6-Substituted 1,4-naphthoquinone oxime derivatives (I): synthesis and evaluation of their cytotoxic activity

Article abstract of DOI:10.1007/s00706-016-1899-z

Abstract: A series of 6-substituted 1,4-naphthoquinone oxime derivatives were synthesized and evaluated for their in vitro cytotoxicity against four cancer cell lines and one normal cell line. Some compounds exhibited moderate to good cytotoxicity towards cancer cells and meanwhile all the synthesized compounds displayed no apparent cytotoxic activity against normal cells (IC₅₀?>?100?μM). Among these oxime derivatives, three compounds showed more potent cytotoxicity against human colon cancer cell lines (HCT-15) than adriamycin and 5-fluorouracil, with an IC₅₀ value of 2.52, 1.96, and 2.27?μM, respectively. Additionally, structure–activity relationship studies revealed that cytotoxic effects of these oxime derivatives were not only largely dependent upon the size of alkyl chain R¹, but also upon substituents R² of the branch chain, indicating that the strong cytotoxicity of these compounds was ascribed to their appropriate lipophilicity. Collectively, this study could provide available strategy for design and synthesis of 6-substituted 1,4-naphthoquinone oxime derivatives as potential anticancer agents. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-016-1899-z

Monatsh Chem (2017) 148:1011–1023
DOI 10.1007/s00706-016-1899-z
ORIGINAL PAPER
6-Substituted 1,4-naphthoquinone oxime derivatives (I): synthesis
and evaluation of their cytotoxic activity
Guang Huang1,2
Hui-ran Zhao3 Wen Zhou1 Jin-yun Dong1
•
•
•
•
Qi-jing Zhang1 Qing-qing Meng1 Bao-quan Zhu2 Shao-shun Li1
•
•
•
Received: 1 November 2016 / Accepted: 24 December 2016 / Published online: 19 April 2017
Ó Springer-Verlag Wien 2017
Abstract A series of 6-substituted 1,4-naphthoquinone
oxime derivatives were synthesized and evaluated for their
in vitro cytotoxicity against four cancer cell lines and one
normal cell line. Some compounds exhibited moderate to
good cytotoxicity towards cancer cells and meanwhile all
the synthesized compounds displayed no apparent cyto-
toxic activity against normal cells (IC50 [ 100 lM).
Among these oxime derivatives, three compounds showed
more potent cytotoxicity against human colon cancer cell
lines (HCT-15) than adriamycin and 5-fluorouracil, with an
IC50 value of 2.52, 1.96, and 2.27 lM, respectively.
Additionally, structure–activity relationship studies
revealed that cytotoxic effects of these oxime derivatives
were not only largely dependent upon the size of alkyl
chain R1, but also upon substituents R2 of the branch chain,
indicating that the strong cytotoxicity of these compounds
was ascribed to their appropriate lipophilicity. Collectively,
this study could provide available strategy for design and
synthesis of 6-substituted 1,4-naphthoquinone oxime
derivatives as potential anticancer agents.
Graphical abstract
oxime moiety
HO
N
O
modification
1
4
R1
R2
6
R
N
O
O
HO
oxime moiety
14 - 31
1,4-napthoquinone skeleton
R
1 = butyl, pentyl, hexyl, octyl, decyl, dodecyl
2 = 3,4,5-trimethoxybenzoyl, isopentyl, H
R
Keywords Naphthoquinone Á Cytotoxicity Á
Anticancer agents Á Structure–activity relationship Á
Aromatization
Introduction
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-016-1899-z) contains supplementary
material, which is available to authorized users.
The 1,4-naphthoquinone scaffold is known to confer
numerous natural products such as shikonin, lapachol,
juglone, and menadione, with diverse biological activities
[1–5] including anti-bacterial, antifungal, anticancer, and
anti-inflammatory activities. Among the naphthoquione
class, 6-substituted 1,4-naphthoquinone derivatives have
attracted a great deal of interest from scientific community
owing to their excellent antineoplastic activities. Our group
and others demonstrated that 6-substituted 5,8-dimethoxy-
1,4-naphthoquinone (DMNQ) derivatives exhibited better
antitumor activities than the corresponding 2-substituted
DMNQ ones due to less steric effects of the quinonoid
moiety [6–9]. Meanwhile, Antonini et al. showed that
mesylates, tosylates, and N-(chloroethyl)carbamates of
& Bao-quan Zhu
baoquanzhu@sipi.com.cn
& Shao-shun Li
ssli@sjtu.edu.cn
1
School of Pharmacy, Shanghai Jiao Tong University,
800 Dongchuan Rd., Shanghai 200240,
People’s Republic of China
2
Shanghai Institute of Pharmaceutical Industry,
285 Copernicus Rd., Shanghai 201203,
People’s Republic of China
3
School of Pharmaceutical Sciences and Chemistry,
Dali University, 2 Hongsheng Rd., Dali 671000,
People’s Republic of China
123

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G. Huang et al.
6-methyl-1,4-naphthoquinone derivatives exhibited strong
cytotoxic activity against Sarcoma 180 ascites cells [10].
Besides, Gordaliza et al. demonstrated that prenylnaph-
thoquinones displayed potent cytotoxicity against various
cancer cell lines [11]. From the standpoint of pharmacol-
ogy, the potent antitumor activity of these compounds
containing the 1,4-naphthoquinone skeleton was closely
associated with the generation of reactive oxygen species
(ROS) and bioreductive alkylation [12]. However, the cell
damage caused by ROS and alkylation might be non-
specific, indiscriminately leading to the dearth of tumor
cells and normal cells.
successfully conducted in the presence of sodium dichro-
mate [24]. Treatment of the intermediate 3 with NBS
produced 6-(bromomethy1)-1,4-naphthoquinone (4) in
75% yield. A noteworthy observation was that longer
reaction time and higher temperature gave rise to 6-(di-
bromomethyl)naphthalene-1,4-dione as the major by-
product. Alcohol 5 was synthesized through hydrolysis of
intermediate 4. The reduction–methylation of 5 in a one-
pot strategy and subsequent oxidation of 2-(hydrox-
ymethy1)-5,8-dimethoxynaphthalene (6) with active MnO2
were carried out to afford 2-formyl-5,8-dimethoxynaph-
thalene (7) in 99% isolated yield, whereas another attempt
through the straightforward formylation of 1,4-
dimethoxynaphthalene for the preparation of 7 via Vils-
meier–Haack reaction was not possible.
Interestingly, our recent investigations have shown that
O-dimethyl shikonin derivatives bearing oxime moiety
exhibited more significant cytotoxic activity against
cancerous cells as well as lower cytotoxicity towards nor-
mal cells than the parent compound [13–17]. Meanwhile,
the mechanism of their strong inhibitory actions was
demonstrated to be not attributed to bioreductive alkylation
and ROS [14, 17]. Specially, shikonin derivative DMAKO-
05, a potential candidate compound for colorectal carci-
noma, exhibited more excellent anticancer activity against
HCT-116 cells both in vitro and in vivo when compared
with 5-fluorouracil (5-FU) [16].
The Grignard addition of alkyl magnesium bromide to
aldehyde 7, followed by nucleophilic substitution reaction
gave 6-substituted-1,4-dimethoxynaphthalenes 9a–9f.
Afterward, oxidation of 9a–9f with cerium(IV) ammonium
nitrate (CAN) gave corresponding 6-substituted 1,4-naph-
thoquinones 10a–10f. Stirring at 50 °C of compounds 10a–
10f with hydroxylamine hydrochloride [14, 17, 25],
respectively, in the presence of pyridine subsequently
yielded 1,4-naphthoquinone oxime derivatives 14–19.
Condensation of 8a-8d with tri-O-methylgallic acid affor-
ded 11a–11f in excellent yield in the presence of DCC and
DMAP. Similarly, title compounds 20–25 and 26–31 were
provided using the synthetic route as described for com-
pounds 14–19. In addition, hydrolysis of compounds 20–25
in aqueous alkaline media and successive neutralization
with hydrochloric acid provided target compounds 26–31
in relatively good isolated yields.
In these investigations mentioned above, the modifica-
tion of shikonin was focused on the 10-OH at its side chain
or the oximation of its carbonyl group. Additionally, taking
the 1,4-naphthoquinone oxime moiety with remarkable
biological activities into consideration, we suppose that the
introduction of various alkyls to the position 6 of 1,4-
naphthoquione oxime and modification of the hydroxyl
group at the side chain might result in the increase of
antitumor activity. Therefore, we herein reported the syn-
thesis of new biologically active 6-substituted 1,4-
naphthoquinone oxime derivatives. Furthermore, the pre-
liminary structure–activity relationship was discussed in
this article.
The cytotoxic activity in vitro of all the synthesized
compounds against HCT-15, MGC-803 (gastric carcinoma),
Bel7402 (liver cancer), MCF-7 (breast cancer), and HSF
(human skin fibroblast) cell lines was evaluated by MTT
assay, using adriamycin (ADM) and 5-FU as positive con-
trols. As shown in Table 1, most of oxime derivatives (14–
17, 20–23, and 29–31) displayed more superior or compar-
ative cytotoxicity to the positive reference ADM
(IC50 = 2.74 lM) and 5-FU (IC50 = 8.24 lM) towards
HCT-15 cells and showed moderate cytotoxicity against
MGC-803, Bel7402 cell lines, whereas 5-FU showed low
cytotoxicity against MGC-803 cells (IC50 [ 100 lM).
Among these compounds, the IC50 value of the most effec-
tive compound 22 against HCT-15 cells was as low as
1.64 lM. Meanwhile, the IC50 values of 22 against MGC-
803, Bel7402, and MCF-7 cells were found to be 3.28, 4.21,
and 6.94 lM, respectively. Importantly, all the prepared
compounds displayed no apparent cytotoxicity towards
normal cell line HSF (IC50 [ 100 lM), indicating that these
oxime derivatives showed good cellular selectivity.
