Studies on the oxidative cyclization of 3-hydroxyalkyl-1,2,4- trialkoxynaphthalenes and synthetic application for the biologically active natural compound rhinacanthone

Article abstract of DOI:10.1016/j.tet.2013.11.025

The oxidative intramolecular cyclization of 3-hydroxyalkyl-1,2,4- trimethoxynaphthalenes was investigated. A series of 1,2-naphthoquinone fused cyclic ethers were synthesized directly from 3-hydroxyalkyl-1,2,4- trimethoxynaphthalenes by exposure to diammonium cerium (IV) nitrate. To understand the reaction mechanism, the intramolecular cyclization of 3-hydroxyalkyl-naphthoquinones that were formed as reaction intermediates was also examined. The results suggested that the reaction proceeds by a stepwise oxidation-cyclization mechanism. Using this methodology, five-step synthesis of rhinacanthone was achieved with high yield.

Full text of DOI:10.1016/j.tet.2013.11.025

Tetrahedron 70 (2014) 502e509
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies on the oxidative cyclization of 3-hydroxyalkyl-1,2,4-
trialkoxynaphthalenes and synthetic application for the biologically
active natural compound rhinacanthone
Tokutaro Ogata a, Misae Doe a, Aya Matsubara a, Eri Torii a, Chiaki Nishiura a,
,
Arisa Nishiuchi a, Yusuke Kobayashi b, Tetsutaro Kimachi a
*
a School of Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien Kyu-bancho, Nishinomiya 663-8179, Hyogo, Japan
b Graduate School and Faculty of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachicho, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2013
Received in revised form 3 November 2013
Accepted 10 November 2013
Available online 27 November 2013
The oxidative intramolecular cyclization of 3-hydroxyalkyl-1,2,4-trimethoxynaphthalenes was in-
vestigated. A series of 1,2-naphthoquinone fused cyclic ethers were synthesized directly from 3-
hydroxyalkyl-1,2,4-trimethoxynaphthalenes by exposure to diammonium cerium (IV) nitrate. To un-
derstand the reaction mechanism, the intramolecular cyclization of 3-hydroxyalkyl-naphthoquinones
that were formed as reaction intermediates was also examined. The results suggested that the reaction
proceeds by a stepwise oxidationecyclization mechanism. Using this methodology, five-step synthesis of
rhinacanthone was achieved with high yield.
Keywords:
Oxidative cyclization
Diammonium cerium (IV) nitrate
Naphthoquinone
Ó 2013 Elsevier Ltd. All rights reserved.
Natural product
1. Introduction
naphthoquinone (lawsone) equivalent afforded (R)-(ꢀ)-dehy-
droiso-b
-lapachone (4) in high yield.1 Initially, we considered that
We previously reported that CAN (diammonium cerium (IV)
nitrate) oxidation of 3-hydroxyalkyl-1,2,4-trialkoxynaphthalene
derivative (1) regarded as the reduced 2-hydroxy-1,4-
the CAN oxidation would give a mixture of 2, 3, 4, and 5. Contrary to
expectation, 2 and 3 were not obtained, but (R)-(ꢀ)-dehydroiso-
b-
lapachone (4) was obtained with a small amount of 5 (Fig. 1).
Fig. 1. Previous study of the synthesis of (ꢀ)-dehydroiso-
b
-lapachone.1
This interesting result prompted us to continue development of
the new method to synthesize 1,2-naphthoquinones containing
cyclic ether functions by CAN oxidation of the naphthalene
* Corresponding author. Tel./fax: þ81 798 45 9952; e-mail address: tkimachi@
mukogawa-u.ac.jp (T. Kimachi).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.025

T. Ogata et al. / Tetrahedron 70 (2014) 502e509
503
derivatives having the hydroxyl group at side chains and accom-
panying intramolecular cyclization. In this study, four 3-
hydroxyalkyl-1,2,4-trimethoxynaphthalenes (8, 9, 11, and 13),
which have a hydroxyl group at the end of each alkyl side chain,
were prepared as substrates and subjected to CAN oxidation
(Fig. 2). The brief consideration of the reaction mechanism of this
oxidation including intramolecular cyclization is also described. We
applied this method to the convenient synthesis of the biologically
active natural product rhinacanthone.
respectively. The spectroscopic data of all derived compounds (8, 9,
11 and 13) supported their chemical structures (Scheme 1) (For
details, see the Experimental procedures).
We carried out CAN oxidation of naphthalenes (8, 9, 11, and 13)
according to our reported procedure.1 Acetonitrile solution of each
compound was stirred at 0 ꢁC with aqueous CAN solution. The re-
action mixture was worked up and purified to give the corre-
sponding products in pure form. The structures of the compounds
have been elucidated by spectroscopic analyses. The results sum-
Fig. 2. Development of the synthesis of novel oxidative naphthoquinones linked by intramolecular ether bond formation (this study).
2. Results and discussion
marized in Table 1 showed that we obtained two sets of isomers.
One of them was a pair of naphthoquinones having hydroxyalkyl
side chains, such as n-I and n-II (n¼14e17), and the other was a pair
of naphthoquinones, such as n-III and n-IV, (n¼14e17) containing
the fused cyclic ether function.
CAN oxidation of naphthalene derivative 8 afforded equal
amounts of 14-I and 14-II, but did not afford four-membered ring
compounds, such as 14-III and 14-IV (entry 1). Oxidation of 9 and
11 mainly afforded naphthoquinones 15-III and 16-III with small
amounts of 15-IV and 16-IV, respectively (entries 2 and 3). On the
other hand, from these same entries, n-I and n-II (n¼15 and 16)
Initial study began with the synthesis of compounds 8, 9, 11, and
13 from 1,2,4-trimethoxynaphthalene (6). According to the known
procedure, directed ortho lithiationesubstitution reaction of 6 and
subsequent quenching with suitable electrophiles afforded the
corresponding 3-substituted-1,2,4-trimethoxynaphthalenes (7, 9,
10, and 12).2 Compound 9 was directly used as the starting sub-
strate. Ester 7 was converted to 8 by lithium aluminum hydride
(LiAlH4) reduction. The silyl ethers 10 and 12 were treated with
acidic tetrabutylammonium fluoride (TBAF) to lead to 11 and 13,
Scheme 1. Synthesis of four 3-hydroxyalkyl-1,2,4-trimethoxynaphthalenes (8, 9, 11, and 13).

