Synthesis of 1,1,3-trisubstituted naphtho[2,3-c]pyran-5,10-dione derivatives as potential redox switches

Article abstract of DOI:10.1002/ejoc.200700426

Five 1,1,3-trisubstituted naphtho[2,3-c]pyran-5,10-dione derivatives were designed and synthesized in five steps from 2-acetyl-1,3-indandione. Prepared quinones 6a-e instantly changed from either red or blue to yellow or orange red, when treated with sodi

Full text of DOI:10.1002/ejoc.200700426

FULL PAPER
DOI: 10.1002/ejoc.200700426
Synthesis of 1,1,3-Trisubstituted Naphtho[2,3-c]pyran-5,10-dione Derivatives as
Potential Redox Switches
Tien-Lan Shie,[a] Chi-Hui Lin,[a] Shih-Lun Lin,[a] and Ding-Yah Yang*[a]
Keywords: Quinones / Redox chemistry / Fluorescence / Donor–acceptor systems
Five 1,1,3-trisubstituted naphtho[2,3-c]pyran-5,10-dione de-
rivatives were designed and synthesized in five steps from 2-
acetyl-1,3-indandione. Prepared quinones 6a–e instantly
changed from either red or blue to yellow or orange red,
when treated with sodium borohydride in methanol. The re-
sulting reduced hydroquinones 9a–e reverted to their origi-
nal colors within a few minutes after the reducing agent was
consumed or removed. Whereas no fluorescence of blue qui-
none 6e was detected prior to reduction, reduced hydroqui-
none 9e emitted red fluorescence with a quantum yield of
0.07.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
The gem-dimethyl groups on the pyran ring at the right-
hand side of the molecule were incorporated to prevent pos-
sible oxygen-promoted aromatization. In addition to serv-
ing as a fluorophore, the N,N-dimethylamino group at the
para position of the benzene ring can further extend the
UV absorption wavelength far into the visible range. The
modified synthesis of the proposed 1,1,3-trisubstituted
naphtho[2,3-c]pyran-5,10-diones is described here and their
potential to function as active redox switches is evaluated.
Introduction
Naphtho[2,3-c]pyran-5,10-diones are an important class
of naturally occurring compounds as they have favorable
antimicrobial, antiparasitic, and phytotoxic activities.[1]
Their broad range of biological activities have made these
molecules attractive synthetic targets for organic chemists.
Various synthetic strategies for the synthesis of pyrano-
naphthoquinones have therefore been reported in the litera-
ture.[2] The core structure of naphtho[2,3-c]pyran-5,10-di-
one contains a pyran-fused naphthoquinone moiety. Qui-
nones are excellent electron acceptors and are known to be
efficient quenchers of the singlet state donor fluorescence
of various fluorophores.[3] The quenching efficiency de-
pends on the redox potentials of the corresponding qui-
none–hydroquinone system. Whereas most of the prepared
naphtho[2,3-c]pyran-5,10-dione derivatives are red because
of the intrinsic pyranonaphthoquinone chromophore, the
corresponding reduced hydroquinones are yellow. This in-
formation prompted us to investigate the possibility of Figure 1. Design of a potential donor–acceptor system containing
an N,N-dimethylaminobenzene moiety and a naphthoquinone
group.
using the naturally occurring naphtho[2,3-c]pyran-5,10-di-
one structure as a reversible redox switch. A suitable redox
switch may function as a noninvasive fluorogenic probe for
the real-time visualization and quantification of molecular
processes in vivo.[4] Figure 1 shows the structure of the
Results and Discussion
rationally designed potential donor–acceptor system with
an electron-donating N,N-dimethylaminophenyl moiety as
the fluorophore and an electron-withdrawing naphthoqui-
none as the fluorescence quencher. The quinonic moiety
was directly attached to the π system of the fluorophore.
The seven-step preparation of 1,3-disubstituted naph-
tho[2,3-c]pyran-5,10-diones from naphthoquinone was pre-
viously reported.[5] The common intermediate in the syn-
thesis was 2-acetyl-4-methoxy-1-naphthol (1), which was
prepared from naphthoquinone in three steps. Here, a di-
azomethane-mediated ring expansion reaction was ex-
ploited to construct this key naphthol derivative in one pot
to reduce the overall number of synthetic steps. The synthe-
sis started with an exhaustive diazotization of commercially
[a] Department of Chemistry and Center for Nanoscience and
Technology, Tunghai University,181,
Taichung-Kang Rd. Sec.3, Taichung, Taiwan 407
Fax: +886-4-2359-0426
E-mail: yang@thu.edu.tw
Eur. J. Org. Chem. 2007, 4831–4836
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4831

T.-L. Shie, C.-H. Lin, S.-L. Lin, D.-Y. Yang
FULL PAPER
Scheme 1. Reagents and conditions: (a) CH2N2, CH2Cl2, 0 °C, 1 h; (b) K2CO3, CH3I, CH3CN, room temp., 4 d; (c) 1. R1MgBr, THF,
room temp., 1 h, 2. aqueous NH4Cl; (d) CAN, CH3CN/H2O, room temp., 15 min; (e) N-acylmethylpyridinium salt, Et3N, CH3CN,
50 °CǞroom temp., 12 h; (f) TsOH (cat.), benzene, reflux, 10 min.
