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(R)-5d. Light yellow powder (hygroscopic). Yield 27%. chiral
purity: 99.81%; H NMR (400 MHz, DMSO) δ = 7.34 (d, J =
11.2, 1H), 6.98 (s, 1H), 6.72−6.750 (m, 1H), 4.08−4.13 (m,
1H), 3.75 (s, 1H),1.39 (d, J = 8.8, 1H); 13C NMR (100 MHz,
DMSO) δ = 167.73, 159.68, 157.40, 155.55, 115.97, 110.72,
97.79, 55.74, 46.22, 23.43.
EXPERIMENTAL SECTION
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1
General Methods. All of the experiments sensitive to
moisture and air were conducted using standard Schlenk
techniques under an argon atmosphere. Toluene (Industrial
grade, purity ≥99.5%, water content ≤0.05%, Shanghai
Demand Chemical Co., Ltd.) was used as purchased or
distilled over CaH2 prior to use. MeOH (GR grade, Aladdin
Reagent Co.), EtOH (GR grade, Aladdin Reagent Co.), i-PrOH
(GR grade, Aladdin Reagent Co.), t-BuOH (GR grade, Aladdin
Reagent Co.), hexane (HPLC grade, Aladdin Reagent Co.), and
CH2Cl2 (HPLC grade, Aladdin Reagent Co.) were used as
purchased. Methyl tert-butyl ether (GR grade, Aladdin Reagent
Co.) and DMF (AR grade, Aladdin Reagent Co.) were distilled
over CaH2 prior to use. 1-(3,5-Bis(trifluoromethyl)phenyl)-
ethanone (Industrial grade) was used as purchased from
supplier 1 (Beijing Pure Chem. Co., Ltd.), supplier 2 (Fuxin
Jintelai Fluoring Chemical Co., Ltd.), and supplier 3 (Beijing
Golden Olive Co., Ltd.).
Preparation of Catalysts. The catalysts were synthesized
according to the established method for RuCl2[(S)-Diop][(S)-
BIMAH] by modifying the benzimidazole and phosphorus
ligands.15
1
(R)-6c. Yellow powder. Yield 75%. H NMR (400 MHz,
CDCl3) δ = 11.60 (br, 1H), 7.98−6.50 (m, 22H), 5.40−4.68
(m, 2H), 3.69−3.47 (m, 1H), 2.94−2.12 (m, 13H), 1.35−0.76
(m, 13H); 13C NMR (100 MHz, CDCl3) δ = 161.87, 139.19−
125.10 (m, aromatic carbons), 122.52, 122.28, 117.61, 106.77,
94.27, 87.76, 87.52, 79.78, 71.59, 35.48, 30.86, 30.50 (J = 20.1),
26.03 (J = 7.4), 25.77, 25.64, 25.39, 22.53, 21.62, 21.27, 15.96,
13.09; 31P NMR (161 MHz, CDCl3), major isomer: δ = 46.93
2
2
(d, J(P,P) = 36.5), 34.74 (d, J(P,P) = 36.5).
All reactions were monitored by gas chromatography (GC),
and the conversions and ee values were determined by using
GC. GC analysis was conducted on Agilent 7890A with
Supelco BETA-DEXPTMP 225 column (30 m × 250 μm, 0.25
μm).
Typical Pilot Hydrogenation Procedure. 1-(3,5-Bis-
(trifluoromethyl)phenyl)ethanone (170 g) was dissolved in a
̈
solvent (1 L) in a 5 L autoclave (BUCHI), and the solution was
degassed by running argon through the solution (1 h).
Stoichiometric amounts of solid catalyst and potassium t-
butoxide were added to the autoclave under argon atmosphere.
The charged autoclave was purged three times with 5 atm of
hydrogen and then pressurized to 30 atm of hydrogen. The
resulting mixture was stirred at room temperature. After the
reaction completed, the hydrogen was released, and the
conversion and ee were determined by using GC. GC (Supelco
BETA-DEXPTMP 225 column (30 m × 250 μm, 0.25 μm)); P =
118.6 kPa; T = 105 °C; tR of (R)-isomer, 22.9 min (major); tR
of (S)-isomer, 19.9 min; 1H NMR (400 MHz, CDCl3) δ = 7.85
(s, 2H), 7.80 (s, 1H), 5.06−5.02 (m, 1H), 1.57 (d, J = 5.2, 3H).
