Alternative route for the synthesis of 6-methoxy-5-methyl-α-tetralone and 6-methoxy-2,5-dimethyl-α-tetralone

Article abstract of DOI:10.1080/00397910701572431

The ketoesters 3 and 4, obtained by the condensation of 2-cyclohexanone carboxylate and 1-chloro-3-pentanone, were heated with 2,3-dichloro-5,6- dicyanobenzoquinone (DDQ) to yield the dienones 5 and 6, which on hydrolysis with potassium t-butoxide and dimethyl sulfoxide afforded tetralin 8. These were converted to tetralone 10 by methylation and oxidation respectively. Further methylation of 10 yielded tetralone 11. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701572431

This article was downloaded by: [University of Louisville]
On: 21 December 2014, At: 14:02
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Alternative Route for the Synthesis of
6‐Methoxy‐5‐methyl‐α‐tetralone and
6‐Methoxy‐2,5‐dimethyl‐α‐tetralone
Ajoy K. Banerjee a , Johan J. Pineda a , Henry D. Mora a & Manuel S. Laya a
a Department of Chemistry , Venezuelan Institute of Scientific Investigations
(IVIC) , Caracas, Venezuela
Published online: 19 Nov 2007.
To cite this article: Ajoy K. Banerjee , Johan J. Pineda , Henry D. Mora & Manuel S. Laya (2007) Alternative
Route for the Synthesis of 6‐Methoxy‐5‐methyl‐α‐tetralone and 6‐Methoxy‐2,5‐dimethyl‐α‐tetralone,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
37:22, 3917-3922, DOI: 10.1080/00397910701572431
To link to this article: http://dx.doi.org/10.1080/00397910701572431
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 37: 3917–3922, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701572431
Alternative Route for the Synthesis
of 6-Methoxy-5-methyl-a-tetralone
and 6-Methoxy-2,5-dimethyl-a-tetralone
Ajoy K. Banerjee, Johan J. Pineda, Henry D. Mora, and
Manuel S. Laya
Department of Chemistry, Venezuelan Institute of Scientific
Investigations (IVIC), Caracas, Venezuela
Abstract: The ketoesters 3 and 4, obtained by the condensation of 2-cyclohexanone
carboxylate and 1-chloro-3-pentanone, were heated with 2,3-dichloro-5,6-dicyanoben-
zoquinone (DDQ) to yield the dienones 5 and 6, which on hydrolysis with potassium
t-butoxide and dimethyl sulfoxide afforded tetralin 8. These were converted to
tetralone 10 by methylation and oxidation respectively. Further methylation of 10
yielded tetralone 11.
Keywords: annelation, aromatization, dehydrogenation, hydrolysis, tetralone
INTRODUCTION
Martin and Robinson[1] reported the synthesis of tetralin 8 and its conversion
into tetralone 10 for the construction of the fundamental skeleton of steroid–
hormone analogs. On methylation[2] this yielded the dimethyl-a-tetralone 11
which proved to be useful as an intermediate for the synthesis[3] of cloven-3-
one and epiclovane-3-one. The published synthesis[1] of tetralin 8 consists of
reductive cleavage of methylene dinaphthol, followed by catalytic hydrogen-
ation with Raney-nickel at l008C/100 atm. We believe that this method
requires modification, because the hydrogenation with Raneynickel at high
Received in the USA April 9, 2007
Address correspondence to Ajoy K. Banerjee, Centro de Quımica, Venezuelan
´
Institute of Scientific Investigations (IVIC), Caracas, Venezuela. E-mail: abanerje@
ivic.ve
3917

