Table 1. Enantioselective hydrogenation of 1 over CD-
modified Pd/C.a
the deuterium labeled products for the first time. Interaction
of the substrate with the CD modifier may be responsible for
the enantioselective double bond migration as well as the
hydrogenation.
Entry
Solvent
H2 (MPa)
ee (%)b
1
2
3
4
5
6
7
8
toluene
toluene
methanol
methanol
ethanol
ethanol
2.5% H2O in dioxane
2.5% H2O in dioxane
0.1
5
0.1
5
0.1
5
0.1
5
20
42
15
32
32
46
50
60
2. Experimental
A 5% Pd/C catalyst was obtained from N.E.Chemcat (5%
STD type) in a 51% wet form. The 5% Pd/C catalyst (20 mg)
was pretreated at 80 °C in 2.5% (v/v) aqueous dioxane (5 mL)
under atmospheric hydrogen for 30 min. After cooling to 23 °C,
a solution of cinchonidine (12 mg, 0.04 mmol) in the aqueous
dioxane (1 mL) was added to the catalyst, and the mixture was
stirred further for 30 min. A solution of 1 (50 mg, 0.5 mmol)
and benzylamine (0.5 mmol) in the aqueous dioxane (4 mL)
was added to the cinchonidine-modified catalyst while stirring.
After the substrate was fully converted to the expected product
as measured by hydrogen consumption, the reaction mixture
was quenched with HCl aqueous solution and filtered. The
filtrate was extracted with ether, and analyzed by 1H NMR,
ESI-MS, and GC. Enantiomeric ratio of 3 was determined by
gas chromatography equipped with a chiral column (Chirasil-
DEX-CB, 25 m © 0.25 mm © 0.25 ¯m film thickness). Reten-
tion times of (S)-3 and (R)-3 were 17.8 and 19.2 min, respec-
tively, when the column temperature was maintained at 95 °C.
Initial rates for the hydrogenation were calculated from the
hydrogen-uptake up to 25% conversion.
Hydrogenation under 5 MPa of H2 was carried out using a
reactor made of stainless steel (SUS 316). The mixed suspen-
sion containing 1 and CD-modified Pd/C was prepared by the
same procedures described above, and poured into the metal
reactor. Hydrogen was introduced from an inlet of the reactor,
and the reaction was carried out at 23 °C for 5 h while stirring.
Deuteration of 1 was similarly carried out using D2 and D2O
instead of H2 and H2O. Typically, 40 mg of Pd/C, 6 mg (0.02
mmol) of CD, and benzylamine (0.5 mmol) were used for the
reaction of 0.5 mmol of 1 in 10 mL of the solvent. The deuter-
ated product 3 obtained was analyzed by 1H NMR (JEOL ECA-
600) and ESI-MS (JEOL JMS-T100LC). GC-MS was per-
formed using a Shimadzu GCMS-QP 2010 equipped with the
DEX-CB column. The 1H NMR signals of 3 were assigned
according to previous reports.7
aReaction was carried out in the presence of cinchonidine
(0.04 mmol), 5 wt% Pd/C (20 mg), 1 (0.5 mmol), and benzyl-
b
amine (0.5 mmol) in 10 mL of solvent at rt. Determined by a
chiral GC column (Chirasil-DEX-CB). (S)-3 preferentially
forms.
88%D
38%D
D2 (0.1MPa)
DA DB
CO2H
Pd/C
α
CO2H
(a)
H3C
β
cinchonidine
D
1
D3C
2.5%D2O dioxane
88%D
32%D
93%D
31%D
DA DB
H3C
D
2 (1.9 MPa)
Pd/C
CO2H
1
(b)
cinchonidine
2.5%D2O dioxane
D
D3C
98%D
27%D
1
Scheme 2. Deuterium content determined by H NMR.
genation of 1 under a high pressure of H2 was previously
reported to be due to the suppression of the migration of the
alkene carbon-carbon double bond leading to 2 and the
subsequent hydrogenation of 2.4,5
In this study, the use of the aqueous dioxane solvent resulted
in optimal enantioselectivity during the hydrogenation of 1
over the CD-modified Pd/C.9 The hydrogenation under atmos-
pheric pressure H2 in aqueous dioxane yielded (S)-3 with 50%
ee (Entry 7) at an initial rate (r0) of 19 mmol h¹1 g¹1. Under
5 MPa of H2, the enantioselectivity improved to 60% ee
(Entry 8).
Esterification of 3 with (R)-methyl mandelate was carried out
in dichloromethane containing 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide hydrochloride (1.5 eq) and a small amount
of N,N-dimethylaminopyridine. The reaction mixtures were
purified by SiO2 column chromatography (eluent: 10% ethyl
acetate in hexane), and the purified product was analyzed by
1H NMR. The NMR data agrees well with the reported values.8
We also examined the enantioselective hydrogenation of 2,
which is an isomer generated by the migration of the double
bond of 1. The hydrogenation of 2 yielded (R)-3 with 2% ee
at r0 = 140 mmol h¹1 g¹1 under the same conditions as those of
Entry 7. The formation of antipodal enantiomer (R)-3 from 2
has been reported in the hydrogenation over CD-modified Pd/
Al2O3.4,5 Therefore, the double bond migration from 1 to 2 and
the subsequent hydrogenation may decrease the overall enan-
tiomeric purity of the hydrogenated product 3. The fast hydro-
genation rate for the terminal alkene of 2 suggests difficulty in
isolating 2 as an intermediate during the hydrogenation of 1.
The optimal reaction conditions using the aqueous dioxane
solvent were applied for the deuteration of 1 in the presence of
D2 and D2O, as shown in Scheme 2.10 The isotopic distribution
3. Results and Discussion
We began our study with the hydrogenation of 1 with the
usual H2 gas over CD-modified Pd/C in various solvents as
summarized in Table 1. The hydrogenation was carried out
under atmospheric pressure and high (5 MPa) pressure of H2 to
quantitatively yield 3. An enantiomeric excess (ee) of hydro-
genated product 3 was determined by using gas chromatog-
raphy (GC) with a chiral column (DEX-CB). The ee under high
pressure H2 was greater than that under atmospheric pressure.
A similar increase in the enantioselectivity during the hydro-
1
in 3 was determined by H NMR measurements. The signal
owing to the β-methyl group was used as an internal standard
for evaluation of the deuterium content because the β-methyl
group tolerates H/D exchange in the presence of a Pd catalyst.6
© 2019 The Chemical Society of Japan