.3 mmol), metal precursor, ligand, KOtBu, under
2
o
b
1
2
H , toluene (1.5 mL) at 25 C. Yields are determined by H-NMR spectra
c
summarized in Table 1. The reaction using ligand 3a bearing a iPr
group in the oxazoline ring and Ph subsituents at the the P-atom
occurred smoothly to furnish the amine product 5a in good yield
with excellent enantioselectivity (78% yield, 99% ee, entry 1). The
run with ligand 3b, a diasteroisomer of 3a with a reversed chiral
center at the oxazoline part, led to the product with a reversed
configuration, but the yield and the ee value were significantly
lower than that obtained with 3a (68% yield, 62% ee, entry 2). The
results indicate the enantioselectivity is predominantly controlled
by the chirality of the oxazoline ligand, and the two chiral centers
of ligand (3R,6S)-3a are more matched than that of the
using mesitylene as an internal standard. The ee values were determined
by HPLC analysis. The absolute configurations were assigned by
d
comparison with the reported optical rotations. 10-15 mol% of ligand
3
e-3i was used, see the detailed information in Supporting Information
(table S1).
and 13).
Next, we evaluated the scope of this ruthenium-catalyzed
asymmetric hydrogenation with PAO ligand 3a. A variety of aryl
methyl N-phosphinylimines were hydrogenated smoothly at room
temperature to form the corresponding amines, which could be
readily converted to free chiral amine salts under mild acidic
conditions. The method was effective for substrates bearing
electron-donating (5f, 5h) and -withdrawing groups (5b-5e),
(
3S,6S)-isomer 3b. Ligands 3c and 3d with tBu substituents at the
P-atom were less effective than 3a and 3b with Ph substituents.
While ligand 3c gave (S)-5a in low yield with high ee (entry 3), its
diasteroisomer 3d gave (R)-5a with moderate yield and ee (entry
affording
high
enantioselectivity
in
most
cases.
4
), which further confirms that the configuration of product stems
Halogen-functionalities (5b-5e) that enable versatile further
transformations were tolerated in the system to give the products
in good yields with 94-97% ee. The position of substituents on the
phenyl group of the substrates appears to have a profound impact
on the activity and enantioselectivity. While the reaction of
para-OMe and para-iBu substituted substrates (5f, 5g) led to
moderate yields and enantioselectivity, excellent asymmetric
inductions were achieved for substrates with meta-OMe and
meta-Me group (5h, 5i). The method was also applicable to
asymmetric hydrogenation of 2-naphthalene substituted imine 5j,
delivering the product in 70% yield and 90% ee. Unfortunately,
imines derived from ortho substituted phenyl ketones could not
be reduced in this system.
Aryl alkyl ketimines bearing an alkyl group larger than methyl
group were also surveyed in the asymmetric hydrogenation. The
reduction of phenyl propyl ketimine gave the desired product 5k
in 68% yield and 99% ee. Similarly, good yield and
enantioselectivity was achieved for phenyl butyl ketimine (5l),
while the substrate with a cyclopropyl group showed low
from the chirality of the oxazoline component. Next, ligands 3e-3i,
containing different substituents (iBu, Bn, Ph) on the oxazoline
ring, were surveyed for the hydrogenation reaction. Unfortunately,
these ligands resulted in rather sluggish reactions, giving the
product in less than 10% yields (entry 5). Some other metal
precursors were also tested with 3a as the ligand (entries 6-8).
Whereas
RuCl (p-cymene)]
enantioselectivity.
RuH
2
(CO)(PPh
and
3
)
3
exhibited
[IrCl(cod)]
no
gave
activity,
moderate
[
2
2
2
After identifying the optimal ligand, the effects of the reaction
conditions on the reactivity and enantioselectivity were
investigated. With a reduced H pressure (20 atm), the product
2
was obtained with excellent enantioselectivity, albeit with a
slightly reduced yield (entry 9). Reducing the catalyst loading to 4
mol% resulted in 55% yield and 92% ee (entry 10). The yield was
also affected by the molar ratio of ligand/metal and base/metal,
although these factors did not influence the enantioselectivity
significantly (entries 11-13). The run with 5 mol% of Ru precursor
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reactivity (5m). It was worth noting that the reduction of cyclic
phenyl imine occurred effectively, as demonstrated by the
isolation of the cyclic amine product 5n in good yield with high ee
value. Low enantioselectivity and activity was obtained when the
challenging diaryl ketimine 4o was used as the substrate.
