Efficient synthesis of aurone Mannich bases and evaluation of their antineoplastic activity in PC-3 prostate cancer cells

Article abstract of DOI:10.1007/s11696-018-0485-8

Abstract: An efficient method for regioselective synthesis of C-7 Mannich bases of 6-hydroxyaurones was accomplished by the N,N-dialkylaminomethylation using aminals prepared from dimethylamine, dipropylamine, bis(2-methoxyethyl)amine, N-methylbutylamine, N-methylbenzylamine, morpholine, piperidine, and 1-methylpiperazine. Further transformation of 7-(N,N-dialkylamino)methyl group in these aurones led to formation of C-7 acetoxymethyl and methoxymethyl derivatives of 6-hydroxyaurones, some of which showed promising inhibition of PC-3 prostate cancer cell proliferation in the high nanomolar to low micromolar range that exceeded that of cisplatin. Graphical abstract: Compound 12c (R³ = Ac, Ar = 3,4-OMePh) displays 75% inhibition of PC-3 prostate cancer cells proliferation at 300 nM concentration.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s11696-018-0485-8

Chemical Papers
https://doi.org/10.1007/s11696-018-0485-8
ORIGINAL PAPER
Efcient synthesis of aurone Mannich bases and evaluation of their
antineoplastic activity in PC‑3 prostate cancer cells
Antonina V. Popova1 · Mykhaylo S. Frasinyuk1,2,3 · Svitlana P. Bondarenko4 · Wen Zhang2,5 · Yanqi Xie2,3
·
Zachary M. Martin2,3 · Xianfeng Cai2,5 · Michael V. Fiandalo6 · James L. Mohler6 · Chunming Liu2,5 · David S. Watt2,3,5
Vitaliy M. Sviripa3,7
·
Received: 15 January 2018 / Accepted: 25 April 2018
© Institute of Chemistry, Slovak Academy of Sciences 2018
Abstract
An efcient method for regioselective synthesis of C-7 Mannich bases of 6-hydroxyaurones was accomplished by the
N,N-dialkylaminomethylation using aminals prepared from dimethylamine, dipropylamine, bis(2-methoxyethyl)amine,
N-methylbutylamine, N-methylbenzylamine, morpholine, piperidine, and 1-methylpiperazine. Further transformation of
7-(N,N-dialkylamino)methyl group in these aurones led to formation of C-7 acetoxymethyl and methoxymethyl derivatives
of 6-hydroxyaurones, some of which showed promising inhibition of PC-3 prostate cancer cell proliferation in the high
nanomolar to low micromolar range that exceeded that of cisplatin.
Graphical abstract Compound 12c (R3 = Ac, Ar = 3,4-OMePh) displays 75% inhibition of PC-3 prostate cancer cells pro-
liferation at 300 nM concentration.
O
O
O
CH2(NR1R2)2
O
Ar
O
HO
R1
Ar
HO
R3
O
Ar
HO
55-91%
yield
N
O
R2
Keywords 6-hydroxyaurones · Mannich base · Aminomethylation · Prostate cancer
Introduction
2-Benzylidenebenzofuran-3(2H)-ones, commonly known
as aurones, represent a subclass of favonoids with phar-
macological potential (Haudecoeur and Boumendjel 2012;
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-018-0485-8) contains
supplementary material, which is available to authorized users.
4
* Vitaliy M. Sviripa
National University of Food Technologies, Kyiv 01601,
vitaliy.sviripa@uky.edu
Ukraine
5
Lucille Parker Markey Cancer Center, University
1
Institute of Bioorganic and Petrochemistry, National
of Kentucky, Lexington, KY 40536-0509, USA
Academy of Science of Ukraine, Kyiv 02094, Ukraine
6
Department of Urology, Elm & Carlton Streets, Roswell Park
2
Department of Molecular and Cellular Biochemistry,
Comprehensive Cancer Center, Bufalo, NY 14263, USA
College of Medicine, University of Kentucky, Lexington,
7
KY 40536-0509, USA
Department of Pharmaceutical Sciences, College
of Pharmacy, University of Kentucky, Lexington,
3
Center for Pharmaceutical Research and Innovation,
KY 40536-0596, USA
College of Pharmacy, University of Kentucky, Lexington,
KY 40536-0596, USA
Vol.:(0123456789)
1 3

Chemical Papers
Boumendjel 2003; Sim et al. 2011). Semisynthetic aurones
display antitubercular (Horváti et al. 2012), anticancer (Sch-
oepfer et al. 2002), antimalarial (Carrasco et al. 2014) activ-
ity, and aurones with tertiary amines, including Mannich
bases, were reported as inhibitors of AChE (Sheng et al.
2009), PIM1 (Nakano et al. 2012), and p38 MAP kinase
(Choi et al. 2012). Structure–activity relationships among
the favonoids, isofavonoids, and semisynthetic aurones
do not necessarily parallel one another (Lewin et al. 2012),
but the high CDK1/Cyclin B inhibitory activity of favo-
noid Mannich bases (Liu et al. 2007; Zhang et al. 2008)
prompted us to consider auronoid Mannich bases for evalu-
ation as antineoplastic agents. In contrast to flavonoids
and isofavonoids, reports on the synthesis and evaluation
of auronoid Mannich bases were scarce. We ascribed this
defciency to poor yields encountered in the application of
“classical Mannich reactions” to 6-hydroxyaurones 2 using
aqueous paraformaldehyde and secondary amines in ethanol
(Carrasco et al. 2014). Alternative methods for the synthesis
of semisynthetic aurones introduced aminomethyl groups
on alkoxy- or hydroxy-substituted benzofuran-3(2H)-one
derivatives (Nakano et al. 2012; Gao et al. 2013) 1 prior to
condensation with aryl or heteroaryl aldehydes to secure the
semisynthetic aurones 2 (Ar=aryl or heteroaryl). Amino-
methylation of benzofuran-3(2H)-one (1) generally proceed
in poor yields because of competitive condensation at C-2
leading to 2,2-bis-(N,N-dialkylamino)methyl 6-hydroxyben-
zofuran-3(2H)-one derivatives (Bandgar et al. 2010; Lipeeva
et al. 2013) (Fig. 1).
the structure of the substrate, the dialkylamine, solvent,
the catalyst, the pH, and in particular, the aminomethylat-
ing agent. These agents include iminium salts or hemiami-
nals (Nguyen et al. 2011; Frasinyuk et al. 2015), imines
(MacLeod et al. 2010; Cimarelli et al. 2011; Nguyen et al.
2012), and aminals (Mrug et al. 2013; Bondarenko et al.
2003) that efect the aminomethylation of a range of phe-
nolic substrates.
For these reasons, we investigated the aminomethylation
of 6-hydroxyaurones using various reagents and under con-
ditions that included the following: [1] 40% aqueous formal-
dehyde and a secondary amine in refuxing ethanol; [2] 40%
aqueous formaldehyde and a secondary amine hydrochloride
in refuxing ethanol; and [3] 40% aqueous formaldehyde and
a secondary amine under basic catalysis by 4-dimethylami-
nopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) or Et3N in refuxing ethanol. We obtained the best
yields using DMAP as a catalyst and using paraformalde-
hyde in place of aqueous formaldehyde. For example, the
aminomethylation of aurone 2c with 1-methylpiperazine
gave 21% yield of the compound 10c using aqueous formal-
dehyde without base, 32% yield using aqueous formaldehyde
with DMAP, and 46% yield using paraformaldehyde with
DMAP. The formation of 5,7-bisaminomethyl derivatives
was observed in all cases under these reaction conditions.
Carrying out the aminomethylation using N-hydroxymethy-
lamines and N,N-bisaminomethanes (aminals) proved to be
the most promising pathway for the synthesis of Mannich
bases of aurones. For example, aminomethylation of aurone
2c using 4,4’-methylenebis(1-methylpiperazine) increased
the yield of 10c to 80% of the desired product and simpli-
fed the purifcation of 10c by minimizing the amount of the
5,7-bisaminomethyl derivatives.
As a consequence, we explored a procedure for the direct
aminomethylation of semisynthetic 6-hydroxyaurones 2 as
a means of acquiring compounds for biological evaluation.
Further studies revealed that the aminomethylation of
most 6-hydroxyaurones 2 with aminals in isopropanol or,
in case of aurone 2d, in 1,4-dioxane gave the best yields.
In these cases, we observed the regiospecifc formation of
7-N,N-dialkylaminomethyl derivatives of these aurones.
When using aminals prepared from dimethylamine, dipro-
pylamine, bis(2-methoxyethyl)amine, N-methylbutyl-
amine, N-methylbenzylamine, morpholine, piperidine,
and 1-methylpiperazine, we did not observe formation of
any 5,7-bisaminomethyl derivatives. The desired 7-(N,N-
dialkylamino)methyl-6-hydroxyaurones 3–11 were iso-
lated in 51-86% yield (Scheme 1). Formation of 7-(N,N-
dialkylamino)methyl derivatives was confrmed by 1H NMR
in which the coupling constant (J=8.4–8.5 Hz) between H-4
and H-5 excluded the regioisomeric 5-(N,N-dialkylamino)
methyl-6-hydroxyaurones.
Results and discussion
The important criteria to consider in developing of a
synthesis of N,N-dialkylaminomethyl derivatives of
6-hydroxyaurones included efciency, simplicity, and regi-
oselectivity. 6-Hydroxy-2-benzylidenebenzofuran-3(2H)-
one 2 (Ar = C6H5) possessed two nucleophilic centers at
C-5 and C-7, excluding possible centers in the benzylidene
ring, for Mannich reactions. The efcient and selective
aminomethylation of unsymmetrical phenols depended on
O
O
5
2a
2
2
O
O
Ar
6
HO
HO
7
7
Heating 7-(N,N-dialkylamino)methyl-6-hydroxyaurones
3a–3d with acetic anhydride in presence of potassium ace-
tate aforded the corresponding diacetates 12a–12d in excel-
lent yield.
1
2
Fig. 1 6-Hydroxybenzofuran-3-(2H)-one 1 and 6-hydroxyaurones 2
1 3

Chemical Papers
Scheme 1 Synthesis of Mannich bases of 6-hydroxyaurones 3–11. Reagents and conditions: a) CH2(NR5R6)2, i-PrOH, 80 °C, 4-8 h; b)
CH2(NC4H8X)2, i-PrOH, 80 °C, 4–6 h
(Scheme 2). Hydrolysis of 12 in methanol using hydro-
chloric acid led directly to the formation of 7-methoxym-
ethyl derivatives 13a–13d.
growth of PC-3 cells at 1 µM concentration to the extent of
86.0 2.2% and 87.1 4.0, respectively. Additional testing
of 12c at a concentration of 300 nM showed good retention
of this inhibition of cell proliferation (75.4 15.6%).
A screening program using inhibition of the prolif-
eration of PC-3 prostate cancer cells revealed that several
6-hydroxyaurones 2–13 with C-7 N,N-dialkylaminomethyl,
acetoxymethyl or methoxymethyl substituents exhibited anti-
proliferative activity in the low micromolar range (Table 1).
In general, 7-(N,N-dialkylamino)methyl-6-hydroxyaurones
possessed weak activity at these concentrations, but pro-
vided access to 7-acetoxymethylaurones that were the
most potent. Thus, compounds 12c and 12d inhibited the
Conclusions
Various aminals (i.e., bis(N,N-dialkylamino)methanes)
derived from aliphatic and alicyclic amines aforded the
regiospecific aminomethylation of 6-hydroxyaurones 2
(Scheme 1). The resulting Mannich bases in turn provided
Scheme 2 Conversion of N,N-
O
O
dimethylaminomethyl deriva-
R1
tives 3a–3d to acetoxymethyl-
R1
R3
a
b
and methoxymethyl derivatives.
O
-
HO
MeO
3a 3d
O
AcO
AcO
12a 12d
Reagents and conditions: a,
Ac2O, KOAc; b, HCl, MeOH
R2
R2
R4
R3
R4
-
-
13a 13d
1 3

