Highly efficient synthesis of heterocyclic and alicyclic β2-amino acid derivatives by catalytic asymmetric hydrogenation

Article abstract of DOI:10.1002/asia.201300339

A valuable class of new heterocyclic and alicyclic prochiral α-aminomethylacrylates has been conveniently synthesized through a three-step transformation involving a Baylis-Hillman reaction, O-acetylation, and a subsequent allylic amination. The correspon

Full text of DOI:10.1002/asia.201300339

FULL PAPER
DOI: 10.1002/asia.201300339
Highly Efficient Synthesis of Heterocyclic and Alicyclic b2-Amino Acid
Derivatives by Catalytic Asymmetric Hydrogenation
Lanning Li,[a] Bin Chen,[a] Yuanyuan Ke,[a] Qing Li,[a] Yue Zhuang,[a] Kun Duan,[a]
Yichun Huang,[a] Jiyan Pang,[a] and Liqin Qiu*[a, b]
Abstract: A valuable class of new het-
erocyclic and alicyclic prochiral a-ami-
nomethylacrylates has been conven-
iently synthesized through a three-step
transformation involving a Baylis–Hill-
man reaction, O-acetylation, and a sub-
sequent allylic amination. The corre-
sponding novel b2-amino acid deriva-
tives were prepared with excellent
enantioselectivities and high yields by
catalytic asymmetric hydrogenation
using the catalyst rhodium(Et-Duphos)
(Et-Duphos=2’,5’,2’’,5’’-tetraethyl-1,2-
bis(phospholanyl)benzene)) under mild
reaction conditions (up to 99% ee and
S/C=1000). The influence of the sub-
strate on the enantioselectivity and re-
activity is investigated, and the most
suitable substrate configuration for the
highly efficient enantioselective hydro-
genation of b-substituted a-aminome-
thylacrylates under the Rh–Duphos
system is reported. The current proto-
col provides a very practical, facile, and
scalable method for the preparation of
heterocyclic and alicyclic b2-amino
acids and their derivatives.
Keywords: amino acids
metric catalysis heterocycles
hydrogenation · rhodium
· asym-
·
·
Introduction
an alicyclic ring was part of the substrate.[7] Among all these
catalytic asymmetric protocols, the hydrogenation of prochi-
ral substrates appears to be a preferable method for achiev-
ing high efficiency and atom economy. Although asymmetric
hydrogenation has been successfully applied for the synthe-
sis of some heterocyclic and alicyclic a-, b3-, g-amino acids
and their derivatives during the past two decades,[6] its use
in the preparation of the chiral b2-counterparts has been
rarely reported. One example has been recently reported by
Zheng and co-workers, whose method provided the hydro-
genated product methyl 2-(phthalimidomethyl)-3-(2-thien-
yl)-propanoate in only 60% conversion and 55.4% ee (85
atm, S/C=25, 36 h).[7b] During the preparation of this manu-
script, Holz, Bçrner and co-workers reported the hydroge-
nation of dehydro b2-amino acid derivatives with a furyl or
thienyl group. In their study, the incomplete conversion of
the thienyl-based substrate was ascribed to the negative
effect of the sulfur atom in the heteroaromatic cycle on the
active metal.[7c] To the best of our knowledge, no report has
been disclosed on the preparation of enantioenriched acyclic
b2-amino acids and their derivatives by an enantioselective
hydrogenation. We have previously developed a synthetic
strategy for the preparation of b2-amino acids and their de-
rivatives that possess an aromatic ring or aliphatic chain at
the b-position with remarkable activities (S/C up to 10000)
and excellent enantioselectivities (up to 99.5% ee).[9g,h]
Herein, we disclose its further application in the synthesis of
novel chiral b2-amino acid derivatives with heterocyclic or
alicyclic rings. The corresponding free b2-amino acids can be
prepared through ester group cleavage by employing LiOH
and subsequent hydrogenolysis with Pd/C.[9h]
Enantiopure b-amino acids have drawn extensive attention
because they can be used as important building blocks for
the construction of new peptidomimetics and are key struc-
tural units in some natural products and pharmaceuticals.
The b2-amino acid (a-substituted b-amino acid) subclass is
particularly attractive as the alkyl substituent at the a-posi-
tion of the scaffold favors the folded conformations in the b-
peptides.[1–5] In this amino acid family, the heterocyclic and
alicyclic amino acids and their derivatives are very interest-
ing because of their unique structures and properties.[6a,b] In
the past decade, several stoichiometric[7a,8c,d] and catalytic
methods such as asymmetric hydrogenation,[7b,c,9] asymmet-
ric transfer hydrogenation,[7d] carbenoid-induced C H acti-
ꢀ
vation,[7e] and enantioselective H-atom transfer[7f] have been
investigated for the preparation of b2-amino acids and their
derivatives. However, low reactivities, poor stability and
enantioselectivities were often met when a heteroatom or
[a] L. Li, B. Chen, Y. Ke, Q. Li, Y. Zhuang, K. Duan, Y. Huang,
Dr. J. Pang, Prof. Dr. L. Qiu
School of Chemistry and Chemical Engineering
Guangdong Engineering Research Center of Chiral Drugs
Sun Yat-sen University
No. 135 Xingangxi Road, Guangzhou 510275 (People’s Republic of
China)
Fax : (+86)20-8411-0996
E-mail: qiuliqin@mail.sysu.edu.cn
[b] Prof. Dr. L. Qiu
Huizhou Research Institute of Sun Yat-sen University
Sun Yat-sen University
Dayawan, Huizhou (People’s Republic of China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300339.
Chem. Asian J. 2013, 8, 2167 – 2174
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Liqin Qiu et al.
Results and Discussion
phanyl)-1,1ꢁ-binaphthyl), 1,2-bis(2,5-dimethylphospholanyl)-
benzene (Me-Duphos), or iPr-Duphos (iPr-Duphos: 1,2-
bis(2,5-diisopropylphospholanyl)benzene) was used instead
(Table 2, entries 1, 2, 4–6, and 8). iPrOH was found to be
the best solvent to achieve high enantioselectivity and high
reactivity. Having established the optimized reaction condi-
tions, a series of novel heterocy-
As reported in our previous studies, prochiral substrates 4
were generally prepared in a three-step transformation by
a Baylis–Hillman reaction, O-acetylation, and a subsequent
allylic amination (Scheme 1).[9h,10] Among the substrates
clic or alicyclic b2-amino acid
derivatives 5 were prepared in
high yields with outstanding re-
activities and enantioselectivi-
ties. The results are shown in
Table 3.
As shown in Table 3, except
for 4b and 4e with a 5-bromo-
2-furyl and 4-pyridyl group as
the R group, respectively, all
the E/Z- and E-substrates in
the current study showed high
Scheme 1. Synthesis of prochiral substrates 4.
reactivities towards hydrogena-
shown in Scheme 1, the acetylation product 4-pyridyl acetate
3e was found to be unstable and decomposed quickly even
when it was kept under nitrogen and at a low temperature.
To circumvent this problem, we attempted to synthesize 4e
from 2e in a one-pot reaction. Upon completion of the ace-
tylation reaction, the amination reaction was allowed to pro-
ceed in the same reaction vessel successively without separa-
tion of 3e, and 4e was isolated successfully in 30% yield.
