Synthesis of new avenalumic carboxamide derivatives in the ferulic series

Article abstract of DOI:10.1080/00397910802238817

A seven-step synthesis of (2E,4E)-5-[4-hydroxy-3-methoxyphenyl]penta-2,4- dienoic acid from ferulic acid was developed. The use of a natural by-product found in rice bran as a raw material provided the ferulic acid vinylogous in an overall high yield. This compound will be useful for the preparation of a wide variety of avenalumic carboxamide derivatives. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802238817

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Synthesis of New Avenalumic
Carboxamide Derivatives in the
Ferulic Series
Marc-Antoine Bazin a , Laïla El Kihel a , Marie
Jouanne a , Jean-Charles Lancelot a & Sylvain Rault a
a Centre d'Etudes et de Recherche sur le
Médicament de Normandie, Faculty of
Pharmaceutical Sciences, University of Caen Basse-
Normandie, Caen Cedex, France
Published online: 20 Oct 2008.
To cite this article: Marc-Antoine Bazin , Lala El Kihel , Marie Jouanne , Jean-
Charles Lancelot & Sylvain Rault (2008) Synthesis of New Avenalumic Carboxamide
Derivatives in the Ferulic Series, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:22, 3947-3959, DOI:
10.1080/00397910802238817
To link to this article: http://dx.doi.org/10.1080/00397910802238817
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Synthetic Communications1, 38: 3947–3959, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802238817
Synthesis of New Avenalumic Carboxamide
Derivatives in the Ferulic Series
Marc-Antoine Bazin, La¨ıla El Kihel, Marie Jouanne,
Jean-Charles Lancelot, and Sylvain Rault
´
Centre d’Etudes et de Recherche sur le Medicament de Normandie,
Faculty of Pharmaceutical Sciences, University of Caen Basse-Normandie,
Caen Cedex, France
Abstract: A seven-step synthesis of (2E,4E)-5-[4-hydroxy-3-methoxyphenyl]-
penta-2,4-dienoic acid from ferulic acid was developed. The use of a natural
by-product found in rice bran as a raw material provided the ferulic acid vinylo-
gous in an overall high yield. This compound will be useful for the preparation of
a wide variety of avenalumic carboxamide derivatives.
Keywords: Avenalumic acids, avenanthramides, ferulic acid, Horner–Emmons
olefination
Avenanthramides are a group of natural compounds occurring in oat
groats and hulls (Avena sativa L.). They consist of conjugated forms con-
taining various hydroxy=methoxy-substituted cinnamic or phenylpenta-
dienoic acids linked to an anthranilic acid (Fig. 1).[1,2]
In the cinnamic series (n¼1), avenanthramides have been character-
ized as antioxidants in vitro in several studies.[3] Fungal infection and
treatment with various elicitors induced their production in oat leaves,
and they were thus also classified in the phytoalexins family.[4]
In the avenalumic series (n¼2), avenanthramides are considered
as trans-ethylenic homologs of the previous series. In 1991, Collins
Received May 20, 2008.
Address correspondence to La¨ıla El Kihel, Centre d’Etudes et de Recherche
´
sur le Medicament de Normandie, UPRES EA-4258, FR CNRS INC3M,
U.F.R. des Sciences Pharmaceutiques, Universite de Caen Basse-Normandie,
´
´
5 rue Vaubenard, 14032, Caen Cedex, France. E-mail: laila.elkihel@unicaen.fr
3947

3948
M.-A. Bazin et al.
Figure 1. General structure of avenanthramides.
identified and characterized avenalumic acid 2 and N-anthranilic carbox-
amides 3 derivated from 2 (Fig. 2).[5]
In contrast with avenanthramides in the cinnamic series, avenalumic
carboxamide derivative chemistry is not well known, and the antioxidant
capacity and the UV absorbant potential of 2 and 3 were only sug-
gested.[5] Indeed, these compounds have not been the subject of extended
studies. This lack of knowledge prompted us to investigate an efficient
synthesis of this type of compound, and we publish herein the first results
of our synthetic studies.
Besides, (2E,4E)-5-arylpenta-2,4-dienamides have been of great inter-
est because many biologically active avenalumic carboxamide derivatives
such as piperine analogs,[6] antiallergic agents,[7] platelet-activating factor
(PAF) inhibitors,[8] 5-lipoxygenase inhibitors,[9] ultraviolet (UV) absor-
bers,[10] or cell proliferation modulators[11] have been developed.
The increasing interest in such bioactive (2E,4E)-5-arylpenta-2,4-
dienamides and our focus on cinnamic acids chemistry[12] and the synth-
esis of ferulic acid derivatives[13] led us to undertake the preparation of
ferulic acid vinylogous 11 starting from ferulic acid 4. Ferulic acid is an
extremely abundant hydroxycinnamic acid in the plant cell wall (mainly
in cereals such as rice bran, oats, and wheat).[14] Agricultural by-products
such as rice bran oil are commonly used for manufacturing ferulic
acid.[15] Ferulic acid itself exhibits a wide range of biological actions
including antioxidant,[16] anti-inflammatory,[17] and anticancer[18]
Figure 2. Structures of avenalumic acid 2 and avenalumic carboxamide derivatives 3.