Results and discussion
The general synthetic routes of title compounds were
illustrated in Schemes 1 and 2. 6-Methyl-1,4-naphtho-
quione (3) was prepared by the Diels–Alder addition of 1
equivalent of isoprene to 1,4-benzoquinone (1), followed
by aromatisation of the ( )-6-methyl-c-4a,5,8,8a-tetrahy-
dro-1,4-naphthoquinone (2). However, it was unnecessary
to isolate the olefin 2 since extensive decomposition could
occur on silica gel column. In addition, many attempts
using DDQ [18, 19], active MnO2 [20], CuBr/LiBr [21],
NH4NO3/HOAc [22], 35% HNO3 [23] as oxidative
reagents for aromatisation of 2 provided 3 with unsatis-
factory yields, but this oxidative reaction could be
123

6-Substituted 1,4-naphthoquinone oxime derivatives (I): synthesis and evaluation of their…
1013
Scheme 1
O
O
O
O
O
O
a
.4H
2O
2SO4
N
2Cr2O4
H
NBS, AIBN
isoprene, AcOH
-CHCl3
CCl4
CH3
Br
CH2
CH3
O
1
O
4
3
2
OCH3
OCH3
O
i. Na
, Bu4NBr
MnO2
CH Cl
,
2S2O4
2
2
1,4-dioxane
ii. (CH3)2SO4, KOH
H
2O
CH2OH
CHO
CH
2OH
OCH3
6
OCH3
OCH3
O
5
7
OCH3
O
60% NaH, DMF
isopentyl iodide
R1Br, Mg
THF
CAN, EtOAc
R1
R1
R2
H
2O
R1
OCH3
OH
OCH3
O
O
O
8a-8f
R2
9a-9f
10a-10f
HO
N
NH2OH.HCl
R1 = butyl, pentyl, hexyl, octyl, decyl, dodecyl
R1
R2
2 = isopentyl
R
N
O
HO
14 - 19
Scheme 2
O
O
OCH3
OCH3
OCH3
tri-O-methylgallic acid
CAN, EtOAc
H2O
R1
R2
R1
R1
DCC, DMAP
O
O
OCH3
OH
R2
12a-12f
11a-11f
8a-8f
NH2OH.HCl
CAN, EtOAc
O
O
HO
HO
HO
N
N
N
N
NH2OH.HCl
R1
OH
i. KOH, MeOH, H2O
ii. 6 N HCl
R1
R1
OH
O
R2
HO
13a-13f
26 - 31
20 - 25
R1 = butyl, pentyl, hexyl, octyl, decyl, dodecyl
R2 = 3,4,5-trimethoxybenzoyl
Compounds 20–25 bearing 3,4,5-trimethoxybenzoyl
moiety exhibited much stronger inhibitory action than the
corresponding compounds 14–19 containing isopentenyl
group, which was in good agreement with our previous
investigation that introduction of acyl groups at the 10-OH of
shikonin resulted in an increase of its cytotoxic effects [6].
For example, compound 20 showed significant cytotoxicity
at lower concentration (IC50 = 4.42, 8.23, 9.98, and
16.2 lM), which was superior to the cytotoxicity induced by
compound 14 (IC50 = 6.71, 15.5, 18.6, and 30.8 lM) in
HCT-15 cells, MGC-803 cells, Bel7402 cells, and MCF-7
cells, respectively. Meanwhile, it should be pointed that the
123

1014
G. Huang et al.
Table 1 In vitro cytotoxicity of target compounds against HCT-15, MGC-803, Bel7402, MCF-7, and HSF cell lines
Compounds
cLogPa
ICb50/lM on cell lines
HCT-15
MGC-803
Bel-7402
MCF-7
HSF
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
ADM
5-FU
a
4.69
5.10
5.52
6.35
7.19
8.02
4.50
4.92
5.33
6.17
7.0
6.71
4.62
2.52
8.16
20.4
72.8
4.42
2.98
1.64
6.35
11.4
17.3
46.5
30.2
13.4
7.56
2.27
4.96
2.74
8.24
15.5
8.43
5.68
12.3
27.1
[100
8.23
4.45
3.28
9.23
17.8
43.5
56.3
43.6
33.7
14.2
4.21
12.8
1.19
[100
18.6
11.4
9.02
17.8
36.4
[100
9.98
5.76
4.21
15.3
21.2
39.6
67.4
53.1
32.5
19.7
6.32
8.65
1.32
21.9
30.8
19.7
15.3
33.6
62.9
[100
16.2
10.1
6.94
13.6
29.7
57.2
85.8
59.2
39.4
16.1
8.76
10.5
0.42
29.5
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
4.52
7.84
2.75
3.17
3.59
4.42
5.26
6.09
-1.34
–0.90
[100
Indicates that the values of cLogP for all compounds were calculated through ChemDraw 12.0
b
IC50 values were calculated from three independent experiments
cytotoxicities of oxime derivatives seemed to be closely
isopentyloxy or 3,4,5-trimethoxybenzoyl group expressed
relatively low cytotoxicity against cancer cell lines with
higher cLogP values.
related with their sizes of alkyl chain. The optimal size of
alkyl group (R1) for anticancer activities of oxime deriva-
tives (R2 = isopentyloxy or 3,4,5-trimethoxybenzoyl) was
hexyl because the larger or smaller one would lead to the
decline in inhibitory activity. However, the cytotoxicity of
some oxime derivatives (R2 = H) tended to increase with
the length of alkyl chain (Table 1, R1 = butyl, pentyl, hexyl,
octyl, or decyl). Obviously, the anticancer activity of these
compounds was maximal for compound 30 (R1 = decyl),
which showed IC50 values of 2.27 lM against HCT-15 cells.
On the other hand, the cytotoxicity of these oxime
derivatives correlated well with their cLogP values
(Table 1). For instance, compounds 16, 22, and 30
exhibited potent cytotoxicity against HCT-15 cells with
cLogP value of 5.52, 5.53, and 5.26, respectively, whereas
compounds 18, 19, and 25 with higher cLogP value
(7.19–8.02) or compounds 26–28 with lower cLogP value
(2.75–3.59) showed minor anticancer activity. Therefore,
cLogP value was commendably responsible for the strong
cytotoxicity of oxime derivatives 30 and 31 (R2 = H),
while the corresponding compounds possessing
Conclusion
In conclusion, eighteen 6-substituted 1,4-naphthoquinone
oxime derivatives were synthesized and screened for their
cytotoxicity against four cancer cell lines and one normal
cells, wherein, compounds 16, 22, and 30 exhibited much
stronger cytotoxic activity against HCT-15 cells than ADM
and 5-FU. Meanwhile, all the prepared compounds showed
low cytotoxicity towards HSF cells. Moreover, the cyto-
toxicity of these compounds was closely associated with
their sizes of alkyl chain R1 and substituents R2 of branch
chain, implying that the appropriate lipophilicity was
responsible for their potent cytotoxicity. Thus, the syn-
thesis of 6-substituted 1,4-naphthoquinone oxime
derivatives with enhanced antitumor activity and further
modification of branch chain (R1 or R2) and aromatic ring
is suggested in the following work.
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6-Substituted 1,4-naphthoquinone oxime derivatives (I): synthesis and evaluation of their…
1015
General procedure for the synthesis of compounds
8a–8f
Experimental
Reagents and solvents were obtained from commercial
suppliers. Column chromatography was conducted on sil-
ica gel (100-200 mesh) from Qingdao Ocean Chemical
Factory. Melting points were determined on an SGW X-4
1-Bromoalkane (14.1 mmol) was added dropwise at 50 °C
to a stirred suspension of 0.34 g of magnesium powder
(14.3 mmol) and a catalytic amount of iodine in 10.0 cm3
anhydrous THF. After stirring at 50 °C for 2 h, a solution of
0.61 g of aldehyde 7 (2.82 mmol) in 4.0 cm3 dry THF was
added to the solution of alkylmagnesium bromide prepared
above. The solution was stirred for 5 h at room temperature
and then quenched with saturated NH4Cl solution. The
mixture was extracted with dichloromethane and washed
with brine, dried, and concentrated. The residue was purified
by flash column chromatography to afford 8a–8f.
1
micromelting point apparatus. H NMR (400 MHz) and
13C NMR (100 MHz) spectra were recorded on a Varian
MERCURY plus-400 spectrometer with TMS as an inter-
nal standard. Mass spectra and HRMS spectra were
recorded on a Shimadzu LC–MS-2010EV mass spec-
trometer and Waters Q-TOF Premier Mass Spectrometer,
respectively. Compounds 3, 4 [24], and 5 [11] were pre-
pared according to known procedures.
1-(5,8-Dimethoxynaphthalen-2-yl)pentan-1-ol
5,8-Dimethoxy-2-naphthalenemethanol (6, C13H14O3)
To a suspension solution of 2.50 g of 5 (13.3 mmol) and
0.64 g of N-butylammonium bromide (2.0 mmol) in
60 cm3 THF-H2O (V/V = 3:1) was added 23.2 g of sodium
dithionite (133.0 mmol) in portion. The reaction mixture
was stirred at room temperature for 30 min. An aqueous
KOH (17.9 g (319.2 mmol) in 20.0 cm3 H2O) was added
to the reaction mixture at 0 °C. After 20 min, 30.0 cm3
dimethyl sulfate (319.2 mmol) was added dropwise. The
solution was allowed to stir at room temperature for 16 h,
which was extracted with dichloromethane and washed
with brine, dried, and concentrated to yield yellow oil. The
residue was then purified by flash column chromatography
to afford compound 6 as white solid. Yield 2.32 g (80%);
m.p.: 75–77 °C; 1H NMR (400 MHz, CDCl3):
d = 8.19–8.14 (m, 2H, ArH), 7.49 (dd, J = 8.4, 1.6 Hz,
1H, ArH), 6.70–6.65 (m, 2H, ArH), 4.83 (s, 2H, CH2OH),
3.93 (s, 6H, 29 OCH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 149.4, 138.4, 126.2, 125.7, 125.1, 122.3,
119.5, 103.6, 103.2, 65.6 (OCH3), 55.7 (OCH3) ppm.
(8a, C17H22O3)
Colorless oil; yield 0.70 g (91%); 1H NMR (400 MHz,
CDCl3): d = 8.09 (d, J = 8.6 Hz, 1H, ArH), 8.04 (s, 1H,
ArH), 7.41 (dd, J = 8.6, 1.6 Hz, 1H, ArH), 6.62–6.57 (m, 2H,
ArH), 4.73 (t, J = 6.6 Hz, 1H, CHOH), 3.87 (s, 3H, OCH3),
3.86 (s, 3H, OCH3), 1.81–1.75 (m, 1H, 1/29 (CHCH2)),
1.74–1.66 (m, 1H, 1/29 (CHCH2)), 1.34–1.20 (m, 4H,
CH2CH2), 0.78 (t, J = 6.8 Hz, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 148.4, 141.4, 125.1, 124.7, 122.9,
121.2, 117.6, 102.4, 102.1, 74.0, 54.7, 54.6, 37.7, 27.0, 21.6,
13.0 ppm; MS (ESI): m/z = 289 ([M ? H]?).
1-(5,8-Dimethoxynaphthalen-2-yl)hexan-1-ol
(8b, C18H24O3)
Colorless oil; yield 0.74 g (90%); 1H NMR (400 MHz,
CDCl3): d = 8.11 (d, J = 8.6 Hz, 1H, ArH), 8.05 (s, 1H,
ArH), 7.42 (dd, J = 8.6, 1.6 Hz, 1H, ArH), 6.63-6.58 (m,
2H, ArH), 4.75 (t, J = 6.6 Hz, 1H, CHOH), 3.88 (s, 3H,
OCH3), 3.87 (s, 3H, OCH3), 1.82–1.77 (m, 1H,
1/29 (CHCH2)), 1.73–1.67 (m, 1H, 1/29 (CHCH2)),
1.39–1.32 (m, 1H, 1/29 CH2), 1.23–1.18 (m, 5H,
1/29 CH2 and CH2CH2), 0.79 (t, J = 6.8 Hz, 3H, CH3)
ppm; 13C NMR (100 MHz, CDCl3): d = 148.4, 141.4,
125.1, 124.7, 122.9, 121.2, 117.6, 102.4, 102.1, 74.0, 54.7,
54.6, 38.0, 30.7, 24.5, 21.6, 13.0 ppm.
