Palladium(II)-Catalyzed Enantioselective Synthesis of α-(Trifluoromethyl)arylmethylamines

Article abstract of DOI:10.1021/acs.joc.6b00657

We describe a method for the synthesis of α-(trifluoromethyl)arylmethylamines that consists of the palladium(II)-catalyzed addition of arylboroxines to imines derived from trifluoroacetaldehyde. Palladium acetate is used as a catalyst with electron-neutral or electron-rich arylboroxines, and it was found that addition of an ammonium or silver salt was crucial to promote the reaction of electron-poor boroxines. With (S)-t-Bu-PyOX as the chiral ligand, this method delivers a variety of α-trifluoromethylated amines in 57-91% yield and with greater than 92% ee in most cases.

Full text of DOI:10.1021/acs.joc.6b00657

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Palladium(II)-Catalyzed Enantioselective Synthesis of
α‑(Trifluoromethyl)arylmethylamines
Thomas Johnson,† Bo Luo,† and Mark Lautens*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6
S
* Supporting Information
ABSTRACT: We describe a method for the synthesis of α-
(trifluoromethyl)arylmethylamines that consists of the
palladium(II)-catalyzed addition of arylboroxines to imines
derived from trifluoroacetaldehyde. Palladium acetate is used as
a catalyst with electron-neutral or electron-rich arylboroxines,
and it was found that addition of an ammonium or silver salt
was crucial to promote the reaction of electron-poor boroxines.
With (S)-t-Bu-PyOX as the chiral ligand, this method delivers a
variety of α-trifluoromethylated amines in 57−91% yield and with greater than 92% ee in most cases.
chiral ligand) was, however, only applicable to electron-neutral
and electron-rich arylboroxines. In order to overcome this
limitation, we recognized that modifications would have to be
made to the catalytic system to improve its activity. Herein, we
describe the development of such a system, which ultimately
enabled a broad scope of arylboroxines, including electron-poor
ones, to participate in this palladium(II)-catalyzed reaction.
INTRODUCTION
■
Chiral amines are structures commonly found in natural and
synthetic biologically active compounds where their ability to
form hydrogen bonds is one of their most desirable features.1
As a subset of this class of compounds, α-(trifluoromethyl)-
amines have attracted the interest of organic and medicinal
chemists, more intensely so over the past two decades. The
presence of the electron-withdrawing CF3 group adjacent to the
C−N bond decreases the basicity of the nitrogen lone pair
while preserving the hydrogen bond donor ability of the amine,
making them good amide bond isosteres.2 The most prominent
application of an α-(trifluoromethyl)amine in a biologically
active compound is undoubtedly odanacatib, a late-stage drug
candidate (cathepsin K inhibitor) for the treatment of
osteoporosis.3 This motif has also been featured in other
potential medicines.4 Previous reports on the enantioselective
synthesis of α-(trifluoromethyl)amines are in the fields of
catalytic hydrogenation (high pressure5 or transfer hydro-
genation6), nucleophilic addition to fluorinated imines,7
trifluoromethylation of CN bonds,8 and the cinchona
alkaloid-catalyzed isomerization of fluorinated imines.9 Among
these methods, those involving nucleophilic addition to
fluorinated imines (or their N,O-acetals) have received the
most attention, likely due to the variety of nucleophiles that can
be used (Grignard,7d,e,10 organolithium,7a,e,11 organozinc,7b,12
boronic acids7c,13) in racemic or asymmetric versions. In this
area, palladium has emerged as a viable alternative to rhodium
for the enantioselective addition of arylboron reagents to
activated imines.14 The functional group tolerance and the large
number of commercially available boronic acids are particularly
attractive features.
RESULTS AND DISCUSSION
■
The scope under our original reaction conditions is shown in
Table 1.
Screening chiral nitrogen-based ligands of the BOX, PyBOX,
and PyOx classes led to the identification of t-Bu-PyOX as the
optimal ligand, which performed best with DCE as the
solvent.13 We initially studied the effect of the electronic
character of the nitrogen-bound aryl ring on the N,O-acetal and
found consistently good to high yields and high enantiose-
lectivity (2a−g), with the exception of 2h, bearing an o-
methoxy group. The reactivity of arylboroxines was also
examined, with substrate 1a bearing a p-methoxyphenyl
(PMP) group. We observed that electron-neutral and
moderately electron-rich boroxines reacted to give the products
2i−k in 80−87% yield and with 92−95% ee. More electron-rich
boroxines delivered products 2l−n with somewhat diminished
enantioselectivity (76−84% ee) but still in high yield. A
different result was observed when a substrate with a 3-Br-
substituted nitrogen-bound aryl ring was used, delivering 2m
with 92% ee using (4-methoxyphenyl)boroxine. While (4-
fluorophenyl)boroxine was reactive after a prolonged reaction
time of 48 h, other electron-poor arylboroxines, such as those
bearing a 3-Cl, 4-Cl, or 4-Ac substituents, as well as ortho-
substituted ones, performed poorly. Cognizant of the lower rate
of transmetalation of electron-poor boronic acids15 and the
In 2013, we reported the palladium(II)-catalyzed enantiose-
lective addition of arylboroxines to N,O-acetals of trifluor-
oacetaldehyde for the preparation of α-(trifluoromethyl)-
arylmethylamines.13 This operationally simple protocol (i.e.,
no rigorous exclusion of air and moisture, easily accessible
Received: March 28, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b00657
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Table 1. Scope of the Pd(II)-Catalyzed Enantioselective Synthesis of α-(Trifluoromethyl)arylmethylamines with Electron-
a
Neutral and Electron-Rich Boroxines
a
Reaction conditions: N,O-acetal (0.20 mmol, 1 equiv), boroxine (0.20 mmol, 1 equiv), Pd(OAc)2 (0.020 mmol, 10 mol %), ligand (0.024 mmol, 12
mol %), solvent (1.1. mL), 60 °C, 8 h, under air. Yields of products isolated after purification by flash chromatography. Enantiomeric excess
b
determined by HPLC on a chiral stationary phase. Reaction time was 48 h.
tendency of Pd(II) catalysts to be deactivated by reduction to
Pd(0), we sought to find a catalyst that would be longer-lived
under the reaction conditions. Recently, Stoltz16 and Hayashi14c
reported the use of NH4PF6 and AgBF4 as additives in Pd(II)-
catalyzed additions of boronic acids to enones and cyclic
sulfonimines, respectively. Each of these additives can generate
cationic palladium, either by replacement of a TFA ligand from
Pd(TFA)2 or by chloride abstraction from Pd(PyOX)Cl2 by
Ag. Silver can also potentially oxidize Pd(0) to Pd(II).17 We
wondered if we could take advantage of these features in the
present reaction. To test this idea, arylboroxines with electron-
withdrawing substituents were employed with N,O-acetal 1a as
the model substrate under a variety of conditions (Table 2).