The E- and Z-isomers of 4c–4e and 4i were simply separat-
ed by silica-gel column chromatography.[11] For 4a, 4b, 4 f–
4h, the two geometric isomers were inseparable and the cor-
responding mixture was directly used in the ensuing catalyt-
ic hydrogenation (Table 1).
tion. The reactions were complete within a short period of
time (maximum 2 h) at room temperature under low-pres-
sure hydrogenation (50 psi) in the presence of 1 mol%
[Rh(Et-Duphos)ACHTNUTRGNEUNG(cod)]BF4 catalyst (Table 3, entries 1, 6, 10,
14, 15, 18, 19, and 22). Notably, (E/Z)-4a, (E)-4c, and (E/
Z)-4 f–4h were fully converted into the desired products
within only 20 min (Table 3, entries 1, 6, 15, 18, and 19). In-
terestingly, (E)-4d was transformed completely into the cor-
responding product 5d with excellent enantioselection
within 120 min (Table 3, entry 10; 98% ee). The catalytic
result is very different from and significantly better than
that reported in the literature for the hydrogenation of
other analogues.[7b,c] This suggests that the undesired interac-
tion between the active metal
and the sulfur atom of the sub-
strate does not exist in our cata-
lytic system. Hydrogenation of
(E)-4i was also achieved with
Table 1. Synthesis of prochiral substrates 4.[a]
Entry
R
Yield [%][b]
Yield of (E)-4 [%][b]
Yield of (Z)-4 [%][b]
1
2-furyl (4a)
79 (E/Z=5:1)
2
3
4
5-bromo-2-furyl (4b)
2-benzofuryl (4c)
2-thienyl (4d)
91 (E/Z=10:3)
86
89
30
63 (E/Z=10:9)
82 (E/Z=7:10)
91 (E/Z=3:5)
96
excellent enantioselectivity and
74
70
30
12
19
trace
reactivity (Table 3, entry 22).
With an alicyclic substituent at
the b-position of the carbon–
carbon double bond, direct hy-
drogenation of the mixture of
E/Z-isomers of 4 f–4h led to ex-
5[c]
6
4-pyridyl (4e)
cyclopropyl (4 f)
cyclopentyl (4g)
cyclohexyl (4h)
1-benzyl-4-piperidyl (4i)
7
8
9
33
63
[a] Reaction conditions: 3, Na2CO3, and O-benzylhydroxylamine hydrochloride were allowed to stir in THF at
room temperature under N2. [b] Yield of isolated product. [c] One-pot synthesis from 2e.
cellent
enantioselectivities,
thereby yielding 5 f–5h in 99%,
98%, and 96% ee, respectively
Following the same procedures as those in our previous
studies,[9g,h] the asymmetric hydrogenation of a mixture of E/
Z-4a was performed at room temperature under low-pres-
sure hydrogenation (50 psi) using 1 mol% [Rh(Et-Duphos)-
(Table 3, entries 15, 18, and 19). By further increasing the S/
C to 1,000, full conversion of 4 f and 4h was achieved with
reaction times of 180 and 120 min, respectively. These reac-
tivities were not only significantly better than those sub-
strates with an alkyl chain group but also superior to the
substrates bearing a phenyl group[9g] (Table 3, entries 17 and
20). The presence of the alicyclic substituent is beneficial to
the substrate activity. In comparison with substrates 4c, 4d,
and 4 f–4i, hydrogenation of (E/Z)-4a with a 2-furyl sub-
ACHTUNGTRENNUNG(cod)]BF4 (cod=cyclooctadiene) as the catalyst. The cata-
lyst system was found to be highly effective and enantiose-
lective as 5a was obtained in >99% yield and 94% ee
(Table 2, entry 7). In contrast, both the reactivity and enan-
tioselectivity were low when binap (2,2ꢁ-bis(diphenylphos-
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Liqin Qiu et al.
Table 2. Screening of the ligands and optimization of the reaction
conditions.[a]
93% ee within 60 min (Table 3, entry 14). This result might
be ascribed to the partial complexation of the bare nitrogen
atom of the 4-pyridyl group to the catalyst, thus causing
a significant decrease in the catalytic activity. Protonation of
HBF4 to the basic pyridyl nitrogen atom of (E)-4e could in-
hibit the unfavorable nitrogen coordination to the catalyst.
In our previous work,[9g,h] Z-a-aminomethylacrylates with
an aromatic ring showed lower reactivity and enantiodiffer-
entiation than the corresponding E-isomers. Similar phe-
nomena were also observed in the reaction of heteroaromat-
ic substrates 4c and 4d (Table 4, entries 1–3). However, the
exact behavior of the single isomer with an alkyl R group
has not been investigated before because the pure E- or Z-
isomeric substrate could not be obtained conveniently. By
introducing a large alkyl group (1-benzyl-4-piperidyl) into
the substrates, (E)- and (Z)-4i were successfully separated
by silica-gel column chromatography. Furthermore, (Z)-4i
was found to be more reactive than (E)-4i. The obtained
enantioselectivities were also comparable (Table 4, entry 5
vs. Table 3, entry 22). Thus, hydrogenation of a mixture of
(E/Z)-4i gave an excellent result (Table 4, entry 8). This out-
come was very different from that observed in the hydroge-
nation of the aromatic and heteroaromatic moieties. On the
basis of this result, a general speculation could be made for
the hydrogenation of b-substituted a-aminomethylacrylates
under the Rh–Duphos system: the reactivity and enantiose-
lectivity are high for both E- and Z-isomers if the R group
of the prochiral substrate is not conjugated with the carbon–
carbon double bond of the acrylates. The hydrogention re-
sults for the mixture of E/Z-isomers bearing the aliphatic
and alicyclic substituents all supported this hypothesis
(Table 3, entries 15–20; Table 4, entry 8 and the previous
studies[9h]). On the contrary, the Z-a-aminomethylacrylate
with an aromatic or heteroaromatic R group provided less
favorable results in comparison with the corresponding E-
isomer. That is, only the pure E-isomers were good for ach-
ieving excellent reactivities and enantioselectivities.
Entry Catalyst
Solvent t [min] Yield [%][b] ee [%][c]
1
2
[Rh(R)-binap
[Rh(R,R)-Me-Duphos- MeOH 600
(cod)]BF4
[Rh(S,S)-Et-Duphos-
(cod)]BF4
[Rh(R,R)-iPr-Duphos-
(cod)]BF4
[Rh(R)-binap
[Rh(R,R)-Me-Duphos- iPrOH 600
(cod)]BF4
[Rh(S,S)-Et-Duphos-
(cod)]BF4
[Rh(R,R)-iPr-Duphos-
(cod)]BF4
[Rh[(S,S)-Et-Duphos-
(cod)]BF4
[Rh[(S,S)-Et-Duphos-
(cod)]BF4
[Rh[(S,S)-Et-Duphos-
(cod)]BF4
[Rh[(S,S)-Et-Duphos-
(cod)]BF4
[Rh[(S,S)-Et-Duphos-
(cod)]BF4
[Rh[(S,S)-Et-Duphos-
(cod)]BF4
G
trace
4[d]
nd
76 (+)
G
ACHTUNGTRENNUNG
3
4
E
>99
90 (ꢀ)
42 (ꢀ)
ACHTUNGTRENNUNG
E
3[d]
ACHTUNGTRENNUNG
5
6
trace
1[d]
nd
nd
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
7
R
>99
<1[d]
46[d]
99
94 (ꢀ)
nd
ACHTUNGTRENNUNG
8
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
9
G
93 (ꢀ)
94 (ꢀ)
nd
ACHTUNGTRENNUNG
10
11
12
13
14
N
ACHTUNGTRENNUNG
G
23[d]
99
ACHTUNGTRENNUNG
N
91 (ꢀ)
nd
ACHTUNGTRENNUNG
U
9[d]
ACHTUNGTRENNUNG
N
52[d]
88 (ꢀ)
ACHTUNGTRENNUNG
[a] All reactions were run at room temperature, solvent=1.5 mL, sub-
strate=0.1 mmol, substrate/catalyst (S/C)=100, hydrogen pressure=
50 psi; nd=not determined. [b] Yield of isolated product. [c] Enantiomer-
ic excesses were determined by HPLC analysis (Chiralcel OD-H).
1
[d] The conversions were determined by H NMR spectroscopy.
stituent had a slightly lower enantioselectivity (94% ee,
Table 3, entry 1), but our system still has a remarkable ad-
vantage over other reported methods for the hydrogenation
of analogues (mixture of E/Z-isomers, 94% ee, 20 min vs
pure E-substrate, 90% ee, 5 h).[7c] Changing the furyl group
of 4a into a 5-bromo furyl group ((E/Z)-4b) led to a signifi-
cant decrease in the reaction activity (Table 3, entry 4). By
raising the hydrogen pressure to 1450 psi and using 2 mol%
Other parameters such as reaction temperature and H2
pressure were also examined. It was found that the enantio-
selectivity was unaffected by H2 pressure (Table 4, entry 6
vs. entry 5), but the high H2 pressure was beneficial for the
reactivity. In separate observations, the reactions performed
at higher temperatures almost always yielded more side
products as compared to those performed at ambient tem-
perature.
