A practical and efficient synthesis of (E)-β-aryl-α,β-unsaturated amides

Article abstract of DOI:10.1016/j.tet.2008.08.057

In this paper, we report a one-step convergent synthesis of (E)-β-monosubstituted α,β-unsaturated amides 3 from α-sulfonyl acetamide 1 and benzyl bromide derivatives 2.

Full text of DOI:10.1016/j.tet.2008.08.057

Tetrahedron 64 (2008) 10350–10354
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A practical and efficient synthesis of (E)-b-aryl-a,b-unsaturated amides
*
Chih-Ching Chen, Jung-Chieh Ho, Nein-Chen Chang
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2008
Received in revised form 20 August 2008
Accepted 21 August 2008
Available online 27 August 2008
In this paper, we report a one-step convergent synthesis of (E)-
amides 3 from -sulfonyl acetamide 1 and benzyl bromide derivatives 2.
Ó 2008 Elsevier Ltd. All rights reserved.
b-monosubstituted a,b-unsaturated
a
1. Introduction
2. Results and discussion
2.1. Synthesis of (E)- -aryl-a,b-unsaturated amides (3a)
The development of methodologies for the formation of carbon–
carbon double bonds could be considered one of the most impor-
b
tant challenges in organic synthesis.1
a
,
b
-Unsaturated amides are
The procedure used for this approach is exemplified by the re-
action of -toluenesulfonyl acetamide 1a with 4-nitrobenzyl bro-
an important class of compounds because of their presence in the
structure of natural products2 and their role as a reaction partner in
many useful reactions such as conjugate addition of copper3 and
Grignard4 reagents and other reactions.5 They are often employed
as starting materials to obtain many natural products6 as exem-
plified by the recent syntheses of deplancheine, tacamonine, and
paroxetine.6e Furthermore, a number of non-natural acrylamide
derivatives have also shown both important biological and in-
secticidal activities.1,7
a
mide 2a. After the reaction of 1 in THF with 2.2 equiv of sodium
hydride, the resulting anion was reacted with 4-nitrobenzyl bro-
mide to afford the corresponding (E)-b-aryl acrylamide derivative
3aa in 90% yield.
As shown in Table 1, reactions of 1a with benzyl bromide
bearing strong electron-withdrawing substituents (such as nitro
and cyano groups) furnished the corresponding (E)-b-aryl-a,b-un-
saturated acetamides at room temperature in a short period of time
(entries 1–6). Apparently, the strong electron-withdrawing groups
activate the substitution–elimination process. When 1a was reac-
ted with halogen substituted benzyl bromides, higher temperature
and longer reaction times were required to yield the desired
products (entries 7–11).
Although many methods have been developed for the synthesis
of
a,b
-unsaturated amides,3d,7c,8 the development of simple and
efficient routes toward their synthesis remains an area of research
interest. However, to the best of our knowledge, no synthetic
method for (E)-
b
-monosubstituted
a
,
b
-unsaturated amides from
benzyl halide derivatives and
reported.
a
-sulfonyl acetamides has been
It is interesting to note that besides entry 2,10 all of the benzyl
halides afforded b-aryl-a,b-unsaturated amides in moderate to high
Recently, we have been interested in the chemistry of
a
-sulfonyl
yields and with (E)-selectivity. The geometry of the products was
determined by the characteristic coupling constants between the
two olefinic protons from 1H NMR.
acetamides and successfully applied them to the synthesis of glu-
tarimide and pyroglutamate skeletons via Michael addition and
substitution reactions (Fig. 1).9
In this paper, we report a new approach to (E)-b-aryl-a,b-un-
saturated amides. Instead of using aldehydes, phosphorus, silicon
containing compounds, and metal catalysts for the synthesis of
double bonds, a-sulfonyl acetamide 1 and various benzyl bromides
2 were used as starting materials (Fig. 2).
R1
R2 CO2R
R1
Br CO2Et
Ts
R3
CO2Et
Ts
O
R2
O
O
R3
GP
Ts
O
N
H
N
PG
N
Base
Base
PG
glutarimides
pyroglutamates
R = Me or Et
R1, R2, R3 = Alkyl, Aryl groups
* Corresponding author.
Figure 1. The application of
a
-sulfonyl acetamides to glutarimide and pyroglutamate
E-mail address: ncchang@mail.nsysu.edu.tw (N.-C. Chang).
skeletons.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.057

C.-C. Chen et al. / Tetrahedron 64 (2008) 10350–10354
10351
O
O
O
i) NaH, THF
ii)
1) Cl
R2
Ts
THF
R2
O
Cl
MeO
N
R1
N
R1
R3
NH2
MeO
Ts
2) TsNa, dioxane-H2O
reflux
86% for 2 steps
N
H
R3
1
Br
a: R1 = H, R2 = Bn
b: R1 = R2 = Et
3
5
4
2
R3 = NO2, CN, Br, Cl
O
NaH, THF
MeO
Figure 2. The application of a-sulfonyl acetamides to a,b-unsaturated amides.