Chemical Papers
Table 1 IC50 Values (µM) and percent inhibition of PC-3 cell proliferation by cisplatin (positive control) and selected aurones
Aurone
R1
R2
R3
R4
C-7
Inhibition at
10 µM (%)
IC50 (µM)
2a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
OMe
H
OMe
OMe
H
OMe
H
OMe
H
H
OMe
H
H
H
OMe
H
H
H
7.1 22.6
52.9 31.7
9.3 6.5
22.4 8.3
25.9 12.9
8.8 13.8
63.0 4.8
2e
3a
CH2NMe2
CH2NMe2
3e
OMe
OMe
OCH2O
OMe
OCH2O
H
OCH2O
OMe
H
OMe
OMe
OMe
OCH2O
5c
CH2N(Me)CH2Ph
CH2N(Me)CH2Ph
CH2N(Me)CH2Ph
CH2NiPr2
1-piperidinylmethyl
1-piperidinylmethyl
4-morpholinomethyl
4-(1-methylpiperazinyl)-methyl
4-(1-methylpiperazinyl)-methyl
4-(1-(2-hydroxyethyl)piperazinyl)-methyl
acetoxymethyl
5d
5e
OMe
H
3.9 0.28
8.8 0.1
6d
84.51 0
8a
6.5 19.5
11.7 4.8
31.4 2.5
40.6 5.6
45.8 10.0
47.9 19.8
99.5 0.1
87.9 2.3
8d
9e
OMe
OMe
OMe
OMe
OMe
10b
10c
11c
12c
12d
cisplatin
H
H
H
H
0.74 0.03
3.7 0.42
> 10
acetoxymethyl
ready access to aurones 12 and 13 bearing either acetoxy or
methoxy groups, respectively. Although the initial focus of
this work required the identifcation of a viable synthetic
route to the desired compounds, we were pleased to fnd
that various aurones possessed in vitro activity in a PC-3
cell proliferation assay. Several analogs (i.e., 5e, 6d, 12c
and 12d) possessed IC50 values against prostate cancer PC-3
cells that were larger than the IC50 of cisplatin (i.e., cis-
diamminedichloridoplatinum(II)), a therapeutic antineo-
plastic agent in current use. In general, the aurones 3-11
possessing 3,4-dimethoxy or 3,4-methylenedioxy groups in
the C-2 benzylidene subunit were more active in a PC-3
cell proliferation assay than those aurones with no alkoxy
groups in the C-2 benzylidene subunit (i.e., 2e > 2a; and
3e > 3a). In general, the diacetoxy-substituted aurones 12
were more active in a PC-3 cell proliferation than the corre-
sponding Mannich bases 3-11 (i.e., 12c>10–11c,>5c; and
12d > 8d > 5d). Exceptions to these generalizations were,
however, noted (e.g., 6d–12d), and future, additional SAR
work will further defne these distinctions.
slightly basic aqueous solution. Future studies will focus
on: defning the stability of the most promising diacetoxy-
substituted aurones 12 to esterases (i.e., metabolism stud-
ies); determining if these aurones generate ortho-quinone
methide intermediates; utilizing biotinylated intermediates
to determine molecular target(s); evaluating toxicity issues;
and performing xenograft studies to evaluate in vivo activity.
Experimental
Chemistry
Cisplatin was obtained from Sigma-Aldrich (St. Louis, MO
1
63146 USA). H and 13C NMR spectra were recorded on
a Varian 500 spectrometer (at 500 MHz or at 125 MHz,
respectively) or on a Varian 400 spectrometer (at 400 MHz
or at 100 MHz, respectively) in deuterochloroform (CDCl3)
or deuterated dimethylsulfoxide (DMSO-d6). IR spectra
were recorded on a Bruker Vertex 70 FT/IR spectrometer.
Melting points were determined in open capillarity tubes
with a Buchi B-535 apparatus and were uncorrected. Mass
spectra were obtained with an Agilent 1100 spectrometer
under chemical ionization conditions.
Other factors, such as solubility and in vitro stability,
presumably played a role in the results of these cell prolif-
eration assays. The Mannich bases of aurones 3-11 were,
as expected, slightly soluble in water, and aurone 6d with
a C-7 N,N-(diisopropylamino)methyl substituent and with
promising inhibitor activity was soluble at pH 5-6 in phos-
phate, citrate and acetate bufers. The corresponding diace-
toxy compound 12d also showed promising activity but was
insoluble in water. The methoxymethyl derivatives 13 were
also insoluble in water, but were soluble, as expected, in
General procedure for the synthesis of 6‑hydroxyaurones
2a–2f
To a stirred solution of 0.75 g (5 mmol) 6-hydroxybenzo-
furanone (1) in ethanol (5 mL) and N,N-dimethylformamide
1 3

Chemical Papers
(DMF) (5 mL) was added aldehyde (5 mmol) and 1.15 mL
of 50% KOH. The mixture was stirred at room temperature
for 4–6 h. The mixture was poured into 30 mL of hot water
with vigorous stirring and neutralized with concentrated
HCl at pH of 1–2. The precipitate was fltered, washed with
water, dried and recrystallized from DMF-MeOH.
(2Z)‑2‑(1,3‑Benzodioxol‑5‑ylmethylene)‑6‑hydroxy‑1‑ben‑
zofuran‑3(2H)‑one (2d)
Yellow solid (91% yield); mp: 321–323 °C (decomp); IR
(KBr): νmax 3057, 2890, 1668, 1616, 1542, 1446, 1405,
1
1329, 1253, 1102, 1034 cm−1; H NMR (400 MHz,
DMSO-d6): δ 6.11 (2H, s, OCH2O), 6.71 (1H, dd,
4
3J = 8.5 Hz, J = 1.8 Hz, H-5), 6.74 (1H, s, H-2a), 6.81
(2Z)‑2‑Benzylidene‑6‑hydroxy‑1‑benzofuran‑3(2H)‑one (2a)
(1H, d, 4J = 1.8 Hz, H-7), 7.04 (1H, d, 3J = 8.1 Hz, H-7ʹ),
3
4
7.47 (1H, dd, J = 8.1 Hz, J = 1.7 Hz, H-6ʹ), 7.55 (1H,
d, 4J = 1.7 Hz, H-4ʹ), 7.60 ppm (1H, d, 3J = 8.5 Hz, H-4);
13C NMR (100 MHz, DMSO-d6): δ 98.58, 101.59, 108.80,
109.95, 110.64, 112.78, 112.93, 125.66, 126.12, 126.79,
146.15, 147.70, 148.50, 166.35, 167.52, 181.04 ppm; MS
(CI): m/z 283.3 (MH+, 100). Anal. calcd for C16H10O5: C,
68.09; H, 3.57. Found: C, 67.95; H, 3.68.
Yellow solid (87% yield); mp: 259–260 °C; IR (KBr): νmax
3072, 2960, 1674, 1644, 1580, 1455, 1376, 1285, 1109,
770 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 6.72 (1H, dd,
3J=8.4 Hz, 4J=1.7 Hz, H-5), 6.78 (1H, s, H-2a), 6.80 (1H,
4
d, J = 1.7 Hz, H-7), 7.38–7.53 (3H, m, H-3′, 4′, 5′), 7.63
(1H, d, 3J=8.4 Hz, H-4), 7.94 (2H, d, 3J=8.5 Hz, H-2′, 6′),
11.30 ppm (1H, br. s, OH-6); 13C NMR (100 MHz, DMSO-
d6): δ 98.71, 110.41, 112.79, 113.18, 126.08, 129.04, 129.72,
131.12, 132.14, 147.45, 166.70, 168.05, 181.55 ppm; MS
(CI): m/z 238.9 (MH+, 100). Anal. calcd for C15H10O3: C,
75.62; H, 4.23. Found: C, 75.41; H, 4.05.
(2Z)‑6‑Hydroxy‑2‑(3,4,5‑trimethoxybenzylidene)‑1‑benzo‑
furan‑3(2H)‑one (2e)
Yellow solid (81% yield); mp: 254–256 °C; IR (KBr):
νmax 3271, 1678, 1637, 1582, 1454, 1315, 1242, 1129,
1
(2Z)‑6‑Hydroxy‑2‑(4‑methoxybenzylidene)‑1‑benzo‑
furan‑3(2H)‑one (2b)
1108, 998 cm−1; H NMR (400 MHz, DMSO-d6): δ 3.72
(3H, s, OMe-4ʹ), 3.85 (6H, s, OMe-3ʹ, 5ʹ), 6.72 (1H, dd,
2
3J = 8.4 Hz, J = 2.0 Hz, H-5), 6.75 (1H, s, H-2a), 6.82
4
Yellow solid (85% yield); mp: 268–270 °C; IR (KBr):
(1H, d, J = 2.0 Hz, H-7), 7.30 (2H, s, H-2ʹ, 6ʹ), 7.61
3
νmax 3081, 2899, 2598, 1675, 1566, 1455, 1285, 1256,
(1H, d, J = 8.4 Hz, H-4), 11.19 ppm (1H, br. s, OH-6);
1108 cm−1; H NMR (400 MHz, DMSO-d6): δ 3.81 (3H,
13C NMR (100 MHz, DMSO-d6): δ 55.94, 60.12, 98.68,
108.73, 110.73, 112.74, 112.92, 125.73, 127.38, 139.03,
146.68, 152.83, 166.28, 167.61, 181.13 ppm; MS (CI): m/z
329.1 (MH+, 100). Anal. calcd for C18H16O6: C, 65.85; H,
4.91. Found: C, 65.62; H; 5.04.
1
3
4
s, OMe-4ʹ), 6.71 (1H, dd, J = 8.5 Hz, J = 2.0 Hz, H-5),
6.77–6.81 (2H, m, H-2a, H-7), 7.05 (2H, d, 3J=8.4 Hz, H-3ʹ,
5ʹ), 7.61 (1H, d, 3J=8.5 Hz, H-4), 7.91 (2H, d, 3J=8.4 Hz,
H-2ʹ, 6ʹ), 11.17 ppm (1H, s, OH-6); 13C NMR (100 MHz,
DMSO-d6): δ 55.28, 98.46, 110.62, 112.81, 112.96, 114.48,
124.50, 125.65, 132.82, 146.05, 160.30, 166.11, 167.47,
181.08 ppm; MS (CI): m/z 269.1 (MH+, 100). Anal. calcd
for C16H12O4: C, 71.64; H, 4.51. Found: C, 71.45; H 4.38.
(2Z)‑6‑Hydroxy‑2‑(2,3,4‑trimethoxybenzylidene)‑1‑benzo‑
furan‑3(2H)‑one (2f)
Yellow solid (78% yield); mp: 249–251 °C; IR (KBr):
νmax 3169, 2941, 1680, 1582, 1492, 1266, 1136, 1103,
1090, 976 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 3.78,
3.87, 3.88 (each 3H, s, OMe-2ʹ, 3ʹ, 4ʹ), 6.71 (1H, dd,
(2Z)‑2‑(3,4‑Dimethoxybenzylidene)‑6‑hydroxy‑1‑benzo‑
furan‑3(2H)‑one (2c)
4
4
Yellow solid (87% yield); mp: 224–226 °C; IR (KBr): νmax
3122, 1679, 1582, 1509, 1259, 1235, 1125, 1092, 1015 cm−1;
1H NMR (400 MHz, DMSO-d6): δ 3.82, 3.83 (each 3H, 2 s,
3J = 8.3 Hz, J = 1.9 Hz, H-5), 6.77 (1H, d, J = 1.9 Hz,
3
H-7), 6.90 (1H, s, H-2a), 6.98 (1H, d, J = 8.9 Hz, H-5ʹ),
3
3
7.61 (1H, d, J = 8.3 Hz, H-4), 7.93 (1H, d, J = 8.9 Hz,
H-6ʹ), 11.15 ppm (1H, br. s, OH-6); 13C NMR (100 MHz,
DMSO-d6): δ 55.96, 60.42, 61.61, 98.50, 104.01, 108.45,
112.86, 112.92, 118.25, 125.73, 126.25, 141.55, 146.79,
152.80, 154.95, 166.19, 167.48, 181.09 ppm; MS (CI): m/z
329.1 (MH+, 100). Anal. calcd for C18H16O6: C, 65.85; H,
4.91. Found: C, 65.98; H, 5.12.
3
4
OMe-3ʹ,4ʹ), 6.68 (1H, dd, J = 8.5 Hz, J = 1.8 Hz, H-5),
6.73 (1H, s, H-2a), 6.75 (1H, d, 4J=1.8 Hz, H-7), 7.07 (1H,
d,3J=8.5 Hz, H-5ʹ), 7.54-7.60 ppm (3H, m, H-4, 2ʹ, 6ʹ); 13
C
NMR (100 MHz, DMSO-d6): δ 55.50, 55.55, 98.56, 111.07,
111.86, 112.83, 112.96, 114.13, 124.65, 124.98, 125.66,
146.11, 148.61, 150.25, 166.11, 167.45, 181.06 ppm; MS
(CI): m/z 299.1 (MH+, 100). Anal. calcd for C17H14O5: C,
68.45; H, 4.73. Found: C, 68.31; H 4.51.
1 3

