Microwave-assisted synthesis and evaluation of naphthalimides derivatives as free radical scavengers

Article abstract of DOI:10.1007/s00044-010-9384-4

A facile and efficient microwave-assisted reaction of 1,8-naphthalic anhydride derivatives with primary amines, leading to the synthesis of 1,8-naphthalimides, has been developed. Subsequently, the free radical scavenging properties of the 1,8-naphthalimide derivatives were evaluated against 2,2-diphenyl-1-picrylhydrazyl (DPPH). The results showed that the scavenging activities of compounds 2a, NBNA, 3b, and 3c were more efficient than that of the common synthetic antioxidant 2,6-diterbutyl- 4-methylphenol (BHT), with IC₅₀ values of 61.9, 54.0, 42.2, and 43.1 μM, respectively. The imide groups introduced at position 4 as well as the nitro functionality at position 3 of the naphthalene moiety were the major contributors to the free radical scavenging activities. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9384-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:752–759
DOI 10.1007/s00044-010-9384-4
ORIGINAL RESEARCH
Microwave-assisted synthesis and evaluation of naphthalimides
derivatives as free radical scavengers
•
Ye Zhang Shaobo Feng Qiang Wu Kai Wang
•
•
•
•
Xianghui Yi Hengshan Wang Yingming Pan
•
Received: 17 November 2009 / Accepted: 25 June 2010 / Published online: 9 July 2010
ꢀ Springer Science+Business Media, LLC 2010
Abstract
A
facile and efficient microwave-assisted
constantly generate free radicals and active oxygen. High
levels of the endogenous metabolic products, including
hydrogen peroxide (H2O2), extremely reactive hydroxyl,
and several other free radicals produced by cells, cause
damage to lipids, proteins, and DNA (Ames, 1998). Sup-
plementation with radical scavengers could be important to
prevent or minimize the damage (Ames, 1998). During the
last few years, there has been considerable investment in
efforts to develop cost-effective and efficient free radical
scavenging agents by our workgroup (Pan et al., 2004,
2007, 2008). Recently, the derivatives of naphthalimides
were unexpectedly found to exhibit radical scavenging
activities against DPPH• radical in the initial test, and it
aroused our interest to design and evaluate the naphthali-
mides as radical scavengers. The synthetic route was pre-
sented in Fig. 1.
reaction of 1,8-naphthalic anhydride derivatives with pri-
mary amines, leading to the synthesis of 1,8-naphthali-
mides, has been developed. Subsequently, the free radical
scavenging properties of the 1,8-naphthalimide derivatives
were evaluated against 2,2-diphenyl-1-picrylhydrazyl
(DPPH•). The results showed that the scavenging activities
of compounds 2a, NBNA, 3b, and 3c were more efficient
than that of the common synthetic antioxidant 2,6-diter-
butyl-4-methylphenol (BHT), with IC50 values of 61.9,
54.0, 42.2, and 43.1 lM, respectively. The imide groups
introduced at position 4 as well as the nitro functionality at
position 3 of the naphthalene moiety were the major con-
tributors to the free radical scavenging activities.
Keywords Naphthalimides derivatives Á Microwave Á
Radical scavenging capacities
Naphthalimides, which are characterized by the pres-
ence of a coplanar chromophore and, usually, a p-deficient
aromatic system, as well as one or two basic side chains,
constitute an important class of prodrugs in anticancer
therapy (Kamal et al., 2002; Bran˜a et al., 2003; Malviya
et al., 1992). They display high levels of antitumor activity
toward multifarious murine and human tumor cells (Mal-
viya et al., 1992; Bran˜a and Ramos, 2001). Two members
of this class of compounds, amonifide and mitonafide, are
undergoing clinical trials (Malviya et al., 1992). Although
the synthesis of 1,8-naphthalimide derivatives has been the
object of numerous efforts, to the best of our knowledge,
no 1,8-naphthalimide derivatives have been reported as
free radical scavengers.
