Facile synthesis of 5,6-dimethoxy-1-tetralone

Article abstract of DOI:10.1021/op970111r

A facile synthesis of 5,6-dimethoxy-1-tetralone, a key intermediate in the synthesis of an antidepressant compound, ABT-200, was developed from the inexpensive starting material guaiacol.

Full text of DOI:10.1021/op970111r

Organic Process Research & Development 1999, 3, 71−72
Facile Synthesis of 5,6-Dimethoxy-1-tetralone†
Saswata Lahiri, C. Ramarao, B. Venkateswara Rao, and A. V. Rama Rao*
Indian Institute of Chemical Technology, Hyderabad 500007, India
Mukund S. Chorghade
CP Consulting, 241 Walnut Street, Wellesley, Massachusetts 02181
Scheme 1a
Abstract:
A facile synthesis of 5,6-dimethoxy-1-tetralone, a key intermedi-
ate in the synthesis of an antidepressant compound, ABT-200,
was developed from the inexpensive starting material guaiacol.
5,6-Dimethoxy tetralone (1) is a key intermediate in the
synthesis of some novel antidepressants which are R-2-
antagonists and norepinephrine uptake inhibitors e.g., ABT-
200 (2).1 It can also be a synthon for certain 2-substituted
a Conditions: (a) allyl bromide, K2CO3, acetone, reflux; (b) N,N-dimethyl-
aniline, 200 °C; (c) DMS, K2CO3, acetone, reflux; (d) NaIO4, NaHCO3, OsO4,
CH3OH (aq); (e) Ph3PdCHCOOEt; (f) Pd-C/H2; (g) (i) H2SO4 (85%), 85-90
°C, (ii) DMS, K2CO3.
octabenzo(f)quinolines2 which are dopamine agonists. An
efficient, high-yielding route for the tetralone 1 will be of
potential utility in large-scale synthesis of these bioactive
compounds for the complete preclinical and clinical evalu-
ation. Various approaches2,3 have been used in the literature
for the synthesis of 1; these involve long reaction sequences
or expensive starting materials, such as 2,3-dimethoxy
benzaldehyde.2 Herein we present an efficient and high-
yielding route for the synthesis of 1 starting from guaiacol,
an inexpensive and readily available material.
Compound 1 was prepared as follows. Treatment of
guaiacol with allyl bromide and K2CO3 in acetone under
reflux gave O-allyl guaiacol (3, Scheme 1). Compound 3
was subjected to Claisen rearrangement by heating at 195-
200 °C in N,N-dimethylaniline. N,N-Dimethylaniline was
distilled out, and the crude compound 4 was carried to the
next step without further purification. To obviate the hazard-
ous condition (heating to high temperature) involved in the
above reaction, the compound 3 was subjected to clay-
mediated Claisen rearrangement.4 Compound 3 was refluxed
in dry benzene in the presence of montmorillonite K-10 for
4 h to get the desired compound 4 (81%). The crude Claisen
rearrangement product was methylated by treating it with
dimethylsulphate/K2CO3 and then distilled to get the pure
compound 5 (60%). Oxidative cleavage of the double bond
with OsO4 (catalytic) and sodium metaperiodate in aqueous
methanol furnished the aldehyde 6, which on immediate
treatment with carbethoxymethylene triphenylphosphorane
gave the Wittig product 7 (combined yield is 50% for the
last two steps). Hydrogenation of the compound 7 with Pd-C
yielded 2,3-dimethoxyphenyl butyrate 8 (90%). Heating of
8 in 85% H2SO4 at 85-90 °C for 15 min provided compound
1 (75%) as white crystals. In conclusion, the above method
helps in making the compound 1 in good overall yield and
The key feature of the synthesis is the efficient preparation
of 3-(2,3-dimethoxyphenyl) propionic ester (five steps),
which can be converted to tetralone in one step with good
yields.3h
† IICT Communication No. 3831.
(1) Zelle, R. E.; Hancock, A. A.; Buckner, S. A.; Basha, F. Z.; Tietje, K.;
Debenardis, J. F; Meyer, M. D. Bioorg. Med. Chem. Lett. 1994, 4 (11),
1319.
