Catalytic Asymmetric Reduction of α-Trifluoromethylated Imines with Catecholborane by BINOL-Derived Boro-phosphates

Article abstract of DOI:10.1021/acs.joc.0c03009

A catalytic enantioselective reduction of α-trifluoromethylated imines by a BINOL-derived boro-phosphate employing catecholborane as hydride source has been developed. This method provides an efficient route to prepare synthetically useful chiral α-triflu

Full text of DOI:10.1021/acs.joc.0c03009

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Note
Catalytic Asymmetric Reduction of α‑Trifluoromethylated Imines
with Catecholborane by BINOL-Derived Boro-phosphates
Hualing He, Xiaoxue Tang, Yang Cao, and Jon C. Antilla*
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ABSTRACT: A catalytic enantioselective reduction of α-trifluorome-
thylated imines by a BINOL-derived boro-phosphate employing
catecholborane as hydride source has been developed. This method
provides an efficient route to prepare synthetically useful chiral α-
trifluoromethylated amines in high yields and with excellent
enantioselectivities (up to 98% yield and 96% ee) under mild
conditions.
rganofluorine compounds, frequently used as pharma-
ceuticals and agrochemicals, have received extensive
Scheme 1. Organocatalytic Reduction of
Trifluoromethylated Imines
O
attention because the introduction of fluorinated groups into
drug candidates can lead to significant changes in the chemical,
physical, and biological properties.1 Optically pure α-
trifluoromethylated amines are important building blocks as
fluorinated biologically active compounds are desirable targets
in organic synthesis.2
The asymmetric reduction of ketimines to provide amines
represents a simple and direct route to access chiral amines.
Great progress has been achieved in the field of enantiose-
lective imine reduction during the past decades.3 However,
limited examples of catalytic asymmetric hydrogenation of
perfluoroalkylimines have been reported. Most examples
reported to date rely on transition-metal catalysis (e.g., Pd,4
Ru,5 and Ir6). Although good to high yields and enantiose-
lectivities have been achieved, the handling of high pressure
hydrogen and/or the difficulties in separating metal complexes
from the resulting chiral amines often limited their applications
in synthesis. Therefore, the development of more practical and
economical methods, preferably under metal-free conditions,
to provide enantioenriched α-trifluoromethylated amines could
be desirable. However, the organocatalytic reduction of such
compounds is limited. In 1996, Uneyama disclosed the
catalytic reduction of trifluoromethylated imino esters by an
oxazaborolidine system and catecholborane as reductant with
moderate stereoselectivities (Scheme 1).7 In 2011, Akiyama
reported the organocatalytic hydrogenation of α-trifluorome-
thylated imines catalyzed by chiral phosphoric acids (CPA).
This innovative work relied on the use of stoichiometric
amounts of benzothiazolines as reducing agents, with the
byproduct of the oxidant having to be purified from the
resulting chiral products (Scheme 1).8 In 2013, Benaglia’s
group developed the enantioselective Lewis base catalyzed
hydrosilylation of trifluoromethyl ketimines, but it required the
use of hazardous trichlorosilane (Scheme 1).9 Though these
methods could find importance going forward, we feel that
Received: December 23, 2020
Published: February 15, 2021
https://dx.doi.org/10.1021/acs.joc.0c03009
J. Org. Chem. 2021, 86, 4336−4345
© 2021 American Chemical Society
4336

The Journal of Organic Chemistry
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Note
a
additional methods could compliment these approaches. In
2011, our group reported that, with catecholborane as a
hydride source, the catalytic asymmetric reduction of simple
ketones was realized by employing a conceptually unique boro-
phosphate catalyst, which was formed in situ by the reaction of
a CPA and catecholborane (Scheme 1, b).10 Utilizing this
catalytic system combining chiral phosphoric acids or N-triflyl
phosphoramides and boranes, several asymmetric hydro-
genation reactions such as reduction of ketoimines,11
enamine-type esters,11b α-imino esters,12 indoles,13 and C
C bonds14 have been successfully developed in recent years.
To the best of our knowledge, the asymmetric reduction of the
more challenging perfluoroalkylimine substrates employing this
catalytic system has not been described thus far. Herein, we
reported the asymmetric hydrogenation of trifluorinated
imines using our catalytic system (Scheme 1, c). We also
apply the method to the synthesis of perfluoroalkylated
analogues of NPS R-568 and fendiline.
We started our investigation by optimizing the reaction
conditions with catecholborane as the reducing agent.
Considering that the p-methoxyphenyl (PMP) group can be
easily removed, CF3-substituted ketimine 1a was chosen as the
model substrate. We observed that the reduction proceeded
rapidly with the boro-phosphate catalytic system; a slow
addition of the substrate is required to reach high
enantioselectivity. Initial results favored using CH2Cl2 as
solvent and (R)-P1 as catalyst, with the desired chiral product
obtained in good yield (Table 1, entry 1). Inspired by this
result, a series of chiral phosphoric acids were screened at
room temperature. The results showed that BINOL-derived
phosphoric acids provide superior enantiocontrol compared to
H8-BINOL-derived phosphoric acids. The best result was
obtained when using catalyst (R)-P4, with a 2,4,6-(iPr)3C6H2
group in the 3,3′-position of the BINOL (Table 1, entry 4). To
further improve the enantiocontrol, a series of solvents were
screened. We were happy to find a 93% ee was obtained when
cyclopentane was used as the solvent (Table 1, entry 12), while
no desired product was detected using THF as solvent.
Additional investigation showed that the ee decreased when
using a lower catalyst loading (Table 1, entry 15). Notably, no
hydrogenated product was isolated when using pinacolborane
as the hydride source (Table 1, entry 16). Moreover, both
reactivity and enantioselectivity decreased slightly when
reducing the equivalents of catecholborane (Table 1, entries
17 and 18). Finally, screening the reaction temperature showed
that a lower temperature has a negative effect on
enantioselectivity (Table 1, entries 19 and 20).
Table 1. Optimization of the Reduction Reaction
b
c
entry
CPA
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
toluene
cyclohexane
cyclopentane
THF
n-Hexane
cyclopentane
cyclopentane
cyclopentane
cyclopentane
cyclopentane
cyclopentane
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
(R)-P1
(R)-P2
(R)-P3
(R)-P4
(R)-P5
(R)-P6
(R)-P7
(R)-P8
(R)-P4
(R)-P4
(R)-P4
(R)-P4
(R)-P4
(R)-P4
(R)-P4
(R)-P4
(R)-P4
(R)-P4
(R)-P4
(R)-P4
93
95
94
95
97
94
93
96
94
93
92
94
46
33
45
86
40
31
24
80
84
80
87
93
10
11
12
13
14
d
ND
93
93
ND
85
90
e
15
f
d
16
g
17
91
89
92
93
92
87
90
79
h
18
i
19
j
20
a
Reaction conditions: 1a (0.05 mmol), catecholborane (0.15 mmol,
3.0 equiv), CPA (10 mol %), solvent (2.0 mL) under argon. Isolated
yield. Enantiomeric excess was determined by chiral HPLC analysis
using a chiral column. No reaction. Reaction performed with 5 mol
% CPA. Pinacolborane was used instead of catecholborane. 2.5
equiv of catecholborane. 1.5 equiv of catecholborane. Reaction
b
c
d
e
f
g
h
i
j
performed at 0 °C. Reaction performed at −30 °C.
ortho substituents on the aryl ring, while the reactivity
remained. For example, the reaction of 1l generated the
product in 42% ee value and 92% yield (Table 2, entry 12) and
the reaction of 1m with a 2-chloro substituent gave only an 8%
ee (Table 2, entry 13). Besides the substituted phenyl imines,
the use of the 2-naphthyl and heteroaromatic substituted
imines was also applicable for this method and gave the chiral
products in good yields and ee (Table 2, entries 14 and 15).
However, no desired product was observed using the nitrogen
containing heterocyclic 3-pyridyl imine 1p as a substrate
(Table 2, entry 16), even at 50 °C. Lower enantioselectivities
were obtained for the reduction of imines derived from
trifluoromethylated alkyl ketones (Table 2, entries 17 and 18).
Subsequently, we investigated different protecting groups on
the imine. The results showed that the prochiral imine
substrates bearing both electron-donating and electron-with-
drawing groups as the protecting group could be successfully
reduced to afford the chiral fluorinated amines with good
Under the optimized conditions, a wide variety of α-
trifluoromethylated imines were investigated to examine the
scope of the reaction. The results are shown in Table 2. The
substrates bearing different groups at the meta or para position
of the aryl ring can be tolerated well, affording the
corresponding chiral products with good yields and ee.
Electron-donating groups such as −Me, −OMe on the phenyl
ring furnished the resulting chiral trifluoromethylated amines
with good yields and stereoselectivities (Table 2, entries 2−5).
