Pd(OAc)2-Catalyzed Asymmetric Hydrogenation of α-Iminoesters

Article abstract of DOI:10.1021/acs.orglett.9b03452

An efficient Pd(OAc)₂-catalyzed asymmetric hydrogenation of α-iminoesters was realized for the first time at 1 atm hydrogen pressure and room temperature. Pd(OAc)₂, a less expensive Pd salt with low toxicity, was found to be the most suitable catalyst precursor rather than Pd(TFA)₂ which is usually the catalyst of choice for homogeneous asymmetric hydrogenation. The chiral α-arylglycine fragments are widely found in many chiral products and bioactive molecules.

Full text of DOI:10.1021/acs.orglett.9b03452

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd(OAc)2‑Catalyzed Asymmetric Hydrogenation of α‑Iminoesters
Jianzhong Chen,† Feilong Li,§ Fang Wang,§ Yawen Hu,‡ Zhenfeng Zhang,‡ Min Zhao,*,§
and Wanbin Zhang*,†,‡
†Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering,‡School of
Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R. China
§School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, P.R. China
S
* Supporting Information
ABSTRACT: An efficient Pd(OAc)2-catalyzed asymmetric
hydrogenation of α-iminoesters was realized for the first time
at 1 atm hydrogen pressure and room temperature. Pd(OAc)2,
a less expensive Pd salt with low toxicity, was found to be the
most suitable catalyst precursor rather than Pd(TFA)2 which
is usually the catalyst of choice for homogeneous asymmetric
hydrogenation. The chiral α-arylglycine fragments are widely
found in many chiral products and bioactive molecules.
ptically active α-arylglycines and their derivatives have
found widespread application in asymmetric synthesis
hydrogen source would be a more attractive method for the
preparation of chiral α-arylglycines owing to its efficiency and
ease of use in industry. Thus, as early as 1986, a cobalt-
mediated reduction of CN bonds with hydrogen was
described by Okamoto and Tanimoto, giving the correspond-
ing product in low 20% ee.8a In 2006, the group of Zhang
reported the Rh-catalyzed asymmetric hydrogenation of α-aryl
iminoesters with 50 atm H2 at 50 °C with the desired products
being obtained in up to 95% ee.8b In 2012, an example of the
Ir-catalyzed asymmetric hydrogenation of an α-imino ester was
reported, providing the corresponding α-amino acid derivative
in 86% ee.8c Beller and co-workers developed the enantiose-
lective hydrogenation of benzoxazinones via a relay iron/chiral
Brønsted acid catalyst system with up to 98:2 er in 2015.8d The
Pd-catalyzed asymmetric hydrogenation of α-fluorinated
iminoesters was disclosed in 2001 by Amii and Uneyama
with the products being obtained in up to 91% ee.8e Another
α-aryl iminoester substrate, which was hydrogenated using Pd
catalysis, was mentioned by Zhou in 2007, with the desired
product being obtained in only 33% ee.8f
O
and are essential parts of many chiral drugs, bioactive
molecules, and nonproteinogenic α-amino acids (Figure 1).1
Figure 1. Representative chiral bioactive molecules bearing optically
active α-arylglycine skeletons.
Since the 1960s, various transition metals have been widely
employed in asymmetric hydrogenation with excellent results.9
However, palladium-catalyzed homogeneous asymmetric
hydrogenation was investigated first in 2001.8e Furthermore,
only a Pd(TFA)2-catalyst has shown effective catalytic
activity.9b,c In 2013, a useful chiral cyclic amine was obtained
via the Pd-catalyzed asymmetric hydrogenation of cyclic
imines. Pd(OAc)2 can replace Pd(TFA)2 with similar perform-
ance.10 Very recently, the Pd(OAc)2-catalyzed asymmetric
hydrogenation of sterically hindered N-tosylimines has been
developed by our group, with excellent results.11 As part of our
studies on asymmetric catalytic hydrogenations,11,12 we herein
Consequently, since the 1980s, a variety of methods have been
developed for the synthesis of these important chiral
compounds. Significant progress has been made with regard
to the catalytic asymmetric synthesis of chiral α-arylglycines
over the past 30 years. Methodologies, such as the asymmetric
Strecker reaction, asymmetric amination and asymmetric
Friedel−Crafts reaction, have been developed.2,3 On the
other hand, the asymmetric reduction of various imines
would allow for a direct route to the preparation of chiral
arylglycines via transfer hydrogenations,4 silylation reactions,5
diastereoselective L-Selectride reductions,6 chiral substrate
controlled diastereoselective hydrogenations,7 and asymmetric
hydrogenations.8 Among these, the transition-metal-catalyzed
asymmetric hydrogenation of imines using H2 gas as a
Received: September 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03452
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
report the synthesis of a series of chiral α-arylglycines via the
Pd(OAc)2-catalyzed asymmetric hydrogenation of α-iminoest-
ers.
