Substituted cinnamic anhydrides act as selective inhibitors of acetylcholinesterase

Article abstract of DOI:10.1016/j.bioorg.2019.103058

Cinnamic anhydrides have been shown to be more than reactive reagents, but they also act as inhibitors of the enzyme acetylcholinesterease (AChE). Thus, out of a set of 33 synthesised derivatives, several of them were mixed type inhibitors for AChE (from electric eel). Thus, (E)-3-(2,4-dimethoxyphenyl)acrylic anhydride (2c) showed K_i = 8.30 ± 0.94 μM and K_i′ = 9.54 ± 0.38 μM, and for (E)-3-(3-chlorophenyl)acrylic anhydride (2u) K_i = 8.23 ± 0.93 μM and K_i′ = 13.07 ± 0.46 μM were measured. While being not cytotoxic to many human cell lines, these compounds showed an unprecedented and noteworthy inhibitory effect for AChE but not for butyrylcholinesterase (BChE).

Full text of DOI:10.1016/j.bioorg.2019.103058

BioorganicChemistry90(2019)103058
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Substituted cinnamic anhydrides act as selective inhibitors of
acetylcholinesterase
Josephine M. Gießel, Immo Serbian, Anne Loesche, René Csuk⁎
Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes Str. 2, D-06120 Halle (Saale), Germany
A R T I C L E I N F O
A B S T R A C T
Keywords:
Cinnamic anhydrides have been shown to be more than reactive reagents, but they also act as inhibitors of the
enzyme acetylcholinesterease (AChE). Thus, out of a set of 33 synthesised derivatives, several of them were
mixed type inhibitors for AChE (from electric eel). Thus, (E)-3-(2,4-dimethoxyphenyl)acrylic anhydride (2c)
Cinnamic anhydrides
Acetylcholinesterase
Butyrylcholinesterase
Inhibitors
showed Ki = 8.30
0.94 µM and Ki′ = 9.54
0.93 µM and Ki′ = 13.07
0.38 µM, and for (E)-3-(3-chlorophenyl)acrylic anhydride (2u)
Ki = 8.23
0.46 µM were measured. While being not cytotoxic to many human
cell lines, these compounds showed an unprecedented and noteworthy inhibitory effect for AChE but not for
butyrylcholinesterase (BChE).
1. Introduction
anhydrides, however cinnamic anhydrides are remarkable stable in
aqueous solutions [16], and they should be investigated in more detail.
Cinnamic acid moieties are part of a large number of natural pro-
ducts. Since many of them can be found in our daily nutrition [1–3] an
investigation of their biological effects is of major interest. While some
of these compounds have been investigated in detail [4–7], many de-
rivatives have not been a subject of biological investigations at all. The
effects of cholinesterase inhibitors in combating Alzheimer’s disease
(AD) remain interesting but still not completely understood. Acetyl- and
butyrylcholinesterase are enzymes which influence the cognitive func-
tion and memory, thus making these enzymes of special interest in
humans being affected by AD [8–10]. Approximately one percent of the
world’s population suffers from some kind of dementia; as a con-
sequence, 50 million people are affected by AD [11]. Recent work from
Kim et al. [12] showed derivatives of cinnamic acid to hold promising
cholinesterase (ChE) inhibitory effects. Hence, we were looking for
unexplored derivatives close to cinnamic acids, and interestingly cin-
namic anhydrides revealed to be a class of compounds having never
before tested for their ability to act as inhibitors of ChE (Fig. 1). In-
terestingly, quite recently another anhydride, 2,3-dimetylmaleic anhy-
As a consequence, anhydrides did not seem to be very appealing as
potential drugs, and investigations of them are scarcely found in lit-
erature. Thus, a mixed anhydride between a triterpene and cinnamic
acid [17] has been investigated as novel anti-malarial agent, and cy-
totoxic properties have been reported for plant extracts [18,19].
2. Results and discussion
2.1. Chemistry
Knoevenagel-Doebner-condensations [20,21] are well-known to
access carboxylic acids from malonic acid and an appropriate aldehyde.
To investigate the influence of the electronic profile of the aromatic
system on reactivity and biologically activity, a variety of differently
substituted benzaldehydes holding both electron-withdrawing and
-donating substituents in various substitution patterns has been in-
cluded in our investigations (Table 1).
Substituted benzaldehydes were used to prepare 13 commercially
not available cinnamic acids applying Knoevenagel-Doebner reactions.
These compounds are characterized by the presence of the olefinic
protons in their 1H NMR spectra (as exemplified for 1a: δ = 7.74 and
6.33 ppm); in the 13C NMR spectra the olefinic carbons were detected at
δ = 147.1 and 115.0 ppm, respectively. The yields in these condensa-
tion reactions differed between moderate to very good, a fact that can
be explained by the different electronic properties due to the differences
dride has been found to act as
ylcholinestase from insects [13].
a strong inhibitor on an acet-
Usually, carboxylic anhydrides are seen as reactive species to syn-
thesize carboxylic acids derivatives that cannot be obtained directly
from the carboxylic acid [14,15]. Furthermore, due to this reactivity, it
is generally assumed that they are easily hydrolysed, hence resulting in
a short lifetime in the presence of water. This holds true for many
⁎ Corresponding author.
E-mail address: rene.csuk@chemie.uni-halle.de (R. Csuk).
https://doi.org/10.1016/j.bioorg.2019.103058
Received 11 March 2019; Received in revised form 1 June 2019; Accepted 7 June 2019
Availableonline08June2019
0045-2068/©2019ElsevierInc.Allrightsreserved.

J.M. Gießel, et al.
BioorganicChemistry90(2019)103058
Table 2
Results from the biological screening (Ellman’s assay; %-inhibition at a con-
centration of 10 μM) of compounds 1a-1m (compounds not mentioned in the
table were insoluble under the conditions of the assay) with AChE (from elec-
trophorus electricus) and BChE (from equine serum); the inhibition [22] constants
Ki and Ki′ are given in µM and galantamine hydrobromide (GH) was used as a
standard); the values are averaged from experiments performed in triplicate,
and binding energies are reported in kcal/mol for AChE (PDB:1C2O).
Fig. 1. Structure of cinnamic anhydrides and of 2,3-dimethylmaleic anhydride.
Table 1
AChE
BChE
Substitution pattern for cinnamic acids (1) and anhydrides (2).
R1
R2
R3
R4
Compounds
Inhibition [%]
Binding energy [kcal/mol]
Inhibition [%]
a
b
c
d
e
f
H
OMe
OMe
H
OMe
OMe
OMe
H
H
GH
1a
1b
1c
1d
1e
1g
1h
1i
87.70
33.70
7.22
−7.94
−5.30
−5.24
−5.88
−5.67
−4.84
−5.22
−5.29
−5.67
−6.29
−6.33
−6.35
−5.87
53.00
12.3
1.91
18.34
0.00
2.72
1.58
2.09
3.08
0.79
2.11
0.73
1.28
H
H
OMe
H
H
OMe
OMe
OMe
OH
OMe
OMe
Me
H
OMe
OMe
H
25.91
12.65
9.75
H
OMe
H
OH
H
g
h
i
OMe
OH
OAc
Me
H
H
6.89
H
H
12.32
12.09
11.85
8.52
H
H
j
H
H
1j
k
l
NO2
H
H
1k
1l
NO2
H
H
H
10.60
13.61
m
n
o
p
q
r
H
N(Me)2
H
H
1m
H
H
H
H
OH
OMe
H
OH
OH
H
H
H
OMe
H
bind to the active site of the enzyme. In Fig. 2, the active site is located
at the lower right with the corresponding amino acids His447, Glu334
and Ser203.
OMe
H
OMe
H
H
H
s
H
OMe
H
H
t
Cl
H
H
H
As depicted in Fig. 2, the anhydrides were also docked into the
enzyme pocket of AChE. Although these compounds are larger, it is
obvious that they fit even better than the parent acids into the pocket
thus blocking the active site. The results from the biological assays
showed cinnamic anhydrides 2a-2x (Table 3) to be able of binding to
the enzyme, and revealed some of them as good inhibitors. These an-
hydrides were only weak inhibitors for butyrylcholinesterase. Mole-
cular modelling calculations (PDB:6EMI) revealed that these com-
pounds have less interaction with the amino acid residues of the active
site (Fig. 3).
u
v
w
x
Cl
H
H
Cl/H
H
H/Cl
F
H
H
H
H
H
H
F
H
in the substitution pattern.
Symmetrical and non-symmetrical anhydrides were prepared ac-
cording to Scheme 1. For the synthesis, a combination of cinnamic acids
from previous reactions and commercially available compounds was
used. Again, reaction yields were moderate to very good, with com-
pounds 1f–1h being the exceptions, reacting to polymeric structures
and not forming anhydrides.
The assays were carried out in aqueous solution, and thus it might
be a valid assumption that the cinnamic anhydrides will be hydrolysed
in this environment. Furthermore, one would assume that the products
of hydrolysis induce the inhibitory effect. However, cinnamic acid an-
hydrides are rather stable under the conditions of the assays, and - as
checked by TLC - even after a prolonged period of 72 h less than 10
percent of the anhydride was hydrolyzed into their corresponding acids.
Therefore, the anhydride but not the cinnamic acid acts as inhibitor for
AChE. The assumption that cinnamic anhydrides act as irreversible
inhibitors of the enzyme could also not be confirmed since measure-
ments of the enzyme kinetic showed these compounds as mixed type
inhibitors for AChE. Thus, in this series, compounds 2c, 2d, 2j, 2t, 2u
and 2v showed good to moderate inhibition of AChE. These biological
activities are not entirely unexpected because these cinnamic anhy-
drides can be considered as isosteric derivatives of curcumin. Of the
latter, inhibitory activity is known with respect to AChE [24–28].