Introduction
It is known that free radicals have an important role in the
pathogenesis of aging, many diseases, and cancers (Ames
et al., 1995; Halliwell and Grootveld, 1987; McDermott,
2000). The normal metabolic actions in the human body
Y. Zhang Á S. Feng Á Q. Wu Á H. Wang (&) Á Y. Pan
Key Laboratory for the Chemistry and Molecular Engineering
of Medicinal Resources, College of Chemistry and Chemical
Engineering, Guangxi Normal University, Guilin 541004,
People’s Republic of China
In order to explore the potential utility of naphthalimides
as an economical free radical scavengers, the 1,8-naph-
thalimides (1–3) were synthesized using microwave irra-
diation as the energy source (Fig. 1). Microwave irradiation
(Varma, 1999; Nu¨chter et al., 2004; Kappe, 2004) has been
e-mail: wang_hengshan@yahoo.com.cn
Y. Zhang Á K. Wang Á X. Yi
Department of Chemistry and Engineering Technology, Guilin
Normal College, Guilin 541001, People’s Republic of China
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753
(BRUKER DALTON company, USA). Elemental analyses
were determined in the apparatus Carlo Erba model 1106
(Carlo Erba company, Italy).
R3
R3
N
O
N
O
O
O
R4NH2
m.w
Synthesis
R1
R1
R2
NHR4
The reactions of 1,8-naphthalic anhydride (NA) or
4-bromo-1,8-naphthalic anhydride (BNA) with different
amines were done in a sealed and pressurized tube to
prepare N-substituted naphthalimides 1 in an ethanol
mixture under 450 W of microwave irradiation. The reac-
tion was completed within 5–10 min and the N-substituted
products 1 were obtained in 65–92% yield (Table 1). It is
important to point out that the work-up after the completion
of this reaction is very simple. The mixture was cooled to
room temperature, and the deposited product/crystals were
obtained by filtration through Buchner funnel and then
washed with a small volume of ethanol.
1
2a-2d
m.w
R3NH2
O
R5
N
O
O
R5NH2
m.w
O
O
R1
R1
NHR5
2e-2g and 3
R2
NA: R1=H, R 2=H;
BNA: R1=H, R 2=Br;
NBNA: R1=NO2, R2=Br
The synthesis of compounds 2a–2d began with the
condensation of naphthalimide 1k with benzylamine, eth-
anolamine, propylamine, and butylamine in methoxyetha-
nol, respectively, using microwave irradiation as the
energy source. The products were purified by preparative
silica gel thin-layer chromatography (TLC) using petro-
leum ether/ethyl acetate (5:1, v/v) as the eluent. Coupling
of 4-bromo-1,8-naphthalic anhydride with benzylamine,
butylamine, and propylamine at 850 W in a microwave
oven afforded yellow crystals of 2e–2g in good yield
within a few minutes (Table 1).
Fig. 1 Synthetic route of compounds 1–3
considered as a green technology, and its level of energy
consumption is low compared with that of most traditional
methods. As well as being energy efficient, microwave
heating can enhance the rate of chemical reactions and, in
many cases, improve product yield. Thus, microwave irra-
diation was included in the synthesis of 1,8-naphthalimides
1–3. And their free radical scavenging properties were
determined using the stable free radical 2,2-diphenyl-1-
picrylhydrazyl (DPPH•) (Shimada et al., 1992; Lee et al.,
2005).
In DMF, the condensation of 3-nitro-4-bromo-1,8-
naphthalic anhydride (NBNA) and amines under 850 W
microwave irradiation produced 3-nitro-4-amic-alkyl
naphthalimides 3 in good yield (82–92%) (Table 1). The
presence of the nitro group in 1,8-naphthalic anhydride led
to higher yields than those of 2e–2g. The work-up after the
reaction was the same as that described for 1, and afforded
red powder or crystals of 3.