available 2-acetyl-1,3-indandione in dichloromethane to
give the ring-expansion product 2-acetyl-4-methoxy-1-
naphthol (1) (Scheme 1) in 40% yield.[6] Naphthol 1 was
then treated with an excess amount of methyl iodide and
potassium carbonate in dry acetone to afford the corre-
sponding 2-acetyl-1,4-dimethoxynaphthalene (2) in 90%
yield, which underwent reaction with either methyl or phen-
ylmagnesium bromide in THF to form tertiary alcohols 3a
and 3b in 80 and 35% yields, respectively. Oxidative de-
methylation of alcohols 3a,b with 4 equiv. of cerium(IV)
ammonium nitrate in aqueous acetonitrile at room tem-
perature gave the corresponding quinones 4a,b in 72–75%
yields. The phenacylmethyl group was introduced into qui-
nones 4a,b by using various N-acylmethylpyridinium salts
and triethylamine in acetonitrile under an atmosphere of
nitrogen at 50 °C. The final intramolecular condensation of
transient compound 5 into targets 6a–e was performed in
toluene, which allowed complete dehydration by treatment
with 0.2 equiv. of p-toluenesulfonic acid over a period of
10 min in 90–97% yields.[5] Scheme 2 shows the preparation
of the commercially unavailable N-acylmethylpyridinium
bromide 8, which was used for the synthesis of 9e in
Scheme 1. 4Ј-N,N-Dimethylaminoacetophenone was ini-
tially brominated in the presence of hydrobromic acid at
0 °C for 1 h to give bromomethyl ketone 7,[7] followed by
treatment with pyridine in acetone under reflux conditions
to afford the corresponding pyridinium bromide 8 quantita-
tively. The structure of compound 6c was confirmed by X-
ray crystal crystallography, as presented in Figure 2.
Figure 2. X-ray crystal structure of compound 6c.
When red quinones 6a–d and blue 6e were reduced with
sodium borohydride in methanol, the solutions instantly
turned yellow and orange red, respectively. The resulting
reduced hydroquinones 9a–d returned to their original col-
ors within a few minutes after the reducing agent was either
consumed or removed (Figure 3). UV absorption measure-
ments indicated high yields (Ͼ98%) for the chemical con-
version of 6a–e into 9a–e as well as in the opposite direc-
tion. The structure of the air-sensitive hydroquinone was
verified by trapping 9c in situ with dimethyl sulfate under
basic conditions to give the corresponding 1,4-dimethylated
hydroquinone 10c, as shown in Scheme 3.[8]
Cyclic voltammetry measurements of 6a–e were per-
formed in acetonitrile to explore the substituent effects on
their redox potentials. Two one-electron reversible re-
duction waves were observed at a scan rate of 100 mVs–1
for all synthesized compounds. Figure 4 shows the cyclic
voltammogram of 6a. The first reversible reduction wave
(–0.74 V vs. Ag/AgCl) represents the addition of one elec-
tron to the quinone core to form a semiquinone anion radi-
Scheme 2. Reagents and conditions: (a) Br2, HBr, 0 °C, 1 h; (b)
pyridine, acetone, reflux, 6 h.
4832
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4831–4836

Substituted Naphthopyrandione Derivatives as Potential Redox Switches
Table 1. Reduction potentials of naphthoquinone and compounds
6a–e in acetonitrile with tetra-n-butylammonium hexafluorophos-
phate (0.1 ) as the supporting electrolyte.
Compound
E1 [V][a]
E2 [V][a]
1/2
1/2
Naphthoquinone
–0.68
–0.74
–0.71
–0.65
–0.69
–0.76
–1.06
–1.34
–1.34
–1.19
–1.31
–1.34
6a
6b
6c
6d
6e
[a] with Ag/AgCl as a reference electrode.
