Zinc-mediated facile synthesis of α,β-unsaturated primary amides

Article abstract of DOI:10.3184/030823410X520741

A general method for the synthesis of α,β-unsaturated primary amides was achieved by an one-pot, triphenylphosphine-and zinc powder-promoted Wittig reaction of bromoacetamide and aldehydes under solvent-free conditions.

Full text of DOI:10.3184/030823410X520741

382 RESEARCH PAPER
JULY, 382–384
JOURNAL OF CHEMICAL RESEARCH 2010
Zinc-mediated facile synthesis of a,b-unsaturated primary amides
Sunlin Feng, Zhiying Zhang, Shilei Jiang and Xiaochun Yu*
College of Chemistry and Materials Engineering, Wenzhou Universtity, Wenzhou 325035, P. R. China
A general method for the synthesis of a,b-unsaturated primary amides was achieved by an one-pot, triphenylphos-
phine- and zinc powder-promoted Wittig reaction of bromoacetamide and aldehydes under solvent-free conditions.
Keywords: unsaturated primary amide, solvent-free, zinc powder, triphenylphosphine
α,β-Unsaturated amides have been used as building blocks in
the preparation of deplancheine, tacamonine and paroxetine.1
A number of synthetic acrylamide derivatives have also
shown important biological and insecticidal activities.2 Many
methods for the synthesis of α,β-unsaturated primary amides
have been developed,3–11 including the condensation of α,β-
unsaturated carboxylic acid and carbonyl compounds with
different reagents,4–8 the hydrolysis of α,β-unsaturated nitriles,9
the coupling reaction of acrylamides with aryl halides,10 and
the rearrangement of oximes.11 However, in many cases these
methods were of limited scope. The Wittig reaction12 is one of
the most important general methods for the construction
of carbon–carbon double bonds, and as a part of our studies
on developing new Wittig reactions,13–16 we considered devel-
oping a general route to α,β-unsaturated primary amide via a
Wittig method.
Since there has been no report of the Wittig synthesis of α,β-
unsaturated primary amides from an amidomethylene triphe-
nylphosphoraneylide1withaldehydes,weinitiallyinvestigated
the reaction by mixing 1 with 4-nitrobenzaldehyde 2a under
the usual conditions (Scheme 1). However, the product 3a was
only obtained in less than 10% yield even after a series of
modifications to the conditions. Satoshi and coworkers’s have
reported that more complicated phosphines could be employed
to replace triphenyl phosphine to improve the reactivity of the
ylid.17 Consequently we concluded that it might not be a
good method to use 1 as the starting material, since it might
be too stable and thus difficult to react with aldehydes.
Various modifications were attempted including changing the
substrates. Subsequently, we found that the reaction using
bromoacetamide 4 as the substrate to react with aryl aldehydes
in the presence of triphenylphosphine and metal powders was
a direct and efficient method (Scheme 2). Zinc powder was the
metal of choice (see Table 1).
As shown in Table 1, the reaction did not occur in the
absence of a metal (entry 1). However, when Fe, Zn, or Zn-Cu
powder was added, there was a low yield at 60 °C in CH2Cl2
when the reactions were carried out in a sealed tube (entries
2–4). Zinc powder was then used in the following modifica-
tions of the conditions to examine the solvent and temperature
effects (entries 5–10). Firstly, prolonged reaction time gave no
obvious enhancement in product yield. Then other solvents
were investigated and it was found the reaction was best
run under solvent-free conditions (entry 10). Later 150 °C
(entry 12) was found to be a better temperature than lower or
higher ones (entries 10–13), giving high yield of 3a. As to the
stereoselectivity of the reaction, it has been reported that the
chemical shifts of the vinyl protons of (Z)-α,β-unsaturated
Table 1 Condition optimisation for the metal-mediated
synthesis of a,b-unsaturated primary amides
Entry Solvent
Temp
/°C
Metallic
reagent
Time
/h
Yield
/%a
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3OH
THF
60
60
—
Fe
3
3
3
3
6
3
3
3
3
3
3
3
3
—
25
43
42
44
42
44
40
41
50
75
90
86
3
60
Zn
4
60
Zn-Cu
Zn
5
60
6
60
Zn
7
80
Zn
8
CH3CN
DMF
—
80
Zn
9
120
120
140
150
160
Zn
10
11
12
13
Zn
—
Zn
—
Zn
—
Zn
a Isolated combined yield of (E)- and (Z)-isomers of 3a, with E/Z
ratios around 88/12.
Scheme 1
Scheme 2
* Correspondent. E-mail: chinaxiaochunyu@126.com

