Eco-friendly synthesis of amidochloroalkylnaphthols and its related oxazepinones with biological evaluation

Article abstract of DOI:10.1007/s00706-015-1536-2

A general mild and efficient protocol for the synthesis of amidochloroalkylnaphthol libraries was achieved utilizing SiO₂-ZnCl₂ (silzic) as a reusable heterogeneous catalyst via Ritter-type reaction, through one-pot, three-component

Full text of DOI:10.1007/s00706-015-1536-2

Monatsh Chem
DOI 10.1007/s00706-015-1536-2
ORIGINAL PAPER
Eco-friendly synthesis of amidochloroalkylnaphthols and its
related oxazepinones with biological evaluation
Hanan A. Soliman1 Ahmed Y. Mubarak2 Ahmed El-Mekabaty2 Hanem M. Awad3 Saad S. Elmorsy2
•
•
•
•
Received: 10 May 2015 / Accepted: 8 July 2015
Ó Springer-Verlag Wien 2015
Abstract A general mild and efficient protocol for the
synthesis of amidochloroalkylnaphthol libraries was
achieved utilizing SiO2–ZnCl2 (silzic) as a reusable
heterogeneous catalyst via Ritter-type reaction, through
one-pot, three-component condensation of various alde-
hydes, chloroacetonitrile, and b-naphthol under solvent-
free reaction conditions. The amidochloroalkylnaphthols
were cyclized to its related oxazepinones, and their anti-
cancer and antioxidant activities were studied.
Introduction
Amidoalkylnaphthol derivatives have important particular
value because of their uses as important biological building
blocks and intermediates in synthesis, for example, they are
important precursors of heterocycles [1–3] as well as of
1-aminomethyl-2-naphtholderivativesarepharmacologically
important compounds [2, 4–8]. Benzoxazepines, naphthox-
azepines,andtheirderivativeshavesomeimportantbiological
and pharmacological activities [9–12] as they act as enzyme
inhibitors on central nervous system [13, 14], analgesic,
antipsychotics [15], and antidepressant [16, 17]. Some oxa-
zepines and benzoxazepines were synthesized from amides
[18–20], aminoacids [21–24], esters [25], acid chlorides [26],
flavones [27, 28], amines [29], and Mannich base [30].
Several reports have described the synthesis of ami-
doalkylnaphthols through multicomponent condensation of
aryl aldehydes, 2-naphthol, and carboxylic acid amides in
the presence of a Lewis or Bronsted acid catalysis, gen-
erally under thermal conditions [31–40]. Thus,
multicomponent condensation of aldehydes, 2-naphthol,
and nitriles to give amidoalkylnaphthols in a Ritter-type
reaction was also reported [41–49]. These protocols lack
the generality to produce arrays of amidoalkylnaphthols as
they are restricted to a few numbers of amides. Compared
to amides, nitriles are more readily available substrates.
Graphical Abstract
Keywords Amidochloroalkylnaphthols Á Silzic Á
Oxazepinone derivatives Á Ritter reaction Á Anticancer Á
Antioxidant
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-015-1536-2) contains supplementary
material, which is available to authorized users.
& Hanan A. Soliman
tarek12_2@yahoo.com
Results and discussion
1
Photochemistry Department, National Research Centre,
Dokki, Cairo, Egypt
Efficient and general method involving chloroacetonitriles
for this multicomponent reaction under milder conditions is
still lacking. Towards the goal, and in conjunction with our
concerns [50–55], we have developed an efficient, general,
and convenient protocol for the one-pot synthesis of
2
Chemistry Department, Faculty of Science, Mansoura
University, 35516 Mansoura, Egypt
3
Department of Tanning Materials and Leather Technology,
National Research Centre, Dokki, Cairo, Egypt
123

H. A. Soliman et al.
Scheme 1
1
The H NMR spectra of 4a–4j displayed a singlet at
10.06–10.33 ppm for OH, doublet at 8.79–9.03 ppm for
NH with J = 8.1–8.7 Hz (exchangeable by D2O), doublet
at 6.95–7.21 for benzylic proton with J = 8.1–8.7 Hz,
singlet for CH2Cl at 4.22–4.39 ppm, and multiplet aro-
matic protons at 7.20–8.05 ppm.
Table 1 Optimization of the reaction conditions
Entry
Amount of catalyst/mg
Yield/%
1
2
3
4
10
15
20
30
30
45
85
85
Stirring of amidoalkylnaphthol derivative 4a–4j in 5 cm3
DMF at 100 °C in the presence of 0.1 g K2CO3 gave 1-aryl-
1,2-dihydronaphtho[1,2-f][1,4]oxazepin-3(4H)-one deriva-
tives 5a–5j in excellent yields (Scheme 2; Table 4).
The structure elucidation of 5 was deduced by ele-
mental and spectral analysis. The IR spectra showed no
absorption for the hydroxyl group and the 1H NMR
showed the disappearance of OH signal and appearance
of two close doublets for the protons of CH2 on seven-
membered ring. This indicates that the rotation about C–
C bonds in seven-membered ring is limited by the ring
structure. In addition, the NH proton appeared at
d = 8.7 ppm as doublet, which disappeared with
D2O.13C NMR for 5f showed signals at d = 170.7 ppm
for CO, 71.1 ppm for CH2–O. Mass spectral measure-
ments of 5a displayed M? at m/z = 289 corresponding
in mass to the molecular ion.
chloroamidoalkylnaphthols via a three-component con-
densation of various aldehydes, 2-naphthol, and
chloroacetonitriles utilizing the inexpensive silica-zinc
chloride catalyst under solvent-free at 100 °C (Scheme 1).
