Bromination products of 2-substituted 5,7-dimethoxy-4-naphthols

Article abstract of DOI:10.1080/00397910500377370

Bromination in acetic acid is favored at C-8 in 5,7-dimethoxy-4-naphthol when the C-2 substituent is methyl carboxylate, whereas C-1 is favored when the C-2 substituent is either acetoxymethylene or methyl. Copyright Taylor & Francis LLC.

Full text of DOI:10.1080/00397910500377370

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Bromination Products of 2‐Substituted
5,7‐Dimethoxy‐4‐Naphthols
Ivan R. Green a , Victor I. Hugo b & Mawonga N. Mei a
a Department of Chemistry , University of the Western Cape , Bellville,
South Africa
b Department of Chemistry , Cape Peninsula University of Technology , Cape
Town, South Africa
Published online: 19 Aug 2006.
To cite this article: Ivan R. Green , Victor I. Hugo & Mawonga N. Mei (2006) Bromination Products of
2‐Substituted 5,7‐Dimethoxy‐4‐Naphthols, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:3, 331-346, DOI: 10.1080/00397910500377370
To link to this article: http://dx.doi.org/10.1080/00397910500377370
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Synthetic Communicationsw, 36: 331–346, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500377370
Bromination Products of 2-Substituted
5,7-Dimethoxy-4-Naphthols
Ivan R. Green
Department of Chemistry, University of the Western Cape,
Bellville, South Africa
Victor I. Hugo
Department of Chemistry, Cape Peninsula University of Technology,
Cape Town, South Africa
Mawonga N. Mei
Department of Chemistry, University of the Western Cape,
Bellville, South Africa
Abstract: Bromination in acetic acid is favored at C-8 in 5,7-dimethoxy-4-naphthol
when the C-2 substituent is methyl carboxylate, whereas C-1 is favored when the
C-2 substituent is either acetoxymethylene or methyl.
Keywords:
2-Acetoxymethyl-5,7-dimethoxy-4-naphthol,
brominations,
dimethoxy-2-methyl-4-napthol, methyl 5,7-dimethoxy-4-hydroxy-2-naphthoate
5,7-
INTRODUCTION
In an earlier communication Giles et al.[1] described the treatment of naphthyl
ester 1 with 2 mol of bromine and 2 mol of sodium acetate in acetic acid to
afford the 3,8-dibromonaphthalene derivative 2, whereas when the same
ester was treated with one mol each of bromine and sodium acetate in
acetic acid, only the 8-bromonaphthyl ester 3 was produced. (The same
Received in the USA July 28, 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
331

332
I. R. Green, V. I. Hugo, and M. N. Mei
numbering system to that used by Giles et al.[1] will be adopted throughout the
described work to maintain continuity.) Bromination in the absence of the
buffer, on the other hand, afforded the 1-bromonaphthyl ester 4 as a single
product. Treatment of a subsequent naphthyldioxolane 5 with titanium(IV)
tetrachloride produced angular naphthopyrans 8 and 9[2] in spite of the expec-
tation that the presence of the bromine atom at C-8 would sterically discourage
ring closure at C-1 and thus favor C-3 to produce the linear naphthopyran
(viz., 10) with C-10 having an isoproxy group (Figure 1).
At the time it was suspected that the relatively large isopropoxy group at
C-4 of naphthyl dioxolane 5 exhibited a sufficient steric effect to hinder
Figure 1. Naphtholenes and naphthopyrans.

Bromination Products of Naphthols
333
cyclization at C-3. Pursuant to this, Green et al.[3] treated naphthyl dioxolane 6
in which C-2 in the dioxolane ring was epimeric and the C-4 group was
replaced by the smaller methoxy, to conditions similar to titanium(IV) tetra-
chloride,[4] and isolated the linear naphthopyran 10 as the C-4 acetate in
13% yield. These linear naphthopyrans are of great importance to our group
because we have been investigating routes toward the synthesis of
Glucoside B 11.[5]
This latter finding was encouraging because it lent support to the hypoth-
esis that reducing the steric size of the C-4 alkoxy group of naphthyl dioxolanes
(viz., 6) would favor attack at C-3, and thus it was decided to further improve
this notion by blocking the C-1 position with bromine and replacing the C-4
alkoxy group with a stronger directing group (viz., an OH as in dioxolane 7)
because it was felt that this latter molecule would undergo the intramolecular
Mukaiyama[4] reaction to afford a much higher yield of linear naphthopyran.
This article describes recent work relating to products obtained by
treatment of C-2 substituted 5,7-dimethoxy-4-naphthols with bromine as a
function of that substituent.
RESULTS AND DISCUSSIONS
Careful hydrolysis of naphthoate 12[6] with sodium methoxide in methyl
alcohol afforded the known naphthol 13[7] in 94% yield, which represented
the first naphthol to be investigated. Treatment of naphthol 13 with
1 molar equivalent of bromine in acetic acid produced two products (viz.,
8-bromonaphthol 14 and 3,8-dibromonaphthol 15) in yields of 57% and
4
21% respectively. We had earlier noted[1–3] that the J value for naphthyl
protons in the 5,7-dimethoxy ring is 2.2 Hz, whereas in the 2,4-disubstituted
ring it is 1.4 Hz, and thus this fact is used inter alia for assigning structures
1
to the various products of bromination throughout this study. The H NMR
spectrum of naphthol 14 displayed three 1-proton signals in the aromatic
region; a singlet at 6.65 ppm for 6-H, a doublet (J 1.4) at 7.32 ppm for 3-H,
and a doublet (J 1.4) at 8.42 ppm for 1-H. This latter deshielding (0.49 ppm)
of 1-H is ascribed to the peri interaction of the C-8 bromine.[1] For the 3,8-
1
dibromonaphthol 15 only two 1-proton singlets were observed in the H
NMR spectrum (viz., 6.62 ppm for 6-H and 8.00 ppm for 1-H). Treatment of
naphthol 13 with 2 molar equivalents of bromine in acetic produced the
3,8-dibromonaphthol 15 in 90% yield as the sole product. In separate
experiments it was found that adding 1 equivalent of sodium acetate to the
reaction mixture when 1 equivalent of bromine was added had no effect on
the outcome of the products nor their respective yields (Scheme 1).
These results suggest that the dimethoxy ring is sufficiently electron rich
to override the C-4 hydroxy group’s activating influence. A most likely reason
for this is the electron-withdrawing ester group at C-2. In spite of this effect
and the steric congestion, naphthol 15 was smoothly converted into the