Different halogen groups on the phenyl ring were well
tolerated under the optimized conditions (Table 2, entries
6−9). With strong electron-withdrawing groups, such as cyano
and trifluoromethyl on the aryl ring, the corresponding chiral
amine products were obtained in high yields and good ee
(Table 2, entries 10 and 11). However, by contrast,
enantioselectivity of the reaction strongly diminished for
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Note
a
Table 2. Substrate Scope for the Reduction Reaction
Scheme 2. Synthesis of the Trifluoromethylated Analogue
NPS R-568 and Fendiline
b
c
entry
2
PG
PMP
R
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
94
95
93
96
96
95
94
95
94
96
95
92
91
98
93
93
92
95
94
96
93
92
94
94
93
92
42
8
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
Ph
4-MeC6H4
3-MeC6H4
4-OMeC6H4
3-OMeC6H4
4-CIC6H4
3-CIC6H4
4-BrC6H4
4-FC6H4
3-CF3CgH4
4-CNC6H4
2-MeC6H4
2-CIC6H4
2-naphthyl
2-thienyl
3-pyridyl
CH3CH2
PhCH2
10
11
12
13
14
15
16
17
2j
2k
21
2m
2n
2o
2p
2q
2r
94
87
d
ND
78
45
90
92
95
25
43
91
89
94
e
18
19
20
21
2s
2t
2u
Ph
Ph
Ph
4-MeC6H4
4-BrC6H4
a
Reaction conditions: 1 (0.05 mmol), catecholborane (0.15 mmol,
3.0 equiv), (R)-P4 (10 mol %), cyclopentane (2.0 mL) under argon.
b
c
in patients with parathyroid carcinoma.18 Following the same
procedure, (S)-2e was obtained with good yield and ee. When
the known deprotection procedure was used, compound 6 was
produced in good yield. Finally, following the reductive
amination of (S)-2e with aldehyde 7, the trifluoromethylated
analogue of NPS R-568 8 was obtained in 72% yield and good
enantioselectivity (96% ee, Scheme 2).
Isolated yield. Enantiomeric excess was determined by chiral HPLC
d
e
analysis using a chiral column. No reaction at 50 °C. The substrate
was a mixture of imine and enamine (ratio 3:2).
yields and ee’s (Table 2, entries 19−21). The absolute
configuration of 2a was confirmed by the comparison of the
optical rotations of known compounds to that reported in the
literature.4a,8
On the basis of previous work with this catalytic system,10,14
we proposed a plausible transition state for this transformation
(Figure 1). The formation of a boro-phosphate from the
To highlight the utility of this method, efficient asymmetric
synthetic routes to two perfluoroalkylated analogues of
pharmaceuticals were realized. Trifluoromethyl-containing
compounds have attracted extensive attention due to their
increasing occurrence in pharmaceuticals and how this
structural change influences the bioactivity of drug candi-
dates.15 We focused first on the synthesis of perfluoroalkylated
analogue fendiline, which is a coronary vasodilator that inhibits
calcium function in muscle cells in excitation-contraction
coupling. It has been proposed as an antiarrhythmic and
antianginal agent.16 When trifluoromethylated imine 1a was
used as the starting material, the chiral product (S)-2a was
obtained with good yield and enantioselectivity catalyzed by
(S)-P4 under the optimal conditions. The PMP group of
hydrogenated products was removed under the known
conditions.17 Oxidative cleavage of the hydrogenation product
(S)-2a with H5IO6/H2SO4 gave 2,2,2-trifluoro-1-phenethyl-
amine 3 in good yield. Next, the reductive amination of 3 with
aldehyde 4 afforded trifluoromethylated analogue of fendiline
(5) with a 69% yield and without a loss of ee (92% ee, Scheme
2). Additionally, the synthesis of a trifluoromethylated
analogue of NPS R-568 was accomplished. NPS R-568 is a
type II calcimimetic drug and was launched onto the market
for the treatment of hyperparathyroidism in patients with
chronic kidney disease, and for the treatment of hypercalcemia
Figure 1. Proposed transition state.
reaction of CPA and borane was confirmed by previous
studies.10 The boron center of the catalyst is believed to
activate the nitrogen atom of imine via a Lewis acid/Lewis base
interaction. Simultaneously, the oxygen of the PO moiety
acts as a Lewis base to coordinate with catecholborane, and the
hydride from borane attacks the activated prochiral imine in a
chiral environment to form the enantioenriched trifluorome-
thylated amine, and regenerate the catalyst.
In summary, an efficient asymmetric transfer hydrogenation
of trifluoromethylated imines catalyzed by a boro-phosphoric
acid using catecholborane as reducing agent has been realized.
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Note
by column chromatography (20:1 petroleum ether/EtOAc): pale
yellow oil, 1.934 g, 66% yield. 1H NMR (600 MHz, CDCl3) δ 7.08−
7.03 (m, 2H), 6.96 (s, 1H), 6.88 (d, J = 7.0 Hz, 1H), 6.65−6.62 (m,
2H), 6.60−6.56 (m, 2H), 3.58 (s, 3H), 2.16 (s, 3H) ppm; 13C{1H}
A series of synthetically useful chiral trifluoromethylated
amines were obtained with high yields and enantioselectivities
under mild conditions. In addition, efficient and practical
synthetic routes of trifluoromethylated analogues of the
pharmaceutical compound fendiline and NPS R-568 have
been developed using inexpensive reagents and nontoxic
transition-metal catalysts or reagents. Further studies on the
application of this exciting boro-phosphate catalytic system are
ongoing in our laboratory.
2
NMR (150 MHz, CDCl3) δ 157.9, 155.5 (C-F, JC‑F = 33.5 Hz),
139.8, 138.6, 130.9, 130.8, 128.9, 128.6, 125.7, 123.4, 120.2 (C-F,
1JC‑F = 278.7 Hz), 114.0, 55.2, 21.3 ppm; 19F NMR (376 MHz,
CDCl3) δ −69.87 ppm; HRMS (ESI) m/z: [M + Na]+ Calcd for
C16H14F3NNaO 316.0920; Found: 316.0914.
4-Methoxy-N-(2,2,2-trifluoro-1-(4-methoxyphenyl)ethylidene)-
aniline (1d). The general procedure was followed, and the product
was purified by column chromatography (20:1 petroleum ether/
EXPERIMENTAL SECTION
1
■
EtOAc): pale yellow solid, 2.658 g, 86% yield, mp: 50−51 °C. H
General Consideration. All reactions were carried out in flame-
dried or oven-dried screw-cap test tubes and were allowed to proceed
under a dry argon atmosphere with magnetic stirring. Anhydrous
cyclopentane was purchased from Energy Chemical and used without
further purification. Substituted BINOL phosphoric acids were
purchased from Daicel Chiral Technologies.
NMR (600 MHz, CDCl3) δ 7.10 (d, J = 8.7 Hz, 2H), 6.75−6.72 (m,
2H), 6.68−6.64 (m, 4H), 3.70 (s, 3H), 3.66 (s, 3H) ppm; 13C{1H}
2
NMR (150 MHz, CDCl3) δ 160.8, 157.6, 155.1 (C-F, JC‑F = 33.3
Hz), 140.2, 130.4, 123.0, 122.5, 120.2 (C-F, 1JC‑F = 279.0 Hz), 114.1,
114.1, 55.3, 55.2 ppm; 19F NMR (376 MHz, CDCl3) δ −69.57 ppm;
HRMS (ESI) m/z: [M + H]+ Calcd for C16H15F3NO2 310.1049;
Found: 310.1049.
Thin layer chromatography was performed from Yantai TLC plates
(silica gel 60 F254). Flash column chromatography was performed
with Yantai silica gel (200−300 mesh). Enantiomeric excess (ee) was
determined using an Agilent HPLC 1260. Column conditions are
reported in the experimental section below. Optical rotations were
performed on a Rudolph Research Analytical Autopol IV polarimeter
4-Methoxy-N-(2,2,2-trifluoro-1-(3-methoxyphenyl)ethylidene)-
aniline (1e). The general procedure was followed, and the product
was purified by column chromatography (20:1 petroleum ether/
1
EtOAc): pale yellow oil, 2.751 g, 89% yield. H NMR (600 MHz,
CDCl3) δ 7.15 (t, J = 8.0 Hz, 1H), 6.84−6.80 (m, 1H), 6.72 (d, J =
(λ 589) using a 700 μL cell with a path length of 1 dm. 1H NMR, 13
C
7.6 Hz, 1H), 6.70−6.62 (m, 5H), 3.64 (s, 3H), 3.61 (s, 3H) ppm;
NMR, and 19F NMR were recorded on Bruker AVANCE IIITM HD
NanoBAY (400 MHz) and Bruker AVANCE III (600 MHz)
instruments with chemical shifts reported relative to tetramethylsilane
(TMS). The HRMS data were measured on an Agilent 1100 LC/MS
ESI/TOF mass spectrometer with electrospray ionization. Com-
pounds described in the literature were characterized by comparing
their data to the reported values.
13C{1H} NMR (150 MHz, CDCl3) δ 159.6, 157.9, 155.1 (C-F, 1JC‑F
=
33.5 Hz), 139.7, 131.9, 129.9, 123.3, 120.9, 120.0 (C-F, 2JC‑F = 278.9
Hz), 115.9, 114.0, 55.3, 55.2 ppm; 19F NMR (376 MHz, CDCl3) δ
−69.92 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C16H15F3NO2
310.1049; Found: 310.1047.
(N-(1-(4-Chlorophenyl)-2,2,2-trifluoroethylidene)-4-methoxyani-
line (1f). The general procedure was followed, and the product was
purified by column chromatography (20:1 petroleum ether/EtOAc):
Trifluoromethyl ketones were purchased from commercial
suppliers and used without further purification. N-(Triphenylphos-
phoranylidene)aniline was prepared according to the reported
procedure.19
1
pale yellow solid, 2.317 g, 74% yield, mp: 54−55 °C. H NMR (600
MHz, CDCl3) δ 7.22 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H),
6.67−6.61 (m, 4H) ppm; 3.64 (s, 3H) ppm; 13C{1H} NMR (150
2
General Procedure for the Synthesis of α-Trifluoromethy-
lated Ketimines 1.8,20 Trifluoromethyl ketone (1.0 equiv, 10.0
mmol) and N-(triphenylphosphoranylidene)aniline (1.2 equiv, 12.0
mmol) were dissolved in toluene (30 mL) and refluxed at 120 °C for
overnight. After completion, the reaction mixture was cooled to room
temperature and the solvent was removed under reduced pressure.
