Synthesis of Chiral β-Fluoroalkyl β-Amino Acid Derivatives via Palladium-Catalyzed Hydrogenation

Article abstract of DOI:10.1021/acs.joc.9b01523

An enantioselective palladium-catalyzed hydrogenation of β-fluoroalkyl β-amino acrylic acid derivatives has been successfully developed, providing the corresponding chiral β-fluoroalkyl β-amino acid derivatives in good yields with excellent enantioselectivities. In addition, chiral γ-fluoroalkyl γ-amino alcohol could be synthesized by a simple reduction of the corresponding hydrogenated product. The mechanism of the reaction was explored by deuterium-labeling experiments.

Full text of DOI:10.1021/acs.joc.9b01523

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Article
Synthesis of Chiral #-Fluoroalkyl #-Amino Acid
Derivatives via Palladium-catalyzed Hydrogenation
Mu-Wang Chen, Qin Yang, Zhihong Deng, Qiuping Ding, and Yiyuan Peng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01523 • Publication Date (Web): 18 Jul 2019
Downloaded from pubs.acs.org on July 18, 2019
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Synthesis of Chiral β-Fluoroalkyl β-Amino Acid Derivatives via
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Palladium-catalyzed Hydrogenation
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Mu-Wang Chen, † ‡ Qin Yang,† Zhihong Deng,† Qiuping Ding† and Yiyuan Peng*†
†Key Laboratory of Small Functional Organic Molecule, Ministry of Education,
Jiangxi’s Key Laboratory of Green Chemistry and College of Chemistry & Chemical
Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
‡ State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian
116024, China
*E-mail: yypeng@jxnu.edu.cn, yiyuanpeng@yahoo.com.
ABSTRACT
Pd(OCOCF3)2/(S,S)-Ph-BPE
Ar
Ar
NH
NH
HFIP, 60 oC, H2 (800 psi)
R
R
Rf
Rf
p-anisic acid (20 mol%), 24 h
Rf = CF3, CF2H
72-96% ee
R = ester or amide
An enantioselective palladium-catalyzed hydrogenation of β-fluoroalkyl-β-amino acrylic acid derivatives
has been successfully developed, providing the corresponding chiral β-fluoroalky β-amino acid derivatives
in good yields with excellent enantioselectivities. In addition, chiral γ-fluoroalkyl-γ-amino alcohol could be
synthesized by simple reduction of the corresponding hydrogenated product. The mechanism of the reaction
was explored by deuterium labeling experiments.
Introduction
Fluorine substituted organic compounds had received increasing attention due to the fact that fluorine’s
electronegativity, small steric size, lipophilicity and electrostatic interactions can dramatically influence the
chemical reactivity and biological activity of the parent molecules.1 Thus, numerous of research have been
devoted to this field and a large number of fluorinated molecules have been synthesized.2 Among them,
chiral β-fluoroalkyl β-amino acids and their derivatives are a prominent class of building blocks for the
construction of various useful compounds including pharmaceuticals, agrochemicals and biologically active
natural products.3 For example, CF3-Ac docetaxel is used against human cancer cell lines (Figure 1, I),4a-c
and  [CH(CF3)NH]-retro-thionphane is used as neutral endopeptidase inhibitor (Figure 1, II).4d Thus, the
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enantioselective syntheses of β-fluoroalkyl β-amino acid derivatives have attracted a great deal of interests,5
and many efficient methods have been developed including chiral auxiliaries strategies6 and catalytic
methods,7-10 such as isomerization of fluorinated imines,7 catalytic asymmetric Mannich reaction of
fluorinated imines8 and aza-Michael addition of fluorinated imines.9 Although some progress has been made
in synthesis of β-fluoroalkyl β-amino acid derivatives, these existing routes have several drawbacks
involving poor enantioselectivities or stoichiometric amount of chiral auxiliaries needed and so on, thus
prohibiting their further application. Therefore, developing an efficient and atom-economic method for the
synthesis of chiral β-fluoroalkyl β-amino acid derivatives is of great significance in both organic synthesis
and drug research.
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AcO
O
OH
Ph
CF3
Boc
F3C
NH
O
HO2C
SH
O
N
H
O
H
HO
OAc
OBz
OH
I,
Cancer chemotherapeutic agents
CF3-Ac Docetaxel
II
, [CH(CF3)NH]-retro-thionphane
Neutral endopeptidase inhibitor
Figure 1. Selected bioactive chiral β‑fluoroalkyl β‑amino acid derivatives.
In the past decades, catalytic asymmetric hydrogenation as an efficient and economic approach has drawn
a lot of attention and has been successfully introduced to synthesis of chiral β-amino acid derivatives.11
However, the synthesis of chiral β-fluoroalkyl β-amino acid derivatives through hydrogenation is still a
challenging area which has been rarely explored to date, probably due to the strong electron withdrawing
property of CF3 group in the olefinic substrates.10,12 In 2005, the Rh-catalyzed asymmetric hydrogenation for
synthesis of β-amino acid derivatives was reported by Zhang and co-workers, in which only one example of
chiral β-fluoroalkyl β-amino acid ester with 79% ee and moderate 48% conversion was observed (Scheme 1,
Eq. 1).10 We speculated that the major obstacles to advancement in this research area are as follows: the
fluorinated enamino ester is easily hydrolyzed even with trace amount of water in solvent,13 leading to the
low chemoselectivity; the enamine and imine tautomerization impeded the stereoselectivity and the former
disclosed C-F bond cleavage of the fluorinated compounds14 in the presence of transition metal-catalyzed
systems which is a challenge for the hydrogenation of fluorinated enamino derivatives (Scheme 1, Eq 2).
Considering asymmetric synthesis of chiral trifluoromethyl amines has made great progress in Pd,15 Ir,16
Rh,14 Ru17 and organocatalysts18 catalyzed reduction of corresponding trifluoromethyl imines, we envisioned
that the asymmetric hydrogenation of β-fluoroalkyl-β-amino acrylic acid derivatives could be realized
through the reduction of imine-tautomer of the substrates via enamine-imine tautomerization, providing the
chiral β-fluoroalkyl β-amino acid derivatives. Herein, we reported the palladium-catalyzed asymmetric
hydrogenation of fluorinated enamino derivatives, giving the chiral β-fluoroalkyl β-amino acid derivatives
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with up to 95% ee.
Scheme 1. Asymmetric Hydrogenation of β-Fluoroalkyl-β-Amino Acrylic Acid Derivatives
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7
8
9
Zhang's Work:
Rh-catalyzed Asymmetric Hydrogenation of Fluorinated Enamino Esters
Ph
Ph
NH
O
[Rh(TangPhos)(nbd)]BF4
NH
O

(Eq. 1)
H2 (6 atm), TFE, 50 oC, 18 h
F3C
OEt
F3C
OEt
79% ee, 48% conv.