To optimize the reaction conditions, we examined the
reaction of 2-naphthol (1 equiv), benzaldehyde (1 equiv),
and chloroacetonitrile (1.2 equiv) using different concen-
tration of catalyst (Table 1). It is found that the appropriate
concentration is 20 mg and the increase of the catalyst does
not lead to increased output.
As seen from the results in Table 3 and Scheme 1, the
reaction proved to be general and tolerated a variety of
aromatic aldehydes with substituents carrying either elec-
tron-donating (Table 2, entries 5–10) or electron-
withdrawing groups (Table 3, entries 2–4).
Identification of compounds 4a, 4b, and 4d–4f was
carried out by recorded analytical spectral data as well as
with comparison of their melting points with that reported
[31]. The IR spectra showed absorption at m = 3385–3250,
820 cm-1 for OH, NH, and C–Cl, respectively.
In vitro antioxidant activity
In the present study, ten newly synthesized compounds
have been investigated for their antioxidant activity using
Table 2 Comparison of SiO2/
ZnCl2 with some reported
catalyst systems in the synthesis
Nitrile
Catalyst
Conditions
Time/ Yield/ References
h
%
of amidoalkylnaphthols via
MeCN
MCR-Ritter-type reaction
HClO4–SiO2
FeCl3–SiO2
NaHSO4ÁH2O
Ph3CCl
CH3CN/85 °C
CH3CN/85 °C
CH3CN/85 °C
20
20
20
60–88 [41]
72–88 [42]
71–88 [43]
MeCN
MeCN
MeCN
Sealed tube/r.t. 0.75–4 86–94 [45]
[MeC(OH)2]?ClO4 Solvent free/
5.5–7 84–91 [46]
-
Aryl nitriles
80 °C
DCE/r.t.
Alkyl, aryl, cyanoester, unsaturated SiCl4/ZnCl2
nitriles
9–17 65–83 [56]
Chloroacetonitrile
Silzic
Solvent free/
100 °C
2–3.5 75–90 Present
work
123

Eco-friendly synthesis of amidochloroalkylnaphthols and its related oxazepinones with…
Table 3 SiO2–ZnCl2 induced one-pot, three-component reaction of aldehydes, b-naphthol, and chloroacetonitrile giving the corresponding
haloamidoalkylnaphthols
Entry
Aldehyde Ar
Product
Time/h
Yield/%a
M.p./°C
Lit. m.p./°C
1
2
3
4
5
6
7
8
9
10
a
Ph
4a
4b
4c
4d
4e
4f
2.5
2.2
2.3
2
85
74
85
75
82
70
78
71
77
79
206–207
197–199
175–177
215–217
172–174
172–174
215–217
158–160
203–205
210–212
206–207 [31]
4-ClC6H4
198–199 [31]
4-BrC6H4
–
4-O2NC6H4
4-MeC6H4
217–218 [31]
2.5
2.75
3.5
3
174–175 [31]
4-MeOC6H4
2,5-diOMeC6H3
3,4,5-triOMeC6H2
3,4-(OCH2O-)C6H3
2-Naphthyl
173–174 [31]
4g
4h
4i
–
–
–
–
3
4j
3.5
Isolated yields after column chromatography
Scheme 2
Yield/%a
M.p./°C
Table 4 Synthesis of 1,4-
oxazepin-3(4H)-ones
Entry
Substrate
Product
Time/min
1
2
3
4
5
6
7
8
9
10
a
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
55
55
50
60
45
45
50
50
55
50
95
94
95
95
92
90
98
96
97
95
172–174
200–202
214–216
209–211
194–196
197–199
191–193
108–110
168–170
203–205
4g
4h
4i
5g
5h
5i
4j
5j
Isolated yields
In vitro anticancer activity
DPPH assay. The results reveal that all the tested com-
pounds show a dose-dependent activity (Fig. 1). From
these results, we obtain that six out of ten compounds (5a–
5f) showed good antioxidant activity. However, com-
pounds 5 g, 5i, 5 h, and 5j showed weak antioxidant
activity compared to the standard compounds, rutin, and
ascorbic acid (Table 5).
In this study, the ten newly synthesized compounds were
examined in vitro for their antitumor activities against
HepG2 and HCT-116 cancer cell lines using LDH assay, to
measure the cellular membrane permeabilization (rupture)
and severe irreversible cell damage (Fig. 2). The results
123

H. A. Soliman et al.
5a
5e
5i
5b
5f
5j
5c
5d
100
80
60
40
20
0
HepG-2
HCT-116
100
80
60
40
20
0
5g
5h
Ruꢀn
Vit C
Fig. 2 The antitumor activities of the newly synthesized compound
using LDH assay at 100 ppm
0
0.78
1.56
3.125
6.25
12.5
25
50
100
Experimental
Concentraꢀon/μM
Melting points were determined using a Griffin melting point
apparatus. The IR spectra were recorded with Mattson FTIR
spectrometer 5000. Absorption maxima were measured in
cm-1. The 1H NMR and 13C NMR spectra were recorded with
Bruker200, 300 MHzspectrometerinstrumentsinDMSO-d6.