334
I. R. Green, V. I. Hugo, and M. N. Mei
Scheme 1.
benzyloxy analogue 16 in 75% yield with benzyl bromide and potassium
carbonate in boiling acetone.
As a consequence, 2-acetoxymethylnaphthol 21, in which the deactivat-
ing ester group at C-2 has been transformed into a slightly electron-
donating group, was investigated because this molecule was considered to
be a pivotal precursor for the synthesis of dioxolane 7. Thus large-scale
benzylation of naphthol 13 with benzyl bromide and potassium carbonate in
boiling acetone afforded the expected benzyloxynaphthalene 17 in 93%
yield together with a trace amount (1%) of the 3-benzylnaphthol 18. Assign-
ment of the latter structure 18 to the minor product is based inter alia on the 1H
NMR spectrum in which two 1-proton doublets (J 2.2) at 6.58 and 6.80 ppm
were assigned to 6- and 8-H respectively and a 1-proton singlet at 7.80 ppm
that was assigned to 1-H. This latter product most likely arose from an
electrophilic substitution reaction at the less congested C-3 position by a
benzylic carbocation arising from ionization of benzyl bromide.
Ester 17 was subsequently reduced with lithium aluminium hydride in
THF to produce alcohol 19 in 85% yield, which in turn was acetalated in
acetic anhydride and pyridine to give acetate 20 in a yield of 97%. Finally,
very careful catalytic hydrogenation of acetate 20 afforded the desired
naphthol 21 in 91% yield (Scheme 2).

Bromination Products of Naphthols
335
Scheme 2.
Although the overall yield for the four transformation steps
(13 ! 17 ! 19 ! 20 ! 21) was 70%, an alternative route was also inves-
tigated. Thus naphthol 13 was reduced to diol 22 in a yield of 90% with
LAH in THF.[8] Acetalation of diol 22 as described previously produced the
diacetate 23 in a yield of 85%. However, all attempts to chemoselectively
mono-deacetalate 23 into naphthol 21 under basic conditions, even using
0.1 mol equivalent of potassium hydroxide per mol of 23 in methyl alcohol
proved unsuccessful. In all cases diol 22 was the major product with minor
quantities of naphthol 21 being produced (GC-MS). In some cases of low
concentrations of base, the starting material was also observed.
Treatment of naphthol 21 with 1 mol equivalent of bromine in acetic acid
afforded two monobrominated naphthols 24 and 25 in yields of 70% and 27%
1
respectively. Assignment of the structures is based inter alia on the H NMR
spectra. In the case of 1-bromonaphthol 24, three 1-proton signals were evident:
namely, a doublet (J 2.2) at 6.51 ppm assigned to 6-H, a doublet (J 2.2) at
7.21 ppm assigned to 8-H deshielded by the peri 1-Br, and a singlet at 6.81 ppm
for 3-H. On the other hand, 3-bromonaphthol 25 displayed three 1-proton
signals as follows: a doublet (J 2.2) at 6.50 ppm assigned to 6-H, a doublet
(J 2.2) at 6.69 ppm assigned to 8-H, and a singlet at 7.24 ppm assigned to 1-H.
Repeating the bromination of naphthol 21 with 1 mol equivalent of
bromine in acetic acid containing 1 and 2 mol equivalents of sodium
acetate as buffer resulted in the recovery of starting material (80%) together
with a mixture of 1-bromonaphthol 24 and 3,8-dibromonaphthol 26 (20%)
1
in a ratio of 3 : 7 (by H NMR).
On the other hand, treatment of naphthol 21 with 1 mol equivalent of
bromine in a 1 : 1 ratio by volume of acetic acid and dichloromethane
yielded the same two monobrominated naphthols (viz., 24 and 25) in quanti-
tative yield and in a 1 : 1 ratio by 1H NMR. Finally, treatment of naphthol 21
with 2.7 mol equivalents of bromine in dichloromethane afforded two dibro-
minated naphthols (viz., 3,8-dibromonaphthol 26 and 1,3-dibromonaphthol

336
I. R. Green, V. I. Hugo, and M. N. Mei
27) in yields of 70% and 25% respectively. The 1H NMR spectrum of naphthol
26 exhibited two 1-proton signals in the aromatic region [viz., a singlet at
6.65 ppm assigned to 6-H and a doublet (J 0.6) at 7.77 ppm assigned to
4
1-H]. A similar J of 0.6 was observed for the methylene protons at C-2,
which appeared as a 2-proton doublet at 5.31 ppm. In the case of the minor
product (viz., 1,3-dibromonaphthol 27), two 1-proton doublets (J 2.2)
appeared at 6.56 and 7.23 ppm and are assigned to 6- and 8-H respectively
(Scheme 3).
During the catalytic hydrogenation of naphthyl ester 20 into naphthol 21,
a minor amount (5%) of 2-methylnaphthol 28 was produced. It occurred to us
that this molecule presented itself as a further candidate for our investigations
because it would be expected to enhance bromination at the phenolic side of
naphthol 28. Consequently, extended (48 h) hydrogenation of naphthyl ester
20 with Pd/C (5%) in ethyl acetate and a trace of conc. HCl produced the
2-methylnaphthol 28[9,10] in 93% yield, typified by a 3-proton singlet at
1
2.39 ppm in the H NMR spectrum.
Treatment of naphthol 28 with 1 mol equivalent of bromine in acetic acid
afforded three products (viz., 1-bromonaphthol 29, 3-bromonaphthol 30, and
1
1,3-dibromonaphthol 31) in the ratio 4 : 2 : 1 by H NMR spectral analysis.
Assignment of structures for the isolated and purified products was based
1
inter alia on the H NMR spectra, and just a few pertinent signals are a
deshielded 1-proton doublet (J 2.2) at 7.21 ppm assigned to 8-H for
naphthol 29, a 1-proton doublet (J 0.6) at 7.08 ppm assigned to 1-H and a
3-proton doublet (J 0.6) at 2.49 ppm for the C-2 methyl group of naphthol
30, and two 1-proton doublets (J 2.2) at 6.51 and 7.24 ppm for 6-and 8-H
for naphthol 31 (Scheme 4). As a matter of course naphthols 29 and 31
Scheme 3.

