An alternative procedure for the synthesis of 1,8-dimethyl-5- methoxytetralin-6-ol

Article abstract of DOI:10.3184/174751913X13663119523020

The commercially available 3-hydroxy-4-methoxy-benzaldehyde 3 was subjected to hydrogenation and protection to give the methoxy methyl ether of 2-methoxy-5-methylphenol. This was converted to 1,8-dimethyl-5-methoxytetralin- 6-ol by alkylation with 5-bromopent-1-ene, cyclisation and deprotection.

Full text of DOI:10.3184/174751913X13663119523020

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 309
MAY, 309–310
An alternative procedure for the synthesis of 1,8-dimethyl-5-methoxy-
tetralin-6-ol
Ajoy K. Banerjee, Po S. Poon* and Liadis Bedoya
Centro de Química, IVIC, Aptdo. 21827, Caracas-1020A, Venezuela
The commercially available 3-hydroxy-4-methoxy-benzaldehyde 3 was subjected to hydrogenation and protection to
give the methoxy methyl ether of 2-methoxy-5-methylphenol. This was converted to 1,8-dimethyl-5-methoxytetralin-
6-ol by alkylation with 5-bromopent-1-ene, cyclisation and deprotection.
Keywords: cacalol, 1,8-dimethyl-5-methoxytetralin-6-ol, n-butylithium, cyclisation
1,8-Dimethyl-5-methoxytetralin-6-ol 2 has proved to be a
potential intermediate1,9 for the synthesis of the sesquiterpene
cacalol 1 which exhibits antihyperglycemic, anti-inflamatory,
antimicrobial, and antioxidant activities.2–4 In 1964, Romo
et al.5,6 isolated cacalol 1, as a solid, from the roots of the
Psacalium decompositum in the northern part of Mexico. To
date, seven synthetic studies of cacalol 1 have been reported
in the literature.1,7–12 The interesting biological activities of
cacalol 1 encouraged us to develop another concise route to the
compound 2.
expensive it had to be prepared in the laboratory. The spectro-
scopic data strongly supported the structure assigned to the
phenol 4. The hydroxyl group of the compound 4 was
protected with the MOM group by treatment with chlorometh-
oxymethane and sodium hydride in dimethylformamide to
give compound 5 in 80% yield. This was ortho-lithiated with
n-BuLi (1.3 equiv.) in tetrahydrofuran and subsequently alkyl-
ated with a slight excess of 5-bromo-1-pentene. The resulting
material was immediately employed in an intramolecular
Friedel–Crafts cyclisation with aluminum chloride at 0 °C to
give the ether 6 in 63% yield. Finally, upon treatment with
hydrochloric acid solution at room temperature, the protecting
group in compound 6 was cleaved to form 1,8-dimethyl-5-
methoxytetralin-6-ol 2 in 75% yield. The spectroscopic data of
2 were identical with those reported.1
Retrosynthetic analysis (Scheme 1) of cacalol revealed that
the aldehyde 3 would be a suitable staring material for the
present investigation. The synthetic route is described in
Scheme 2.
Results and discussions
In summary, a mild and short method for the preparation of
1,8-dimethyl-5-methoxytetralin-6-ol 2 has been developed in
five steps (31% overall yield). The three-step conversion of 2
to cacalol 1 has already been reported9 and thus our alternative
Catalytic hydrogenation (Pd/C 10%) of the commercially
available 3-hydroxy-4-methoxy-benzaldehyde 3 yielded the
phenol 4 in quantitative yield. Since the phenol 4 is very
Scheme 1
Scheme 2
* Correspondent. E-mail: ppoonng@ivic.gob.ve

