Practical syntheses of N-acetyl (E)-β-arylenamides

Article abstract of DOI:10.1055/s-0033-1339976

A facile and practical method for the preparation of (E)-β- arylenamides [(E)-N-(1-arylprop-1-en-2-yl]acetamides] has been developed by reductive acetylation of the corresponding oximes with iron(II) acetate as the reducing reagent. Employment of hexamethylphosphoramide as the solvent was found to be critical for the high E/Z selectivity. The methodology has been applied in efficient syntheses of a key chiral intermediate of tamsulosin by asymmetric hydrogenation. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0033-1339976

PAPER
▌3355
paper
Practical Syntheses of N-Acetyl (E)-β-Arylenamides
Practical Syntheses of N-Acetyl (E)-β-Arylenamides
Zhihua Cai,a Guodu Liu,a Guangjun Jiao,a Chris H. Senanayake,b Wenjun Tang*a
a
State Key Laboratory of Biorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
E-mail: tangwenjun@sioc.ac.cn
b
Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT 06877, USA
Received: 20.08.2013; Accepted after revision: 21.09.2013
ent hydrogenation properties of (E)- and (Z)-β-arylen-
amides, it is imperative to access geometrically pure β-
arylenamides for asymmetric hydrogenation. Unfortu-
nately, there remains lack of methods for the practical
Abstract: A facile and practical method for the preparation of (E)-
β-arylenamides [(E)-N-(1-arylprop-1-en-2-yl]acetamides] has been
developed by reductive acetylation of the corresponding oximes
with iron(II) acetate as the reducing reagent. Employment of hexa-
methylphosphoramide as the solvent was found to be critical for the synthesis of geometrically pure β-arylenamides, which
high E/Z selectivity. The methodology has been applied in efficient
syntheses of a key chiral intermediate of tamsulosin by asymmetric
hydrogenation.
has hampered the syntheses of chiral β-arylamines by
asymmetric hydrogenation. Herein, we report a facile and
practical method for the synthesis of (E)-β-arylenamides
by reductive acylation of ketoximes mediated by iron(II)
Key words: β-arylenamides, iron(II) acetate, reductive acylation,
β-arylamines, tamsulosin
acetate.
A number of methods have been reported for the synthe-
ses of β-arylenamides including: (1) the reduction of nitro
Chiral β-arylamines exist in numerous biologically inter-
alkenes;8 (2) the direct condensation of a ketone with an
esting natural products and therapeutic agents.1 For exam-
amide;5,9 (3) Beckmann rearrangement of ketoximes;6,10
ples, such moieties commonly exist in a series of
and (4) the palladium-catalyzed cross coupling between
naphthylisoquinoline alkaloids2 such as michellamine B
vinyl triflates and amides.11 Unfortunately, most of them
and korupensamine A. They also serve as pivotal structur-
suffered from low yields or E/Z selectivities (Scheme 1).
al units for many active pharmaceutical ingredients such
The palladium-catalyzed cross-coupling method is less
as MDA,3a tamsulosin,3b selegiline,3c arformoterol,3d roti-
cost effective, albeit providing high E/Z selectivities.11
gotine,3e and silodosin3f (Figure 1). The development of
Thus, the development of a facile and practical synthesis
efficient asymmetric methods for the synthesis of chiral β-
of N-acetyl (E)- or (Z)-β-arylenamides remains a signifi-
arylamines by asymmetric hydrogenation of N-acetyl (E)-
cant challenge. Reductive acylation of ketoximes have
or (Z)-β-arylenamides has gained significant interest.4 Re-
been frequently applied in the synthesis of α-arylen-
cent work led by Zhang,5 Zhou,6 and our group7 have
amides.8,12 However, this method has not been successful-
shown excellent enantioselectivities in the hydrogenation
ly employed for stereoselective synthesis of β-
of N-acetyl (E)- or (Z)-β-arylenamides. Due to the differ-
arylenamides. We herein report the reductive acylation of
OH
OMe
H
N
H
O
O
O
NH2
O
O
N
H
S
NH
O
NH2
O
(S)-MDA
psychedelic
tamsulosin
alpha blocker
MeO
arformoterol
COPD
O
H
N
Me
N
N
H2N
O
O
CF3
S
N
selegiline
MAO-B inhibitor
OH
OH
rotigotine
dopamine agonist
silodosin
α1-adrenoceptor antagonist
Figure 1 Several therapeutic agents containing chiral β-arylamine moieties
SYNTHESIS 2013, 45, 3355–3360
Advanced online publication: 14.10.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339976; Art ID: SS-2013-H0581-OP
© Georg Thieme Verlag Stuttgart · New York

3356
Z. Cai et al.
PAPER
reported methods
NO2
NHAc
Fe, AcOH
Ac2O
E/Z ratio: <3:1
a.
b.