5,8-Dimethoxynaphthalene-2-carbaldehyde
(7, C13H12O3)
A mixture of 2.18 g of 6 (10.0 mmol) and 13.0 g of
activated MnO2 power (150 mmol) in 40 cm3 dichloro-
methane was refluxed for 16 h. After cooling, the resulting
precipitate was filtered and evaporation of the filtrate
afforded yellow solid. The residue was purified by flash
column chromatography to afford compound 7 as light
yellow solid. Yield 2.14 g (99%); m.p.: 93–94 °C; 1H
NMR (400 MHz, CDCl3): d = 10.13 (s, 1H, CHO), 8.69
(s, 1H, ArH), 8.27 (d, J = 8.4 Hz, 1H, ArH), 7.93 (t,
J = 4.0 Hz, 1H, ArH), 6.85 (d, J = 8.4 Hz, 1H, ArH),
6.76 (d, J = 8.4 Hz, 1H, ArH), 3.97 (s, 3H, OCH3), 3.95 (s,
3H, OCH3) ppm; 13C NMR (100 MHz, CDCl3): d = 192.6
(CHO), 150.3, 149.3, 133.8, 129.0, 125.5, 123.0, 122.5,
107.0, 104.4, 55.8 (OCH3), 55.7 (OCH3) ppm; MS (ESI):
m/z = 275 ([M ? H]?).
1-(5,8-Dimethoxynaphthalen-2-yl)heptan-1-ol
(8c, C19H26O3)
Colorless oil; yield 0.75 g (88%); 1H NMR (400 MHz,
CDCl3): d = 8.09 (d, J = 8.4 Hz, 1H, ArH), 8.04 (s, 1H,
ArH), 7.41 (dd, J = 8.4, 1.6 Hz, 1H, ArH), 6.62–6.57 (m,
2H, ArH), 4.73 (t, J = 6.4 Hz, 1H, CHOH), 3.87 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 1.81–1.75 (m, 1H,
1/29 (CHCH2)), 1.71–1.66 (m, 1H, 1/29 (CHCH2)),
1.36–1.29 (m, 1H, 1/29 CH2), 1.24–1.14 (m, 7H,
1/29 CH2 and 39 CH2), 0.77 (t, J = 6.8 Hz, 3H, CH3)
ppm; 13C NMR (100 MHz, CDCl3): d = 149.4, 142.4,
123

1016
G. Huang et al.
126.1, 125.7, 124.0, 122.2, 118.6, 103.4, 103.0, 75.0, 55.7,
55.6, 39.0, 31.8, 29.2, 25.8, 22.6, 14.1 ppm.
was purified by flash column chromatography to afford 9a–
9f as colorless oil.
1-(5,8-Dimethoxynaphthalen-2-yl)nonan-1-ol
6-[1-(Isopentyloxy)pentyl]-1,4-dimethoxynaphthalene
(9a, C22H32O3)
(8d, C21H30O3)
Colorless oil; yield 0.80 g (86%); 1H NMR (400 MHz,
CDCl3): d = 8.08 (d, J = 8.4 Hz, 1H, ArH), 8.02 (s, 1H,
ArH), 7.39 (d, J = 8.4 Hz, 1H, ArH), 6.61–6.53 (m, 2H,
ArH), 4.70 (J = 6.4 Hz, 1H, CHOH), 3.84 (s, 6H,
29 OCH3), 1.75–1.67 (m, 2H, CH(OH)CH2), 1.33-1.29
(m, 1H, 1/29 CH2), 1.17–1.14 (m, 11H, 1/29 CH2 and
59 CH2), 0.77 (t, J = 6.8 Hz, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 149.4, 142.5, 126.1, 125.7, 124.0,
122.2, 118.7, 103.3, 103.0, 74.9, 55.7, 55.6, 39.1, 32.7,
31.9, 29.6, 29.3, 25.9, 22.7, 14.2 ppm.
Yield 0.42 g (81%); 1H NMR (400 MHz, CDCl3):
d = 8.12 (d, J = 8.6 Hz, 1H, ArH), 7.98 (s, 1H, ArH),
7.42 (d, J = 8.6 Hz, 1H, ArH), 6.64-6.57 (m, 2H, ArH),
4.25 (t, J = 6.4 Hz, 1H, CHOH), 3.88 (s, 3H, OCH3), 3.87
(s, 3H, OCH3), 3.27–3.15 (m, 2H, OCH2CH2), 1.85–1.76
(m, 1H, CH(CH3)2), 1.65–1.60 (m, 1H, 1/29 (CHCH2)),
1.51–1.44 (m, 1H, 1/29 (CHCH2)), 1.39–1.32 (m, 2H,
OCH2CH2), 1.25–1.17 (m, 4H, CH2CH2), 0.81–0.71 (m,
9H, 39 CH3) ppm; 13C NMR (100 MHz, CDCl3):
d = 148.5, 148.4, 139.9, 124.9, 124.7, 121.1, 118.8,
102.3, 101.9, 81.8, 66.4, 54.7, 54.6, 37.8, 37.0, 28.6,
27.1, 24.0, 21.6, 21.5, 13.0 ppm; MS (ESI): m/z = 345
([M ? H]?).
1-(5,8-Dimethoxynaphthalen-2-yl)undecan-1-ol
(8e, C23H34O3)
Colorless oil; yield 0.91 g (90%); 1H NMR (400 MHz,
CDCl3): d = 8.09 (d, J = 8.4 Hz, 1H, ArH), 8.04 (s, 1H,
ArH), 7.41 (d, J = 8.4 Hz, 1H, ArH), 6.62–6.56 (m, 2H,
ArH), 4.72 (t, J = 6.6 Hz, 1H, CHOH), 3.86 (s, 6H,
29 OCH3), 1.76–1.70 (m, 2H, CH(OH)CH2), 1.46-1.41
(m, 2H, CH2), 1.18–1.15 (m, 14H, 79 CH2), 0.79 (t,
J = 6.8 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):
d = 149.4, 142.5, 126.1, 125.7, 124.0, 122.2, 118.6, 103.4,
103.0, 75.0, 55.7, 55.6, 39.0, 32.8, 31.9, 29.6, 29.6, 29.6,
29.3, 25.7, 22.7, 14.1 ppm.
6-[1-(Isopentyloxy)hexyl]-1,4-dimethoxynaphthalene
(9b, C23H34O3)
Yield 0.45 g (83%); 1H NMR (400 MHz, CDCl3):
d = 8.12 (d, J = 8.6 Hz, 1H, ArH), 7.98 (s, 1H, ArH),
7.42 (d, J = 8.6 Hz, 1H, ArH), 6.59 (t, J = 6.0 Hz, 2H,
ArH), 4.25 (t, J = 6.4 Hz, 1H, CHOH), 3.88 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 3.26–3.16 (m, 2H, OCH2),
1.84–1.77 (m, 1H, CH(CH3)2), 1.65–1.57 (m, 2H, CHCH2),
1.50–1.44 (m, 1H, 1/29 (OCH2CH2)), 1.39–1.34 (m, 2H,
1/29 (OCH2CH2) and 1/29 CH2), 1.20–1.15 (m, 5H,
1/29 CH2 and 29 CH2), 0.78–0.72 (m, 9H, 39 CH3)
ppm; 13C NMR (100 MHz, CDCl3): d = 148.5, 148.4,
141.4, 125.1, 124.7, 122.9, 121.2, 118.8, 102.4, 102.1,
81.8, 67.8, 54.7, 54.6, 38.0, 37.3, 28.6, 27.4, 24.5, 24.0,
21.5, 13.0 ppm; MS (ESI): m/z = 359 ([M ? H]?).
1-(5,8-Dimethoxynaphthalen-2-yl)tridecan-1-ol
(8f, C25H38O3)
Colorless oil; yield 1.0 g (92%); 1H NMR (400 MHz,
CDCl3): d = 8.08 (d, J = 8.4 Hz, 1H, ArH), 8.03 (s, 1H,
ArH), 7.40 (d, J = 8.4 Hz, 1H, ArH), 6.61–6.54 (m, 2H,
ArH), 4.71 (t, J = 6.6 Hz, 1H, CHOH), 3.85 (s, 6H,
29 OCH3), 1.76–1.67 (m, 2H, CH(OH)CH2), 1.47–1.40
(m, 2H, CH2), 1.17–1.14 (m, 18H, 99 CH2), 0.80 (t,
J = 6.8 Hz, 3H) ppm; 13C NMR(100 MHz, CDCl3):
d = 149.4, 142.5, 126.0, 125.7, 124.0, 122.2, 118.6,
103.3, 102.9, 75.0, 55.7, 55.6, 39.0, 32.8, 31.9, 29.7,
29.6, 29.5, 29.4, 25.9, 25.8, 22.7, 14.2 ppm.
6-[1-(Isopentyloxy)heptyl]-1,4-dimethoxynaphthalene
(9c, C24H36O3)
Yield 0.48 g (86%); 1H NMR (400 MHz, CDCl3):
d = 8.11 (d, J = 8.4 Hz, 1H, ArH), 7.98 (s, 1H, ArH),
7.42 (d, J = 8.4 Hz, 1H, ArH), 6.58 (t, J = 6.4 Hz, 2H,
ArH), 4.25 (t, J = 6.4 Hz, 1H, CHOH), 3.87 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 3.26–3.15 (m, 2H, OCH2),
1.64–1.58 (m, 2H, CH(CH3)2 and 1/29 (CHCH2)),
1.38–1.33 (m, 3H, 1/29 (CHCH2) and OCH2CH2),
1.20–1.16 (m, 8H, 49 CH2), 0.77–0.72 (m, 9H, 39 CH3)
ppm; 13C NMR (100 MHz, CDCl3): d = 149.5, 149.4,
140.9, 126.0, 125.8, 124.3, 122.2, 119.9, 103.2, 102.8,
82.8, 67.2, 55.7, 55.6, 38.8, 38.4, 31.8, 29.8, 29.3, 26.0,
25.0, 22.7, 22.5, 14.1 ppm.
General procedure for the synthesis of compounds
9a–9f
NaH (60%; 0.24 g, 6.0 mmol) was added in portion at 0 °C
to a stirred solution of alcohol 8 (1.50 mmol) in 10 cm3
anhydrous DMF. After 45 min, a solution of alkyl iodide
(6.0 mmol) in 2.0 cm3 anhydrous DMF was added to the
reaction mixture, which was stirred at 60 °C for 12 h. After
cooling, the reaction mixture was quenched with saturated
NH4Cl solution, and then extracted with dichloromethane,
washed with brine, dried, and concentrated. The residue
6-[1-(Isopentyloxy)nonyl]-1,4-dimethoxynaphthalene
(9d, C26H40O3)
Yield 0.49 g (82%); 1H NMR (400 MHz, CDCl3):
d = 8.12 (d, J = 8.4 Hz, 1H, ArH), 7.98 (s, 1H, ArH),
123

6-Substituted 1,4-naphthoquinone oxime derivatives (I): synthesis and evaluation of their…
1017
7.42 (d, J = 8.4 Hz, 1H, ArH), 6.63–6.57 (m, 2H, ArH),
4.25 (t, J = 6.4 Hz, 1H, CHOH), 3.87 (s, 3H, OCH3), 3.86
(s, 3H, OCH3), 3.35–3.24 (m, 2H, OCH2), 1.63–1.58 (m,
2H, CH(CH3)2 and 1/29 (CHCH2)), 1.39–1.34 (m, 3H,
1/29 (CHCH2) and OCH2CH2), 1.18–1.14 (m, 12H,
69 CH2), 0.78 (m, 9H, 39 CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 149.5, 149.4, 140.9, 126.0,
125.8, 124.3, 122.2, 119.9, 103.3, 102.9, 82.8, 67.2, 55.7,
55.6, 38.8, 38.4, 31.9, 29.6, 29.5, 29.3, 26.0, 25.0, 22.7,
22.5, 14.1 ppm.