The absorption spectroscopic data for the series 6a–e and
9a–e in methanol are listed in Table 2. Figure 5 presents the
UV/Vis absorption spectra of 6a prior to and after re-
duction. It displays an intense band with a maximum near
280 nm and a long wavelength broad band at 485 nm before
reduction. The former is attributed to π–π* transitions of
the quinonic moiety; the latter is associated with the in-
creased π delocalization of the chromophore. The reduction
of quinone 6a to hydroquinone 9a resulted in the complete
disappearance of the long-wavelength absorbance (485 nm)
and the appearance of a single intense band at 389 nm,
which resembles the absorption behavior of 1,4-dimeth-
Figure 3. The redox switch between 6a–d and 9a–d, and the corre-
sponding colors in the oxidized (left) and reduced forms (right).
Scheme 3. Reagents and conditions: (a) NaBH4, ethanol/H2O, ylated hydroquinone 10c. Similar changes in the UV/Vis ab-
5 min; (b) 1. 10  aqueous KOH, 5 min, 2. SO2(OMe)2, reflux,
overnight.
sorption spectrum of 6e were also observed. This spectrum
displays a long wavelength broad band at 592 nm before
reduction and a shorter wavelength band at 467 nm after
reduction (Figure 6). Figure 7 shows the redox switch be-
tween 6e and 9e and the corresponding colors in the oxid-
ized (deep blue) and the reduced (orange red) forms. Re-
duction of the quinonic group of 6e to a hydroquinone moi-
cal. The second reversible reduction wave (–1.34 V vs. Ag/
AgCl) corresponds to the subsequent addition of a second
electron to the semiquinone anion radical, which produces
a hydroquinone dianion. The detailed reduction potentials
ety converts it from an electron-withdrawing group to an
of naphthoquinone and the series 6a–e are listed in Table 1.
The results indicate that annulation of the pyran ring on
naphthoquinone increases the reduction potentials.
Furthermore, introduction of a benzene moiety at the C-1
or C-3 positions of 6a decreases the reduction potentials,
whereas incorporation of an electron-donating N,N-dimeth-
ylamino group at the para position of the benzene ring of
6d increases the reduction potentials.
Table 2. Absorption parameters for the series 6a–e and 9a–e in
methanol.
Compound
λmax [nm]
logε
6a
6b
6c
6d
6e
9a
9b
9c
9d
9e
280, 485
274, 475
309, 475
311, 502
350, 592
389
252, 378
405
247, 413
255, 311, 467
4.07, 3.48
3.32, 3.45
3.67, 3.29
4.01, 3.62
3.19, 3.04
3.90
3.87, 3.83
3.63
3.87, 3.96
3.01, 2.83, 3.30
Figure 4. Cyclic voltammogram of 6a in CH3CN obtained by using
tetra-n-butylammonium hexafluorophosphate (0.1 ) as the sup-
porting electrolyte at a scan rate of 100 mVs–1.
Figure 5. UV/Vis spectra of 6a (1.97ϫ10–4  in MeOH) prior to
and after reduction.
Eur. J. Org. Chem. 2007, 4831–4836
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4833

T.-L. Shie, C.-H. Lin, S.-L. Lin, D.-Y. Yang
FULL PAPER
electron-donating group, which results in a profound elec-
tronic change in the system and in turn this leads to a
change in the emission profile.
Figure 8. The excitation (478 nm) and emission (594 nm) spectra of
9e (5.4ϫ10–5  in MeOH) at room temperature.
Figure 6. UV/Vis spectra of 6e (3.26ϫ10–4  in MeOH) prior to
and after reduction.
Conclusions
We synthesized five 1,1,3-trisubstituted naphtho[2,3-c]-
pyran-5,10-dione derivatives in five steps with an overall
yield of 10–21%. The prepared quinones can be instantly
reduced by sodium borohydride in methanol with a distinct
change in color. The reduced hydroquinones can be oxid-
ized back to quinones by air. Furthermore, the absorption
and emission properties of reduced hydroquinone 9e are
controlled by the redox state of the quinonic moiety.
Experimental Section
General: Melting points were determined with a Mel-Temp melting
point apparatus in open capillaries and are uncorrected. MS were
performed with a JOEL JMS-SX/SX 102A spectrometer. IR spec-
tra were obtained with a 1725X FTIR spectrophotometer. Absorp-
tion spectra were acquired with an HP8453 spectrophotometer, and
emission spectra were obtained with a Hitachi F-4500 fluorospec-
trometer. Single-crystal structures were determined with a Bruker
Figure 7. The redox switch between 6e and 9e, and the correspond-
ing colors in the oxidized (left) and reduced forms (right).