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Possible Process for Asymmetric Hydrogenation of -Fluoroalkyl--Amino Acrylic Esters
Challenges
: Control of Enantioselectivity and Inhibition of Hydrolysis
Ph
[M]/H2
NH

O
Ph
Ph
Rf
OEt
NH
O
N
O
Desired product
Rf
OEt
Rf
OEt
Ph
NH
O
ref 14
OH
tautomerization

R
OEt
Defluorination
Trace amount of
water in solvent
Hydrolysis
O
+
O
O
[M]/H2
.....
+
PhNH2
(Eq. 2)
Rf
OEt
Rf
OEt
Sideproduct
This Work:
Pd-catalyzed Asymmetric Hydrogenation of -Fluoroalkyl--Amino Acrylic Esters
Ar
Ar
Pd(OCOCF3)2/(S,S)-Ph-BPE
NH
O
NH
O
(Eq. 3)

HFIP, 60 oC, H2 (800 psi)
p-Anisic Acid (20 mol%)
Rf
R
Rf
R
up to 95% ee
Results and Discussion
To test the viability of our proposed protocol, the (Z)-ethyl 4,4,4-trifluoro-3-(phenylamino)but-2-enoate
(1a) was chosen as the model substrate, and the hydrogenation was performed in the presence of
Pd(OCOCF3)2/(S,S’,R,R’-DuanPhos) in trifluroethanol (TFE) at 40 oC. Pleasingly, the reaction was
conducted with full conversion and furnished 2a in 51% yield with 77% ee (Table 1, entry 1). The main
problem of the low yield is ascribed to the hydrolysis of the substrate 1a to amine and ethyl 4,4,4-
trifluoroacetoacetate during the reaction, and then the ethyl 4,4,4-trifluoroacetoacetate could be
hydrogenated to deliver ethyl 4,4,4-trifluoro-3-hydroxybutanoate19 (detected by GC-MS) and other low
boiling point substances. Consequently, a series of solvents were screened (entries 2-5), and HFIP
(1,1,1,3,3,3-hexafluoro-2-propanol) was proved to be the optimal solvent in terms of good yield and ee value
(entry 5). Furthermore, some commercially available chiral diphosphine ligands were examined (entries 5-
10). The results revealed that chiral ferrocenyl phosphine L4 offered moderated yield and enantioselectivity
(entry 8). High reaction activity was obtained using the electron-rich ligands such as Me-Duphos in this
hydrogenation system, which avoid the fluorinated enamino ester hydrolyzed in solvent and no byproduct
was obtained (entry 9). While electron-donating phosphine ligand L6 gave excellent ee value and moderate
yield (entry 10). Dehydrating agents such as 5 Å MS were added in order to improve the yield, but did not
give better results (entry 11). Gratifyingly, the yield can be improved to 74% with the 90% of
enantioselectivity using the 4 mol % of catalyst loading amount (entry 12).
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Table 1. Optimization for Pd-catalyzed Asymmetric Hydrogenation of (Z)-Ethyl 4,4,4-trifluoro-3-
(phenylamino) but-2-enoate (1a) a
6
7
8
9
Ph
Ph
Pd(OCOCF3)2/L
NH
O
NH
O

solvent, 70 oC, H2 (600 psi)
F3C
OEt
F3C
OEt
1a
2a
10
11
12
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60
entry
solvent
L
conv. (%)b
yield (%)b
ee (%)c
1
2
TFE
DCM
THF
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L6
L6
>95
38
51
12
6
77
48
64
18
73
77
84
44
44
89
88
90
3
37
4
MeOH
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
>95
>95
>95
>95
>95
>95
>95
>95
>95
74
74
57
65
56
97
64
47
74
5
6
7
8
9
10
11d
12e
O
tBu
N
N
P
O
O
H
PPh2
PPh2
tBu
P
P
H
P
tBu
tBu
O
L1: (S,S',R,R')-DuanPhos
L2: (R)-SegPhos
L3: (R,R)-QuinoxP*
PCy2
Ph
Ph
P
P
PCy2
Fe
P
P
Ph
Ph
L4: (R,Sp)-Cy-Josiphos
L5: (S,S)-Me-Duphos
L6: (S,S)-Ph-BPE
a
Conditions: 1a (0.125 mmol), Pd(OCOCF3)2 (2.0 mol%), L (2.4
mol% ), solvent (3.0 mL), 48 h, 70 oC. b Determined by 1H NMR, using
c
1,3,5-trimethoxybenzeneas an internal standard. Determined by chiral
HPLC analysis. d 40 mg 5 Å MS was added. e Pd(OCOCF3)2 (4.0 mol%),
L (4.8 mol% ).
Considering the acid can promote the tautomeric transformation between imines and enamines, and also
promote the in situ formation of iminium salts, leading to enhancement of the activity.20 Therefore, a series
of acidic additives were screened systematically. The results were depicted in Table 2. To our delight, both
selectivity and enantioselectivity of the reaction were increased with the addition of a catalytic amount of
benzoic acid (entries 1-2). After evaluation of various acids, the p-anisic acid was verified as the best choice
in terms of yield and enantioslectivity. The effects of temperature and hydrogen pressure on reactivity and
enantioselectivity were also investigated in the next steps (entries 8-10). Finally, the optimal reaction
condition was established as: Pd(OCOCF3)2/(S,S)-Ph-BPE, p-anisic acid, H2 (800 psi), in HFIP and at 60 oC.
Table 2. Optimization of Reaction Conditions a
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Ph
Ph
Pd(OCOCF3)2/(S,S)-Ph-BPE
NH
O
NH
O

HFIP, 70 oC, acid, 48 h
H2 (600 psi)
4
F3C
OEt
F3C
OEt
5
6
1a
2a
7
8
9
entry
1d
2
acid
conv. (%)b
>95
yield (%)b
ee (%)c
93
PhCO2H
PhCO2H
PhCO2H
80
84
72
59
63
84
82
79
86
77
88
10
11
12
13
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60
>95
93
3e
4
>95
93
TsOH.H2O
>95
93
5
(D)-camphoric acid
p-anisic acid
>95
>95
>95
>95
>95
>95
>95
93
6
94
7
p-nitrobenzoic acid
p-anisic acid
92
8f
92
9g
10h
11i
p-anisic acid
95
p-anisic acid
96
p-anisic acid
95
a Conditions: 1a (0.125 mmol), Pd(OCOCF3)2 (4.0 mol%), (S,S)-Ph-BPE (4.8 mol%), acid
o
b
1
(20 mol%), HFIP (3.0 mL), H2 (600 psi), 48 h, 70 C. Determined by H NMR, using
1,3,5-trimethoxybenzene as internal standard. c Determined by chiral HPLC analysis. d 10
mol% of PhCO2H. 30 mol% of PhCO2H. 80 C. g 60 C. h 50 C. 60 C, H2 (800 psi),
e
f
o
o
o
i
o
24 h.