504
T. Ogata et al. / Tetrahedron 70 (2014) 502e509
Table 1
Oxidation of naphthalene derivatives (8, 9, 11, and 13) with CAN
Entry
Compounds (yield%)
O
O
OCH
O
3
OH
OH
condition
O
1
8
O
OCH
O
3
14-IV
14-III
15-III
16-III
O
O
14-I
14-II
O
O
(0%)
(46%)
(0%)
(40%)
O
OCH
3
O
O
OH
OH
condition
condition
2
3
9
O
OCH
O
O
O
3
15-I
15-II
15-IV
O
O
(0%)
O
(56%)
O
(6%)
(8%)
OCH
O
O
3
O
(CH ) OH
2 3
(CH ) OH
2 3
11
O
O
OCH
3
16-II
16-IV
16-I
O
O
(7%)
O
O
(0%)
(0%)
(67%)
OCH3
O
O
O
(CH2)4OH
(CH2)4OH
OCH3
condition
4
13
O
O
O
17-IV
17-II
17-I
17-III
O
(8%)
O
(8%)
O
(34%)
O
(20%)
Reaction conditions: CAN (2.5 equiv), CH3CN/H2O¼1:1, 0 ꢁC, 0.5 h.
were not isolated except a small amount of 15-II. The results of
these three entries suggest that the naphthalene derivatives ini-
tially oxidized by CAN and then the derived naphthoquinones (n-I
and n-II, n¼15 and 16) are facilitated to be cyclized in intra-
molecular manner. The disappearance of n-I and n-II could be
interpreted on the ease of cyclization to form five- or six-mem-
bered ring compounds, which could be supported from the basis of
the Baldwin’s rules. Furthermore, the oxidation of 9 and 11 mainly
afforded the corresponding o-quinone derivatives (15-III and 16-
III) rather than p-quinone derivatives (15-IV and 16-IV). In the
intramolecular cyclization, nucleophilic OH attack of the carbon
CAN oxidation of 13 gave conceivable products with substantial
amounts of 17-II relative to 17-I, 17-III, and 17-IV (entry 4). The
prolonged reaction time, or the reaction under the elevated tem-
perature in the oxidation of 13 did not improve the yield of cyclic
ethers (17-III and 17-IV). Furthermore, the same reaction with the
excess amount of CAN afforded decomposed complex mixtures.
The result that 17-I and 17-II were accumulated and isolated
strongly support stepwise oxidationecyclization reaction. It is
noteworthy that seven-membered ring compounds were directly
formed by the oxidative intramolecular cyclization with a linear
alkyl side chain, although the yields of the cyclized products (17-III
and 17-IV) were not satisfactory. The plausible reaction path of the
oxidative intramolecular cyclization is visualized in Fig. 3. It shows
that the starting 1,2,4-trimethoxynaphthalene derivatives were
oxidized to naphthoquinone intermediates n-I and n-II (n¼14, 15,
16, and 17) with subsequent cyclization to produce n-III and n-IV, if
possible. In order to support this hypothesis, additional experi-
ments were carried out and the results were summarized in Table 2.
Isolated or separately prepared n-I and n-II (n¼15 and 16) were
located at the benzylic position and also the
b-position of the
conjugated system must be preferred.3 To ensure the hypothesis
described above, CAN oxidation of 13 was carried out. The forma-
tion of seven-membered ring is also favorable, but the cyclization is
slower than that of five- or six-membered system according to the
Baldwin’s rules. Thus, it may be possible to isolate 17-I and 17-II as
the intermediates of the oxidative cyclization. This is the reason
why we prepared 13. The result was illustrated in entry 4 in Table 1.
Fig. 3. Plausible reaction paths of the oxidative intramolecular cyclization.

T. Ogata et al. / Tetrahedron 70 (2014) 502e509
505
Table 2
Also, it was found that the water in the reaction might slow the
cyclization, probably due to the nucleophilicity of the oxygen atom
in a water molecule to the alcohol moiety of naphthoquinones (n-I
and n-II). Thus, these results indicate that the one-pot reaction of
1,2,4-trimethoxynaphthalene derivatives with CAN proceeds by an
initial oxidation to form naphthoquinones followed by highly
regioselective intramolecular cyclization.
With the aim of advancing this methodology based on the new
CAN oxidation intramolecular cyclization connection, we report an
application for the synthesis of 3,4-dihydro-3,3-dimethyl-2H-
naphtho[1,2-b]pyran-5,6-dione (rhinacanthone) (Scheme 2).
Rhinacanthone, which is isolated from a shrub widely distrib-
uted in Southeast Asia; Rhinacanthus nasutus, is a naturally occur-
ring biologically active compound having antitumor activity against
various cancer cells.5 To date, there have been reports on the syn-
thesis of rhinacanthone by two groups.6,7 Both groups reported
eight-step synthesis in 17% and 48% total yields, respectively.
However, the reported methods are insufficient to enable expan-
sion of the study of rhinacanthone and its analogs from the me-
dicinal chemistry viewpoint. Improvement of the chemical yield
and shortening of the reaction steps for the synthesis of this natural
Additional experiments for the intramolecular cyclization and ring re-opening of n-I,
n-II, n-III, and n-IV with CANa
Entry
Substrate
Product ratio (%)b
I
II
III
IV
1
2
14-I
14-II
15-I
15-II
16-I
16-II
16-II
17-I
17-I
17-II
n-III
n-IV
100
d
d
d
5
d
d
d
d
d
100
d
3
83
d
17
4c
5
d
d
d
d
d
d
d
d
d
100
d
95
6
d
d
62
50
d
d
d
81
29
d
19
71
38
50
7d
8
9d
10
11e
12e
d
100
d
d
100
d
d
a
Reaction conditions: CAN (2.5 equiv), CH3CN/H2O¼5:3, 0 ꢁC, 0.5 h.
b
The ratio of these compounds was calculated from the crude mixture of the
products by 1H NMR analysis.
c
A complex mixture was formed with no assignable product.
The reaction was performed in the absence of H2O.
n¼15, 16, 17.
d
e
Scheme 2. Five-step synthesis of rhinacanthone. Reagents and conditions: i) 1) n-BuLi, THF, 0 ꢁC to rt. 2) CH3I, ꢀ80 ꢁC. ii) NBS, CHCl3, reflux, 3 h. iii) LDA, ethyl isobutyrate, ꢀ80 ꢁC.
iv) LiAlH4, THF, rt. v) CAN (2.5 equiv), CH3CN/H2O (1/1), 0 ꢁC, 0.5 h.
solely mixed with aqueous CAN solution.4 Further reaction of 14-I
or 14-II did not occur (entries 1, 2). The reaction of 15-I with
aqueous CAN gave cyclized compound 15-III as a major product
with a small amount of 15-IV (entry 3). Similar reaction of 16-I or
16-II with aqueous CAN gave the cyclized compound 16-III with
complete selectivity against the compound 16-IV (entries 5, 6). On
the other hand, oxidation of 17-I afforded 17-III with recovery of
the starting material, while 17-II was intact against the reaction
mixture containing CAN (entries 8, 10). The cyclization of 1,4-
naphthoquinones n-II was effectively accelerated when the re-
action was carried out in the absence of water (entries 7, 9). In
addition, the probability of inter-conversion between n-III and n-IV
was tested, but the ring re-opening reaction of n-III and n-IV was
not observed under the same conditions (entries 11, 12). These re-
sults suggest that cyclization of naphthoquinone intermediates n-I
and n-II (except 17-II) proceeds smoothly to afford n-III (n¼15, 16,
and 17) but intramolecular cyclization of 17-II occurs very slowly. In
particular, the reaction pathway from n-I to n-III (path a) seems
much faster than the others. The order of the rate of this intra-
molecular cyclization is considered to be path a>path b, c>>path d.
product are needed. The construction of this naphthopyrandione
structure was initiated by novel four-step synthesis of 21 using
a conventional ortho-lithiation method through the known pre-
cursors 18, 19, and 20 shown in Scheme 2. Precursor 21 was con-
verted to rhinacanthone by exposure to CAN oxidation. The
obtained rhinacanthone and a small amount of the isomer showed
analytical and spectroscopic data consistent with those reported
elsewhere.6 Finally, five-step synthesis of rhinacanthone in excel-
lent yield (78% overall) proved the utility of this methodology.