Then the residue was treated with hexanes, the precipitate was
filtered, and the solvent was removed in vacuo. The crude product
was purified by flash column chromatography on a silica gel
(petroleum ester/EtOAc = 20/1) to afford the pure trifluorome-
thylketimine.
4-Methoxy-N-(2,2,2-trifluoro-1-phenylethylidene)aniline (1a).
The general procedure was followed, and the product was purified
by column chromatography (20:1 petroleum ether/EtOAc): pale
yellow oil, 2.232 g, 80% yield. 1H NMR (600 MHz, CDCl3) δ 7.29−
7.24 (m, 1H), 7.24−7.19 (m, 2H), 7.16−7.11 (m, 2H), 6.67−6.58
(m, 4H), 3.61 (s, 3H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ
157.9, 155.4 (C-F, 2JC‑F = 33.6 Hz), 139.8, 130.8, 130.1, 128.7, 128.6,
123.4, 120.1 (C-F, 1JC‑F = 278.8 Hz), 114.0, 55.3 ppm; 19F NMR (376
MHz, CDCl3) δ −69.88 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for
C15H13F3NO 280.0944; Found: 280.0945.
MHz, CDCl3) δ 158.0, 154.1 (C-F, JC‑F = 34.0 Hz), 139.5, 136.5,
130.1, 129.2, 129.0, 123.2, 119.9 (C-F, 1JC‑F = 278.8 Hz), 114.2, 55.3
ppm; 19F NMR (376 MHz, CDCl3) δ −69.83 ppm; HRMS (ESI) m/
z: [M + H]+ Calcd for C15H12ClF3NO 314.0554; Found: 314.0544.
N-(1-(3-Chlorophenyl)-2,2,2-trifluoroethylidene)-4-methoxyani-
line (1g). The general procedure was followed, and the product was
purified by column chromatography (20:1 petroleum ether/EtOAc):
1
pale yellow solid, 2.004 g, 64% yield, mp: 49−50 °C. H NMR (600
MHz, CDCl3) δ 7.29−7.24 (m, 1H), 7.19−7.14 (m, 2H), 6.99 (d, J =
7.7 Hz, 1H), 6.68−6.61 (m, 4H), 3.64 (s, 3H) ppm; 13C{1H} NMR
2
(150 MHz, CDCl3) δ 158.2, 153.5 (C-F, JC‑F = 34.0 Hz), 139.2,
1
134.9, 132.5, 130.4, 130.1, 128.5, 126.9, 123.4, 119.9 (C-F, JC‑F
=
278.8 Hz), 114.2, 55.3 ppm; 19F NMR (376 MHz, CDCl3) δ −69.91
ppm; HRMS (ESI) m/z: [M + Na]+ Calcd for C15H11ClF3NNaO
336.0373; Found: 336.0384.
N-(1-(4-Bromophenyl)-2,2,2-trifluoroethylidene)-4-methoxyani-
line (1h). The general procedure was followed, and the product was
purified by column chromatography (20:1 petroleum ether/EtOAc):
1
pale yellow solid, 2.713 g, 76% yield, mp: 60−61 °C. H NMR (600
MHz, CDCl3) δ 7.39 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H),
6.68−6.62 (m, 4H), 3.66 (s, 3H) ppm; 13C{1H} NMR (150 MHz,
2
4-Methoxy-N-(2,2,2-trifluoro-1-(p-tolyl)ethylidene)aniline (1b).
The general procedure was followed, and the product was purified
by column chromatography (20:1 petroleum ether/EtOAc): pale
yellow oil, 2.491 g, 85% yield. 1H NMR (600 MHz, CDCl3) δ 7.07−
6.99 (m, 4H), 6.69−6.59 (m, 4H), 3.63 (s, 3H), 2.23 (s, 3H) ppm;
CDCl3) δ 158.1, 154.2 (C-F, JC‑F = 34.2 Hz), 139.4, 132.1, 130.2,
1
129.5, 124.8, 123.2, 119.9 (C-F, JC‑F = 278.9 Hz), 114.2, 55.3 ppm;
19F NMR (376 MHz, CDCl3) δ −69.83 ppm; HRMS (ESI) m/z: [M
+ H]+ Calcd for C15H12BrF3NO 358.0049; Found: 358.0056.
N-(4-Methoxyphenyl)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-
imine (1i). The general procedure was followed, and the product was
purified by column chromatography (20:1 petroleum ether/EtOAc):
2
13C{1H} NMR (150 MHz, CDCl3) δ 157.7, 155.6 (C-F, JC‑F = 33.3
1
Hz), 140.4, 140.0, 129.4, 128.6, 127.7, 123.2, 120.2 (C-F, JC‑F
=
1
278.7 Hz), 114.0, 55.3, 21.4 ppm; 19F NMR (376 MHz, CDCl3) δ
−69.81 ppm; HRMS (ESI) m/z: [M + Na]+ Calcd for
C16H14F3NNaO 316.0920; Found: 316.0920.
pale yellow oil, 1.396 g, 64% yield. H NMR (600 MHz, CDCl3) δ
7.18−7.12 (m, 2H), 6.96−6.90 (m, 2H), 6.67−6.61 (m, 4H), 3.65 (s,
1
3H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 163.4 (C-F, JC‑F
=
2
251.8 Hz), 157.9, 154.3 (C-F, JC‑F = 33.8 Hz), 139.6, 130.9 (C-F,
4-Methoxy-N-(2,2,2-trifluoro-1-m-tolylethylidene)aniline (1c).
The general procedure was followed, and the product was purified
3JC‑F = 8.4 Hz), 126.7 (C-F, 4JC‑F = 3.8 Hz), 123.2, 120.0 (C-F, 1JC‑F
=
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https://dx.doi.org/10.1021/acs.joc.0c03009
J. Org. Chem. 2021, 86, 4336−4345

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
2
278.7 Hz), 116.1 (C-F, JC‑F = 22.0 Hz), 114.2, 55.3 ppm; 19F NMR
CDCl3) δ −68.31 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for
C13H11F3NOS 286.0508; Found: 286.0503.
(376 MHz, CDCl3) δ −69.91, −108.78 ppm; HRMS (ESI) m/z: [M
+ H]+ Calcd for C15H12F4NO 298.0850; Found: 298.0844.
2,2,2-Trifluoro-N-(4-methoxyphenyl)-1-(pyridin-3-yl)ethan-1-
imine (1p). The general procedure was followed, and the product was
purified by column chromatography (5:1 petroleum ether/EtOAc):
4-Methoxy-N-(2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl)-
ethylidene)aniline (1j). The general procedure was followed, and the
product was purified by column chromatography (20:1 petroleum
ether/EtOAc): pale yellow solid, 2.674 g, 90% yield, mp: 45−46 °C.
1H NMR (600 MHz, CDCl3) δ 7.55 (d, J = 7.8 Hz, 1H), 7.43 (s, 1H),
1
pale yellow solid, 1.789 g, 66% yield, mp: 68−69 °C. H NMR (600
MHz, CDCl3) δ 8.61 (dd, J = 4.9, 1.7 Hz, 1H), 8.46 (d, J = 2.3 Hz,
1H), 7.58 (dt, J = 8.0, 2.0 Hz, 1H), 7.29 (dd, J = 7.7, 5.0 Hz, 1H),
6.74−6.70 (m, 4H), 3.73 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3)
7.37 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.66−6.59 (m, 4H),
2
3.63 (s, 3H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 158.3, 153.5
δ 158.2, 152.5 (C-F, JC‑F = 34.6 Hz), 150.9, 149.2, 139.1, 136.2,
1
2
2
127.0, 123.4, 123.1, 119.8 (C-F, JC‑F = 278.5 Hz), 114.3, 55.3 ppm;
(C-F, JC‑F = 34.3 Hz), 139.1, 132.0, 131.6, 131.4 (C-F, JC‑F = 33.1
19F NMR (376 MHz, CDCl3) δ −70.12 ppm; HRMS (ESI) m/z: [M
4
4
Hz), 129.4, 126.9 (C-F, JC‑F = 3.7 Hz), 125.6 (C-F, JC‑F = 4.0 Hz),
+ H]+ Calcd for C14H12F3N2O 281.0896; Found: 281.0906.
1,1,1-Trifluoro-N-(4-methoxyphenyl)butan-2-imine (1q). The
general procedure was followed, and the product was purified by
column chromatography (30:1 petroleum ether/EtOAc): pale yellow
oil, 0.924 g, 40% yield. 1H NMR (600 MHz, CDCl3) δ 6.85−6.82 (m,
2H), 6.70−6.66 (m, 2H), 3.74 (s, 3H), 2.37 (q, J = 7.7 Hz, 2H), 1.06
(t, J = 7.5 Hz, 3H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 161.9
(C-F, 2JC‑F = 31.8 Hz), 157.2, 140.6, 120.1, 120.1 (C-F, 1JC‑F = 280.1
Hz) 114.4, 55.4, 21.8, 11.3 ppm; 19F NMR (376 MHz, CDCl3) δ
−71.69 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C11H13F3NO
232.0944; Found: 232.0943.