After establishing the optimal condition, we next examined the substrate scope, and the results were
summarized in Table 3. Esters with different alkoxy groups were firstly examined in this reaction, the target
products were obtained in good yields with excellent enantioselectivities (entries 1-3). The moderate yield
and enantioselectivity was obtained, when the amide was introduced as the substrate (entry 4). Notably,
different electronic properties and positions of substituents on the aromatic ring had marginal effect on the
reactivity and enantioselectivity (entries 5-11). What’s more, the difluoroalkyl-substituted substrate was also
tolerated, giving the desirable product in 77% yield and 72% ee (entry 12).
Table 3. Substrate Scope of Chiral β‑Fluoroalkyl β‑Amino Derivatives a
Ar
Rf
Ar
Rf
Pd(OCOCF3)2/(S,S)-Ph-BPE
NH
O
NH
O
HFIP, 60 oC, H2 (800 psi),
p-anisic acid (20 mol%), 24 h
R
R
1
2
entry
1
Rf
R
Ar
yield (%)b
74 (2a)
79 (2b)
58 (2c)
33 (2d)
66 (2e)
ee (%)c
95
CF3
CF3
CF3
CF3
CF3
OEt
OMe
OBn
C6H5
C6H5
2
95
3d
4d
5
C6H5
92
NHPh
OEt
C6H5
76
4-MeOC6H4
94
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6d
7d
8
CF3
CF3
CF3
CF3
CF3
CF3
CF2H
OEt
OEt
OEt
OEt
OEt
OEt
OEt
3-MeOC6H4
2-MeOC6H4
4-MeC6H4
4-ClC6H4
4-FC6H4
70 (2f)
50 (2g)
71 (2h)
73 (2i)
54 (2j)
84 (2k)
77 (2l)
95
93
93
95
91
96
72
9
10d
11
12
10
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1-naphthyl
C6H5
a Conditions: 1 (0.25 mmol), Pd(OCOCF3)2 (4.0 mol%), (S,S)-Ph-BPE (4.8 mol%), p-
o
b
c
anisic acid (20 mol%), HFIP (3.0 mL), H2 (800 psi), 24 h, 60 C. Isolated yields.
Determined by chiral HPLC analysis. d 48 h.
Moreover, α-methyl β-fluoroalkyl β-enamino ester could also be hydrogenated successfully under the
standard conditions, giving the α-methyl β-fluoroalkyl β-amino ester with 84% yield & 90% ee, and poor
selectivity of 1.3:1 dr (Scheme 2, Eq. 4). Subsequently, the direct catalytic asymmetric reductive amination
was explored in this study. At the beginning, only 9% NMR yield of desired product 2e was observed with
ethyl 4,4,4-trifluoroacetoacetate and p-anisidine under the optimal conditions. When TsOH.H2O in place of
p-anisic acid was introduced, the desirable product was obtained in 25% yield and 93% ee (Scheme 2, Eq. 5).
Scheme 2. Asymmetric Synthesis of α-Methyl β-Fluoroalkyl β-Amino Acrylic Ester and Reductive
Amination.
PMPNH
F3C
O
PMPNH
F3C
O
PMPNH
F3C
O
Pd(OCOCF3)2/(S,S)-Ph-BPE
+
(Eq. 4)
OEt
OEt
HFIP, 60 oC, H2 (800 psi)
p-anisic acid (20 mol%)
OEt
2m1
84% ee, 43% yield
2m2
90% ee, 34% yield
1m
O
O
Pd(OCOCF3)2/(S,S)-Ph-BPE
PMPNH
F3C
O
+
PMP-NH2
(Eq. 5)
F3C
OEt
HFIP, 60 oC, H2 (800 psi)
TsOH.H2O
OEt
2e
93% ee, 25% yield
To further demonstrate the utility of this method, product 2a (recrystallize from n-hexane to upgrade ee to
99%) was reduced by lithium aluminum hydride (LiAlH4), giving the chiral γ-fluoroalkyl-γ-amino alcohol 5a
without loss of optical purity.21 Moreover, the 2.0 mmol scale (579 mg) experiment was carried out, and the
desired chiral enamino ester 2e was obtained without the loss of activity and enantioselectivity (70% yield,
94% ee). Meanwhile, chiral primary amine 5e could be obtained by removing the p-methoxyphenyl group
through oxidative cleavage of the hydrogenated product 2e, and the optical purity still remained.15c,18g In
addition, this method provides a concise and effective way to synthesize 4-CF3-ezetimibe.3f The absolute
configuration of hydrogenation product 2a was determined by X-ray diffraction analysis by recrystallization
from n-hexane (Scheme 3).
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Scheme 3. Transformations of Chiral β ‑ Fluoroalkyl β ‑ Amino Ester 2a, Deprotection of 2e and X-ray
Crystal Structure of 2a
7
8
LiAlH4, THF, -50 o
C
NH
O
NH OH
9
F3C
OEt
F3C
10
11
12
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52
53
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57
58
59
60
5a
2a
(99% ee)
99% ee, 89% yield
PMP
F3C
PMP
Pd(OCOCF3)2/(S,S)-Ph-BPE
NH
O
NH
O
HFIP, 60 oC, H2 (800 psi),
p-anisic acid (20 mol%), 24 h
OEt
F3C
OEt
1e
2e
(579 mg, 2.0 mmol)
(70% yield, 94% ee)
PMP
Ce(NH4)2(NO3)6
NH2
O
NH
O
CH3CN/ H2O (2:1), 0 o
C
F3C
OEt
F3C
OEt
2e
5e
(93% ee)
(94% ee)
NH
O
F3C
OEt
2a
In order to investigate the reaction mechanism, two isotopic labeling experiments were carried out
1
(Scheme 4). When the hydrogenation was carried out in D2-HFIP, H NMR analysis of the hydrogenation
product showed that the deuterium atom was taken up to the α-position with >95% of deuterium isotopic
content (Eq. 6). When 1a was subjected to hydrogenation under D2, the deuterium atoms was incorporated to
the β-position exclusively with >95% of deuterium isotopic content (Eq. 8). As well as, enamine (1ab) and
o
imine (1ac) can be obtained in the presence of D2-HFIP and D-p-anisic acid at 60 C (Eq. 7), at the same
time 1ab and 1ac can be rapidly isomerized under acidic conditions, the ratio of 1ac to 1ab was increased
with prolonged time (See Figure S1). Considering that in general palladium-catalyzed hydrogenation of
imines is easier than enamines,20a,e so we speculate that the asymmetric hydrogenation of β-fluoroalkyl-β-
amino acrylic esters proceeds through asymmetric reductive of the iminium form other than enamine form of
the substrate in the presence of Brønsted acid, but the direct hydrogenation of enamine cannot be ruled out.