New Avenalumic Carboxamide Derivatives
3949
activities and is now widely used in the food and cosmetic industries.[19]
Because these activities are shown to be moderate, pharmacomodulations
of ferulic acid may improve them.
To our knowledge, only one method of the preparation of (2E,4E)-
5-[4-hydroxy-3-methoxyphenyl]penta-2,4-dienoic acid 11 has been repor-
ted. It needs the use of both an expensive cinnamaldehyde and the ben-
zene as solvent.[11] In terms of strategy, the Horner–Wadsworth–
Emmons reaction using (2E)-triethylphosphonocrotonate and vanillin
could be used (Scheme 1). Nevertheless, this reaction needs the use of
the single E-isomer, which is difficult to isolate from the commercial ethyl
bromocrotonate isomer mixture.
Because of these difficulties, we searched for a better way, and we
now report a multistep stereoselective synthesis of the (2E,4E)-5-[4-
hydroxy-3-methoxyphenyl]penta-2,4-dienoic acid from ferulic acid in a
high overall yield and the application of this methodology to prepare
N-anthranilic carboxamides. The key step of the sequence is the stereose-
lective carbon–carbon double-bond formation. E-Selective Horner–
Emmons olefination involving a cinnamaldehyde intermediate has
been carried out, as described by some authors.[20] Reduction of alkyl
cinnamates is a common strategy for converting cinnamic acids into
aldehydes.[21] The Horner–Emmons reaction needs the protection of the
phenol function. This group must be a suitable protective group for
subsequent reduction and oxidation steps. After several attempts using
benzyl, acetyl, or tetrahydropyrannyl protective groups, we found that
the tert-butyldimethylsilyl ether was the best one.
As depicted in Scheme 2, the phenolic group of methyl ferulate 5 was
protected with tert-butyldimethylsilyl chloride (TBDMSCl) to afford
compound 6 in quantitative yield. Reduction of this cinnamate with
diisobutylaluminium hydride (DIBAL-H) gave the coniferyl alcohol 7,
which was oxidized with MnO2 to provide (O-TBDMS) coniferaldehyde
8. Condensation of this aldehyde with triethylphosphonoacetate at room
temperature gave the expected (2E,4E) diene 9a in a very good yield
(97%). The presence (1%) of the (2Z,4E) isomer 9b can be detected by
Thin-Layer Chromatography (TLC), and the two isomers were easily
separated using silica-gel column chromatography.
Scheme 1. Possible retrosynthetic pathway of alkyl (2E,4E)-5-arylpenta-2,4-
dienoate.

3950
M.-A. Bazin et al.
Scheme 2. Reagents and conditions: i) MeOH, H2SO4, reflux, 24 h, 97%; ii)
TBDMSCL, imidazole, DMF, rt, 2 h, 99%; iii) DIBAL-H, THF, ꢁ 10 ꢀC to rt,
6 h, 93%; iv) MnO2, CH2Cl2, rt, 24 h, 89%; v) triethylphosphonoacetate, NaH;
DMF, 0 ꢀC to rt, 1 h, 97% (9a) and 1% (9b); vi) TBAF, AcOH, THF, 0 ꢀC,
30 min, 93%; vii) 15% aqueous KOH, MeOH, reflux 4 h, 90%.
The latter 9b was readily identified by the cis JH2-H3 value of 11.2 Hz
1
in the H NMR spectrum, whereas the trans JH2-H3 value for 9a was
15.4 Hz. After selective cleavage of the silyl group with tetrabutylammo-
nium fluoride (TBAF), the ester 10 was saponified using aqueous
potassium hydride (KOH) solution in MeOH, and the desired acid 11
was obtained in 84% yield (two steps).
It can be noticed that alkaline hydrolysis of 9a was attempted, but
this reaction gave a complex mixture of partially O-deprotected esters
and acids (Scheme 3).
The second part of our work consisted in synthesizing an N-anthra-
nilic carboxamide derivative. The strategy involved the carboxylic acid
Scheme 3. Reagents and conditions: i) 15% aqueous KOH, EtOH, reflux, 4 h;
ii) TBAF, AcOH, THF, 0 ꢀC, 30 min, 93%.