N
H
Cl
Br
Cl
The scope of the reaction appears to be limited to benzyl bro-
mides with electron-withdrawing substituent at the benzene ring.
In the reaction of benzyl bromides bearing no substituents or
electron-donating groups, the major products obtained are
C-alkylated amides, in which the tosyl group is retained. Using
6
80%
ref
MeO
N
H
Cl
Table 1
Reaction of
a
-sulfonyl acetamide 1a with benzyl halide derivatives 2a
(R)-(+)-NPS R-568
O
O
Scheme 1. Formal synthesis of (þ)-NPS R-568.
i) NaH, THF
ii)
R2
N
Ts
R2
N
R1
R3
R3
R1
Br
1a
Table 2
Reaction of N,N-diethyl acetamide 1b with benzyl halide derivatives 2a
R1 = H, R2 = Bn
2
3a
E/Zb
O
O
i) NaH, THF
ii)
Entry
3a
R3
Temp (ꢁC)
Rxn time (min)
Yieldc (%)
R2
Ts
R2
N
R1
N
R1
R3
1
2
3
4
5
6
7
8
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
p-NO2
rt
10
20
15
30
40
100:0
82:18
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
90
82
88
74
66
43
85
76
53
72
79
R3
m-NO2
o-NO2
p-CN
m-CN
o-CN
p-Br
rt
rt
rt
rt
Br
1b
R1 = R2 = Et
2
3b
rt
30
Yieldc (%)
Reflux
Reflux
Reflux
Reflux
Reflux
120
120
120
150
120
Entry
3b
R3
Temp (ꢁC)
Rxn time (h)
E/Zb
o-Br
p-Cl
m-Cl
o-Cl
1
2
3
3ba
3bb
3bc
p-NO2
o-CN
m-Cl
rt
rt
rt
12
12
12
100:0
100:0
100:0
85
81
79
9
10
11
3aj
3ak
a
THF was used as solvent.
a
THF was used as solvent.
Determined by 1H NMR spectra.
The yield of (E)-olefins was based on 1a.
Determined by 1H NMR spectra.
b
c
b
c
The yield of (E)-olefins was based on 1b.
1 equiv of sodium hydride affords complicated result. Replacing
sodium hydride with stronger bases, such as LDA or LHMDS, gave
3. Conclusion
no desired b-substituted acrylamides under various reaction con-
ditions and the reason still remains unclear.
In summary, a sequential substitution–elimination reaction in-
volving readily available -sulfonyl acetamide and substituted
benzyl bromides to afford (E)- -aryl- -unsaturated amides has
a
b
a,b
been developed. This practical and efficient process is highly stereo-
selective. There is no limitation in the position of the substituent on
the benzene ring of the benzyl bromide as long as it is electron
withdrawing. We also applied this methodology to the formal
synthesis of (þ)-NPS R-568. Further studies directed toward the
development of synthetic applications of this method are currently
under investigation in our laboratory.
2.2. Formal synthesis of the calcimimetic (D)-NPS R-568
To demonstrate the synthetic applications of our approach, we
then applied it to the formal synthesis of the calcimimetic (þ)-NPS
R-568, which has shown great potential as an innovative medical
approach for the treatment of primary and secondary hyperpara-
thyroidisms.11 As shown in Scheme 1, (R)-sulfonyl acetamide 5 can
be obtained in two steps from the commercially available (R)-
(þ)-1-(3-methoxyphenyl)-ethylamine 4. Similar to 1a, treatment of
5 with sodium hydride and 2-chlorobenzyl bromide provided the
4. Experimental
4.1. General
corresponding (E)-b-aryl acrylamide derivative 6 in 80% yield,
which has previously been further transformed into the calcimi-
metic (þ)-NPS R-568.12
Melting points were determined with Fargo micro-melting
point apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded on a Varian VRX 500 spectrometer. NMR spectra were
recorded in CDCl3 (1H at 500 MHz and 13C at 125 MHz), and
2.3. Synthesis of N,N-disubstituted (E)-acrylamides (3b)
We next focused our attention on the reaction of N,N-diethyl
acetamide 1b, which was needed as a starting material (Table 2).
The corresponding N,N-disubstituted (E)-a,b-unsaturated am-
ides 3ba–3bc were obtained exclusively and with good yields. Be-
chemical shifts are expressed in parts per million (d) relative to
internal Me4Si. HRMS was recorded on a BRUKER DALTONICS APEX
II30e spectrometer. Infrared spectra were recorded on a Perkin–
Elmer Spectrum 100 FTIR spectrometer as KBr plates and peaks are
sides, all of the reactions could be carried out at room temperature.
reported in cmꢀ1
.