Materials and methods
Reagents and apparatus
Scavenging activity on DPPH• radical
2,6-Diter-butyl-4-methylphenol (BHT) and 1,1-diphenyl-2-
picrylhydrazyl (DPPH•) were purchased from Sigma
Chemicals Co. (St. Louis, MO, USA). Other chemicals
were purchased from China National Medicine Group
Shanghai Corporation (Shanghai, China). All chemicals
and solvents used were of analytical grade. The reactions
of 1,8-naphthalic anhydride derivatives with amines were
done in WF-4000M microwave oven (Xian DEPA Biology
technologies inc, Shanghai, China), and the UV-1100
spectrophotometer (Beijing Rayleigh Analytical Instrument
Corporation, Beijing, China) was used to evaluate the
radical activity. The NMR study was carried out by the
instrument NMR (BRUKER AVANCE 500, BRUKER
company, Switzerland), and the mass spectral studies
were done using BRUKER ESQUIRE HCT instrument
To evaluate the free radical scavenging activity, each
compound was allowed to react with a stable free radical,
1,1-diphenyl-2-picrylhydrazyl radical (DPPH•) according
to the method of Shimada et al. (1992) and Lee et al. (2005)
with a little modification. In brief, each scavenger solution
(0.1 ml) in DMF at different concentrations was added to
solution [3.9 ml, 0.004% (w/v)] of DPPH• in ethanol. The
reaction mixture was incubated at 37ꢁC. The scavenging
activity on DPPH• radical was determined by measuring the
absorbance at 517 nm after 30 min. The scavenging activity
was expressed as a percentage of scavenging activity
on DPPH• radical: SC% = [(Acontrol - Atest)/Acontrol)] 9
100%, where Acontrol is the absorbance of the control
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Med Chem Res (2011) 20:752–759
(DPPH• solution without test sample) and Atest is the
absorbance of the test sample (DPPH• solution plus scav-
enger). The control contains all reagents except the scav-
enger. The values of IC50 for radical scavengers, the
effective concentration at which 50% of DPPH• radicals
were scavenged were tested to evaluate the radical activity.
All tests were performed in triplicate, and the mean was
centered. A blank experiment was also conducted.
Results and discussion
We explored the free radical scavenging ability of the pure
compounds 1–3. Each compound was allowed to react
with DPPH• essentially as described (Shimada et al., 1992;
Lee et al., 2005) but with a little modification. The values
of IC50 for compounds 1–3, the effective concentration at
which 50% of DPPH• radicals were scavenged were tested
to evaluate the radical activity (Table 2). The IC50 of BHT
was determined for comparison.
Table 2 shows that the radical scavenging ability of
compounds 1 was less than that of BHT. The IC50 values
were: BHT, 65.8 lM; 1a, 149.4 lM; 1c, 154.8 lM; 1g,
179.2 lM; and 1f, 182.6 lM. On the basis of this obser-
vation, it can be suggested that the presence of N-substituent
groups in the imide segment had an important influence on
the free radical scavenging ability. Neither the introduction
of bromine at position 4 on the naphthalene moiety nor the
chiral dehydroabiatyl substituent in the imide moiety
improved their DPPH• scavenging activity.
Table 2 Scavenging activity of compounds 1–3 against DPPH
Compounds
IC50 (lM)a
Compound
IC50 (lM)a
NA
1a
1b
1c
1d
1e
1f
1773.8
149.4
186.7
154.8
147.1
142.6
182.6
179.2
129.5
165.6
237.8
208.1
na
2b
221.3
209.9
205.9
84.6
2c
2d
2e
2f
320.1
351.1
54.0
2g
NBNA
3a
1g
1h
1i
230.7
42.2
3b
3c
43.1
1j
3d
214.7
231.1
65.8
1k
BNA
2a
a
3e
BHT
61.9
IC50 = the effective concentration at which 50% of DPPH• radicals
were scavenged. Each experiment was done in duplicate at least three
times, and the data presented are the average values (na not active)
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757
The presence of an electron-donating substituent in
position 4 of naphthalimides is known to increase both the
electronic mobility (Bojinov et al., 2003) and the electron
densities and, hence, the stability of the radical. This would
also contribute to their radical scavenging ability. On the
basis of these hypotheses, some alkyl-amino groups were
designed to inject into the naphthalene section to afford
2a–2g. We expected compounds 2 to advance the scav-
enging ability against DPPH•. However, the scavenging
activity was clearly weakened, except 2a and 2e, which
were shown to be as potent as BHT, with IC50 61.9 and
84.6 lM, respectively, implying the importance of the
4-substituent in the naphthalene moiety for the scavenging
activity against DPPH•. Since all of the 2 compounds,
except 2a and 2e, contain one or two soft side chains, we
conclude that the flexibility of these side chains in naph-
thalimides should reduce the structural rigidity of the
compounds and, consequently, their scavenging activity. In
contrast, rigid groups in the naphthalene moiety, e.g.,
benzylamino, would lead to a favorable scavenging activ-
ity, such as that of 2a and 2e.