New Avenalumic Carboxamide Derivatives
3951
Scheme 4. Reagents and conditions: i) Ac2O, DMAP, pyridine, rt, 18 h, 92%; ii a)
ethyl chloroformate, Et3N, CH3CN, 0 ꢀC, 2 h, ii b) methyl anthranilate, CH3CN,
reflux, 4 h, 65%; iii) LiOH monohydrate, H2O, 60 ꢀC, 4 h, 60%.
activation using an anhydride intermediate. As shown in Scheme 4,
protection of the phenol with acetic anhydride afforded acid 12, which
was treated with ethyl chloroformate in the presence of triethylamine
to give the corresponding mixed anhydride, whose amidation with methyl
anthranilate provided the carboxamide 13 in 65% yield. Removal of the
acetyl group and ester hydrolysis were achieved using lithium hydroxide
monohydrate and afforded the dienamide 14 in a good yield (60%).
In conclusion, we have developed a strategy starting from ferulic acid
for the synthesis of useful avenalumic carboxamide derivatives. The
stereocontrolled seven-step synthesis of the ferulic acid vinylogous was
successfully achieved in a high overall yield (64%) thanks to an appropri-
ate phenol protective group. This acid allowed the easy preparation of N-
anthranilic carboxamides with potent antioxidant and UV absorption
properties.
EXPERIMENTAL
Reagents and materials were obtained from commercial suppliers and
were used without further purification. The reactions were monitored
by TLC on Kieselgel-G (Merck Si 254 F) layers (0.25 mm thick). Column
chromatography was carried out using silica gel 60 (0.063–0.2 mm)
(Merck). Melting points were determined on a Kofler block. IR spectra
were recorded on a Perkin-Elmer 1600 FT-IR spectrometer. EI mass
spectra were recorded on a Jeol-GCmate (GC-MS system) spectrometer.
1
ESI mass spectra were recorded on a LC=MS Waters alliance. H NMR
and 13C NMR spectra were recorded using CDCl3 or DMSO-d6 respec-
tively at 400 MHz (Jeol Lambda 400 spectrometer) and at 100 MHz.
Chemical shifts are reported relative to TMS; J values are given in hertz.
1
13C NMR spectra are H-decoupled. Chemical shifts (ꢂ) could be inter-
changed. Elemental analyses were performed at the Institut de Recherche
en Chimie Organique Fine (Rouen).

3952
M.-A. Bazin et al.
Methyl Ferulate (5)
Five drops of conc. H2SO4 were added to a stirred solution of ferulic acid
(30.0 g, 154.5 mmol) in MeOH (200 mL). The mixture was refluxed for
24 h. The solvent was evaporated under reduced pressure, and the residue
was dissolved in CH2Cl2 (500 mL). The organic layer was washed with
saturated aqueous NaHCO3 (2 ꢃ 100 mL), dried over MgSO4, and con-
centrated. The crude product was purified by column chromatography
(silica gel, cyclohexane=ethyl acetate: 7=3) to give compound 5 (31.2 g,
97% yield) as white crystals. Mp 68 ꢀC; IR (KBr): 3399 (O–H), 1698
(C¼O ester), 1634, 1603, 1513, 1434, 1371, 1266, 1160, 1123, 1031, 981,
861, 817, 604, 570 cmꢁ1 1H NMR (CDCl3): 3.80 (s, 3H, –CO2Me),
;
3.93 (s, 3H, –OMe), 5.86 (s, 1H, –OH), 6.29 (d, J2–3¼15.9 Hz, 1H, H2),
0
0
0
0
0
0
6.92 (d, J5 -6 ¼8.3 Hz, 1H, H5 ), 7.02 (d, J2 -6 ¼1.7 Hz, 1H, H2 ), 7.07
0
0
0
0
0
(dd, J6 -5 ¼8.3 Hz and J6 -2 ¼1.7 Hz, 1H, H6 ), 7.62 (d, J3–2¼15.9 Hz,
1H, H3) ppm; 13C NMR (CDCl3): 51.6 (–CO2Me), 55.9 (–OMe), 109.3,
114.7, 115.2, 123.0, 127.0, 144.9, 146.7, 147.9, 167.7 (–CO2Me) ppm;
MS (ESI): [M þ H]þ 209; HRMS (EI) m=z [Mþ] calcd. for C11H12O4:
208.0736, found: 208.0732.