Chemical Papers
General procedure for the synthesis of Mannich bases 3–11
113.63, 125.39, 125.43, 125.63, 147.10, 149.04, 150.54,
165.39, 167.46, 182.63 ppm; MS (CI): m/z 356.2 (MH+,
100). Anal. calcd for C20H21NO5: C, 67.59; H, 5.96; N, 3.94.
Found: C, 67.83; H, 6.17; N, 4.07.
To a suspension of 2 mmol of 2a–f in 10 mL of isopro-
pyl alcohol or 1,4-dioxane (in case of compound 1d) was
added 2.2 mmol of aminal, and the mixture was refuxed for
4-6 h. The mixture was diluted with 10 mL of hexanes and
cooled. The residue was fltered and recrystallized from an
isopropanol-hexanes mixture.
(2Z)‑2‑(1,3‑Benzodioxol‑5‑ylmethylene)‑7‑[(dimethylam
ino)methyl]‑6‑hydroxy‑1‑benzofuran‑3(2H)‑one (3d)
Yellow solid (84% yield); mp: 158–160 °C; IR (KBr): νmax
2963, 2899, 1689, 1601, 1444, 1331, 1242, 1038 cm−1; 1H
NMR (400 MHz, CDCl3): δ 2.47 (6H, s, NMe2), 3.94 (2H,
s, CH2-7), 6.05 (2H, s, OCH2O), 6.64 (1H, d, 3J=8.5 Hz,
(2Z)‑2‑Benzylidene‑7‑[(dimethylamino)methyl]‑6‑hy‑
droxy‑1‑benzofuran‑3(2H)‑one (3a)
3
Yellow solid (77% yield); mp: 248–250 °C; IR (KBr): νmax
H-5), 6.72 (1H, s, H-2a), 6.89 (1H, d, J = 8.1 Hz, H-7ʹ),
4
3051, 2394, 1682, 1598, 1507, 1444, 1333, 1272, 1123,
7.24–7.27 (1H, m, H-6ʹ), 7.47 (1H, d, J = 1.6 Hz, H-4ʹ),
1049 cm−1; H NMR (500 MHz, CDCl3): δ 2.51 (6H, s,
7.60 ppm (1H, d, J=8.4 Hz, H-4); 13C NMR (125 MHz,
1
3
NMe2), 3.99 (2H, s, CH2-7), 6.67 (1H, d, 3J=8.4 Hz, H-5),
6.78 (1H, s, H-2a), 7.36–7.49 (3H, m, H-3ʹ, 4ʹ, 5ʹ), 7.61
(1H, d, 3J=8.4 Hz, H-4), 7.82 (2H, d, 3J=8.8 Hz, H-2ʹ, 6ʹ),
10.69 ppm (1H, br. s, OH-7); 13C NMR (125 MHz, CDCl3):
δ 44.55, 54.64, 104.19, 111.37, 113.16, 113.84, 125.53,
129.00, 129.55, 131.21, 132.72, 148.08, 165.86, 168.12,
182.78 ppm; MS (CI): m/z 296.2 (MH+, 100). Anal. calcd
for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.04;
H, 5.54; N, 4.61.
CDCl3): δ 44.62, 54.98, 101.61, 104.50, 108.91, 110.31,
111.61, 113.37, 113.68, 125.17, 126.96, 127.12, 147.02,
148.20, 148.91, 165.37, 167.82, 182.64 ppm; MS (CI): m/z
340.0 (MH+, 100). Anal. calcd for C19H17NO5: C, 67.25; H,
5.05; N, 4.13. Found: C, 66.98; H, 5.31; N, 4.42.
(2Z)‑7‑[(Dimethylamino)methyl]‑6‑hydroxy‑2‑(3,4,5‑trimet
hoxybenzylidene)‑1‑benzofuran‑3(2H)‑one (3e)
Yellow solid (76% yield); mp: 191–193 °C; IR (KBr): νmax
(2Z)‑7‑[(Dimethylamino)methyl]‑6‑hydroxy‑2‑(4‑methoxyb
enzylidene)‑1‑benzofuran‑3(2H)‑one (3b)
3433, 2955, 1670, 1614, 1510, 1450, 1344, 1273, 1130,
1
1051 cm−1; H NMR (400 MHz, CDCl3): δ 2.43 (6H, s,
NMe2), 3.88 (2H, s, CH2-7), 3.92 (3H, s, OMe-4ʹ), 3.95 (6H,
s, OMe-3ʹ, 5ʹ), 6.66 (1H, d, 3J=8.5 Hz, H-5), 6.73 (1H, s,
H-2a), 7.14 (2H, s, H-2ʹ, 6ʹ), 7.62 ppm (1H, d, 3J=8.5 Hz,
H-4); 13C NMR (100 MHz, DMSO-d6): δ 43.62, 52.26,
55.82, 60.14, 103.65, 108.15, 108.89, 109.11, 115.07,
124.78, 127.90, 138.43, 147.63, 152.80, 166.27, 171.55,
179.71 ppm; MS (CI): m/z 386.2 (MH+, 100). Anal. calcd
for C21H23NO6: C, 65.44; H, 6.02; N, 3.63. Found: C, 65.21;
H, 6.15; N, 3.49.
Yellow solid (83% yield); mp: 171–173 °C; IR (KBr):
νmax 2960, 2836, 1692, 1600, 1509, 1252, 1126, 1036,
1
821 cm−1; H NMR (400 MHz, CDCl3): δ 2.49 (6H, s,
NMe2), 3.85 (3H, s, OMe-4ʹ), 3.96 (2H, s, CH2-7), 6.64
(1H, d, 3J=8.5 Hz, H-5), 6.74 (1H, s, H-2a), 6.97 (2H, d,
3J = 8.9 Hz, H-3′, 5′), 7.58 (1H, d, 3J = 8.5 Hz, H-4), 7.77
(2H, d, 3J=8.9 Hz, H-2′, 6′), 7.95 ppm (1H, br. s, OH-6);
13C NMR (100 MHz, CDCl3): δ 44.55, 54.72, 55.46, 104.21,
111.68, 113.43, 113.62, 114.56, 125.27, 125.35, 133.00,
146.97, 160.76, 165.48, 167.74, 182.73 ppm; MS (CI): m/z
326.2 (MH+, 100). Anal. calcd for C19H19NO4: C, 70.14; H,
5.89; N, 4.30. Found: C, 69.90; H, 5.62; N, 4.55.
(2Z)‑7‑[(Dimethylamino)methyl]‑6‑hydroxy‑2‑(2,3,4‑trimet
hoxybenzylidene)‑1‑benzofuran‑3(2H)‑one (3f)
Yellow solid (87% yield); mp: 152–154 °C; IR (KBr): νmax
2940, 1678, 1599, 1496, 1453, 1278, 1122, 1090 cm−1; 1H
NMR (400 MHz, CDCl3): δ 2.47 (6H, s, NMe2), 3.90, 3.95,
3.97 (each 3H, 3 s, OMe-2ʹ, 3ʹ, 4ʹ), 3.93 (2H, s, CH2-7),
(2Z)‑2‑(3,4‑Dimethoxybenzylidene)‑7‑[(dimethylamino)
methyl]‑6‑hydroxy‑1‑benzofuran‑3(2H)‑one (3c)
3
3
Yellow solid (78% yield); mp: 91–93 °C; IR (KBr): νmax
6.65 (1H, d, J = 8.4 Hz, H-5), 6.84 (1H, d, J = 8.9 Hz,
3
3451, 3387, 2834, 1672, 1588, 1514, 1455, 1336, 1266,
H-5ʹ), 7.21 (1H, s, H-2a), 7.62 (1H, d, J = 8.5 Hz, H-4),
1122 cm−1; H NMR (400 MHz, CDCl3): δ 2.45 (6H, s,
7.94 (1H, d, 3J=8.9 Hz, H-6ʹ), 8.24 ppm (1H, br. s, OH-7);
13C NMR (100 MHz, CDCl3): δ 44.37, 54.32, 56.07, 60.90,
61.84, 103.80, 105.74, 107.73, 113.47, 119.63, 125.36,
126.53, 142.21, 147.57, 153.86, 155.13, 165.38, 167.43,
182.51 ppm; MS (CI): m/z 386.2 (MH+, 100). Anal. calcd
for C21H23NO6: C, 65.44; H, 6.02; N, 3.63. Found: C, 65.17;
H, 5.83; N, 3.90.
1
NMe2), 3.91 (2H, s, CH2-7), 3.95, 3.98 (each 3H, 2 s, OMe-
3
3ʹ,4ʹ), 6.65 (1H, d, J = 8.3 Hz, H-5), 6.77 (1H, s, H-2a),
3
6.96 (1H, d,3J = 8.4 Hz, H-5ʹ), 7.42 (1H, dd, J = 8.3 Hz,
4J=1.9 Hz, H-6ʹ), 7.50 (1H, d, 4J=1.9 Hz, H-2ʹ), 7.61 ppm
(1H, d, 3J=8.4 Hz, H-4); 13C NMR (125 MHz, CDCl3): δ
44.74, 54.78, 55.85, 56.08, 104.22, 111.40, 111.95, 113.54,
1 3