Extra screening of cinnamic acids 1a-1m and of anhydrides 2a-2x
showed them being not cytotoxic for a variety of human tumor cells
lines [cut off: EC50 > 30 μM; cell lines: FaDu (hypopharyngeal
2.2. Biological evaluation
2.2.1. Inhibition of ChE
The inhibitory activity of the compounds for AChE and BChE was
determined by Ellman’s assays [22]. To support these experiments,
some extra molecular docking calculations with the enzyme AChE
(from electric eel) were performed using Autodock4 [23]. The results
from the biological assays and calculations from the docking of cin-
namic acid derivatives are compiled in Table 2. Interestingly, while
some compounds proved to be good inhibitors for AChE, none of them
was a good inhibitor for BChE.
The results from the biological assays are in excellent agreement
with the results from the molecular modelling calculations. Thus, the
cinnamic acid finds its way inside the enzyme pocket of AChE (Fig. 2),
but shows only show weak interactions with the enzyme and cannot
Scheme 1. . Synthesis of cinnamic acid derivatives and the appropriate anhydrides: (i): piperidine, pyridine, reflux 120 °C, 4 h; (ii): (1) oxalyl chloride, CH2Cl2,
0 °C → 25 °C, 2 h (2) pyridine, toluene, 25 °C, overnight.
2

J.M. Gießel, et al.
BioorganicChemistry90(2019)103058
Fig. 2. Compounds 1a-1m (left) and 2a-2x (right) inside the AChE active site pocket.
carcinoma), A2780 (ovarian carcinoma), HT29 (colorectal carcinoma),
MCF7 (breast carcinoma), SW1736 (thyroid carcinoma), A375 (malig-
nant melanoma), A549 (epithel carcinoma)] and to non-malignant NIH
3T3 (mouse fibroblasts) cells. This finding is a prerequisite for devel-
oping anhydrides of improved properties.
3. Conclusion
As a result, cinnamic anhydrides have been shown to represent a
class of interesting and promising compounds with unforeseen prop-
erties. In this study, 33 derivatives were prepared and screened for their
biological activity. While these compounds exhibited no cytotoxic effect
neither on malignant human tumor cells nor on non-malignant mouse
fibroblasts, they proved to be moderate to good inhibitors of the en-
zyme acetylcholinesterase while being only negligible inhibitors for
butyrylcholinesterase. As the cinnamic anhydrides are of remarkable
stability in aqueous solution, derivatives of this kind might may be of
interest to develop AChE inhibitors.
4. Experimental
Fig. 3. Compounds 2c (yellow), 2j (beige), 2l (red) and 2p (blue) inside the
4.1. General
BChE active site pocket.
The reagents were bought from commercial suppliers and used
without further purification. The solvents were dried according to usual
procedures. Melting points were determined on Büchi Melting Point M-
565 or LEICA hot stage microscope and are uncorrected, NMR spectra
were recorded on a Varian spectrometer Unity 500 (δ given in ppm, J in
Hz), mass spectra were obtained on a Finnigan MAT LCQ 7000 (elec-
trospray, voltage 4.1 kV, sheath gas nitrogen) instrument. The optical
rotations were measured on a Perkin-Elmer polarimeter at 20 °C.
Table 3
Results from the biological screening (Ellman’s assay; %-inhibition at a concentration of 10 μM) of compounds 2a–2x with AChE (from electrophorus electricus) and
BChE (from equine serum); the inhibition constants Ki and Ki′ are given in µM and galantamine hydrobromide (GH) was used as a standard); the values are averaged
from experiments performed in triplicate, and binding energy are reported in kcal/mol for AChE (PDB:1C2O). All compounds were mixed type inhibitors.
AChE
BChE
Compounds
Inhibition [%]
Ki [μM]
Ki’ [μM]
Binding energy for top 1 pose [kcal/mol]
Inhibition [%]
GH
2c
2d
2j
87.70
79.13
33.33
77.41
15.36
9.02
0.54
0.01
0.94
–
−7.94
−8.46
−8.30
−10.47
−10.68
−9.33
−9.03
−7.26
−9.05
−9.11
−9.94
−9.99
−9.91
−9.04
−8.85
53.00
27.50
0.00
13.83
5.22
5.56
1.70
1.15
4.30
1.84
3.60
13.15
14.42
2.17
0.43
8.30
9.54
53.70
0.38
1.19
17.81
11.15
0.95
1.36
2k
2m
2n
2p
2q
2r
14.14
9.14
34.85
10.54
54.55
72.82
79.19)
15.70
17.15
2t
13.42
8.23
1.06
> 50
13.07
21.46
2u
2v
2w
2x
0.93
1.16
0.46
0.13
12.19
3

J.M. Gießel, et al.
BioorganicChemistry90(2019)103058
Macherey-Nagel ALUGRAM® Xtra SIL G/UV254 pre-coated silica gel 60
F254 plates were used for thin layer chromatography (detection with
cerium molybdate spray reagent and UV absorption). IR spectra were
recorded on a Perkin-Elmer FT-IR spectrometer Spectrum 1000 and
wave numbers are expressed in cm−1. The absorption spectra were
measured on Perkin Elmer Lambda14 spectrometer. Microanalyses
were performed with a Foss-Heraeus Vario EL (CHNS) instrument.
147.8 (C-3′), 132.9 (C-1′), 120.3 (C-5′), 115.5 (C-2′), 111.8 (C-6′), 56.1
(C-8′), 56.0 (C-7′), 35.8 (C-3), 30.4 (C-2) ppm; MS (ESI, MeOH): m/z
(%) = 209.1 ([M−H]−, 100), 441 ([2M−2H + Na]−, 71); analysis
calcd for C11H14O4 (210.23): C 62.85, H 6.71; found C 62.65, H 6.92.
4.4.4. (E)-3-(2,4-Dimethoxyphenyl)acrylic acid (1c)
Recrystallization from ethanol gave 1c (1.33 g, 64%) as an off-white
solid; RF = 0.25 (silica gel, n-hexane/ethyl acetate, 4:1); m.p. 190 °C
(lit.: [34] 187–189 °C); IR (KBr): ν = 3448m, 3004w, 2944w, 2838w,
2586w, 1681s, 1599s, 1505s, 1459m, 1418m, 1329s, 1313s, 1298m,
1268s, 1210s, 1160s, 1117s, 1043m, 1028m, 987m, 829m cm−1; UV–vis
(CHCl3): λmax (log ε) = 254 (3.47), 316 (3.84), 354 (3.97) nm ; 1H NMR
(400 MHz, CDCl3): δ = 8.01 (d, J = 16.1 Hz, 1H, 3-H), 7.47 (d,
J = 8.6 Hz, 1H, 3′-H), 6.52 (dd, J = 8.6, 2.3 Hz, 1H, 6′-H), 6.46 (d,
J = 2.3 Hz, 1H, 5′-H), 6.45 (d, J = 16.0 Hz, 1H, 2-H), 3.88 (s, 3H, 7′-H),
3.85 (s, 3H, 8′-H) ppm; 13C NMR (100 MHz, CDCl3): δ = 172.6 (C-1),
163.3 (C-4′), 160.3 (C-2′), 142.5 (C-3), 131.0 (C-3′), 116.5 (C-1′), 115.0
(C-2), 105.5 (C-6′), 98.6 (C-5′), 55.7 (C-7′ + C-8′) ppm; MS (ESI,
MeOH): m/z (%) = 191.1 ([M+H-H2O]+, 100), 208.9 ([M+H]+, 81),
223.0 ([M + H + MeOH-H2O]+, 25), 231.1 ([M + Na]+, 8); analysis
calcd for C11H12O4 (208.21): C 63.45, H 5.81; found: C 62.35, H 6.13.
4.2. Molecular docking
The crystal structures of the eeAChE (PDB = 1C2O) hBChE-7
(PDB = 6EMI) were retrieved from the protein databank (rcsb.org). The
enzyme was prepared according to usual procedures. Polar hydrogen
atoms were added, water molecules removed, and Gasteiger charges
were added. The ligand minimisation and preparation was performed
with the MMFF94 force field in Datawarrior. Openbabel was used to
create the pdbqt files for Autodock. Calculations were done with
Autodock4 [23] Lamarckian genetic algorithm, and the analysis of the
docking poses was done with MGLTools 1.5.6.; figures were created
with PyMOL.
4.3. Biological screening
4.4.5. (E)-3-(3,5-Dimethoxyphenyl)acrylic acid (1d)
The Ellman’s assay have been performed as previously described
[29,30].
Compound 1d was obtained by recrystallization from ethanol as a
white solid (1.16 g, 60%); RF = 0.08 (silica gel, n-hexane/ethyl acetate,
4:1); m.p. 173 °C (lit.: [35] 174 °C); IR (ATR): ν = 2835w, 1682s,
1632m, 1593s, 1469m, 1433m, 1356w, 1320m, 1285s, 1206s, 1163s,
1057s, 927m, 852m, 837s, 808m, 670m, 645m, 606m, 540m,
472m cm−1; UV–vis (MeOH): λmax (log ε) = 226 (4.39), 284 (4.25) nm;
1H NMR (500 MHz, DMSO-d6): δ = 7.51 (d, J = 16.0 Hz, 1H, 3-H), 6.86
(d, J = 2.2 Hz, 2H, 2′-H), 6.56 (d, J = 16.1 Hz, 1H, 2-H), 6.53 (d,
J = 2.2 Hz, 1H, 4′-H), 3.77 (s, 6H, 5′-H) ppm; 13C NMR (125 MHz,
DMSO-d6): δ = 167.6 (C-1), 160.7 (C-3′), 143.9 (C-3), 136.2 (C-1′),
119.9 (C-2), 106.0 (C-2′), 102.4 (C-4′), 55.4 (C-5′) ppm; MS (ESI,
ASAP): m/z (%) = 207.1 ([M−H]−, 100); analysis calcd for C11H12O4
(208.21): C 63.45, H 5.81; found C 62.29, H 6.11.