R
R
R
O
AcNH2
Cl
Z/E ratio: <2.8:1
NHAc
R
N
N
NOH
Cl
N
Cl
NHAc
E/Z ratio: <7.6:1
(5 mol%)
c.
MeCN, 60 °C
R
R
this method
NOH
NHAc
NO2
Fe(OAc)2
HMPA
Pd/C
HCOONH4
R
R
R
1
2
(E)-3
E/Z ratio: up to 16:1
Scheme 1 New synthetic strategy of (E)-β-arylenamides
ketoximes 2, which can be easily prepared from ni- 2a–f were preferentially converted into (E)-β-arylen-
troalkenes 1, to form (E)-β-arylenamides stereoselective- amides (E)-3a–f with high E/Z ratios (E/Z 5:1 to 16:1) in
ly with up to 16:1 E/Z ratios.
good to excellent yields. Both electron-donating and elec-
tron-withdrawing substituents were well tolerated (entries
1–4). Naphthyl and 2-thiophenyl groups were also com-
patible (entries 5 and 6). The high E/Z ratios allow the sep-
aration of pure (E)-β-arylenamides (E)-3a–f by simple
crystallization, providing a practical method for the syn-
thesis of (E)-β-arylenamides that could be scaled up.
We have developed a facile and practical method for the
syntheses of N-acetyl α-arylenamides by reductive acyla-
tion of corresponding oximes with iron(II) acetate as the
reagent.13 We envision this mild condition could also be
applied to the stereoselective syntheses of (E)-β-arylen-
amides. Thus, the reductive acylation of 1-(4-methoxy-
phenyl)propan-2-one oxime (2a, E/Z 2.8:1) was chosen To demonstrate the synthetic utilities of this methodolo-
for study (Table 1). Initial work with toluene as the sol- gy, pure (E)-β-arylenamide (E)-3a was isolated from the
vent provided a nonselective E/Z ratio (~1:1, entry 1). Fur- crude reaction mixture without column chromatography
ther screening of various solvents such as acetic acid, in 73% isolated yield on an 18 gram scale by simple crys-
acetonitrile, ethyl acetate, dichloromethane, dioxane, and tallization (EtOAc–hexanes). Asymmetric hydrogenation
tetrahydrofuran all provided <3:1 E/Z ratio (entries 2–7). of pure (E)-3a in the presence of 0.01 mol%
When dipolar aprotic solvents were applied, a significant [Rh(NBD)((S,S,S,S)-WingPhos)]BF4 as the catalyst pro-
increase in E/Z ratio was observed. Thus, N,N-dimethyl- vided the hydrogenation product 4 in 99% ee and 98%
formamide, N,N-dimethylacetamide, and DMPU all pro- yield (Scheme 2).7 Installation of the aminosulfonyl
vided 3~4:1 E/Z ratios (entries 8–10). When group16 on amide 4 by chlorosulfonylation followed by
hexamethylphosphoramide was employed as the solvent, amination led to the key chiral intermediate of tamsulosin
an excellent E/Z ratio (10:1) was achieved with 80% iso- 5 in 69% yield and 99% ee.
lated yield of (E)-β-arylenamides 3a (entry 11). Further
In summary, a facile and practical preparation of (E)-β-ar-
screening of mixed solvents with hexamethylphos-
ylenamides has been developed by reductive acetylation
phoramide all provided diminished E/Z ratios. A high re-
of corresponding oximes with iron(II) acetate as the
reducing reagent. Employment of hexamethyl-
phosphoramide as the solvent is crucial for the high E/Z
selectivity. The methodology has been applied to the syn-
thesis of enamide (E)-3a without column chromatogra-
phy, which was successfully transformed into a key chiral
action temperature (~80 °C) also led to a lower E/Z ratio.