3. Conclusion
Four 3-hydroxyalkyl-1,2,4-trimethoxynaphthalenes (8, 9, 11,
and 13), which have a hydroxyl group at the end of each alkyl side
chain, were prepared and subjected to CAN oxidation reaction to
afford naphthoquinone derivatives containing a fused cyclic ether
function. The reaction was suggested to proceed by the stepwise
oxidationecyclization mechanism. Using this methodology, five-
step synthesis of rhinacanthone from known 1,2,4-trimetho-
xynaphthalene was achieved in high yield.

506
T. Ogata et al. / Tetrahedron 70 (2014) 502e509
4. Experimental
5 mmol) in anhydrous tetrahydrofuran (THF) (6 mL) under argon
atmosphere. n-BuLi (3.75 mL, 6 mmol, 1.6 M in n-hexane solution)
was added to the solution prepared above at 0 ꢁC and the reaction
mixture was stirred for 2 h at room temperature. The mixture was
cooled to ꢀ80 ꢁC and ethylene oxide solution (6.0 mL, 1 M solution
in THF) was added. The dry ice bath was removed and the mixture
was warmed to room temperature. After checking by TLC, the re-
action mixture was worked up with addition of satd aqueous NH4Cl
and AcOEt. The mixture was separated and the aqueous layer was
extracted three times with AcOEt. The combined organic layer was
washed with water, brine and dried over MgSO4, and concentrated
in vacuo. The resulting residue was purified by flash chromatog-
raphy (hexane/AcOEt¼2:1) to afford 1.17 g, 90% of 2-(1,3,4-
trimethoxynaphthalen-2-yl)-ethanol (9) as a white solid. Mp
4.1. General
All materials not explicitly mentioned were purchased from
Wako Pure Chemical Products Co., Kanto Chemical Co., TCI Labora-
tory Chemical Co., and Aldrich Chemical Co. 1H NMR spectra were
recorded on a JEOL JNM-ECP400 or JNM-ECP500 spectrometer using
tetramethylsilane (TMS) as an internal standard. Chemical shifts are
recorded in parts per million (ppm) relative to TMS. 13C NMR spectra
were proton decoupled and recorded on a JEOL JNM-ECP400 or JNM-
ECP500 spectrometer using the carbon signal of the deuterated
solvent as the internal standard. Mass spectra (MS) were obtained on
JEOL JMS-700 instruments. Melting points were measured on
a Yanaco micro melting point apparatus and are uncorrected. Flash
chromatography was performed with silica gel (Wakosil C-200) ob-
tained from Wako Pure Chemical Products Co. Analytical thin layer
chromatography was performed on Merck Silica Gel 60 F254 alumi-
num sheets and the visualization was performed using a UV lamp.
56e61 ꢁC. 1H NMR (400 MHz, CDCl3)
d 2.30 (br s, 1H, OH), 3.13 (t,
2H, J¼6.2 Hz, CH2), 3.89 (t, 2H, J¼6.2 Hz, CH2), 3.92 (s, 3H, OCH3),
3.96 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 7.43 (m, 1H, aryleH), 7.47 (m,
1H, aryleH), 7.99 (dd, 1H, J¼1.5, 7.0 Hz, aryleH), 8.09 (dd, 1H, J¼1.0,
7.0 Hz, aryleH). 13C NMR (100 MHz, CDCl3)
d 28.3 (CH2), 60.85
(CH3), 60.9 (CH3), 62.2 (CH3), 63.4 (CH2), 121.7 (CH), 122.1 (CH),
124.0 (CH), 125.1 (CH), 125.4 (C), 125.9 (CH), 128.7 (C), 143.7 (C),
148.0 (C), 150.7 (C). HRMS calcd for C15H18O4: 262.1205. Found:
262.1202.
4.1.1. 1,3,4-Trimethoxy-2-naphthalenecarboxylic acid methyl ester
(7). A frame-dried round bottom flask was charged with a solution
of 1,2,4-trimethoxynaphthalene (6) (2.18 g, 10 mmol) in anhydrous
tetrahydrofuran (THF) (12 mL) under argon atmosphere. n-BuLi
(7.5 mL, 12 mmol, 1.6 M in n-hexane solution) was added to the
solution prepared above at 0 ꢁC and the reaction mixture was
stirred for 2 h at room temperature. The mixture was re-cooled to
4.1.4. tert-Butyl-diphenyl-[3-(1,3,4-trimethoxynaphthalen-2-yl)-pro-
poxy]-silane (10). A frame-dried round bottom flask was charged
with a solution of 6 (872 mg, 4.0 mmol) in anhydrous tetrahydro-
furan (THF) (5 mL) under argon atmosphere. n-BuLi (3.7 mL,
4 mmol, 1.6 M n-hexane solution) was added to the solution pre-
pared above at 0 ꢁC and the reaction mixture was stirred for 2 h at
room temperature. Next, the mixture was cooled to ꢀ80 ꢁC, and (3-
bromo-propoxy)-tert-butyl-diphenylsilane (1.9 g, 6.0 mmol) solu-
tion in THF (5 mL) was added via cannula and the mixture was
stirred for 15 h. The reaction mixture was worked up by addition of
satd aqueous NH4Cl and AcOEt. The mixture was separated and the
aqueous layer was extracted with AcOEt. The combined organic
layer was washed with water, brine and dried over MgSO4, and
concentrated in vacuo. The resulting residue was purified by flash
chromatography (hexane/AcOEt¼6:1) to afford 975 mg (47%) of
tert-butyl-diphenyl-[3-(1,3,4-trimethoxynaphthalen-2-yl)-pro-
0
ꢁC and methyl chloroformate (3.1 mL, d¼1.22 g/cm3, 40 mmol)
was added dropwise. After checking by thin layer chromatography
(TLC), the reaction mixture was worked up with addition of satd
aqueous NH4Cl and AcOEt. The mixture was separated and the
aqueous layer was extracted with AcOEt. The combined organic
layer was washed with 1% aqueous Na2S2O3, water, brine and dried
over MgSO4, and concentrated in vacuo. The resulting residue was
purified by flash chromatography (hexane/AcOEt¼8:1) to afford
2.58 g (93%) of 1,3,4-trimethoxy-2-naphthalenecarboxylic acid
methyl ester (7). 1H NMR (500 MHz, CDCl3)
d 3.98 (s, 3H, OCH3),
3.99 (s, 6H, OCH3 ꢂ2), 4.00 (s, 3H, OCH3), 7.47 (t, 1H, J¼8.2 Hz,
aryleH), 7.54 (t, 1H, J¼8.2 Hz, aryleH), 8.06 (d, 1H, J¼8.2 Hz,
aryleH), 8.11 (d, 1H, J¼8.2 Hz, aryleH). 13C NMR (125.8 MHz, CDCl3)
d
52.5 (CH3), 61.1 (CH3), 61.6 (CH3), 63.3 (CH3),121.1 (CH),121.9 (CH),
poxy]-silane (10). 1H NMR (400 MHz, CDCl3)
d 1.09 (s, 9H, Si(CH3)3),
122.8 (CH), 125.3 (CH), 125.5 (C), 127.4 (C), 130.2 (C), 143.5 (C), 145.3
1.88 (m, 2H, CH2), 2.90 (m, 2H, CH2), 3.81 (t, 2H, J¼6.2 Hz, CH2OH),
3.88 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 7.35e7.47
(m, 8H, aryleH), 7.71 (m, 4H, aryleH), 8.00 (m, 1H, aryleH), 8.07 (m,
(C), 149.8 (C), 166.6 (C). IR (cmꢀ1
)