4.4. Syntheses
4.4.1. General procedure A
To a solution of the substituted benzaldehyde (1 eq.) and malonate
(1.2 eq.) in pyridine (2.5 mL/mmol) at 120 °C piperidine (0.04 eq.) was
added, and the reaction mixture was heated under reflux for 4 h [31].
The solvents were removed in vacuo as an azeotrope with toluene
(3 × 70 mL). Water (100 mL) was added, and the aqueous phase was
extracted with ethyl acetate (3 × 100 mL), brine (1 × 100 mL), dried
(MgSO4) and concentrated. Compounds 1a and 1c–1m were prepared
following procedure A.
4.4.6. (E)-3-(3,4,5-Trimethoxyphenyl)acrylic acid (1e)
4.4.2. (2E)-3-(3,4-Dimethoxyphenyl)-2-propenoic acid (1a)
Compound 1e was obtained by recrystallization from ethanol as an
off-white solid (4.36 g, 36%); RF = 0.04 (silica gel, n-hexane/ethyl
acetate, 4:1); m.p. 125 °C (lit.: [36] 124–125 °C); IR (ATR): ν = 3004w,
2837w, 2653w, 1684w, 1625m, 1583m, 1502m, 1470w, 1454m, 1417m,
1393m, 1321m, 1283m, 1202m, 1189m, 1156m, 1117s, 997s, 982s,
826m, 739m, 731m, 620m, 609m, 527m, 513m cm−1; UV–vis (MeOH):
λmax (log ε) = 231 (4.30), 302 (4.25) nm; 1H NMR (400 MHz, DMSO-
d6): δ = 7.52 (d, J = 15.9 Hz, 1H, 3-H), 7.02 (s, 2H, 2′-H), 6.53 (d,
J = 15.9 Hz, 1H, 2-H), 3.81 (s, 6H, 5′-H), 3.68 (s, 3H, 6′-H) ppm; 13C
NMR (100 MHz, DMSO-d6): δ = 167.7 (C-1), 153.1 (C-3′), 144.1 (C-3),
139.3 (C-4′), 129.9 (C-1′), 118.5 (C-2), 105.8 (C-2′), 60.1 (C-6′), 56.0
(C-5′) ppm; MS (ESI, MeOH): m/z (%) = 221.1 ([M + H-H2O]+, 56),
Recrystallization from ethanol gave 1a (8.28 g, 80%) as an off-white
solid; RF = 0.05 (silica gel, n-hexane/ethyl acetate, 4:1); m.p. 178 °C
(lit.: [32] 181–183 °C); IR (KBr): ν = 3440m, 2939m, 2839m, 1683s,
1625s, 1597s, 1516s, 1464m, 1426m, 1340m, 1298m, 1264s, 1210m,
1168m, 1142s, 1025m cm−1; UV–vis (CHCl3): λmax (log ε) = 238
(4.05), 324 (4.20) nm; 1H NMR (400 MHz, CDCl3): δ = 7.74 (d,
J = 15.9 Hz, 1H, 3-H), 7.14 (dd, J = 8.3, 1.6 Hz, 1H, 6′-H), 7.08 (s, 1H,
5′-H), 6.88 (d, J = 8.3 Hz, 1H, 2′-H), 6.33 (d, J = 15.9 Hz, 1H, 2-H),
3.92 (s, 6H, 7′-H + 8′-H) ppm; 13C NMR (100 MHz, DMSO-d6):
δ = 172.4 (C-1), 151.7 (C-4′), 149.4 (C-3′), 147.1 (C-3), 127.2 (C-1′),
123.3 (C-6′), 115.0 (C-2), 111.2 (C-2′), 109.9 (C-5′), 56.1 (C-8′), 56.0
(C-7′) ppm; MS (ESI, MeOH): m/z (%) = 207.0 ([M−H]−, 11), 415.1
([2M−H]−, 100), 436.9 ([2M−2H+Na]–, 13); analysis calcd for
C11H12O4 (208.21): C 63.45, H 5.81; found C 63.11, H 6.18.
239.0 ([M + H]+, 100), 255.9 ([M + NH4]+, 10), 261.1 ([M + Na]+
,
37), 276.9 ([M + K]+, 5), 292.7 ([M + Na + MeOH]+, 10); analysis
calcd for C12H14O7 (238.24): C 60.50, H 5.92; found: C 62.39, H 6.18.
4.4.3. 3-(3,4-Dimethoxyphenyl)propanoic acid (1b)
4.4.7. (E)-3-(3-Hydroxy-4-methoxyphenyl)acrylic acid (1g)
A solution of 1a (1.0 g, 4.8 mmol) in THF (20 mL) was hydrogenated
at 75 psi pressure in the presence of Pd/C (10%, 0.116 g) for 12 h. Usual
work-up gave 1b (0.83 g, 82%) as a colorless solid; RF = 0.09 (silica
gel, n-hexane/ethyl acetate, 4:1); m.p. 98 °C (lit.: [33] 98–99 °C); IR
(ATR): ν = 2935w, 1697s, 1591w, 1516m, 1463m, 1430m, 1343w,
1306w, 1236s, 1146s, 1027s, 840m, 809s, 768m, 567m cm−1; UV–vis
(MeOH): λmax (log ε) = 202 (4.42), 229 (3.75), 280 (3.32) nm; 1H NMR
(400 MHz, CDCl3): δ = 6.80 (dd, J = 8.4, 3.2 Hz, 1H, 6′-H), 6.76 (s, 1H,
5′-H), 6.73 (d, J = 5.5 Hz, 1H, 2′-H), 3.87 (s, 3H, 8′-H), 3.86 (s, 3H, 7′-
H), 2.91 (td, J = 7.8, 5.2 Hz, 2H, 3-H), 2.64 (td, J = 7.7, 5.1 Hz, 2H, 2-
H) ppm; 13C NMR (100 MHz, CDCl3): δ = 177.9 (C-1), 149.1 (C-4′),
Compound 1g was obtained by recrystallization from ethanol as an
off-white solid (5.63 g, 58%); RF = 0.02 (silica gel, n-hexane/ethyl
acetate, 4:1); m.p. 232 °C (lit.: [37] 230–232 °C); IR (ATR): ν = 1612m,
1509s, 1442m, 1261s, 1134s, 1023m, 936s, 857s, 815s, 760s, 570s,
504s cm−1; UV–vis (MeOH): λmax (log ε) = 219 (4.19), 242 (4.11), 296
(4.20), 321 (4.23) nm; 1H NMR (500 MHz, DMSO-d6): δ = 7.44 (d,
J = 15.9 Hz, 1H, 3-H), 7.08 (dd, J = 8.2, 2.2 Hz, 1H, 6′-H), 7.06 (d,
J = 2.1 Hz, 1H, 2′-H), 6.94 (d, J = 8.2 Hz, 1H, 5′-H), 6.23 (d,
J = 15.9 Hz, 1H, 2-H), 3.80 (s, 3H, 7′-H) ppm; 13C NMR (125 MHz,
DMSO-d6): δ = 167.7 (C-1), 149.8 (C-4′), 146.6 (C-3′), 144.1 (C-3),
127.1 (C-1′), 120.9 (C-6′), 116.3 (C-2), 114.1 (C-2′), 112.0 (C-5′), 55.6
4

J.M. Gießel, et al.
BioorganicChemistry90(2019)103058
(C-7′) ppm; MS (ESI, MeOH): m/z (%) = 193.0 ([M−H]−, 100), 386.8
([2M−H]−, 16); analysis calcd for C10H10O4 (194.19): C 61.85, H 5.19;
found: C 62.03, H 5.22.
7.07.
4.4.12. (E)-3-(3-Nitrophenyl)acrylic acid (1l)
After recrystallization from ethanol compound 1l was obtained as
an off-white solid (1.20 g, 62%); RF = 0.02 (silica gel, n-hexane/ethyl
acetate, 4:1); m.p. 204 °C; IR (KBr): ν = 2539w, 1683s, 1630m, 1521s,
1485w, 1434w, 1418m, 1360s, 1319s, 1306s, 1285s, 1223m, 1177m,
1108w, 985m, 922s, 869m, 825m, 805s, 747m, 716s, 667s, 596m, 567m,
544m, 486m cm−1; UV–vis (EtOH): λmax (log ε) = 295 (3.91) nm; 1H
NMR (400 MHz, DMSO-d6): δ = 12.60 (s, 1H, OH), 8.51 (t, J = 2.0 Hz,
1H, 4′-H), 8.23 (ddd, J = 8.2, 2.3, 0.9 Hz, 1H, 6′-H), 8.18 (dt, J = 7.7,
1.2 Hz, 1H, 5′-H), 7.72 (d, J = 16.2 Hz, 1H, 3-H), 7.71 (d, J = 7.9 Hz,
1H, 2′-H), 6.74 (d, J = 16.1 Hz, 1H, 2-H) ppm; 13C NMR (100 MHz,
DMSO-d6): δ = 167.1 (C-1), 148.3 (C-3′), 141.4 (C-3), 136.1 (C-1′),
134.0 (C-5′), 130.3 (C-2′), 124.4 (C-6′), 122.8 (C-4′), 122.3 (C-2) ppm;
4.4.8. (E)-3-(4-Hydroxy-3-methoxyphenyl)acrylic acid (1h)
Compound 1h was obtained by recrystallization from ethanol as a
white solid (5.61 g, 57%); RF = 0.06 (silica gel, n-hexane/ethyl acetate,
4:1); m.p. 170 °C (lit.: [37] 168–169 °C); IR (ATR): ν = 3435w, 1662m,
1590m, 1511m, 1465m, 1431m, 1323w, 1265s, 1163s, 1112m, 1033s,
942s, 851s, 803s, 751m, 685m, 598s, 572s, 519s cm−1; UV–vis (MeOH):
λmax (log ε) = 218 (3.89), 321 (4.00) nm; 1H NMR (500 MHz, DMSO-
d6): δ = 7.48 (d, J = 15.9 Hz, 1H, 3-H), 7.27 (d, J = 1.9 Hz, 1H, 2′-H),
7.08 (dd, J = 8.2, 1.9 Hz, 1H, 6′-H), 6.78 (d, J = 8.1 Hz, 1H, 5′-H), 6.35
(d, J = 15.9 Hz, 1H, 2-H), 3.81 (s, 3H, 7′-H) ppm; 13C NMR (125 MHz,
DMSO-d6): δ = 167.9 (C-1), 149.1 (C-4′), 147.9 (C-3′), 144.5 (C-3),
125.7 (C-1′), 122.8 (C-6′), 115.6 (C-2), 115.5 (C-5′), 111.2 (C-2′), 55.7
(C-7′) ppm; MS (ESI, ASAP): m/z (%) = 178.1 ([M−H-CH3]−, 100),
193.1 ([M−H]−, 98); analysis calcd for C10H10O4 (194.19): C 61.85, H
5.19; found C 61.75, H 6.19.
