Rh-Catalyzed Asymmetric Hydrogenation of (Z)-β-Phosphorylated Enamides: Highly Enantioselective Access to β-Aminophosphines

Article abstract of DOI:10.1021/acs.orglett.9b03174

A catalytic asymmetric hydrogenation of β-phosphorylated enamides for enantioselective access to optically active β-aminophosphine derivatives is reported. Critical to the success of this method was the employment of rhodium catalysis in concert with an u

Full text of DOI:10.1021/acs.orglett.9b03174

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rh-Catalyzed Asymmetric Hydrogenation of (Z)‑β-Phosphorylated
Enamides: Highly Enantioselective Access to β‑Aminophosphines
Hong-Quan Du†,‡ and Xiang-Ping Hu*,†
†Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
‡University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: A catalytic asymmetric hydrogenation of β-
phosphorylated enamides for enantioselective access to
optically active β-aminophosphine derivatives is reported.
Critical to the success of this method was the employment of
rhodium catalysis in concert with an unsymmetrical hybrid
chiral phosphine-phosphoramidite ligand. A wide range of
aromatic β-phosphorylated enamides could be hydrogenated
in full conversion and with perfect enantioselectivity even at
low catalyst loadings (S/C = 1000). β-Aminophosphine
oxides could be readily hydrolyzed and reduced, thus
providing an efficient route to catalytically important chiral
β-aminophosphines.
ptically active β-aminophosphine derivatives have been
sulfide9 has been extensively studied, highlighting the
Owell established as chiral scaffolds for the construction of challenging nature of this substrate class. By the employment
of the Rh-catalysis in combination with a chiral 1-phenylethyl-
amine-derived phosphine-phosphoramidite ligand developed
within our group, herein we report the first catalytic
asymmetric hydrogenation of β-phosphorylated enamides,
affording various chiral β-aminophosphine oxides in full
conversions and with up to >99% ee even at low catalyst
loading of 0.1 mol %. In particular, chiral β-aminophosphine
oxides could be readily converted into optically active β-
aminophosphines by the hydrolysis and reduction, thus
providing a facile and efficient access to structurally diverse
chiral β-aminophosphines (Scheme 1).
a diversity of ligands or organocatalysts, thus playing an
important role in the areas of asymmetric catalysis and
coordination chemistry.1 β-Aminophosphines are typically
prepared using enantiopure starting materials (mostly natural
or unnatural amino acids) and chiral auxiliaries or by
resolution of the racemic aminophosphines.1a In contrast,
catalytic asymmetric synthesis of chiral β-aminophosphines
remains elusive, all focusing on the metal-catalyzed or
organocatalytic phospha-Michael addition of diarylphosphines
to nitroalkenes following a nitro group reduction step.2 As the
reported catalytic systems mostly suffered from the relatively
narrow substrate scope, high catalyst loading, or insufficient
enantioselectivity, the development of new catalytic protocols
for highly efficient and enantioselective synthesis of structurally
diverse chiral β-aminophosphine derivatives is therefore highly
desirable and remains a challenge.
Scheme 1. Strategy for Asymmetric Synthesis of Chiral β-
Aminophosphines via Rh-Catalyzed Hydrogenation
Over the past decade, our laboratory has reported an array of
structurally diverse aminophosphines and demonstrated their
importance in asymmetric catalysis.3 In keeping with our long-
standing goal in the construction of the structural diversity of
chiral aminophosphine skeletons for asymmetric catalysis, we
sought to develop a general method for catalytic asymmetric
synthesis of optically active β-aminophosphines. For its
inherent efficiency and atom economy,4 catalytic asymmetric
hydrogenation of β-phosphorylated enamides should be one of
the most direct and convenient alternatives to chiral β-
aminophosphine derivatives. Unexpectedly, there is no
example that details the success to date, although catalytic
asymmetric hydrogenation of various β-functionalized enam-
ides including ester,5 sulfone,6 nitrate,7 phosphonate,8 and
β-Phosphorylated enamides could be readily prepared via
Mn(acac)3-mediated oxidative coupling of enamides with
phosphine oxide as reported by Zhang and Xiong recently,
and only (Z)-isomers were obtained as the products.10 Initially,
Rh-catalyzed asymmetric hydrogenation of (Z)-N-(2-(diphe-
nylphosphoryl)-1-phenylvinyl)acetamide 1a was chosen as the
model reaction to optimize the reaction conditions. The
Received: September 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03174
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reaction was conducted in CH2Cl2 under an H2 pressure of 50
bar at room temperature for 24 h in the presence of 1 mol % of
[Rh(COD)2]BF4, evaluating a variety of chiral phosphorus
ligands available from commercial sources or developed within
our group (Figure 1). As shown in Table 1, commercially
Scheme 2. Scope Study for the Rh-Catalyzed Asymmetric
Hydrogenation of (Z)-β-Phosphorylated Enamides 1
a
Figure 1. Ligands for Hydrogenation.
Table 1. Optimization Studies on Rh-Catalyzed Asymmetric
Hydrogenation of (Z)-N-(2-(Diphenylphosphoryl)-1-
a
phenylvinyl)acetamide 1a
b
c
entry
ligand
solvent
H2 (bar)
conv (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
L-1
L-2
L-3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
PhMe
THF
TFE
TFE
CH2Cl2
TFE
50
50
50
50
50
50
50
60
60
60
60
60
60
60
60
<10
95
<10
85
98
90
99
>99
99
<10
<10
>99
>99
<10
>99
−
52
−
73
92
97
>99
>99
88
−
d
L-4a
L-4b
L-5a
L-5b
L-5b
L-5b
L-5b
L-5b
L-5b
L-5b
L-5b
L-5b
−
98
>99
