Products of an acetylation protocol on two pentaalkoxynaphthalenes

Article abstract of DOI:10.1080/00397910600616693

The benzyl and isopropyl groups were evaluated as O-protecting entities in 1,2,4,5,8-pentaalkoxynaphthalene systems upon treatment with a proven acetylation protocol. Only the benzyl group demonstrated moderate stability. Copyright Taylor & Francis Group,

Full text of DOI:10.1080/00397910600616693

Synthetic Communicationsw, 36: 1695–1706, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600616693
Products of an Acetylation Protocol on Two
Pentaalkoxynaphthalenes
Robin G. F. Giles
Department of Chemistry, Murdoch University, Murdoch, Australia
Ivan R. Green and Nester van Eeden
Department of Chemistry, University of the Western Cape, Bellville,
South Africa
Abstract: The benzyl and isopropyl groups were evaluated as O-protecting entities in
1,2,4,5,8-pentaalkoxynaphthalene systems upon treatment with a proven acetylation
protocol. Only the benzyl group demonstrated moderate stability.
Keywords: Bromination, debromination, benzyne, Diels-Alder, naphthalenes
INTRODUCTION
In recent studies about the synthesis of ventiloquinone J 1,[1] the prospect of
developing a general synthetic strategy that would include the synthesis of
6-hydroxy-7-methoxyeleutherin 2, one of a-number of biologically active
naphthopyranquinones isolated from Ventilago madderaspatana[2] and
Karwinskia humboldtiana,[3] was undertaken.
To this end, a suitably oxygenated and substituted naphthalene precursor
3 was considered, which had an O-differentiating protecting group at C-1,
because acetylation of 3 would be expected to allow for its elaboration into
a naphthopyran system as previously demonstrated in the synthesis of 1[1]
(Figure 1). This article describes the products formed upon subjecting
naphthalene 3 to a specific acetylation protocol.
Received in the USA December 12, 2005
Address correspondence to Ivan R. Green, Department of Chemistry, University of
the Western Cape, Private Bag X17, Bellville 7530, South Africa. E-mail: igreen@
uwc.ac.za
1695

1696
R. G. F. Giles, I. R. Green, and N. van Eeden
Figure 1. Oxygenated naphthalenic systems.
It has previously been established that acetylation using premixed trifluor-
oacetic anhydride and acetic acid of naphthalene 4 produced the C-1 acetyl-
ated naphthalene 6 as the major (66%) and the C-3 acetylated naphthalene
7 as the minor (22%) product.[4] Subsequently, by blocking the C-1 position
with a methoxy group viz. pentamethoxynaphthalene 5 and subjecting this
compound to the same conditions of acetylation led to the isolation of the
C-2 acetylated isomer 8 as the sole product.[5]
We were interested in investigating two O-protecting groups viz.
benzyl[6,7] and isopropyl[6,8] because these groups are most suitable for
large-scale syntheses and can easily be removed in the latter stages of the
synthesis for naphthopyrans viz. 2.[6] The two naphthalenes identified as
being most suitable for acetylations were 18 and 19, respectively (Scheme 1).
Thus 3-bromovanillin 9[9] was treated separately with benzyl bromide and
isopropyl bromide in dry dimethylformamide at 80 8C in the presence of
potassium carbonate with vigorous stirring in an atmosphere of nitrogen to
afford the corresponding benzyloxybenzaldehyde 10 (90%) and isopropylox-
ybenzaldehyde 11 (100%) respectively. Baeyer–Villiger oxidation[10] of each
of the aldehydes followed by alkaline hydrolysis of the formate esters afforded
the expected phenols 12 (77%) and 13 (88%), which were subsequently
methylated with dimethyl sulphate and potassium carbonate in boiling
acetone to produce the trialkoxybromobenzenes 14 (78%) and 15 (88%)
respectively. Finally, bromination of each of these compounds with bromine

Acetylation of Pentaalkoxynaphthalenes
1697
Scheme 1. (i) RX/K2CO3/DMF/80 8C; (ii) mCPBA/DCM/reflux; (iii) Me2SO4/
K2CO3/acetone/reflux; (iv) Br2/acetic acid/25 8C; (v) BuLi/2-methoxyfuran/
THF/-78 8C and then Me2SO4/K2CO3/acetone/reflux.
in acetic acid afforded the ortho dibromobenzenes 16 (90%) and 17 (86%)
respectively, as demonstrated by their subsequent transformations.
Treatment of each the dibromobenzenes 16 and 17 with 0.9 molar equiv
of n-butyllithium at 278 8C generated the expected benzynes,[11] which were
treated with 2-methoxyfuran to form the intermediate 1,4-oxa adducts, which
were not isolated but immediately hydrolysed and methylated under akaline
conditions to produce the two pentaalkoxynaphthalenes 18 (42%) and 19
(54%), respectively (Scheme 1).
Each of the naphthalenes were subsequently treated under the acetylation
conditions developed in our laboratories for consistent results.[4,10] Thus
treatment of naphthalene 18 with premixed trifluoroacetic anhydride and
acetic acid in dichloromethane at 20 8C produced a chromatographically
separable mixture comprising the starting material 18 (12%), followed by
the desired product of acetylation viz. 20 (28%), and finally the acetoxyacetyl-
naphthalene 21 (27%) (Scheme 2).
All structural assignments are based inter alia on spectral evidence, and
consequently only diagnostic data is presented. A strong absorption at
1660 cm21 in the infrared spectrum of naphthalene 20 supported the ketone