MS (ESI, MeOH): m/z (%) = 192.0 ([M−H]−
,
100), 237.9
([M + HCO2]−
,
3), 260.0 ([M−H + NaHCO2]−
, 2), 384.8
([2M−H]−, 44), 407.0 ([2M−2H + Na]−, 14); analysis calcd for
C9H7NO2 (193.16): C 55.96, H 3.65, N 7.25; found: C 55.71, H 3.91, N
6.96.
4.4.9. (E)-3-(4-Acetoxy-3-methoxyphenyl)acrylic acid (1i)
Compound 1i was obtained by recrystallization from ethanol as a
yellowish solid (2.52 g, 62%); RF = 0.02 (silica gel, n-hexane/ethyl
acetate, 4:1); m.p. 195 °C; IR (ATR): ν = 2944w, 1760m, 1682s, 1632m,
1601m, 1506m, 1469w, 1421m, 1371w, 1316m, 1260s, 1222s, 1198s,
1154s, 1120s, 1033m, 985s, 913m, 855s, 837m, 691m, 648m, 599m,
527m cm−1; UV–vis (MeOH): λmax (log ε) = 277 (3.83) nm; 1H NMR
(500 MHz, DMSO-d6): δ = 7.57 (d, J = 16.0 Hz, 1H, 3-H), 7.48 (d,
J = 1.8 Hz, 1H, 2′-H), 7.26 (dd, J = 8.2, 1.8 Hz, 1H, 6′-H), 7.12 (d,
J = 8.1 Hz, 1H, 5′-H), 6.58 (d, J = 16.0 Hz, 1H, 2-H), 3.82 (s, 3H, 7′-H),
2.26 (s, 3H, 9′-H) ppm; 13C NMR (125 MHz, DMSO-d6): δ = 168.4 (C-
8′), 167.5 (C-1), 151.1 (C-3′), 143.3 (C-3), 140.8 (C-4′), 133.2 (C-1′),
123.2 (C-5′), 121.3 (C-6′), 119.6 (C-2), 111.8 (C-2′), 56.0 (C-7′), 20.4
(C-9′) ppm; MS (ESI, ASAP): m/z (%) = 235.1 ([M−H]−, 100); analysis
calcd for C12H12O5 (236.22): C 61.02, H 5.12; found: C 6 59.77, H 5.31.
4.4.13. (E)-3-(4-Dimethylamino)phenyl)acrylic acid (1m)
Compound 1m was obtained by recrystallization from ethanol as an
yellowish solid (3.86 g, 40%); RF = 0.08 (silica gel, n-hexane/ethyl
acetate, 4:1); m.p. 212 °C (lit.: [38] 210–212 °C); IR (ATR): ν = 2803w,
1665m, 1590m, 1523m, 1434m, 1366m, 1308m, 1260m, 1227m,
1163m, 987m, 940m, 858m, 812s, 675m, 513s, 479m cm−1; UV–vis
(MeOH): λmax (log ε) = 242 (3.80), 358 (4.27) nm; 1H NMR (500 MHz,
DMSO-d6): δ = 7.49 (d, J = 2.5 Hz, 2H, 2′-H), 7.46 (d, J = 15.8 Hz, 1H,
3-H), 6.70 (d, J = 8.9 Hz, 2H, 3′-H), 6.20 (d, J = 15.8 Hz, 1H, 2-H),
2.96 (s, 6H, 5′-H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 168.1 (C-
1), 151.6 (C-4′), 144.6 (C-3), 129.7 (C-2′), 121.5 (C-1′), 112.9 (C-2),
111.8 (C-3′), 39.7 (C-5′) ppm; MS (ESI, ASAP): m/z (%) = 190.2
([M−H]−, 100); analysis calcd for C11H13NO2 (191.23): C 69.09, H
6.85, N 7.32; found: C 68.88, H 7.02, N 7.15.
4.4.10. (E)-3-(3,4-Dimethylphenyl)acrylic acid (1j)
4.4.14. General procedure B
Compound 1j was obtained by recrystallization from ethanol as a
white solid (1.69 g, 57%); RF = 0.19 (silica gel, n-hexane/ethyl acetate,
4:1); m.p. 174 °C; IR (ATR): ν = 2919w, 1672s, 1621s, 1421m, 1318s,
1285s, 1219s, 956s, 925s, 866s, 815s, 688s, 582m, 546s cm−1; UV–vis
(MeOH): λmax (log ε) = 223 (4.00), 286 (4.14) nm; 1H NMR (500 MHz,
DMSO-d6): δ = 7.56 (d, J = 16.0 Hz, 1H, 3-H), 7.45 (d, J = 1.9 Hz, 1H,
5′-H), 7.38 (dd, J = 7.7, 1.9 Hz, 1H, 6′-H), 7.17 (d, J = 7.7 Hz, 1H, 2′-
H), 6.43 (d, J = 16.0 Hz, 1H, 2-H), 2.23 (s, 6H, 7′-H + 8′-H) ppm; 13C
NMR (125 MHz, DMSO-d6): δ = 167.7 (C-1), 144.1 (C-3), 139.0 (C-4′),
136.8 (C-3′), 131.8 (C-1′), 130.0 (C-6′), 129.1 (C-2′), 125.8 (C-5′), 117.8
(C-2), 19.3 (C-7′), 19.2 (C-8′) ppm; MS (ESI, ASAP): m/z (%) = 175.1
([M−H]−, 100); analysis calcd for C11H12O2 (176.21): C 74.98, H 6.86;
found: C 74.75, H 7.00.
Under argon atmosphere, to a solution of the acid (1 eq.) in dry
DCM (10 mL/mmol) at 0 °C oxalyl chloride (3 eq.) and DMF (2 drops)
were added. After stirring for 1 h at 0 °C followed by 1 h at room tem-
perature the solvent was removed in vacuo, and the residue was washed
with dry DCM (10 mL/mmol). The residue was re-dissolved in toluene
(5 mL/mmol), pyridine (2 eq.) and the corresponding acid (1 eq.) was
added. The mixture was stirred over night at room temperature. Usual
aqueous work-up gave a residue that was washed with ethanol.
4.4.15. (E)-3-(3,4-Dimethoxyphenyl)acrylic anhydride (2a)
Compound 2a was obtained as
a white solid (0.53 g, 55%);
RF = 0.42 (silica gel, chloroform); m.p. 177 °C; IR (ATR): ν = 2931w,
2835w, 1754m, 1707s, 1625s, 1598m, 1581w, 1510s, 1460m, 1438w,
1424m, 1354w, 1311w, 1266s, 1240s, 1214s, 1162m, 1144s, 1075s,
1021s, 1001s, 986s, 972m, 943s, 868s, 810s, 773m, 731m, 707m, 602m,
570m, 548m cm−1; UV–vis (CHCl3): λmax (log ε) = 227 (3.89), 250
(3.93), 347 (4.26) nm; 1H NMR (500 MHz, CDCl3): δ = 7.80 (d,
J = 15.8 Hz, 2H, 3-H), 7.17 (dd, J = 8.3, 1.9 Hz, 2H, 6′-H), 7.09 (d,
J = 1.9 Hz, 2H, 5′-H), 6.90 (d, J = 8.3 Hz, 2H, 2′-H), 6.40 (d,
J = 15.8 Hz, 2H, 2-H), 3.94 (s, 6H, 7′-H), 3.93 (s, 6H, 8′-H) ppm; 13C
NMR (125 MHz, CDCl3): δ = 163.1 (C-1), 152.2 (C-4′), 149.5 (C-3′),
148.7 (C-3), 127.0 (C-1′), 123.7 (C-6′), 114.6 (C-2), 111.3 (C-2′), 110.1
(C-5′), 56.2 (C-8′), 56.1 (C-7′) ppm; MS (ESI, MeOH): m/z (%) = 421.5
4.4.11. (E)-3-(2-Nitrophenyl)acrylic acid (1k)
After recrystallization from ethanol compound 1k was obtained as
an off-white solid (0.89 g, 46%); RF = 0.07 (silica gel, n-hexane/ethyl
acetate, 4:1); m.p. 247 °C; IR (KBr): ν = 1694m, 1519m, 1419m, 1280s,
1202s, 981m, 865m, 789s, 754s, 701s, 594m, 542m, 486m cm−1
;
UV–vis (EtOH): λmax (log ε) = 286 (3.73) nm; 1H NMR (400 MHz,
CDCl3): δ = 8.07 (dd, J = 8.1, 1.2 Hz, 1H, 6′-H), 7.94 (dd, J = 7.8,
1.2 Hz, 1H, 3′-H), 7.86 (d, J = 15.9 Hz, 1H, 3-H), 7.78 (td, J = 7.7,
1.5 Hz, 1H, 4′-H), 7.69–7.65 (m, 1H, 5′-H), 6.54 (d, J = 15.8 Hz, 1H, 2-
H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 166.8 (C-1), 148.3 (C-2′),
138.7 (C-3), 133.8 (C-4′), 130.8 (C-5′), 129.3 (C-1′), 129.2 (C-3′), 124.6
([M + Na]+
,
100),
437.5
([M + K]+
,
25),
453.6
([M + Na + MeOH]+); analysis calcd for C22H22O7 (398.41): C 66.32,
H 5.57; found: C 66.18, H 6.73.
