Convenient synthesis of 7,8-dimethoxytetralin-2-one

Article abstract of DOI:10.1080/00397910500187753

7,8-Dimethoxytetralin-2-one (1), an important intermediate for the synthesis of compounds possessing biological activity, was synthesized by simple reaction steps from commercially available starting materials. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500187753

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Convenient Synthesis of
7,8‐Dimethoxytetralin‐2‐one
Á. Gorka a , B. Czuczai a , P. Szoleczky a , L. Hazai b ,
Cs. Szántay Jr. c , V. Háda c & Cs. Szántay a b
a Department of Organic Chemistry , University of
Technology and Economics , Budapest, Hungary
b Research Group for Alkaloid Chemistry of the
Hungarian Academy of Sciences , Budapest, Hungary
c Spectroscopic Research Division , Gedeon Richter
Ltd. , Budapest, Hungary
Published online: 18 Aug 2006.
To cite this article: Á. Gorka , B. Czuczai , P. Szoleczky , L. Hazai , Cs. Szántay Jr. ,
V. Háda & Cs. Szántay (2005) Convenient Synthesis of 7,8‐Dimethoxytetralin‐2‐one,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:18, 2371-2378
To link to this article: http://dx.doi.org/10.1080/00397910500187753
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Synthetic Communicationsw, 35: 2371–2378, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500187753
Convenient Synthesis of
7,8-Dimethoxytetralin-2-one
´
A. Gorka, B. Czuczai, and P. Szoleczky
Department of Organic Chemistry, University of Technology and
Economics, Budapest, Hungary
L. Hazai
Research Group for Alkaloid Chemistry of the Hungarian Academy of
Sciences, Budapest, Hungary
´
´
Cs. Szantay, Jr. and V. Hada
Spectroscopic Research Division, Gedeon Richter Ltd., Budapest,
Hungary
´
Cs. Szantay
Department of Organic Chemistry, University of Technology and
Economics, Budapest, Hungary and Research Group for Alkaloid
Chemistry of the Hungarian Academy of Sciences, Budapest, Hungary
Abstract: 7,8-Dimethoxytetralin-2-one (1), an important intermediate for the synthesis
of compounds possessing biological activity, was synthesized by simple reaction steps
from commercially available starting materials.
Keywords: Cinnamic esters, deethoxycarbonylation, Dieckmann condensation,
2-tetralones
Received in Poland April 28, 2005
´
Address correspondence to Cs. Szantay, Research Group for Alkaloid Chemistry
´ ´
of the Hungarian Academy of Sciences, H-1111 Budapest, Gellert ter 4, Hungary.
Tel.: þ 36-1-463-1195; E-mail: szantay@mail.bme.hu
2371

´
A. Gorka et al.
2372
INTRODUCTION
2-Tetralones containing hydroxy and/or methoxy substituent(s) in the
aromatic ring are known as important sources of synthetic precursors of a
wide range of compounds, including steroids, heterocycles, and pharmaceuti-
cals.[1] The synthesis of 7,8-dimethoxytetralin-2-one (1) has been described in
the literature,[2] but most of the methods use difficult starting materials and
inconvenient reagents.[3] In many cases poor or uncertain yields were
reported.[4]
In this article we report an efficient methodology to synthesize the title
compound 1 using simple reaction steps and commercially available starting
materials and reagents.
RESULTS AND DISCUSSION
The synthesis starts from 3-methylcatechol (2a), which could be O-methylated
to 2,3-dimethoxytoluene (2b) with dimethyl sulfate.[5,6] Introduction of the
formyl group into the ortho position in relation to the methyl substituent
(2c) could be achieved by using a,a-dichloromethyl methyl ether as formyl-
ating reagent in the presence of tin(IV) chloride.[6] Both intermediates 2b and
2c are described in the literature and their preparation was successful in high
yields: 82.5% and 98%, respectively.
