Synthesis of Methoxy-2-hydroxy-1,4-naphthoquinones and Reaction of One Isomer with Aldehydes under Basic Conditions

Article abstract of DOI:10.1081/SCC-120030312

Two protocols for the synthesis of methoxy-2-hydroxy-1,4-naphthoquinones were investigated in order to evaluate their behavior towards aldehydes under amine-basic conditions. Both the nature of the quinone and aliphatic aldehyde contribute to the viability of this condensation as well as further transformations.

Full text of DOI:10.1081/SCC-120030312

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Synthesis of
Methoxy‐2‐hydroxy‐1,4‐naphthoquinones and
Reaction of One Isomer with Aldehydes Under Basic
Conditions
Farouk Ameer a , Robin G. F. Giles b , Ivan R. Green a & René Pearce a
a Department of Chemistry , University of the Western Cape , Private Bag X17, Bellville,
7530, South Africa
b Department of Chemistry , Murdoch University , Murdoch, Western Australia, Australia
Published online: 21 Aug 2006.
To cite this article: Farouk Ameer , Robin G. F. Giles , Ivan R. Green & René Pearce (2004) Synthesis of
Methoxy‐2‐hydroxy‐1,4‐naphthoquinones and Reaction of One Isomer with Aldehydes Under Basic Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:7, 1247-1258, DOI:
10.1081/SCC-120030312
To link to this article: http://dx.doi.org/10.1081/SCC-120030312
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 7, pp. 1247–1258, 2004
Synthesis of Methoxy-2-hydroxy-
1,4-naphthoquinones and Reaction of
One Isomer with Aldehydes Under
Basic Conditions
Farouk Ameer,1 Robin G. F. Giles,2 Ivan R. Green,1, and
*
1
´
Rene Pearce
1Department of Chemistry, University of the Western Cape,
Bellville, South Africa
2Department of Chemistry, Murdoch University, Murdoch,
Western Australia, Australia
ABSTRACT
Two protocols for the synthesis of methoxy-2-hydroxy-1,4-naphtho-
quinones were investigated in order to evaluate their behavior towards
aldehydes under amine-basic conditions. Both the nature of the quinone
and aliphatic aldehyde contribute to the viability of this condensation
as well as further transformations.
Key Words: Methoxy-2-hydroxy-1,4-naphthoquinones; Methoxy-
naphtho[2,3-b]pyran-5,10-diones; Aldehydes; Isomer.
*
Correspondence: Ivan R. Green, Department of Chemistry, University of the Western
Cape, Private Bag X17, Bellville 7530, South Africa; E-mail: igreen@uwc.ac.za.
1247
DOI: 10.1081/SCC-120030312
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Ameer et al.
INTRODUCTION
Erythrostominone 1, isolated from Gnomonia erythrostoma, belongs to
the broad class of naphtho[2,3-b]pyranquinone antibiotics and has a demon-
strated in vitro activity against both Gram positive and Gram negative bac-
teria.[1,2] In seeking out routes for constructing the naphtho[2,3-b]pyran
nucleus, the earlier work of Hooker regarding condensation of 2-hydroxy-
1,4-naphthoquinone with aldehydes under acid conditions[3] and later devel-
oped by Giles et al.[4] who employed DDQ for intramolecular cyclizations
of these intermediates into the naphtho[2,3-b]pyran nucleus, was considered
to offer good prospects. Since the aldehydes envisaged to be used were acid
labile, we developed a protocol employing an amine base to facilitate conden-
sation with 2-hydroxy-1,4-naphthoquinone.[5,6]
Thus far, we[7,8] and others[9] have concentrated efforts on the reactions of
nor-methoxy-2-hydroxy-1,4-naphthoquinones in the expectation that should
good protocols be developed, then application to mompain trimethyl ether
2, which has the correct oxygenation pattern, would lead to a synthesis of
erythrostominone 1 (Fig. 1). This article describes our best syntheses of
some methoxy-2-hydroxy-1,4-napthoquinones and the condensation of the
8-methoxy isomer with two hexanals under amine-base conditions.
In searching for the most appropriate synthetic protocol to our target mol-
ecules, it was clear that a route providing regiospecific control would be a
Friedel Crafts acylation between a methoxylated benzene 3 and succinic
anhydride 4 affording the corresponding ketobutyric acids 5. Clemmenson
reduction of the keto moiety followed by acid-assisted intramolecular cycliza-
tion of the derived 4-arylbutyric acid would produce the corresponding
a-tetralones 6. Finally, regiospecific oxidation of tetralones 6 would afford
the corresponding 2-hydroxynaphthoquinones 7. (Sch. 1).