Bromination Products of Naphthols
337
Scheme 4.
were transformed into the corresponding acetates 32 and 33 respectively to
verify structural assignments. Finally, treatment of naphthol 28 with 1 mol
equivalent of bromine in acetic acid in the presence of a 2 mol equivalent of
sodium acetate buffer produced the same three brominated naphthols (viz.,
1
29, 30, and 31) in the same ratio as before (4 : 2 : 1) by H NMR. However,
in this case, a new monobrominated naphthol was isolated in 5% yield and
eluted from the column after naphthol 31 and was assigned the structure 34
on the basis of inter alia the following 1H NMR spectral data [viz., a
3-proton double (J 0.6) at 2.45 ppm assigned to the C-2 methyl group, a
1-proton singlet at 6.51 ppm for 6-H, a 1-proton doublet (J 1.4) at 6.66 pm
for 3-H, and a 1-proton dd (J 1.4 and 0.6) at 7.49 ppm for the deshielded
1-H] (Scheme 4).
CONCLUSION
Thus an array of brominated products is produced upon treatment of
2-substituted, 5,7-dimethoxy-4-naphthols with the dimethoxy nucleus
being favored when the C-2 group is electron withdrawing, whereas the
phenol nucleus is favored when C-2 is electron donating. In all cases no
single product is produced although as expected, a-bromination predominates
over b-bromination in acetic acid. Bromination in the presence of a
buffer (viz., sodium acetate) does not affect the outcome relative to the
nonbuffered regime for the naphthols studied.

338
I. R. Green, V. I. Hugo, and M. N. Mei
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.
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.
Methyl 8-Bromo-4-hydroxy-5,7-dimethoxy-2-naphthoate 14 and
Methyl 3,8-Dibromo-4-hydroxy-5,7-dimethoxy-2-naphthoate 15
Method A
Bromine (308 mg, 1.92 mmol) in AcOH (2 mL) was dripped into a solution of
naphthol 13[7] (500 mg; 1.91 mmol) in AcOH (10 mL) at 24 8C, and the
resulting solution was stirred 15 min and then poured into water (150 mL) to
form a precipitate, which was chromatographed using EtOAc–hexane (3 : 7)
as eluent to produce the bromonaphthol 14 (371 mg; 57%) as light brown
needles. Mp 190–1918C (from ethanol). vmax 3360 and 1714 cm21; dH 3.96,
4.01, and 4.09 (each 3H, s, OCH3), 6.65 (1H, s, 6-H), 7.32 (1H, d, J 1.4,
3-H), 8.42 (1H, d, J 1.4, 1-H), and 9.25 (1H, s, D2O exchangeable, 4-OH).
dC 52.4, 56.7, and 57.1 (OCH3), 95.6 (C-6), 102.6 (C-8)a, 108.9 (C-3)a,
113.6 (C-2)a, 119.9 (C-1)a, 130.9 (C-4a)6, 134.7 (C-8a)b, 154.3 (C-4)c, 155.1
(C-5)c, 156.9 (C-7)c, and 166.9 (C55O). [Found: C, 49.2; H, 3.6%; Mþ
341:343 (1 : 1). Calc. for C14H13BrO5: C; 49.3; H, 3.8%; M 341:343 (1 : 1)].
Further elution afforded the dibromonaphthol 15 (168 mg; 21%) as light
brown needles, mp 194–195 8C (from ethanol). vmax 3340 and 1726 cm21
;
dH 3.99, 4.01, and 4.11 (each 3H, s, OCH3), 6.62 (1H, s, 6-H), 8.00 (1H, s,
1-H), and 10.07 (1H, s, D2O exchangeable, 4-OH). dH 52.8, 56.9, 57.2
(OCH3), 95.8 (C-6), 100.9 (C-8)a, 101.9 (C-2)a, 112.3 (C-3)a, 119.7 (C-1),
133.1 (C-4a)b, 134.2 (C-8a)b, 151.9 (C-4)c, 154.6 (C-5)c, 155.9 (C-7)c, and
167.3 (C55O). [Found: C, 40.3; H, 3.0%; Mþ 420 : 422 : 424 (1 : 2 : 1). Calc.
for C14H12Br2O5: C, 40.0; H, 2.9%. M 420 : 422 : 424 (1 : 2 : 1)].
Method B
Bromine (700 mg; 4.38 mmol) in AcOH (4 mL) was dripped into a solution of
naphthol 13 (500 mg; 1.91 mmol) containing sodium acetate (410 mg;