10352
C.-C. Chen et al. / Tetrahedron 64 (2008) 10350–10354
Tetrahydrofuran was distilled prior to use. All other reagents
4.2.2. (E)-N-Benzyl-3-(3-nitrophenyl)acrylamide (3ab)
and solvents were obtained from commercial sources and were
used without any further purification. Reactions were routinely
carried out under an atmosphere of dry nitrogen with magnetic
stirring. Solutions of products in organic solvents were dried over
anhydrous magnesium sulfate before concentration under
vacuum.
Yield 67%; yellow solid; mp¼133–134 ꢁC; IR (CH2Cl2, cmꢀ1):
3473, 1645; 1H NMR (500 MHz, CDCl3)
d
8.34 (d, J¼2.0 Hz, 1H), 8.17
(ddd, J¼8.5, 2.0, 1.0 Hz, 1H), 7.74 (d, J¼15.5 Hz, 1H), 7.69 (d,
J¼15.5 Hz, 1H), 7.54 (d, J¼8.0 Hz, 1H), 7.36–7.26 (m, 5H), 6.57 (d,
J¼15.5 Hz, 1H), 6.25 (br s, 1H), 4.58 (d, J¼6.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3)
d 164.8, 148.6, 138.7, 137.8, 136.5, 133.9, 129.9,
(R)-(þ)-1-(3-Methoxyphenyl)ethylamine 4 was purchased from
Lancaster (ChiPros 99þ%, ee 98%). Compounds 5 and 1b were
synthesized according to the reported procedures9b and their
spectral data are described below:
128.8 (2C), 127.9 (2C), 127.7, 124.0,123.5, 121.7, 44.0; HRMS m/z (ESI,
Mþþ1) calcd for C16H15N2O3 283.1083, found 283.1082.
4.2.3. (Z)-N-Benzyl-3-(3-nitrophenyl)acrylamide (3ab-Z)
Yield 15%; yellow solid; IR (CH2Cl2, cmꢀ1): 3349, 1678; 1H NMR
(500 MHz, CDCl3)
d
8.48 (d, J¼2.5 Hz, 1H), 8.25 (dd, J¼9.5, 2.5 Hz,
4.1.1. N-[1-(3-Methoxyphenyl)ethyl]-2-(toluene-4-
sulfonyl)acetamide (5)
1H), 7.83 (d, J¼10.0 Hz,1H), 7.36–7.31 (m, 5H), 7.19 (d, J¼6.5 Hz, 2H),
6.93 (d, J¼10.0 Hz, 1H), 5.58 (br s, 1H); 13C NMR (125 MHz, CDCl3)
Yield 86%; colorless oil; IR (CH2Cl2, cmꢀ1): 3328, 2976, 2932,
1660,1598,1534; 1H NMR (500 MHz, CDCl3)
d
7.64 (d, J¼8.0 Hz, 2H),
d
162.1, 143.5, 142.2, 139.1, 135.2, 129.2, 129.1 (2C), 127.8, 126.4 (2C),
125.2, 124.6, 123.86, 120.4, 115.7, 46.4.
7.27 (d, J¼8.0 Hz, 1H), 7.23 (d, J¼9.0 Hz, 2H), 7.21 (d, J¼9.0 Hz, 1H),
6.88–6.87 (m, 2H), 6.79 (dd, J¼8.0, 2.5 Hz, 1H), 4.98 (m, 1H), 4.02 (d
of a pair of ABq type, J¼14.0 Hz, 1H), 3.96 (d of a pair of ABq type,
J¼14.0 Hz, 1H), 3.75 (s, 3H), 2.38 (s, 3H), 1.42 (d, J¼7.0 Hz, 3H); 13C
4.2.4. (E)-N-Benzyl-3-(2-nitrophenyl)acrylamide (3ac)
Yield 88%; yellow solid; mp¼184–185 ꢁC; IR (CH2Cl2, cmꢀ1):
3452, 1685; 1H NMR (500 MHz, CDCl3)
d
8.02 (d, J¼8.0 Hz, 1H), 8.01
NMR (125 MHz, CDCl3) d 159.8, 159.5, 145.1, 144.0, 134.9, 129.6 (2C),
(d, J¼15.5 Hz, 1H), 7.62–7.54 (m, 2H), 7.52–7.49 (m, 2H), 7.38–7.26
(m, 4H), 6.33 (d, J¼15.5 Hz, 1H), 5.96 (br s, 1H), 4.58 (d, J¼6.0 Hz,
129.4, 128.0 (2C), 118.2, 112.6, 111.8, 61.9, 55.0, 49.2, 21.40, 21.38;
HRMS m/z (ESI, MþþNa) calcd for C18H21NO4SNa 370.1089, found
370.1091.
2H); 13C NMR (125 MHz, CDCl3)
d 164.7, 148.3, 137.8, 136.5, 133.4,
131.1, 129.8, 129.1, 128.8 (2C), 128.0 (2C), 127.7, 125.8, 124.9, 44.0;
HRMS m/z (ESI, Mþþ1) calcd for C16H15N2O3 283.1083, found
283.1082.