(2) Craig, J. C.; Torkelson, S. M.; Findell, P. R.; Weiner, R. I. J. Med. Chem.
1989, 32, 961.
(3) (a) Thibonnet, J.; Abarbri, M.; Parrain, J. L.; Duche`ne, A. Tetrahedron
Lett. 1996, 37 (42), 7507. (b) Klix, R. C.; Cain, M. H.; Bhatia, A. V.
Tetrahedron Lett. 1995, 36 (36), 6413. (c) Date, M.; Watanabe, M.;
Furukawa, S. Chem. Pharm. Bull. 1990, 38 (4), 902. (d) Rigby, J. H.; Kotnis,
A.; Kramer, J. J. Org. Chem. 1990, 55, 5078. (e) Beetz, T.; Meuleman, D.
G.; Wieringa, J. H. J. Med. Chem. 1982, 25, 714. (f) Oka, Y.; Motohashi,
M.; Sugihara, H.; Miyashita, O.; Itoh, K.; Nishikawa, M.; Yurugi, S. Chem.
Pharm. Bull. 1977, 25, 632. (g) Koo, J.; Fish, M. S.; Walker, G. N.; Blake,
J. Organic Syntheses; Wiley: New York, 1963; Collect Vol. IV, p 327.
(h) Elmore, N. F.; King, T. J. J. Chem. Soc. 1961, 4425. (i) Braude, E. A.;
Linstead, R. P.; Mitchell, P. W. D. J. Chem. Soc. 1954, 3578. (j) Bachman,
W. E.; Struve, W. S. Org. React. 1942, 1, 38.
(4) Dauben, W. G.; Cogen, J. M.; Behar, V. Tetrahedron Lett. 1990, 31 (23),
3241.
10.1021/op970111r CCC: $18.00 © 1999 American Chemical Society and Royal Society of Chemistry
Published on Web 12/29/1998
Vol. 3, No. 1, 1999 / Organic Process Research & Development
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in optimal time. This approach also helps in making
5-hydroxy or -alkoxy tetralones from corresponding phenols.
HRMS: calculated for C11H14O2, 178.0993; found,
178.1000.
4-(2,3-Dimethoxyphenyl) Ethyl But-2-enate (7). To a
solution of compound 5 (2 g, 11.23 mmol) in methanol and
water (15 mL + 2 mL) were added sodium metaperiodate
(7.2 g, 33.7 mmol) and sodium bicarbonate (0.94 g, 11.23
mmol), followed by OsO4 (1.45 mL, 0.56 mmol; 10%
solution in toluene). Stirring for 20 min at room temperature
and filtering furnished a mixture which was carried to the
next reaction.
Carbethoxymethylene triphenylphosphorane (6 g, 17.2
mmol) was added to the solution of compound 6, and the
solution was stirred for 2 h. It was concentrated, and the
residue was triturated in a mixture of diisopropyl ether and
hexane (7:3). It was filtered, and the filtrate was concentrated
to get the compound 7, which was carried to the next step
without further purification.
Experimental Section
NMR spectra were recorded on a Varian Gemini (200
MHz) instrument. Tetramethylsilane was used as the internal
standard. IR spectra were recorded on a Shimadzu IR-470
spectrometer. Mass spectra were obtained with a Finnigan
Mat 1020B instrument.
2-Methoxy O-Allyl Benzene (3). To a mixture of guaiacol
(12.5 g, 100.69 mmol) and allyl bromide (12.18 g, 100.69
mmol) in acetone (300 mL) was added potassium carbonate
(41.75 g, 302.07 mmol), was added and the mixture was
refluxed for 4 h. It was filtered and the filtrate concentrated
under reduced pressure. The residue was disolved in dichlo-
romethane and washed with 1 N NaOH, water, and brine,
respectively. The organic portion was dried and concentrated
1
in vacuo to get the compound 3 (15.39 g, 93%). H NMR
(CDCl)3: δ 3.85 (s, 3 H), 4.58 (m, 2 H), 5.24 (m, 1 H), 5.38
(m, 1 H), 6.04 (m, 1 H), 6.84 (m, 4 H).
HRMS: calculated for C10H12O2, 164.0837; found,
164.0845.