[Rh(Et-Duphos)ACHTUNGTRENNUNG(cod)]BF4 as the catalyst, product 5b was fi-
nally afforded in 99% yield with 90% ee in 72 h (Table 3,
entry 5). Presumably the steric influence of the bromine
atom had an negative effect on the reactivity.
An interesting phenomenon was also noticed. Although
pyridyl, furyl, and thienyl are all aromatic heterocycles at-
tached to substrates 4e, 4a, and 4d, respectively, the hydro-
genation behavior of 4e was significantly different from
those of 4a and 4d. No reaction took place for (E)-4e
under the general reaction conditions (Table 3, entry 11). By
increasing the hydrogen pressure or the amount of catalyst,
the reactivity increased but it was still far from satisfactory
(Table 3, entries 12 and 13). Gratifyingly, favorable changes
occurred after the addition of HBF4 during the hydrogena-
tion. Product 5e was readily afforded in >99% yield and
Conclusions
In summary, we have demonstrated an efficient synthetic
route to a-aminomethylacrylates possessing b-heterocyclic
or alicyclic groups. The prochiral precursors were easily ac-
cessible by the Baylis–Hillman reaction of aldehydes with
methyl acrylate followed by the acetylation of the resulting
allylic alcohols and SN2’-type amination of the allylic ace-
tates. The corresponding novel b2-amino acid derivatives
were prepared in high yields and with excellent enantiose-
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Liqin Qiu et al.
Table 3. Hydrogenation of E/Z- and E-a-aminomethylacrylates.[a]
acids and their derivatives with a broad scope of ar-
omatic, aliphatic, alicyclic, and heterocyclic sub-
stituents was established. The simple and highly ef-
ficient approach to the new b2-amino acid deriva-
tives provides an exceptional platform for their fur-
ther applications.
Entry R (Substrate)
S/C
P [psi] t [min] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
2-furyl (E/Z)-4a
2-furyl (E/Z)-4a
2-furyl (E/Z)-4a
5-bromo-2-furyl (E/Z)-4b
5-bromo-2-furyl (E/Z)-4b
2-benzofuryl (E)-4c
2-benzofuryl (E)-4c
2-benzofuryl (E)-4c
2-thienyl (E)-4d
2-thienyl (E)-4d
4-pyridyl (E)-4e
4-pyridyl (E)-4e
4-pyridyl (E)-4e
100
500
1000 50
100
50
100
500
500
100
100
100
100
50
100
100
500
1000 50
100
100
50
50
20
>99
>99
>99
trace
99
>99
44[d]
>99
88[d]
>99
trace
91[d]
98
>99
>98
>99
>99
>99
99
>99
84[d]
>99
94 (ꢀ)
93 (ꢀ)
93 (ꢀ)
nd
90 (ꢀ)
98 (ꢀ)
97 (ꢀ)
98 (ꢀ)
98 (ꢀ)
98 (ꢀ)
nd
90 (ꢀ)
90 (ꢀ)
93 (ꢀ)
99 (ꢀ)
98 (ꢀ)
99 (ꢀ)
98 (ꢀ)
96 (ꢀ)
96 (ꢀ)
97 (ꢀ)
98 (ꢀ)
240
96 h
60
72 h
20
120
240
60
120
120
96 h
144 h
60
20
60
180
20
20
120
60
120
Experimental Section
50
1450
50
50
50
50
50
50
1450
1450
50
50
50
General Information
1H and 13C NMR spectra were recorded on a 300 and 75 MHz
FT-NMR spectrometer. Chemical shifts (d) are given in ppm
and are referenced to residual solvent peaks. HR-MS was car-
ried out on an ESI FT-ICR mass spectrometer. Melting points
determined are uncorrected. Optical rotations were recorded
on a polarimeter in a 10 cm cell. HPLC analysis was performed
9
10
11
12
13
14[e]
15
16
17
18
19
20
21
22
using a Daicel Chiralpak OD-H column. [Rh
ACHTUNGTREN(NUGN S,S)-Et-Duphos-
4-pyridyl (E)-4e
AHCTUNGTRENNUNG
cyclopropyl (E/Z)-4 f
cyclopropyl (E/Z)-4 f
cyclopropyl (E/Z)-4 f)
cyclopentyl (E/Z)-4g
cyclohexyl (E/Z)-4h
cyclohexyl (E/Z)-4h
port, USA). iPrOH was distilled from calcium hydride before
use. Ethyl acetate and petroleum ether (boiling range 60–
908C) used for column chromatography were purchased from
Shanghai Titanchem Co. Ltd (Shanghai, China).
50
50
1000 50
General Procedure for the Synthesis of 2
1-benzyl-4-piperidyl (E)-4i 100
1-benzyl-4-piperidyl (E)-4i 100
50
50
A
mixture of aldehyde
1 (20 mmol) and 1,4-diazabicyclo-
AHCTUNGTREG[NNUN 2.2.2]octane (DABCO; 2 mmol) in MeOH (40 mL) was added
[a] Catalyst=[RhACHTUNGTRENNUNG(S,S)-Et-DuphosACHUTNGTRENN(UGN cod)]BF4, iPrOH=1.5 mL, substrate=0.1 mmol,
to methyl acrylate (60 mmol). The solution was stirred at room
temperature until the reaction was complete (monitored by
TLC). The mixture was diluted with ethyl acetate (100 mL).
The organic layer was washed with water (100 mL), brine
(100 mL), dried over Na2SO4, filtered, and concentrated. Prod-
ucts were purified by column chromatography (SiO2; ethyl ace-
tate/petroleum ether 1:5).
room temperature; nd=not determined. [b] Yield of isolated product. [c] Enantiomer-
ic excesses were determined by HPLC analysis (Chiralcel OD-H). [d] The conversions
were determined by 1H NMR spectroscopy. [e] The hydrogenation was conducted in
the presence of HBF4 (1.5 equiv).
Table 4. Hydrogenation of Z-a-aminomethylacrylates and (E/Z)-4i.[a]
Methyl 2-(furan-2-ylACTHNUTRGNEUNG
(hydroxy)methyl)acrylate (2a)[12a]
Light yellow oil: 2.81 g, 77%; 1H NMR (300 MHz, CDCl3): d=7.36–7.32
(m, 1H), 6.36 (s, 1H), 6.30 (dd, J=3.2, 1.8 Hz, 1H), 6.23 (d, J=3.2 Hz,
1H), 5.93 (s, 1H), 5.57 (d, J=6.2 Hz, 1H), 3.74 (s, 3H), 3.29 ppm (d, J=
6.5 Hz, 1H).
Entry R (Substrate)
S/
C
P [psi] t [min] Yield [%][b] ee [%][c]
Methyl 2-((5-bromofuran-2-yl)ACHTUNGTRNEUNG
(hydroxy)methyl)acrylate (2b)[12b]
1
2
3
4
2-benzofuryl (Z)-4c 100 50
20
120
60
>99
30[d]
99
11 (ꢀ)
nd
2-thienyl (Z)-4d
2-thienyl (Z)-4d
100 50
100 1000
Light brown oil: 1.83 g, 35%; 1H NMR (300 MHz, CDCl3): d=6.41 (t,
J=0.7 Hz, 1H), 6.25 (d, J=3.3 Hz, 1H), 6.23 (d, J=3.3, 0.6 Hz, 1H), 5.99
(t, J=0.7 Hz, 1H), 5.53 (d, J=6.9 Hz, 1H), 3.78 (s, 3H), 3.17 ppm (d, J=
6.9, 1.0 Hz, 1H).
