A short synthesis of 7-amino alkoxy homoisoflavonoides

Article abstract of DOI:10.1039/c7ra08990b

The synthesis of novel derivatives of homoisoflavonoids as potentially interesting medicinally important heterocycles in an efficient catalytic two step route is introduced. In the first step, 7-aminoalkoxychromane-4-ones are synthesized via reaction between 7-hydroxychroman-4-one and aminoethylchlorides in the presence of potassium carbonate as a Br?nsted base catalyst. In the next step, obtained 7-aminoalkoxychromane-4-ones are reacted with a wide range of arylaldehydes in the presence of hydrochloric acid as Br?nsted acid catalyst to obtain homoisoflavonoids. Target products are medicinally very important heterocycles, because their analogs show cytotoxic activities towards human cancer cell lines.

Full text of DOI:10.1039/c7ra08990b

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A short synthesis of 7-amino alkoxy
homoisoflavonoides†
Cite this: RSC Adv., 2017, 7, 44680
ab
a
Ali Asadipour,a Yaghoub Pourshojaei,
Khalil Eskandari
*
*
and Alireza Foroumadic
The synthesis of novel derivatives of homoisoflavonoids as potentially interesting medicinally important
heterocycles in an efficient catalytic two step route is introduced. In the first step, 7-
aminoalkoxychromane-4-ones are synthesized via reaction between 7-hydroxychroman-4-one and
aminoethylchlorides in the presence of potassium carbonate as a Brønsted base catalyst. In the next
step, obtained 7-aminoalkoxychromane-4-ones are reacted with a wide range of arylaldehydes in the
presence of hydrochloric acid as Brønsted acid catalyst to obtain homoisoflavonoids. Target products
are medicinally very important heterocycles, because their analogs show cytotoxic activities towards
human cancer cell lines.
Received 14th August 2017
Accepted 13th September 2017
DOI: 10.1039/c7ra08990b
rsc.li/rsc-advances
is another homoisoavonoid type compounds which exhibits
antioxidant activity (Fig. 2).17
Introduction
Considering above and existence the great interest in
synthesis of important pharmacological active heterocycles,18
the synthesis of homoisoavonoids has also attracted the
interest of chemists and pharmaceutics.
Nowadays, there are numerous successful attempts to the
laboratory synthesis of these kinds of compounds. In general,
there are two protocols for the synthesis of these compounds. In
the rst approach, homoisoavonoids are obtained from
condensation reaction between 4-chromanones and arylalde-
hydes in methanol as solvent and by passing HCl gas as
Brønsted acid catalyst or by using piperidine as a Brønsted base
Homoisoavonoids are a class of avonoid-type natural prod-
ucts which have been isolated from numerous plants,1 notably
in the Hyacinthaceae family.2 Their chemical structures consist
of two aromatic carbocycles (phenyl) and one non-aromatic
heterocycle (dihydropyran-4-one). The homoisoavonoids can
be divided into ve categories: the 3-benzyl-4-chromanones (A),
the 3-hydroxy-3-benzyl-4-chromanones (B), the 3-benzyl-chrom-
2-en-4-ones (C), the scillascillins (D), and the 3-benzylidene-4-
chromanones (E or Z) (E) (Fig. 1).3
To date, a wide range of biological behaviors of homoiso-
avonoids, their synthesis and biosynthesis have been studied
and reported in the literature.1,4 These types of compounds have
shown many biological activities such as antiangiogenic,5 anti-
fungal,6 hypocholesterolemic,7 antimutagenic,8 anti-inamma-
tory,9 and antiviral activities.10,11
Among natural products containing homoisoavonoid
scaffold, Bonducellin (isolated from Caesalpinia bonducella and
Caesalpinia pulcherrima)12 acts as inhibitor of multidrug resis-
tance efflux pump.13 Also, isobonducellin, (the Z-isomer of
Bonducellin), and 8-methoxybonducellin (isolated from C. pul-
cherrima)14,15 have been shown anti-oxidant activity.16 In addi-
tion, Sappanone A (isolated from the heartwood of Caesalpinia)
aDepartment of Medicinal Chemistry, Faculty of Pharmacy & Pharmaceutics Research
Center, Institute of Neuropharmacology, Kerman University of Medical Sciences,
Kerman, Iran. E-mail: y.pourshoja@kmu.ac.ir; khalileskandari@yahoo.com
bNeuroscience Research Center, Institute of Neuropharmacology, Kerman University of
Medical Sciences, Kerman, Iran
cDrug Design and Development Research Center, Tehran University of Medical
Sciences, Tehran, Iran
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra08990b
Fig. 1 Chemical structure classification of homoisoflavonoids.