Scheme 4. Deuterium-Labeling Experiment
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Ph
Ph
Pd(OCOCF3)2/(S,S)-Ph-BPE
NH
O
NH
D
O
(Eq. 6)
D2-HFIP, 60 oC, p-anisic acid, H2 (800 psi)
F3C
OEt
F3C
OEt
(>95%)
D
1aa
, 55% yield, 94% ee
1a
7
8
9
Ph
Ph
Ph
D2-HFIP, 60 o
MeO CO2D
C
NH
O
N
O
NH
O
O
(Eq. 7)
+
F3C
OEt
F3C
OEt
F3C
OEt
OEt
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D
D
1ac
D
1ab
1a
Ph
Ph
Pd(OCOCF3)2/(S,S)-Ph-BPE
HFIP, 60 oC, p-anisic acid, D2 (450 psi)
NH
NH
O
(Eq. 8)
F3C
F3C
1ad
OEt
D (>95%)
, 57% yield, 97% ee
1a
In summary, we have successfully developed an efficient method for synthesis of chiral β-fluoroalkyl β-
amino derivatives through palladium-catalyzed asymmetric hydrogenation of β-fluoroalkyl-β-amino acrylic
acid derivatives with up to 96% ee. A reductive amination between 4,4,4-trifluoroacetoacetate and p-
anisidine was also achieved. Moreover, the synthetic utility of hydrogenation products was performed to
construct chiral γ-fluoroalkyl-γ-amino alcohol. Further investigations on asymmetric hydrogenation of
fluorinate compounds are currently on going in our laboratory.
EXPERIMENTAL SECTION
Commercially All reactions were carried out under an atmosphere of nitrogen using the standard Schlenk
techniques, unless otherwise noted. Commercially available reagents were used without further purification.
Solvents were treated prior to use according to the standard methods. H NMR, 13C NMR spectra were
1
recorded at 400 MHz and 100 MHz with the Brucker spectrometer. 19F was recorded at 376 MHz with
Brucker spectrometer. Chemical shifts are reported in ppm using tetramethylsilane as internal standard when
1
using CDCl3 as solvent for H NMR spectra. The following abbreviations were used to symbolize the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Flash column
chromatography was performed on silica gel (200-300 mesh). All reactions were monitored by TLC analysis.
Optical rotations were measured by the polarimeter. Enantiomeric excess was determined by HPLC analysis
using chiral column described below in detail. High-resolution mass spectrometry (HRMS) was measured on
an electrospray ionization (ESI) apparatus using time-of-flight (TOF) mass spectrometry.
Procedures for Synthesis of β-Fluoroalkyl-β-Amino Acrylic Esters 1. A mixture of the 3 (10.0 mmol),
4 (10.0 mmol) and p-toluenesulfonic acid monohydrate (0.192 g, 1.0 mmol) were didsolved in ehanol or
toluene (10 mL) and refluxed overnight. After the reaction mixture was cooled to room temperature, the
solution was dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by
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passing through a silica gel column to give the final product.22 The compounds 1a, 22a 1b, 22b 1d-1h & 1j,22c
1i22d and 1l22e were the known compounds.
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Benzyl (Z)-4,4,4-trifluoro-3-(phenylamino)but-2-enoate (1c): 0.918g, 29% yield, yellow oil, Rf = 0.40
8
9
1
(hexanes/ethyl acetate = 30/1), H NMR (400 MHz, CD3OD) δ 7.41 – 7.36 (m, 5H), 7.36 – 7.32 (m, 2H),
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7.30 – 7.24 (m, 1H), 7.20 (d, J = 7.8 Hz, 2H), 5.41 (s, 1H), 5.19 (s, 2H); 13C{1H} NMR (100 MHz, CD3OD)
δ 168.7, 146.6 (q, J = 30.0 Hz), 138.5, 136.2, 128.7, 128.2, 127.9, 127.8, 126.3, 125.4, 120.4 (q, J = 273.0
Hz), 88.2 (q, J = 5.0 Hz), 65.6; 19F{1H} NMR (376 MHz, CD3OD) δ -65.2; HRMS (ESI-TOF) m/z
Calculated for C17H15F3NO2 [M+H]+ 322.1049, found 322.1053.
Ethyl (Z)-4,4,4-trifluoro-3-(naphthalen-1-ylamino)but-2-enoate (1k) : 0.590 g, 19% yield, pale yellow
oil, Rf = 0.51 (hexanes/ethyl acetate = 30/1), 1H NMR (400 MHz, CD3OD) δ 8.02 – 7.94 (m, 1H), 7.91 (t, J =
5.4 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.60 – 7.49 (m, 2H), 7.49 – 7.34 (m, 2H), 5.43 (d, J = 1.5 Hz, 1H), 4.32
– 4.09 (m, 2H), 1.29 (t, J = 4.4 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 169.5, 147.8 (q, J = 30.0 Hz),
134.3 (d), 131.0, 127.9, 127.6, 126.5, 126.1, 124.6, 124.5, 122.0, 120.4 (q, J = 275.0 Hz), 88.2 (q, J = 5.0
Hz), 59.9, 13.2; 19F{1H} NMR (376 MHz, CD3OD) δ -65.7; HRMS (ESI-TOF) m/z Calculated for
C16H15F3NO2 [M+H]+ 310.1049, found 310.1044.
Typical Procedure for Palladium-catalyzed Asymmetric Hydrogenation of β-Fluoroalkyl-β-Amino
Acrylic Esters.
(S,S)-Ph-BPE (6.2 mg, 0.012 mmol) and Pd(OCOCF3)2 (3.3 mg, 0.010 mmol) were placed in a dried
Schlenk tube under nitrogen atmosphere, and degassed anhydrous acetone was added. The mixture was
stirred at room temperature for 1 h. The solvent was removed under vacuum to give the catalyst. This
catalyst was taken into a glovebox filled with nitrogen and dissolved in dry HFIP (3 mL). To a mixture of
substrates 1 (0.25 mmol) and p-anisic acid (7.6 mg, 0.05 mmol), the catalyst solution was added, and then
o
the mixture was transferred to an autoclave. The hydrogenation was performed at 60 C under 800 psi of
hydrogen. The autoclave was stirred under directed conditions for 24 h, then the hydrogen was carefully
released, the autoclave was opened, and saturated aqueous sodium bicarbonate (5 mL) was added to the
mixture and stirred for 10-15 min. The mixture was extracted with dichloromethane twice and the combined
organic extracts dried over sodium sulfate. The resulting mixture was concentrated in vacuo and further
purification was performed by a silica gel column eluted with hexanes/ethyl acetate to give the desired
product 2. The enantiomeric excesses were determined by chiral HPLC after the purification by column
chromatography on silica gel (ethyl acetate/hexanes).