In order to investigate and establish a viable route to be adopted for the
synthesis of mompain trimethyl ether 2, anisole 3a (1-MeO) was transformed
Figure 1. Structures of compounds 1 and 2.

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Synthesis of Methoxy-2-hydroxy-1,4-naphthoquinones
1249
Scheme 1. (i) Lewis acid/solvent; (ii) Clemmensen reduction of benzilic carbonyl
group with Zn/HCL/toluene; (iii) ring closure with PPA; and (iv) regiospecific auto-
xidation.
into the 7-methoxy a-tetralone 6a (7-MeO) by the methodology of Yang
et al.[10] in an overall yield of 53% for the three steps. Similarly 1,4-dimethoxy
benzene 3b (1,4-dimethoxy) was transformed into the a-tetralone 6b
(5,8-dimethoxy) in an overall yield of 60% while the trimethoxybenzene 3c
(1,2,4-trimethoxy) was efficiently transformed into a-tetralone 6c (5,7,8-
trimethoxy) in 45% yield. Use of a recently proposed Lewis acid to catalyze
the intramolecular cyclization of 4-arylbutyric acids to a-tetralones viz.,
[11]
Bi(NTf2)3
was discounted due to scale-up difficulties and neither was
the recent report describing the oxidation of alkoxy-1,2,3,4-tetrahydro-
naphthalenes to a-tetralones using DDQ[12] considered due to the inherent
difficulties in synthesizing the precursor molecules.
Methods which were investigated for the oxidative conversion of tetra-
lones 6 into the corresponding 2-hydroxy-1,4-naphthoquinones 7 include
the following, reaction with N,N-dimethyl-4-nitrosoaniline,[13] potassium
superoxide in 18-crown-6,[14] potassium superoxide in toluene/pyridine and
toluene/THF,[15] selenium dioxide in acetic acid followed by potassium
superoxide in dichloromethane,[16] and the method by Malinovskaya et al.[17]
using the harsh conditions of MnO2 in concentrated H2SO4 at 558C seemed
unappealing. Of the forgoing methods, those of Bekaert et al.[16] and Anderson
et al.[13] gave at best yields of 10–20% in our hands. We thus turned our atten-
tion to the methods published contiguously by Baillie and Thomson[18] and by
Kasturi and Arunachalam[19] in spite of the poor yield quoted by Thomson[18]
for trimethoxy mompain 7c (5,7,8-trimethoxy).

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Ameer et al.
Thus, treatment of a-tetralone 6a (7-methoxy) in t-butanol in the presence
of 5 mol equivalents of potassium t-butoxide under vigorous oxygen bubbling at
258C afforded the expected 2-hydroxy-1,4-naphthoquinone 7a (7-methoxy) in
75% yield, while treatment of a-tetralone 6b (5,8-dimethoxy) under these con-
ditions afforded the corresponding 2-hydroxynaphthoquinone 7b (5,8-
dimethoxy) in a lower yield of 60%. These two examples represent oxygenation
patterns bearing similarities to trimethoxy mompain 7c (5,7,8-trimethoxy).
Applying the above autoxidative protocol to a-tetralone 6c (5,7,8-trimethoxy)
afforded the mompain trimethyl ether 7c (5,7,8-trimethoxy) in 58% yield. A
major drawback of our findings was the scale of the autoxidation ranging
from 500 mg for 6a to 200 mg for 6c. Thus, in order to test the influence of a
methoxy group on the condensation between methoxy-2-hydroxynaphthoqui-
nones with aldehydes under amine-base conditions, the Diels Alder approach
used by Giles et al.[4,20] was adopted and modified to obtain large quantities
of quinone 13, a further precursor to an analogue of erythrostominone 1.
Thus, condensation between 1-methoxycyclohexadiene 8 and 2-methoxy-
benzoquinone 9 afforded quinol 10 in 96% yield after passage through a silica
gel column. Oxidation of quinol 10 to quinone 11 was accomplished in 76%
yield with aqueous acetonitrile containing cerium(IV) ammonium nitrate, and
after pyrolysis of the bridged quinone 11 at 1408C, the crude product 12 was
hydrolyzed under basic conditions to give the target molecule 13 in 68% yield
for the last two steps (Sch. 2).
Scheme 2. (i) Reflux/benzene; (ii) column chromatography; (iii) CAN oxidation;
(iv) pyrolysis; and (v) NaOH/H2O.