Table 2. Reaction Optimization
Initially, as a model, the asymmetric hydrogenation of (Z)-
benzyl-2-phenyl-2-(tosylimino)acetate was carried out under 1
atm H2 pressure at room temperature in TFE (Table 1). As we
b
c
entry
solvent
temp (°C)
H2 (atm)
conv (%)
ee (%)
a
Table 1. Ligand and Pd Salt Optimization
1
2
3
4
5
6
7
8
9
TFE
rt
rt
rt
rt
rt
rt
rt
−10
−40
60
1
1
1
1
1
1
30
1
1
1
>95
ND
94
NR
NR
NR
>95
>95
91
94
0
MeOH
EtOH
i-PrOH
THF
DCM
TFE
TFE
TFE
TFE
d
94
94
94
94
d
10
>95
a
Conditions: 1a (0.2 mmol), Pd(OAc)2/(R,R)-QuinoxP* (2 mol %),
b
1
H2, solvent (1.5 mL), 24 h. Conversions were calculated from H
NMR spectra. The ee values were determined by HPLC using chiral
columns. Reaction time, 2 h.
c
d
used (entries 1−4). Excellent results (94% ee and >95%
conversion) were only obtained in TFE (entry 1). Unfortu-
nately, the substrate decomposed completely in MeOH (entry
2). Compared with the excellent enantioselectivity obtained in
TFE, reaction in EtOH gave the desired product in 94% yield
but as a racemic mixture (entry 3). No reaction occurred in i-
PrOH (entry 4). The low polarity solvents THF and DCM
also showed no catalytic activities (entries 5 and 6). Next, the
hydrogenation pressure was examined, and a similar result was
obtained in 2 h when the hydrogen pressure was increased to
30 atm (entry 7). Lowering the temperature to −10 °C had no
effect on the reaction conversion and enantioselectivity (entry
8). The desired product could be obtained in 91% conversion
and 94% ee even at −40 °C (entry 9). Raising the temperature
to 60 °C also provided full conversion and 94% ee in 2 h
(entry 10).
The effects of the ester group and sulfonyl substituent in the
substrate were investigated using the optimized reaction
conditions (Table 2, Table 3, entry 1). When R1 was changed
to a Me, t-Bu, Ph, or 4-Me-Ph group, similar results were
obtained (Table 3, entries 1−5, 95−98% yields and 92−94%
ee). Changing R2 to Ph, 4-t-Bu-Ph, 4-F-Ph, 4-MeO-Ph, or 2-
Me-Ph had no effect or resulted in a slight decrease in the
enantioselectivities of the products (Table 3, entries 6−10).
The aliphatic Me and t-Bu groups were also employed as R2
groups giving their corresponding products with good yields
and in 89 and 73% ee, respectively (Table 3, entries 11 and
12).
The substrate scope of the catalytic system was explored
using the above optimized reaction conditions (Scheme 1). All
of the tested N-tosylimine substrates were converted to their
corresponding products in quantitative conversions. Excellent
enantioselectivities (93−96% ee) were obtained via asym-
metric hydrogenation of para-substituted substrates with
different electron-donating groups (2m−q). Substrates bearing
para-electron-withdrawing groups (Cl and F) gave their
corresponding products with slightly lower enantioselectivities
(91/94% ee, 2r/s). The substrate bearing p-CF3-substituent
only gave its reduced counterpart in 83% ee (2t). The presence
of a methyl or methoxy group at the meta-position of the
b
c
entry
ligand
Pd salt
conv (%)
ee (%)
1
2
3
4
5
6
7
8
(R,R)-QuinoxP*
(R,R)-QuinoxP*
(R,R)-QuinoxP*
(R,R)-QuinoxP*
(R,R)-QuinoxP*
(R,R)-QuinoxP*
(R)-Binap
Pd(OAc)2
Pd(TFA)2
PdCl2
>95
52
53
<5
75
<5
82
>95
>95
83
94
94
0
PdBr2
Pd(OH)2
Pd(acac)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
0
41
69
13
46
13
(R)-SegPHOS
9
10
11
(R)-DTBM-SegPHOS
(R)-C10-BridgePHOS
(S,S)-RuPHOX
37
a
Conditions: 1a (0.2 mmol), Pd/ligand (2 mol %), H2 (1 atm), TFE
b
(1.5 mL), rt, 24 h. Conversions were calculated from 1H NMR
c
spectra. The ee values were determined by HPLC using chiral
columns. The absolute configuration of product was determined as S
by comparison of the specific rotations with the literature data.13
TFA: OCOCF3.
had expected, the reaction proceeded smoothly with 94% ee
and quantitative conversion with (R,R)-QuinoxP*14 as chiral
ligand and Pd(OAc)2 as Pd source (entry 1). However, quite
unexpectedly, the conversion was only 52% when the catalyst
was changed from Pd(OAc)2 to Pd(TFA)2 (entry 2). Other Pd
precursors, such as PdBr2, PdCl2, Pd(OH)2 and Pd(acac)2,
were also screened with (R,R)-QuinoxP* in the hydrogenation,
but no improvement in the reaction was observed (entries 3−
6). A number of other commonly used ligands, such as (R)-
BINAP, (R)-SegPHOS, (R)-DTBM-SegPHOS, (R)-C10-
BridgePHOS, and (S,S)-RuPHOX, could also catalyze this
reaction but only gave the desired hydrogenation product with
moderate conversions and/or low enantioselectivities (entries
7−11).