1698
R. G. F. Giles, I. R. Green, and N. van Eeden
Scheme 2. (i) TFAA/AcOH/DCM/20 8C and (ii) KOH.MeOH; BnBr/K2CO3/
acetone/reflux.
group, and a 3-proton singlet at 2.39 ppm in the 1H NMR spectrum confirmed
the acetyl group. Two 1-proton singlets at 6.41 and 6.70 ppm were assigned to
7- and 3-H respectively. On the other hand, two strong absorptions at 1758 and
1658 cm21 in the infrared spectrum of acetoxyacetylnaphthalene 21 indicated
the presence of both an ester and ketone functionality. This was confirmed by
two 3-proton singlets at 2.36 and 2.74 ppm in the 1H NMR spectrum. Signals
associated with the benzyl group were absent, whereas two 1-proton singlets at
6.78 and 7.08 ppm were assigned to 7- and 3-H of the hexasubstituted naphtha-
lene ring.
In a separate experiment, naphthalene 21 was hydrolysed under mild
basic conditions, and the resultant naphthol was benzylated to afford the
same acetylbenzyloxynapthlene 20, isolated earlier, in an overall yield of
78% for the two steps.
Acetylation of the isopropyloxynaphthalene 19 afforded four products,
which eluted from a chromatographic column in the following order:
isopropyloxynaphthalene 22 (14%), acetoxynaphthalene 23 (28%), acetoxy-
acetylnaphthalene 21 (42%), and the diacetoxyacetylnaphthalene 24 (13%)
(Scheme 3). However, none of the desired acetylnaphthalene 25 was isolated.
A strong absorption at 1747 cm21 in the infrared spectrum and a 3-proton
1
singlet at 2.33 ppm in the H NMR spectrum confimed the presence of an
acetoxy ester group in compound 22. The presence of the isopropyloxy
group was also obvious in the spectrum while three 1-proton signals at 6.64
(d, J 8.8), 6.71 (s), and 6.94 (d, J 8.8) ppm were assigned to 2-, 7-, and
3-H, respectively, all of which indicated that the naphthalene ring was still
pentaoxygenated. Significantly, a 9-proton singlet at 3.93 ppm suggested
that the C-4-OMe group had undergone replacement by acetoxy because an
analogous replacement of any of the other methoxy groups would generate
a molecule having a symmetry in which the remaining three groups are
highly unlikely to have their signals coalesce. Finally, in a Nuclear Overhauser
Enhancement (NOE) experiment, irradiation of the signal at 2.33 ppm showed
an enhancement of the signals for the isopropyl group as well for the doublet at
6.94 ppm assigned to 3-H.

Acetylation of Pentaalkoxynaphthalenes
1699
Scheme 3. (i) TFAA/AcOH/DCM/20 8C.
Assignment of structure 23 to the next naphthalene to elute was based on
the similarities of its 1H NMR spectrum to that of naphthalene 19 except that
the signals associated with the isopropyloxy group had been replaced by a
3-proton singlet at 2.37 ppm, whereas a strong absorption at 1764 cm21
supported the acetoxy group. The third fraction to elute had spectral properties
identical to naphthalene 21, isolated earlier.
Assignment of structure 24 to the last compound to elute was based on
two strong absorptions at 1755 and 1690 cm21 in the infrared spectrum for
the ester and ketone groups, and three 3-proton singlets at 2.36, 2.40, and
1
2.59 ppm in the H NMR spectrum suggested the presence of two acetoxy
and one acetyl group, respectively. Three further 3-proton singlets at 3.91,
3.95, and 4.00 ppm for the three methoxy groups and two 1-proton singlets
at 6.74 and 7.15 ppm assigned to 7- and 3-H, respectively, lent additional
support for the suggested structural assignment. Absence of signals for the iso-
propyloxy group confirmed that the C-5-O was acylated, whereas the acyl
group at C-2[5] would be expected to promote demethylation at the adjacent
C-1-O[11] under the conditions used and thus places the second acetoxy
group at C-1 of naphthalene 24.
Thus, upon treatment of naphthalenes 18 and 19 under the acetylation
protocol described, the benzyl is a more stable O-protecting group than the
isopropyl and is thus the preferred group for large-scale usuage.
EXPERIMENTAL
1H and 13C NMR spectra were recorded using a Varian 200-MHz spec-
trometer at 20 8C in deuterochloroform, and J values are given in Hz.