60 (ꢀ)
1-benzyl-4-piperidyl 100 50
(Z)-4i
1-benzyl-4-piperidyl 100 50
(Z)-4i
1-benzyl-4-piperidyl 100 1000
(Z)-4i
1-benzyl-4-piperidyl 500 1000
(Z)-4i
20
74[d]
nd
5
6
7
8
60
>99
>99
>99
>99
97 (ꢀ)
97 (ꢀ)
97 (ꢀ)
97 (ꢀ)
Methyl 2-(benzofuran-2-ylACHTNUTRGNE(UNG hydroxy)methyl)acrylate (2c)
20
Light yellow oil: 4.51 g, 97%; 1H NMR (300 MHz, CDCl3): d=7.51–7.46
(m, 1H), 7.43–7.38 (m, 1H), 7.26–7.12 (m, 2H), 6.61 (s, 1H), 6.41 (s, 1H),
6.00 (s, 1H), 5.69 (d, J=6.6 Hz, 1H), 3.71 (s, 3H), 3.69 ppm (s, 1H);
13C NMR (75 MHz, CDCl3): d=166.5, 156.9, 155.1, 139.1, 128.3, 127.8,
124.5, 123.1, 121.4, 111.6, 104.2, 68.0, 52.5 ppm; HR-MS (ESI): m/z calcd.
for C13H12O4Na+ [M+Na]+: 255.0628, found 255.0623.
36 h
120
1-benzyl-4-piperidyl 100 50
(E/Z)-4i
[a] Catalyst=[RhACHTUNGTRENNUNG(S,S)-Et-DuphosACHTUNGTNER(NUGN cod)]BF4, iPrOH=1.5 mL, substrate=
Methyl 2-(hydroxy(2-thienyl)methyl)acrylate (2d)[12c]
0.1 mmol, room temperature; nd=not determined. [b] Yield of isolated
product. [c] Enantiomeric excesses were determined by HPLC analysis
(Chiralcel OD-H). [d] The conversions were determined by 1H NMR
spectroscopy.
Light yellow oil: 3.49 g, 88%; 1H NMR (300 MHz, CDCl3): d=7.23–7.18
(m, 1H), 6.94–6.89 (m, 2H), 6.32 (s, 1H), 5.95 (s, 1H), 5.73 (d, J=5.7 Hz,
1H), 3.79 (d, J=6.0 Hz, 1H), 3.70 ppm (s, 3H).
Methyl 2-(hydroxy(pyridin-4-yl)methyl)acrylate (2e)[12d]
lectivities by catalytic asymmetric hydrogenation of the pro-
chiral substrates (up to 99% ee, S/C=1000). The relation-
ship between the nature of the substrate and catalytic be-
havior was further explored. In combination with our previ-
ous research, a general method for the synthesis of b2-amino
White solid: 3.36 g, 87%, M.p. 139–1408C; 1H NMR (300 MHz,
[D6]DMSO): d=8.48 (dd, J=4.5, 1.5 Hz, 2H), 7.29 (dd, J=4.5, 1.5 Hz,
2H), 6.24 (s, 1H), 6.07 (d, J=4.5 Hz, 1H), 6.00 (t, J=1.2 Hz, 1H), 5.44
(d, J=3.2 Hz, 1H), 3.61 ppm (s, 3H).
Chem. Asian J. 2013, 8, 2167 – 2174
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Liqin Qiu et al.
Methyl 2-(cyclopropyl
G
Methyl 2-(acetoxy(2-thienyl)methyl)acrylate (3d)[12f]
Colorless oil: 1.87 g, 60%; 1H NMR (300 MHz, CDCl3): d=6.23 (d, J=
1.0 Hz, 1H), 5.91–5.88 (m, 1H), 3.79 (s, 3H), 3.75–3.68 (m, 1H), 2.85 (d,
J=5.5 Hz, 1H), 1.21–1.07 (m, 1H), 0.68–0.40 (m, 3H), 0.33–0.23 ppm (m,
1H); 13C NMR (75 MHz, CDCl3): d=167.3, 142.1, 125.2, 75.1, 52.2, 16.6,
3.9, 3.1 ppm; HR-MS (ESI): m/z calcd. for C8H12O3Na+ [M+Na]+:
179.0679; found 179.0679.
Light yellow oil: 3.53 g, 98%; 1H NMR (300 MHz, CDCl3): d=7.27 (dd,
J=5.1, 1.2 Hz, 1H), 7.07–7.04 (m, 1H), 6.97–6.91 (m, 2H), 6.42 (s, 1H),
6.02–5.96 (m, 1H), 3.74 (s, 3H), 2.11 ppm (s, 3H).
Methyl 2-(acetoxy(pyridin-4-yl)methyl)acrylate (3e)
Brown oil: 0.18 g, 5%; 1H NMR (300 MHz, CDCl3): d=8.59 (dd, J=4.5,
1.6 Hz, 2H), 7.34–7.30 (m, 2H), 6.63 (s, 1H), 6.46–6.44 (m, 1H), 5.92 (dd,
J=1.3, 0.6 Hz, 1H), 3.73 (s, 3H), 2.15 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=169.1, 165.0, 149.9, 147.2, 138.7, 127.3, 122.2, 72.0, 52.3,
Methyl 2-(cyclopentylACHTUNGTRENNUNG(hydroxy)methyl)acrylate (2g)
Colorless oil: 2.43 g, 66%; 1H NMR (300 MHz, CDCl3): d=6.19 (s, 1H),
5.77 (s, 1H), 4.15 (t, J=7.4 Hz, 1H), 3.76 (s, 3H), 3.01 (d, J=7.1 Hz,
1H), 2.26–2.11 (m, 1H), 1.81–1.44 ppm (m, 8H); 13C NMR (75 MHz,
CDCl3): d=167.3, 142.2, 125.6, 75.9, 52.0, 45.0, 29.9, 29.0, 25.9, 25.8 ppm;
HR-MS (ESI): m/z calcd. for C10H16O3Na+ [M+Na]+: 207.0992; found
207.0999
+
21.1 ppm; HR-MS (ESI): m/z calcd. for C12H14NO4 [M+H]+: 236.0917;
found 236.0919.
Methyl 2-(acetoxy(cyclopropyl)methyl)acrylate (3 f)[12g]
Colorless oil: 2.71 g, 91%; 1H NMR (300 MHz, CDCl3): d=6.30 (d, J=
0.8 Hz, 1H), 5.89 (t, J=1.0 Hz, 1H), 5.09 (d, J=7.9 Hz, 1H), 3.77 (s,
3H), 2.08 (s, 3H), 1.26–1.12 (m, 1H), 0.60–0.53 (m, 2H), 0.49–0.37 ppm
(m, 2H).
Methyl 2-(cyclohexylACHTUNGTRENNUNG
(hydroxy)methyl)acrylate (2h)[12e]
Colorless oil: 2.58 g, 65%; 1H NMR (300 MHz, CDCl3): d=6.24 (d, J=
1.3 Hz, 1H), 5.74 (t, J=1.1 Hz, 1H), 4.09 (d, J=6.9 Hz, 1H), 3.77 (s,
3H), 2.80 (brs, 1H), 1.77–1.52 (m, 5H), 1.30–0.89 ppm (m, 6H).
Methyl 2-(acetoxy(cyclopentyl)methyl)acrylate (3g)
Colorless oil: 3.09 g, 91%; 1H NMR (300 MHz, CDCl3): d=6.26 (d, J=
1.0 Hz, 1H), 5.76 (t, J=1.0 Hz, 1H), 5.52 (d, J=7.0 Hz, 1H), 3.77 (s,
3H), 2.36–2.22 (m, 1H), 2.06 (s, 3H), 1.68–1.25 ppm (m, 8H); 13C NMR
(75 MHz, CDCl3): d=170.1, 166.0, 140.3, 125.9, 74.9, 52.2, 43.6, 29.1, 28.5,
25.8, 25.5, 21.3 ppm; HR-MS (ESI): m/z calcd. for C12H18O4Na+
[M+Na]+: 249.1097; found 249.1099.