of radical scavengers. More work is in progress to evaluate
the intrinsic toxicities of compounds 1–3.
Synthesis of the derivatives
Synthesis
(a) General procedure for the preparation of 1: The mixture
of primary amine (1.1–1.8 mmol), ethanol (10 ml), and
1,8-naphthalic anhydride (or 4-bromo-1,8-naphthalic anhy-
dride) (1.0 mmol) was blended together in a sealed and
pressurized tube and reacted at 80ꢁC and 450 W under
microwave irradiation for a few minutes. Once cooled to
room temperature, pale powder or crystals of 1 were
obtained.
(b) General procedure for the preparation of 2a–2d: The
mixture of amines (2.3–2.5 mmol), methoxyethanol
(10 ml), and 1k (1.0 mmol) was blended together in a
sealed and pressurized tube and reacted at 100ꢁC and
850 W under microwave irradiation for a few minutes.
After reaction, the gum obtained was purified by silica
column chromatography with petroleum ether/ethyl acetate
(5:1) as the eluent. Yellow powders of 2a–2d were
obtained.
Nitryl was a good electron-withdrawal group, and it
would damage the stabilization of DPPH• for its capability
of absorbing electron or radicals. In the presence of nitro
group at 3-position of naphthalene portion, the scavenging
activities of compounds NBNA, 3b, and 3c were found to
be more efficient than that of BHT, with respective IC50
54.0, 42.2, and 43.1 lM, indicating the importance of nitro
functionality for the radical scavenging activities. Com-
plexes 3a, 3d, and 3e showed weaker activities for the
presence of tender chain sides, which reduced their struc-
tural rigidity and then their free scavenging activities.
Based on the above observation, the groups introduced
in imide and 4-position of naphthalene moiety, as well as
nitro functionality appeared to be major contributors to the
radical scavenging activity. The order was nitro function-
ality [ the substituents introduced in 4-position of naph-
thalene moiety [ the groups in imide.
(c) General procedure for the preparation of 2e–2g: The
mixture of amines (2.3–2.5 mmol), methoxyethanol
(10 ml), and 4-bromo-1,8-naphthalic anhydride (1.0 mmol)
was blended together in a sealed and pressurized tube and
reacted at 100ꢁC and 850 W under microwave irradiation
for a few minutes. Once cooled to the room temperature,
yellow crystals of 2e–2g were obtained.
(d) General procedure for the preparation of 3: The
mixture of amines (2.0–2.3 mmol), DMF (10 ml), and
4-bromo-3 nitro-1,8-naphthalic anhydride (1.0 mmol) was
blended together in a sealed and pressurized tube and
reacted at 100ꢁC and 850 W under microwave irradiation
for a few minutes. Once cooled to room temperature, red
crystals of 3 were obtained.