1700
R. G. F. Giles, I. R. Green, and N. van Eeden
Infrared 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 fraction of bp 70–75 8C. In 13C spectra, assignments with the same
superscript may be interchanged.
4-Benzyloxy-3-bromo-5-methoxybenzaldehyde 10
3-Bromovanillin 9 (16.0 g, 0.069 mol)[9] and benzyl bromide (41 mL,
0.345 mol) were dissolved in dry dimethylformamide (150 mL) to which
potassium carbonate (47 g, 0.345 mol) was added. The mixture was vigorously
stirred at 80 8C (oil bath) under nitrogen for 5 h. After cooling, the filtered
solution was poured into water (700 mL), and the aqueous solution was
extracted with ether. The residue obtained upon workup was chromatographed
using EtOAc–hexane (1:4) as eluent to give the benzyloxy benzaldehyde 10
(19.8 g, 90%) as white needles. Mp 44 8C (from hexane) (lit.[12] mp 46 8C); dH
3.90 (3H, s, OCH3), 5.10 (2H, s, CH2Ph), 7.20–7.74 (7H, m, Aryl-H and
PhCH2), and 9.85 (lH, s, CHO).
3-Bromo-4-isopropyloxy-5-methoxybenzaldehyde 11
In a protocol similar to that described previously, 3-bromovanillin 9 (21.15 g,
0.092 mmol) and 2-bromopropane (56.58 g, 0.460 mmol) were condensed to
afford the 4-isopropyloxy benzaldehyde 11 (25.11 g, 100%) as white
needles. Mp 41–42 8C (from hexane) vmax 1698 cm21, dH 1.36 [H, d, J 6.2,
C(CH3)2], 3.92 (3H, s, OCH3), 4,75 [1H, heptet, J 6.2, CH(CH3)2], 7.38
(1H, d, J 1.8, 6-H), 7.55 (lH, d, J 1.8, 2-H), and 9.84 (lH, s, CHO). dC 22.6
[C(CH3)2], 56.1 (OCH3), 77.4 (OCH(CH3)2], 109.7 (C-2)a, 116.6 (C-6)a,
129.0 (C-3), 132.5 (C-1), 15.02 (C-4)b, 154.3 (C-5)b, 190.2 (C55O). (Found:
C, 48.15; H, 4.65%; Mþ 274/272. Calc. for C11H13BrO3: C, 48.35; H,
4.80%; M 274/272.)
4-Benzyloxy-3-bromo-5-methoxyphenol 12
A solutuion of aldehyde 10 (16.8 g, 0.052 mol) and m-chloroperbenzoic acid
(19.8 g, 0.11 mol) in dichloromethane (200 mL) was stirred and heated
under reflux (4 h). The cooled solution was rinsed with saturated sodium
hydrogen carbonate (3ꢀ150 mL) and water (150mL), and the organic phase
was evaporated to an oi1, which was then treated with a potassium hydroxide