We reasoned that the dramatic hexamethylphosphoramide
effect on the E/Z ratio could be largely due to the large di-
pole moment of hexamethylphosphoramide in stabilizing
the (E)-β-arylenamides product.
We then investigated the substrate scope of this method- intermediate of tamsulosin 5 by asymmetric hydrogena-
ology. As can be seen in Table 2, the ketoximes 2 (E/Z tion. Further applications of this methodology in conjunc-
0.8~2.8:1) could be easily prepared from corresponding tion with asymmetric hydrogenation technology for the
nitroalkenes 114 via transfer hydrogenation in 57–80% un- synthesis of various chiral β-aryl amides are currently on-
optimized yields.15 By using iron(II) acetate as the reduc- going in our laboratory.
ing reagent and hexamethylphosphoramide as the solvent,
Synthesis 2013, 45, 3355–3360
© Georg Thieme Verlag Stuttgart · New York

PAPER
Practical Syntheses of N-Acetyl (E)-β-Arylenamides
3357
Table 1 Reductive Acylation of 1-Phenylpropan-2-one Oxime (2a)
NHOH
NHAc
Fe(OAc)2
+
NHAc
MeO
MeO
MeO
2a
(E)-3a
(Z)-3a
Entrya
Solvent
Temp (°C)
Ketone (%)
Yield (%)b
Ratioc E/Z
(E)-3a
(Z)-3a
1
toluene
AcOH
MeCN
EtOAc
CH2Cl2
dioxane
THF
60
60
60
60
40
60
60
60
60
60
60
60
60
60
80
–
–
–
–
10
–
–
–
9
–
–
–
–
–
–
48
48
56
59
58
54
75
79
73
77
81
82
78
70
75
52
52
44
41
32
25
25
21
17
23
19
8
0.9
0.9
1.3
1.4
1.8
2.2
3.0
3.8
4.3
3.5
4.2
10
2
3
4
5
6
7
8
DMAc
NMP
9
10
11
12
13
14
15
DMF
DMPU
HMPA
DMF–HMPA (10:1)
DMPU–HMPA (4:1)
HMPA
22
22
15
3.6
3.2
5.1
a The reactions were carried out under N2 for 5 h, Fe(OAc)2 was prepared in situ by refluxing Fe powder in AcOH for 4 h.
b Isolated yield.
c Determined by RP-HPLC on a C18 column.
Table 2 Syntheses of (E)-β-Arylenamides
NHAc
Fe(OAc)2
HMPA
Pd/C, HCOONH4
toluene
NOH
NO2
Ar
Ar
Ar
1
2
(E)-3
Entrya
1
Ar
Yieldb (%) of 2 (ratio E/Z) Yieldc of (E)-3 (%)
Ratiod E/Z
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
4-MeOC6H4
2-MeOC6H4
Ph
60 (2a, 2.8:1)
57 (2b, 1.4:1)
72 (2c, 2.1:1)
74 (2d, 2.8:1)
63 (2e, 0.8:1)
80 (2f, 2.4:1)
82 [(E)-3a]
60 [(E)-3b]
75 [(E)-3c]
60 [(E)-3d]
74 [(E)-3e]
60 [(E)-3f]
10
14
13
11
16
5
4-FC6H4
2-naphthyl
2-thienyl
a The preparation of oximes were performed according to a reported procedure.15 The reductive acylations were run under N2 for 5 h. Fe(OAc)2
was prepared in situ by refluxing Fe powder in AcOH for 4 h.
b Isolated yield, the E/Z ratios were determined by 1H NMR.
c Isolated yield.
d The E/Z ratios observed during the reductive acylation step were determined by HPLC on a C18 column.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3355–3360

3358
Z. Cai et al.
PAPER
[Rh(NBD)((S,S,S,S)-WingPhos)]BF4
NHAc
NHAc
(0.01 mol%)
H2 (20 bar), CH2Cl2, 80 °C, 12 h
MeO
MeO
(E)-3a
4
99% ee
98% yield
H
H
O
O
P
P
NHAc
ClSO2OH
NH3•H2O
t-Bu
t-Bu
MeO
SO2NH2
5
(S,S,S,S)-WingPhos
99% ee
69% yield
Scheme 2 Synthesis of a key chiral intermediate 5 of tamsulosin
Unless otherwise indicated, all reactions were conducted under a N2
atmosphere in oven-dried glassware with a magnetic stirrer bar or
mechanical stirring. THF, CH2Cl2, dioxane, toluene, and HMPA
were purchased from China Reagents and used after standard puri-
fications. All reagents were purchased from either China Reagents
or J & K Chemicals Inc. and used directly without further purifica-
13C NMR (125 MHz, CDCl3): δ = 157.7, 157.0, 136.7, 129.2, 129.0,
128.6, 126.8, 126.5, 42.1, 34.8, 19.7, 13.3.