310 JOURNAL OF CHEMICAL RESEARCH 2013
To a solution of the alkene in dry dichloromethane (5 mL) was
cooled to 0 °C under an atmosphere of nitrogen and sublimed
aluminium chloride (1.42 g, 10.65 mmol) was added. After 15 min,
the mixture was stirred at room temperature for 6 h. The reaction was
quenched with 10% aqueous HCl, and extracted with CH2Cl2. The
organic layer was washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by column
chromatography on silica gel using hexane-diethyl ether (9:1) as an
eluent to give 6 (57.6%, 1.02g). IR (cm−1): 2930, 2868, 1589, 1483. 1H
NMR (300 MHz, CDCl3) δ (ppm): 1.13 (s, 3H), 1.65–1.92 (m, 4H),
2.25 (s, 3H), 2.72–3.02 (m, 3H), 3.51 (s, 3H), 3.78 (s, 3H), 5.18
(s, 2H), 6.81 (s, 1H). 13C δ (ppm): 16.80, 18.75, 20.76, 23.52, 28.94,
29.80, 56.06, 59.86, 95.19, 116.29, 130.67, 131.51, 135.22, 145.49,
147.08. EM m/z: 250 (32, M+), 235 (29, M+-CH3), 220 (15,
M+-CH3OCH2), 207 (100, M+- C2H4O2). Anal. Calcd for C15H22O3: C,
71.97; H, 8.86. Found: C, 71.76; H, 8.79%.
route constitutes a formal total synthesis of cacalol 1. Further
studies concerning its pharmacological evaluation are in
progress in our laboratories.
Experimental
Reagents were obtained from commercial sources and were used
without purification. Solvents were dried by distillation from appro-
priate drying agents immediately prior to use. Flash column chroma-
tography was performed with the indicated solvents on silica gel 60
(0.04–0.063 mm) and TLC plates were coated with silica gel 60 F254
,
layer thickness 0.2 mm and the spots were located by exposing the
plate to UV light. IR spectra were obtained with a Nicolet Fourier
transform (FT) spectrometer, NMR spectra were recorded on a Bruker
300 MHz spectrometer in CDCl3. Mass spectra were recorded on
a Thermo Finnigan TSQ Quantum Ultra AM mass spectrometer.
Microanalyses were carried out in the Chemistry center, IVIC.
2-Methoxy-5-methylphenol (4): A solution of aldehyde 3 (3.28 g,
21.56 mmol) in AcOEt (15 mL) was hydrogenated over 10% Pd/C
(0.16 g) at 100 psi for 24 h. The mixture was filtered and the filtrate
concentrated under vacuum. Flash chromatography on silica gel pro-
vided 4 as a colourless solid (92%, 2.74 g), m.p. 34–36 °C (hexane)
(lit.13, CAS Database reference 1195-09-1, m.p. 37 °C). IR (cm−1):
3464 (OH), 2961, 2863, 1658. 1H NMR δ: 2.25 (s, 3H), 3.84 (s, 3H,
OCH3), 5.56 (s, 1H, OH), 6.62 (dd, 1H, J = 8.15 Hz, J = 1.3 Hz),
6.73 (d, 1H, J = 8.2 Hz), 6.74 (d, 1H, J = 1.5 Hz). 13C NMR δ: 20.76
(ArCH3), 56.04 (OCH3), 110.62, 115.35, 120.24, 131.14, 144.42,
145.34. EM m/z: 139 (M++1), 138 (M+). Anal. Calcd for C8HI0O2: C,
69.54; H, 7.30. Found: C, 69.35; H 7.21%.
1,8-Dimethyl-5-methoxytetralin-6-ol (2): A mixture of the MOM-
protected alcohol 6 (0.87g, 3.48 mmol), methanol (8 mL) and concen-
trated HCl (1 mL) was stirred overnight. The solvent was removed
carefully and the residue was partitioned with ethyl acetate and water.
The organic layer was separated, washed with water and dried over
MgSO4. Removal of solvent followed by flash column chromatogra-
phy on silica gel (1:9 ethyl acetate/hexane) afforded 5-methoxy-
1,8-dimethyltetralin-6-ol 2 (75%, 0.53 g) as a clear colourless oil.
1
IR (cm−1): 3436, 2957, 2932, 1602, 1450. H NMR δ: 1.14 (d, 3H,
J = 6.90 Hz), 1.73–1.82 (m, 4H), 2.23 (s, 3H), 2.51–2.63 (m, 1H),
2.87–3.02 (m, 2H), 3.74 (s, 3H, OCH3), 5.45 (s, 1H, OH), 6.76 (s, 1H).
13C NMR δ:16.90, 18.65, 21.05, 23.58, 28.84, 29.99, 60.12, 115.06,
129.62, 132.52, 133.12, 142.61, 145.74. EM m/z: 206(M+), 191
(M+-OCH3), 159 (M+-CH3-CH3OH). Anal. Calcd for C13HI8O2: C,
75.69; H, 8.80. Found: C, 75.48; H, 8.67%.
1-Methoxy-2-(methoxymethoxy)-4-methylbenzene (5): Phenol 4
(2.56 g, 18.55 mmol) in dry dimethylformamide (15 mL) was cooled
to 0 °C and treated sequentially with pre-washed NaH (60% disper-
sion oil, 37.10 mmol) and chloro(methoxymethane) (3 mL, 37.81 mmol).
After 12 h at room temperature, the reaction mixture was quenched
with NaHCO3 solution, poured into water and extracted with ether.
The organic extracts were washed successively with water and brine,
then dried over MgSO4 and concentrated. Flash chromatography using
hexane as eluent yielded the ether 5 (80%, 2.7 g) as colourless oil.
Received 6 March 2013; accepted 14 March 2013
Paper 1301822 doi: 10.3184/174751913X13663119523020
Published online: 15 May 2013
1
IR (cm−1): 2997, 2836, 1595. H NMR (300 MHz, CDCl3) δ (ppm):
References
2.26 (s, 3H), 3.50 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 5.20 (s, 2H),
6.76 (m, 2H), 6.96 (s, 1H). 13C δ (ppm): 20.61, 55.76, 55.94, 95.29,
111.59, 117.25, 122.46, 130.31, 146.05, 147.43. EM m/z: 182 (100,
M+), 152 (94, M+- CH2O), 137 (31, M+–CH3OCH2). Anal. Calcd for
C10HI4O3: C, 65.91; H, 7.74. Found: C, 65.68; H, 7.69%.
1
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5-Methoxy-6-(methoxymethoxy)-1,8-dimethyl-1,2,3,4-tetrahydro-
naphthalene (6): The methoxymethyl derivative 5 (1.29 g, 7.09 mmol)
dissolved in anhydrous tetrahydrofuran (6 mL) was cooled to –78 °C
and a solution of n-butyl lithium (1.6 M in hexane, 5.30 mL) added
dropwise, under an atmosphere of nitrogen. After 30 min at this
temperature a solution of 5-bromo-1-pentene (8.51 mmol, 1 mL) in
THF (2 mL) was added dropwise, with stirring. The resulting mixture
was warmed to room temperature and stirred 24 h. Water was added
and the organic layer was extracted with ether. The combined ether
extracts were washed with brine, dried over MgSO4 and concentrated.
The crude product filtered through a column of silica gel in hexane-
ether. The oily product obtained was used immediately in the next
step.
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