We were pleased to find that replacement of Pd(OAc)2 by
Pd(TFA)2 and the addition of 30 mol % of NH4PF6 enabled
the reaction of 4-chlorophenylboroxine (Table 2, entry 1) to
give the product in 60% yield and with 95% ee. No reaction
occurred in the absence of NH4PF6. Under the same
conditions, [4-(trifluoromethyl)phenyl]boroxine gave similar
results (Table 2, entry 2). Such was not the case for (4-
bromophenyl)boroxine (Table 2, entry 3), indicating that
further refinement of the reaction conditions was necessary. We
prepared palladium complex Pd-1 and postulated that in the
presence of silver it would generate a cationic Pd species that
would be more reactive toward transmetalation. Indeed, when
(4-bromophenyl)boroxine was subjected to these modified
conditions, an 85% yield of the desired product with 95% ee
was obtained (Table 2, entry 4).18 The same conditions applied
to [4-(methoxycarbonyl)phenyl]boroxine gave the correspond-
ing product in 72% yield and with 95% ee (Table 2, entry 5).
Having achieved a marked increase in reactivity compared to
our initial system (Table 1), it remained that some boroxines,
such as (4-acetylphenyl)boroxine, did not react under either set
of conditions outlined in Table 2. Since we observed the
gradual conversion of N,O-acetal 1a to its corresponding imine
over the course of the reaction, it seemed logical to employ the
analogous imine as the starting material to accelerate the
reaction. A second screening of reaction conditions with imine
3 was thus undertaken (Table 3).
With (4-bromophenyl)boroxine, results similar to those
observed when starting with N,O-acetal 1a (Table 2, entry 5)
were observed with imine 3 as the starting material (Table 3,
entries 1 and 2). (4-Acetylphenyl)boroxine, which was
unreactive under the previous conditions, was finally engaged,
B
DOI: 10.1021/acs.joc.6b00657
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a
Table 2. Evaluation of Conditions for the Reaction of Electron-Poor Arylboroxines with N,O-Acetal 1a
b
c
entry
Ar
Pd source
ligand
additive
yield (%)
ee (%)
1
2
3
4
5
6
7
4-ClC6H4
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd-1
(S)-t-Bu-PyOX
(S)-t-Bu-PyOX
(S)-t-Bu-PyOX
NH4PF6
NH4PF6
NH4PF6
60 (2q)
65 (2r)
<5 (2s)
85 (2s)
72 (2t)
<5 (2u)
<5 (2u)
95
97
4-CF3C6H4
4-BrC6H4
d
4-BrC6H4
AgBF4
95
95
d
4-MeO2CC6H4
4-AcC6H4
4-AcC6H4
Pd-1
AgBF4
Pd(TFA)2
Pd-1
(S)-t-Bu-PyOX
NH4PF6
d
AgBF4
a
Reaction conditions: N,O-acetal (0.20 mmol, 1 equiv), boroxine (0.10 mmol, 0.50 equiv), Pd source (0.020 mmol, 10 mol %), ligand (0.024 mmol,
b
12 mol %), additive (0.06 mmol, 30 mol %), solvent (1.1. mL), 60 °C, 20 h, under air. Yields of products isolated after purification by flash
c
chromatography (yields <5% estimated by 19F NMR of the crude reaction mixture). Enantiomeric excess determined by HPLC on a chiral
d
stationary phase. 50 mg of powdered 4 Å MS were added PMP = p-methoxyphenyl.
a
Table 3. Evaluation of Conditions for the Reaction of Electron-Poor Arylboroxines with Imine 3
b
c
entry
Ar
Pd source
ligand
additive
yield (%)
ee (%)
1
2
3
4
5
4-Br C6H4
4-Br C6H4
4-Ac C6H4
4-Ac C6H4
4-Ac C6H4
Pd(TFA)2
Pd-1
(S)-t-BuPyOX
NH4PF6
AgBF4
86 (2s)
91 (2s)
<5 (2u)
<5 (2u)
62 (2u)
96
91
Pd(TFA)2
Pd(TFA)2
Pd-1
(S)-t-BuPyOX
(S)-t-BuPyOX
NH4PF6
NH4BF4
AgBF4
95
a
Reaction conditions: N,O-acetal (0.20 mmol, 1 equiv), boroxine (0.10 mmol, 0.50 equiv), Pd source (0.020 mmol, 10 mol %), ligand (0.024 mmol,
b
12 mol %), additive (0.06 mmol, 30 mol %), solvent (1.1. mL), powdered 4 Å molecular sieves (50 mg), 65 °C, 20 h, under air. Yields of products
c
isolated after purification by flash chromatography (yields <5% estimated by 19F NMR of the crude reaction mixture). Enantiomeric excess
determined by HPLC on a chiral stationary phase. PMP = p-methoxyphenyl.
delivering amine 2u in 62% yield and with 95% ee (Table 3,
entry 5). It was ultimately found that addition of 4 Å molecular
sieves was beneficial, preventing partial hydrolysis of the
starting imine. In all cases, reactions proceeded to full
conversion in 20 h, and the desired amine 2 is the only
fluorinated product observed by 19F NMR.
From the results in Tables 2 and 3, it appeared that the Pd-
1/AgBF4 couple would allow the largest number of boroxines
to react, and for that reason, it was selected to study the scope
of the reaction (Table 4).