1-(4-Fluorophenyl)propan-2-one Oxime (2d)
Oil; yield: 9.9 g (74%); ratio E/Z 2.8:1.
1H NMR (400 MHz, CDCl3): δ = 7.22–7.16 (m, 2 H), 7.03–6.95 (m,
2 H), 3.70, 3.47 (2 s, 2 H), 1.81, 1.80 (2 s, 3 H).
1
tion. H and 13C NMR spectra were recorded on Bruker-Biospin
DRX500 and DRX400 NMR spectrometers with CDCl3 or DMSO-
d6 as the solvent. 1H shifts were referenced to CDCl3 at δ = 7.26 as
external standard and obtained with 1H decoupling. 13C shifts were
referenced to CDCl3 at δ = 77 and obtained with 1H decoupling. MS
was measured on an Agilent 1100 Series LC/MSD mass spectrom-
eter. Column chromatography was performed with silica gel (300–
400 mesh).
13C NMR (125 MHz, CDCl3): δ = 161.8 (d, J = 243.7 Hz), 161.7 (d,
J = 243.7 Hz), 157.5, 156.8, 132.2 (d, J = 3.7 Hz), 130.6 (d, J = 8.7
Hz), 130.4 (d, J = 7.5 Hz), 115.5 (d, J = 21.2 Hz), 115.4 (d, J = 21.2
Hz), 41.3, 34.0, 19.6, 13.2.
1-(Naphthalen-2-yl)propan-2-one Oxime (2e)
White solid; yield: 10.0 g (63%); ratio E/Z 0.8:1.
1H NMR (400 MHz, CDCl3): δ = 7.84–7.74 (m, 3 H), 7.67 (s, 1 H),
7.48–7.41 (m, 2 H), 7.40–7.33 (m, 1 H), 3.92, 3.67 (2 s, 2 H), 1.85,
1.84 (2 s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 157.8, 157.0, 134.1, 133.6, 132.3,
128.3, 127.7, 127.6, 127.2, 126.1, 125.6, 42.3, 35.0, 19.8, 13.4.
Reduction of Nitroalkenes to Oximes 2; General Procedure15
To a dry three-necked flask was charged nitroalkene (80 mmol), dry
ammonium formate (25.2 g, 400 mmol) and MeOH–toluene (1:1,
200 mL). Pd/C (9.5 g, 5 mol%, wet) was added to the solution under
stirring. The resulting mixture was stirred at r.t. until the complete
disappearance of the starting material. The mixture was filtered and
the filter cake was washed with CH2Cl2 (50 mL). The combined fil-
trates were concentrated, retreated with CH2Cl2 (50 mL), filtered to
remove the insoluble salt, and concentrated. The residue was puri-
fied by column chromatography (silica gel, hexanes–EtOAc, 15:1)
to afford the desired product as a mixture of E/Z isomers (E/Z 0.8:1
to 2.8:1).
1-(Thiophen-2-yl)propan-2-one Oxime (2f)
Oil; yield: 9.9 g (80%); ratio E/Z 2.4:1.
1H NMR (400 MHz, CDCl3): δ = 7.19–7.14 (m, 1 H), 6.97–6.91 (m,
1 H), 6.90–6.86 (m, 1 H), 3.91, 3.69 (2 s, 2 H), 1.89, 1.88 (2 s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 156.9, 156.1, 138.9, 137.9, 127.0,
126.9, 126.4, 126.2, 124.6, 124.4, 36.2, 28.9, 19.4, 13.1.
1-(4-Methoxyphenyl)propan-2-one Oxime (2a)
White solid; yield: 8.6 g (60%); ratio E/Z 2.8:1.
(E)-β-Arylenamides (E)-3; General Procedure
To a 50-mL three-necked flask equipped with a dropping funnel,
thermometer, and reflux condenser was charged iron powder (1.0 g,
18 mmol), AcOH (2.2 mL, 36 mmol), and Ac2O (1.7 mL, 18 mmol).