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Synthesis of Methoxy-2-hydroxy-1,4-naphthoquinones
1251
With quinone 13 in hand, its condensation with two hexanals pertinent to
the planned synthetic protocol of erythrostominone and its analogs was inves-
tigated. Thus, condensation between 13 and caproaldehyde in acetonitrile
containing 1 equiv. of triethylamine6 afforded the trans olefin 14 in 78%
yield. Clear evidence of the trans nature of the double bond was provided
1
by the H NMR spectrum in which the signal assigned to 10-H appeared as
a dt at 6.56 ppm (J 16.6 and 1.4) while that assigned to 20-H appeared as a
dt at 7.02 ppm (J 16.6 and 7.0). Intramolecular cyclization of quinone 14 to
the corresponding naphtho[2,3-b]pyrenequinone 15 was effected using DDQ
in hot benzene[8] in 83% yield. Evidence for the cyclization was provided
1
by the H NMR spectrum viz., a dd at 5.74 ppm (J 10.0 and 3.8) assigned
to 3-H and a dd at 7.64 ppm (J 10.0 and 1.6) assigned to 4-H of the pyrene
ring. Finally, reduction of the double bond of the pyrene 15 under catalytic
hydrogenation afforded the naphtho[2,3-b]pyranquinone 16 in 99% yield
(Sch. 3).
Scheme 3. (i) Aldehyde/triethylamine/acetonitrile; (ii) DDQ/benzene; and (iii) H2/
Pd/C/EtOAc.

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Ameer et al.
Attention was then focussed on the condensation between quinone 13 and
the acid sensitive aldehyde, 5-dioxolanohexanal which had earlier been con-
densed with Lawsone in a moderate yield of 56%.[8] After numerous attempts,
including variations of temperature, base, ratio of base to quinone, we were
able to isolate the desired product 17 in a best yield of 16%. Sharp bands at
3468, 1670, and 1645cm21 in the infrared spectrum attest to the functionalities
while the 1H NMR spectrum confirmed the trans nature of the C-10, C-20 double
bond. Intramolecular cyclization of quinone 17 to the corresponding
naphtho[2,3-b]pyrenequinone 18 gave a best yield of 15% under similar con-
ditions of DDQ used earlier. Finally catalytic hydrogenation of naphthopyrene-
quinone 18 afforded the expected quinone 19 in 80% isolated yield.
In conclusion we have found that the most convenient transformation of
methoxy-a-tetralones 6 into 2-hydroxy-1,4-naphthoquinones 7 is by employing
potassium t-butoxide in t-butanol under vigorous passage of oxygen. Whereas,
amine-base-catalysed condensation between 2-hydroxy-8-methoxy-1,4-
naphthoquinone 13 with hexanal occurs in good yield, similar condensation
with the acid-sensitive aldehyde, 5-dioxolanohexanal is not viable. In addition,
whereas, methoxy-2-hydroxy-3-(10-hexenyl)-1,4-naphthoquinone 14 undergoes
intramolecular cyclization to the pyrene 15 in good yield, similar cyclization of
an acid-sensitive system 17 is nonviable.
Ways of improving yields of both condensation and cyclization are being
sought.
EXPERIMENTAL
1H and 13C NMR spectra were recorded using a Varian 200 MHz spec-
trometer at 208C in deuterochloroform and J values are given in Hz. Infra-
red spectra were measured as Nujol mulls on a Perkin Elmer FT-IR 1000
PC spectrometer. Melting points were determined on a Fischer–Johns melting
point stage and are uncorrected. Mass spectra were recorded on a Finnigan–
Matt GCQ instrument. Column chromatography was carried out using Merck
Kieselgel 60 (70–230 mesh) as dry columns. The residue obtained upon
workup refers to material obtained from the dried (magnesium sulphate)
organic extract after filtration and solvent removal. Hexane refers to that frac-
tion of b.p. 70–758C. In 13C-spectra, assignments with the same superscript
may be interchanged.
General Protocol for Autoxidation of a-Tetralones
To a stirred solution of the tetralone (1 mmol) in dry t-butanol (10 mL)
at 258C saturated with oxygen for 15 min was added at once, potassium

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Synthesis of Methoxy-2-hydroxy-1,4-naphthoquinones
1253
t-butoxide (5 mmol), and stirring was continued under a stream of oxygen for
45 min after which time the reaction mixture was acidified with dilute aqueous
hydrogen chloride (0.5 M) and extracted with methylene dichloride. The com-
bined organic extracts were washed with aqueous sodium hydrogen carbonate
(0.5 M) and this basic extract was then acidified with dilute sulphuric acid
(0.5 M) and finally extracted with methylene dichloride. The residue obtained
upon workup was chromatographed using EtOAc as eluent to yield the
product.