Chemical Papers
(2Z)‑7‑{[Butyl(methyl)amino]methyl}‑6‑hydroxy‑2‑(4‑meth
oxybenzylidene)‑1‑benzofuran‑3(2H)‑one (4b)
125.61, 128.08, 139.75, 147.67, 153.37, 165.69, 167.71,
182.50 ppm; MS (CI): m/z 428.2 (MH+, 100). Anal. calcd
for C24H29NO6: C, 67.43; H, 6.84; N, 3.28. Found: C, 67.18;
H, 7.07; N, 3.08.
Yellow solid (76% yield); mp: 112–114 °C; IR (KBr): νmax
3421, 2958, 1664, 1606, 1510, 1460, 1257, 1130 cm−1; 1H
3
NMR (400 MHz, DMSO-d6): δ 0.88 (3H, t, J = 7.3 Hz,
(2Z)‑7‑{[Benzyl(methyl)amino]methyl}‑2‑(3,4‑dimethoxybe
nzylidene)‑6‑hydroxy‑1‑benzofuran‑3(2H)‑one (5c)
CH2CH2CH2CH3), 1.24–1.38 (2H, m, CH2CH2CH2CH3),
1.52–1.69 (2H, m, CH2CH2CH2CH3), 2.43 (3H, s, NMe),
2.63–2.78 (2H, m, CH2CH2CH2CH3), 3.82 (3H, s, OMe-4ʹ),
Yellow solid (71% yield); mp: 141–143 °C; IR (KBr): νmax
3
4.04 (2H, s, CH2-7), 6.48 (1H, d, J = 8.6 Hz, H-5), 6.68
2946, 2835, 1698, 1601, 1515, 1420, 1261, 1142, 1117,
1
(1H, s, H-2a), 7.05 (2H, d, 3J=8.8 Hz, H-3′, 5′), 7.45 (1H,
d, 3J=8.6 Hz, H-4), 7.90 ppm (2H, d, 3J=8.8 Hz, H-2′, 6′);
13C NMR (100 MHz, DMSO-d6): δ 13.71, 19.75, 27.87,
40.68, 51.17, 55.24, 55.73, 104.07, 109.03, 109.52, 114.41,
114.67, 124.33, 124.93, 132.53, 146.83, 159.91, 165.85,
171.15, 179.93 ppm; MS (CI): m/z 368.1 (MH+, 100). Anal.
calcd for C22H25NO4: C, 71.91; H, 6.86; N, 3.81. Found: C,
72.09; H, 6.63; N, 3.65.
1024 cm−1; H NMR (400 MHz, CDCl3): δ 2.38 (3H, s,
NMe), 3.73 (2H, s, NCH2Ph), 3.92, 3.96 (each 3H, 2 s,
OMe-3ʹ, 4ʹ), 3.98 (2H, s, CH2-7), 6.68 (1H, d, 3J=8.5 Hz,
H-5), 6.77 (1H, s, H-2a), 6.95 (1H, d,3J = 8.4 Hz, H-5ʹ),
7.28–7.43 (6H, m, H-6ʹ, NCH2Ph), 7.49 (1H, d, 4J=1.9 Hz,
3
H-2ʹ), 7.62 ppm (1H, d, J = 8.4 Hz, H-4); 13C NMR
(100 MHz, DMSO-d6): δ 40.87, 50.48, 55.30, 55.54, 60.46,
106.10, 110.50, 111.60, 111.78, 113.41, 124.32, 124.88,
125.13, 127.29, 128.23, 129.06, 137.02, 146.41, 148.56,
150.07, 165.58, 167.56, 180.79 ppm; MS (CI): m/z 432.2
(MH+, 100). Anal. calcd for C26H25NO5: C, 72.37; H, 5.84;
N, 3.25. Found: C, 72.16; H, 5.95; N, 3.42.
(2Z)‑7‑{[Butyl(methyl)amino]methyl}‑2‑(3,4‑dimethoxyben
zylidene)‑6‑hydroxy‑1‑benzofuran‑3(2H)‑one (4c)
Yellow solid (73% yield); mp: 101–102 °C; IR (KBr):
νmax 2959, 1676, 1605, 1512, 1458, 1260, 1118 cm−1
;
(2Z)‑2‑(1,3‑Benzodioxol‑5‑ylmethylene)‑7‑{[benzyl(methyl)
amino]methyl}‑6‑hydroxy‑1‑benzofuran‑3(2H)‑one (5d)
3
1H NMR (400 MHz, CDCl3): δ 0.92 (3H, t, J = 7.4 Hz,
CH2CH2CH2CH3), 1.27– 1.46 (2H, m, CH2CH2CH2CH3),
1.48–1.70 (2H, m, CH2CH2CH2CH3), 2.41 (3H, s, NMe),
2.53– 2.65 (2H, m, CH2CH2CH2CH3), 3.92, 3.95 (each
3H, 2 s, OMe-3ʹ,4ʹ), 3.98 (2H, s, CH2-7), 6.65 (1H, d,
3J=8.5 Hz, H-5), 6.73 (1H, s, H-2a), 6.93 (1H, d,3J=8.5 Hz,
H-5ʹ), 7.38 (1H, dd, 3J=8.5 Hz, 4J=2.0 Hz, H-6ʹ), 7.45 (1H,
Yellow solid (69% yield; mp: 159–161 °C; IR (KBr): νmax
2851, 1697, 1602, 1499, 1243, 1188, 1035 cm−1; 1H NMR
(400 MHz, CDCl3): δ 2.40 (3H, s, NMe), 3.77 (2H, s,
NCH2Ph), 4.03 (2H, s, CH2-7), 6.07 (2H, s, OCH2O), 6.68
(1H, d, 3J=8.4 Hz, H-5), 6.74 (1H, s, H-2a), 6.90 (1H, d,
3J=8.1 Hz, H-7ʹ), 7.22–7.43 (6H, m, H-6ʹ, NCH2Ph), 7.48
4
3
d, J = 2.0 Hz, H-2ʹ), 7.58 ppm (1H, d, J = 8.5 Hz, H-4);
13C NMR (100 MHz, CDCl3): δ 13.95, 20.41, 28.72, 41.37,
53.31, 55.83, 56.07, 57.09, 104.08, 111.39, 111.86, 113.47,
113.61, 113.67, 125.35, 125.40, 125.64, 147.12, 149.05,
150.52, 165.50, 167.62, 182.56 ppm; MS (CI): m/z 398.2
(MH+, 100). Anal. calcd for C23H27NO5: C, 69.50; H, 6.85;
N, 3.52. Found: C, 69.77; H, 7.03; N, 3.64.
4
3
(1H, d, J = 1.7 Hz, H-4ʹ), 7.62 ppm (1H, d, J = 8.4 Hz,
H-4); 13C NMR (100 MHz, CDCl3): δ 41.38, 52.52, 61.31,
100.09, 101.64, 104.46, 108.94, 110.34, 111.76, 113.66,
125.35, 126.90, 127.16, 128.31, 128.93, 129.67, 135.39,
146.95, 148.23, 148.97, 165.49, 167.31, 182.62 ppm; MS
(CI): m/z 416.2 (MH+, 100). Anal. calcd for C25H21NO5: C,
72.28; H, 5.10; N, 3.37. Found: C, 72.43; H, 5.36; N, 3.09.
(2Z)‑7‑{[Butyl(methyl)amino]methyl}‑6‑hydroxy‑2‑(3,4,5‑tri
methoxybenzylidene)‑1‑benzofuran‑3(2H)‑one (4e)
(2Z)‑7‑{[Benzyl(methyl)amino]methyl}‑6‑hydroxy‑2‑(3,4,5‑t
rimethoxybenzylidene)‑1‑benzofuran‑3(2H)‑one (5e)
Yellow solid (82% yield); mp: 147–149 °C; IR (KBr): νmax
2959, 1677, 1603, 1511, 1459, 1334, 1274, 1117 cm−1;
Yellow solid (68% yield); mp: 144–146 °C; IR (KBr):
1H NMR (400 MHz, CDCl3): δ 0.93 (3H, t, J = 7.4 Hz,
νmax 2938, 2837, 1685, 1599, 1452, 1262, 1132 cm−1; H
3
1
CH2CH2CH2CH3), 1.31–1.43 (2H, m, CH2CH2CH2CH3),
1.56–1.68 (2H, m, CH2CH2CH2CH3), 2.43 (3H, s, NMe),
2.55– 2.77 (2H, m, CH2CH2CH2CH3), 3.91 (3H, s, OMe-4ʹ),
3.93 (6H, s, OMe-3ʹ, 5ʹ), 3.99 (2H, s, CH2-7), 6.58–6.78
(2H, m, H-2a, 5), 7.12 (2H, s, H-2ʹ, 6ʹ), 7.60 (1H, d,
3J=8.5 Hz, H-4), 10.29 ppm (1H, br. s, OH-6); 13C NMR
(100 MHz, CDCl3): δ 13.95, 20.40, 28.50, 41.34, 53.12,
56.18, 57.10, 61.13, 103.95, 108.64, 111.67, 113.34, 113.84,
NMR (400 MHz, CDCl3): δ 2.39 (3H, s, NMe), 3.73 (2H, s,
NCH2Ph), 3.91 (6H, s, OMe-3ʹ, 5ʹ), 3.94 (3H, s, OMe-4ʹ),
3.97 (2H, s, CH2-7), 6.70 (1H, d, 3J=8.4 Hz, H-5), 6.74 (1H,
s, H-2a), 7.14 (2H, s, H-2ʹ, 6ʹ), 7.29–7.41 (5H, m, NCH2Ph),
3
7.64 ppm (1H, d, J=8.4 Hz, H-4); 13C NMR (100 MHz,
CDCl3): 41.63, 52.22, 56.12, 61.13, 61.36, 104.45, 108.60,
111.75, 113.61, 113.70, 125.52, 128.06, 128.41, 128.95,
129.76, 134.88, 139.71, 147.62, 153.34, 165.50, 167.24,
1 3

Chemical Papers
182.59 ppm; MS (CI): m/z 462.0 (MH+, 100). Anal. calcd
for C27H27NO6: C, 70.27; H, 5.90; N, 3.03. Found: C, 70.50;
H, 6.18; N, 3.31.
125.09, 127.11, 127.12, 147.18, 148.24, 148.89, 165.56,
168.34, 182.67 ppm; MS (CI): m/z 396.0 (MH+, 100). Anal.
calcd for C23H25NO5: C, 69.86; H, 6.37; N, 3.54. Found: C,
69.60; H, 6.20; N, 3.48.
(2Z)‑7‑{[Benzyl(methyl)amino]methyl}‑6‑hydroxy‑2‑(2,3,4‑t
rimethoxybenzylidene)‑1‑benzofuran‑3(2H)‑one (5f)
(2Z)‑7‑[(Dipropylamino)methyl]‑6‑hydroxy‑2‑(3,4,5‑trimeth
oxybenzylidene)‑1‑benzofuran‑3(2H)‑one (6e)
Yellow solid (76% yield); mp: 139–141 °C; IR (KBr):
1
νmax 2940, 1692, 1601, 1460, 1256, 1133, 1091 cm−1; H
Yellow solid (65% yield); mp: 172–174 °C; IR (KBr): νmax
NMR (400 MHz, CDCl3): δ 2.40 (3H, s, NMe), 3.78 (2H,
s, NCH2Ph), 3.89, 3.95, 3.96 (each 3H, 3 s, OMe-2ʹ, 3ʹ, 4ʹ),
4.04 (2H, s, CH2-7), 6.71 (1H, d, 3J=8.5 Hz, H-5), 6.82 (1H,
d, 3J=8.9 Hz, H-5ʹ), 7.21 (1H, s, H-2a), 7.29–7.44 (5H, m,
NCH2Ph), 7.63 (1H, d, 3J=8.5 Hz, H-4), 7.92 ppm (1H, d,
3J=8.9 Hz, H-6ʹ); 13C NMR (100 MHz, CDCl3): δ 41.40,
52.43, 56.23, 61.04, 61.30, 61.98, 104.34, 105.93, 107.87,
113.51, 113.97, 119.82, 125.46, 126.71, 128.33, 128.95,
129.72, 135.33, 142.40, 147.70, 154.05, 155.29, 165.47,
167.01, 182.69 ppm; MS (CI): m/z 462.0 (MH+, 100). Anal.
calcd for C27H27NO6: C, 70.27; H, 5.90; N, 3.03. Found: C,
70.02; H, 5.65; N, 2.84.
3472, 2962, 1686, 1603, 1460, 1269, 1134, 1009 cm−1;
3
1H NMR (400 MHz, CDCl3): δ 0.94 (6H, t, J = 7.4 Hz,
N(CH2CH2CH3)2), 1.57–1.65 (4H, m, N(CH2CH2CH3)2),
2.57–2.60 (4H, m, N(CH2CH2CH3)2), 3.91 (3H, s, OMe-4ʹ),
3.94 (6H, s, OMe-3ʹ, 5ʹ), 4.00 (2H, s, CH2-7), 6.63 (1H, d,
3J=8.5 Hz, H-5), 6.72 (1H, s, H-2a), 7.14 (2H, s, H-2ʹ,6ʹ),
3
7.61 ppm (1H, d, J=8.5 Hz, H-4); 13C NMR (100 MHz,
DMSO-d6): δ 11.41, 18.21, 49.35, 54.41, 55.72, 60.11,
103.92, 108.31, 109.78, 110.21, 114.28, 124.45, 127.67,
138.61, 147.28, 152.76, 165.26, 170.30, 180.21 ppm; MS
(CI): m/z 442.3 (MH+, 100). Anal. calcd for C25H31NO6: C,
68.01; H, 7.08; N, 3.17. Found: C, 68.15; H, 6.79; N, 2.99.
(2Z)‑2‑(3,4‑Dimethoxybenzylidene)‑7‑[(dipropylamino)
methyl]‑6‑hydroxy‑1‑benzofuran‑3(2H)‑one (6c)
(2Z)‑2‑Benzylidene‑7‑{[bis(2‑methoxyethyl)amino]
methyl}‑6‑hydroxy‑1‑benzofuran‑3(2H)‑one (7a)
Yellow solid (73% yield); mp: 135–137 °C; IR (KBr): νmax
Yellow solid (69% yield); mp: 81–82 °C; IR (KBr): νmax
2966, 1666, 1597, 1514, 1458, 1263, 1114, 1019 cm−1;
2879, 1697, 1604, 128, 1187, 1128, 1105, 1039 cm−1
;
3
3
1H NMR (400 MHz, CDCl3): δ 0.91 (6H, t, J = 7.4 Hz,
1H NMR (400 MHz, CDCl3): δ 2.96 (4H, t, J = 5.3 Hz,
N(CH2CH2OMe)2), 3.35 (6H, s, CH2OCH3), 3.59 (4H, t,
3J=5.3 Hz, N(CH2CH2OMe)2), 4.19 (2H, s, CH2-7), 6.68
(1H, d, 3J=8.4 Hz, H-5), 6.79 (1H, s, H-2a), 7.33–7.51 (3H,
m, H-3ʹ, 4ʹ, 5ʹ), 7.61 (1H, d, 3J=8.4 Hz, H-4), 7.85 ppm (2H,
N(CH2CH2CH3)2), 1.53 –1.72 (4H, m, N(CH2CH2CH3)2),
2.50–2.67 (4H, m, N(CH2CH2CH3)2), 3.91, 3.94 (each 3H,
2 s, OMe-3ʹ,4ʹ), 4.01 (2H, s, CH2-7), 6.61 (1H, d, 3J=8.5 Hz,
H-5), 6.71 (1H, s, H-2a), 6.91 (1H, d,3J = 8.2 Hz, H-5ʹ),
3
4
3
7.36 (1H, dd, J = 8.2 Hz, J = 2.0 Hz, H-6ʹ), 7.45 (1H, d,
4J=2.0 Hz, H-2ʹ), 7.56 (1H, d, 3J=8.5 Hz, H-4), 8.30 ppm
(1H, br. s, OH-6); 13C NMR (100 MHz, CDCl3): δ 11.77,
19.27, 50.41, 55.71, 55.73, 56.02, 104.33, 111.32, 111.70,
113.26, 113.49, 113.71, 125.12, 125.37, 125.65, 147.14,
148.98, 150.44, 165.45, 167.94, 182.51 ppm; MS (CI): m/z
412.2 (MH+, 100). Anal. calcd for C24H29NO5: C, 70.05; H,
7.10; N, 3.40. Found: C, 69.86; H, 7.35; N, 3.12.
d, J = 8.8 Hz, H-2ʹ, 6ʹ); 13C NMR (125 MHz, CDCl3): δ
50.15, 53.62, 58.93, 69.87, 105.39, 111.28, 113.35, 113.92,
125.25, 128.95, 129.51, 131.22, 132.76, 148.12, 165.94,
167.58, 182.94 ppm; MS (CI): m/z 384.0 (MH+, 100). Anal.
calcd for C22H25NO5: C, 68.91; H, 6.57; N, 3.65. Found: C,
69.15; H, 6.39; N, 3.71.
(2Z)‑7‑{[Bis(2‑methoxyethyl)amino]methyl}‑6‑hydroxy‑2‑(4
‑methoxybenzylidene)‑1‑benzofuran‑3(2H)‑one (7b)
( 2 Z ) - 2 -( 1 , 3 -B e n z o d i oxo l - 5 - yl m ethyl e n e ) -
7-[(dipropylamino)methyl]-6-hydroxy-1-benzofuran-
3(2H)-one (6d). Yellow solid (72% yield); mp: 117–119 °C;
IR (KBr): νmax 2963, 2875, 1690, 1596, 1486, 1442, 1254,
Yellow solid (83% yield); mp: 109–111 °C; IR (KBr):
νmax 3421, 2935, 1687, 1601, 1512, 1400, 1255, 1132,
1
1
1188, 1110, 1040 cm−1; H NMR (400 MHz, CDCl3): δ
1038 cm−1; H NMR (400 MHz, DMSO-d6): δ 2.84 (4H,
0.94 (6H, t, 3J=7.4 Hz, N(CH2CH2CH3)2), 1.59 –1.76 (4H,
m, N(CH2CH2CH3)2), 2.59–2.70 (4H, m, N(CH2CH2CH3)2),
4.05 (2H, s, CH2-7), 6.04 (2H, s, OCH2O), 6.64 (1H,
t, 3J=5.3 Hz, N(CH2CH2OMe)2), 3.22 (6H, s, CH2OCH3),
3
3.51 (4H, t, J = 5.5 Hz, N(CH2CH2OMe)2), 3.82 (3H, s,
3
OMe-4ʹ), 4.10 (2H, s, CH2-7), 6.63 (1H, d, J = 8.4 Hz,
3
d, J = 8.5 Hz, H-5), 6.71 (1H, s, H-2a), 6.88 (1H, d,
H-5), 6.76 (1H, s, H-2a), 7.05 (2H, d, 3J=8.8 Hz, H-3′, 5′),
7.52 (1H, d, 3J=8.4 Hz, H-4), 7.91 ppm (2H, d, 3J=8.8 Hz,
H-2′, 6′); 13C NMR (100 MHz, DMSO-d6): δ 48.68, 52.56,
55.30, 57.99, 69.13, 106.22, 110.44, 112.22, 113.18, 114.49,
124.14, 124.62, 132.83, 146.19, 160.26, 165.12, 166.96,
3J = 8.1 Hz, H-7ʹ), 7.21–7.27 (1H, m, H-6ʹ), 7.45 (1H, d,
4J=1.7 Hz, H-4ʹ), 7.59 ppm (1H, d, 3J=8.4 Hz, H-4); 13
C
NMR (125 MHz, CDCl3): δ 11.86, 19.67, 50.76, 56.01,
101.63, 104.66, 108.97, 110.35, 111.47, 113.21, 113.90,
1 3

