Diaza-Crown Ether-Bridged Chiral Diphosphoramidite Ligands: Synthesis and Applications in Asymmetric Catalysis

Article abstract of DOI:10.1021/acs.joc.0c00223

A small library of diaza-crown ether-bridged chiral diphosphoramidite ligands was prepared. In the rhodium-catalyzed asymmetric hydrogenation and hydroformylation reactions, these ligands exhibited distinct properties in catalytic activity and/or enantioselectivity. Hydrogenated products with opposite absolute configurations could be obtained in high yields with excellent ee values by utilizing (S,S)-L1 and (S,S)-L3, respectively. Meanwhile, the addition of alkali metal cations caused variations in catalytic outcomes, showing the supramolecular tunability of these Rh/diphosphoramidite catalytic systems.

Full text of DOI:10.1021/acs.joc.0c00223

Subscriber access provided by Uppsala universitetsbibliotek
Note
Diaza-Crown Ether-Bridged Chiral Diphosphoramidite
Ligands: Synthesis and Applications in Asymmetric Catalysis
Yier Luo, Guanghui Ouyang, Yuping Tang, Yan-Mei He, and Qinghua Fan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00223 • Publication Date (Web): 13 May 2020
Downloaded from pubs.acs.org on May 13, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 11
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Diaza-Crown Ether-Bridged Chiral Diphosphoramidite Ligands:
Synthesis and Applications in Asymmetric Catalysis
Yier Luo,†,‡ Guanghui Ouyang,† Yuping Tang,†,‡ Yan-Mei He,*,† Qing-Hua Fan*,†,‡
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute
of Chemistry, Chinese Academy of Sciences (CAS), Beijing 100190 (P. R. China)
‡University of Chinese Academy of Sciences, Beijing 100049 (P. R. China)
E-mail: fanqh@iccas.ac.cn; heym@iccas.ac.cn
Supporting Information Placeholder
Asymmetric Hydrogenation:
m
COOMe
NHAc
COOMe
O
Rh(NBD)2BF4/L
*
R
O
O
R
O
O
N
P
NHAc
5 atm H2, 1 h, r.t.
P
N
O
n
NHAc
*
NHAc
n = 0, 1, 2, 3
m = 1, 2, 3
Rh(NBD)2BF4/L
R
R
20 atm H2, 12 h, r.t.
Cation-tuned Asymmetric Catalysis
Absolute configuration reversal of product
Enhancement in reactivity and selectivity
Asymmetric Hydroformylation:
Rh(acac)(CO)2/L
H
*
R
R
10 atm (H2:CO = 1:1)
24 h, r.t.
O
ABSTRACT: A small library of diaza-crown ether-bridged chiral diphosphoramidite ligands was prepared. In the rhodium-
catalyzed asymmetric hydrogenation and hydroformylation reactions, these ligands exhibited distinct properties in catalytic activity
and/or enantioselectivity. Hydrogenated products with opposite absolute configurations could be obtained in high yields with
excellent ee values by utilizing (S,S)-L1 and (S,S)-L3, respectively. Meanwhile, the addition of alkali metal cations caused
variations in catalytic outcomes, showing the supramolecular tunability of these Rh/diphosphoramidite catalytic systems.
Nowadays, transition metal catalysis is playing more and
more important roles in organic synthesis as well as in modern
chemical industry. The evolution of transition metal catalysis
is usually accompanied with and based on the development of
novel ligands, especially for phosphorus ligands.1 In this
process, covalent and/or supramolecular modifications2,3 of
ligands have always brought us new findings, new functions,
and even new reactions in catalysis. As a major
macromolecular host in supramolecular chemistry,
(aza-)crown ethers have been introduced into the phosphorus
ligand design since 1978.4 To date, a number of (aza-)crown
ether-based phosphorus ligands have been reported and
employed in the preparation of transition metal complexes,
which proved to be promising catalysts capable of facilitating
cation-tuned catalysis.3 Among them, however, chiral
phosphorus ligands and their applications in asymmetric
catalysis are very limited.5-9 In 1992, Ito and co-workers
developed an array of chiral ferrocenyldiphosphine ligands
bearing an aza-crown ether unit away from the coordination
site (Scheme 1).5 a In the asymmetric allylation of
unsymmetrically substituted β-diketones, up to 75%
enantiomeric excess was observed. Recently, Vidal-Ferran and
co-workers disclosed a set of chiral diphosphine ligands with a
biphenyl backbone which is incorporated in a crown ether
frame.6 The Rh-catalyzed asymmetric hydrogenation with
these ligands provided moderate enantioselectivity and slightly
positive regulation effects of cation additive. Similarly, chiral
d i p h o s p h i n e l i g a n d w i t h t w o
Scheme 1. (Aza-)crown ether-based chiral phosphorus ligands
O
n
O
O
H3C
O
O
O
N
N
O
m
N
P
O
CH3
O
O
O
H
PPh2
Fe
2015, Fan
1992, Ito
PPh2
PAr2 PAr2
O
O
N
N
O
O
O
O
PPh2
PPh2
O
O
O
O
O
O
O
O
Ar = 3,5-C6H4(CH3)2
2015, Vidal-Ferran
2016, Wu and Li
pyridyl-containing crown ethers was reported by Wu, Li and
co-workers,7 which was efficient in the Rh- and Ir-catalyzed
asymmetric hydrogenation of α-dehydroamino acid esters and
quinolines in the presence of NaBArF, respectively. The
addition of alkali metal cations could obviously elevate the
enantioselectivity of the reaction. Despite these progresses, it
is still highly desirable to develop new kind of (aza-)crown
ether-based phosphorus ligands for asymmetric catalysis.
Our group has been focusing on the development of
supramolecular transition metal catalytic systems based on
(aza-)crown ethers and their counterparts, like metallacrown
ethers8a,8b and pseudo rotaxanes.8c Very recently, we realized a
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 11
cation-triggered ‘On-Off’ switchable asymmetric catalysis
with chiral aza-crown ether-based monodentate
ring also affected the reaction, the smaller (S,S)-L4 provided
similar results as (S,S)-L1, while using the bigger (S,S)-L5 led
1
a
2
3
4
5
6
7
8
9
phosphoramidite ligand (Scheme 1).8d More importantly, it
was found that the aza-crown ether motif not only acted as a
host for alkali metal cations, but also associated with the ionic
transition metal center. To further explore the potential of this
kind of aza-crown ether-based ligands, herein, we disclose the
synthesis of a small library of diaza-crown ether-bridged chiral
diphosphoramidite ligands (Scheme 2).9 With the phosphorus
atoms directly connected to the diaza-crown ether, the crown
ether backbone and the transition metal are brought in a close
to the decreases in both reactivity and enantioselectivity.
Table 1. Ligand screening for the asymmetric
hydrogenation of α-dehydroamino acid ester 1da
COOMe
NHAc
COOMe
L
Rh(NBD)2BF4/
*
NHAc
S/C = 100, DCM, 5 atm H2, 1 h, r.t.
F
F
2d
1d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
proximity.
In
the
rhodium-catalyzed
asymmetric
hydrogenation and hydroformylation reactions, these ligands
exhibited distinct properties in catalytic activity and/or
enantioselectivity. Meanwhile, the addition of alkali metal
cations caused variations in catalytic outcomes, showing the
supramolecular tunability of these Rh/diphosphoramidite
catalytic systems.
additive
(mol %)
conv.
(%)b
ee
entry
Ligand
(%)b
1
2
(S,S)-L1
(S,S)-L2
(S,S)-L3
(S,S)-L4
(S,S)-L5
(S,S)-L1
(S,S)-L1
none
none
>99
<5
>99 (R)
n.d.
3
none
>99
>99
39
94 (S)
98 (R)
84 (R)
>99 (R)
97 (R)
97 (S)
96 (S)
4
none
Scheme 2. Chiral diphosphoramidite ligands with a diaza-
crown ether backbone
5
none
O
N
O
O
O
O
6c
7c
none
70
O
O
O
O
O
O
O
P
N
P
N
N
P
KBArF (1.1)
NaBArF (1.1)
KBArF (1.1)
34
O
O
P
O
L1
L2
O
>99
>99
8
9
(S,S)-L3
(S,S)-L3
O
O
O
O
O
P
N
KBArF (1.1)/
N
O
>99
94 (S)
Kryptofix 222 (1.1)
P
O
O
O
O
O
O
N
P
P
N
O
a Reaction conditions: Rh(NBD)2BF4 (1.0 mol %), L (1.1 mol %),
additive, substrate (0.05 mmol), CH2Cl2 (2 mL), H2 (5 atm), r.t.
O
b
L3
L4
for 1 h. Based on GC analysis with a Chirasil-L-Val column
CP7495 (25 m×0.25 mm). c H2 (1 atm), r.t. for 1 h.
O
O
O
O
O
O
O
O
P
N
P
N
O
The effect of alkali metal additives on catalytic properties
was further investigated (Table 1). When (S,S)-L1 was used,
the addition of KBArF reduced the catalytic activity and
enantioselectivity (entry 6 vs entry 7). To our delight, a
positive regulatory effect of alkali metal salts was observed for
(S,S)-L3, and a higher enantioselectivity was achieved (entry 3
vs entry 8). Additionally, introducing Kryptofix 222 into the
reaction, which has a stronger binding affinity to K+ than
diaza-18-crown-6, caused the ee value to fall back to 94%
(entry 9). These results suggest that the positive effect is
originated from the supramolecular recognition between alkali
metal cation and the diaza-crown ether backbone.11
Subsequently, a variety of α-dehydroamino acid esters were
hydrogenated using (S,S)-L1 and (S,S)-L3 as ligand (Table 2).
Full conversions were found for all reactions tested. And
excellent enantioselectivities (98%->99% ee) were achieved
with (S,S)-L1. Meantime, (S,S)-L3 offered slightly lower ees
of amino acid products in opposite configuration. The
supramolecular regulating with KBArF for Rh/(S,S)-L3
provided increased enantioselectivities (entries 1, 2, 4, and 5).
A scale-up hydrogenation of 1a with (S,S)-L1 was also
conducted, and 218 mg (R)-2a was obtained in 99% isolated
yield with >99% ee.
O
L5
To synthesize the designed diaza-crown ether-bridged chiral
diphosphoramidite ligands, we first prepared a library of
diaza-crown ethers with the two nitrogen atoms at different
relative positions or of varied ring sizes according to the
modified published methods.10 Subsequent reactions with (S)-
BINOL-derived chlorophosphite and the diaza-crown ethers
gave the chiral diphosphoramidite ligands in high yield.8d
These new ligands were fully characterized by 1H NMR,
13C{1H} NMR, 31P{1H} NMR spectroscopy and high
resolution mass spectrometry.