Methyl 2-((1-benzylpiperidin-4-yl)ACTHNUGTRNEUNG(hydroxy)methyl)acrylate (2i)
Light yellow oil: 2.49 g, 43%; 1H NMR (300 MHz, CDCl3): d=7.32–7.20
(m, 5H), 6.25 (s, 1H), 5.73 (s, 1H), 4.06 (d, J=7.7 Hz, 1H), 3.77 (s, 3H),
3.49 (s, 2H), 2.99–2.83 (m, 2H), 1.92 (dt, J=5.9, 3.6 Hz, 3H), 1.67–1.53
(m, 1H), 1.48–1.22 ppm (m, 4H); 13C NMR (75 MHz, CDCl3): d=167.2,
141.2, 138.3, 129.5, 128.3, 127.1, 126.7, 76.3, 63.6, 53.8, 53.7, 52.2, 41.1,
Methyl 2-(acetoxy(cyclohexyl)methyl)acrylate (3h)[12h]
+
29.3, 28.2 ppm; HR-MS (ESI): m/z calcd. for C17H24NO3 [M+H]+:
Colorless oil: 3.35 g, 93%; 1H NMR (300 MHz, CDCl3): d=6.30 (s, 1H),
5.70 (s, 1H), 5.44 (d, J=5.8 Hz, 1H), 3.77 (s, 3H), 2.07 (s, 3H), 1.78–1.58
(m, 6H), 1.25–0.97 ppm (m, 5H).
290.1751; found 290.1752.
General Procedure for the Synthesis of 3
Acetic anhydride (18 mmol) was added dropwise into a mixture of 2
(15 mmol) and 4-dimethylaminopyridine (DMAP; 1.5 mmol) in toluene
(20 mL) over 30 min at 0–58C. The resulting solution was allowed to
warm to room temperature in 1 h. After stirring for 1 h at room tempera-
ture, the reaction mixture was cooled to 0–58C, and 1n HCl (5 mL) was
added over 20 min. The organic layer was separated and washed sequen-
tially with water, saturated aqueous sodium bicarbonate, and water. The
organic layer was concentrated to afford 3 as a colorless liquid. Products
were purified by column chromatography (SiO2; ethyl acetate/petroleum
ether 1:5).
Methyl 2-(acetoxy(1-benzylpiperidin-4-yl)methyl)acrylate (3i)
Light yellow oil: 4.47 g, 90%; 1H NMR (300 MHz, CDCl3): d=7.29–7.16
(m, 5H), 6.29 (d, J=1.0 Hz, 1H), 5.69 (d, J=1.0 Hz, 1H), 5.49 (d, J=
5.4 Hz, 1H), 3.74 (s, 3H), 3.46 (s, 2H), 2.93–2.83 (m, 2H), 2.05 (s, 3H),
1.97–1.81 (m, 2H), 1.69–1.35 ppm (m, 5H); 13C NMR (75 MHz, CDCl3):
d=170.0, 165.8, 138.9, 138.5, 129.3, 128.3, 127.1, 126.4, 75.1, 63.5, 53.8,
53.7, 52.3, 39.6, 28.9, 27.3, 21.3 ppm; HR-MS (ESI): m/z calcd. for
+
C19H26NO4 [M+H]+: 332.1856; found 332.1854.
General Procedure for the Synthesis of 4
Methyl 2-(acetoxy(furan-2-yl)methyl)acrylate (3a)[12f]
A mixture of 3 (14.5 mmol), Na2CO3 (43.5 mmol), and O-benzylhydroxyl-
amine hydrochloride (43.5 mmol) in THF (20 mL) was allowed to stir at
room temperature under N2 until the reaction was complete (as moni-
tored by TLC). The reaction mixture was concentrated under reduced
pressure. The residue was dissolved in ethyl acetate (50 mL) and washed
with saturated aqueous sodium bicarbonate (25 mL). The ethyl acetate
layer was concentrated to afford a colorless liquid. The crude material
was purified by column chromatography (SiO2; acetone/petroleum ether
1:20) to afford 4 (E-isomer, Z-isomer, and an E/Z-isomeric mixture).
Light yellow oil: 3.09 g, 92%; 1H NMR (300 MHz, CDCl3): d=7.39–7.36
(m, 1H), 6.75–6.71 (m, 1H), 6.45 (s, 1H), 6.34–6.29 (m, 2H), 6.00–5.97
(m, 1H), 3.72 (s, 3H), 2.10 ppm (s, 3H).
Methyl 2-(acetoxy(5-bromofuran-2-yl)methyl)acrylate (3b)
Light brown oil: 4.14 g, 91%; 1H NMR (300 MHz, CDCl3): d=6.61 (s,
1H), 6.42 (d, J=0.5 Hz, 1H), 6.25 (d, J=3.3 Hz, 1H), 6.20 (d, J=3.3 Hz,
1H), 5.98–5.96 (m, 1H), 3.69 (s, 3H), 2.06 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=169.2, 164.9, 152.4, 136.5, 127.3, 122.9, 112.7, 66.0,
52.4, 21.2 ppm; HR-MS (ESI): m/z calcd. for C11H11BrO5Na+ [M+Na]+:
324.9682; found 324.9690.
AHCTUNGTERG(NNUN E/Z)-Methyl 2-((benzyloxyamino)methyl)-3-(furan-2-yl)acrylate ((E/Z)-
4a)
Light yellow oil: 3.29 g, 79%, E/Z=5:1; 1H NMR (300 MHz, CDCl3):
d=7.50 (s, 0.83ꢂ1H), 7.49 (s, 0.83ꢂ1H), 7.40 (d, J=1.7 Hz, 0.17ꢂ1H),
7.36–7.19 (m, 5H), 7.00 (d, J=3.5 Hz, 0.17ꢂ1H), 6.68 (s, 0.17ꢂ1H), 6.64
(d, J=3.5 Hz, 0.83ꢂ1H), 6.45 (dd, J=3.5, 1.8 Hz, 0.83ꢂ1H), 6.42 (dd,
J=3.5, 1.8 Hz, 0.17ꢂ1H), 6.04 (brs, 1H), 4.71 (s, 0.83ꢂ2H), 4.69 (s,
0.17ꢂ2H), 4.23 (s, 0.83ꢂ2H), 3.78 (s, 0.17ꢂ3H), 3.77 (s, 0.83ꢂ3H),
3.76 ppm (s, 0.17ꢂ2H); 13C NMR (75 MHz, CDCl3): d=168.4, 168.0,
151.1, 150.4, 145.2, 143.8, 138.2, 138.1, 129.0, 128.7, 128.0, 127.9, 126.9,
125.0, 124.3, 117.3, 114.7, 112.5, 112.4, 76.4, 75.9, 56.7, 52.4, 52.0,
Methyl 2-(acetoxy(benzofuran-2-yl)methyl)acrylate (3c)
Light yellow oil: 4.03 g, 98%; 1H NMR (300 MHz, CDCl3): d=7.49 (d,
J=7.5 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.19 (dt, J=14.7, 7.1 Hz, 2H),
6.89 (s, 1H), 6.70 (s, 1H), 6.51 (s, 1H), 6.06 (s, 1H), 3.69 (s, 3H),
2.10 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=169.3, 165.1, 155.3,
153.1, 136.8, 127.9, 127.7, 125.1, 123.2, 121.6, 111.7, 106.7, 66.8, 52.5,
21.2 ppm; HR-MS (ESI): m/z calcd. for C15H14O5Na+ [M+Na]+:
297.0733; found 297.0739.
+
48.6 ppm; HR-MS (ESI): m/z calcd. for C16H18NO4 [M+H]+: 288.1230;
found 288.1237.
Chem. Asian J. 2013, 8, 2167 – 2174
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Liqin Qiu et al.
A
128.4, 127.9, 127.9, 125.0, 124.7, 76.2, 76.1, 56.1, 51.9, 51.6, 48.3, 12.8, 12.2,
9.4, 9.4 ppm; HR-MS (ESI): m/z calcd. for C15H19NO3Na+ [M+Na]+:
284.1257; found 284.1268.