Methyl (2E)-3-[4-[[Tert-butyldimethylsilyl]oxy]-3-methoxyphenyl]-
prop-2-enoate (6)
Imidazole (24.5 g, 359.9 mmol) was added to a stirred solution of com-
pound 5 (30.0 g, 144.1 mmol) and tert-butyldimethylsilyl chloride
(26.1 g, 173.2 mmol) in DMF (100 mL). The solution was stirred at room
temperature for 2 h. Water (200 mL) was added, and the mixture was
extracted with diethyl ether (4 ꢃ 150 mL). The organic layer was washed
with brine (200 mL) and water (200 mL) successively, dried over MgSO4,
and concentrated. The crude product was purified by column chromato-
graphy (silica gel, cyclohexane=ethyl acetate: 9=1) to give compound 6
(45.8 g, 99% yield) as white needles. Mp 65 ꢀC; IR (KBr): 1711 (C¼O
ester), 1643, 1599, 1512, 1471, 1423, 1342, 1288, 1163, 1127, 1032, 994,
1
912, 843, 781, 722, 693, 653, 607, 556, 495 cmꢁ1; H NMR (CDCl3):
0.17 [s, 6H, (CH3)2-Si], 0.99 [s, 9H, (CH3)3C–Si], 3.79 (s, 3H, –OMe),
3.83 (s, 3H, –CO2Me), 6.30 (d, J2–3¼16.0 Hz, 1H, H2), 6.84 (d,
0
0
0
0
0
J5 -6 ¼8.5 Hz, 1H, H5 ), 6.99–7.03 (m, 2H, H2 , and H6 ), 7.62 (d,
J3–2¼16.0 Hz, 1H, H3) ppm; 13C NMR (CDCl3): ꢁ4.6 [(CH3)2–Si], 18.5
[(CH3)3C–Si], 25.7 [(CH3)3 C–Si], 51.6 (–CO2Me), 55.5 (–OMe), 110.9,
115.5, 121.1, 122.2, 128.3, 145.0, 147.6, 151.2, 167.7 (–CO2Me) ppm;
MS (ESI): [M þ H]þ 323; HRMS (EI) m=z [Mþ] calcd. for C17H26O4Si:
322.1600, found: 322.1597.

New Avenalumic Carboxamide Derivatives
3953
(2E)-3-[4-[[Tert-butyldimethylsilyl]oxy]-3-methoxyphenyl]
prop-2-en-1-ol (7)
DIBAL-H (1 M in THF, 340 mL, 340.0 mmol) was added dropwise over
30 min to a solution of compound 6 (21.9 g, 67.9 mmol) in THF (300 mL)
at ꢁ10 ꢀC under argon. The solution was stirred at room temperature for
6 h. Water (100 mL) was carefully added dropwise at 0 ꢀC. The mixture
was acidified to pH¼5 with a 2 M HCl aqueous solution. The phases were
separated, and the aqueous layer was extracted with diethyl ether
(2 ꢃ 100 mL). The combined organic layers were washed with water,
dried over MgSO4, and concentrated. The crude product was purified
by column chromatography (silica gel, cyclohexane=ethyl acetate: 9=1)
to give compound 7 (18.6 g, 93% yield) as a colorless oil. IR (KBr):
3350 (O–H), 1654, 1600, 1577, 1513, 1464, 1417, 1362, 1281, 1255,
1160, 1126, 1092, 1037, 965, 900, 840, 804, 782, 703, 661, 623 cmꢁ1
;
1H NMR (CDCl3): 0.15 [s, 6H, (CH3)2–Si], 0.99 [s, 9H, (CH3)3 C–Si],
3.82 (s, 3H, –OMe), 4.30 (d, J1–2¼5.9 Hz, 2H, –CH2OH), 6.24 (dt,
J2–3¼15.7 Hz and J2–1¼5.9 Hz, 1H, H2), 6.54 (d, J3–2¼15.7 Hz, 1H, H3),
0
0
0
0
0
0
0
6.79 (d, J5 –6 ¼8.1 Hz, 1H, H5 ), 6.85 (dd, J6 –5 ¼8.1 Hz and J6 –2 ¼2.1 Hz,
1H, H6 ), 6.91 (d, J2 –6 ¼2.1 Hz, 1H, H2 ) ppm; 13C NMR (CDCl3): ꢁ 4.8
[(CH3)2–Si], 18.3 [(CH3)3C–Si], 25.6 [(CH3)3C–Si], 55.2 (–OMe), 63.3
(C1), 109.8, 119.4, 120.7, 126.5, 130.6, 130.8, 144.7, 150.8 ppm; MS (EI,
70 eV) m=z (%): 294 (30) [Mþ], 237 (100) [Mþ –t-Bu], 222 (41), 209
(45), 194 (36), 179 (26), 166 (20), 119 (31), 117 (32). HRMS (EI) m=z
[Mþ] calcd. for C16H26O3Si: 294.1651, found: 294.1648.