Conclusions
Spectra data for representative compounds
1
In conclusion, we have demonstrated a rapid, simple, clean,
and efficient method for the synthesis of 1,8-naphthali-
mides under microwave irradiation, and evaluated their
scavenging ability against the free radical DPPH•. To our
knowledge, this synthesis has not been described before,
and it is very simple and useful. All of the synthetic
1,8-naphthalimide derivatives presented good free radical
scavenging activity against DPPH•. Especially 2a, NBNA,
3b, and 3c are more potent than the common synthetic
antioxidant BHT. Besides, the production costs will be
very low and that is of great importance for the production
(a) Compound 2a: H NMR (500 MHz, CDCl3) d 8.57 (d,
J = 7.3 Hz, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.11 (d,
J = 8.1 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.37–7.45 (m,
5H), 7.14 (t, J = 8.1 Hz, 2H), 6.94 (t, J = 8.02 Hz, 2H),
6.78 (d, J = 8.3 Hz, 1H), 5.56 (s, 1H, NH), 4.6 (d,
J = 5.0 Hz, 2H), 4.20–4.33 (dd, J = 13.2 Hz, 2H), 3.01
(d, J = 5.6 Hz, 2H), 2.80 (t, J = 5.4 Hz, 2H), 2.22 (m,
2H), 1.61 (m, 1H), 1.1.36–1.47 (m, 7H), 1.45 (m, 3H), 1.29
(m, 10H), 1.24 (s, 3H), 1.10 (s, 1H); 13C NMR (125 MHz,
CDCl3) d 165.7, 148.8, 147.7, 145.4, 135.2, 134.4, 131.3,
129.5, 126.9, 125.8, 124.7, 123.9, 123.6, 123.1, 120.2,
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Med Chem Res (2011) 20:752–759
110.7, 104.4, 60.5, 49.6, 46.6, 45.5, 39.9, 38.2, 37.8, 37.5,
33.4, 30.5, 26.0, 24.0, 19.9, 19.2, 18.7; MS (ESI) m/z: 569
(M–H); Anal. calcd for C34H40N2O3: C, 82.07; H, 7.42; N,
4.91. Found: C, 82.21; H, 7.26; N, 4.86.
5H), 7.30–7.36 (m, 5H), 6.78 (d, J = 7.4 Hz, 1H), 5.58 (s,
NH), 5.54 (s, 2H), 4.63 (d, J = 5.1 Hz, 2H); MS (ESI) m/z:
436 (M–H); Anal. calcd for C26H20N2O2: C, 79.57; H,
5.14; N, 7.14. Found: C, 79.44; H, 5.26; N, 7.28.
1
1
(b) Compound 2b: H NMR (500 MHz, CDCl3) d 8.45
(f) Compound 2f: H NMR (500 MHz, CDCl3) d 8.60
(d, J = 7.3 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.04 (d,
J = 8.1 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.13 (d,
J = 8.2 Hz, 1H), 6.94 (t, J = 8.02 Hz, 2H), 6.61 (d,
J = 8.3 Hz, 1H), 5.76 (s, 1H, NH), 4.15–4.29 (d,
J = 5.0 Hz, 2H), 4.05 (m, J = 13.2 Hz, 2H), 3.52 (dd,
J = 13.2 Hz, 2H), 3.01 (d, J = 5.6 Hz, 2H), 2.22 (m, 2H),
1.61 (m, 1H), 1.1.36–1.47 (m, 7H), 1.45 (m, 3H), 1.29 (m,
10H), 1.24 (s, 3H), 1.10 (s, 1H), 1.07 (s, 3H, CH3); 13C
NMR (125 MHz, CDCl3): 165.6, 165.2, 149.3, 147.6,
145.4, 135.1, 134.4, 131.2, 129.6, 126.9, 125.8, 124.7,
123.9, 123.6, 123.1, 120.2, 110.7, 104.4, 60.5, 49.6, 46.6,
45.5, 39.9, 38.2, 37.8, 37.5, 33.4, 30.5, 26.0, 24.0, 19.9,
19.2, 18.6; MS (ESI) m/z: 523 (M–H); Anal. calcd for
C34H40N2O3: C, 77.83; H, 7.68; N, 5.34. Found: C, 73.94;
H, 7.30; N, 5.07.
(d, J = 8.5 Hz, 1H), 8.49 (d, J = 7.5 Hz, 1H), 8.09 (d,
J = 8.6 Hz, 1H), 7.65 (d, J = 7.5 Hz, 2H), 6.74 (d,
J = 7.4 Hz, 1H), 5.24 (s, 1H, NH), 4.17 (t, J = 7.6 Hz,
2H), 3.44 (t, J = 7.5 Hz, 2H), 1.86 (m, 2H), 1.60 (m, 2H),
1.45–1.48 (m, 4H), 1.01–1.06 (m, 6H, CH3); MS (ESI) m/z:
323 (M–H); Anal. calcd for C20H24N2O2: C, 74.01; H,
7.46; N, 8.64. Found: C, 74.15; H, 7.62; N, 8.46.