As noted previously, arylboroxines with electron-withdrawing
substituents at the para position gave the desired products in
good to high yield and with greater than 90% ee (Table 4, 2q−
u). The synthesis of 2q was also carried out on a 1 mmol scale,
using 4 mol % of Pd-1 and 25 mol % of AgBF4 in 81% yield and
with 93% ee. Various functional groups (e.g., halogen, −OMe,
−Ac, and −CO2Me) could be introduced at the meta position
of the boroxine, giving products 2v−ab in 64−88% yield and
with greater than 93% ee. A few electron-rich boroxines were
also employed. Products with an aryl ring bearing a 3-Me (2ac),
4-NHCOCF3 (2ad), and methylenedioxy (2ae) substituents
were prepared in 57−83% yield and with 93% to 96% ee. When
an ortho-substituent is introduced, as in the 2-Me (2af) and 1-
naphthyl (2ag) cases, a drop in ee to 72−74% is observed.19
Finally, amine 2ah bearing a 2-naphthyl group was prepared in
75% yield and with 90% ee. The absolute configuration of 2b
was previously established13 by comparing the value of the
optical rotation of the corresponding primary amine HCl salt to
that of the known compound. Assuming a uniform reaction
mechanism, the same configuration is assigned to the other
products. As noted in our previous communication,13 boroxines
were used instead of boronic acids because the latter fail to
react in our reaction.20 This situation is not without
precedent14a,21 and may be due to the lower transmetalation
rate of boronic acids, although a definitive explanation has not
been put forth. Boroxines can be obtained by heating boronic
acids (which already contain variable amounts of boroxine)
under vacuum or in toluene solution in a Dean−Stark
apparatus. We were unfortunately not able to obtain furan-,
thiophene-, or pyridine-containing boroxines due to their
apparent instability.22 A distinguishing feature of our method is
the absence of a strongly electron-withdrawing group (e.g.,
SO2R) on nitrogen, which is usually necessary to activate the
substrate in Pd- or Rh-catalyzed addition to imines. In our
C
DOI: 10.1021/acs.joc.6b00657
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a
Table 4. Scope of the Pd(II)-Catalyzed Enantioselective Synthesis of α-(trifluoromethyl)arylmethylamines with Catalyst Pd-1
a
Reaction conditions: imine (0.20 mmol, 1 equiv), boroxine (0.10 mmol, 0.5 equiv), Pd-1 (0.020 mmol, 10 mol %), AgBF4 (0.06 mmol, 30 mol %),
powdered 4 Å molecular sieves (50 mg), 65 °C, 20 h, under air. Yields of products isolated after purification by flash chromatography. Enantiomeric
b
excess determined by HPLC on a chiral stationary phase. With AgSbF6 instead of AgBF4, 48 h reaction time.
reaction, the CF3 group plays that role23 in the presence of the
electron-donating (and easily cleavable) PMP group on
nitrogen.
or their corresponding N,O-acetals. With electron-neutral or
electron-rich boroxines, a simple combination of Pd(OAc)2 and
(S)-t-Bu-PyOx is used as catalyst. The reaction of electron-poor
and ortho-substituted boroxines was enabled after modification
of the catalytic system by changing the palladium source and
adding an ammonium or silver salt. While each of them was
effective in several cases, it was ultimately found that a
Pd(PyOx)Cl2 catalyst with AgBF4 was the most versatile
system. Under these sets of conditions, we prepared 34 α-
(trifluoromethyl)arylmethylamines in 57−91% yield and in
most cases with greater than 92% ee.
With the scope of the reaction now delineated, it was applied
to the synthesis of trifluoromethylated analogues of cinacalcet, a
calcimimetic drug (Scheme 1). The synthesis of
(trifluoromethyl)amines 2ag and 2ah was accomplished on a
1−2 mmol scale using a reduced palladium loading with
outcomes nearly identical to those seen on a smaller scale
(Table 4). Following oxidative removal of the PMP group, the
primary amine was combined with aldehyde 4 via reductive
amination to obtain the desired analogs 5 and 6 in 40 and 49%
overall yield, respectively. To the best of our knowledge, these
compounds related to cinacalcet have not previously been
reported.
EXPERIMENTAL SECTION
■
General Experimental Methods. All reactions were performed
without taking any precautions to exclude air or moisture except for
the addition of molecular sieves, when stated. Analytical thin-layer
chromatography (TLC) was performed with normal-phase silica plates
(60 Å pore diameter, F254 indicator). Visualization was accomplished
under UV light (254 nm) followed by immersion in a KMnO4 solution
and heating with a heat gun. Purification of reaction products was
done by flash chromatography with 230−400 mesh silica gel. DCE was
CONCLUSION
■
We have developed a palladium(II)-catalyzed enantioselective
synthesis of α-(trifluoromethyl)arylmethylamines involving 1,2-
addition of arylboroxines to α-(trifluoromethyl)acetaldimines
D
DOI: 10.1021/acs.joc.6b00657
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were dissolved in 1 mL of DCE, giving a purple solution. After both
solutions were stirred for 15 min at room temperature, the starting
material solution was added to the catalyst solution. The vial was
capped and placed in a preheated 65 °C oil bath. After the indicated
amount of time, the reaction was diluted with ethyl acetate and filtered
through a short plug of silica, washing with ethyl acetate. The solvent
was evaporated, and the crude mixture was purified by flash
chromatography, eluting with a mixture of hexanes and ethyl acetate.
Racemic products were synthesized according to the same protocol,
but with bipy or (rac)-t-Bu-PyOx as the ligand.
Scheme 1. Synthesis of Trifluoromethylated Analogues of
Cinacalcet
(S)-N-(1-(4-Chlorophenyl)-2,2,2-trifluoroethyl)-4-methoxyaniline
(2q).6b Colorless oil. 46 mg, 73% yield, 94% ee. Eluent: hexanes/
1
EtOAc 25:1. H NMR (400 MHz, CDCl3): δ 7.41−7.36 (m, 4H),
6.76−6.74 (m, 2H), 6.59−6.57 (m, 2H), 4.82−4.79 (brm, 1H), 4.08−
4.06 (br, 1H), 3.72 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 153.6,
139.2, 135.2, 132.9, 129.5, 129.3, 125.0 (q, J(C−F) = 282 Hz), 115.9,
115.0, 61.3 (q, J(C−F) = 30 Hz), 55.8. 19F NMR (CDCl3): −74.2 (d, J
= 7.6 Hz). IR (ATR, cm−1): 3378, 2835, 1597, 1513, 1492, 1236, 1173,
1124. [α]D20: +45.5 (c 1.0, CHCl3). HPLC: AD-H column, hexanes−
2-propanol (90:10), flow rate: 1.0 mL/min, 9.0 min (major), 11.0 min
(minor).
(S)-4-Methoxy-N-(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)-
ethyl)aniline (2r).6b Colorless oil. 63 mg, 90% yield, 96% ee. Eluent:
1
hexanes/EtOAc 25:1. H NMR (400 MHz, CDCl3): δ 7.67−7.65 (m,
2H), 7.61−7.58 (m, 2H), 6.76−6.73 (m, 2H), 6.58−6.56 (m, 2H),
4.91−4.87 (brm, 1H), 4.12−4.10 (br, 1H), 3.72 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 153.7, 139.0, 138.4, 131.5 (q, J(C−F) = 32 Hz),
128.6, 126.0 (q, J(C−F) = 3.8 Hz), 124.9 (q, J(C−F) = 282 Hz),
124.0 (q, J(C−F) = 272 Hz), 115.9, 115.1, 61.6 (q, J(C−F) = 30 Hz),
55.8. 19F NMR (CDCl3): −62.8 (s), −74.0 (d, J = 7.6 Hz). IR (ATR,
cm−1): 3391, 2837, 1621, 1514, 1325, 1236, 1168, 1123, 1068, 820.
[α]D20: +28.8 (c 1.0, CHCl3). HPLC: IA column, hexanes−2-propanol
(90:10), flow rate: 0.7 mL/min, 9.2 min (minor), 9.7 min (major).
