An Efficient Solvent-Free Microwave-Assisted Synthesis of Cinnamamides by Amidation Reaction Using Phenylboronic Acid/Lewis Base Co-catalytic System

Article abstract of DOI:10.1055/s-0039-1690132

A microwave-assisted dehydrative amide condensation reaction is reported as an efficient access to cinnamamide derivatives under solvent-free conditions. This protocol between conjugated carboxylic acids and amines is based on the use of a co-catalytic system, including the presence of the commercially available phenylboronic acid and 4-(N, N-dimethylamino)pyridine N-oxide (DMAPO), with a complete chemoselectivity in favor of the corresponding α,β-unsaturated amides. The implementation of the reaction needs no special precaution, and less reactive amines, such as substituted anilines, are also efficient under these conditions. A series of novel conjugated amides have been evaluated for their cytotoxic activities against several human cancer cell lines.

Full text of DOI:10.1055/s-0039-1690132

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
paper
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en
K. Khaldoun et al.
Paper
Synthesis
An Efficient Solvent-Free Microwave-Assisted Synthesis of
Cinnamamides by Amidation Reaction Using Phenylboronic
Acid/Lewis Base Co-catalytic System
Khadidja Khaldouna
PhB(OH)2 (cat.)
Lewis base (cat.)
O
O
Abdelmounaim Safera
Salima Saidi-Besbesa
Bertrand Carbonib
Rémy Le Guévelc
0
0
0
0-
0
0
0
2-9
8
0
3-7
0
1
7
R
+
R
NH2
Ar
N
Ar
OH
H
32 examples
42–72%
Microwave
Highly chemoselective
Solvent-free conditions
Efficient with aromatic
amines
François Carreaux*b
0
0
0
0-0
0
0
2-7
4
0
6-
8
3
5
3
Metal-free conditions
a Laboratoire de synthèse organique appliqué, Université
Oran1, Bp 1524 El M’naouer 31000 Oran, Algeria
b Univ Rennes, CNRS, ISCR, UMR 6226, 263 avenue du Général
Leclerc, Campus de Beaulieu, 35000 Rennes, France
francois.carreaux@univ-rennes1.fr
c Univ Rennes, ImPACell Platform, SFR Biosit, 2 avenue du Prof.
Léon Bernard, 35043 Rennes, France
Short reaction time
Received: 14.06.2019
Accepted after revision: 08.07.2019
Published online: 29.07.2019
O
O
O
O
R1
R2
O
N
H
N
DOI: 10.1055/s-0039-1690132; Art ID: ss-2019-t0333-op
H
O
Abstract A microwave-assisted dehydrative amide condensation reac-
tion is reported as an efficient access to cinnamamide derivatives under
solvent-free conditions. This protocol between conjugated carboxylic
acids and amines is based on the use of a co-catalytic system, including
the presence of the commercially available phenylboronic acid and 4-
(N,N-dimethylamino)pyridine N-oxide (DMAPO), with a complete che-
moselectivity in favor of the corresponding ,-unsaturated amides.
The implementation of the reaction needs no special precaution, and
less reactive amines, such as substituted anilines, are also efficient un-
der these conditions. A series of novel conjugated amides have been
evaluated for their cytotoxic activities against several human cancer cell
lines.
Cinnamamide derivatives
Dioxamin
O
O
O
O
O
O
N
O
O
N
H
O
O
Rubescenamin
Piplartine
Figure 1 Some examples of natural cinnamamides
transient-activated carboxylic acid.11 Coupling reagents are
generally employed in an efficient manner but the process
generates one equivalent of waste that renders the purifica-
tion of the expected amide in a pure form much more diffi-
cult. Considering the relevance of amide functionality in
the drug development process,12 the implementation of cat-
alytic systems to perform the dehydrative condensation re-
action starting from carboxylic acids and amines has be-
come a very challenging goal.13 Several metal-based cata-
lysts have been developed to this end.14 Among metal-free
methods, the use of boronic acids as catalysts is particularly
suitable for the preparation of compounds of biological in-
terest due to their easy removal from the reaction mixture
and their apparent non-toxicity.15 Moreover, they are stable
to air and moisture making them easier to handle. Different
effective boron-based catalysts have been investigated suc-
cessfully since the pioneering works of Yamamoto’s group
in this field.16
Key words cinnamamide derivatives, direct amide formation, boronic
acid, microwave heating, catalytic system
Cinnamamide derivatives constitute a class of com-
pounds with an important therapeutic potential. Some of
them are natural products which can be found, more specif-
ically, in plants of Rutaceae such as Zanthoxylum rubescens1
as well as in several Piper species (Piperaceae)2 (Figure 1). In
the field of anticancer therapy, piplartine represents a very
interesting compound as shown by in vitro and in vivo pre-
clinical researches.3 This class of compounds also exhibits
other biological activities, such as antimicrobial,4 antioxi-
dant,5 antiviral,6 antidepressant,7 and anti-inflammatory
effects.8 Moreover, the introduction of a cinnamamide scaf-
fold in organic compounds can improve or modify their
pharmacological activities, for instance, in the case of cen-
tral and peripheral nervous system disorders.9,10
Generally, the use of commercially available arylboronic
acids with electron-withdrawing substituents as catalysts
requires elevated temperatures in an organic solvent and
extremely long reaction times for a good conversion into
The ,-unsaturated amide moiety can be prepared by
condensation from cinnamic acids and amines using tradi-
tional, stoichiometric approaches via the formation of a
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
K. Khaldoun et al.
Paper
Synthesis
the desired amide. Nevertheless the direct amidation reac-
tion can take place in more mild conditions using specially
designed catalysts obtained by several more or less tedious
synthetic transformations.17 Immobilized boronic acids as
reusable catalysts have also been prepared.18 In view of the
existing literature, it is interesting to note that aliphatic
amines are generally employed in most catalytic processes
developed with arylboronic acids. In contrast, arylamines
are scarcely used as model substrates to assess the generali-
ty of methods probably due to their weaker nucleophilicity.
On the other hand, to the best of our knowledge, only few
examples of cinnamamide derivatives have been prepared
using these boron-catalytic systems.19 That may be ex-
plained by the low reactivity of conjugated acids, but also
by the presence of two electrophilic sites, which can gener-
ate the formation of a side-product resulting from an aza-
Michael addition. Indeed, this issue of chemoselectivity is a
major drawback with this class of substrates that was previ-
ously recognized in the works of Ishihara et al.19b Using a
cooperative catalytic process in the presence of arylboronic
acids under azeotropic reflux conditions during several
hours, the reaction between cinnamic acid derivatives and
amines led to the formation of the corresponding conjugat-
ed amides in the presence of Michael adducts with a selec-
tivity ranging from 82 to 99%.
try 2). A longer irradiation time had no significant impact
on the conversion (entry 3). Note that in the absence of bo-
ric acid, a very low conversion rate was obtained (entry 4).