The mixture was stirred under N2 at 130 °C for 5 h and then cooled
to 60 °C. Oxime (6 mmol) in HMPA (5 mL) was added dropwise
through a dropping funnel over 5 min. The mixture was stirred at 60
°C for 6–12 h until complete disappearance of the oxime monitored
by HPLC. The mixture was diluted with EtOAc (50 mL) and then
filtered through celite. The filtrate was washed with H2O (2 × 20
mL), dried (Na2SO4), concentrated, and purified by column chro-
matography (silica gel, petroleum ether–EtOAc, 4:1) to afford the
target product.
1H NMR (400 MHz, CDCl3): δ = 7.18–7.10 (m, 2 H), 6.87–6.80 (m,
2 H), 3.78 (s, 3 H), 3.68, 3.44 (2 s, 2 H), 1.80, 1.79 (2 s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 158.5, 157.9, 130.2, 130.0, 128.7,
114.0, 55.3, 41.2, 33.9, 19.6, 13.2.
1-(2-Methoxyphenyl)propan-2-one Oxime (2b)
Oil; yield: 8.2 g (57%); ratio E/Z 1.4:1.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.10 (m, 2 H), 6.94–6.82 (m,
2 H), 3.81 (d, J = 1.1 Hz, 3 H), 3.75, 3.53 (2 s, 2 H), 1.83, 1.75 (2 s,
3 H).
13C NMR (125 MHz, CDCl3): δ = 157.5 (d, J = 2.5 Hz), 157.4,
130.7, 130.5, 128.0, 127.8, 125.2, 125.0, 120.6, 120.5, 110.5, 110.3,
55.4, 55.3, 35.6, 29.2, 19.5, 13.3.
(E)-N-[1-(4-Methoxyphenyl)prop-1-en-2-yl]acetamide [(E)-3a]
White solid; yield: 1.0 g (82%).
1H NMR (400 MHz, CDCl3): δ = 7.15 (d, J = 8.6 Hz, 2 H), 6.90 (s,
1 H), 6.85 (d, J = 8.6 Hz, 2 H), 6.83 (br s, 1 H), 3.80 (s, 3 H), 2.09
(s, 3 H), 2.07 (s, 3 H).
1-Phenylpropan-2-one Oxime (2c)
Oil; yield: 8.6 g (72%); ratio E/Z 2.1:1.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.26 (m, 2 H), 7.25–7.20 (m,
3 H), 3.75, 3.50 (2 s, 2 H), 1.82, 1.81 (2 s, 3 H).
Synthesis 2013, 45, 3355–3360
© Georg Thieme Verlag Stuttgart · New York

PAPER
Practical Syntheses of N-Acetyl (E)-β-Arylenamides
3359
13C NMR (125 MHz, CDCl3): δ = 169.2, 157.8, 132.0, 130.0, 129.5,
116.4, 113.6, 55.2, 24.4, 17.8.
5 min at r.t., and then it was transferred to an autoclave. The auto-
clave was purged with H2 (3 ×) and charged to 50 bar. The mixture
was stirred at 50 °C for 12 h, then cooled to r.t., and depressurized
carefully in a well-ventilated hood. A reaction sample was filtered
through celite to remove metal species and directly analyzed by chi-
ral HPLC to determine the conversion and ee value. Concentration
of the mixture and crystallization (EtOAc–hexanes, 1:2, 20 mL)
provided 4 (4.12 g, 98%, 99% ee) as a white solid.
(E)-N-[1-(2-Methoxyphenyl)prop-1-en-2-yl]acetamide [(E)-3b]
White solid; yield: 0.74 g (60%).
1H NMR (400 MHz, CDCl3): δ = 7.19 (d, J = 7.6 Hz, 2 H), 6.92 (t,
J = 7.4 Hz, 1 H), 6.87 (s, 1 H), 6.85 (s, 1 H), 6.73 (br s, 1 H), 3.82
(s, 3 H), 2.09 (s, 3 H), 2.07 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.5, 157.0, 133.1, 130.3, 127.7,
125.7, 120.1, 111.7, 110.2, 55.4, 24.7, 17.8.
