A facile and practical synthesis of N-acetyl enamides

Article abstract of DOI:10.1021/jo902259u

(Chemical Equation Presented) A facile and practical method for the synthesis of N-acetyl α-arylenamides has been developed from corresponding ketoximes as the starting materials with ferrous acetate as the reducing reagent. This methodology offers mild reaction conditions, simple purification procedures, and high yields for a variety of N-acetyl enamides.

Full text of DOI:10.1021/jo902259u

Supporting Information
for
A Facile and Practical Synthesis of N-Acetyl Enamides
Wenjun Tang,* Andrew Capacci, Max Sarvestani, Xudong Wei, Nathan K. Yee, and
Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc.,
Ridgefield, Connecticut 06877, U.S.A
General procedure for the synthesis of N-acetyl arylenamides----------------------------S2-3
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H NMR of N-(1-(4-bromophenyl)vinyl)acetamide (2a)-------------------------------------S4
3
C NMR of N-(1-(4-bromophenyl)vinyl)acetamide (2a)------------------------------------S5
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H NMR of N-(1-phenylvinyl)acetamide (2b)-------------------------------------------------S6
H NMR of N-(1-(4-methoxyphenyl)vinyl)acetamide (2c)----------------------------------S7
H NMR of N-(1-(4-(trifluoromethyl)phenyl)vinyl)acetamide (2d)------------------------S8
H NMR of N-(1-(2-methoxyphenyl)vinyl)acetamide (2e)----------------------------------S9
H NMR of N-(1-(4-nitrophenyl)vinyl)acetamide (2f)---------------------------------------S10
H NMR of N-(1-(naphthalen-2-yl)vinyl)acetamide (2g)------------------------------------S11
H NMR of N-(1-(4-methoxyphenyl)prop-1-enyl)acetamide (2h)-------------------------S12
H NMR of N-(2-methyl-1-phenylprop-1-enyl)acetamide (2i) ----------------------------S13
H NMR of N-(cyclohexylidene(phenyl)methyl)acetamide (2j)---------------------------S14
H NMR of N-(3,4-dihydronaphthalen-1-yl)acetamide (2k)------------------------------- S15
H NMR of N-(1H-inden-3-yl)acetamide (2l)------------------------------------------------ S16
H NMR of N-(2-Methyl-3,4-dihydronaphthalen-1-yl)acetamide (2m)-------------------S17
H NMR of N-(6-Methoxy-3,4-dihydronaphthalen-1-yl)acetamide (2n)------------------S18
H NMR of N-(5,7-dimethyl-3,4-dihydronaphthalen-1-yl)acetamide (2o)----------------S19
S1

General Methods. All reactions were carried out under a nitrogen atomosphere. Actic
anhydride and acetic acid were purchased from Aldrich and used directly. THF (<0.02%
water content) was purchased from J. T. Baker and used directly without further
purifications. Anhydrous ferrous acetate was purchased from Strem Chemicals, Inc. All
the ketoximes substrates 1a-o were prepared from corresponding ketones and
1
,8 1
13
hydroxylamine hydrochloride following reported procedures.
were recorded on a Bruker-Biospin DRX500 or DRX400 NMR Spectrometer with
H and C NMR data
DMSO-d as the solvent. Melting points were determined on a Fisher-Johns melting-
6
point apparatus.
General procedure for the synthesis of N-acetyl arylenamides: Acetic anhydride (8
mmol, 2 equiv) and acetic acid (12 mmol, 3 equiv) were added to a solution of ketoxime
1
a-o (4 mmol, 1 equiv, 0.2 M) in THF (20 mL). The solution was purged with nitrogen
for 15 minutes. Iron (II) acetate (8 mmol, 2 equiv) was then added and the resulting
mixture was stirred at reflux under nitrogen for 5-12 hours and then cooled to room
temperature. The reaction mixture was diluted with water ( 20 mL) and neutralized with
10% NaHCO solution (~ 10 mL) until the pH was approximately 5.0. The mixture was
3
then extracted twice with EtOAc (2 × 20 mL). The combined organic solution was
washed sequentially with 10% NaHCO solution (20 mL) and brine (20 mL), dried over
3
sodium sulfate, and concentrated. The pure desired compound 2a-o was obtained by
silica gel column chromatography (EtOAc/hexanes as eluent).
1
N-(1-(4-Bromophenyl)vinyl)acetamide (2a): 90% yield; mp 112-113 °C; H NMR (500
1
MHz, DMSO-d ) δ 9.38 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 5.56
6
1
3
(
s, 1H), 5.03 (s, 1H), 2.00 (s, 3H); C NMR (125 MHz, DMSO-d ) δ 169.0, 140.6, 137.1,
6
1
31.1, 128.3, 121.3, 102.9, 23.6.
N-(1-Phenylvinyl)acetamide (2b): 78% yield; mp 82-84 °C; H NMR (500 MHz,
2
,3
1
DMSO-d ) δ 9.32 (s, 1H), 7.45-7.42 (m, 2H), 7.39-7.33 (m, 3H), 5.62 (s, 1H), 4.98 (s,
6
1
N-(1-(4-Methoxyphenyl)vinyl)acetamide (2c): 82% yield; mp 94-95 °C; H NMR (500
H), 2.01 (s, 3H).
3
,4
1
MHz, DMSO-d ) δ 9.22 (s, 1H), 7.37 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 5.52
6
(s, 1H), 4.90 (s, 1H), 3.77 (s, 3H), 2.00 (s, 3H).
N-(1-(4-(Trifluoromethyl)phenyl)vinyl)acetamide (2d): 87% yield; mp 113-115 °C; H
3
,4
1
NMR (500 MHz, DMSO-d ) δ 9.51 (s, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.3 Hz,
6
2
H), 5.61 (s, 1H), 5.13 (s, 1H), 2.02 (s, 3H).
N-(1-(2-Methoxyphenyl)vinyl)acetamide (2e): 77% yield; mp 124-125 °C; H NMR
500 MHz, DMSO-d ) δ 9.15 (s, 1H), 7.33 (td, J = 8.0, 1.8 Hz, 1H), 7.19 (dd, J = 7.4, 1.8
5
1
(
6
3
Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 5.82 (s, 1H), 4.54 (s, 1H),
.77 (s, 3H), 1.92 (s, 3H).
3
N-(1-(4-Nitrophenyl)vinyl)acetamide (2f): 45% yield; mp 148-149 °C; H NMR (400
6
1
MHz, CDCl ) δ 8.22 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 6.87 (brs, 1H), 5.83 (s,
3
1
N-(1-(Naphthalen-2-yl)vinyl)acetamide (2g): 77% yield; mp 123-124 °C; H NMR (400
H), 5.26 (s, 1H), 2.17 (s, 3H).
2
1
MHz, CDCl ) δ 7.87-7.82 (m, 5H), 7.52-7.48 (m, 2H), 6.91 (br s, 1H), 5.96 (s, 1H), 5.24
3
(s, 1H), 2.19 (s, 3H).
N-(1-(4-Methoxyphenyl)prop-1-enyl)acetamide (2h, 1/1.5 E/Z mixtures): 80% yield; Z
3
1
isomer: H NMR (500 MHz, DMSO-d ) δ 9.03-8.99 (m, 1H), 7.19 (d, J = 8.5 Hz, 2H),
6
6
.94 (d, J =8.5 Hz, 2H), 5.97 (q, J = 7.1 Hz, 1H), 3.77-3.73 (m, 3H), 1.89 (s, 3H), 1.65-
S2