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Results and discussion
Following to our continuous attempts to develop the new and
green strategies for the synthesis of newly prepared organic
compounds23 especially new chemical intermediates and
heterocycles,24,25 and also alternative multi-steps routes to the
synthesis of medicinally important and biological active
heterocycles,26 in this study, our attention, is turned towards the
synthesis of new homoisoavonoid derivatives. For this
purpose, we rst had to prepare 7-hydroxychroman-4-one 4 via
a two-step reported method17 including the Friedel–Cras
acylation and then intramolecular cyclization (Scheme 1). As
can be seen from Scheme 1, at rst, 20,40-dihydroxy-3-chloro
propiophenone
3 is synthesized from acylation reaction
between resorcinol (1) and 3-chloropropionic acid (2), in the
presence of CF3SO3H as catalyst. Then, 20,40-dihydroxy-3-chloro
propiophenone 3 in the presence of NaOH, undergoes intra-
molecular cyclization to obtain 7-hydroxychroman-4-one 4.
In the next step, 7-hydroxychroman-4-one 4 via a reaction
which is well-known as Williamson ether synthesis is reacted
Fig. 2 Some selected homoisoflavonoids having pharmacological
activity.
with appropriate aminoethylchlorides
5
to obtain 7-
aminoalkoxychroman-4-ones 6. The role of KI in this reaction is
activation of aminoethylchloride to nucleophilic attack. Also
K2CO3 has been used as Brønsted catalyst to activation of
phenolic OH. Aer preparation, purication, and characteriza-
tion of 7-aminoalkoxychroman-4-ones 6, they are employed in
the reaction with a wide range of arylaldehydes 7 containing
both electron donor and electron withdrawing groups via
Knoevenagel condensation reaction to give novel homoiso-
avonoid derivatives 8 (Scheme 2). The role of HCl in this
reaction is inevitable and acts as Brønsted acid catalyst to
Scheme 1 Alternative two steps route to the synthesis of 7-hydrox-
ychroman-4-one.
catalyst19,20 followed by isomerisation of the double bond in the activation of both 7-aminoalkoxychroman-4-ones and aryl
ꢀ
presence of Pd/C at 250 C. In second ones homoisoavonoids aldehydes to condense together.
are obtained by hydrogenation of chalcones followed by one
By this achievement, a broad range of novel homoiso-
carbon extension by the use of ethyl formate/sodium21 or avonoids as important potentially interesting biological active
methanesulfonyl chloride/DMF.22 Based on all the above, products were synthesized and the scope of these compounds
herein, we wish to report an efficient route to the synthesis of were developed (Table 1).
a wide range of novel homoisoavonoids by rely on rst
It was clearly observed that the process can tolerate both
mentioned protocol. By this achievement the scope of homo- electron-withdrawing and electron-donating groups on the
isoavonoids as medicinally important molecules was phenyl ring. All target products were fully characterized by
developed.
spectral data (H NMR, C NMR, and IR), along with elemental
Scheme 2 Cascade two step routes to the synthesis of homoisoflavonoid derivatives.
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Table 1 Alternative synthesis of 7-amino alkoxy homoiso-flavonoides
Entry
Product
Yielda (%)
M.p. (ꢀC)
1
90
194–196
2
3
4
57
69
77
222–223
228–230
174–176
5
6
7
66
57
90
170–172
235–237
189–192
8
66
63
83
205–207
189–191
174–176
9
10
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Table 1 (Contd.)