Racemates of 2 were prepared by the reduction of the corresponding substrates 1 using 1,2-
bis(dicyclohexylphosphanyl)ethane and Pd(OCOCF3)2 as catalyst.
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(R)-Ethyl-4,4,4-trifluoro-3-(phenylamino)butanoate (2a): 48 mg, 74% yield, pail yellow soild: 50-51
oC, Rf = 0.31 (hexanes/ethyl acetate = 20/1), 95% ee, [α]20 = -12.50 (c 0.48, CHCl3) [lit.10: [α]20 = 1.4 (c
D
D
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7
8
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1.0, CHCl3) for 79% ee]; 1H NMR (400 MHz, CDCl3) δ 7.24 – 7.17 (m, 2H), 6.81 (t, J = 7.4 Hz, 1H), 6.73 (d,
J = 7.8 Hz, 2H), 4.56 – 4.42 (m, 1H), 4.19 – 4.05 (m, 2H), 3.90 (d, J = 9.9 Hz, 1H), 2.83 (dd, J = 15.6, 4.5
Hz, 1H), 2.62 (dd, J = 15.6, 8.8 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.4,
145.7, 129.4, 125.6 (q, J = 282.0 Hz), 119.5, 114.0, 61.4, 53.4 (q, J = 30 Hz), 35.1 (q, J = 1.0 Hz), 14.0;
19F{1H} NMR (376 MHz, CDCl3) δ -76.1; HPLC (OJ-H, elute: Hexanes/i-PrOH = 90/10, detector: 230 nm,
flow rate: 1.0 mL/min), 30 oC, t1 = 8.8 min, t2 = 10.0 min (maj).
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(R)-Methyl-4,4,4-trifluoro-3-(phenylamino)butanoate (2b) :22a 49 mg, 79% yield, pale yellow oil, Rf =
1
0.23 (hexanes/ethyl acetate = 30/1), 95% ee, [α]20 = -8.37 (c 0.49, CHCl3); H NMR (400 MHz, CDCl3) δ
D
7.21 (dd, J = 8.6, 7.4 Hz, 2H), 6.81 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 7.7 Hz, 2H), 4.56 – 4.44 (m, 1H), 3.68 (s,
3H), 2.84 (dd, J = 15.7, 4.6 Hz, 1H), 2.64 (dd, J = 15.7, 8.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
1670, 145.6, 129.8, 125.5 (q, J = 282.0 Hz), 119.6, 114.1, 53.4 (q, J = 30 Hz) , 52.3, 34.7 (q, J = 1.0 Hz);
19F{1H} NMR (376 MHz, CDCl3) δ -76.1; HPLC (OD-H, elute: Hexanes/i-PrOH = 90/10, detector: 230 nm,
flow rate: 1.0 mL/min), 30 oC, t1 = 7.0 min, t2 = 8.8 min (maj).
(R)-Benzyl-4,4,4-trifluoro-3-(phenylamino)butanoate (2c) : 47 mg, 58% yield, pale yellow oil, Rf =
0.35 (hexanes/ethyl acetate = 20/1), 92% ee, [α]20 = -9.79 (c 0.47, CHCl3); 1H NMR (400 MHz, CDCl3) δ
D
7.34 – 7.28 (m, 3H), 7.27 – 7.22 (m, 2H), 7.22 – 7.16 (m, 2H), 6.85 – 6.75 (m, 1H), 6.69 (d, J = 7.7 Hz, 2H),
5.09 (d, J = 0.9 Hz, 2H), 4.50 (tdd, J = 9.2, 6.8, 4.4 Hz, 1H), 3.85 (d, J = 10.1 Hz, 1H), 2.88 (dd, J = 15.6,
4.4 Hz, 1H), 2.66 (dd, J = 15.6, 9.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.3, 145.6, 135.1, 129.4,
128.6, 128.5, 128.4, 125.5 (q, J = 282.0 Hz), 119.5, 114.0, 67.2, 53.4 (q, J = 30.0 Hz), 35.1 (q, J = 1.0 Hz);
19F{1H} NMR (376 MHz, CDCl3) δ -76.1; HPLC (OD-H, elute: Hexanes/i-PrOH = 90/10, detector: 230 nm,
o
flow rate: 1.0 mL/min), 30 C, t1 = 9.8 min (maj), t2 = 12.3 min; HRMS (ESI-TOF) m/z Calculated for
C17H17F3NO2 [M+H]+ 324.1206, found 324.1206.
(R)-4,4,4-trifluoro-N-phenyl-3-(phenylamino)butanamide (2d) : 25 mg, 33% yield, pale yellow oil, Rf
= 0.19 (hexanes/ethyl acetate = 5/1), 76% ee, [α]20D = -11.2 (c 0.25, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.75 (brs, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 7.9 Hz, 2H), 7.24 (dd, J = 8.4, 7.5 Hz, 2H), 7.14 (t, J =
7.4 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 6.80 (d, J = 8.1 Hz, 2H), 4.58 (s, 1H), 4.14 (s, 1H), 2.87 (dd, J = 15.2,
3.9 Hz, 1H), 2.63 (dd, J = 15.2, 8.5 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.8, 145.6, 137.2, 129.5,
129.1, 125.7 (q, J = 283.0 Hz), 125.0, 120.4, 119.9, 114.5, 53.9 (q, J = 30.0 Hz), 37.1; 19F{1H} NMR (376
MHz, CDCl3) δ -75.6; HPLC (OJ-H, elute: Hexanes/i-PrOH = 90/10, detector: 230 nm, flow rate: 1.0
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mL/min), 30 C, t1 = 25.6 min, t2 = 32.9 min (maj); HRMS (ESI-TOF) m/z Calculated for C16H16F3N2O
[M+H]+ 309.1209, found 309.1214.
