The construction of novel perylenequinone core via efficient synthesis of versatile ortho-naphthoquinone as a key intermediate

Article abstract of DOI:10.1016/j.tet.2009.03.057

The novel perylenequinone core, 1,12-diacetonitrile-3,10-perylenequinone, was successfully prepared from the dimerization of the key intermediate, 3-acetonitrile-1,2-naphthoquinone, which was synthesized by an efficient synthetic route in relatively short

Full text of DOI:10.1016/j.tet.2009.03.057

Tetrahedron 65 (2009) 4625–4628
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The construction of novel perylenequinone core via efficient synthesis
of versatile ortho-naphthoquinone as a key intermediate
,
,
,b,
Beom-Tae Kim a d, Ho-Seok Kim b, Woo Sung Moon c d, Ki-Jun Hwang a
*
a Research Center of Bioactive Materials, Chonbuk National University, Dukjindong 664-14, Chonju 561-756, Republic of Korea
b Department of Chemistry, Chonbuk National University, Dukjindong 664-14, Chonju 561-756, Republic of Korea
c Department of Pathology, Chonbuk National University Medical School, Chonbuk National University, Dukjindong 664-14, Chonju 561-756, Republic of Korea
d The Center for Healthcare Technology Development, Chonbuk National University, Dukjindong 664-14, Chonju 561-756, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The novel perylenequinone core, 1,12-diacetonitrile-3,10-perylenequinone, was successfully prepared
from the dimerization of the key intermediate, 3-acetonitrile-1,2-naphthoquinone, which was synthe-
sized by an efficient synthetic route in relatively short reaction steps (seven steps) and satisfactory
overall yield. The perylenequinone core containing the acetonitrile functionality is notable in the sense
that the versatile acetonitrile group could be utilized to prepare various compounds at a later synthetic
stage for the development of new and novel perylenequinone derivatives as potential photodynamic
agents.
Received 18 February 2009
Received in revised form 17 March 2009
Accepted 18 March 2009
Available online 27 March 2009
Keywords:
1,12-Diacetonitrile-3,10-perylenequinone
3-Acetonitrile-1,2-naphthoquinone
Photodynamic agents
Ó 2009 Elsevier Ltd. All rights reserved.
Anticancer agents
1. Introduction
to the development of an efficient method for the synthesis of
perylenequinones, which avoids pretty lengthy reaction steps.
4,9-Dihydroxy-3,10-perylenequinones are known to be bi-
ologically active natural pigments that contain a common extended
aromatic unit in their molecules.1 This class of compounds identi-
fied to date includes hypocrellins, cercosporin, phleichrome,
and calphostines, etc. (Fig. 1). Most of these pigments are produced
mainly by a wide variety of molds, and they act as photodynamic
phototoxins to their hosts.2 Due to their unique photosensitive
properties, considerable attention has been paid to the promising
application of these perylenequinones to the photodynamic
therapy (PDT) of anticancer agents.3 More specifically, some
compounds of this class, such as cercosporin, phleichrome, and
calphostins, are known to be potent and specific inhibitors of
protein kinase C (PKC),4 which is a regulatory enzyme crucial to
cell division and differentiation. This inhibitory activity demon-
strates that these compounds may act as promising anticancer and
anti-HIV agents.5 In addition, a recent report demonstrated that
perylenequinones act as broad-spectrum fungicides by generating
reactive oxygen species.6 Therefore, because of their interesting
bioactivities and potential application to the promising research
areas mentioned above, considerable efforts7 have been devoted
OH
O
OH
O
OMe
OMe
R1
MeO
MeO
R1
R2
MeO
MeO
R2
OMe
OMe
OH
O
OH
O
Calphostin A R1 = R2 = COPh
Calphostin B R1 = H,R2 = COPh
Calphostin C R1 = COPh, R2 = H
Calphostin D R1 = R2 = H
Elsinochrome A R1 =R2 = COMe
Elsinochrome B R1 = COMe, R2 = CH(OH)Me
Elsinochrome C R1 = R2 = CH(OH)Me
OH
O
OH
O
OMe
OH
OMe
O
O
MeO
MeO
CH3
COCH3
OH
OMe
OMe
OH
O
OH
O
Cercosporin
Hypocrellin B
* Corresponding author. Tel.: þ82 63 270 3577; fax: þ82 63 270 4322.