1
(g) Compound 2g: H NMR (500 MHz, CDCl3) d 8.58
(d, J = 7.2 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.09 (d,
J = 8.4 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 6.72 (d,
J = 8.4 Hz, 1H), 5.31 (s, 1H, NH), 4.13 (t, J = 7.68 Hz,
2H), 3.38 (dd, 2H), 1.81 (dd, 2H), 1.74 (dd, 2H), 1.14 (t,
J = 7.4 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H); MS (ESI) m/z:
295 (M–H); Anal. calcd for C18H20N2O2: C, 72.95; H,
6.80; N, 9.45. Found: C, 72.81; H, 6.98; N, 9.62.
1
1
(c) Compound 2c: H NMR (500 MHz, CDCl3) d 8.54
(h) Compound 3a: H NMR (500 MHz, DMSO) d 9.84
(d, J = 7.2 Hz, 1H), 8.43 (1H, d, J = 8.4 Hz), 8.08 (1H, d,
J = 8.3 Hz), 7.57 (1H, t, J = 7.9 Hz), 7.15 (1H, d,
J = 8.1 Hz), 6.96 (2H, t, J = 8.1 Hz), 6.71 (1H, d,
J = 8.4 Hz), 5.33 (1H, s, NH), 4.20–4.32 (2H, dd,
J = 13.2 Hz), 3.37 (2H, m), 2.84–3.04 (3H, m), 2.21–2.25
(2H, m), 1.75 (1H, m), 1.36–1.47 (6H, m), 1.45 (2H, m),
1.29 (4H, m), 1.31 (3H, s), 1.24 (6H, s), 1.10 (1H, s); 13C
NMR (125 MHz, CDCl3): 165.7, 165.1, 149.3, 147.7,
145.4, 135.2, 134.5, 131.2, 129.7, 126.9, 125.6, 124.6,
123.9, 123.4, 120.1, 110.5, 104.4, 49.6, 46.6, 39.9, 38.2,
37.9, 37.5, 33.5, 30.6, 26.0, 24.0, 22.8, 19.9, 19.2, 18.7,
11.6; MS (ESI) m/z: 521 (M–H); Anal. calcd for
C35H42N2O2: C, 80.42; H, 8.10; N, 5.36. Found: C, 80.59;
H, 8.14; N, 5.28.
(s, 1H, NH), 8.78 (d, J = 8.5 Hz, 1H), 8.70 (s, 1H), 8.43
(d, J = 7.4 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 5.24 (t,
J = 4.8 Hz, 1H), 4.78 (t, J = 6.0 Hz, 1H), 4.02 (t,
J = 6.7 Hz, 2H), 3.86 (s, 2H, OH), 3.73 (dd, J = 4.9 Hz,
2H), 3.56 (m, 2H); MS (ESI) m/z: 344 (M–H); Anal. calcd
for C16H15N3O6: C, 55.65; H, 4.38; N, 12.17. Found: C,
55.51; H, 4.51; N, 12.35.
(i) Compound 3b: 1H NMR (500 MHz, CDCl3) d 10.74
(s, 1H, NH), 9.37 (s, 1H), 8.63 (d, J = 7.4 Hz, 1H), 8.24
(d, J = 8.6 Hz, 1H), 7.45 (t, J = 8.3 Hz, 1H), 7.37 (d,
J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 4H), 7.06 (d,
J = 8.2 Hz, 2H), 2.47 (s, 3H, CH3), 2.41 (s, 3H, CH3); MS
(ESI) m/z: 436 (M–H); Anal. calcd for C26H19N3O4: C,
71.39; H, 4.38; N, 9.61. Found: C, 71.51; H, 4.20; N, 9.48.