The chemical shifts (d) were measured in ppm and with the
solventsasreferences(forDMSO-d6, 1H:d = 2.52 ppm, 13C:
d = 39.49 ppm). MS spectra were recorded on GC–MS QP-
1000 EX Shimadzu mass spectrometer. Thin-layer chro-
matography (TLC) was performed on Merck silica gel GF254
plates and visualized by UV light (254 nm).
Fig. 1 Dose-dependent antioxidant activities of the newly synthe-
sized compounds using DPPH assay
Table 5 The IC50 values of the radical scavenging activities of the
newly synthesized compounds using DPPH assay
Compound
IC50/lM
5a
77.8
84.1
5b
5c
81.3
5d
61.8
5e
70.6
General procedure for the synthesis
of amidoalkylnaphthols 4a–4j
5f
83.6
5g
197.5
158.9
140.3
147.8
27.3
5h
To a mixture of aldehyde 2 (1 mmol), 2-naphthol (1 mmol),
and chloroacetonitrile (1.2 mmol), 0.2 g silzic was added
[57], and the mixture was allowed to stir at 100 °C for the
total recorded time. After completion, the reaction was
monitored by TLC, and 20 cm3 EtOAc was added to the
reaction mixture. Then the mixture was filtered off, the
extract was vaporized, and the residue was subjected to short
column chromatography using pet ether-EtOAc (2:1) to give
pure 4. Some of the products are known compounds and all
spectroscopic data were in agreement with literature.
5i
5j
Rutin
Vit C
48.7
reveal that only two compounds 5c and 5i showed signif-
icantly high anticancer activity compared to DoxorubicinÒ
(positive control). The same compounds 5c and 5i showed
IC50 of 76.9 and 77.2 lM against the liver cancer cells,
respectively. Both compounds showed IC50 of 56.1 and
52.3 lM against the colon cancer cells, respectively. The
other compounds showed significantly weak anticancer
activity against the liver and colon cancer cells.
N-[(4-Bromophenyl)(2-hydroxynaphthalen-1-yl)methyl]-2-
chloroacetamide (4c, C19H15ClNO2)
M.p.: 175-177 °C; IR (KBr): vꢀ = 3352, 3068, 2958,
1
1633 cm-1; H NMR (300 MHz, DMSO-d6): d = 10.21
(bs, 1H, OH), 8.92 (d, J = 8.1 Hz, 1H, NH), 7.79-7.84 (m,
3H, Ar–H), 7.44–7.48 (m, 3H, Ar–H), 7.30 (t, J = 6.4 Hz,
1H, Ar–H), 7.23 (d, J = 8.9 Hz, 1H, Ar–H), 7.13 (d,
J = 7.1 Hz, 2H), 7.05 (d, J = 8.5 Hz, 1H, CH), 4.31 (s,
2H, CH2Cl) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 165.1, 153.2, 140.2, 133.5, 132.0, 130.1, 128.6,
126.3, 124.9, 123.1, 118.3, 114.5, 48.1, 42.6 ppm.
In conclusion, we have reported silzic as an efficient
reagent for one-pot, three-component synthesis of ami-
dochloroalkylnaphthol libraries, biologically active drug-
like molecules, under very mild conditions. Cyclization of
the product using K2CO3/DMF at 100 °C leads to the
formation of naphthoxazepinones which have anticancer
and antioxidant effect.
123

Eco-friendly synthesis of amidochloroalkylnaphthols and its related oxazepinones with…
N-[(2,5-Dimethoxyphenyl)(2-hydroxynaphthalen-1-yl)-
methyl]-2-chloroacetamide (4 g, C21H20ClNO4)
with water and extracted with ethyl acetate, and evaporated
to give pure products 5a–5j.
Mp.: 215–216 °C; IR (KBr): vꢀ = 3333, 3278, 2937,
1-Phenyl-1,2-dihydronaphtho[1,2-f][1,4]oxazepin-3(4H)-
one (5a, C19H15NO2)
1
1655 cm-1; H NMR (300 MHz, DMSO-d6): d = 10.06
(s, 1H), 8.79 (d, J = 8.7 Hz, 1H), 8.16 (d, J = 9 Hz, 1H),
7.70–7.78 (m, 2H), 7.45 (t, J = 7.65 Hz, 1H), 7.10–7.30
(m, 4H), 6.83 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 8.7 Hz,
1H), 4.22 (s, 2H), 3.65 (s, 3H), 3.54 (s, 3H) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 165.2, 153.2, 150.1, 133.1,
131.0, 129.1, 128.3, 126.9, 124.5, 123.6, 118.9, 112.4,
56.2, 55.5, 43.2, 42.3 ppm; MS: m/z (%) = 385.11 (M?,
100.0), 387.11 (35.3).