(C-6′), 123.8 (C-2) ppm; MS (ESI, MeOH): m/z (%) = 191.9 ([M−H]−
,
41), 237.8 ([M + HCO2]−, 11), 259.9 ([M−H + NaHCO2]−, 6), 384.9
([2 M−H]−, 100), 406.9 ([2M−2H + Na]−, 5); analysis calcd for
C9H7NO2 (193.16): C 55.96, H 3.65, N 7.25; found: C 5571, H 3.79, N
4.4.16. 3-(3,4-Dimethoxyphenyl)propanoic anhydride (2b)
Compound 2b was obtained as an off-white solid (0.09 g, 46%);
5

J.M. Gießel, et al.
BioorganicChemistry90(2019)103058
RF = 0.04 (silica gel, n-hexane/ethyl acetate, 4:1); m.p. 178 °C; IR
(ATR): ν = 2935w, 2838w, 1697s, 1591w, 1516m, 1463m, 1430m,
1409w, 1346w, 1306m, 1251m, 1236s, 1213m, 1146s, 1026m, 840m,
809m, 768m cm−1; UV–vis (MeOH): λmax (log ε) = 299 (3.80), 279
(3.57) nm; 1H NMR (500 MHz, CDCl3): δ = 6.80 (dd, J = 8.3, 5.0 Hz,
2H, 5′-H + 5″′-H), 6.77–6.72 (m, 4H, 2′-H + 2″′-H + 6′-H + 6″′-H),
3.88 (s, 3H, 7′-H), 3.87 (s, 3H, 7″′-H), 3.86 (s, 3H, 8′-H), 3.85 (s, 3H,
8″′-H), 2.91 (td, J = 7.5, 1.2 Hz, 4H, 2-H + 2″-H), 2.73 (t, J = 7.6 Hz,
2H, 3-H), 2.67 (t, J = 7.7 Hz, 2H, 3″-H) ppm; 13C NMR (125 MHz,
CDCl3): δ = 168.8 (C-1), 149.2 (C-3′), 149.1 (C-3″′), 147.9 (C-4′), 147.8
(C-4″′), 132.9 (C-1′), 132.4 (C-1″′), 120.3 (C-6′), 120.2 (C-6″′), 111.9
(C-2′ + C-2″′), 111.6 (C-5′ + C-5″′), 56.1 (C-7′ + C-7″′), 56.0 (C-8′+
C-8″′), 37.3 (C-2), 35.7 (C-2″), 30.4 (C-3), 30.0 (C-3″) ppm; MS (ESI,
MeOH): m/z (%) = 425.1 ([M + Na]+, 100), 826.9 ([2M + Na]+, 8);
analysis calcd for C22H26O7 (402.44): C 65.66, H 6.51; found: C 65.41,
H 6.72.
(lit.: [40] 178–180 °C); IR (ATR): ν = 1763s, 1702w, 1627m, 1586w,
1461w, 1419w, 1371w, 1305w, 1257m, 1222m, 1169w, 1123w, 1054s,
1034m, 1001m, 966m cm−1; UV–vis (CHCl3): λmax (log ε) = 206 (4.27),
297 (4.20) nm; 1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 15.9 Hz,
2H, 3-H), 7.19 (dd, J = 8.1, 1.9 Hz, 2H, 6′-H), 7.14 (d, J = 1.9 Hz, 2H,
2′-H), 7.10 (d, J = 8.1 Hz, 2H, 5′-H), 6.47 (d, J = 15.9 Hz, 2H, 2-H),
3.89 (s, 6H, 7′-H), 2.33 (s, 6H, 9′-H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 168.8 (C-8′), 162.4 (C-1), 151.8 (C-3′), 148.1 (C-3), 142.5 (C-4′),
132.8 (C-1′), 123.7 (C-5′), 122.0 (C-6′), 117.0 (C-2), 111.8 (C-2′), 55.2
(C-7′), 20.8 (C-9′) ppm; MS (ESI, MeOH): m/z (%) = 477.1
([M + Na]+
,
55), 930.9 ([2M + Na]+
, 100); analysis calcd for
C24H22O9 (454.43): C 63.43, H 4.88; found: C 63.21, H 5.02.
4.4.21. (E)-3-(3,4-Dimethylphenyl)acrylic anhydride (2j)
Compound 2j was obtained as
a white solid (0.23 g, 60%);
RF = 0.58 (silica gel, n-hexane/ethyl acetate, 4:1); m.p. 195 °C; IR
(ATR): ν = 2919w, 1751s, 1704s, 1626m, 1605w, 1505w, 1450w,
1268w, 1234w, 1206w, 1121s, 1021w, 987s, 944s, 929s, 890m, 865m,
826s, 813s, 567m cm−1; UV–vis (CHCl3): λmax (log ε) = 206 (4.44), 232
(4.36), 310 (4.64) nm; 1H NMR (400 MHz, CDCl3): δ = 7.80 (d,
J = 15.9 Hz, 2H, 3-H), 7.35 (d, J = 2.0 Hz, 2H, 2′-H), 7.32 (dd, J = 7.8,
2.0 Hz, 2H, 6′-H), 7.18 (d, J = 7.8 Hz, 2H, 5′-H), 6.47 (d, J = 15.9 Hz,
2H, 2-H), 2.31 (s, 6H, 7′-H), 2.30 (s, 6H, 8′-H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 163.0 (C-1), 149.0 (C-3), 140.8 (C-3′), 137.5 (C-4′), 131.7
(C-1′), 130.5 (C-5′), 129.9 (C-2′), 126.4 (C-6′), 115.7 (C-2), 20.1 (C-7′),
19.9 (C-8′) ppm; MS (ESI, MeOH): m/z (%) = 357.1 ([M + Na]+, 74),
691.0 ([2M + Na]+, 100); analysis calcd for C22H22O3 (344.41): C
79.02, H 6.63; found: C 78.83, H 6.82.
4.4.17. (E)-3-(2,4-Dimethoxyphenyl)acrylic anhydride (2c)
Compound 2c was obtained as
a white solid (0.85 g, 89%);
RF = 0.35 (silica gel, chloroform); m.p. 105–108 °C; IR (KBr):
ν = 3448w, 2946w, 2843w, 1754m, 1711m, 1602s, 1566m, 1505m,
1457m, 1439w, 1418m, 1330m, 1296s, 1268m, 1215s, 1164s, 1118m,
1066s, 985m, 830m cm−1; UV–vis (CHCl3): λmax (log ε) = 265 (3.81),
385 (4.35) nm; 1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 16.0 Hz,
2H, 3-H), 7.48 (d, J = 8.6 Hz, 2H, 3′-H), 6.54 (d, J = 15.9 Hz, 2H, 2-H),
6.53 (dd, J = 8.6, 2.3 Hz, 2H, 6′-H), 6.46 (d, J = 2.3 Hz, 2H, 5′-H), 3.89
(s, 6H, 7′-H), 3.86 (s, 6H, 8′-H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 164.1 (C-1), 163.7 (C-4′), 160.6 (C-2′), 144.0 (C-3), 131.5 (C-3′),
116.4 (C-1′), 114.9 (C-2), 105.7 (C-6′), 98.6 (C-5′), 55.7 (C-7′), 55.6 (C-
8′) ppm; MS (ESI, MeOH): m/z (%) = 191.1 ([M-C11H11O4]+, 38),
4.4.22. (E)-3-(2-Nitrophenyl)acrylic anhydride (2k)
209.0 ([M-C11H11O4 + H2O]+, 3), 223.0 ([M-C11H11O4 + MeOH]+
,
Compound 2k was obtained as a yellowish solid (0.23 g, 60%);
RF = 0.31 (silica gel, n-hexane/ethyl acetate, 4:1); m.p. 184 °C; IR
(ATR): ν = 1756m, 1706m, 1624w, 1570w, 1516m, 1341m, 1288w,
1263w, 1205w, 1148m, 1121s, 979m, 935s, 891m, 867m, 789s, 751s,
712m, 681m, 536m, 503m, 487m cm−1; UV–vis (CHCl3): λmax (log
ε) = 252 (4.29) nm; 1H NMR (500 MHz, CDCl3): δ = 8.34 (d,
J = 15.7 Hz, 1H, 3-H), 8.12 (dd, J = 8.1, 1.0 Hz, 1H, 6′-H), 7.72–7.68
(m, 2H, 4′-H + 3′-H), 7.62 (ddd, J = 8.6, 6.8, 2.1 Hz, 1H, 5′-H), 6.46 (d,
J = 15.8 Hz, 1H, 2-H) ppm; 13C NMR (125 MHz, CDCl3): δ = 161.0 (C-
1), 148.4 (C-2′), 144.3 (C-3), 133.9 (C-4′), 131.3 (C-5′), 130.1 (C-1′),
129.5 (C-3′), 125.3 (C-6′), 121.7 (C-2) ppm; MS (ESI, MeOH): m/z
(%) = 391.0 ([M + Na]+, 100), 758.8 ([2M + Na]+, 79); analysis
calcd for C18H12N2O7 (368.30): C 58.70, H 3.28, N 7.61; found: C
58.55, H 3.51, N 7.34.