2,3-Dimethoxyphenyl Butyrate (8). Compound 7 (1.1
g, 4.4 mmol) was taken in methanol, Pd-C (10 mg) was
added, and the mixture was stirred under H2 atmosphere
(balloon) for 10 h. It was filtered and concentrated to yield
1
the compound 8 (1 g, 90%) as an oil. H NMR (CDCl)3: δ
2-Hydroxy-3-methoxy Allyl Benzene (4). Compound 4
(13.15 g, 80.18 mmol) was taken in N,N-dimethylaniline (50
mL) and heated under N2 at 195-200 °C for 6 h. N,N-
Dimethylaniline was distilled out, and the residue was
dissolved in ethyl acetate. The organic portion was washed
with dilute HCl (2 N) and water, dried, and concentrated to
get compound 4, which was carried to the next step without
further purification.
Clay-Mediated Claisen Rearrangement. A mixture of
3 (1 g, 6.09 mmol) and montmorillonite K-10 (1.8 g,
unactivated) in dry benzene was refluxed for 5 h. The
reaction mixture was filtered and concentrated. The residue
was column chromatographed to get the compound 4 (0.81
g, 81%). IR (neat): 3500, 1480 cm-1. 1H NMR (CDCl)3: δ
3.41 (d, 2 H, J ) 7.8 Hz), 3.88 (s, 3 H), 5.0-5.15 (m, 2 H),
5.64 (s, 1 H), 6.0 (m, 1 H), 6.75 (m, 3 H).
1.26 (t, 3 H, J ) 7 Hz), 1.92 (m, 2 H), 2.32 (t, 2 H, J ) 7.5
Hz), 2.65 (t, 2 H, J ) 7.0 Hz), 3.8 (s, 3 H), 3.86 (s, 3 H),
4.12 (q, 2 H), 6.75 (m, 2 H), 6.95 (dd, 1 H, J ) 7.5 Hz).
HRMS: calculated for C14H20O4, 252.1361; found,
252.1374.
5,6-Dimethoxy Tetralone (1). Compound 8 (1 g, 3.96
mmol) was heated at 85-90 °C for 15 min with sulphuric
acid (85%). The resulting dark red solution was poured on
ice, and the precipitate was collected. It was dissolved in
acetone and refluxed for 2 h with dimethylsulphate (0.5 g,
3.96 mmol) and potassium carbonate (1.63 g, 11.88 mmol).
The reaction mixture was filtered and concentrated. The
residue was crystallised to get compound 1 (0.612 g, 75%)
1
as white crystals. IR (KBr): 1670, 1600 cm-1. H NMR
(CDCl)3: δ 2.0 (m, 2 Η), 2.5 (t, 2 H, J ) 7.5 Hz), 2.85 (t,
2 H, J ) 6 Hz), 3.7 (s, 3 H), 3.82 (s, 3 H), 6.77 (d, 1 H, J
) 8.0 Hz), 7.75 (d, 1 H, J ) 8 Hz). Mp 102 °C (lit.3h mp
104-105 °C).
HRMS: calculated for C12H14O3, 206.0942; found,
206.0947.
HRMS: calculated for C10H12O2, 164.0837; found,
164.0845.
2,3-Dimethoxy Allyl Benzene (5). To a mixture of crude
allyl benzene (10 g, 61 mmol) and dimethylsulphate (8.2 g,
65 mmol) in acetone (200 mL) was added potassium
carbonate (25.2 g, 183 mmol), and the mixture was refluxed
for 2 h. The reaction mixture was filtered and concentrated.
The residue was dissolved in dichloromethane and washed
with NaHCO3 solution, water, and brine, respectively. The
organic portion was concentrated and distilled under vaccum
Acknowledgment
We thank Dr. Richard Pariza of CP Consulting Inc. for
valuable discussions and encouragement. S.L. (SRF) thanks
CSIR for financial support.
1
to get the compound 5 (6.5 g, 60%). H NMR (CDCl)3: δ
3.4 (d, 2 H, J ) 6.0 Hz), 3.8 (s, 3 H), 3.86 (s, 3 H), 4.98-
5.12 (m, 2 H), 5.95 (m, 1 H), 6.78 (m, 2 H), 6.97 (dd, 1 H,
J ) 7 Hz).
Received for review June 9, 1997.
OP970111R
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