Stereoselective synthesis of dehydroamino acids using malonic acid half oxyester and aromatic aldehydes

Article abstract of DOI:10.1016/j.tet.2016.03.043

An efficient and direct approach was developed for the synthesis of α,β-dehydroamino acid derivatives with a broad range of substrates. Amido-substituted Malonic Acid Half Oxyesters (MAHOs) have proven to be excellent partners of various aromatic aldehyde

Full text of DOI:10.1016/j.tet.2016.03.043

Accepted Manuscript
Stereoselective synthesis of dehydroamino acids using malonic acid half oxyester and
aromatic aldehydes
Yuttapong Singjunla, Silvia Colombano, Jérôme Baudoux, Jacques Rouden
PII:
S0040-4020(16)30174-0
10.1016/j.tet.2016.03.043
TET 27583
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 February 2016
Revised Date: 2 March 2016
Accepted Date: 13 March 2016
Please cite this article as: Singjunla Y, Colombano S, Baudoux J, Rouden J, Stereoselective synthesis
of dehydroamino acids using malonic acid half oxyester and aromatic aldehydes, Tetrahedron (2016),
doi: 10.1016/j.tet.2016.03.043.
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malonic acid half oxyester and aromatic aldehydes
Yuttapong Singjunla, Silvia Colombano, Jérôme Baudoux,* Jacques Rouden*
Laboratoire de Chimie Moléculaire et Thio-organique, ENSICAEN, Université de Normandie, CNRS, 6
Boulevard du Maréchal Juin, 14050 Caen, France.

1
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Tetrahedron
journal homepage: www.elsevier.com
Stereoselective synthesis of dehydroamino acids using malonic acid half oxyester and
aromatic aldehydes
Yuttapong Singjunla, Silvia Colombano, Jérôme Baudoux,* Jacques Rouden*
Laboratoire de Chimie Moléculaire et Thio-organique, ENSICAEN, Université de Normandie, CNRS, 6 boulevard du Maréchal Juin, 14050 Caen, France.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and direct approach was developed for the synthesis of α,β-dehydroamino acid
derivatives with a broad range of substrates. Amido-substituted Malonic Acid Half Oxyesters
(MAHOs) have proven to be excellent partners of various aromatic aldehydes in the presence of
secondary amine, trifluoromethanesulfonic acid to perform
a
Knoevenagel-Doebner
Available online
condensation under mild conditions with good to excellent yields. A mechanistic study revealed
that the sequence involved the formation of an iminium intermediate to provide stereoselectively
Z-α,β-unsaturated amino acids.
Keywords:
Amino acid
2016 Elsevier Ltd. All rights reserved
.
Doebner condensation
Malonic half oxyester
Organocatalysis
Decarboxylation
requires restrictive conditions with the use of EDC/Cu(OTf)2,15
1. Introduction
TsCl/DCC/CuCl2, EDC/CuCl2, Ts2O/DABCO17 or PPh3/DEAD18
16
and very recently an interesting study has been realized by Ess and
Castle to selectively generate Z or E-∆Ile by using Martin
sulfurane.19 In recent years, malonic acid half oxyesters (MAHOs)
have been utilized with aliphatic aldehyde to perform
α,β-Dehydroamino acids (∆AAs) are a new class of non-
proteinogenic amino acids occurring in recently characterized natural
peptides.1 Several bioactive products are composed of trisubstituted
dehydroamino acids derived from valine (∆Val), isoleucine (∆Ile),
leucine (∆Leu) and phenylalanine (∆Phe) such as Tentoxin.1,2 The
incorporation of ∆AAs into a peptide could modify the backbone
decarboxylative aldol reactions followed by
a
subsequent
dehydration step but very low overall yields of
α,β-dehydroamino
esters were observed in all cases.20
In this context, the Knoevenagel-Doebner condensation21
represents a convenient and mild method to create a double bond
from unsubstituted malonic acid or malonic acid half oxyesters
(MAHOs) and aldehydes via a one-pot domino decarboxylative
aldol-elimination process. The recent report by List and co-workers
who developed a set of mild conditions for this transformation is
particularly attractive, but only unsubstituted malonates were used
(scheme 1a).21d To the best of our knowledge, only one example
reported by Xu and co-workers involves this methodology starting
from a substituted 2-amido MAHO with an alkyl aldehyde to
synthesize a ∆AA derivative in moderate yield and as a mixture of
stereoisomers (Z-dehydroamino acid as the major).22
geometry of the chain by increasing its rigidity. Moreover,
α,β-
dehydroamino acids may be involved in biological processes as
biochemical intermediates to bring better stability in biological
media.3 As a result, the development of new approaches for the
synthesis of α,β-dehydroamino acid derivatives is essential to
evaluate their biological reactivity and to facilitate the preparation of
new synthetic peptides. In synthetic chemistry, dehydroamino acids
have been used as starting materials for several reactions, mainly in
asymmetric hydrogenations4 but also epoxidations,5 conjugated
additions,6 cyclopropanations7 and Diels-Alder reactions.8
The most commonly used strategy for the one-pot synthesis of
α,β
-dehydroamino acids involves Wittig reaction9 and alternative
methods.10 Ito et al. used the Schöllkopf method, isolating an
oxazoline intermediate which was opened in the presence of Pd(0).11
Alvarez-Ibarra et al. used a Schiff base in the presence of ethyl
propynoate and potassium tert-butoxide to induce a [1.3]-hydride
shift followed by a double bond migration to the α,β-position of the
amino acid moiety.12 Alternatively, Henry's reaction followed by
dehydration was used to access α-nitroesters-α,β-unsaturated esters
from nitroacetate.13 Other transformations reported for the synthesis
With the aim of developing a short and flexible methodology to
synthesize
α,β-dehydroamino esters of various structural and
electronic properties and with our experience in the use of 2-amido
MAHO,23 we report hereafter a straightforward synthesis of ∆AAs
under mild conditions using the Doebner reaction (scheme 1b).
of α,β-dehydroamino acids involve the elimination of β-hydroxy-α-
amino ester derivatives.14 Although the synthesis of β-hydroxy-α-
amino esters is well described, easy access to these compounds is
still challenging. Furthermore, the dehydration step sometimes
*Corresponding authors. E-mail address: jerome.baudoux@ensicaen.fr (J.