2-Hydroxy-7-methoxy-1,4-naphthoquinone (7a). Tetralone 6a[21] (500 mg,
2.84 mmol) afforded quinone 7a (435 mg, 75%) as an orange solid, m.p.
212–2148C (from hexane), lit.[19] m.p. 214–2158C. vmax 3200–2700 cm21
(broad) OH, 1672 and 1640 cm21 (C55O), dH 3.95 (3H, s, OCH3), 6.29
(1H, s, 3-H), 7.25 (1H, dd, J 8.4 and 3.0, 6-H), 7.55 (1H, d, J 3.0, 8-H), and
8.05 (1H, d, J 8.4, 5-H). dC 56.1 (OCH3), 110.4 (C-5)a, 110.7 (C-6)a, 118.9
(C-8a)b, 121.3 (C-8)b, 129.1 (C-3)b, 131.3 (C-4a)b, 138.2 (C-2), 156.1 (C-7),
184.1 and 188.9 (C55O). [Found: C, 64.8%; H, 3.9%; Mþ 204 (10), 176
(60), 135 (70). Calc. for C11H8O4: C, 64.7%; H, 3.9%; M 204].
2-Hydroxy-5,8-dimethoxy-1,4-naphthoquinone (7b). Tetralone 6b[10]
(320 mg, 155 mmol) afforded quinone 7b (218 mg, 60%) as orange crystals,
m.p. . 3008C (decomp.) (from ethanol). vmax 3220–2800 cm21 (OH), 1668
and 1660 cm21 (C55O), dH 3.96 and 4.00 (each 3H, s, OCH3), 6.21 (1H, s,
3-H), 7.27 (1H, d, J 9.4, 7-H) and 7.42 (1H, d, J 9.4, 6-H). dC 56.8 and
57.3 (OCH3), 110.7 (C-6)a, 119.0 (C-7)a, 123.6 (C-3), 132.6 (C-4a)b, 138.2
(C-8a)b, 147.8 (C-2), 151.8 (C-8)c, 153.9 (C-5)c, 181.3 and 184.1 (C-1 and
C-4). [Found: C, 61.8%; H, 4.3%; Mþ 234. Calc. for C12H10O5: C, 61.5%;
H, 4.1%; M 234].
2-Hydroxy-5,7,8-trimethoxy-1,4-naphthoquinone (7c). Tetralone 6c[13]
(200 mg, 0.847 mmol) afforded mompain trimethyl ether 7c (130 mg, 58%)
as light brown crystals (from methanol–water), m.p. 173–1748C, (lit.[18]
m.p. 1748C). vmax 3300–2700 cm21 (broad) OH, 1679 and 1635 cm21
(C55O); dH 3.88 and 3.99 (ꢀ2) (each 3H, s, OCH3), 6.18 (1H, s, 6-H), 6.82
(1H, s, 3-H). dC 56.4, 57.2, and 61.3 (OCH3), 104.0 (C-6), 123.7 (C-3),
133.6 (C-4a)a, 134.6 (C-8a)a, 154.7 (C-2)b, 158.8 (C-5)b, 162.8 (ꢀ2) (C-8
and C-7)b, 181.5 and 186.5 (C55O). [Found: C, 58.9%; H, 4.7%; Mþ 264.
Calc. for C13H12O6: C, 59.2%; H, 4.5%; M 264].
1,4-Dihydro-1,7-dimethoxy-1,4-ethanonaphthalene-5,8-diol
(10).
1-Methyoxycyclohex-1,3-diene 8 (6.4 g, 58.2 mmol) was heated under reflux
in benzene (100 mL), containing quinone 9[4] (3.0 g, 21.7 mmol) for 1.5 hr, at
which stage all the quinone was consumed. The solvent was evaporated off
and the residue chromatographed using EtOAc : hexane (3 : 7) as eluent to
give the product 10, as white crystals (2.8 g, 96%), m.p. 108–1108C. vmax
3400–2500 cm21 (broad) OH; dH 1.59 (4H, m, –CH2CH2–), 3.67 and 3.77

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Ameer et al.