3918
A. K. Banerjee et al.
Scheme 1. Reagents: (i) ClCH2CH2COCH2CH3,C6H6, PTS; (ii) DDO, dioxane; (iii)
C4H9OK, DMSO; (iv) Me2SO4, K2CO3, Me2CO; (v) CrO3, MeCOOH; (vi) MeI, NaH,
Et3B, THE.
temperature may be hazardous, and if the alkalinity of the reaction mixture is
not controlled,[4] alcohol instead of phenol is obtained in major yield.
Therefore we devised a practical method for the synthesis of the tetralin 8
and its conversion into tetralones 10 and 11. The synthetic route is described in
Scheme 1.
RESULTS AND DISCUSSION
The condensation of the commercially available ethyl 2-cyclohexanonecar-
boxylate 1 (mixed with methyl 2-cyclohexane carboxylate 2) (60:40) with
l-chloro-3-pentanone under Dean–Stark conditions in benzene in the
presence of a catalytic amount of p-toluene-sulfonic acid yielded a mixture
of a,b-unsaturated ketoesters 3 and 4 in 72% as oil. The spectral data (IR
1
and MS) gave strong support in favor of the structures of 3 and 4. Its H
and 13C NMR were difficult to interpret because of the mixture of two
esters. However, no attempt was made to separate the ketoesters 3 and 4
and determine their percentage in the reaction mixture as the completion of
the synthesis did not require their separations. This mixture of ketoesters 3
and 4 was heated with 2,3-dichloro-5,6-dicyano benzoquinone (DDQ) in
dioxane[5] to obtain the dienones 5 and 6 in 66% yield. The dienone
mixtures were subjected to hydrolysis[6] with potassium t-butoxide in
dimethylsulfoxide, and we expect to obtain the acid 7. The spectroscopic
data of the resulting product indicated the formation of tetralin 8 instead. Its
IR spectrum exhibited a hydroxyl band at 3423 cm21 and molecular ion
peak at 162 (Mþ) in the mass spectrum. The signals at d 6.56 (d, J ¼ 8 Hz,
1H) and 6.79 (d, J ¼ 8 Hz, lH) (two aromatic protons) as well as 2.6l
(t, J ¼ 6 Hz, 2H) and 2.69 (t, J ¼ 6 Hz, 2H) (benzylic protons at C-1 and
C-4) 4.57 (s, 1H, OH) nicely supported the structure of tetralin 8. Its
melting point was identical with that reported.[1] On methylation with

Synthesis of 6-Methoxy-5-methyl-a-tetralone
3919
dimethylsufate, this produced compound 9 which was oxidized[7] with
chromic acid in acetic acid to yield tetralone 10 in 76% yield. Its metting
point was identical with that reported.[1] Its spectral data agreed with the
assigned structure.
Tetralone 10 was methylated[8] with methyl iodide in the presence of
sodium hydride and triethylborane in tetrahydrofuran to obtain the dimethyl-
tetralone 11 in 71% yield. This one-step methylation procedure has this
advantage over the published procedure,[2] which require three steps.
In conclusion, we have developed a simple and efficient synthesis of
6-methoxy-5-methyl-a-tetralone and 6-methoxy-2,5-dimethyl-a-tetralone.
The experimental procedures are simple, and the yields are very satisfactory.
EXPERIMENTAL
1
Unless otherwise stated, IR spectra were taken on Nicolet FT instrument. H
NMR and 13C spectra were recorded on Brucker AM 300- Hz instrument in
CDCl3. Mass spectra were run on gas chromatograph Hewlett Packard 5890
Quadrupolar 5972 series S. Melting points were recorded on an electrothermal
melting-point apparatus. The expression workup indicates that the solution
was diluted with water, extracted with ether, washed with brine, dried
(MgSO4), and evaporated under reduced pressure. Column chromatography
was performed on silica gel (Merck grade 60, 70–230 mesh). The spectral
and analytical data of all new compounds have been reported in the Exper-
imental section. Microanalyses were carried out at the Chemistry Department,
IVIC, Caracas, Venezuela.
10-Carboethoxy-4-methyl-3-oxo-octahydronaphthalene
3 and 10-Carbomethoxy-4-methyl-3-oxo-octahydronaphthalene 4
A mixture containing cyclohexanone carboxylate 1 and 2 (4.35 g), 1-chloro-3-
pentanone (11.21 g, 93.05 mmol), and p-toluenesulfonic acid (351 mg,
1.89 mmol) in toluene (100 mL) was refluxed for 30 h under a Dean–Stark
trap. The reaction mixture was cooled, washed with 10% aqueous sodium
bicarbonate solution followed by brine, dried, evaporated, and purified on
silica gel (hexane–diethyl ether 8:2) to obtain ketoesters 3 and 4 (4.52 g);
m/z 236 (Mþ), l62 (Mþ-EtCOOH), 222 (Mþ), l62 (Mþ-MeCOOH); nmax
1727(CO), 1667 cm21(CO).
10-Carboethoxy-4-methyl-3-oxo-hexahydrophenanthrene 5 and 10-
Carboethoxy-4-methyl-3-oxo-hexahydrophenanthrene 6
To a solution of ketoesters 3 and 4 (481 mg) in freshly distilled dry dioxane
(100 mL), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (2.3l g, 10.16 mmol)