n
2940, 1728, 1620, 1598, 1230,
1060. HRMS calcd for C15H16O5: 276.0998. Found: 276.1002.
1H, aryleH).13C NMR (100 MHz, CDCl3)
d 19.3 (C), 21.8 (CH2), 26.9
4.1.2. (1,3,4-Trimethoxynaphthalen-2-yl)-methanol (8). To a stirred
60 mL ethereal solution of methyl ester (7) (2.58 g, 9.3 mmol), was
added lithium aluminum hydride (LAH) (777 mg, 20.4 mmol) at
0 ꢁC. The ice bath was removed and the mixture was stirred for 2 h
at room temperature. The excess LAH was quenched with addition
of AcOEt. The mixture was extracted three times with diethyl ether.
The combined ether layer was washed with water, brine, and then
dried over MgSO4, and concentrated under reduced pressure. The
resulting residue was purified by flash chromatography (hexane/
AcOEt¼3:1) to afford (1,3,4-trimethoxynaphthalen-2-yl)-methanol
(CH3), 33.7 (CH2), 60.8 (CH3), 62.2 (CH3), 64.3 (CH2), 121.5 (CH),
122.1 (CH), 124.8 (CH), 125.5 (CH), 127.6 (CH), 127.8 (CH), 128.2 (CH),
129.5 (C),134.2 (C),135.5 (C),135.6 (C),143.5 (C), 148.5 (C),150.2 (C).
HRMS calcd for C32H38O4Si: 514.2539. Found: 514.2537. LRMS (EI)
m/z 514 (Mþ53), 457 (86), 442 (100), 427 (30), 333 (22).
4.1.5. 3-(1,3,4-Trimethoxynaphthalen-2-yl)-propan-1-ol (11). TBDPS
ether (10) (900 mg, 1.75 mmol) was dissolved in THF (10 mL) and
cooled in ice bath. To the mixture, was added tetrabutylammonium
fluoride (TBAF) (5.3 mL, 5.3 mmol, 1 M solution in THF) and acetic
acid (0.2 mL, 3.5 mmol) followed by stirring for 40 min at 40 ꢁC and
working up. AcOEt and water was added to the mixture and sep-
arated. The aqueous layer was saturated by the addition of NaCl
solid and then extracted twice with AcOEt. The combined organic
layer was washed with satd aqueous NaHCO3, brine and dried over
MgSO4. The filtrate was concentrated in vacuo and purified by flash
chromatography (AcOEt) to afford 433 mg (1.57 mmol, 90%) of 3-
(1,3,4-trimethoxynaphthalen-2-yl)-propan-1-ol (11) as a white
(8) (2.2 g, 8.8 mmol) (95%). 1H NMR (270 MHz, CDCl3)
d 2.62 (m, 1H,
CH2OH), 3.98 (s, 6H, OCH3 ꢂ2), 4.07 (s, 3H, OCH3), 7.43e7.54 (m, 2H,
aryleH), 8.03e8.12 (m, 2H, aryleH). 13C NMR (125.8 MHz, CDCl3)
d
56.4 (CH3), 61.0 (CH3), 61.3 (CH3), 121.7 (CH), 122.5 (CH ꢂ2), 125.3
(C), 125.5 (CH), 126.5 (C), 129.5 (C), 143.5 (C), 147.9 (C), 150.7 (C). IR
(cmꢀ1
3500, 2920, 1620, 1598, 1360, 1060. HRMS calcd for
)
n
C
14H16O4: 248.1049. Found: 248.1055. LRMS (EI) m/z 248 (Mþ100),
233 (62), 205 (45), 173 (11), 161 (12), 15 (7), 129 (7).
solid. Mp 72e73 ꢁC. 1H NMR (400 MHz, CDCl3)
d 1.89 (quint, 2H,
4.1.3. 2-(1,3,4-Trimethoxynaphthalen-2-yl)-ethanol (9). A frame-
dried round bottom flask was charged with a solution of 6 (1.1 g,
J¼7.0 Hz, CH2), 2.51 (t, 1H, J¼7.0 Hz, OH), 2.94 (t, 2H, J¼7.0 Hz, CH2),
3.54 (q, 2H, J¼5.9 Hz, CH2), 3.93 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 4.0

T. Ogata et al. / Tetrahedron 70 (2014) 502e509
507
(s, 3H, OCH3), 7.45 (m, 2H, ArH), 8.04 (m, 2H, ArH). 13C NMR
(100 MHz, CDCl3) 20.5 (CH2), 32.7 (CH2), 60.9 (CH3), 61.0 (CH3),
J¼8.0, 1.5 Hz, ArH), 8.09 (dd, 1H, J¼8.0, 1.5 Hz, ArH). 13C NMR
d
(100 MHz, CDCl3) d 55.0 (CH2), 63.1 (CH3), 123.8 (C), 125.8 (CH),
61.3 (CH2), 62.3 (CH3), 121.7 (CH), 122.0 (CH), 125.0 (CH), 125.7 (CH),
126.3 (C), 128.4 (C), 143.7 (C), 148.2 (C), 150.2 (C). HRMS calcd for
129.4 (CH), 130.2 (C), 131.3 (C), 133.1 (CH), 135.4 (CH), 167.8 (C),
178.6 (C), 182.1 (C). HRMS calcd for C12H10O4: 218.0579. Found:
218.0579. Compound (14-II); mp 100e106 ꢁC. 1H NMR (400 MHz,
C
16H20O4: 276.1362. Found: 276.1361.
CDCl3) d 2.95 (s, 1H, OH), 4.22 (s, 3H, CH3), 4.70 (s, 2H, CH2), 7.72 (m,
4.1.6. tert-Butyldimethyl-[4-(1,3,4-trimethoxynaphthalen-2-yl)-bu-
toxy]-silane (12). A frame-dried round bottom flask was charged
with a solution of 6 (1.09 g, 5.0 mmol) in anhydrous THF (7 mL)
under argon atmosphere. n-BuLi (3.6 mL, 6 mmol, 1.6 M n-hexane
solution) was added to the solution prepared above at 0 ꢁC and the
reaction mixture was stirred for 2 h at room temperature. The
mixture was cooled to ꢀ80 ꢁC and (4-bromobutoxy)-tert-butyldi-
methylsilane (1.9 g, 5.1 mmol) solution in THF (1 mL) was added via
cannula and the mixture was stirred for 48 h. The reaction mixture
was worked up by addition of satd aqueous NH4Cl and AcOEt. The
mixture was separated and the aqueous layer was extracted with
AcOEt. The combined organic layer was washed with water, brine
and dried over MgSO4, and concentrated in vacuo. The resulting
residue was purified by flash chromatography (hexane/AcOEt¼6:1)
to afford 1.42 g (70%) of desired tert-butyldimethyl-[4-(1,3,4-
2H, ArH ꢂ2), 8.05 (m, 2H, ArH ꢂ2). 13C NMR (100 MHz, CDCl3)
d 55.2
(CH2), 61.7 (CH3), 126.0 (CH), 126.3 (CH), 130.5 (C), 131.5 (C), 131.7
(C), 133.5 (CH), 134.1 (CH), 157.4 (C), 181.6 (C), 186.3 (C). HRMS calcd
for C12H10O4: 218.0579. Found: 218.0580.