No fluorescence emission was observed for the synthe-
sized series 6a–d in methanol, whereas their reduced prod-
ucts 9a–d exhibit weak fluorescence emission under the
same conditions. Blue quinone 6e emitted no fluorescence
in methanol at room temperature, but the corresponding
reduced hydroquinone 9e was red fluorescent with a quan-
tum yield of 0.07. Table 3 lists the fluorescence parameters
of compounds 9a–e in methanol. Figure 8 shows the exci-
tation (478 nm) and emission spectra (594 nm) of 9e in
methanol. The quenching of the intrinsic N,N-dimethyl-
aminobenzene fluorescence in 6e is probably caused by the
efficient electronic coupling between the N,N-dimethyl-
aminobenzene donor and the quinonic acceptor. Thus, the
AXS SMART-1000 X-ray single-crystal diffractometer. 1H and 13
C
NMR spectra were recorded at 300 and 75 MHz with a Varian
VXR300 spectrometer. Chemical shifts are reported in parts per
million on the δ scale relative to an internal standard (tetramethyl-
silane, or appropriate solvent peaks) with coupling constants given
1
in Hertz. H NMR multiplicity data are denoted by s (singlet), d
(doublet), t (triplet), q (quartet), and m (multiplet). Analytical thin-
layer chromatography (TLC) was carried out on Merck silica gel
60G-254 plates (25 mm). Flash chromatography was performed in
columns of various diameters with Merck silica gel (230–400 mesh
ASTM 9385 kieselgel 60 H). Solvents, unless otherwise specified,
were of reagent grade and distilled once prior to use.
Calculation of Fluorescence Quantum Yields: UV/Vis spectra were
reversible redox process between quinone 6e and hydroqui- measured with an HP8453 spectrometer with a 1-cm path length
quartz cell. Fluorescence spectra were measured with a Hitachi F-
4500 fluorescence spectrophotometer. Coumarin 6 (Φf = 0.82, λmax
= 458 nm in ethanol) was used as an external standard for the
measurement of fluorescence quantum yields of 9e. Fluorescence
quantum yields were measured by comparing the integrated area
under the fluorescence curve for compound 9e and coumarin 6 at
equal absorbance at the same excitation wavelength. The quantum
yields were corrected for the refractive index of the solvent.
none 9e can be regarded as a molecular switching system,
in which the absorption and emission properties are con-
trolled by the redox state of the quinonic moiety.
Table 3. Fluorescence parameters for the series 9a–e in methanol.
Compound
λex [nm]
λem [nm]
Stork’s shift [cm–1]
9a
9b
9c
9d
9e
309
301
342
344
478
512
501
451
521
594
12831
13263
7067
9876
4085
Cyclic Voltammetry Measurements: Electrochemical cyclic voltam-
metry experiments were performed in a three-electrode single-com-
partment cell by using a platinum disk working electrode, a plati-
num wire counter electrode and a Ag/AgCl (in a saturated KCl
solution) reference electrode. The cell was driven with a PAR
4834
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4831–4836

Substituted Naphthopyrandione Derivatives as Potential Redox Switches
Model 273A. The electrochemical reaction vessel was charged with
5 mL of an acetonitrile solution of 6a–e (1ϫ10–3 ) and tetra-n-
butylammonium hexafluorophosphate (0.1 ) as the electrolyte.
The solutions were deoxygenated by bubbling nitrogen through
them for approximately 5 min.
3-(1-Hydroxy-1,1-dimethyl)-1,4-naphthoquinone (4a): Yellow solid.
Yield: 156 mg (72%). M.p. 84–85 °C. 1H NMR (300 MHz, CDCl3):
δ = 8.13–8.05 (m, 2 H), 7.80–7.73 (m, 2 H), 6.97 (s, 1 H), 3.37 (s,
1 H), 1.61 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 186.5,
185.4, 153.9, 134.0, 133.9, 133.0, 132.7, 131.6, 126.8, 125.9, 71.9,
29.2 ppm. IR (KBr): ν = 3333 (OH), 1662 (C=O), 1612 (C=O),
˜
2-Acetyl-4-methoxy-1-naphthol (1): To a solution of 2-acetyl-1,3-
indandione (500 mg, 2.66 mmol) in dichloromethane (10 mL) was
added an excess amount of diazomethane. After the mixture was
stirred at 0 °C for 1 h, water (20 mL) was added to the mixture,
and the product was extracted twice with dichloromethane. The
extract was dried with MgSO4, filtered, and concentrated. The re-
sulting crude product was purified by column chromatography
(EtOAc/hexanes, 1:9) to give 1 (230 mg, 40%) as a yellow solid.
M.p. 116–117 °C (ref.[6a] 115–116 °C). 1H NMR (300 MHz,
1592, 1337, 1307, 1260, 1182, 785, 722 cm–1. HRMS (EI): calcd.
for C13H12O3 [M]+ 216.0786; found 216.0787.