1
1
123.4 (C-F, JC‑F = 272.7 Hz), 123.2, 119.8 (C-F, JC‑F = 278.6 Hz),
114.2, 55.3 ppm; 19F NMR (376 MHz, CDCl3) δ −63.07, −69.86
ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C16H12F6NO 348.0818;
Found: 348.0806.
4-(2,2,2-Trifluoro-1-((4-methoxyphenyl)imino)ethy-l)benzonitrile
(1k). The general procedure was followed, and the product was
purified by column chromatography (15:1 petroleum ether/EtOAc):
1
pale yellow solid, 1.642 g, 54% yield, mp: 137−138 °C. H NMR
(600 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.1 Hz,
2H), 6.68−6.60 (m, 4H), 3.68 (s, 3H) ppm; 13C{1H} NMR (150
2
MHz, CDCl3) δ158.4, 153.1 (C-F, JC‑F = 34.6 Hz), 138.8, 135.3,
1
1,1,1-Trifluoro-N-(4-methoxyphenyl)-3-phenylpropan-2-imine
(1r). The general procedure was followed, and the product was
purified by column chromatography (20:1 petroleum ether/EtOAc):
pale yellow oil, 0.997 g, 34% yield. 1p and 1p′ mixture (major:minor
132.5, 129.5, 123.4, 119.7 (C-F, JC‑F = 278.5 Hz), 117.7, 114.3,
114.2, 55.4 ppm; 19F NMR (376 MHz, CDCl3) δ −69.69 ppm;
HRMS (ESI) m/z: [M + H]+ Calcd for C16H12F3N2O 305.0896;
Found: 305.0885.
1
= 3:2). H NMR (600 MHz, CDCl3) δ 7.43−7.38 (m, 1.30H), 7.30
2,2,2-Trifluoro-N-(4-methoxyphenyl)-1-(o-tolyl)ethan-1-imine
(1l). The general procedure was followed, and the product was
purified by column chromatography (20:1 petroleum ether/EtOAc):
(dd, J = 8.0, 6.4 Hz, 2.00H), 7.29−7.20 (m, 2.96H), 7.07 (d, J = 7.3
Hz, 1.83H), 6.95−6.89 (m, 2.25H), 6.86−6.80 (m, 1.91H), 6.75−
6.69 (m, 1.97H), 6.68−6.62 (m, 1.30H), 5.17 (s, 0.65H), 3.89 (s,
2.00H), 3.83 (s, 3.00H), 3.73 (s, 1.96H) ppm; 13C{1H} NMR (150
1
pale yellow oil, 1.524 g, 52% yield. H NMR (600 MHz, CDCl3) δ
7.20−7.13 (m, 2H), 7.11 (td, J = 7.5, 1.3 Hz, 1H), 6.99 (d, J = 7.6 Hz,
1H), 6.70−6.65 (m, 2H), 6.57−6.53 (m, 2H), 3.54 (s, 3H), 1.86 (s,
3H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 158.5, 155.2 (C-F,
2JC‑F = 34.1 Hz), 139.3, 135.8, 131.2, 130.7, 130.0, 128.6, 126.0, 124.1,
2
MHz, CDCl3) δ 158.2 (C-F, JC‑F = 32.0 Hz), 157.5, 154.1, 140.3,
3
135.3, 134.1, 132.9, 132.1 (C-F, JC‑F = 9.8 Hz), 129.5, 128.7, 128.7,
128.5 (C-F, 3JC‑F = 12.1 Hz), 128.4, 128.3, 127.1, 120.9 (C-F, 1JC‑F
=
4
280.2 Hz), 120.5, 120.1 (C-F, JC‑F = 4.2 Hz), 117.5, 114.5, 114.4,
55.5, 55.5, 34.4 ppm; 19F NMR (376 MHz, CDCl3) δ −69.96, −70.37
ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C16H15F3NO 294.1100;
Found: 294.1091.
120.3 (C-F, 1JC‑F = 278.8 Hz), 113.9, 55.2, 19.5 ppm; 19F NMR (376
MHz, CDCl3) δ −70.89 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for
C16H15F3NO 294.1100; Found: 294.1096.
1-(2-Chlorophenyl)-2,2,2-trifluoro-N-(4-methoxyphenyl)ethan-1-
imine (1m). The general procedure was followed, and the product
was purified by column chromatography (20:1 petroleum ether/
2,2,2-Trifluoro-N,1-diphenylethan-1-imine (1s). The general
procedure was followed, and the product was purified by column
chromatography (20:1 petroleum ether/EtOAc): pale yellow oil,
1
EtOAc): pale yellow oil, 2.191 g, 70% yield. H NMR (600 MHz,
1
2.142 g, 86% yield. H NMR (600 MHz, CDCl3) δ 7.42−7.18 (m,
CDCl3) δ 7.25−7.13 (m, 4H), 6.71 (d, J = 8.6 Hz, 2H), 6.59 (d, J =
8.9 Hz, 2H), 3.58 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ
157.4, 151.6 (C-F, 2JC‑F = 35.2 Hz), 138.2, 131.4, 130.3, 129.8, 129.0,
7H), 7.08 (t, J = 7.4 Hz, 1H), 6.85−6.70 (m, 2H) ppm; 13C{1H}
2
NMR (150 MHz, CDCl3) δ 157.1 (C-F, JC‑F = 34.0 Hz), 147.2,
1
130.2, 130.1, 128.8, 128.7, 128.5, 125.3, 120.6, 119.9 (C-F, JC‑F
=
1
129.0, 126.0, 122.4, 118.7 (C-F, JC‑F = 278.7 Hz), 112.8, 54.1 ppm;
279.3 Hz) ppm; 19F NMR (376 MHz, CDCl3) δ −69.97 ppm; HRMS
(ESI) m/z: [M + H]+ Calcd for C14H11F3N 250.0838; Found:
250.0828.
19F NMR (376 MHz, CDCl3) δ −70.43 ppm. HRMS (ESI) m/z: [M
+ H]+ Calcd for C15H12ClF3NO 314.0554; Found: 314.0553.
4-Methoxy-N-(2,2,2-trifluoro-1-(naphthalen-2-yl)ethylidene)-
aniline (1n). The general procedure was followed, and the product
was purified by column chromatography (20:1 petroleum ether/
4-Methyl-N-(2,2,2-trifluoro-1-phenylethylidene)aniline (1t). The
general procedure was followed, and the product was purified by
column chromatography (20:1 petroleum ether/EtOAc): pale yellow
solid, 2.342 g, 89% yield, mp: 52−53 °C. 1H NMR (600 MHz,
CDCl3) δ 7.27−7.23 (m, 1H), 7.22−7.18 (m, 2H), 7.15−7.11 (m,
2H), 6.89 (d, J = 8.3 Hz, 2H), 6.56 (d, J = 8.3 Hz, 2H), 2.15 (s, 3H)
1
EtOAc): pale yellow solid, 2.698 g, 82% yield, mp: 81−82 °C. H
NMR (600 MHz, CDCl3) δ 7.77 (s, 1H), 7.69 (t, J = 7.5 Hz, 2H),
7.63 (d, J = 8.5 Hz, 1H), 7.45−7.36 (m, 2H), 7.08 (d, J = 8.4 Hz,
1H), 6.69 (d, J = 9.0 Hz, 2H), 6.57 (d, J = 8.9 Hz, 2H), 3.57 (s, 3H)
2
ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 156.4 (C-F, JC‑F = 33.8
ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 156.9, 154.1 (C-F, 2JC‑F
=
Hz), 144.4, 135.3, 130.5, 130.1, 129.4, 128.7, 128.6, 121.0, 120.0 (C-
1
F, JC‑F = 279.0 Hz), 20.9 ppm; 19F NMR (376 MHz, CDCl3) δ
33.5 Hz), 138.7, 132.5, 131.7, 127.9, 127.6, 127.5, 127.1, 126.8, 126.6,
1
−69.93 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C15H13F3N
264.0995; Found: 264.0985.
125.8, 124.1, 122.5, 119.2 (C-F, JC‑F = 278.8 Hz), 113.1, 54.2 ppm;
19F NMR (376 MHz, CDCl3) δ −69.43 ppm; HRMS (ESI) m/z: [M
+ H]+ Calcd for C19H15F3NO 330.1100; Found: 330.1111.
N-(4-Bromophenyl)-2,2,2-trifluoro-1-phenylethan-1-imine (1u).
The general procedure was followed, and the product was purified
by column chromatography (20:1 petroleum ether/EtOAc): pale
yellow solid, 2.452 g, 75% yield, mp: 49−50 °C. 1H NMR (600 MHz,
CDCl3) δ 7.44−7.38 (m, 1H), 7.38−7.30 (m, 4H), 7.24 (d, J = 7.7
Hz, 2H), 6.67 (d, J = 8.3 Hz, 2H) ppm; 13C{1H} NMR (150 MHz,
4-Methoxy-N-(2,2,2-trifluoro-1-(thiophen-2-yl)ethylidene)aniline
(1o). The general procedure was followed, and the product was
purified by column chromatography (20:1 petroleum ether/EtOAc):
1
pale yellow oil, 2.223 g, 78% yield. H NMR (600 MHz, CDCl3) δ
7.44−7.41 (m, 1H), 7.34 (d, J = 5.0 Hz, 1H), 6.94−6.90 (m, 1H),
6.85−6.81 (m, 2H), 6.70−6.66 (m, 2H), 3.74 (s, 3H) ppm; 13C{1H}
2
CDCl3) δ 157.8 (C-F, JC‑F = 33.9 Hz), 146.1, 132.0, 130.5, 129.7,
2
1
128.7, 128.6, 122.4, 119.9 (C-F, JC‑F = 279.4 Hz), 118.8 ppm; 19F
NMR (150 MHz, CDCl3) δ 157.8, 149.1 (C-F, JC‑F = 33.6 Hz),
4
141.2, 133.2 (C-F, JC‑F = 2.7 Hz), 132.0, 129.4, 126.6, 120.3, 119.9
NMR (376 MHz, CDCl3) δ −70.00 ppm; HRMS (ESI) m/z: [M +
(C-F, JC‑F = 279.8 Hz), 115.0, 55.4 ppm; 19F NMR (376 MHz,
H]+ Calcd for C14H10BrF3N 327.9943; Found: 327.9947.