4.1.2. N,N-Diethyl-2-(toluene-4-sulfonyl)acetamide (1b)
Yield 90%; white solid; mp¼87–88 ꢁC; IR (CH2Cl2, cmꢀ1):
2976, 1648, 1452; 1H NMR (500 MHz, CDCl3)
d
7.80 (d, J¼8.0 Hz,
4.2.5. (E)-N-Benzyl-3-(4-cyanophenyl)acrylamide (3ad)
2H), 7.35 (d, J¼8.0 Hz, 2H), 4.18 (s, 2H), 3.50 (q, J¼7.0 Hz, 2H),
3.34 (q, J¼7.0 Hz, 2H), 2.44 (s, 3H), 1.22 (t, J¼7.0 Hz, 3H), 1.10 (t,
Yield 74%; white solid; mp¼173–174 ꢁC; IR (CH2Cl2, cmꢀ1):
3426, 2230, 1664; 1H NMR (500 MHz, CDCl3)
d
7.68 (d, J¼15.5 Hz,
J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 160.6, 145.2, 135.8,
1H), 7.66 (d, J¼8.5 Hz, 2H), 7.58 (d, J¼8.5 Hz, 2H), 7.38–7.30 (m, 5H),
129.7 (2C), 128.6 (2C), 59.9, 43.1, 40.8, 21.7, 14.2, 12.7; HRMS m/z
(ESI, MþþNa) calcd for C13H19NO3SNa 292.0983, found 292.0981.
Compound 1b was recrystallized from ethyl acetate as a color-
less prism.
6.49 (d, J¼15.5 Hz, 1H), 5.94 (br s, 1H), 4.6 (d, J¼5.5 Hz, 2H); 13C
NMR (125 MHz, CDCl3)
d 164.7, 139.4, 139.1, 137.8, 132.6 (2C), 128.8
(2C), 128.2 (2C), 128.0 (2C), 127.8, 123.8, 118.4, 112.9, 44.0; HRMS
m/z (ESI, Mþþ1) calcd for C17H15N2O 263.1184, found 263.1183.
4.2.6. (E)-N-Benzyl-3-(3-cyanophenyl)acrylamide (3ae)
4.2. General procedure for the preparation of (E)-
b
-aryl-
Yield 66%; white solid; mp¼140–141 ꢁC; IR (CH2Cl2, cmꢀ1):
a
,b-unsaturated amides (3a)
3428, 3274, 2232, 1666; 1H NMR (500 MHz, CDCl3)
d 7.77 (s, 1H),
7.70 (d, J¼8.0 Hz, 1H), 7.65 (d, J¼15.5 Hz, 1H), 7.63 (d, J¼9.0 Hz, 1H),
7.49 (dd, J¼8.5, 8.0 Hz, 1H), 7.38–7.29 (m, 5H), 6.46 (d, J¼15.5 Hz,
1H), 5.99 (br s, 1H), 4.59 (d, J¼6.0 Hz, 2H); 13C NMR (125 MHz,
A
solution of a-toluenesulfonyl acetamide 1a (303 mg,
1.0 mmol) in dry THF (5.0 mL) was added to a rapidly stirred sus-
pension of sodium hydride (88 mg, 2.2 mmol, 60%) in dry THF
(10 mL). After the reaction mixture was stirred at room tempera-
ture for 30 min, the benzyl bromide derivative 2 (1.0 mmol) was
added to the solution. The resulting mixture was stirred at room
temperature (for 3aa–3af) for 10–40 min or refluxed (for 3ag–3ak)
for 120–150 min (as show in Table 1). After the reaction was com-
plete (as indicated by TLC), the reaction mixture was quenched
with a saturated ammonium chloride solution (1 mL) and the sol-
vent was removed with a rotary evaporator under reduced pres-
sure. The residue was diluted with water (10 mL) and extracted
with EtOAc (3ꢂ10 mL). The combined organic layer was washed
with brine, dried over anhydrous MgSO4, filtered, and concen-
trated. The crude product was purified by silica gel chromatography
(n-hexane/ethyl acetate¼4:1 to 2:1) to afford amides 3.
CDCl3)
d 164.7, 139.0, 137.8, 136.4, 132.7, 132.0, 130.8, 129.8, 128.8
(2C), 127.9 (2C), 127.8, 122.9, 118.3, 113.2, 44.0; HRMS m/z (ESI,
Mþþ1) calcd for C17H15N2O 263.1184, found 263.1185.
