Readily Accessible and Highly Efficient Ferrocene-Based Amino-Phosphine-Alcohol (f-Amphol) Ligands for Iridium-Catalyzed Asymmetric Hydrogenation of Simple Ketones

Article abstract of DOI:10.1002/chem.201604855

We have successfully developed a series of novel and modular ferrorence-based amino-phosphine-alcohol (f-Amphol) ligands, and applied them to iridium-catalyzed asymmetric hydrogenation of various simple ketones to afford the corresponding chiral alcohols with excellent enantioselectivities and conversions (98–99.9 % ee, >99 % conversion, turnover number up to 200 000). Control experiments and density functional theory (DFT) calculations have shown that the hydroxyl group of our f-Amphol ligands played a key role in this asymmetric hydrogenation.

Full text of DOI:10.1002/chem.201604855

A Journal of
Accepted Article
Title: Readily Accessible and Highly Efficient Ferrocene-based Amino-
phosphine-alcohol (f-Amphol) Ligands for Iridium-Catalyzed
Asymmetric Hydrogenation of Simple Ketones
Authors: Xumu Zhang, Jianfei Yu, Meng Duan, Weilong Wu, Xiaotian
Qi, Peng Xue, Yu Lan, and Xiu-Qin Dong
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To be cited as: Chem. Eur. J. 10.1002/chem.201604855
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Readily Accessible and Highly Efficient Ferrocene-based Amino-
phosphine-alcohol (f-Amphol) Ligands for Iridium-Catalyzed
Asymmetric Hydrogenation of Simple Ketones
Jianfei Yu,† Meng Duan,‡ Weilong Wu,† Xiaotian Qi,‡ Peng Xue,† Yu Lan,*‡ Xiu-Qin Dong,*† and Xumu
Zhang*§†
Abstract: We successfully developed a series of novel and modular
ferrorence-based amino-phosphine-alcohol (f-Amphol) ligands, and
applied them into iridium-catalyzed asymmetric hydrogenation of
various simple ketones to afford corresponding chiral alcohols with
excellent enantioselectivities and conversions (98%-99.9% ee, >99%
conversion, TON up to 200 000). Control experiments and density
functional theory (DFT) calculations have shown that the hydroxyl
group of our f-Amphol ligands played a key role in this asymmetric
hydrogenation.
asymmetric
hydrogenation
of
ketones
with
poor
enantioselectivities.[9] Herein, we introduced chiral amino alcohol
into chiral ferrocenylphosphine motif forming novel ferrorence-
based amino-phosphine-alcohol ligands (called as f-Amphol
ligand, Scheme 1). The readily available modular ferrorence-
based amino-phosphine-alcohol f-Amphol ligands are attractive
ligands for iridium-catalyzed asymmetric hydrogenation of various
simple ketones with excellent enantioselectivities (up to 99.9%
ee) and high activities (TON up to 200 000). In addition, control
experiments and density functional theory (DFT) calculations
have shown that the hydroxyl group of our f-Amphol ligands
played a key role to obtain high reactivities and excellent
enantioselectivities.
Introduction
Catalytic asymmetric hydrogenation of C=O and C=N bonds
is regarded as an important method to access chiral molecules.[1]
Homogeneous hydrogenation of prochiral ketones is one of the
most powerful methodologies to approach enantiopure secondary
alcohols, which are versatile building blocks in many
pharmaceuticals and natural products.[2] This landmark progress
of reduction of simple ketones was reported by Noyori’s group in
the 1990s through the effective catalytic system BINAP-
ruthenium-diamine complexes (Scheme 1).[3] The excellent
reactivities and enantioselectivities are mainly owing to the
cooperative action of the Ru-H and NH2 group through metal-
ligand bifunctional mechanism involving “NH effect”. Encouraged
by these results, a lot of bidentate and tridentate ligands have
been developed for asymmetric hydrogenation of ketones in last
decades, such as PP,[4] NN,[5] NNN,[6] PNN,[7] PNS-type[8] ligands.