3-(1-Hydroxy-1-methylphenyl)-1,4-naphthoquinone (4b): Yellow so-
lid. Yield: 209 mg (75%). M.p. 128–129 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.10–8.07 (m, 1 H), 7.99–7.96 (m, 1 H), 7.76–7.71 (m,
2 H), 7.47–7.28 (m, 5 H), 7.07 (s, 1 H), 4.42 (s, 1 H), 1.82 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 186.4, 185.3, 152.0, 145.5,
134.1, 133.9, 133.8, 132.3, 131.6, 128.4, 127.3, 126.8, 125.9, 124.4,
3
75.6, 28.8 ppm. IR (KBr): ν = 3506 (OH), 1656 (C=O), 1616
˜
CDCl3): δ = 13.75 (s, 1 H), 8.45 (d, JH,H = 8.3 Hz, 1 H), 8.19 (d,
(C=O), 1593, 1306, 1252, 1044, 775, 720 cm–1. HRMS (EI): calcd.
for C18H14O3 [M]+ 278.0943; found 278.0941.
3JH,H = 8.3 Hz, 1 H), 7.69–7.55 (m, 2 H), 6.80 (s, 1 H), 3.97 (s, 3
H), 2.67 (s, 3 H) ppm.
2-Acetyl-1,4-dimethoxynaphthalene (2):[5] To
a solution of 1
General Procedure for the Preparation of Compounds 6a–e: To a
solution of 4 (1 mmol) and pyridinium salt (1 mmol) in acetonitrile
(10 mL) under a N2 atmosphere at 50 °C was added dropwise a
solution of Et3N (1 mmol) in acetonitrile (5 mL). The mixture was
stirred for 2–4 h at room temp. The solvent was evaporated in
vacuo, and the residue was quenched with water and extracted with
dichloromethane. The extract was washed with 1  HCl, water, and
dried with MgSO4. The solvent was evaporated to give the crude
intermediate reaction product. To a solution of this crude product
in benzene (10 mL) was added TsOH (0.2 mmol). The mixture was
heated at reflux for 10 min and then poured into water and ex-
tracted with EtOAc. The extract was washed with 2  HCl, water,
and dried with MgSO4. The solution was then evaporated to give
the crude product, which was purified by flash chromatography on
silica gel to give the desired product.
(500 mg, 2.31 mmol) in acetonitrile (10 mL) was added K2CO3
(800 mg, 5.78 mmol) and methyl iodide (1200 mg, 9.24 mmol). The
mixture was stirred at room temp. for 4 d. The reaction was then
quenched with water (10 mL), and the product was extracted twice
with dichloromethane. The extract was dried with MgSO4, filtered,
and concentrated. The resulting crude product was purified by col-
umn chromatography (EtOAc/hexanes, 1:9) to give 2 (479 mg,
1
90%) as a yellow liquid. H NMR (300 MHz, CDCl3): δ = 8.26–
8.21 (m, 1 H), 8.18–8.12 (m, 1 H), 7.60–7.55 (m, 2 H), 7.08 (s, 1
H), 3.99 (s, 3 H), 3.94 (s, 3 H), 2.80 (s, 3 H) ppm.
General Procedure for the Preparation of Compounds 3a,b: To a
solution of 2 (500 mg, 2.17 mmol) in dried THF (10 mL) under a
N2 atmosphere at room temp. was added a methylmagnesium or
phenylmagnesium bromide solution (8.68 mmol in THF). The mix-
ture was stirred for 1 h and then quenched with saturated aqueous
ammonium chloride. The product was extracted twice with dichlo-
romethane. The organic layer was dried with MgSO4, filtered, and
concentrated. The crude product was purified by column
chromatography to give the desired product.
1,1,3-Trimethyl-1H-naphtho[2,3-c]pyran-5,10-dione (6a): Red solid.
Yield: 242 mg (95%). M.p. 84–85 °C. 1H NMR (300 MHz, CDCl3):
δ = 8.05–8.01 (m, 2 H), 7.73–7.62 (m, 2 H), 5.88 (d, 3JH,H = 0.6 Hz,
3
1 H), 1.99 (d, JH,H = 0.6 Hz, 3 H), 1.74 (s, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 183.2, 182.0, 163.0, 137.2, 133.8, 133.4,
132.6, 131.2, 129.2, 125.9, 125.8, 93.0, 80.0, 26.7, 21.2 ppm. IR
3-(1-Hydroxy-1,1-dimethyl)-1,4-dimethoxynaphthalene (3a):[5] Yel-
low liquid. Yield: 428 mg (80%). 1H NMR (300 MHz, CDCl3): δ
= 8.24–8.21 (m, 1 H), 8.01–7.98 (m, 1 H), 7.55–7.46 (m, 2 H), 6.78
(s, 1 H), 4.92 (s, 1 H), 4.01 (s, 3 H), 3.99 (s, 3 H), 1.72 (s, 6 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 151.6, 145.9, 135.6, 128.5,
126.5, 125.8, 125.2, 122.3, 121.8, 102.1, 73.7, 63.1, 55.6, 31.7 ppm.