E-mail address: kijun@chonbuk.ac.kr (K.-J. Hwang).
Figure 1. Molecular structures of some naturally occurring perylenequinones.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.057

4626
B.-T. Kim et al. / Tetrahedron 65 (2009) 4625–4628
OMe
OMe
OMe
CO2Et
CO2Et
CO2Et
CO2Et
b
a
(96%)
(97%)
MeO
CHO
MeO
MeO
3
1
2
c (82%),
d (93%),
e (94%)
OMe
OMe
OMe
O
O
R
O
g
f
R
CN
CN
(45-75%)
(89%)
MeO
MeO
MeO
4 R = OH
8
7
5 R = OMs
6 R = CN
Scheme 1. The synthetic route to 1,2-naphthoquinone (8); (a) Ethyl malonate, piperidine, benzoic acid, rt; (b) NaBH4; (c) LAH, THF, rt; (d) MsCl, pyridine, O ꢁC; (e) NaCN, DMSO, rt;
(f) (i) ZnCl2, HCl, (ii) Hþ, H2O, reflux; (g) SeO2, AcOH, 70 ꢁC.
Our literature survey showed that most research has focused on
the total synthesis of some natural perylenequinones,7b,c,g,i,m or
on the investigation of the dimerization reaction conditions of
1,2-naphthoquinones,7a,d–f which are considered to be the key in-
termediates for perylenequinones. However, the synthetic routes
reported previously required relatively lengthy reaction steps. In
addition, there are only a few reports on the synthetic efforts to
prepare the perylenequinone derivatives with diverse structural
features on the perylenequinone core. The analysis of the structural
features of perylenequinones reported previously also showed that
the functional diversity of substitutions at the 1- and 12-position of
perylenequinones is likely to play a crucial role in the dimerization
step in terms of the successful formation of the perylenequinones.
The diversity of these substitutions may also be responsible for large
fluctuation in yields.7
So, the preparation of new and novel perylenequinone de-
rivatives may be dependent on the efficient introduction of side
substituents in early synthetic stages. In our synthetic program, we
designed the target perylenequinone substituted with acetonitrile
functionality at the 1- and 12-position of perylenequinones, which
could be easily converted to other important functionalities such as
ketones or amines by a common chemical process. Herein, we re-
port the synthetic details to prepare the key intermediate, 3-ace-
tonitrile-1,2-naphthoquinone (8), and its dimerized product,
perylenequinones 9.
(8), was successfully synthesized by oxidizing ketonitrile 7 with
selenium dioxide in acetic acid.9 However, the isolation yield fluc-
tuated (45–75%) because this material showed a strong affinity for
adsorbent, i.e., silica gel in separation column. Efforts to search for
better separation options, such as different packing materials and
solvent systems are now under progress. Our synthetic route re-
quires relatively short reaction steps (seven steps) and the overall
yield is fairly good compared with previous reports2,7b,i,m for other
functionalized 1,2-naphthoquinones.