Acetylation of Pentaalkoxynaphthalenes
1701
solution [8.0 g, 0.143 mol in water (280 mL)] and stirred at 25 8C for 8 h. The
reaction mixture was then acidified (litmus) with aqueous hydrogen chloride
(1 M) and extracted with ethyl acetate. The residue obtained upon workup
was chromatographed and eluted with EtOAc–hexane (2 : 5) to afford
phenol 12 (12.4 g, 77%) as colorless needles Mp 100–101 8C (from
EtOAc–hexane). vmax 3360 cm21, dH 3.68 (3H, s, OCH3), 4.93 (2H, s,
OCH2Ph), 5.89 (1H, bs, D2O exchangeable, C1-OH), 6.28 (1H, d, J 2.8,
6-H), 6.51 (1H, d, J 2.8, 2-H), 7.27–7.29 (3H, m, Ph), and 7.50–7.54 (2H,
m, Ph). dC 55.9 (OCH3), 75.3 (CH2Ph), 100.2 (C-6), 110.8 (C-2), 117.7 (C-
10), 128.2 (C-40), 128.3 (C-30/50)a, 128.7 (C-20/60)a, 135.6 (C-3), 139.4 (C-
1)b, 152.9 (C-4)b, and 154.1 (C-5)b. (Found: C, 54.8; H, 4.3%; M+ 310/308.
Calc. for C14H13BrO3: C, 54.4; 4.2%; M 310/308.)
3-Bromo-4-isopropyloxy-5-methoxyphenol 13
In a way similar to that described previously, aldehyde 11 (23.85 g, 0.087 mol)
and m-chloroperbenzoic acid (22.7 g, 0.13 mol) afforded phenol 13 (20.0 g,
88%) as colorless needles. Mp 119–120 8C (from hexane). vmax 3623 cm21
;
dH 1.32 [6H, d, J 6.2, C(CH3)2], 3.71 (3H, s, OCH3), 4.44 [1H, heptet, J
6.2, OCH(CH3)2], 6.35 (1H, d, J 2.8, 6-H), 6.52 (1H, bs, D2O exchangeable,
C1-OH), and 6.63 (1H, d, J 2.8, 2-H). dC 22.3 [C(CH3)2], 55.8 (OCH3), 76.6
[OCH(CH3)2], 100.1 (C-6), 111.0 (C-2), 116.4 (C-3), 137.5 (C-1), 152.7
(C-4)a, and 154.3 (C-5)a. (Found: C, 46.3; H, 5.1%; Mþ 263/261. Calc. for
C10H13BrO3: C, 46.0; H, 5.0%; M 263/261.)
2-Benzyloxy-3,5-dimethoxybromobenzene 14
A mixture of phenol 12 (19.0 g, 0.062 mol) in dry acetone (500 mL) and
dimethyl sulphate (31.0 g, 0.246 mol) containing potassium carbonate
(33.9 g, 3.246 mol) was vigorously stirred and heated under reflux in a
nitrogen atmosphere for 18 h. The cooled mixture was filtered, and the
residue obtained by evaporation of the filtrate was dissolved in ether
(300 mL) and washed with an ammonia solution (100 mL of 25%) followed
by water (100 mL) and finally with aqueous hydrogen chloride (100 mL of
0.1 M). The residue obtained upon workup was chromatographed using
EtOAC–hexane (1 : 4) as eluent to afford the product 14 (15.5 g, 78%) as a
thick yellow oil. vmax 1250 cm21; dH 3.74 and 3.80 (each 3H, s, OCH3),
4.94 (2H, s, OCH2Ph), 6.44 (1H, d, J 2.8, 4–H), 6.64 (1H, d, J 2.8, 6-H),
7.36 (3H, m, OCH2Ph), 7.54 (2H, m OCH2Ph). dC 55.7 and 56.0 (OCH3),
74.8 (OCH2Ph), 99.9 (C-4), 107.9 (C-6) 117.8 (C-10)a, 127.9 (C-40)a, 128.2
(C-30/50)b, 128.4 (C-20/60)b, 137.2 (C-1), 139.5 (C-2)c, 154.2 (C-3)c, and
156.5 (C-5)c. (Found: C, 56.0; H, 4.8% Mþ 324/322. Calc. for
C15H15BrO3: C, 55.7; H, 4.6%; M 324/322.)