Having these diphosphoramidite ligands in hand, we
anticipated to evaluate their catalytic properties. Our initial
studies were carried out with the Rh-mediated asymmetric
hydrogenation of α-dehydroamino acid esters. After screening
the reaction conditions (Table S1-S4 in SI) with 1d as model
substrate, we investigated the ligand performance in this
reaction. As shown in Table 1, (S,S)-L1 showed its superiority
in catalysis, offering the reduced product (R)-2d in full
conversion and >99% ee. To our surprise, when (S,S)-L2 was
used, the reaction could not happen. It is more interesting to
find that the chiral induction was completely reversed with
(S,S)-L3, giving product (S)-2d in full conversion albeit with a
slightly lower enantioselectivity. The size of the crown ether
Given the inspiring results in the asymmetric hydrogenation
of α-dehydroamino acid esters, we then applied the catalytic
systems for the reduction of α-arylenamides. The screening of
ACS Paragon Plus Environment

Page 3 of 11
The Journal of Organic Chemistry
Table 3. Asymmetric hydrogenation of enamides:
Table 2. Asymmetric hydrogenation of α-dehydroamino
substrate scopea
acid esters: substrate scopea
1
2
3
4
5
6
NHAc
*
NHAc
COOMe
COOMe
L
Rh(NBD)2BF4/
*
L
Rh(NBD)2BF4/
R
R
NHAc
1a 1n
NHAc
2a-2n
CH2Cl2, 5 atm H2, 1 h, r.t.
R
R
CH2Cl2/n-hexane = 1:1
20 atm H2, r.t., 12 h
-
4a 4j
3a 3j
-
-
7
8
9
(S,S)-L1
(S,S)-L3
(S,S)-L1
(S,S)-L3
entry
R
entry
R
ee (%)b
ee (%)b
ee (%)b
ee (%)b
94 [97] (S)
94 [97] (S)
95 (S)
1
2
3
4
5
6
7
8
9
H (4a)
4-Me (4b)
4-MeO (4c)
4-F (4d)
97 (R)
94 (R)
89 (R)
93 (R)
96 (R)
>99 (R)
98 (R)
86 (R)
98 (R)
86 [91] (S)
84 [91] (S)
82 [90] (S)
83 [90] (S)
87 [92] (S)
90 [92] (S)
87 [93] (S)
68 [79] (S)
86 [92] (S)
1
2
H (2a)
>99 (R)
>99 (R)
>99 (R)
>99 (R)
>99 (R)
>99 (R)
>99 (R)
>99 (R)
>99 (R)
>99 (R)
>99 (R)
98 (R)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Me (2b)
4-MeO (2c)
4-F (2d)
3
94 [96] (S)
93 [96] (S)
91 (S)
4
4-Cl (4e)
4-Br (4f)
4-CF3 (4g)
2-F (4h)
5
4-Cl (2e)
6
4-Br (2f)
87 (S)
7
4-NO2 (2g)
2-Me (2h)
2-MeO (2i)
2-Cl (2j)
93 (S)
8
97 (S)
3-Cl (4i)
9
NHAc
94 (S)
10
11
12
13
14
10
39 (R)
23 [76] (S)
96 (S)
(4j)
2-NO2 (2k)
3-MeO (2l)
3-F (2m)
a Reaction conditions: Rh(NBD)2BF4 (1.0 mol %), L (1.1 mol %),
substrate (0.05 mmol), n-hexane:CH2Cl2 = 1:1 (2 mL), H2 (20
atm), r.t. for 12 h. Data in brackets were obtained with 1.1 mol %
KBArF as additive. Full conversions were observed for all
substrates tested. Based on GC analysis with a chrompack
Chirasil-Dex CB column CP7502 (25 m×0.25 mm).
95 (S)
>99 (R)
99 (R)
93 (S)
92 (S)
3-Cl (2n)
b
a
Reaction conditions: Rh(NBD)2BF4 (1.0 mol %), L1 (1.1
mol %), substrate (0.05 mmol), CH2Cl2 (2 mL), H2 (5 atm), r.t. for
1 h. Data in brackets were obtained with 1.1 mol % KBArF as
additive. Full conversions were observed for all substrates tested.
b Based on GC analysis with a Chirasil-L-Val column CP7495 (25
m×0.25 mm).
these crown ether-bridged diphosphoramidite ligands in
asymmetric hydrogenation, we then investigated the
asymmetric hydroformylation of olefins with these
supramolecularly tunable rhodium catalytic systems.
After optimizing the reaction conditions (see SI), (S,S)-L3
was demonstrated to be the most effective and enantioselective
in the asymmetric hydroformylation of styrene in the presence
of NaBArF. Then, several substituted styrene derivatives were
subjected to the reaction (Table 4). High conversions
(89%->99%), high b/l ratios (92:8 to 95:5), and moderate ees
(62%-73%) were obtained. It is quite worthy to note that the
addition of NaBArF not only led to the increase of reactivity,
but also gave rise to the reversal of product absolute
configuration and an obvious enhancement of the level of
enantioselectivity.
In conclusion, we have designed and synthesized a set of
chiral diphosphoramidite ligands with a diaza-crown ether
backbone which features varied ring size and different N-atom
embedded position. In the Rh-catalyzed asymmetric
hydrogenation and hydroformylation reactions, these ligands
exhibited good to excellent reactivity and selectivity with or
without supramolecular regulation. The positive effects of
host-guest recognition between alkali metal cations with the
diaza-crown ether backbone of (S,S)-L3 on catalytic property
are obvious although the nature of these distinct
supramolecular effects was not elucidated at present. Further
applications of these ligands in other asymmetric catalysis are
being studied in our laboratory.
ligands gave similar results as those obtained for α-
dehydroamino acid esters (see SI). The best performance was
given by (S,S)-L1, providing the (R)-product in full conversion
and 99% ee. Lower activity and/or enantioselectivity were
observed when (S,S)-L3, (S,S)-L4 and (S,S)-L5 were utilized,
while (S,S)-L2 was totally inactive. The reversal of product
absolute configuration was detected for both (S,S)-L3 and (S,S)-
L5. Similarly, the regulating effect of alkali metal salts was
obvious, decrease or increase of ee values for (S,S)-L1 and
(S,S)-L3 were found, respectively.
The substrate scope of enamides was further studied by
using L1 and L3 with or without the addition of KBArF
(Table 3). Excellent enantioselectivities ( ≥ 89% ee) were
observed for para- and meta-substituted substrates with (S,S)-
L1 or (S,S)-L3/KBArF, albeit the products in opposite
absolute configurations. Low ee values were attained with the
ortho-substituted and cyclic enamides (3h and 3j). It is
noteworthy that a 53% enhancement of enantioselectivity for
(S,S)-L3 (entry 10) could be achieved for cyclic enamide 3j
upon the addition of KBArF.
Asymmetric hydroformylation of olefins is an important
and useful methodology to prepare chiral aldehydes which can
be easily derived into other fine chemicals and pharmaceutical
products.12 Having established the successful application of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 11
standard, published methods and were distilled before use. All
1
2
3
4
5
6
7
8
Table 4. Asymmetric hydroformylation of styrene
derivatives: substrate scopea
other chemicals were used as received from Aldrich, Acros
and Alfa without further purification. The diaza-crown
ethers,10.13 phosphoramidites9 and substrates14,15 were
synthesized according to the modified literature methods.
General procedure A: Synthesis of Diaza-Crown Ethers.
The 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane was bought
from TCI and used without purification. The 1,4,7,13-
tetraoxa-10,16-diazacyclooctadecane, 1,4,7,10-tetraoxa-13,16-
O
Rh(acac)(CO)2

O
R
R
+
R
L3
(S,S)- /NaBArF = 1:1
10 atm (H2:CO = 1:1)
CH2Cl2, 24 h, r.t.
7a-7f
5a-5f
6a-6f
diazacyclooctadecane,
dihydrobromide
1,7-dioxa-4,10-diazacyclododecane
1,4,7,13,16,19-hexaoxa-10,22-
conv.
(%)b
ee
entry
R
additive
b/lb
9
(%)c
and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
diazacyclotetracosane were prepared according to literature
procedures.[10.13] The yield of crown ether is the isolate yield
for the last step.
1d
2d
3d
4
H (5a)
H (5a)
none
NaBArF
KBArF
NaBArF
none
90:10
92:8
82:18
93:7
92:8
93:7
92:8
92:8
91:9
92:8
93:7
94:6
94:6
95:5
10
+26 (S)
43
-70 (R)
-16 (R)
-70 (R)
+15
1,4,7,13-tetraoxa-10,16-diazacyclooctadecane.
Known
10
H (5a)
compound.13f An amorphous white solid (1.34 g, 58% yield).
1H NMR (500 MHz, CDCl3): δ (ppm) 3.65-3.63 (m, 4H),
3.60-3.55 (m, 12H), 2.79-2.76 (m, 8H), 2.15 (brs, 2H).
13C{1H} NMR (125 MHz, CDCl3): δ (ppm) 70.6, 70.6, 70.5,
49.7, 49.5.
H (5a)
>99
52
5
4-Me (5b)
4-Me (5b)
4-MeO (5c)
6
NaBArF
none
98
-73
1,4,7,10-tetraoxa-13,16-diazacyclooctadecane.
Known
7
13
+17
compound.13d A yellow oil (2.16 g, 30% yield). 1H NMR (300
MHz, CDCl3): δ (ppm) 3.67-3.58 (m, 16H), 2.80-2.76 (m,
8H), 1.84 (brs, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ (ppm)
70.8, 70.6, 70.5, 70.3, 49.2, 49.2.
8
4-MeO (5c) NaBArF
89
-68
9
4-F (5d)
4-F (5d)
4-Cl (5e)
4-Cl (5e)
4-Br (5f)
4-Br (5f)
none
NaBArF
none
90
+32
10
11
12
13
14
>99
42
-65
1,7-dioxa-4,10-diazacyclododecane
dihydrobromide.
Known compound.13c An amorphous white solid (1.17 g, 79%
yield). 1H NMR (300 MHz, D2O): δ (ppm) 3.89 (t, J = 4.7 Hz,
8H), 3.43 (t, J = 4.8 Hz, 8H). 13C{1H} NMR (75 MHz, D2O):
δ (ppm) 64.8, 46.3 (MeOH as the internal standard).
+30
NaBArF
none
>99
47
-63
+21
1,4,7,13,16,19-hexaoxa-10,22-diazacyclotetracosane.
1
Known compound.10b A yellow oil (845 mg, 94% yield). H
NaBArF
>99
-62
NMR (300 MHz, CDCl3): δ (ppm) 3.69-3.59 (m, 24H), 2.83
(t, J = 5.1 Hz, 8H), 2.51 (brs, 2H). 13C{1H} NMR (75 MHz,
CDCl3): δ (ppm) 70.8, 70.7, 70.4, 49.0.
a
Reaction conditions: Rh(acac)(CO)2 (2.0 mol %), (S,S)-L3 (2.0
mol %), NaBArF (2.0 mol %), substrate (0.1 mmol), CH2Cl2 (1
b
mL), syngas (H2/CO = 1:1, 10 atm), r.t. for 24 h.
The
conversions and b/l ratios were determined by 1H NMR (entries 4-
General procedure B: Synthesis of Crown Ether-Based
c
Bisphosphoramidite Ligands. To a solution of diaza-crown
13) and GC (entries 1-3) analysis. Based on GC analysis with a
Supelco’s Beta Dex 225 column (30 m×0.25 mm×0.25 µm).