0
0
0
0
(2E)-3-[4-[[Tert-butyldimethylsilyl]oxy]-3-methoxyphenyl]
acrylaldehyde (8)
To a solution of compound 7 (15.9 g, 54.0 mmol) in CH2Cl2 (200 mL),
MnO2 (70.4 g, 810.1 mmol) was added, and the solution was then stirred
at room temperature for 24 h. The mixture was filtered through celite,
washing by EtOAc. The filtrate was concentrated to give compound 8
(14.1 g, 89% yield) as a white solid. Mp 79 ꢀC; IR (KBr): 1670 (C¼O alde-
hyde), 1621, 1596, 1511, 1464, 1424, 1283, 1164, 1129, 1034, 984, 906,
1
837, 783 cmꢁ1; H NMR (CDCl3): 0.18 [s, 6H, (CH3)2 –Si], 1.00 [s, 9H,
(CH3)3 C-Si], 3.85 (s, 3H, –OMe), 6.60 (dd, J2–3¼15.9 Hz and
0
0
0
J2-Hald¼7.8 Hz, 1H, H2), 6.88 (d, J5 –6 ¼8.0 Hz, 1H, H5 ), 7.05–7.09 (m,
0
0
2H, H2 and H6 ), 7.40 (d, J3–2¼15.9 Hz, 1H, H3), 9.66 (d, JHald-2¼7.8 Hz,
Hz, 1H, Hald) ppm; 13C NMR (CDCl3): ꢁ 4.5 [(CH3)2–Si], 18.4 [(CH3)3
C–Si], 25.6 [(CH3)3 C–Si], 55.3 (–OMe), 111.0, 121.2, 123.1, 126.7,
127.9, 148.6, 151.4, 153.1, 193.7 (C1) ppm; MS (ESI): [M þ H]þ

3954
M.-A. Bazin et al.
293; HRMS (EI) m=z [Mþ] calcd. for C16H24O3 Si: 292.1495, found:
292.1500.
Ethyl (2E,4E)-5-[4-[[Tert-butyldimethylsilyl]oxy]-3-methoxyphenyl]-
penta-2,4-dienoate (9a) and Ethyl (2Z,4E)-5-[4-[[Tert-butyldimethylsilyl]-
oxy]-3-methoxyphenyl]penta-2,4-dienoate (9b)
NaH (2.1 g, 89.1 mmol) was added in a small amount to a solution of
compound 8 (13.0 g, 44.5 mmol) and triethyl phosphonoacetate (11.0 g,
49.0 mmol) in DMF (100 mL) at 0 ꢀC. The solution was then stirred at
room temperature for 1 h. Ice water (200 mL) was added to the solution,
and the mixture was extracted with diethyl ether (4ꢃ100 mL). The
organic layer was washed with water (100 mL), dried over MgSO4, and
concentrated. The crude product was purified by column chromato-
graphy (silica gel, cyclohexane=ethyl acetate: 95=5) to give compound
9a (15.60 g, 97% yield) as a colorless solid and compound 9b (0.16 g,
1% yield) as a colorless oil.
Compound 9a: Mp 48 ꢀC; IR (KBr): 1710 (C¼O ester), 1625, 1594,
1511, 1464, 1418, 1367, 1313, 1285, 1264, 1174, 1132, 1038, 998, 905,
841, 806, 783, 703 cmꢁ1 1H NMR (CDCl3): 0.16 [s, 6H, (CH3)2–Si],
;
0.99 [s, 9H, (CH3)3 C–Si], 1.31 (t, J¼7.1 Hz, 3H, –OCH2CH3), 3.84
(s, 3H, –OMe), 4.22 (q, J¼7.1 Hz, 2H, –OCH2CH3), 5.94 (d,
J2–3¼15.4 Hz, 1H, H2), 6.73 (dd, J4–5¼15.6 Hz and J4–3¼10.6 Hz, 1H,
0
0
0
H4), 6.81–6.85 (m, 2H, H5 and H5 ), 6.93–6.96 (m, 2H, H2 and H6 ),
7.43 (dd, J3–2¼15.4 Hz and J3–4¼10.6 Hz, 1H, H3) ppm; 13C NMR
(CDCl3): ꢁ 4.6 [(CH3)2–Si], 14.3 (–OCH2 CH3), 18.5 [(CH3)3C–Si], 25.7
[(CH3)3C–Si], 55.5 (–OMe), 60.2 (–OCH2CH3), 110.2, 120.2, 121.0,
121.1, 124.4, 130.0, 140.5, 144.9, 146.4, 151.2, 167.3 (C1) ppm; MS
(ESI): [M þ H]þ 363. Anal. calcd. for C20H30O4Si: C, 66.26; H, 8.34.
Found: C, 66.47; H, 8.69.
Compound 9b: IR (KBr): 1712 (C¼O ester), 1621, 1593, 1510, 1464,
1285, 1255, 1177, 1128, 1036, 998, 905, 840, 808, 783, 701 cmꢁ1; 1H NMR
(CDCl3): 0.16 [s, 6H, (CH3)2–Si], 0.99 [s, 9H, (CH3)3 C–Si], 1.33
(t, J¼7.1 Hz, 3H, –OCH2CH3), 3.84 (s, 3H, –OMe), 4.22 (q, J¼7.1 Hz,
2H, –OCH2CH3), 5.66 (d, J2–3¼11.2 Hz, 1H, H2), 6.69–6.85 (m, 3H, H4,
0
0
0
0
0
0
H5 and H5 ), 6.97 (dd, J6 –5 ¼8.3 Hz and J6 -2 ¼2.0 Hz, 1H, H6 ), 7.05 (d,
0
0
0
J2 –6 ¼2.0 Hz, 1H, H2 ), 8.01 (dd, J3–4¼11.5 Hz and J3–2¼11.2 Hz, 1H,
H3) ppm; 13C NMR (CDCl3): ꢁ4.6 [(CH3)2–Si], 14.3 (–OCH2 CH3),
18.5 [(CH3)3C–Si], 25.7 [(CH3)3 C–Si], 55.4 (–OMe), 59.9 (–OCH2CH3),
110.0, 116.1, 121.0, 121.5, 123.1, 124.4, 130.3, 141.5, 145.3, 151.1, 166.8
(C1) ppm; MS (ESI): [M þ H]þ 363, [M þ MeCN þ H]þ 402. Anal. calcd.