HRMS (EI): calcd. for C15H18O3 [M]+ 246.1256; found 246.1254.
(KBr): ν = 1662 (C=O), 1622 (C=O), 1588, 1557, 1300, 721 cm–1.
˜
HRMS (EI): calcd. for C16H14O3 [M]+ 254.0943; found 254.0953.
1,3-Dimethyl-1-phenyl-1H-naphtho[2,3-c]pyran-5,10-dione (6b): Red
solid. Yield: 297 mg (94%). M.p. 135–136 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.06–7.97 (m, 2 H), 7.70–7.60 (m, 2 H), 7.49–7.45 (m,
2 H), 7.36–7.24 (m, 2 H), 5.94 (s, 1 H), 2.18 (s, 3 H), 2.03 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 183.0, 182.1, 163.2, 144.2,
137.7, 133.9, 133.1, 132.7, 131.2, 128.0, 127.9, 127.8, 126.1, 125.8,
3-(1-Hydroxy-1-methylphenyl)-1,4-dimethoxynaphthalene
(3b):
White solid. Yield: 234 mg (35%). M.p. 131–132 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.31–8.28 (m, 1 H), 7.39–7.89 (m, 1 H),
7.53–7.48 (m, 4 H), 7.34–7.21 (m, 3 H), 7.05 (s, 1 H), 4.08 (s, 3 H),
3.14 (s, 3 H), 1.97 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
151.5, 150.5, 146.6, 135.9, 128.5, 127.9, 126.6, 126.0, 125.3, 125.1,
125.4, 94.0, 82.4, 27.0, 21.1 ppm. IR (KBr): ν = 1668 (C=O), 1616
˜
(C=O), 1548, 1387, 1298, 767, 702 cm–1. HRMS (EI): calcd. for
C21H16O3 [M]+ 316.1099; found 316.1100.
1,3-Diphenyl-1-methyl-1H-naphtho[2,3-c]pyran-5,10-dione (6c): Red
solid. Yield: 367 mg (97%). M.p. 179–180 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.13–8.04 (m, 2 H), 7.88–7.85 (m, 2 H), 7.76–7.66 (m,
2 H), 7.53–7.41 (m, 5 H), 7.34–7.26 (m, 3 H), 6.77 (s, 1 H), 2.31 (s,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 183.1, 182.1, 159.6,
143.8, 138.1, 134.1, 133.4, 132.8, 131.4, 130.8, 128.9, 128.6, 128.1,
128.0, 126.3, 126.1, 126.0, 125.6, 93.0, 82.7, 77.4, 27.3 ppm. IR
122.4, 121.7, 102.7, 76.6, 61.4, 55.8, 30.9 ppm. IR (KBr): ν = 3515,
˜
2936, 1591, 1464, 1346, 1225, 1103, 1058, 778, 704, 540 cm–1.
HRMS (EI): calcd. for C20H20O3 [M]+ 308.1412; found 308.1407.
General Procedure for the Preparation of Compounds 4a,b: To a
solution of 3 (1 mmol) in a mixture of water (10 mL) and acetoni-
trile (10 mL) was added cerium(IV) ammonium nitrate (4 mmol) at (KBr): ν = 1668 (C=O), 1608 (C=O), 1592, 1531, 1449, 1299,
˜
room temp. The mixture was stirred for 15 min, and the product
was then extracted twice with dichloromethane. The organic layer
was dried with MgSO4, filtered, and concentrated. The crude prod-
uct was purified by column chromatography to give the desired
product.
715 cm–1. HRMS (EI): calcd. for C26H18O3 [M]+ 378.1256; found
378.1265. CCDC-616177 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Eur. J. Org. Chem. 2007, 4831–4836
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4835

T.-L. Shie, C.-H. Lin, S.-L. Lin, D.-Y. Yang
FULL PAPER
1,1-Dimethyl-3-phenyl-1H-naphtho[2,3-c]pyran-5,10-dione (6d): Red
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 151.2, 148.4, 145.9,
145.8, 134.7, 129.0, 128.7, 128.3, 128.1, 127.8, 127.4, 126.4, 125.1,
solid. Yield: 300 mg (95%). M.p. 105–107 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.09–8.03 (m, 2 H), 7.83–7.80 (m, 2 H), 7.72–7.67 (m, 124.9, 123.2, 122.2, 121.7, 95.1, 82.1, 77.2, 62.3, 61.8, 27.8 ppm. IR
2 H), 7.44–7.42 (m, 3 H), 6.71 (s, 1 H), 1.84 (s, 6 H) ppm. 13C (KBr): ν = 1595, 1451, 1367, 1237, 1096 cm–1. HRMS (EI): calcd.
