An efficient multigram synthesis of juglone methyl ether

Article abstract of DOI:10.3184/174751915X14405203456709

Based on the regioselective oxidation of 1,4,5-trimethoxynaphthalene by cerium (IV) ammonium nitrate, an efficient synthesis of juglone methyl ether has been achieved with high overall yield (74%) and good purity (98.6%). Compared with the reported methods, the reaction conditions are milder and the work-up of each step is much simpler. Moreover, the new strategy considerably reduces the cost in the synthesis of juglone methyl ether and is suitable for large-scale preparations.

Full text of DOI:10.3184/174751915X14405203456709

JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39 SEPTEMBER, 553–554
RESEARCH PAPER 553
An efficient multigram synthesis of juglone methyl ether
Jia-hua Cui, Qing Cui, Qi-jing Zhang and Shao-shun Li*
School of Pharmacy, Shanghai Jiaotong University, Minhang, Shanghai 200240, P.R. China
Based on the regioselective oxidation of 1,4,5-trimethoxynaphthalene by cerium (IV) ammonium nitrate, an efficient synthesis of juglone
methyl ether has been achieved with high overall yield (74%) and good purity (98.6%). Compared with the reported methods, the reaction
conditions are milder and the work-up of each step is much simpler. Moreover, the new strategy considerably reduces the cost in the
synthesis of juglone methyl ether and is suitable for large-scale preparations.
Keywords: juglone methyl ether, ceric ammonium nitrate oxidation, juglone derivatives
Juglone methyl ether (1), a naturally occurring naphthoquinone
in Juglans mandshurica Maxim. Cortex,1 exhibits a wide variety
of biological activities and attracted considerable interests from
scientists. It showed much more potent antitumour effects against
a series of cancer cell lines than its parent compound, juglone
(2).2 The strong antiviral, antibacterial and antifungal activity of
1 was also reported.3,4 In the synthesis of pharmacologically active
naphthoquinones5-10 and anthraquinones,11,12 it served as a key
intermediate. Recently, the irreversible inactivation of the fatal
botulinum neurotoxin serotype A by this natural naphthoquinone
was also disclosed.13
design a favourable method for the multigram synthesis of 1 with
an efficient route and inexpensive starting materials.
Results and discussion
Rested on the regioselective oxidation of 1,4,5-trimeth-
oxynaphthalene (3), an efficient synthesis of 1 was established
(Scheme 1). The synthetic study started from juglone, which
was prepared by the oxidation of 1,5-naphthalenediol using
the Fremy’s radical.22, 23 Due to the instability of juglone under
alkaline conditions, the reported method24 for the preparation of
3 employed the methylation of the chelated phenolic hydroxyl
group of 2 and further reduction-methylation of the quinone ring.
In our synthetic route, the quinone ring of 2 was firstly reduced to a
hydroquinone moiety and the resulting polyhydroxyl-naphthalene
was successfully converted into the methylated product 3 in the
presence of dimethyl sulfate and sodium hydroxide with high
yield. The 1,4,5-trimethoxynaphthalene was quickly oxidised by
cerium(IV) ammonium nitrate (CAN) to the title compound in
mild conditions.
For the preparation of 1, the methylation of 2 might be the
simplest method. However, because the strongly chelated hydroxyl
group in juglone sensitised the molecule towards alkali reagents,
several attempts to methylate juglone employing nucleophilic
substitutions under alkaline conditions failed.14 At present, the
only reported method for this purpose was confined to the use
in an excess of silver(I) oxide and methyl iodide.7-9,15 This is not
an attractive procedure for large-scale preparations since silver-
containing chemicals are expensive. The oxidation of 4-hydroxy-
8-methoxy-1-naphthaldehyde by the Fremy’s radical16 and the
hypervalent iodine oxidation of 4,8-dimethoxynaphthalen-1-ol17
could afford the desired compound but the two naphthols used in
According to the mechanism of CAN-mediated oxidation25,26
,
the reaction proceeded via the formation of aryl radicals (4
and 5, Fig. 1). The methoxyl group at position 1 as an electron-
18
the oxidation were not easy to obtain. Miller’s synthetic strategy
H
OC
3
O
O
H
H
3
OC OC
H
O
O
rested on the Diels–Alder cycloaddition between benzoquinone and
1,4-dimethoxy-1,3-butadiene and a further oxidation–elimination
reaction. But the yield of the strategy was unsatisfactory and
the synthesis of the diene intermediate was somewhat tedious.
The anodic oxidation of 1,4,5-trimethoxynaphthalene19 and the
chemical oxidation of this compound using Jones reagent20 or
silver-catalysed ammonium peroxodisulfate21 would provide the
desired product, but none of these processes has been extensively
employed for large-scale preparations. Thus it was necessary to
3
5
4
a
b
1
8
H
OC
O
3
3
1
2
Scheme 1 (a) Na2S2O4, Bu4N+Br-, THF/H2O; then (CH3)2SO4, NaOH; 89%.
(b) CAN, CH3CN/DCM; 83%.
H
2O
H
H
3
OC OC
H
H
3
OC OC
H
H
OC OC
3
H
H
3
OC OC
3
3
3
3
H
O
H
O
[Ce(NO3)6]2-
[Ce(NO3)6]2-
[Ce(NO3)6]3-
B
A
[Ce(NO3)6]3-
3
H
OC
H
OC
H
OC
3
H
OC
3
3
3
4
5
6
H
2O
H
H
OC OC
H
OC
O
3
3
3
H
H
O
O
O
H
OC
3
1
Fig. 1 The plausible mechanism for the oxidative demethylation of 3.
* Correspondent. E-mail: trueyangjian@163.com