In the next reaction step aldehyde 2c was treated with malonic acid in
refluxing pyridine in the presence of piperidine. In the course of the Knoe-
venagel condensation cinnamic acid derivative 3 was obtained in 92.7%
yield (Scheme 1) that was subsequently esterified with ethanol to yield
ethyl 3,4-dimethoxy-2-methylcinnamate (4) (93%). To build an ester
function into the methyl group, compound 4 was subjected to N-bromosucci-
nimide under the usual reaction conditions with catalytic amount of benzoyl
peroxide in carbon tetrachloride at reflux temperature. The corresponding bro-
momethyl derivative 5 was obtained in 65% yield.
The conversion of the bromo atom of the cinnamic ester 5 into the
cyano group was carried out by sodium cyanide in DMF solution at
room temperature, resulting in nitrile 6 in 90% yield. The Pinner reaction

Synthesis of 7,8-Dimethoxytetralin-2-one
2373
Scheme 1.
Scheme 2.

´
A. Gorka et al.
2374
of nitrile (6) was performed in refluxing ethanol in the presence of dry
hydrochloric acid, resulting in diester 7 in 92.8% yield (Scheme 2).
The compound 7 was subjected to catalytic hydrogenation in dichloro-
methane–methanol 1 : 1 mixture at room temperature and at atmospheric
pressure using palladium on charcoal catalyst to give the saturated deriva-
tive 8 in 94% yield. The saturated diester 8 proved to be the appropriate
intermediate for the next Dieckmann condensation reaction to form the
2-tetralone ring via the corresponding b-ketoester 9. The diester 8 was
treated with potassium tert-butoxide in benzene under reflux and the
expected b-ketoester 9 was obtained in 55% yield. Deethoxycarbonylation
for removal of ethoxycarbonyl group from position 1 proved to be more
effective than hydrolysis and decarboxylation. Thus, the preparation of
the title compound 1 was successful using sodium chloride and water in
DMF solution at 1508C (73%).
We may conclude that the synthesis of 7,8-dimethoxytetralin-2-one
(1) is favored starting from the commercially available 3-methylcatechol
(2a) and using the simple reaction steps presented. Investigation of the
scope and limitations of the procedure as well as its utilization in the
synthesis of biologically active compounds are in progress.
EXPERIMENTAL
General
Melting points are uncorrected. IR spectra were recorded on Zeiss IR 75 and 80
instruments. 1H and 13C NMR spectra were recorded on a Varian INOVA 300
spectrometer. High-resolution MS measurements were carried out on a
Finnigan MAT 95XP mass spectrometer; perfluorotributylamine was used as
a reference compound (EI, 70eV). TLC was carried out using Kieselgel
60F254 (Merck) glass plates. 3-Methylcatechol (2a) was purchased from
Aldrich. 2,3-Dimethoxytoluene (2b) and 3,4-dimethoxy-2-methylbenzaldehyde
(2c) were obtained according to procedures described in the literature.[5,6]
3-(3,4-Dimethoxy-2-methylphenyl)-2-propenoic Acid (3)
To a solution of 10.16 g (56.4 mmol) of 3,4-dimethoxy-2-methylbenzaldehyde
(2c) in pyridine (28 ml), 14.7 g (0.141 mol) of malonic acid and 1.1 ml of
piperidine were added and the reaction mixture was heated with stirring in
an oil bath at 100–1108C for 1.5 h and then at 130–1408C for 30 min. After
cooling the mixture was poured into 300 ml of a 2M hydrochloric acid
solution, and the precipitate was filtered off and dried at rt. Carboxylic acid
(3) (11.6 g, 92.7%) was obtained, which was suitable for the next esterification
reaction without any purification. Mp 189–1918C (ethanol). TLC (ethyl

Synthesis of 7,8-Dimethoxytetralin-2-one
2375
acetate–hexane 10 : 1) Rf 0.7. IR (KBr) 3430, 2950, 1700, 1640, 1595, 1495,
1
1270, 1085, 800 cm21. H NMR (300 MHz, CDCl3) 2.30 (s, 3H, CH3), 3.71
(s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.2 (d, J ¼ 15.9 Hz, 1H, 55CH–), 6.73
(d, J ¼ 8.7 Hz, 1H, ArH), 7.35 (d, J ¼ 8.7 Hz, 1H, ArH), 7.94
(d, J ¼ 15.9 Hz, 1H, –CH55) ppm. Anal. calcd. for C12H14O4: C, 64.85; H,
6.35: Found C, 64.64; H, 6.31.