((E/Z)-4b)
Light yellow oil: 4.83 g, 91%, E/Z=10:3; 1H NMR (300 MHz, CDCl3,):
d=7.39 (s, 0.77ꢂ1H), 7.33–7.19 (m, 5H), 7.00 (d, J=3.5 Hz, 0.23ꢂ1H),
6.60 (s, 0.23ꢂ1H), 6.55 (d, J=3.5 Hz, 0.77ꢂ1H), 6.37 (d, J=3.5 Hz,
0.77ꢂ1H), 6.34 (d, J=3.5 Hz, 0.23ꢂ1H), 5.92 (brs, 1H), 4.72 (s, 0.77ꢂ
2H), 4.67 (s, 0.23ꢂ2H), 4.17 (s, 0.77ꢂ2H), 3.77 (s, 0.23ꢂ3H), 3.75 (s,
0.77ꢂ3H), 3.74 ppm (d, J=0.9 Hz, 0.23ꢂ2H); 13C NMR (75 MHz,
CDCl3): d=168.1, 167.6, 152.9, 152.5, 138.2, 138.0, 128.7, 128.5, 128.0,
127.9, 126.0, 125.7, 125.4, 124.8, 119.2, 117.2, 114.4, 114.2, 76.4, 75.9, 56.4,
AHCTUNGTERG(NNUN E/Z)-Methyl 2-(((benzyloxy)amino)methyl)-3-cyclopentylacrylate ((E/Z)-
4g)
Light yellow oil: 3.44 g, 82%, E/Z=7:10; 1H NMR (300 MHz, CDCl3):
d=7.39–7.26 (m, 5H), 6.84 (d, J=10.2 Hz, 0.41ꢂ1H), 6.03 (d, J=9.8 Hz,
0.59ꢂ1H), 5.86 (s, 1H), 4.68 (s, 0.41ꢂ2H), 4.68 (s, 0.59ꢂ2H), 3.75 (s,
0.41ꢂ2H), 3.73 (s, 0.59ꢂ3H), 3.73 (s, 0.41ꢂ3H), 3.66 (s, 0.59ꢂ2H), 3.43–
3.28 (m, 0.59ꢂ1H), 2.82–2.67 (m, 0.41ꢂ1H), 1.88–1.30 ppm (m, 8H);
13C NMR (75 MHz, CDCl3): d=168.0, 167.9, 152.5, 138.2, 138.1, 128.7,
128.5, 128.4, 127.9, 126.2, 125.9, 76.2, 56.3, 52.0, 51.6, 48.2, 40.3, 39.7, 34.0,
52.5, 52.1, 48.5 ppm; HR-MS (ESI): m/z calcd. for C16H17BrNO4
[M+H]+: 366.0335; found 366.0336.
+
33.8, 25.9 ppm; HR-MS (ESI): m/z calcd. for C17H24NO3 [M+H]+:
(E)-Methyl 3-(benzofuran-2-yl)-2-(((benzyloxy)amino)methyl) acrylate
290.1751; found 290.1757.
((E)-4c)
White solid: 3.62 g, 74%, M.p. 59–608C; 1H NMR (300 MHz, CDCl3):
d=7.61 (s, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.33 (t,
J=7.6 Hz, 1H), 7.28–7.16 (m, 6H), 6.96 (s, 1H), 6.03 (brs, 1H), 4.74 (s,
2H), 4.39 (s, 2H), 3.80 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=
168.2, 155.9, 152.6, 138.1, 129.2, 128.5, 128.5, 128.1, 127.9, 127.7, 126.7,
123.7, 122.0, 113.6, 111.8, 75.9, 52.7, 48.6 ppm; HR-MS (ESI): m/z calcd.
for C20H19NO4Na+ [M+Na]+: 360.1206; found 360.1200.
AHCTUNGTERG(NNUN E/Z)-Methyl 2-(((benzyloxy)amino)methyl)-3-cyclohexylacrylate ((E/Z)-
4h)
Light yellow oil: 4.00 g, 91%, E/Z=3:5; 1H NMR (300 MHz, CDCl3):
d=7.25–7.13 (m, 5H), 6.65 (d, J=10.2 Hz, 0.37ꢂ1H), 5.84 (d, J=9.7 Hz,
0.63ꢂ1H), 5.52 (s, 1H), 4.58 (s, 0.37ꢂ2H), 4.57 (s, 0.63ꢂ2H), 3.63 (s,
0.37ꢂ2H), 3.62 (s, 0.63ꢂ3H), 3.60 (s, 0.37ꢂ3H), 3.54 (s, 0.63ꢂ2H), 2.93–
2.78 (m, 0.63ꢂ1H), 2.35–2.20 (m, 0.37ꢂ1H), 1.64–0.95 ppm (m, 10H);
13C NMR (75 MHz, CDCl3): d=168.2, 167.7, 152.8, 152.6, 152.5, 138.1,
138.1, 128.7, 128.5, 127.9, 125.8, 125.6, 76.4, 76.2, 76.1, 56.3, 52.0, 51.7,
48.2, 38.5, 38.0, 32.9, 32.5, 26.3, 26.1, 25.9, 25.8 ppm; HR-MS (ESI): m/z
(Z)-Methyl 3-(benzofuran-2-yl)-2-(((benzyloxy)amino)methyl) acrylate
((Z)-4c)
Light yellow oil: 0.59 g, 12%; 1H NMR (300 MHz, CDCl3): d=7.57–7.51
(m, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.34–7.24 (m, 6H), 7.22–7.15 (m, 1H),
7.13 (s, 1H), 6.71 (s, 1H), 5.79 (brs, 1H), 4.71 (s, 2H), 3.85 (s, 3H),
3.83 ppm (s, 2H); 13C NMR (75 MHz, CDCl3): d=168.5, 155.1, 151.7,
137.9, 130.0, 128.7, 128.6, 128.1, 125.8, 124.9, 123.3, 121.9, 111.3, 109.8,
76.6, 56.7, 52.3 ppm; HR-MS (ESI): m/z calcd. for C20H19NO4Na+
[M+Na]+: 360.1206; found 360.1214.
+
calcd. for C18H26NO3 [M+H]+: 304.1907; found 304.1906.
(E)-Methyl 2-(((benzyloxy)amino)methyl)-3-(1-benzylpiperidin-4-
yl)acrylate ((E)-4i)
Light yellow oil: 1.89 g, 33%; 1H NMR (300 MHz, CDCl3): d=7.35–7.28
(m, 10H), 6.78 (d, J=10.1 Hz, 1H), 5.90 (brs, 1H), 4.68 (s, 2H), 3.74 (s,
2H), 3.74 (s, 3H), 3.53 (s, 2H), 2.92–2.83 (m, 2H), 2.43–2.33 (m, 1H),
1.99 (td, J=11.3, 3.4 Hz, 2H), 1.59–1.47 ppm (m, 4H); 13C NMR
(75 MHz, CDCl3): d=168.0, 151.2, 138.4, 138.2, 129.4, 128.7, 128.5, 128.4,
128.0, 127.2, 126.6, 76.3, 63.8, 53.2, 52.1, 48.3, 36.2, 31.8 ppm; HR-MS
(E)-Methyl 2-((benzyloxyamino)methyl)-3-(2-thienyl) acrylate ((E)-4d)
Light yellow oil: 3.08 g, 70%; 1H NMR (300 MHz, CDCl3): d=7.93 (s,
1H), 7.47 (d, J=5.1 Hz, 1H), 7.35–7.24 (m, 6H), 7.06 (dd, J=5.1, 3.7 Hz,
1H), 5.98 (brs, 1H), 4.75 (s, 2H), 4.17 (s, 2H), 3.79 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=168.3, 138.2, 137.7, 136.0, 133.6, 130.4,
128.7, 128.5, 127.9, 127.8, 124.0, 76.3, 52.5, 49.2 ppm; HR-MS (ESI): m/z
calcd. for C16H17NO3SNa+ [M+Na]+: 326.0821; found 326.0829.
+
(ESI): m/z calcd. for C24H31N2O3 [M+H]+: 395.2329; found 395.2339.