4.2.7. (E)-N-Benzyl-3-(2-cyanophenyl)acrylamide (3af)
Yield 43%; white solid; mp¼150–151 ꢁC; IR (CH2Cl2, cmꢀ1):
3262, 2226, 1652; 1H NMR (500 MHz, CDCl3)
d 7.87 (d,
J¼15.5 Hz, 1H), 7.70 (d, J¼8.5 Hz, 1H), 7.64 (d, J¼8.0 Hz, 1H), 7.60
(dd, J¼8.0, 7.5 Hz, 1H), 7.45 (dd, J¼8.0, 7.5 Hz, 1H), 7.38–7.28 (m,
5H), 6.70 (d, J¼155 Hz, 1H), 6.02 (br s, 1H), 4.60 (d, J¼6 Hz, 2H);
13C NMR (125 MHz, CDCl3)
d 164.6, 137.8, 137.6, 136.5, 133.8,
133.0, 129.5, 128.8 (2C), 128.1, 128.0 (2C), 127.7, 125.6, 117.6, 117.7,
44.0; HRMS m/z (ESI, Mþþ1) calcd for C17H15N2O 263.1184,
found 263.1186.
4.2.1. (E)-N-Benzyl-3-(4-nitrophenyl)acrylamide (3aa)
4.2.8. (E)-N-Benzyl-3-(4-bromophenyl)acrylamide (3ag)
Yield 90%; yellow solid; mp¼185–186 ꢁC; IR (CH2Cl2, cmꢀ1):
Yield 85%; white solid; mp¼173–174 ꢁC; IR (CH2Cl2, cmꢀ1):
3445, 3058, 1682; 1H NMR (500 MHz, CDCl3)
d
8.23 (d, J¼8.5 Hz,
3280, 1654, 1620; 1H NMR (500 MHz, CDCl3)
d
7.62 (d, J¼15.5 Hz,
2H), 7.72 (d, J¼15.5 Hz, 1H), 7.64 (d, J¼8.5 Hz, 2H), 7.38–7.29 (m,
1H), 7.50 (d, J¼8.5 Hz, 2H), 7.38–7.30 (m, 7H), 6.39 (d, J¼15.5 Hz,
5H), 6.53 (d, J¼15.5 Hz, 1H), 6.0 (br s, 1H), 4.60 (d, J¼5.5 Hz, 2H); 13
C
1H), 5.88 (br s, 1H), 4.59 (d, J¼6 Hz, 2H); 13C NMR (125 MHz, CDCl3)
NMR (125 MHz, CDCl3)
d
164.6, 148.2, 141.0, 138.9, 137.7, 128.9 (2C),
d 165.3, 140.2, 138.0, 133.7, 132.1 (2C), 129.2 (2C), 128.8 (2C), 127.9
128.4 (2C), 128.0 (2C), 127.8, 124.5, 124.2 (2C), 44.1; HRMS m/z (ESI,
Mþþ1) calcd for C16H15N2O3 283.1083, found 283.1082.
(2C), 127.7, 123.9, 121.0, 43.9; HRMS m/z (ESI, Mþþ1) calcd for
C16H15NOBr 316.0337, found 316.0337.

C.-C. Chen et al. / Tetrahedron 64 (2008) 10350–10354
10353
4.2.9. (E)-N-Benzyl-3-(2-bromophenyl)acrylamide (3ah)
suspension of sodium hydride (88 mg, 2.2 mmol, 60%) in dry THF
(10 mL). After the reaction mixture was stirred at room tempera-
ture for 30 min, the benzyl bromide derivative 2 (1.0 mmol) was
added to the solution. The resulting mixture was stirred at room
temperature for 12 h. After the reaction was complete (as indicated
by TLC), the reaction mixture was quenched with a saturated am-
monium chloride solution (1 mL) and the solvent was removed
with a rotary evaporator under reduced pressure. The residue was
diluted with water (10 mL) and extracted with EtOAc (3ꢂ10 mL).
The combined organic layer was washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated. The crude product
was purified by silica gel chromatography (n-hexane/ethyl
acetate¼4:1 to 2:1) to afford amides 3b.
Yield 76%; white solid; mp¼142–143 ꢁC; IR (CH2Cl2, cmꢀ1): 3276,
1650, 1612; 1H NMR (500 MHz, CDCl3)
d
8.0 (d, J¼16.0 Hz,1H), 7.61 (d,
J¼8.0 Hz,1H), 7.54 (d, J¼8.0 Hz,1H), 7.38–7.29 (m, 6H), 7.20 (dd, J¼9.0,
7.5 Hz, 1H), 6.37 (d, J¼16.0 Hz, 1H), 5.92 (br s, 1H), 4.60 (d, J¼5.5 Hz,
2H);13CNMR(125 MHz, CDCl3)
d165.1,139.9,138.0,135.0,133.4,130.7,
128.8 (2C), 128.0 (2C), 127.7, 127.59, 127.57, 125.1, 123.5, 43.9; HRMS
m/z (ESI, Mþþ1) calcd for C16H15NOBr 316.0337, found 316.0338.
