A practical synthesis of 7,8-dimethoxy-2-tetralone

Full text of DOI:10.1080/00304948.2011.594008

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Organic Preparations and Procedures
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A Practical Synthesis of 7,8-
Dimethoxy-2-tetralone
Elvia V. Cabrera a , Jennifer L. Sanchez b & Ajoy K. Banerjee b
a Department of Chemistry , Faculty of Sciences, University of
Zulia , Maracaibo, Venezuela
b Chemistry Center , Venezuelan Institute of Scientific Research
(IVIC) , Caracas, Venezuela
Published online: 02 Aug 2011.
To cite this article: Elvia V. Cabrera , Jennifer L. Sanchez & Ajoy K. Banerjee (2011) A Practical
Synthesis of 7,8-Dimethoxy-2-tetralone, Organic Preparations and Procedures International: The New
Journal for Organic Synthesis, 43:4, 364-367, DOI: 10.1080/00304948.2011.594008
To link to this article: http://dx.doi.org/10.1080/00304948.2011.594008
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Organic Preparations and Procedures International, 43:364–367, 2011
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2011.594008
OPPI BRIEFS
A Practical Synthesis of 7,8-Dimethoxy-2-tetralone
Elvia V. Cabrera,1 Jennifer L. Sanchez,2 and Ajoy K. Banerjee2
1Department of Chemistry, Faculty of Sciences, University of Zulia,
Maracaibo, Venezuela
2Chemistry Center, Venezuelan Institute of Scientific Research (IVIC),
Caracas, Venezuela
Muchinterest has beenshownrecentlyin2-tetralones bearinghydroxy, methyl and methoxy
substituents in the aromatic ring because of their high reactivity and importance as raw ma-
terials for the synthesis of natural products.1,2 Among the methoxy-substituted compounds,
7,8-dimethoxy-2-tetralone (5) has drawn the attention of organic chemists for a long time
due to its importance as an intermediate in the synthesis of analgesics, morphines3 and
steroids.4 Recently tetralone 5 has been synthesized by Gorka at al.5 in ten steps with an
overall yield of 18%. In addition, tetralone 5 had also been prepared by other authors.6,7 but
most of the published syntheses report low yields of tetralone 5 and use starting materials
that are not easily accessible. In connection with our studies on substituted tetralones,8,9
we devised a concise route for the synthesis of tetralone 5 (Scheme 1).
Br
O
OMe
O
O
8
MeO
MeO
MeO
(i)
(ii)
3
1
2
OMe
OMe
8
MeO
O
MeO
7
(iii)
(iv), (v)
4
5
Reagents: (i) NBS, CH3CN, rt; (ii) NaOMe, CuBr, DMF-H 2O, reflux; (iii) 2,4-pentanediol,
p-TsOH, reflux; (iv) MCPBA, CH2Cl 2, 0ºC; (v) H2SO4 (10%), EtOH
Scheme 1
Submitted April 7, 2011.
Address correspondence to Ajoy K. Banerjee, Centro de Qu´ımica, IVIC, Apartado-21827
Caracas-1020 A, Venezuela. E-mail: abanerje@ivic.gob.ve or aabanerje@gmail.com
364