1-(5,8-Dimethoxynaphthalen-2-yl)pentyl 3,4,5-trimethoxy-
benzoate (11a, C27H32O7)
Yield 0.44 g (94%); 1H NMR (400 MHz, CDCl3): d = 8.18
(s, 1H, ArH), 8.12 (d, J = 8.6 Hz, 1H, ArH), 7.48 (dd,
J = 8.6, 1.6 Hz, 1H, ArH), 7.28 (s, 2H, ArH), 6.61 (s, 2H,
ArH), 6.06 (t, J = 7.0 Hz, 1H, ArCHOCO), 3.87 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 3.84 (s, 6H, 29 OCH3), 3.82
(s, 3H, OCH3), 2.13–2.04 (m, 1H, 1/29 (CHCH2)),
1.98–1.89 (m, 1H, 1/29 (CHCH2)), 1.34–1.24 (m, 4H,
CH2CH2), 0.81 (t, J = 7.0 Hz, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 164.6, 151.9, 148.4, 141.1, 137.2,
125.0, 124.9, 124.7, 123.2, 121.3, 118.7, 117.6, 105.9,
102.5, 102.4, 59.9, 55.2, 54.7, 54.6, 35.1, 28.7, 26.7, 21.5,
13.0 ppm; MS (ESI): m/z = 469 ([M ? H]?).
6-[1-(Isopentyloxy)undecyl]-1,4-dimethoxynaphthalene
(9e, C28H44O3)
Yield 0.50 g (78%); 1H NMR (400 MHz, CDCl3):
d = 8.12 (d, J = 8.4 Hz, 1H, ArH), 7.98 (s, 1H, ArH),
7.42 (d, J = 8.4 Hz, 1H, ArH), 6.64–6.57 (m, 2H, ArH),
4.25 (t, J = 6.8 Hz, 1H, CHOH), 3.88 (s, 3H, OCH3), 3.87
(s, 3H, OCH3), 3.36–3.29 (m, 2H, OCH2), 1.63–1.57 (m,
2H, CH(CH3)2 and 1/29 (CHCH2)), 1.39–1.34 (m, 3H,
1/29 (CHCH2) and OCH2CH2), 1.18–1.15 (m, 16H,
89 CH2), 0.83–0.77 (m, 9H, 39 CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 149.5, 149.4, 140.9, 125.9, 125.7,
124.3, 122.1, 119.9, 103.3, 102.9, 82.8, 67.2, 55.7, 55.6,
38.8, 38.3, 31.9, 29.8, 29.6, 29.5, 29.3, 26.2, 26.0, 25.0,
22.7, 22.7, 14.1 ppm.
1-(5,8-Dimethoxynaphthalen-2-yl)hexyl 3,4,5-trimethoxy-
benzoate (11b, C28H34O7)
Yield 0.44 g (92%); 1H NMR (400 MHz, CDCl3): d = 8.18
(s, 1H, ArH), 8.12 (d, J = 8.6 Hz, 1H, ArH), 7.48 (dd,
J = 8.6, 1.6 Hz, 1H, ArH), 7.29 (s, 2H, ArH), 6.62 (s, 2H,
ArH), 6.06 (t, J = 7.0 Hz, 1H, ArCHOCO), 3.87 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 3.84 (s, 6H, 29 OCH3), 3.82 (s,
3H, OCH3), 2.12–2.03 (m, 1H, 1/29 (CHCH2)), 1.97–1.88
(m, 1H, 1/29 (CHCH2)), 1.40–1.33 (m, 1H, 1/29 CH2),
1.28–1.20 (m, 5H, 1/29 CH2 and CH2CH2), 0.78 (t,
J = 7.0 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):
d = 164.6, 151.9, 148.4, 141.1, 137.2, 125.0, 124.9, 124.7,
123.2, 121.3, 118.7, 105.9, 102.5, 102.4, 59.9, 55.2, 54.7,
54.6, 35.3, 30.5, 28.7, 24.2, 21.5, 13.0 ppm; MS (ESI):
m/z = 483 ([M ? H]?).
6-[1-(Isopentyloxy)tridecyl]-1,4-dimethoxynaphthalene
(9f, C30H48O3)
Yield 80%; colorless oil; 1H NMR (400 MHz, CDCl3):
d = 8.11 (d, J = 8.4 Hz, 1H, ArH), 7.97 (s, 1H, ArH),
7.41 (d, J = 8.4 Hz, 1H, ArH), 6.59–6.54 (m, 2H, ArH),
4.24 (t, J = 6.4 Hz, 1H, CHOH), 3.85 (s, 3H, OCH3), 3.83
(s, 3H, OCH3), 3.34–3.23 (m, 2H, OCH2), 1.63–1.58 (m,
2H, CH(CH3)2 and 1/29 (CHCH2)), 1.38–1.33 (m, 3H,
1/29 (CHCH2) and OCH2CH2), 1.16–1.13 (m, 20H,
109 CH2), 0.80–0.74 (m, 9H, 39 CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 149.5, 149.4, 140.9, 126.0, 125.8,
124.3, 122.2, 119.9, 103.2, 102.8, 82.8, 67.2, 55.7, 55.6,
38.8, 38.4, 32.0, 29.8, 29.7, 29.6, 29.4, 26.0, 25.0, 22.7,
22.5, 14.2 ppm; MS (ESI): m/z = 457 ([M ? H]?).
1-(5,8-Dimethoxynaphthalen-2-yl)heptyl 3,4,5-trimethoxy-
benzoate (11c, C29H36O7)
Yield 0.47 g (94%); 1H NMR (400 MHz, CDCl3): d = 8.18
(s, 1H, ArH), 8.12 (d, J = 8.6 Hz, 1H, ArH), 7.48 (d,
J = 8.6 Hz, 1H, ArH), 7.28 (s, 2H, ArH), 6.61 (s, 2H, ArH),
6.05 (t, J = 7.0 Hz, 1H, ArCHOCO), 3.87 (s, 3H, OCH3),
3.86 (s, 3H, OCH3), 3.84 (s, 6H, 29 OCH3), 3.82(s, 3H,
OCH3), 2.13–2.04 (m, 1H, 1/29 (CHCH2)), 1.97–1.88 (m,
1H, 1/29 (CHCH2)), 1.38–1.25 (m, 4H, 29 CH2), 1.21–1.18
(m, 4H, 29 CH2), 0.77 (t, J = 7.0 Hz, 3H, CH3) ppm; 13C
NMR (100 MHz, CDCl3): d = 164.6, 151.8, 148.4, 148.3,
141.0, 137.2, 125.0, 124.8, 124.7, 123.2, 121.3, 118.7, 105.8,
102.4, 102.3, 59.9, 55.2, 54.7, 54.6, 35.4, 30.6, 28.0, 24.5,
21.5, 13.0 ppm; MS (ESI): m/z = 497 ([M ? H]?).
General procedure for the synthesis of compounds
11a–11f
To a stirred solution of alcohol 8 (1.0 mmol) and 0.32 g of
3,4,5-trimethoxybenzoic acid (1.5 mmol) in 10.0 cm3
anhydrous dichloromethane were added 0.31 g of DCC
(1.5 mmol) and 61 mg of DMAP (0.5 mmol). After stirring
overnight at room temperature, petroleum ether was added
to the reaction mixture at 4 °C to facilitate precipitates, and
then the solution was filtered and concentrated in vacuo.
The residue was purified by flash chromatography to afford
11a–11f as colorless oil.
1-(5,8-Dimethoxynaphthalen-2-yl)nonyl 3,4,5-trimethoxy-
benzoate (11d, C31H40O7)
Yield 0.45 g (86%); 1H NMR (400 MHz, CDCl3):
d = 8.18 (s, 1H, ArH), 8.13 (d, J = 8.6 Hz, 1H, ArH),
7.48 (d, J = 8.6 Hz, 1H, ArH), 7.18 (s, 1H, ArH), 6.62 (s,
2H, ArH), 6.06 (t, J = 7.0 Hz, 1H, ArCHOCO), 3.87 (s,
6H, 29 OCH3), 3.84 (s, 6H, 29 OCH3), 3.83 (s, 3H,
OCH3), 2.10–2.03 (m, 1H, 1/29 (CHCH2)), 1.95–1.88 (m,
123

1018
G. Huang et al.
1H, 1/29 (CHCH2)), 1.40–1.34 (m, 1H, 1/29 CH2),
1.28–1.24 (m, 3H, 1/29 CH2 and CH2), 1.18–1.16 (m,
8H, 49 CH2), 0.78 (t, J = 7.0 Hz, 3H, CH3) ppm; MS
(ESI): m/z = 525 ([M ? H]?).
6-[1-(Isopentyloxy)pentyl]-1,4-naphthoquinone
(10a, C20H26O3)
Yield 0.20 g (80%); 1H NMR (400 MHz, CDCl3):
d = 8.00 (d, J = 8.0 Hz, 1H, ArH), 7.91 (s, 1H, ArH),
7.65 (dd, J = 8.0, 1.4 Hz, 1H, ArH), 6.90 (s, 2H, QuinH),
4.24 (t, J = 6.8 Hz, 1H, ArCHOCH2), 3.25–3.18 (m, 2H,
OCH2), 1.76–1.67 (m, 1H, CH(CH3)2), 1.65–1.60 (m, 1H,
1/29 (CHCH2)), 1.58–1.52 (m, 1H, 1/29 (CHCH2)),
1.41–1.34 (m, 2H, OCH2 CH2), 1.26–1.21 (m, 4H,
CH2CH2), 0.83–0.75 (m, 9H, 39 CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 184.2 (C=O), 183.8 (C=O), 149.7,
137.7, 137.6, 130.9, 130.7, 130.1, 125.8, 123.6, 109.0,
80.8, 66.8, 37.7, 36.9, 28.5, 26.8, 23.9, 21.6, 21.5,
13.0 ppm; MS (ESI): m/z = 315 ([M ? H]?).
