A convenient and efficient synthesis of 2,6-dihydroxynaphthalene

Article abstract of DOI:10.3184/174751912X13497085947943

A convenient synthesis of 2,6-dihydroxynaphthalene from 6-bromo-2-naphthol has been achieved with high overall yield (52%) and good purity (95.7%) based on the conversion of 6-(methoxymethoxy)-2-naphthaldehyde to 6- (methoxymethoxy)-2-naphthol formate by a Baeyer-Villiger oxidation- rearrangement. Compared with the reported methods, the reaction conditions are milder and the work-up of each step is much simpler. Moreover, 6-bromo-2-naphthol as the starting material for the synthesis is readily available.

Full text of DOI:10.3184/174751912X13497085947943

JOURNAL OF CHEMICAL RESEARCH 2012
NOVEMBER, 675–677
RESEARCH PAPER 675
A convenient and efficient synthesis of 2,6-dihydroxynaphthalene
Jia-hua Cui and Shao-shun Li*
School of Pharmacy, Shanghai Jiaotong University, Minhang, Shanghai 200240, P. R. China
A convenient synthesis of 2,6-dihydroxynaphthalene from 6-bromo-2-naphthol has been achieved with high overall
yield (52%) and good purity (95.7%) based on the conversion of 6-(methoxymethoxy)-2-naphthaldehyde to 6-
(
methoxymethoxy)-2-naphthol formate by a Baeyer–Villiger oxidation-rearrangement. Compared with the reported
methods, the reaction conditions are milder and the work-up of each step is much simpler. Moreover, 6-bromo-2-
naphthol as the starting material for the synthesis is readily available.
Keywords: 2,6-dihydroxynaphthalene, Baeyer–Villiger oxidation-rearrangement, 6-bromo-2-naphthol, 6-(methoxymethoxy)-2-
naphthaldehyde
2
,6-Dihydroxynaphthalene (1) is an important fine chemical in
the conversion of 6-(methoxymethoxy)-2-naphthaldehyde (4)
to 6-(methoxymethoxy)-2-naphthol formate (5) by a Baeyer–
Villiger oxidation-rearrangement. The synthetic method
used 6-bromo-2-naphthol (2) as the starting material which
was easily prepared from β-naphthol according to Koelsch’s
organic synthesis and has attracted considerable interest from
scientists. It is one of the essential building blocks for ‘intelli-
gent’ materials such as molecular tubes and liquid crystalline
polymers. It serves as the starting material for the prepara-
tion of several drugs such as the 2-aminotetralins, which
act as dopaminergic agonists in the treatment of Parkinson’s
1–3
4
–8
20
method. The phenolic hydroxyl group of 2 was first protected
as the methoxymethyl (MOM) ether under mild conditions.
Halogen-metal exchange in the presence of n-butyllithium was
followed by the addition of DMF to afford the aldehyde 4.
The Baeyer–Villiger oxidation-rearrangement of 4 was con-
ducted using m-chloroperoxybenzoic acid (m-CPBA) to give 5
in high yield. The spectroscopic data of 5 were in agreement
with the structural change. Upon the oxidation-rearrangement
reaction, the strong absorption band of the carbonyl group
9
disease. It is also used as the key intermediate in the synthesis
of many other naphthalene derivatives.
1
0,11
2
,6-Dihydroxynaphthalene (1) has been prepared by two
12–17
general methods.
One was the alkali fusion of sodium
2
-naphthol-6-sulfonate or sodium naphthalene-2,6-disulfonate
12,13
followed by the acidification of the reaction mixture.
This
is not an economically attractive process because of the exces-
sive use of strong alkali and it is accompanied by a low yield
and poor purity of the product.
The other method involved the oxidation of the expensive
chemical 2,6-diisopropylnaphthalene by oxygen under strin-
gent conditions and the subsequent decomposition of the
resultant 2,6-bis(2-hydroperoxy-2-propyl)naphthalene.
mixture obtained not only contained the desired 2,6-dihydroxy-
naphthalene but also the large amount of by-products which
were formed in the oxidation and acid decomposition.
The demethylation of 6-methoxy-2-naphthol with butyl-
pyridinium bromide under microwave irradiation and the
−1
−1
shifted from 1682 cm to 1739 cm in IR spectra and the
partially positive carbon in this group was shield to an extent
1
6
1
3
of 32 ppm in C NMR spectra. These characteristics were
ascribed to an increase of the electron density in the C=O bond
from the aldehyde 4 to the formate 5. We devised a series of
experiments to find the best ratio of 4 to m-CPBA which was
1: 1.3 whilst the optimum reaction temperature was 10 °C.
When the reaction temperature was lower than 10 °C, the reac-
tion preceded more slowly. However, an increase in the number
of impurities was observed at a much higher temperature.
Afterwards 1 was obtained by the acidic hydrolysis of the
MOM ether and the formate group with hydrochloric acid as
the catalyst in one-pot.
14–17
The
1
6
1
8
1
9
oxidation of β-naphthol by hydrogen peroxide in the pres-
ence of SbF –HF have also been reported, but they have not
5
been employed for large-scale preparations. Thus a convenient
synthesis of 1 with efficient steps and inexpensive starting
materials is desirable.
Conclusion
A convenient synthesis of 1 has been achieved with high
overall yield (52%) and good purity (95.7%) based on the
conversion of the aldehyde 4 to the formate 5 through Baeyer–
Villiger oxidation-rearrangement. Compared with the reported
Results and discussion
A convenient synthesis of 1 has been achieved with high over-
all yield (52%) and good purity (95.7%), (Scheme 1) based on
1
2–17
methods,
the reaction conditions are milder and the
Scheme 1 (a) NaH, MOMCl, DMF; 93%. (b) n-BuLi, THF, –78 °C; DMF; 81%. (c) m-CPBA, CH
2 2
Cl , 10 °C; 72%.
(
d) HCl, MeOH–H O; 95%.
2
*
Correspondent. E-mail: ssli@sjtu.edu.cn