For example, Zhou and co-workers had developed a tridentate
spiro pyridine-aminophosphine ligands SpiroPAP by introducing
an additional coordinating pyridyl group into SpiroAP ligand
(Scheme 1), and chiral alcohols were formed with excellent
results in the iridium-SpiroPAP catalytic system.[7b] However,
phosphine-amino-alcohol PNO ligands were rarely explored for
asymmetric hydrogenation of ketones. To the best of our
knowledge, only Clarke’s group developed chiral tridentate
phosphine-amino-alcohol PNO ligands (Scheme 1) deriving from
chiral amino alcohols and applied them into ruthenium-catalyzed
Scheme 1. Examples of typical catalysts or ligands in asymmetric
hydrogenation of ketones.
Results and Discussion
Preparation of the chiral f-Ampha ligands
The novel and modular ferrorence-based amino-phosphine-
alcohol f-Amphol ligands L1-L6 were efficiently accessible via a
simple three-step reaction synthetic route starting from easily
commercially available (S)-Ugi’s amine (S)-1 (Scheme 2). The
(S)-1-[(R)-2-(diphosphanyl)ferrocenyl]ethylamines (SC, RP)-2
were easily prepared from the amine (S)-1 through a one-pot
process.[10] Then the aminophosphines (SC, RP)-2 were converted
into the acetates (SC, RP)-3 with high yield by heating the solution
of aminophosphines (SC, RP)-2 in acetic anhydride.[11] The
desired phosphine-amino-alcohol (f-Amphol) ligands L1-L6 were
obtained through the condensation of the acetates (SC, RP)-3 with
cheap and easily available chiral amino alcohols.[12] We also
synthesized the ligand L4 to investigate the relationship between
[*] J. Yu, W. Wu, P. Xue, X.-Q. Dong, X. Zhang
College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan, Hubei, 430072, P. R. China.
E-mail: xumu@whu.edu.cn, xiuqindong@whu.edu.cn
M. Duan, X. Qi, Y. Lan
School of Chemistry and Chemical Engineering, Chongqing University,
Chongqing, 400030, P. R. China.
E-mail: lanyu@cqu.edu.cn.
X. Zhang
Department of Chemistry, South University of Science and Technology
of China, Shenzhen, Guangdong, 518055, P. R. China.
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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[a] Reaction conditions 0.2 mmol scale, S/C = 1 000, 0.05 mmol% [Ir(COD)Cl]2,
0.105 mmol% ligand, 10 mol% tBuOK, 1.0 mL solvent, room temperature (25–
30 oC). [b] Determined by 1H NMR. [c] Determined by HPLC analysis. NR is no
reaction, NA is not available.
enantioselectivity and configuration of the ligand, which is the
diasteroisomer of ligand L1.
Screening bases for the asymmetric hydrogenation of
acetophenone 4a
Subsequently, we screened different bases for this
asymmetric hydrogenation reaction of acetophenone 4a
catalyzed by Ir-L1 (S/C = 10 000) in iPrOH. These transformations
t
t
proceeded smoothly in the presence of BuOK, MeOK, BuOLi,
NaOH, KOH, Cs2CO3 with excellent resluts (91%-95% ee, >99%
conversion, Table 2, entries 1-5, 7). And we found that tBuOK and
NaOH can afford 95% ee and >99% conversion (Table 2, entries
1, 4). NaOH was selected as the best choice, which is more easily
t
available and cheaper than BuOK (Table 1, entry 4). When the
amount of NaOH was reduced to 1.0 mol%, we obtained the
similar result (Table 2, entry 8 vs entry 4). The control reaction
without NaOH didn’t occur and revealed the important role of the
base (Table 1, entry 9).
Scheme 2. The synthetic route of novel f-Amphol ligands L1-L6.
Table 2. Screening bases for the asymmetric hydrogenation of acetophenone
4a.[a]
Investigation of the solvent effects for the asymmetric
hydrogenation of acetophenone 4a
With the readily accessible f-Amphol ligand L1 in hand, we
initially began our studies by evaluating it in the asymmetric
hydrogenation of acetophenone 4a serving as the model
substrate with the catalyst generated in situ by mixing
[Ir(COD)Cl]2 with ligand L1 (S/C = 1 000) in different solvents. As
shown in Table 1, the solvents had a significant effect in this
catalytic reaction. To our delight, the transformation proceeded
Entry
Base
tBuOK
MeOK
tBuOLi
NaOH
KOH
Conv.% [b]
>99
Ee% [c]
95
1
2
i
>99
94
well in CH2Cl2, THF and PrOH with excellent conversions and
enantioselectivities (>99% conversions, 83%-95% ee, Table 1,
entries 1, 2, 6). Poor conversions were observed in toluene and
1,4-dioxane, albeit with excellent enantioselectivities (90% ee,
Table 1, entries 3, 7). iPrOH was identified as the best solvent with
>99% conversion and 95% ee (Table 1, entry 6).