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(R)-Ethyl-4,4,4-trifluoro-3-((4-methoxyphenyl)amino)butanoate (2e):
48 mg, 66% yield, pale
9
yellow oil, Rf = 0.22 (hexanes/ethyl acetate = 20/1), 94% ee, [α]20D = -23.12 (c 0.48, CHCl3); 1H NMR (400
MHz, CDCl3) δ 6.79 (d, J = 8.9 Hz, 2H), 6.70 (d, J = 8.9 Hz, 2H), 4.35 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H),
3.75 (s, 3H), 3.61 (d, J = 8.6 Hz, 1H), 2.80 (dd, J = 15.6, 4.5 Hz, 1H), 2.59 (dd, J = 15.6, 8.9 Hz, 1H), 1.21 (t,
J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.6, 153.5, 139.7, 125.7 (q, J = 282.0 Hz), 115.9,
114.8, 62.3, 55.7, 54.9 (q, J = 30 Hz), 35.1 (q, J = 2.0 Hz), 14.0; 19F{1H} NMR (376 MHz, CDCl3) δ -76.0;
HPLC (OJ-H, elute: Hexanes/i-PrOH = 90/10, detector: 230 nm, flow rate: 1.0 mL/min), 30 oC, t1 = 12.7 min,
t2 = 15.0 min (maj).
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(R)-Ethyl-4,4,4-trifluoro-3-((3-methoxyphenyl)amino)butanoate (2f) : 51 mg, 70% yield, pale yellow
oil, Rf = 0.16 (hexanes/ethyl acetate = 20/1), 95% ee, [α]20 = -12.35 (c 0.51, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 7.03 (t, J = 8.1 Hz, 1H), 6.30-6.20 (m, 2H), 6.21 (t, J = 2.1 Hz, 1H), 4.42-4.36 (m, 1H), 4.06 (q, J
= 7.1 Hz, 2H), 3.69 (s, 3H), 2.75 (dd, J = 15.6, 4.6 Hz, 1H), 2.54 (dd, J = 15.6, 8.6 Hz, 1H), 1.13 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.4, 160.8, 147.1, 130.2, 125.5 (q, J = 282.0 Hz), 106.7,
104.6, 100.2, 61.4, 55.2, 53.3 (q, J = 30.0 Hz), 35.2 (q, J = 2.0 Hz), 14.0; 19F{1H} NMR (376 MHz, CDCl3)
δ -76.1; HPLC (OD-H, elute: Hexanes/i-PrOH = 95/5, detector: 230 nm, flow rate: 0.8 mL/min), 30 oC, t1 =
16.9 min (maj), t2 = 23.7 min; HRMS (ESI-TOF) m/z Calculated for C13H16F3NNaO3 [M+H]+ 314.0974,
found 314.0975.
(R)-Ethyl-4,4,4-trifluoro-3-((2-methoxyphenyl)amino)butanoate (2g) : 36 mg, 50% yield, pale yellow
solid, Rf = 0.27 (hexanes/ethyl acetate = 20/1), 93% ee, [α]20D = + 3.33 (c 0.36, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 6.90 – 6.86 (m, 1H), 6.83 – 6.72 (m, 3H), 4.57 – 4.45 (m, 1H), 4.18 – 4.08 (m, 2H), 3.85 (s, 3H),
2.85 (dd, J = 15.7, 4.6 Hz, 1H), 2.66 (dd, J = 15.7, 8.8 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 169.4, 147.0, 135.6, 125.6 (q, J = 281.0 Hz),121.2, 118.5, 111.3, 110.1, 61.3, 55.6, 53.0 (q, J
= 30.0 Hz), 35.3 (q, J = 1.0 Hz), 14.0; 19F{1H} NMR (376 MHz, CDCl3) δ -76.3; HPLC (OD-H, elute:
Hexanes/i-PrOH = 95/5, detector: 230 nm, flow rate: 0.7 mL/min), 30 oC, t1 = 9.1 min, t2 = 10.3 min (maj);
HRMS (ESI-TOF) m/z Calculated for C13H16F3NNaO3 [M+H]+ 314.0974, found 314.0957.
(R)-Ethyl-4,4,4-trifluoro-3-(p-tolylamino)butanoate (2h) : 49 mg, 71% yield, pale yellow oil, Rf = 0.26
(hexanes/ethyl acetate = 20/1), 93% ee, [α]20D = -23.26 (c 0.49, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.02
(d, J = 8.0 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 4.51 – 4.33 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.43 (s, 1H), 2.81
(dd, J = 15.6, 4.6 Hz, 1H), 2.61 (dd, J = 15.6, 8.8 Hz, 1H), 2.25 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13C{1H}
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NMR (100 MHz, CDCl3) δ 169.5, 143.4, 129.9, 128.8, 125.6 (q, J = 282.0 Hz), 114.3, 61.3, 53.9 (q, J = 30
Hz), 35.1(q, J = 1.0 Hz), 20.4, 14.0; 19F{1H} NMR (376 MHz, CDCl3) δ -76.1; HPLC (OD-H, elute:
Hexanes/i-PrOH = 90/10, detector: 230 nm, flow rate: 1.0 mL/min), 30 oC, t1 = 5.2 min (maj), t2 = 5.5 min;
HRMS (ESI-TOF) m/z Calculated for C13H17F3NO2 [M+H]+ 276.1206, found 276.1173.
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(R)-Ethyl-3-((4-chlorophenyl)amino)-4,4,4-trifluorobutanoate (2i) : 54 mg, 73% yield, pale soild: 116-
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118 C, Rf = 0.20 (hexanes/ethyl acetate = 20/1), 95% ee, [α]20 = -28.70 (c 0.54, CHCl3); 1H NMR (400
D
MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 8.8 Hz, 2H), 4.51 – 4.35
(m, 1H), 4.26 – 4.07 (m, 2H), 4.03 – 3.82 (m, 1H), 2.83 (dd, J = 15.8, 4.3 Hz, 1H), 2.60 (dd, J = 15.8, 9.0 Hz,
1H), 1.20 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.3, 144.4, 129.3, 125.4 (q, J = 282.0
Hz), 124.2, 115.1, 61.5, 53.5 (t, J = 30.0 Hz), 34.9 (q, J = 2.0 Hz), 14.0; 19F{1H} NMR (376 MHz, CDCl3) δ
o
-76.1; HPLC (OD-H, elute: Hexanes/i-PrOH = 97/3, detector: 230 nm, flow rate: 0.5 mL/min), 30 C, t1 =
17.8 min (maj), t2 = 21.1 min; HRMS (ESI-TOF) m/z Calculated for C12H14ClF3NO2 [M+H]+ 296.0660,
found 296.0655.