6
76 JOURNAL OF CHEMICAL RESEARCH 2012
work-up of each step is much simpler. Moreover, 6-bromo-2-
naphthol (2) as the starting material for the synthesis is cheap
and easy to obtain.
dithionite (Na S O , 8.70 g, 50 mmol) in water (15 mL) was added.
2 2 4
The reaction mixture was stirred for 30 min and poured into a satu-
rated NaHCO solution (20 mL) and shaken vigorously. The organic
3
layer was separated and the aqueous phase was extracted with CH Cl2
2
(
10 mL×5). Then the combined organic layer was successively washed
Experimental
with a Na S O solution (8.70 g of Na S O in 30 mL of water) and
brine, dried over Na SO and concentrated. The crude formate was
2 4
purified by column chromatography (petroleum-ether:ethyl acetate,
2
2
4
2
2
4
Reagents and solvents were obtained from commercial suppliers.
21
Solvents were dried and purified using standard techniques. Column
chromatography was conducted on silica gel (100–200 mesh) from
Qingdao Ocean Chemical Factory. 6-Bromo-2-naphthol (2) was
prepared by Koelsch’s method. Melting points were determined on
a SGW X-4 micromelting point apparatus. H NMR spectra were
recorded on a Varian Mercury-300 spectrometer (300 MHz) and
NMR spectra were determined on a Bruker Avance 400 spectrometer
10:1) to give 5 as a white solid. Yield: 1.67 g (72%). m.p. 53–54 °C.
1
H NMR (300 MHz, CDCl ): δ 8.38 (s, 1H, HCOO), 7.75 (t, 2H, H-4,
3
2
0
H-8), 7.54 (s, 1H), 7.42 (s, 1H), 7.24 (m, 2H, H-3, H-7), 5.29 (s, 2H,
CH O), 3.52 (s, 3H, CH O). C NMR (100 MHz, CDCl ): δ 159.5
(C=O), 155.1, 146.2, 132.6, 129.4 (quat., C-2, C-6, C-4a, C-8a),
129.0, 128.7, 120.8, 120.0, 118.0, 109.9 (C H, C-1, C-3, C-4, C-5,
1
13
2
3
3
13
C
Ar
1
13
−1
(
400 MHz). Chemical shifts in H and C spectra were recorded with
C-7, C-8), 94.5 (CH O), 56.1 (CH O). IR (KBr), ν/cm : 2957, 2925,
2
3
tetramethylsilane as the internal standard. IR spectra were measured
using a ThermoFisher Nicolet-6700 FT-IR spectrometer. HRMS were
measured on a Waters Q-TOF Premier mass spectrometer.
The HPLC analysis was performed on an Agilent 1260 liquid
chromatograph system (Agilent Technologies), equipped with a diode
array detector that recorded the UV spectra in the range of 210–
1739 vs (C=O), 1602, 1509, 1217, 1154, 1126, 995. HRMS: Calcd for
C H O 231.0657; found 231.0661 [M-H]
−
.
13
11
4
2,6-Dihydroxynaphthalene (1): Conc. hydrochloride acid (12 M,
.1 mL) was added dropwise to a solution of 5 (2.32 g, 10 mmol) in
2
methanol (35 mL), and the colourless solution was stirred at room
temperature under a nitrogen atmosphere for 5 h. Then the solvent
was evaporated to one-half volume under reduced pressure and water
4
00 nm. Chromatography was carried out using a SUPELCO Discov-
ery® C18 column (150×4.6 mm, 5 mm) at room temperature. The
mobile phase consisted of water (A) and methanol (B) and a gradient
elution (20% of B at 0–5 min, 20% to 40% of B at 5–7 min and 40%
(
(
(
30 mL) was added. The mixture was extracted with ethyl acetate
15 mL×5). The extract was washed with water, a phosphate buffer
0.23 g of KH PO and 0.31 g of K HPO in 30 mL of water, pH 7.0)
2
4
2
4
−1
of B at 7–20 min) was employed. The flow rate was 1.0 mL min and
and brine, dried over Na SO and concentrated in vacuo. The residue
2
4
the injection volume was 20 µL. The detecting wavelength was set at
was suspended in n-hexane (80 mL) and the mixture was refluxed for
min. Then the suspension was cooled to room temperature over
2
54 nm. The Agilent ChemStation for LC&LC/MS systems was used
for the data capture and processing.
-Bromo-6-(methoxymethoxy)naphthalene (3): NaH (0.48 g, 12 mmol,
3
about 1.5 h and the light-yellow crystals were collected by simple
filtration and washed with n-hexane (10 mL). Yield: 1.52 g (95%).
m.p. 212–216 °C. The crystals contained 95.7% of pure 1 based on the