The influence of the solvent, hydrogenation pressure, and
reaction temperature on this reaction were also studied (Table
2). Alcohols such as TFE, MeOH, EtOH, and i-PrOH were
B
DOI: 10.1021/acs.orglett.9b03452
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Organic Letters
Letter
a
a
Table 3. Effect of R1 and R2 Group on the Reaction
Scheme 1. Substrate Scope
a
Conditions: 1a (0.2 mmol), Pd(OAc)2/(R,R)-QuinoxP* (2 mol %),
b
c
H2, solvent (1.5 mL), 24 h. Isolated yields. The ee values were
determined by HPLC using chiral columns.
benzene ring did not influence the stereoselectivity significantly
(94, 92% ee, 2u,v). Additionally, ortho-substituents were also
tested in the hydrogenation conditions. Unfortunately, the
presence of a methyl group at the ortho position led to a
marked decrease in enantioselectivity (55% vs 94% ee, 2w vs
2a). The protecting groups of R1 and R2 were changed in
consideration of the impact of steric hindrance. When the Bn
group was replaced with Me, the enantioselectivity increased
slightly to 59% (2x). Changing the Ts group to Ms led to an
increase in ee of the corresponding product to 88% (2y). The
o-Cl substituent product was obtained in 65% ee (2z), even
with the Z/E ratio of 1z being only 3/2 (Z/E mixture cannot
be separated). The disubstituted substrates also gave excellent
enantioselectivities (2aa−ad, 93−97% ee). Changing the
benzene ring to 2-naphthyl groups also gave good results
(2ae,af, 93, 94% ee). Substrates bearing a furyl or thienyl group
were also reduced with high ee (2ag, ah, 91, 96% ee). The
hydrogenation of a tert-butyl iminoester provided the
corresponding product in 37% yield and 18% ee (2ai).
Other alkyl iminoesters, such as the cyclohexyl and isopropyl
derivatives, could not be synthesized, probably due to
enolization. In addition, substrates bearing amide groups
were also investigated, and 2aj was obtained in 94% yield and
90% ee. However, 2ak was obtained in only 54% ee (92%
yield).
To examine the efficiency of this catalytic system, the
hydrogenation of 1a was tested with a relatively low catalyst
loading (2000 S/C). The reaction proceeded smoothly with
quantitative conversion and 94% ee albeit requiring a higher
reaction temperature and H2 pressure (Scheme 2). The chiral
compounds 2 have the potential for use in simple trans-
formations for the synthesis of chiral α-amino acid compounds
commonly found in some optically active substances.1 The
chiral aldose reductase inhibitor (S)-3a was obtained in 96%
yield and 94% ee by hydrolysis from (S)-2a. This product (S)-
a
Conditions: 1a (0.2 mmol), Pd(OAc)2/(R,R)-QuinoxP* (2 mol %),
H2, solvent (1.5 mL), 24 h. Isolated yields. The ee values were
determined by HPLC using chiral columns.
3a could be further transformed to the α-aminoamide (S)-2ak
(94% ee) which was obtained with only 54% ee via asymmetric
hydrogenation of corresponding amide substrates 1ak
(Scheme 1). According to the above procedures, the histone
deacetylase inhibitor precursor (S)-4 was prepared from (S)-
2g via intermediate (S)-3g with no loss of ee (Scheme 2). We
tried to remove the Ts group using several methods such as
sodium naphthalene, magnesium powder, sodium hydroxide,
SmI2, and (Boc)2O. Unfortunately, conditions to remove the
Ts group have not yet been successful. Only complex
byproducts, NR, or hydrolysates are observed.
This enantiomeric outcome can be explained in Figure 2.
The Ts group is located opposite to the more bulky Ph group
(compared to the benzyl ester group) according to the
structure of Z-1a. In the favored transition state, the more
sterically hindered Ts group (compared to the lone pair
electrons of the N atom) and Ph group (compared to benzyl
C
DOI: 10.1021/acs.orglett.9b03452
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Organic Letters
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Scheme 2. Further Transformation of a Chiral α-Arylglycine
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03452.
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhaomin6502@sina.com.
*E-mail: wanbin@sjtu.edu.cn.
ORCID
Zhenfeng Zhang: 0000-0003-3295-6966
Wanbin Zhang: 0000-0002-4788-4195
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would thank the National Natural Science Foundation of
China (Nos. 21702134, 21620102003 and 21772119) and
Science and Technology Commission of Shanghai Municipal-
ity (No. 17ZR1415200) for financial support. We thank the
Instrumental Analysis Center of SJTU for characterization.
REFERENCES
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