M.p.: 172–174 °C; IR (KBr): vꢀ = 3426, 3321, 3062, 2915,
2857, 1660 cm-1
;
1H NMR (300 MHz, DMSO-d6):
d = 8.95 (d, J = 7.8 Hz, 1H, disappeared with D2O),
8.04 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 6.9 Hz, 1H), 7.88
(d, J = 8.7 Hz, 1H), 7.75-7.64 (m, 2H), 7.26-7.33 (m, 6H),
6.33 (d, J = 7.8 Hz, 1H, exchanged with D2O), 4.84 (d,
J = 16.8 Hz, 1H), 4.40 (d, J = 16.2 Hz, 1H) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 170.7, 153.8, 144.5,
133.1, 130.0, 129.1, 128.3, 127.5, 125.9, 124.1, 123.3,
120.4, 118.3, 113.5, 71.1, 50.6 ppm; MS: m/z (%) = 290
(M??1, 13.5), 289 (M?, 58), 231 (17), 230 (14.5), 212
(100), 184 (28), 157 (23.6), 115 (18.3), 95 (12.8), 77 (18.8),
51 (21.6).
N-[(2,3,5-Trimethoxyphenyl)(2-hydroxynaphthalen-1-
yl)methyl]-2-chloroacetamide (4 h, C22H22ClNO5)
M.p.: 160–161 °C; IR (KBr): vꢀ = 3374, 3190, 3005,
1
1648 cm-1; H NMR (300 MHz, DMSO-d6): d = 10.23
(bs, 1H), 8.95 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 8.1 Hz,
1H), 7.77–7.84 (m, 2H), 7.45 (t, J = 7.35 Hz, 1H),
7.22–7.32 (m, 2H), 7.03 (d, J = 8.7 Hz, 1H), 6.56 (s,
2H), 4.30 (s, 2H), 3.64 (s, 6H), 3.61 (s, 3H) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 164.9, 154.4, 153.4, 145.9,
141.5, 133.5, 128.6, 126.3, 125.6, 119.6, 118.6, 115.2,
108.7, 98.9, 59.9, 55.7, 53.2, 43.1 ppm.
1-(4-Chlorophenyl)-1,2-dihydronaphtho[1,2-f][1,4]-
oxazepin-3(4H)-one (5b, C19H14ClNO2)
M.p.: 200–203 °C; IR (KBr): vꢀ = 3345, 3063, 2913, 2843,
1662 cm-1; 1H NMR (300 MHz, DMSO-d6): d = 8.94 (d,
J = 7.5 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.98-8.03 (m,
2H), 7.52–7.69 (m, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.25 (d,
J = 8.1 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.27 (d,
J = 7.5 Hz, 1H), 4.70 (d, J = 16.2 Hz, 1H), 4.28 (d,
J = 16.2 Hz, 1H) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 170.7, 154.5, 135.4, 132.0, 131.1, 129.2, 128.3, 126.9,
126.5, 124.6, 123.4, 122.3, 116.5, 111.8, 74.1, 50.2 ppm.
N-[(Benzo[d][1,3]dioxol-5-yl)(2-hydroxynaphthalen-1-
yl)methyl]-2-chloroacetamide (4i, C20H16ClNO4)
M.p.: 203–205 °C; IR (KBr): vꢀ = 3377, 3178, 3070, 2920,
1649, 813 cm-1
;
1H NMR (300 MHz, DMSO-d6):
d = 10.27 (s, 1H), 8.95 (d, J = 8.4 Hz, 1H), 7.89 (d,
J = 7.8 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.79 (d,
J = 9 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.31 (d,
J = 7.2 Hz, 1H), 7.23 (d, J = 9 Hz, 1H), 7.00 (d,
J = 8.4 Hz, 1H), 6.76 (d, J = 7.2 Hz, 2H), 6.64 (d,
J = 8.1 Hz, 1H), 5.95 (s, 2H), 4.31 (s, 2H) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 165.3, 153.4, 149.2,
145.6, 136.3, 133.0, 128.6, 126.3, 123.3, 118.9, 115.5,
112.3, 101.2, 48.5, 42.4 ppm; MS: m/z (%) = 369.08 (M?,
100.0), 371.07 (32.0).
1-(4-Bromophenyl)-1,2-dihydronaphtho[1,2-f][1,4]-
oxazepin-3(4H)-one (5c, C19H14BrNO2)
M.p.: 214–216 °C; IR (KBr): vꢀ = 3424, 3352, 3058, 2925,
2856, 1661 cm-1
;
1H NMR (300 MHz, DMSO-d6):
d = 8.90 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H),
7.93 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.63 (t,
J = 7.2 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.39 (d,
J = 8.1 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.11 (d,
J = 8.1 Hz, 1H), 6.27 (brs, 1H), 4.83 (d, J = 16.8 Hz,
1H), 4.40 (d, J = 16.5 Hz, 1H) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 172.7, 154.5, 140.5, 133.8, 131.9, 130.1,
129.6, 128.3, 127.9, 125.5, 124.6, 122.1, 118.3, 113.5,
74.1, 50.6 ppm.