Baudoux), Jacques.rouden@ensicaen.fr (J. Rouden).

2
Tetrahedron
8
D
-
-
trace
19%
70%
74%
59%
49%
82%
19%
35%
<2%
<2%
trace
trace
8%
53%
34%
11%
<2%
trace
trace
8%
ACCEPTED MANUSCRIPT
9
E
A
A
A
F
-
-
10
11f
12d,g
13d
14h
TfOH
TfOH
TfOH
TfOH
TfOH
4 Å MSe
4 Å MSe
4 Å MSe
4 Å MSe
4 Å MSe
A
a Reactions performed on 0.2 mmol scale at 0.33 M 1a. b Isolated yields. c 1H
g
NMR conversion. d Without Et3N. e Molecular sieves. f Performed at 10 °C.
Performed at 10 °C with 1 eq. of benzaldehyde, 1 eq. of TfOH and 2 eq. of
pyrrolidine. h Performed at 10 °C with 2 eq. of benzaldehyde, pyrrolidine and
TfOH.
Scheme 1: Previous work and our strategy using MAOHs in the
Doebner reaction.
Three strong acids, trifluoroacetic acid (TFA), trifluoromethane
sulfonic acid (TfOH) and 4-nitrobenzoic acid, were tested in
stoichiometric amounts (entries 3-5). TfOH initially provided the
best improvement allowing the isolation of Doebner product 3a in
61% yield along with 4 and 5. With TfOH, the use of piperidine or
morpholine, two amines with similar nucleophilicity to pyrrolidine,25
afforded product 3a in low yield (entries 6-7).
2. Results and discussion
Our first attempt to transform 2-benzamido MAHO 1a into a
∆AA derivative was carried out by using the efficient conditions
developed by List and co-worker with unsubstituted malonates.21d
The reaction led quantitatively to decarboxylative aldol product 4
and no traces of Doebner compound 3a was detected even after a
prolonged reaction time (entry 1, table 1). Compared to unsubstituted
malonates, amido-substituted MAHO appeared to behave quite
differently and the Doebner reaction with these starting materials
therefore represent an interesting synthetic challenge.
Reassessment of these conditions started using a secondary
amine such as pyrrolidine to transform benzaldehyde 2 into a more
reactive iminium intermediate as Xu recently developed with an
alkyl aldehyde.22 Again, the reaction led to a mixture of three
different compounds, the expected Z-dehydroamino ester 3a,24 the
decarboxylative-aldol ester 4 and the decarboxylative-protonated
ester 5, all in very poor yields (entry 2, table 1). Based on previous
works including ours, we envisaged a double activation of the
substrates, basic for MAHO and nucleophilic for the aldehyde. We
attempted the reaction by adding triethylamine to deprotonate
MAHO but also a strong acid as co-catalyst with pyrrolidine to
facilitate the iminium formation from benzaldehyde 2. Compared to
alkyl aldehyde, a careful optimization had to be performed in order
to determine the best catalyst combination working for all types of
aromatic aldehydes.
To enhance cooperation between the acid and the pyrrolidine in
order to increase the concentration of iminium in the reaction
mixture, we selected proline
D and pyrrolidine-NHTf E as
bifunctionnal catalysts. In the case of proline, only trace of 3a was
observed, probably due to the poor solubility of this catalyst in THF
(entry 8). It is noteworthy that proline in ethanol as solvent afforded
8% yield of 3a while the use of proline-Boc in THF with in-situ
deprotection by TfOH gave 18% yield of 3a (data not shown).
Pyrrolidine N-triflimide E gave only a slight improvement (entry 9)
compared to proline with 19% yield. In all cases when changing the
nucleophilic catalyst, glycine was observed as a major product
(product of protodecarboxylation).
To shift the equilibrium toward the formation of iminium, we
added molecular sieves and a significant enhancement was observed
to afford 3a in 70% yield (entry 10). Performing the reaction at 10
°C, a 74% yield of Doebner product was achieved with very low
amounts of side products 4 and 5 (entry 11). The selected
combination of acid, tertiary and secondary amines to simultaneously
activate MAHO 1a and aldehyde 2 was confirmed during additional
experiments. Without deprotonation of MAHO (no Et3N) but with
optimal iminium formation, the reaction lead to 3a in only 59% yield
(entry 12). Diamine F containing the base and the nucleophile on the
same molecule afforded 49% yield (entry 13). Finally, the yield of 3a
was improved to 82% with a stoichiometric amount of Et3N, two
equivalents of pyrrolidine, TfOH and aldehyde (entry 14). All these
experiments afforded the same stereoisomer and exclusively the Z-
dehydroamino ester 3a.
Table 1
Optimization of the Knoevenagel-Doebner condensation
Scheme 2: Assessment of various protecting groups.
With these optimized conditions in hand, the effect on the
reaction of various protecting groups at the nitrogen of MAHO was
investigated (Scheme 2). N-acetyl 1b afforded a similar yield of
85%. The reaction with N-(4-methylbenzoyl) 1c and N-(4-
methoxybenzoyl) 1d gave slightly lower yields, 3c in 74% and 3d in
70% yield respectively. Benzyl carbamate N-Cbz 1e generated
Doebner product 3e in 65% yield.