1702
R. G. F. Giles, I. R. Green, and N. van Eeden
2-Isopropyloxy-3,5-dimethoxybromobenzene 15
In a protocol similar to that described previously, phenol 13 (3.14 g, 12 mmol)
in dry acetone (100 mL) containing dimethyl sulphate (7.58 g, 60 mmol) and
potassium carbonate (8.30 g, 60 mmol) was converted into the bromobenzene
15 (2.89 g, 88%) as a yellow oil. vmax 1255 cm21; dH 1.31 (6H, d, J 6.2,
CH(CH3)2], 6.43 (1H, d, J 2.8, 4-H), and 6.64 (1H, d, J 2.8, 6-H); dC 22.3
[OCH(CH3)3], 55.6 and 55.8 (OCH3), 75.7 [OCH(CH3)2], 99.6 (C-4), 108.0
(C-6), 116.3 (C-1), 138.7 (C-2)a, 154.2 (C-3)a, 155.6 (C-5)a. (Found: C, 48.2;
H, 5.4%; Mþ 276/274. Calc. for C11H15BrO3: C, 48.0; H, 5.5%; M 276/274.)
1,2-Dibromo-3-benzyloxy-4,6-dimethoxybenzene 16
A solution of bromine (2.43 g, 15.2 mmol) in acetic acid (70 mL) was added
dropwise to a solution of triether 14 (4.90 g, 15.2 mmol) and sodium acetate
(1.90 g, 22.8 mmol) in acetic acid (100 mL) at 25 8C. After a further period
of stirring (15 min) the solution was poured into water (60 mL), and the pre-
cipitate was collected by filtration to afford the dibromo product 16 (5.51 g,
90%) was white plates. Mp 106 8C (from methanol). vmax 1260 cm21, dH
3.87 and 3.88 (each 3H, s, OCH3), 4.94 (2H, s, OCH2Ph), 6.53 (1H, s, 5-H),
7.35 (3H, m, OCH2Ph), and 7.53 (2H, m, OCH2Ph). dC 56.4 and 56.9
(OCH3), 74.8 (OCH2Ph), 97.2 (C-5), 105.4 (C-1)a, 122.5 (C-2)a, 128.1 (C-
40)b, 128.3 (C-30/50)c, 128.4 (C-20/60)c, 136.9 (C-10)b, 140.4 (C-3)d, 153.1
(C-4)d, and 153.7 (C-6)d. (Found: C, 45.0: H, 3.9%; Mþ 404/402/400.
Calc. for C15H14Br2O3: C, 44.8; H, 3.5%; M 404/402/400.)
1,2-Dibromo-4,6-dimethoxy-3-isopropyloxybenzene 17
In a protocol similar to that described previously, the bromobenzene 15 (2.89 g,
10.51 mmol) in acetic acid (60 mL) containing sodium acetate (1.29 g,
15.8 mmol) was brominated by bromine (1.68 g, 10.51 mmol) in acetic acid
(40 mL) to afford the dibromo product 17 (2.82 g, 86%) as fine white
needles. Mp 76–77 8C (from methanol), vmax 1260 cm21; dH 1.31 [6H, d, J
6.2, OCH(CH3)2], 3.86 and 3.88 (each 3H, s, OCH3), 4.47 [1H, heptet, J 6.2,
OCH(CH3)2] and 6.53 (1H, s, 5-H). dC 22.3 [OCH(CH3)2], 56.3 and 56.7
(OCH)3, 76.6 (OCH(CH3)2], 97.3 (C-5), 105.6 (C-1)a, 123.0 (C-2)a, 139.8
(C-3)b, 153.0 (C-4)b, and 153.1 (C-6)b. (Found: C, 37.45; H, 4.05%; Mþ
356/354/352. Calc. for C11H14Br2O3: C, 37.3; H, 3.95%; M 356/354/352.)
1-Benzyloxy-2,4,5,8-tetramethoxynaphthalene 18
To a solution of dibromobenzene 16 (6.50 g, 16.2 mmol) and 2-methoxyfuran
(1.80 g, 18.6 mmol) in tetrahydrofuran (55 mL) at 278 8C and under nitrogen

Acetylation of Pentaalkoxynaphthalenes
1703
was added dropwise over 15 min n-butyllithium (10 mL of a 1.45 M solution,
l4.5 mmol). The solution was stirred a further 10 min and then allowed to
warm to 25 8C, after which it was poured into water (250 mL). The organic
material was extracted into ether (4ꢀ100 mL). The residue obtained after
workup was partially purified by flash chromatography using EtOAc–
hexane (2 : 3) as eluent to afford a yellow oil, which was dissolved in
acetone (170 mL) and treated with dimethyl sulphate (10.2 g, 80.9 mmol)
and potassium carbonate (112.2 g, 80.9 mmol), and the resulting mixture
was vigorously stirred under reflux in a nitrogen atmosphere for 48 h. The
cooled solution was filtered, and the residue obtained by evaporation of the
solvent was taken up in ether (400 mL) and washed consecutively with
ammonia solution (100 mL of 25% concentration), water (100 mL), and
aqueous hydrogen chloride (100 mL of 0.5 M). The residue obtained upon
workup was chromatographed using EtOAc–hexane (2 : 3) as eluent to give
the product 18 (2.36 g, 42%) as brown needles. Mp 106–107 8C (from dichlor-
omethane–hexane). vmax 1258 cm21; dH 3.81 and 3.91 (each 3H, s, OCH3),
3.96 (6H, s, OCH3), 4.95 (2H, s, OCH2Ph), 6.66 (1H, d, J 8.8, 6-H), 6.76
(1H, s, 3-H), 6.80 (1H, d, J 8.8, 7-H), 7.36 (3H, m, OCH2Ph), and 7.58
(2H, m, OCH2Ph). dC 57.4, 57.5, 57.6 (ꢀ2) (OCH3), 76.2 (OCH2Ph), 99.2
(C-3), 105.3 (C-6), 108.8 (C-7), 115.8 (C-4a)a, 124.6 (C-8a)a, 127.6 (C-40),
128.3 (C-30/50)b, 128.4 (C-20/60)b, 137.1 (C-10), 138.8 (C-1)c, 150.3 (C-2)c,
150.7 (C-4)c, 151.7 (C-5)c and 151.9 (C-8)c. (Found: C, 71.6; H, 6.5%; Mþ
354. Calc. for C21H22O5: C, 71.2; H, 6.2%; M 354.)
2,4,5,8-Tetramethoxy-1-isopropyloxynapthalene 19
In a protocol similar to that described previously, dibromobenzene 17 (6.61 g,
18.6 mmol) and 2-methoxyfuran (2.25 g, 23.0 mmol) in THF (70 mL) at
278 8C were treated with n-butyllithium (11.7 mL of a 1.45 M solution,
17.0 mmol) to ultimately afford the naphthalene 19 (3.07 g, 54%) as a
brown oil. vmax 1258 cm21; dH 1.26 [6H, d, J 6.2, OCH(CH3)2], 3.86, 3.89,
3.94, and 3.95 (each 3H, s, OCH3), 4.29 [1H, heptet, J 6.2, OCH(CH3)2],
6.65 (1H, d, J 8.5, 6-H), 6.74 (1H, s, 3-H), and 6.78 (1H, d, J 8.5, 7-H). dC
21.9 [OCH(CH3)2], 57.3 (ꢀ2) and 57.5 (ꢀ2) (OCH3), 75.9 [OCH(CH3)3],
99.5 (C-3), 105.2 (C-6), 109.0 (C-7), 115.7 (C-4a)a, 124.8 (C-8a)a, 135.4
(C-1), 150.1 (C-2)b, 150.6 (C-4)b, 151.6 (C-5)b, and 153.5 (C-8)b. (Found:
C, 66.8; H, 7.5%; Mþ 306. Calc. for C17H22O5: C, 66.7; H, 7.2%; M 306.)
2-Acetyl-5-benzyloxy-1,4,6,8-tetramethoxynaphthalene 20 and
2-Acetyl-5-acetyloxy-1,4,6,8-tetramethoxynaphthalene 21
To a solution of pentaalkoxynaphthalene 18 (1.44 g, 4.07 mmol) in dichloro-
methane (50 mL) was added dropwise a premixed solution of triflouroacetic