3920
A. K. Banerjee et al.
was added. The resulting solution was refluxed under N2 for 72 h. The reaction
mixture was cooled, filtered, concentrated, and purified on silica gel (hexane–
ether 85:15) to yield dienones 5 and 6 (357 mg); m/z 234 (Mþ), l60 (Mþ-
EtCOOH), 220 (Mþ), l60 (M þ-EtCOOH); nmax l73l, l660 cm21 (CO).
6-Hydroxy-5-methyltetralin 8
To a solution of dienones 5 and 6 (181 mg) in dry dimethylsulfoxide (35 ml),
freshly prepared potassium t-butoxide (3.7l g, 33 mmol) was added and heated
in an oil bath (908C) for 40 min. The resulting dark solution was diluted with
water and extracted with ether. The ethereal extract was dried, evaporated, and
purified on silica gel (hexane–diethylether 14:1) to give tetralin 8 (115 mg,
92%); mp 113–1148C (from hexane) (lit.[1] 113.5–114.58C); m/z 162
1
(Mþ); nmax 3229 cm21. (OH): H NMR: d 1.75–1.85 (m, 4H, C-2 and C-3),
2.11 (s, 3H, Me, C-5), 2.61 (t, 2H, J ¼ 6 Hz), 2.69 (t, 2H, J ¼ 7 Hz) (C-1
and C-4), 4.57 (s, OH, C-5), 6.56 (d, lH, J ¼ 8 Hz), 6.79 (d, 1H, J ¼ 8 Hz)
(C-7 and C-8); 13C: d 29.9 (C-1), 23.3 (C-2), 22.8 (C-3), 27.1 (C-4), 121.8
(C-5), 151.1 (C-6), 112.3 (C-7), 126.9 (C-8), 129.5 (C-9), 136.7 (C-10),
10.9 (C-11). Found: C, 81.66; H, 8.88. C11H14O requires C, 81.44%; H,
8.70%.
6-Methoxy-5-methyltetralene 9
To a solution of tetralin 8 (301 mg, 1.85 mmol) in dry acetone (10 mL),
dimethyl sulphate (3.13 mL, 32.98 mmol) and potassium carbonate (301 mg,
3.15 mmol) were added and heated under reflux for 5 h. The solution was con-
centrated, diluted with water, and extracted with ether. The extracts were
washed, dried, evaporated, and purified on silica gel (hexane) to obtain
6-methoxy-5-methyltetralene 9 (172 mg; 88%), mp 48–508C (from hexane);
m/z 176 (Mþ); 1H d 1.81–1.86 (m, 4H, C-2 and C-3), 2.14 (s, 3H, Me, C-5),
2.68 (t, 2H, J ¼ 6 Hz), 2.76 (t, 2H, J ¼ 6 Hz), (C-1 and C-4), 3.84 (s, 3H,
C-6), 6.7l (d, 1H, J ¼ 8 Hz), 6.93 (d, 1H, J ¼ 8 Hz) (C-7 and C-8); 13C: d
29.2 (C-1), 23.1 (C-2), 22.6 (C-3), 26.8 (C-4), 124.3 (C-5), 155.1 (C-6),
107.8 (C-7), 126.3 (C-8), 129.1 (C-9), 136.3 (C-10), 10.6 (C-11), 55.4 (C-12).
Found: C, 82.06; H, 9.33. C12H16O requires C, 81.77%; H, 9.15%.
6-Methoxy-5-methyl-a-tetralone 10
To a stirred solution of methoxymethyltetralin 9 (950 mg, 0.54 mmol) in
acetic acid (1.4 mL, 24.5 mmol), a solution (2.24 mL) of 10% aqueous
chromic–acetic acid solution was added dropwise over a period of 30 min.
The reaction temperature was maintained at l5–208C, and the reaction was