Bromination Products of Naphthols
339
5.0 mmol) at 248C and after 30 min stirring, the reaction mixture was
poured into water (150 mL) to yield a precipitate of the dibromonaphthol 15
(722 mg; 90%) identical to material prepared before, vide supra.
Methyl 4-Benzyloxy-3,8-dibromo-5,7-dimethoxy-2-naphthoate 16
A mixture of naphthol 15 (485 mg, 1.15 mmol) and benzyl bromide (983 mg,
5.75 mmol) in acetone (35 mL) containing potassium carbonate (794 mg,
5.75 mmol) was vigorously stirred and heated under reflux for 18 h. The
cooled solution was filtered and evaporation of the solvent gave a residue,
which was carefully chromatographed using EtOAc–hexane (1 : 4) as eluent
to give the naphthoate 16 (440 mg, 75%) as white crystals. Mp 152–153 8C
(from ethanol). vmax 1725 cm21; dH 3.90 (3H, s, CO2CH3), 4.01 and 4.04
(each 3H, s, OCH3), 5.00 (2H, s, CH2Ph), 6.75 (1H, s, 6-H), 7.40 (3H, m,
aryl-H), 7.61 (2H, m, aryl-H), and 8.41 (1H, s, 1-H). dC 52.9, 56.6, 57.1
(OCH3), 75.9 (CH2Ph), 97.5 (C-6), 100.7 (C-3)a, 111.3 (C-8)a, 118.9 (C-2)a,
125.3 (C-1), 128.1 (C-20/60)b, 128.5 (C-30/60)b, 133.5 (C-40)c, 133.8 (C-4a)c,
137.4 (C-8a)c, 153.2 (C-4)d, 155.1 (C-5)d, 156.7 (C-7)d, and 167.1 (C55O).
[Found: C, 49.3; H, 3.6%; Mþ 510 : 512 : 514 (1 : 2 : 1). Calc. for
C21H18Br2O5: C, 49.6; H, 3.6%; M 510 : 512 : 514 (1 : 2 : 1)].
Methyl 4-Benzyloxy-5,7-dimethoxy-2-naphthoate 17 and Methyl
2-Benzyl-4-hydroxy-5,7-dimethoxy-2-naphthoate 18
Benzyl bromide (6.72 g, 39.3 mmol) was added to a solution of naphthol 13
(4.11 g; 15.7 mmol) in acetone (50 mL) containing potassium carbonate
(5.42 g; 39.3 mmol) and the resulting mixture was vigorously stirred under
reflux for 18 h, cooled, and filtered. The residue obtained upon removal of
solvent was chromatographed using EtOAc–hexane (3 : 7) as eluent to yield
benzyloxynaphthalene 17 (5.14 g, 93%) as white needles. Mp 122–124 8C
(from hexane). vmax 1721 cm21; dH 3.91, 3.94, 3.94 (each 3H, s, OCH3),
5.26 (2H, s, CH2Ph), 6.61 (1H, d, J 2.2, 6-H), 6.82 (1H, d, J 2.2, 8-H), 7.37
(1H, d, J 1.4, 3-H), 7.40 (3H, m, aryl-H), 7.65 (2H, m, aryl-H), and 8.06
(1H, d, J 1.4, 1-H). dC 52.4, 55.4, 56.2 (OCH3), 71.2 (CH2Ph), 100.1
(C-6)a, 101.1 (C-8)a, 105.0 (C-3), 113.9 (C-2), 123.2 (C-4), 127.0
(C-30/50)b, 127.6 (C-40), 128.4 (C-20/60)b, 128.5 (C-10), 137.4 (C-4a)c, 137.5
(C-8a)c, 156.7 (C-4)d, 158.5 (C-5)d, 158.8 (C-7)d, and 167.3 (C55O).
(Found: C, 71.5; H, 5.6%; Mþ 352. Calc. for C21H20O5: C, 71.6; H, 5.7%;
M 352). Further elution afforded naphthol 18 (50 mg; 0.9%) as white
crystals. Mp 137–138 8C (from hexane). vmax 3310 and 1717 cm21; dH
3.88, 3.94, and 4.06 (each 3H, s, OCH3), 4.50 (2H, s, CH2Ph), 6.58 (1H, d,
J 2.2, 6-H), 6.80 (1H, d, J 2.2, 8-H), 7.26 (5H, m, aryl-H), 7.80 (1H, s,
1-H), and 9.59 (1H, s, D2O exchangeable, 4-OH). dC 31.6 (CH2Ph), 51.2,