for C20H30O4 Si: C, 66.26; H, 8.34. Found: C, 66.19; H, 8.14.

New Avenalumic Carboxamide Derivatives
3955
Ethyl (2E,4E)-5-[4-Hydroxy-3-methoxyphenyl]penta-2,4-dienoate (10)
To a solution of compound 9a (15.0 g, 41.4 mmol) in THF (100 mL),
glacial acetic acid (8 mL) was added at 0 ꢀC under argon. TBAF (1 M
in THF, 82.7 mL, 82.7 mmol) was then added dropwise, and the mixture
was stirred at the same temperature for 1 h. THF was evaporated under
reduced pressure. The mixture was acidified to pH¼5 with a 0.5 M HCl
aqueous solution. The aqueous layer was extracted with diethyl ether
(4 ꢃ 100 mL). The organic layer was washed with water (50 mL) and brine
(50 mL) successively, dried over MgSO4, and concentrated. The crude
product was purified by column chromatography (silica gel, cyclohexa-
ne=ethyl acetate: 8=2) to give compound 10 (9.6 g, 93% yield) as a pale
yellow solid. Mp 90 ꢀC; IR (KBr): 3430 (O–H), 1684 (C¼O ester),
1624, 1587, 1512, 1336, 1259, 1208, 1185, 1137, 1031, 1017, 1004, 864,
1
806 cmꢁ1; H NMR (CDCl3): 1.31 (t, J¼7.1 Hz, 3H, –OCH2CH3), 3.93
(s, 3H, –OMe), 4.22 (q, J¼7.1 Hz, 2H, –OCH2CH3), 5.78 (br s, 1H,
OH), 5.94 (d, J2–3¼15.2 Hz, 1H, H2), 6.72 (dd, J4–5¼15.3 Hz
and J4–3¼10.7 Hz, 1H, H4), 6.82 (d, J5–4¼15.3 Hz, 1H, H5), 6.89 (d,
0
0
0
0
0
0
J5 –6 ¼8.1 Hz, 1H, H5 ), 6.97 (d, J2 –6 ¼1.7 Hz, 1H, H2 ), 6.99 (dd,
0
0
0
0
0
J6 –5 ¼8.1 Hz and J6 -2 ¼1.7 Hz, 1H, H6 ), 7.43 (dd, J3–2¼15.2 Hz
and J3–4¼10.7 Hz, 1H, H3) ppm; 13C NMR (CDCl3): 14.3 (–OCH2CH3),
56.0 (–OMe), 60.3 (–OCH2CH3), 108.7, 114.7, 120.1, 121.7, 124.1, 128.7,
140.5, 144.9, 146.8, 146.9, 167.3 (C1) ppm; MS (ESI): [M–H]ꢁ 247. Anal.
calcd. for C14H16O4: C, 67.73; H, 6.50. Found: C, 67.39; H, 6.76.
(2E,4E)-5-[4-Hydroxy-3-methoxyphenyl]penta-2,4-dienoic Acid (11)
Aqueous KOH (15%, 75 mL) was added to a solution of compound 10
(8.0 g, 32.3 mmol) in MeOH (75 mL). The mixture was refluxed for 4 h.
MeOH was evaporated under reduced pressure, and the aqueous solution
was acidified to pH¼4 with a 2 M HCl aqueous solution. The aqueous
layer was extracted with ethyl acetate (2ꢃ150 mL). The organic layer
was washed with water (100 mL), dried over MgSO4, and concentrated.
Recrystallization from MeOH=H2O (1:1) gave compound 11 (6.4 g,
90% yield) as a yellow solid. Mp 199 ꢀC; IR (KBr): 3525 (O–H), 3457
(O–H carboxylic acid), 1681 (C¼O carboxylic acid), 1587, 1514, 1429,
1336, 1311, 1267, 1209, 1164, 1125, 1022, 994, 926, 853, 819, 761, 699,
1
606, 549 cmꢁ1; H NMR (DMSO-d6): 3.80 (s, 3H, –OMe), 5.89 (d, J2–
0
0
0
¼15.0 Hz, 1H, H2), 6.76 (d, J6 -5 ¼8.1 Hz, 1H, H6 ), 6.92–6.98 (m, 3H,
3
0
0
H4, H5 and H5 ), 7.15 (s, 1H, H2 ), 7.30 (ddd, J3–2¼15.1 Hz, J3–
¼6.9 Hz and J3–5¼3.0 Hz, 1H, H3), 9.76 (brs, 1H, OH phenol), 12.12
4
(brs, 1H, OH acid) ppm; 13C NMR (DMSO-d6): 56.0 (–OMe), 110.6,

3956
M.-A. Bazin et al.