Under the same conditions, with the replacement of boric
acid by phenylboronic acid as stronger Lewis acid, the con-
version rate reached 45% (entry 5). The additional use of a
catalytic amount of nucleophilic additives such as N,N-di-
isopropylethylamine (i-Pr2EtN) and 4-(N,N-dimethylami-
no)pyridine (DMAP) was not effective (entries 6 and 7). In
contrast, the addition of DMAPO as co-catalyst was crucial
for the formation of the conjugated amide in a good conver-
sion (entry 8). Under these new conditions, the chemose-
lectivity observed was very high (>95%) since no product
resulting from a Michael reaction was detected by 1H NMR
analysis of the crude mixture. The reaction was very clean
allowing the purification of compound 3aa in a simple
manner, by solvent extraction processes in order to elimi-
nate the unreacted starting materials, thus avoiding a col-
umn chromatography. The order of addition of catalysts had
no effect on the yield (65%). The significance of two cata-
lysts for an efficient amidation reaction was highlighted
when only DMAPO was used (entry 9). It is important to
mention that the implementation of this cooperative cata-
Table 1 Optimization of Protocola
Considering our interest to develop efficient environ-
mentally friendly methodologies giving access to com-
pound libraries of biological interest,20 we envisaged to in-
vestigate the utility of the microwave technology as a non-
conventional energy source, coupled with the use of inex-
pensive catalytic boronic acids, for a new practical and gen-
eral preparation of cinnamamide derivatives by direct ami-
dation.21 Indeed, to the best of our knowledge, this is the
first study for this kind of reaction combining these two pa-
rameters. In this paper, we report our outcomes on this mi-
crowave-assisted approach for this kind of reaction using
boronic acids. The dehydrative condensation between cin-
namic acid derivatives and amines using a catalytic amount
of phenylboronic acid and 4-(dimethylamino)pyridine N-
oxide (DMAPO) can be performed efficiently under micro-
wave dielectric heating with an excellent selectivity in
moderate-to-good yields. The reaction takes place in a short
time (15 min) without solvent and the conditions are also
effective with arylamines. The new conjugated amides ob-
tained were evaluated for their in vitro possible antitumor
activity against several human cancer cell lines.
As amine of choice to optimize the protocol, 4-me-
thoxyaniline (2a) was selected to react with (E)-3-(3,4-di-
methoxyphenyl)acrylic acid (1a) in an equimolar ratio (Ta-
ble 1). First of all, the reaction was tried using boric acid as
catalyst (5 mol%) under different solvent-free microwave
conditions taking into account that no formation of the de-
sired amide was observed in toluene at reflux for 12 hours
(Table 1, entry 1). The best conversion of 3aa was obtained
at 200 °C with 100 W microwave power for 15 minutes (en-
O
O
OH
O
1a
RB(OH)2 (5 mol%)
Additive (5 mol%)
O
O
O
Ar
Ar
N
+
H
ArNH2
3aa
NH
2
Conditions A:
reflux, toluene, 12 h
Conditions B:
MWI, 200 °C, 100 W,
15 min
Conditions C:
Ar
O
Ar = 4-MeOC6H4, 2a
O
N
H
O
not observed
200 °C, neat, 45 min
Entry
R
Additive
Conditions Conv (%)b
Yield (%)c
1
2
OH
OH
OH
–
–
Ad
B
–
–
–
–
30
35
8
3
–
Be
B
–
4
–
–
5
Ph
Ph
Ph
Ph
–
–
B
45
45
48
80
15
17
–
6
i-Pr2NEt
DMAP
DMAPO
DMAPO
DMAPO
B
–
7
B
–
8
B
65
–
9
B
10
Ph
C
–
a Reaction scale: 1a (0.5 mmol), 2a (0.5 mmol).
b Conversion based on 1a.
c Isolated yield of pure product.
d Toluene (0.1 M).
e Reaction time: 30 min instead of 15 min.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

C
K. Khaldoun et al.
Paper
Synthesis
lytic system under conventional thermal conditions
(200 °C, neat, 45 min) led to the formation of 3aa in a low
conversion rate showing the utility of microwave dielectric
heating under solventless conditions (entry 10).
With these optimized conditions in hands, we explored
the scope of this method employing a series of arylamines 2
and unsaturated carboxylic acids 1 (Scheme 1).
diate generated from the carboxylic acid and phenylboronic
acid before reaction with the nucleophile.24 The steric hin-
drance had no major impact on the yield (3aa vs 3ab). Elec-
tron-deficient arylamines have also been tested with less
success. In effect, the conjugated amide 3ae coming from
the reaction between 1a and 4-bromoaniline can be ob-
tained with a low conversion rate by increasing the micro-
wave power and irradiation time. Using alkylamines 4 as
more reactive nucleophiles, no significant effect on the iso-
lated yield was observed regardless of the electron density
of conjugated carboxylic acid engaged (Scheme 2). The high
PhB(OH)2 (5 mol%)
DMAPO (5 mol%)
Ar
O
O
ArNH2
+
Ar
OH
Ar
N
H
200 °C, 100 W, 15 min
2
1
3
O
O
PhB(OH)2 (5 mol%)
DMAPO (5 mol%)
O
O
O
O
O
O
NH2
N
H
R
N
R
+
Ar
OH
Ar
N
H
O
H
200 °C, 100 W, 15 min
O
1
4
5
3aa, 65%
3ab, 71%
O
R = alkyl
O
O
O
O
O
O
O
O
O
O
O
N
H
N
N
N
H
H
H
3ba, 57%
O
3ac, 55%
5ab, 68%
5aa, 65%
O
O
O
O
O
O
O
O
O
O
N
N
H
N
N
N
H
H
H
O
3bc, 49%
5ad, 62%
5ac, 60%
3bb, 61%
O
O
O
O
O
N
H
O
N
N
N
H
H
H
3bd, 50%
5bb, 60%
3be, 55%
5ba, 58%
O
O
O
O
O
N
N
H
N
H
N
H
N
H
O
5bc, 63%
5bd, 55%
F
3ca, 40%
F
3cb, 48%
O
O
O
O
O
O
N
H
N
H
N
N
H
H
O
CF3
5bf, 64%
5be, 64%
F
F
3ce, 42%
3cd, 42%
O
O
N
Br
O
N
H
N
N
H
O
O
N
H
5bg, 44%
5bh, 49%
3ae, conv. 30%a
O
O
Scheme 1 Substrate scope of the reaction using aryl amines. Reagents
and conditions: 1 (0.5 mmol), 2 (0.5 mmol), PhB(OH)2 (5 mol%),
DMAPO (5 mol%), 200 °C, 100 W, 15 min. Isolated yields are shown.
a 200 °C, 200 W, 30 min.
N
H
N
H
F
F
5ca, 58%
5cb, 60%
O
O
N
N
H
N
H
All compounds 3 were obtained in a highly chemoselec-
tive manner with moderate-to-good isolated yields. Some
of them can be regarded as new analogues of very potent
vanilloid receptor TRPV1 antagonists, such as AMG-981022
and SB-366791.23 For the same arylamine, the better yields
were obtained from the more electron-rich conjugated car-
boxylic acid 1a when compared with 1b and 1c (see for ex-
ample, 3aa, 3ba, and 3ca). That could be explained by a po-
tentially easier formation of the mixed anhydride interme-
F
CF3
F
5cc, 65%
5cf, 64%
O
N
H
F
Br
5ci, 67%
Scheme 2 Substrate scope of the reaction using alkyl amines. Reagents
and conditions: 1 (0.5 mmol), 4 (0.5 mmol), PhB(OH)2 (5 mol%),
DMAPO (5 mol%), 200 °C, 100 W, 15 min. Isolated yields are shown.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

D
K. Khaldoun et al.
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Synthesis
chemoselectivity in favor of the conjugated amide forma-
tion was maintained. All compounds 5 were generally ob-
tained in a pure form without having to perform a chro-
matographic purification, except for 5ad, 5bc, 5bg, and
5bh.25 Our efforts to introduce secondary amines such as N-
allylbenzylamine in a satisfactory way failed.