Entry
Product
Yielda (%)
M.p. (ꢀC)
11
12
72
218–220
53
249–252
a
Isolated yield.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
40 C, 60 C, 80 C, 100 C, and 120 C, and also the effect of
other homogeneous and heterogeneous basic and acidic cata-
lysts such as SSC, K2CO3, NaOH, KOH, piperidine, and trie-
thylamine, ZnO, MgCl2, FeCl3, CF3COOH, CH3COOH, H3PO4 on
model reaction (8j) was evaluated. The results obtained from
this experiment show that only using HCl(g) at room tempera-
ture in ethanol provides best conditions to obtain our products
with highest yields. Because of our target products have con-
taining amine side chain, the use of HCl(g) in our procedure
cause to obtain amine containing HCl as salt products which
leads to precipitate target products and subsequently results to
improve the yield of reaction.
Fig. 3 Atom numbering refers to the order of real atoms in interpre-
tation of NMR data.
analysis. The data of all products were in good agreement with
the expected structures (see ESI†). Also, the numbering of atoms
in the target compounds for interpretation of NMR data is
indicated in Fig. 3.
As all of our synthesized products are novel compounds, for
comparison of our current approach to others available, we
selected compound 8j as model and compared its obtaining
In another investigation, we examined other conditions such
as using various solvents including H2O, CHCl4, CH3CN,
dioxane, toluene, DMF, DMSO in different temperatures at r.t.,
Scheme 3 Comparison of homoisoflavonoids synthesis under different conditions with our current protocol.
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method with other homoisoavonoids containing 4-OR 2 h. Aerwards, the reaction mixture was re-cooled to 5 ꢀC, and
substituted on benzylidene moiety under different conditions by the use of H2SO4 (6 M, 100 mL), the pH was adjusted to 2. At
(Scheme 3). The results show that best and more efficient the end, the mixture was extracted three times with EtOAc (3 ꢁ
condition to the synthesis of homoisoavonoids is provided by 200 mL), washed with brine, dried over Na2SO4, and then
using HCl in ethanol at room temperature which leads to ach- ltered. The crude product was obtained by concentration in
ieve the product with highest yield than others.27–34
vacuum as a tan solid. The crude product was soened by
Based on the above, by this achievement, the scope of hexanes, ltrated, and then recrystallized by water to give
homoisoavonoids as very medicinally important compounds colorless crystals (18.4 g, 61%): mp: 143 ꢀC; 1H-NMR d 7.84 (lH,
was developed. Rapid formation and easily purication of target d, J ¼ 9.4 Hz), 6.73 (1H, brd s), 6.55 (1H, dd, J ¼ 9.4, 1.8 Hz), 6.43
products, needing a little of HCl(g) to accelerate reaction can be (1H, d, J ¼ 1.8 Hz), 4.54 (2H, t, J ¼ 6.5 Hz), 2.78 (2H, t, J ¼ 6.5
countered as other advantages of this protocol. However, this Hz); IR (cmꢂ1): 3160, 1660, 1596, 1451, 1370, 1254.
protocol tolerate some disadvantages such as using HCl(g) as
hazardous material, the excessing use of HCl(g) lead to obtain General procedure for the synthesis of 7-(2-aminoethoxy)
unfavorable products, and working with HCl(g) needs to observe chroman-4-ones 623b
more safety principles in the laboratory.
To a mixture of 7-hydroxychroman-4-one 1 (1 mmol) and
appropriate aminoethyl chloride hydrochloride (1.1 mmol) in
acetonitrile (10 mL) in a single-neck round bottom ask,
Experimental
potassium carbonate (3 mmol) and a catalytic amount of
All reagents, starting materials, and solvents applied in this
potassium iodide (5% mol) were added. The mixture was stirred
work were purchased from commercial Merck AG, Aldrich, and
Acros Organics chemical companies. Melting points of
compounds were determined on Kolfer hot stag apparatus and
are uncorrected. IR spectra were taken using Nicolet FT-IR
under reux for 10–14 h and regularly monitored for reaction
progress by TLC using 10% methanol/dichloromethane as the
solvent system. Aer cooling down to room temperature, the
entire content was ltered under suction and the solid inor-
Magna 550 spectrographs on KBr plates. The NMR spectra
ganic salts were washed with acetonitrile (3 ꢁ 10 mL). The
were recorded on Bruker Avance 400 or 500 MHz, FT-NMR
resulting ltrate was evaporated to dryness under reduced
spectrometers, Germany. 1H NMR data are reported in the
pressure and residue was puried by silica column chroma-
following order: chemical shis (d) in part per million (ppm)
tography (1–9% methanol in dichloromethane, v/v as eluent) to
down eld from TMS as internal standard; approximate
afford compounds 6 in 70–90% yields.