The scope of the reaction with various aromatic aldehydes was
then evaluated (table 2). We started with 2-naphthyl-carboxaldehyde
and the hindered 2-phenylbenzaldehyde. The corresponding
dehydroamino esters 6 and 7 were obtained in 71% and 77% yields,
respectively. With benzaldehydes bearing an electron donating group
(4-MeO, 3,4-diMeO and 3-OMe), the reaction afforded products 8, 9
Entrya
Nu
Co-acid
Additive
3ab
4 b
5 b
1
2d
3
List’s conditions 21d
-
>95%c
12%
6%
-
A
A
A
A
B
C
-
TFA
-
-
-
-
-
-
26%
42%
61%
55%
trace
27%
23%
21%
20%
27%
38%
68%
4
TfOH
16%
7%
5
4-nitrobenzoic acid
TfOH
6
21%
trace
7
TfOH

3
and 10 in very good yields (up to 89%). In the presence of a
hydroxyl group, 4-hydroxybenzaldehyde reacted slowly to provide
the compound 11 in 42% yield. Even with 4-nitrobenzaldehyde (one
equivalent) which is difficult to transform into an iminium
intermediate, the desired compound 12 was isolated, albeit in
moderate yield (38%). This low yield was due to a competitive
decarboxylative aldol reaction.26 Halogen-substituted benzaldehydes
were successfully tested with MAHO 1a at 0 °C. At this temperature,
Doebner condensation prevails to provide the compounds 13 (58%),
14 (50%) and 15 (72%). Furthermore, we extended our study to
heterocyclic aldehydes such as furfural, 2- and 3-
thiophenecarboxaldehyde, 2- and 4-pyridinecarboxaldehyde.
Electron-rich or -poor aromatic aldehydes reacted similarly in our
conditions and the π-conjugated heterocyclic products 16-20 were
obtained in very good yields between 75% and 85%.
not lead to the desired products, only glycine 5 was observed after
ACCEPTED MANUSCRIPT
72 h of reaction (data not shown). However, the conditions
developed by Xu and co-workers should provide the Doebner
products with these aliphatic aldehydes.22
Next, we investigated the mechanism operating under our conditions
by performing a few additional experiments. Our initial strategy was
based on a nucleophilic addition of an amine to aldehyde forming an
iminium species. After the addition of the
spontaneous decarboxylative -elimination reaction would occur
from the intermediate -ammonium carboxylate B to generate the
α-amido MAHO 1a, a
β
β
double bond under mild conditions. Thus, the reaction begins
simultaneously by deprotonation of MAHO with triethylamine
(activated MAHO A) and by the iminium formation in presence of
TfOH (scheme 3). The key step could be the addition of the
secondary amine to the aldehyde in order to generate the highly
electrophilic iminium species. To confirm this hypothesis, we tested
Eschenmoser’s salt with MAHO 1a and Et3N, the reaction was
complete in less than 20 minutes to give product 23 in a quantitative
yield (scheme 4a). Similarly, the isolated iminium triflate 2425
reacted completely with 1a after only 2 h and compound 3a was
obtained in an excellent yield without side products (Scheme 4b).
These experiments prove a rapid addition of the activated MAHO 1a
to the electrophilic iminium followed by the spontaneous
Table 2
Synthesis of various substituted Z-dehydroamino esters
decarboxylative
β-elimination to afford the Doebner product.
Therefore, the limiting step of this overall process is the slow
condensation of the aldehyde with pyrrolidine to form the highly
electrophilic iminium which was confirmed by the reaction of 1a and
4-nitrobenzaldehyde affording the expected dehydroamino esters 12
in a low yield (table 2).
Scheme 3: Plausible mechanism for the Doebner condensation.
Moreover, adding pyrrolidine and trifluoromethanesulfonic acid
to
β-hydroxy-α-amino ester 25 did not generate the dehydrated
product 12 even after 72 h (scheme 4c). This result completes the
previous experiments insofar as, during the Doebner condensation,
dehydroamino esters are not formed by dehydration of putative
hydroxyl amino ester intermediates such as 25 or 4.
a performed with 1 eq. of aldehyde, TfOH, and pyrrolidine.26b Performed at 0
°C.
Indole carboxaldehyde proposed a significant challenge. In our
first attempts, indole-3-carboxaldehyde or 1-methylindole-3-
carboxaldehyde were unreactive substrates (data not shown).
However, with a Cbz group the reaction led to the product 21 in 59%
NMR yield.27 Finally the Doebner condensation with
cinnamaldehyde afforded diene-amino ester 22 in 33% yield.
Enolizable aldehydes such as crotonaldehyde or butyraldehyde did

4
Tetrahedron
experiments were performed. Mass spectra were obtained on a
ACCEPTED MANUSCRIPT
GC/MS Saturn 2000 spectrometer. High-resolution mass spectra
(HRMS) were performed on Q-TOF Micro WATERS by electrospray
ionisation (ESI). Infrared (IR) spectra were recorded with a Perkin
Elmer 16 PC FT-IR ATR spectrometer, using the pure product (oil or
solid). Thin Layer Chromatography (TLC) was run on pre-coated
aluminum plates of silica gel 60 F-254 (Merck). Flash
chromatography was performed on silica gel column (Merck silica
gel, 40-63 µm) using air pressure. Compounds 1b29, 1e30 were known
in literature and synthesized as described below.
4.2. General procedure for the preparation of malonic half
oxyesters (MAOHs)
Diethylmalonate (1 eq.) was diluted in EtOH. A KOH solution (1
eq.) in 10:1 EtOH/water was added dropwise at 0 °C. The mixture
was stirred 15 h. A 1M HCl solution was added dropwise until pH =
1, then the mixture was saturated with NaCl and extracted twice with
ethyl acetate. The organic layer was dried over MgSO4 and solvents
removed under reduced pressure. All malonic half oxyesters were
easily detected by TLC (Rf = 0 in 60/40 cyclohexane/EtOAc)
Scheme 4: Additional experiments for mechanistic studies.