3
>99
92
4
>99
95
5
>99
94
6
K2CO3
Cs2CO3
NaOH
-
>99
85
Table 1. Screening solvents for the asymmetric hydrogenation of acetophenone
4a.[a]
7
>99
91
8[d]
9
>99
95
NR
NA
[a] Reaction conditions: 2.0 mmol scale, S/C = 10 000, 0.005 mmol% [Ir(COD)Cl]2,
Entry
Solvent
DCM
Conv.% [b]
>99
Ee% [c]
83
0.0105 mmol% ligand, 10 mol% base, 3.0 mL solvent, room temperature (25–
[b]
[d]
30 oC).
Determined by 1H NMR. [c] Determined by HPLC analysis.
The
1
2
3
4
5
6
7
amount of NaOH was 1.0 mol%. NR is no reaction, NA is not available.
THF
>99
90
toluene
MeOH
EtOH
trace
NR
90
Screening ligands for the asymmetric hydrogenation of
acetophenone 4a
NA
NA
95
Encouraged by these excellent results, we investigated the
efficiency of novel chiral f-Amphol ligands L1-L6. We found that
ligands L1-L2 and L5-L6 displayed high reactivities and excellent
enantioselectivities (>99% conversion, 95%-99% ee, Table 3,
entries1-2 and 5-6). Ligands screening results demonstrated that
the substituents on P atom have a significant effect on the
NR
iPrOH
>99
1,4-dioxane
trace
90
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enantioselectivity. The ligand L2 with bulkily steric hindered 3,5-
di-tert-phenyl group provided 99% ee and >99% conversion
(Table 3, entry 2). Low enantioselectivity was obtained when the
ligand L3 bearing cyclohexyl ring was applied into this
transformation (59% ee, Table 3, entry 3). The ligand L4 which is
the diasteroisomer of ligand L1 displayed low activity and
moderate enantioselectivity with opposite configuration of the
product (Table 3, entry 4, 20% conversion, -81% ee). It shows that
the configuration of the ligand is very critical for enantioselectivity
and reactivity.
Table 4. Asymmetric hydrogenation of various ketones with Ir-L2. [a]
Table 3. Screening ligands for the asymmetric hydrogenation of acetophenone
4a.[a]
Entry
Ligand
L1
Conv.% [b]
>99
Ee% [c]
95
1
2
3
4
5
6
L2
>99
99
L3
>99
59
L4
20
-81
98
L5
>99
L6
>99
98
[a] Reaction conditions: 2.0 mmol scale, S/C = 10 000, 0.005 mmol% [Ir(COD)Cl]2,
0.0105 mmol% ligand, 1.0 mol% NaOH, 3.0 mL solvent, room temperature (25–
30 oC). [b] Determined by 1HNMR. [c] Determined by HPLC on a Chiralcel chiral
OD-H solid phase.
Substrate scope study for the asymmetric hydrogenation of
various simple ketones
Gram-scale of asymmetric hydrogenation of acetophenone
4a with high S/C.
After we optimized the reaction conditions (Ir-L2/20 atm
H2/1.0 mol% NaOH/room temperature, S/C = 10 000), we turned
our attention to investigate the substrate scope of the asymmetric
hydrogenation of simple ketones. As shown in Table 4, a wide
range of various alkyl aryl ketones were hydrogenated smoothly
to obtain the corresponding chiral alcohols in full conversions and
quantitative yields with 98-99.9% ee. The alkyl group of alkyl aryl
ketones from methyl to isopropyl group performed well in this
transformation (4a~4c) with 99->99% ee. The substrates bearing
electron-donating groups (4d~4i) and electron-withdrawing
groups (4j~4q) on the phenyl ring performed well with excellent
results (98-99.9% ee). The position of the substituent groups on
the phenyl group of the substrates had little influence on both the
reactivity and enantioselectivity. In addition, the 1-(naphthalen-1-
yl)ethan-1-one (4r) and 1-(naphthalen-2-yl)ethan-1-one (4s) were
proceeded well with 99%->99% ee and >99% conversion.