JOURNAL OF CHEMICAL RESEARCH 2010 383
Scheme 3
Preparation of 3a–i; general procedure
amides were usually at lower field than the corresponding
(E)-isomers.18 Thus, chemical shifts of vinyl protons of
(E)-4-nitrocinnamamide 3a (6.65 ppm) and the (Z)-isomer
(6.24 ppm) obtained in present reactions were in accordance
with the literature data.18 The conditions employed as above
did not alter the (E)- and (Z)-isomer ratios, which were usually
88/12.
The mixture of triphenylphosphine (0.314 g, 1.2 mmol), bromoacet-
amide (0.164 g, 1.2 mmol), aldehydes (1.0 mmol) and zinc (1.2 mmol)
in a sealed oven-dried tube was heated at 150 °C for 3 h. The products
were purified by chromatography on silica gel using ethyl acetate and
petroleum ether (60–90 °C) as the eluent but the E/Z isomers could
not be separated.
4-Nitrocinnamamide (3a):18 1H NMR (300 MHz, DMSO) of
(E)-isomers: δ 6.22 (d, J = 15 Hz, 1H), 6.80 (d, J = 15 Hz, 1H), 7.80–
7.84 (m, 2H), 8.16–8.26 (m, 2H). EI-MS m/z (%): 51.10 (14.50),
77.15 (22.91), 152.15 (11.67), 183.05 (14.69), 192.05 (M+, 24.63). IR
(cm−1): 3370, 3175, 1665, 1520, 1340, 980.
The method was then applied to various substrates to inves-
tigate the scope of the reaction for the synthesis of different
α,β-unsaturated primary amides (Scheme 3). As shown in
Table 2, all aromatic aldehydes reacted well under the optimal
solvent-free condition, giving moderate to high product yields
(entries 1–8). The reaction of aliphatic aldehydes was not
always successful (entry 10), and a vinylic aldehyde gave
moderate yield (entry 9). The results also showed that more
electrophilic aldehydes bearing electon-withdrawing groups
(entries 1–5) gave higher yields (86–90%). Benzaldehyde gave
only a moderate yield (72%, entry 6), and aromatic aldehydes
with electron-donating groups (entries 7–8) even lower yields
2-Nitrocinnamamide (3b):19 1H NMR (300 MHz, DMSO) of
(E)-isomers: δ 6.61 (d, J = 16.0 Hz, 1H), 7.54–7.78 (m, 5H). EI-MS
m/z (%): 51.10 (53.70), 59.60 (0.15), 65.15 (72.51), 77.15 (59.50),
92.15 (65.59), 102.15 (46.21), 117.15 (49.94), 192.20 (M+, 100). IR
(cm−1): 3453, 3145, 1624, 1392, 966, 861.
4-Bromocinnamamide (3c):20 1H NMR (300 MHz, DMSO) of
(E)-isomers: δ 6.62 (d, J = 16.0 Hz, 1H), 7.35–7.65 (m, 5H); EI-MS
m/z (%): 51.10 (31.56), 58.65 (5.88), 76.15 (22.97), 130.20 (12.52),
226.05 (M+, 27.33). IR (cm−1): 3340, 3163, 1671, 1386, 987, 820.
4-Chlorocinnamamide (3d):18 1H NMR (300 MHz, DMSO) of
(E)-isomers: δ 6.61 (d, J = 16.0 Hz, 1H), 7.37–7.65 (m, 5H). EI-MS
m/z (%): 51.10 (45.29), 58.65 (11.76), 76.10 (17.57), 128.20 (14.03),
137.15 (72.66), 181.10 (M+, 52.89). IR (cm−1): 3335, 3150, 1670,
1090, 990, 830.
1
(61–63%). All products were identified by MS, IR and H
NMR spectra. The E/Z ratios of the isomers were determined
1
by H NMR spectra but it was not possible to separate the
isopmers.
In conclusion, α,β-unsaturated primary amides, which could