(each 3H, s, OCH3), 4.10 (1H, m, 4-H), 4.48 (1H, D2O exchangeable, 5-OH),
6.22 (1H, s, 6-H), 6.49 (1H, dd, J 8.4 and 5.8, 3-H), 6.65 (1H, dd, J 8.4 and 1.2,
2-H), and 8.69 (1H, s, D2O exchangeable, 8-OH). dC 26.0 (CH2)a, 28.3 (CH2)a,
32.3 (C-4), 52.2 and 56.5 (OCH3), 86.3 (C-1), 99.2 (C-6), 120.4 (C-4a)b, 127.7
(C-8a)b, 134.3 (C-2)c, 134.8 (C-3)c, 136.8 (C-8)d, 141.1 (C-5)d, and 146.2 (C-
7)d. [Found: C, 68.0%; H, 6.1%; Mþ 248 (2), 220 (100), 205 (70). Calc. for
C14H16O4: C, 67.7%; H, 6.5%; M 248].
1,4-Dihydro-1,7-dimethoxy-1,4-ethanonaphthalene-5,8-dione (11). To
a stirred solution of adduct 10 (2.48 g, 10 mmol) in acetonitrile (60 mL) and
water (10 mL), was added dropwise a solution of cerium(IV) ammonium
nitrate (10.96 g, 20 mmol) in water (10 mL). Stirring was continued for an
additional 30 min, followed by the addition of water (400 mL) and then extrac-
tion with dichloromethane. The residue obtained upon workup afforded
quinone 11 (1.87 g, 76%), as an olive-green solid, m.p. 116–1178C (from
ethanol); (lit.[4] 118–118.58C). vmax 1668 and 1645 cm21 (C55O), dH 1.60
(4H, m, –CH2CH2–), 3.67 and 3.78 (each 3H, s, OCH3, 4.30 (1H, m, 4-H),
5.77 (1H, s, 6-H), 6.35 (1H, dd, J 8.2 and 5.8, 3-H) and 6.55 (1H, dd,
J 8.2 and 1.0, 2-H). [Found: C, 68.3%; H, 5.3%; Mþ 246 (60). Calc. for
C14H14O4: C, 68.5%; H, 5.7%; M 246].
2,8-Dimethoxy-1,4-naphthoquinone (12). The crude quinone 11 (1.8 g,
7.6 mmol), was pyrolyzed at 1408C under an atmosphere of nitrogen for
30 min to afford the naphthoquinone 12 (1.18 g, 71%) as green crystals;
m.p. 198–2018C (from ethanol), (lit.[4] 202–202.58C). vmax 1670 and
1665 cm21 (C55O), dH 3.86 and 3.99 (each 3H, s, OCH3), 6.08 (1H, s,
3-H), 7.25 (1H, dd, J 8.0 and 1.8, 7-H), 7.66 (1H, t, J, 8.0, 6-H), and 7.73
(1H, dd, J 8.0 and 1.8, 5-H). dC 56.5 and 56.6 (OCH3), 108.0 (C-7), 117.5
(C-3)a, 119.0 (C-6)a, 119.1 (C-8a)b, 134.5 (C-4a)b, 135.4 (C-5)a, 160.3
(C-2)c, 161.2 (C-8)c, 178.6 and 184.8 (C55O). [Found: C, 59.3%; H, 3.9%;
Mþ 218 (80), 203 (100). Calc. for C12H10O4: C, 59.5%; H, 4.1%; M 218].
2-Hydroxy-8-methoxy-1,4-naphthoquinone (13). The naphthoquinone
12 (1.0 g, 4.6 mmol) in aqueous 4% sodium hydroxide (20 mL) was stirred
until it had dissolved. The solution was washed with ether and then acidified
with 5 M hydrochloric acid. The resulting solution was extracted with dichlor-
omethane, and the residue afforded the quinone 13 (0.6 g, 64%) as yellow
crystals; m.p. 211–2148C (decomp.), (from ethanol); [lit.[4] 209–2118C
(decomp.)]. vmax 3200–2700 cm21 (broad) OH, 1670 and 1667 cm21
(C55O). dH 4.05 (3H, s, OCH3), 6.29 (1H, s, 3-H), 7.27 (1H, dd, J 7.2 and
2.2, 7-H), 7.73 (1H, t, J 7.2, 6-H), 7.70 (1H, s, D2O exchangeable, 2-OH),
and 7.79 (1H, dd, J 7.2 and 2.2, 5-H). dC 56.6 (OCH3), 108.6 (C-7), 117.0
(C-3)a, 117.1 (C-4a)b, 119.7 (C-5)a, 135.4 (C-8a)b, 136.9 (C-6)a, 156.9
(C-2)c, 160.5 (C-8)c, 180.2 and 184.7 (C55O). [Found: C, 65.0%; H, 3.9%;
Mþ 204 (60), 186 (30). Calc. for C11H8O4: C, 64.7%; H, 3.95%; M 204].

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1255
In a subsequent experiment, naphthoquinone 11 (1.45 g, 6 mmol) was pyr-
olyzed at 1408C under nitrogen for 30 min and the crude product hydrolyzed
with aqueous sodium hydroxide (25 mL of the 4% solution) and worked up as
described earlier to afford quinone 13 (835 mg, 68%) identical with the
material synthesized earlier vide infra.
2-Hydroxy-8-methoxy-3-(10-hexenyl)-1,4-naphthoquinone (14). Cap-
roaldehyde (1.0 g, 0.7 mL; 10 mmol) was added to a stirred mixture of quinone
13 (1.0 g, 4.9 mmol) in acetonitrile (25 mL) over 3 min after which triethyla-
mine (1.0 g, 1.4 mL; 10 mmol) was added dropwise and the reaction mixture
was allowed to stir for 6 hr under reflux in an atmosphere of nitrogen. After
12 hr stirring at 258C the solvent was removed to leave a dark red oil,
which was taken up in acetonitrile (20 mL) and ether (200 mL) and washed
with 0.5 M sulphuric acid (50 mL). The residue obtained upon workup was
purified using column chromatography with EtOAc : hexane (3 : 7) as eluent
to yield the quinone 14 (1.10 g, 78%) as a dark red solid; m.p. 153–1558C
(from hexane–ethyl acetate). vmax 3200–2500 cm21 (broad) OH, 1685 and
1635 cm21 (C55O). dH 0.92 (3H, t, J 7.0, 60-H), 1.42 (4H, m, 40- and 50-H),
2.30 (2H, m, 30-H), 4.03 (3H, s, OCH3), 6.56 (1H, dt, J 16.6 and 1.4, 10-H),
7.02 (1H, dt, J 16.6 and 7.0, 20-H), 7.23 (1H, dd, J 7.6 and 1.4, 7-H), 7.73
(1H, t, J 7.6, 6-H), 7.80 (1H, dd, J 7.6 and 1.4, 5-H), and 8.17 (1H, s,
2-OH), dC 14.0 (C-60), 22.4 (C-50), 31.4 (C-40), 34.7 (C-30), 56.6 (OCH3),
116.8 (C-7)a, 116.9 (C-3)a, 118.5 (C-20)a, 120.0 (C-6)a, 135.2 (C-4a)b, 136.4
(ꢀ2) (C-8a)b and (C-10)b, 143.1 (C-5)b, 151.9 (C-2), 159.9 (C-8), 180.0 and
184.2 (C55O). [Found: C, 71.3%; H, 6.3%; Mþ 286 (38), 229 (100). Calc.
for C17H18O4: C, 71.0%; H, 6.2%; M 286].
8-Methoxy-2-(10-propyl)-3,4-dehydronaphtho[2,3-b]pyran-5,10-
dione (15). To a solution of quinone 14 (0.227 g, 0.794 mmol) in benzene
(3 mL), 1.2 equiv. of dichlorodicyanobenzoquinone (0.216 g, 0.951 mmol) in
benzene (3 mL) were added and stirred at 658C for 2 hr; filtered and evapor-
ated to obtain a residue which was purified by column chromatography
using EtOAc : hexane (3 : 7) as eluent, to afford the pyranquinone 15
(0.187 g, 83%) as an orange-brown solid; m.p. 45–488C (from hexane).
vmax 1667 cm21; dH 0.94 (3H, t, J 7.0, 30-H), 1.50 (2H, m, 20-H), 1.65 (2H,
m, 10-H), 3.99 (3H, s, OCH3), 5.15 (1H, m, 2-H), 5.74 (1H, dd, J 10.0 and
3.8, 3-H), 6.66 (1H, dd, J 10.0 and 1.6, 4-H), 7.24 (1H, dd, J 7.5 and 1.4,
8-H), 7.64 (1H, t, J 7.5, 7-H), and 7.75 (1H, dd, J 7.5 and 1.4, 6-H). dC
13.9 (C-30), 17.6 (C-20), 37.8 (C-10), 56.6 (OCH3), 77.9 (C-2), 116.9 (ꢀ2)
(C-8 and C-4a)a, 117.6 (C-6)a, 119.2 (C-3)a, 125.4 (ꢀ2), (C-7 and C-5a)a,
134.0 (C-9a)a, 135.2 (C-4)a, 153.9 (C-10a)a, 159.9 (C-9)a, 178.6 and 181.7
(C55O). [Found: C, 71.8%; H, 5.3%; Mþ 284. Calc. for C17H15O4: C,
71.5%; H, 5.6%; M 284].

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Ameer et al.
8-Methoxy-3,4-dihydro-2-(10-propyl)-naphtho[2,3-b]pyran-5,10-
dione (16). Quinone 15 (30 mg, 0.106 mmol) in ethyl acetate (20 mL) and
palladium–charcoal (5%) (10 mg), was hydrogenated until 2 mol of hydrogen
were absorbed. The solution was filtered and the solvent removed. The residue
obtained upon workup was purified by flash chromatography using
EtOAc : hexane (3 : 7) as eluent to afford the pyranquinone 16 (30 mg,
99%); yellow crystals m.p. 78–818C (from hexane). vmax 1672 cm21; dH
0.96 (3H, t, J 7.0, 30-H), 1.64 (2H, m, 20-H), 2.04 (2H, m, 10-H), 2.42 (1H,
2
3
2
3
ddd, J 18.8, J 9.6 and 5.8, 3-Ha), 2.49 (1H, ddd, J 18.8, J 5.8 and 4.4,
2
3
2
3-He), 2.63 (1H, ddd, J 18.4, J 9.6 and 4.4, 4-Ha), 2.68 (1H, ddd, J 18.2,
3J 5.8 and 4.4, 4-He), 3.97 (3H, s, OCH3), 4.08 (1H, m, 2-H), 7.21 (1H, dd,
J 8.2 and 1.4, 8-H), 7.61 (1H, t, J 8.4, 7-H), and 7.73 (1H, dd, J 8.2 and
1.4, 6-H). dC 14.0 (C-30), 18.0 (C-20), 18.6 (C-10), 25.5 (C-3), 36.5 (C-4),
55.6 (OCH3), 77.9 (C-2), 117.3 (C-8), 119.0 (C-7)a, 119.2 ( ꢀ 2), (C-5a and
C-4a)a, 134.6 (C-9a)a, 134.9 (C-6)a, 156.3 (C-10a). 159.9 (C-9), 178.6 and
184.4 (C55O). [Found: C, 71.7%; H, 6.3%; Mþ 286 (25), 216 (100). Calc.
for C17H18O4: C, 71.3%; H, 6.5%; M 286].
2-Hydroxy-8-methoxy-3-(50-dioxolano-10-hexenyl)-1,4-naphtho-
quinone (17). Quinone 13 (1.0 g, 6.4 mmol) in acetonitrile (30 mL) contain-
ing 5-dioxolanohexanal[8] (1.82 g, 11.5 mmol) was treated with triethylamine
(5.0 g, 49.5 mmol), and the red solution was stirred under nitrogen at 608C for
8 hr. After cooling the solution, water (150 mL) was added and the resultant
solution was extracted with ether (4 ꢀ 60 mL). The ether extract was washed
with sulphuric acid (40 mL of a 0.5 M solution) and the residue obtained upon
workup was flash chromatographed using EtOAc : hexane (2 : 3) as eluent to
afford quinone 17 (346 mg, 16%) as a red oil. vmax 3468, 1670, and
1645 cm21; dH 1.36 (3H, s, 60-H), 1.84 (2H, m, 40-H), 2.39 (2H, m, 30-H),
3.96 (4H, sharp, m, OCH2CH2O), 4.03 (3H, s, OCH3), 6.64 (1H, dt, J 16.0
and 1.0, 10-H), 7.03 (1H, dt, J 16.0 and 6.8, 20-H), 7.23 (1H, dd, J 7.6 and
1.0, 7-H), 7.69 (1H, t, J 7.6, 6-H), 7.80 (1H, dd, J 7.6 and 1.0, 5-H),
and 8.16 (1H, s, D2O exchangeable, 2-OH). dC 24.1 (C-60), 29.6 (C-40),
38.5 (C-30), 56.6 (OCH3), 64.8 (ꢀ2) (OCH2CH2O), 109.9 (ꢀ2) (C-50 and
C-7), 116.8 (C-20)a, 116.9 (C-3)a, 118.6 (C-6)a, 120.1 (C-5)a, 135.2 (C-4a)b,
136.4 (C-8a)b, 142.2 (C-10)a, 152.0 (C-2), 160.0 (C-8), 180.0 and 184.1
(C55O). [Found: C, 66.7%; H, 6.1%; Mþ 344. Calc. for C19H20O6: C,
66.3%; H, 5.8%; M 344].