115.9, 120.4, 121.9, 124.0, 128.1, 141.1, 145.7, 148.2 (2 C), 168.3 (Cl) ppm;
MS (ESI): [M–H]ꢁ 219. Anal. calcd. for C12H12O4: C, 65.45; H, 5.49.
Found: C, 65.57; H, 5.53.
(2E,4E)-5-[4-Acetyloxy-3-methoxyphenyl]penta-2,4-dienoic Acid (12)
To a solution of compound 11 (5.0 g, 22.7 mmol) in pyridine (50 mL),
DMAP (0.1 g, 1.1 mmol) and acetic anhydride (2.4 mL, 25.0 mmol) were
added successively at room temperature. The solution was then stirred
for 18 h. The solution was acidified to pH¼3 with a 1 M HCl aqueous
solution. The aqueous layer was extracted with ethyl acetate
(3ꢃ150 mL). The organic layer was washed successively with brine and
water and dried over MgSO4. Concentration in vacuo afforded compound
12 (5.5 g, 92% yield) as a beige solid. Mp 210 ꢀC; IR (KBr): 3436 (O–H),
1766 (C¼O ester), 1674 (C¼O carboxylic acid), 1612, 1511, 1423, 1313,
1268, 1208, 1125, 1032, 996, 909, 861, 824, 699 cmꢁ1; 1H NMR (CDCl3):
2.33 (s, 3H, –OCOCH3), 3.88 (s, 3H, –OMe), 6.01 (d, J2–3¼15.2 Hz, 1H,
H2), 6.84 (dd, J4–5¼15.5 Hz and J4–3¼10.1 Hz, 1H, H4), 6.92 (d,
0
0
0
J5–4¼15.5 Hz, 1H, H5), 7.03 (d, J5 -6 ¼8.1 Hz, 1H, H5 ), 7.06–7.09 (m,
0
0
2H, H2 and H6 ), 7.52 (dd, J3–2¼15.2 Hz and J3–4¼10.1 Hz, 1H, H3)
ppm; 13C NMR (DMSO-d6): 20.4 (–OCOCH3), 55.9 (–OMe), 110.7,
120.1, 122.3, 123.2, 127.0, 135.0, 139.3, 139.9, 144.3, 151.1, 167.6
(–OCOCH3), 168.5 (C1) ppm; MS (ESI): [M–H]ꢁ 261; HRMS (EI) m=z
[Mþ] calcd. for C14H14O5: 262.0841, found: 262.0838. Anal. calcd. for
C14H14O5: C, 64.12; H, 5.38. Found: C, 64.22; H, 4.95.
Methyl 2-({(2E,4E)-5-[4-Acetyloxy-3-methoxyphenyl]penta-
2,4-dienoyl}amino)benzoate (13)
Triethylamine (2.1 mL, 15.3 mmol) was added to a solution of compound
12 (4.0 g, 15.3 mmol) in acetonitrile (50 mL) at 0 ꢀC. The mixture was then
stirred for 1 h at 0 ꢀC. Ethyl chloroformate (1.5 mL, 15.3 mmol) was added
dropwise, and the solution was stirred for 1 h at the same temperature.
The white precipitate was filtered and washed with acetonitrile (10 mL),
and the filtrate was concentrated. Water (50 mL) was added, and the mix-
ture was extracted with ethyl acetate (2 ꢃ 150 mL). The organic layer was
dried over MgSO4 and concentrated to give a yellowish solid. The crude
product was used in the next step without purification. To a solution of
crude anhydride (15.3 mmol) in acetonitrile (75 mL), methyl anthranilate
(2.0 mL, 15.3 mmol) was added, and the solution was then refluxed for
4 h. The solvent was removed under reduced pressure. Water (100 mL)

New Avenalumic Carboxamide Derivatives
3957
was added, and the mixture was extracted with ethyl acetate (3 ꢃ 150 mL).