coupling constant values (J) in Hertz (HZ); spin multiplicities (s,
singlet; d, doublet; t, triplet; m, multiplet; q, quartet; br, broad;
quin, quintet). Thin-layer chromatography (TLC) was performed
on pre-coated Silica Gel F254 plates for controlling the reaction
progress.
General procedure for the synthesis of E-7-(2-aminoethoxy)-3-
aryliden-2,3-dihydrochromen-4-one hydrochloride derivatives 8
A solution of 7-aminoalkoxychroman-4-ones 6 (1 mmol), and
appropriate arylaldehyde (1 mmol) in EtOH (5 mL) was stirred at
room temperature for 1 min, under passing a steam of HCl gas.
Typical procedure to the synthesis of 20,40-dihydroxy-3-chloro
Aer the time, the insertation of HCl was blockade, and the
propiophenone 335
mixture was stirred overnight at room temperature to precipi-
Triuoromethanesulfonic acid (100 g, 0.67 mol) was added to
a stirred mixture of resorcinol (1) (20.0 g, 0.182 mol) and 3-
chloropropionic acid (2) (20.0 g, 0.184 mol) at room tempera-
ture. It was allow to solution reaching 80 ꢀC for 30 min, and
then cooled to room temperature over 15 min. In the following
step, the solution was poured into chloroform (400 mL), and
then slowly poured into water (400 mL). Aerwards, the layers
were separated from each other. The aqueous phase was
extracted with 2 ꢁ 200 mL of CHCl3. The combined organic
phases were washed with brine, dried over Na2SO4, and nally
ltered. The highly viscous product was obtained by concen-
tration in vacuum as an orange semisolid (24.1 g, 66%). 1H-
NMR d 12.56 (lH, s), 7.63 (lH, d, J ¼ 7.6 Hz), 6.37–6.46 (2H,
m), 3.92 (2H, t, J ¼ 6.3 Hz), 3.41 (2H, t, J ¼ 6.3 Hz).
tate product. Subsequently, lter-off the precipitated product
and crystallized from EtOH to give compounds 8. In some cases
which the crystals need to further purication, silica gel column
chromatography with ethyl acetate/n-hexane (1 : 2) as eluent
was applied to obtain crystalline pure products.
Typical procedure for the synthesis of E-7-(2-morpholino-
ethoxy)-3-(4-nitrobenzyliden)-2,3-dihydrochromen-4-one
hydrochloride 8a
To a stirred mixture of 7-morpholinoethoxychroman-4-one 6
(0.277 g, 1 mmol) in EtOH (5 mL) at room temperature equipped
with bypassing HCl(g) valve, 4-nitrobenzaldehyde 7a (0.151 g, 1
mmol) was added. Aerwards, it was permitted to HCl(g) to
insert in reaction mixture for 1 min. When inserting of HCl to
the mixture was completed, it was allowed to the mixture to
remain overnight at room temperature to precipitate product.
Then, the mixture was ltered, and obtained crude product was
Typical procedure to the synthesis of 7-hydroxychroman-4-one
435
20,40-Dihydroxy-3-chloro propiophenone 3 (24.1 g, 0.12 mol) was recrystallized in boiling EtOH to afford crystalline pure 8a. The
1
added to a stirred solution of NaOH (2 M, 1.0 L) at 5 ꢀC. Then the obtained product was characterized by IR, H NMR, 13C NMR
solution was allowed to warm around room temperature over and elemental analysis (C, H and N).