N-[(Naphthalen-2-yl)(2-hydroxynaphthalen-1-yl)methyl]-
2-chloroacetamide (4j, C23H18ClNO2)
M.p.: 210–212 °C; IR (KBr): vꢀ = 3364, 3223, 3057, 1647,
816, 745 cm-1
;
1H NMR (300 MHz, DMSO-d6):
d = 10.23 (s, 1H), 9.03 (d, J = 8.1 Hz, 1H), 7.24–7.85
(m, 14H), 4.37 (s, 2H) ppm; 13C NMR (75 MHz, DMSO-
d6): d = 165.2, 153.5, 135.2, 133.5, 133.0, 131.1, 128.2,
127.4, 125.7, 123.6, 115.4, 1118.1, 48.1, 43.6 ppm.
1-(4-Nitrophenyl)-1,2-dihydronaphtho[1,2-f][1,4]-
oxazepin-3(4H)-one (5d, C19H14N2O4)
M.p.: 209–211 °C; IR (KBr): vꢀ = 3374, 3078, 2923, 2852,
1709, 1667 cm-1
;
1H NMR (300 MHz, DMSO-d6):
General procedure for the synthesis of 1,4-oxazepin-3(4H)-
ones 5a–5j
d = 8.94 (d, J = 6.0 Hz, 1H, NH), 8.15 (d, J = 8.0 Hz,
1H, Ar–H), 7.89–8.09 (m, 2H, Ar–H), 7.59-7.75 (m, 1H,
Ar–H), 7.55 (t, J = 7.5 Hz, 1H, Ar–H), 7.35 (d,
J = 8.5 Hz, 2H, Ar–H), 7.28 (d, J = 8.8 Hz, 2H, Ar–H),
7.16 (d, J = 8.4 Hz, 1H, Ar–H), 6.27 (d, J = 7.2 Hz, 1H,
CH), 4.71 (d, J = 16.3 Hz, 1H, CH2), 4.28 (d,
Amidochloroalkylnaphthols 4a–4j (5 mmol) and 0.1 g
K2CO3 in 5 cm3 DMF were stirred at 100 °C for 1 h.
After completion of the reaction as indicated by TLC, the
reaction mixture was cooled to room temperature, diluted
123

H. A. Soliman et al.
J = 16.3 Hz, 1H, CH2) ppm; 13C NMR (75 MHz, DMSO-
d6): d = 170.7, 154.5, 147.4, 145.1, 133.0, 129.1, 128.6,
126.3, 125.9, 124.5, 123.6, 122.1, 121.3, 113.5, 71.1,
50.6 ppm; MS: m/z (%) = 334.10 (M?, 55.0).
4.26 (d, J = 15.9 Hz, 1H, CH2), 3.62 (s, 3H, OCH3), 3.59
(s, 6H, 2OCH3) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 170.9, 154.5, 152.4, 138.9, 131.1, 130.3, 130.1, 128.6,
127.3, 125.6, 124.6, 122.1, 121.2, 103.7, 71.2, 59.9, 55.7,
51.2 ppm; MS: m/z (%) = 380 (M??1, 21.54), 379 (M?,
79.54), 212 (54.39), 208 (92.33), 193 (26.78), 184 (30.97),
183 (37.73), 168 (17.23), 157 (32.66), 144 (21.31), 127
(32.81), 115 (33.02), 88 (25.28), 80 (100), 77 (20.93), 64
(58.30).
1-(p-Tolyl)-1,2-dihydronaphtho[1,2-f][1,4]-
oxazepin-3(4H)-one (5e, C20H17NO2)
M.p.: 194–196 °C; IR (KBr): vꢀ = 3427, 3347, 3055, 3034,
1
2912, 2856, 1661 cm-1; H NMR (300 MHz, DMSO-d6):
d = 8.90 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H),
7.91 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 9 Hz, 1H), 7.59 (d,
J = 7.2 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.09-7.28 (m,
5H), 6.30 (d, J = 7.2 Hz, 1H), 4.84 (d, J = 16.5 Hz, 1H),
4.39 (d, J = 16.2 Hz, 1H), 2.31 (s, 3H) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 170.6, 153.5, 138.1, 135.2,
130.0, 129.1, 128.6, 127.3, 126.9, 125.5, 124.6, 122.1,
121.3, 113.5, 71.1, 50.6, 22.3 ppm; MS: m/z (%) = 304.13
(M?, 21.9).
1-(Benzo[d][1,3]dioxol-5-yl)-1,2-dihydronaphtho[1,2-f]-
[1,4]oxazepin-3(4H)-one (5i, C20H15NO4)
M.p.: 168–170 °C; IR (KBr): vꢀ = 3420, 3347, 3064, 2957,
2909, 1664 cm-1
;
1H NMR (300 MHz, DMSO-d6):
d = 8.92 (d, J = 7.2 Hz, 1H, disappeared with D2O),
8.02 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 8.7 Hz, 2H), 7.51-
7.62 (m, 2H), 7.26 (d, J = 8.7 Hz, 1H), 6.80 (d,
J = 8.4 Hz, 1H), 6.72 (d, J = 1.5 Hz, 1H), 6.56 (d,
J = 8.4 Hz, 1H), 6.17 (d, J = 7.8 Hz, 1H, exchanged
with D2O), 5.97 (s, 2H), 4.73 (d, J = 15.9 Hz, 1H), 4.26
(d, J = 15.9 Hz, 1H), 5.95 (s, 2H), 4.31(s, 2H) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 171.7, 153.5, 149.4,
135.1, 133.0, 129.1, 128.6, 124.3, 118.9, 116.5, 114.1,
112.3, 101.2, 71.4, 55.0, 50.4 ppm.