22), 421.0 ([M + Na]+, 49), 818.9 ([2 M + Na]+, 100); analysis calcd
for C22H22O7 (398.41): C 66.32, H 5.57; found: C 66.11, H 5.69.
4.4.18. (E)-3-(3,5-Dimethoxyphenyl)acrylic anhydride (2d)
Compound 2d was obtained as an off-white solid (0.31 g, 81%);
RF = 0.21 (silica gel, n-hexane/ethyl acetate, 4:1); m.p. 140 °C; IR
(ATR): ν = 1778m, 1706m, 1630m, 1593s, 1471w, 1431m, 1356w,
1302w, 1284w, 1208s, 1158s, 1085s, 1065s, 1055s, 977m, 952s, 925m,
850m, 837s, 818m cm−1; UV–vis (CHCl3): λmax (log ε) = 206 (4.45),
231 (4.29), 309 (4.34) nm; 1H NMR (500 MHz, CDCl3): δ = 7.77 (d,
J = 15.9 Hz, 2H, 3-H), 6.71 (d, J = 2.2 Hz, 4H, 2′-H), 6.55 (t,
J = 2.2 Hz, 2H, 4′-H), 6.49 (d, J = 15.9 Hz, 2H, 2-H), 3.83 (s, 12H, 5′-
H) ppm; 13C NMR (125 MHz, CDCl3): δ = 162.5 (C-1), 161.3 (C-3′),
148.8 (C-3), 135.7 (C-1′), 117.4 (C-2), 106.6 (C-2′), 103.7 (C-4′), 55.7
(C-5′) ppm; MS (ESI, MeOH): m/z (%) = 421.1 ([M + Na]+, 44), 818.9
([2M + Na]+, 100); analysis calcd for C22H22O7 (398.41): C 66.32, H
5.57; found: C 66.15, H 5.80.
4.4.23. (E)-3-(3-Nitrophenyl)acrylic anhydride (2l)
Compound 2l was obtained as an off-white solid (0.19 g, 64%);
RF = 0.07 (silica gel, n-hexane/ethyl acetate, 4:1); m.p. 174 °C; IR
(ATR): ν = 3077w, 1787m, 1714w, 1637w, 1523s, 1481w, 1443w,
1354s, 1268w, 1227w, 1204m, 1091s, 974s, 938m, 804m, 741m, 710m,
660m cm−1; UV–vis (MeOH): λmax (log ε) = 205 (3.98), 262 (3.95) nm;
1H NMR (500 MHz, CDCl3): δ = 8.46 (t, J = 2.0 Hz, 2H, 4′-H), 8.31
(ddd, J = 8.2, 2.3, 1.0 Hz, 2H, 6′-H), 7.91 (d, J = 16.0 Hz, 2H, 3-H),
7.91–7.88 (m, 2H, 5′-H), 7.65 (t, J = 8.0 Hz, 2H, 2′-H), 6.67 (d,
J = 16.0 Hz, 2H, 2-H) ppm; 13C NMR (125 MHz, CDCl3): δ = 161.4 (C-
1), 149.0 (C-3′), 146.0 (C-3), 135.4 (C-1′), 134.2 (C-5′), 130.4 (C-2′),
125.7 (C-6′), 123.0 (C-4′), 119.8 (C-2) ppm; MS (ESI, MeOH): m/z
(%) = 390.9 ([M + Na]+, 58), 758.7 ([2M + Na]+, 100); analysis
calcd for C18H12N2O7 (368.30): C 58.70, H 3.28, N 7.61; found: C
58.61, H 3.43, N 7.47.
4.4.19. (E)-3-(3,4,5-Trimethoxyphenyl)acrylic anhydride (2e)
Compound 2e was obtained as
a white solid (0.30 g, 77%);
RF = 0.06 (silica gel, n-hexane/ethyl acetate, 4:1); m.p. 174 °C (lit.:
[39] 190–192); IR (ATR): ν = 1802w, 1757w, 1698w, 1623w, 1582m,
1505m, 1455w, 1422m, 1342w, 1323w, 1267m, 1251m, 1159w, 1125s,
1040s, 1008s, 987m, 959m, 840m cm−1; UV–vis (CHCl3): λmax (log
ε) = 236 (4.23), 335 (4.31) nm; 1H NMR (400 MHz, CDCl3): δ = 7.77
(d, J = 15.8 Hz, 2H, 3-H), 6.80 (s, 4H, 2′-H), 6.43 (d, J = 15.8 Hz, 2H,
2-H), 3.91 (s, 12H, 5′-H + 6′-H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 162.7 (C-1), 153.7 (C-3′), 148.8 (C-3), 141.3 (C-4′), 129.3 (C-1′),
116.0 (C-2), 106.0 (C-2′), 61.2 (C-6′), 56.4 (C-5′) ppm; MS (ESI, MeOH):
m/z (%) = 481.1 ([M + Na]+, 44), 938.9 ([2M + Na]+, 100); analysis
calcd for C24H26O9 (458.46): C 62.88, H 5.72; found: C 62.75, H 5.90.
4.4.24. (E)-3-(4-(Dimethylamino)phenyl)acrylic anhydride (2m)
Compound 2m was obtained as a yellowish solid (0.18 g, 48%);
RF = 0.1 (silica gel, n-hexane/ethyl acetate, 4:1); m.p. 145 °C; IR (ATR):
ν = 2816w, 1668m, 1594m, 1523m, 1435m, 1368m, 1309m, 1261m,
1228m, 1186s, 988m, 941m, 814s, 676m, 514m, 481m cm−1; UV–vis
4.4.20. (E)-3-(4-Acetoxy-3-methoxyphenyl)acrylic anhydride (2i)
Compound 2i was obtained as
a white solid (0.29 g, 76%);
RF = 0.06 (silica gel, n-hexane/ethyl acetate, 4:1); m.p. 122–124 °C
6

J.M. Gießel, et al.
BioorganicChemistry90(2019)103058
(MeOH): λmax (log ε) = 246 (2.49), 349 (3.02) nm; 1H NMR (500 MHz,
CDCl3): δ = 7.71 (d, J = 15.8 Hz, 2H, 3-H), 7.44 (d, J = 8.8 Hz, 4H, 2′-
H), 6.68 (d, J = 8.9 Hz, 4H, 3′-H), 6.22 (d, J = 15.8 Hz, 2H, 2-H), 3.03
(s, 12H, 5′-H) ppm; 13C NMR (125 MHz, CDCl3): δ = 171.6 (C-1), 152.2
(C-4′), 147.6 (C-3), 130.3 (C-2′), 122.1 (C-1′), 112.0 (C-3′), 111.2 (C-2),
40.3 (C-5′) ppm; MS (ESI, MeOH): m/z (%) = 387.1 ([M + Na]+, 15),
751.0 ([2M + Na]+, 16); analysis calcd for C22H24N2O3 (364.44): C
72.51, H 6.64, N 7.69; found: C 72.39, H 6.87, N 7.51.
4.4.29. (E)-3-(3-Methoxyphenyl)acrylic anhydride (2r)
Compound 2r was obtained as a white solid (0.317 g, 84%);
RF = 0.28 (silica gel, n-hexane/ethyl acetate, 4:1); m.p. 71 °C; IR (ATR):
ν = 2842w, 1759s, 1694m, 1628m, 1609w, 1579m, 1491m, 1462m,
1434m, 1319w, 1272m, 1247m, 1158m, 1122s, 1046m, 978s, 935s,
873m, 849s, 775s, 720m, 671m, 577m, 552m, 510m cm−1; UV–vis
(MeOH): λmax (log ε) = 216 (3.56), 285 (3.65) nm; 1H NMR (500 MHz,
CDCl3): δ = 7.82 (d, J = 15.9 Hz, 2H, 3-H), 7.34 (t, J = 7.9 Hz, 2H, 5′-
H), 7.17 (d, J = 7.7 Hz, 2H, 6′-H), 7.09–7.08 (m, 2H, 2′-H), 7.00 (ddd,
J = 8.3, 2.6, 0.7 Hz, 2H, 4′-H), 6.51 (d, J = 15.9 Hz, 2H, 2-H), 3.85 (s,
6H,7′-H) ppm; 13C NMR (125 MHz, CDCl3): δ = 162.6 (C-1), 160.2 (C-
3′), 148.7 (C-3), 135.2 (C-1′), 130.2 (C-5′), 121.4 (C-6′), 117.3 (C-4′),
117.2 (C-2), 113.5 (C-2′), 55.5 (C-7′) ppm; MS (ESI, MeOH): m/z
(%) = 361.0 ([M + Na]+, 100), 698.8 ([2M + Na]+, 77); analysis
calcd for C20H18O5 (338.36): C 71.00, H 5.36; found: C 70.81, H 5.51.
4.4.25. Cinnamic anhydride (2n)
Compound 2n was obtained as
a white solid (0.61 g, 65%);
RF = 0.12 (silica gel, chloroform); m.p. 136 °C (lit.: [41] 136–137 °C);
IR (ATR): ν = 1764m, 1699s, 1630m, 1495w, 1450m, 1304w, 1269w,
1227m, 1200m, 1068s, 958s, 857m, 750s, 689s, 674s, 551s, 510m,
476s cm−1; UV–vis (CHCl3): λmax (log ε) = 227 (4.14), 298 (4.50) nm;
1H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 15.9 Hz, 2H, 3-H),
7.60–7.57 (m, 4H, 3′-H), 7.46–7.41 (m, 6H, 2′-H + 4′-H), 6.54 (d,
J = 15.9 Hz, 2H, 2-H) ppm; 13C NMR (100 MHz, CDCl3): δ = 162.6 (C-
1), 148.8 (C-3), 133.9 (C-1′), 131.4 (C-4′), 129.2 (C-2′), 128.7 (C-3′),
116.9 (C-2) ppm; MS (ESI, ASAP): m/z (%) = 301.3 ([M + Na]+, 100),
333.4 ([M + Na + MeOH]+, 96); analysis calcd for C18H14O3 (278.31):
C 77.68, H 5.07; found: C 77.46, H 5.18.