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(dd, 1H, H-6, J ¼ 8.8 and 2.4 Hz), 6.66 (d, 1H, vinylic-H, J ¼ 2 Hz),
5.42 (d, 2H, H-2, J ¼ 2 Hz), 4.53 (t, 2H, H-10, J ¼ 5 Hz), 3.92 (br s,
4H, H-b0), 3.55 (t, 2H, H-20, J ¼ 5 Hz), 3.45 (br s, 2H, H-a0), 3.20
(br s, 2H, H-a0), 2.37 (s, 3H, –CH3). 13C NMR (100 MHz, DMSO-d6)
d: 180.3, 164.2, 162.9, 140.1, 136.5, 131.5, 130.8, 130.3, 129.9,
129.6, 116.1, 111.3, 102.4, 68.2, 63.6, 63.2, 55.0, 52.1, 21.5. Anal.
calcd for C23H25NO4$HCl (415.91): C, 66.42; H, 6.30; N, 3.37.
Found: C, 66.66; H, 6.39; N, 3.39.
Spectral data of product 8
(E)-3-(4-Nitrobenzyliden)-7-(2-morpholinoethoxy)-2,3-dihydro
chromen-4-one hydrochloride (8a). FT-IR (KBr, cmꢂ1) nmax: 3374
(N–H), 1654 (C]O), 1613 (C]C alkene); H NMR (CDCl3, 500
1
MHz) d: 8.31 (d, 2H, H-a, J ¼ 8 Hz), 7.97 (d, 1H, H-6, J ¼ 8 Hz),
7.83 (s, 1H, H-8), 7.46 (d, 2H, H-b, J ¼ 8 Hz), 6.68 (d, 1H, H-5, J ¼ 8
Hz), 6.24 (s, 1H, vinylic-H), 5.28 (s, 2H, H-2), 4.16 (br s, 2H, H-10),
3.74 (br, 4H, H-b0), 2.82 (br s, 2H, H-20), 2.58 (br s, 4H, H-a0); 13C
NMR (125 MHz, CDCl3) d: 180.1, 165.5, 163.1, 147.7, 140.9, 133.9,
133.7, 130.4, 129.8, 123.9, 115.7, 115.5, 111.2, 101.5, 67.4, 66.8,
66.4, 57.2, 54.0. Anal. calcd for C22H22N2O6$HCl (446.88): C,
59.13; H, 5.19; N, 6.27. Found: C, 59.18; H, 5.21; N, 6.29.
(E)-3-(4-Fluorobenzyliden)-7-(2-morpholinoethoxy)-2,3-dihydro
chromen-4-one hydrochloride (8b). IR (KBr, cmꢂ1) nmax: 3348 (N–
H), 1662 (C]O), 1614 (C]C alkene); 1H NMR (DMSO-d6, 400
MHz), d: 11.56 (s, 1H, NH), 7.87 (d, 1H, H-5, J ¼ 8.8 Hz), 7.72 (s,
1H, H-8), 7.53 (dd, 1H, H–Ar, J ¼ 5.6 and 3.2 Hz), 7.34 (m, 2H, H–
Ar), 6.79 (dd, 1H, H-6, J ¼ 8.8 and 2.4 Hz), 6.67 (d, 1H, vinylic-H, J
¼ 2.2 Hz), 5.41 (d, 2H, H-2, J ¼ 2.2 Hz), 4.55 (t, 2H, H-10, J ¼ 5 Hz),
3.96–3.82 (br m, 4H, H-b0), 3.56 (br s, 2H, H-20), 3.47 (br s, 2H, H-
a0), 3.20 (br s, 2H, H-a0). 13C NMR (100 MHz, DMSO-d6) d: 180.2,
164.3, 163.0, 161.8, 135.4, 133.2, 133.1, 130.9, 129.6, 116.4, 116.2,
116.0, 111.4, 102.4, 68.1, 63.6, 63.2, 55.0, 52.0. Anal. calcd for
C22H22FNO4$HCl (419.87): C, 62.93; H, 5.52; N, 3.34. Found: C,
62.91; H, 5.50; N, 3.34.