Synthesis of 6-Methoxy-5-methyl-a-tetralone
3921
allowed to proceed to completion (2 h) as evidenced by thin-layer
chromatography (TLC). The reaction mixture was diluted with water,
extracted with ether, washed with saturated aqueous solution of sodium
bicarbonate, dried, and purified (hexane–diethyl ether 19:1) to yield methox-
ymethyltetralin 10 (779 mg; 76%), mp 112–112.58C (from hexane) (lit.[1]
1
112–1138C); m/z 190 (Mþ); nmax 1678 cm21 (CO); H: d 2.13 (m, 2H,
C-3), 2.16 (s, 3H, Me, C-5), 2.61 (t, 2H, J ¼ 7 Hz), 2.88 (t, 2H, J ¼ 7 Hz),
(C-2 and C-4), 3.91 (s, 3H, OMe), 6.85 (d, 1H, J ¼ 9 Hz), 8.0l (d, 1H,
J ¼ 9 Hz) (aromatic protons); 13C d 197.9 (C-1), 38.4 (C-2), 22.7 (C-3),
26.9 (C-4), 123.6 (C-5), 161.3(C-6), 108.2 (C-7), 126.2 (C-8), 127.1 (C-9),
144.2 (C-10), 11.2 (C-11), and 55.5 (C-12). Found: C, 75.95; H, 7.54.
C12H14O2 requires C, 75.76%; H, 7.42%.
6-Methoxy-2,5-dimethyl-a-tetralone 11
To a suspension of sodium hydride (52 mg) in tetrahydrofuran (3 mL) triethyl-
borane (0.034 mL, 0.31 mmol) was added and stirred for 3 min. Tetralone 10
(43 mg, 0.24 mmol) dissolved in dry tetrahydrofuran (3 mL) was then added.
The resulting solution was stirred for 1 h at room temperature, methyl iodide
(0.017 mL, 0.27 mmol) was added, and it was stirred for 30 min at room temp-
erature. To the resulting dark brown solution, hydrochloric acid (4 mL, 10%)
was slowly added, and the mixture was extracted with ether. The combined
extracts were washed, dried, and purified (hexane) to give the dimethyl
tetralone 11 (32.6 mg; 71%), mp 112–1138C (from hexane) (lit.[2] mp 111–
1
1138C); m/z 204 (Mþ); nmax l660 cm21 (CO) H: d 1.23 (d, 3H, J ¼ 7 Hz)
(C-2), 2.01 (m, 1H) (C-3), 2.13 (s, 3H) (C-5), 2.51 (m, 1H) (C-2), 2.79-2.99
(m, 2H) (C-4), 3.81 (s, 3H) (C-6), 6.81 (d, 1H, J ¼ 9 Hz), 7.96 (d, 1H,
J ¼ 9 Hz) (C-7 and C-8); 13C: d 200.2 (C-1), 41.5 (C-2), 30.7 (C-3), 26.2
(C-4), 123.5 (C-5), 161.1 (C-6), 108.3 (C-7), 125.9 (C-8), 127.1 (C-9),
143.8 (C-10), 11.1 (C-11), 55.5 (C-12) and 15.3 (C-13). Found: C, 76.66;
H, 8.08. C13H16O2 requires C, 76.44%; H, 7.90%.
REFERENCES
1. Martin, R. H.; Robinson, R. Experiments on the synthesis of substances related to
the sterols, part XLI: Androstenedione. J. Chem. Soc. 1943, 491.
2. Robinson, M. J. T. Synthesis of 1:2:3:4:9:10:11:12-octahydro-7-methoxy-2,8,11-
trimethyl-3-oxophenanthrene. Tetrahedron 1957, 1, 49.
3. Paul, T.; Mukerjee, D. Stereocontrolled total synthesis of (+)-clovan-3-one and
(+)-epiclovan-3-one and a facile total synthesis of (+)-pseudocloven-A. Tetrahe-
dron Lett. 2003, 44, 4985.
4. Adkins, H.; Krsek, G. Comparison of nickel catalyst in the hydrogenation of
naphthol. J. Am. Chem. Soc. 1948, 70, 412.

3922
A. K. Banerjee et al.
5. Banerjee, A. K.; Hurtado, H. Acid catalysed novel rearrangement of bicyclic
dienone, Tetrahedron 1985, 41, 3029.
6. Chang, F. C.; Wood, N. F. Reactions of potassium tert-butoxide in dimethyl
sulfoxide: Hydrolysis of hindered carbocyclic esters. Tetrahedron Lett. 1964, 2969.
7. Burham, J. W.; Duncan, W. P.; Eisenbraun, E. J.; Keen, G. W.; Hamming, M. C.
Effects of alkyl substituents in the chromic acid oxidation, of tetralins. J. Org.
Chem 1974, 39, 1417.
8. Negishi, E.; Idacavage, M. J. A highly selective for a-alkylation of ketones via
potassium enoxytrialkylborates. Tetrahedron. Lett. 1979, 845.