Chemical Papers
181.10 ppm; MS (CI): m/z 414.0 (MH+, 100). Anal. calcd
for C23H27NO6: C, 66.81; H, 6.58; N, 3.39. Found: C, 66.93;
H, 6.73; N, 3.53.
7.61 ppm (1H, d, J=8.5 Hz, H-4); 13C NMR (125 MHz,
3
CDCl3): δ 50.26, 53.64, 56.17, 58.95, 61.11, 69.69, 105.08,
108.61, 111.60, 113.46, 113.94, 125.37, 128.11, 139.68,
147.67, 153.34, 165.67, 167.25, 182.63 ppm; MS (CI): m/z
474.2 (MH+, 100). Anal. calcd for C25H31NO8: C, 63.41; H,
6.60; N, 2.96. Found: C, 63.30; H, 6.86; N, 3.11.
(2Z)‑7‑{[Bis(2‑methoxyethyl)amino]methyl}‑2‑(3,4‑dimetho
xybenzylidene)‑6‑hydroxy‑1‑benzofuran‑3(2H)‑one (7c)
Yellow solid (83% yield); mp: 80–82 °C; IR (KBr): νmax
(2Z)‑7‑{[Bis(2‑methoxyethyl)amino]methyl}‑6‑hydroxy‑2‑(2,
3,4‑trimethoxybenzylidene)‑1‑benzofuran‑3(2H)‑one (7f)
2835, 1687, 1593, 1519, 1322, 1261, 1123, 1021 cm−1;
3
1H NMR (400 MHz, CDCl3): δ 2.95 (4H, t, J = 5.2 Hz,
N(CH2CH2OMe)2), 3.32 (6H, s, CH2OCH3), 3.59 (4H, t,
3J = 5.2 Hz, N(CH2CH2OMe)2), 3.93, 3.96 (each 3H, 2 s,
OMe-3ʹ,4ʹ), 4.18 (2H, s, CH2-7), 6.69 (1H, d, 3J=8.4 Hz,
H-5), 6.74 (1H, s, H-2a), 6.93 (1H, d,3J = 8.4 Hz, H-5ʹ),
Yellow solid (79% yield); mp: 105–107 °C; IR (KBr): νmax
2943, 1691, 1605, 1594, 1303, 1130, 1091, 1041 cm−1;
3
1H NMR (400 MHz, CDCl3): δ 2.93 (4H, t, J = 5.2 Hz,
N(CH2CH2OMe)2), 3.35 (6H, s, CH2OCH3), 3.59 (4H, t,
3J = 5.2 Hz, N(CH2CH2OMe)2), 3.90, 3.94, 3.97 (each
3H, 3 s, OMe-2ʹ, 3ʹ, 4ʹ), 4.15 (2H, s, CH2-7), 6.66 (1H, d,
3J=8.4 Hz, H-5), 6.82 (1H, d, 3J=8.9 Hz, H-5ʹ), 7.20 (1H,
3
4
7.40 (1H, dd, J = 8.4 Hz, J = 2.0 Hz, H-6ʹ), 7.49 (1H, d,
4J=2.0 Hz, H-2ʹ), 7.59 ppm (1H, d, 3J=8.4 Hz, H-4); 13
C
NMR (125 MHz, CDCl3): δ 50.23, 53.67, 55.88, 56.07,
58.96, 69.80, 105.09, 111.35, 111.86, 113.60, 113.67,
113.81, 125.24, 125.47, 125.69, 147.12, 149.06, 150.53,
165.56, 167.08, 182.69 ppm; MS (CI): m/z 444.2 (MH+,
100). Anal. calcd for C24H29NO7: C, 65.00; H, 6.59; N, 3.16.
Found: C, 64.81; H, 6.82; N, 3.00.
3
s, H-2a), 7.61 (1H, d, J=8.4 Hz, H-4), 7.96 ppm (1H, d,
3J=8.9 Hz, H-6ʹ); 13C NMR (125 MHz, CDCl3): δ 50.24,
53.71, 56.15, 58.90, 60.97, 61.92, 70.01, 105.35, 105.58,
107.80, 113.59, 113.71, 119.84, 125.00, 126.67, 142.30,
147.74, 153.93, 155.15, 165.46, 167.08, 182.74 ppm; MS
(CI): m/z 474.2 (MH+, 100). Anal. calcd for C25H31NO8: C,
63.41; H, 6.60; N, 2.96. Found: C, 63.70; H, 6.36; N, 2.75.
(2Z)‑2‑(1,3‑Benzodioxol‑5‑ylmethylene)‑7‑{[bis(2‑methox‑
yethyl)amino]methyl}‑6‑hydroxy‑1‑benzofuran‑3(2H)‑one
(7d)
(2Z)‑2‑Benzylidene‑6‑hy‑
droxy‑7‑(piperidin‑1‑ylmethyl)‑1‑benzofuran‑3(2H)‑one
Yellow solid (77% yield); mp: 114–116 °C; IR (KBr):
(8a)
νmax 3421. 1645, 1614, 1564, 1450, 1402, 1257, 1107,
1
1036 cm−1; H NMR (400 MHz, CDCl3): δ 2.97 (4H, t,
Yellow solid (85% yield); mp: 187–189 °C; IR (KBr): νmax
3J = 5.3 Hz, N(CH2CH2OMe)2), 3.35 (6H, s, CH2OCH3),
2950, 1678, 1608, 1502, 1451, 1371, 1279, 1179, 1117,
3
1
3.60 (4H, t, J = 5.3 Hz, N(CH2CH2OMe)2), 4.19 (2H, s,
1066 cm−1; H NMR (400 MHz, CDCl3): δ 1.36–3.46
3
CH2-7), 6.03 (2H, s, OCH2O), 6.68 (1H, d, J = 8.5 Hz,
(10H, m, piperidine moiety), 4.06 (2H, s, CH2-7), 6.73 (1H,
3
3
H-5), 6.71 (1H, s, H-2a), 6.87 (1H, d, J = 8.0 Hz, H-7ʹ),
d, J = 8.5 Hz, H-5), 6.79 (1H, s, H-2a), 7.35–7.50 (3H,
3
4
3
7.25 (1H, dd, J = 8.0 Hz, J = 1.8 Hz, H-6ʹ), 7.48 (1H, d,
m, H-3ʹ, 4ʹ, 5ʹ), 7.62 (1H, d, J = 8.5, H-4), 7.82 (2H, d,
4J=1.8 Hz, H-4ʹ), 7.59 ppm (1H, d, 3J=8.5 Hz, H-4); 13
C
3J=8.5 Hz, H-2ʹ, 6ʹ), 10.08 ppm (1H, br. s, OH-6); 13C NMR
(100 MHz, CDCl3): δ 23.40, 25.35, 53.43, 53.87, 103.34,
111.49, 113.26, 113.97, 125.74, 129.05, 129.63, 131.21,
132.69, 148.05, 166.21, 168.01, 182.76 ppm; MS (CI): m/z
336.1 (MH+, 100). Anal. calcd for C21H21NO3: C, 75.20; H,
6.31; N, 4.18. Found: C, 75.03; H, 6.09; N, 4.34.
NMR (125 MHz, CDCl3): δ 50.32, 53.61, 58.97, 70.03,
101.63, 105.54, 108.93, 110.36, 111.58, 113.56, 113.83,
125.07, 127.08, 127.15, 147.12, 148.26, 148.93, 165.60,
167.42, 182.81 ppm; MS (CI): m/z 428.1 (MH+, 100). Anal.
calcd for C23H25NO7: C, 64.63; H, 5.90; N, 3.28. Found: C,
64.78; H, 5.67; N, 3.52.
(2Z)‑6‑Hydroxy‑2‑(4‑methoxybenzylidene)‑7‑(piperidin‑
1‑ylmethyl)‑1‑benzofuran‑3(2H)‑one (8b)
(2Z)‑7‑{[Bis(2‑methoxyethyl)amino]methyl}‑6‑hydroxy‑2‑(3,
4,5‑trimethoxybenzylidene)‑1‑benzofuran‑3(2H)‑one (7e)
Yellow solid (91% yield); mp: 125–126 °C; IR (KBr):
Yellow solid (88% yield); mp: 119–120 °C; IR (KBr):
νmax 2935, 1692, 1598, 1509, 14477, 1256, 1187, 1124,
νmax 2878, 1692, 1602, 1502, 1344, 1185, 1117 cm−1
;
1035 cm−1; H NMR (400 MHz, CDCl3): δ 1.24–1.95,
1
3
1H NMR (400 MHz, CDCl3): δ 2.91 (4H, t, J = 5.2 Hz,
N(CH2CH2OMe)2), 3.33 (6H, s, CH2OCH3), 3.58 (4H, t,
3J = 5.2 Hz, N(CH2CH2OMe)2), 3.92 (3H, s, OMe-4ʹ),
3.95 (6H, s, OMe-3ʹ, 5ʹ), 4.14 (2H, s, CH2-7), 6.67 (1H, d,
3J=8.5 Hz, H-5), 6.72 (1H, s, H-2a), 7.15 (2H, s, H-2ʹ, 6ʹ),
2.21–3.37 (6H, 4H, 2 m, piperidine moiety), 3.80 (3H, s,
OMe-4ʹ), 3.92 (2H, s, CH2-7), 6.57 (1H, d, 3J=8.5 Hz, H-5),
6.69 (1H, s, H-2a), 6.92 (2H, d, 3J=8.5 Hz, H-3′, 5′), 7.52
(1H, d, 3J=8.5 Hz, H-4), 7.72 (2H, d, 3J=8.8 Hz, H-2′, 6′),
11.51 ppm (1H, br. s, OH-6); 13C NMR (100 MHz, CDCl3):
1 3