(S)-N-(1-(4-Bromophenyl)-2,2,2-trifluoroethyl)-4-methoxyaniline
(2s).6b White amorphous solid. 65 mg, 91% yield, 91% ee. Eluent:
distilled under nitrogen from CaH2 before use. Arylboroxines were
prepared by heating the corresponding boronic acid at 120 °C (oil
bath) under high-vacuum (approximately 0.1 mbar) for 8−16 h.
1
Conversion can be monitored by H NMR in anhydrous DMSO-d6;
1
up to 10% boronic acid sometimes remains. H, 19F, and 13C NMR
spectra were acquired on a 300 or 400 MHz spectrometer. Shifts for
proton spectra are reported in parts per million and are referenced to
residual CHCl3 (δ= 7.26 ppm). Chemical shifts for fluorine spectra are
reported in parts per million (δ scale) and referenced to external
CFCl3 (δ = 0 ppm). Chemical shifts for carbon resonances are
reported in parts per million and are referenced to the carbon
resonance of the solvent (δ = 77.16 ppm). Data are represented as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, br = broad), coupling constant (J, Hz), and
integration. High-resolution mass spectra were obtained in positive
ESI mode with a triple quadrupole detector or in DART mode with a
time-of-flight (TOF) detector. Enantiomeric excesses (ee) were
determined by normal-phase HPLC analysis with a chiral stationary
phase using a mixture of hexanes−2-propanol as eluent and with the
UV detector set at 254 nm. HPLC conditions for all compounds are
reported below.
1
hexanes/EtOAc 25:1. H NMR (400 MHz, CDCl3): δ 7.54−7.51 (m,
2H), 7.35−7.32 (m, 2H), 6.76−6.73 (m, 2H), 6.58−6.56 (m, 2H),
4.82−4.75 (brm, 1H), 4.07−4.05 (br, 1H), 3.72 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 153.6, 139.2, 133.4, 132.2, 129.8, 124.9 (q,
J(C−F) = 282 Hz), 123.4, 115.9, 115.0, 61.4 (q, J(C−F) = 30 Hz),
55.8. 19F NMR (CDCl3): −74.2 (d, J = 7.6 Hz). IR (ATR, cm−1):
3378, 2835, 1593, 1512, 1489, 1234, 1171, 1122, 1035, 1011, 818.
[α]D20: +46.8 (c 1.0, CHCl3). HPLC: AD-H column, hexanes−2-
propanol (90:10), flow rate: 1.0 mL/min, 9.6 min (major), 11.2 min
(minor).
N,O-Acetals 1,13 imine 3,24 aldehyde 4,25 Pd-1,26 and (S)-t-Bu-
PyOX16 were synthesized as previously described. Products 2a−p were
prepared according to our original report and have been fully
characterized.13
(S)-Methyl 4-(2,2,2-Trifluoro-1-((4-methoxyphenyl)amino)ethyl)-
benzoate (2t). White amorphous solid. 52 mg, 77% yield, 95% ee.
1
Eluent: hexanes/EtOAc 5:1. H NMR (400 MHz, CDCl3): δ 8.07−
8.05 (m, 2H), 7.55−7.52 (m, 2H), 6.74−6.72 (m, 2H), 6.59−6.56 (m,
2H), 4.90−4.86 (brm, 1H), 4.14−4.12 (br, 1H), 3.91 (s, 3H), 3.71 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 166.6, 153.6, 139.3, 139.1,
131.1, 130.2, 128.2, 125.0 (q, J(C−F) = 282 Hz), 115.9, 115.0, 61.7 (q,
J(C−F) = 30 Hz), 55.8, 52.4. 19F NMR (CDCl3): −74.2 (d, J = 7.6
Hz). IR (film, NaCl): 3375, 2840, 1720, 1514, 1437, 1268, 1236, 1178,
1119, 1035, 820. HRMS (DART): m/z calcd for C17H17F3NO3 [M +
H] 340.11605, found 340.11561. [α]D20: +63.8 (c 1.0, CHCl3). HPLC:
AD-H column, hexanes−2-propanol (90:10), flow rate: 0.7 mL/min,
31.2 min (minor), 33.0 min (major).
General Procedure for the Synthesis of α-(Trifluoromethyl)-
arylmethylamines from N,O-Acetals in Table 2. Palladium
complex Pd-1 (0.020 mmol, 10 mol %) or Pd(TFA)2 (0.020 mmol,
10 mol %) and (S)-t-Bu-PyOX (0.024 mmol, 12 mol %), the additive
(0.030 mmol, 15 mol %), arylboroxine (0.10 mmol, 0.50 equiv), and 1
mL of DCE were introduced in a 2-dram vial. In a separate 2-dram vial,
N,O-acetal 1a (0.20 mmol, 1 equiv) and the additive (0.030 mmol, 15
mol %) were dissolved in 1 mL of DCE. After both solutions were
stirred for 15 min at room temperature, the starting material solution
was added to the catalyst solution. The vial was capped and placed in a
preheated 65 °C oil bath. After the indicated amount of time, the
reaction was diluted with ethyl acetate and filtered through a short
plug of silica, washing with ethyl acetate. The solvent was evaporated,
and the crude mixture was purified by flash chromatography, eluting
with a mixture of hexanes and ethyl acetate.
(S)-1-(4-(2,2,2-Trifluoro-1-((4-methoxyphenyl)amino)ethyl)-
phenyl)ethanone (2u). Clear oil. 42 mg, 62% yield, 95% ee. Eluent:
1
hexanes/EtOAc 5:1. H NMR (400 MHz, CDCl3): δ 7.98−7.96 (m,
2H), 7.57−7.55 (m, 2H), 6.74−6.72 (m, 2H), 6.59−6.57 (m, 2H),
4.91−4.88 (brm, 1H), 4.19−4.18 (br, 1H), 3.71 (s, 3H), 2.59 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 197.5, 153.6, 139.4, 139.1, 137.8,
128.9, 128.4, 124.9 (q, J(C−F) = 282 Hz), 115.9, 115.0, 61.6 (q, J(C−
F) = 30 Hz), 55.7, 26.7. 19F NMR (CDCl3): −73.8 (d, J = 7.2 Hz). IR
(film, NaCl): 1720, 1683, 1514, 1359, 1267, 1236, 1175, 1124, 817.