As shown in Scheme 3, we conducted gram-scale reaction
with much lower catalyst loading in order to demonstrate the
practical use of our catalytic system. To our delight, Ir-L2 complex
is very stable and highly active. When the catalyst loading was
decreased to 0.0005 mol % (S/C = 200 000), this asymmetric
hydrogenation was conducted with 2.4
g
of substrate
acetophenone 4a and the product (R)-5a can be obtained in 99%
ee and >99 % conversion within only 24 h at room temperature
under the hydrogen pressure of 40 atm.
Scheme 3. Asymmetric hydrogenation of acetophenone 4a with high S/C
Control experiments for evaluating the role of hydroxyl group
of the chiral f-Amphol ligand
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In order to evaluate the role of hydroxyl group of the chiral f-
Amphol ligands, we synthesized the ligand L7 with the hydroxyl
group protected by methyl group and ligand L8 without the
hydroxyl group. And then we applied ligands L7-L8 into the
asymmetric hydrogenation of acetophenone 4a, very poor
reactivities (5%-7% conversions) and enantioselectivities (5%-
15% ee) were obtained (Scheme 4). These results show that the
hydroxyl group of the ligand plays a key role in this transformation.
complex CP1 contains both the hydroxyl hydrogen and the amino
hydrogen, the hydrogenation of acetophenone 4a might occur at
the hydroxyl site or the amino site. Through the concerted
transition state TS1, the hydroxyl-promoted hydrogenation would
take place on Re-face of 4a, generating an iridium(III) complex
CP2 and the product (R)-5a. Activation free energy for this step is
found to be 18.1 kcal/mol. Alternatively, the hydrogenation on Si-
face of 4a might also occur through transition state TS2, which
leads to the formation of enantiomer (S)-5a and complex CP2 with
an activation free energy of 21.4 kcal/mol. As the relative free
energy of TS2 is 3.3 kcal/mol higher than that of TS1, the
generation of enantiomer (S)-5a is demonstrated to be kinetically
unfavorable. Moreover, the calculated ee value is determined to
be 99%, which is in good accordance with the experiment.
Subsequent hydrogenation of CP2 with one hydrogen molecule
would proceed via transition state TS3 and regenerate the active
catalyst CP1. The corresponding activation free energy for this
process is 23.3 kcal/mol.
On the other hand, the asymmetric hydrogenation of
acetophenone 4a at the amino site is also considered. In this case,
the hydrogenation on Re-face of 4a would occur through transition
state TS4 with an activation free energy of 19.3 kcal/mol. The
intermediate CP4 and product 5a are then formed, this process is
exergonic by 2.3 kcal/mol. The enantiomer (S)-5a could be
generated through transition state TS5, the relative free energy of
which is 1.4 kcal/mol higher than that of TS4. Thus, the generation
of (S)-5a is also unfavorable when the hydrogenation occurs at
the amino site. Followed by coordination of one hydrogen
molecule to complex CP4 forms an intermediate CP5 with an
energy increase of 14.6 kcal/mol. The active species CP1 is
regenerated via a four-membered ring transition state TS6,
activation free energy for this step is 22.3 kcal/mol. As shown
above, the relative free energy of TS4 is 1.2 kcal/mol higher than
that of TS1, which implies that the asymmetric hydrogenation of
acetophenone 4a would preferentially occur at the hydroxyl site.
Scheme 4. Control experiments of asymmetric hydrogenation of acetophenone
4a with various ligands.
Density functional theory (DFT) calculations study
To understand the reaction mechanism and to further
rationalize the role of the hydroxyl group, density functional theory
(DFT) calculations were performed to elucidate the mechanism
and enantioselectivity of [Ir(COD)Cl]2/L2 catalyzed asymmetric
hydrogenation of acetophenone 4a based on previous studies [13-
14]
Iridium(III) hydride complex CP1 was chosen as the active
species and set to the relative zero free energy point.[15] Since
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Computational results also reveal that the regeneration of active
iridium(III) complex is the rate-determining step of the whole
catalytic cycle.