Table 2 Antiproliferative Activity of Cinnamamides 3 and 5 on Seven
Representative Tumor Cell Linesa
Compound Huh7
Caco2
MDA
MCF7 HCT116 PC3
NCI
Roscovitine 71 (14)b 80 (18)b 68 (15)b 30 (9)b 30 (9)b 73 (10)b 74 (28)b
3aa
3ab
3be
3ca
3cb
3ce
5ad
97
99
89
87
71
86
99
100
87
104
110
110
107
108
113
107
87
68
63
65
62
54
107
103
114
90
101
100
99
109
92
87
91
93
88
It should be emphasized that the natural product 5bb26
was obtained in 15% yield under conventional thermal con-
ditions using the same catalyst.19b Subsequently in order to
assess the functional group tolerance of this process, we de-
cided to prepare a cinnamamide derivative possessing a bo-
ryl substituent, which could be a useful synthetic building
block (Scheme 3). At first, we speculated that the trans-4-
(2-carboxyethenyl)benzeneboronic acid (1d), prepared
from (4-formylphenyl)boronic acid, could serve both as
starting material and catalyst. Unfortunately, treatment of
1d with the (4-trifluoromethyl)phenyl)methanamine (4f)
in the presence of DMAPO under microwave irradiation
(200 °C, 100 W, 15 min) afforded a complex mixture of
compounds. The addition of catalytic amount of phenylbo-
ronic acid in the reaction medium had no effect. Finally, the
desired new organoboron compound was obtained under
the previously optimized conditions, after esterification of
boronic acid group with pinacol. The yield of 5df was mod-
erate (30% over two steps), but can be considered as accept-
able due to its difficult purification on silica gel.
94
94
92
98
100
97
89
95
94
90
97
62
81
100
(>25)b
(>25)b
(>25)b
(22)b (27)b
(73)b
(>25)b
5bc
5bg
5ca
5cb
5cc
5cf
96
104
95
102
107
9 4
104
104
100
96
99
112
104
92
106
94
109
112
101
110
114
109
106
107
106
112
92
101
118
103
93
97
96
88
103
94
98
123
115
92
102
100
105
100
100
95
105
98
5ci
89
a Percentage of survival measured at 25 M.
b IC50 values in parentheses are expressed in M and are the average of three
assays, standard error ± 0.5 M.
In conclusion, the synthesis of a library of cinnamamide
derivatives was reported based on a new catalytic direct
amidation reaction under microwave conditions. Using a
convenient solventless procedure, the combination of
phenylboronic acid with DMAPO proved to be an efficient
co-catalytic system for the highly chemoselective prepara-
tion of conjugated amides. This methodology is comple-
mentary with those described employing boronic acid cata-
lysts since a large variety of less reactive amines such as an-
iline derivatives also led to the formation of the desired
amides. Unfortunately, electron-deficient arylamines con-
tinue to be not suitable substrates under these conditions.
Besides that these new ,-unsaturated amides could also
be useful as building blocks in organic synthesis.27 A mod-
erate cytotoxic activity of some of them was unveiled.
O
Malonic acid, pyridine
CHO
OH
piperidine, reflux, 12 h
(HO)2B
(HO)2B
90%
1d
O
N
1) Pinacol, Et2O, r.t., 12 h
H
O
B
CF3
2) 4f, PhB(OH)2 (5 mol%)
DMAPO (5 mol%), MWI
200 °C, 100 W, 15 min
5df, 30%
O
Scheme 3 Synthesis of a borylated derivative 5df
Given that some cinnamamide derivatives were new, we
took the opportunity to evaluate them for their in vitro po-
tential cytotoxicity against selected human cancer lines
such as hepatocellular carcinoma (Huh7), colorectal adeno-
carcinoma (Caco 2), breast (MDA and MCF7), colorectal car-
cinoma (HCT 116), prostate (PC3), and lung (NCI) (Table 2).
The percentage of cell survival was measured at single
dose of 25 M. The IC50 values were determined only for the
compounds exhibiting a survival percentage below 55% in
triplicate, using roscovitine as reference (Table 2). Only
compound 5ad exhibited a moderate antitumor activity
All commercially available chemicals were used without further puri-
fication. NMR spectra were recorded at 300 or 400 MHz for 1H and 75
or 101 MHz for 13C. Chemical shifts for 1H are expressed in parts per
million downfield from TMS as an internal standard. Data are given in
the following order: chemical shift, multiplicity (standard abbrevia-
tions), coupling constant J (Hz), and integration. Microwave reactions
(S2 Wave platform SPS ScanMAT, Rennes) were carried out using an
Anton Paar Monowave 300® microwave reactor (Anton Paar France)
using 10 mL borosilicate glass vials equipped with snap-caps (at the
end of the irradiation, cooling the reaction mixture was realized by
compressed air). The microwave consists of a continuous focused mi-
crowave power output from 0 to 300 W. All the experiments were
performed using stirring option. The target temperature is reached
against MCF7 and HCT 116 cell lines (IC = 22 M and 27
50
M, respectively). However, a certain selectivity must be
underlined with respect to other cell lines tested, which
could justify further structure–activity relationship studies.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

E
K. Khaldoun et al.
Paper
Synthesis
with a ramp of 4 min and the chosen microwave power stay constant
to hold the mixture at this temperature. The reaction temperature
was monitored using calibrated infrared sensor and the reaction time
includes the ramp period. All high-resolution mass spectra (HRMS)
were recorded on a Bruker Micro-Tof-Q II or on a Waters Q-Tof 2 at
the CRMPO (Centre Régional de Mesures de Physiques de l’Ouest,
Rennes, France) using positive ion electronspray. Melting points were
measured on a melting point apparatus Stuart SMP10. Purifications
on a silica gel were carried out on an Acros silica gel 0.006–0.200 nm,
60 A. Analytical TLC was performed on Merck Silica gel 60 F254 plates.
Cinnamic acid (1b) is commercially available [CAS Reg. No. 140-10-3].
1H NMR (300 MHz, CDCl3):  = 8.53 (d, J = 7.5 Hz, 1 H), 7.97–7.92 (br s,
1 H), 7.68 (d, J = 15.5 Hz, 1 H), 7.15 (dd, J = 8.3, 1.8 Hz, 1 H), 7.12–6.96
(m, 3 H), 6.93–6.85 (m, 2 H), 6.46 (d, J = 15.5 Hz, 1 H), 3.94 (s, 3 H),
3.92 (s, 6 H).
13C NMR (75 MHz, CDCl3):  = 163.9, 150.7, 149.1, 147.8, 127.9, 127.7,
123.6, 122.3, 121.2, 119.9, 119.1, 111.0, 109.9, 109.7, 55.9, 55.7.
HRMS (EI): m/z calcd for C18H19NO4Na [M + Na]+: 336.1206; found:
338.1208.
(E)-N-(Benzo[d][1,3]dioxol-5-yl)-3-(3,4-dimethoxyphenyl)acryl-
amide (3ac)
Prepared from 1a and benzo[d][1,3]dioxol-5-amine (2c). Purified by
column chromatography using cyclohexane/EtOAc (3:1) as eluent.
The product 3ac was isolated as a light brown solid; yield: 90 mg
(55%); mp 190–191 °C.