According to the literature, the reaction between unsubstituted
hemimalonates and aldehydes in presence of pyridine (or DMAP)
and Ac2O gives a mixture of E- and Z-alkenes. With -amido
α
4.3. General procedure for Doebner reaction
MAHOs, Xu et al. have observed a significant evolution of the ratio
in favor of the Z-alkene (a ratio similar to Horner-Wadsworth-
Emmons condensation) but the E-isomer is always present in small
amounts and contaminates the crude reaction.22 Hengartner et al.
were able to convert E-alkene into the more stable Z-isomer by
treatment with NaOEt.28 Under our conditions, the Doebner
condensation of α-amido MAHOs gives exclusively the
thermodynamically more stable Z-dehydroamino esters and the
minor diastereomers were not observed during the process (1H NMR
monitoring).
Procedure I: With aldehyde
Under inert atmosphere, triethylamine (0.2 mmol) was added to a
solution of malonic acid half ester (0.2 mmol) in dry THF (0.6 ml) in
the presence of molecular sieve (50 mg). At 0 °C, pyrrolidine (0.4
mmol) was added dropwise followed by trifluoromethanesulfonic
acid (0.4 mmol) and aldehyde (0.4 mmol). The mixture was stirred at
10 °C for 24-120 h. The solution was concentrated under reduced
pressure. The residue was directly purified by flash chromatography.
Procedure II: With iminium
Triethylamine (0.2 mmol) was added to a solution of malonic
acid half ester 2 (0.2 mmol) in dry THF (0.6 ml). Iminium (0.4
mmol) was added to the solution and the reaction mixture was stirred
at room temperature for 0.3-2 h. The solution was concentrated
under reduced pressure. The residue was directly purified by flash
chromatography.
3. Conclusion
In summary, we have developed an efficient and direct approach
to prepare Z-dehydroamino acid derivatives according to the
Knoevenagel-Doebner reaction. A variety of α-amido MAHOs and
aromatic aldehydes in the presence of pyrrolidine, triethylamine and
trifluoromethanesulfonic acid afforded various dehydroamino esters
in moderate to excellent yields. The developed Doebner reaction
using 2-amido MAHOs with aromatic aldehydes complements well
the already known conditions. The methodology displays interesting
features such as readily available starting materials and a simple
experimental procedure which could be useful for large-scale
applications. It is therefore a practical tool to access new scaffolds
for making synthetic peptides.
4.3.1. 3-Ethoxy-2-benzamido-3-oxopropanoic acid (1a). White solid,
mp 105-106 °C, 95% yield. 1H NMR (400 MHz, CDCl3) δ 7.83 (2H,
t, J = 7.2 Hz), 7.51-7.55 (1H, m), 7.39-7.45 (3H, m), 5.37 (d, J = 6.8
Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 168.8, 168.3, 166.6, 132.8, 132.6, 129.0, 127.7,
63.5, 57.2, 14.2. IR (neat) 3299, 2926, 1748, 1709, 1639, 1520,
1248, 1197, 1172, 711, 691 cm-1. HRMS m/z (ESI): calcd. for
C12H13NO5Na [M+Na]+: 274.0691, found: 274.0703.
4. Experimental section
4.1. General
4.3.2. 3-Ethoxy-2-(4-methylbenzamido)-3-oxopropanoic acid (1c).
White solid, mp 114-115 °C, 61% yield. 1H NMR (400 MHz,
CDCl3) δ 7.81 (d, J = 8.8 Hz, 2H), 7.26 (b, 1 H), 6.93 (d, J = 8.8 Hz,
2 H), 5.81 (b, 1H), 5.33 (d, J = 6.4 Hz, 1H), 3.04 (s, 3H), 4.32 (q, J =
7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
168.4, 167.5, 166.6, 162.9, 129.4, 124.5, 113.9, 63.1, 57.0, 55.5,
13.9. IR (neat) 3397, 2982, 1738, 1605, 1497, 1257, 1183, 1024, 767
cm-1. HRMS m/z (ESI) calcd for C13H14NO6 [M-H]-: 280.0821,
found: 280.0814.
All reagents were purchased from Acros Organics, Sigma
Aldrich, Alfa Aesar, TCI or Fluka and were used without further
purification and used as received. Solvents were used in RPE grade
without further purification. Anhydrous solvents were obtained from
a
PURESOLV SPS400 apparatus developed by Innovative
Technology Inc. 1H and 13C NMR spectra were recorded on a Bruker
DRX 400 MHz or a Bruker DRX 500 MHz spectrometer. Samples
were dissolved in an appropriate deuterated solvent (CDCl3, acetone-
d6, D2O). The chemical shifts (δ) are expressed in ppm relative to
internal tetramethylsilane for 1H and 13C nuclei, and coupling
constants are indicated in Hz. Abbreviations for signal coupling are
as follows: s = singlet; d = doublet; dd = doublet of doublets; t =
triplet; q = quartet; quin = quintet; m = multiplet; br = broad signal.
To assign the signals to the different proton and carbon atoms, as
well as the relative stereochemistry of the cycloadducts, additional
2D NMR experiments (COSY, HSQC, HMBC) and NOESY
4.3.3. 3-Ethoxy-2-(4-methoxybenzamido)-3-oxopropanoic acid (1d).