Chemical Papers
3
4
δ 23.64, 25.66, 53.97, 54.16, 55.38, 103.94, 111.41, 113.27,
113.57, 114.48, 124.89, 125.32, 132.89, 146.95, 160.65,
165.52, 167.83, 182.60 ppm; MS (CI): m/z 366.0 (MH+,
100). Anal. calcd for C22H23NO4: C, 72.31; H, 6.34; N, 3.83.
Found: C, 72.39; H, 6.62; N, 3.59.
7.39 (1H, dd, J = 8.3 Hz, J = 1.9 Hz, H-6ʹ), 7.45 (1H, d,
4J=1.9 Hz, H-2ʹ), 7.60 ppm (1H, d, 3J=8.4 Hz, H-4); 13
C
NMR (125 MHz, CDCl3): δ 53.22, 53.76, 55.84, 56.07,
66.55, 103.40, 103.47, 111.41, 112.28, 113.52, 113.60,
114.02, 125.48, 125.52, 146.92, 149.06, 150.65, 165.58,
166.34, 182.56 ppm; MS (CI): m/z 398.0 (MH+, 100). Anal.
calcd for C22H23NO6: C, 66.49; H, 5.83; N, 3.52. Found: C,
66.21; H, 6.08; N, 3.30.
(2Z)‑2‑(3,4‑Dimethoxybenzylidene)‑6‑hy‑
droxy‑7‑(piperidin‑1‑ylmethyl)‑1‑benzofuran‑3(2H)‑one
(8c)
(2Z)‑2‑(1,3‑Benzodioxol‑5‑ylmethylene)‑6‑hy‑
droxy‑7‑(morpholin‑4‑ylmethyl)‑1‑benzofuran‑3(2H)‑one
(9d)
Yellow solid (82% yield); mp: 180–182 °C; IR (KBr): νmax
3446, 2937, 2677, 1676, 1616, 1512, 1458, 1269, 1144,
1
1022 cm−1; H NMR (400 MHz, CDCl3): δ 1.33– 3.46
(10H, m, piperidine moiety), 3.92 (2H, s, CH2-7), 3.95,
Yellow solid (59% yield); mp: 189–191 °C; IR (KBr): νmax
3419, 1668, 1599, 1502, 1442, 1254, 1119, 1038 cm−1;
1H NMR (400 MHz, DMSO-d6): δ 2.52–2.61 (4H, m,
N(CH2CH2)O), 3.57–3.65 (4H, m, N(CH2CH2)O), 3.78 (2H,
s, CH2-7), 6.10 (2H, s, OCH2O), 6.65–6.77 (2H, m, H-2a,
5), 7.03 (1H, d, 3J=8.1 Hz, H-7ʹ), 7.45 (1H, dd, 3J=8.1 Hz,
4J=1.7 Hz, H-6ʹ), 7.52 (1H, d, 3J=8.3 Hz, H-4), 7.58 ppm
3
3.98 (each 3H, 2 s, OMe-3ʹ,4ʹ), 6.63 (1H, d, J = 8.4 Hz,
3
H-5), 6.76 (1H, s, H-2a), 6.95 (1H, d, J = 8.4 Hz, H-5ʹ),
3
4
7.40 (1H, dd, J = 8.4 Hz, J = 2.0 Hz, H-6ʹ), 7.51 (1H, d,
4J=2.0 Hz, H-2ʹ), 7.59 ppm (1H, d, 3J=8.4 Hz, H-4); 13
C
NMR (100 MHz, DMSO-d6): δ 23.05, 24.85, 52.06, 53.05,
55.29, 55.54, 104.08, 110.17, 110.65, 111.80, 113.39,
114.05, 124.34, 124.92, 125.02, 146.54, 148.55, 149.99,
165.53, 169.26, 180.35 ppm; MS (CI): m/z 396.2 (MH+,
100). Anal. calcd for C23H25NO5: C, 69.86; H, 6.37; N, 3.54.
Found: C, 69.97; H, 6.51; N, 3.36.
4
(1H, d, J = 1.6 Hz, H-4ʹ); 13C NMR (100 MHz, DMSO-
d6): δ 50.80, 52.93, 66.04, 101.60, 106.36, 108.79, 109.79,
110.64, 112.44, 112.74, 124.31, 126.25, 126.95, 146.18,
147.75, 148.51, 165.49, 165.86, 181.24 ppm; MS (CI): m/z
382.3 (MH+, 100). Anal. calcd for C21H19NO6: C, 66.14; H,
5.02; N, 3.67. Found: C, 65.96; H, 5.21; N, 3.90.
(2Z)‑2‑(1,3‑Benzodioxol‑5‑ylmethylene)‑6‑hy‑
droxy‑7‑(piperidin‑1‑ylmethyl)‑1‑benzofuran‑3(2H)‑one
(8d)
(2Z)‑6‑Hydroxy‑7‑(morpholin‑4‑ylmethyl)‑2‑(3,4,5‑trimeth‑
oxybenzylidene)‑1‑benzofuran‑3(2H)‑one (9e)
Yellow solid (74% yield); mp: 163–165 °C; IR (KBr):
νmax 3406, 2949, 1678, 1595, 1448, 1331, 1250, 1132,
1038 cm−1; 1H NMR (400 MHz, CDCl3): δ 1.32– 3.56 (10H,
m, piperidine moiety), 3.95 (2H, s, CH2-7), 6.05 (2H, s,
OCH2O), 6.62 (1H, d, 3J=8.4 Hz, H-5), 6.72 (1H, s, H-2a),
Yellow solid (74% yield); mp: 197–199 °C; IR (KBr): νmax
2956, 2835, 1691, 1603, 1504, 1448, 1120 cm−1; 1H NMR
(400 MHz, CDCl3): δ 2.48–2.93 (4H, m, N(CH2CH2)O),
3.78–3.87 (4H, m, N(CH2CH2)O), 3.91 (3H, s, OMe-4ʹ),
3.94 (6H, s, OMe-3ʹ, 5ʹ), 3.99 (2H, s, CH2-7),6.63–6.78
(2H, m, H-2a, 5), 7.11 (2H, s, H-2ʹ, 6ʹ), 7.62 ppm (1H, d,
3J = 8.4 Hz, H-4); 13C NMR (100 MHz, CDCl3): δ 53.23,
53.53, 56.20, 61.15, 66.38, 103.26, 108.68, 112.14, 113.76,
113.91, 125.85, 127.90, 139.90, 147.46, 153.39, 165.81,
166.43, 182.53 ppm; MS (CI): m/z 428.2 (MH+, 100). Anal.
calcd for C23H25NO7: C, 64.63; H, 5.90; N, 3.28. Found: C,
64.37; H, 6.18; N, 3.50.
3
6.88 (1H, d, J = 8.1 Hz, H-7ʹ), 7.14–7.33 (1H, m, H-6ʹ),
7.46 (1H, d, 4J=1.7 Hz, H-4ʹ) 7.59 (1H, d, 3J=8.4 Hz, H-4),
10.08 ppm (1H, br. s, OH-6); 13C NMR (100 MHz, DMSO-
d6): δ 23.15, 25.00, 51.88, 53.08, 101.49, 104.46, 108.75,
109.21, 109.68, 109.74, 114.57, 124.19, 126.43, 126.57,
146.87, 147.69, 148.15, 165.91, 170.67, 180.02 ppm; MS
(CI): m/z 380.0 (MH+, 100). Anal. calcd for C22H21NO5: C,
69.65; H, 5.58; N, 3.69. Found: C, 69.74; H, 5.47; N, 3.88.
(2Z)‑2‑(3,4‑Dimethoxybenzylidene)‑6‑hy‑
droxy‑7‑(morpholin‑4‑ylmethyl)‑1‑benzofuran‑3(2H)‑one
(2Z)‑6‑Hydroxy‑2‑(4‑methoxybenzylidene)‑7‑[(4‑methyl‑
piperazin‑1‑yl)methyl]‑1‑benzofuran‑3(2H)‑one (10b)
(9c)
Yellow solid (80% yield); mp: 156–158 °C; IR (KBr):
Yellow solid (67% yield); mp: 179–181 °C; IR (KBr): νmax
2928, 2836, 1671, 1601,1435, 1264, 1133 cm−1; 1H NMR
(500 MHz, CDCl3): δ 2.55–2.88 (4H, m, N(CH2CH2)O),
3.74–3.86 (4H, m, N(CH2CH2)O), 3.93, 3.96 (each 3H, 2 s,
OMe-3ʹ,4ʹ), 3.97 (2H, s, CH2-7), 6.66 (1H, d, 3J=8.4 Hz,
H-5), 6.75 (1H, s, H-2a), 6.94 (1H, d,3J = 8.4 Hz, H-5ʹ),
νmax 2801, 1692, 1601, 1509, 1257, 1183, 1129, 1032,
1
813 cm−1; H NMR (400 MHz, CDCl3): δ 2.36 (3H, s,
Nʹ-CH3), 2.39–3.15 (8H, m, piperazine moiety), 3.85 (3H,
3
s, OMe-4ʹ), 3.98 (2H, s, CH2-7), 6.62 (1H, d, J=8.5 Hz,
3
H-5), 6.75 (1H, s, H-2a), 6.97 (2H, d, J = 8.9 Hz, H-3′,
5′), 7.58 (1H, d, 3J=8.5 Hz, H-4), 7.77 (2H, d, 3J=8.8 Hz,
1 3