HRMS (DART): m/z calcd for C17H17F3NO2 [M + H] 324.12114,
found 324.12079. [α]D20: +75.3 (c 1.0, CHCl3). HPLC: AD-H
General Procedure for the Synthesis of α-(Trifluoromethyl)-
arylmethylamines in Table 4. Palladium complex Pd-1 (0.020
mmol, 10 mol %), AgBF4 (0.030 mmol, 15 mol %), the arylboroxine
(0.10 mmol, 0.50 equiv), powdered 4 Å molecular sieves (50 mg), and
1 mL of DCE were introduced in a 2-dram vial. In a separate 2-dram
vial, imine 3 (0.20 mmol, 1 equiv) and AgBF4 (0.030 mmol, 15 mol %)
E
DOI: 10.1021/acs.joc.6b00657
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The Journal of Organic Chemistry
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1
column, hexanes−2-propanol (80:20), flow rate: 1.0 mL/min, 16.0
min (major), 20.3 min (minor).
25:1. H NMR (400 MHz, CDCl3): δ 7.62−7.61 (m, 1H), 7.52−7.49
(m, 1H), 7.40−7.38 (m, 1H), 7.28−7.24 (m, 1H), 6.77−6.74 (m, 2H),
6.60−6.57 (m, 2H), 4.81−4.75 (brm, 1H), 4.07 (s, 1H), 3.72 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 153.6, 139.1, 136.7, 132.4, 131.2,
130.6, 126.8, 124.9 (q, J(C−F) = 282 Hz), 123.1, 115.9, 115.0, 61.4 (q,
J(C−F) = 30 Hz), 55.8. 19F NMR (CDCl3): −74.0 (d, J = 7.1 Hz). IR
(film, NaCl): 3415, 1514, 1476, 1348, 1236, 1176, 1125, 1036, 820.
HRMS (DART): m/z calcd for C15H14BrF3NO [M + H] 360.02045,
found 360.02109. [α]D20: +43.3 (c 1.0, CHCl3). HPLC: IA column,
hexanes−2-propanol (96:4), flow rate: 0.5 mL/min, 11.4 min (major),
12.7 min (minor).
(S)-4-methoxy-N-(2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl)-
ethyl)aniline (2ab). Colorless oil. 45 mg. 64% yield, 94% ee. Eluent:
hexanes/EtOAc 25:1.1H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H),
7.67−7.63 (m, 2H), 7.55−7.51 (m, 1H), 6.76−6.74 (m, 2H), 6.59−
6.57 (m, 2H), 4.92−4.85 (brm, 1H), 4.12−4.10 (br, 1H), 3.72 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 153.7, 139.1, 135.6, 131.53 (q, J(C−
(S)-Methyl 3-(2,2,2-Trifluoro-1-((4-methoxyphenyl)amino)ethyl)-
benzoate (2v). Colorless oil. 49 mg, 72% yield, 95% ee. Eluent:
1
hexanes/EtOAc 5:1. H NMR (400 MHz, CDCl3): δ 8.15−8.14 (m,
1H), 8.06−8.03 (m, 1H), 7.66−7.64 (m, 1H), 7.49−7.45 (m, 1H),
6.74−6.72 (m, 2H), 6.60−6.58 (m, 2H), 4.90−4.86 (brm, 1H), 4.16−
4.14 (br, 1H), 3.93 (s, 3H), 3.71 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 166.6, 153.6, 139.2, 135.0, 132.5, 131.0, 130.4, 129.3, 129.2,
125.0 (q, J(C−F) = 282 Hz), 115.9, 115.0, 61.6 (q, J(C−F) = 30 Hz),
55.8, 52.4. 19F NMR (CDCl3): −74.1 (d, J = 7.1 Hz). IR (film, NaCl):
3369, 2955, 1712, 1514, 1449, 1435, 1292, 1241, 1201, 1175, 1124,
1082, 821. HRMS (ESI): m/z calcd for C17H17F3NO3 [M + H]
340.1165, found 340.1155. [α]D20: +35.0 (c 1.0, CHCl3). HPLC: AD-
H column, hexanes−2-propanol (85:15), flow rate: 1.0 mL/min, 9.6
min (minor), 10.5 min (major).
(S)-1-(3-(2,2,2-Trifluoro-1-((4-methoxyphenyl)amino)ethyl)-
phenyl)ethanone (2w). Yellow oil. 57 mg, 88% yield, 96% ee. Eluent:
F) = 32 Hz), 131.49, 129.6, 126.20 (q, J(C−F) = 4 Hz), 125.0 (q,
J(C−F) = 4 Hz), 124.9 (q, J(C−F) = 282 Hz), 123.9 (q, J(C−F) =
271 Hz), 115.9, 115.1, 61.6 (q, J(C−F) = 30 Hz), 55.8. 19F NMR
(CDCl3): −62.7 (d, J = 8.0 Hz), −74.1 (d, J = 7.0 Hz). IR (film,
NaCl): 3405, 1514, 1329, 1236, 1166, 1124, 1076, 821. HRMS (ESI):
m/z calcd for C16H14F6NO [M + H] 350.0984, found 350.0974.
[α]D20: +28.3 (c 1.0, CHCl3). HPLC: AD-H column, hexanes−2-
propanol (90:10), flow rate: 0.7 mL/min, 7.8 min (minor), 8.2 min
(major).
1
hexanes/EtOAc 5:1. H NMR (400 MHz, CDCl3): δ 8.07−8.06 (m,
1H), 7.96−7.93 (m, 1H), 7.68−7.66 (m, 1H), 7.52−7.48 (m, 1H),
6.74−6.72 (m, 2H), 6.60−6.58 (m, 2H), 4.92−4.88 (brm, 1H), 4.18−
4.17 (bm, 1H), 3.70 (s, 3H), 2.61 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 197.6, 153.6, 139.2, 137.8, 135.2, 132.6, 129.4, 129.3, 127.9,
125.0 (q, J(C−F) = 282 Hz), 115.9, 115.0, 61.6 (q, J(C−F) = 30 Hz),
55.8, 26.8. 19F NMR (CDCl3): −74.1 (d, J = 7.2 Hz). IR (film, NaCl):
3362, 2933, 1720, 1683, 1514, 1464, 1359, 1236, 1169, 1124, 1036,
822. HRMS (DART): m/z calcd for C17H17F3NO2 [M + H]
324.12104, found 324.12114. [α]D20: +30.0 (c 1.0, CHCl3). HPLC:
AD-H column, hexanes−2-propanol (97:3), flow rate: 0.7 mL/min,
36.2 min (minor), 43.5 min (major).