1
4340
https://dx.doi.org/10.1021/acs.joc.0c03009
J. Org. Chem. 2021, 86, 4336−4345

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
General Procedure for the Synthesis of α-Trifluoromethy-
lated Amines 2. To a screw capped reaction tube (10 mL) was
added catalyst (R)-P4 (3.8 mg, 0.005 mmol), and the atmosphere was
exchanged with argon three times. Cyclopentane (1.0 mL) was added
by syringe, followed by the addition of catecholborane (3.0 equiv, 16
μL), and the mixture was stirred at room temperature for 10 min.
Then substrate 1 (1.0 equiv, 0.05 mmol) dissolved in cyclopentane
(1.0 mL) was added dropwise over 1 h by a syringe pump. The
reaction was completed after the addition. The residue was purified by
silica gel chromatography (Hexane/EtOAc = 10:1) to give the chiral
products 2.
was purified by column chromatography (8:1 petroleum ether/
EtOAc): pale yellow oil, 14.9 mg, 96% yield, 96% ee. The
enantiomeric excess was determined by HPLC (Daicel Chiralpak
OD-H, hexane/i-PrOH = 95:5 (v/v), λ = 254 nm, flow rate = 0.5
mL/min): tminor = 24.020 min, tmajor = 26.088 min; [α]D20 = −66.5 (c
= 0.77 in CHCl3). 1H NMR (600 MHz, CDCl3) δ 7.21 (t, J = 8.0 Hz,
1H), 6.94 (d, J = 7.7 Hz, 1H), 6.90 (s, 1H), 6.81 (dd, J = 8.1, 2.2 Hz,
1H), 6.67−6.63 (m, 2H), 6.52 (d, J = 8.3 Hz, 2H), 4.69 (q, J = 7.3
Hz, 1H), 3.71 (s, 3H), 3.63 (s, 3H) ppm; 13C{1H} NMR (150 MHz,
CDCl3) δ 160.0, 153.4, 139.5, 135.9, 129.9, 125.1 (C-F, 1JC‑F = 281.1
2
Hz), 120.2, 115.8, 114.9, 114.2, 113.9, 61.8 (C-F, JC‑F = 29.6 Hz),
55.6, 55.3 ppm; 19F NMR (376 MHz, CDCl3) δ −73.88 ppm; HRMS
(ESI) m/z: [M + H]+ Calcd for C16H17F3NO2 312.1206; Found:
312.1199.
(R)-4-Methoxy-N-(2,2,2-trifluoro-1-phenylethyl)aniline (2a). The
general procedure was followed, and the product was purified by
column chromatography (10:1 petroleum ether/EtOAc): pale yellow
oil, 13.2 mg, 94% yield, 93% ee. The enantiomeric excess was
determined by HPLC (Daicel Chiralpak OD-H, hexane/i-PrOH =
95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/min): tminor = 9.332 min,
(R)-N-(1-(4-Chlorophenyl)-2,2,2-trifluoroethyl)-4-methoxyaniline
(2f). The general procedure was followed, and the product was
purified by column chromatography (10:1 petroleum ether/EtOAc):
pale yellow oil, 15.0 mg, 95% yield, 93% ee. The enantiomeric excess
was determined by HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH
= 95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/min): tminor = 14.435
20
1
tmajor = 10.132 min; [α]D = −51.4 (c = 0.34 in CHCl3). H NMR
(600 MHz, CDCl3) δ 7.37−7.32 (m, 2H), 7.31−7.23 (m, 3H), 6.66−
6.62 (m, 2H), 6.53−6.47 (m, 2H), 4.72 (q, J = 7.3 Hz, 1H), 3.60 (s,
3H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 152.4, 138.5, 133.3,
128.0, 127.9, 126.9, 124.2 (C-F, 1JC‑F = 282.0 Hz), 114.8, 113.9, 60.8
20
1
min, tmajor = 20.901 min; [α]D = −68.9 (c = 0.59 in CHCl3). H
NMR (600 MHz, CDCl3) δ 7.32−7.22 (m, 4H), 6.64 (dt, J = 8.7, 1.8
Hz, 2H), 6.47 (dt, J = 8.9, 1.8 Hz, 2H), 4.70 (q, J = 7.8 Hz, 1H), 3.61
(s, 3H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 152.5, 138.1,
2
(C-F, JC‑F = 29.6 Hz), 54.6 ppm; 19F NMR (376 MHz, CDCl3) δ
−73.95 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C15H15F3NO
282.1100; Found: 282.1089.
1
134.1, 131.8, 128.3, 128.1, 123.9 (C-F, JC‑F = 281.9 Hz), 114.8,
(R)-4-Methoxy-N-(2,2,2-trifluoro-1-(p-tolyl)ethyl)aniline (2b).
The general procedure was followed, and the product was purified
by column chromatography (10:1 petroleum ether/EtOAc): pale
yellow oil, 14.0 mg, 95% yield, 92% ee. The enantiomeric excess was
determined by HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH =
95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/min): tminor = 11.508 min,
2
113.9, 60.2 (C-F, JC‑F = 29.8 Hz), 54.6 ppm; 19F NMR (376 MHz,
CDCl3) δ −74.10 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for
C15H14ClF3NO 316.0711; Found: 316.0700.
(R)-N-(1-(3-Chlorophenyl)-2,2,2-trifluoroethyl)-4-methoxyaniline
(2g). The general procedure was followed, and the product was
purified by column chromatography (10:1 petroleum ether/EtOAc):
pale yellow oil, 14.8 mg, 94% yield, 92% ee. The enantiomeric excess
was determined by HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH
= 95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/min): tminor = 12.438
20
1
tmajor = 17.056 min; [α]D = −67.1 (c = 0.53 in CHCl3). H NMR
(600 MHz, CDCl3) δ 7.22 (d, J = 7.7 Hz, 2H), 7.08 (d, J = 7.8 Hz,
2H), 6.68−6.60 (m, 2H), 6.54−6.47 (m, 2H), 4.68 (q, J = 7.5 Hz,
1H), 3.60 (s, 3H), 2.24 (s, 3H) ppm; 13C{1H} NMR (150 MHz,
20
1
min, tmajor = 13.115 min; [α]D = −47.8 (c = 0.67 in CHCl3). H
NMR (600 MHz, CDCl3) δ 7.36 (s, 1H), 7.27−7.17 (m, 3H), 6.68−
6.61 (m, 2H), 6.53−6.44 (m, 2H), 4.69 (q, J = 7.2 Hz, 1H), 3.98 (s,
CDCl3) δ 153.4, 139.6, 139.0, 131.4, 129.6, 127.8, 125.3 (C-F, 1JC‑F
=
282.2 Hz), 115.8, 114.9, 61.6 (C-F, 2JC‑F = 29.3 Hz), 55.6, 21.1 ppm;
19F NMR (376 MHz, CDCl3) δ −74.05 ppm; HRMS (ESI) m/z: [M
+ H]+ Calcd for C16H17F3NO 296.1257; Found: 296.1254.
1H), 3.61 (s, 3H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 153.6,
1
139.1, 136.4, 134.9, 130.1, 129.4, 128.2, 126.2, 124.9 (C-F, JC‑F
=
(R)-4-Methoxy-N-(2,2,2-trifluoro-1-(m-tolyl)ethyl)aniline (2c).
The general procedure was followed, and the product was purified
by column chromatography (10:1 petroleum ether/EtOAc): pale
yellow oil, 13.7 mg, 93% yield, 95% ee. The enantiomeric excess was
determined by HPLC (Daicel Chiralpak OD-H, hexane/i-PrOH =
95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/min): tminor = 8.518 min,
281.9 Hz), 115.8, 115.0, 61.4 (C-F, JC‑F = 29.8 Hz), 55.6 ppm; 19F
NMR (376 MHz, CDCl3) δ −73.93 ppm; HRMS (ESI) m/z: [M +
H]+ calcd for C15H14ClF3NO 316.0711; Found: 316.0699.