White solid, mp 109-112 °C. 52% yield. 1H NMR (400 MHz,
CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2 H), 6.71 (b,
1H), 5.35 (d, J = 6.4 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 1.33 (t, J =
7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 168.4, 168.0, 166.3,
143.2, 129.5, 129.4, 127.4, 63.1, 56.9, 21.5, 13.9. IR (neat) 3305,
3131, 1749, 1726, 1634, 1523, 1499, 1238, 1185, 1164, 759, 669 cm-
1. HRMS m/z (ESI) calcd for C13H16NO5 [M+H]+: 266.1028, found:
266.1035.

5
4.3.4. (Z)-Ethyl 2-benzamido-3-phenylacrylate (3a). White solid, mp
128-130 °C, 48.6 mg, 82% yield. 1H NMR (400 MHz, CDCl3) δ 7.87
(d, J = 8.2 Hz, 2H), 7.77 (b, 1H), 7.56 (t, J = 8.4 Hz, 1H), 7.47-7.51
(m, 5H), 7.30-7.36 (m, 3H), 4.33 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.9, 165.7, 134.2, 133.9,
132.4, 131.6, 129.9, 129.6, 129.0, 128.8, 127.7, 124.7, 62.2, 14.5. IR
(neat) 3262, 2924, 1709, 1644, 1635, 1518, 1486, 1239, 1141, 1090,
712 cm-1. HRMS m/z (ESI) calcd. for C18H18NO3 [M+H]+: 296.1287;
found 296.1274.
4.3.11. (Z)-Ethyl 2-benzamido-3-(4-methoxyphenyl)acrylate (8).
ACCEPTED MANUSCRIPT
1
Solid, mp 136-137 °C, 58.0 mg, 89% yield. H NMR (400 MHz,
CDCl3) δ 7.89 (d, J = 7.4 Hz, 2H), 7.77 (s, 1H), 7.54-7.58 (m, 1H),
7.47-7.50 (m, 5H), 6.85 (d, J = 8.8 Hz, 2H), 4.30 (q, J = 7.2 Hz, 2H),
3.79 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
165.7, 165.6, 160.5, 133.9, 132.2, 131.8, 131.7, 128.8, 127.5, 126.5,
121.9, 114.1, 61.7, 55.3, 14.3. IR (neat) 3289, 2927, 1713, 1649,
1603, 1509, 1477, 1244, 1173, 728, 706 cm-1. HRMS m/z (ESI)
calcd. for C19H20NO4 [M+H]+: 326.1392; found 326.1386.
4.3.5. (Z)-Ethyl 2-acetamido-3-phenylacrylate (3b). Solid, mp 92-93
°C, 39.5 mg, 85% yield. H NMR (400 MHz, CDCl3) δ 7.46 (d, J =
4.3.12. (Z)-Ethyl 2-benzamido-3-(3,4-dimethoxyphenyl)acrylate (9).
White solid, mp 112-114 °C, 50.5 mg, 71% yield. H NMR (400
1
1
6.8 Hz, 2H), 7.35-7.38 (m, 4H), 6.97 (b, 1H), 4.31 (q, J = 7.2 Hz,
2H), 2.14 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 169.1, 165.6, 134.1, 132.1, 129.9, 129.6, 128.8, 124.8,
62.1, 23.7, 14.5. IR (neat) 3242, 2983, 1716, 1665, 1642, 1513,
1490, 1371, 1251, 1203, 691 cm-1. HRMS m/z (ESI) calcd. for
C13H15NO3Na [M+Na]+: 256.0950; found 256.0943.
MHz, CDCl3) δ 7.90 (d, J = 7.4 Hz, 2H), 7.74 (t, J = 7.2 Hz, 1H),
7.46-7.50 (m, 3H), 7.10-7.14 (m, 2H), 6.83 (d, J = 8.2 Hz, 2H), 4.32
(q, J = 7.2 Hz, 2H), 3.87 (s, 1H), 3.68 (s, 1H), 1.36 (t, J = 7.2 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 165.6 (2C), 150.2, 148.6, 133.8,
132.2, 132.1, 128.8, 127.4, 127.0, 126.7, 124.1, 112.2, 110.8, 61.8,
55.8, 55.6, 14.3. IR (neat) 3309, 2980, 1713, 1649, 1513, 1480,
1246, 1140, 1023, 721 cm-1. HRMS m/z (ESI) calcd. for
C20H21NO5Na [M+Na]+: 378.1317; found: 378.1318.
4.3.6. (Z)-Ethyl 2-(4-methylbenzamido)-3-phenylacrylate (3c). Solid,
1
mp 120-123 °C, 45.8 mg, 74% yield. H NMR (400 MHz, CDCl3) δ
7.92 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H), 7.39
(s, 1H), 7.23-7.30 (m, 3H), 7.19 (d, J = 8.0 Hz, 2H), 4.24 (q, J = 7.2
Hz, 2H), 2.36 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 165.5 (2C), 142.8, 134.1, 130.9, 130.8, 129.6, 129.4, 129.3,
128.6, 127.5, 124.5, 61.9, 21.5, 14.3. IR (neat) 3304, 2981,1724,
1636, 1525, 1497, 1490, 1250, 1189, 752, 667 cm-1. HRMS m/z
(ESI) calcd. for C19H20NO3 [M+H]+: 310.1443; found 310.1451.
4.3.13. (Z)-Ethyl 2-benzamido-3-(3-methoxyphenyl)acrylate (10).
White solid, mp 82-84 °C, 47.5 mg, 73% yield. 1H NMR (400 MHz,
CDCl3) δ 7.69 (d, J = 7.4 Hz, 2H), 7.59 (s, 1H), 7.37-7.40 (m, 1H),
7.28-7.32 (m, 2H), 7.05-7.09 (m, 2H), 6.92 (d, J = 7.7 Hz, 1H), 6.87
(s, 1H), 6.69 (dd, J = 2.2, 8.2 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.53
(s, 3H), 1.19 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
165.6, 165.3, 135.2, 133.6, 132.2, 131.1, 129.6, 128.8, 127.4, 124.7,
122.2, 115.5, 114.4, 61.9, 55.1, 14.3. IR (neat) 3279, 2982, 1716,
1651, 1511, 1478, 1295, 1271, 1236, 709, 689 cm-1. HRMS m/z
(ESI) calcd. for C19H19NO4Na [M+Na]+: 348.1212; found 348.1219.