Chiral HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min;
n-hexane–i-PrOH, 95:5, 210 nm): tR = 19.05 (R), 20.17 min (S).
[α]D20 +45.8 (c 0.5, CHCl3).
(E)-N-(1-Phenylprop-1-en-2-yl)acetamide [(E)-3c]
White solid; yield: 0.79 g (75%).
1H NMR (400 MHz, CDCl3): δ = 7.14–7.03 (m, 2 H), 6.87–6.78 (m,
2 H), 5.66 (br, 1 H), 4.20 (dp, J = 13.7, 6.7 Hz, 1 H), 3.78 (s, 3 H),
2.77 (dd, J = 13.6, 5.7 Hz, 1 H), 2.64 (dd, J = 13.6, 7.2 Hz, 1 H),
1.92 (s, 3 H), 1.09 (d, J = 6.7 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 169.3, 158.3, 130.4, 129.9, 113.8,
55.2, 46.2, 41.4, 23.5, 19.9.
1H NMR (400 MHz, CDCl3): δ = 7.31 (t, J = 7.7 Hz, 2 H), 7.24–7.15
(m, 3 H), 7.01 (s, 1 H), 6.64 (br s, 1 H), 2.10 (s, 3 H), 2.08 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 169.2, 137.1, 133.1, 128.9, 128.1,
126.0, 116.4, 24.6, 17.8.
(E)-N-[1-(4-Fluorophenyl)prop-1-en-2-yl]acetamide [(E)-3d]
(R)-N-[1-(4-Methoxy-3-sulfamoylphenyl]propan-2-yl)acet-
amide (5)16
White solid; yield: 0.70 g (60%).
1H NMR (400 MHz, CDCl3): δ = 7.18–7.10 (m, 3 H), 7.05–6.88 (m,
3 H), 2.10 (s, 3 H), 2.03 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.0, 161.2 (d, J = 224.0 Hz),
132.9 (d, J = 22.0 Hz), 130.5, 130.4, 115.2, 115.0 (d, J = 21.0 Hz),
24.65, 17.82.
HRMS (ESI): m/z [M + Na]+ calcd for C11H12FNONa: 216.0795;
found: 216.0793.
To acetamide 4 (4.0 g, 19.2 mmol) held in an oven-dried Schlenk
tube at 0–5 °C was charged dropwise with chlorosulfonic acid (40.4
g, 342 mmol) over 5 min. The mixture was stirred at 0–5 °C for 3 h,
and then carefully added to cold H2O (100 mL). The resulting mix-
ture was extracted with EtOAc (3 × 30 mL), and the organic phase
was washed sequentially with sat. NaHCO3 (20 mL) and H2O (20
mL), dried (anhyd Na2SO4), concentrated, and re-dissolved in
MeCN (60 mL) and concd aq NH3 solution (15 N, 120 mL). The
mixture was stirred at r.t. for 3 h, and it was concentrated and ex-
tracted with EtOAc (40 mL). The EtOAc layer was washed with
H2O (20 mL), concentrated, and crystallized (MeOH) to afford 5
(3.8 g, 13.3 mmol, 69%, 99% ee) as a white solid.
(E)-N-[1-(Naphthalen-2-yl)prop-1-en-2-yl]acetamide [(E)-3e]
White solid; yield: 1.0 g (74%).
1H NMR (400 MHz, CDCl3): δ = 7.84–7.75 (m, 3 H), 7.66 (s, 1 H),
7.50–7.40 (m, 2 H), 7.36 (d, J = 8.3 Hz, 1 H), 7.18 (s, 1 H), 6.60 (br
s, 1 H), 2.16 (s, 3 H), 2.13 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.9, 134.6, 133.4, 133.3, 131.9,
127.8, 127.6, 127.5, 127.3, 126.0, 125.5, 116.3, 24.7, 18.1.
Chiral HPLC (Chiralcel AD-H, 25 °C, flow rate: 1 mL/min,
n-hexane–i-PrOH, 80:20, 210 nm): tR = 7.717 min (R), 9.433 min (S).
[α]D28 +9.8 (c 0.5, MeOH) {Lit.15 [α]D20 +13.3}.