(Z)-Methyl 2-(((benzyloxy)amino)methyl)-3-(1-benzylpiperidin-4-
yl)acrylate ((Z)-4i)
Light yellow oil: 3.60 g, 63%; 1H NMR (300 MHz, CDCl3): d=7.38–7.23
(m, 10H), 5.97 (d, J=9.6 Hz, 1H), 5.81 (brs, 1H), 4.68 (s, 2H), 3.74 (s,
3H), 3.66 (s, 2H), 3.52 (s, 2H), 3.05–2.95 (m, 1H), 2.91 (d, J=11.7 Hz,
2H), 2.06 (td, J=11.6, 2.3 Hz, 2H), 1.78–1.68 (m, 2H), 1.48 ppm (ddd,
J=15.6, 12.3, 3.7 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=167.6, 151.3,
138.5, 138.1, 129.4, 128.5, 128.5, 128.4, 128.0, 127.2, 126.9, 76.3, 63.8, 56.2,
(Z)-Methyl 2-((benzyloxyamino)methyl)-3-(2-thienyl) acrylate ((Z)-4d)
Light yellow oil: 0.84 g, 19%; 1H NMR (300 MHz, CDCl3): d=7.45 (d,
J=5.1 Hz, 1H), 7.37–7.28 (m, 6H), 7.10 (s, 1H), 7.04 (dd, J=5.1, 3.7 Hz,
1H), 5.88 (brs, 1H), 4.73 (s, 2H), 3.83 (s, 3H), 3.83 ppm (s, 2H);
13C NMR (75 MHz, CDCl3): d=167.7, 138.1, 137.8, 134.8, 134.6, 130.8,
128.7, 128.6, 128.0, 126.7, 123.2, 76.4, 57.0, 52.0 ppm; HR-MS (ESI): m/z
calcd. for C16H17NO3SNa+ [M+Na]+: 326.0821; found 326.0827.
+
53.4, 51.7, 36.7, 32.1 ppm; HR-MS (ESI): m/z calcd. for C24H31N2O3
[M+H]+: 395.2329; found 395.2341.
General Procedure for Asymmetric Hydrogenation
(E)-Methyl 2-((benzyloxyamino)methyl)-3-(pyridin-4-yl)acrylate ((E)-4e)
This compound was directly prepared from compound 2e through a one-
The catalyst was added to a solution of the substrate and degassed sol-
vent in a glass-lined stainless steel autoclave under a nitrogen atmos-
phere. After purging three times with H2, the autoclave was pressurized
to the desired pressure with H2. The solution was stirred well at the given
temperature for the time specified in Table 3 or Table 4. After releasing
the hydrogen pressure, the reaction mixture was concentrated. The resi-
due was filtered through a short SiO2 column with ethyl acetate/petrole-
um ether (1:1) to remove the catalyst. The filtrate was concentrated. The
1
pot synthesis. Light yellow oil: 1.30 g, 30%; H NMR (300 MHz, CDCl3):
d=8.51 (dd, J=4.5, 1.5 Hz, 2H), 7.67 (s, 1H), 7.30–7.21 (m, 7H), 5.72
(brs, 1H), 4.63 (s, 2H), 3.81 (s, 2H), 3.76 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=167.5, 150.1, 142.5, 140.6, 138.0, 131.5, 128.6, 128.5,
128.1, 123.7, 76.3, 52.7, 48.8 ppm; HR-MS (ESI): m/z calcd. for
+
C17H19N2O3 [M+H]+: 299.1390; found 299.1396.
1
conversion of the reaction was determined by H NMR spectroscopy and
HPLC. The enantiomeric excess was determined by chiral HPLC.
ACHTUNGTRENNUNG(E/Z)-Methyl 2-(((benzyloxy)amino)methyl)-3-cyclopropylacrylate ((E/
Z)-4 f)
Methyl 3-((benzyloxy)amino)-2-(furan-2-ylmethyl) propanoate (5a)
Light yellow oil: 2.39 g, 63%, E/Z=10:9; 1H NMR (300 MHz, CDCl3):
d=7.38–7.18 (m, 5H), 6.27 (d, J=10.8 Hz, 0.53ꢂ1H), 5.90 (s, 1H), 5.39
(d, J=10.8 Hz, 0.47ꢂ1H), 4.69 (s, 0.53ꢂ2H), 4.65 (s, 0.47ꢂ2H), 3.84 (s,
0.53ꢂ2H), 3.73 (s, 0.47ꢂ3H), 3.68 (s, 0.53ꢂ3H), 3.61 (s, 0.47ꢂ2H), 2.67–
2.53 (m, 0.47ꢂ1H), 1.72–1.58 (m, 0.53ꢂ1H), 0.99–0.88 (m, 2H), 0.65–
0.59 (m, 0.53ꢂ2H), 0.56–0.49 ppm (m, 0.47ꢂ2H); 13C NMR (75 MHz,
CDCl3): d=168.0, 167.7, 153.9, 152.9, 138.2, 138.2, 128.7, 128.5, 128.5,
Light yellow oil: 28.6 mg, 99%; ee=94%; ½aꢁ2D0 =ꢀ9.0 (c=1.0, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.23–7.18 (m, 6H), 6.15 (dd, J=3.1,
1.9 Hz, 1H), 5.92 (dd, J=3.2, 0.7 Hz, 1H), 4.56 (s, 2H), 3.54 (s, 3H),
3.06–2.81 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d=174.7, 152.8,
141.7, 137.9, 128.6, 128.5, 128.0, 110.4, 106.8, 76.5, 53.3, 52.1, 43.2,
+
28.7 ppm; HR-MS (ESI): m/z=290.1376, calcd. for C16H20NO4
Chem. Asian J. 2013, 8, 2167 – 2174
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Liqin Qiu et al.
[M+H]+; found 290.1387. The enantiomeric excess was determined by
HPLC (Daicel Chiralpak OD-H, iPrOH/n-hexane=4:96, UV 220 nm,
(d, J=1.2 Hz, 2H), 3.64 (s, 3H), 3.06 (ddd, J=17.4, 13.0, 6.9 Hz, 2H),
2.78 (ddd, J=14.4, 9.3, 5.0 Hz, 1H), 1.78–1.43 (m, 9H), 1.13–0.98 ppm
(m, 2H); 13C NMR (75 MHz, CDCl3): d=176.2, 138.0, 128.6, 128.5, 128.0,
76.5, 54.6, 51.8, 43.8, 38.5, 37.1, 33.2, 32.9, 25.4 ppm; HR-MS (ESI): m/z
flow rate 0.3 mLminꢀ1): t
rACHTNUGTRENNUG(minor)=35.9 min, trACHTUNGTREN(NGUN major)=33.7 min.
Methyl 3-((benzyloxy)amino)-2-((5-bromofuran-2-yl)methyl) propanoate
(5b)
+
calcd. for C17H26NO3 [M+H]+: 292.1907; found 292.1904. The enantio-
meric excess was determined by HPLC (Daicel Chiralpak OD-H, iPrOH/
n-hexane=4:96, UV 220 nm, flow rate 0.3 mLminꢀ1):
trACHTUNGTRENNUNG(minor)=
Light yellow oil: 26.3 mg, 99%; ee=90%; ½aꢁ2D0 =ꢀ3.5 (c=3.4, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.36–7.26 (m, 5H), 6.16 (d, J=3.2 Hz,
1H), 6.00 (d, J=3.2 Hz, 1H), 5.73 (brs, 1H), 4.66 (s, 2H), 3.66 (s, 3H),
3.16–2.86 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d=174.4, 155.0,
137.8, 128.7, 128.6, 128.1, 120.2, 112.0, 109.7, 76.5, 53.2, 52.2, 43.0,
28.9 ppm; HR-MS (ESI): m/z calcd. for C16H18BrNO4Na+ [M+Na]+:
390.031; found 390.0327. The enantiomeric excess was determined by
HPLC (Daicel Chiralpak OD-H, iPrOH/n-hexane=4:96, UV 220 nm,
24.2 min, trACTHNUTRGNE(NUG major)=21.6 min.