340
I. R. Green, V. I. Hugo, and M. N. Mei
55.5, 56.4 (OCH3), 99.7 (C-6), 100.2 (C-8), 112.3 (C-1)a, 119.2 (C-2)a, 120.6
(C-3)a, 125.4 (C-40), 128.1 (C-20/60)b, 128.5 (C-30/50)b, 131.6 (C-10), 135.0
(C-4a)c, 142.1 (C-8a)c, 153.0 (C-4)d, 156.8 (C-5), 157.9 (C-7), and 168.7
(C55O). (Found: C, 71.5; H, 5.8%; Mþ 352. Calc. for C21H20O5: C, 71.6;
H, 5.7%; M 352).
4-Benzyloxy-2-hydroxymethyl-5,7-dimethoxynaphthalene 19
A solution of ester 17 (360mg, 1.02mmol) in THF (15 mL) at 23 8C was
dripped into a stirred slurry of LAH (100mg, 2.6 mmol) in THF (10 mL)
under N2 and stirring was continued until reduction was complete (TLC).
Saturated ammonium chloride was added (3 drops) to destroy the excess of
LAH, and the residue obtained upon workup was chromatographed using
EtOAc–hexane (2 : 3) as eluent to give the alcohol 19 (280mg, 85%) as
white needles. Mp 155–157 8C (from ethanol). vmax 3420cm21; dH 1.92 (1H,
s, D2O exchangeable, –CH2OH), 3.89 and 3.92 (each 3H, s, OCH3), 4.76
(2H, s, -CH2OH), 5.18 (2H, s, –CH2Ph), 6.50 (1H, d, J 2.2, 6-H), 6.69 (1H,
d, J 2.2, 8-H), 6.79 (1H, d, J 1.4, 3-H), 7.26 (1H, d, J 1.4, 1-H), 7.42 (3H, m,
aryl-H), and 7.60 (2H, m, aryl-H). dC 55.3 and 56.1 (OCH3), 65.6 (CH2OH),
71.3 (CH2Ph), 98.9 (C-6), 99.0 (C-8), 105.2 (C-3), 113.2 (C-2), 117.9 (C-1),
127.0 (C-30/50)a, 127.6 (C-40), 128.4 (C-20/60)a, 128.5 (C-10), 137.7 (C-4a)b,
138.3 (C-8a)b, 156.8 (C-4)b, 158.5 (C-5)b and 158.6 (C-7)b. (Found: C, 73.9;
H, 6.1%; Mþ 324. Calc. for C20H20O4: C, 74.1; H, 6.2%; M 324).
2-Acetoxymethyl-4-benzyloxy-5,7-dimethoxynaphthalene 20
Alcohol 19 (190 mg; 0.59 mmol) in acetic anhydride (2.0 mL) and pyridine
(0.7 mL) was stirred at 23 8C for 24 h, after which water (80 mL) was added
and the mixture extracted with ether. The extract was rinsed with 0.1 M
hydrogen chloride followed by water, and the residue obtained upon
workup was chromatographed using EtOAc–hexane (1 : 5) as eluent to
give the acetate 20 (210 mg; 97%) as white crystals. Mp 102–103 8C
(from hexane). vmax 1744 cm21; dH 2.14 (3H, s, COCH3), 3.90 and 3.92
(each 3H, s, OCH3), 5.18 (2H, s, CH2OAc), 5.20 (2H, s, CH2Ph), 6.51
(1H, d, J 2.2, 6-H), 6.71 (1H, d, J 2.2, 8-H), 6.75 (1H, d, J 1.4, 3-H), 7.28
(1H, d, J 1.4, 1-H), 7.38 (3H, m, aryl-H), and 7.60 (2H, m, aryl-H). dC 21.1
(COCH3), 55.4 and 56.2 (OCH3), 66.5 (CH2OAc), 71.4 (CH2Ph),
99.1 (C-6), 99.4 (C-8), 106.3 (C-3), 113.6 (C-2), 119.8 (C-1), 127.1 (C-
20/60)a, 127.6 (C-40), 128.4 (C-30/50)a, 134.8 (C-10), 138.2 (C-4a)b, 138.8
(C-8a)b, 156.1 (C-4)c, 158.6 (C-5)c, 158.7 (C-7)c, and 171.0 (C55O).
(Found: C, 72.0; H, 5.9%; Mþ 366. Calc. for C22H22O5: C, 72.1; H, 6.0%;
M 366).

Bromination Products of Naphthols
341
2-Acetoxymethyl-5,7-dimethoxy-4-naphthol 21
A mixture of ester 20 (900 mg, 2.46 mmol) in EtOAc (35 mL) containing Pd/C
(23 mg of a 10% mixture) and concentrated hydrogen chloride (1 drop) was
hydrogenated at atmospheric pressure and 23 8C and monitored for the
uptake of 1 mol equivalent of H2. The filtered solution was evaporated, and
the residue chromatographed to afford the naphthol 21 (620 mg, 91%) as
white crystals. Mp 93–95 8C (from hexane). vmax 3400 and 1739 cm21. dH
2.13 (3H, s, COCH3), 3.88 and 4.01 (each 3H, s, OCH3), 5.14 (2H, s,
CH2OAc), 6.45 (1H, d, J 2.2, 6-H), 6.70 (2H, m, 8- and 3-H), 7.15 (1H, d,
J 1.4, 1-H), and 9.14 (1H, s, D2O exchangeable, 4-OH). dC 21.1 (COCH3),
55.5 and 56.3 (OCH3), 66.2 (CH2OAc), 98.1 (C-6), 99.7 (C-8), 108.1 (C-3),
110.6 (C-2), 117.1 (C-1), 136.3 (C-4a)a, 137.4 (C-8a)a, 155.0 (C-4)b, 157.2
(C-5)b, 158.1 (C-7)b, and 170.9 (C55O). (Found: C, 65.0; H, 5.7%; Mþ 276.
Calc. for C15H16O5: C, 65.2; H, 5.8%; M 276).
2-Hydroxymethyl-5,7-dimethoxy-4-naphthol 22
A solution of ester 13 (830 mg, 3.16 mmol) in THF (40 mL) under nitrogen
was dripped into a slurry of LAH (480 mg, 12.6 mmol) in THF (20 mL)
After 1 h of stirring, saturated aqueous ammonium chloride was added
dropwise to destroy the excess of LAH. The residue obtained upon workup
was chromatographed using EtOAc–hexane (1 : 1) as eluent to produce the
naphthol 22 (668 mg, 90%) as white crystals. Mp 142–143 8C (from
hexane); lit. mp[1] 144–145 8C. vmax 3450 and 3250 cm21. dH 1.80 (1H, s,
D2O exchangeable, CH2OH), 3.88 and 4.02 (each 3H, s, OCH3), 4.74 (1H,
d, J 2.9, CH2OH), 6.44 (1H, d, J 2.2, 6-H), 6.69 (1H, d, J 2.2, 8-H), 6.71
(1H, d, J 1.2, 3-H), 7.17 (1 h, D, J 1.2, 1-H), and 9.12 (1H, s, D2O exchange-
able, 4-OH). dC 55.4 and 56.2 (OCH3), 65.4 (CH2OH), 97.8 (C-6), 99.7 (C-8),
107.4 (C-3). 110.3 (C-2), 115.4 (C-1), 137.6 (C-4a)a, 141.4 (C-8a)a, 155.0
(C-4)b, 157.3 (C-5)b, and 158.1 (C-7)b. (Found: C; 66.6; H, 6.0%; Mþ 234.
Calc. for C13H14O4: C, 66.65; 6.0%; M 234.)
4-Acetoxy-2-acetoxymethyl-5,7-dimethoxynaphthalene 23
Naphthol 22 (240 mg, 1.03 mmol) was treated with acetic anhydride (4 mL)
and pyridine (1.0 mL) and stirred under nitrogen for 18 h at 23 8C. Workup
as described before (vide supra) afforded the diacetate 23 (280 mg, 85%) as
white crystals. Mp 97–98 8C (from ethanol). vmax 1740 cm21; dH 2.13 and
2.36 (each 3H, s, COCH3), 3.89 (6H, s, OCH3), 5.19 (2H, s, CH2OAc), 6.50
(1H, d, J 2.6, 6-H), 6.74 (1H, d, J 2.6, 8-H), 6.91 (1H, d, J 1.4, 3-H), and
7.54 (1H, d, J 1.4, 1-H). dC 21.0 and 21.1 (COCH3), 55.5 and 56.2 (OCH3),
65.7 (CH2OAc), 99.2 (C-6), 99.9 (C-8), 114.8 (C-2), 116.9 (C-3), 124.5