(R)-Ethyl-4,4,4-trifluoro-3-((4-fluorophenyl)amino)butanoate (2j) : 38 mg, 54% yield, pale yellow oil,
Rf = 0.23 (hexanes/ethyl acetate = 30/1), 91% ee, [α]20D = -8.68 (c 0.38, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 6.96 – 6.85 (m, 2H), 6.75 – 6.62 (m, 2H), 4.45 – 4.29 (m, 1H), 4.14 (qd, J = 7.1, 1.0 Hz, 2H), 3.77 (d, J =
9.7 Hz, 1H), 2.82 (dd, J = 15.7, 4.3 Hz, 1H), 2.60 (dd, J = 15.7, 9.1 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 169.5, 156.9 (d, J = 236.0 Hz), 142.1(d, J = 3.0 Hz), 125.5 (q, J = 282.0 Hz),
115.8 (d, J = 24.0 Hz), 115.3 (d, J = 8.0 Hz), 61.4, 54.5 (q, J = 30.0 Hz), 35.0 (q, J = 1.0 Hz), 14.0; 19F{1H}
NMR (376 MHz, CDCl3) δ -76.1, -125.4; HPLC (OD-H, elute: Hexanes/i-PrOH = 95/5, detector: 230 nm,
o
flow rate: 0.8 mL/min), 30 C, t1 = 7.9 min (maj), t2 = 9.0 min; HRMS (ESI-TOF) m/z Calculated for
C12H14F4NO2 [M+H]+ 280.0955, found 280.0956.
(R)-Ethyl-4,4,4-trifluoro-3-(naphthalen-1-ylamino)butanoate (2k) : 65 mg, 84% yield, pale yellow oil,
1
Rf = 0.32 (hexanes/ethyl acetate = 20/1), 96% ee, [α]20 = +59.23 (c 0.65, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 7.94 – 7.76 (m, 2H), 7.56 – 7.45 (m, 2H), 7.42 – 7.33 (m, 2H), 6.87 (dd, J = 6.3, 2.1 Hz, 1H), 4.89
(d, J = 9.3 Hz, 1H), 4.72 (dt, J = 9.2, 7.1 Hz, 1H), 4.14 (d, J = 7.1 Hz, 2H), 2.93 (dd, J = 15.7, 5.0 Hz, 1H),
2.82 (dd, J = 15.7, 7.5 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.7, 141.0,
134.5, 128.8, 126.3, 126.0, 125.7 (q, J = 282.0 Hz), 125.3, 123.8, 119.8, 119.6, 106.7, 61.5, 53.5 (q, J = 30.0
Hz), 34.8 (q, J = 2.0 Hz), 14.0; 19F{1H} NMR (376 MHz, CDCl3) δ -75.6; HPLC (OD-H, elute: Hexanes/i-
o
PrOH = 95/5, detector: 230 nm, flow rate: 0.8 mL/min), 30 C, t1 = 23.3min (maj), t2 = 26.2 min; HRMS
(ESI-TOF) m/z Calculated for C16H17F3NO2 [M+H]+ 312.1206, found 312.1207.
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(R)-Ethyl-4,4-difluoro-3-(phenylamino)butanoate (2l) :23b 47mg, 77% yield, pale yellow oil, Rf = 0.31
(hexanes/ethyl acetate = 20/1), 72% ee, [α]20D = -11.7 (c 0.47, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.21 (t,
J = 7.8 Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 6.72 (d, J = 8.0 Hz, 2H), 5.94 (td, J = 56.1, 2.5 Hz, 1H), 4.33 –
4.19 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.97 (s, 1H), 2.77 (dd, J = 15.9, 5.3 Hz, 1H), 2.61 (dd, J = 15.9, 7.3
Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 145.8, 129.5, 119.1, 115.1 (t, J
= 245.0 Hz), 113.9, 61.1, 52.6 (q, J = 22.0 Hz), 33.3 (q, J = 2.0 Hz), 14.1; 19F{1H} NMR (376 MHz, CDCl3)
δ -125.4 (d, J = 282.7, 1F), 130.2 (d, J = 282.7, 1F); HPLC (OD-H, elute: Hexanes/i-PrOH = 90/10, detector:
230 nm, flow rate: 1.0 mL/min), 30 oC, t1 = 7.4 min, t2 = 8.2 min (maj).
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(2R,3R)-Ethyl-4,4,4-trifluoro-3-((4-methoxyphenyl)amino)-2-methylbutanoate (2m1) :3c 33mg, 43%
yield, pale yellow oil, Rf = 0.53 (hexanes/ethyl acetate = 30/1), 84% ee, [α]20 = -17.57 (c 0.33, CHCl3); 1H
D
NMR (400 MHz, CDCl3) δ 6.78 (d, J = 8.9 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 4.48 (d, J = 9.5 Hz, 1H), 4.25 –
4.08 (m, 2H), 4.03 – 3.86 (m, 1H), 3.74 (s, 3H), 3.05 – 2.88 (m, 1H), 1.30 (d, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.8, 153.0, 140.8, 125.7 (t, J = 281.0 Hz), 114.9 (d), 61.2,
59.7 (q, J = 28.0 Hz), 55.7, 39.1, 14.9, 14.0; 19F{1H} NMR (376 MHz, CDCl3) δ -73.5; HPLC (OD-H, elute:
Hexanes/i-PrOH = 90/10, detector: 230 nm, flow rate: 0.8 mL/min), 30 oC, t1 = 5.5 min (maj), t2 = 6.0 min.
(2R,3S)-Ethyl-4,4,4-trifluoro-3-((4-methoxyphenyl)amino)-2-methylbutanoate (2m2) :3c 26mg, 34%
yield, pale yellow oil, Rf = 0.52 (hexanes/ethyl acetate = 30/1), 90% ee, [α]20 = -0.77 (c 0.26, CHCl3); 1H
D
NMR (400 MHz, CDCl3) δ 6.77 (d, J = 8.9 Hz, 2H), 6.69 (d, J = 8.9 Hz, 2H), 4.44 (ddd, J = 11.0, 7.5, 5.5
Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 3.55 (d, J = 10.7 Hz, 1H), 2.93 (dd, J = 7.0, 5.5 Hz, 1H), 1.30
(d, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.8, 153.4, 140.1, 125.8
(t, J = 283.0 Hz), 115.8, 114.8, 61.3, 58.4 (q, J = 30.0 Hz), 55.7, 39.8, 14.0, 11.5; 19F{1H} NMR (376 MHz,
CDCl3) δ -73.1; HPLC (OD-H, elute: Hexanes/i-PrOH = 90/10, detector: 230 nm, flow rate: 0.8 mL/min), 30
oC, t1 = 6.1 min (maj), t2 = 6.9 min.