Methyl 3-((benzyloxy)amino)-2-(cyclohexylmethyl) propanoate (5h)
Light yellow oil: 30.2 mg, 99%; ee=96%; ½aꢁ2D0 =ꢀ9.0 (c=1.0, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.40–7.24 (m, 5H), 5.67 (brs, 1H), 4.66
(d, J=1.3 Hz, 2H), 3.65 (s, 3H), 3.04 (ddd, J=17.3, 12.9, 6.8 Hz, 2H),
2.91–2.79 (m, 1H), 1.77–1.55 (m, 6H), 1.32–1.15 (m, 5H), 0.92–0.80 ppm
(m, 2H); 13C NMR (75 MHz, CDCl3): d=176.4, 137.9, 128.7, 128.5, 128.0,
76.6, 54.7, 51.9, 41.7, 38.4, 35.8, 33.8, 33.3, 26.9, 26.6 ppm; HR-MS (ESI):
flow rate 0.3 mLminꢀ1): t
rACHTNUGTRENNUG(minor)=41.7 min, trACHTUNGTREN(NGUN major)=37.6 min.
m/z calcd. for C18H28NO3 [M+H]+: 306.2064; found 306.2060. The enan-
Methyl 3-(benzofuran-2-yl)-2-(((benzyloxy)amino)methyl) propanoate
(5c)
+
tiomeric excess was determined by HPLC (Daicel Chiralpak OD-H,
iPrOH/n-hexane;=4:96, UV 220 nm, flow rate 0.3 mLminꢀ1): t
rACHTUNGTRENNUNG(minor)=
Light yellow oil: 33.6 mg, 99%; ee=98% via (E)-4c, ee=11% via (Z)-
4c; ½aꢁ2D0 =ꢀ2.0 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.47–
7.42 (m, 1H), 7.40–7.35 (m, 1H), 7.31–7.21 (m, 5H), 7.21–7.11 (m, 2H),
6.40 (s, 1H), 5.65 (brs, 1H), 4.65 (s, 2H), 3.64 (s, 3H), 3.22–2.95 ppm (m,
5H); 13C NMR (75 MHz, CDCl3): d=174.5, 156.0, 154.9, 137.8, 128.9,
128.7, 128.6, 128.1, 123.8, 122.8, 120.7, 111.1, 103.9, 76.6, 53.4, 52.2, 42.8,
22.7 min, trACTHNUTRGNE(NUG major)=19.8 min.
Methyl 3-((benzyloxy)amino)-2-((1-benzylpiperidin-4-yl)methyl)
propanoate (5i)
Light yellow oil: 39.3 mg, 99%; ee=98% via (E)-4i, ee=97% via (Z)-
4i; ½aꢁ2D0 =ꢀ4.0 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.32–
7.20 (m, 10H), 5.65 (brs, 1H), 4.64 (d, J=1.0 Hz, 2H), 3.64 (s, 3H), 3.46
(s, 2H), 3.03 (ddd, J=17.5, 13.0, 6.8 Hz, 2H), 2.89–2.79 (m, 3H), 1.91 (td,
J=11.2, 2.8 Hz, 2H), 1.75–1.67 (m, 1H), 1.63–1.53 (m, 2H), 1.32–
1.19 ppm (m, 4H); 13C NMR (75 MHz, CDCl3): d=176.0, 138.6, 137.9,
129.4, 128.6, 128.5, 128.3, 128.0, 127.1, 76.6, 63.7, 54.7, 54.0, 51.9, 41.8,
+
29.2 ppm; HR-MS (ESI): m/z calcd. for C20H22NO4 [M+H]+: 340.1543;
found 340.1549. The enantiomeric excess was determined by HPLC
(Daicel Chiralpak OD-H, iPrOH/n-hexane=30:70, UV 220 nm, flow rate
0.3 mLminꢀ1): t
rACHTUNGTRENNUNG(minor)=13.5 min, trACHTUNGTREN(NGUN major)=10.3 min.
Methyl 3-((benzyloxy)amino)-2-((2-thienyl)methyl) propanoate (5d)
+
37.5, 34.1, 32.9, 32.3 ppm; HR-MS (ESI): m/z calcd. for C24H33N2O3
Light yellow oil: 30.2 mg, 99%; ee=98% via (E)-4d, ee=60% via (Z)-
4d; ½aꢁ2D0 =ꢀ6.0 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.35–
7.25 (m, 5H), 7.11 (dd, J=5.1, 1.2 Hz, 1H), 6.88 (dd, J=5.1, 3.4 Hz, 1H),
6.77 (dd, J=3.4, 1.0 Hz, 1H), 4.65 (s, 2H), 3.64 (s, 3H), 3.19–3.03 ppm
(m, 5H); 13C NMR (75 MHz, CDCl3): d=174.6, 141.1, 137.8, 128.7, 128.6,
128.1, 127.1, 126.0, 124.2, 76.5, 53.2, 52.1, 46.1, 30.4 ppm; HR-MS (ESI):
m/z calcd. for C16H19NO3SNa+ [M+Na]+: 328.0978; found 328.0982. The
enantiomeric excess was determined by HPLC (Daicel Chiralpak OD-H,
[M+H]+: 397.2486; found 397.2479. The enantiomeric excess was deter-
mined by HPLC (Daicel Chiralpak OD-H, iPrOH/n-hexane=30:70, UV
220 nm, flow rate 0.3 mLminꢀ1):
20.4 min.
t
N
trACHTUNGTRENNUNG(major)=
iPrOH/n-hexane=4:96, UV 220 nm, flow rate 0.3 mLminꢀ1): t
37.0 min, trA(major)=34.8 min.
rACHTUNGTRE(NNUG minor)=
Acknowledgements
CHTUNGTRENNUNG
Methyl 3-((benzyloxy)amino)-2-(pyridin-4-ylmethyl) propanoate (5e)
We would like to thank the National Natural Science Foundation of
China (No. 20842005, J1103305) and College Studentsꢁ Innovative Ex-
periment Projects of Guangdong Province for financial support.
Light yellow oil: 29.7 mg, 99%; ee=93% via (E)-4e; ½aꢁ2D0 =ꢀ6.0 (c=1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): d=8.47 (d, J=5.5 Hz, 2H), 7.36–
7.26 (m, 5H), 7.07 (dd, J=4.6, 1.3 Hz, 2H), 5.71 (s, 1H), 4.65 (d, J=
1.5 Hz, 2H), 3.59 (s, 3H), 3.18–2.81 ppm (m, 5H); 13C NMR (75 MHz,
CDCl3): d=174.5, 150.0, 148.1, 137.7, 128.7, 128.6, 128.1, 124.5, 124.4,
76.6, 53.5, 52.2, 45.0, 35.6 ppm; HR-MS (ESI): m/z calcd. for
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+
C17H21N2O3 [M+H]+: 301.1547; found 301.1553. The enantiomeric
´
[3] B. Weiner, W. Szymanski, D. B. Janssen, A. J. Minnaarda, B. L. Fer-
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hexane=20:80, UV 220 nm, flow rate 1.0 mLminꢀ1): t
rACTHNUTRGNE(NUG minor)=16.8 min,
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Methyl 3-((benzyloxy)amino)-2-(cyclopropylmethyl) propanoate (5 f)
Light yellow oil: 26.1 mg, 99%; ee=99%; ½aꢁ2D0 =ꢀ13.0 (c=1.0, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.37–7.26 (m, 5H), 5.71 (brs, 1H), 4.69
(d, J=1.2 Hz, 2H), 3.68 (s, 3H), 3.15 (ddd, J=17.6, 13.0, 6.9 Hz, 2H),
2.95–2.83 (m, 1H), 1.50 (t, J=7.0 Hz, 2H), 0.77–0.61 (m, 1H), 0.51–0.42
(m, 2H), 0.09–0.02 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=175.9,
137.9, 128.6, 128.5, 128.0, 76.5, 53.9, 51.9, 44.6, 35.7, 9.3, 4.9 ppm; HR-MS
+
(ESI): m/z calcd. for C15H22NO3 [M+H]+: 264.1594; found 264.1589.
The enantiomeric excess was determined by HPLC (Daicel Chiralpak
OD-H, iPrOH/n-hexane=4:96, UV 220 nm, flow rate 0.3 mLminꢀ1): tr-
ACHTUNGTRENNUNG(minor)=26.4 min, trACHTUNGTRENNUNG(major)=23.6 min.
Methyl 3-((benzyloxy)amino)-2-(cyclopentylmethyl) propanoate (5g)
Light yellow oil: 28.8 mg, 99%; ee=98%; ½aꢁ2D0 =ꢀ6.0 (c=1.0, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.34–7.22 (m, 5H), 5.67 (brs, 1H), 4.65
ˇ ˇ
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Received: March 14, 2013
Published online: June 17, 2013
Chem. Asian J. 2013, 8, 2167 – 2174
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim