Synthesis of 2,2-dimethyl-3, 4-epoxy-2h-naphtho[2,3-b]pyran-5, 10-dione

Article abstract of DOI:10.1081/SCC-100000588

A short and convenient synthesis of benzopyranoquinone 6 and its application to the preparation of epoxynaphthopyanoquinone 1 is described.

Full text of DOI:10.1081/SCC-100000588

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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SYNTHESIS OF 2,2-DIMETHYL-3, 4-EPOXY-2 H -
NAPHTHO[2,3-b]PYRAN-5, 10-DIONE
Ricardo A. Tapia , Claudia Lizama , Claudio López & Jaime A. Valderrama
To cite this article: Ricardo A. Tapia , Claudia Lizama , Claudio López & Jaime A. Valderrama
(2001) SYNTHESIS OF 2,2-DIMETHYL-3, 4-EPOXY-2 H -NAPHTHO[2,3-b]PYRAN-5, 10-DIONE,
Synthetic Communications, 31:4, 601-606, DOI: 10.1081/SCC-100000588
To link to this article: http://dx.doi.org/10.1081/SCC-100000588
Published online: 16 Aug 2006.
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Date: 21 November 2015, At: 23:25

SYNTHETIC COMMUNICATIONS, 31(4), 601–606 (2001)
SYNTHESIS OF 2,2-DIMETHYL-3,
4-EPOXY-2H-NAPHTHO[2,3-b]PYRAN-5,
10-DIONE
Ricardo A. Tapia,∗ Claudia Lizama, Claudio Lo´pez,
and Jaime A. Valderrama
Facultad de Qu´ımica, Pontificia Universidad Cato´lica de
Chile, Casilla 306, Santiago-22, Chile
ABSTRACT
A short and convenient synthesis of benzopyranoquinone
6 and its application to the preparation of epoxynaphthopyanoqui-
none 1 is described.
Naphtho[2,3-b]pyranoquinones have long been known for their antimicro-
bial and antitumor activity (1–4). Considering that quinone epoxides seem to play
an important role in metabolic processes (5), and that some natural epoxyquinones
have shown antitumor activity (6), the synthesis of a naphtho [2,3-b]pyranoquinone
epoxide arises as an important target in the search for novel anticancer activity. As
part of our ongoing research on the synthesis of bioactive heterocyclic quinones
(7–9), we describe a new synthesis of benzopyranoquinone 6 and the preparation
of epoxynaphthopyranoquinone 1 using dimethyldioxirane.
O
O
O
O
O
O
O
1
2
∗Corresponding author.
601
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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TAPIA ET AL.
OMe
OMe
OMe
OMe
OR
OH
O
a,b
c
OMe OH
OMe
3
4
5
d
O
O
O
6
◦
==
Scheme 1. Reagents: a) DHP, TsOH; b) i, n-Buli, −78 C; ii, (CH3)2C CHCHO, 88%
over 2 steps; c) Acetone-H2O, 55◦C, 85%; d) AgO, HNO3, THF, 25◦C, 78%.
The preparation of naphthopyranoquinone 2 was achieved through a Diels-
Alder reaction of benzopyranoquinone 6 and 1-trimethylsilyloxy-1,3-butadiene.
The known routes to obtain benzopyranoquinone 6 (10,11) gave low yields, so we
explored the approach shown in Scheme 1. This route starts from 2,5-dimethoxyph-
enole (12) and involves the addition of an aryllithium derivative to 3-methyl-2-
butenal (13).
Protection of phenol 3 (14) as the tetrahydropyranyl ether, and treatment
with n-butyllithium followed by reaction with 3-methyl-2-butenal, gave benzyl
alcohol 4. The attempt to hydrolyze the THP protection of compound 4 under
acid conditions led to its decomposition. However, deprotection and cyclization to
obtain benzopyrane 5 was carried out cleanly upon refluxing for 12 h an acetone-
water solution of 4.
Brown et al. (10) tried to obtain benzopyranoquinone 6 by oxidation of
benzopyrane 5 with ceric ammonium nitrate without success. Nevertheless, the
treatment of compound 5 with silver (II) oxide and nitric acid gave 6 in 78% yield.
This sequence gave 58% yield of benzopyranoquinone 6 in four steps from 2,5-
dimethoxyphenol. Reaction of benzopyranoquinone 6 with 1-trimethylsilyloxy-
1,3-butadiene followed by aromatization in situ of the adduct gave naphthopyra-
noquinone 2 (65%).
The reaction of 2-hydroxy-1,4-naphtoquinone with 3-methyl-2-butenal, as
an alternative approach to compound 3, was also evaluated, although some ex-
amples of this reaction are known to give low yield (18–20%) (15). Heating of

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603
2-hydroxy-1,4-naphtoquinone with 3-methyl-2-butenal in the presence of triethy-
lamine gave a very low yield of naphthopyranoquinone 2 (5%). However, without
adding base, the yield was improved to 35%.
Next, the epoxidation of 2 with m-chloroperoxybenzoic acid (m-CPBA) was
investigated. The treatment of 2 with m-CPBA in the presence of a base produced
decomposition of substrate and product. When this reaction was carried out in
the absence of base, the epoxyquinone 1 was obtained, but the purification was
tedious.
After the above result, the use of dimethyldioxirane was considered, based
on recent reports concerning the successful epoxidation of enones with this reagent
(16–18). Treatment of naphthopyranoquinone 2 with dimethyldioxirane in acetone
gave epoxyquinone 1 in 84% yield.
I. EXPERIMENTAL
Melting points were determined with a Kofler hot-stage apparatus and were
not corrected. IR spectra were obtained on a Bruker Model Vector 22 spectropho-
1
tometer. H and 13C NMR spectra were recorded on a Bruker AM-200 spec-
trometer, using tetramethylsilane as internal reference, and coupling constants are
given in Hz. Column chromatography was performed on Merck silica gel 60 (70–
230 mesh). Elemental analyses were performed on a FISONS EA 1108 CHNS-O
analyzer.
1-[2-(2-Tetrahydropyranyloxy)-
3,6-dimethoxyphenyl]-3-methyl-2-buten-1-ol 4
To a solution of 2,5-dimethoxyphenol tetrahydropyranyl ether (14) (1.0 g,
4.20 mmol) in THF (25 mL) at −78◦C under a nitrogen atmosphere, a 1.5-M
solution of n-butyllithium in hexane (3.0 mL, 4.6 mmol) was added, the cool-
ing bath was removed, and the mixture was stirred for 2 h at room temperature.
The reaction mixture was cooled to −78◦C and a solution of 3-methyl-2-butenal
(0.42 g, 5.0 mmol) in THF (7.5 mL) was slowly added. The mixture was al-
lowed to warm to room temperature and then it was stirred overnight. Water was
added (25 mL) and the resulting mixture was extracted with dichloromethane (2 ×
25 mL). The combined organic layers were washed with water (2 × 15 mL), dried
(Na2SO4), and evaporated. The residue was purified by flash chromatography us-
ing hexane-ethyl acetate (4:1) as eluent to give benzyl alcohol 4 (1.25 g, 93%)
as an oil; IR (neat, νmax): 3440, 1620, 1190, 1040 cm−1; 1H-NMR δ: 1.6 (s, 3H,
CH3), 1.7 (s, 3H, CH3), 1.4–2.0 (m, 6H, 3 × CH2), 3.4–3.6 (m, 2H, CH2), 3.70