9-Methoxy-2-(20-dioxolanopropyl)-3,4-dehydronaphtho[2,3-b]pyran-
5,10-dione (18). To a solution of quinone 17 (200 mg, 0.58 mmol) in benzene
(15 mL), was added a solution of dichlorodicyanobenzoquinone (158 mg,
0.70 mmol) in benzene (15 mL) and the resulting solution was stirred at
258C under nitrogen for 12 hr; filtered and the residue was chromatographed
by preparative layer chromatography using EtOAc : hexane (3 : 7) as eluent

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REPRINTS
Synthesis of Methoxy-2-hydroxy-1,4-naphthoquinones
1257
to afford the pyranquinone 18 (30 mg, 15%) as a thick red oil. vmax 1690 and
1670 cm21; dH 1.26 (3H, s, 30-H), 2.17 (1H, m, 10-H), 2.38 (1H, m, 10-H),
3.98 (7H, sharp m, OCH2CH2O and CH3O), 5.35 (1H, m, 2-Ha), 5.81 (1H,
dd, J 9.8 and 3.6, 3-H), 6.65 (1H, dd, J 9.8 and 1.8, 4-H), 7.24 (1H, dd, J 8.0
and 1.2, 8-H), 7.64 (1H, t, J 8.0, 7-H), and 7.76 (1H, dd, J 8.0 and 1.2, 6-H). dC
25.1 (C-30), 44.3 (C-10), 55.8 (OCH3), 64.9 and 65.3 (OCH2CH2O), 74.8 (C-2),
108.8 (C-10), 116.8 (ꢀ2), (C-3 and C-20)a, 117.4 (C-8)a, 119.8 (C-6)a, 124.2
(C-4a)a, 125.6 (C-7)a, 126.0 (C-8a)a, 134.2 (C-9a)a, 136.2 (C-4)a, 153.9
(C-10a), 159.8 (C-9), 181.3 and 185.2 (C55O). [Found: C, 67.1%; H, 4.8%;
Mþ 341. Calc. for C19H20O6: C, 66.9%; H, 5.0%; M 341].
9-Methoxy-2-(20-dioxolanopropyl)-3,4-dihydronaphtho[2,3-b]pyran-
5,10-dione (19). The quinone 18 (10 mg, 0.03 mmol) was hydrogenated as
described earlier to afford after PLC using EtOAc : hexane (3 : 7) as eluent
the product quinone 19 (8 mg, 80%) as a thick red oil. vmax 1674 cm21; dH
1.28 (3H, s, 30-H), 2.21 (1H, m, 10-H), 2.28 (1H, m, 10-H), 2.45 (1H, m,
3-Ha), 2.47 (1H, m, 3-He), 2.64 (1H, m, 4-Ha), 2.70 (1H, m, 4-He), 3.98
(4H, m, OCH2CH2O), 3.99 (3H, s, OCH3), 4.11 (1H, m, 2-H), 7.22 (1H, dd,
J 8.2 and 1.4, 8-H), 7.60 (1H, t, J 8.2, 7-H), 7.74 (1H, dd, J 8.2 and 1.4,
6-H). dC 24.1 (C-30), 26.7 (C-3), 36.8 (C-4), 39.8 (C-10), 55.8 (OCH3), 64.6
and 65.0 (OCH2CH2O), 78.1 (C-2), 115.7 (C-20), 118.6 (C-8)a, 120.1 (C-7)a,
120.4 (C-5a)a, 120.6 (C-4a)a, 134.7 (C-9a)a, 135.2 (C-6)a, 156.3 (C-10a)b,
156.4 (C-9)b, 177.8 and 185.2 (C55O). HRMS: Calc. for C19H20O6:
344.12499. Found: 344.12584.
ACKNOWLEDGMENTS
The authors thank the University of the Western Cape and the National
Research Foundation for financial support.
REFERENCES
1. Thomson, R.H. Naturally Occurring Quinones; Academic Press: London,
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3. Hooker, S.C. J. Am. Chem. Soc. 1936, 58, 1163.
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5. Bock, K.; Jacobsen, N.; Terem, B. J. Chem. Soc., Perkin Trans. I 1986,
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Received in Poland October 28, 2003

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