1H NMR (300 MHz, CDCl3):  = 7.69 (d, J = 15.5 Hz, 1 H), 7.42–7.38 (br
s, 1 H), 7.14 (dd, J = 8.2, 2.0 Hz, 1 H), 7.07 (d, J = 2.0 Hz, 1 H), 6.92–6.86
(m, 2 H), 6.78 (d, J = 8.2 Hz, 1 H), 6.41 (d, J = 15.5 Hz, 1 H), 5.98 (s, 2 H),
3.93 (s, 6 H).
Cinnamic Acid Derivatives 1; General Procedure
To a stirred solution of aldehyde (4.5 mmol) in pyridine (25 mL) was
added malonic acid (10 mmol) and piperidine (4 mL). The resulting
mixture was refluxed for 24 h. After cooling, the reaction mixture was
neutralized with aq 1 M HCl. White crystals formed were filtered and
washed with cold H2O. If necessary, carboxylic acids 1 can be rather
recrystallized from aq EtOH or purified by column chromatography
on silica gel.
13C NMR (75 MHz, CDCl3):  = 164.1, 150.9, 149.2, 147.9, 142.1, 132.4,
127.6, 122.2, 118.5, 112.9, 111.2, 111.1, 109.8, 108.1, 102.7, 101.3.
56.0, 55.9.
HRMS (EI): m/z calcd for C18H17NO5Na [M + Na]+: 350.0999; found:
350.1001.
According to this procedure, the following known carboxylic acids
were prepared: (E)-3-(3,4-Dimethoxyphenyl)acrylic acid (1a; 55%),28
,
(E)-3-(4-fluorophenyl)acrylic acid (1c; 64%),29 and (E)-3-(4-borono-
phenyl)acrylic acid (1d; 90%).30 For the data of these compounds, see
Supporting Information.
(E)-N-(4-Methoxyphenyl)cinnanamide (3ba)21c
Cinnamamide Derivatives 3 and 5; General Procedure
A mixture of carboxylic acid 1 (0.5 mmol), amine 2 or 4 (0.5 mmol),
phenylboronic acid (5 mol%), and DMAPO (5 mol%) was placed in a
cylindrical quartz reactor (∅ = 1.1 cm). The reactor was then intro-
duced into an Anton Paar Monowave 300®. The stirred mixture was
heated at 200 °C (P = 100 W) for 15 min. After microwave dielectric
heating, the crude reaction mixture was allowed to cool down to r.t.
and partitioned between CH2Cl2 (5 mL) and sat. aq NaHCO3 (5 mL).
The aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The com-
bined organic layers were washed with aq 1 N HCl (2 CH2Cl2 5 mL),
dried (MgSO4), filtered, and concentrated under vacuum. The crude
product was purified using cold diisopropyl ether as a trituration sol-
vent or by silica gel chromatography.
Prepared from cinnamic acid (1b) and 4-methoxyaniline (2a). Puri-
fied by trituration using diisopropyl ether as solvent. After filtration,
the product 3ba was isolated as a grey solid; yield: 72 mg (57%); mp
152–153 °C.
1H NMR (300 MHz, CDCl3):  = 7.74 (d, J = 15.5 Hz, 1 H), 7.57–7.33 (m,
8 H), 6.88 (d, J = 8.9 Hz, 2 H), 6.55 (d, J = 15.5 Hz, 1 H), 3.80 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 163.7, 156.5, 142.1, 134.7, 131.1, 129.9,
128.9, 127.9, 121.6, 120.8, 114.3, 55.5.
HRMS (EI): m/z calcd for C16H15NO2Na [M + Na]+: 276.0995; found:
276.0996.
(E)-N-(2-Methoxyphenyl)cinnamamide (3bb)31
(E)-3-(3,4-Dimethoxyphenyl)-N-(4-methoxyphenyl)acrylamide
(3aa)
Prepared from 1b and 2-methoxyaniline (2b). Purified by trituration
using diisopropyl ether as solvent. After filtration, the product 3bb
was isolated as a white solid; yield: 77 mg (61%); mp 143–144 °C.
1H NMR (300 MHz, CDCl3):  = 8.55 (d, J = 7.8 Hz, 1 H), 8.01–7.93 (br s,
1 H), 7.77 (d, J = 15.5 Hz, 1 H), 7.63–7.54 (m, 2 H), 7.45–7.39 (m, 3 H),
7.15–6.97 (m, 2 H), 6.93 (dd, J = 7.8, 1.7 Hz, 1 H), 6.62 (d, J = 15.5 Hz, 1
H), 3.95 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 163.7, 147.9, 142.0, 134.8, 129.9, 128.8,
128.0, 127.8, 123.8, 121.3, 121.2, 120.0, 109.9, 55.7.
HRMS (EI): m/z calcd for C16H15NO2Na [M + Na]+: 276.0995; found:
276.0995.
Prepared from (E)-3-(3,4-dimethoxyphenyl)acrylic acid (1a) and 4-
methoxyaniline (2a). Purified by trituration using diisopropyl ether
as solvent. After filtration, the product 3aa was isolated as a white
solid; yield: 101 mg (65%); mp 109–110 °C.
1H NMR (300 MHz, CDCl3):  = 7.75 (d, J = 15.5 Hz, 1 H), 7.58–7.49 (m,
2 H), 7.35–7.25 (m, 1 H), 7.22–7.05 (m, 2 H), 6.96–6.82 (m, 3 H), 6.44
(d, J = 15.5 Hz, 1 H), 3.93 (s, 6 H), 3.82 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 164.3, 156.4, 150.7, 149.1, 141.6, 131.4,
127.7, 122.0, 121.7, 119.0, 114.2, 111.1, 109.9, 55.9, 55.8, 55.4.
HRMS (EI): m/z calcd for C18H19NO4Na [M + Na]+: 336.1206; found:
336.1207.
(E)-N-(Benzo[d][1,3]dioxol-5-yl)cinnamamide (3bc)
Prepared from 1b and benzo[d][1,3]dioxol-5-amine (2c). Purified by
trituration using diisopropyl ether as solvent. After filtration, the
product 3bc was isolated as a brown solid; yield: 65 mg (49%); mp
206–207 °C.
(E)-3-(3,4-Dimethoxyphenyl)-N-(2-methoxyphenyl)acrylamide
(3ab)
Prepared from 1a and 2-methoxyaniline (2b). Purified by column
chromatography using cyclohexane/EtOAc (9:1) as eluent. The prod-
uct 3ab was isolated as a grey solid; yield: 111 mg (71%); mp 104–
105 °C.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

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K. Khaldoun et al.
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1H NMR (300 MHz, CDCl3):  = 7.73 (d, J = 15.5 Hz, 1 H), 7.56–7.48 (m,
2 H), 7.42–7.33 (m, 5 H), 6.95–6.84 (m, 1 H), 6.76 (d, J = 8.2 Hz, 1 H),
6.55 (d, J = 15.5 Hz, 1 H), 5.96 (s, 2 H).
13C NMR (75 MHz, CDCl3):  = 163.5 (d, JC,F = 276.0 Hz), 163.4, 147.9,
140.8, 131.0 (d, JC,F = 2.3 Hz), 129.7 (d, JC,F = 6.0 Hz), 127.8, 123.8,
121.2, 121.1, 120.0, 115.9 (d, JC,F = 15.8 Hz), 109.9, 55.7.
13C NMR (75 MHz, CDCl3):  = 163.7, 147.8, 144.3, 142.1, 134.6, 132.3,
19F NMR (101 MHz, CDCl3):  = –110.4.
129.9, 128.8, 127.9, 120.7, 113.1, 108.1, 102.7, 101.3.