˜
NMR (75 MHz, CDCl3): δ = 183.1, 181.8, 159.2, 137.4, 134.0,
for C28H24O3 [M]+ 408.1725; found 408.1720.
133.5, 133.4, 132.7, 131.3, 130.6, 128.5, 126.0, 92.3, 80.1, 26.4 ppm.
General Procedure for the Reduction of Compounds 6a–e: To a solu-
tion of 6a (1.9 mg, 5 µmol) in methanol (10 mL) was added sodium
borohydride (0.6 mg, 16 µmol) in one portion at room temp. The
red solution turned yellow instantly with gentle swirling. After con-
sumption of the reducing agent, the red color reappeared within
3 min under aerobic conditions. Note: If excess sodium borohy-
dride were added, the yellow solution would turn colorless presum-
ably due to the further reduction of the double bond adjacent to
the hydroquinone moiety.
IR (KBr): ν = 2925, 1665 (C=O), 1642 (C=O), 1538, 1389, 1305,
˜
709 cm–1. HRMS (EI): calcd. for C21H16O3 [M]+ 316.1099; found
316.1093.
1,1-Dimethyl-3-(4-N,N-dimethylamino)-1H-naphtho[2,3-c]pyran-
5,10-dione (6e): Blue solid. Yield: 345 mg (96%). M.p. 199–200 °C.
1H NMR (300 MHz, CDCl3): δ = 8.09–8.04 (m, 2 H), 7.75–7.61
3
(m, 4 H), 6.71 (d, JH,H = 9.0 Hz, 2 H), 6.58 (s, 1 H), 1.82 (s, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 183.8, 181.1, 160.7, 152.1,
138.3, 134.0, 133.8, 132.2, 131.5, 127.8, 125.9, 125.8, 120.7, 111.4,
89.7, 79.9, 40.1, 26.3 ppm. IR (KBr): ν = 1665 (C=O), 1615 (C=O),
˜
Acknowledgments
1519, 1440, 1376, 1334, 1309, 1021 cm–1. HRMS (EI): calcd. for
C23H21NO3 [M]+ 359.1521; found 359.1523.
The authors would like to thank the National Science Council of
Republic of China, Taiwan for financially supporting this research
under contract no. NSC 95-2113-M-029-003. We also thank Drs.
Cheng-Wen Whang and Wei Jyun Chien for helpful discussions.
2-Bromo-4Ј-N,N-dimethylaminoacetophenone (7): To a solution of
4Ј-N,N-dimethylaminoacetophenone (500 mg, 3.06 mmol) in hy-
drogen bromide (10 mL) at 0 °C was added bromine (490 mg,
3.06 mmol) dropwise over 1 h. After the reaction was complete, the
product was extracted twice with dichloromethane. The organic
layer was dried with MgSO4, filtered, and concentrated. The re-
sulting crude product was purified by column chromatography
(EtOAc/hexanes, 1:9) to give 7 (712 mg, 96%) as a yellow solid.
[1] a) N. Narasimhachari, K. S. Gopalkrishnan, J. Antibiot. 1974,
27, 283–287; b) M. V. Kadkol, K. S. Gopalkrishnan, N. Naras-
imhachari, J. Antibiot. 1971, 24, 245–248; c) E. Thines, H.
Anke, O. Sterner, J. Nat. Prod. 1998, 61, 306–308; d) W. Wang,
T. Li, R. Milburn, J. Yates, E. Hinnant, M. J. Luzzio, S. A.
Noble, G. Attardo, Bioorg. Med. Chem. Lett. 1998, 8, 1579–
1584.
[2] a) R. G. F. Giles, I. R. Green, V. I. Hugo, P. R. K. Mitchell, J.
Chem. Soc. Chem. Commun. 1983, 1, 51–52; b) V. I. Hugo,
Synth. Commun. 1994, 24, 2563–2569; c) H. Uno, J. Org. Chem.
1986, 51, 350–358; d) M. F. Aldersley, S. H. Chishti, F. M.
Dean, M. E. Douglas, E. Mark, D. S. Ennis, J. Chem. Soc. Per-
kin Trans. 1 1990, 8, 2163–2174; e) M. F. Aldersley, F. M.
Dean, A. S. Hamzah, Tetrahedron Lett. 1986, 27, 255–258; f)
K. Kobayashi, M. Uchida, T. Uneda, M. Tanmatsu, O. Mori-
kawa, H. Konishi, Tetrahedron Lett. 1998, 39, 7725–7728.