The organic layer was washed with water (100 mL), dried over MgSO4,
and concentrated. The crude product was purified by column chromato-
graphy (silica gel, cyclohexane=ethyl acetate 8:2) and recrystallized in
MeOH to give compound 13 (3.9 g, 65% yield, two steps) as a pale yellow
solid. Mp 149 ꢀC; IR (KBr): 1761 (C¼O acetyl), 1697 (C¼O –CO2Me),
1677 (C¼O amide), 1612, 1587, 1530, 1511, 1446, 1261, 1201, 1129, 992,
757 cmꢁ1 1H NMR (CDCl3): 2.32 (s, 3H, –OCOCH3), 3.88ꢂ (s, 3H,
;
–OMe), 3.95ꢂ (s, 3H, –CO2Me), 6.22 (d, J2 –3 ¼14.9 Hz, 1H, H2 ), 6.87–
0
0
0
ꢂ
0
0
0
0
0
6.90 (m, 2H, H4 and H5 ), 7.02–7.11 (m, 4H, H2 , H5 , H6 and H4 ),
0
0
0
0
0
0
0
7.50 (ddd, J3 –2 ¼14.9 Hz and J3 –4 ¼7.8 Hz and J3 –5 ¼2.2 Hz, 1H, H3 ),
ꢂ
7.57 (ddd, J5–6¼7.9 Hz and J5–4¼7.9 Hz and J5–3¼1.5 Hz, 1H, H5 ), 8.05
(dd, J3–4¼7.9 Hz and J3–5¼1.5 Hz, 1H, H3), 8.84 (d, J6–5¼8.5 Hz, 1H,
H6), 11.30 (s, 1H, NH) ppm; 13C NMR (CDCl3): 20.6 (–OCOCH3),
52.3 (–CO2 CH3), 55.8 (–OMe), 110.4, 114.8, 119.9, 120.4, 122.4, 123.1,
125.5, 126.6, 130.8, 134.7, 135.2, 139.1, 140.2, 141.8 (2 C), 151.2, 164.þ5
(C10), 168.8ꢂ (–OCOCH3), 168.9ꢂ (–CO2CH3) ppm; MS (ESI): [M þ H]
396; HRMS (EI) m=z [Mþ] calcd. for C22H21NO6: 395.1369, found:
395.1360. Anal. calcd. for C22H21NO6: C, 66.83; H, 5.35; N, 3.54. Found:
C, 66.93; H, 5.35; N, 3.34.
2-({(2E,4E)-5-[4-Hydroxy-3-methoxyphenyl]penta-2,4-
dienoyl}amino)benzoic Acid (14)
LiOH ꢄ H2O (0.2 g, 20.2 mmol) was added to a suspension of compound
13 (2.0 g, 5.1 mmol) in water (75 mL). The solution was warmed for 4 h
at 60 ꢀC. The mixture was then cooled to room temperature and filtered.
The solution was acidified to pH¼1 with a 2 M HCl aqueous solution.
The mixture was extracted with ethyl acetate (2 ꢃ 100 mL). The organic
layer was washed with water, dried over MgSO4, and concentrated.
The crude product was triturated with diethyl ether and filtered to give
compound 14 (1.0 g, 60% yield) as a yellow solid. Mp 203 ꢀC; IR
(KBr): 3429 (O–H), 1686 (C¼O acid), 1657 (C¼O amide), 1606, 1586,
1514, 1452, 1375, 1278, 1250, 1209, 1137, 988, 760 cmꢁ1 1H NMR
;
(DMSO-d6): 3.81 (s, 3H, –OMe), 4.12 (br s, 1H, OH), 6.22 (d,
0
0
0
00 00
00
J2 –3 ¼14.7 Hz, 1H, H2 ), 6.77 (d, J6 -5 ¼8.8 Hz, 1H, H6 ), 6.92–6.98 (m,
0
00
0
0
0
0
0
2H, H5 and H5 ), 7.04 (dd, J4 -5 ¼15.6 Hz and J4 -3 ¼10.8 Hz, 1H, H4 ),
00
0
0
7.12–7.16 (m, 1H, H5), 7.18 (s, 1H, H2 ), 7.36 (dd, J3 -2 ¼14.7 Hz and
0
0
0
J3 -4 ¼10.8 Hz, 1H, H3 ), 7.57–7.61 (m, 1H, H4), 7.99 (d, J3–4¼7.8 Hz,
1H, H3), 8.60 (d, J6–5¼6.8 Hz, 1H, H6), 9.42 (s, 1H, NH), 11.44 (br s,
1H, OH) ppm; 13C NMR (DMSO-d6): 55.6 (–OMe), 110.3, 115.6,
116.4, 119.9, 121.3, 122.4, 123.5, 123.7, 127.7, 131.0, 133.8, 140.1,

3958
M.-A. Bazin et al.
141.0, 142.2, 147.8, 147.9, 163.9 (C1’), 169.5(–CO2H) ppm; MS (ESI):
[M þ H]þ 340; HRMS (EI) m=z [Mþ] calcd. for C19H17NO5: 339.1107,
found: 339.1108. Anal. calcd. for C19H17NO5: C, 67.25; H, 5.05; N,
4.13. Found: C, 67.04; H, 4.87; N, 4.29.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from Laboratoires
´
PCAS and the Conseil Regional de Basse-Normandie.
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