Chemical Papers
H-2′, 6′), 10.25 ppm (1H, br. s, OH-6); 13C NMR (100 MHz,
CDCl3): δ 45.64, 52.40, 53.39, 54.64, 55.37, 103.93, 111.74,
113.33, 113.75, 114.49, 125.03, 125.18, 132.94, 146.77,
160.72, 165.40, 166.68, 182.62 ppm; MS (CI): m/z 381.2
(MH+, 100). Anal. calcd for C22H24N2O4: C, 69.46; H, 6.36;
N, 7.36. Found: C, 69.73; H, 6.55; N, 7.49.
54.67, 56.06, 61.10, 103.98, 108.54, 111.80, 113.59, 113.61,
125.33, 127.98, 139.69, 147.54, 153.30, 165.49, 166.87,
182.56 ppm; MS (CI): m/z 441.0 (MH+, 100). Anal. calcd
for C24H28N2O6: C, 65.44; H, 6.41; N, 6.36. Found: C,
65.15; H, 6.30; N, 6.15.
(2Z)‑6‑Hydroxy‑7‑[(4‑methylpiperazin‑1‑yl)methyl]‑2‑(2,3,4
‑trimethoxybenzylidene)‑1‑benzofuran‑3(2H)‑one (10f)
(2Z)‑2‑(3,4‑Dimethoxybenzylidene)‑6‑hydroxy‑7‑[(4‑meth‑
ylpiperazin‑1‑yl)methyl]‑1‑benzofuran‑3(2H)‑one (10c)
Yellow solid (81% yield); mp: 188–190 °C; IR (KBr): νmax
3425, 1635, 1608, 1556, 1456, 1402, 1279, 1093 cm−1;
1H NMR (400 MHz, DMSO-d6): δ 2.17 (3H, s, Nʹ-CH3),
2.27–2.44 (4H, m) and 2.55–2.72 (4H, m, piperazine moi-
ety), 3.78 (3H, s) and 3.88 (8H, s, OMe-2ʹ, 3ʹ, 4ʹ, CH2-7),
Yellow solid (86% yield); mp: 173–175 °C; IR (KBr): νmax
3423, 2941, 2692, 1662, 1595, 1514, 1452, 1334, 1263,
1
1128 cm−1; H NMR (400 MHz, CDCl3): δ 2.09–3.47
(11H, m, piperazine moiety), 3.95 (3H, s) and 3.97 (5H,
3
m, CH2-7, OMe-3ʹ,4ʹ,), 6.65 (1H, d, 3J=8.4 Hz, H-5), 6.78
6.65 (1H, d, J = 8.6 Hz, H-5), 6.88 (1H, s, H-2a), 7.01
3
3
3
(1H, s, H-2a), 6.95 (1H, d, J = 8.5 Hz, H-5ʹ), 7.38 (1H,
(1H, d, J = 8.9 Hz, H-5ʹ), 7.52 (1H, d, J = 8.6 Hz, H-4),
7.97 ppm (1H, d, 3J=8.9 Hz, H-6ʹ); 13C NMR (100 MHz,
DMSO-d6): δ 45.43, 50.87, 51.99, 54.34, 56.01, 60.42,
61.62, 103.62, 105.67, 108.62, 111.90, 113.19, 118.36,
124.31, 126.16, 141.57, 146.90, 152.80, 154.88, 165.53,
166.80, 180.97 ppm; MS (CI): m/z 441.2 (MH+, 100). Anal.
calcd for C24H28N2O6: C, 65.44; H, 6.41; N, 6.36. Found: C,
65.21; H, 6.67; N, 6.48.
dd, 3J=8.5 Hz, 4J=1,7 Hz, H-6ʹ), 7.55 (1H, d, 4J=1.7 Hz,
3
H-2ʹ), 7.62 ppm (1H, d, J = 8.4 Hz, H-4); 13C NMR
(100 MHz, DMSO-d6): δ 45.53, 50.86, 52.23, 54.35, 55.34,
55.58, 105.74, 110.79, 111.83, 111.92, 113.24, 113.37,
124.35, 124.81, 125.32, 146.26, 148.58, 150.16, 165.57,
166.78, 180.95 ppm; MS (CI): m/z 411.1 (MH+, 100). Anal.
calcd for C23H26N2O5: C, 67.30; H, 6.38; N, 6.82. Found: C,
67.53; H, 6.54; N, 6.65.
(2Z)‑6‑Hydroxy‑7‑{[4‑(2‑hydroxyethyl)piperazin‑1‑yl]methyl
}‑2‑(4‑methoxybenzylidene)‑1‑benzofuran‑3(2H)‑one (11b)
(2Z)‑2‑(1,3‑Benzodioxol‑5‑ylmethylene)‑6‑hy‑
droxy‑7‑[(4‑methylpiperazin‑1‑yl)methyl]‑1‑benzo‑
furan‑3(2H)‑one (10d)
Yellow solid (58% yield); mp: 179–181 °C; IR (KBr):
νmax 3410, 2958, 1668, 1605, 1510, 1443, 1254, 1132,
1028 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 2.40 (2H, t,
3J=6.1 Hz, NʹCH2CH2OH), 2.52–2.69 (8H, m, CH2-2ʹʹ,3ʹʹ,
5ʹʹ,6ʹʹ), 3.49 (2H, t, 3J=6.1 Hz, NʹCH2CH2OH), 3.83 (3H,
Yellow solid (69% yield); mp: 190–912 °C; IR (KBr): νmax
3410, 2937, 1689, 1603, 1500, 1446, 1342, 1257, 1188,
1036 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 2.17 (3H, s,
Nʹ-CH3), 2.25–2.48 (4H, m) and 2.52–2.78 (4 H, m, pipera-
zine ring), 3.84 (2H, s, CH2-7), 6.11 (2H, s, OCH2O), 6.65
(1H, d, 3J=8.5 Hz, H-5), 6.72 (1H, s, H-2a), 7.03 (1H, d,
3
s, OMe-4ʹ), 3.91 (2H, s, CH2-7), 6.65 (1H, d, J=8.4 Hz,
H-5), 6.75 (1H, s, H-2a), 7.07 (2H, d, 3J=8.7 Hz, H-3ʹ, 5ʹ),
7.51 (1H, d, 3J=8.4 Hz, H-4), 7.92 ppm (2H, d, 3J=8.7 Hz,
H-2ʹ, 6ʹ); 13C NMR (100 MHz, DMSO-d6): δ 50.97, 52.14,
52.84, 55.33, 58.44, 59.96, 105.57, 110.26, 111.82, 113.27,
114.55, 124.25, 124.70, 132.83, 146.27, 160.22, 165.59,
167.09, 180.96 ppm; MS (CI): m/z 411.0 (MH+, 100). Anal.
calcd for C23H26N2O5: C, 67.30; H, 6.38; N, 6.82. Found: C,
67.51; H, 6.24; N, 6.66.
3J=8.1 Hz, H-7ʹ), 7.38–7.61 ppm (3H, m, H-4, 4ʹ 6ʹ); 13
C
NMR (100 MHz, DMSO-d6): δ 45.49, 50.77, 52.16, 54.36,
101.58, 105.96, 108.83, 109.81, 110.27, 111.67, 113.34,
124.25, 126.33, 126.84, 146.37, 147.74, 148.43, 165.75,
167.10, 180.90 ppm; MS (CI): m/z 395.1 (MH+, 100). Anal.
calcd for C22H22N2O5: C, 66.99; H, 5.62; N, 7.10. Found: C,
66.84; H, 5.83; N, 6.92.
(2Z)‑2‑(3,4‑Dimethoxybenzylidene)‑6‑hydroxy‑7‑{[4‑(2‑hy‑
droxyethyl)piperazin‑1‑yl]methyl}‑1‑benzofuran‑3(2H)‑one
(11c)
(2Z)‑6‑Hydroxy‑7‑[(4‑methylpiperazin‑1‑yl)methyl]‑2‑(3,4,5
‑trimethoxybenzylidene)‑1‑benzofuran‑3(2H)‑one (10e)
Yellow solid (82% yield); mp: 201–203 °C; IR (KBr): νmax
2936, 2810, 1692, 1603, 1422, 1262, 1124, 1048 cm−1; 1H
NMR (400 MHz, CDCl3): δ 2.02–3.31 (11H, m, piperazine
moiety), 3.91 (3H, s, OMe-4ʹ), 3.93 (6H, s, OMe-3ʹ, 5ʹ), 3.94
(2H, s, CH2-7), 6.66 (1H, d, 3J=8.5 Hz, H-5), 6.73 (1H, s,
H-2a), 7.14 (2H, s, H-2ʹ, 6ʹ), 7.62 ppm (1H, d, 3J=8.5 Hz,
H-4); 13C NMR (125 MHz, CDCl3): δ 45.80, 52.95, 53.54,
Yellow solid (63% yield); mp: 180–182 °C; IR (KBr):
νmax 2947, 1682, 1600, 1513, 1298, 1270, 1139, 1123,
1
1039 cm−1; H NMR (400 MHz, CDCl3): δ 2.08–3.36
(10H, m, NʹCH2CH2OH and piperazine ring), 3.65 (2H,
3
t, J = 5.4 Hz, NʹCH2CH2OH), 3.95, 3.98 (each 3H, 2 s,
OMe-3ʹ,4ʹ), 3.97 (2H, s, CH2-7), 6.65 (1H, d, 3J=8.4 Hz,
H-5), 6.78 (1H, s, H-2a), 6.95 (1H, d,3J = 8.4 Hz, H-5ʹ),
1 3

Chemical Papers
3
4
7.41 (1H, dd, J = 8.4 Hz, J = 2.0 Hz, H-6ʹ), 7.50 (1H, d,
[(2Z)‑6‑(Acetyloxy)‑2‑benzylidene‑3‑oxo‑2,3‑dihy‑
dro‑1‑benzofuran‑7‑yl]methyl acetate (12a)
4J=2.0 Hz, H-2ʹ), 7.62 ppm (1H, d, 3J=8.4 Hz, H-4); 13
C
NMR (125 MHz, CDCl3): δ 52.68, 52.87, 53.56, 55.88,
56.10, 57.93, 59.33, 103.93, 111.43, 112.19, 113.52, 113.63,
113.92, 125.31, 125.54, 125.56, 147.02, 149.08, 150.64,
165.45, 166.66, 182.66 ppm; MS (CI): m/z 441.1 (MH+,
100). Anal. calcd for C24H28N2O6: C, 65.44; H, 6.41; N,
6.36. Found: C, 65.72; H, 6.70; N, 6.09.
Yellow solid (93% yield); mp: 145–147 °C; IR (KBr): νmax
1770, 1738, 1706, 1605, 1434, 1255, 1188, 1129 cm−1;; 1H
NMR (500 MHz, CDCl3): δ 2.09 (3H, s, CH3COO-6), 2.39
(3H, s, CH3COOCH2-7), 5.36 (2H, s, CH2-7), 6.93 (1H, s,
3
H-2a), 7.00 (1H, d, J = 8.3 Hz, H-5), 7.39–7.51 (3H, m,
H-3ʹ, 4ʹ, 5ʹ), 7.82 (1H, d, 3J = 8.4 Hz, H-4), 7.91 ppm (2H,
3
(2Z)‑2‑(1,3‑Benzodioxol‑5‑ylmethylene)‑6‑hy‑
droxy‑7‑{[4‑(2‑hydroxyethyl)piperazin‑1‑yl]methyl}‑1‑ben‑
zofuran‑3(2H)‑one (11d)
d, J = 8.3 Hz, H-2ʹ, 6ʹ); 13C NMR (125 MHz, CDCl3):
δ 20.81, 20.94, 54.73, 114.02, 114.44, 118.87, 119.77,
125.70, 129.16, 130.34, 131.80, 132.15, 147.22, 156.25,
165.79, 168.60, 170.63, 183.39 ppm; MS (CI): m/z 353.0
(MH+, 100). Anal. calcd for C20H16O6: C, 68.18; H, 4.58.
Found: C, 68.33; H, 4.45.
Yellow solid (55% yield); mp: 162–164 °C; IR (KBr):
νmax 2944, 1690, 1608, 1499, 1451, 1291, 1262, 1115,
1
1042 cm−1; H NMR (400 MHz, CDCl3): δ 2.47–2.91
(10H, m, NʹCH2CH2OH and piperazine ring), 3.64 (2H,
3
t, J = 5.3 Hz, NʹCH2CH2OH), 3.96 (2H, s, CH2-7), 6.01
[(2Z)‑6‑(Acetyloxy)‑2‑(4‑methoxybenzylidene)‑3‑oxo‑2,
3‑dihydro‑1‑benzofuran‑7‑yl]methyl acetate (12b)
(2H, s, OCH2O), 6.60 (1H, d, 3J=8.3 Hz, H-5), 6.68 (1H,
3
s, H-2a), 6.84 (1H, d, J = 8.0 Hz, H-7ʹ), 7.19–7.27 (1H,
m, H-6ʹ), 7.40 (1H, d, 4J=1.6 Hz, H-4ʹ), 7.56 ppm (1H, d,
3J = 8.3 Hz, H-4); 13C NMR (100 MHz, CDCl3): δ 52.65,
52.69, 53.51, 57.90, 59.28, 101.64, 104.04, 108.93, 110.32,
111.93, 113.55, 113.75, 125.21, 126.83, 127.20, 146.88,
148.23, 149.02, 165.48, 166.87, 182.66 ppm; MS (CI): m/z
425.2 (MH+, 100). Anal. calcd for C23H24N2O6: C, 65.08; H,
5.70; N, 6.60. Found: C, 65.29; H, 5.93; N, 6.88.
Yellow solid (81% yield); mp: 135–137 °C; IR (KBr): νmax
2936, 2840, 1771, 1735, 1650, 1601, 1512, 1431, 1256,
1
1195, 1134 cm−1; H NMR (400 MHz, CDCl3) δ 2.09
(3H, s, CH3COO-6), 2.39 (3H, s, CH3COOCH2-7), 3.88
(3H, s, OMe-4ʹ), 5.36 (2H, s, CH2-7), 6.92 (1H, s, H-2a),
3
6.96–7.03 (3H, m, H-5, 3′, 5′), 7.82 (1H, d, J = 8.3 Hz,
3
H-4), 7.88 ppm (2H, d, J = 8.8 Hz, H-2′, 6′); 13C NMR
(100 MHz, CDCl3): δ 20.77, 20.87, 54.61, 55.45,
114.10, 114.27, 114.67, 118.51, 119.97, 124.71, 125.49,
133.63, 146.07, 155.81, 161.35, 165.26, 168.60, 170.58,
183.02 ppm; MS (CI): m/z 383.2 (MH+, 100). Anal. calcd
for C21H18O7: C, 65.97; H, 4.75. Found: C, 66.11; H, 5.03.
(2Z)‑6‑Hydroxy‑7‑{[4‑(2‑hydroxyethyl)piperazin‑1‑yl]methyl
}‑2‑(3,4,5‑trimethoxybenzylidene)‑1‑benzofuran‑3(2H)‑one
(11e)
Yellow solid (68% yield); mp: 187–189 °C; IR (KBr):
νmax 2939, 2820, 1688, 1602, 1451, 1309, 1262, 1133,
1
1120 cm−1; H NMR (400 MHz, CDCl3): δ 2.39–3.08
[(2Z)‑6‑(Acetyloxy)‑2‑(3,4‑dimethoxybenzylidene)‑3‑oxo‑2,
3‑dihydro‑1‑benzofuran‑7‑yl]methyl acetate (12c)
(10H, m, NʹCH2CH2OH and piperazine ring), 3.66 (2H,
t, 3J=5.4 Hz, NʹCH2CH2OH), 3.93 (3H, s, OMe-4ʹ), 3.95
(8H, s, CH2-7, OMe-3ʹ, 5ʹ), 6.67 (1H, d, 3J=8.5 Hz, H-5),
6.74 (1H, s, H-2a), 7.15 (2H, s, H-2ʹ, 6ʹ), 7.63 ppm (1H, d,
3J = 8.5 Hz, H-4); 13C NMR (100 MHz, CDCl3): δ 52.59,
53.06, 53.50, 56.12, 58.03, 59.29, 61.10, 103.93, 108.59,
108.67, 111.85, 113.62, 125.35, 127.97, 139.72, 147.53,
153.31, 165.50, 166.85, 182.57 ppm; MS (CI): m/z 471.2
(MH+, 100). Anal. calcd for C25H30N2O7: C, 63.82; H, 6.43;
N, 5.95. Found: C, 64.10; H, 6.71; N, 6.13.
Yellow solid (91% yield); mp: 190–192 °C; IR (KBr): νmax
2963, 2845, 1772, 1736, 1647, 1595, 1514, 1259, 1184,
1
1127, 1065, 1021 cm−1; H NMR (400 MHz, CDCl3): δ
2.06 (3H, s, CH3COO-6), 2.38 (3H, s, CH3COOCH2-7),
3.94, 3.96 (each 3H, 2 s, OMe-3ʹ, 4ʹ), 5.32 (2H, s, CH2-7),
3
6.89 (1H, s, H-2a), 6.94 (1H, d, J = 8.3 Hz, H-5), 6.98
(1H, d,3J = 8.4 Hz, H-5ʹ), 7.35–7.47 (1H, m, H-6ʹ), 7.62
4
3
(1H, d, J = 2.0 Hz, H-2ʹ), 7.81 ppm (1H, d, J = 8.3 Hz,
H-4); 13C NMR (125 MHz, CDCl3): δ 20.81, 20.97, 54.68,
55.92, 56.10, 111.32, 113.56, 114.06, 114.68, 118.74,
120.00, 125.08, 125.70, 126.52, 146.22, 149.29, 151.26,
156.07, 165.25, 168.72, 170.59, 183.00 ppm; MS (CI): m/z
413.2 (MH+, 100). Anal. calcd for C22H20O8: C, 64.08; H,
4.89. Found: C, 63.92; H, 4.60.
General procedure for the synthesis of diacetates 12
A mixture of a Mannich base 3a–3d (2 mmol) and 200 mg
(2 mmol) of potassium acetate in 5 mL of acetic anhydride
was refuxed for 5 min and cooled to room temperature. The
mixture was diluted with water to aford a precipitate of
12a–12d, that was recrystallized from acetonitrile–water.
1 3