With this intermediate, 3-acetonitrile-1,2-naphthoquinone (8),
in hand, we moved on to prepare the target compound, 1,12-diac-
etonitrile-3,10-perylenequinone (9). Since the substituents on the
3-position of 1,2-naphthoquinone are known to be critical in the
dimerization step in terms of the large fluctuation in yields, and
the successful formation of perylenequinones,7 it was very in-
teresting to investigate the dimerization reaction of compound 8
with the novel substituent at this position (Scheme 2). Therefore,
we carefully applied several reaction conditions hitherto reported
in the literature to dimerize 1,2-naphthoquinone 8. Under an oxi-
dative dimerization condition (10% FeCl3, CH3CN),7d,l,m the desired
product, perylenequinone 9, was obtained as a dark red solid, but
the yield was not very satisfactory (18–34%) and inconsistent. The
structure of compound 9 was elucidated by the analysis of 1H and
13C NMR, high resolution mass spectrum, UV, and IR spectra. The
three broad absorption bands at 271, 490, and 562 nm from the UV
spectrum and the strong absorption band at 1620 cmꢀ1 from the IR
spectrum are reported to be typical patterns for the quinone sys-
tem.10 In this reaction, no apparent by-products were observed
except for a large amount of tar materials, suggesting the massive
decomposition of putative chemical species during the reaction
process. Meanwhile, Hauser et al.7i reported the other versatile
condition in which the dimerization occurred through the acid-
catalyzed process. So, by adopting Hauser’s method, 1,2-naphthoquinone
2. Results and discussion
The construction of perylenequinoid chromophore (4,9-dihy-
droxy-3,10-perylenequinone) has generally been accomplished by
the dimerization of an appropriately functionalized 1,2-naph-
thoquinone. So, our primary synthetic work was focused on the
efficient construction of 3-acetonitrile-1,2-naphthoquinone (8) as
a key intermediate for perylenequinone (Scheme 1). The synthesis
began by condensing 3,5-dimethoxybenzaldehyde with ethyl
malonate to produce a conjugated dicarboxylate 2. The next com-
pound 3 was successfully prepared by reducing compound 2 with
NaBH4 in 97% yield. The diester groups of dicarboxylate 3 were
sequentially converted uneventfully to dinitrile 6 via diol 4 and
dimesylate 5 in 72% overall yield. Several attempts were made to
prepare diol 4 from dicarboxylate 2. Thus, the direct reduction
approaches to prepare diol 4 by utilizing either lithium aluminum
hydride (LAH) or hydrogenation in the presence of iodine were
unsuccessful. In the next step, the intramolecular Hoesch conden-
sation method was applied to dinitrile 6 to provide bicyclic ketone 7 in
89% yield.8 Now, the key intermediate, 3-acetonitrile-1,2-naphthoquinone
OMe O
OH
OMe
O
3
4
O
6
CN
a or b or c
MeO
MeO
1
7
12
CN
MeO
CN
9
10
OH
8
OMe O
9
Scheme 2. The dimerization of ortho-naphthoquinone (8) to perylenequinone (9); (a)
10% FeCl3, CH3CN, rt; (b) TFA, 0 ꢁC; (c) TFA, 0 ꢁC, then 6 N HCl, 2 days.

B.-T. Kim et al. / Tetrahedron 65 (2009) 4625–4628
4627
8 was treated with TFA to produce the dimerized compound 9, which
3.3. Diethyl 2-(3,5-dimethoxybenzyl)malonate (3)
resulted in a somewhat improved and consistent yield (40%), along
with a small amount of unreactive starting material (15%) and
massive tar (Scheme 2). To improve the dimerization yield, several
other conditions (temperature, reaction time, acid medium varia-
tion (Scheme 2, Method C), etc.) were varied with no success. So,
while our results showed that the perylenequinone derivative 9
could be prepared via both oxidative and acid-catalyzed di-
merization albeit in moderate yield, any apparent mechanism to
operate in the dimerization process was not clear in this stage, as is
evident from the results of this study.
Sodium borohydride (0.17 g, 4.51 mmol) was added to an ice-
bath cooled solution of dicarboxylate 2 (1.18 g, 4.51 mmol) in ab-
solute ethanol (30 mL). The solution was stirred for 15 min, and
then glacial acetic acid (5 mL) was added cautiously. The mixture
was condensed, and the residue was resolved in ethyl acetate
(150 mL). The organic layer was washed with 1 N HCl (100 mL), satd
NaHCO3 (100 mLꢂ2), and brine (100 mL), dried over Na2CO3, fil-
tered, and evaporated in vacuo to give a colorless oil (1.15 g, 97%). IR
(film): 1731, 1597 cmꢀ1 1H NMR (600 MHz, CDCl3):
; d 6.35 (d, 2H,
In summary, the novel perylenequinone derivative 1,12-diac-
etonitrile-3,10-perylenequinone (9) was successfully prepared
from the dimerization of the key intermediate, 3-acetonitrile-1,2-
naphthoquinone (8), which was synthesized by an efficient syn-
thetic route in terms of relatively short reaction steps (seven
steps) and satisfactory overall yield. However, more elaborate
experimental designs for the dimerization of the naphthoquinone
should be considered to improve the overall yield for the peryl-
enequinone in this multistep synthesis. The perylenequinone
core 9 containing the acetonitrile functional group will be utilized
very efficiently at a later stage to prepare various compounds as
potential photodynamic agents. The further synthetic elaboration
of compound 9 to the final bioactive 3,10-perylenequinone and
the analysis of its photochemical properties are now under
investigation.
J¼1.8 Hz, H-2, 6), 6.31 (t, 1H, J¼1.8 Hz, H-4), 4.17 (m, 4H, –CH2–),
3.75 (s, 6H, –OCH3), 3.63 (t,1H, J¼7.8 Hz, H-20), 3.16 (d, 2H, J¼7.8 Hz,
H-40), 1.22 (t, 6H, J¼7.8 Hz, –CH3); 13C NMR (150 MHz, CDCl3):
d
168.74 (–CO–), 160.74, 140.15, 106.72, 98.69, 61.38, 55.15 (–OCH3),
53.61, 34.83, 13.94; MS [MþH]þ 311.14.
3.4. 2-(3,5-Dimethoxybenzyl)propane-1,3-diol (4)
Diester 3 (17.2 g, 55.5 mmol) in dry THF (50 mL) was slowly
added over 1.5 h to a suspension of lithium aluminum hydride
(8.43 g, 222.2 mmol) in dry THF (50 mL). The mixture was stirred
for 3 h at room temperature. The reaction was quenched by slowly
adding ethyl acetate (30 mL), followed by satd NH4Cl (30 mL). The
sludge was removed by filtration and washed with ethyl acetate
(100 mLꢂ3). The combined organic layer was dried over Na2CO3,
filtered, and evaporated in vacuo to give a colorless oil. This oily
residue was further purified by the Yamazen MPLC system (flow
rate: 20 mL/min, detected at 254 nm) to afford a colorless solid
3. Experimental section
3.1. General
(10.3 g, 82%): mp: 32–34 ꢁC. IR (film): 3450, 1600 cmꢀ1
(400 MHz, CDCl3):
;
1H NMR
d
6.34 (d, 2H, J¼2.4 Hz, H-2, 6), 6.31 (t, 1H,
J¼2.4 Hz, H-4), 3.77 (dd, 2H, J¼10.0, 4.0 Hz, Ha-10, 30), 3.76 (s, 6H,
–OCH3), 3.65 (dd, 2H, J¼10.0, 7.2 Hz, Hb-10, 30), 2.77 (s, 2H, –OH),
2.54 (d, 2H, J¼7.6 Hz, H-40), 2.04 (m, 1H, H-20); 13C NMR (100 MHz,
Melting points were recorded on an Electrothermal melting
point apparatus and were uncorrected. Mass spectra of compounds
2–6 were recorded on an HPLC 1200 series-6130 quadrupole LC/MS
mass spectrometer, and HR mass spectra of compounds 7–9 were
recorded on a Synapt HDMS (Waters). Infrared spectra were
recorded on a Nicolet-Avatar-330 FT-IR spectrophotometer. 1H and
13C NMR spectra were recorded on a Jeol 400 MHz or 600 MHz
CDCl3): d 160.62,142.17,107.00, 97.90, 65.26, 55.24, 43.68, 34.59; MS
[MþH]þ 227.12.
3.5. 2-(3,5-Dimethoxybenzyl)propane-1,3-diol dimesylate (5)
spectrometer. Chemical shifts are shown in
d values (ppm) with
To diol 5 (9.8 g, 43.18 mmol) in methylene chloride (100 mL)
were added triethylamine (14.4 mL, 103.3 mmol) and methane-
sulfonyl chloride (8.02 mL, 103.3 mmol) in an ice-bath. The mixture
was stirred for 3 h at ambient temperature. The mixture was
poured into ice-water and extracted with methylene chloride
(100 mLꢂ2). The combined organic layer was washed with 1% HCl
(100 mLꢂ2), water (100 mLꢂ2), dried over Na2CO3, filtered, and
evaporated in vacuo to give a pale yellow solid (15.4 g, 93%).
Compound 5 was used without further purification: mp: 65–66 ꢁC.
tetramethylsilane (TMS) as an internal standard. UV spectra were
recorded on a HP UV–Visible Chemstation spectrophotometer. All
chemicals were purchased from Sigma–Aldrich Co., U.S.A., and all
solvents for column chromatography were of reagent grade, and
were purchased from commercial sources.
3.2. Diethyl 2-(3,5-dimethoxybenzylidene)malonate (2)
Benzoic acid (0.15 g,1.20 mmol) was added at room temperature
to a mixture of 3,5-dimethoxy benzaldehyde (1) (2.0 g, 12.0 mmol),
diethyl malonate (1.8 mL, 12.1 mmol), and piperidine (0.18 mL,
1.80 mmol) in dry toluene (50 mL). The mixture was refluxed for
4 h, and water was removed using a Dean–Stark condenser. The
mixture was cooled to room temperature and diluted with ethyl
acetate (100 mL). The organic layer was washed with 5% HCl
(100 mL), satd NaHCO3, dried over Na2CO3, filtered, and evaporated
in vacuo. The residue was subjected to flash column chromatog-
raphy (silica gel) to afford 2 (3.55 g, 96%) as a colorless oil, which
was slowly solidified upon standing at room temperature: mp:
IR (film): 1346, 1172 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 6.34 (s, 3H,
H-2, 4, 6), 4.26 (dd, 2H, J¼10.0, 4.4 Hz, Ha-10, 30), 4.18 (dd, 2H, J¼10.0,
6.0 Hz, Hb-10, 30), 3.77 (s, 6H, –OCH3), 3.03 (s, 6H, –CH3), 2.68 (d, 2H,
J¼7.2 Hz, H-40), 2.46 (m, 1H, H-20); 13C NMR (100 MHz, CDCl3):
d
160.88, 139.31, 106.89, 98.63, 67.77, 55.23, 39.81, 37.17, 33.51; MS
[MþH]þ 383.08.
3.6. 3-(3,5-Dimethoxybenzyl)pentanedinitrile (6)
Sodium cyanide (3.19 g, 65.1 mmol) was added to the solution of
dimesylate 5 (8.30 g, 21.7 mmol) in dimethylsulfoxide (80 mL) at
room temperature. The mixture was stirred for 1 h at 80 ꢁC. The
mixture was poured into ice-water and extracted with ether
(200 mLꢂ2). The combined organic layer was washed thoroughly
with water (100 mLꢂ5), dried over Na2CO3, filtered, and evaporated
in vacuo to give an oily residue (4.97 g, 94%). IR (film): 2250,
40 ꢁC. IR (film): 1738, 1695 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 7.65
(s, 1H, H-40), 6.61 (d, 2H, J¼2.0 Hz, H-2, 6), 6.49 (t, 1H, J¼2.0 Hz, H-
4), 4.33 (q, 2H, J¼7.2 Hz, –CH2–), 4.30 (q, 2H, J¼7.2 Hz, –CH2–), 3.77
(s, 6H, –OCH3), 1.33 (t, 3H, J¼7.2 Hz, –CH3), 1.30 (t, 3H, J¼7.2 Hz,
–CH3); 13C NMR (100 MHz, CDCl3):
d 166.52 (–CO–), 163.96 (–CO–),
160.81, 141.95, 134.60, 126.77, 107.16, 102.85, 61.63, 61.58, 55.30
1600 cmꢀ1; 1H NMR (400 MHz, CDCl3):
6.32 (d, 2H, J¼2.4 Hz, H-2, 6), 3.78 (s, 6H, –OCH3), 2.76 (d, 2H,
d
6.37 (t, 1H, J¼2.4 Hz, H-4),
(–OCH3), 14.06, 13.86; MS [MþH]þ 309.13.

4628
B.-T. Kim et al. / Tetrahedron 65 (2009) 4625–4628
J¼6.8 Hz, H-40), 2.54 (dd, 2H, J¼16.4, 5.6 Hz, Ha-10, 30), 2.46 (dd, 2H,
J¼16.4, 6.0 Hz, Hb-10, 30), 2.41 (m, 1H, H-20); 13C NMR (100 MHz,
chloroform (10 mLꢂ3). The combined extracts were evaporated in
vacuo to afford a dark red solid (40 mg, 34%): mp: 212–215 ꢁC
(decomposed). IR (film) 3450, 2253, 1620 (an extended quinone
CDCl3): d 160.98, 138.62, 116.84 (–CN), 106.73, 98.80, 55.20 (–OCH3),
39.04, 34.44, 21.11; MS [MþH]þ 245.12.