chloride ligands. Notably, the submission of the isolated complex
6a, in place of the ruthenium catalyst generated in situ from
RuCl (PPh ) and 3a, to the otherwise identical catalytic conditions
2 3 3
results in no observable activity for the hydrogenation of 4a. We
tentatively attribute the deactivation of 6a to the facile
dimerization. The use of more than one equivalent of ligand
3
relative to metal and the presence of PPh in the catalytic system
Table 2 Ru-Catalyzed Asymmetric Hydrogenation of Various N-diphenyl-
phosphinylimines
generated in situ may inhibit the dimerization process, thus
leading to reasonable catalytic activity. The understanding of the
catalyst decomposition pathway may help devise more efficient
Figure 1 Synthesis of Ru complexes of PAO ligand.
a
Selected bond distances (Å) and angles (deg): Ru1-N1, 2.056 (4); Ru1-N2,
2.130(5); Ru1-P1, 2.2201(15); Ru1-Cl1, 2.4222(14); Ru1-Cl2, 2.4908(15);
N1-Ru1-N2, 80.27(18); N2-Ru1-P1, 91.38 (13); N1-Ru1-P1, 92.29(11);
Cl1-Ru1-Cl2, 85.07(5); N1-Ru1-Cl1, 169.28(12); P1-Ru1-Cl2, 176.02(6).
catalyst for asymmetric hydrogenation.
a
2 3 3
Reaction conditions: 4 (0.3 mmol), RuCl (PPh ) (5 mol%), 3a (15 mol%),
o
Conclusions
2
KOtBu (10 mol%), toluene (1.5 mL) under 50 atm of H , at 25 C for 24 h.
Isolated yields. The ee values were determined by HPLC analysis. The
In summary, we have synthesized a new class of tridentate
phosphine-amine-oxazoline (PAO) ligands which are easily
synthesized (two steps from readily accessible amino oxazoline
absolute configurations were assigned by comparison with the reported
b
optical rotations. A large-scale synthesis of 5a was conducted using 4 (3
mmol), RuCl
mL) under 50 atm of H
2
(PPh
3
)
3
(5 mol%), 3a (15 mol%), KOtBu (10 mol%), toluene (15
and phosphinobenzaldehyde) in a modular manner. Their
o
2
at 25 C for 48 h.
application has been demonstrated in a highly enantioselective
ruthenium-catalyzed hydrogenation of N-phosphinylimines, which
provides an efficient and mild method for the synthesis of
optically active secondary amines. Further studies on the
exploration of new asymmetric transformations using the
tridentate PAO ligands are currently underway in our laboratory.
To gain
hydrogenation catalyst, the complex of chiral ligand 3a was
synthesized. Treatment of RuCl (PPh with 3a (1.1 equiv) in THF
formed a Ru(II) dichloride complex 6a, which contains one PAO,
one PPh , and two Cl ligands per Ru metal according to NMR and
a
structural information of the ruthenium
2
3 3
)
3
elemental analysis. Thus, the structure of 6a is best described as a
six-coordinate mononuclear complex as depicted in Figure 1.
Experimental
However,
attempts to recrystallize 6a for X-Ray diffraction
General Description. Unless otherwise noted, all reagents were
purchased from commercial suppliersand used without further
purification. All manipulations were carried out using standard
Schlenk, high-vacuum and glovebox techniques. Tetrahydrofuran
analysis led to the formation of a dinuclear species 7a (see Figure
[
15]
1
for the solid-state structure),
which is formed upon the
dissociation of PPh
3
and the bridge of two Ru center through two
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(
THF) and toluene were distilled from sodium benzophenone ketyl
2016YFA0202900), National Natural Science Foundation of China
(21422209, 21432011, 21421091, 21572255), and Chinese
Academy of Sciences (XDB20000000) support this work.
prior to use.