Syngas (H2/CO = 1:1, 50 atm), r.t. for 12 h.
o
d
ether (1 mmol) and Et3N (4 mmol) in THF (50 mL) at 0 C,
freshly
prepared
(S)-[1,1’-binaphthyl-2,2’-diyl]
chlorophosphite (2.4 mmol) in THF (10 mL) was added
dropwise. The resulting mixture was stirred at room
temperature overnight. The precipitate was filtered over a pad
of Celite. After the solvent was removed under reduced
pressure, the residue was purified by flash column
chromatography on silica gel to give (S,S)-L as a white foam.
Ligand (S,S)-L1. Known compound.9 An amorphous white
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all
experiments were carried out under an atmosphere of nitrogen
using standard Schlenk techniques or in a nitrogen-filled
25
glovebox. H NMR, 13C{1H} NMR spectra and 31P{1H} NMR
1
solid (648 mg, 73% yield). [α]D = +408.0 (c 0.25, CH2Cl2).
1H NMR (500 MHz, CD2Cl2): δ (ppm) 8.01 (d, J = 8.5 Hz,
2H), 7.97 (d, J = 8.0 Hz, 2H), 7.81 (t, J = 7.5 Hz, 4H), 7.52 (d,
J = 9.0 Hz, 2H), 7.47-7.44 (m, 2H), 7.38-7.25 (m, 10H), 7.10
(t, J = 7.8 Hz, 2H), 3.51-3.46 (m, 12H), 3.41-3.37 (m, 4H),
3.18-3.03 (m, 8H). 13C{1H} NMR (125 MHz, CD2Cl2): δ
(ppm) 150.2, 150.2, 149.9, 133.2, 132.9, 131.9, 131.1, 130.7,
130.5, 128.8, 128.7, 127.2, 127.1, 126.6, 126.4, 125.3, 125.0,
124.4, 124.4, 122.7, 122.4, 122.3, 71.9, 71.8, 71.1, 46.0, 45.8.
31P{1H} NMR (202 MHz, CD2Cl2): δ (ppm) 150.4. HRMS
spectra were recorded on Bruker Model Avance DMX 300
Spectrometer (1H 300 MHz and 13C{1H} 75 MHz,
respectively), Bruker Model Avance DMX 400 Spectrometer
(1H 400 MHz, 13C{1H} 100 MHz and 31P{1H} 162 MHz,
respectively) and Bruker Model Avance DMX 500
Spectrometer (1H 500 MHz, 13C{1H} 125 MHz and 31P{1H}
202 MHz, respectively). Chemical shifts (δ) were given in
ppm and were referenced to residual solvent or TMS peaks.
Optical rotations were measured with Rudolph Autopl VI
polarimeter. High resolution mass spectra (P-ESI HRMS)
+
(ESI-orbitrap): m/z calcd for C52H49O8N2P2 ([M+H]+):
were obtained on Thermo Fisher
Q
Exactive Mass
891.29587, found: 891.29447; and m/z calcd. for
C52H48O8N2NaP2+ ([M+Na]+): 913.27781, found: 913.27620.
Ligand (S,S)-L2. New compound. An amorphous white solid
Spectrometer (ESI-orbitrap mass analyzer). HPLC analyses
were performed on a Varian Prostar 210 liquid chromatograph
and an Agilent Technologies 1260 infinity liquid
chromatograph. GC analyses were obtained on an Agilent
Technologies 7890B. All organic solvents were dried using
25
1
(632 mg, 71% yield). [α]D = +323.2 (c 0.25, CH2Cl2). H
NMR (500 MHz, CD2Cl2): δ (ppm) 8.00 (d, J = 7.5 Hz, 2H),
7.97-7.89 (m, 6H), 7.49 (d, J = 8.5 Hz, 2H), 7.45-7.22 (m,
ACS Paragon Plus Environment

Page 5 of 11
The Journal of Organic Chemistry
Methyl acetylphenylalaninate (2a). Known compound.14b An
14H), 3.57-3.47 (m, 12H), 3.43 (t, J = 5.8 Hz, 4H), 3.21-3.05
(m, 8H). 13C{1H} NMR (125 MHz, CD2Cl2): δ (ppm) 150.2,
150.2, 149.9, 133.1, 132.9, 131.8, 131.2, 130.7, 130.5, 128.8,
128.7, 127.1, 127.1, 126.5, 126.4, 125.2, 125.0, 124.3, 124.3,
122.7, 122.4, 122.3, 72.1, 72.0, 71.2, 70.8, 46.6, 46.4, 46.2,
46.0. 31P{1H} NMR (202 MHz, CD2Cl2): δ (ppm) 150.2.
25
1
2
3
4
5
6
7
8
amorphous white solid (10.7 mg, 97% yield). [α]D = -105 (c
25
0.25, CHCl3) for >99% ee (R)-2a; [α]D = +104 (c 0.25,
CHCl3) for 94% ee (S)-2a, [Lit.14c: [α]D25 = -105 (c 1.0, CHCl3)
1
for 96.5% ee (R)-2a]. H NMR (400 MHz, CDCl3): δ (ppm)
7.31-7.23 (m, 3H), 7.09 (d, J = 6.8 Hz, 2H), 5.93 (d, J = 6.8
Hz, 1H), 4.91-4.86 (m, 1H), 3.73 (s, 3H), 3.18-3.07 (m, 2H),
1.98 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
172.2, 169.7, 136.0, 129.4, 128.7, 127.3, 53.3, 52.5, 38.0,
23.3. Enantiomeric excess was determined by GC with a
Varian Chirasil-L-Val column CP7495 (25 m×0.25 mm); (R)-
2a: t1 = 4.8 min (major); (S)-2a: t1 = 4.9 min (minor), t2 = 5.2
min (major). The absolute configuration of major isomer was
determined by comparing the rotation value with literature
data.
+
HRMS (ESI-orbitrap): m/z calcd. for C52H49O8N2P2
([M+H]+): 891.29587, found: 891.29463; and m/z calcd. for
C52H48O8N2NaP2+ ([M+Na]+): 913.27781, found: 913.27637.
Ligand (S,S)-L3. New compound. An amorphous white solid
9
25
1
(667 mg, 75% yield). [α]D = +324.4 (c 0.25, CH2Cl2). H
NMR (500 MHz, CD2Cl2): δ (ppm) 7.96-7.89 (m, 8H), 7.44-
7.35 (m, 8H), 7.32-7.26 (m, 4H), 7.24-7.18 (m, 4H), 3.60-3.38
(m, 12H), 3.30-3.16 (m, 8H), 2.92-2.79 (m, 4H). 13C{1H}
NMR (125 MHz, CD2Cl2): δ (ppm) 150.4, 150.4, 149.9, 133.1,
133.0, 131.8, 131.1, 130.6, 130.4, 128.7, 128.7, 127.1, 127.0,
126.4, 126.4, 125.1, 124.9, 124.3, 124.3, 122.6, 122.5, 72.1,
71.0, 70.7, 70.6, 45.5, 45.3, 44.8, 44.7. 31P{1H} NMR (202
MHz, CD2Cl2): δ (ppm) 150.1. HRMS (ESI-orbitrap): m/z
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 2-acetamido-3-(p-tolyl)propanoate (2b). Known
compound.14b An amorphous white solid (11.5 mg, 98%
25
yield). [α]D25 = -98 (c 0.25, CHCl3) for >99% ee (R)-2b; [α]D
= +94 (c 0.25, CHCl3) for 94% ee (S)-2b, [Lit.14c: [α]D25 = -100
(c 1.0, CHCl3) for 97% ee (R)-2b]. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.09 (d, J = 7.6 Hz, 2H), 6.97 (d, J = 8.0 Hz,
2H), 5.91 (d, J = 7.2 Hz, 1H), 4.88-4.83 (m, 1H), 3.73 (s, 3H),
3.13-3.03 (m, 2H), 2.31 (s, 3H), 1.98 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 172.3, 169.7, 136.9, 132.8, 129.4,
129.2, 53.3, 52.4, 37.5, 23.3, 21.2. Enantiomeric excess was
determined by GC with a Varian Chirasil-L-Val column
CP7495 (25 m×0.25 mm); (R)-2b: t1 = 6.5 min (major), t2 =
6.9 min (minor); (S)-2b: t1 = 6.6 min (minor), t2 = 7.3 min
(major). The absolute configuration of major isomer was
determined by comparing the rotation value with literature
data.
+
calcd. for C52H49O8N2P2 ([M+H]+): 891.29587, found:
+
891.29474; and m/z calcd. for C52H48O8N2NaP2 ([M+Na]+):
913.27781, found: 913.27645.
Ligand (S,S)-L4. New compound. An amorphous white solid
25
1
(545 mg, 68% yield). [α]D = +320.4 (c 0.25, CH2Cl2). H
NMR (400 MHz, CD2Cl2): δ (ppm) 7.98 (d, J = 8.8 Hz, 2H),
7.94-7.88 (m, 6H), 7.52 (d, J = 8.8 Hz, 2H), 7.43-7.20 (m,
14H), 3.58-3.53 (m, 4H), 3.40-3.35 (m, 4H), 3.23-3.14 (m,
4H), 3.13-3.04 (m, 4H). 13C{1H} NMR (125 MHz, CD2Cl2): δ
(ppm) 150.5, 150.5, 149.8, 133.1, 133.0, 131.9, 131.2, 130.7,
130.6, 128.8, 128.7, 127.2, 127.1, 126.5, 126.5, 125.3, 125.0,
124.4, 124.4, 122.7, 122.7, 122.4, 70.9, 70.9, 47.4, 47.3.
31P{1H} NMR (162 MHz, CD2Cl2): δ (ppm) 150.5. HRMS
Methyl 2-acetamido-3-(4-methoxyphenyl)propanoate (2c).
+
(ESI-orbitrap): m/z calcd. for C48H41O6N2P2 ([M+H]+):
Known compound.14b An amorphous white solid (12.2 mg,
25
803.24344, found: 803.24268; and m/z calcd. for
C48H40O6N2NaP2+ ([M+Na]+): 825.22538, found: 825.22461.