not be obtained by a normal Wittig reaction using an ylid,
could be easily Obtained through a direct, one-pot, zinc- and
triphenylphosphine-mediated reaction with bromoacetamide
and aldehydes under solvent-free conditions. The reaction
did not require the use of any volatile organic solvents and
expensive metallic reagents. Thus, it could be an economic,
convenient, and environmentally-friendly method for the
synthesis of α,β-unsaturated primary amides.
4-Trifluoromethylcinnamamide (3e):21 1H NMR (300 MHz, DMSO)
of (E)-isomers: δ 6.74 (d, J = 16.0 Hz, 1H), 7.45–7.64 (m, 5H). EI-MS
m/z (%): 51.10 (10.46), 58.65 (1.55), 77.10 (3.67), 102.15 (23.88),
151.15 (68.31), 215.10 (M+, 42.79), 215.10 (48.18). IR (cm−1): 3341,
3169, 1669, 1395, 987, 835.
Cinnamamide (3f):22 1H NMR (300 MHz, DMSO) of (E)-isomers:
δ 6.62 (d, J = 16.0 Hz, 1H), 7.29–7.78 (m, 5H). EI-MS m/z (%):
51.10(11.61), 65.15(22.32), 77.15(6.43), 147.20 (M+, 50.18). IR
(cm−1): 3370, 3165, 1664, 1598, 967, 760.
4-Methylcinnamamide (3g):18 1H NMR (300 MHz, DMSO) of
(E)-isomers: δ 2.29 (s, 3H), 6.53 (d, J = 16.0 Hz, 1H), 7.18–7.43
(m, 5H). EI-MS m/z (%): 51.10 (11.61), 65.15 (22.32), 77.15 (6.43),
91.15 (42.95), 145.20 (53.90), 161.20 (M+, 56.76); IR (cm−1): 3320,
3145, 1665, 1390, 990, 820.
Experimental
Starting materials were obtained from commercial suppliers and
used without further purification. DMF was distilled from calcium
hydride and THF was distilled from sodium/benzophenone prior to
2-Methoxycinnamamide (3h):23 1H NMR (300 MHz, DMSO) of
(E)-isomers: δ 3.85 (s, 3H), 6.61 (d, J = 16.0 Hz, 1H), 7.05–7.67
(m, 5H). EI-MS m/z (%): 59.15 (2.14), 77.15 (15.81), 89.15 (14.46),
105.20 (13.12), 118.15 (16.58), 177.15 (M+, 100). IR (cm−1): 3374,
3174, 1658, 1400, 975, 753.
1
use. H NMR (300 MHz) spectra were recorded on a Bruker Avance
(300 MHz) spectrometer, using d6-DMSO as the solvent and TMS as
internal standard. Mass spectra (EI, 70 eV) were recorded on a
HP5989B mass spectrometer. IR spectra were recorded on a Shimadzu
IR-408 spectrometer.
5-Phenylpenta-2,4-dienamide (3i):24 1H NMR (300 MHz, DMSO)
of (E)-isomers: δ 6.12 (d, J = 16.0 Hz, 1H), 7.03–7.65 (m, 8H). EI-MS
m/z (%): 51.10 (16.01), 59.65 (1.85), 77.15 (16.04), 96.15 (24.03),
102.15 (12.09), 173.15 (M+, 22.61). IR (cm−1): 3342, 3145, 1666,
1391, 1001, 752.
Table 2 Zinc-mediated synthesis of a,b-unsaturated primary
amides
We thank the Natural Science Foundation of Zhejiang
Province (Y205540) for the financial support.
Entry
Product
R
Yield /%a
E/Z b
1
2
3a
3b
3c
3d
3e
3f
4-NO2C6H4
2-NO2C6H4
4-BrC6H4
4-ClC6H4
4-CF3C6H4
C6H5
4-CH3C6H4
2-CH3OC6H4
C6H5CH=CH
C3H7
90
89
88
86
89
72
65
63
61
—
88/12
90/10
70/30
70/30
83/17
70/30
75/25
80/20
88/12
—
Received 19 March 2010; accepted 21 May 2010
Paper 1000012 doi: 10.3184/030823410X520741
Published online: 28 July 2010
3
4
5
6
7
3g
3h
3i
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