1-(4-Methoxyphenyl)-1,2-dihydronaphtho[1,2-f][1,4]-
oxazepin-3(4H)-one (5f, C20H17NO3)
M.p.: 197–199 °C; IR (KBr): vꢀ = 3445, 3329, 3064, 2926,
2835, 1661 cm-1
;
1H NMR (300 MHz, DMSO-d6):
d = 8.90 (d, J = 6.9 Hz, 1H), 7.92–8.03 (m, 3H), 7.49-
7.64 (m, 2H), 7.25 (d, J = 8.7 Hz, 1H), 7.08 (d,
J = 7.5 Hz, 2H), 6.85 (d, J = 7.2 Hz, 2H), 6.21 (d,
J = 7.8 Hz, 1H), 4.69 (d, J = 15.9 Hz, 1H), 4.25 (d,
J = 15.6 Hz, 1H), 3.67 (s, 3H) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 170.7, 157.8, 154.5, 135.1, 131.0, 130.1,
128.6, 127.3, 126.9, 125.5, 124.6, 122.1, 121.3, 113.5,
71.1, 55.0, 50.6 ppm; MS: m/z (%) = 320.12 (M?, 22.0).
1-(Naphthalen-2-yl)-1,2-dihydronaphtho[1,2-f][1,4]-
oxazepin-3(4H)-one (5j, C23H17NO2)
M.p.: 203–205 °C; IR (KBr): vꢀ = 3446, 3237, 3062, 2909,
2856, 1659 cm-1
;
1H NMR (300 MHz, DMSO-d6):
d = 9.03 (d, J = 7.2 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H),
7.45-8.04 (m, 11H), 7.27 (d, J = 8.7 Hz, 1H), 6.45 (d,
J = 7.5 Hz, 1H), 4.78 (d, J = 16.5 Hz, 1H), 4.29 (d,
J = 16.2 Hz, 1H) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 170.9, 153.4, 135.5, 133.6, 133.0, 131.2, 128.1, 127.6,
125.5, 123.6, 1118.1, 72.1, 50.6 ppm; MS: m/z (%) = 340
(M??1, 20.19), 339 (M?, 74.40), 281 (23.29), 252 (13.92),
212 (100), 184 (31.81), 183 (30.24), 157 (24.06), 141
(21.02), 127 (40.97), 115 (20.23), 80 (29.39), 77 (10.83),
64 (12.39).
1-(2,5-Dimethoxyphenyl)-1,2-dihydronaphtho[1,2-f][1,4]-
oxazepin-3(4H)-one (5 g, C21H19NO4)
M.p.: 191–193 °C; IR (KBr): vꢀ = 3417, 3189, 3058, 2921,
2851, 1662 cm-1
;
1H NMR (300 MHz, DMSO-d6):
d = 8.62 (d, J = 7.8 Hz, 1H, disappeared with D2O),
8.12 (d, J = 8.4 Hz, 1H), 7.89–7.95 (m, 2H), 7.46–7.65
(m, 2H), 7.21 (d, J = 9 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H),
6.81 (s, 2H), 6.37 (d, J = 7.2 Hz, 1H, exchanged with
D2O), 4.92 (d, J = 16.5 Hz, 1H), 4.26 (d, J = 16.2 Hz,
1H), 3.68 (s, 3H), 3.39 (s, 3H) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 170.7, 154.8, 153.5, 133.1, 131.0, 129.1,
128.6, 127.3, 126.9, 124.5, 123.6, 118.1, 112.3, 111.5,
71.5, 56.1, 55.8, 44.6 ppm.
Biological evaluation
1,1-Diphenyl-2-picryl hydrazyl (DPPH) and Roswell Park
Memorial Institute (RPMI) 1640 medium were purchased
from Sigma Chem. Co. (St. Louis, MO, USA). Fetal bovine
serum (FBS) was purchased from Gibco, UK. Dimethyl
sulfoxide (DMSO) and methanol were of HPLC grade and
all other reagents and chemicals were of analytical reagent
grade.