1H NMR (400 MHz, DMSO-d6): δ = 7.78 (d, J = 8.0 Hz, 1 H), 7.55
(d, J = 2.0 Hz, 1 H), 7.37 (dd, J = 8.4, 2.0 Hz, 1 H), 7.11 (d, J = 8.5
Hz, 1 H), 7.01 (s, 2 H), 3.95–3.80 (m, 4 H), 2.68 (dd, J = 13.4, 7.1
Hz, 1 H), 2.58 (dd, J = 13.4, 6.7 Hz, 1 H), 1.75 (s, 3 H), 0.99 (d, J =
6.6 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): δ = 168.8, 154.8, 134.6, 131.2,
131.1, 128.4, 112.8, 56.5, 46.4, 41.2, 23.2, 20.4.
(E)-N-[1-(Thiophen-2-yl)prop-1-en-2-yl]acetamide [(E)-3f]
Pale yellow solid; yield: 0.65 g (60%).
1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 5.0 Hz, 1 H), 7.00 (t,
J = 3.7 Hz, 1 H), 6.92 (d, J = 3.2 Hz, 1 H), 6.52 (br s, 1 H), 2.20 (s,
3 H), 2.10 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.4, 139.8, 131.6, 127.0, 126.4,
124.2, 109.8, 24.8, 18.9.
HRMS (ESI): m/z [M + Na]+ calcd for C9H11NOSNa: 204.0454;
found: 204.0445.
Acknowledgment
We are grateful to NSFC-21272254; the ‘Thousand Plan’ Youth
program, the Innovation Fund of State Key Laboratory of Bioorga-
nic and Natural Products Chemistry.
Large-Scale Preparation of (E)-N-[1-(4-Methoxyphenyl)prop-
1-en-2-yl]acetamide [(E)-3a]
To a 250-mL three-necked flask equipped with a dropping funnel,
mechanical stirring bar, and reflux condenser was charged iron
powder (20.0 g, 0.36 mol), AcOH (42 mL, 0.72 mol), and Ac2O (34
mL, 0.36 mol). The mixture was stirred under N2 at 130 °C for 7 h,
and then cooled to 60 °C. 1-(4-Methoxyphenyl)propan-2-one oxime
(21.5 g, 0.12 mol) in HMPA (100 mL) was added dropwise over 10
min through a dropping funnel. The mixture was stirred at 60 °C for
~12 h, then diluted with EtOAc (200 mL), and filtered through
celite. The filtrate was washed repeatedly with H2O (2 × 100 mL),
dried (Na2SO4), concentrated, and crystallized (EtOAc–hexanes,
2:1, 90 mL) to afford (E)-3a (18.0 g, 88 mmol, 73%) as a white sol-
id.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
References
(1) Bentley, K. W. Nat. Prod. Rep. 2001, 18, 148.
(2) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M.
Chem. Rev. 2011, 111, 563.
(3) (a) Snyder, H. S.; Tayler, K. M. Science 1970, 168, 1487.
(b) Roehrbom, C. G.; Siami, P.; Barkin, J.; Damião, R.;
Major-Walker, K.; Morrill, B.; Montorsi, F. J. Urol. (N. Y.,
NY, U. S.) 2008, 179, 616. (c) Sano, M.; Ernesto, C.;
Thomas, R. C.; Klauber, M. R. N. N. Engl. J. Med. 1997,
336, 1216. (d) Barnes, B. Formoterol, A New Generation of
Beta-2-agonist; Hogrefe and Huber Pub: Toronto, 1991.
(R)-N-[1-(4-Methoxyphenyl)propan-2-yl]acetamide (4) by
Asymmetric Hydrogenation7
To a 150-mL conical flask equipped with a magnetic stirrer bar was
charged with β-aryl-N-acetylenamide (E)-3a (4.1 g, 20 mmol),
[Rh(NBD)((S,S,S,S)-WingPhos)]BF4 (2 mg, 0.002 mmol, 0.01
mol%) and CH2Cl2 (50 mL) under N2. The mixture was stirred for
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3355–3360

3360
Z. Cai et al.
PAPER
2004, 69, 4177. (d) Allwein, S. P.; McWilliams, J. C.;
Secord, E. A.; Mowrey, D. R.; Nelson, T. D.; Kress, M. H.
Tetrahedron Lett. 2006, 47, 6409. (e) Zhao, H.;
(e) Pharm, D. Q.; Nogid, A. Clin. Ther. 2008, 30, 813.
(f) Yoshida, M.; Homma, Y.; Kawabe, K. Expert Opin.