(S)-4-Methoxy-N-(2,2,2-trifluoro-1-(m-tolyl)ethyl)aniline (2ac).5
Colorless oil. 49 mg, 83% yield, 96% ee. Eluent: hexanes/EtOAc
1
25:1. H NMR (400 MHz, CDCl3): δ 7.30−7.26 (m, 1H), 7.25−7.23
(m, 2H), 7.20−7.17 (m, 1H), 6.76−6.74 (m, 2H), 6.63−6.61 (m, 2H),
4.81−4.73 (brm, 1H), 4.07−4.05 (br, 1H), 3.72 (s, 3H), 2.37 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 153.4, 139.8, 138.8, 134.4, 130.0,
(S)-4-methoxy-N-(2,2,2-trifluoro-1-(3-fluorophenyl)ethyl)aniline
(2x). Colorless oil. 41 mg, 69% yield, 95% ee. Eluent: hexanes/EtOAc
25:1. 1H NMR (400 MHz, CDCl3): δ 7.39−7.34 (m, 1H), 7.25−7.23
(m, 1H), 7.20−7.17 (m, 1H), 7.09−7.04 (m, 1H), 6.76−6.74 (m, 2H),
6.60−6.58 (m, 2H), 4.83−4.80 (brm, 1H), 4.08−4.06 (br, 1H), 3.72
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 163.1 (d, J = 247 Hz), 153.6,
139.2, 136.9 (d, J = 7 Hz), 130.6 (d, J = 8 Hz), 125.0 (q, J = 282 Hz),
123.9 (d, J = 3 Hz), 116.3 (d, J = 21 Hz), 115.9, 115.2 (d, J = 23 Hz),
115.0, 61.5 (q, J(C−F) = 30 Hz), 55.8. 19F NMR (CDCl3): −74.1 (d, J
= 7.1 Hz), −112.5 (m). IR (ATR): 3383, 2837, 1615, 1594, 1511,
128.9, 128.7, 125.3 (q, J(C−F) = 282 Hz), 125.1, 115.8, 115.0, 61.9 (q,
J(C−F) = 30 Hz), 55.8, 21.6. 19F NMR (CDCl3): −74.0 (d, J = 7.1
Hz). IR (film, NaCl): 3410, 2835, 1593, 1514, 1489, 1452, 1240, 1182,
1165, 1124, 1035, 822. [α]D20: +28.3 (c 1.0, CHCl3). HPLC: AD-H
column, hexanes−2-propanol (90:10), flow rate: 0.5 mL/min, 13.0
min (major), 13.7 min (minor).
(S)-2,2,2-Trifluoro-N-(4-(2,2,2-trifluoro-1-((4-methoxyphenyl)-
amino)ethyl)phenyl)acetamide (2ad). Amorphous white solid. 45
1
1489, 1450, 1232, 1179, 1148, 1118, 1034, 819. HRMS (ESI): m/z
mg, 57% yield, 93% ee. Eluent: hexanes/EtOAc 10:1. H NMR (400
20
calcd for C15H14F4NO [M + H] 300.1017, found 300.1006. [α]D
:
MHz, CDCl3): δ 8.04 (s, 1H), 7.61−7.59 (m, 2H), 7.49−7.47 (m,
2H), 6.75−6.72 (m, 2H), 6.58−6.56 (m, 2H), 4.84−4.80 (brm, 1H),
4.10−4.09 (br, 1H), 3.71 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
155.03 (q, J(C−F) = 38 Hz), 153.6, 139.2, 135.9, 132.5, 126.4, 123.6,
120.9, 115.9, 115.7 (q, J(C−F) = 291 Hz), 115.0, 61.3 (q, J(C−F) =
30 Hz), 55.8. 19F NMR (CDCl3): −74.2 (d, J = 7.4 Hz), −75.8(m). IR
(film, NaCl): 1709, 1514, 1294, 1240, 1167, 1124, 1036, 822. HRMS
(DART): m/z calcd for C17H15F6N2O2 [M + H] 393.10445, found
393.10377. [α]D20: +45.6 (c 1.0, CHCl3). HPLC: AD-H column,
hexanes−2-propanol (90:10), flow rate: 1.0 mL/min, 26.7 min
(major), 28.4 min (minor).
+39.6 (c 1.0, CHCl3). HPLC: AD-H column, hexanes−2-propanol
(90:10), flow rate: 1.0 mL/min, 6.5 min (minor), 7.2 min (minor).
(S)-4-Methoxy-N-(2,2,2-trifluoro-1-(3-methoxyphenyl)ethyl)-
aniline (2y).6b Colorless oil. 44 mg, 71% yield, 93% ee. Eluent:
1
hexanes/EtOAc 25:1. H NMR (400 MHz, CDCl3): δ 7.33−7.29 (m,
1H), 7.05−7.04 (m, 1H), 6.99−6.98 (m, 1H), 6.92−6.89 (m, 1H),
6.76−6.73 (m, 2H), 6.62−6.60 (m, 2H), 4.81−4.74 (brm, 1H), 4.07−
4.05 (br, 1H), 3.81 (s, 3H), 3.72 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 160.1, 153.5, 139.7, 136.0, 130.1, 125.2 (q, J(C−F) = 282
Hz), 120.4, 115.8, 115.0, 114.3, 114.1, 61.9 (q, J(C−F) = 30 Hz), 55.8,
55.4. 19F NMR (CDCl3): −74.0 (d, J = 7.6 Hz). IR (ATR): 3378,
2940, 2837, 1603, 1588, 1513, 1492, 1235, 1161, 1120, 1037, 821.
[α]D20: +47.5 (c 1.0, CHCl3). HPLC: OD-H column, hexanes−2-
propanol (96:4), flow rate: 1.0 mL/min, 11.4 min (major), 12.7 min
(minor).
(S)-N-(1-(Benzo[d][1,3]dioxol-5-yl)-2,2,2-trifluoroethyl)-4-methox-
yaniline (2ae). Clear oil. 45 mg, 69% yield, 93% ee. Eluent: hexanes/
1
EtOAc 15:1. H NMR (400 MHz, CDCl3): δ 6.93−6.90 (m, 2H),
6.81−6.79 (m, 1H), 6.76−6.73 (m, 2H), 6.60−6.58 (m, 2H), 5.97−
5.96 (m, 2H), 4.72−4.70 (brm, 1H), 4.03 (s, 1H), 3.72 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 153.5, 148.4, 148.3, 139.5, 128.1, 125.2
(q, J(C−F) = 282 Hz), 122.0, 115.9, 115.0, 108.6, 108.1, 101.5, 61.6
(q, J(C−F) = 30 Hz), 55.8. 19F NMR (CDCl3): −74.4 (d, J = 7.6 Hz).
IR (film, NaCl): 3381, 2940, 1514, 1491, 1445, 1241 1176, 1123,
1037, 932, 820. HRMS (DART): m/z calcd for C16H15F3NO3 [M +
H] 326.09994, found 326.10040. [α]D20: +57.0 (c 1.0, CHCl3). HPLC:
AD-H column, hexanes−2-propanol (90:10), flow rate: 1.0 mL/min,
12.4 min (major), 15.7 min (minor).
