A one-pot synthesis of 6-isopropyl-7-methoxy-1-tetralone and 6-isopropyl-7-methoxy-2-tetralone

Full text of DOI:10.1080/00304948.2014.903146

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Organic Preparations and Procedures
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A One-pot Synthesis of 6-Isopropyl-7-
methoxy-1-tetralone and 6-Isopropyl-7-
methoxy-2-tetralone
Elvia V. Cabreraa, Ariana C. Gila, José G. Ortegaa, Liadis Bedoyab,
Jennifer Sánchezb & Ajoy K. Banerjeeb
a Department of Chemistry, Faculty of Science, University of Zulia,
Maracaibo, Venezuela
b Chemistry Center, Venezuelan Institute of Scientific Research
(IVIC), Caracas, Venezuela
Published online: 27 May 2014.
To cite this article: Elvia V. Cabrera, Ariana C. Gil, José G. Ortega, Liadis Bedoya, Jennifer Sánchez &
Ajoy K. Banerjee (2014) A One-pot Synthesis of 6-Isopropyl-7-methoxy-1-tetralone and 6-Isopropyl-7-
methoxy-2-tetralone, Organic Preparations and Procedures International: The New Journal for Organic
Synthesis, 46:3, 272-276, DOI: 10.1080/00304948.2014.903146
To link to this article: http://dx.doi.org/10.1080/00304948.2014.903146
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Organic Preparations and Procedures International, 46:272–276, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2014.903146
OPPI BRIEF
A One-pot Synthesis
of 6-Isopropyl-7-methoxy-1-tetralone
and 6-Isopropyl-7-methoxy-2-tetralone
Elvia V. Cabrera,1 Ariana C. Gil,1 Jose´ G. Ortega,1 Liadis Bedoya,2
Jennifer Sa´nchez,2 and Ajoy K. Banerjee2
1Department of Chemistry, Faculty of Science, University of Zulia, Maracaibo,
Venezuela
2Chemistry Center, Venezuelan Institute of Scientific Research (IVIC), Caracas,
Venezuela
6-Isopropropyl-7-methoxy-1-tetralone1 (2) and 6-isopropyl-7-methoxy-2-tetralone2 (4)
have been claimed to be potential intermediates for the synthesis of natural products re-
lated to diterpenes miltirone (5) and carnosic acid (6), respectively. Miltirone, a tanshinone
(ortho-quinone diterpene), isolated from S. miltiorrhiza3 and other species,4 has previously
been synthesized5,6 and is cytotoxic against a number of cultured tumor cell lines.7 Carnosic
acid, a naturally occurring catechol-type polyphenolic diterpene, is obtained8 from Rosmar-
inus officinalis (rosemary) leaves and has also been synthesized previously.9,10 Carnosic
acid is known to possess potent anti-oxidant activity as well as anti-cancer and anti-viral
properties.11–13
In 1990, a four-step synthesis of tetralone 2 from 2-isopropylphenol in an overall yield
of 24% was reported1 and the preparation of tetralone 4 from 2,7-dimethoxynaphthalene
was accomplished in six steps with an overall yield of 39%.2
A concise and high-yield approach to tetralones 2 and 4 would be useful for the scale-
up preparation of the previously mentioned and related natural products. In addition, the
synthesis of these two tetralones in high yields would be advantageous for pre-clinical
and clinical evaluations of 5 and 6. Our experience in the studies on the synthesis of α,β-
substituted tetralones14,15 encouraged us to develop a concise approach for the tetralones 2
and 4. The present article describes for the first time a short approach for the tetralones 2
and 4 in high yields.
To a mixture of polyphosphoric acid (PPA) and isopropanol (i-PriOH) previously
heated to 75◦C–80◦C, was added commercially available 7-methoxy-1-tetralone (1) and
Submitted by October 25, 2013.
Address correspondence to Ajoy K. Banerjee, Centro de Qu´ımica, IVIC, Apartado-21827,
Caracas-1020A, Venezuela. E-mail: aabanerje@gmail.com
272