Invest. Drugs 2007, 16, 1955.
(4) For selected reviews of transition-metal-catalyzed
asymmetric hydrogenation, see: (a) Xie, J.-H.; Zhu, S.-F.;
Zhou, Q.-L. Chem. Rev. 2011, 111, 1713. (b) Gopalaiah, K.;
Kagan, H. B. Chem. Rev. 2011, 111, 4599. (c) Nugent, T. C.;
El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753. (d) Tang,
W.; Zhang, X. Chem. Rev. 2003, 103, 3029.
(5) Chen, J.; Zhang, W.; Geng, H.; Li, W.; Hou, G.; Lei, A.;
Zhang, X. Angew. Chem. Int. Ed. 2009, 48, 800.
(6) Zhu, S.-F.; Liu, T.; Yang, S.; Song, S.; Zhou, Q.-L.
Tetrahedron 2012, 68, 7685.
(7) Liu, G.; Liu, X.; Cai, Z.; Jiao, G.; Xu, G. Angew. Chem. Int.
Ed. 2013, 52, 4235.
(8) Laso, N. M.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett.
1996, 37, 1605.
(9) Tschaen, D. M.; Abramson, L.; Cai, D.; Desmond, R.;
Dolling, U.-H.; Frey, L.; Karady, S.; Shi, Y.-J.; Verhoeven,
T. R. J. Org. Chem. 1995, 60, 4324.
Vandenbossche, C. P.; Koenig, S. G.; Singh, S. P.; Bakale,
R. P. Org. Lett. 2008, 10, 505. (f) Guan, Z.-H.; Huang, K.;
Yu, S.; Zhang, X. Org. Lett. 2009, 11, 481. (g) Guang, Z.-H.;
Zhang, Z.-Y.; Ren, Z.-Y.; Wang, Y.-Y.; Zhang, X.-M.
J. Org. Chem. 2011, 76, 339. (h) Reeves, J. T.; Tan, Z.; Han,
Z. S.; Li, G.; Zhang, Y.; Xu, Y.; Reeves, D. C.; Gonnella, N.
C.; Ma, S.; Lee, H.; Lu, B. Z.; Senanayake, C. H. Angew.
Chem. Int. Ed. 2012, 51, 1400.
(13) (a) Tang, W.; Capacci, A.; Sarvestani, M.; Wei, X.; Yee, N.
K.; Senanayake, C. H. J. Org. Chem. 2009, 74, 9528.
(b) Tang, W.; Patel, N. P.; Capacci, A.; Wei, X.; Yee, N. K.;
Senanayake, C. H. Org. Synth. 2013, 90, 62. (c) Li, W.;
Rodriguez, S.; Duran, A.; Sun, X.; Tang, W.; Premasiri, A.;
Wang, J.; Sidhu, K.; Patel, N. D.; Savoie, J.; Qu, B.; Lee, H.;
Haddad, N.; Lorenz, J. C.; Nummy, L.; Hossain, A.; Yee, N.;
Lu, B.; Senanayake, C. H. Org. Process Res. Dev. 2013, 17,
1061.
(10) Brettle, R.; Shibib, S. M.; Wheeler, K. J. J. Chem. Soc.,
Perkin Trans. 1 1985, 831.
(14) Abdolhamid, A.; Khodaei, M.; Eshghi, A. J. Org. Chem.
2010, 75, 8295.
(11) Wallace, D. J.; Klauber, D. J.; Chen, C.-Y.; Volante, R. P.
Org. Lett. 2003, 5, 4749.
(15) Kabalka, G.; Pace, R.; Wadgaonkar, P. Synth. Commun.
1990, 20, 2453.
(12) (a) Burk, M. J.; Casey, G.; Johnson, N. B. J. Org. Chem.
1998, 63, 6084. (b) Zhu, G.; Zhang, X. J. Org. Chem. 1998,
63, 9590. (c) Le, J. C.-D.; Pagenkopf, B. L. J. Org. Chem.
(16) Hwu, J.; Balaachary, M.; Subhasish, C.; Asish, D.; Shwu, T.;
Sheu, K.; Shu, C.; Lu, C.; Chang, W. EP 1,734,036, 2006.
Synthesis 2013, 45, 3355–3360
© Georg Thieme Verlag Stuttgart · New York