118
C. Chen et al. / Journal of Molecular Catalysis A: Chemical 379 (2013) 117–121
Table 1
Enantioselective hydrogenation of (Z)--dehydroamino esters.
.
Entry
Substrate
Modifier
Base
Solvent
ee%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
2
2
2
2
No
No
No
Yes
No
No
Yes
No
Yes
No
Yes
i-PrOH
i-PrOH
i-PrOH
Toluene
Toluene
Toluene
i-PrOH
i-PrOH
Toluene
Toluene
0
3
3
0
2
2
5
6
3
3
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Scheme 1. Synthetic routes of (Z)--dehydroamino esters (a) and acids (b). Benzyl
esters used in route (b) were obtained by the same method as the synthesis of methyl
esters (a) except using benzyl -keto esters as the starting materials.
HPLC-Q-TOF mass spectrometer. TEM images of the commercial
Pd/Al2O3 catalyst (Alfa Aesar) were recorded on a Philips Tecnai G2
Spirit microscope operated at 120 kV. The specimen was prepared
by ultrasonically dispersing the solid powder into ethanol and
drops of the suspension were deposited onto a clean carbon-
enhanced copper grid and then dried in air. Enantiomeric excess
was analyzed by GC and HPLC. Flash column chromatography was
performed on silica gel (200–300 mesh).
10
Reaction conditions: 25 mg Pd/Al2O3, 1 mmol substrate, 0.05 mmol cinchonidine,
1 mmol benzylamine (as noted), 3 mL solvent; 25 ◦C, 2 MPa H2, 4 h.
Substrates: (Z)-methyl 3-acetamidobut-2-enoate (1); (Z)-methyl 3-acetamido-3-
phenylacrylate (2).
isopropanol/2 mM copper sulfate = 15/85, flow = 1 mL/min, detec-
tor: 210 nm, 30 ◦C. Retention time: t1 = 30.096 min, t2 = 33.688 min
for 3; t1 = 90.828 min, t2 = 112.406 min for 4. The products of 3 and 4
were also confirmed by transformed them into methyl esters using
diazomethane ethereal solution and compared with the products of
1 and 2. The enantiomeric excess was calculated with the equation:
ee% = |(E1 − E2)/(E1 + E2)| × 100, where E1 and E2 are the concen-
trations of the product enantiomers. The reactions were repeated
twice and the results were reproducible within 1%.
2.2. Synthesis of the substrates
(Z)--Dehydroamino esters were synthesized by the reaction of
-keto esters with ammonium acetate (Scheme 1a) [25]. A solu-
tion of -keto esters (120 mmol) and NH4OAc (46 g, 600 mmol) in
methanol (150 mL) was stirred at room temperature for 3 days. The
solvent was evaporated under reduced pressure, and the residue
was diluted with dichloromethane (200 mL). The resulting solid
was filtered off and washed with CH2Cl2 (2 × 100 mL). The com-
bined filtrate was washed with water and brine, and dried over
sodium sulfate. Evaporation of the solvent gave the enamine inter-
mediate that was then mixed with 120 mL THF, 16 mL pyridine and
60 mL acetic anhydride. The mixture was refluxed until the start-
ing material was totally dissolved. After being cooled down to room
temperature, the volatiles were evaporated. The residue was dis-
solved in ethyl acetate (200 mL), and the solution was washed with
water (100 mL), 1 N HCl (100 mL), NaHCO3 (saturated, 100 mL),
and brine (100 mL). The solution was dried over sodium sulfate.
The solvent was evaporated while the solid residue was subject
to column chromatography (SiO2; 1:9 EtOAc/hexane) to afford
(Z)--dehydroamino esters. Analyses and identifications of these
substrates are detailed in the Supporting Information.
3.1. Enantioselective hydrogenation of (Z)-ˇ-dehydroamino
esters
Fig. 1a shows a TEM image of the commercial Pd/Al2O3; Pd par-
ticles were uniformly dispersed on the Al2O3 support. The average
size of Pd particles was about 3 nm estimated by counting approx-
imate 500 particles (Fig. 1b). Table 1 summarizes the reaction
results of enantioselective hydrogenation of (Z)--dehydroamino
esters (1 and 2) on the Pd/Al2O3 catalyst. Full conversions were
achieved within 4 h but nearly racemic products were obtained;
the enantioselectivity was almost independent of the presence of
the chiral modifier, the use of base additive and the polarity of the
solvent. These results indicate that the Pd/Al2O3 catalyst is poorly
inum catalysts provided much higher enantioselectivities toward
optically active alcohols; the origin was attributed to the strong
interaction between the carbonyl group in the substrate and the
chiral modifier through hydrogen bond [30]. Therefore, it is reason-
able to infer that the acetamido group in -dehydroamino esters
interacted insufficiently with the chiral modifier for generating
appreciable enantioselectivity.
2.3. Enantioselective hydrogenation
Enantioselective hydrogenation reactions were carried out in a
stainless steel autoclave with a quartz liner (50 mL) under mag-
netic stirring (650 rpm). The reaction mixture included: 25 mg
Pd/Al2O3 (5 wt% Pd, Alfa Aesar), 1 mmol substrate, certain amounts
of cinchonidine and benzylamine, 3 mL solvent. The reaction tem-
perature was 5 or 25 ◦C and the pressure of H2 was 0.5–4.0 Mpa.
Before the reaction, the mixture was stirred for 15 min and flushed
with hydrogen for five times. After the reaction, the catalyst was
filtered off. A small amount of sample was subjected to chiral anal-
ysis. The products of 1 and 2 were analyzed using off-line gas
chromatography (Agilent 6890N) equipped with a -cyclodextrin
capillary column (Chirasil-Dex CB, Varian) and a flame ioniza-
tion detector. The following GC conditions were used: initial
temperature 110 ◦C for 2 min, then heated to 180 ◦C at a rate
5 ◦C/min and maintained at 180 ◦C for 10 min. Retention time:
t1 = 8.859 min, t2 = 9.393 min for 1; t1 = 19.237 min, t2 = 20.314 min
for 2. The products of 3 and 4 were analyzed using a HPLC (Agilent
1200) equipped with a Chirex 3126 Chiral column (Phenomenex)
and a UV detector. The following HPLC conditions were used:
It is known that the interaction between the carboxylic group in
␣,-unsaturated carboxylic acids and the amine group in cinchona
type chiral modifiers through an acid–base type governed the
enantioselectivity [30]. Therefore, the (Z)--dehydroamino esters
were transformed into (Z)--dehydroamino acids (Scheme 1b). It
should be noted that (Z)--dehydroamino acids could not be sim-
ply obtained from the hydrolysis of the methyl esters because
it would preferentially deacylate the amide group, which would
strongly absorb to the palladium surface and subsequently hinder