Practical Synthesis of 7,8-Dimethoxy-2-tetralone
365
The commercially available 7-methoxy-1-tetralone (1) was brominated with N-bromo-
succinimide (NBS) in acetonitrile to yield the known10 bromotetralone 2, as a colorless
solid in 96% yield. Though the bromination of tetralone 1 was carried out according to a
literature procedure, the yield (96%) obtained by us was superior to that reported (70%).10
A higher yield (92%) of bromotetralone 2 was also reported by Tsotinis at al.11 who
carried out the bromination of tetralone 1 by the published method.10 Bromotetralone 2 was
subjected to methoxylation12 by heating at 110◦C with a mixture of excess cupric bromide,
a solution of sodium methoxide (25%) in methanol and dimethylformamide:water (95:5)
to give tetralone 3 in 72% yield. The use of a low concentration of sodium methoxide in
methanol and dimethylformamide with water was essential for the methoxylation of the
tetralone 2. The use of a more concentrated solution of sodium methoxide in methanol and
dimethylformamide13 led to the formation of many uncharacterized secondary products
and only 8% of the tetralone 3. The conversion of the tetralone 3 into the olefin 4 in 98%
yield was accomplished14 by heating under reflux with 2,4-pentanediol and a catalytic
amount of p-toluenesulfonic acid (p-TsOH). Epoxidation of the olefin was performed with
m-chloroperoxybenzoic acid (MCPBA) and without purification, the resulting epoxide was
heated under reflux with ethanolic sulfuric acid (10%) to afford tetralone 5 in 53% yield
(overall yield 36% from 1 to 5), mp.74–76◦C. The spectral data agreed with the published
data.5
In conclusion, a concise approach to 7,8-dimethoxy 2-tetralone (5) has been developed
in a very high overall yield (36%). To the best of our knowledge this is the first report of
the synthesis of tetralone 5 with a high overall yield. The starting material is commercially
available. Most of the intermediates were sufficiently stable to permit isolation. The present
method can be utilized in the synthesis of tetralone 5 in gram quantities for the synthesis
of bioactive compounds.
Experimental Section
Unless otherwise stated all melting points are uncorrected and were determined on an
Electrothermal melting point apparatus. Infrared (IR) spectra were recorded on a Nicolet-
Fourier Transform (FT) Instrument and NMR (1H and 13C) spectra were determined on a
Bruker AM-300 spectrometer in CDCl3. Chemical shifts (δ) are expressed in ppm. Mass
spectra (MS) were determined on a Dupont 21-492B. Column chromatography was carried
out on silica gel 60 (Merck). Thin layer chromatography (TLC) plates were coated with
silica gel and the spots were visualized using ultraviolet light. Elemental analyses were
performed on a Carlo-Erba 1108 elemental analyser.
7,8-Dimethoxy-1-tetralone (3)
A solution of the bromotetralone 2 (500 mg, 2.47 mmol) in 8 mL DMF:H2O (95:5) was
heated at 80◦C for 30 min. To this was added a solution of 25% NaOMe (720 mg of
Na in 7.8 mL MeOH) in four portions. The temperature of the resulting solution was
raised to 110◦C, the catalyst CuBr (56 mg, 0.392 mmol) was added and then the reac-
tion mixture was heated under reflux for 3 h. The progress of the reaction was moni-
tored by TLC (7:3 hexane:ether, Rf 0.17). The reaction was cooled, filtered, diluted with