Scale-up Hydrogenation Representative Procedure. 1-
(3,5-Bis(trifluoromethyl)phenyl)ethanone (5.1 kg) was intro-
duced to the 100 L autoclave under argon atmosphere,
followed with 30 L of toluene. A bubbler was connected to
the autoclave, and the resulting mixture was charged with argon
and bubbled with argon for 2 h to degas the oxygen of the
mixture. After degassing completed, a suspension of the catalyst
(1.0 g) and potassium t-butoxide (5.6 g) in toluene (0.5 L) was
transferred by means of standard Schlenk technique. The
charging port was shut up quickly, and the valve of the argon
pipeline was closed up. After washing the hydrogen pipeline
with hydrogen for 3 times, the charged autoclave was purged
three times with 10 atm of hydrogen and then pressurized to 30
atm of hydrogen. The resulting mixture was stirred at 25 °C at
an agitation speed of 800 rpm. After completion of the reaction,
the hydrogen was released, and the mixture was filtered, and the
filtrate was evaporated to give crude product. The crude
product was recrystallized from hexane/isopropanol according
to a protocol reported by Hansen et al.16 to afford pure 3 (yield
65−70%, ee 98−98.75%).
1H NMR, 13C NMR, and 31P NMR spectra were recorded on
a Bruker BioSpin GmbH spectrometer at 400 and 100 MHz
using TMS as the internal standard, respectively. Mass spectra
(MS) was recorded on a Shimadzu LCMS-2010A instrument
with an ESI or ACPI mass selective detector. Melting points
(m.p.) were determined using an SRS-OptiMelt automated
melting point instrument without correction. Flash column
chromatography was performed with silica gel (200−300 mesh)
purchased from Qingdao Haiyang Chemical Co., Ltd. The
chiral purity of synthesized ligand was confirmed to be higher
than 99.5% by using analytical HPLC with a dual pump
Shimadzu LC-20AB system equipped with an OD-H column
(DAIEL OD-H column, 4.6 cm × 250 mm, λ = 254 nm, v = 1.0
mL/min, hexane/i-PrOH = 90:10). All exploratory experiments
were carried out following the previously established method.15
Preparation of (R)-5. Ligands (R)-5a, (R)-5b, and (R)-5d
were prepared according to the established method for (S)-
BIMAH16 with modification of the starting material of R-isomer
amino acids. (R)-5c was synthesized by the (R)-5a method
using 3,6-dimethylbenzene-1,2-diamine (9) instead of o-
diaminobenzene (Scheme 1).
(R)-5a. Off-white powder. Yield 37%. M.p.: 188−190 °C;
1
chiral purity: 99.67%; MS (ESI): m/z = 161 [M + H]+; H
NMR (400 MHz, CDCl3) δ = 7.56−7.53 (m, 2H), 7.23−7.19
(m, 2H), 4.46−4.41 (m, 1H), 1.58 (d, J = 6.8, 6H); 13C NMR
(100 MHz, CDCl3) δ = 159.27, 138.39, 122.33, 114.94, 46.30,
23.80.
(R)-5b. Off-white powder. Yield 35%. M.p.: 193−195 °C;
1
chiral purity: 99.54%; MS (ESI): m/z = 190 [M + H]+; H
NMR (400 MHz, CDCl3) δ = 7.50−7.48 (m, 2H), 7.16−7.14
(m, 2H), 4.04 (d, J = 4.8, 1H), 2.26−2.21 (m, 1H), 0.92−0.85
(dd, J1 = 6.8, J2 = 24, 6H); 13C NMR (100 MHz, CDCl3) δ =
1557.77, 138.21, 122.20, 114.96, 56.50. 33.98, 19.36, 17.58.
(R)-5c. Off-white powder. Yield 25%. M.p.: 184−185.5 °C;
ASSOCIATED CONTENT
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S
* Supporting Information
Table S1: Scale-up batches of crude 3, mass, H NMR, 13C
1
1
NMR spectrum of 5a, mass, H NMR, 13C NMR spectrum of
1
chiral purity: 99.75%; MS (ESI): m/z = 190 [M + H]+; H
1
1
5b, mass, H NMR, 13C NMR spectrum of 5c, H NMR, 13C
1
1
NMR spectrum of 5d, H NMR spectrum of 3, H NMR, 31P
NMR, 13C NMR spectrum of 6c, spectrum of chiral purity of
5a, 5b, 5c, and 5d, representative GC spectrum of Table 1 and
NMR (400 MHz, CDCl3) δ = 6.93 (s, 2H), 4.55−4.50 (m,
1H), 2.54 (s, 6H),1.57 (d, J = 6.4, 3H); 13C NMR (100 MHz,
CDCl3) δ = 158.07, 122.71, 46.43, 24.09, 16.86.
D
dx.doi.org/10.1021/op500148k | Org. Process Res. Dev. XXXX, XXX, XXX−XXX