(S)-N-(1-(3-Chlorophenyl)-2,2,2-trifluoroethyl)-4-methoxyaniline
(2z).6c Yellow oil. 45 mg, 71% yield, 95% ee. Eluent: hexanes/EtOAc
25:1. 1H NMR (400 MHz, CDCl3): δ 7.46−7.45 (m, 1H), 7.36−7.34
(m, 3H), 6.76−6.74 (m, 1H), 6.59−6.57 (m, 2H), 4.83−4.75 (brm,
1H), 4.08−4.06 (d, 1H), 3.72 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 153.6, 139.2, 136.5, 135.0, 130.3, 129.5, 128.3, 126.3, 124.9 (q, J(C−
F) = 282 Hz), 115.9, 115.0, 61.5 (q, J(C−F) = 30 Hz), 55.8. 19F NMR
(CDCl3): −74.0 (d, J = 7.0 Hz). IR (ATR): 3410, 2835, 1513, 1235,
1175, 1123, 1035, 820. [α]D20: +43.0 (c 1.0, CHCl3). HPLC: AD-H
column, hexanes−2-propanol (90:10), flow rate: 0.7 mL/min, 10.4
min (major), 11.0 min (minor).
(S)-4-Methoxy-N-(2,2,2-trifluoro-1-(o-tolyl)ethyl)aniline (2af).5
Colorless oil. 34 mg, 58% yield, 74% ee. Eluent: hexanes/EtOAc
1
25:1. H NMR (400 MHz, CDCl3): δ 7.50−7.48 (s, 1H), 7.26−7.23
(m, 3H), 6.76−6.74 (m, 2H), 6.60−6.58 (m, 2H), 5.16−5.09 (brm,
(S)-N-(1-(3-Bromophenyl)-2,2,2-trifluoroethyl)-4-methoxyaniline
(2aa). Yellow oil. 56 mg, 78% yield, 96% ee. Eluent: hexanes/EtOAc
1H), 4.05 (s, 1H), 3.72 (s, 3H), 2.44 (s, 3H). 13C NMR (100 MHz,
F
DOI: 10.1021/acs.joc.6b00657
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Featured Article
CDCl3): δ 153.4, 139.9, 137.0, 133.1, 131.0, 128.9, 126.8, 126.6, 125.7
(q, J(C−F) = 282 Hz), 115.5, 115.0, 57.4 (q, J(C−F) = 30 Hz), 55.8,
19.9. 19F NMR (CDCl3): −73.6 (d, J = 7.4 Hz). [α]D20: +30.8 (c 1.0,
CHCl3). HPLC: AD-H column, hexanes−2-propanol (90:10), flow
rate: 0.7 mL/min, 8.3 min (major), 11.0 min (minor)
(S)-4-Methoxy-N-(2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl)aniline
(2ag). Colorless oil. 40 mg, 60% yield, 72% ee. Eluent: hexanes/
EtOAc 25:1. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 8.4 Hz, 1H),
7.94−7.87 (m, 2H), 7.77 (d, J = 7.3 Hz, 1H), 7.62−7.48 (m, 3H),
6.72−6.70 (m, 2H), 6.60−6.58 (m, 2H), 5.77−5.71 (brm, 1H), 4.26−
4.24 (bm, 1H), 3.69 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 153.4,
139.7, 134.1, 131.8, 130.3, 129.8, 129.4, 127.1, 126.1, 125.7 (q, J(C−F)
= 282 Hz), 125.5, 125.4, 122.5, 115.4, 115.0, 56.7 (q, J = 30 Hz), 55.8.
19F NMR (CDCl3): −72.8 (d, J(C−F) = 7.0 Hz). IR (film, NaCl):
3401, 2957, 2926, 2835, 1514, 1462, 1240, 1165, 1120, 1036, 820, 800.
HRMS (DART): m/z calcd for C19H17F3NO [M + H] 332.12595,
found 332.12622. [α]D20: −45.8 (c 1.0, CHCl3). HPLC: AD-H
column, hexanes−2-propanol (90:10), flow rate: 0.7 mL/min, 12.8
min (minor), 15.2 min (major).
(S)-4-Methoxy-N-(2,2,2-trifluoro-1-(naphthalen-2-yl)ethyl)aniline
(2ah).6b Colorless oil. 50 mg, 75% yield, 90% ee. Eluent: hexanes/
EtOAc 25:1. 1H NMR (400 MHz, CDCl3): δ 7.94 (s, 1H), 7.90−7.85
(m, 3H), 7.57−7.51 (m, 3H), 6.75−6.73 (m, 2H), 6.66−6.64 (m, 2H),
5.01−4.98 (brm, 1H), 3.71 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
153.5, 139.6, 133.7, 133.3, 131.8, 129.0, 128.3, 127.9, 126.8, 126.7,
125.4 (q, J(C−F) = 282 Hz), 125.1, 115.9, 115.0, 62.1 (q, J = 30 Hz),
55.8. 19F NMR (CDCl3): −73.6 (d, J = 7.6 Hz). IR (ATR): 3385,
3060, 2935, 2834, 1512, 1235, 1164, 1120, 1035, 817. [α]D20: +42.0 (c
1.0, CHCl3). HPLC: AD-H column, hexanes−2-propanol (90:10),
flow rate: 1.0 mL/min, 12.2 min (major), 15.7 min (minor)
2.7, CHCl3). HPLC: OD-H column, hexanes−2-propanol (90:10),
flow rate: 0.7 mL/min, 7.6 min (minor), 9.0 min (major)
(S)-N-(2,2,2-Trifluoro-1-(naphthalen-2-yl)ethyl)-3-(3-
(trifluoromethyl)phenyl)propan-1-amine (6). (S)-4-Methoxy-N-
(2,2,2-trifluoro-1-(naphthalen-2-yl)ethyl)aniline (2ah) (272 mg, 0.82
mmol, 1 equiv) was prepared according to the general procedure with
6 mol % of Pd-1 and 25 mol % of AgBF4 on a 1 mmol scale (5 mL of
DCE in a 6-dram vial). It was dissolved in 5 mL of MeCN and 5 mL of
H2O. Periodic acid (374 mg, 1.64 mmol, 2 equiv) was added, followed
by 3 drops of concentrated H2SO4. The mixture was stirred overnight
and diluted with 40 mL of DCM and 40 mL saturated aqueous
NaHCO3. The organic layer was washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
mixture was purified by flash chromatography (hexanes/EtOAc 5:1)
yielding the primary amine as an orange oil (142 mg, 0.63 mmol, 77%
1
yield). H NMR (400 MHz, CDCl3): δ 7.92 (s, 1H), 7.89−7.85 (m,
3H), 7.56−7.52 (m, 3H), 4.57 (q, J = 7.4 Hz, 1H), 1.92 (s, 2H). 19F
NMR (CDCl3): −76.4 (d, J = 7.5 Hz). [α]D20: +20.8 (c 1.2, CHCl3).