342
I. R. Green, V. I. Hugo, and M. N. Mei
(C-1), 134.7 (C-4a)a, 137.7 (C-8a)a, 147.1 (C-4), 156.4 (C-5), 158.7 (C-7),
170.2 and 170.9 (C55O). (Found: C, 64.3; H, 5.6%; Mþ 318. Calc. for
C17H18O6: C, 64.2; H, 5.7%; M 318.)
2-Acetoxymethyl-1-bromo-5,7-dimethoxy-4-naphthol 24 and
2-Acetoxymethyl-3-bromo-5,7-dimethoxy-4-naphthol 25
Bromine (58 mg, 0.36 mmol) in acetic acid (1 mL) was added to a stirred
solution of naphthol 21 (100 mg, 0.36 mmol) in acetic acid (10 mL), and
stirring was maintained at 23 8C under nitrogen for 15 min, after which
water (100 mL) was added and the products extracted into dichloromethane.
The organic extract was rinsed with saturated sodium hydrogen carbonate,
and the residue obtained upon workup was chromatographed using EtOAc–
hexane (1 : 4) as eluent to afford the 1-bromonaphthol 24 (89 mg, 70%) as
white needles. Mp 144–145 8C (from ethanol). vmax 3340 and 1737 cm21
;
dH 2.18 (3H, s, COCH3), 3.94 and 4.04 (each 3H, s, OCH3), 5.31 (2H, s,
CH2OAc), 6.51 (1H, d, J 2.2, 6-H), 6.81 (1H, s, 3-H), 7.21 (1H, d, J 2.2,
8-H), and 9.28 (1H, s, D2O exchangeable, 4-OH). dC 21.0 (COCH3), 55.6
and 56.6 (OCH3), 66.6 (CH2OAc), 98.5 (C-6), 99.6 (C-8), 108.9 (C-3),
110.6 (C-1)a, 111.4 (C-2)a, 135.6 (C-4a)b, 136.1 (C-8a)b, 154.6 (C-4)c,
157.4 (C-5)c, 159.1 (C-7)c, and 170.7 (C55O). [Found: C, 50.8; H, 4.1%;
Mþ 355 : 357 (1 : 1). Calc. for C15H15BrO5: C, 50.85; H, 4.3%; M 355 : 357
(1 : 1)]. Further elution afforded the 3-bromonaphthol 25 (34 mg; 27%) as
olive rosettes. Mp 138–139 8C (from ethanol). vmax 3330 and 1735 cm21
;
dH 2.18 (3H, s, COCH3), 3.88 and 4.03 (each 3H, s, OCH3), 5.28 (2H, s,
CH2OAc), 6.50 (1H, d, J 2.2, 6-H), 6.69 (1H, d, J 2.2, 8-H), 7.24 (1H, s,
1-H), and 9.89 (1H, s, D2O exchangeable, 4-OH). dC 21.1 (COCH3), 55.5
and 56.6 (OCH3), 66.3 (CH2OAc), 98.9 (C-6), 99.8 (C-8), 102.9 (C-3)a,
110.8 (C-2)a, 118.1 (C-1), 135.0 (C-4a)b, 135.7 (C-8a)b, 151.2 (C-4)c, 156.3
(C-5)c, 158.4 (C-7)c, and 170.7 (C55O). [Found: C, 50.7; H, 4.0%; Mþ
355 : 357 (1 : 1). Calc. for C15H15BrO5: C, 50.85; H, 4.3%; M 355 : 357 (1 : 1)].
2-Acetoxymethyl-3,8-dibromo-5,7-dimethoxy-4-naphthol 26 and
2-Acetoxymethyl-1,3-dibromo-5,7-dimethoxy-4-naphthol 27
A solution of bromine (320mg; 2.0 mmol) in dichloromethane (10 mL) was
added dropwise to a solution of naphthol 21 (202mg; 0.73mmol) in dichloro-
methane (10 mL), and after stirring an additional 10min at 23 8C the solvent
was removed to afford a residue that was chromatographed using EtOAc–
hexane (3: 7) as eluent to yield the 3,8-dibromonaphthol 26 (221mg, 70%) as
olive-colored needles. Mp 209–210 8C (from ethyl alcohol). vmax 3310 and
1740cm21; dH 2.21 (3H, s, COCH3), 4.02 and 4.12 (each 3H, s, OCH3), 5.31
(2H, d, J 0.6, CH2OAc), 6.65 (1H, s, 6-H), 7.77 (1H, d, J 0.6, 1-H), and 10.01