Synthesis of 6-Isopropyl-7-methoxy-1-and 2-tetralones
273
O
CHMe2
O
O
MeO
Me2CH
2
5
OH
HO
CHMe2
HO2C
O
MeO
Me2CH
4
6
the resulting mixture was heated under reflux for 5 h to yield the tetralone 2 in 85% yield
(Scheme 1). The same experiment carried out using conc. sulfuric acid or boron trifluoride
etherate did not afford 2 in acceptable yield. The spectral data of tetralone 2 agreed with
the published data.1
O
O
MeO
MeO
i
ii
Me2CH
1
2
MeO
MeO
O
iii, iv
Me2CH
Me2CH
3
4
Reagents and conditions: (i) PriOH, PPA, 5h reflux; (ii) 2,4-PD, PTSA, Tol, 16h
reflux; (iii) MCPBA, CHCl3, 0°C/ 12h; (iv) H2SO4 10% en EtOH, 3h reflux.
Scheme 1
The conversion of tetralone 2 into the olefin 3 was achieved in 90% yield by
heating in toluene under reflux with 2,4-pentanediol (2,4-PD)16 and a catalytic amount
of p-toluenesulfonic acid (p-TsOH). Epoxidation of the olefin was performed with m-
chloroperoxybenzoic (MCPBA) and the resulting epoxide was, without purification, heated

274
Banerjee et al.
under reflux with a 10% solution of sulfuric acid (10%) in ethanol to afford the tetralone
4 in 69% yield (overall yield 53% from 1 to 4). The spectral data of 4 matched with that
reported.2 In conclusion, a concise approach to 6-isopropyl-7-methoxy-1-tetralone (2) and
6-isopropyl-7-methoxy-2-tetralone (4) has been developed in very high overall yields of
85% (for 2) and of 53% (for 4), respectively.
Experimental Section
Infrared spectra were recorded on a Nicolet-Fourier Transform (FT) Instrument and 1H and
13C NMR spectra were obtained on a Bruker AM-300 spectrometer in CDCl3. Chemical
shifts are expressed in δ (ppm). Mass spectra (MS) were determined on a DuPont 21-
492B. Column chromatography was carried out with indicated solvents on silica gel 60
(0.04–0.063 mm) (Merck). The organic extracts were washed with brine, dried (MgSO4),
and evaporated under reduced pressure. Thin layer chromatography (TLC) plates were
coated with silica gel 60 F254, layer thickness 0.2 mm and the spots were visualized using
ultraviolet light. Elemental analyses were performed on a Carlo-Erba 1108 Elemental
Analyzer.
6-Isopropyl-7-methoxy-1-tetralone (2)
To a preheated (75◦C–80◦C) solution of commercially available polyphosphoric acid (6 ml,
126 mmol) and isopropanol (1 ml) was added in portions the tetralone 1 (0.49 g, 2.8 mmol)
maintaining the temperature (75◦C–80◦C). The resulting solution, which initially developed
a blue color, was heated under reflux for 5 h. The progress of the reaction was monitored
by TLC (hexane-Et2O 9:1). The reaction mixture was cooled, diluted with water (15 ml),
and extracted with chloroform (30 ml). The organic extracts were washed with brine, dried
and evaporated in vacuo to afford an oil, which was chromatographed (hexane:Et2O 9:1) to
afford tetralone 2 (0.51 g, 85%) as a pale yellow oil; Rf 0.79 (hexane:Et2O 8:2); IR (cm−1):
3019, 1674 (CO), 1601; MS (m/z): 219 (MH+); 1H NMR: δ 7.44 (s, 1H) (H at C-8), 7.04
(s, 1H) (H at C-5), 3.84 (s, 3H) (H at C-11), 3.38–3.24 (m, 1H) (H at C-12), 2.87 (t, 2H,
J = 6 Hz) (H at C-2), 2.59 (t, 2H, J = 6 Hz, H-4), 2.09 (q, 2H, H-3), 1.19 (d, 6H, J = 6. Hz)
(H at C-13 and H-14); 13C NMR: δ 198.28 (CO), 155.81 (C-7), 143.88 (C-6), 137.28 (C-9),
130.95 (C-10), 128.31 (C-8), 107.15 (C-5), 55.50 (OMe), 38.86 (C-2), 29.02 (CHMe2),
26.96 (C-4), 23.61 (C-3), 22.35 (2Me).
Anal. Calcd. for C14H18O2: C, 77.03; H, 8.31. Found: C, 77.29; H, 8.49
7-Methoxy-6-isopropyl-1,2-dihydronaphthalene (3)
To a solution of the tetralone 2 (0.42 g, 1.93 mmol) in toluene (40 ml) in a flask fitted
with a Dean-Stark trap was added a catalytic amount of p-toluenesulfonic acid (0.014 g,
0.074 mmol), 2,4-pentanediol (1 ml, 9.22 mmol) and the resulting solution was heated
under reflux for 16 h. The reaction mixture was cooled, quenched with an aqueous solution
of NaHCO3 (8 ml, 5%), and extracted with ether (25 ml). The organic extracts were washed
with brine, dried and evaporated in vacuo. The resulting brown oil was chromatographed
(hexane) to afford the compound 3 (0.35 g, 90%) as a pale yellow oil; Rf 0.81 (hexane:Et2O
9:1); IR (cm−1): 3031, 2598, 1597, 1486, 1462; MS (m/z): 202 (M+); 1H NMR: δ 6.98 (s,
1H) (H at C-8), 6.59 (s, 1H) (H at C-5), 6.44 (d, 1H, J = 7.98 Hz) (H at C-1), 6.05–5.99

Synthesis of 6-Isopropyl-7-methoxy-1-and 2-tetralones
275
(m, 1H, H-2), 3.84 (s, 3H) (H at C-11), 3.37–3.28 (m, 1H, H-12), 2.76 (t, 2H, J = 8.16 Hz,
H-4), 2.37–2.27 (m, 2H, H-3), 1.24 (dd, 6H, J = 6.89 Hz, H-13, H-14); 13C NMR: δ 155.28
(C-7), 135.35 (C-9), 132.26 (C-10), 128.08 (C-2), 127.67 (C-1), 127.21 (C-6), 125.30 (C-8),
108.58 (C-5), 55.55 (OMe), 26.79 (C-4), 26.52 (C-3), 23.57 (Me2CH), 22.79 (2 Me).
Anal. Calcd for C14H18O: C, 83.12; H, 8.97. Found: C, 83.35; H, 9.13.
6-Isopropyl-7-methoxy-2-tetralone (4)
To a suspension of m-CPBA (0.60 g, 3.48 mmol) in dichloromethane (5 ml), cooled to 0◦C,
was added a solution of alkene 3 (0.30g 1.49 mmol) in dichloromethane (2 ml) and the
mixture was stirred for 16 h at room temperature. Then an aqueous solution of NaHCO3
(5 ml, 5%) was added and the mixture was stirred for 30 min. The organic layer was
separated, washed with water, dried, and evaporated to afford a solid (0.36 g), which was
dissolved in a 10% ethanolic solution of sulfuric acid (5 ml) and heated under reflux for 3 h.
The reaction mixture was cooled, diluted with water (10 ml), and extracted with chloroform
(25 ml). The organic extracts were washed with brine, dried and evaporated to afford an oil
which, on chromatographic purification (hexane:Et2O 9:1), gave tetralone 4 (0.22 g, 69%)
as a pale yellow oil, Rf 0.61 (hexane:Et2O 8:2); IR (cm−1):1732 (CO); MS (m/z) 218 (M+);
1H NMR: δ 7.03 (s, 1H, H-5), 6.58 (s, 1H, H-8), 3.78 (s, 3H, H at C-11), 3.53 (s, 2H, H-1),
3.33–3.24 (m, 1H, H-12), 2.99 (t, 2H, J = 6.57 Hz, H-3), 2.54 (t, 2H, J = 6.36 Hz, H-4),
1.22 (d, 6H, J = 6.93 Hz, H-13, H-14); 13C NMR: δ 211.33 (CO), 155.68 (C-7), 135.61
(C-6), 131.13 (C-9), 128.16 (C-10), 125.42 (C-8), 110.40 (C-5), 55.54 (OMe), 44.77 (C-1),
38.76 (CHMe2), 27.75 (C-3), 26.46 (C-4), 23.04 (Me).
Anal. Calcd for C14H18O2: C, 77.03; H, 8.31. Found: C, 77.25; H, 8.45.
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