system) cmꢀ1; UV lmax (CHCl3) 271 (lg
3
¼2.99), 490 (2.01), 562
(0.70); 1H NMR (400 MHz, CDCl3):
d 8.42 (s, 2H, 2, 11-OH), 6.79 (s,
3.7. 2-(5,7-Dimethoxy-4-oxo-1,2,3,4-tetrahydronaphthalen-2-
yl)acetonitrile (7)
2H, H-5 and H-8), 4.23 (s, 6H, –OCH3ꢂ2), 4.15 (s, 6H, –OCH3ꢂ2),
3.99 (d, 2H, J¼16.8 Hz, Ha-20, Ha-200), 3.64 (d, 2H, J¼16.8 Hz, Hb-20,
Hb-200); 13C NMR (100 MHz, CDCl3):
d 174.74 (–CO–), 165.82, 165.24,
Zinc chloride (4.71 g, 34.58 mmol) was added to a solution of
dinitrile 6 (4.97 g, 20.34 mmol) in dry ether (100 mL). Hydrogen
chloride gas was passed through the mixture for 2 h. The ether
layer was discarded, and the resultant white solid was resolved
in water and refluxed for 2 h. After cooling, the mixture was
diluted with water and extracted with methylene chloride
(200 mLꢂ2). The combined organic layer was washed with satd
NaHCO3 (100 mLꢂ2), brine (100 mL), and water (100 mLꢂ2),
dried over Na2CO3, filtered, and evaporated in vacuo to produce
an off-white solid (4.45 g, 89%). Compound 7 was used without
further purification: mp: 122–123 ꢁC. IR (film): 2250, 1685,
151.39, 130.72, 127.66, 116.27 (–CN), 112.08, 108.43, 105.93, 94.47,
55.78, 56.42, 18.50; HRMS (ESI): m/z 513.1293 ([MþH]þ, calcd for
C28H21N2O8 513.1298). Method B. A neat solution of 1,2-naph-
thoquinone 8 (100 mg, 0.39 mmol) in trifluoroacetic acid (2 mL)
was stirred at 0 ꢁC for 4 h. The solution instantly turned green and
then dark blue over 30 min. The mixture was poured into ice-cold
water, and then the same purification process described in Method
A was applied to afford compound 9 (40 mg, 40%). The chloroform
layer after treatment with the solution of zinc acetate was con-
centrated in vacuo and subjected to flash column chromatography
to produce the starting material 8 (elution solvent system: CHCl3/
MeOH¼15:1 v/v, 15 mg, 15%) and an unknown material (10 mg).
Method C. A neat solution of 1,2-naphthoquinone 8 (124 mg,
0.48 mmol) in trifluoroacetic acid (2 mL) was stirred at 0 ꢁC for 4 h.
Aqueous HCl (6 N, 5 mL) was added to the resultant blue solution
and stirred for 2 days in air at the ambient temperature. The mix-
ture was poured into ice-cold water, and then the same purification
process described in Method A was applied to afford compound 9
(30 mg, 24%).
1600 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
6.38 (d, 1H, J¼2.0 Hz,
H-6), 6.35 (d, 1H, J¼2.0 Hz, H-8), 3.89 (s, 3H, –OCH3), 3.86 (s, 3H,
–OCH3), 3.09 (dd, 1H, J¼15.6, 2.0 Hz, Ha-3), 2.86 (dd, 1H, J¼16.8,
10.8 Hz, Ha-1), 2.77 (dd, 1H, J¼16.8, 2.0 Hz, Hb-3), 2.54 (m, 1H, H-
2), 2.51 (dd, 1H, J¼19.2, 6.0 Hz, Ha-20), 2.44 (dd, 1H, J¼16.8,
10.8 Hz, Hb-1), 2.43 (dd, 1H, J¼16.8, 6.0 Hz, Hb-20); 13C NMR
(100 MHz, CDCl3):
d 193.10 (–CO–), 164.57, 162.88, 146.16, 117.63
(–CN), 115.56, 105.19, 97.79, 56.11, 55.60, 45.68, 36.43, 31.67,
23.11; HRMS (ESI): m/z 246.1030 ([MþH]þ, calcd for C14H16NO3
246.1052).
Acknowledgements
3.8. 2-(5,7-Dimethoxy-3,4-dioxo-3,4-dihydronaphthalen-2-
yl)acetonitrile (8)
This work was supported by the Grant of the Korean Ministry
of Education, Science and Technology in 2008 (The Regional
Core Research Program/Center for Healthcare Technology
Development).