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TAPIA ET AL.
(s, 3H, OCH3), 3.80 (s, 3H, OCH3), 5.30 (br s, 1H, OH, exchangeable with D2O),
5.70–5.80 (m, 1H, HC =), 5.90 (d, 1H, J = 7.1, CH), 6.0 (t, 1H, J = 9.2, CH), 6.50
(d, 1H, J = 9.0, ArH), 6.60 (d, 1H, J = 9.0, ArH); Anal. calcd. for C18H26O5: C,
67.06, H, 8.13: Found: C, 66.85; H, 8.30.
2,2-Dimethyl-5,8-dimethoxy-2H-1-benzopyrane 5
A mixture of benzyl alcohol 4 (1.0 g, 3.1 mmol), acetone (10 mL), and water
(1.0 mL) was heated to reflux for 12 h. Dichloromethane (25 mL) was then added
and the mixture was dried (Na2SO4) and evaporated. The residue was purified by
column chromatography using dichloromethane as eluent to afford benzopyrane
5 (0.58 g, 85%); mp 64◦–65◦C. (Lit. (10) 65◦C).
5,8-Dihydro-2,2-dimethyl-2H-1-benzopyran-5,8-dione 6
To a mixture of benzopyrane 5 (150 mg, 0.68 mmol), silver (II) oxide
(340 mg, 2.73 mmol) and THF (10 mL), 6N nitric acid (0.8 mL) was added. After
3min, water(10mL)wasaddedandthemixturewasextractedwithdichloromethane
(2 × 20 mL). The organic extracts were dried (Na2SO4) and evaporated. The
residue was purified by column chromatography using dichloromethane as elu-
ent to afford benzopyranoquinone 6 (100 mg, 78%); mp 79◦–80◦C. (Lit. (10)
79◦–80◦C).
2,2-Dimethyl-2H-naphtho [2,3-b] pyran-5,10-dione 2
A: To a solution of quinone 3 (100 mg, 0.52 mmol) in dichloromethane
(10 mL) was added 1-trimethylsilyloxy-1,3-butadiene (100 mg, 0.52 mmol) and
the mixture was stirred at room temperature for 4 h. Silica gel and pyridine were
added and the reaction mixture was stirred at room temperature for 24 h. After
filtration and evaporation, the residue was purified by column chromatography
using dichloromethane as eluent to afford naphthopyranoquinone 2 (80 mg, 65%);
mp 140◦–141◦C. (Lit. (19) 141◦C).
B: A mixture of 2-hydroxy-1,4-naphthoquinone (174 mg, 1.0 mmol), 3-
methyl-2-butenal (0.1 mL, 1.04 mmol) in benzene (15 mL) was heated to reflux
for 4 h. Evaporation of the solvent and purification of the residue by chromatog-
raphy on silica gel deactivated with 20% of water using dichloromethane as elu-
ent, gave naphthopyranoquinone 2 (85 mg, 35%); mp 140◦–141◦C. (Lit. (19)
141◦C).

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BENZOPYRANOQUINONE
2,2-Dimethyl-3,4-epoxy-2H-naphtho[2,3-b]pyran-5,10-dione 1
605
A stirred mixture of quinone 2 (50 mg, 0.21 mmol) in dichloromethane
(3 mL) was treated with dimethyldioxirane (20) (0.09 M in acetone, 3 mL) at 0◦C
for 3 h. Evaporation of the solvent and purification of the residue by chromatogra-
phy on silica gel using dichloromethane as eluent afforded epoxyquinone 1 (45 mg,
84%); mp 138◦–140◦C; IR (KBr, νmax): 1680, 1650, 1620 cm−1. 1H-NMR δ: 1.45
(s, 3H, CH3), 1.70 (s, 3H, CH3), 3.55 (d, 1H, J = 4.4, CH), 4.35 (d, 1H, J = 4.4,
CH), 7.60–7.80 (m, 2H, ArH), 8.00–8.15 (m, 2H, ArH). 13C-NMR δ: 23.3, 25.1,
43.8, 61.4, 78.0, 117.1, 126.2, 126.6, 131.1, 131.8, 133.4, 134.3, 153.8, 179.1,
183.0. Anal. calcd. for C15H12O4: C, 70.31, H, 4.72: Found: C, 70.15; H, 4.93
ACKNOWLEDGMENTS
The authors acknowledge FONDECYT, Research Grant 8980003.
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Received in the USA May 26, 2000

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