1704
R. G. F. Giles, I. R. Green, and N. van Eeden
anhydride (2.42 g, 16.3 mmol) and acetic acid (1.0 g, 16.3 mmol) at 20 8C
under nitrogen. The purple solution was stirred 24 h at the same temperature,
after which it was treated with methanol (10 mL) and then saturated aqueous
sodium hydrogen carbonate until the solution was neutral (litmus). The
mixture was then poured into water (350 mL) and extracted with dichloro-
methane (3ꢀ100 mL), and the residue obtained upon workup was chro-
matographed using EtOAc–hexane (3:7) as eluent to give three fractions.
The first compound to elute was identified as the pentaalkoxynaphthalene
18 (170 mg, 12%) by spectroscopy. The second compound to elute was
the desired 2-acetylnaphthalene 20 (450 mg, 28%) as light brown plates.
Mp 168–169 8C (from ethanol). nmax 1660 cm21; dH 2.39 (3H, s, COCH3),
3.68 and 3.78 (each 3H, s, OCH3), 3.95 (6H, s, 2 ꢀ OCH3), 4.13 (2H, s,
OCH2Ph), 6.41 (1H, s, 7-H), 6.70 (1H, s, 3-H), and 7.25 (5H, m,
OCH2Ph). dC 20.6 (CH3CO), 56.7, 56.9, 57.4, 62.4, (OCH3), 76.5
(OCH2Ph), 96.1 (C-7), 107.6 (C-3), 116.5 (C-4a)a, 125.0 (C-8a)a, 126.2
(C-40), 128.6 (C-30/50)b, 129.1 (C-20/60)b, 132.1 (C-l0), 139.9 (C-2), 140.9
(C-1)c, 145.8 (C-4)c, 149.3 (C-5)c, 153.7 (C-6), 156.6 (C-8)c, and 199.8
(C55O). (Found: C, 69.7; H, 6.4%; HRMS 396.4397. Calc. for C23H24O6:
C, 69.7; H, 6.1%; HRMS 396.4400.) Further elution gave the acetylacetox-
ynaphthalene 21 (380 mg, 27%) as off-white needles. Mp 157–159 8C (from
ethanol). vmax 1758 and 1658 cm21; dH 2.36 (OCOCH3), 2.74 (COCH3),
3.78. 3.88, 3.96, and 4.05 (each 3H, s, OCH3), 6.78 (1H, s, 7-H), and 7.08
(1H, s, 3-H). dC 20.7 (COCH3), 31.4 (OCOCH3), 56.5, 56.7, 56.8, 63.9
(OCH3), 96.4 (C-7), 106.1 (C-3), 116.4 (C-4a)a, 125.2 (C-8a)a, 127.1 (C-
2)a, 127.5 (C-5), 150.9 (C-l)b, 151.0 (C-4)b, 153.0 (C-6)b, 156.3 (C-8),
170.2 (C¼O of ester), and 200.3 (C¼O of ketone). (Found: C, 62.2; H,
6.0%; HRMS: 348.3520. Calc. for C18H20O7: C, 62.1; H, 5.8%; HRMS:
348.352.)
2-Acetyl-5-benzyloxy-1,4,6,8-tetramethoxynaphthalene 20
To a solution of the acetylacetoxynaphthalene 21 (100 mg, 0.28 mmol) in
methyl alcohol (10 mL) was added 5% (w/v,) of potassium hydroxide in
methyl alcohol (0.5 mL, 0.45 mmol) at 25 8C, and stirring was continued
for 10 min, after which water (50 mL) was added and the solution was
acidified (litmus) by the addition of aqueous hydrogen chloride (0.5 M).
The solution was extracted with dichloromethane, and the residue
obtained upon workup was dissolved in acetone (25 mL) and treated with
benzyl bromide (150 mg, 0.88 mmol) and potassium carbonate (125 mg,
0.91 mmol). It was then vigorously stirred and heated under reflux for
8 h. The cooled solution was filtered and evaporated to a residue, which
was chromatographed using EtOAc–hexane (3:7) as eluent to afford
naphthalene 20 (87 mg, 78%), identical spectroscopically to material
isolated previously.