The primary amine (50 mg, 0.22 mmol, 1.1 equiv) and aldehyde 4 (40
mg, 0.20 mmol, 1 equiv) were dissolved in 2 mL of DCE. Sodium
triacetoxyborohydride (59 mg, 0.28 mmol, 1.4 equiv) was added in
one portion, and the mixture was stirred for 1 h at room temperature.
Twenty milliliters of EtOAc and 20 mL of a saturated aqueous solution
of NaHCO3 were added, and the organic layer was separated. The
aqueous layer was extracted three times with 10 mL of EtOAc. The
combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude mixture
was purified by flash chromatography (hexanes/EtOAc 30:1) yielding
1
the product as a clear oil (64 mg, 0.16 mmol, 78% yield, 91% ee). H
NMR (400 MHz, CDCl3): δ 7.90−7.85 (m, 4H), 7.55−7.51 (m, 3H),
7.45−7.41 (m, 2H), 7.37−7.30 (m, 2H), 4.28 (q, J = 7.5 Hz, 1H),
2.77−2.60 (m, 4H), 1.90−1.77 (m, 2H), 1.70 (s, 1H). 13C NMR (100
MHz, CDCl3): δ 142.8, 133.7, 133.2, 132.1, 131.91 (q, J(C−F) = 1.3
Hz), 130.80 (q, J(C−F) = 32 Hz), 128.9, 128.8, 128.5, 128.2, 127.9,
126.8, 126.6, 125.4, 125.30 (q, J(C−F) = 282 Hz), 125.18 (q, J(C−F)
= 3.8 Hz), 124.37 (q, J(C−F) = 271 Hz), 122.91 (q, J(C−F) = 3.8
Hz), 65.1 (q, J(C−F) = 30 Hz), 47.0, 33.1, 31.5. 19F NMR (CDCl3):
−62.6 (s), −73.8 (d, J = 7.5 Hz). IR (film, NaCl): 2933, 2862, 1450,
1330, 1263, 1163, 1121, 1074, 798, 779. HRMS (DART): m/z calcd
for C22H20F6N [M + H] 412.14999, found 412.14999. [α]D20: +29.8 (c
4.0, CHCl3). HPLC: OD-H column, hexanes−2-propanol (90:10),
flow rate: 0.7 mL/min, 7.7 min (major), 8.5 min (minor).
Procedures for Compounds in Scheme 1. (S)-N-(2,2,2-
Trifluoro-1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)-
propan-1-amine (5). (S)-4-Methoxy-N-(2,2,2-trifluoro-1-(naphtha-
len-1-yl)ethyl)aniline (2ag) (455 mg, 1.37 mmol, 1 equiv) was
prepared according to the general procedure with 6 mol % of Pd-1 and
40 mol % of AgSbF6 on a 2 mmol scale (10 mL of DCE in a 10-dram
vial). It was dissolved in 10 mL of MeCN and 10 mL of H2O. Periodic
acid (624 mg, 2.74 mmol, 2 equiv) was added followed by 5 drops of
concentrated H2SO4. The mixture was stirred overnight and diluted
with 40 mL of DCM and 40 mL of saturated aqueous NaHCO3. The
organic layer was washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude mixture was purified
by flash chromatography (hexanes/EtOAc 5:1) yielding the primary
1
amine as an orange oil (244 mg, 1.08 mmol, 79% yield). H NMR
ASSOCIATED CONTENT
■
(400 MHz, CDCl3): δ 8.11−8.09 (m, 1H), 7.92−7.88 (m, 2H), 7.80−
7.77 (m, 1H), 7.61−7.51 (m, 3H), 5.34 (q, J = 7.2 Hz, 1H), 1.92 (s,
2H). 19F NMR (CDCl3): −75.3 (d, J = 7.1 Hz). [α]D20: +3.1 (c 2.5,
CHCl3). The primary amine (50 mg, 0.22 mmol, 1.1 equiv) and
aldehyde 4 (40 mg, 0.20 mmol, 1 equiv) were dissolved in 2 mL of
DCE. Sodium triacetoxyborohydride (59 mg, 0.28 mmol, 1.4 equiv)
was added in one portion, and the mixture was stirred for 1 h at room
temperature. Twenty milliliters of EtOAc and 20 mL of a saturated
aqueous solution of NaHCO3 were added, and the organic layer was
separated. The aqueous layer was extracted three times with 10 mL
EtOAc. The combined organic layers were washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure. The
crude mixture was purified by flash chromatography (hexanes/EtOAc
30:1) yielding the product as a clear oil (61 mg, 0.15 mmol, 74% yield,
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00657.
1H and 13C NMR spectra and HPLC chromatograms
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mlautens@chem.utoronto.ca.
Author Contributions
†T.J. and B.L. contributed equally to this work.
1
72% ee). H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.4 Hz, 1H),
Notes
7.93−7.89 (m, 2H), 7.75 (d, J = 7.2 Hz, 1H), 7.61−7.52 (m, 3H),
7.45−7.28 (m, 4H), 5.10−5.04 (m, 1H), 2.74−2.63 (m, 4H), 1.86−
1.76 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 142.8, 134.0, 132.3,
131.9 (q, J(C−F) = 1.5 Hz), 130.81, 130.80, 130.78 (q, J(C−F) = 32
Hz), 129.6, 129.2, 128.9, 126.8, 125.9 (q, J(C−F) = 282 Hz), 125.8,
125.5, 125.2 (q, J(C−F) = 4 Hz), 124.4 (q, J(C−F) = 271 Hz), 122.9
(q, J(C−F) = 4 Hz), 122.8, 47.3, 33.1, 31.7. Note: C(CF3)(1-
naphthyl) (NHR) is visible only in the baseline 19F NMR (CDCl3):
−62.6 (s), −72.9 (d, J = 6.5 Hz). IR (film, NaCl): 2933, 2862, 1450,
1330, 1263, 1163, 1121, 1074, 798, 779. HRMS (DART): m/z calcd
for C22H20F6N [M + H] 412.14999, found 412.14989. [α]D20: −5.3 (c
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported financially by the Natural Sciences
and Engineering Research Council of Canada (NSERC), the
University of Toronto, and Alphora Research Inc. T.J. thanks
́
NSERC and the Fonds de recherche du Quebec (FRQNT) for
graduate scholarships. B.L. thanks the China Scholarship
Council and Professor Jinming Gao (Northwest A&F
G
DOI: 10.1021/acs.joc.6b00657
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(17) AgY (Y = weakly coordinating anion) can also introduce trace
HY, which might help cleave the Pd−N bond, facilitating catalyst
turnover.
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in the course of his doctoral studies.
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DOI: 10.1021/acs.joc.6b00657
J. Org. Chem. XXXX, XXX, XXX−XXX