Ethyl 3-(3,4-Dimethoxy-2-methylphenyl)-2-propenoate (4)
Carboxylic acid (3) (10.37g, 46.7mmol) was dissolved in ethanol (155ml) and
1.5 ml of cc. H2SO4 was added. The reaction mixture was refluxed for 2 h,
solvent was evaporated to dryness under reduced pressure, and the residue
was shared between saturated aqueous sodium hydrogencarbonate solution
(70ml) and dichloromethane (100ml). The aqueous layer was extracted with
dichloromethane (100ml), the combined organic layers were washed with
water (3 ꢀ 100 ml), and after drying (MgSO4) was evaporated to dryness
under vacuum. Product (4) (10.86g, 93%) was obtained as a crystallizable oil,
used in the next bromination step without any purification. TLC (benzene–
MeOH 14: 3) Rf 0.8. IR (KBr) 2990, 2940, 1720, 1640, 1600, 1500, 1260,
1
1180, 1080, 870, 820 cm21. H NMR (300 MHz, CDCl3) 1.33 (t, J ¼ 7.0 Hz,
3H, OCH2CH3), 2.36 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 3.87 (s, 3H, OCH3),
4.25 (q, J ¼ 7.0 Hz, 2H, OCH2CH3), 6.25 (d, J ¼ 15.6Hz, 1H, 55CH–), 6.77
(d, J ¼ 8.7 Hz, 1H, ArH), 7.33 (d, J ¼ 8.7 Hz, 1H, ArH), 7.92 (d, J ¼ 15.6Hz,
1H, –CH55) ppm. HRMS: calcd. 250.1200, found 250.1201 (delta: 0.7 ppm).
Ethyl 3-(2-Bromomethyl-3,4-dimethoxyphenyl)-2-propenoate (5)
To a solution of ester (4) (7.27 g, 29.1mmol) in carbon tetrachloride (180 ml),
200 mg of benzoyl peroxide and 7.87g (44.2 mmol) of N-bromosuccinimide
was added. After refluxing the reaction mixture for 8 h with stirring, precipitate
was filtered off and the filtrate was evaporated to dryness under reduced pressure.
The residue was recrystallized from ethanol, and from the ethanolic mother
liquor another part of product was isolated by column chromatography on
silica gel (dichloromethane) and by preparative layer chromatography (silica,
dichloromethane). Yield: 6.22g (65%). Mp 93–948C. TLC (dichloromethane)
Rf 0.65. IR (KBr) 2990, 2936, 1720, 1640, 1600, 1500, 1280, 1190, 1090,
1040, 820 cm21
.
1H NMR (300MHz, CDCl3) 1.35 (t, J ¼ 7.2 Hz, 3H,
OCH2CH3), 3.90 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 4.27 (q, J ¼ 7.2 Hz, 2H,
OCH2CH3), 4.71 (s, 2H, CH2Br), 6.35 (d, J ¼ 15.6Hz, 1H, 55CH–), 6.90
(d, J ¼ 8.7 Hz, 1H, ArH), 7.35 (d, J ¼ 8.7 Hz, 1H, ArH), 7.95 (d, J ¼ 15.6Hz,
1H, –CH55) ppm. Anal. calcd. for C14H17BrO4: Br, 24.27. Found: Br, 24.20.