366
Cabrera, Sanchez, and Banerjee
water and extracted with CHCl3. The organic extract was washed with a diluted solution
of hydrochloric acid (5%), brine, dried and evaporated in vacuo to afford an oil which
was chromatographed (8:2 hexane:ether) to give tetralone 3 (291 mg, 72%) as a pale
1
brown oil; IR (cm−1): 1680 (CO); MS (m/z): 207 (M+1); H NMR: δ 6.97 (d, 1H, J =
8.3 Hz) (H at C-5), 6.87 (d, 1H, J = 8.3 Hz) (H at C-6), 3.79 (s, 3H, OMe), 3.76 (s, 3H,
OMe), 2.78 (t, 2H, J = 6.1 Hz) (2H at C-2), 2.41 (t, 2H, J = 6.5 Hz) (2H at C-4), 1.98–1.93
(m, 2H at C-3); 13C NMR: δ 197.54 (C-1), 151.93 (C-7), 149.62 (C-8), 137.39 (C-10),
126.99 (C-9), 123.79 (C-5), 117.24 (C-6), 61.04 (C-12), 56.23 (C-11), 40.73 (C-2), 29.79
(C-3), 23.08 (C4).
Anal. Calcd. for C12H14O3: C, 69.88; H, 6.84. Found: C, 70.09; H, 6.98
1,2-Dimethoxy-ꢀ7,8-dihydronaphthalene (4)
To a solution of the tetralone 3 (1.00 g, 4.85 mmol) in toluene (97 mL) was added a catalytic
amount of p-toluenesulfonic acid (34 mg, 0.18 mmol) and 2,4-pentanediol (2.2 mL, 20.29
mmol) and the mixture was heated under reflux for 24 h using a Dean-Stark apparatus. The
reaction mixture was cooled, quenched with an aqueous solution of NaHCO3 (5%) and
extracted with ether. The organic extract was washed with brine, dried and evaporated in
vacuo. The resulting brown oil was chromatographed (hexane) to afford compound 4 (903
mg, 98%) as a faint yellow oil; IR (cm−1): 2934, 2831 and 1572; MS (m/z): 190 (M+); 1H
NMR: δ 6.84 (t, 1H, J = 1.6 Hz) (H at C-8), 6.81 (d, 1H, J = 8 Hz) (H at C-4), 6.70 (d, 1H,
J = 8 Hz) (H at C-3), 6.11 (dt, J = 4.4 Hz and J = 9 Hz) (H at C-7), 3.83 (s, 3H, OMe),
3.81 (s, 3H, OMe), 2.73 (t, J = 8 Hz) (H at C-5), 2.31–2.25 (m, 2H) (2H at C-6); 13C NMR:
δ 152.08 (C-1), 144.63 (C-2), 129.18 (C-3), 128.73 (C-9), 127.77 (C-10), 122.65 (C-1),
121.87 (C-7), 110.31 (C-4), 61.04 (C-11), 55.68 (C-12), 27.01 (C-5), 23.28 (C-6).
Anal. Calcd. for C12H14O2: C, 75.76; H, 7.42. Found: C, 75.99; H, 7.61.
7,8-Dimethoxy-2-tetralone (5)
To a suspension of MCPBA (1.5 g, 7.85 mmol) in dichloromethane (16 mL), cooled at 0◦C,
was added a solution of the compound 4 (653 mg, 3.44 mmol) in dichloromethane (5 mL)
and the mixture was stirred for 16 h at room temperature. To the reaction mixture was then
added a solution of sodium bicarbonate (10 mL, 5%) and the resulting solution was stirred
for 2 h at room temperature. The organic layer was separated, washed with water, dried
and evaporated to afford a solid (670 mg) which was dissolved in ethanolic sulfuric acid (5
mL, 10%) and heated under reflux for 3 h. The reaction was cooled, diluted with water and
extracted with chloroform. The organic extract was washed with brine, dried and evaporated
in vacuo to afford a solid which on chromatographic purification (1:1 hexane:ether) yielded
the tetralone 2 (374 mg, 53%) as a crystalline solid, mp. 73–75◦C (petroleum ether) (lit.5
1
73–74◦C). IR (cm−1): 1713 (CO); MS (m/z): 206 (M+); H NMR: δ 6.86 (d, 1H, J = 9
Hz), 6.75 (d, 2H, J = 9 Hz) (H at C-5 and C-6), 3.81 (s, 3H, OCH3), 3.75 (s, 3H, OCH3),
3.54 (s, 2H) (H at C-1), 2.97 (t, 2H, J = 7 Hz) (H at C-4), 2.50 (t, 2H, J = 7 Hz) (H at
C-3); 13C NMR: 210.43 (C-2), 151.20 (C-7), 146.22 (C-8), 129.79 (C-11), 126.45 (C-12),
123.47 (C-6), 60.37 (C-10), 55.83 (C-9), 38.69 (C-1), 38.50 (C-3), 28.63 (C-4).
Anal. Calcd. for C12 H14O3: C, 69.88; H, 6.84. Found: C, 70.01; H, 6.92

Practical Synthesis of 7,8-Dimethoxy-2-tetralone
367
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