4.1.9. CAN oxidation of 9. According to the procedure described for
CAN oxidation of 8, CAN (1.37 g, 2.5 mmol) in water (9.0 mL) was
added to a stirred solution of 9 (262 mg, 1.0 mmol) in CH3CN
(14.0 mL) at 0 ꢁC. The crude mixture was purified by flash chroma-
tography (hexane/AcOEt¼1:2) to provide 15-II (17.3 mg, 8%), 15-III
(112.6 mg, 56%), and 15-IV (12.3 mg, 6%). Compound (15-II); mp
107e108 ꢁC. 1H NMR (400 MHz, CDCl3)
3.81 (t, 2H, J¼6.2 Hz, CH2), 4.17 (s, 3H, OCH3), 7.70 (m, 2H, ArH), 8.06
(m, 2H, ArH).13C NMR (100 MHz, CDCl3)
27.4 (CH2), 61.4 (CH3), 62.0
d
2.92 (t, 2H, J¼6.2 Hz, CH2),
d
(CH2), 125.2 (CH), 126.0 (C), 129.6 (CH), 130.1 (C), 130.7 (CH), 132.9
(C), 135.4 (CH), 167.6 (C), 178.8 (C), 182.1 (C). HRMS calcd for
trimethoxynaphthalen-2-yl)-butoxy]-silane
(12).
1H
NMR
(400 MHz, CDCl3) 0.04 (s, 6H, Si(CH3)2), 0.89 (s, 9H, Si-tert-
d
C
13H12O4: 232.0736. Found: 232.0734. Compound (15-III); mp
C(CH3)3), 1.62e1.71 (m, 4H, CH2 ꢂ2), 2.81 (t, 2H, J¼7.3 Hz, CH2), 3.66
(m, 2H, CH2OSi), 3.90 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 3.99 (s, 3H,
OCH3), 7.39 (td, 2H, J¼6.0, 2.0 Hz, aryleH ꢂ2), 7.99 (dd, 1H, J¼2.0,
7.0 Hz, aryleH), 8.08 (dd, 1H, J¼2.0, 7.0 Hz, aryleH). 13C NMR
229e236 ꢁC. 1H NMR (400 MHz, CDCl3)
d
3.21 (t, 2H, J¼9.9 Hz, CH2),
4.78 (t, 2H, J¼9.9 Hz, OCH2), 7.66 (td, 1H, J¼8.0,1.5 Hz, ArH), 7.71 (td,
1H, J¼8.0, 1.5 Hz, ArH), 8.06 (dd, 2H, J¼8.0, 1.5 Hz, ArH). 13C NMR
(100 MHz, CDCl3) d 26.5 (CH2), 74.8 (CH2),115.6 (C),124.5 (CH),127.5
(100 MHz, CDCl3)
d
ꢀ2.9 (CH3), 18.3 (C), 26.0 (CH3), 60.8 (CH3), 62.3
(C), 129.4 (CH), 130.7 (C), 131.9 (CH), 134.5 (CH), 170.5 (C), 175.4 (C),
181.2 (C). HRMS calcd for C12H8O3: 200.0473. Found: 200.0473.
Compound (15-IV); mp 194e200 ꢁC. 1H NMR (400 MHz, CDCl3)
(CH3), 63.1 (CH3), 121.6 (CH), 122.1 (CH), 124.8 (CH), 125.4 (C), 125.5
(CH), 128.0 (C), 128.2 (C), 143.5 (C), 148.5 (C), 150.1 (C). HRMS calcd
for C23H36O4Si: 404.2383. Found: 404.2382.
d
3.16 (t, 2H, J¼9.2 Hz, CH2), 4.88 (t, 2H, J¼9.2 Hz, OCH2), 7.58 (td,1H,
J¼8.0, 2.6 Hz), 7.64 (m, 2H, ArH), 8.09 (d,1H, J¼8.0 Hz, ArH).13C NMR
4.1.7. 4-(1,3,4-Trimethoxynaphthalen-2-yl)-butanol (13). TBS ether
(12) (1.37 g, 3.4 mmol) was dissolved in THF (20 mL) and cooled in
an ice bath. To the mixture, was added TBAF (9.5 mL, 9.5 mmol, 1 M
solution in THF) and acetic acid (0.4 mL, 6.8 mmol), and the mixture
was stirred for 40 min at 40 ꢁC then for 18 h at room temperature
and worked up. AcOEt and water were added to the mixture, and
after separation, the aqueous layer was saturated by the addition of
NaCl solid and then extracted twice with AcOEt. The combined
organic layer was washed with satd aqueous NaHCO3, brine and
dried over MgSO4. The filtrate was concentrated in vacuo and pu-
rified by flash chromatography (AcOEt) to afford 830 mg
(2.86 mmol, 84%) of 4-(1,3,4-trimethoxynaphthalen-2-yl)-butan-1-
(100 MHz, CDCl3) d 27.4 (CH2), 73.3 (CH2),124.5 (C),126.1 (CH),126.3
(CH),131.6 (C),133.0 (C),133.1 (C),134.1 (C),145.1 (C),160.8 (C),177.8
(C). HRMS calcd for C12H8O3: 200.0473. Found: 200.0470.
4.1.10. CAN oxidation of 11. According to the procedure described
for CAN oxidation of 8, diammonium cerium (IV) nitrate (CAN)
(493 mg, 0.9 mmol) in water (3.0 mL) was added to a stirred so-
lution of 11 (100 mg, 0.36 mmol) in acetonitrile (CH3CN) (5.0 mL) at
0
ꢁC. The crude mixture was purified by flash chromatography
(hexane/AcOEt¼1:2) to provide 16-III (51.6 mg, 67%), 16-IV (5.2 mg,
7%). Compound (16-III); mp 168e176 ꢁC. 1H NMR (400 MHz, CDCl3)
d
2.05 (m, 2H, CH2), 2.62 (t, 2H, J¼6.2 Hz, CH2), 4.34 (t, 2H, J¼5.5 Hz,
ol (13) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d
1.38 (t, 1H,
CH2), 7.68 (td, 1H, J¼7.0, 1.5 Hz, ArH), 7.71 (td, 1H, J¼7.0, 1.5 Hz, ArH),
J¼6.0 Hz, OH), 1.71 (m, 4H, CH2 ꢂ2), 2.83 (t, 2H, J¼7.3 Hz, CH2), 3.72
(quint, 2H, J¼6.0 Hz, CH2), 3.91 (s, 3H, OCH3), 3.96 (s, 3H, OCH3),
4.00 (s, 3H, OCH3), 7.43 (td, 2H, J¼7.0, 1.5 Hz, ArH ꢂ2), 7.99 (dd, 1H,
J¼2.0, 7.0 Hz, ArH), 8.08 (dd, 1H, J¼2.0, 7.0 Hz, ArH). 13C NMR
8.08 (dd, 1H, J¼7.0, 1.5 Hz, ArH), 8.10 (dd, 1H, J¼7.0, 1.5 Hz, ArH). 13
C
NMR (100 MHz, CDCl3) d 17.8 (CH2), 20.7 (CH2), 68.3 (CH2),114.0 (C),
123.9 (CH), 128.4 (CH), 129.9 (C), 130.6 (CH), 132.1 (C), 134.7 (CH),
162.9 (C), 178.5 (C), 179.5 (C). HRMS calcd for C13H10O3: 214.0630.