4.3.7. (Z)-Ethyl 2-(4-methoxybenzamido)-3-phenylacrylate (3d).
1
Solid, mp 117-119 °C, 45.5 mg, 70% yield. H NMR (400 MHz,
CDCl3) δ 7.83 (d, J = 8.8 Hz, 2H), 7.69 (s, 1H), 7.49 (d, J = 8.0 Hz,
2H), 7.43 (s, 1H), 7.29-7.34 (m, 3H), 6.95 (d, J = 8.8 Hz, 2H), 4.32
(q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 165.5, 165.1, 162.8, 134.1, 130.6, 129.6, 129.4,
129.3, 128.6, 126.0, 124.6, 113.9, 61.9, 55.5, 14.3. IR (neat) 3286,
2972, 1709, 1643, 1603, 1479, 1246, 1175, 1026, 761, 690 cm-1.
HRMS m/z (ESI) calcd. for C19H19NO4Na [M+Na]+: 348.1212;
found 348.1214.
4.3.14. (Z)-Ethyl 2-benzamido-3-(4-hydroxyphenyl)acrylate (11).
White solid, mp 100-103 °C, 26.2 mg, 42% yield. H NMR (400
1
MHz, CD3OD) δ 7.97 (d, J = 7.4 Hz, 2H), 7.53-7.56 (m, 6H), 7.79
(d, J = 8.6 Hz, 2H), 4.28 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 165.5, 165.7, 159.2, 135.7, 133.6,
131.8, 128.3, 127.3, 124.7, 122.4, 115.2, 61.8, 13.2. IR (neat) 3264,
2928, 1695, 1644, 1602, 1508, 1478, 1202, 1251, 1165, 708 cm-1.
HRMS m/z (ESI) calcd. for C18H18NO4 [M+H]+: 312.1236; found:
312.1225.
4.3.8. (Z)-Ethyl 2-(((benzyloxy)carbonyl)amino)-3-phenylacrylate
(3e). Colorless oil, 42.3 mg, 65% yield. 1H NMR (400 MHz, CDCl3)
δ 7.43-7.53 (m, 2H), 7.25-7.27 (m, 8H), 6.29 (b, 1H), 5.04 (s, 2H),
4.21 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 165.3, 153.9, 136.0, 133.8, 136.0, 133.8,
131.4, 129.8, 129.4, 128.6, 128.5, 128.3, 128.2, 124.5, 67.5, 61.8,
14.2. IR (neat) 3296, 2977, 1699, 1498, 1312, 1254, 1221, 1201,
1039, 1024, 734, 690 cm-1. HRMS m/z (ESI) calcd. for
C19H19NO4Na [M+Na]+: 348.1212; found 348.120.
4.3.15. (Z)-Ethyl 2-benzamido-3-(4-nitrophenyl)acrylate (12). White
solid, mp 165-166 °C, 25.9 mg, 38% yield. 1H NMR (400 MHz,
CDCl3) δ 8.21 (br, 1H), 8.16 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz,
2H), 7.56-7.59 (m, 3H), 7.47-7.51 (m, 3H), 4.38 (q, J = 8.0 Hz, 2H),
1.40 (t, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.1, 164.8,
147.3, 141.6, 133.4, 132.8, 130.0, 129.1, 127.6, 126.4, 126.1, 123.7,
62.8, 14.4. IR (neat) 3273, 2984, 1719, 1660, 1517, 1478, 1343,
1305, 1253 cm-1. HRMS m/z (ESI) calcd. for C18H16N2O5Na
[M+Na]+: 363.0957; found: 363.0947.
4.3.9. (Z)-Ethyl 2-benzamido-3-(naphthalen-2-yl)acrylate (6). White
solid, mp 99-102 °C, 49.1 mg, 71% yield. 1H NMR (400 MHz,
CDCl3) δ 8.03 (d, J = 8.2 Hz, 1H), 7.78-7.89 (m, 3H), 7.68-7.71 (m,
3H), 7.46-7.61 (m, 4H), 7.36-7.43 (m, 3H), 4.39 (q, J = 7.2 Hz, 2H),
1.39 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.6, 165.0,
133.0, 133.5, 132.1, 131.2, 131.1, 129.5, 128.8, 128.7, 127.5, 127.4,
127.3, 126.7, 126.3, 126.2, 125.3, 124.3, 62.0, 14.3. IR (neat) 3229,
2977, 1636, 1509, 1481, 1292, 1241, 768, 689 cm-1. HRMS m/z
(ESI) calcd. for C22H20NO3 [M+H]+: 346.1443; found: 346.1437.
4.3.16. (Z)-Ethyl 2-benzamido-3-(3-fluorophenyl)acrylate (13). The
experiment was performed at 0 °C.White solid, mp 135-136 °C, 36.4
1
mg, 58% yield. H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.6 Hz,
3H), 7.57 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.43 (s, 1H),
7.27-7.32 (m, 2H), 7.19 (d, J = 9.9 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H),
4.34 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). 13C NMR (125
MHz, CDCl3) δ 165.4, 165.2, 162.2 (d, J = 246.4 Hz), 136.3 (d, J =
8.2 Hz), 133.5, 132.3, 130.0 (d, J = 8.3 Hz), 129.4, 128.8, 127.4,
125.4 (d, J = 2.8 Hz), 124.9, 116.2 (d, J = 21.3 Hz), 116.1 (d, J =
22.4 Hz), 62.2, 14.2. 19F NMR (376 MHz, CDCl3) δ -112.7. IR (neat)
3272, 2985, 1719, 1652, 1509, 1479, 1291, 1230, 1153, 709, 686 cm-
1. HRMS m/z (ESI) calcd. for C18H16NO3FNa [M+Na]+: 336.1012;
found: 336.1004.