Acetylation of Pentaalkoxynaphthalenes
1705
4-Acetoxy-5-isopropyloxy-l,6,8-trimethoxynaphthalene 22ꢁ,
5-Acetoxy-1,4,6,8-tetramethoxynaphthalene 23ꢁ, 5-Acetoxy-2-
acetyl-1,4,6,8-tetramethoxy-naphthalene 21, and 1,5-Diacetoxy-2-
acetyl-4,6,8-trimethoxynaphthalene 24
To a solution of the pentaalkoxynaphthalene 19 (3.07 g, 10.0 mmol) in
dichloromethane (60 mL) at 20 8C was added premixed trifluoroacetic
anhydride (10.5 g, 50 mmol) and acetic acid (3.0 g, 50 mmol) dropwise
under nitrogen. The mixture was stirred for 24 h and worked up as
described before to give four fractions after chromatographic separation.
Thus the first fraction to elute was naphthalene 22 (452 mg, 14%) as white
flakes. Mp 128–130 8C (from hexane–EtOAc). nmax 1747 cm21; dH 1.25
[6H, d, J 6.2, OCH(CH3)2], 2.33 (3H, s, OCOCH3), 3.93 (9H, s, OCH3),
4.30 [1H, heptet, J 6.2, OCH(CH3)2], 6.64 (1H, d, J 8.8, 2-H), 6.71 (1H, s,
7-H), and 6.94 (1H, d, J 8.8, 3-H). dC 21.5 (COCH3), 22.2 [OCH(CH3)2],
56.7, 56.8, 57.7 (OCH3), 75.7 (OCH(CH3)2], 98.9 (C-7), 103.5 (C-2)a, 115.0
(C-3)a, 120.4 (C-4a)b, 126.4 (C-8a)b, 134.2 (C-5)c, 139.4 (C-6)c, 150.6
(C-1)c, 154.4 (C-8)c, 155.6 (C-4)c, and 170.1 (C55O). (Found: C, 64.9; H,
6.9%; HRMS: 334.3701. Calc. for C18H22O6: C, 64.7; H, 6.6%; HRMS:
334.3691.)
The second fraction to elute was naphthalene 23 (850 mg, 28%) as off-
white flakes. Mp 161–162 8C (from hexane–EtOAc). nmax 1764 cm21; dH
2.37 (3H, s, OCOCH3), 3.84, 3.88, 3.93, 3.96 (each 3H, s, OCH3), 6.65
(1H, d, J 9.3, 2-H), 6.74 (1H, s, 7-H), and 6.77 (1H, d, J 9.3, 3-H). dC
20.8 (OCOCH3), 56.9, 57.1, 57.4, 57.5 (OCH3), 97.1 (C-7), 105.6 (C-2
and C-3), 108.3 (C-4a)a 122.8 (C-8a)a, 148.9 (C-1)b, 149.4 (C-4)b, 151.6
(C-6)b, 156.1 (C-8)b, 170.3 (C-5)b, and 181.8 (C55O). (Found: C, 62.7; H,
6.15%; HRMS: 306.3148. Calc. for C16H18O6: C, 62.75; H, 5.9%; HRMS:
306.3153.)
The third fraction to elute was naphthalene 21 (1.450 g, 42%) identical in
all respects spectroscopically to material isolated earlier.
The fourth fraction to elute was identified as the acetyldiacetoxynaphtha-
lene 24 (500 mg, 13%) as off-white plates. Mp 145–146 8C (from hexane–
EtOAc) nmax 1755 and 1690 cm21; dH 2.36 and 2.40 (each 3H, s,
OCOCH3), 2.59 (3H, s, COCH3), 3.91, 3.95, 4.00 (each 3H, s, OCH3), 6.74
(1H, s, 7-H), and 7.15 (1H, s, 3-H). d 20.6 and 21.3 (OCOCH3), 31.1
C
(COCH3), 56.6, 56.7, 56.8 (OCH3), 96.9 (C-7), 100.8 (C-3), 105.6 (C-4a)a,
132.4 (C-8a)a, 141.4 (C-2)a, 151.1 (C-4)b, 152.6 (C-6)b, 155.9 (C-8)b, 170.1
(C-5)c, 181.5 (C-1)c, 189.4 (C55O), and 197.4 (C55O.) (Found: C, 60.3; H,
5.7%; HRMS: 376.3635. Calc. for C19H20O8: C, 60.6; H, 5.3%; HRMS:
376.3630.)
*
Numbering to maintain consistency with 20, 21, and 24.