4.4.30. (E)-3-(4-Methoxyphenyl)acrylic anhydride (2s)
Compound 2s was obtained as a white solid (0.18 g, 46%); RF = 0.7
(silica gel, chloroform); m.p. 103 °C (lit.: [40] 104–105 °C); IR (ATR):
ν = 1754w, 1717m, 1624w, 1597m, 1571w, 1509m, 1455w, 1439w,
1423w, 1304w, 1289w, 1255m, 1176w, 1150w, 1061s, 1022m, 972s,
923m, 824s, 804m, 535m, 518m cm−1; UV–vis (CHCl3): λmax (log
ε) = 206 (4.19), 235 (3.73), 331 (4.13) nm; 1H NMR (400 MHz, CDCl3):
δ = 7.80 (d, J = 15.9 Hz, 2H, 3-H), 7.53 (d, J = 8.8 Hz, 4H, 2′-H), 6.94
(d, J = 8.8 Hz, 4H, 3′-H), 6.39 (d, J = 15.8 Hz, 2H, 2-H), 3.86 (s, 6H, 5′-
H) ppm; 13C NMR (100 MHz, CDCl3): δ = 163.2 (C-1), 162.3 (C-4′),
148.4 (C-3), 130.6 (C-2′), 126.7 (C-1′), 114.7 (C-3′), 114.4 (C-2), 55.6
(C-5′) ppm; MS (ESI, MeOH): m/z (%) = 361.1 ([M + Na]+, 68), 698.9
([2M + Na]+, 100); analysis calcd for C20H18O5 (338.36): C 71.00, H
5.36; found: C 70.72, H 5.52.
4.4.26. (E)-3-(3,4-Dihydroxyphenyl)acrylic anhydride (2o)
Compound 2o was obtained as an off-white solid (0.51 g, 53%);
RF = 0.62 (silica gel, chloroform); m.p. 178 °C; 1H NMR (400 MHz,
CD3OD): δ = 7.56 (d, J = 15.9 Hz, 2H, 3-H), 7.06 (d, J = 2.1 Hz, 2H, 5′-
H), 6.96 (dd, J = 8.2, 2.0 Hz, 2H, 6′-H), 6.80 (d, J = 8.2 Hz, 2H, 2′-H),
6.24 (d, J = 15.9 Hz, 2H, 2-H) ppm; 13C NMR (100 MHz, CD3OD):
δ = 171.0 (C-1), 149.5 (C-4′), 147.0 (C-3), 146.8 (C-3′), 127.8 (C-1′),
122.8 (C-6′), 116.5 (C-2′), 115.5 (C-2), 115.1 (C-5′) ppm; MS (ESI,
MeOH): m/z (%) = 365.1 ([M + Na]+, 21), 706.9 ([2M + Na]+, 26);
analysis calcd for C18H14O7 (342.30): C 63.16, H 4.12; found: C 62.89,
H 4.36.
4.4.31. (E)-3-(2-Chlorophenyl)acrylic anhydride (2t)
Compound 2t was obtained as white crystals (0.324 g, 92%);
RF = 0.88 (silica gel, chloroform); m.p. 156–157 °C; IR (ATR):
ν = 1762m, 1709m, 1626w, 1588w, 1471w, 1442w, 1324w, 1259w,
1203w, 1138s, 1117s, 1051m, 1034m, 981m, 934s, 878m, 754s, 734m,
701m, 573m cm−1; UV–vis (CHCl3): λmax (log ε) = 206 (4.02), 228
(3.38), 290 (4.09) nm; 1H NMR (500 MHz, CDCl3): δ = 8.29 (d,
J = 16.0 Hz, 2H, 3-H), 7.68 (dd, J = 7.7, 1.7 Hz, 2H, 6′-H), 7.46 (dd,
J = 7.9, 1.2 Hz, 2H, 4′-H), 7.38 (td, J = 7.7, 1.7 Hz, 2H, 5′-H),
7.34–7.31 (m, 2H, 3′-H), 6.54 (d, J = 16.0 Hz, 2H, 2-H) ppm; 13C NMR
(125 MHz, CDCl3): δ = 161.9 (C-1), 144.4 (C-3), 135.7 (C-2′), 132.1 (C-
1′), 132.0 (C-5′), 130.5 (C-4′), 128.1 (C-6′), 127.4 (C-3′), 119.4 (C-2)
ppm; MS (ESI, ASAP): m/z (%) = 369.3 ([M + Na]+, 52), 385.3
4.4.27. (E)-3-(4-Hydroxy-3,5-dimethoxyphenyl)acrylic anhydride (2p)
Compound 2p was obtained as an off-white solid (0.52 g, 52%);
RF = 0.56 (silica gel, chloroform); m.p. 187 °C; IR (ATR): ν = 2837w,
1659w, 1620w, 1594w, 1516m, 1460m, 1423m, 1335m, 1296m, 1268m,
1214m, 1156m, 1119s, 973m, 909m, 833m, 816m, 629s, 551m cm−1
;
UV–vis (MeOH): λmax (log ε) = 237 (4.40), 323 (4.46) nm; 1H NMR
(500 MHz, CDCl3): δ = 7.70 (d, J = 15.8 Hz, 2H, 3-H), 6.80 (s, 4H, 2′-
H), 6.32 (d, J = 15.8 Hz, 2H, 2-H), 3.94 (s, 6H, 5′-H) ppm; 13C NMR
(125 MHz, CDCl3): δ = 171.5 (C-1), 147.5 (C-3′), 147.4 (C-3), 137.8 (C-
4′), 125.7 (C-1′), 114.9 (C-2), 105.6 (C-2′), 56.5 (C-5′) ppm; MS (ESI,
MeOH): m/z (%) = 453.0 ([M + Na]+, 35); analysis calcd for C22H22O9
(430.41): C 61.39, H 5.15; found: C 61.04, H 5.31.
([M + K]+
,
3),
387.2
([M + Na + H2O]+
,
7),
401.3
([M + Na + MeOH]+, 100); analysis calcd for C18H12Cl2O3 (347.19): C
62.27, H 3.48, Cl 20.42; found: C 62.01, H 3.64.
4.4.32. (E)-3-(3-Chlorophenyl)acrylic anhydride (2u)
Compound 2u was obtained as
a white solid (0.20 g, 52%);
4.4.28. (E)-3-(2-Methoxyphenyl)acrylic anhydride (2q)
RF = 0.98 (silica gel, chloroform); m.p. 117 °C; IR (ATR): ν = 1759m,
1709m, 1630w, 1565w, 1271w, 1204w, 1130s, 986m, 939s, 862m,
785m, 721m, 687m, 666s, 564m, 545m cm−1; UV–vis (CHCl3): λmax (log
ε) = 228 (4.14), 291 (4.35) nm; 1H NMR (400 MHz, CDCl3): δ = 7.78
(d, J = 15.9 Hz, 2H, 3-H), 7.58–7.56 (m, 2H, 6′-H), 7.47–7.43 (m, 2H,
2′-H), 7.41 (t, J = 1.7 Hz, 2H, 5′-H), 7.40–7.35 (m, 2H, 4′-H), 6.52 (d,
J = 15.9 Hz, 2H, 2-H); 13C NMR (100 MHz, CDCl3): δ = 162.0 (C-1),
147.2 (C-3), 135.6 (C-1′), 135.3 (C-3′), 131.3 (C-5′), 130.5 (C-4′), 128.4
(C-6′), 126.9 (C-2′), 118.2 (C-2) ppm; MS (ESI, ASAP): m/z (%) = 369.3
Compound 2q was obtained as
a white solid (0.18 g, 44%);
RF = 0.26 (silica gel, n-hexane/ethyl acetate, 4:1); m.p. 101 °C (lit.:
[40] 104–106 °C); IR (ATR): ν = 2962w, 2838w, 1765m, 1710m,
1623m, 1599m, 1488m, 1464m, 1438m, 1324w, 1299w, 12630m,
1245m, 1198w, 1163m, 1126s, 1104s, 1046m, 1028s, 988m, 871m,
784m, 753s, 518m cm−1; UV–vis (CHCl3): λmax (log ε) = 232 (3.87),
288 (4.05), 339 (3.97) nm; 1H NMR (400 MHz, CDCl3): δ = 8.15 (d,
J = 16.1 Hz, 2H, 3-H), 7.55 (dd, J = 7.7, 1.5 Hz, 2H, 6′-H), 7.43–7.38
(m, 2H, 4′-H), 7.02–6.93 (m, 4H, 5′-H + 3′-H), 6.65 (d, J = 16.1 Hz, 2H,
2-H), 3.89 (s, 6H, 7′-H), 3.86 (s, 6H, 8′-H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 163.5 (C-1), 158.9 (C-2′), 144.2 (C-3), 132.6 (C-4′), 129.8
(C-6′), 123.0 (C-1′), 121.0 (C-5′), 117.6 (C-2), 111.4 (C-3′), 55.7 (C-7′)
ppm; MS (ESI, MeOH): m/z (%) = 361.1 ([M + Na]+, 100), 698.9
([2M + Na]+, 92); analysis calcd for C20H18O5 (338.36): C 71.00, H
5.36; found: C 70.73, H 5.47.
([M + Na]+, 61), 385.3 ([M + K]+, 13), 387.2 ([M + Na + H2O]+
,
14), 401.3 ([M + Na + MeOH]+, 100); analysis calcd for C18H12Cl2O3
(347.19): C 62.27, H 3.48; found: C 61.97, H 3.65.