´
A. Gorka et al.
2376
Ethyl 3-(2-Cyanomethyl-3,4-dimethoxyphenyl)-2-propenoate (6)
Bromomethyl derivative (5) (5.7 g, 17.3 mmol) was dissolved in DMF (52 ml),
5.13 g (0.105 mol) of sodium cyanide was added, and it was stirred at room
temperature for 1.5 h. The reaction mixture was poured into water (100 ml),
extracted with dichloromethane (3 ꢀ 100 ml), and the combined organic
layers were washed with water (3 ꢀ 150 ml). After drying (MgSO4) the
solvent was evaporated to dryness in vacuum and the product (6) was
isolated by column chromatography on silica (hexane–ethyl acetate 3 : 1) to
give 4.3 g (90%) of nitrile 6. Mp 82–838C. TLC (hexane–ethyl acetate
3 : 1) Rf 0.25. IR (KBr) 2990, 2950, 2245, 1705, 1640, 1600, 1505, 1290,
1
1270, 1240, 1180, 1080, 1040, 810 cm21. H NMR (300 MHz, CDCl3) 1.34
(t, J ¼ 7.2 Hz, 3H, OCH2CH3), 3.84 (s, 2H, CH2CN), 3.91 (s, 3H, OCH3),
3.95 (s, 3H, OCH3), 4.27 (q, J ¼ 7.2 Hz, 2H, OCH2CH3), 6.30
(d, J ¼ 15.6 Hz, 1H, 55CH–), 6.93 (d, J ¼ 8.7 Hz, 1H, ArH), 7.35
(d, J ¼ 8.7 Hz, 1H, ArH), 7.81 (d, J ¼ 15.6 Hz, 1H, –CH55) ppm. Anal.
calcd. for C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.39; H, 6.24;
N, 5.11.
Ethyl 3-(3,4-Dimethoxy-2-ethoxycarbonylmethylphenyl)-2-
propenoate (7)
Dry hydrochloric acid was introduced for 1 h into a suspension of 2.4 g
(8.8mmol) of nitrile (6) in ethanol (68ml). Then, the reaction mixture was
refluxed for 1 h and evaporated to dryness under reduced pressure, and the
residue was shared between saturated aqueous sodium hydrogencarbonate
solution (150ml) and dichloromethane (200ml). The water phase was
extracted with dichloromethane (100ml) and the combined organic layers
were washed with water (100ml), dried (MgSO4), and evaporated to dryness
in vacuum. The residue was purified by column chromatography on silica gel
(hexane–ethyl acetate 3 : 1) to give 2.63g (92.8%) of diester (7) as a crystalliz-
able oil. Mp 39–408C. TLC (hexane–ethyl acetate 2 : 1) Rf 0.6. IR (KBr) 1735,
1710, 1630, 1585, 1280, 1260, 1180, 1080, 1030, 800 cm21. 1H NMR (300MHz,
CDCl3) 1.26 (t, J ¼ 7.2 Hz, 3H, OCH2CH3), 1.32 (t, J ¼ 7.2 Hz, 3H,
OCH2CH3), 3.83 (s, 3H, OCH3), 3.86 (s, 2H, CH2CO), 3.89 (s, 3H, OCH3),
4.16 (q, J ¼ 7.2 Hz, 2H, OCH2CH3), 4.25 (q, J ¼ 7.2 Hz, 2H, OCH2CH3),
6.25 (d, J ¼ 15.6Hz, 1H, 55CH–), 6.87 (d, J ¼ 8.7 Hz, 1H, ArH), 7.36
(d, J ¼ 8.7 Hz, 1H, ArH), 7.83 (d, J ¼ 15.6Hz, 1H, –CH55) ppm. Anal.
calcd. for C17H22O6: C, 63.34; H, 6.88. Found: C, 63.42, H, 7.08.
Ethyl 3-(3,4-Dimethoxy-2-ethoxycarbonylmethylphenyl)-
propionate (8)
Unsaturated ester (7) (2.04 g, 6.33 mmol) was hydrogenated in a mixture of
dichloromethane (14 ml) and ethanol (14 ml) in the presence of 10%

Synthesis of 7,8-Dimethoxytetralin-2-one
2377
palladium on charcoal (0.6 g) at room temperature under atmospheric
pressure. The catalyst was filtered off, the filtrate was evaporated to
dryness, and the residue was isolated by column chromatography on silica
gel (hexane–ethyl acetate 4 : 1) to give 1.92 g (94%) of saturated diester (8).
Mp 38–398C. TLC (hexane–ethyl acetate 2 : 1) Rf 0.65. IR (KBr) 1735,
1710, 1630, 1585, 1280, 1260, 1180, 1080, 1030, 800 cm21 1H NMR
.
(300 MHz, CDCl3) 1.24 (t, J ¼ 7.2 Hz, 3H, OCH2CH3), 1.26 (t, J ¼ 7.2 Hz,
3H, OCH2CH3), 2.54 (m, 2H) and 2.86 (m, 2H) [–CH2CH2CO–], 3.74
(s, 2H, –CH2CO–), 3.81 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.15
(q, J ¼ 7.2 Hz, 2H, OCH2CH3), 4.16 (q, J ¼ 7.2 Hz, 2H, OCH2CH3), 6.80
(d, J ¼ 8.7 Hz, 1H, ArH), 7.36 (d, J ¼ 8.7 Hz, 1H, ArH) ppm. Anal. calcd.
for C17H24O6: C, 62.95; H, 7.46. Found: C 62.81; H, 7.23.
7,8-Dimethoxy-1-ethoxycarbonyl-1,2,3,4-tetrahydro-
naphthalene-2-one (9)
To a solution of 200 mg (0.62 mmol) of diester (8) in benzene (9 ml), 180 mg
(1.6 mmol) of potassium tert-butoxide was added. The reaction mixture was
refluxed for 30 min and after cooling ca. 0.3 ml of water was added and evap-
orated to dryness under reduced pressure. The residue was treated with 1 N
hydrochloric acid (9 ml), extracted with dichloromethane (3 ꢀ 5 ml) and
after drying the solvent was evaporated under vacuum. The product was
isolated from the residue by preparative layer chromatography on silica gel
(hexane–ethyl acetate 2 : 1) as an oil, yield 95 mg (55%). TLC (hexane–
ethyl acetate 2 : 1) Rf 0.45. IR (KBr) 3480, 1750, 1730, 1500, 1280, 1240,
810 cm21
.
1H NMR (300 MHz, CDCl3) (mainly enolic form) 1.39
(t, J ¼ 7.0 Hz, 3H, OCH2CH3), 2.67 (t, J ¼ 9.0 Hz, 2H) and 2.97
(t, J ¼ 9.0 Hz, 2H) [–CH2CH2–], 3.83 (s, 3H, OCH3), 3.87 (s, 3H, OCH3),
4.37 (q, J ¼ 7.0 Hz, 2H, OCH2CH3), 7.02 (s, 2H, ArH) ppm. HRMS: calcd
278.1149, found 278.1143 (delta: 22.0 ppm).
7,8-Dimethoxytetralin-2-one (1)
b-Oxoester (9) (380 mg, 1.36 mmol) was dissolved in DMSO (1.5 ml); 106 mg
(1.8 mmol) of sodium chloride and 0.1 ml (5.6 mmol) of water were added.
The reaction mixture was heated at 1508C for 2.5 h. The mixture after
cooling was diluted with 15 ml of dichloromethane, the organic layer was
washed with water (3 ꢀ 10 ml), and after drying (MgSO4) was evaporated
to dryness under reduced pressure. The product (1) was isolated by preparative
layer chromatography on silica gel (dichloromethane-methanol 100 : 1; Rf 0.6)
to give 204 mg (73%) of tetralone (1). Mp 73–748C (hexane) (lit.,[2] 75–
1
768C). IR (KBr) 2950, 1705, 1495, 1280,1080, 860, 795 cm21. H NMR
(300 MHz, CDCl3) 2.54 (t, 2H, H2-4), 3.00 (t, 2H, H2-3), 3.60 (s, 2H,

´
A. Gorka et al.
2378
H2 2 1), 3.81 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 6.79 (d, J ¼ 8.4 Hz, 1H,
ArH), 6.93 (d, J ¼ 8.4 Hz, 1H, ArH) ppm.
ACKNOWLEDGMENTS
The authors are grateful to H. Medzihradszky-Schweiger and her staff for the
microanalyses, and to OTKA (Hungarian Academic Research Found Grant
T 042491) and to Gedeon Richter Ltd. for financial assistance. The
technical assistance of Attila Fu¨rjes and Imre Sinka in recording the NMR
´
spectra is gratefully acknowledged. Moreover, one of the authors (A. G.) is
´
indebted to Jozsef Varga Foundation for financial support.
REFERENCES
1. Silveira, C. C.; Braga, A. L.; Kaufman, T. S.; Lenardao, E. J. Synthetic approaches
to 2-tetralones. Tetrahedron 2004, 60 (38), 8295–8328 and references cited therein.
2. Mannito, P.; Speranza, G.; Monti, D.; Fontana, G.; Panosetti, E. Baker’s yeast
mediated reduction of aromatic ring substituted 2-tetralones. Tetrahedron 1995,
51 (42), 11531–11546.
3. (a) Soffer, M. D.; Cavagnol, J. C.; Gellerson, H. E. Syntheses in the direction of
morphine. I. 7-Methoxy- and 7,8-dimethoxy-2-tetralone. J. Am. Chem. Soc. 1949,
71 (11), 3857; (b) Soffer, M. D.; Stewart, R. A.; Cavagnol, J. C.; Gellerson, H. E.
Syntheses in the direction of morphine. II. Some intermediates and model
compounds. J. Am. Chem. Soc. 1950, 72 (8), 3704–3709; (c) Soffer, M. D.;
Diamond, G. B. Electrolytic reduction of 2-naphthyl ethers. J. Am. Chem. Soc.
1952, 74 (16), 4126–4127.
4. (a) Dolson, M. G.; Swenton, J. S. Product and mechanistic studies of the anodic
oxidation of methoxylated naphthalenes. The EECrCp mechanism. J. Am. Chem.
Soc. 1981, 103 (9), 2361–2371; (b) McKervey, M. A.; Tuladhar, S. M.;
Twohig, M. F. Efficient synthesis of bicyclo[5.3.0]decatrienones and of 2-tetralones
via rhodium(II) acetate-catalysed cyclisation of a-diazoketones derived from
3-arylpropionic acids. J. Chem. Soc., Chem. Commun. 1984 (2), 129–130;
(c) Kennedy, M.; McKervey, M. A.; Maguire, M.; Tuladhar, S. M.; Twohig, M. F.
The intramolecular Buchner reaction of aryl diazoketones. Substituent effects and
scope in synthesis. J. Chem. Soc., Perkin Trans. 1 1990 (4), 1047–1054.
5. (a) Chromartie, R. I. T.; Harley-Mason, J. Melanin and its precursors. Part IV.
Synthesis of b-3:4-dihydroxy-2- and -5-methylphenylalanine. J. Chem. Soc.
1952, 1052–1053; (b) Vickery, E. H.; Pahler, L. F.; Eisenbraun, E. J. Selective
O-demethylation of catechol ethers. Comparison of boron tribromide and iodoti-
methylsilane. J. Org. Chem. 1979, 44 (24), 4444–4446.
6. Meier, H.; Kretzschmann, H.; Kolshorn, H. [ABC]Annelated [18]annulenes. J. Org.
Chem. 1992, 57 (25), 6847–6852.