Ligand (S,S)-L5. New compound. An amorphous white solid
97% yield). [α]D = -98 (c 0.25, CHCl3) for >99% ee (R)-2c;
25
[α]D25 = +96 (c 0.25, CHCl3) for 95% ee (S)-2c, [Lit.14c: [α]D
1
= +102 (c 1.2, CHCl3) for 99% ee (S)-2c]. H NMR (400
25
1
(620 mg, 63% yield). [α]D = +295.2 (c 0.25, CH2Cl2). H
NMR (400 MHz, CD2Cl2): δ (ppm) 7.99 (d, J = 8.8 Hz, 2H),
7.96-7.91 (m, 6H), 7.51 (d, J = 8.8 Hz, 2H), 7.45-7.23 (m,
14H), 3.57-3.54 (m, 16H), 3.49 (t, J = 5.8 Hz, 8H), 3.14-3.09
(m, 8H). 13C{1H} NMR (100 MHz, CD2Cl2): δ (ppm) 150.4,
150.3, 150.0, 133.2, 133.0, 131.8, 131.2, 130.6, 130.5, 128.8,
127.2, 127.1, 126.5, 126.4, 125.2, 125.0, 124.4, 124.4, 122.8,
122.5, 122.4, 71.5, 71.4, 71.2, 70.8, 46.1, 45.9. 31P{1H} NMR
(162 MHz, CD2Cl2): δ (ppm) 150.0. HRMS (ESI-orbitrap):
MHz, CDCl3): δ (ppm) 7.00 (d, J = 8.4 Hz, 2H), 6.82 (d, J =
8.4 Hz, 2H), 5.91 (d, J = 7.2 Hz, 1H), 4.86-4.81 (m, 1H), 3.78
(s, 3H), 3.72 (s, 3H), 3.11-3.00 (m, 2H), 1.98 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 172.3, 169.7, 158.9, 130.4,
127.9, 114.2, 55.3, 53.4, 52.4, 37.1, 23.3. Enantiomeric excess
was determined by GC with a Varian Chirasil-L-Val column
CP7495 (25 m×0.25 mm); (R)-2c: t1 = 12.0 min (major), t2 =
12.9 min (minor); (S)-2c: t1 = 11.8 min (minor), t2 = 12.8 min
(major). The absolute configuration of major isomer was
determined by comparing the rotation value with literature
data.
+
m/z calcd. for C56H57O10N2P2 ([M+H]+): 979.34830, found:
+
979.34814; and m/z calcd. for C56H56O10N2NaP2 ([M+Na]+):
1001.33024, found: 1001.32940.
Methyl 2-acetamido-3-(4-fluorophenyl)propanoate (2d).
Known compound.14b An amorphous white solid (11.5 mg,
General procedure C: Asymmetric Hydrogenation of -
Dehydroamino Acid Esters. Rh(NBD)2BF4 (0.0050 mmol)
and L (0.0055 mmol) in DCM (1.0 mL) was stirred at room
temperature for 1 min under nitrogen atmosphere in a glove
box. Then a 30 mL glass-lined stainless-steel reactor equipped
25
96% yield). [α]D = -80 (c 0.25, CHCl3) for >99% ee (R)-2d;
25
25
[α]D = +78 (c 0.25, CHCl3) for 91% ee (S)-2d, [Lit.8d: [α]D
= +85 (c 1.0, CHCl3) for 95% ee (S)-2d]. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.07-7.03 (m, 2H), 6.99-6.95 (m, 2H), 5.94
(d, J = 6.4 Hz, 1H), 4.88-4.83 (m, 1H), 3.72 (s, 3H), 3.15-3.03
(m, 2H), 1.99 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 172.1, 169.7, 162.2 (d, J = 243 Hz), 131.7 (d, J = 3 Hz),
130.9 (d, J = 8 Hz), 115.6 (d, J = 21 Hz), 53.3, 52.5, 37.3,
23.3. Enantiomeric excess was determined by GC with a
Varian Chirasil-L-Val column CP7495 (25 m×0.25 mm); (R)-
2d: t1 = 5.2 min (major), t2 = 5.5 min (minor); (S)-2d: t1 = 7.4
min (minor), t2 = 8.1 min (major). The absolute configuration
of major isomer was determined by comparing the rotation
value with literature data.
with
a magnetic stirrer bar was charged with the
dehydroamino acid ester (0.05 mmol) in DCM (1.9 mL) and
the above in situ prepared catalyst (0.1 mL, 0.0005 mmol).
The autoclave was closed and pressurized with hydrogen gas
to 5 atm. The mixture was stirred at room temperature for 1 h.
Then the hydrogen gas was carefully released, the conversion
and enantiomeric excess of the product were determined by
GC with a chiral column. The reaction mixture was filtered
through a short pad of silica eluted with EtOAc/petroleum
ether to give the pure product.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 11
25
25
[α]D = +50 (c 0.25, CHCl3) for 97% ee (S)-2i, [Lit.14d: [α]D
Methyl 2-acetamido-3-(4-chlorophenyl)propanoate (2e).
1
Known compound.14b An amorphous white solid (12.5 mg,
1
2
3
4
5
6
7
8
= -64 (c 1.0, CHCl3) for 99% ee (R)-2i]. H NMR (400 MHz,
CDCl3): δ (ppm) 7.27-7.22 (m, 1H), 7.09-7.06 (m, 1H), 6.92-
6.86 (m, 2H), 6.22 (d, J = 6.4 Hz, 1H), 4.78-4.72 (m, 1H), 3.84
(s, 3H), 3.71 (s, 3H), 3.11 (d, J = 6.4 Hz, 2H), 1.93 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 172.6, 169.8,
157.7, 131.3, 128.7, 124.7, 121.0, 110.7, 55.5, 53.2, 52.3,
32.5, 23.2. Enantiomeric excess was determined by GC with a
Varian Chirasil-L-Val column CP7495 (25 m×0.25 mm); (R)-
2i: t1 = 9.30 min (major), t2 = 9.8 min (minor); (S)-2i: t1 = 9.2
min (minor), t2 = 10.2 min (major). The absolute configuration
of major isomer was determined by comparing the rotation
value with literature data.
25
98% yield). [α]D = -96 (c 0.25, CHCl3) for >99% ee (R)-2e;
25
[α]D25 = +90 (c 0.25, CHCl3) for 93% ee (S)-2e, [Lit.14c: [α]D
= -110 (c 1.0, CHCl3) for 97% ee (R)-2e]. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.25 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz,
2H), 5.95 (d, J = 6.8 Hz, 1H), 4.89-4.84 (m, 1H), 3.72 (s, 3H),
3.16-3.03 (m, 2H), 1.99 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 172.0, 169.7, 134.5, 133.2, 130.7, 128.9,
53.2, 52.6, 37.4, 23.3. Enantiomeric excess was determined by
GC with a Varian Chirasil-L-Val column CP7495 (25 m×0.25
mm); (R)-2e: t1 = 10.0 min (major), t2 = 10.8 min (minor); (S)-
2e: t1 = 10.0 min (minor), t2 = 11.2 min (major). The absolute
configuration of major isomer was determined by comparing
the rotation value with literature data.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 2-acetamido-3-(2-chlorophenyl)propanoate (2j).
Known compound.14b An amorphous white solid (12.5 mg,
25
98% yield). [α]D = -58 (c 0.25, CHCl3) for >99% ee (R)-2j;
Methyl 2-acetamido-3-(4-bromophenyl)propanoate (2f).
25
25
[α]D = +51 (c 0.25, CHCl3) for 94% ee (S)-2j, [Lit.14d: [α]D
Known compound.14a An amorphous white solid (14.7 mg,
= +58 (c 1.0, CHCl3) for 99% ee (S)-2j]. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.37-7.34 (m, 1H), 7.21-7.18 (m, 3H), 6.02
(d, J = 7.2 Hz, 1H), 4.93-4.88 (m, 1H), 3.72 (s, 3H), 3.33-3.16
(m, 2H), 1.96 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 172.2, 169.8, 134.6, 134.3, 131.4, 129.8, 128.7, 127.1,
52.6, 35.6, 23.2. Enantiomeric excess was determined by GC
with a Varian Chirasil-L-Val column CP7495 (25 m×0.25
mm); (R)-2j: t1 = 8.8 min (major), t2 = 9.4 min (minor); (S)-2j:
t1 = 8.6 min (minor), t2 = 9.3 min (major). The absolute
configuration of major isomer was determined by comparing
the rotation value with literature data.
25
98% yield). [α]D = -89 (c 0.25, CHCl3) for >99% ee (R)-2f;
25
25
[α]D = +87 (c 0.25, CHCl3) for 91% ee (S)-2f, [Lit.14d: [α]D
= +79 (c 1.0, CHCl3) for 81% ee (S)-2f]. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.41 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz,
2H), 5.95 (d, J = 7.2 Hz, 1H), 4.89-4.84 (m, 1H), 3.72 (s, 3H),
3.14-3.01 (m, 2H), 1.99 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 172.0, 169.7, 135.0, 131.8, 131.1, 121.3,
53.1, 52.6, 37.4, 23.3. Enantiomeric excess was determined by
GC with a Varian Chirasil-L-Val column CP7495 (25 m×0.25
mm); (R)-2f: t1 = 14.2 min (major), t2 = 15.4 min (minor); (S)-
2f: t1 = 14.4 min (minor), t2 = 16.4 min (major). The absolute
configuration of major isomer was determined by comparing
the rotation value with literature data.
Methyl 2-acetamido-3-(2-nitrophenyl)propanoate (2k).
Known compound.14f An amorphous white solid (13.0 mg,
25
98% yield). [α]D = -14 (c 0.25, CHCl3) for >99% ee (R)-2k;
Methyl 2-acetamido-3-(4-nitrophenyl)propanoate (2g).
[α]D25 = +12 (c 0.25, CHCl3) for 96% ee (S)-2k. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.91 (d, J = 8.0 Hz, 1H), 7.57-7.54 (m,
1H), 7.43-7.39 (m, 2H), 6.22 (d, J = 7.2 Hz, 1H), 4.94-4.88
(m, 1H), 3.72 (s, 3H), 3.53-3.30 (m, 2H), 1.93 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 171.8, 170.0,
150.0, 133.2, 132.8, 131.6, 128.4, 125.0, 53.1, 52.8, 34.8,
23.1. Enantiomeric excess was determined by GC with a
Varian Chirasil-L-Val column CP7495 (25 m×0.25 mm); (R)-
2k: t1 = 19.1 min (major), t2 = 20.5 min (minor); (S)-2k: t1 =
19.2 min (minor), t2 = 21.4 min (major). The configuration of
the chiral product was assigned by analogy.
Known compound.14a An amorphous white solid (12.9 mg,
25
97% yield). [α]D = -92 (c 0.25, CHCl3) for >99% ee (R)-2g;
25
[α]D25 = +84 (c 0.25, CHCl3) for 87% ee (S)-2g, [Lit.14b: [α]D
1
= +113.4 (c 1.1, CHCl3) for 99% ee (S)-2g]. H NMR (400
MHz, CDCl3): δ (ppm) 8.15 (d, J = 8.4 Hz, 2H), 7.28 (d, J =
8.4 Hz, 2H), 6.03 (d, J = 7.2 Hz, 1H), 4.95-4.90 (m, 1H), 3.74
(s, 3H), 3.32-3.15 (m, 2H), 2.00 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 171.7, 169.8, 147.3, 144.0, 130.3,
123.8, 53.0, 52.8, 38.0, 23.3. Enantiomeric excess was
determined by GC with a Varian Chirasil-L-Val column
CP7495 (25 m×0.25 mm); (R)-2g: t1 = 14.5 min (major), t2 =
15.6 min (minor); (S)-2g: t1 = 14.2 min (minor), t2 = 15.6 min
(major). The absolute configuration of major isomer was
determined by comparing the rotation value with literature
data.
Methyl 2-acetamido-3-(3-methoxyphenyl)propanoate (2l).