1-(5,8-Dimethoxynaphthalen-2-yl)undecyl
3,4,5-
trimethoxybenzoate (11e, C33H44O7)
Yield 0.48 g (87%); 1H NMR (400 MHz, CDCl3):
d = 8.18 (s, 1H, ArH), 8.13 (d, J = 8.6 Hz, 1H, ArH),
7.48 (d, J = 8.6 Hz, 1H, ArH), 7.29 (s, 2H, ArH),
6.65–6.59 (m, 2H, ArH), 6.05 (t, J = 6.8 Hz, 1H,
ArCHOCO), 3.87 (s, 6H, 29 OCH3), 3.84 (s, 6H,
29 OCH3), 3.83 (s, 3H, OCH3), 2.13–2.05 (m, 1H,
1/29 (CHCH2)), 1.97–1.88 (m, 1H, 1/29 (CHCH2)),
1.39–1.34 (m, 1H, 1/29 CH2), 1.28–1.23 (m, 3H,
1/29 CH2 and CH2), 1.18–1.15 (m, 12H, 69 CH2), 0.79
(t, J = 7.0 Hz, 3H, CH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 164.6, 151.8, 148.4, 141.0, 137.2, 125.0,
124.8, 124.7, 123.2, 121.3, 118.7, 117.6, 105.8, 102.4,
102.3, 59.9, 55.2, 54.7, 54.6, 38.0, 35.4, 30.9, 28.6, 28.5,
28.4, 28.3, 24.6, 21.7, 13.1 ppm.
6-[1-(Isopentyloxy)hexyl]-1,4-naphthoquinone
(10b, C21H28O3)
Yield 0.22 g (85%); 1H NMR (400 MHz, CDCl3):
d = 8.00 (d, J = 8.0 Hz, 1H, ArH), 7.91 (s, 1H, ArH),
7.64 (d, J = 8.0 Hz, 1H, ArH), 6.90 (s, 2H, QuinH),
4.27–4.22 (m, 1H, ArCHOCH2), 3.25–3.18 (m, 2H,
OCH2), 1.67–1.60 (m, 1H, CH(CH3)2), 1.56–1.47 (m, 2H,
CHCH2), 1.41–1.36 (m, 2H, CH2), 1.21–1.16 (m, 6H,
39 CH2), 0.81–0.75 (m, 9H, 39 CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 184.2 (C=O), 183.9 (C=O), 149.7,
137.7, 137.6, 130.9, 130.7, 130.1, 125.8, 123.6, 80.8, 66.8,
37.7, 37.1, 30.6, 28.5, 24.3, 23.9, 21.6, 21.5, 13.0 ppm; MS
(ESI): m/z = 329 ([M ? H]?).
1-(5,8-Dimethoxynaphthalen-2-yl)tridecyl
3,4,5-
trimethoxybenzoate (11f, C35H48O7)
Yield 0.52 g (90%); 1H NMR (400 MHz, CDCl3):
d = 8.18 (s, 1H, ArH), 8.13 (d, J = 8.6 Hz, 1H, ArH),
7.49 (d, J = 8.6 Hz, 1H, ArH), 7.29 (s, 2H, ArH), 6.63 (d,
J = 8.6 Hz, 2H, ArH), 6.06 (t, J = 6.8 Hz, 1H, ArCH-
OCO), 3.88 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.85 (s,
6H, 29 OCH3), 3.83 (s, 3H, OCH3), 2.13–2.03 (m, 1H,
1/29 (CHCH2)), 1.98–1.90 (m, 1H, 1/29 (CHCH2)),
1.40–1.33 (m, 1H, 1/29 CH2), 1.29–1.24 (m, 3H,
1/29 CH2 and CH2), 1.18–1.15 (m, 16H, 89 CH2), 0.81
(d, J = 7.0 Hz, 3H, CH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 164.6, 151.8, 148.4, 141.0, 137.2, 125.0,
124.8, 124.7, 123.2, 121.3, 118.7, 105.8, 102.4, 102.3,
59.9, 55.2, 54.7, 54.6, 35.4, 30.9, 28.6, 28.5, 28.4, 28.3,
24.6, 21.7, 13.1 ppm.
6-[1-(Isopentyloxy)heptyl]-1,4-naphthoquinone
(10c, C22H30O3)
Yield 0.21 g (75%); 1H NMR (400 MHz, CDCl3):
d = 8.01 (d, J = 8.0 Hz, 1H, ArH), 7.91 (s, 1H, ArH),
7.65 (d, J = 8.0 Hz, 1H, ArH), 6.91 (s, 2H, QuinH),
4.28–4.21 (m, 1H, ArCHOCH2), 3.23 (t, J = 6.8 Hz, 2H,
OCH2), 1.75–1.68 (m, 1H, CH(CH3)2), 1.66–1.61 (m, 1H,
1/29 (CHCH2)), 1.58–1.51 (m, 1H, 1/29 (CHCH2)),
1.41–1.36 (m, 2H, CH2), 1.22–1.13 (m, 8H, 49 CH2),
0.81–0.76 (m, 9H, 39 CH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 184.2 (C=O), 183.9 (C=O), 149.7, 137.7,
137.6, 130.8, 130.7, 130.0, 125.8, 123.5, 80.8, 66.8, 37.6,
37.2, 30.7, 28.1, 24.6, 23.9, 21.6, 21.5, 13.1 ppm.
General procedure for the synthesis of compounds
10a–10f and 12a–13f
A solution of 1.15 g of CAN (2.10 mmol) in 1.2 cm3 water
was dropwise added to a solution of 5,8-dimethoxynaph-
thalene derivatives (0.80 mmol) in 8 cm3 ethyl acetate at
0 °C. After 8 min, the reaction mixture was diluted with
water and extracted with ethyl acetate, washed with brine,
dried over anhydrous magnesium sulfate, and then con-
centrated. The residue was purified by flash column
chromatography to afford 10a–10f and 12a–13f as yellow
oils.
6-[1-(Isopentyloxy)nonyl]-1,4-naphthoquinone
(10d, C24H34O3)
Yield 0.25 g (83%); 1H NMR (400 MHz, CDCl3):
d = 8.00 (d, J = 8.0 Hz, 1H, ArH), 7.90 (s, 1H, ArH),
7.64 (d, J = 8.0 Hz, 1H, ArH), 6.90 (s, 2H, QuinH),
4.26–4.22 (m, 1H, ArCHOCH2), 3.22 (t, J = 6.8 Hz, 2H,
OCH2), 1.75–1.69 (m, 1H, CH(CH3)2), 1.68–1.60 (m, 1H,
1/29 (CHCH2)), 1.57–1.49 (m, 1H, 1/2 9 (CHCH2)),
123

6-Substituted 1,4-naphthoquinone oxime derivatives (I): synthesis and evaluation of their…
1019
1.41–1.36 (m, 2H, CH2), 1.16 (m, 12H, 69 CH2),
0.81–0.75 (m, 9H, 39 CH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 184.2 (C=O), 183.8 (C=O), 149.7, 137.7,
137.6, 130.8, 130.7, 130.0, 125.8, 123.5, 80.8, 66.8, 37.6,
37.2, 30.8, 28.4, 28.2, 24.6, 23.9, 21.6, 21.6, 21.5,
13.1 ppm.
7.70 (d, J = 8.0 Hz, 1H, ArH), 7.26 (s, 2H, ArH), 6.90 (s,
2H, QuinH), 5.95–5.90 (m, 1H, ArCHOCO), 3.85 (s, 6H,
29 OCH3), 3.84 (s, 3H, OCH3), 2.06–1.99 (m, 1H,
1/29 (CHCH2)), 1.91–1.82 (m, 1H, 1/29 (CHCH2)),
1.42–1.35 (m, 1H, 1/29 CH2), 1.29–1.21 (m, 5H,
1/29 CH2 and 29 CH2), 0.80 (t, J = 7.0 Hz, 3H, CH3)
ppm; 13C NMR (100 MHz, CDCl3): d = 183.9 (C=O),
183.6 (C=O), 164.5, 152.0, 146.7, 141.5, 137.7, 137.6,
131.1, 130.7, 130.3, 125.9, 123.8, 123.0, 105.9, 75.1, 59.9,
55.3, 35.2, 30.4, 24.1, 21.4, 12.9 ppm.
6-[1-(Isopentyloxy)undecyl]-1,4-naphthoquinone
(10e, C26H38O3)
Yield 0.26 g (81%); 1H NMR (400 MHz, CDCl3): d = 8.00
(d, J = 8.0 Hz, 1H, ArH), 7.91 (s, 1H, ArH), 7.65 (d,
J = 8.0 Hz, 1H, ArH), 6.90 (s, 2H, QuinH), 4.26–4.22 (m,
1H, ArCHOCH2), 3.22 (t, J = 6.8 Hz, 2H, OCH2), 1.74–1.67
(m, 1H, CH(CH3)2), 1.66–1.61 (m, 1H, 1/29 (CHCH2)),
1.58–1.49 (m, 1H, 1/29 (CHCH2)), 1.41–1.36 (m, 2H, CH2),
1.22–1.13 (m, 16H, 89 CH2), 0.82–0.75 (m, 9H, 39 CH3)
ppm; 13C NMR (100 MHz, CDCl3): d = 184.2 (C=O), 183.9
(C=O), 149.7, 137.7, 137.6, 130.8, 130.7, 130.0, 125.8, 123.5,
80.8, 66.8, 37.6, 37.1, 30.9, 28.5, 28.4, 28.3, 24.6, 23.9, 21.7,
21.6, 21.5, 13.1 ppm.
6-[1-(3,4,5-Trimethoxybenzoyloxy)heptyl]-1,4-naphtho-
quinone (12c, C27H30O3)
Yield 0.3 g (82%); 1H NMR (400 MHz, CDCl3): d = 8.06
(s, 1H, ArH), 8.01 (d, J = 8.0 Hz, 1H, ArH), 7.70 (d,
J = 8.0 Hz, 1H, ArH), 7.26 (s, 2H, 2ArH), 6.90 (s, 2H,
QuinH), 5.95–5.90 (m, 1H, ArCHOCO), 3.86 (s, 6H,
29 OCH3), 3.84 (s, 3H, OCH3), 2.08–1.98 (m, 1H,
1/29 (CHCH2)), 1.91–1.82 (m, 1H, 1/29 (CHCH2)),
1.41–1.35 (m, 1H, 1/29 CH2), 1.32–1.25 (m, 3H,
1/29 CH2 and CH2), 1.22–1.17 (m, 4H, CH2CH2), 0.79
(t, J = 7.0 Hz, 3H, CH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 183.9 (C=O), 183.6 (C=O), 164.5, 152.0,
146.7, 141.4, 137.7, 137.6, 131.1, 130.7, 130.2, 125.9,
123.7, 123.0, 109.0, 105.8, 75.2, 59.9, 55.2, 35.2, 30.6,
27.9, 24.4, 21.5, 13.0 ppm.
6-[1-(Isopentyloxy)tridecyl]-1,4-naphthoquinone
(10f, C28H42O3)
Yield 0.27 g (79%); 1H NMR (400 MHz, CDCl3):
d = 8.00 (d, J = 8.0 Hz, 1H, ArH), 7.91 (s, 1H, ArH),
7.64 (d, J = 8.0 Hz, 1H, ArH), 6.90 (s, 2H, QuinH),
4.27–4.22 (m, 1H, ArCHOCH2), 3.22 (t, J = 6.8 Hz, 2H,
OCH2), 1.75–1.71 (m, 1H, CH(CH3)2), 1.67–1.61 (m, 1H,
1/29 (CHCH2)), 1.57–1.50 (m, 1H, 1/29 (CHCH2)),
1.41–1.36 (m, 2H, CH2), 1.16 (m, 20H, 109 CH2),
0.81–0.75 (m, 9H, 39 CH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 184.2 (C=O), 183.8 (C=O), 149.7, 137.7,
137.6, 130.8, 130.7, 130.0, 125.8, 123.5, 80.8, 66.8, 37.6,
37.2, 30.9, 28.6, 28.5, 28.4, 28.3, 24.6, 23.9, 21.7, 21.6,
21.5, 13.1 ppm; MS (ESI): m/z = 427 ([M ? H]?).
