6632
Generally, the last step in the preparation of the 5,8-dihydroxy-1,4-naphthoquinone nucleus
involves the deprotection of the 5,8-methoxy groups. Many deprotection methods have been
reported in the literature; however, it was found that those methods were not compatible with the
protecting groups present in the side chain.2,7,15,16 Ceric ammonium nitrate and aluminium
chloride, or silver oxide±nitric acid, were evaluated with dierent reaction conditions, but the
results were poor or unsatisfactory. The mixed chemical±electrochemical synthesis according to
Torii and co-workers was not found to be suitable.17
We decided to investigate the electrochemical oxidation±deprotection more deeply to obtain
the 5,8-dihydroxy-1,4-naphthoquinone core from the 1,4,5,8-tetramethoxynaphthalene. An elec-
trolytic cell with two platinum electrodes separated by a glass sinter was used, with a saturated
calomel electrode (SCE) as the reference electrode. The reaction medium was 10% aqueous ace-
tonitrile containing 0.15 M lithium perchlorate as supporting electrolyte. The reaction is shown
in Scheme 1.y
Scheme 1. R1=H, OCH3; R2=H, CH(OH)CH2NO2
To understand the oxidation pathway better, we performed the electrooxidation in two steps: the
®rst one at 0.90±1.30 V, and the second one at 1.50±2.00 V (versus SCE). As shown in the cyclic
voltammograms of 2-(1-hydroxy-2-nitroethyl)-1,4,5,8-tetramethoxynaphthalene (see Figs. 1 and
2), during the ®rst oxidative step the starting material was quantitatively transformed into the
mono- or di-methoxy-1,4-naphthoquinone, with the consumption of 2 (for substrates 1, 2 and 4)
and 4 (for substrate 3) faraday/mole.
During the second oxidative step the methoxylated intermediates were transformed into the
5,8-dihydroxy-1,4-naphthoquinone derivatives, which have been completely characterized.{ In the
second oxidation step the charge was higher than the expected amount due to the contemporary
y
General procedure: the methoxynaphthalene derivative (10^2 M) and the lithium perchlorate (0.15 M) dissolved in 30
ml of 10% aqueous acetonitrile were introduced in the electrolytic cell. The solution was electrolyzed in two steps at
the potentials corresponding to the chemically irreversible oxidation peaks detected by cyclic voltammetry. The solvent
was removed under reduced pressure to a reduced volume and the resulting solution extracted with ethyl acetate and
water. The organic layer was washed several times with water and dried over anhydrous sodium sulphate. After the
removal of the solvent and puri®cation by column chromatography (when necessary) the pure 5,8-dihydroxy-1,4-
naphthoquinone derivative was obtained. HPLC (reverse phase, 2 m): A=water (0.05% TFA), B=90% aqueous ace-
tonitrile (0.05% TFA). The gradient started from A 100% ramped in 10 min to A=40%.
{ 1H NMR (CDCl3) (for 5,8-dihydroxy-2-(1-hydroxy-2-nitroethyl)-1,4-naphthoquinone) d=12.56, (1H, s, phenol
OH), 12.44 (1H, s, phenol OH), 7.45 (1H, d, J 1 Hz, H3), 7.20 (2H, s, H6 and H0), 5.64±5.60 (1H, m, CHOH), 4.91±4.86
(1H, dd, J 3, 12 Hz, CH2NO2), 4.57±4.50 (1H, dd, J 9, 12 Hz, CH2NO2). 13C NMR (CDCl3) d=177.2, CO; 175.8,
CO; 169.3, C5-OH, C8-OH; 147.1, C2C3; 134, C2C3; 133.7, C4a; 133.5, C8a; 112.1, C6 and C7; 80.0, CH2NO2; 65.6,
CHOH: Elemental analysis, on a puri®ed sample, (C, H, N) was within 0.40% of the calculated values. For the other
compounds spectra and melting points were identical to that obtained from an authentic sample of naphthazarin.