For 2.0 mmol Experiment
(S,S)-Ph-BPE (49.6 mg, 0.096 mmol) and Pd(OCOCF3)2 (26.6 mg, 0.08 mmol) were placed in a dried
Schlenk tube under nitrogen atmosphere, and degassed anhydrous acetone was added. The mixture was
stirred at room temperature for 1 h. The solvent was removed under vacuum to give the catalyst. This
catalyst was taken into a glovebox filled with nitrogen and dissolved in dry HFIP (15 mL). To a mixture of
substrates 1e (2.0 mmol) and p-anisic acid (60.8 mg, 0.4 mmol), the catalyst solution was added, and then
o
the mixture was transferred to an autoclave. The hydrogenation was performed at 60 C under 800 psi of
hydrogen. The autoclave was stirred under directed conditions for 24 h, then the hydrogen was carefully
released, the autoclave was opened, and saturated aqueous sodium bicarbonate (15 mL) was added to the
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mixture and stirred for 10-15 min. The mixture was extracted with dichloromethane twice and the combined
organic extracts dried over sodium sulfate. The resulting mixture was concentrated in vacuo and further
purification was performed by a silica gel column eluted with hexanes/ethyl acetate to give the desired
product 2e. The enantiomeric excesses were determined by chiral HPLC after the purification by column
chromatography on silica gel (ethyl acetate/hexanes), 0.409 g, 70% yield, 94% ee.
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Synthesis of (R)-4,4,4-trifluoro-3-(phenylamino)butan-1-ol.
LiAlH4 (23 mg, 0.6 mmol) was added to a solution of 1a (52.0 mg, 0.2 mmol) in THF (4.0 mL) at -50 oC.
The resulting mixture was stirred for 2h at -50 oC under argon atmosphere. The reaction was quenchesd with
saturated ammonium chloride solution and the aqueous layer was exacted with 3 x 10 mL of EtOAc. The
organic layer was dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure to get
the crude product. The crude product was chromatographed on a silica gel column using 2:1 hexanes /EtOAc
as eluent to afford the analytically pure product 5a in 38 mg (99% ee, 89% yield). 3c.
(R)-4,4,4-trifluoro-3-(phenylamino)butan-1-ol (5a) : 38 mg, 89% yield, pale yellow oil, Rf = 0.35
(hexanes/ethyl acetate = 2/1), 99% ee, [α]20D = +56.84 (c 0.38, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.25 –
7.16 (m, 2H), 6.84 – 6.77 (m, 1H), 6.72 (d, J = 7.7 Hz, 2H), 4.18 (s, 1H), 3.81 (dd, J = 6.7, 4.6 Hz, 2H), 3.73
(s, 1H), 2.20 – 2.08 (m, 1H), 1.75 (ddt, J = 14.7, 10.4, 4.4 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
146.6, 129.5, 126.3 (q, J = 282.0 Hz), 119.1, 113.6, 58.6, 53.2 (q, J = 30.0 Hz), 31.9 (q, J = 2.0 Hz); 19F{1H}
NMR (376 MHz, CDCl3) δ -76.0; HPLC (OD-H, elute: Hexanes/i-PrOH = 85/15, detector: 230 nm, flow rate:
1.0 mL/min), 30 oC, t1 = 10.1 min (maj), t2 = 12.1 min.
Synthesis of (R)-ethyl-3-amino-4,4,4-trifluorobutanoate.
o
To a solution of cerium ammonium nitrate (CAN, 5.0 eq) in acetonitrile/water (10 mL, 1:1) at 0 C was
added a solution of (R)-2e (158.0 mg, 0.54 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at
0 oC for 1 h and quenched with saturated aqueous sodium hydrogen sulfite (4 mL). The reaction mixture was
exacted with ethyl acetate and concentrated under vacuum. The resulting phase was redissolved in 10 mL
H2O and CH2Cl2 (15 mL), 1N HCl aq. was added to the mixture until the solution became pH 2. The mixture
was washed with CH2Cl2 (15 mL × 2). The aqueous layer was made alkaline by adding 1N NaOH, and then
extracted CH2Cl2 (15 mL × 2). The combined organic solution was washed with brine and dried over Na2SO4.
The solvent was removed under vacuum to afford pure chiral primary amine (R)-(+)-5e.15c, 18g, 24
(R)-Ethyl-3-amino-4,4,4-trifluorobutanoate (5e) : 48 mg, 48% yield, colourless oil, 93% ee, [α]20
=
D
+10.62 (c 0.48, CHCl3); 1H NMR (400 MHz, CDCl3) δδ 4.21 (q, J = 7.1 Hz, 2H), 3.76 – 3,73(m, 1H), 2.73
(dd, J = 16.1, 3.5 Hz, 1H), 2.46 (dd, J = 16.1, 10.1 Hz, 1H), 1.73 (brs, 2H), 1.29 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 170.2, 126.0 (q, J = 279.0 Hz), 61.2, 51.1 (q, J = 30.0 Hz), 35.6, 14.1; 19F{1H}
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NMR (376 MHz, CDCl3) δ -78.9; Enantiomeric excess was determined by HPLC for the corresponding
benzamide, Rf = 0.16 (hexanes/ethyl acetate = 5/1), HPLC (OJ-H, elute: Hexanes/i-PrOH = 90/10, detector:
230 nm, flow rate: 1.0 mL/min), 30 oC, t1 = 8.3 min (maj), t2 = 9.1 min.
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For Deuterium-Labeling Experiment of Eq. 7
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p-Anisic acid (7.6 mg, 0.05 mmol) was placed in a dried Schlenk tube under nitrogen atmosphere, and
degassed anhydrous CD3OD (1.0 mL) was added. The mixture was stirred at room temperature for 0.5 h.
The solvent was removed under vacuum to give the catalyst. The substrates 1a (64.8 mg, 0.25 mmol) and D-
HFIP (1.0 mL) were added. The ratio of imine (1ac) to enamine (1ab) is 1:5 under room temperature for 10
minute. When the reaction was performed at 60 oC for 10 minute, the atio of 1ac to 1ab is 1:2. Under 60 oC
for 1 h, the 1a is almost completely converted into 1ac and 1ab, and the ratio of 1ac to 1ab is 2.6:1.
Subsequently, the ratio of 1ac to 1ab was increased with time prolonged (see Figure S1).
ASSOCIATED CONTENT
Supporting information
NMR spectra of products, and HPLC for racemic and chiral products of all compounds. This material is
available free of charge via the internet at http://pubs.acs.org.
X-ray crystallography data 2a (CCDC 1909865) (CIF)
AUTHOR INFORMATION
Corresponding author
*E-mail: yypeng@jxnu.edu.cn, yiyuanpeng@yahoo.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the National Natural Science Foundation of China (Nos: 21502188, 21362014,
21762020) and the Open Project Program of Key Laboratory of Functional Small Organic Molecule,
Ministry of Education, Jiangxi Normal University (No. KLFS-KF-201705) and State Key Laboratory of Fine
Chemicals, Dalian University of Technology (KF1709) is acknowledged.
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