(E)-3-(4-Chlorobenzyliden)-7-(2-morpholinoethoxy)-2,3-dihydro
chromen-4-one hydrochloride (8c). IR (KBr, cmꢂ1) nmax: 3435
(N–H), 1666 (C]O), 1613 (C]C alkene); 1H NMR (DMSO-d6, 400
MHz), d: 11.47 (br s, 1H, NH), 7.87 (d, 1H, H-5, J ¼ 8.8 Hz), 7.71 (s,
1H, H-8), 7.55 (d, 2H, H-a, J ¼ 8.4 Hz), 7.50 (d, 2H, H-b, J ¼ 8.4 Hz),
6.79 (dd, 1H, H-6, J ¼ 8.8 and 2.4 Hz), 6.67 (d, 1H, vinylic-H, J ¼ 2.2
Hz), 5.41 (d, 2H, H-2, J ¼ 2.2 Hz), 4.55 (t, 2H, H-10, J ¼ 4.8 Hz),
3.93–3.86 (br d, 4H, H-b0), 3.55 (br s, 2H, H-20), 3.47 (br s, 2H, H-a0),
3.19 (br s, 2H, H-a0). 13C NMR (100 MHz, DMSO-d6) d: 180.1, 164.3,
163.0, 135.1, 134.7, 133.2, 132.5, 131.7, 129.7, 129.3, 116.0, 111.4,
102.4, 68.1, 63.6, 63.3, 55.0, 52.1. Anal. calcd for C22H22ClNO4$HCl
(436.33): C, 60.56; H, 5.31; N, 3.21. Found: C, 60.57; H, 6.19; N,
3.34.
(E)-3-(4-Hydroxybenzyliden)-7-(2-morpholinoethoxy)-2,3-
dihydro chromen-4-one hydrochloride (8f). IR (KBr, cmꢂ1) nmax
:
3077 (N–H), 1670 (C]O), 1582 (C]C alkene); 1H NMR (DMSO-
d6, 500 MHz), 11.54 (s, 1H, NH), 10.22 (s, 1H, OH), 7.83 (d, 1H,
H-5, J ¼ 8.8 Hz), 7.63 (s, 1H, H-8), 7.32 (d, 2H, H-a, J ¼ 8.6 Hz),
6.90 (d, 2H, H-b, J ¼ 8.6 Hz), 6.76 (dd, 1H, H-6, J ¼ 8.8 and 2.35
Hz), 6.64 (d, 1H, vinylic-H, J ¼ 2 Hz), 5.41 (d, 2H, H-2, J ¼ 2 Hz),
4.54 (br s, 2H, H-10), 3.96–3.81 (br m, 4H, H-b0), 3.56–3.44 (br s,
4H, H-a0), 3.22 (t, 2H, H-20, J ¼ 9.2 Hz). 13C NMR (125 MHz,
DMSO-d6) d: 179.8, 163.5, 162.3, 159.3, 159.1, 136.4, 132.7,
129.0, 127.4, 124.8, 115.8, 110.6, 101.8, 67.9, 63.1, 62.7, 54.5,
51.6. Anal. calcd for C22H23NO5$HCl (417.88): C, 63.23; H, 5.79;
N, 3.35. Found: C, 63.61; H, 5.88; N, 3.37.
(E)-3-(4-Nitrobenzyliden)-7-((2-piperidine-1-yl)ethoxy)-2,3-
dihydro chromen-4-one hydrochloride (8g). IR (KBr, cmꢂ1) nmax
:
3355 (N–H), 1657 (C]O), 1609 (C]C alkene); 1H NMR (DMSO-
d6, 500 MHz) d: 10.55 (br s, 1H, NH), 8.31 (d, 2H, H-a, J ¼ 6.75
Hz), 7.87 (d, 1H, H-5, J ¼ 8.8 Hz), 7.79 (s, 1H, H-8), 7.72 (d, 2H,
H-b, J ¼ 6.75 Hz), 6.79 (d, 1H, H-6, J ¼ 8.8 Hz), 6.67 (s, 1H,
vinylic-H), 5.42 (s, 2H, H-2), 4.51 (br s, 2H, H-10), 3.48 (br s, 4H,
H-a0), 2.99 (br s, 2H, H-20), 1.78–1.37 (br m, 6H, H-c0 and H-b0).