6-[1-(3,4,5-Trimethoxybenzoyloxy)nonyl]-1,4-naphtho-
quinone (12d, C29H34O3)
Yield 0.26 g (65%); 1H NMR (400 MHz, CDCl3):
d = 8.06 (s, 1H, ArH), 8.01 (d, J = 8.0 Hz, 1H, ArH),
7.70 (d, J = 8.0 Hz, 1H, ArH), 7.26 (s, 2H, ArH), 6.91 (s,
2H, QuinH), 5.95–5.90 (m, 1H, ArCHOCO), 3.86 (s, 6H,
29 OCH3), 3.84 (s, 3H, OCH3), 2.07–1.98 (m, 1H,
1/29 (CHCH2)), 1.89–1.82 (m, 1H, 1/29 (CHCH2)),
1.41–1.35 (m, 1H, 1/29 CH2), 1.30–1.26 (m, 2H),
1.22–1.13 (m, 9H), 0.79 (t, J = 7.0 Hz, 3H, CH3) ppm;
13C NMR (100 MHz, CDCl3): d = 183.9, 183.6, 164.5,
152.0, 146.7, 141.5, 137.7, 137.6, 131.1, 130.7, 130.3,
125.9, 123.7, 123.0, 105.8, 75.2, 60.0, 55.2, 35.2, 30.8,
28.3, 28.2, 28.1, 24.4, 21.6, 13.1 ppm.
6-[1-(3,4,5-Trimethoxybenzoyloxy)pentyl]-1,4-naphtho-
quinone (12a, C25H26O3)
Yield 0.25 g (71%); 1H NMR (400 MHz, CDCl3): d = 8.06
(s, 1H, ArH), 8.01 (d, J = 8.0 Hz, 1H, ArH), 7.70 (d,
J = 8.0 Hz, 1H, ArH), 7.26 (s, 2H, 2ArH), 6.90 (s, 2H,
QuinH), 5.95–5.91 (m, 1H, ArCHOCO), 3.86 (s, 6H,
29 OCH3), 3.84 (s, 3H, OCH3), 2.07–2.00 (m, 1H,
1/29 (CHCH2)), 1.92–1.84 (m, 1H, 1/29 (CHCH2)),
1.35–1.25 (m, 4H, 29 CH2), 0.83 (t, J = 7.0 Hz, 3H,
CH3) ppm; 13C NMR (100 MHz, CDCl3): d = 183.9
(C=O), 183.6 (C=O), 164.5, 152.0, 146.7, 141.6, 137.7,
137.6, 131.1, 130.7, 130.3, 125.9, 123.8, 123.0, 105.9, 75.1,
59.9, 55.3, 34.9, 26.6, 21.4, 12.9 ppm; MS (ESI): m/z = 439
([M ? H]?).
6-[1-(3,4,5-Trimethoxybenzoyloxy)undecyl]-1,4-naphtho-
quinone (12e, C31H38O3)
Yield 0.31 g (74%); 1H NMR (400 MHz, CDCl3):
d = 8.06 (s, 1H, ArH), 8.01 (d, J = 8.0 Hz, 1H, ArH),
7.70 (d, J = 8.0 Hz, 1H, ArH), 7.26 (s, 2H, 2ArH), 6.91 (s,
2H, QuinH), 5.95–5.90 (m, 1H, ArCHOCO), 3.86 (s, 6H,
29 OCH3), 3.84 (s, 3H, OCH3), 2.08–1.99 (m, 1H,
1/29 (CHCH2)), 1.91–1.82 (m, 1H, 1/29 (CHCH2)),
1.30–1.26 (m, 2H, CH2), 1.23–1.15 (m, 14H, 79 CH2),
0.80 (t, J = 7.0 Hz, 3H, CH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 183.9, 183.6, 164.5, 152.0, 146.7, 141.4,
137.7, 137.6, 131.1, 130.7, 130.2, 125.9, 123.7, 123.0,
6-[1-(3,4,5-Trimethoxybenzoyloxy)hexyl]-1,4-naphtho-
quinone (12b, C26H28O3)
Yield 0.27 g (75%); 1H NMR (400 MHz, CDCl3):
d = 8.06 (s, 1H, ArH), 8.00 (d, J = 8.0 Hz, 1H, ArH),
123

1020
G. Huang et al.
105.8, 75.2, 59.9, 55.2, 35.2, 30.8, 28.5, 28.4, 28.3, 28.2,
24.4, 21.6, 13.1 ppm.
General procedure for the synthesis of target
compounds 14–27
6-[1-(3,4,5-Trimethoxybenzoyloxy)tridecyl]-1,4-naphtho-
quinone (12f, C33H42O3)
A mixture of 1,4-naphthoquione derivatives (0.50 mmol),
0.24 g of hydroxylamine hydrochloride (3.5 mmol), and
0.28 g of pyridine (3.5 mmol) in 12.0 cm3 anhydrous
ethanol was stirred at 50 °C for 12 h. After cooling, the
reaction mixture was extracted with dichloromethane and
washed with brine, dried, and concentrated. The residue
was purified by flash column chromatography to afford 14–
27.
Yield 0.31 g (71%); 1H NMR (400 MHz, CDCl3):
d = 8.06 (s, 1H, ArH), 8.01 (d, J = 8.0 Hz, 1H, ArH),
7.70 (d, J = 8.0 Hz, 1H, ArH), 7.26 (s, 2H, ArH), 6.91 (s,
2H, QuinH), 5.95–5.89 (m, 1H, ArCHOCO), 3.86 (s, 6H,
29 OCH3), 3.84 (s, 3H, OCH3), 2.07–1.98 (m, 1H,
1/29 (CHCH2)), 1.91–1.82 (m, 1H, 1/29 (CHCH2)),
1.41–1.35 (m, 1H), 1.32–1.25 (m, 3H), 1.21–1.16 (m,
16H), 0.80 (t, J = 7.0 Hz, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 183.9, 183.6, 164.5, 152.0, 146.7,
141.4, 137.7, 137.6, 131.1, 130.7, 130.2, 125.9, 123.7,
123.0, 109.0, 105.8, 75.2, 60.0, 55.2, 35.2, 30.9, 28.6, 28.5,
28.4, 28.3, 28.2, 24.4, 21.7, 13.1 ppm; MS (ESI): m/
z = 551 ([M ? H]?).
(1E,4E)-6-[1-(Isopentyloxy)pentyl]-1,4-naphthoquinone
dioxime (14, C20H28N2O3)
1
White solid; yield 90.2 mg (54%); m.p.: 171–173 °C; H
NMR (400 MHz, CDCl3): d = 8.03 (d, J = 8.2 Hz, 1H,
ArH), 7.96 (s, 1H, ArH), 7.52 (s, 2H, ArH), 7.37 (d,
J = 8.2 Hz, 1H, ArH), 4.19 (t, J = 6.8 Hz, 1H,
ArCHOCH2), 3.33–3.25 (m, 1H, 1/29 OCH2), 3.24–3.17
(m, 1H, 1/29 OCH2), 1.82–1.74 (m, 1H, CH(CH3)2),
1.66–1.56 (m, 2H, ArCHCH2), 1.43–1.38 (m, 1H,
1/29 (OCH2CH2)), 1.27–1.18 (m, 7H, 1/29 (OCH2CH2)
and 39 CH2), 0.80–0.75 (m, 9H, 39 CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 148.1, 148.0, 144.8, 128.8, 128.0,
127.6, 123.1, 121.0, 119.5, 119.4, 82.3, 67.4, 38.7, 37.8,
29.7, 28.0, 24.9, 22.7, 22.6, 14.0 ppm; HRMS (ESI): m/
z = 345.2180 ([M ? H]?).
6-(1-Hydroxypentyl)-1,4-naphthoquione
(13a, C15H16O3)
Yield 0.14 g (70%); 1H NMR (400 MHz, CDCl3):
d = 7.99–7.93 (m, 2H, 2ArH), 7.68 (d, J = 8.0 Hz, 1H,
ArH), 6.89 (s, 2H, QuinH), 4.78–4.74 (m, 1H, ArCHOH),
1.74–1.65 (m, 2H, CHCH2), 1.36–1.23 (m, 4H, CH2CH2),
0.81 (t, J = 8.0 Hz, 3H, CH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 184.1, 183.8, 150.7, 137.7, 137.6, 130.9,
130.2, 130.0, 125.8, 122.7, 72.8, 37.9, 26.6, 21.5,
12.9 ppm; MS (ESI): m/z = 245 ([M ? H]?).
(1E,4E)-6-[1-(Isopentyloxy)hexyl]-1,4-naphthoquinone
dioxime (15, C21H30N2O3)
6-(1-Hydroxyhexyl)-1,4-naphthoquione (13b, C16H18O3)
Yield 0.14 g (70%); 1H NMR (400 MHz, CDCl3):
d = 7.97–7.90 (m, 2H, ArH), 7.67 (dd, J = 8.0, 1.6 Hz,
1H, ArH), 6.88 (s, 2H, QuinH), 4.77–4.73 (m, 1H,
ArCHOH), 1.73–1.62 (m, 2H, CHCH2), 1.38–1.31 (m,
1H), 1.25–1.17 (m, 5H), 0.79 (t, J = 7.0 Hz, 3H, CH3)
ppm; 13C NMR (100 MHz, CDCl3): d = 184.1, 183.8,
150.8, 137.7, 137.6, 130.8, 130.2, 125.8, 122.7, 105.9,
72.8, 38.1, 30.6, 24.2, 21.5, 13.0 ppm; MS (ESI): m/
z = 259 ([M ? H]?).
1
White solid; yield 85.7 mg (48%); m.p.: 165–166 °C; H
NMR (400 MHz, DMSO-d6): d = 12.18 (s, 2H,
29 (= NOH)), 8.07 (d, J = 8.4 Hz, 1H, ArH), 8.00 (s,
1H, ArH), 7.43 (s, 2H, ArH), 7.39 (d, J = 8.4 Hz, 1H,
ArH), 4.28 (t, J = 6.4 Hz, 1H, ArCHOCH2), 3.28–3.21 (m,
2H, OCH2), 1.73–1.64 (m, 2H, CH(CH3)2 and
1/29 (ArCHCH2)), 1.59–1.43 (m, 2H, 1/29 (ArCHCH2)
and 1/29 (OCH2CH2)), 1.39–1.33 (m, 2H, 1/29 (OCH2-
CH2) and 1/29 CH2), 1.29–1.20 (m, 5H, 1/29 CH2 and
CH2CH2), 0.86–0.78 (m, 9H, 39 CH3) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 146.8, 146.7, 144.1, 129.2,
128.5, 127.5, 122.9, 120.4, 118.9, 81.4, 66.8, 38.7, 37.9,
31.5, 25.2, 24.9, 22.9, 22.7, 22.5, 14.3 ppm; HRMS (ESI):
m/z = 359.2335 ([M ? H]?).