Preparation of phosphine-amino-alcohol (f-Amphol) Ligands
To a solution of (S)-Ugi’s amine 1 (2.57 g, 10 mmol) in anhydrous Et2O
(20 mL) was added 1.6 M tBuLi solution in pentane (11.2 mmol, 7.0 mL)
at 0 oC. After addition was complete, the mixture was warmed to room
temperature and stirred for 2 h. The mixture was then cooled to to -78 oC
and fresh distilled PCl3 (11.46 mmol, 1 mL) was added dropwise, and the
mixture was warmed to room temperature overnight. The mixture was then
cooled to -78 oC again, and a suspension of RMgBr (prepared from
corresponding RBr (30 mmol) and magnesium turnings (0.8 g, 33.3 mmol)
in THF at reflux temperature) was added slowly via cannula. After addition,
the mixture was stirred overnight from -78 oC to room temperature and
quenched with 20 mL saturated NH4Cl aq. The organic layer was
separated and the aqueous layer was extracted with Et2O (320 mL). The
combined organic phase was dried over Na2SO4 and concentrated. The
residue was purified by chromatography to afford the aminophosphine (Sc,
Rp)-2 with little impurity, which was used directly in next step without further
purification.
To further illustrate the steric repulsions at different regions
of CP1, 2D contour map along the z axis of the van der Waals
surface of CP1 is plotted in Figure 2. The red region on the right
of amino hydrogen (H2) indicates that there is stronger repulsion
with the substrate in this area. Since the hydroxyl hydrogen (H3)
is farther from this hindered area than H2, the hydrogenation
transition state at the amino site would bear more spatial
resistance, thereby results in the higher energy barrier of TS4 and
TS5. In addition to regioselectivity, the enantioselectivity could
also be explained by this 2D contour map. Because of the plane
structure of phenyl group, the steric hindrance of phenyl group is
larger than that of methyl group. When the hydroxyl-promoted
hydrogenation occurs on Re-face of acetophenone 4a, the methyl
group is located at the left of H3 and phenyl is located at the right,
which exactly avoids the steric repulsion between ligand and
substrate. Therefore, the generation of product (R)-5a is favored
in this catalytic system.
A solution of crude aminophosphine (Sc, Rp)-2 (1 mmol) in acetic
anhydride (1.5 mL) was heated to 70-100 oC (R = Cy, 70 oC (a); R = Ph,
o
o
100 C (b); R = 3,5-(tBu)2C6H3, 90 C (c) ) for 1-2 h (monitored by TLC).
After the starting material disappeared, the volatiles were removed in
vacuo and then toluene (2 mL) was added, concentrated. The operation
was repeated 3 times to remove excess acetic anhydride. To the residue,
a small amout of iPrOH or EtOH was added and the mixture was subjected
to ultrasound for several minutes until the appearing of yellow solid. The
alcohol was then removed by high vaccum, and the obtained yellow solid
(> 95% yield) was pure enough for next step. A mixture of the acetate (Sc,
Rp)-3 (1 mmol) and corresponding chiral amino alcohol (5 mmol) in dry
MeOH (5 mL) was refluxed overnight under nitrogen. The solvent was
evaporated in vaccum to afford the crude product. After chromatography
on silica-gel column with petroleum ether/ethylacetate (v/v = 20:1 to 5:1)
as eluent, the corresponding phosphine-amino-alcohol (f-Amphol) Ligands
were obtained as yellow solids in medium to good yields.
Procedure for asymmetric hydrogenation of ketones
General procedure for S/C = 10 000: To a 2.5 mL vial was added the
catalyst precursor [Ir(COD)Cl]2 (3.4 mg, 0.005 mmol), ligand L2 (8.5 mg,
0.011 mmol) and anhydrous iPrOH (1 mL) under argon atomosphere. The
mixture was stirred for 1.0 h at room temperature to give a clear yellow
solution. An aliquot of the catalyst solution (20 uL, 0.0002 mmol) was
transferred into a 5.0 mL hydrogenation vessel, then a solution of NaOH
Figure 2. 2D contour map of the van der Waals surface of CP1. Distances are
given in Å. The Ir-H1 bond is set as the z axis of the van der Waals surface, and
H1 atom is located at the origin of the coordinate system in the contour maps.
