Transformation of 5-methoxy-1-tetralone into 8-methoxy-1-tetralone

Article abstract of DOI:10.3184/030823410X12843943759969

The transformation of 1-hydroxy-5-methoxtetralin into 4-hydroxy-8-methoxy- 1-tetralone was accomplished in three steps (benzoylation, oxidation and alkaline hydrolysis). Treatment of the corresponding ketotosylate with sodium iodide and zinc dust in dimet

Full text of DOI:10.3184/030823410X12843943759969

522 RESEARCH PAPER
SEPTEMBER, 522–524
JOURNAL OF CHEMICAL RESEARCH 2010
Transformation of 5-methoxy-1-tetralone into 8-methoxy-1-tetralone
Ajoy K. Banerjeea*, Liadis Bedoyaa, Maria E. Adheríana, William J. Veraa, Elvia V. Cabrerab and
Elidig R. Karineyb
aCentro de Química, IVIC, Apartado-21827, Caracas-1020-A, Venezuela
bDepartamento de Química, Facultad de Ciencias, Universidad de Zulia, Maracaibo, Venezuela
The transformation of 1-hydroxy-5-methoxtetralin into 4-hydroxy-8-methoxy-1-tetralone was accomplished in three
steps (benzoylation, oxidation and alkaline hydrolysis). Treatment of the corresponding ketotosylate with sodium
iodide and zinc dust in dimethoxyethane yielded the 8-methoxy-1-tetralone in 22% yield. The ketotosylate also under-
went detosylation with sodium cyanoborohydride but afforded tetraol in 45% yield which on oxidation was con-
verted into the required tetralone in 87% yield.
Keywords: 5-methoxy-1-tetralone, cyclisation, 8-methoxy-1-tetralone, bromination, aromatisation
tetralone 1 in 22% yield. The ketotosylate 9 on heating with
with sodium cyanoborohydride (NaBH3CN) and hexamethyl-
phosphoramide (HMPA) underwent detosylation14 yielding
the tetraol 12 (45%) as a brown oil. The other products could
not be identified. Tetraol 12 on oxidation15 with Jones reagent
produced tetralone 1 in 87% yields.
We consider it worthwhile to provide a mechanism for the
formation of the naphthol 10 and the the tosylate 11 and this is
depicted in Scheme 2. The tosylate 9 with pyridine forms an
enolate anion and the tosylate a good leaving undergoes base
promoted E2 elimination yielding the intermediate 9a which
produces naphthol 10 and its derivative 11.
8-Methoxy1-tetralone 1 is a valuable starting material in the
synthesis of ARQ-501, which is a fully synthetic version of
β-lapachone and a promising anticancer agent currently in
multiple Phase II clinical trials.1 ARQ-501 is also effective
against human ovarian cancer and prostrate cancer xenografs
in mice.2 Tetralone 1 can also be used in the synthesis of previ-
ously reported tetralone3 2 and tetralone4 3. Tetralone 2 is an
important starting material in the synthesis of compounds for
the study of dopamine (DA) and serotin (5-HT) receptors.
Tetralone 3 can be considered to provide an easy access to dio-
spyrol,5 a very potent anthelmintic drug from Diospyros mollis
(Ebenaceae)
In order to improve the yield of the tetralone 1, an alterna-
tive route was tried and this is depicted in Scheme 3. The
ketoalcohol 8 was heated under reflux with ethylene glycol
and catalytic amount of p-toluenesulfonic acid expecting to
obtain the ketal 13. The resulting product which was a mixture
of several compounds as evidenced by TLC was subjected
to chromatographic purification. To our surprise the naphthol
10 was the only product that could be isolated and formed
the major component. We believe that during ketalisation the
ketoalcohol 8 underwent acid-catalysed dehydration affording
the naphthol 10. We failed to isolate and identify the compound
13. Similar experience was also met during the ketalisation of
the ketobenzoate 7. Therefore we were forced to abandon our
plan to achieve the transformation of the compound 13 to the
tetralone 1 by tosylation, detosylation with lithium aluminium
hydride and dekealisation successively. It is known16 that
aromatisation reactions involving tetralones are very common
but we never thought that it would be impossible to isolate the
compound 13 even in poor yield.
8-Methoxy-1-tetralone has been synthesised by the three
routes.6–8 Except for the first route,6 tetralone 1 was obtained
in very poor yield by the other published procedures.7,8 The
first route6, though it affords an acceptable yield (41%) of
tetralone 1, utilises a starting material whose preparation
involves seven steps which consume a considerable amount of
time. In relation of our studies on the synthesis9 of substituted
1-tetralones and because of the notable biological activities of
tetralone 1 we have devised a concise and convenient approach
for the synthesis of the tetralone 1. The synthetic route is
described in Scheme 1.
In conclusion a new synthesis of 8-methoxy-1-tetralone has
been achieved from 5-methoxy-1-tetralone. Although the yield
by the present procedure is not high when compared to the
published method6 it is superior to the other methods.
In addition, the present procedure is easily reproducible
because it does not involve any complicated experimental
procedure.
Results and discussion
5-Methoxy-1-tetralone 4 was considered to be promising start-
ing material for the synthesis of the 8-methoxy-1-tetralone 1.
The synthetic route is shown in Scheme 1.
The known alcohol10 5 was treated with benzoyl chloride
(BzCl) and pyridine (Py). The resulting derivative 6 (81%)
on oxidation11 with pyridinium dichromate (PDC) and t-
butylhydroperoxide (TBHP) (70% in water) produced the
ketobenzoate 7 (75%). Alkaline hydrolysis of 7 yielded the
ketoalcohol8(95%)whichontosylationwithp-toluenesulfonyl
chloride (TsCl) and pyridine (Py) yielded the ketotosylate
9 (12%), naphthol12 10 (31%) and tosylate 11 (30%). The
spectroscopic data gave strong support to their structures.
Detosylation13 of 9 on heating under reflux with sodium iodide
(NaI) and zinc (Zn) in dimethoxyethane (DME) furnished
Experimental
Unless otherwise stated, all melting points are uncorrected on an
electrothermal melting point apparatus, infrared (IR) spectra were
taken on a Nicolet Fourier Transform (FT) instrument. Only selected
1
absorbances (υmax in cm−1) were recorded. H and 13C NMR spectra
were recorded on a Bruker AM-300 spectrometer in CDCl3. 1H NMR
spectra are reported as follows: chemical shift in ppm (δ), integration,
multiplicities (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br, broadened and coupling constant (J) in Hz. 13C NMR spectra are
reported in ppm (δ). Mass spectra (MS) were determined on a Dupont
21-492B. Column chromatography was carried out on silica gel 60
(Merck). The expression workup indicates that the solution was
diluted with water, extracted with Et2O or CHCl3, washed with brine,
* Correspondent. E-mail: abanerje@ivic.gob.ve

JOURNAL OF CHEMICAL RESEARCH 2010 523
Scheme 1
Scheme 2
dried (MgSO4) and evaporated under reduced pressure. TLC plates
were coated with silica gel and the spots were located by exposure to
UV light. Microanalyses were performed on a Carlo-Erba model 1108
elemental analyser, IVIC, Caracas.
1-Benzoyloxy-5-methoxytetralin (6):A solution of alcohol 5 (2.27 g,
12.7 mmol) in dry Py (25 mL) and BzCl (7.71 g, 58.3 mmol) was
stirred for 20 h at room temperature. The reaction mixture was diluted
with water and extracted with Et2O. The organic extract was washed
with dilute HCl, aqueous NaHCO3, brine, dried and evaporated to
yield a dense material which was chromatographed over silica gel.
Evaporation of the hexane eluate afforded the benzoate 6 (2.91 g,
81%), m.p. 53–55 °C; IR υmax (cm−1): 1713 (CO); MS(m/z): 282 (M+),
1
160 (M+ -C6H5COOH); H δ(ppm): 8.05 (dd, 2H, J = 7.01, J = 1.5),
7.54 (tt, 1H, J = 6.7) (H-16), 7.42 (t, 2H, J = 7.5) (H-15, H-17), 7.18
(t, 1H, J = 7.9) (H-7), 6.98 (d,1H, J = 7.7) (H-8), 6.79 (d, 1H, J = 8)
(H-6), 6.24 (t,1H,J = 4.2) (H-1), 3.83 (s, 3H,OMe), 2.91–2.64 (m,
2H) (H-4), 2.08–1.87 (m, 4H) (H-2, H-3); 13C δ(ppm): 166.16 (C-12),
156.98 (C-5), 135.73 (C-9), 132.77 (C-16), 130.66 (C-13), 129.67
(C-14, C-18), 128.22 (C-15, C-17), 127.07 (C-7), 126.34 (C-10),
121.40 (C-8), 109.07 (C-6) , 70.58 (C-1), 55.30 (C-11), 28.70 (C-2),
Scheme 3

524 JOURNAL OF CHEMICAL RESEARCH 2010
22.77 (C-4), 18.27 (C-3) (Found: C, 76.75; H, 6.43. C18H18O3 requires:
C, 76.57; H, 6.43%).
8-Methoxy-1-tetralone (1): Method A: To a solution of the ketoto-
sylate 9 (40 mg, 0.12 mmol) dissolved in HMPA (2 mL) was added
NaBH3CN (0.6 mL, 8.73 mmol), refluxed at 70 °C for 6 h and stirred
at room temperature for 18 h. The reaction mixture was diluted with
water and extracted with Et2O. The organic extract was washed, dried
and evaporated to obtain an oil which on preparative chromatographic
purification (eluant hexane) yielded tetraol 12 (9.5 mg, 45%); IR
υmax(cm−1): 3452 (OH); MS (m/z): 179 (M+i);1H δ(ppm) 9.25 (s,1H, 1-H),
7.41–7.26 (m, 1H, 7-H), 6.88–6.85 (dd, 1H, J = 8.71 Hz, J = 1.47,
6-H), 6.77–6.75 (d, 1H, J = 7.81 Hz, 5-H), 3.98 (s, 3H, OMe), 1.59
(s, 1H, OH). As the tetraol 12 was obtained in small amounts, the,
reactions were repeated to prepare additional amounts of tetraol. To a
solution of tetraol 12 (80 mg, 0.45 mmol) in Me2CO (5 mL) at 0 °C,
was added Jones reagent (2 mL). The mixture was stirred at room
temperature for 30 min and 2-propanol (4 mL) was added. The result-
ing dark blue solution was diluted with water and extracted with Et2O.
The organic extract was washed, dried, evaporated and chromato-
4-Benzoyloxy-8-methoxy-1-tetralone (7): To a solution of the
benzoate 6 (202 mg, 0.72 mmol) in dry C6H6 (12 mL) at 0 °C was
added at 0 °C Celite (602 mg), PDC (1.03 mg, 2.73 mmol) and TBHP
(70%) (1.74 mL, 8.41 mmol). The whole operation was done with a
period of 15 min and then the mixture was stirred at room temperature
for 24 hr. The mixture was diluted with Et2O (20 mL) and then filtered
through a column of celite. The column of the Celite was eluted with
Et2O (3 x 10 mL). The combined filtrate was evaporated and the
residue was washed with Et2O to obtain the ketobenzoate 7 (159 mg,
75%), m.p. 95–96o C; IR υmax (cm−1): 1720, 1678 (CO); MS(m/z): 296
(M+), 175 (M+ -C6H5COOH); 1H δ(ppm): 8.03 (dd, 2H, J = 9.6 Hz,
J = 1.9 Hz ) (H-14, 18), 7.59–7.38 (m, 4H) (H-6, 15, 16, 17), 7.12
(d, 1H, J = 7.5 Hz) (H-5), 7.01 (d, 1H, J = 8.4 Hz), 6.31 (t, 1H, J =
4.7 Hz), 3.92 (s, 3H, OMe), 3.03–2.92 (m, 1H) , 2.71–2.66 (m, 1H)
(H-2), 2.48–2.34 (m,2H) (H-3); 13C δ(ppm): 192.02 (C-1), 165.08 (C-8),
143.05 (C-10), 134.66 (C-6), 133.26 (C-16), 129.91 (C-13), 129.72
(C-14, C-18), 128.44 (C-15, C-17), 121.47 (C-5), 120.34 (C-9),
112.67 (C-7), 70.35 (C-4), 56.17 (C-11), 35.74 (C-2), 27.96 (C-3)
(Found: C, 72.72; H, 5.56. C18H16O4 requires C, 72.96; H, 5.44% ).
4-Hydroxy-8-methoxy-1-tetralone (8): To a solution of the ketoben-
zoate 7 (974 mg, 3.29 mmol) dissolved in EtOH (60 mL) was added
K2CO3 (2.14 g, 7.24 mmol) and stirred at room temperature for 24 h.
The alkaline solution was concentrated, diluted with water and
extracted with CHCl3. The organic extract was washed with brine,
dried ,.evaporated under reduced pressure and chromatographed.
The chromatographic purification (hexane:ether 1:1) afforded the
ketoalcohol 8 (599 mg, 95%); IR υmax (cm−1): 3411 (OH), 1611 (CO);
graphed. Elotion with hexane:Et2O (7:3) yielded the tetralone 1
1
(69 mg, 87%); υmax(cm−1) 1674 (CO); MS (m/z): 176 (M+); H δ(ppm)
:
7.38 (dd, 1H, J = 8.01 Hz, J = 7.9 Hz, 6-H), 6.82–6.78 (m, 2H, 5-H,
7-H), 3.87 (s, 3H, OMe), 2.89 (t, 2H, J = 6 Hz, 2-H), 2.60 (t, 2H, J = 6
Hz, 4-H), 2.07–2.01 (m, 2H, 3-H); 13C δ(ppm): 156.10 (C-1), 154.42
(C-8), 136.68 (C-10), 127.66 (C-6); 125.53 (C-3), 121.80 (C-4),
118.80 (C-5), 115.01 (C-9), 110.75 (C-2), 103.83 (C-7), 56.04 (C-11)
(Found: C, 74.82; H, 6.95. C11H12O2 requires C 74.97; H, 6.86%).
Method B: To a solution of the ketotosylate 9 (343 mg, 0.99 mmol)
in DME (15 mL) was added NaI (811 mg, 5.41 mmol) and Zn dust
(3.33 g, 50.98 mmol). The mixture was stirred and heated under reflux
for 8 h. The progress of the reaction was monitored by TLC. After
removal of the zinc, the solution was diluted with water and extracted
with Et2O. The organic extract was washed, dried and evaporated to
obtain a brown oil which was chromatographed (hexane: ether 7:3) to
obtain the tetralone 1 (37 mg, 21%) whose spectroscopic data were
identical with the tetralone 1 obtained by Method A.
1
MS (m/z): 192 (M+), 174 (M+ - H2O); H δ(ppm): 7.49 (t, 1H, J = 8)
(H-6), 7.16 (d, 1H, J = 7.6) (H-5), 6.93 (d, 1H, J = 8.4) (H-7), 3.87
(s, 3H, OMe), 2.91–2.81 (m, 1H), 2.59–2.48 (m, 1H) (H-2), 2.33–2.23
(m, 1H), 2.16–2.04 (m, 1H) (H-3), 1.83 (s, 1H, OH); 13C δ(ppm): 196.67
(C-1), 159.94 (C-8), 147.94 (C-10), 134.72 (C-6), 120.41 (C-5),
118.76 (C-9), 111.75 (C-7), 68.31 (C-4), 56.05 (C-11), 36.33 (C-2),
31.21 (C-3) (Found: C, 68.55; H, 6.41. C11H12O3 requires C, 68.73;
H, 6.29%).
Received 2 August 2010; accepted 27 August 2010
Paper 1000280 doi: 10.3184/030823410X12843943759969
Published online: 7 October 2010
Tosylation of the ketoalcohol (8): To a solution of the ketoalcohol 8
(793 mg, 4.13 mmol) in dry Py ( 25 mL), cooled at 0 °C, was added
TsCl (4.88 g, 25.88 mmol), stirred at room temperature for 48 h,
poured on ice and extracted with Et2O. The organic extract was dried
and evaporated to obtain a dense liquid which was purified by chro-
matography. Hexane elute yielded (i) 4-Toluene-p-sulfonoxy-8-
methoxy-1-tetralone 9: 428 mg (30%). It was contaminated with other
products and had a tendency of decomposition as evidenced in TLC
and therefore it was used directly for the next step. (ii) 1-Hydroxy-8-
methoxynaphthalene 10: 222 mg (31%), m.p. 43–45 °C (lit.12 m.p.
44–46 °C); IR υmax (cm−1) 3355 (OH); MS (m/z): 174 (M+ ); 1H δ(ppm)
:9.31 (s,1H,OH), 7.42–7.21 (m, 4H) (H-3,4,5,6), 6.87 (dd,1H, J =
8.7 Hz, J = 1.47 Hz) (H-7), 6.77 (dd, 1H, J = 7.88 Hz, J = 0.57 Hz)
(2-H), 4.03 (s, 3H, OMe); 13C δ(ppm): 156.10 (C-1), 154.42 (C-8),
136.68 (C-10), 127.66 (C-6), 125.53 (C-3), 121.80 (C-4), 118.80
(C-5), 115.01 (C-9), 110.75 (C-2), 103.83 (C-7), 56.04 (C-11) (Found:
C, 75.69; H, 5.87. C11H10O2 requires C, 75.84; H, 5.79%). (iii) 1-
Toluene-p-sulfonoxy8-methoxynaphthalene 11: 405 mg (30%), m.p.
121–123 °C; MS(m/z): 329 (M+1); 1H δ(ppm): 7.74–7.66 (m, 3H) (H-3,
13, 17), 7.41–7.32 (m, 2H) (H-4,5), 7.30–7.22 (m, 3H) (H-6,14, 16),
6.89-6.81 (m, 2H) (H-2, 7), 3.91 (s, 3H, OMe), 2.45 (s, 3H,Me);
13C δ(ppm): 155.39 (C-1), 145.27 (C-12), 144.65 (C-8), 136.95 (C-15),
133.92 (C-10), 129.40 (C-14, C-16), 128.41 (C-13, C-17), 127.41
(C-3), 126.83 (C-6), 125.41(C-4, C-5), 120.31(C-9), 119.63 (C-7),
106.42 (C-2), 55.53 (C-11), 21.62 (C-18) (Found: C, 65.59; H, 5.02.
C18H16O4S requires C, 65.85; H, 4.91%).
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