6-(1-Hydroxytridecyl)-1,4-naphthoquione
(13f, C23H32O3)
Yield 0.21 g (72%); 1H NMR (400 MHz, CDCl3):
d = 7.98–7.94 (m, 2H, ArH), 7.68 (d, J = 8.0 Hz, 1H,
ArH), 6.89 (s, 2H, QuinH), 4.78–4.73 (m, 1H, ArCHOH),
1.73–1.62 (m, 2H, CHCH2), 1.39–1.29 (m, 1H, 1/29 CH2),
1.23–1.16 (m, 17H, 1/29 CH2 and 89 CH2), 0.80 (t,
J = 7.0 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3)
d = 148.4, 141.4, 125.0, 124.7, 123.0, 121.1, 117.6, 102.3,
101.9, 73.9, 54.6, 38.0, 31.7, 30.9, 28.6, 28.4, 24.9, 24.7,
21.7, 13.1 ppm.
(1E,4E)-6-[1-(Isopentyloxy)heptyl]-1,4-naphthoquinone
dioxime (16, C22H32N2O3)
White solid; yield 0.14 g (74%); m.p.: 157–159 °C; 1H
NMR (400 MHz, DMSO-d6): d = 12.15 (d, J = 2.2 Hz,
2H, 29 (= NOH)), 8.03 (d, J = 8.4 Hz, 1H, ArH), 7.95 (s,
1H, ArH), 7.38 (s, 2H, 2ArH), 7.32 (d, J = 8.4 Hz, 1H,
123

6-Substituted 1,4-naphthoquinone oxime derivatives (I): synthesis and evaluation of their…
1021
ArH), 4.20 (t, J = 6.4 Hz, 1H, ArCHOCH2), 3.18 (t,
J = 6.4 Hz, 2H, OCH2), 1.64–1.58 (m, 2H, CH(CH3)2 and
1/29 (ArCHCH2)), 1.52–1.45 (m, 1H, 1/29 (ArCHCH2)),
1.33–1.27 (m, 2H, CH2, OCH2CH2), 1.19–1.13 (m, 8H,
49 CH2), 0.78–0.72 (m, 9H, 39 CH3) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 146.8, 146.7, 144.1, 129.2,
128.5, 127.4, 122.9, 120.4, 118.9, 81.4, 66.8, 38.7, 38.1,
31.7, 29.0, 25.6, 24.9, 22.9, 22.7, 22.5, 14.3 ppm; HRMS
(ESI): m/z = 373.2489 ([M ? H]?).
128.5, 127.3, 122.8, 120.4, 118.9, 81.5, 66.8, 38.7, 38.1,
31.8, 29.5, 29.4, 29.3, 29.2, 25.6, 24.9, 22.9, 22.7, 22.6,
14.3 ppm; HRMS (ESI): m/z = 457.3427 ([M ? H]?).
(1E,4E)-6-[1-(3,4,5-Trimethoxybenzoyloxy)pentyl]-1,4-
naphthoquinone dioxime (20, C25H28N2O7)
1
Light-yellow oil; yield 0.17 g (74%); H NMR (400 MHz,
CDCl3): d = 8.08 (s, 1H, ArH), 7.99 (d, J = 8.4 Hz, 1H,
ArH), 7.45 (s, 2H, ArH), 7.42 (d, J = 8.4 Hz, 1H, ArH),
7.29 (s, 2H, ArH), 5.94 (t, J = 6.8 Hz, 1H, ArCHOCO),
3.82 (s, 9H, 39 OCH3), 2.07–2.00 (m, 1H,
1/29 (ArCHCH2)), 1.91–1.84 (m, 1H, 1/29 (ArCHCH2)),
1.34–1.25 (m, 4H, CH2CH2), 0.81 (t, J = 6.8 Hz, 3H,
CH3) ppm; 13C NMR (100 MHz, CDCl3): d = 164.8,
151.9, 146.9, 146.7, 141.3, 141.1, 128.0, 127.5, 126.3,
124.2, 122.3, 119.7, 118.5, 118.4, 106.0, 59.9, 55.3, 35.0,
28.7, 26.6, 21.4, 12.9 ppm; HRMS (ESI): m/z = 469.1977
([M ? H]?).
(1E,4E)-6-[1-(Isopentyloxy)nonyl]-1,4-naphthoquinone
dioxime (17, C24H36N2O3)
White solid; yield 0.13 g (65%); m.p.: 150–152 °C; 1H
NMR (400 MHz, DMSO-d6): d = 12.14 (s, 2H,
29 (=NOH)), 8.02 (d, J = 8.4 Hz, 1H, ArH), 7.95 (s,
1H, ArH), 7.38 (s, 2H, ArH), 7.32 (d, J = 8.4 Hz, 1H,
ArH), 4.21 (t, J = 6.4 Hz, 1H, ArCHOCH2), 3.19 (t,
J = 6.4 Hz, 2H, OCH2), 1.65–1.57 (m, 2H, CH(CH3)2 and
1/29 (ArCHCH2)), 1.53–1.44 (m, 1H, 1/29 (ArCHCH2)),
1.34–1.25 (m, 3H, OCH2CH2 and 1/29 CH2), 1.19–1.13
(m, 11H), 0.79–0.73 (m, 9H, 39 CH3) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 146.8, 146.7, 144.1, 129.2,
128.5, 127.4, 122.8, 120.4, 118.9, 81.4, 66.8, 38.7, 38.0,
31.7, 29.4, 29.3, 29.0, 25.5, 24.9, 22.9, 22.7, 22.5,
14.3 ppm; HRMS (ESI): m/z = 401.2801 ([M ? H]?).
(1E,4E)-6-[1-(3,4,5-Trimethoxybenzoyloxy)hexyl]-1,4-
naphthoquinone dioxime (21, C26H30N2O7)
1
Light-yellow oil; yield 0.19 g (79%); H NMR (400 MHz,
CDCl3): d = 8.08 (s, 1H, ArH), 8.01 (d, J = 8.4 Hz, 1H,
ArH), 7.45 (s, 2H, ArH), 7.42 (d, J = 8.4 Hz, 1H, ArH),
7.28 (s, 2H, ArH), 5.93 (t, J = 6.8 Hz, 1H, ArCHOCO),
3.83 (s, 9H, 39 OCH3), 2.04–1.98 (m, 1H,
1/29 (ArCHCH2)), 1.89–1.83 (m, 1H, 1/29 (ArCHCH2)),
1.38–1.33 (m, 1H, 1/29 CH2), 1.26–1.21 (m, 5H), 0.78 (t,
J = 6.8 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):
d = 164.8, 151.9, 146.9, 146.8, 141.3, 141.1, 128.0, 127.5,
126.3, 124.2, 122.3, 119.7, 118.5, 118.4, 106.0, 59.9, 55.3,
35.2, 30.5, 24.1, 21.4, 13.0 ppm; HRMS (ESI):
m/z = 483.2135 ([M ? H]?).
(1E,4E)-6-[1-(Isopentyloxy)undecyl]-1,4-naphthoquinone
dioxime (18, C26H40N2O3)
White solid; yield 76%; m.p.: 147–148 °C; 1H NMR
(400 MHz, DMSO-d6): d = 12.14 (d, J = 4.0 Hz, 2H,
29 (=NOH)), 8.02 (d, J = 8.4 Hz, 1H, ArH), 7.95 (s, 1H,
ArH), 7.38 (s, 2H, ArH), 7.31 (d, J = 8.4 Hz, 1H, ArH),
4.20 (t, J = 6.4 Hz, 1H, ArCHOCH2), 3.18 (t, J = 6.4 Hz,
2H, OCH2), 1.66–1.56 (m, 2H, CH(CH3)2 and
1/29 (ArCHCH2)), 1.51–1.46 (m, 1H, 1/29 (ArCHCH2)),
1.33–1.26 (m, 3H, OCH2CH2 and 1/29 CH2), 1.19–1.12
(m, 15H), 0.79–0.72 (m, 9H, 39 CH3) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 146.7, 146.6, 144.0, 129.2,
128.5, 127.3, 122.8, 120.4, 118.9, 81.5, 66.8, 38.7, 38.0,
31.7, 30.2, 29.4, 29.3, 29.2, 25.5, 24.9, 22.9, 22.7, 22.5,
14.4 ppm; HRMS (ESI): m/z = 429.3122 ([M ? H]?).
(1E,4E)-6-[1-(3,4,5-Trimethoxybenzoyloxy)heptyl]-1,4-
naphthoquinone dioxime (22, C27H32N2O7)
1
Light-yellow oil; yield 0.21 g (82%); H NMR (400 MHz,
CDCl3): d = 8.08 (s, 1H, ArH), 8.00 (d, J = 8.4 Hz, 1H,
ArH), 7.46 (s, 2H, 2ArH), 7.43 (d, J = 8.4 Hz, 1H, ArH),
7.29 (s, 2H, ArH), 5.94 (t, J = 6.8 Hz, 1H, ArCHOCO),
3.83 (s, 9H, 39 OCH3), 2.07–1.99 (m, 1H,
1/29 (ArCHCH2)), 1.91–1.84 (m, 1H, 1/29 (ArCHCH2)),
1.31–1.24 (m, 3H), 1.20–1.16 (m, 5H), 0.77 (t, J = 6.8 Hz,
3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): d = 165.8,
152.9, 147.8, 147.7, 142.1, 129.0, 128.4, 127.4, 125.2,
123.3, 120.6, 119.6, 119.5, 106.9, 61.0, 56.3, 36.3, 31.6,
29.7, 29.0, 25.5, 22.5, 14.1 ppm; HRMS (ESI):
m/z = 497.2285 ([M ? H]?).
(1E,4E)-6-[1-(Isopentyloxy)tridecyl]-1,4-naphthoquinone
dioxime (19, C28H44N2O3)
White solid; yield 0.18 g (78%); m.p.: 144–145 °C; 1H
NMR (400 MHz, DMSO-d6): d = 12.13 (d, J = 4.8 Hz,
2H, 29 (=NOH)), 8.02 (d, J = 8.4 Hz, 1H, ArH), 7.95 (s,
1H, ArH), 7.38 (s, 2H, ArH), 7.30 (d, J = 8.4 Hz, 1H,
ArH), 4.19 (t, J = 6.4 Hz, 1H, ArCHOCH2), 3.18 (t,
J = 6.4 Hz, 2H, OCH2), 1.66–1.56 (m, 2H, CH(CH3)2 and
1/29 (ArCHCH2)), 1.51–1.44 (m, 1H, 1/29 (ArCHCH2)),
1.33–1.27 (m, 3H, OCH2CH2 and 1/29 CH2), 1.19–1.12
(m, 19H), 0.79–0.72 (m, 9H, 39 CH3) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 146.7, 146.6, 144.0, 129.3,
(1E,4E)-6-[1-(3,4,5-Trimethoxybenzoyloxy)nonyl]-1,4-
naphthoquinone dioxime (23, C29H36N2O7)
1
Light-yellow oil; yield 0.22 g (85%); H NMR (400 MHz,
CDCl3): d = 9.31 (s, 2H, 29 (= NOH)), 8.08 (s, 1H, ArH),
8.00 (d, J = 8.4 Hz, 1H, ArH), 7.46 (s, 2H, ArH), 7.43 (d,
J = 8.4 Hz, 1H, ArH), 7.29 (s, 2H, ArH), 5.94 (t,
123

1022
G. Huang et al.
J = 6.8 Hz, 1H, ArCHOCO), 3.83 (s, 9H, 39 OCH3),
2.08–1.97 (m, 1H, 1/29 (ArCHCH2)), 1.91–1.82 (m, 1H,
1/29 (ArCHCH2)), 1.29–1.24 (m, 3H), 1.20–1.15 (m, 9H),
0.78 (t, J = 6.8 Hz, 3H, CH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 165.8, 152.9, 147.9, 147.7, 142.3, 142.1,
129.0, 128.4, 127.4, 125.2, 123.3, 120.6, 119.6, 119.5,
106.9, 61.0, 56.3, 36.3, 31.8, 29.4, 29.3, 29.2, 25.5, 22.6,
14.1 ppm; HRMS (ESI): m/z = 525.2597 ([M ? H]?).