2
(R)-N-(1-(4-Bromophenyl)-2,2,2-trifluoroethyl)-4-methoxyaniline
(2h). The general procedure was followed, and the product was
purified by column chromatography (10:1 petroleum ether/EtOAc):
pale yellow oil, 17.1 mg, 95% yield, 94% ee. The enantiomeric excess
was determined by HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH
= 95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/min): tminor = 16.999
20
1
tmajor = 9.057 min; [α]D = −57.3 (c = 0.82 in CHCl3). H NMR
(600 MHz, CDCl3) δ 7.19−7.09 (m, 3H), 7.09−7.03 (m, 1H), 6.68−
6.60 (m, 2H), 6.55−6.47 (m, 2H), 4.66 (q, J = 7.4 Hz, 1H), 3.95 (s,
1H), 3.60 (s, 3H), 2.25 (s, 3H) ppm; 13C{1H} NMR (150 MHz,
CDCl3) δ 153.4, 139.7, 138.7, 134.4, 129.9, 128.8, 128.6, 125.3 (C-F,
20
1
min, tmajor = 24.982 min; [α]D = −61.4 (c = 0.97 in CHCl3). H
NMR (600 MHz, CDCl3) δ 7.46−7.40 (m, 2H), 7.24 (d, J = 8.2 Hz,
2H), 6.68−6.63 (m, 2H), 6.49 (d, J = 8.4 Hz, 2H), 4.69 (q, J = 7.2
Hz, 1H), 3.63 (s, 3H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ
2
1JC‑F = 282.1 Hz), 125.0, 115.8, 114.9, 61.8 (C-F, JC‑F = 29.6 Hz),
55.6, 21.4 ppm; 19F NMR (376 MHz, CDCl3) δ −73.87 ppm; HRMS
(ESI) m/z: [M + H]+ Calcd for C16H17F3NO 296.1257; Found:
296.1245.
1
153.6, 139.0, 133.3, 132.1, 129.7, 124.8 (C-F, JC‑F = 281.9 Hz),
123.3, 115.9, 114.9, 61.4 (C-F, 2JC‑F = 29.6 Hz), 55.6 ppm; 19F NMR
(376 MHz, CDCl3) δ −74.08 ppm; HRMS (ESI) m/z: [M + Na]+
Calcd for C15H13BrF3NNaO 382.0025; Found: 382.0015.
(R)-4-Methoxy-N-(2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl)-
aniline (2d). The general procedure was followed, and the product
was purified by column chromatography (8:1 petroleum ether/
EtOAc): pale yellow oil, 14.9 mg, 96% yield, 94% ee. The
enantiomeric excess was determined by HPLC (Daicel Chiralpak
AD-H, hexane/i-PrOH = 95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/
(R)-4-Methoxy-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)aniline
(2i). The general procedure was followed, and the product was
purified by column chromatography (10:1 petroleum ether/EtOAc):
pale yellow oil, 14.1 mg, 94% yield, 94% ee. The enantiomeric excess
was determined by HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH
= 95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/min): tminor = 13.600
20
min): tminor = 13.969 min, tmajor = 20.897 min; [α]D = −71.4 (c =
0.73 in CHCl3). 1H NMR (600 MHz, CDCl3) δ 7.28−7.23 (m, 2H),
6.83−6.77 (m, 2H), 6.67−6.62 (m, 2H), 6.54−6.47 (m, 2H), 4.66 (q,
J = 7.3 Hz, 1H), 3.69 (s, 3H), 3.61 (s, 3H) ppm; 13C{1H} NMR (150
20
1
min, tmajor = 22.097 min; [α]D = −36.3 (c = 0.79 in CHCl3). H
NMR (600 MHz, CDCl3) δ 7.37−7.32 (m, 2H), 7.02−6.95 (m, 2H),
6.68−6.63 (m, 2H), 6.50 (d, J = 8.4 Hz, 2H), 4.72 (q, J = 7.3 Hz,
1H), 3.63 (s, 3H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 163.1
MHz, CDCl3) δ 160.1, 153.4, 139.6, 129.1, 126.3, 125.3 (C-F, 1JC‑F
=
282.0 Hz), 115.8, 114.9, 114.3, 61.2 (C-F, 2JC‑F = 29.6 Hz), 55.6, 55.2
ppm; 19F NMR (376 MHz, CDCl3) δ −74.27 ppm; HRMS (ESI) m/
z: [M + H]+ Calcd for C16H17F3NO2 312.1206; Found: 312.1197.
(R)-4-Methoxy-N-(2,2,2-trifluoro-1-(3-methoxyphenyl)ethyl)-
aniline (2e). The general procedure was followed, and the product
1
3
(C-F, JC‑F = 248.2 Hz), 153.6, 139.2, 130.0, 129.8 (C-F, JC‑F = 8.3
1
2
Hz), 125.0 (C-F, JC‑F = 280.8 Hz), 115.9, 115.9 (C-F, JC‑F = 21.7
Hz), 114.9, 61.2 (C-F, JC‑F = 30.0 Hz), 55.6 ppm; 19F NMR (376
2
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Note
MHz, CDCl3) δ −74.26, −112.50 ppm; HRMS (ESI) m/z: [M + H]+
Calcd for C15H14F4NO 300.1006; Found: 300.1013.
7.71 (m, 3H), 7.44 (d, J = 8.5 Hz, 1H), 7.41−7.37 (m, 2H), 4.88 (q, J
= 7.3 Hz, 1H), 3.58 (s, 3H) ppm; 13C{1H} NMR (150 MHz, CDCl3)
δ 152.4, 138.4, 132.5, 132.2, 130.7, 127.8, 127.1, 126.7, 126.7, 125.7,
(R)-4-Methoxy-N-(2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl)-
ethyl)aniline (2j). The general procedure was followed, and the
product was purified by column chromatography (10:1 petroleum
ether/EtOAc): pale yellow oil, 16.8 mg, 96% yield, 93% ee. The
enantiomeric excess was determined by HPLC (Daicel Chiralpak AD-
H, hexane/i-PrOH = 95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/
min): tminor = 9.010 min, tmajor = 7.843 min; [α]D20 = −34.5 (c = 0.75
1
125.5, 124.2 (C-F, JC‑F = 281.9 Hz), 123.9, 114.9, 113.9, 61.0 (C-F,
2JC‑F = 29.7 Hz), 54.6 ppm; 19F NMR (376 MHz, CDCl3) δ −73.61
ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C19H17F3NO 332.1257;
Found: 332.1243.
(S)-4-Methoxy-N-(2,2,2-trifluoro-1-(thiophen-2-yl)ethyl)aniline
(2o). The general procedure was followed, and the product was
purified by column chromatography (10:1 petroleum ether/EtOAc):
pale yellow oil, 13.3 mg, 93% yield, 87% ee. The enantiomeric excess
was determined by HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH
= 95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/min): tminor = 11.156
1
in CHCl3). H NMR (600 MHz, CDCl3) δ 7.64 (s, 1H), 7.59−7.53
(m, 2H), 7.43 (t, J = 7.8 Hz, 1H), 6.69−6.63 (m, 2H), 6.52−6.47 (m,
2H), 4.80 (q, J = 6.6 Hz, 2H), 3.63 (s, 3H) ppm; 13C{1H} NMR (150
2
MHz, CDCl3) δ 153.7, 138.9, 135.5, 131.4 (C-F, JC‑F = 28.2 Hz),
131.4, 129.4, 126.0 (C-F, 4JC‑F = 3.7 Hz), 124.9 (C-F, 4JC‑F = 4.1 Hz),
20
1
min, tmajor = 13.774 min; [α]D = −65.1 (c = 0.59 in CHCl3). H
NMR (600 MHz, CDCl3) δ 7.22 (dd, J = 5.1, 1.2 Hz, 1H), 7.07 (d, J
= 3.5 Hz, 1H), 6.92 (ddd, J = 5.0, 3.6, 0.9 Hz, 1H), 6.69 (dd, J = 8.8,
1.8 Hz, 2H), 6.59 (d, J = 8.7 Hz, 2H), 5.04−4.98 (m, 1H), 3.64 (s,
3H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 153.8, 139.2, 137.3,
127.2, 127.0, 126.2, 124.7 (C-F, 1JC‑F = 281.7 Hz), 116.2, 114.9, 58.1
1
1
124.8 (C-F, JC‑F = 280.0 Hz), 123.8 (C-F, JC‑F = 272.6 Hz), 115.9,
115.0, 61.6 (C-F, JC‑F = 30.1 Hz), 55.6 ppm; 19F NMR (376 MHz,
2
CDCl3) δ −62.65, −74.02 ppm; HRMS (ESI) m/z: [M + H]+ calcd
for C16H14F6NO 350.0974; Found: 350.0971.
(R)-4-(2,2,2-Trifluoro-1-((4-methoxyphenyl)amino)ethyl)-
benzonitrile (2k). The general procedure was followed, and the
product was purified by column chromatography (5:1 petroleum
ether/EtOAc): pale yellow oil, 14.5 mg, 95% yield, 92% ee. The
enantiomeric excess was determined by HPLC (Daicel Chiralpak OD-
H, hexane/i-PrOH = 80:20 (v/v), λ = 254 nm, flow rate = 1.0 mL/
2
(C-F, JC‑F = 31.3 Hz), 55.6 ppm; 19F NMR (376 MHz, CDCl3) δ
−74.73 ppm; HRMS (ESI) m/z: [M + Na]+ Calcd for
C13H12F3NNaOS 310.0484; Found: 310.0473.