−
e
e
f
15
93
a
a
All reactions were carried out with a [Rh(COD)2]BF4/(Rc,Ra)-L-5b/
Unless otherwise noted, all reactions were carried out with a Rh/
1 (0.125 mmol) ratio of 1:1.1:100 in 2.5 mL of CF3CH2OH at room
temperature under a H2 pressure of 60 bar for 24 h, except S/C = 10/
1 for 1o. Full conversions were achieved in all cases. Isolated yields
were provided in all cases. Ee was determined by HPLC analysis using
a chiral stationary phase.
ligand/1a (0.125 mmol) ratio of 1:1.1:100 in 2.5 mL of solvent at
b
room temperature under H2 for 24 h. Conversion was determined by
c
GC. Ee was determined by HPLC analysis using a chiral stationary
d
e
f
phase. Rh/L-3 = 1:2. S/C = 200. S/C = 1000. COD = 1,5-
cyclooctadiene, TFE = CF3CH2OH.
available BINAP (L-1) and MonoPhos (L-3) exhibited poor
activity toward this hydrogenation (entries 1 and 3), while
DuPhos (L-2) displayed good activity but moderate
enantioselectivity (entry 2).
To our delight, unsymmetrical hybrid chiral phosphine-
phosphoramidite ligands developed within our group were
found to be a suitable ligand class for the hydrogenation with
chiral 1-phenylethylamine-derived phosphine-phosphoramidite
ligand (Rc,Ra)-PEAPhos L-5b as the optimized one (entries 4−
7). Promoting H2 pressure to 60 bar led to the hydrogenation
in full conversion and >99% ee (entry 8). The nature of the
solvent dramatically affected the hydrogenation (entries 8−
12). Thus, very low conversions were observed in toluene and
THF, while good catalytic performance was achieved in
MeOH, CH2Cl2, and trifluoroethanol (TFE). TFE proved to
be the best solvent, as the perfect catalytic performance was
B
DOI: 10.1021/acs.orglett.9b03174
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maintained even by lowering the catalyst loading to 0.5 mol %
(entry 13). In this case, the hydrogenation in CH2Cl2 only
showed low conversion (entry 14). The high efficiency of the
present catalytic system was further demonstrated by perform-
ing the hydrogenation at a catalyst loading as low as 0.1 mol %,
in which full conversion with 93% ee was achieved (entry 15).
The absolute stereochemistry of the resulting β-amino-
phosphine oxide 2a was determined to be S by the comparison
of the optical rotation with the reported value in the
literature11 after the derivation to the corresponding 2-
(diphenylphosphino)-1-phenylethanamine.
Under the optimized conditions, the scope of (Z)-β-
phosphorylated enamides 1 was examined, and the results
are summarized in Scheme 2. Initially, various 1-phenyl
substituted enamides 1b−j were submitted to the hydro-
genation. Both electron-donating and -withdrawing substitu-
ents were well tolerated, regardless of the position (ortho-,
meta-, or para-position) of the phenyl ring. In all cases, the
hydrogenation led to the corresponding β-aminophosphine
oxides 2b−j in full conversions and with perfect enantiose-
lectivities (98 → 99% ee). 2-Naphthyl substrate 1k was
hydrogenated smoothly to give the desired product 2k in full
conversion and >99% ee. Heteroaromatic enamide 1l worked
well in the hydrogenation, resulting in the hydrogenation
product 2l in full conversion and with >99% ee. Of note,
aliphatic enamides 1m−o were also well tolerated and could be
hydrogenated in full conversion and with high to perfect
enantioselectivities. We also investigated the effect of the N-
acyl group in the hydrogenation, and the results indicated the
hydrogenation of all enamides 1p−q with different acyl groups
led to excellent outcomes although the increased steric
hindrance of acyl group slightly decreased the enantioselectiv-
ity. An alkyl substituent at the P-atom was also well tolerated,
giving the hydrogenation product 2r in full conversion and
with >99% ee.
catalytically important β-aminophosphine (S)-3a and 3b in
72% and 65% yield, respectively.
In conclusion, we have developed an efficient approach for
asymmetric hydrogenation of (Z)-β-phosphorylated enamides
to generate optically active β-aminophosphine derivatives.
Using a combination of [Rh(COD)2]BF4 with an unsym-
metrical hybrid phosphine-phosphoramidite ligand as the
catalyst, a series of (Z)-β-phosphorylated enamides could be
hydrogenated smoothly to provide the desired β-amino-
phosphine oxides in in full conversions and with perfect
enantioselectivity (up to >99% ee) even at low catalyst
loadings (S/C = 1000). Furthermore, β-aminophosphine
oxides could be readily hydrolyzed and reduced, thus providing
an effective and concise route to catalytically important and
structurally diverse chiral β-aminophosphines. Further inves-
tigations on the application of chiral β-aminophosphines in
asymmetric hydrogenation are underway in our laboratory.
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.9b03174.
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xiangping@dicp.ac.cn.
ORCID
Xiang-Ping Hu: 0000-0002-8214-1338
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
To explore the synthetic potential of this Rh-catalyzed
hydrogenation, two gram-scale experiments were performed
with 1a and 1b under the standard conditions. The
hydrogenations proceeded smoothly and gave the desired
products (S)-2a and (S)-2b in high isolated yields and with
perfect enantioselectivity (Scheme 3). The acetyl group of (S)-
2a or 2b was readily removed in aq HCl to afford the
corresponding β-aminophosphine oxide. The reduction of β-
aminophosphine oxides with HSiCl3/Et3N in toluene led to
Financial support from the National Natural Science
Foundation of China (21572226 and 21772196) and Dalian
Science and Technology Innovation Project (2018J12GX054)
is gratefully acknowledged.
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