1706
R. G. F. Giles, I. R. Green, and N. van Eeden
ACKNOWLEDGMENTS
The authors thank the National Research Foundation and the University of the
Western Cape for financial assistance.
REFERENCES
1. Giles, R. G. F.; Green, I. R.; van Eeden, N. The synthesis of ventiloquinone F and
isoventiloquinone F as racemates. Eur. J. Org. Chem. 2004, 4416–4423.
2. Hanumaiah, T.; Marshall, D. S.; Rao, B. K.; Rao, C. P.; Rao, G. S. R.; Rao, J. U.
M.; Rao, K. V. J.; Thomson, R. H. Benzoisochromanquinones in ventilago species.
Phytochemistry 1985, 24, 2373–2378.
3. Dreyer, D. L.; Arai, I.; Bachman, C. D.; Anderson, W. R.; Smith, R. G.;
Daves, G. D. Toxins causing non-flammatory paralytic neuronopathy: Isolation
and structure elucidation. J. Am. Chem. Soc. 1975, 97, 4985–4990.
4. Chorn, T. A.; Giles, R. G. F.; Green, I. R.; Hugo, V. I.; Mitchell, P. R. K.;
Yorke, S. C. The acylation of naphthoquinones: The synthesis of 3-acetyl-5-
methoxy- and 3-acetyl-5,7-dimethoxy-1,4-naphthoquinones. J. Chem. Soc.
Perkin Trans. 1 1984, 1339–1343.
5. de Koning, C. B.; Giles, R. G. F.; Skelton, B. W.; White, A. M. Convenient
synthesis of a naturally occurring benzo[b]xanthen-12-one bikaverin: X-ray crys-
tallographic confirmation of the product regiochemistry. J. Chem. Soc. Perkin
Trans. 1 1998, 3209–3216.
6. Greene, T. W.; Wats, P. G.M. Protective Groups in Organic Sysnthesis, 2nd ed.;
Wiley: New york, 1989.
7. Elsworth, J. F.; Giles, R. G. F.; Green, I. R.; Ramdohr, J. E.; Yorke, S. C. Synthesis
of the aphid pigment derivatives quinone A, quinone A0 and deoxyquinone A as
racemates. J. Chem Soc. Perkin Trans. 1 1988, 2469–2476.
8. Sala, T.; Sargent, M. V. The total synthesis of psoromic acid: isopropyl ethers as
useful phenolic protective groups. J. Chem. Soc. Perkin Trans. 1 1979,
2593–2598.
9. Dorn, H. W.; Warren, W. H.; Bullock, J. L. Certain Derivatives of the ethers of
hydroxyhydroquinone. J. Am Chem. Soc. 1939, 61, 144–147.
10. Godfrey, I. M.; Sargent, M. V.; Elix, J. A. Preparation of methoxyphenols by
Baeyer–Villiger oxidation of methoxybenzaldehydes. J. Chem. Soc. Perkin
Trans. 1 1974, 1353–1354.
11. de Koning, C. B.; Giles, R. G. F.; Green, I. R. Naphthopyranquinones: Confir-
mation of the structures of ventiloquinones E, G and J by synthesis. J. Chem.
Soc. Perkins Trans. 1 1991, 2743–2748.
12. Freudenberg, K.; Renner, K. C. Biphenyls and diaryl ethers among the precursors
of lignin. Chem. Ber. 1965, 98, 1879–1892.