Selenium dioxide (0.64 g, 5.75 mmol) was added to a solution of
bicyclic ketone 7 (0.47 g, 1.92 mmol) in glacial acetic acid (5 mL)
with stirring and the mixture was kept for 2 h at 70 ꢁC. The mixture
was poured into ice-water and extracted with methylene chloride
(50 mLꢂ2). The organic layer was washed with satd NaHCO3 and
water, dried over Na2CO3, filtered, and evaporated in vacuo. The
residue was applied to flash column chromatography (silica gel) to
afford 8 (0.38 g, 77%) as a brown-red solid: mp: 198–215 ꢁC
References and notes
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(decomposed). IR (film): 2250, 1666, 1649 cmꢀ1
(400 MHz, DMSO-d6): 7.56 (s, 1H, H-1), 6.90 (s, 1H, H-6), 6.71 (s,
1H, H-8), 3.92 (s, 3H, –OCH3), 3.90 (s, 3H, –OCH3), 3.67 (s, 2H, H-10);
13C NMR (100 MHz, DMSO-d6):
179.15 (–CO–), 174.16 (–CO–),
;
1H NMR
d
d
5. (a) Pollack, I. F.; Kawecki, S. J. Neurooncol. 1997, 31, 255–266; (b) Dubauskas, Z.;
Beck, T. P.; Chmura, S. J.; Kovar, D. A.; Kadkhodaian, M. M.; Shrivastav, M.;
Chung, T.; Stadler, W. M.; Rinker-Schaefer, C. W. Clin. Cancer Res. 1998, 4, 2391–
2398; (c) Zhu, D.-M.; Narla, R.-K.; Fang, W.-H.; Chia, N.-C.; Uckun, F. M. Clin.
Cancer Res. 1998, 4, 2967–2976; (d) Beck, T. P.; Kirsh, E. J.; Chmura, S. J.; Kovar,
D. A.; Chung, T.; Rinker-Schaefer, C. W.; Stadler, W. M. Urology 1999, 54, 573–
577.
166.17, 165.04, 142.10, 137.18, 130.09, 117.53 (–CN), 112.17, 110.77,
99.83, 56.35 (–OCH3), 56.22 (–OCH3), 17.55; HRMS (ESI): m/z
280.0588 ([MþNa]þ, calcd for C14H11NO4Na 280.0586).
3.9. 2,20-(2,11-Dihydroxy-4,6,7,9-tetramethoxy-3,10-dioxo-
3,10-dihydroperylene-1,12-diyl)diacetonitrile (1,12-
diacetonitrile-3,10-perylenequinone) (9)
6. Xing, M.-Z.; Zhang, X.-Z.; Sun, Z.-L.; Zhang, H. Y. J. Agric. Food Chem. 2003, 51,
7722–7724.
7. (a) Chao, C.; Zhang, P. Tetrahedron Lett. 1988, 29, 225–226; (b) Broka, C. A.
Tetrahedron Lett. 1991, 32, 859–862; (c) Coleman, R. S.; Grant, E. B. J. Org. Chem.
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Zhao, C.; Zhang, X.-s; Zhang, P. Liebigs Ann. Chem. 1993, 35–41; (f) Liu, J.; Diwu,
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B. Tetrahedron Lett. 1993, 34, 2225–2228; (h) Coleman, R. S.; Grant, E. B. J. Am.
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914–916; (k) Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1995, 117, 10889–
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1683–1684.
Method A.
A solution of 1,2-naphthoquinone 8 (170 mg,
0.66 mmol) and anhydrous ferric chloride (170 mg, 1.06 mmol) in
2 mL of anhydrous acetonitrile was stirred at room temperature for
3 h. The reaction mixture was poured into 3% aqueous HCl, and
then extracted with chloroform (50 mLꢂ3). The organic layer was
washed with water, dried over Na2CO3, filtered, and evaporated in
vacuo to afford a dark red solid. This solid was redissolved in
chloroform and then mixed with a 10% aqueous ethanol solution of
zinc acetate. This Zn-complex thus formed was washed with
chloroform (50 mLꢂ3), and then decomposed by 10% aqueous HCl
to release perylenequinone 9, which was again extracted with