4.2.10. (E)-N-Benzyl-3-(4-chlorophenyl)acrylamide (3ai)
Yield 53%; white solid; mp¼136–137 ꢁC; IR (CH2Cl2, cmꢀ1):
3430, 3278, 1666, 1626, 1512; 1H NMR (500 MHz, CDCl3)
d 7.63 (d,
J¼15.5 Hz, 1H), 7.42 (d, J¼8.0 Hz, 2H), 7.37–7.28 (m, 7H), 6.38 (d,
J¼15.5 Hz, 1H), 5.92 (br s, 1H), 4.58 (d, J¼5.5 Hz, 2H); 13C NMR
(125 MHz, CDCl3)
d
165.4, 140.1, 138.0, 135.6, 133.2, 129.1 (2C), 129.0
4.3.1. N,N-Diethyl-3-(4-nitrophenyl)acrylamide (3ba)
(2C),128.8 (2C),127.9 (2C),127.7,120.9, 43.9; HRMS m/z (ESI, Mþþ1)
Yield 85%; pale yellow solid; mp¼156–157 ꢁC; IR (CH2Cl2,
calcd for C16H15NOCl 272.0842, found 272.0840.
cmꢀ1): 2978, 1650, 1608, 1520; 1H NMR (500 MHz, CDCl3)
d 8.24 (d,
J¼9.0 Hz, 2H), 7.73 (d, J¼15.5 Hz, 1H), 7.66 (d, J¼9.0 Hz, 2H), 6.96
4.2.11. (E)-N-Benzyl-3-(3-chlorophenyl)acrylamide (3aj)
(d, J¼15.5 Hz, 1H), 3.54–3.48 (m, 4H), 1.29 (t, J¼7.0 Hz, 3H), 1.21
Yield 72%; white solid; mp¼108–109 ꢁC; IR (CH2Cl2, cmꢀ1):
(t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 164.7, 148.0, 141.7,
139.6, 128.3 (2C), 124.1 (2C), 122.1, 42.4, 41.2, 15.2, 13.1; HRMS m/z
3430, 3286, 1664, 1512; 1H NMR (500 MHz, CDCl3)
d
7.62 (d,
J¼15.5 Hz, 1H), 7.49 (s, 1H), 7.38–7.29 (m, 8H), 6.41 (d, J¼15.5 Hz,
(ESI, MþþNa) calcd for C13H16N2O3Na 271.1059, found 271.1057.
1H), 5.91 (br s, 1H), 4.59 (d, J¼5.5 Hz, 2H); 13C NMR (125 MHz,
CDCl3)
d
165.2, 140.0, 138.0, 136.6, 134.8, 130.1, 129.6, 128.8 (2C),
4.3.2. N,N-Diethyl-3-(2-cyanophenyl)acrylamide (3bb)
127.9 (2C), 127.7, 127.4, 126.2, 121.7, 43.9; HRMS m/z (ESI, Mþþ1)
Yield 81%; yellowish oil; IR (CH2Cl2, cmꢀ1): 3430, 2226, 1650,
calcd for C16H15NOCl 272.0842, found 272.0840.
1608; 1H NMR (500 MHz, CDCl3)
d
7.83 (d, J¼16.0 Hz, 1H), 7.70 (d,
J¼8.5 Hz, 1H), 7.64–7.59 (m, 2H), 7.43 (td, J¼7.5, 1.5 Hz, 1H), 7.17
4.2.12. (E)-N-Benzyl-3-(2-chlorophenyl)acrylamide (3ak)
(d, J¼16.0 Hz, 1H), 3.53–3.47 (m, 4H), 1.28 (t, J¼7.0 Hz, 3H), 1.21
Yield 79%; white solid; mp¼158–159 ꢁC; IR (CH2Cl2, cmꢀ1):
(t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 164.8, 138.4, 137.2,
3268, 1650; 1H NMR (500 MHz, CDCl3)
d
8.04 (d, J¼16.0 Hz, 1H),
133.8, 132.8, 129.0, 128.6, 123.5, 117.9, 111.2, 42.4, 41.1, 15.0, 13.1;
HRMS m/z (ESI, MþþNa) calcd for C14H16N2ONa 251.1160, found
251.1158.
7.56 (d, J¼7.5 Hz, 1H), 7.41 (d, J¼8.0 Hz, 1H), 7.38–7.24 (m, 7H), 6.42
(d, J¼16.0 Hz, 1H), 5.96 (br s, 1H), 4.59 (d, J¼6.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3)
d 165.2, 138.1, 137.3, 134.8, 133.1, 130.5, 130.2,
128.8 (2C),128.0 (2C),127.7,127.5,126.9,123.3, 43.9; HRMS m/z (ESI,
4.3.3. N,N-Diethyl-3-(3-chlorophenyl)acrylamide (3bc)
Mþþ1) calcd for C16H15NOCl 272.0842, found 272.0840.