Bromination Products of Naphthols
343
(1H, s, D2O exchangeable, 4-OH). dC 21.1 (COCH3), 56.9 and 57.2 (OCH3),
66.3 (CH2OAc), 94.6 (C-6), 101.6 (C-3)a, 104.0 (C-8)a, 111.3 (C-2)a, 117.6
(C-1), 133.5 (C-4a)b, 136.5 (C-8a)b, 151.2 (C-4)c, 154.4 (C-5)c, 156.1 (C-7)c,
and 170.7 (C55O). [Found: C, 41.6; H, 3.4%; Mþ 434 : 436 : 438 (1: 2 : 1).
Calc. for C15H14Br2O5: C, 41.5; H, 3.25%; M 434 : 436 : 438 (1 : 2 : 1)].
Further elution afforded the 1,3-dibromonaphthol 27 (80 mg, 25%) as olive
crystals. Mp 174–175 8C (from ethanol). vmax 3360 and 1732cm21; dH 2.12
(3H, s, COCH3), 3.94 and 4.06 (each 3H, s, OCH3), 5.63 (2H, s, CH2OAc),
6.56 (1H, d, J 2.2, 6-H), 7.23 (1H, d, J 2.2, 8-H), and 10.11 (1H, s, D2O
exchangeable, 4-OH). dC 20.8 (COCH3), 55.6 and 56.9 (OCH3), 68.3
(CH2OAc), 99.8 (C-6), 100.5 (C-8), 105.6 (C-3)a, 111.6 (C-1)a, 115.1 (C-2)a,
134.0 (C-4a)b, 134.4 (C-8a)b, 151.2 (C-4)c, 156.4 (C-5)c, 159.2 (C-7)c, and
170.8 (C55O). [Found: C, 41.3; H, 3.4%; Mþ 434:436:438 (1:2:1). Calc. for
C15H14Br2O5: C, 41.5; H, 3.25%; M 434 : 436 : 438 (1: 2 : 1)].
5,7-Dimethoxy-2-methyl-4-naphthol 28
Benzyloxynaphthalene 20 (2.0 g, 5.50 mmol) in EtOAc (30 mL) containing
Pd/C (5%) (40 mg) and concentrated hydrogen chloride (1 drop) was vigor-
ously stirred under hydrogen (1 atm) for 48 h. The filtered solution was
washed with water (30 mL), and the residue obtained upon workup was chro-
matographed using EtOAc–hexane (1 : 4) as eluent to afford the naphthol 28
(1.12 g, 93%) as tan-colored needles. Mp 83–84 8C (from hexane); lit. mp
83–84 8C[9]; 82 8C[10]. vmax 3340 cm21; dH 2.39 (3H, s, 2-CH3), 3.88 and
4.01 (each 3H, s, OCH3), 6.38 (1H, d, J 2.2, 6-H), 6.58 (1H, d, J 1.4, 3-H),
6.63 (1H, d, J 2.2, 8-H), 6.97 (1H, d, J 1.4, 1-H), and 9.03 (1H, s, D2O
exchangeable, 4-OH). dC 21.7 (2-CH3), 55.4 and 56.2 (OCH3), 96.9 (C-6),
99.1 (C-8), 109.1 (C-2), 110.5 (C-3), 117.6 (C-1), 137.7 (C-4a)a, 138.6 (C-
8a)a, 154.4 (C-4)b, 157.3 (C-5)b, and 157.9 (C-7)b. (Found: C, 71.4; H,
6.2%; Mþ 218. Calc. for C13H14O3: C, 71.5; H, 6.5%; M 218).
1-Bromo-5,7-dimethoxy-2-methyl-4-naphthol 29, 3-Bromo-5,7-
dimethoxy-2-methyl-4-naphthol 30, and 1,3-Dibromo-5,7-
dimethoxy-2-methyl-4-naphthol 31
Bromine (320mg, 2.0 mmol) in acetic acid (4 mL) was added to a stirred
solution of naphthol 28 (436 mg, 2.0 mmol) in acetic acid (40 mL) dropwise
at 23 8C under nitrogen. After stirring for 30min, water (300 mL) was added,
and the resulting emulsion was extracted with dichloromethane and backwashed
with aqueous sodium hydrogen carbonate. The residue obtained upon workup
(600mg) was recrystallized from ethanol, and the crystalline product was chro-
matographed over a long column (1200 ꢀ 25mm) using EtOAc–hexane (1 : 4)
as eluent to afford the 1-bromonaphthol 29 (320mg, 54%) as light brown