Known compound.14f An amorphous white solid (12.3 mg,
25
98% yield). [α]D = -88 (c 0.25, CHCl3) for 98% ee (R)-2l;
25
25
[α]D = +83 (c 0.25, CHCl3) for 95% ee (S)-2l, [Lit.14d: [α]D
1
= -105 (c 1.1, CHCl3) for 97.8% ee (R)-2l]. H NMR (400
MHz, CDCl3): δ (ppm) 7.20 (t, J = 8.0 Hz, 1H), 6.80-6.77 (m,
1H), 6.68-6.63 (m, 2H), 5.94 (d, J = 7.2 Hz, 1H), 4.90-4.85
(m, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.14-3.04 (m, 2H), 1.99 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 172.2, 169.7,
159.9, 137.5, 129.7, 121.7, 115.2, 112.6, 55.3, 53.2, 52.5,
38.0, 23.3. Enantiomeric excess was determined by GC with a
Varian Chirasil-L-Val column CP7495 (25 m×0.25 mm); (R)-
2l: t1 = 10.6 min (major), t2 = 11.4 min (minor); (S)-2l: t1 =
10.7 min (minor), t2 = 11.7 min (major). The absolute
configuration of major isomer was determined by comparing
the rotation value with literature data.
Methyl 2-acetamido-3-(o-tolyl)propanoate (2h). Known
compound.14e An amorphous white solid (11.5 mg, 98%
yield). [α]D25 = -53 (c 0.25, CHCl3) for >99% ee (R)-2h; [α]D
25
= +50 (c 0.25, CHCl3) for 93% ee (S)-2h. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.17-7.09 (m, 3H), 7.02 (d, J = 7.2 Hz, 1H),
5.97 (d, J = 7.2 Hz, 1H), 4.89-4.83 (m, 1H), 3.68 (s, 3H), 3.17-
3.01 (m, 2H), 2.33 (s, 3H), 1.96 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 172.8, 169.8, 136.9, 134.4, 130.7,
129.8, 127.3, 126.1, 52.5, 52.4, 35.8, 23.2, 19.4. Enantiomeric
excess was determined by GC with a Varian Chirasil-L-Val
column CP7495 (25 m×0.25 mm); (R)-2h: t1 = 6.7 min
(major), t2 = 7.0 min (minor); (S)-2h: t1 = 6.6 min (minor), t2 =
7.3 min (major). The configuration of the chiral product was
assigned by analogy.
Methyl 2-acetamido-3-(3-fluorophenyl)propanoate (2m).
Known compound.14f An amorphous white solid (11.4 mg,
95% yield). [α]D25 = -95 (c 0.25, CHCl3) for >99% ee (R)-2m;
Methyl 2-acetamido-3-(2-methoxyphenyl)propanoate (2i).
[α]D25 = +94 (c 0.25, CHCl3) for 93% ee (S)-2m, [Lit.14b: [α]D
25
Known compound.14e An amorphous white solid (12.1 mg,
1
25
= +99.7 (c 0.7, CHCl3) for 99% ee (S)-2m]. H NMR (400
96% yield). [α]D = -53 (c 0.25, CHCl3) for >99% ee (R)-2i;
ACS Paragon Plus Environment

Page 7 of 11
The Journal of Organic Chemistry
MHz, CDCl3): δ (ppm) 7.28-7.22 (m, 1H), 6.96-6.92 (m, 1H),
1.49 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
1
2
3
4
5
6
7
8
6.87 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 9.6 Hz, 1H), 5.98 (d, J =
6.4 Hz, 1H), 4.90-4.85 (m, 1H), 3.73 (s, 3H), 3.18-3.06 (m,
2H), 2.00 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
172.0, 169.7, 162.9 (d, J = 244 Hz), 138.5 (d, J = 7 Hz), 130.2
(d, J = 8 Hz), 125.1 (d, J = 3 Hz), 116.3 (d, J = 21 Hz), 114.2
(d, J = 21 Hz), 53.1, 52.6, 37.7 (d, J = 1 Hz), 23.3.
Enantiomeric excess was determined by GC with a Varian
Chirasil-L-Val column CP7495 (25 m×0.25 mm); (R)-2m: t1 =
4.9 min (major), t2 = 5.3 min (minor); (S)-2m: t1 = 5.0 min
(minor), t2 = 5.5 min (major). The absolute configuration of
major isomer was determined by comparing the rotation value
with literature data.
(ppm) 169.2, 143.3, 128.8, 127.5, 126.3, 48.9, 23.6, 21.8.
Enantiomeric excess was determined by GC with a Chirasil-
Dex CB column CP7502 (25m×0.25 mm); (R)-4a: t1 = 8.2 min
(minor), t2 = 8.6 min (major); (S)-4a: t1 = 6.7 min (major), t2 =
7.1 min (minor). The absolute configuration of major isomer
was determined by comparing the rotation value with literature
data.
N-(1-(p-tolyl)ethyl)acetamide (4b). Known compound.15e An
25
amorphous white solid (8.1 mg, 92% yield). [α]D = +138 (c
9
0.25, CHCl3) for 94% ee (R)-4b; [α]D25 = -120 (c 0.25, CHCl3)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
25
for 84% ee (S)-4b; [Lit.15c: [α]D = +146 (c 1.0, CHCl3) for
97% ee (R)-4b]. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.21 (d,
J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 5.70 (brs, 1H), 5.13-
5.06 (m, 1H), 2.33 (s, 3H), 1.97 (s, 3H), 1.47 (d, J = 6.8 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 169.1, 140.3,
137.2, 129.5, 126.3, 48.7, 23.6, 21.8, 21.2. Enantiomeric
excess was determined by GC with a Chirasil-Dex CB column
CP7502 (25 m×0.25 mm); (R)-4b: t1 = 12.5 min (minor), t2 =
13.1 min (major); (S)-4b: t1 = 12.3 min (major), t2 = 12.8 min
(minor). The absolute configuration of major isomer was
determined by comparing the rotation value with literature
data.
Methyl 2-acetamido-3-(3-chlorophenyl)propanoate (2n).
Known compound.14b An amorphous white solid (12.4 mg,
25
97% yield). [α]D = -100 (c 0.25, CHCl3) for 99% ee (R)-2n;
25
[α]D25 = +94 (c 0.25, CHCl3) for 92% ee (S)-2n, [Lit.14b: [α]D
1
= +102 (c 1.2, CHCl3) for 99% ee (S)-2n]. H NMR (400
MHz, CDCl3): δ (ppm) 7.24-7.19 (m, 2H), 7.08 (s, 1H), 7.00-
6.96 (m, 1H), 5.98 (d, J = 6.8 Hz, 1H), 4.89-4.84 (m, 1H), 3.73
(s, 3H), 3.16-3.03 (m, 2H), 2.00 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 171.9, 169.8, 138.1, 134.5, 129.9,
129.6, 127.5, 127.5, 53.2, 52.6, 37.7, 23.3. Enantiomeric
excess was determined by GC with a Varian Chirasil-L-Val
column CP7495 (25 m×0.25 mm); (R)-2n: t1 = 9.2 min
(major), t2 = 9.9 min (minor); (S)-2n: t1 = 9.0 min (minor), t2 =
9.9 min (major). The absolute configuration of major isomer
was determined by comparing the rotation value with literature
data.
Scale-up Asymmetric Hydrogenation of -Dehydroamino
Acid Ester. In a glove box, a 100 mL glass-lined stainless-
steel reactor equipped with a magnetic stirrer bar was charged
with the Rh(NBD)2BF4 (0.010 mmol, 3.7 mg) and L1 (0.011
mmol, 9.8 mg) in DCM (20.0 mL) under nitrogen atmosphere.
The mixture was stirred at room temperature for 2 min. Then
1a (1 mmol, 219 mg) was added. The autoclave was closed
and pressurized with hydrogen gas to 10 atm. The mixture was
stirred at room temperature for 5 h. The hydrogen gas was
carefully released, and the reaction mixture was filtered
through a short pad of silica eluted with EtOAc/petroleum
ether to give the pure product 2a (218 mg, 99% yield, >99%
ee).
N-(1-(4-methoxyphenyl)ethyl)acetamide
(4c).
Known
compound.15e An amorphous white solid (8.8 mg, 91% yield).
[α]D25 = +116 (c 0.25, CHCl3) for 89% ee (R)-4c; [α]D25 = -107
25
(c 0.25, CHCl3) for 82% ee (S)-4c; [Lit.15c: [α]D = +145 (c
1
1.0, CHCl3) for 98% ee (R)-4c]. H NMR (400 MHz, CDCl3):
δ (ppm) 7.26-7.23 (m, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.64 (brs,
1H), 5.12-5.05 (m, 1H), 3.79 (s, 3H), 1.97 (s, 3H), 1.47 (d, J =
6.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
169.1, 159.0, 135.4, 127.6, 114.2, 55.5, 48.4, 23.7, 21.7.
Enantiomeric excess was determined by GC with a Chirasil-
Dex CB column CP7502 (25 m×0.25 mm); (R)-4c: t1 = 27.1
min (minor), t2 = 28.6 min (major); (S)-4c: t1 = 27.4 min
(major), t2 = 28.7 min (minor). The absolute configuration of
major isomer was determined by comparing the rotation value
with literature data.
N-(1-(4-fluorophenyl)ethyl)acetamide
(4d).
Known
compound.14b An amorphous white solid (8.5 mg, 94% yield).
[α]D25 = +120 (c 0.25, EtOH) for 93% ee (R)-4d; [α]D25 = -104
(c 0.25, EtOH) for 83% ee (S)-4d; [Lit.14b: [α]D25 = -126 (c 1.0,
1
General procedure D: Asymmetric Hydrogenation of
Enamides. Rh(NBD)2BF4 (0.0050 mmol) and L (0.0055
mmol) in DCM (1.0 mL) was stirred at room temperature for 1
min under nitrogen atmosphere in a glove box. Then a 30 mL
glass-lined stainless-steel reactor equipped with a magnetic
stirrer bar was charged with the enamide (0.05 mmol) in the
mixed solvent (n-hexane 1.0 mL, DCM 0.9 mL) and the above
in situ prepared catalyst (0.1 mL, 0.0005 mmol). The
autoclave was closed and pressurized with hydrogen gas to 20
atm. The mixture was stirred at room temperature for 12 h.
Then the hydrogen gas was carefully released, the conversion
and enantiomeric excess of the product were determined by 1H
NMR spectroscopy and GC with a chiral column. The reaction
mixture was filtered through a short pad of silica eluted with
EtOAc/petroleum ether to give the pure product.
EtOH) for 99% ee (S)-4d]. H NMR (400 MHz, CDCl3): δ
(ppm) 7.29-7.27 (m, 2H), 7.04-6.99 (m, 2H), 5.73 (brs, 1H),
5.13-5.06 (m, 1H), 1.98 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 169.2, 162.1 (d, J
= 244 Hz), 139.1 (d, J = 3 Hz), 128.0 (d, J = 8 Hz), 115.6 (d, J
= 21 Hz), 48.3, 23.6, 21.9. Enantiomeric excess was
determined by GC with a Chirasil-Dex CB column CP7502
(25 m×0.25 mm); (R)-4d: t1 = 8.9 min (minor), t2 = 9.4 min
(major); (S)-4d: t1 = 9.0 min (major), t2 = 9.4 min (minor). The
absolute configuration of major isomer was determined by
comparing the rotation value with literature data.