Found: 214.0628. Compound (16-IV); mp 216e218 ꢁC. 1H NMR
(100 MHz, CDCl3)
d 24.5 (CH2), 26.7 (CH2), 32.7 (CH2), 60.8 (CH3),
60.9 (CH3), 62.2 (CH3), 62.6 (CH2), 121.6 (CH), 122.1 (CH), 124.8 (CH),
125.3 (C), 125.5 (CH), 127.6 (C), 128.2 (C), 143.5 (C), 148.3 (C), 150.0
(C). HRMS calcd for C17H22O4: 290.1518. Found: 290.1516.
(400 MHz, CDCl3)
d
2.05 (m, 2H, CH2), 2.63 (t, 2H, J¼6.3 Hz, CH2),
4.36 (t, 2H, J¼5.3 Hz, CH2), 7.69 (td, 1H, J¼7.0, 1.5 Hz, CH), 7.73 (td,
1H, J¼7.0, 1.5 Hz, CH), 8.09 (dd, 1H, J¼7.0, 1.5 Hz, CH), 8.11 (dd, 1H,
J¼7.0, 1.5 Hz, CH). 13C NMR (100 MHz, CDCl3)
d 19.0 (CH2), 21.1
4.1.8. CAN oxidation of 8. To a stirred solution of 8 (100 mg,
0.4 mmol) in acetonitrile (CH3CN) (6.0 mL) at 0 ꢁC, diammonium
cerium (IV) nitrate (CAN) (548 mg, 1.0 mmol) in water (4.0 mL) was
added dropwise. The red-orange solution was stirred for 30 min at
(CH2), 68.3 (CH2), 122.3 (C), 126.7 (CH), 126.9 (CH), 131.5 (C), 132.6
(C), 133.3 (C), 134.6 (C), 156.1 (C), 180.3 (C), 184.8 (C). HRMS calcd for
C13H10O3: 214.0630 Found: 214.0630.
0
ꢁC, and worked up by addition of CHCl3 and water. The aqueous
4.1.11. CAN oxidation of 13. According to the procedure described
for CAN oxidation of 8, CAN (411 mg, 0.75 mmol) in water (3.0 mL)
was added to a stirred solution of 13 (87 mg, 0.3 mmol) in CH3CN
(4.0 mL) at 0 ꢁC. The crude mixture was purified by flash chroma-
tography (hexane/AcOEt¼1:2) to provide 17-I (26.8 mg, 34%), 17-II
(6.5 mg, 8%),17-III (13.8 mg, 20%), and 17-IV (5.7 mg, 8%). Compound
layer was extracted with CHCl3. The combined organic layer was
washed with water, dried over MgSO4, and concentrated under
reduced pressure. The crude product was purified by flash chro-
matography (hexane/AcOEt¼1:2) to provide 14-I (40.1 mg, 46%)
and 14-II (34.8 mg, 40%). Compound (14-I); mp 105e112 ꢁC. 1H
NMR (400 MHz, CDCl3)
d
4.26 (s, 3H, CH3), 4.65 (s, 2H, CH2), 7.65 (td,
(17-I): mp 88e95 ꢁC, 1H NMR (400 MHz, CDCl3)
ꢂ2), 2.62 (t, 2H, J¼6.6 Hz, CH2), 3.69 (t, 2H, J¼6.6 Hz, CH2), 4.13 (s, 3H,
d 1.61 (m, 4H, CH2
1H, J¼8.0, 1.5 Hz, ArH), 7.70 (td, 1H, J¼8.0, 1.5 Hz, ArH), 7.80 (dd, 1H,

508
T. Ogata et al. / Tetrahedron 70 (2014) 502e509
OCH3), 7.68 (td, 2H, J¼7.5, 2.0 Hz, ArH ꢂ2), 8.03 (m, 2H, ArH ꢂ2). 13
C
(6.25 mL), N-bromosuccinimide (NBS) (356 mg, 2 mmol) was added
and the mixture was heated under reflux for 3 h. After removing the
precipitates by filtration, the filtrate was washed with 1% sodium
thiosulfate solution, 2 M NaOH, and then dried over MgSO4. The
filtrate was concentrated under reduced pressure to afford 2-
bromomethyl-1,3,4-trimethoxynaphthalene (616 mg, 99%) as
NMR (100 MHz, CDCl3)
d 23.2 (CH2), 25.0 (CH2), 32.5 (CH2), 61.2
(CH2), 62.4 (CH3), 126.0 (CH), 126.1 (CH), 131.5 (C), 131.9 (C), 133.2
(CH), 133.7 (CH), 135.3 (C), 157.8 (C), 181.4 (C), 185.4 (C). HRMS calcd
for C15H16O4: 260.1049. Found: 260.1048. Compound (17-II): yellow
oil. 1H NMR (400 MHz, CDCl3)
d
1.63 (m, 4H, CH2 ꢂ2), 2.56 (t, 2H,
J¼7.0 Hz, CH2), 3.70 (t, 2H, J¼6.2 Hz, CH2), 4.00 (s, 3H, OCH3), 7.50 (td,
1H, J¼1.5, 7.0 Hz, ArH), 7.64 (dd, 1H, J¼1.5, 7.0 Hz, ArH), 7.68 (dt, 1H,
J¼1.5, 7.0 Hz, ArH), 8.07 (dd, 1H, J¼1.5, 7.0 Hz, ArH). 13C NMR
a colorless solid. Mp 45.5e50 ꢁC 1H NMR (270 MHz, CDCl3)
d 3.97 (s,
3H, OCH3), 4.07 (s, 3H, OCH3), 4.13 (s, 3H, OCH3), 4.83 (s, 2H, CH2),
7.44 (m, 2H, ArH), 8.12 (m, 2H, ArH). 13C NMR (125.8 MHz, CDCl3)
(100 MHz, CDCl3)
d
23.4 (CH2), 25.1 (CH2), 32.5 (CH2), 61.6 (CH2), 62.5
d
23.4 (CH2), 60.9 (CH3), 61.2 (CH3), 62.6 (CH3), 121.8 (CH), 122.7
(CH), 123.7 (C), 125.3 (CH), 127.1 (CH), 130.0 (C), 143.8 (C), 147.4 (C),
151.4 (C). IR (cmꢀ1
2920, 1620, 1590, 1460, 1360, 1060, 1000.