1
1
(d) Compound 2d: H NMR (500 MHz, CDCl3) d 8.55
(j) Compound 3c: H NMR (500 MHz, CDCl3) d 10.02
(d, J = 7.2 Hz, 1H), 8.43 (d, J = 8.3 Hz, 1H), 8.07 (d,
J = 8.3 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.15 (d,
J = 8.1 Hz, 1H), 6.95 (t, J = 8.1 Hz, 2H), 6.71 (d,
J = 8.4 Hz, 1H), 5.30 (s, 1H, NH), 4.20–4.34 (dd,
J = 13.2 Hz, 2H), 3.39 (m, 2H), 2.84–3.04 (m, 3H), 2.21–
2.25 (m, 2H), 1.75 (m, 1H), 1.36–1.47 (m, 6H), 1.45 (m,
2H), 1.29 (m, 4H), 1.31 (s, 3H, CH3), 1.24 (s, 3H, CH3),
1.10 (s, 1H); 13C NMR (125 MHz, CDCl3): 165.7, 165.1,
149.3, 147.7, 145.4, 135.2, 134.5, 131.2, 129.7, 126.9,
125.6, 124.6, 123.9, 123.6, 123.4, 120.1, 110.4, 104.3,
49.5, 46.6, 43.4, 39.9, 38.2, 37.8, 37.5, 33.5, 31.1, 30.6,
26.1, 24.0, 20.3, 19.9, 19.2, 18.7, 13.8; MS (ESI) m/z: 535
(M–H); Anal. calcd for C36H44N2O2: C, 80.56; H, 8.26; N,
5.22. Found: C, 80.44; H, 8.38; N, 5.11.
(s, 1H, NH), 9.36 (s, 1H), 8.70 (d, J = 7.4 Hz, 1H), 8.63
(d, J = 8.5 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.26–7.65
(m, 10H), 5.38 (s, 2H), 5.10 (s, 2H); MS (ESI) m/z: 436
(M–H); Anal. calcd for C26H19N3O4: C, 71.39; H, 4.38; N,
9.61. Found: C, 71.25; H, 4.51; N, 9.72.
1
(k) Compound 3d: H NMR (500 MHz, CDCl3) d 9.92
(s, 1H, NH), 9.32 (s, 1H), 8.68 (dd, J = 7.4 and 8.5 Hz,
2H), 7.71 (t, J = 7.8 Hz, 1H), 4.16–4.19 (t, J = 7.5 Hz,
2H), 3.97–4.00 (t, J = 5.5 Hz, 2H), 1.45–1.88 (m, 8H),
1.00 (s, 6H, CH3); MS (ESI) m/z: 368 (M–H); Anal. calcd
for C20H19N3O4: C, 65.03; H, 6.28; N, 11.37. Found: C,
65.16; H, 6.47; N, 11.24.
1
(l) Compound 3e: H NMR (500 MHz, CDCl3) d 9.91
(s, 1H, NH), 9.25 (s, 1H), 8.65 (t, J = 7.1 Hz, 2H), 7.71 (t,
J = 7.8 Hz, 1H), 4.18 (t, J = 7.5 Hz, 2H), 3.96 (t,
J = 5.4 Hz, 2H), 1.73–1.91 (m, 4H), 1.03 (s, 6H, CH3);
MS (ESI) m/z:340 (M–H); Anal. calcd for C18H19N3O4: C,
1
(e) Compound 2e: H NMR (500 MHz, CDCl3) d 8.61
(d, J = 7.3 Hz, 1H), 8.48 (d, J = 8.5 Hz, 1H), 7.64 (d,
J = 7.8 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.32–7.37 (m,
123

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Acknowledgments This study was supported by the National
Natural Science Foundation of China (No. 20762001), the open fund
of Key Laboratory of Development and Application of Forest
Chemicals of Guangxi (GXFC08-05), the Natural Science Foundation
of Guangxi Province (No. 0832096 and 0832024), the Project of the
Key Laboratory of Medicinal Chemical Resources and Molecular
Engineering, Guangxi Normal University, China (0630006-5D09),
and Guangxi’s Medicine Talented Persons Small Highland Foundation
(0808).
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