13C NMR (125 MHz, DMSO-d6) d: 180.1, 164.8, 163.1, 133.9,
133.7, 130.4, 130.0, 129.6, 123.9, 123.5, 115.9, 111.0, 101.5, 67.5,
65.7, 55.3, 53.8, 22.6, 22.2. Anal. calcd for C23H24N2O5 HCl
(444.91): C, 62.09; H, 5.66; N, 6.30. Found: C, 62.26; H, 5.79; N,
6.34.
(E)-3-(4-Fluorobenzyliden)-7-((2-piperidine-1-yl)ethoxy)-2,3-
dihydro chromen-4-one hydrochloride (8h). IR (KBr, cmꢂ1) nmax
:
3387 (N–H), 1667 (C]O), 1616 (C]C alkene); 1H NMR (CDCl3,
300 MHz) d: 12.53 (s, 1H, NH), 7.97 (br s, 1H, H-5), 7.80 (s, 1H, H-
8), 7.30–7.14 (m, 4H, H-a and H-b), 6.63 (br s, 1H, H-6), 6.45
(br s, 1H, vinylic-H), 5.31 (s, 2H, H-2), 4.68 (br s, 2H, H-10), 3.66–
3.50 (br s, 4H, H-a0), 2.84 (br s, 2H, H-20), 1.92–1.47 (br m, 6H, H-
b0 and H-c0). 13C NMR (75 MHz, CDCl3) d: 180.8, 164.8, 163.3,
163.0 (d, J ¼ 112.4), 136.1, 135.9, 132.0, 131.9, 130.4, 130.1,
116.1, 115.8, 110.7, 102.2, 67.9, 63.6, 55.0, 52.0, 23.0, 22.0. Anal.
calcd for C23H24FNO3$HCl (417.9): C, 66.10; H, 6.03; N, 3.35.
Found: C, 66.26; H, 6.14; N, 3.37.
(E)-3-(4-Methoxybenzyliden)-7-(2-morpholinoethoxy)-2,3-
dihydro chromen-4-one hydrochloride (8d). FT-IR (KBr, cmꢂ1
)
nmax: 3417 (N–H), 1728 (C]O), 1663 (C]C alkene); 1H NMR
(DMSO-d6, 400 MHz) d: 11.51 (s, 1H, NH), 7.85 (d, 1H, H-5, J ¼
8.8 Hz), 7.68 (s, 1H, H-8), 7.44 (d, 2H, H-a, J ¼ 8.4 Hz), 7.07 (d,
2H, H-b, J ¼ 8.4 Hz), 6.77 (dd, 1H, H-6, J ¼ 8.8 and 2 Hz), 6.65 (d,
1H, vinylic-H, J ¼ 2 Hz), 5.43 (d, 2H, H-2, J ¼ 2 Hz), 4.54 (br s, 2H,
H-10), 3.92 (br s, 4H, H-b0), 3.82 (s, 3H, –OMe), 3.55 (br s, 2H, H-
20), 3.47 (br s, 2H, H-a0), 3.19 (br s, 2H, H-a0). 13C NMR (100 MHz,
DMSO-d6) d: 180.2, 164.1, 162.8, 136.4, 132.2, 132.1, 129.6,
129.1, 128.9, 126.8, 116.2, 114.8, 111.2, 102.3, 68.3, 67.9, 63.6,
63.2, 55.9, 55.0, 52.1. Anal. calcd for C23H25ClNO5$HCl (431.91):
C, 63.96; H, 6.07; N, 3.24. Found: C, 63.97; H, 6.12; N, 3.31.