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.58 (m, 3H); E isomer: H NMR (500 MHz, DMSO-D ) δ 9.03-8.99 (m, 1H), 7.29 (d, J
6
=
(
8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.77 (q, J = 6.8 Hz, 1H), 3.77-3.73 (m, 3H), 1.99
s, 3H), 1.65-1.58 (m, 3H).
N-(2-Methyl-1-phenylprop-1-enyl)acetamide (2i): 66% yield; mp 82-83 °C; H NMR
500 MHz, DMSO-d ) δ 9.00 (s, 1H), 7.33-7.29 (m, 2H), 7.24-7.19 (m, 3H), 1.89 (s, 3H),
1
,7
1
(
6
1
N-(Cyclohexylidene(phenyl)methyl)acetamide (2j): 67% yield; mp 130-131 °C; H
.71 (s, 3H), 1.69 (s, 3H).
1
,7
1
NMR (500 MHz, DMSO-d ) δ 8.98 (s, 1H), 7.31 (m, 2H), 7.22 (m, 1H), 7.18 (m, 2H),
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2
N-(3,4-Dihydronaphthalen-1-yl)acetamide (2k):
.17-2.11 (m, 4H), 1.87 (s, 3H), 1.57-1.52 (m, 4H), 1.50-1.46 (m, 2H).
1
,7,8
1
80% yield; mp 133-134 °C; H NMR
(
500 MHz, DMSO-d ) δ 9.11 (s, 1H), 7.22-7.14 (m, 4H), 6.16 (t, J = 4.6 Hz, 1H), 2.69 (t,
6
J = 7.9 Hz, 2H), 2.29-2.23 (m, 2H), 2.02 (s, 3H).
1
N-(1H-inden-3-yl)acetamide (2l):
,7,8
1
50% yield; mp 126-127 °C; H NMR (500 MHz,
DMSO-d ) δ 9.72 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 7.4 Hz, 1H),7.33 (t, J =
6
7
2
.3 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 6.75 (t, J = 2.2 Hz, 1H), 3.37 (d, J = 2.2 Hz, 2H),
.13 (s, 3H).
7
,8
N-(2-Methyl-3,4-dihydronaphthalen-1-yl)acetamide (2m): 55% yield; mp 153-154 °C;
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H NMR (500 MHz, DMSO-d ) δ 8.93 (s, 1H), 7.15-7.07 (m, 3H), 7.04 (d, J = 7.6 Hz,
6
1
N-(6-Methoxy-3,4-dihydronaphthalen-1-yl)acetamide (2n): 82% yield; mp 126-128 °C;
H), 2.73 (t, J = 8.1 Hz, 2H), 2.29 (t, J = 8.1 Hz, 2H), 2.03 (s, 3H), 1.77 (s, 3H).
7
1
H NMR (500 MHz, DMSO-d ) δ 9.03 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.79-6.71 (m,
6
2
H), 6.03 (t, J = 4.5 Hz, 1H), 3.74 (s, 3H), 2.68-2.63 (m, 2H), 2.26-2.20 (m, 2H), 2.00 (s,
H).
3
N-(5,7-Dimethyl-3,4-dihydronaphthalen-1-yl)acetamide (2o): 74% yield; mp 162-163
7
1
°C; H NMR (500 MHz, DMSO-d ) δ 9.01 (s, 1H), 6.89 (s, 1H), 6.87 (s, 1H), 6.14 (t, J =
6
4
.6 Hz, 1H), 2.57 (t, J = 7.8 Hz, 2H), 2.25-2.18 (m, 8H), 2.01 (s, 3H).
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