HRMS (EI): m/z calcd for C16H13NO3Na [M + Na]+: 290.0788; found:
HRMS (EI): m/z calcd for C16H14FNO2Na [M + Na]+: 294.0901; found:
294.0902.
290.0787.
(E)-3-(4-Fluorophenyl)-N-phenylacrylamide (3cd)32
(E)-N-Phenylcinnamamide (3bd)31
Prepared from 1c and aniline (2d). Purified by trituration using diiso-
propyl ether as solvent. After filtration, the product 3cd was isolated
as a white solid; yield: 51 mg (42%); mp 158–159 °C.
1H NMR (300 MHz, CDCl3):  = 7.75 (d, J = 15.5 Hz, 1 H), 7.65–7.59 (m,
2 H), 7.58–7.52 (m, 2 H), 7.42–7.35 (m, 3 H), 7.25–7.05 (m, 3 H), 6.49
(d, J = 15.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3):  = 163.8, 163.7 (d, JC,F = 247.0 Hz), 141.2,
127.9, 130.8 (d, JC,F = 3.8 Hz), 129.8 (d, JC,F = 9.0 Hz), 129.1, 124.5,
120.5, 120.0, 116.0 (d, JC,F = 21.8 Hz).
Prepared from 1b and aniline (2d). Purified by trituration using diiso-
propyl ether as solvent. After filtration, the product 3bd was isolated
as a beige solid; yield: 56 mg (50%); mp 150–152 °C.
1H NMR (300 MHz, CDCl3):  = 7.79 (d, J = 15.5 Hz, 1 H), 7.71–7.62 (m,
2 H), 7.58–7.52 (m, 2 H), 7.48–7.32 (m, 6 H), 7.21–7.12 (m, 1 H), 6.58
(d, J = 15.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3):  = 164.2, 142.4, 138.1, 134.6, 129.9, 129.1,
128.8, 127.9, 124.5, 120.9, 120.1.
HRMS (EI): m/z calcd for C15H13NONa [M + Na]+: 246.0889; found:
HRMS (EI): m/z calcd for C15H12FNONa [M + Na]+: 264.0796; found:
246.0889.
264.0796.
(E)-N-(3,4-Dimethoxyphenyl)cinnamamide (3be)
(E)-3-(4-Fluorophenyl)-N-(4-methoxy-2-methylphenyl)acryl-
amide (3ce)
Prepared from 1b and 3,4-dimethoxyaniline (2e). Purified by column
chromatography using cyclohexane/EtOAc (7:3) as eluent. The prod-
uct 3be was isolated as a brown solid; yield: 78 mg (55%); mp 153–
154 °C; Rf = 0.3 (EtOAc/cyclohexane 3:7).
1H NMR (300 MHz, CDCl3):  = 7.77 (d, J = 15.5 Hz, 1 H), 7.61–7.50 (m,
3 H), 7.44–7.35 (m, 4 H), 7.00–6.92 (m, 1 H), 6.84 (d, J = 8.5 Hz, 1 H),
6.56 (d, J = 15.5 Hz, 1 H), 3.93 (s, 3 H), 3.90 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 164.2, 149.1, 145.9, 141.9, 134.7, 131.9,
129.9, 128.8, 127.9, 121.0, 112.1, 111.4, 105.0, 56.1, 55.9.
HRMS (EI): m/z calcd for C17H17NO3Na [M + Na]+: 306.1101; found:
306.1102.
Prepared from 1c and 4-methoxy-2-methylaniline (2e). Purified by
trituration using diisopropyl ether as solvent. After filtration, the
product 3ce was isolated as a purple solid; yield: 60 mg (42%); mp
210–211 °C.
1H NMR (300 MHz, CDCl3):  = 7.80–7.7.65 (m, 2 H), 7.60–7.45 (m, 1
H), 7.40–7.30 (m, 1 H), 7.20–6.95 (m, 3 H), 6.30–6.20 (m, 2 H), 6.51 (d,
J = 15.5 Hz, 1 H), 3.79 (s, 3 H), 2.27 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 164.0, 163.6 (d, JC,F = 187.0 Hz), 157.1,
140.7, 132.1, 131.0, 129.7 (d, JC,F = 4.5 Hz), 128.6, 125.5, 120.5, 116.0
(d, JC,F = 16.5), 115.9, 111.6, 55.4, 18.2.
19F NMR (101 MHz, CDCl3):  = –110.4.
HRMS (EI): m/z calcd for C17H16FNO2Na [M + Na]+: 308.1057; found:
(E)-3-(4-Fluorophenyl)-N-(4-methoxyphenyl)acrylamide (3ca)
308.1056.
Prepared from (E)-3-(4-fluorophenyl)acrylic acid (1c) and 4-me-
thoxyaniline (2a). Purified by trituration using diisopropyl ether as
solvent. After filtration, the product 3ca was isolated as a grey solid;
yield: 54 mg (40%); mp 194–195 °C.
1H NMR (300 MHz, CDCl3):  = 7.73 (d, J = 15.5 Hz, 1 H), 7.62–7.49 (m,
4 H), 7.27–7.23 (br s, 1 H), 7.15–7.05 (m, 2 H), 6.92 (d, J = 8.7 Hz, 2 H),
6.47 (d, J = 15.5 Hz, 1 H), 3.90 (s, 3 H).
(E)-N-Benzyl-3-(3,4-dimethoxyphenyl)acrylamide (5aa)33
Prepared from (E)-3-(3,4-dimethoxyphenyl)acrylic acid (1a) and
phenylmethanamine (4a). Purified by trituration using diisopropyl
ether as solvent. After filtration, the product 5aa was isolated as a
white solid; yield: 96 mg (65%); mp 118–120 °C.
13C NMR (75 MHz, CDCl3):  = 163.6, 163.5 (d, JC,F = 240.0 Hz), 156.9,
140.7, 131.1, 130.9 (d, JC,F = 3.7 Hz), 129.7 (d, JC,F = 8.2 Hz), 121.8,
120.7, 116.0 (d, JC,F = 21.8 Hz), 114.3, 55.5.
19F NMR (101 MHz, CDCl3):  = –110.2.
HRMS (EI): m/z calcd for C16H14FNO2Na [M + Na]+: 294.0901; found:
1H NMR (300 MHz, CDCl3):  = 8.53 (t, J = 6.0 Hz, 1 H), 7.42 (d, J = 15.7
Hz, 1 H), 7.38–7.25 (m, 5 H), 7.18–7.10 (m, 2 H), 6.98 (d, J = 8.3 Hz, 1
H), 6.59 (d, J = 15.7 Hz, 1 H), 4.40 (d, J = 6.0 Hz, 2 H), 3.79 (s, 3 H), 3.78
(s, 3 H).
13C NMR (75 MHz, CDCl3):  = 165.7, 150.5, 149.3, 140.0, 139.5, 128.8,
128.1, 127.8, 127.3, 121.8, 120.2, 112.1, 110.4, 56.0, 55.8, 42.7.
294.0903.
HRMS (EI): m/z calcd for C18H19NO3Na [M + Na]+: 320.1257; found:
320.1258.
(E)-3-(4-Fluorophenyl)-N-(2-methoxyphenyl)acrylamide (3cb)
Prepared from 1c and 2-methoxyaniline (2b). Purified by trituration
using diisopropyl ether as solvent. After filtration, the product 3cb
was isolated as a brown solid; yield: 65 mg (48%); mp 151–152 °C.