(CH3), 125.1 (CH), 129.2 (C), 129.6 (CH), 130.1 (C), 130.4 (CH), 133.2
(C), 135.4 (CH), 166.2 (C), 178.9 (C), 181.8 (C). HRMS calcd for
)
n
C
15H16O4: 260.1049. Found: 260.1048. Compound: (17-III):
HRMS calcd for C14H15O3Br: 310.0205, 312.0186. Found: 310.0204,
312.0186. LRMS (EI) m/z 312 (55), 310 (56), 297 (4), 231 (100), 216
(34), 201 (41), 200 (50), 173 (21), 143 (13).
133e138 ꢁC, 1H NMR (400 MHz, CDCl3)
d
1.91 (quint, 2H, J¼6.2 Hz,
CH2), 2.09 (quint, 2H, J¼6.2 Hz, CH2), 2.80 (t, 2H, J¼6.2 Hz, CH2), 4.51
(t, 2H, J¼6.2 Hz, OCH2) 7.48 (td, 1H, J¼1.1, 7.7 Hz, ArH), 7.64 (dt, 1H,
J¼1.1, 7.7 Hz, ArH), 7.80 (dd,1H, J¼7.7,1.1 Hz, ArH), 8.03 (dd,1H, J¼1.1,
4.1.15. Ethyl 2,2-dimethyl-3-(1,3,4-trimethoxynaphthalen-2-yl)prop-
anoate 20. A frame-dried round bottom flask was charged with
diisopropylamine (4.5 mL, 31.8 mmol) in anhydrous THF (140 mL)
under argon atmosphere, and added n-BuLi (21 mL, 31.8 mmol,
1.54 M in n-hexane) at 0 ꢁC. The mixture was cooled to ꢀ80 ꢁC and
ethyl isobutyrate (4.2 mL, 31.8 mmol) was added via cannula. After
30 min stirring at this temperature, 2-bromomethyl-1,3,4-
trimethoxynaphthalene (4.95 g, 15.9 mmol) in THF (70 mL) was
slowly added via cannula. The mixture was warmed to room tem-
perature and worked up as follows. The mixture was cooled in an
ice bath then satd aqueous NH4Cl was added, and the mixture was
concentrated to remove THF. The aqueous layer was extracted three
times with AcOEt, and the combined organic layer was washed
with water, brine and dried over MgSO4. Filtration and concentra-
tion of the organic solvent under reduced pressure afforded a crude
product (5.69 g).
7.7 Hz, ArH).13C NMR (100 MHz, CDCl3)
d 22.4 (CH2), 23.5 (CH2), 28.9
(CH2), 73.2 (CH2), 122.0 (C), 124.9 (CH), 128.6 (CH), 129.4 (C), 130.4
(CH),134.0 (C),135.0 (C),167.5 (C),179.1 (C),180.6 (C). H-MS calcd for
C
14H12O3: 228.0786. Found: 228.0786. Compound: (17-IV): mp
83e91 ꢁC,1H NMR (400 MHz, CDCl3)
d
1.91 (quint, 2H, J¼6.2 Hz, CH2),
2.06 (quint, 2H, J¼6.2 Hz, CH2), 2.88 (t, 2H, J¼6.2 Hz, CH2), 4.40 (t, 2H,
J¼6.2 Hz, OCH2), 7.67 (dt, 1H, J¼1.5, 7.3 Hz, ArH), 7.70 (dt, 1H, J¼1.5,
7.3 Hz, ArH), 7.80 (m, 2H, ArH). 13C NMR (100 MHz, CDCl3)
d 23.1
(CH2), 23.3 (CH2), 29.1 (CH2), 73.3 (CH2),126.2 (CH),126.4 (CH),129.9
(C), 131.0 (C), 132.1 (C), 133.1 (CH), 133.8 (CH), 160.2 (C), 180.9 (C),
185.5 (C). HRMS calcd for C14H12O3: 228.0786. Found: 228.0788.
4.1.12. Additional experiments for cyclization of n-I, n-II and for the
inter-conversion between n-III and n-IV (a typical procedure for the
listed reactions in Table 2) (entries 1e12). To a stirred solution of 15-
I (9.3 mg, 0.04 mmol) in CH3CN (0.5 mL) at 0 ꢁC, CAN (55 mg,
0.1 mmol) in water (0.3 mL) was added dropwise. The red-orange
solution was stirred for 30 min at 0 ꢁC, and worked up by addi-
tion of CHCl3 and water. The aqueous layer was extracted with
CHCl3. The combined organic layer was washed with water, dried
over MgSO4, and concentrated under reduced pressure. The crude
mixture was directly dissolved in CDCl3, and analyzed by 1H NMR.
The ratio of the products is listed in Table 2.
Purification by flash chromatography (hexane/AcOEt¼8:1) gave
5.5 g of ethyl 2,2-dimethyl-3-(1,3,4-trimethoxynaphthalen-2-yl)
propanoate (20) as a colorless oil. 1H NMR (270 MHz, CDCl3)
d 1.17
(s, 6H, CH3), 1.24 (t, 3H, J¼7.3 Hz, CH3), 3.09 (s, 2H, CH2), 3.84 (s, 3H,
OCH3), 3.93 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 4.14 (q, 2H, J¼7.3 Hz,
CH2), 7.44 (m, 2H, ArH ꢂ2), 7.99 (dd,1H, J¼7.0,1.5 Hz, ArH), 8.07 (dd,
1H, J¼7.0, 1.5 Hz, ArH). 13C NMR (125.8 MHz, CDCl3)
d 14.1 (CH3),
25.1 (CH3), 34.4 (CH2), 43.5 (C), 60.4 (CH3 ꢂ2), 60.8 (CH2), 61.5
(CH3), 121.5 (CH), 122.4 (CH), 123.5 (C), 124.8 (CH), 125.2 (C), 125.8
4.1.13. 1,2,4-Trimethoxy-3-methylnaphthalene 18. A frame-dried
(CH), 128.8 (C), 143.2 (C), 148.8 (C), 151.5 (C), 178.0 (C]O). IR (cmꢀ1
)
round bottom flask was charged with
a
solution of 1,2,4-
n
2920, 1710, 1590, 1460, 1360, 1140, 1060, 1000. HRMS calcd for
trimethoxynaphthalene (6) (2.5 g, 11.5 mmol) in anhydrous THF
(25 mL) under argon atmosphere. n-BuLi (8.8 mL, 13 mmol, 1.57 M
in n-hexane solution) was added to the solution prepared above at
C
20H26O5; 346.17808. Found: 346.1774. LRMS (EI) m/z 346 (Mþ100),
331 (12), 301 (3), 273 (10), 231 (86), 216 (24), 200 (37).
0
ꢁC and the reaction mixture was stirred for 2 h at room temper-
4.1.16. 2,2-Dimethyl-3-(1,3,4-trimethoxynaphthalen-2-yl)propan-1-
ol (21). To a stirred THF (87 mL) solution of lithium aluminum
hydride (LAH) (456 mg, 12 mmol) at 0 ꢁC, ethyl ester (20) (3.44 g,
10 mmol) in THF (87 mL) was slowly added. The ice bath was re-
moved and the mixture was stirred for 2 h at room temperature.
The excess LAH was quenched with addition of AcOEt and water.