4.4.33. (E)-3-(2-Chlorophenyl)acrylic-(E)-3-(3-Chlorophenyl)acrylic
anhydride (2v)
Compound 2v was obtained as an off-white solid (0.17 g, 44%);
7

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BioorganicChemistry90(2019)103058
RF = 0.98 (silica gel, chloroform); m.p. 117 °C; IR (ATR): ν = 1758m,
1708m, 1626w, 1589w, 1565w, 1472w, 1442w, 1290w, 1203w, 1136s,
1052m, 1038m, 986m, 935s, 866m, 788m, 757s, 733m, 702m, 686m,
672m, 570m cm−1; UV–vis (CHCl3): λmax (log ε) = 228 (3.99), 290
(4.22) nm; 1H NMR (400 MHz, CDCl3): δ = 8.28 (dd, J = 16.0, 6.7 Hz,
1H, 3-H), 7.79 (dd, J = 15.9, 3.9 Hz, 1H, 3′-H), 7.68 (dt, J = 7.6,
2.1 Hz, 1H, 6″-H), 7.58–7.55 (m, 1H, 6″′-H), 7.48–7.46 (m, 1H, 4″-H),
7.46–7.44 (m, 1H, 2″′-H), 7.44–7.42 (m, 1H, 5″′-H), 7.41 (t, J = 1.6 Hz,
1H, 5″-H), 7.39–7.36 (m, 1H, 4″′-H), 7.35–7.32 (m, 1H, 3″-H), 6.53 (dd,
J = 16.0, 3.5 Hz, 2H, 2-H + 2′-H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 162.0 (C-1′), 161.9 (C-1), 147.1 (C-3′), 144.5 (C-3), 135.6 (C-1″),
135.5 (C-2″), 135.3 (C-1″′), 135.2 (C-3″′), 132.2 (C-5″), 131.3 (C-5″′),
130.6 (C-4″), 130.5 (C-4″′), 128.4 (C-6″′), 128.1 (C-6″), 127.4 (C-3″),
126.9 (C-2″′), 119.3 (C-2), 118.3 (C-2′) ppm; MS (ESI, ASAP): m/z
physiological effects of trans-cinnamic acid and its hydroxylated derivatives on
maize root types, Plant Growth Regul. 78 (2) (2016) 263–273.
[5] E.L.D. Niero, G.M. Machado-Santelli, Cinnamic acid induces apoptotic cell death
and cytoskeleton disruption in human melanoma cells, J. Exp. Clin. Cancer Res. 32
(2013).
[6] D. Raffa, B. Maggio, M.V. Raimondi, M.G. Cusimano, G. Amico, A. Carollo,
P.G. Conaldi, R.L. Bai, E. Hamel, G. Daidone, 2-Cinnamamido, 2-(3-phenylpropio-
lamido), and 2-(3-phenylpropanamido)benzamides: Synthesis, antiproliferative
activity, and mechanism of action, Eur. J. Med. Chem. 65 (2013) 427–435.
[7] T. Ernawati, Y. Anita, P.D. Lotulung, M. Hanafi, Synthesis of Methyl 2-cinnama-
mido-3-hydroxy propanoate having activity against P388 leukemia cells, J. Appl.
Pharm. Sci. 4 (3) (2014) 92–95.
[8] N. Öztaskin, R. Kaya, A. Maras, E. Sahin, I. Gülcin, S. Göksu, Synthesis and char-
acterization of novel bromophenols: Determination of their anticholinergic, anti-
diabetic and antioxidant activities, Bioorg. Chem. 87 (2019) 91–102.
[9] C. Bayrak, P. Taslimi, H.S. Karaman, I. Gulcin, A. Menzek, The first synthesis,
carbonic anhydrase inhibition and anticholinergic activities of some bromophenol
deriuvatives with S including natural products, Bioorg. Chem. 85 (2019) 128–139.
[10] S. Burmaoglu, A.O. Yilmaz, M.F. Polat, R. Kaya, I. Gulcin, O. Algul, Synthesis and
biological evaluation of novel tris-chalcones as potent carbonic anhydrase, acet-
ylcholinesterase, butyrylcholinesterase and α-glycosidase inhibitors, Bioorg. Chem.
85 (2019) 191–197.
(%) = 369.3 ([M + Na]+
,
60), 385.3 ([M + K]+
,
7), 387.2
([M + Na + H2O]+, 8), 401.3 ([M + Na + MeOH]+, 100); analysis
calcd for C18H12Cl2O3 (347.19): C 62.27, H 3.48; found: C 62.11, H
3.69.
[11] M.J. Prince, A. Comas-Herrera, M. Knapp, M.M. Guerchet, M. Karagiannidou, World
Alzheimer Report 2016 - Improving healthcare for people living with dementia:
Coverage, quality and costs now and in the future, Alzheimer's Disease
International, London, 2016.
4.4.34. (E)-3-(3-Fluorophenyl)acrylic anhydride (2w)
[12] J.H. Kim, N.P. Thao, Y.K. Han, Y.S. Lee, B.T.T. Luyen, H.V. Oanh, Y.H. Kim,
S.Y. Yang, The insight of in vitro and in silico studies on cholinesterase inhibitors
from the roots of Cimicifuga dahurica (Turcz.), Maxim, J. Enzym. Inhib. Med. Ch.
33 (1) (2018) 1174–1180.
Compound 2w was obtained as a white solid (0.37 g, 99%);
RF = 0.48 (silica gel, n-hexane/ethyl acetate, 4:1); m.p. 192 °C; IR
(ATR): ν = 1771m, 1705m, 1634m, 1585m, 1486w, 1448w, 1286w,
1270w, 1238w, 1204m, 1170w, 1149w, 1065s, 985m, 964s, 878m,
863m, 784s, 716m, 665s, 562m, 486m cm−1; UV–vis (CHCl3): λmax (log
ε) = 206 (4.19), 226 (3.71), 291 (4.22) nm; 1H NMR (400 MHz, CDCl3):
δ = 7.81 (d, J = 15.9 Hz, 2H, 3-H), 7.44–7.38 (m, 2H, 5′-H), 7.35 (dt,
J = 7.7, 1.3 Hz, 2H, 6′-H), 7.30–7.26 (m, 2H, 2′-H), 7.18–7.12 (m, 2H,
4′-H), 6.52 (d, J = 15.9 Hz, 2H, 2-H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 164.4 (C-3′), 162.0 (C-1), 147.4 (C-3), 136.0 (C-1′), 130.9 (C-5′),
124.8 (C-6′), 118.5 (C-4′), 118.2 (C-2), 114.9 (C-2′) ppm; MS (ESI,
MeOH): m/z (%) = 337.1 ([M + Na]+, 100), 650.8 ([2M + Na]+, 48);
analysis calcd for C18H12F2O3 (314.29): C 68.79, H 3.85; found: C
68.51, H 4.02.
[13] K.D. Singh, T.B. Devi, N.I. Singh, H.D. Chanu, S. Sougrakpam, B.S. Nameirakpam,
Y. Rajashekar, R.K. Labala, D. Sahoo, Biochemical efficacy, molecular docking and
inhibitory effect of 2, 3-dimethylmaleic anhydride on insect acetylcholinesterase,
Sci. Rep. 7 (1) (2017) 12483.
[14] J.K. Makrandi, V. Kumari, A convenient synthesis of 2-styrylchromones by modified
Baker-Venkataraman transformation using phase-transfer catalysis, Synthetic
Commun. 19 (11–12) (1989) 1919–1922.
[15] D.T. Khong, Z.M.A. Judeh, Short synthesis of phenylpropanoid glycosides calceo-
larioside A and syringalide B, Synlett 29 (8) (2018) 1079–1083.
[16] S.-F. Li, K.A. Connors, Kinetics of trans-cinnamic anhydride reactions catalyzed by
pyridine, 4-dimethylaminopyridine, and N-methylimidazole, J. Pharm. Sci. 70 (3)
(1981) 235–238.
[17] J.D. Habila, F.O. Shode, G.I. Ndukwe, J.O. Amupitan, A.J. Nok, Novel antimalarial
agent (Cinnamic 3β-hydroxyolean-12-en-28-carboxylic anhydride): synthesis,
characterization and in vivo studies, Afr. J. Pharm. Pharmacol. 5 (24) (2011)
2667–2675.
4.4.35. (E)-3-(4-Fluorophenyl)acrylic anhydride (2x)
[18] B. Liu, L. Jian, G. Chen, X. Song, C. Han, J. Wang, Chemical constituents and in vitro
anticancer cytotoxic activities of Polyalthia plagioneura, Chem. Nat. Compd. 49 (6)
(2014) 1172–1174.
Compound 2x was obtained as white needles (0.18 g, 49%);
RF = 0.89 (silica gel, chloroform); m.p. 128 °C (lit.: [40] 125–126 °C);
IR (ATR): ν = 3078w, 1756m, 1700m, 1627m, 1595m, 1508s, 1412w,
1320w, 1301w, 1272w, 1227s, 1205w, 1163m, 1126m, 989s, 932m,
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862m, 827s, 816s, 784m, 731m, 684m, 551m, 535m, 510s, 468m cm−1
;
UV–vis (CHCl3): λmax (log ε) = 206 (4.32), 228 (4.31), 303 (4.63) nm;
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 15.9 Hz, 2H, 3-H),
7.61–7.55 (m, 4H, 2′-H), 7.16–7.09 (m, 4H, 3′-H), 6.45 (d, J = 15.9 Hz,
2H, 2-H) ppm; 13C NMR (100 MHz, CDCl3): δ = 165.9 (C-4′), 162.5 (C-
1), 147.5 (C-3), 130.7 (C-2′), 130.2 (C-1′), 116.6 (C-3′), 116.4 (C-2)
ppm; MS (ESI, MeOH): m/z (%) = 337.1 ([M + Na]+, 100), 650.8
([2 M + Na]+, 44); analysis calcd for C18H12F2O3 (314.29): C 68.79, H
3.85; found: C 68.51, H 3.13.
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Many thanks are due to Dr. D. Ströhl and his team for the NMR
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