1H NMR (300 MHz, CDCl3):  = 8.51 (d, J = 7.8 Hz, 1 H), 7.99–7.89 (br s,
1 H), 7.71 (d, J = 15.5 Hz, 1 H), 7.60–7.50 (m, 2 H), 7.13–6.95 (m, 4 H),
6.90 (dd, J = 7.8, 1.6 Hz, 1 H), 6.52 (d, J = 15.5 Hz, 1 H), 3.92 (s, 3 H).
(E)-3-(3,4-Dimethoxyphenyl)-N-phenylethylacrylamide (5ab)34
Prepared from 1a and 2-phenylethan-1-amine (4b). Purified by tritu-
ration using diisopropyl ether as solvent. After filtration, the product
5ab was isolated as a white solid; yield: 106 mg (68%); mp 120–
121 °C.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

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K. Khaldoun et al.
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Synthesis
1H NMR (300 MHz, CDCl3):  = 7.56 (d, J = 15.6 Hz, 1 H), 7.37–7.20 (m,
5 H), 7.10–7.05 (m, 1 H), 7.03–6.97 (m, 1 H), 6.85 (d, J = 8.3 Hz, 1 H),
6.18 (d, J = 15.6 Hz, 1 H), 5.63–5.50 (br s, 1 H), 3.90 (s, 6 H), 3.67 (dt, J =
6.7, 6.7 Hz, 2 H), 2.89 (t, J = 6.7 Hz, 2 H).
1H NMR (300 MHz, CDCl3):  = 7.62 (d, J =15.6 Hz, 1 H), 7.54–7.44 (m,
2 H), 7.40–7.29 (m, 6 H), 7.29–7.20 (m, 2 H), 6.32 (d, J = 15.6 Hz, 1 H),
5.71–5.55 (br s, 1 H), 3.67 (dt, J = 6.7, 6.7 Hz, 2 H), 2.90 (t, J = 6.7 Hz, 2
H).
13C NMR (75 MHz, CDCl3):  = 166.2, 150.5, 149.1, 140.8, 138.9, 128.8,
128.7, 128.6, 128.5, 127.8, 126.5, 121.9, 118.6, 111.1, 109.8, 55.9, 55.8,
40.8, 35.7.
13C NMR (75 MHz, CDCl3):  = 165.8, 141.0, 138.9, 134.8, 129.6, 128.8,
128.7, 127.8, 126.6, 120.6, 40.8, 35.7.
HRMS (EI): m/z calcd for C17H17NONa [M + Na]+: 274.1202; found
274.1203.
HRMS (EI): m/z calcd for C19H21NO3Na [M + Na]+: 334.1413; found:
334.1413.
(E)-N-(2-(Pyridin-3-yl)ethylcinnamamide (5bc)
(E)-3-(3,4-Dimethoxyphenyl)-N-[2-(pyridin-3-yl)ethyl]acrylamide
(5ac)
Prepared from 1b and 2-(pyridin-3-yl)ethan-1-amine (4c). Purified
by column chromatography using cyclohexane/EtOAc (1:1) as eluent.
The product 5bc was isolated as a white solid; yield: 79 mg (63%); mp
160–161 °C; Rf = 0.23 (EtOAc/cyclohexane 1:1).
1H NMR (300 MHz, CDCl3):  = 8.52–8.47 (m, 2 H), 7.63 (d, J = 15.6 Hz,
1 H), 7.60–7.55 (m, 1 H), 7.52–7.48 (m, 2 H), 7.39–7.33 (m, 3 H), 6.33
(d, J = 15.6 Hz, 1 H), 5.68–5.55 (br s, 1 H), 3.67 (td, J = 6.8, 6.8 Hz, 2 H),
2.92 (t, J = 6.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3):  = 165.2, 150.0, 147.8, 141.1, 136.4, 134.7,
134.6, 129.7, 128.8, 127.7, 124.0, 120.5, 40.6, 32.9.
HRMS (EI): m/z calcd for C16H16N2ONa [M + Na]+: 275.1155; found:
275.1155.
Prepared from 1a and 2-(pyridin-3-yl)ethan-1-amine (4c). Purified by
trituration using diisopropyl ether as solvent. The product 5ac was
isolated as a beige solid; yield: 93 mg (60%); mp 115–116 °C.
1H NMR (300 MHz, CDCl3):  = 8.52–8.47 (m, 2 H), 7.60–7.52 (m, 2 H),
7.10 (d, J = 8.3 Hz, 1 H), 7.00 (s, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 6.21 ( d,
J = 15.5 Hz, 1 H), 5.82–5.65 (br s, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.65
(td, J = 6.8, 6.8 Hz, 2 H), 2.90 (t, J = 6.8 Hz, 2 H). 13C NMR (75 MHz,
CDCl3):  = 166.3, 150.6, 150.0, 149.1, 147.9, 141.1, 136.4, 134.6,
127.7, 123.6, 122.0, 118.3, 111.1, 109.7, 55.9, 55.8, 40.5, 32.9.
HRMS (EI): m/z calcd for C18H20N2O3Na [M + Na]+: 335.1366; found:
335.1369.
(E)-N-(2-Cyclohexylethyl)cinnamamide (5bd)
(E)-N-(2-Cyclohexylethyl)-3-(3,4-dimethoxyphenyl)acrylamide
(5ad)
Prepared from 1b and 2-cyclohexylethan-1-amine (4d). Purified by
trituration using diisopropyl ether as solvent. After filtration, the
product 5bd was isolated as a beige solid; yield: 71 mg (55%); mp
108–110 °C.
1H NMR (300 MHz, CDCl3):  = 7.62 (d, J = 15.6 Hz, 1 H), 7.56–7.44 (m,
2 H), 7.42–7.32 (m, 3 H), 6.37 (d, J = 15.6 Hz, 1 H), 5.61–5.45 (br s, 1
H), 3.42 (dt, J = 8.7, 8.7 Hz, 2 H), 1.82–1.64 (m, 6 H), 1.52–1.45 (m, 1
H), 1.41–1.15 (m, 4 H), 1.12–0.87 (m, 2 H).
13C NMR (75 MHz, CDCl3):  = 165.9, 140.7, 134.9, 129.5, 128.8, 127.7,
121.0, 37.6, 37.1, 35.4, 33.2, 26.5, 26.2.
HRMS (EI): m/z calcd for C17H23NONa [M + Na]+: 280.1672; found:
280.1670.
Prepared from 1a and 2-cyclohexylethan-1-amine (4d). Purified by
column chromatography using cyclohexane/EtOAc (1:1) as eluent.
The product 5ad was isolated as a hygroscopic solid; yield: 98 mg
(62%); Rf = 0.30 (EtOAc/cyclohexane 1:1).
1H NMR (300 MHz, CDCl3):  = 7.54 (d, J = 15.5 Hz, 1 H), 7.05 (d, J = 8.3
Hz, 1 H), 7.00–6.98 (m, 1 H), 6.81 (d, J = 8.3 Hz, 1 H), 6.28 (d, J = 15.5
Hz, 1 H), 5.85–5.77 (br s, 1 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.58 (td, J =
6.5, 6.5 Hz, 2 H), 1.75–1.63 (m, 6 H), 1.48–1.38 (m, 3 H), 1.32–1.12 (m,
2 H), 0.98–0.85 (m, 2 H).
13C NMR (75 MHz, CDCl3):  = 166.1, 150.4, 149.0, 140.5, 127.9, 121.8,
118.8, 111.0, 109.6, 55.9, 55.8, 37.5, 37.1, 35.4, 33.2, 26.5, 26.2.