N-(1-(4-chlorophenyl)ethyl)acetamide
(4e).
Known
compound.14b An amorphous white solid (9.0 mg, 91% yield).
[α]D25 = +142 (c 0.25, EtOH) for 96% ee (R)-4e; [α]D25 = -128
(c 0.25, EtOH) for 87% ee (S)-4e; [Lit.14b: [α]D25 = -128 (c 1.0,
N-(1-phenylethyl)acetamide (4a). Known compound.14f An
1
EtOH) for 99% ee (S)-4e]. H NMR (400 MHz, CDCl3): δ
25
amorphous white solid (7.2 mg, 88% yield). [α]D = +131 (c
(ppm) 7.29 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 5.76
(brs, 1H), 5.12-5.05 (m, 1H), 1.98 (s, 3H), 1.45 (d, J = 6.8 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 169.3, 141.9,
133.2, 128.9, 127.7, 48.3, 23.5, 21.8. Enantiomeric excess was
determined by GC with a Chirasil-Dex CB column CP7502
0.25, CHCl3) for 97% ee (R)-4a; [α]D25 = -120 (c 0.25, CHCl3)
25
for 86% ee (S)-4a; [Lit.15c: [α]D = +141 (c 1.0, CHCl3) for
1
98% ee (R)-4a]. H NMR (400 MHz, CDCl3): δ (ppm) 7.34-
7.30 (m, 5H), 5.74 (brs, 1H), 5.16-5.09 (m, 1H), 1.98 (s, 3H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 11
(25 m×0.25 mm); (R)-4e: t1 = 22.8 min (minor), t2 = 24.2 min (major); (S)-4i: t1 = 18.7 min (major), t2 = 19.6 min (minor).
1
2
3
4
5
6
7
8
(major); (S)-4e: t1 = 22.4 min (major), t2 = 23.7 min (minor).
The absolute configuration of major isomer was determined by
comparing the rotation value with literature data.
The absolute configuration of major isomer was determined by
comparing the rotation value with literature data.
N-(1,2,3,4-tetrahydronaphthalen-1-yl)acetamide
(4j).
N-(1-(4-bromophenyl)ethyl)acetamide
(4f).
Known
Known compound.15b An amorphous white solid (8.5 mg, 90%
compound.15e An amorphous white solid (11.6 mg, 96%
25
25
yield). [α]D = +46 (c 0.25, CHCl3) for 39% ee (R)-4j; [α]D
25
25
= -28 (c 0.25, CHCl3) for 23% ee (S)-4j; [Lit.14b: [α]D = -93
(c 1.0, CHCl3) for 87% ee (S)-4j]. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.28-7.08 (m, 4H), 5.72 (brs, 1H), 5.20-5.15
(m, 1H), 2.85-2.71 (m, 2H), 2.08-2.01 (m, 4H), 1.84-1.81 (m,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 169.3, 137.7,
136.8, 129.3, 128.9, 127.4, 126.4, 47.6, 30.2, 29.4, 23.7, 20.0.
Enantiomeric excess was determined by GC with a Chirasil-
Dex CB column CP7502 (25 m × 0.25 mm); (R)-4j: t1 = 31.9
min (minor), t2 = 37.5 min (major); (S)-4j: t1 = 31.7 min
(major), t2 = 37.2 min (minor). The absolute configuration of
major isomer was determined by comparing the rotation value
with literature data.
yield). [α]D = +118 (c 0.25, CHCl3) for >99% ee (R)-4f;
[α]D25 = -104 (c 0.25, CHCl3) for 90% ee (S)-4f; [Lit.15d: [α]D
25
= -85 (c 1.2, CHCl3) for 95.4% ee (S)-4f]. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.45 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz,
2H), 5.68 (brs, 1H), 5.11-5.04 (m, 1H), 1.98 (s, 3H), 1.46 (d, J
= 6.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
169.2, 142.4, 131.9, 128.1, 121.3, 48.4, 23.6, 21.8.
Enantiomeric excess was determined by GC with a Chirasil-
Dex CB column CP7502 (25 m×0.25 mm); (R)-4f: t2 = 38.6
min (major); (S)-4f: t1 = 36.3 min (major), t2 = 38.6 min
(minor). The absolute configuration of major isomer was
determined by comparing the rotation value with literature
data.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure E: Asymmetric Hydroformylation of
Styrenes. Rh(acac)(CO)2 (0.01 mmol), L3 (0.01 mmol) and
NaBArF (0.01 mmol) in DCM (1.0 mL) was stirred at room
temperature for 1 min under nitrogen atmosphere in a glove
box. Then a 30 mL glass-lined stainless-steel reactor equipped
with a magnetic stirrer bar was charged with styrene 5 (0.1
mmol) in DCM (0.8 mL) and the above in situ prepared
catalyst (0.2 mL, 0.002 mmol). The autoclave was closed and
pressurized with syngas (H2/CO = 1:1) to 10 atm. The mixture
was stirred at room temperature for 24 h. Then the syngas was
carefully released, the conversion, b/l value and enantiomeric
excess of the product were determined by 1H NMR
spectroscopy and GC with a chiral column. The reaction
mixture was filtered through a short pad of silica eluted with
EtOAc/petroleum ether to give the pure product.
N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide
(4g).
Known compound.15e An amorphous white solid (10.3 mg,
25
89% yield). [α]D = +96 (c 0.25, CHCl3) for 98% ee (R)-4g;
25
25
[α]D = -86 (c 0.25, CHCl3) for 87% ee (S)-4g; [Lit.15c: [α]D
= +89 (c 1.0, CHCl3) for 98% ee (R)-4g]. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.59 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz,
2H), 5.79 (brs, 1H), 5.19-5.12 (m, 1H), 2.00 (s, 3H), 1.49 (d, J
= 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
169.4, 147.5, 129.7 (q, J = 32.3 Hz), 126.6, 125.8 (q, J = 3.7
Hz), 124.2 (q, J = 270.3 Hz), 48.7, 23.5, 22.0. Enantiomeric
excess was determined by GC with a Chirasil-Dex CB column
CP7502 (25 m×0.25 mm); (R)-4g: t1 = 10.0 min (minor), t2 =
10.7 min (major); (S)-4g: t1 = 9.8 min (major), t2 = 10.5 min
(minor). The absolute configuration of major isomer was
determined by comparing the rotation value with literature
data.
(R)-2-phenylpropanal ((R)-6a). Known compound.16c
A
25
colorless oil (11.7 mg, 87% yield). [α]D = -146 (c 0.25,
25
CHCl3) for 70% ee (R)-6a, [Lit.16a: [α]D = +197.7 (c 1.0,
N-(1-(2-fluorophenyl)ethyl)acetamide
(4h).
Known
1
compound.14b An amorphous white solid (8.7 mg, 96% yield).
CHCl3) for 99% ee (S)-6a]. H NMR (300 MHz, CDCl3): δ
25
25
(ppm) 9.68 (s, 1H), 7.40-7.27 (m, 3H), 7.21 (d, J = 7.8 Hz,
2H), 3.63 (q, J = 7.0 Hz, 1H), 1.44 (d, J = 7.2 Hz, 3H).
13C{1H} NMR (75 MHz, CDCl3): δ (ppm) 201.2, 137.9, 129.2,
128.4, 127.7, 53.1, 14.7. Enantiomeric excess was determined
by GC with a Supelco’s Beta Dex 225 column (30 m×0.25
mm×0.25 µm); t1 = 12.5 min (major); t2 = 12.8 min (minor),
[Lit.16b: t1 = 12.0 min (R); t2 = 12.2 min (S), enantiomeric
excess was determined by GC analysis with a Supelco’s Beta
Dex 225 column (30 m×0.25 mm×0.25 µm)]. The absolute
configuration was determined by comparing the retention time
and the rotation value with literature data.16b
[α]D = +94 (c 0.25, CHCl3) for 86% ee (R)-4h; [α]D = -75
25
(c 0.25, CHCl3) for 68% ee (S)-4h; [Lit.14b: [α]D = -106 (c
1
0.9, CHCl3) for 99% ee (S)-4h]. H NMR (400 MHz, CDCl3):
δ (ppm) 7.30-7.21 (m, 2H), 7.12-7.00 (m, 2H), 5.95 (brs, 1H),
5.30-5.22 (m, 1H), 1.98 (s, 3H), 1.49 (d, J = 7.2 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 169.1, 161.0 (d, J
= 244 Hz), 130.3 (d, J = 13 Hz), 129.1 (d, J = 9 Hz), 128.5 (d,
J = 5 Hz), 124.5 (d, J = 3 Hz), 116.1 (d, J = 21 Hz), 46.0, 23.6,
21.7 (d, J = 1 Hz). Enantiomeric excess was determined by
HPLC with a Chira-cel AD-H (n-hexane : isopropanol = 95:5,
1 mL/min, 210 nm); (R)-4i: t1 = 9.51 min (major), t2 = 11.50
min (minor); (S)-4i: t1 = 9.49 min (minor), t2 = 11.37 min
(major). The absolute configuration of major isomer was
determined by comparing the rotation value with literature
data.
(R)-2-(p-tolyl)propanal ((R)-6b). Known compound.16c
A
25
colorless oil (11.8 mg, 80% yield). [α]D = -106 (c 0.25,
1
CHCl3) for 73% ee (R)-6b. H NMR (300 MHz, CDCl3): δ
(ppm) 9.65 (s, 1H), 7.18 (d, J = 7.8 Hz, 2H), 7.09 (d, J = 7.8
Hz, 2H), 3.58 (q, J = 7.0 Hz, 1H), 2.34 (s, 3H), 1.41 (d, J = 7.2
Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ (ppm) 201.2,
137.3, 134.7, 129.9, 128.3, 52.7, 21.1, 14.7. Enantiomeric
excess was determined by GC with a Supelco’s Beta Dex 225
column (30 m×0.25 mm×0.25 µm); t1 = 29.4 min (major); t2 =
30.6 min (minor). The configuration of the chiral product was
assigned by analogy.
N-(1-(3-chlorophenyl)ethyl)acetamide
(4i).
Known
compound.14b An amorphous white solid (9.1 mg, 92% yield).
[α]D25 = +138 (c 0.25, EtOH) for 98% ee (R)-4i; [α]D25 = -116
(c 0.25, EtOH) for 86% ee (S)-4i; [Lit.14b: [α]D25 = -106 (c 1.0,
1
EtOH) for 99% ee (S)-4i]. H NMR (400 MHz, CDCl3): δ
(ppm) 7.28-7.18 (m, 4H), 5.78 (brs, 1H), 5.12-5.05 (m, 1H),
1.99 (s, 3H), 1.46 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 169.3, 145.5, 134.6, 130.1, 127.6,
126.4, 124.6, 48.5, 23.5, 21.9. Enantiomeric excess was
determined by GC with a Chirasil-Dex CB column CP7502
(25 m×0.25 mm); (R)-4i: t1 = 18.5 min (minor), t2 = 19.7 min
(R)-2-(4-methoxyphenyl)propanal
((R)-6c).