Yield 79%; pale yellow oil; IR (CH2Cl2, cmꢀ1): 3412, 2976, 1650;
1H NMR (500 MHz, CDCl3)
d
7.64 (d, J¼15.5 Hz, 1H), 7.51 (s, 1H),
4.2.13. Synthesis of 3-(2-chlorophenyl)-N-[1-(3-
methoxyphenyl)ethyl] acrylamide (6)
7.39–7.30 (m, 3H), 6.82 (d, J¼15.5 Hz, 1H), 3.52–3.46 (m, 4H), 1.27 (t,
J¼7.0 Hz, 3H), 1.19 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
A solution of
a
-toluenesulfonyl acetamide 5 (347 mg, 1.0 mmol)
d 165.2, 140.7, 137.3, 134.7, 130.0, 129.3, 127.1, 126.2, 119.2, 42.3, 41.1,
in dry THF (5.0 mL) was added to a rapidly stirred suspension of
sodium hydride (88 mg, 2.2 mmol, 60%) in dry THF (10 mL). After
the reaction mixture was stirred at room temperature for 30 min, 2-
chlorobenzyl bromide 2k (1.0 mmol) was added to the solution. The
resulting mixture was stirred at room temperature for 12 h. After
the reaction was complete (as indicated by TLC), the reaction
mixture was quenched with a saturated ammonium chloride so-
lution (1 mL) and the solvent was removed with a rotary evaporator
under reduced pressure. The residue was diluted with water
(10 mL) and extracted with EtOAc (3ꢂ10 mL). The combined or-
ganic layer was washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated. The crude product was purified by silica
gel chromatography (n-hexane/ethyl acetate¼4:1 to 2:1) to afford
15.1, 13.1; HRMS m/z (ESI, MþþNa) calcd for C13H16ClNONa
260.0818, found 260.0819.
Acknowledgements
The authors would like to thank the National Science Council of
the Republic of China for financial support.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.08.057.
amides 6 as a white solid. 1H NMR (500 MHz, CDCl3)
d 7.99 (d,
References and notes
J¼15.5 Hz, 1H), 7.53 (dd, J¼7.5, 1.5 Hz, 1H), 7.39 (dd, J¼7.5, 1.0 Hz,
1H), 7.28–7.21 (m, 3H), 6.95 (d, J¼7.5 Hz, 1H), 6.91–6.90 (m, 1H),
6.81 (dd, J¼8.5, 2.5 Hz, 1H), 6.40 (d, J¼15.5 Hz, 1H), 6.02 (br d, 1H),
5.24 (m, 1H), 3.80 (s, 3H), 1.55 (d, J¼7.0 Hz, 3H); 13C NMR (125 MHz,
1. (a) The Chemistry of Alkenes; Patai, S., Ed.; Interscience: New York, NY, 1968; Vol.
2; (b) Shen, Y. Acc. Chem. Res. 1998, 31, 584.
2. (a) Andersen, R. J.; Coleman, J. E.; Piers, E.; Wallace, D. J. Tetrahedron Lett. 1997,
38, 317; (b) Toshima, K.; Arita, T.; Kato, K.; Tanaka, D.; Matsumura, S. Tetrahe-
dron Lett. 2001, 42, 8873; (c) Moses, J. E.; Baldwin, J. E.; Marquez, R.; Adlington,
R. M.; Cowley, A. R. Org. Lett. 2002, 4, 3731; (d) Davies, I. R.; Cheeseman, M.;
Niyadurupola, G.; Bull, S. D. Tetrahedron Lett. 2005, 46, 5547.
3. (a) Tomioka, K.; Suenaga, T.; Koga, K. Tetrahedron Lett. 1986, 27, 369; (b)
Oppolzer, W.; Kingma, A. J.; Poli, G. Tetrahedron 1989, 45, 479; (c) Melnyk, O.;
Stephan, E.; Pourcelot, G.; Cresson, P. Tetrahedron 1992, 48, 841; (d) Nicolas, E.;
Russell, K. C.; Hruby, V. J. J. Org. Chem. 1993, 58, 766; (e) Arai, Y.; Ueda, k.; Xie, j.;
Masaki, Y. Chem. Pharm. Bull. 2001, 49, 1609.
CDCl3)
d 164.4, 159.8, 144.7, 137.1, 134.7, 133.1, 130.4, 130.1, 129.8,
127.5, 126.9, 123.5, 118.5, 112.6, 112.3, 55.2, 49.0, 21.6; HRMS m/z
(ESI, Mþþ1) calcd for C18H19Cl NO2 316.1104, found 316.1106.
4.3. General procedure for the preparation of N,N-
disubstituted (E)-acrylamides (3b)
4. Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1981, 913.