(E)-3-(4-Methylbenzyliden)-7-(2-morpholinoethoxy)-2,3-dihydro
chromen-4-one hydrochloride (8e). IR (KBr, cmꢂ1) nmax: 3390 (N–
H), 1659 (C]O), 1603 (C]C alkene); 1H NMR (DMSO-d6, 400
MHz), 11.38 (s, 1H, NH), 7.86 (d, 1H, H-5, J ¼ 8.8 Hz), 7.69 (s, 1H,
H-8), 7.35 (d, 2H, H-a, J ¼ 8.4 Hz), 7.32 (d, 2H, H-b, J ¼ 8.4 Hz), 6.77
(E)-3-(4-Chlorobenzyliden)-7-((2-piperidine-1-yl)ethoxy)-2,3-
dihydro chromen-4-one hydrochloride (8i). IR (KBr, cmꢂ1) nmax
:
3420 (N–H), 1664 (C]O), 1583 (C]C alkene); 1H NMR (DMSO-
d6, 500 MHz) d: 10.84 (br s, 1H, NH), 7.84 (d, 1H, H-5, J ¼ 8.8 Hz),
7.69 (s, 1H, H-8), 7.55 (d, 2H, H-a, J ¼ 7.5 Hz) 7.48 (d, 2H, H-b, J
¼ 7.5 Hz), 6.77 (d, 1H, H-6, J ¼ 8.8 Hz), 6.65 (s, 1H, vinylic-H),
5.39 (s, 2H, H-2), 4.51 (br s, 2H, H-10), 3.47 (br s, 4H, H-a0),
2.98 (br s, 2H, H-20), 1.78–1.37 (br m, 6H, H-c0 and H-b0). 13C
NMR (125 MHz, DMSO-d6) d: 179.6, 163.9, 162.6, 134.7, 134.3,
132.8, 132.1, 131.2, 129.2, 128.8, 115.5, 111.0, 101.8, 67.6, 62.9,
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54.3, 52.5, 23.3, 21.2. Anal. calcd for C23H24ClNO3$HCl (434.36):
C, 63.60; H, 5.80; N, 3.22. Found: C, 63.66; H, 6.09; N, 3.34.
(E)-3-(4-Methoxybenzyliden)-7-((2-piperidine-1-yl)ethoxy)-
Acknowledgements
The authors gratefully acknowledge from Pharmaceutics
Research Center, Institute of Neuropharmacology, Kerman
University of Medical Sciences for partial support of this work.
2,3-dihydro chromen-4-one hydrochloride (8j). IR (KBr, cmꢂ1
)
nmax: 3417 (N–H), 1728 (C]O), 1663 (C]C alkene); 1H NMR
(DMSO-d6, 400 MHz) d: 11.51 (s, 1H, NH), 7.85 (d, 1H, H-5, J ¼
8.8 Hz), 7.68 (s, 1H, H-8), 7.44 (d, 2H, H-a, J ¼ 8.4 Hz), 7.07 (d,
2H, H-b, J ¼ 8.4 Hz), 6.77 (dd, 1H, H-6, J ¼ 8.8 and 2 Hz), 6.65 (d,
1H, vinylic-H, J ¼ 2 Hz), 5.43 (d, 2H, H-2, J ¼ 2 Hz), 4.54 (br s, 2H,
H-10), 3.92 (br s, 4H, H-b0), 3.82 (s, 3H, OMe), 3.55 (br s, 2H, H-
20), 3.47 (br s, 2H, H-a0), 3.19 (br s, 2H, H-a0). 13C NMR (100 MHz,
DMSO-d6) d: 180.2, 164.1, 162.8, 136.4, 132.2, 132.1, 129.6,
129.1, 128.9, 126.8, 116.2, 114.8, 111.2, 102.3, 68.3, 67.9, 63.6,
63.2, 55.9, 55.0, 52.1. Anal. calcd for C24H27ClNO4$HCl (431.91):
C, 63.96; H, 6.07; N, 3.24. Found: C, 63.97; H, 6.12; N, 3.31.
(E)-3-(4-Methylbenzyliden)-7-((2-piperidine-1-yl)ethoxy)-2,3-
Notes and references
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