2
6
2
0% dispersion in mineral oil) was added in portions to a solution of
(2.23 g, 10 mmol) in dry DMF (16 mL), and the mixture was stirred
HPLC analysis (t 9.26 min, the purity was calculated by the area
R
vigorously for 5 min. Freshly distilled methoxymethyl chloride
MOMCl, 1.05 g, 15 mmol) was added dropwise over 3 min under a
normalisation method) and its spectroscopic characters were consis-
(
25 1
6
tent with the reported values. H NMR (300 MHz, d -DMSO): δ 9.29
nitrogen atmosphere to the mixture which was cooled in an ice-water
bath. After the addition, the temperature of the solution was allowed
to rise to room temperature and the mixture was stirred for 1 h. After
completion of the reaction, the mixture was poured into a saturated
NaHCO3 solution (200 mL) at 0 °C. The white precipitate was
collected by simple filtration and was carefully washed with cold
water (60 mL). The crude product was dried in vacuo and purified
by column chromatography (petroleum-ether:ethyl acetate, 10:1) to
(
7
s, 2H, D O exchangeable, 2 OH), 7.51 (d, J = 8.4 Hz, 2H, H-4, H-8),
.04–6.90 (m, 4H, H-1, H-3, H-5, H-7). IR (KBr), ν/cm : 3267 (broad,
2
−1
OH), 1605, 1514, 1420, 1375, 1265, 1224, 1149, 1112, 941. Purified
was obtained as white crystals by flash chromatography of the light-
1
yellow crystals on silica gel with petroleum-ether:ethyl acetate (3:1,
26
V/V) as the eluent. m.p. 221–223 °C (lit. 220.5–223 °C).
Its structure was also confirmed by the conversion of it to 2,6-dime-
thoxynaphthalene, which was prepared by the methylation of 1 with
5
1
22
give 3 as white solid. Yield: 2.48 g (93%). m.p. 50–51 °C (lit. 46.8–
.0 equivalent of K CO and 2.8 equivalent of CH I in dry DMF. m.p.
2 3 3
27 1
1
6
4
9.2 °C). H NMR (300 MHz, d -DMSO): δ 8.12 (s, 1H, H-1), 7.86 (d,
J = 9.0 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.47
s, 1H, H-5), 7.30 (d, J = 9.0 Hz, 1H), 5.32 (s, 2H, CH O), 3.42 (s, 3H,
48–149 °C (lit. 149.5 °C). H NMR (300 MHz, CDCl ): δ 7.63 (d,
3
J = 8.7 Hz, 2H, H-4, H-8), 7.15–7.06 (m, 4H, H-1, H-3, H-5, H-7),
.89 (s, 6H, 2 CH O).
(
2
3
3
−
1
CH O). IR (KBr), ν/cm : 1589, 1498, 1253, 1200, 1158, 1079, 1000.
3
6
-(Methoxymethoxy)-2-naphthaldehyde (4):A solution of 3 (2.67 g,
0 mmol) in dry THF (30 mL) cooled in an acetone-dry ice bath
to –78 °C was treated with n-BuLi (2.4 M in n-hexane, 5.0 mL,
2 mmol). The mixture was stirred at –78 °C for 30 min and dry DMF
3.8 mL) was slowly added at the same temperature. After the addi-
The research is supported by the State Key Laboratory Cultiva-
tion Base for the Chemistry and Molecular Engineering of
Medicinal Resources, Ministry of Science and Technology
of China (CHEMR2012-B08). We are grateful to the Instru-
mental Analysis Center of Shanghai Jiaotong University for
1
1
(
tion, the reaction temperature was allowed to rise to 0 °C over 2 h.
Then the reaction was quenched with a saturated NH Cl solution
30 mL) and the organic layer was separated. The aqueous phase was
13
4
recording the IR and C NMR spectra.
(
extracted with ethyl acetate (15 mL×5). The combined organic layer
Received 5 September 2012; accepted 19 September 2012
Paper 1201499 doi: 10.3184/174751912X13497085947943
Published online: 12 November 2012
was washed with a saturated NH Cl solution (15 mL) and brine, dried
4
over Na SO and concentrated. The residue was subject to column
2
4
chromatography (petroleum-ether:ethyl acetate, 6:1) to afford 4 first
as a light-yellow oil, which gradually solidified into a homogeneous
white solid upon standing at room temperature. Yield: 1.75 g (81%).
The white solid melted from 67 °C to 69 °C and the crystalline sample
obtained by the recrystallisation of the solid from n-hexane exhibited
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