5. (a) Nahm, M. R.; Potnick, J. R.; White, P. S.; Johnson, J. S. J. Am. Chem. Soc. 2006,
128, 2751; (b) Okitsu, T.; Saito, M.; Tamura, O.; Ishibashi, H. Tetrahedron 2006,
A
solution of
a-toluenesulfonyl acetamide 1b (269 mg,
1.0 mmol) in dry THF (5.0 mL) was added to a rapidly stirred

10354
C.-C. Chen et al. / Tetrahedron 64 (2008) 10350–10354
61, 9180; (c) Shintani, R.; Kitamura, T.; Hayashi, T. Chem. Commun. 2005, 3213;
Chem. Lett. 2004, 14, 1279; (e) Xu, J.; Burton, D. J. J. Org. Chem. 2005, 70, 4346; (f)
Park, J. H.; Kim, S. Y.; Kim, S. M.; Chung, Y. K. Org. Lett. 2007, 9, 2465; (g)
Concello´n, J. M.; Rodrıguez-Solla, H.; Dıaz, P. J. Org. Chem. 2007, 72, 7974.
9. For the glutaimide skeleton and its recent application, see: (a) Chen, H. W.; Hsu,
R. T.; Chang, M. Y.; Chang, N. C. Org. Lett. 2006, 8, 3033; (b) Tsai, T. H.; Chung, W.
H.; Chang, J. K.; Hsu, R. T.; Chang, N. C. Tetrahedron 2007, 63, 9825; (c) Huang, C.
C.; Chang, N. C. Org. Lett. 2008, 10, 673; (d) Chang, J. K.; Chang, N. C. Tetrahedron
2008, 64, 3483 For the glutamate skeleton and its recent application, see: (a)
Sun, P. P.; Chang, M. Y.; Chiang, M. Y.; Chang, N. C. Org. Lett. 2003, 5, 1761; (b)
Chang, M. Y.; Hsu, R. T.; Tseng, T. W.; Sun, P. P.; Chang, N. C. Tetrahedron 2004,
60, 5545.
(d) Koltunov, K. Y.; Walspurger, S.; Sommer, J. Eur. J. Org. Chem. 2004, 4039; (e)
Tosaki, S.-y.; Horiuchi, Y.; Nemoto, T.; Oshima, T.; Shibasaki, M. Chem.dEur.
J. 2004, 10, 1527; (f) Riber, D.; Skrydstrup, T. Org. Lett. 2003, 5, 229.
6. (a) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder Methodology in Organic
Synthesis; Academic: San Diego, CA, 1987; p 240; (b) Wei, L.-L.; Hsung, R. P.;
Sklenicka, H. M.; Gerasyuto, A. I. Angew. Chem., Int. Ed. 2001, 40, 1516; (c)
Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379; (d)
Takasu, K.; Nishida, N.; Ihara, M. Tetrahedron Lett. 2003, 44, 7429; (e) Takasu, K.;
Nishida, N.; Tomimura, A.; Ihara, M. J. Org. Chem. 2005, 70, 3957.
7. (a) Choo, H. Y. P.; Peak, K. H.; Park, J.; Kim, D. H.; Chung, H. S. Eur. J. Med. Chem.
2000, 35, 643; (b) Marrano, C.; de Macedo, P.; Keillor, J. W. Bioorg. Med. Chem.
2001, 9, 1923; (c) Zhang, H. Q.; Xia, Z.; Kolasa, T.; Dinges, J. Tetrahedron Lett.
2003, 44, 8661; (d) Schultz, T. W.; Yarbrough, J. W.; Koss, S. K. Cell Biol. Toxicol.
2006, 22, 339; (e) Putt, K. S.; Nesterenko, V.; Dothager, R. S.; Hergenrother, P. J.
ChemBioChem 2006, 7, 1916.
8. (a) Kojima, S.; Inai, H.; Hidaka, T.; Ohkata, K. Chem. Commun. 2000, 1795; (b)
Kojima, S.; Inai, H.; Hidaka, T.; Fukuzaki, T.; Ohkata, K. J. Org. Chem. 2002, 67,
4093; (c) Fortin, S.; Dupont, F.; Deslongchamps, P. J. Org. Chem. 2002, 67, 5437;
(d) Weber, C.; Bielik, A.; Szendrei, G. I.; Keseru, G. M.; Greiner, I. Bioorg. Med.
10. There is no clear rationale for the production of (E)-3ab and (Z)-3ab in an 82:18
ratio.
11. (a) Nagano, N. Pharmacol. Ther. 2006, 109, 339; (b) Steddon, S. J.; Cunningham, J.
Lancet 2005, 365, 2237; (c) Nemeth, E. F. Curr. Pharm. Des. 2002, 8, 2077; (d)
Steffey, M. E.; Fox, J.; Van Wagenen, B. C.; Delmar, E. G.; Balandrin, M. F.;
Nemeth, E. F. J. Bone Miner. Res. 1993, 8, S175; (e) Silverberg, S. J.; Bone, H. G.;
Marriott, T. B., III; Locker, F. G.; Thys-Jacobs, S.; Dziem, G.; Kaatz, S.; Sanguinetti,
E. L.; Bilezikian, J. P. N. Engl. J. Med. 1997, 337, 1506.
12. Ferna´ndez, I.; Valdivia, V.; Khiar, N. J. Org. Chem. 2008, 73, 745.