[3] a) S. L. Mecklenburg, D. G. McCafferty, J. R. Schoonover,
B. M. Peek, B. W. Erickson, T. J. Meyer, Inorg. Chem. 1994, 33,
2974–2983; b) K. A. Opperman, S. L. Mecklenburg, T. J.
Meyer, Inorg. Chem. 1994, 33, 5295–5301; c) M. R. Wasielew-
ski, Chem. Rev. 1992, 92, 435–461.
1
M.p. 88–89 °C (ref.[7] 91–92 °C). H NMR (300 MHz, CDCl3): δ =
3
3
7.89 (d, JH,H = 9.0 Hz, 2 H), 6.66 (d, JH,H = 9.0 Hz, 2 H), 4.36
(s, 2 H), 3.08 (s, 6 H) ppm.
1-(4Ј-N,N-Dimethylaminophenacyl)pyridinium Bromide (8): To a
solution of 7 (500 mg, 2.07 mmol) in acetone (5 mL) was added
pyridine (163 mg, 2.07 mmol). The resulting mixture was then
heated at reflux for 6 h. The solution was cooled to room temp.,
and the precipitate was collected to give 8 (650 mg, 98%) as a yel-
low liquid. M.p. 250–251 °C. 1H NMR (300 MHz, CD3OD): δ =
3
3
8.90 (d, JH,H = 6.6 Hz, 2 H), 8.67 (t, JH,H = 6.6 Hz, 1 H), 8.16
3
3
(t, JH,H = 6.6 Hz, 2 H), 7.94 (d, JH,H = 9.0 Hz, 2 H), 6.81 (d,
3JH,H = 9.0 Hz, 2 H), 6.32 (s, 2 H), 3.11 (s, 6 H) ppm. 13C NMR
(75 MHz, CD3OD): δ = 188.0, 156.2, 147.6, 147.3, 131.8, 128.9,
121.8, 112.1, 66.9, 40.1 ppm. IR (KBr): ν = 3514, 3037, 1652, 1343,
˜
1006, 682 cm–1. HRMS (EI): calcd. for C15H17BrN2O [M]+
320.0524; found 320.0527.
[4] a) D. J. Yee, V. Balsanek, D. Sames, J. Am. Chem. Soc. 2004,
126, 2282–2283; b) T. Suzuki, A. Migita, H. Higuchi, H. Ka-
wai, K. Fujiwara, T. Tsuji, Tetrahedron Lett. 2003, 44, 6837–
6840; c) H. Higuchi, K. Ichioka, H. Kawai, K. Fujiwara, M.
Ohkita, T. Tsuji, T. Suzuki, Tetrahedron Lett. 2004, 45, 3027–
3030; d) T. Suzuki, S. Tanaka, H. Higuchi, H. Kawai, K. Fuji-
wara, Tetrahedron Lett. 2004, 45, 8563–8567.
5,10-Dimethoxy-1-methyl-1,3-diphenyl-1H-benzo[g]isochromene
(10c): To a solution of 6c (50 mg, 0.13 mmol) in ethanol (5 mL) and
water (5 mL) was added sodium borohydride (10 mg, 0.26 mmol) at
room temp. The mixture was stirred for 5 min and then a solution
of KOH (10 , 5 mL) was added. The resulting mixture was stirred
for another 5 min and then heated at reflux; dimethyl sulfate
(75 mg, 0.59 mmol) was then added. The mixture was heated at
reflux overnight and then cooled to room temp. The product was
extracted with EtOAc and purified by column chromatography
(EtOAc/hexanes, 1:9) to give 10c (16 mg, 30%) as a yellow solid.
[5] T. Nguyen Van, B. Kesteleyn, N. De Kimpe, Tetrahedron 2001,
57, 4213–4219.
[6] a) A. A. Akhrem, F. A. Lakhvich, N. A. Fil’chenkov, Russ. J.
Org. Chem. 1979, 15, 2333–2337; b) Y. S. Chen, P. Y. Kuo, T. L.
Shie, D. Y. Yang, Tetrahedron 2006, 62, 9410–9416.
[7] M. Suzuki, M. Nagawa, Yakugaku Zasshi 1955, 75, 54–56.
[8] R. G. Harvey, Q. Dai, C. Ran, T. M. Penning, J. Org. Chem.
2004, 69, 2024–2032.
1
3
M.p. 144–145 °C. H NMR (300 MHz, CDCl3): δ = 8.09 (d, JH,H
3
= 7.8 Hz, 1 H), 8.0 (d, JH,H = 8.4 Hz, 1 H), 7.83–7.80 (m, 2 H),
Received: May 14, 2007
7.53–7.18 (m, 4 H), 6.83 (s, 1 H), 3.98 (s, 3 H), 3.48 (s, 3 H), 2.33
Published Online: August 3, 2007
4836
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4831–4836