The contour line of zero is defined as in the same plane of the H1 atom. Negative
distance (blue) indicates that the ligand is farther away from the substrate;
positive distance (red) indicates that the ligand is closer to the substrate.
i
in PrOH (10.0 mg/mL, 0.08 mL, 0.02 mmol), ketone (2.0 mmol) and
i
anhydrous PrOH (3.0 mL) was added. The vessels were placed in an
autoclave which was then charged with 20 atm of H2 and stirred at 25-30
oC for 7 h. After slowly releasing the hydrogen pressure, the reaction
mixture was passed through a short column of silica gel to remove the
metal complex. The product was analyzed by GC or 1H NMR to determine
the conversion. The ee values were determined by HPLC or GC analysis
on a chiral stationary phase.
Conclusions
In summary, we successfully developed a series of novel
and modular ferrorence-based amino-phosphine-alcohol f-
Amphol ligands, and applied them into iridium-catalyzed
asymmetric hydrogenation of various simple ketones to afford
corresponding chiral alcohols with excellent results (98%-99.9%
ee, >99% conversions, TON up to 200 000). We found the
catalysts Ir-f-Amphol owned high stability, activity and
enantioselectivity. Control experiments and DFT calculations
have shown that the hydroxyl group of our f-Amphol ligands
played a key role in this asymmetric hydrogenation. The great
performance of this catalytic system will provide wide application
in various asymmetric reactions. Further investigation for more
substrates is underway and will be reported in due course.
Asymmetric hydrogenation of acetophenone at S/C = 200 000 : To a
2.5 mL vial was added the catalyst precursor [Ir(COD)Cl]2 (3.4 mg, 0.005
mmol), ligand L2 (8.5 mg, 0.011 mmol) and anhydrous iPrOH (1 mL) under
argon atomosphere. The mixture was stirred for 1 h at room temperature
to give a clear yellow solution. An aliquot of the catalyst solution ( 10 uL,
0.0001 mmol) was transferred into a 10 mL hydrogenation vessel, then a
solution of NaOH in iPrOH (10 mg/mL, 0.04 mL, 0.01 mmol), ketone 4a
(20 mmol) and anhydrous iPrOH (1.5 mL) was added. The vessel was
placed in an autoclave which was then charged with 40 atm of H2 and
stirred at 25-30 oC for 24 h. The work-up was identical to that described for
the asymmetric hydrogenation at S/C = 10,000. (R)-1-Phenylethanol (5a):
> 99% conversion, 99% ee (R).
Experimental Section
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Acknowledgements
We are grateful for financial support by the grant from
Wuhan University (203410100064), the support of the Important
Sci-Tech Innovative Project of Hubei Province (2015ACA058),
“111” Project of the Ministry of the Education of China and the
National Natural Science Foundation of China (Grant No.
21372179, 21432007, 21502145, 21372266, 51302327).
Keywords: Asymmetric hydrogenation• Chiral alcohol
Ferrocenyl • Ligand • Ketone
•
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10.1002/chem.201604855
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Jianfei Yu, Meng Duan, Weilong Wu,
Xiantian Qi, Peng Xue, Yu Lan,* Xiu-Qin
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Highly
Efficient Ferrocene-based Amino-
phosphine-alcohol
Ligands for
Asymmetric Hydrogenation of Simple
Ketones
(f-Amphol)
Iridium-Catalyzed
We successfully developed a series of novel and modular ferrorence-based amino-
phosphine-alcohol f-Amphol ligands, and applied them into iridium-catalyzed
asymmetric hydrogenation of various simple ketones to afford corresponding chiral
alcohols with excellent enantioselectivities and conversions (98%-99.9% ee, >99%
conversion, TON up to 200 000). Control experiments and DFT calculations have
shown that the hydroxyl group of our f-Amphol ligands played a key role in this
asymmetric hydrogenation.
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