(R)-4-Methoxy-N-(1,1,1-trifluorobutan-2-yl)aniline (2q). The gen-
eral procedure was followed, and the product was purified by column
chromatography (10:1 petroleum ether/EtOAc): pale yellow oil, 9.1
mg, 78% yield, 25% ee. The enantiomeric excess was determined by
HPLC (Daicel Chiralpak IB, hexane/i-PrOH = 95:5 (v/v), λ = 254
nm, flow rate = 1.0 mL/min): tminor = 7.629 min, tmajor = 6.661 min;
[α]D20 = +16.7 (c = 0.47 in CHCl3). 1H NMR (600 MHz, CDCl3) δ
6.73−6.69 (m, 2H), 6.59−6.54 (m, 2H), 3.67 (s, 3H), 3.57 (ddq, J =
13.9, 7.0, 3.5 Hz, 1H), 1.85 (dqd, J = 14.9, 7.5, 3.8 Hz, 1H), 1.48
(ddq, J = 14.6, 9.7, 7.4 Hz, 1H), 0.97 (t, J = 7.5 Hz, 3H) ppm;
20
min): tminor = 15.808 min, tmajor = 18.996 min; [α]D = −71.1 (c =
0.67 in CHCl3). 1H NMR (600 MHz, CDCl3) δ 7.60 (d, J = 8.4 Hz,
2H), 7.51 (d, J = 8.1 Hz, 2H), 6.68−6.63 (m, 2H), 6.49−6.44 (m,
2H), 4.81 (q, J = 7.1 Hz, 1H), 3.63 (s, 3H) ppm; 13C{1H} NMR (150
MHz, CDCl3) δ 153.8, 139.5, 138.6, 132.6, 128.9, 124.6 (C-F, 1JC‑F
=
2
282.1 Hz), 118.2, 115.9, 115.0, 113.2, 61.5 (C-F, JC‑F = 29.8 Hz),
55.6 ppm; 19F NMR (376 MHz, CDCl3) δ −73.73 ppm; HRMS
(ESI) m/z: [M + Na]+ Calcd for C16H13F3N2NaO 329.0872; Found:
329.0875.
13C{1H} NMR (150 MHz, CDCl3) δ 152.9, 141.0, 126.4 (C-F, 1JC‑F
=
2
(R)-4-Methoxy-N-(2,2,2-trifluoro-1-(o-tolyl)ethyl)aniline (2l). The
general procedure was followed, and the product was purified by
column chromatography (10:1 petroleum ether/EtOAc): pale yellow
oil, 13.6 mg, 92% yield, 42% ee. The enantiomeric excess was
determined by HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH =
95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/min): tminor = 9.005 min,
283.8 Hz), 114.9, 58.5 (C-F, JC‑F = 28.7 Hz), 55.7, 22.9 (d, J = 2.1
Hz), 10.1 ppm; 19F NMR (376 MHz, CDCl3) δ −75.89 ppm; HRMS
(ESI) m/z: [M + H]+ Calcd for C11H15F3NO 234.1100; Found:
234.1087.
(R)-4-Methoxy-N-(1,1,1-trifluoro-3-phenylpropan-2-yl)-aniline
(2r). The general procedure was followed, and the product was
purified by column chromatography (10:1 petroleum ether/EtOAc):
pale yellow oil, 6.6 mg, 45% yield, 43% ee. The enantiomeric excess
was determined by HPLC (Daicel Chiralpak IB, hexane/i-PrOH =
95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/min): tminor = 9.856 min,
20
1
tmajor = 13.156 min; [α]D = −21.4 (c = 0.43 in CHCl3). H NMR
(600 MHz, CDCl3) δ 7.43−7.37 (m, 1H), 7.18−7.09 (m, 3H), 6.68−
6.61 (m, 2H), 6.54−6.45 (m, 2H), 5.03 (s, 1H), 3.61 (s, 3H), 2.33 (s,
3H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 152.4, 138.7, 135.9,
t
major = 8.992 min; [α]D20 = +28.8 (c = 0.61 in CHCl3). 1H NMR (600
1
131.9, 129.9, 127.7, 125.7, 125.6 (C-F, JC‑F = 282.7 Hz), 125.5,
2
114.5, 113.9, 56.4 (C-F, JC‑F = 29.9 Hz), 54.6, 18.6 ppm; 19F NMR
MHz, CDCl3) δ 7.23−7.17 (m, 2H), 7.18−7.10 (m, 3H), 6.66−6.60
(m, 2H), 6.46−6.39 (m, 2H), 3.98−3.89 (m, 1H), 3.64 (s, 3H), 3.29
(s, 1H), 3.13 (dd, J = 14.5, 4.1 Hz, 1H), 2.76 (dd, J = 14.5, 9.3 Hz,
1H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 153.1, 140.4, 135.9,
(376 MHz, CDCl3) δ −73.42 ppm; HRMS (ESI) m/z: [M + H]+
Calcd for C16H17F3NO 296.1257; Found: 296.1246.
(R)-N-(1-(2-Chlorophenyl)-2,2,2-trifluoroethyl)-4-methoxyaniline
(2m). The general procedure was followed, and the product was
purified by column chromatography (10:1 petroleum ether/EtOAc):
pale yellow oil, 14.3 mg, 91% yield, 8% ee. The enantiomeric excess
was determined by HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH
= 95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/min): tminor = 12.634
1
129.2, 128.7, 127.1, 126.2 (C-F, JC‑F = 284.3 Hz) 115.5, 114.8, 58.5
2
(C-F, JC‑F = 28.4 Hz), 55.7 ppm; 19F NMR (376 MHz, CDCl3) δ
−75.27 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C16H17F3NO
296.1257; Found: 296.1266.
(R)-N-(2,2,2-Trifluoro-1-phenylethyl)aniline (2s). The general
procedure was followed, and the product was purified by column
chromatography (10:1 petroleum ether/EtOAc): pale yellow oil, 11.3
mg, 90% yield, 91% ee. The enantiomeric excess was determined by
HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH = 95:5 (v/v), λ =
254 nm, flow rate = 1.0 mL/min): tminor = 6.999 min, tmajor = 9.525
20
1
min, tmajor = 14.954 min; [α]D = −1.84 (c = 0.82 in CHCl3). H
NMR (600 MHz, CDCl3) δ 7.56−7.51 (m, 1H), 7.47−7.42 (m, 1H),
7.33−7.27 (m, 2H), 6.78−6.72 (m, 2H), 6.63−6.58 (m, 2H), 5.56 (p,
J = 7.2 Hz, 1H), 4.19 (d, J = 7.5 Hz, 1H), 3.72 (s, 3H) ppm; 13C
NMR (150 MHz, CDCl3) δ 153.4, 138.9, 134.8, 132.3, 130.2, 129.9,
20
1
1
min; [α]D = −42.1 (c = 0.71 in CHCl3). H NMR (600 MHz,
CDCl3) δ 7.41−7.32 (m, 2H), 7.32−7.21 (m, 3H), 7.10−7.01 (m,
2H), 6.71−6.63 (m, 1H), 6.59−6.49 (m, 2H), 4.85−4.78 (m, 1H)
ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 145.6, 134.2, 129.4, 129.1,
128.4, 125.0 (C-F, JC‑F = 282.3 Hz), 127.4, 115.4, 114.9, 57.1 (C-F,
2JC‑F = 30.3 Hz), 55.6 ppm; 19F NMR (376 MHz, CDCl3) δ −73.88
ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C15H14ClF3NO
316.0711; Found: 316.0707.
1
128.9, 127.9, 125.2 (C-F, JC‑F = 281.9 Hz), 119.3, 114.0, 60.7 (C-F,
(R)-4-Methoxy-N-(2,2,2-trifluoro-1-(naphthalen-2-yl)ethyl)-
aniline (2n). The general procedure was followed, and the product
was purified by column chromatography (10:1 petroleum ether/
EtOAc): pale yellow oil, 16.2 mg, 98% yield, 94% ee. The
enantiomeric excess was determined by HPLC (Daicel Chiralpak
AD-H, hexane/i-PrOH = 95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/
2JC‑F = 29.9 Hz) ppm; 19F NMR (376 MHz, CDCl3) δ −73.93 ppm;
HRMS (ESI) m/z: [M + H]+ calcd for C14H13F3N 252.0995; Found:
252.0984.
(R)-4-Methyl-N-(2,2,2-trifluoro-1-phenylethyl)aniline (2t). The
general procedure was followed, and the product was purified by
column chromatography (10:1 petroleum ether/EtOAc): pale yellow
oil, 12.2 mg, 92% yield, 89% ee. The enantiomeric excess was
20
min): tminor = 21.716 min, tmajor = 28.373 min; [α]D = −70.2 (c =
0.91 in CHCl3). 1H NMR (600 MHz, CDCl3) δ 7.82 (s, 1H), 7.77−
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Note
determined by HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH =
95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/min): tminor = 7.467 min,
Procedure for Synthesis of (S)-2e. The same as the synthesis of
(R)-2e using catalyst (S)-P4.
20
1
tmajor = 12.098 min; [α]D = −48.8 (c = 0.57 in CHCl3). H NMR
(600 MHz, CDCl3) δ 7.40−7.32 (m, 2H), 7.32−7.23 (m, 3H), 6.92−
6.83 (m, 2H), 6.52−6.43 (m, 2H), 4.83−4.75 (m, 1H), 2.16−2.08
(m, 3H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 143.3, 134.3,
(S)-4-Methoxy-N-(2,2,2-trifluoro-1-(3-methoxyphen-yl)-ethyl)-
aniline ((S)-2e). The general procedure was followed, and the product
was purified by column chromatography (10:1 petroleum ether/
EtOAc): pale yellow oil, 14.8 mg, 95% yield, 94% ee. The
enantiomeric excess was determined by HPLC (Daicel Chiralpak
OD-H, hexane/i-PrOH = 95:5 (v/v), λ = 254 nm, flow rate = 0.5
mL/min): tminor = 27.388 min, tmajor = 24.264 min; [α]D20 = +54.8 (c
= 1.06 in CHCl3).