1-(3,4,5-Trimethoxyphenyl)-1,2-dihydronaphtho[1,2-f][1,4]-
oxazepin-3(4H)-one (5 h, C22H21NO5)
M.p.: 108–110 °C; IR (KBr): vꢀ = 3546, 3432, 3065, 2936,
2835, 1653 cm-1
;
1H NMR (300 MHz, DMSO-d6):
d = 8.89 (d, J = 7.5 Hz, 1H, NH), 8.06 (d, J = 9 Hz,
1H, Ar–H), 7.95–8.01 (m, 2H, Ar–H), 7.63 (t, J = 7.5 Hz,
1H, Ar–H), 7.53 (d, J = 8.1 Hz, 1H, Ar–H), 7.28 (d,
J = 9 Hz, 1H, Ar–H), 6.44 (s, 2H, Ar–H), 6.19 (d,
J = 7.5 Hz, 1H, CH), 4.79 (d, J = 15.9 Hz, 1H, CH2),
In vitro antioxidant activity
Radical scavenging activities of ten compounds in com-
parison to the standards compounds (ascorbic acid and
123

Eco-friendly synthesis of amidochloroalkylnaphthols and its related oxazepinones with…
rutin) were assessed based on the radical scavenging effect
of stable DPPH free radical [58, 59]. Ten mm3 of a series
of different concentrations in DMSO of each compound or
standard was added to 90 mm3 of a 100 lM methanolic
solution of DPPH in a 96-well microtitre plate (Sigma-
Aldrich Co., St. Louis, MO, US). After incubation in dark
at 37 °C for 30 min, the decrease in absorbance of each
solution was measured at 520 nm using SpectraMaxÒ
ParadigmÒ Multi-Mode microplate reader (Molecular
Devices). Absorbance of blank sample containing the same
amount of DMSO and DPPH solution was also prepared
and measured. All experiments were carried out in tripli-
cate. The scavenging potential was compared with a
solvent control (0 % radical scavenging) and the standard
compounds. Radical scavenging activity was calculated by
the following formula:
0.1 M potassium phosphate buffer (100 mm3, pH 7.5)
containing 0.4 mg/cm3 reduced b-NADH was added to the
wells. The kinetic changes were read for 1 min using
ELISA microplate reader in absorbance at wavelength
340 nm. This procedure was repeated with 40 mm3 of the
total cell lysate to determine total LDH. The percentage of
LDH release was determined by dividing the LDH released
into the media by the total LDH following cell lysis in the
same well [62].
Statistical analysis
All the values were represented as mean SD. Significant
differences between the means of parameters as well as
IC50s were determined by probit analysis using SPSS
software program (SPSS Inc., Chicago, IL, USA).
% Reduction of absorbance ¼ ½ðAB À AAÞ =ABŠ  100;
Acknowledgments Financial support by National Research Center
(Cairo, Egypt) is gratefully appreciated.
where AB is the absorbance of blank sample and AA is the
absorbance of tested compound (t = 30 min). The con-
centration of each compound required to scavenge 50 % of
DPPH (IC50) was determined as well [60, 61].
References
1. Damodiran M, Selvam NP, Perumal PT (2009) Tetrahedron Lett
50:5474
In vitro anticancer activity
2. Abou-Elmagd WSI, Hashem AI (2013) Med Chem Res 22:2005
3. Dabiri M, Delbari AS, Bazgir A (2007) Synlett 821–823
4. Ghomi JS, Zahedi S (2013) Monatsh Chem 144:687
5. Dingermann T, Steinhilber D, Folkers G (2004) Molecular biol-
ogy in medicinal chemistry. Wiley-VCH, Weinheim
6. Shen AY, Tsai CT, Chen CL (1999) Eur J Med Chem 34:877
7. Shen AY, Chen CL, Lin CI (1992) Chin J Physiol 35:45
8. Szatmari I, Fu¨lop F (2004) Curr Org Synth 1:155
9. Schenker K (1971) Benzoxazepinones. Swiss Patent 505 850, Apr
15, 1971
Cell culture
HepG-2 (human liver carcinoma) and HCT116 (human
colorectal carcinoma) cell lines were kindly supplied by
Applied Research Sector, VACSERA-Egypt and main-
tained in RPMI-1640 medium which was supplemented
with 10 % heat-inactivated FBS, 100 U/cm3 penicillin and
100 U/cm3 streptomycin. The cells were grown at 37 °C in
a humidified atmosphere of 5 % CO2. All experiments
were conducted thrice in triplicate (n = 3). All the values
were represented as mean SD.
10. Schenker K (1971) Chem Abstr 75:98600
11. Hirohashi T, Izumi T, Yamamoto H (1970) 7-Chloro-5-phenyl-
2,3-dihydro-1,4-benzoxazepine and its 4,5-dihydro derivative
with effects on the central nervous system. Ger Offen 2 014 223,
Oct 1, 1970
12. Hirohashi T, Izumi T, Yamamoto H (1970) Chem Abstr
73:120697
13. Standridge RT (1978) Substituted 5-phenyl-2,3,4,5-tetrahydro-
1,4-benzoxazepines. US Patent 4125538, Nov 14, 1978
14. Standridge RT (1979) Chem Abstr 90:72246
Lactate dehydrogenase (LDH) assay
To determine the effect of each synthesized compound on
membrane permeability in both HepG2 and HCT-116
cancer cell lines, a lactate dehydrogenase (LDH) release
assay was used [58]. The cells were seeded in 24-well
culture plates at a density of 2 9 104 cells/well in 500 mm3
volume and allowed to grow for 18 h before treatment.