Synthesis of ligand 3a. To a solution of chiral amino oxazoline 1a
(
3.1 g, 14.9 mmol) and (2-formylphenyl)-diphenylphosphine 2a
(4.4 g, 14.9 mmol) in dichloromethane (40 mL) was added
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without purification. The crude imine (14.9 mmol) was dissolved
o
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with EtOAc/petroleum ether 1:8 (v/v) to afford the title
1
compound as colorless oil (4.8 g, 70%). H NMR (400 MHz, CDCl
3
)
δ 7.61-7.59 (m, 1H), 7.34-7.30 (m, J = m, 7H), 7.28-7.20 (m, 4H),
7
=
1
.16-7.12 (m, 1H), 6.87-6.84 (m, 1H), 4.24-4.11 (m, 1H), 4.04 (dd, J
13.7, 2.3 Hz, 1H), 3.90 (d, J = 4.3 Hz, 1H), 3.09 (s, 1H), 1.96 (br s,
H), 1.86-1.69 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.94 (s, 9H), 0.91 (d,
1
3
J = 6.7 Hz, 3H); C NMR (101 MHz, CDCl
3
) δ 167.6, 144.6 (d, J =
2
1
1
3
3.9 Hz), 137.0 (d, J = 11.3 Hz), 135.6 (d, J = 14.4 Hz), 133.9 (d, J =
3.1 Hz), 133.7 (d, J = 13.1 Hz), 133.4, 128.8, 128.5 (d, J = 8.1 Hz),
28.4 (d, J = 6.1 Hz), 127.0, 71.9, 69.5, 65.2, 50.6 (d, J = 22.7 Hz),
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1
3.9, 32.5, 26.8, 19.2, 18.5; P NMR (162 MHz, CDCl
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) δ -15.50;
OP: 473.2720, found:
73.2716; IR (thin film): 3053.99, 1657.80, 1586.21, 1467.54,
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HRMS (ESI) m/z (M+H) calcd for C30H N
4
1
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-
1
433.97, 981.90, 908.69, 803.59, 742.39, 695.73, 617.84 cm .
2
8
Rotation: *α+D = 17.63 (c = 0.48, CH
General procedure for asymmetric hydrogenation of
N-diphenyl-phosphinylimines. In filled glovebox,
RuCl (PPh (0.14 g, 0.015 mmol) and KOtBu (3.40 mg, 0.015
2 2
Cl ).
a
N
2
2
3 3
)
mmol) were added to a solution of 3a (0.21 g, 0.045 mmol) in
toluene (1.5 mL) at 25 C in a 10 mL tube. After the mixture was
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o
stirred for minutes, the color was changed from brown to dark
green and substrate 4 (0.3 mmol) was added. The reaction tube
was then placed in an autoclave. The autoclave was closed,
purged three times with hydrogen (less than the pressure needed),
and finally pressurized to 50 atm. The reaction mixture was stirred
o
at 25 C for 24h. After release of the hydrogen, the reaction was
quenched by exposing the mixture to air. The reaction mixture
was evaporated and the residue was purified by flash column
chromatography with EtOAc/petroleum ether (1:2) to give the
title compound 5 as white solid. The ee value was determined by
chiral HPLC.
5
a: white solid (85 mg, 88% yield). 98% ee [Daicel Chiralpak OD-H
-1
(
0.46x25 cm), n-hexane/i-propanol = 90/10, v = 0.7 mL⋅min , λ =
1
2
14 nm, t (minor) = 10.70 min, t (major) = 13.96 min]; H NMR
400 MHz, CDCl ) δ 7.98-7.85 (m, 2H), 7.87-7.76 (m, 2H), 7.50-7.40
m, 4H), 7.39-7.30 (m, 2H), 7.29-7.19 (m, 2H), 6.98-6.94 (m, 2H),
(
(
3
1
3
.41-4.35 (m, 1H), 3.32 (s, 1H), 1.56 (d, J = 6.7 Hz, 3H); C NMR
) δ 145.0 (d, J = 6.6 Hz), 132.4 (d, J = 9.6 Hz),
3
1
3
32.0-131.7 (m), 128.6-128.3 (m), 127.0, 125.9, 51.0, 25.9 (d, J =
3
1
28
.3 Hz); P NMR (126 MHz, CDCl
Cl
3
) δ 23.2. Rotation: *α+D = -28.8
(c = 0.32, CH
2
2
). These spectroscopic data correspond to the
[
16]
reported data.
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Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
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Acknowledgement (optional)
The National Key R&D Program of China (2015CB856600,
This article is protected by copyright. All rights reserved.

50, 7329. (f) Wu, W.; Liu, S.; Duan, M.; Tan, X.; Chen, C.; Xie, Y.; Lan, Y.;
The Cambridge Crystallographic Data Centre.
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(The following will be filled in by the editorial staff)
[
[
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14] The addition of base is critical to this Ru catalyzed hydrogenation and
no reaction happened without the base additive. Based on the
precedent literature (see ref 9 and 10), we proposed that base can
activate PAO-[Ru]-Cl species by elimination of HCl, forming the active
Manuscript received: XXXX, 2017
Revised manuscript received: XXXX, 2017
Accepted manuscript online: XXXX, 2017
Version of record online: XXXX, 2017
16e Ru-complex.
[
15] CCDC 1856505 (7a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
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Entry for the Table of Contents
Page No.
A New Phosphine-Amine-Oxazoline Ligand
for
Ru-Catalyzed
Asymmetric
Hydrogenation of N-Phosphinylimines
‡
‡
Xiaochen Ma, Lin Qiao, Guixia Liu,*
Zheng Huang*
This article is protected by copyright. All rights reserved.