(1E,4E)-6-(1-Hydroxyhexyl)-1,4-naphthoquinone dioxime
(27, C16H20N2O3)
1
White solid; yield 119.0 mg (83%); m.p.: 182–184 °C; H
NMR (400 MHz, DMSO-d6): d = 12.14 (d, J = 7.4 Hz, 2H,
29 (= NOH)), 8.05 (s, 1H, ArH), 8.03 (d, J = 8.4 Hz, 1H,
ArH), 7.41 (s, 2H, ArH), 7.40 (s, 1H, ArH), 5.25 (d,
J = 4.2 Hz, 1H, CHOH), 4.57 (dd, J = 10.6, 5.4 Hz, 1H,
ArCHOH), 1.64–1.56(m, 2H, ArCHCH2), 1.37–1.30(m, 1H),
1.26–1.20 (m, 5H), 0.84 (t, J = 6.8 Hz, 3H, CH3) ppm; 13
C
(1E,4E)-6-[1-(3,4,5-Trimethoxybenzoyloxy)undecyl]-1,4-
NMR (100 MHz, DMSO-d6):d = 147.5,146.9,146.8,129.0,
127.9,127.2,122.5,119.7,119.0,118.9,72.4, 31.7, 25.3, 22.5,
14.4 ppm; HRMS (ESI): m/z = 289.1550 ([M ? H]?).
naphthoquinone dioxime (24, C31H40N2O7)
1
Light-yellow oil; yield 0.21 g (82%); H NMR (400 MHz,
CDCl3): d = 9.59 (s, 2H, 29 (= NOH)), 8.07 (s, 1H, ArH),
7.98 (d, J = 8.4 Hz, 1H, ArH), 7.44 (s, 2H, ArH), 7.41 (d,
J = 8.4 Hz, 1H, ArH), 7.29 (s, 2H, ArH), 5.95 (t,
J = 6.8 Hz, 1H, ArCHOCO), 3.83 (s, 9H, 39 OCH3),
2.07–1.98 (m, 1H, 1/29 (ArCHCH2)), 1.91–1.83 (m, 1H,
1/29 (ArCHCH2)), 1.38–1.33 (m, 1H, 1/29 CH2),
1.30–1.26 (m, 3H, 1/29 CH2 and CH2), 1.20–1.13 (m,
12H, 69 CH2), 0.76 (t, J = 6.8 Hz, 3H, CH3) ppm; 13C
NMR (100 MHz, CDCl3): d = 165.9, 152.9, 147.8, 147.7,
142.2, 142.1, 129.0, 128.4, 127.4, 125.2, 123.3, 120.6,
119.6, 119.5, 106.9, 61.0, 56.3, 36.3, 31.9, 29.6, 29.5, 29.4,
29.3, 25.5, 22.7, 14.1 ppm; HRMS (ESI): m/z = 553.2917
([M ? H]?).
General procedure for the synthesis of target
compounds 28–31
A solution of 5.0 cm3 sodium hydroxide (10 N) was
dropwise added to a solution of ester oxime (0.2 mmol) in
15 cm3 MeOH. The reaction mixture was stirred at 80 °C
for 5 h. After cooling, the solution was brought to acidic
pH by careful addition of 6 N HCl and then extracted with
dichloromethane and washed with brine, dried, and con-
centrated. The residue was purified by flash column
chromatography to afford 28–31.
(1E,4E)-6-(1-Hydroxyheptyl)-1,4-naphthoquinone dioxime
(1E,4E)-6-[1-(3,4,5-Trimethoxybenzoyloxy)tridecyl]-1,4-
naphthoquinone dioxime (25, C33H44N2O7)
(28, C17H22N2O3)
1
White solid; yield 35.4 mg (59%); m.p. 167–169 °C; H
Light-yellow oil; yield 225.3 mg (78%); 1H NMR (400 MHz,
CDCl3): d = 8.08 (s, 1H, ArH), 8.00 (d, J = 8.4 Hz, 1H,
ArH), 7.46 (s, 2H, ArH), 7.43 (d, J = 8.4 Hz, 1H, ArH), 7.29
(s, 2H, ArH), 5.94 (t, J = 6.8 Hz, 1H, ArCHOCO), 3.84 (s,
9H, 39 OCH3), 2.07–1.99 (m, 1H, 1/29 (ArCHCH2)),
1.91–1.82 (m, 1H, 1/29 (ArCHCH2)), 1.30–1.26 (m, 3H),
NMR (400 MHz, DMSO-d6): d = 12.14 (d, J = 7.4 Hz,
2H, 29 (=NOH)), 8.05 (s, 1H, ArH), 8.03 (d, J = 8.4 Hz,
1H, ArH), 7.42 (s, 2H, 2ArH), 7.40 (s, 1H, ArH), 5.25 (d,
J = 4.2 Hz, 1H, CHOH), 4.57 (dd, J = 10.6, 5.4 Hz, 1H,
ArCHOH), 1.64–1.56 (m, 2H, ArCHCH2), 1.35–1.29 (m,
1H), 1.26–1.19 (m, 7H), 0.84 (t, J = 6.8 Hz, 3H, CH3)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 147.5, 146.9,
146.8, 129.0, 127.9, 127.2, 122.5, 119.7, 119.0, 118.9,
72.4, 31.7, 29.1, 25.6, 22.5, 14.4 ppm; HRMS (ESI): m/
z = 303.1711 ([M ? H]?).
1.21–1.15 (m, 17H), 0.79 (t, J = 6.8 Hz, 3H, CH3) ppm; 13
C
NMR (100 MHz, CDCl3): d = 165.8, 152.9, 147.9, 147.7,
129.0, 128.4, 127.4, 125.2, 123.3, 120.6, 119.6, 119.5, 106.9,
61.0, 56.2, 36.3, 31.9, 31.5, 31.4, 30.2, 30.1, 29.7, 29.6, 29.5,
29.4, 25.5, 22.7, 14.1 ppm; HRMS (ESI): m/z = 581.3232
([M ? H]?).
(1E,4E)-6-(1-Hydroxynonyl)-1,4-naphthoquinone dioxime
(29, C19H26N2O3)
(1E,4E)-6-(1-Hydroxypentyl)-1,4-naphthoquinone dioxime
1
White solid; yield 42.0 mg (64%); m.p.: 162–164 °C; H
(26, C15H18N2O3)
NMR (400 MHz, DMSO-d6): d = 12.14 (d, J = 6.2 Hz,
2H, 29 (= NOH)), 8.05 (s, 1H, ArH), 8.02 (d, J = 8.4 Hz,
1H, ArH), 7.41 (s, 2H, ArH), 7.40 (d, J = 2.0 Hz, 1H, ArH),
5.25 (d, J = 4.2 Hz, 1H, CHOH), 4.57 (dd, J = 10.6,
5.4 Hz, 1H, ArCHOH), 1.65–1.56 (m, 2H, ArCHCH2),
1.25–1.19 (m, 12H, 69 CH2), 0.83 (t, J = 6.8 Hz, 3H, CH3)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 147.5, 146.9,
146.8, 129.0, 127.9, 127.2, 122.5, 119.7, 119.0, 118.9, 72.5,
31.7, 29.4, 29.1, 25.6, 22.5, 14.4 ppm; HRMS (ESI): m/
z = 331.2023 ([M ? H]?).
1
White solid; yield 103.3 mg (75%); m.p.: 187–189 °C; H
NMR (400 MHz, DMSO-d6): d = 12.16 (d, J = 9.6 Hz,
2H, 29 (=NOH)), 8.05 (s, 1H, ArH), 8.03 (d, 1H,
J = 8.4 Hz, ArH), 7.41 (s, 3H, ArH), 5.26 (d,
J = 4.2 Hz, 1H, CHOH), 4.57 (dd, J = 10.6, 5.4 Hz, 1H,
ArCHOH), 1.65–1.57 (m, 2H, ArCHCH2), 1.30–1.57 (m,
4H, CH2CH2), 0.84 (t, J = 6.8 Hz, 3H, CH3) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 147.5, 146.9, 146.8,
129.0, 127.9, 127.1, 122.5, 119.7, 118.9, 72.4, 27.9, 22.5,
14.4 ppm; HRMS (ESI): m/z = 275.1396 ([M ? H]?).
123

6-Substituted 1,4-naphthoquinone oxime derivatives (I): synthesis and evaluation of their…
1023
Acknowledgements The research was supported by National Natural
Science Foundation of China (No. 81373274 and No. 81673281) and
Ph.D. Programs Foundation of Ministry of Education China (No.
20120073110068). We are also grateful to the Instrumental Analysis
(1E,4E)-6-(1-Hydroxyundecyl)-1,4-naphthoquinone diox-
ime (30, C21H30N2O3)
1
White solid; yield 46.7 mg (65%); m.p.: 154–157 °C; H
Center of Shanghai Jiao Tong University for recording the 1H and 13
NMR spectra.
C
NMR (400 MHz, DMSO-d6): d = 12.13 (d, J = 6.2 Hz,
2H, 29 (=NOH)), 8.05 (s, 1H, ArH), 8.03 (d, J = 8.4 Hz,
1H, ArH), 7.42 (s, 2H, ArH), 7.40 (d, J = 2.0 Hz, 1H,
ArH), 5.24 (d, J = 4.2 Hz, 1H, CHOH), 4.57 (J = 10.6,
5.4 Hz, 1H, ArCHOH), 1.65–1.56 (m, 2H, ArCHCH2),
1.26–1.18 (m, 16H, 89 CH2), 0.84 (t, J = 6.8 Hz, 3H,
CH3) ppm; 13C NMR (100 MHz, DMSO-d6): d = 147.4,
146.9, 146.8, 129.0, 127.9, 127.1, 122.5, 119.7, 118.9,
118.8, 72.5, 31.7, 29.4, 29.1, 25.6, 22.5, 14.4 ppm; HRMS
(ESI): m/z = 359.2335 ([M ? H]?).
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White solid; yield 53.4 mg (69%); m.p.: 142–143 °C; H
NMR (400 MHz, DMSO-d6): d = 12.11 (d, J = 4.8 Hz,
2H, 29 (=NOH)), 8.02 (s, 1H, ArH), 7.99 (d, J = 8.4 Hz,
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