HRMS (EI): m/z calcd for C19H27NO3Na [M + Na]+: 340.1883; found:
340.1885.
(E)-N-(Benzol[d][1,3]dioxol-5-ylmethyl)cinnamamide (5be)
Prepared from 1b and benzo[d][1,3]dioxol-5-ylmethanamine (4e).
Purified by trituration using diisopropyl ether as solvent. After filtra-
tion, the product 5be was isolated as a beige solid; yield: 89 mg (64%);
mp 160–161 °C.
1H NMR (300 MHz, CDCl3):  = 7.69 (d, J = 15.6 Hz, 1 H), 7.58–7.47 (m,
2 H), 7.42–7.36 (m, 3 H), 6.90–6.76 (m, 3 H), 6.41 (d, J = 15.6 Hz, 1 H),
5.97 (s, 2 H), 5.89–5.78 (br s, 1 H), 4.50 (d, J = 5.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3):  = 165.8. 147.9, 147.0, 141.3, 134.8, 132.1,
129.7, 128.8, 127.8, 121.2, 120.5, 108.5, 108.3, 101.0, 43.6.
HRMS (EI): m/z calcd for C17H15NO3Na [M + Na]+: 304.0944; found:
304.0946.
(E)-N-Benzyl-3-phenylacrylamide (5ba)21c
Prepared from cinnamic acid (1b) and phenylmethanamine (4a). Pu-
rified by trituration using diisopropyl ether as solvent. After filtration,
the product 5ba was isolated as a white solid; yield: 69 mg (58%); mp
100–102 °C.
1H NMR (300 MHz, CDCl3):  = 7.70 (d, J = 15.6 Hz, 1 H), 7.56–7.47 (m,
2 H), 7.42–7.33 (m, 8 H), 6.44 (d, J = 15.6 Hz, 1 H), 6.20–5.80 (br s, 1
H), 4.58 (dd, J = 5.9, 2.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3):  = 165.7, 141.4, 138.2, 134.8, 129.7, 128.8,
128.7, 127.9, 127.8, 127.6, 120.4, 43.9.
HRMS (EI): m/z calcd for C16H15NONa [M + Na]+: 260.1045; found:
260.1046.
(E)-N-[4-(Trifluoromethyl)benzyl]cinnamamide (5bf)6
Prepared from 1b and (4-(trifluoromethyl)phenyl)methanamine (4f).
Purified by trituration using diisopropyl ether as solvent. After filtra-
tion, the product 5bf was isolated as a white solid; yield: 98 mg (64%);
mp 129–130 °C.
(E)-N-Phenethylcinnamamide (5bb)35
Prepared from 1b and 2-phenylethan-1-amine (4b). Purified by tritu-
ration using diisopropyl ether as solvent. After filtration, the product
5bb was isolated as a white solid; yield: 75 mg (60%); mp 126–127 °C.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

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K. Khaldoun et al.
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Synthesis
1H NMR (300 MHz, CDCl3):  = 7.69 (d, J = 15.6 Hz, 1 H), 7.65–7.55 (m,
2 H), 7.53–7.42 (m, 4 H), 7.40 (m, 3 H), 6.43 (d, J = 15.6 Hz, 1 H), 6.08–
5.95 (br s, 1 H), 4.54 (d, J = 6.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3):  = 165.1, 142.4, 141.9, 134.6, 129.9, 129.7
(q, JC,F = 32.3 Hz), 128.8, 127.9, 127.8, 125.6 (q, JC,F = 3.8 Hz), 124.1 (q,
JC,F = 285 Hz), 120.0, 43.2.
1H NMR (300 MHz, CDCl3):  = 7.58 (d, J = 15.5 Hz, 1 H), 7.49–7.43 (m,
2 H), 7.37–7.28 (m, 2 H), 7.26–7.21 (m, 2 H), 7.05 (t, J = 8.6, 8.6 Hz, 2
H), 6.23 (d, J = 15.5 Hz, 1 H), 5.63–5.52 (br s, 1 H), 3.67 (dt, J = 6.7, 6.7
Hz, 2 H), 2.89 (t, J = 6.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3):  = 165.8, 163.5 (d, JC,F = 186.8 Hz), 139.7,
138.8, 131.0 (d, JC,F = 3.4 Hz), 129.5 (d, JC,F = 8.4 Hz), 128.8, 128.7,
126.6, 120.4, 115.8 (d, JC,F = 21.9 Hz), 40.9, 35.7.
HRMS (EI): m/z calcd for C17H14F3NONa [M + Na]+: 328. 0919; found:
328.0920.
19F NMR (101 MHz, CDCl3):  = –110.7.
HRMS (EI): m/z calcd for C17H16FNONa [M + Na]+: 292.1108; found:
292.1109.
(E)-N-[2-(Pyridin-4-yl)ethyl]cinnamamide (5bg)
Prepared from 1b and 2-(pyridin-4-yl)ethan-1-amine (4g). Purified
by column chromatography using cyclohexane/EtOAc (1:1) as eluent.
The product 5bg was isolated as a beige solid; yield: 56 mg (44%); mp
136–137 °C; Rf = 0.25 (EtOAc/cyclohexane 1:1)
1H NMR (300 MHz, CDCl3):  = 8.51 (d, J = 5.0 Hz, 2 H), 7.63 (d, J = 15.6
Hz, 2 H), 7.51–7.43 (m, 2 H), 7.38–7.32 (m, 3 H), 7.17 (d, J = 5.0 Hz, 1
H), 6.35 (d, J = 15.6 Hz, 1 H), 5.92 (t, J = 6.0 Hz, 1 H), 3.67 (dt, J = 6.0, 6.0
Hz, 2 H), 2.91 (t, J = 6.0 Hz, 2 H).
(E)-3-(4-Fluorophenyl)-N-[2-(pyridine-3-yl)ethyl]acrylamide (5cc)
Prepared from 1c and 2-(pyridin-3-yl)ethan-1-amine (4c). Purified by
trituration using diisopropyl ether as solvent. After filtration, the
product 5cc was isolated as a white solid; yield: 88 mg (65%); mp
135–136 °C.
1H NMR (300 MHz, CDCl3):  = 8.51–8.46 (m, 2 H), 7.60 (d, J = 15.6 Hz,
1 H), 7.58–7.53 (m, 1 H), 7.50–7.43 (m, 2 H), 7.30–7.23 (m, 1 H), 7.10–
7.00 (m, 2 H), 6.25 (d, J = 15.60 Hz, 1 H), 5.80–5.70 (br s, 1 H), 3.65 (td,
J = 6.9, 6.9 Hz, 2 H), 2.91 (t, J = 6.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3):  = 166.1, 149.8, 148.2, 141.3, 134.7, 129.8,
128.8, 127.8, 124.2, 120.3, 39.9, 35.1.
HRMS (EI): m/z calcd for C16H16N2ONa [M + Na]+: 275.1155; found:
275.1156.
13C NMR (75 MHz, CDCl3):  = 165.8, 163.6 (d, JC,F = 249.0 Hz), 150.1,
148.1, 140.2, 136.3, 134.4, 130.9 (d, JC,F = 3.0 Hz), 129.6 (d, JC,F = 9.0
Hz), 123.6, 120.0, 119.9, 115.9 (d, JC,F = 22.0 Hz), 40.6, 32.9.
(E)-N-[2-(Pyridin-2-yl)ethyl]cinnamamide (5bh)36
HRMS (EI): m/z calcd for C16H15FN2ONa [M + Na]+: 293.1061; found:
293.1061.