Chemical Papers
[(2Z)‑6‑(Acetyloxy)‑2‑(1,3‑benzodi‑
oxol‑5‑ylmethylene)‑3‑oxo‑2,3‑dihydro‑1‑benzofuran‑7‑yl]
methyl acetate (12d)
DMSO-d6): δ 55.37, 57.62, 61.62, 108.27, 110.86, 112.44,
112.78, 114.67, 124.66, 125.28, 132.99, 146.16, 160.49,
164.54, 166.50, 181.49 ppm; MS (CI): m/z 313.2 (MH+,
100). Anal. calcd for C18H16O5: C, 69.22; H, 5.16. Found:
C, C, 69.48; H, 5.41.
Yellow solid (88% yield); mp: 170–172 °C; IR (KBr): νmax
1765, 1737, 1704, 1649, 1611, 1257, 1200, 1031 cm−1; 1H
NMR (400 MHz, CDCl3): δ 2.09 (3H, s, CH3COO-6), 2.39
(3H, s, CH3COOCH2-7), 5.35 (2H, s, CH2-7), 6.05 (2H, s,
OCH2O), 6.86 (1H, s, H-2a), 6.89 (1H, d, 3J=8.3 Hz, H-5),
(2Z)‑2‑(3,4‑Dimethoxybenzylidene)‑6‑hy‑
droxy‑7‑(methoxymethyl)‑1‑benzofuran‑3(2H)‑one (13c).
3
6.99 (1H, d, J = 8.3 Hz, H-7ʹ), 7.29–7.35 (1H, m, H-6ʹ),
Yellow solid (69% yield); mp: 225–227 °C; IR (KBr):
7.58 (1H, d, 4J=1.6 Hz, H-4ʹ), 7.81 ppm (1H, d, 3J=8.3 Hz,
H-4); 13C NMR (125 MHz, CDCl3): δ 20.87, 20.99, 54.71,
101.85, 109.03, 110.75, 114.34, 114.46, 118.74, 119.98,
125.61, 126.42, 128.12, 146.20, 148.51, 149.74, 155.95,
165.36, 168.74, 183.12 ppm; MS (CI): m/z 397.0 (MH+,
100). Anal. calcd for C21H16O8: C, 63.64; H, 4.07. Found:
C, 63.87; H, 4.22.
νmax 2917, 1664, 1605, 1581, 1515, 1303, 1303, 1274,
1
1136 cm−1; H NMR (500 MHz, DMSO-d6): δ 3.30 (3H,
s, CH3OCH2-7), 3.82, 3.86 (each 3H, 2 s, OMe-3ʹ,4ʹ),
4.57 (2H, s, CH2-7), 6.77 (1H, s, H-2a), 6.80 (1H, d,
3J=8.4 Hz, H-5), 7.07 (1H, d,3J=8.4 Hz, H-5ʹ), 7.48 (1H,
dd, 3J=8.3 Hz, 4J=1.9 Hz, H-6ʹ), 7.58 (1H, d, 3J=8.4 Hz,
H-4), 7.69 (1H, d, 4J=1.9 Hz, H-2ʹ), 11.24 ppm (1H, br. s,
OH-6); 13C NMR (125 MHz, DMSO-d6): δ 55.21, 55.56,
57.54, 61.72, 108.20, 111.28, 111.84, 112.42, 112.80,
113.32, 124.80, 125.25, 125.57, 146.15, 148.70, 150.37,
164.52, 166.42, 181.40 ppm; MS (CI): m/z 343.2 (MH+,
100). Anal. calcd for C19H18O6: C, 66.66; H, 5.30. Found:
C, 66.90; H, 5.48.
General procedure for the synthesis of 7‑methoxyme‑
thyl‑6‑hydroxyaurones 13a–13d
A mixture of diacetate 12a–12d (2 mmol) and 0.1 mL of
concentrated hydrochloric acid in 10 mL of methanol was
refuxed for 16–24 h. The mixture was cooled and diluted
with water, and the resulting precipitate was collected by
fltration. The products were purifed by chromatography
using 1:20 methanol-dichloromethane.
(2Z)‑2‑(1,3‑Benzodioxol‑5‑ylmethylene)‑6‑hy‑
droxy‑7‑(methoxymethyl)‑1‑benzofuran‑3(2H)‑one (13d)
Yellow solid (54% yield); mp: 310–311 °C; IR (KBr): νmax
2900, 1671, 1603, 1442, 1295, 1258, 1147, 1033 cm−1; 1H
NMR (400 MHz, DMSO-d6): δ 3.32 (3H, s, CH3OCH2-7),
4.56 (2H, s, CH2-7), 6.11 (2H, s, OCH2O), 6.76 (1H, s, H-2a),
(2Z)‑2‑Benzylidene‑6‑hydroxy‑7‑(methoxymethyl)‑1‑ben‑
zofuran‑3(2H)‑one (13a)
3
3
Yellow solid (43% yield); mp: 332–333 °C; IR (KBr): νmax
2893, 1677, 1583, 1442, 1305, 1284, 1135, 1061 cm−1; 1H
NMR (400 MHz, DMSO-d6): δ 3.34 (3H, s, CH3OCH2-7),
4.59 (2H, s, CH2-7), 6.76–6.86 (2H, m, H-2a, 5), 7.41–7.55
6.79 (1H, d, J = 8.5 Hz, H-5), 7.04 (1H, d, J = 8.1 Hz,
H-7ʹ), 7.43–7.50 (1H, m, H-6ʹ), 7.53–7.61 (2H, m, H-4, 4ʹ),
11.26 ppm (1H, br. s, OH-6); 13C NMR (100 MHz, DMSO-
d6): δ 57.66, 61.77, 101.68, 108.28, 108.93, 109.87, 110.92,
112.48, 112.71, 125.27, 126.29, 127.10, 146.22, 147.87,
148.69, 164.50, 166.49, 181.43 ppm; MS (CI): m/z 327.0
(MH+, 100). Anal. calcd for C18H14O6: C, 66.26; H, 4.32.
Found: C, 66.03; H, 4.58.
3
(3H, m, H-3ʹ, 4ʹ, 5ʹ), 7.61 (1H, d, J = 8.5 Hz, H-4),
7.95–8.01 (2H, d, 3J=8.8 Hz, H-2ʹ, 6ʹ), 11.34 ppm (1H, br.
s, OH-6); 13C NMR (100 MHz, DMSO-d6): δ 57.63, 61.60,
108.36, 110.43, 112.47, 112.61, 125.49, 129.02, 129.68,
131.08, 132.17, 147.37, 164.88, 166.86, 181.70 ppm; MS
(CI): m/z 251.0 (MH+-32, 100). Anal. calcd for C17H14O4:
C, 72.33; H, 5.00. Found: C, 72.46; H, 5.19.
Cell proliferation assay
Prostate cancer PC-3 cells (American Type Culture Col-
lection, Manassas, VA 20110 USA) were cultured in
DMEM/F-12 HAM Mixture (Sigma D8437) containing
10% Fetal Bovine Serum (Atlanta Biological S11150).
Cells (3.5 × 104 cells per well) were split into 12-well plates.
After 24 h, 10 mM of each compound were added to each
well. DMSO was used as a control. Each experiment was
done in triplicate. Cell viability and number were analyzed
using the Vi-Cell XR Cell Viability Analyzer (Beckman
Coulter). Compounds were tested in triplicate at concentra-
tions of 100, 300 nM, 1, 3 and 10 µM, and IC50 values were
(2Z)‑6‑Hydroxy‑2‑(4‑methoxybenzylidene)‑7‑(methoxymet
hyl)‑1‑benzofuran‑3(2H)‑one (13b)
Yellow solid (53% yield); mp: 185–187 cels; IR (KBr):
νmax 3097, 2926, 1674, 1600, 1446, 1287, 1263, 1137,
1
1064 cm−1; H NMR (400 MHz, DMSO-d6): δ 3.33 (3H,
s, CH3OCH2-7), 3.83 (3H, s, OMe-4ʹ), 4.59 (2H, s, CH2-7),
6.76–6.84 (2H, m, H-2a, 5), 7.09 (2H, d, 3J=8.5 Hz, H-3′,
5′), 7.59 (1H, d, 3J=8.4 Hz, H-4), 7.94 (2H, d, 3J=8.5 Hz,
H-2′, 6′), 11.25 ppm (1H, br. s, OH-6); 13C NMR (100 MHz,
1 3

Chemical Papers
Cimarelli C, Fratoni D, Mazzanti A, Palmieri G (2011) Eur J Org Chem
2011:2094–2100
calculated using GraphPad Prism6 (GraphPad Software, La
Jolla, CA, 92037, USA)
Frasinyuk MS, Bondarenko SP, Khilya VP, Liu C, Watt DS, Sviripa
VM (2015) Org Biomol Chem 13:1053–1067
Acknowledgments CL and DSW were supported by NCI CA172379.
CL and DSW have partial ownership of a new-start company, Epionc,
Inc., that seeks to develop these compounds as commercial agents. CL
and DSW disclosed this information and complied with requirements
to mitigate any potential conficts of interest in accord with University
of Kentucky policy. DSW was also supported by the Ofce of the Dean
of the College of Medicine, by the Center for Pharmaceutical Research
and Innovation in the College of Pharmacy, and by NIH Grant Number
P30 GM110787 from the National Institute of General Medical Sci-
ences to L. Hersh, PI. Its contents are solely the responsibility of the
authors and do not necessarily represent the ofcial views of the NIH
or the NIGMS. DSW was also supported by the Ofce of the Assistant
Secretary of Defense for Health Afairs, through the Prostate Cancer
Research Program (PCRP) under Award No. W81XWH-16-1-0635.
Opinions, interpretations, conclusions and recommendations are those
of the authors and are not necessarily endorsed by the Department of
Defense. JLM and MVF were supported by NCI R21 CA205108, PCRP
W81XWH-16-1-0633, and NCI P30 CA016056.
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