Known
25
compound.16c A colorless oil (12.3 mg, 75% yield). [α]D = -
1
98 (c 0.25, CHCl3) for 68% ee (R)-6c. H NMR (300 MHz,
CDCl3): δ (ppm) 9.65 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.92
ACS Paragon Plus Environment

Page 9 of 11
The Journal of Organic Chemistry
(d, J = 8.4 Hz, 2H), 3.80 (s, 3H), 3.58 (q, J = 7.0 Hz, 1H), 1.41
(s, 1H), 7.17-7.13 (m, 2H), 7.00-6.94 (m, 2H), 2.93 (t, J = 7.4
Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H). 13C{1H} NMR (75 MHz,
CDCl3): δ (ppm) 201.4, 161.6 (d, J = 244.5 Hz), 136.1, 129.8
(d, J = 8.3 Hz), 115.5 (d, J = 21.1 Hz), 45.5, 27.4.
(d, J = 7.2 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ (ppm)
201.3, 159.1, 129.7, 129.5, 114.6, 55.4, 52.3, 14.8.
Enantiomeric excess was determined by GC with a Supelco’s
Beta Dex 225 column (30 m×0.25 mm×0.25 µm); t1 = 39.5
min (major); t2 = 41.1 min (minor). The configuration of the
chiral product was assigned by analogy.
1
2
3
4
5
6
7
8
3-(4-chlorophenyl)propanal (7e). Known compound.16c
A
colorless oil (6% NMR yield, minor product of
hydroformylation).1H NMR (300 MHz, CDCl3): δ (ppm) 9.81
(s, 1H), 7.25 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 2.92
(t, J = 7.4 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H). 13C{1H} NMR (75
MHz, CDCl3): δ (ppm) 201.1, 139.0, 132.2, 129.8, 128.8,
45.2, 27.5.
(R)-2-(4-fluorophenyl)propanal
((R)-6d).
Known
25
compound.16c A colorless oil (13.4 mg, 88% yield). [α]D = -
1
114 (c 0.25, CHCl3) for 65% ee (R)-6d. H NMR (300 MHz,
9
CDCl3): δ (ppm) 9.65 (s, 1H), 7.20-7.15 (m, 2H), 7.09-7.03
(m, 2H), 3.62 (q, J = 7.0 Hz, 1H), 1.43 (d, J = 7.2 Hz, 3H).
13C{1H} NMR (75 MHz, CDCl3): δ (ppm) 200.8, 162.3 (d, J =
244.5 Hz), 133.5 (d, J = 3.0 Hz), 129.9 (d, J = 8.3 Hz), 116.1
(d, J = 21.0 Hz), 52.3, 14.8. Enantiomeric excess was
determined by GC with a Supelco’s Beta Dex 225 column (30
m×0.25 mm×0.25 µm); t1 = 17.0 min (major); t2 = 17.9 min
(minor). The configuration of the chiral product was assigned
by analogy.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(4-bromophenyl)propanal (7f). Known compound.16d
A
colorless oil (5% NMR yield, minor product of
hydroformylation). 1H NMR (300 MHz, CDCl3): δ (ppm) 9.80
(s, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H), 2.91
(t, J = 7.4 Hz, 2H), 2.76 (t, J = 7.2 Hz, 2H). 13C{1H} NMR (75
MHz, CDCl3): δ (ppm) 201.1, 139.5, 131.8, 130.2, 120.2,
45.2, 27.6.
ASSOCIATED CONTENT
Supporting Information
(R)-2-(4-chlorophenyl)propanal
((R)-6e).
Known
25
compound.16c A colorless oil (15.0 mg, 89% yield). [α]D = -
1
118 (c 0.25, CHCl3) for 63% ee (R)-6e. H NMR (300 MHz,
The Supporting Information is available free of charge on the
ACS Publications website.
CDCl3): δ (ppm) 9.66 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.14
(d, J = 8.1 Hz, 2H), 3.62 (q, J = 7.1 Hz, 1H), 1.43 (d, J = 6.9
Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ (ppm) 200.6,
136.3, 133.6, 129.8, 129.4, 52.4, 14.7. Enantiomeric excess
was determined by GC with a Supelco’s Beta Dex 225 column
(30 m×0.25 mm×0.25 µm); t1 = 42.4 min (major); t2 = 45.9
min (minor). The configuration of the chiral product was
assigned by analogy.
Experimental procedures, the synthesis method of the starting
materials, and compound characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: fanqh@iccas.ac.cn; heym@iccas.ac.cn
(R)-2-(4-bromophenyl)propanal
((R)-6f).
Known
25
compound.16d A colorless oil (19.1 mg, 90% yield). [α]D = -
ORCID
1
55 (c 0.25, CHCl3) for 62% ee (R)-6f. H NMR (300 MHz,
Qing-Hua Fan: 0000-0001-9675-2239
CDCl3): δ (ppm) 9.65 (s, 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.08
(d, J = 8.1 Hz, 2H), 3.60 (q, J = 7.0 Hz, 1H), 1.43 (d, J = 7.2
Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ (ppm) 200.4,
136.8, 132.3, 130.1, 121.7, 52.5, 14.7. Enantiomeric excess
was determined by GC with a Supelco’s Beta Dex 225 column
(30 m×0.25 mm×0.25 µm); t1 = 69.1 min (major); t2 = 75.3
min (minor). The configuration of the chiral product was
assigned by analogy.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China
(21772204 and 21521002) and CAS (QYZDJ-SSW-SLH023) for
financial support.
3-phenylpropanal (7a). Known compound.16c A colorless oil
(7% NMR yield, minor product of hydroformylation). 1H
NMR (300 MHz, CDCl3): δ (ppm) 9.81 (s, 1H), 7.32-7.18 (m,
5H), 2.96 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H). 13C{1H}
NMR (75 MHz, CDCl3): δ (ppm) 201.7, 140.5, 128.7, 128.4,
126.4, 45.4, 28.2.
REFERENCES
(1) (a) Tang, W.; Zhang, X. New Chiral Phosphorus Ligands for
Enantioselective Hydrogenation. Chem. Rev. 2003, 103, 3029-3069.
(b) Zhou, Q.-L. Privileged chiral ligands and catalysts; Wiley-VCH:
Weinheim, Germany, 2011.
3-(p-tolyl)propanal (7b). Known compound.16c A colorless
(2) For selected recent reviews, see: (a) Vaquero, M.; Rovira, L.;
Vidal-Ferran, A. Supramolecularly Fine-Regulated Enantioselective
Catalysts. Chem. Commun. 2016, 52, 11038-11051. (b) Meeuwissen,
J.; Reek, J. N. H. Supramolecular Catalysis beyond Enzyme Mimics.
Nat. Chem. 2010, 2, 615-621. (c) Raynal, M.; Ballester, P.; Vidal-
Ferran, A; van Leeuwen, P. W. N. M. Supramolecular Catalysis. Part
1: Non-Covalent Interactions as a Tool for Building and Modifying
Homogeneous Catalysts. Chem. Soc. Rev. 2014, 43, 1660-1733.
(3) Yoo, C.; Dodge, H. M.; Miller, A. J. M. Cation-Controlled
Catalysis with Crown Ether-Containing Transition Metal Complexes.
Chem. Commun. 2019, 55, 5047-5059.
(4) For selected examples, see: (a) Hyde, E. M.; Shaw, B. L.;
Shepherd, I. Complexes of Platinum Metals with Crown Ethers
Containing Tertiary Phosphine-Substituted Benzo Groups. J. Chem.
Soc., Dalton 1978, 1696-1705. (b) McLain, S. J. Organometallic
Crown Ethers. 1. Metal Acyl Binding to a Crown Ether Held Cation. J.
Am. Chem. Soc. 1983, 105, 6355-6357. (c) Okano, T.; Iwahara, M.;
Suzuki, T.; Konishi, H.; Kiji, J. Transition Metal Phosphine
1
oil (7% NMR yield, minor product of hydroformylation). H
NMR (300 MHz, CDCl3): δ (ppm) 9.80 (s, 1H), 7.11-7.06 (m,
4H), 2.91 (t, J = 7.5 Hz, 2H), 2.74 (t, J = 7.5 Hz, 2H), 2.31 (s,
3H). 13C{1H} NMR (75 MHz, CDCl3): δ (ppm) 201.8, 137.3,
135.9, 129.4, 128.3, 45.5, 27.8, 21.1.
3-(4-methoxyphenyl)propanal (7c). Known compound.16c
A
colorless oil (7% NMR yield, minor product of
hydroformylation). 1H NMR (300 MHz, CDCl3): δ (ppm) 9.81
(s, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 3.78
(s, 3H), 2.91 (t, J = 7.4 Hz, 2H), 2.74 (t, J = 7.4 Hz, 2H).
13C{1H} NMR (75 MHz, CDCl3): δ (ppm) 201.9, 158.2, 132.5,
129.4, 114.1, 55.4, 45.7, 27.4.
3-(4-fluorophenyl)propanal (7d). Known compound.16c
A
colorless oil (8% NMR yield, minor product of
hydroformylation). 1H NMR (300 MHz, CDCl3): δ (ppm) 9.81
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 11
Complexes Possessing a Phase Transfer Function. Preparation and
L. W.; Putnis, A.; Risthaus, P.; Stackhouse, S.; Whiting, A. The
Catalytic Reactivity of Palladium Phosphine Complexes Containing
Crown Ethers. Chem. Lett. 1986, 1467-1470. (d) Gordillo, Á.; de
Jesús, E.; López-Mardomingo, C. C-C Coupling Reactions of Aryl
Bromides and Arylsiloxanes in Water Catalyzed by Palladium
Complexes of Phosphanes Modified with Crown Ethers. Org. Lett.
2006, 8, 3517-3520. (e) Martin, J. R.; Cagle, E. C.; Lucius, A. L.;
Gray, G. M. Correlating the Activity of Rhodium(I)-Phosphite-Lariat
Ether Styrene Hydroformylation Catalysts with Alkali Metal Cation
Binding through NMR Spectroscopic Titration Methods.
Organometallics 2016, 35, 2609-2620. (f) Kita, M. R.; Miller, A. J. M.
An Ion-Responsive Pincer-Crown Ether Catalyst System for Rapid
and Switchable Olefin Isomerization. Angew. Chem., Int. Ed. 2017,
56, 5498-5502.
(5) (a) Sawamura, M.; Nagata, H.; Sakamoto, H.; Ito, Y. Chiral
Phosphine Ligands Modified by Crown Ethers: an Application to
Palladium-Catalyzed Asymmetric Allylation of β-Diketones. J. Am.