Prepared from 1b and 2-(pyridin-2-yl)ethan-1-amine (4h). Purified
by column chromatography using cyclohexane/EtOAc (1:1) as eluent.
The product 5bh was isolated as a beige solid; yield: 62 mg (49%); mp
92–93 °C; Rf = 0.25 (EtOAc/cyclohexane 1:1)
(E)-3-(4-Fluorophenyl)-N-[4-(trifluoromethyl)benzyl]acrylamide
(5cf)
1H NMR (300 MHz, CDCl3):  = 8.58 (d, J = 4.9 Hz, 1 H), 7.69–7.58 (m, 2
H), 7.56–7.45 (m, 2 H), 7.42–7.33 (m, 3 H), 7.25–7.17 (m, 2 H), 6.82–
6.70 (br s, 1 H), 6.40 (d, J = 15.6 Hz, 1 H), 3.83 (dt, J = 6.2, 6.2 Hz, 2 H),
3.09 (t, J = 6.2 Hz, 2 H).
Prepared from 1c and [4-(trifluoromethyl)phenyl]methanamine (4f).
Purified by trituration using diisopropyl ether as solvent. After filtra-
tion, the product 5cf was isolated as a white solid; yield: 103 mg
(64%); mp 140–141 °C.
13C NMR (75 MHz, CDCl3):  = 165.8, 159.7, 149.1, 140.6, 136.7, 135.0,
129.5, 128.7, 127.7, 123.5, 121.6, 121.1, 38.8, 36.8.
HRMS (EI): m/z calcd for C16H16N2ONa [M + Na]+: 275.1155; found:
1H NMR (300 MHz, CDCl3):  = 7.64 (d, J = 15.6 Hz, 1 H), 7.58 (d, J = 8.0
Hz, 2 H), 7.50–7.40 (m, 4 H), 7.08–7.00 (m, 2 H), 6.36 (d, J = 15.6 Hz, 1
H), 6.25–6.12 (br s, 1 H), 4.61 (d, J = 6.0 Hz, 2 H).
275.1155.
13C NMR (75 MHz, CDCl3):  = 165.8, 163.6 (d, JC,F = 249.0 Hz), 142.3,
140.7, 130.8 (d, JC,F = 3.4 Hz), 129.5 (d, JC,F = 7.5 Hz), 127.9, 125.6 (q,
JC,F = 3.8 Hz), 124.0 (q, JC,F = 270.0 Hz), 122.2, 119.7, 116.0 (d, JC,F = 21.7
Hz), 43.3.
19F NMR (101 MHz, CDCl3):  = –62.3, –110.2.
HRMS (EI): m/z calcd for C17H13F4NONa [M + Na]+: 346.0825; found:
(E)-N-Benzyl-3-(4-fluorophenyl)acrylamide (5ca)
Prepared from (E)-3-(4-fluorophenyl)acrylic acid (1c) and phenyl-
methanamine (4a). Purified by trituration using diisopropyl ether as
solvent. After filtration, the product 5ca was isolated as a white solid;
yield: 75 mg (58%); mp 121–122 °C.
346.0824.
1H NMR (300 MHz, CDCl3):  = 7.64 (d, J = 15.6 Hz, 1 H), 7.51–7.42 (m,
2 H), 7.40–7.27 (m, 5 H), 7.15–6.96 (m, 2 H), 6.33 (d, J = 15.6 Hz, 1 H),
6.02–5.87 (br s, 1 H), 4.57 (d, J = 5.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3):  = 165.6, 163.6 (d, JC,F = 250,4 Hz), 140.2,
138.1, 131.0 (d, JC,F = 3.5 Hz), 129.6 (d, JC,F = 8.4 Hz), 128.8, 127.9,
127.6, 120.1 (d, JC,F = 2.4 Hz), 115.9 (d, JC,F = 13.5 Hz), 43.9.
(E)-N-(4-Bromobenzyl)-3-(4-fluorophenyl)acrylamide (5ci)
Prepared from 1c and (4-bromophenyl)methanamine (4i). Purified by
trituration using diisopropyl ether as solvent. After filtration, the
product 5ci was isolated as a white solid; yield: 111 mg (67%); mp
182–183 °C.
19F NMR (101 MHz, CDCl3):  = –110.4.
HRMS (EI): m/z calcd for C16H14FNONa [M + Na]+: 278.0952; found:
1H NMR (300 MHz, CDCl3):  = 7.64 (d, J = 15.6 Hz, 1 H), 7.54–7.40 (m,
4 H), 7.20 (d, J = 8.4 Hz, 2 H), 7.06 (dd, J = 8.6, 8.6 Hz, 2 H), 6.32 (d, J =
15.6 Hz, 1 H), 5.93–5.86 (br s, 1 H), 4.53 (d, J = 5.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3):  = 165.7, 163.6 (d, JC,F = 249.8 Hz), 140.5,
137.2, 131.8, 130.8 (d, JC,F = 2.3 Hz), 129.6 (d, JC,F = 9.8 Hz), 129.5,
121.5, 119.8, 116.0 (d, JC,F = 21.8 Hz), 43.2.
278.0952.
(E)-3-(4-Fluorophenyl)-N-phenylethylacrylamide (5cb)
Prepared from 1c and 2-phenylethan-1-amine (4b). Purified by tritu-
ration using diisopropyl ether as solvent. After filtration, the product
5cb was isolated as a beige solid; yield: 81 mg (60%); mp 154–155 °C.
19F NMR (101 MHz, CDCl3):  = –110.4.
HRMS (EI): m/z calcd for C16H13BrFNONa [M + Na]+: 356.0057; found:
356.0055.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

I
K. Khaldoun et al.
Paper
Synthesis
(E)-3-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-
[4-(trifluoromethyl)benzyl]acrylamide (5df)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690132.
Prepared from (E)-3-(4-boronophenyl)acrylic acid (1d) after esterifi-
cation and [4-(trifluoromethyl)phenyl]methanamide (4f). Purified by
column chromatography using cyclohexane/diisopropyl ether (1:1) as
eluent (pretreatment of silica gel with Et3N is advised). The product
5df was isolated as a hygroscopic solid; yield: 64 mg (30%) over two
steps.
1H NMR (300 MHz, CDCl3):  = 7.83 (d, J = 7.8 Hz, 2 H), 7.71 (d, J = 15.6
Hz, 1 H), 7.62 (d, J = 8.0 Hz, 2 H), 7.52 (d, J = 7.8 Hz, 2 H), 7.46 (d, J = 8.0
Hz, 2 H), 6.50 (d, J = 15.6 Hz, 1 H), 6.02 (br s, 1 H), 4.66 (d, J = 6.0 Hz, 2
H), 1.36 (s, 12 H).
13C NMR (75 MHz, CDCl3):  = 165.7, 142.3, 141.8, 137.1, 135.3, 128.0,
127.0, 125.7, 125.6, 125.4, 120.8, 84.0, 43.3, 24.9. Carbon atom  to
boron is often not visible.
19F NMR (101 MHz, CDCl3):  = –62.6.
HRMS (EI): m/z calcd for C23H25BF3NO3Na [M + Na]+: 454.1771; found:
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Some compounds 3 and 5 were solubilized in DMSO at a concentra-
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Acknowledgment
This work was supported by the University of Rennes 1 and the Cen-
tre National de la Recherche Scientifique (CNRS). K.K thanks the Min-
istry of Higher Education and Scientific Research (MESRS) of Algeria
for a research fellowship (369/PNE). The authors would like to thank
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