4.3.10. (Z)-Ethyl 3-([1,1'-biphenyl]-2-yl)-2-benzamidoacrylate (7).
1
White solid, mp 138-140 °C, 57.2 mg, 77% yield. H NMR (400
MHz, CDCl3) δ 7.58-7.63 (m, 3H), 7.44 (d, J = 7.7 Hz, 1H), 7.33-
7.37 (m, 3H), 7.06-7.28 (m, 9H), 4.07 (q, J = 7.2 Hz, 2H), 1.07 (t, J =
7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.3, 165.2, 141.9,
140.4, 133.9, 132.7, 132.0, 130.6, 130.2, 129.9, 129.0, 128.7, 128.3,
128.1, 128.0, 127.5, 127.4, 127.1, 124.8, 61.7, 14.2. IR (neat) 3281,
2967, 1709, 1651, 1509, 1476, 1266, 1244, 730, 705 cm-1. HRMS
m/z (ESI) calcd. for C24H22NO3 [M+H]+: 372.1600; found: 372.1594.
4.3.17. (Z)-Ethyl 2-benzamido-3-(4-fluorophenyl)acrylate (14). The
experiment was performed at 0 °C. White solid, mp 120-121 °C,
1
31.4 mg, 50% yield. H NMR (400 MHz, CDCl3) δ 7.62-6.66 (m,
3H), 7.36 (t, J = 7.4 Hz, 1H), 7.27-7.29 (m, 4H), 7.04 (s, 1H), 6.80 (t,

6
Tetrahedron
J = 8.6 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H).
1254, 1208, 1145, 698 cm-1. HRMS m/z (ESI) calcd. for
ACCEPTED MANUSCRIPT
13C NMR (125 MHz, CDCl3) δ 165.4 (2C), 162.6 (d, J = 250.0 Hz),
133.6, 132.3, 131.7 (d, J = 8.4 Hz), 130.3 (d, J = 3.3 Hz), 130.2,
128.8, 127.5, 123.6, 115.6 (d, J = 21.8 Hz), 62.0, 14.3. 19F NMR
(376 MHz, CDCl3) δ -110.2. IR (neat) 3273, 2986, 1717, 1652, 1601,
1507, 1479, 1251, 1230, 708 cm-1. HRMS m/z (ESI) calcd. for
C18H16NO3FNa [M+Na]+: 336.1012; found: 336.1013.
C17H16N2O3Na [M+Na]+: 319.1059; found: 319.1073.
4.3.24. (Z)-Benzyl 3-(2-benzamido-3-ethoxy-3-oxoprop-1-en-1-yl)-
1H-indole-1-carboxylate (21). Yellow solid, mp 122-124 °C, 54.2
mg, 59% NMR yield. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.5
Hz, 1H), 7.68-7.83 (m, 6H), 7.53 (t, J = 7.3 Hz, 1H), 7.41 (t, J = 7.5
Hz, 2H), 7.22-7.34 (m, 7H), 5.31 (s, 2H), 4.31 (q, J = 7.2 Hz, 2H),
1.34 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.2 (2C),
150.3, 134.9, 134.5, 133.8, 132.1, 129.5, 128.8, 128.74, 128.72,
128.3, 127.4, 127.3, 125.4, 123.6, 122.3, 119.0, 115.3, 115.1, 69.0,
61.9, 14.3. IR (neat) 3255, 2977, 1742, 1711, 1666, 1481, 1453,
1339, 1233, 1216, 1082, 753, 698 cm-1. HRMS m/z (ESI) calcd. for
C28H24N2O5Na [M+Na]+: 491.1583; found: 491.1591.
4.3.18. (Z)-Ethyl 2-benzamido-3-(2-bromophenyl)acrylate (15). The
experiment was performed at 0 °C. White solid, mp 106-107 °C,
53.9 mg, 72% yield. H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.1
1
Hz, 3H), 7.62 (dd, J = 1.1, 8.0 Hz, 1H), 7.51-7.55 (m, 2H), 7.42-7.47
(m, 3H), 7.21 (td, J = 0.8, 7.6 Hz, 1H), 7.14 (td, J = 1.6, 7.6 Hz, 1H),
4.36 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 165.1, 165.0, 135.1, 133.6, 132.9, 132.2, 130.1,
129.3, 128.8, 128.5, 127.4, 127.2, 126.0, 124.4, 62.2, 14.2. IR (neat)
3286, 2977, 1714, 1648, 1509, 1479, 1287, 1249, 1024, 705 cm-1.
HRMS m/z (ESI) calcd. for C18H16NO3BrNa [M+Na]+: 396.0211;
found: 396.0208.
4.3.25. (2Z,4E)-Ethyl 2-benzamido-5-phenylpenta-2,4-dienoate (22).
Yellow solid, mp 95-96 °C, 21.2 mg, 33% yield. 1H NMR (400
MHz, CDCl3) δ 7.90 (d, J = 7.2 Hz, 2H), 7.82 (br s, 1H), 7.54 (t, J =
7.2 Hz, 1H), 7.42-7.53 (m, 4H), 7.23-7.29 (m, 4H), 6.87-7.01 (m,
2H), 4.27 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).13C NMR (101
MHz, CDCl3) δ 165.9, 165.4, 140.1, 136.7, 134.3, 132.3, 131.7,
129.1, 129.0, 128.9, 127.7, 127.6, 124.5, 123.3, 62.0, 14.5 IR (neat)
3288, 2924, 1713, 1647, 1508, 1478, 1276, 1230, 967, 705 cm-1.