554 JOURNAL OF CHEMICAL RESEARCH 2015
H-7), 6.91 (d, J = 7.7 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 8.5
Hz, 1H), 3.97 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 3.92 (s, 3H, OCH3).
5-Methoxy-1,4-naphthoquinone (1): A solution of CAN (14.47 g,
26.4 mmol) in water (25 mL) was dropwise added to a solution of 3
(2.62 g, 12 mmol) in a mixture of acetonitrile-dichloromethane (1:3,
V/V, 40 mL) under water-ice cooling. After the addition, the yellow-
orange solution was stirred for another 15 min until all the starting
material was consumed. Then the solution was diluted with water (100
mL) and extracted with ethyl acetate (40 mL×4), washed with brine
(100 mL), dried over anhydrous Na2SO4 and concentrated to about one-
tenth volume at 35 °C under reduced pressure. Petroleum-ether (1.2 L)
was added and the mixture was cooled in a refrigerator at 0 °C for 6 h.
The title compound as short yellow-orange needles was then obtained
by simple filtration and washed with petroleum-ether (30 mL).
Yield 1.88 g (83%). m.p. 184–186 °C (lit.7 184–189 °C). The crystal
contained 98.6% of pure 1 according to the HPLC analysis (area
normalisation method, tR=11.13 min). 1H NMR (400 MHz, CDCl3): δ
7.74 (dd, J = 7.6, 1.2 Hz, 1H, H-8), 7.69 (dd, J = 7.6, 8.2 Hz, 1H, H-7),
7.32 (dd, J = 8.2, 1.2 Hz, 1H, H-6), 6.87 (s, 2H, H-2, H-3), 4.02 (s, 3H,
OCH3).
donating group could increase the electron density of A-ring
of 3 and help in the formation and stabilisation of these aryl
radicals. The radical 5 underwent an oxidation to form cation
(6) that then afforded the desired compound. The presence
of the 1-methoxyl group was the reason that the oxidative
demethylation occurred regioselectively at the A-ring and that
no B-ring oxidation was observed. In the oxidation, the best
ratio of 3 to CAN (1: 2.2) and the optimum reaction temperature
(5 °C) were established by analysis of a series of experimental
conditions. When the reaction temperature was much higher
than 5 °C, the amount of by-products increased. However, at
much lower temperatures, the reaction proceeded more slowly.
After the oxidation, compound 1 with high purity was obtained
by simple extraction and further crystallisation from a mixture
of petroleum-ether and ethyl acetate.
Conclusion
Based on the regioselective oxidative demethylation of
1,4,5-trimethoxynaphthalene (3) by CAN, an efficient synthesis
of juglone methyl ether (1) has been achieved with high overall
yield (74%) and good purity (98.6%). Compared with the
The research is supported by China Postdoctoral Science
Foundation (grant no. 2014M561479). We are grateful to the
Instrumental Analysis Center of Shanghai Jiaotong University
for recording the 1H NMR spectra.
15-21
reported methods,7-9,
our synthetic strategy have several
advantages. First, the reaction conditions are milder and the
work-up of each step is much simpler. Second, the starting
materials are cheaper and readily available. Thirdly, all the
reactions in the strategy are suitable for large-scale preparations.
Received 14 June 2015; accepted 21 August 2015
Paper 1503420 doi: 10.3184/174751915X14405203456709
Published online: 1 September 2015
Experimental
CAUTION: Dimethyl sulfate is highly toxic and should only be used
when suitable safety precautions have been taken.
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1,4,5-Trimethoxynaphthalene (3): Juglone (2, 3.48 g, 20 mmol)
was dissolved in THF (60 mL) and a solution of sodium dithionite
(17.41 g, 100 mmol) and tetrabutyl ammonium bromide (TBAB, 4.84
g, 15 mmol) in water (50 mL) was added. The mixture was stirred at
room temperature under a nitrogen atmosphere until the colour of the
organic layer turned from orange to light-yellow. Then dimethyl sulfate
(10.09 g, 80 mmol) and a solution of sodium hydroxide (10.0 M, 20
mL) was dropwise added to the light-yellow solution under water-ice
cooling. After the addition, the mixture was allowed to warm to room
temperature and was stirred for another 4 h. After completion of the
reaction, the mixture was diluted with water and extracted with ethyl
acetate (30 mL×5). The combined organic layer was washed with
a solution of sodium hydroxide (1.0 M, 60 mL), water (100 mL) and
brine (100 mL) in sequence and then dried over anhydrous Na2SO4.
o
The solvent was evaporated under reduced pressure at 35 C and the
residue was subjected to flash column chromatography (petroleum-
ether:ethyl acetate, 10:0.5, V/V) to give 3 as white solid. Yield
3.88 g (89%). Recrystallisation of the solid from n-hexane gave 3 as
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1
colourless plates; m.p. 117–118 °C (lit.24 117–118 °C). H NMR (400
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