After treatment with a series of different concentrations of
each compound or DoxorubicinÒ (positive control), the
plates were incubated for 48 h. Then, the supernatant
(40 mm3) was transferred to a new 96-well plates to
determine LDH release and 6 % triton X-100 (40 mm3)
was added to the original plate for determination of total
LDH. An aliquot of 0.1 M potassium phosphate buffer
(100 mm3, pH 7.5) containing 4.6 mM pyruvic acid was
mixed with the supernatant using repeated pipetting. Then,
¨
15. Liao Y, Venhuis BJ, Rodenhuis N, Timmerman W, Wikstrom H,
Meier E, Bartoszyk GD, Bottcher H, Seyfried CA, Sundell S
¨
(1999) J Med Chem 42:2235
16. Nagarajan K, Venkateswarlu A, Kulkarni CL, Nagana GA, Shah
RK (1974) Indian J Chem 12:236
17. Nagarajan K, David J, Kulkarn YS, Hendi SB, Shenoy SJ,
Upadhyaya P (1986) Eur J Med Chem 21:21
18. Agirbas H, Sagdinc S, Kandemirli F, Kemal B (2008) J Mol
Struct 892:132
19. Sanchez-Viesca F, Gomez MR (1982) Rev Latinoam Quim 13:67
20. Katsuhide K, Noriko M, Ryoko O, Makoto K, Mika N, Toshio T,
Tomochika O, Teruyoshi I (2001) Bioorg Med Chem Lett 11:595
21. Schenker K, Druey J (1963) Helv Chim Acta 46:1696
22. Derieg ME, Sternbach LH (1966) J Heterocycl Chem 3:237
23. Walker GN, Smith RT (1971) J Org Chem 36:305
123

H. A. Soliman et al.
24. Katritzky AR, Xu Y-J, He H-Y (2002) J Chem Soc Perkin Trans
1:592
25. Kost AN (1971) Khim Geterosikl Soedin 7:1288
¨
26. Bilgic¸ S, Bilgic¸ O, Bilgic¸ MO, Gu¨ndu¨z M, Karakoc¸ N (2009)
Arkivoc 13:185
27. Misiti D, Rimatory V (1973) Ann Ist Super Sanita 9:150
28. Kaye PT, Whittal RDS (1991) Afr J Chem 44:30
29. Katritzky AR, Xu Y-J, He H-Y, Mehta S (2001) J Org Chem
66:5590
45. Heravi MM, Tavakoli-Hoseini N, Bamoharram FF (2011) Bulg
Chem Commun 43:423
46. Khazaei A, Zolfigol MA, Moosavi-Zare AR, Zare A, Parhami A,
Khalafi-Nezhad AK (2010) Appl Cat A: Gen 386:179
47. Das B, Laxminarayana K, Thirupathi PR (2007) Synlett 3103
48. Silvam NP, Perumal PT (2008) Tetrahedron 64:2972
49. Tamaddon F, Bistgani JM (2011) Synlett 2947
50. Soliman HA, Mubarak AY, El-Mekabati A, Elmorsy SS (2014)
Chem Sci Trans 3:618
30. Kiran B, Archana K, Ashok K (2004) Eur J Med Chem 39:369
31. Nandi GC, Samai S, Kumar R, Singh MS (2009) Tetrahedron
Lett 50:7220
32. Hajipour AR, Ghayeb Y, Sheikhan N, Ruoho AE (2009) Tetra-
hedron Lett 50:5649
33. Lei M, Ma L, Hu L (2009) Tetrahedron Lett 50:6393
34. Kumar A, Rao MS, Ahmad I, Khungar B (2009) Can J Chem
87:714
51. Soliman HA, Salama TA (2014) Org Chem: An Indian J 10:63
52. Soliman HA, Salama TA (2013) Chin Chem Lett 24:404
53. Salama TA, Ismail MA, Khalil AM, Elmorsy SS (2012) Arkivoc
9:242
54. Salama TA, Elmorsy SS (2011) Chin Chem Lett 22:1171
55. Elmorsy SS, Badawy DS, Khatab TK (2006) Phosphorus Sulfur
Silicon Relat Elem 181:2005
56. Salama TA (2013) Synlett 24:713
35. Gawand P, Deokar H, Langi B, Yadav A, Chaskar A (2009)
Synth Commun 39:4171
36. Ghorbani-Vaghei R, Malaekehpour SM (2010) Cent Eur J Chem
8:1086
37. Lue J, Zhang Q (2011) Monatsh Chem 142:923
38. Kotadia DA, Soni SS (2011) J Mol Cat A: Chem 44:353
39. Shaterian HR, Ghashang M, Asadi N, Riki NT (2012) J Iran
Chem Soc 9:1
40. Zali A, Shokrolahi A (2012) Chin Chem Lett 23:269
41. Selvam NP, Perumal PT (2006) Tetrahedron Lett 47:7481
42. Shaterian HR, Yarahmadi H, Ghashang M (2008) Tetrahedron
64:1263
57. Upadhya DJ, Samant SD (2008) Appl Catal A: Gen 340:42
58. Hamdy NA, Anwar MM, Abu-Zied KM, Awad HM (2013) Acta
Pol Pharm Drug Res 70:987
59. Michael HN, Awad HM, El-Sayed NH, Pare PW (2010) Pharm
Biol 48:534
60. Soliman HA, Yousif MNM, Said MM, Hassan NA, Ali MM,
Awad HM, Abdel-Megeid FME (2014) Pharma Chem 6:394
61. Awad HM, Abd-Alla HI, Mahmoud KH, El-Toumy SA (2014)
Med Chem Res 23:3298
62. Almajhdi FN, Fouad H, Khalil KA, Awad HM, Mohamed SHS
(2014) J Mater Sci Mater Med 25:1
43. Shaterian HR, Yarahmadi H (2008) Tetrahedron Lett 49:1297
44. Shaterian HR, Yarahmadi H (2008) Arkivoc 2:105
123