HRMS m/z (ESI) calcd. for C20H20NO3 [M+H]+: 322.1443; found:
322.1440.
4.3.19. (Z)-Ethyl 2-benzamido-3-(furan-2-yl)acrylate (16). White
solid, mp 124-125 °C, 45.1 mg, 79% yield. 1H NMR (400 MHz,
CDCl3) δ 8.23 (s, 1H), 7.93 (d, J = 6.8 Hz, 2H), 7.56-7.59 (m, 1H),
7.48-7.52 (m, 3H), 7.08 (s, 1H), 6.57 (d, J = 3.4 Hz, 1H), 6.47 (dd, J
= 1.8, 3.4 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 165.6, 164.9, 150.1, 144.4, 133.7,
132.2, 128.8, 127.6, 123.2, 115.9, 115.3, 112.3, 61.7, 14.2. IR (neat)
3292, 2982, 1715, 1650, 1509, 1480, 1286, 1259, 1210, 1182, 1022,
716 cm-1. HRMS m/z (ESI) calcd. for C16H15NO4Na [M+Na]+:
308.0899; found: 308.0907.
4.3.26. Ethyl 2-benzamidoacrylate (23). Colorless oil, 43.0 mg, 98%
yield. 1H NMR (400 MHz, CDCl3) δ 8.55 (br s, 1H), 7.83 (d, J = 8.0
Hz 2H), 7.45-7.56 (m, 3H), 6.78 (s, 1H), 5.99 (s, 1H), 4.33 (q, J =
8.0 Hz, 2H), 1.37 (t, J = 8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
166.1, 164.6, 134.6, 132.3, 131.5, 129.1, 127.2, 108.9, 62.7, 14.4. IR
(neat) 3355, 2983, 1730, 1651, 1604, 1244, 1095, 1024, 710, 691 cm-
1. HRMS m/z (ESI) calcd. for C12H14NO3 [M+H]+: 220.0974; found:
220.0974.
4.3.20. (Z)-Ethyl 2-benzamido-3-(thiophen-2-yl)acrylate (17). White
solid, mp 170-173 °C, 45.2 mg, 75% yield. 1H NMR (400 MHz,
CDCl3) δ 7.96 (d, J = 7.2 Hz, 2H), 7.87 (s, 1H), 7.42-7.60 (m, 5H),
7.35 (d, J = 3.4 Hz, 1H), 7.07 (dd, J = 3.4, 4.9 Hz, 1H), 4.30 (q, J =
7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
166.7, 164.9, 136.5, 133.9, 133.2, 132.2, 130.7, 128.8, 128.7, 127.6,
127.2, 121.6, 61.7, 14.3. IR (neat) 3281, 2972, 1714, 1648, 1628,
1512, 1471, 1261, 1198, 705 cm-1. HRMS m/z (ESI) calcd. for
C16H15NO3SNa [M+Na]+: 324.0670; found: 324.0679.
Acknowledgements
The Ministery of Higher Education and Research, the
“Region Basse Normandie” (fellowships to Y.S.), CNRS, and
the European Union (FEDER) are gratefully acknowledged for
funding this work. We thank the LABEX SynOrg (ANR-11-
LABX-0029) for financial support.
4.3.21. (Z)-Ethyl 2-benzamido-3-(thiophen-3-yl)acrylate (18). White
solid, mp 177-179 °C, 51.3 mg, 85% yield. 1H NMR (400 MHz,
CDCl3) δ 7.90 (d, J = 7.4 Hz, 2H), 7.68 (s, 1H), 7.46-7.57 (m, 5H),
7.26-7.28 (m, 2H), 4.29 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 165.9, 165.5, 135.1, 133.7, 132.4,
129.3, 128.8, 127.9, 127.5, 126.9, 126.1, 122.6, 61.8, 14.3. IR (neat)
3260, 2987, 1699, 1630, 1514, 1476, 1256, 1203, 1140, 1087, 705,
690 cm-1. HRMS m/z (ESI) calcd. for C16H15NO3SNa [M+Na]+:
324.0670; found: 324.0685.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at
References and notes
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solid, mp 117-120 °C, 45.0 mg, 76% yield. 1H NMR (400 MHz,
CDCl3) δ 8.57 (d, J = 3.7 Hz, 2H), 8.17 (s, 1H), 7.83-7.85 (m, 2H),
6.57 (d, J = 3.4 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.4 Hz,
2H), 7.32-7.34 (m, 3H), 4.37 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 164.7, 164.6, 148.8, 143.6,
133.2, 132.7, 128.9, 127.5, 127.2, 125.5, 123.4, 62.7, 14.2. IR (neat)
3265, 2967, 1721, 1633, 1514, 1476, 1287, 1249, 1016, 710, 685 cm-
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297.1245.
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Colorless oil, 44.5 mg, 75% yield. H NMR (400 MHz, CDCl3) δ
1
12.9 (s, 1H), 8.05 (d, J = 4.6 Hz, 1H), 7.71 (td, J = 1.8, 7.8 Hz, 1H),
7.50-7.60 (m, 3H), 7.26 (d, J = 7.8 Hz, 1H), 7.18 (dd, J = 4.6, 7.8
Hz, 1H), 6.34 (s, 1H) 4.40 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 165.4, 165.1, 155.3, 148.2,
137.2, 135.0, 133.4, 132.3, 128.7, 127.9, 125.4, 121.9, 113.3, 61.8,
14.1. IR (neat) 3063, 1724, 1673, 1635, 1469, 1421, 1309, 1279,

7
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ACCEPTED MANUSCRIPT
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