344
I. R. Green, V. I. Hugo, and M. N. Mei
needles. (Masses given refer to the final masses of products obtained after
pooling together.) Mp 144–145 8C (from ethyl alcohol). vmax 3315cm21; dH
2.51 (3H, s, 2-CH3), 3.94 and 4.03 (each 3H, s, OCH3), 6.46 (1H, d, J 2.2,
6-H), 6.67 (1H, s, 3-H), 7.21 (1H, d, J 2.2, 8-H) and 9.18 (1H, s, D2O exchange-
able, 4-OH). dC 24.4 (2-CH3), 55.5 and 56.5 (OCH3), 97.6 (C-6), 99.6 (C-8),
110.3 (C-1)a, 111.5 (C-3), 112.4 (C-2)a, 135.7 (C-4a)b, 138.8 (C-8a)b, 153.9
(C-4)c, 157.5 (C-5)c, and 158.9 (C-7)c. [Found: C, 52.4; H, 4.6%; Mþ
296:298 (1:1). Calc. for C13H13BrO3: C, 52.7; H, 4.4%; M 296 : 298 (1: 1)].
Further elution gave a slight mixture of 29, 30, and 31, which was added to
the mother liquor of the recrystallization. The next product to elute was the
1,3-dibromonaphthol 31 (74 mg, 9.9%) as light brown needles. (Masses given
refer to the final masses of products obtained after pooling together.) Mp
175–177 8C (from ethanol). vmax 3390cm21; dH 2.79 (3H, s, 2-CH3), 3.94
and 4.05 (each 3H, s, OCH3), 6.51 (1H, d, J 2.2, 6-H), 7.24 (1H, d, J 2.2,
8-H) and 10.08 (1H, s, D2O exchangeable, 4-OH). dC 25.7 (2-CH3), 55.6
and 56.8 (OCH3), 98.5 (C-6), 100.3 (C-8), 106.5 (C-1)a, 110.0 (C-2)a, 113.4
(C-3)a, 134.4 (C-4a)b, 137.9 (C-8a)b, 150.5 (C-4)c, 156.5 (C-5)c, and 158.9
(C-7)c. [Found: C, 41.2; H; 3.0%; Mþ 374 : 376 : 378 (1 : 2 : 1). Calc. for
C13H12Br2O3: C, 41.7; H, 3.2%; M 374 : 376 : 378 (1: 2 : 1)].
The mother liquors from the recrystallization were evaporated to a
residue, which was chromatographed on a similar column (1200 ꢀ 25 mm)
to afford 1-bromo-naphthol 29[11] followed by the 3-bromonaphthol 30
(118 mg, 19.9%) as olive needles. (Masses given refer to the final masses of
products obtained after pooling together.) Mp 132–133 8C (from hexane).
vmax 3345 cm21; dH 2.49 (3H, d, J 0.6, 2-CH3), 3.87 and 4.02 (each 3H, s,
OCH3), 6.43 (1H, d, J 2.2, 6-H), 6.61 (1H, d, J 2.2, 8-H), 7.08 (1H, d, J
0.6, 1-H), and 9.82 (1H, s, D2O exchangeable, 4-OH). dC 23.7 (C-2 CH3),
55.4 and 56.4 (OCH3), 97.8 (C-6), 99.0 (C-8), 105.9 (C-2)a, 109.6 (C-3)a,
118.7 (C-1), 135.8 (C-4a)b, 138.1 (C-8a)b, 150.7 (C-4)c, 156.3 (C-5)c, 158.1
(C-7)c. [Found: C, 52.9; H, 4.6%; Mþ 296 : 298 (1 : 1). Calc. for
C13H13BrO3: C, 52.7; H, 4.4%; M 296 : 298 (1 : 1)].
4-Acetoxy-1-bromo-5,7-dimethoxy-2-methylnaphthalene 32
Naphthol 29 (20 mg, 0.07 mmol) was acetylated in acetic anhydride (0.5 mL)
and pyridine (0.2 mL) as described earlier to give the corresponding acetate 32
(22 mg, 93%) as white needles. Mp 150–151 8C (from ethyl alcohol). vmax
1740 cm21; dH 2.34 (3H, s, COCH3), 2.55 (3H, s, 2-CH3), 3.88 and 3.94
(each 3H, s, OCH3), 6.50 (1H, d, J 2.2, 6-H), 6.83 (1H, s, 3-H), and 7.27
(1H, d, J 2.2, 8-H). dC 21.0 (COCH3), 24.3 (C-2 CH3), 55.5 and 56.4
(OCH3), 99.2 (C-6)a, 99.3 (C-8)a, 114.4 (C-2)b, 119.7 (C-3), 120.7 (C-1)b,
136.3 (C-4a)c, 137.5 (C-8a)c, 145.8 (C-4)d, 156.7 (C-5)d, 159.5 (C-7)d, and
170.1 (C55O). [Found: C, 53.3; H, 4.2%; Mþ 338 : 340 (1 : 1). Calc. for
C15H15BrO4: C, 53.1; H, 4.5%; M 338 : 340 (1 : 1)].

Bromination Products of Naphthols
345
4-Acetoxy-1,3-dibromo-5,7-dimethoxy-2-methylnaphthalene 33
Naphthol 31 (26 mg, 0.07 mmol) was transformed in a similar way as described
previously into the acetate 33 (26 mg, 90%) as white needles. Mp 160–161 8C
(from ethyl alcohol). vmax 1737 cm21; dH 2.41 (3H, s, COCH3), 2.82 (3H, s,
2-CH3), 3.89 and 3.94 (each 3H, s, OCH3), 6.52 (1H, d, J 2.2, 6-H), and
7.27 (1H, d, J 2.2, 8-H). dC 20.9 (COCH3), 26.0 (C-2 CH3), 55.5 and 56.5
(OCH3), 99.6 (C-6), 100.3 (C-8), 115.1 (C-1)a, 115.5 (C-2)b, 121.3 (C-3)a,
135.0 (C-4a)b, 137.1 (C-8a)b, 156.3 (C-4)c, 159.6 (C-5 and C-7)c, and 168.8
(C55O). [Found: C, 42.8; H, 3.1%; Mþ 416 : 418 : 420 (1 : 2 : 1). Calc. for
C15H14Br2O4: C, 43.1; H, 3.4%; M 416 : 418 : 420 (1 : 2 : 1)].
8-Bromo-5,7-dimethoxy-2-methyl-4-naphthol 34
Bromine (160 mg, 1.0 mmol) in acetic acid (2 mL) was added to a stirred
solution of naphthol 28 (218 mg, 1.0 mmol) in acetic acid (20 mL) containing
sodium acetate (162 mg, 2 mmol) at 23 8C under nitrogen. After stirring for
75 min, water (150 mL) was added, and the resulting emulsion was worked
up as described before. The ratio of brominated products 29, 30, and 31 that
eluted were the same as found earlier. However, a fourth fraction to elute
was assigned to the 8-bromonaphthol 34 (14 mg, 5%) as olive needles. Mp
137–138 8C (from ethyl alcohol). vmax 3420 cm21; dH 2.45 (3H, d, J 0.6,
2-CH3), 3.98 and 4.05 (each 3H, s, OCH3), 6.51 (1H, s, 6-H), 6.66 (1H, d, J
1.4, 3-H), 7.49 (1H, dd, J 1.4 and 0.6, 1-H), and 9.14 (1H, s, D2O exchange-
able, 4-OH). dC 22.1 (C-2 CH3), 56.4 and 57.2 (OCH3), 93.1 (C-6), 100.9 (C-
8)a, 109.9 (C-2)a, 113.3 (C-3), 117.1 (C-1), 135.2 (C-4a)b, 140.1 (C-8a)b,
153.8 (C-4)c, 154.5 (C-5)c, and 157.1 (C-8)c. [Found: C, 52.3; H, 4.5%; Mþ
296 : 298 (1 : 1). Calc. for C13H13BrO3: C, 52.7; H, 4.4%; M 296 : 298 (1 : 1)].
ACKNOWLEDGMENTS
The authors thank the National Research Foundation and the University of the
Western Cape for financial assistance.
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