The mixture was extracted three times with diethyl ether. The
combined ether layer was washed with water, brine, and then dried
over MgSO4, and concentrated under reduced pressure. The
resulting residue was purified by crystallization (hexane/AcOEt) to
afford 2,2-dimethyl-3-(1,3,4-trimethoxynaphthalen-2-yl)propan-
1-ol (21) (2.61 g, 8.6 mmol) (86%) as a colorless solid. Mp
ature. The mixture was cooled to ꢀ80 ꢁC and added iodomethane
(2.2 mL, d¼2.28 g/cm3, 34 mmol) dropwise. After 30 min and
checking by TLC, the reaction mixture was warmed up to room
temperature and worked up with addition of satd aqueous
NH4Cl and AcOEt. The mixture was separated and the aqueous layer
was extracted with AcOEt. The combined organic layer was washed
with 1% aqueous Na2S2O3, water, brine and dried over MgSO4, and
concentrated in vacuo. The resulting residue was purified by flash
chromatography (hexane/AcOEt¼6:1) to afford 2.7 g (>99%) of
1,2,4-trimethoxy-3-methylnaphthalene (18) as a colorless oil. 1H
NMR (400 MHz, CDCl3)
(s, 3H, OCH3), 3.97 (s, 3H, OCH3), 7.42 (m, 2H, ArH), 8.01 (m, 1H,
ArH), 8.08 (m, 1H, ArH). 13C NMR (100 MHz, CDCl3)
9.8 (CH3), 60.5
d 2.37 (s, 3H, CH3), 3.88 (s, 3H, OCH3), 3.96
138e141 ꢁC. 1H NMR (400 MHz, CDCl3)
(s, 2H, CH2), 3.01 (d, 2H, J¼6.3 Hz, CH2), 3.75 (t, 1H, J¼6.3 Hz, OH),
3.89 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 7.47 (m,
2H, ArH), 7.98 (m, 1H, ArH), 8.10 (m, 1H, ArH). 13C NMR (100 MHz,
d
0.95 (s, 6H, CH3 ꢂ2), 2.77
d
(CH3), 61.0 (CH3), 61.3 (CH3), 121.6 (CH), 121.8 (CH), 123.1 (C), 124.9
(CH), 125.4 (CH), 125.5 (C), 127.9 (C), 143.6 (C), 148.4 (C), 150.2 (C).
HRMS calcd for C14H16O3: 232.1099. Found: 232.1100.
CDCl3)
(CH3), 69.7 (CH2), 121.7 (CH), 122.2 (CH), 124.0 (C), 125.0 (C), 125.2
(CH), 126.0 (CH), 128.6 (C), 143.6 (C), 148.6 (C), 150.9 (C). IR (cmꢀ1
3470, 2920,1590,1450,1360,1060, 1000. HRMS calcd for C18H24O4
d 25.2 (CH3), 32.0 (CH2), 38.4 (C), 60.8 (CH3), 61.0 (CH3), 62.0
4.1.14. 2-Bromomethyl-1,3,4-trimethoxynaphthalene 19. To a stirred
solution of 18 (464 mg, 2 mmol) in carbon tetrachloride (CCl4)
)
d

T. Ogata et al. / Tetrahedron 70 (2014) 502e509
509
304.1675. Found: 304.1674. LRMS (EI) m/z 304 (Mþ100), 273 (3),
was included in less polar crude mixture of the fraction (12 mg, 5%
yield by 1H NMR analysis). 1H NMR (400 MHz, CDCl3)
1.07 (s, 6H,
257 (25), 231 (43), 200 (26), 173 (10).
d
CH3 ꢂ2), 2.39 (s, 2H, CH2eC), 3.90 (s, 2H, CH2eO), 7.66e7.75 (m, 2H,
4.1.17. 3,4-Dihydro-3,3-dimethyl-2H-naphtho[1,2-b]pyran-5,6-
dione; rhinacanthone. To a stirred solution of 21 (304 mg, 1.0 mmol)
in CH3CN (14.3 mL) at 0 ꢁC, CAN (1.37 g, 2.5 mmol) in water (8.6 mL)
was added dropwise. The red-orange solution was stirred for
30 min at 0 ꢁC, and worked up by addition of CHCl3 and water. The
aqueous layer was extracted with CHCl3. The combined organic
layer was washed with water, dried over MgSO4, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (chloroform) to provide 3,4-dihydro-3,3-
dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione; rhinacanthone as an
orange solid (224.2 mg, 93%). Mp 152e153 ꢁC. 1H NMR (400 MHz,
ArH ꢂ2), 8.07e8.12 (m, 2H, ArH ꢂ2).7i
References and notes
1. Kimachi, T.; Torii, E.; Kobayashi, Y.; Doe, M.; Ju-ichi, M. Chem. Pharm. Bull. 2011,
59, 753e756.
2. Snieckus, V. Chem. Rev. 1990, 90, 879e933.
3. Gupta, R. B.; Franck, R. W. Synlett 1990, 355e357.
4. The prepared benzyl ethers of 9, 11, 13 were oxidized by CAN at first to obtain O-
benzyl protected o- and p-naphthoquinones, and then debenzylation by catalytic
hydrogenolysis was carried out to afford 15-I and 15-II, 16-I and 16-II, 17-I and
17-II in pure form, respectively.
5. Kodama, O.; Ichikawa, H.; Akatsuka, T. J. Nat. Prod. 1993, 56, 292e294.
6. (i) Kuwahara, S.; Nemoto, A.; Hiramatsu, A. Agric. Biol. Chem. 1991, 55,
2909e2911; (ii) Kuwahara, S.; Awai, N.; Kodama, O. J. Nat. Prod. 1995, 58,
1455e1458.
7. (i) Kongkathip, N.; Kongkathip, B.; Siripong, P.; Sangma, C.; Luangkamin, S.;
Niyomdecha, M.; Pattanapa, S.; Piyaviriyagul, S.; Kongsaeree, P. Bioorg. Med.
Chem. 2003, 11, 3179e3191; (ii) Kongkathip, N.; Pradidphol, N.; Hasitapan, K.;
Grigg, R.; Kao, W.-C.; Hunte, C.; Fisher, N.; Warman, A. J.; Biagini, C. A.;
Kongsaeree, P.; Chuawong, P.; Kongkathip, B. J. Med. Chem. 2010, 53,
1211e1221.
CDCl3)
d
1.08 (s, 6H, CH3 ꢂ2), 2.35 (s, 2H, CH2eC), 3.97 (s, 2H,
CH2eO), 7.52 (td, 1H, J¼6.6, 1.1 Hz, ArH), 7.65 (td, 1H, J¼6.6, 1.1 Hz,
ArH), 7.80 (dd, 1H, J¼6.6, 1.1 Hz, ArH), 8.07 (dd, 1H, J¼6.6, 1.1 Hz,
ArH). 13C NMR (100 MHz, CDCl3)
d 24.8 (CH3), 28.0 (C), 32.0 (CH2),
77.2 (CH2), 113.3 (C), 124.1 (CH), 128.7 (CH), 129.9 (C), 130.7 (CH),
131.9 (C), 134.8 (CH), 161.9 (C), 179.0 (C), 179.6 (C). HRMS calcd for
C
15H14O3: 242.0943. Found: 242.0941. The isomer of rhinacanthone