1
129.9, 129.1, 128.9, 128.6, 128.0, 125.2 (C-F, JC‑F = 283.6 Hz),
2
114.3, 61.0 (C-F, JC‑F = 29.5 Hz), 20.4 ppm; 19F NMR (376 MHz,
CDCl3) δ −73.93 ppm; HRMS (ESI) m/z: [M + H]+ Calcd for
C15H15F3N 266.1151; Found: 266.1140.
Procedure for Synthesis of (S)-2,2,2-Trifluoro-1-(3-
methoxyphenyl)ethan-1-amine (6). The p-methoxyphenyl
(PMP) group of products was removed under the same conditions
as the synthesis of 3, and the product was used in the next step
without purification.
(R)-4-Bromo-N-(2,2,2-trifluoro-1-phenylethyl)aniline (2u). The
general procedure was followed, and the product was purified by
column chromatography (10:1 petroleum ether/EtOAc): pale yellow
oil, 15.6 mg, 95% yield, 94% ee. The enantiomeric excess was
determined by HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH =
90:10 (v/v), λ = 254 nm, flow rate = 1.0 mL/min): tminor = 8.445 min,
tmajor = 12.592 min; [α]D = −52.3 (c = 0.87 in CHCl3). H NMR
(600 MHz, CDCl3) δ 7.36−7.32 (m, 2H), 7.32−7.27 (m, 3H), 7.17−
7.13 (m, 2H), 6.45−6.39 (m, 2H), 4.77 (q, J = 7.2 Hz, 1H), 4.25 (s,
1H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 144.5, 133.6, 132.1,
129.3, 129.0, 127.9, 124.9 (C-F, 1JC‑F = 281.9 Hz), 115.6, 111.2, 60.6
(C-F, 2JC‑F = 29.9 Hz) ppm; 19F NMR (376 MHz, CDCl3) δ −73.95
ppm; HRMS (ESI) m/z: [M + H]+ Calcd for C14H12BrF3N 330.0100;
Found: 330.0086.
Procedure for Synthesis of (S)-3-(2-Chlorophenyl)-N-(2,2,2-
trifluoro-1-(3-methoxyphenyl)ethyl)propan-1-amine (8). The
crude product chiral primary amine 6 (0.058 g, 0.29 mmol) and 3-(2-
chlorophenyl)propanal 7 (0.058 g, 0.34 mmol) were dissolved in 5
mL of MeOH, and the mixture was heated in an oil bath to reflux for
8 h. Then the reaction mixture was cooled to room temperature and
NaBH4 (0.054 g, 1.43 mmol) was added in small portions. The
reaction was quenched with aq. NH4Cl solution (5 mL) and extracted
with ethyl acetate (10 mL). The organic layer was collected, dried
over Na2SO4, and filtered, and the solvent was removed under
reduced pressure. Purification via a flash chromatography on silica gel
(petroleum ether/EtOAc = 10:1) afforded compound 8 as a colorless
oil.
(S)-3-(2-Chlorophenyl)-N-(2,2,2-trifluoro-1-(3-methoxyphenyl)-
ethyl)propan-1-amine (8). Colorless oil, 73 mg, 72% yield, 96% ee.
The enantiomeric excess was determined by HPLC (Daicel Chiralpak
AD-H, hexane/i-PrOH = 95:5 (v/v), λ = 254 nm, flow rate = 0.5 mL/
min): tminor = 9.365 min, tmajor = 10.542 min; [α]D20 = +49.2 (c = 1.44
in CHCl3). 1H NMR (600 MHz, CDCl3) δ 7.24−7.18 (m, 2H),
7.09−7.00 (m, 3H), 6.91−6.86 (m, 2H), 6.84−6.79 (m, 1H), 4.01 (q,
J = 7.4 Hz, 1H), 3.72 (s, 3H), 2.73−2.60 (m, 2H), 2.58−2.52 (m,
2H), 1.77−1.69 (m, 2H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ
159.9, 139.4, 135.9, 133.9, 130.4, 129.7, 129.5, 127.4, 126.8, 125.3 (C-
F, 1JC‑F = 281.6 Hz), 120.9, 114.4, 114.2, 64.6 (C-F, 2JC‑F = 28.6 Hz),
55.3, 47.0, 31.0, 29.7 ppm; 19F NMR (376 MHz, CDCl3) δ −67.26
ppm; HRMS (ESI) m/z: [M + H]+ calcd for C18H20ClF3NO
358.1180; Found: 358.1164.
20
1
Procedure for Synthesis of (S)-2a. The same as the synthesis of
(R)-2a using catalyst (S)-P4.
(S)-4-Methoxy-N-(2,2,2-trifluoro-1-phenylethyl)aniline ((S)-2a).
The general procedure was followed, and the product was purified
by column chromatography (10:1 petroleum ether/EtOAc): pale
yellow oil, 13.4 mg, 95% yield, 92% ee. The enantiomeric excess was
determined by HPLC (Daicel Chiralpak OD-H, hexane/i-PrOH =
95:5 (v/v), λ = 254 nm, flow rate = 1.0 mL/min): tminor = 10.224 min,
20
tmajor = 9.297 min; [α]D = +61.5 (c = 0.29 in CHCl3).
Procedure for Synthesis of (S)-2,2,2-Trifluoro-1-phenyl-
ethan-1-amine (3). The p-methoxyphenyl (PMP) group of products
can be removed under the known conditions.17 (S)-2a (0.083 g, 0.30
mmol) was dissolved into a mixture of MeCN/H2O (8 mL, 1:1, v/v).
H5IO6 (0.068 g, 0.30 mmol) and conc. H2SO4 (0.030 g, 0.30 mmol)
were added in one portion. The resulting mixture was stirred for
overnight at room temperature. Upon completion, 1 N NaOH
solution was added until the pH became 8. The mixture was then
extracted three times with ethyl acetate, and the organic solutions
were collected, dried over Na2SO4, and filtered. The solvent was
removed in vacuo, which was used in the next step without
purification.
Procedure for Synthesis of (S)-3,3-Diphenyl-N-(2,2,2-tri-
fluoro-1-phenylethyl)propan-1-amine (5). The crude product
chiral primary amine 3 (0.047 g, 0.27 mmol) and 3,3-diphenylpro-
panal 4 (0.068 g, 0.32 mmol) were dissolved in MeOH (5 mL), and
the mixture was heated in an oil bath to reflux for 8 h. Then the
reaction mixture was cooled to room temperature and NaBH4 (0.051
g, 1.35 mmol) was added in small portions. The reaction was
quenched with aq. NH4Cl solution (5 mL) and extracted with ethyl
acetate (10 mL). The organic layer was collected, dried over Na2SO4,
and filtered, and the solvent was removed under reduced pressure.
Purification via a flash chromatography on silica gel (petroleum ether/
EtOAc = 10:1) afforded compound 5 as a colorless oil.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c03009.
Copies of NMR spectra for all compounds and HPLC
chromatograms (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Jon C. Antilla − Institute for Molecular Design and Synthesis,
School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, People’s Republic of China;
orcid.org/0000-0002-8471-3387; Email: jantilla@
tju.edu.cn
(S)-3,3-Diphenyl-N-(2,2,2-trifluoro-1-phenylethyl)propan-1-
amine (5). Colorless oil, 69 mg, 69% yield, 92% ee. The enantiomeric
excess was determined by HPLC (Daicel Chiralpak AD-H, hexane/i-
PrOH = 95:5 (v/v), λ = 254 nm, flow rate = 0.4 mL/min): tminor
=
11.977 min, tmajor = 12.548 min; [α]D20 = +31.3 (c = 1.08 in CHCl3).
1H NMR (600 MHz, CDCl3) δ 7.28−7.18 (m, 5H), 7.19−7.03 (m,
10H), 3.93 (q, J = 7.4 Hz, 2H), 2.45 (t, J = 6.9 Hz, 2H), 2.21−2.06
(m, 2H), 1.48 (s, 1H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ
144.7, 144.4, 134.6, 128.9, 128.6, 128.5, 128.4, 127.9, 127.8, 126.3,
125.4 (C-F, 1JC‑F = 282.2 Hz), 64.7 (C-F, 2JC‑F = 28.4 Hz), 48.6, 45.9,
35.8 ppm; 19F NMR (376 MHz, CDCl3) δ −74.02 ppm; HRMS
(ESI) m/z: [M + H]+ Calcd for C23H23F3N 370.1777; Found:
370.1772.
Authors
Hualing He − Institute for Molecular Design and Synthesis,
School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, People’s Republic of China
Xiaoxue Tang − Institute for Molecular Design and Synthesis,
School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, People’s Republic of China
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J. Org. Chem. 2021, 86, 4336−4345

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
2307−2340. (h) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M.
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(i) Sharma, M.; Mangas-Sanchez, J.; Turner, N. J.; Grogan, G.
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Yang Cao − Jiangsu Key Laboratory of Marine
Pharmaceutical Compound Screening, Jiangsu Ocean
University, Lianyungang 222005, People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c03009
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Our work was supported by financial support from the
National 1000 Talent Plan of China and from Tianjin
University for start-up funds. We are grateful to all members
of the Instrumental Analysis Center of the School of
Pharmaceutical Science and Technology.
(4) (a) Chen, M.-W.; Duan, Y.; Chen, Q.-A.; Wang, D.-S.; Yu, C.-B.;
Zhou, Y.-G. Enantioselective Pd-Catalyzed Hydrogenation of
Fluorinated Imines: Facile Access to Chiral Fluorinated Amines.
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