Chem. Soc. 1992, 114, 2586-2592. (b) Sawamura, M.; Nakayama, Y.;
Tang, W. M.; Ito, Y. Enantioselective Allylation of Nitro Group-
Stabilized Carbanions Catalyzed by Chiral Crown Ether Phosphine-
Palladium Complexes. J. Org. Chem. 1996, 61, 9090-9096. (c) Landis,
C. R.; Sawyer, R. A.; Somsook, E. Synthesis and Characterization of
Rational Design, Synthesis and Demonstration of the Recognition and
Binding of a Diaza-Dioxa-12-Crown-4 Diphosphonate Macrocycle to
All Crystal Growth Faces of Barium Sulfate. J. Chem. Soc., Perkin
Trans. 2 2002, 1238-1245. (d) Maeda, H.; Furuyoshi, S.; Nakatsuji,
Y.; Okahara, M. Synthesis of N-Unsubstituted Di- and Triaza Crown
Ether. Bull. Chem. Soc. Jpn. 1983, 56, 3073-3077. (e) Bradshaw, J. S.;
Krakowiak, K. E. A Simple and Convenient Method for the
Preparation of N,N'-Dibenzyldiaza-crown Compounds. J. Org. Chem.
1988, 53, 1808-1810. (f) Biernat, J. F.; Luboch, E. Macrocyclic
Polyfunctional Lewis Bases. IX: Azacrown Ethers. Tetrahedron 1984,
40, 1927-1929. (g) Krakowiak, K. E.; Bradshaw, J. S.; Izatt, R. M.
Preparation of Triaza-, Tetraaza- and Peraza-Crown Compounds
Containing Aminoalkyl Side Groups or Unsubstituted Ring Nitrogen
Atoms. J. Org. Chem. 1990, 55, 3364-3368.
(14) (a) Jia, J.; Ling Z.; Zhang, Z.; Tamura, K.; Gridnev, I. D.;
Imamoto, T.; Zhang, W. An Atropos Chiral Biphenyl Bisphosphine
Ligand Bearing Only 2,2’-Substituents and Its Application in Rh-
Catalyzed Asymmetric Hydrogenation. Adv. Synth. Catal. 2018, 360,
738-743. (b) Mohar, B.; Stephan, M. Practical Enantioselective
Hydrogenation of α-Aryl- and α-Carboxyamidoethylenes by
Rhodium(I)-{1,2-Bis[(ο-tert-
butoxyphenyl)(phenyl)phosphino]ethane}. Adv. Synth. Catal. 2013,
355, 594-600. (c) Huang, J.; Hong, M.; Wang, C.-C.; Kramer, S.; Lin,
G.-Q.; Sun, X.-W. Asymmetric Synthesis of Chiral Spiroketal
Bisphosphine Ligands and Their Application in Enantioselective
Olefin Hydrogenation. J. Org. Chem. 2018, 83, 12838-12846. (d)
Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. Access to
Enantioenriched α-Amino Esters via Rhodium-Catalyzed 1,4-
Addition/Enantioselective Protonation. J. Am. Chem. Soc. 2008, 130,
6159-6169. (e) Tang, W.-J.; Huang, Y.-Y.; He, Y.-M.; Fan, Q.-H.
Dendritic MonoPhos: Synthesis and Application in Rh-Catalyzed
Asymmetric Hydrogenation. Tetrahedron: Asymmetry 2006, 17, 536-
543. (f) Zhao, B.; Wang, Z.; Ding, K. Practical by Ligand Design: A
New Class of Monodentate Phosphoramidite Ligands for Rhodium-
Catalyzed Enantioselective Hydrogenations. Adv. Synth. Catal. 2006,
348, 1049-1057. (g) Storch, G.; Trapp, O. Temperature-Controlled
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Chiral, Aza-15-Crown-5-Functionalized Ferrocenyldiphosphine
Ligand for Asymmetric Catalysis. Organometallics 2000, 19, 994-
1002.
(6) Fernández-Pérez, H.; Mon, I.; Frontera, A.; Vidal-Ferran, A.
Enantiopure Bisphosphine Ligands with Appended Crown Ether
Groups as Regulation Sites for Rh-Mediated Hydrogenations.
Tetrahedron 2015, 71, 4490-4494.
(7) Zhang, X.-C.; Hu, Y.-H.; Chen, C.-F.; Fang, Q.; Yang, L.-Y.; Lu,
Y.-B.; Xie, L.-J.; Wu, J.; Li, S.; Fang, W. A Supramolecularly
Tunable Chiral Diphosphine Ligand: Application to Rh and Ir-
Catalyzed Enantioselective Hydrogenation. Chem. Sci. 2016, 7, 4594-
4599.
(8) (a) Li, Y.; Ma, B.; He, Y.-M.; Zhang, F.; Fan, Q.-H. Chiral
Metallacrown Ethers for Asymmetric Hydrogenation: Alkali-Metal
Ion Mediated Enhancement of Enantioselectivity. Chem. Asian J.
2010, 5, 2454-2458. (b) Song, F.-T.; Ouyang, G.-H.; He, Y.-M.; Fan,
Q.-H. Metallacrown Ether Catalysts Containing Phosphine-Phosphite
Polyether Ligands for Rh-Catalyzed Asymmetric Hydrogenation-
Enhancements in Activity and Enantioselectivity. Eur. J. Org. Chem.
2014, 30, 6713-6719. (c) Li, Y.; Feng, Y.; He, Y.-M.; Chen, F.; Pan,
J.; Fan, Q.-H. Supramolecular Chiral Phosphorous Ligands Based on
Bidirectional Enantioselectivity in
a
Dynamic Catalyst for
Asymmetric Hydrogenation. Angew. Chem., Int. Ed. 2015, 54, 3580-
3586.
(15) (a) Guan, Z.-H.; Zhang, Z.-Y.; Ren, Z.-H.; Wang, Y.-Y.; Zhang,
X. Synthesis of Enamides via CuI-Catalyzed Reductive Acylation of
Ketoximes with NaHSO3. J. Org. Chem. 2011, 76, 339-341. (b) Tang,
W.; Chi, Y.; Zhang, X. An ortho-Substituted BIPHEP Ligand and Its
Applications in Rh-Catalyzed Hydrogenation of Cyclic Enamides.
Org. Lett. 2002, 4, 1695-1698. (c) Kim, M.-J.; Kim, W.-H.; Han, K.;
Choi, Y. K.; Park, J. Dynamic Kinetic Resolution of Primary Amines
with a Recyclable Pd Nanocatalyst for Racemization. Org. Lett. 2007,
9, 1157-1159. (d) Ou, W.; Espinosa, S.; Meléndez, H. J.; Farré, S. M.;
Alvarez, J. L.; Torres, V.; Martínez, I.; Santiago, K. M.; Ortiz-
Marciales, M. Asymmetric Synthesis of Nonracemic Primary Amines
via Spiroborate-Catalyzed Reduction of Pure (E)- and (Z)-O-
Benzyloximes: Applications toward the Synthesis of Calcimimetic
Agents. J. Org. Chem. 2013, 78, 5314-5327. (e) Jia, X.; Li, X.; Xu, L.;
Li, Q.; Yao, X.; Chan, A. S. C. Highly Efficient
Rhodium/Monodentate Phosphoramidite Catalyst and Its Application
in the Enantioselective Hydrogenation of Enamides and α-
Dehydroamino Acid Derivatives. J. Org. Chem. 2003, 68, 4539-4541.
(f) Li, X.; Jia, X.; Xu, L.; Kok, S. H. L.; Yip, C. W.; Chan, A. S. C.
Highly Air-and Water-Stable Fluorinated Ferrocenylphosphine-
Aminophosphine Ligands and their Applications in Asymmetric
Hydrogenations. Adv. Synth. Catal. 2005, 347, 1904-1908.
(16) (a) Schüler, P.; Fischer, S. N.; Marsch, M.; Oberthür, M.
Efficient α-Mannosylation of Phenols: The Role of Carbamates as
Scavengers for Activated Glycosyl Donors. Synthesis 2013, 45, 27-39.
(b) Mon, I.; Jose, D. A.; Vidal-Ferran, A. Bis(phosphite) Ligands with
Distal Regulation: Application in Rhodium-mediated Asymmetric
Hydroformylations. Chem. Eur. J. 2013, 19, 2720-2725. (c) Yan, Y.;
Zhang, X. A Hybrid Phosphorus Ligand for Highly Enantioselective
Asymmetric Hydroformylation. J. Am. Soc. Chem., 2006, 128, 7198-
7202. (d) Hammerer, T.; Leitner, W.; Franciò, G. Synthesis of
a
[2]Pseudorotaxane Complex for Asymmetric Hydrogenation.
Tetrahedron Lett. 2008, 49, 2878-2881. (d) Ouyang, G.-H.; He, Y.-M.;
Li, Y.; Xiang, J.-F.; Fan, Q.-H. Cation-Triggered Switchable
Asymmetric Catalysis with Chiral Aza-CrownPhos. Angew. Chem.,
Int. Ed. 2015, 54, 4334-4337.
(9) For ligand L3, see: Reetz, M. T.; Mehler, G. Chiral P
hosphoramidites. Studiengesellschaft Kohle MBH; WO Patent No.
2007/031065, 2007; Chem. Abstr. 2007, 146, 338008.
(10) (a) Gatto, V. J.; Miller, S. R.; Gokel, G. W.; Prabhakaran, P. C.;
White, J. D. 4,13-Diaza-18-Crown-6: 1,4,10,13-Tetraoxa-7,16-
diazacyclooctadecane. Org. Synth. 1990, 68, 227-230. (b)
Lukyanenko, N. G.; Basok, S. S.; Filonova, L. K. Macroheterocycles.
Part 44. Facile Synthesis of Azacrown Ethers and Cryptands in a
Two-Phase System. J. Chem. Soc., Perkin Trans. 1 1988, 3141-3147.
(11) The association of alkali metal cations with the synthesized
ligands L1 and L3 was investigated. For details, see the Supporting
Information.
(12) Franke, R.; Selent, D.; Börner, A. Applied Hydroformylation.
Chem. Rev. 2012, 112, 5675-5732.
(13) (a) Griffin, J. L. W.; Coveney, P. V.; Whiting, A.; Davey, R.
Design and Synthesis of Macrocyclic Ligands for Specific Interaction
with Crystalline Ettringite and Demonstration of a Viable Mechanism
for the Setting of Cement. J. Chem. Soc., Perkin Trans. 2 1999, 1973-
1981. (b) Coveney, P. V.; Davey, R.; Griffin, J. L. W.; He, Y.;
Hamlin, J. D.; Stackhouse, S.; Whiting, A. A New Design Strategy
for Molecular Recognition in Heterogeneous Systems: A Universal
Crystal-Face Growth Inhibitor for Barium Sulfate. J. Am. Chem. Soc.
2000, 122, 11557-11558. (c) Bosbach, D.; Coveney, P. V.; Griffin, J.
ACS Paragon Plus Environment

Page 11 of 11
The Journal of Organic Chemistry
Phospholane–Phosphoramidite Ligands and their Application in
Asymmetric Catalysis. ChemCatChem 2015, 7, 1583-1592.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment