Transformation of 5,8-dimethyl-1-tetralone: Synthesis of ar-occidol

Article abstract of DOI:10.3184/030823410X12724713859947

Reduction of 5,8-dimethyl-1-tetralone 1 with sodium borohydride in methanol followed by methylation of the resulting alcohol with methyl iodide and sodium hydride yielded a methyl ether. This was oxidised with potassium permanganate and acetonitrile to give 4-methoxy-5,8-dimethyle-1-tetralone. Methoxycarbonylation of the ketone with dimethylcarbonate (DMC) in the presence of sodium hydride in dimethoxyethane (DME) afforded β-ketoester 5 which on heating with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dioxane underwent aromatisation and elimination to furnish a naphthalene. The mesyl derivative the phenol on hydrogenation produced methyl 5,8-dimethyl-2- naphthoate. The transformation of naphthoate into ar-occidol was accomplished by a Grignard reaction with methyllithium in ether.

Full text of DOI:10.3184/030823410X12724713859947

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JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 243
MAY, 243–245
Transformation of 5,8-dimethyl-1-tetralone: synthesis of ar-occidol
Ajoy K. Banerjeea*, Willam J. Veraa, Elvia V. Cabrerab and Jennifer L. Sanchezb
aCentro de Quimica,IVIC, Aptdo-21827, Caracas-1020ª,Venezuela
bDepartamento de Quimica, Facultad de Ciencias, Universidad de Maracaibo, Zulia, Venezuela
Reduction of 5,8-dimethyl-1-tetralone 1 with sodium borohydride in methanol followed by methylation of the result-
ing alcohol with methyl iodide and sodium hydride yielded a methyl ether. This was oxidised with potassium
permanganate and acetonitrile to give 4-methoxy-5,8-dimethyle-1-tetralone. Methoxycarbonylation of the ketone
with dimethylcarbonate (DMC) in the presence of sodium hydride in dimethoxyethane (DME) afforded β-ketoester
5 which on heating with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dioxane underwent aromatisation
and elimination to furnish a naphthalene. The mesyl derivative the phenol on hydrogenation produced methyl
5,8-dimethyl-2-naphthoate. The transformation of naphthoate into ar-occidol was accomplished by a Grignard
reaction with methyllithium in ether.
Keywords: reduction, methylation, methoxycarbonylation, aromatisation, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
methyllithium
The importance of the substituted 1-tetralone in the synthesis
of natural products and other synthetic products has recently
been described.1 The previously reported2,3 5,8-dimethyltete-
tralone 1 has been utilised for the synthesis of bicyclic
sesquiterpene occidol 12 and the ar-occidol5 11, the aromatic
analogue of occidol (Scheme 1). Having observed the utility
of the tetralone 1 in the synthesis of sesquiterpenes and as
a part of a program aimed at expanding the synthetic utility6
of 1-tetralone, we tried to achieve the transformation of the
tetralone 1 into the compound 7 whose conversion into the
emmotin-H 13 can easily be performed following the pub-
lished procedure7.Emmotin H 13 is an aromatic sesquiterpene
which has been isolated8 from the trunk wood of Emmotunitens
(Icacinaceae). Unfortunately the synthetic route led the forma-
tion of the phenol 8 instead of the desired ester 7. The phenol
8 proved to be a potential intermediate for the synthesis of
ar-occidol 11. The details of our synthetic endeavours are
described below (Scheme 2).
methylation with methyl iodide and sodium hydride in tetrahy-
drofuran yielded the oily compound 3. The tetralone 4, obtained
by the oxidation [9] of 3 with potassium permanganate and
acetonitrile was treated with dimethyl carbonate in the pres-
ence of sodium hydride in 1,2-dimethoxyethane. The resulting
ketoester 5, obtained in 40% yield, displayed absorption at
1744 and 1683 cm−1 in the IR spectrum indicating the presence
of an ester and a carbonyl group respectively. Its mass spec-
trum exhibited a parent peak at m/z 261 (M+–1). The NMR
spectrum of the compound 5 in chloroform was complicated
because of the probable contamination by the enol tautomer 6.
The presence of the signal in the 1H NMR spectrum at δ 12.34
(s, OH) indicated the presence of the enol ester 6. Its 13C NMR
spectrum in chloroform also confirmed the presence of a
tautomeric mixture of keto and enol esters.
The signals at δ 193.60 and 173.02 in the 13C NMR spec-
trum correspond to the C-1 and C-11 respectively of the keto-
ester 5 whereas the signals at δ 170.99 and 164.52 correspond
to the C-11 and C-1 of the enol ester 6. The formation of keto-
enol ester in solution prevented the reduction of the carbonyl
group of the keto-ester 5. Therefore it was subjected to dehy-
drogenation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
Results and discussion
In order to achieve the goal, the tetralone 1 was reduced
with sodium borohydride to obtain the alcohol 2 which on
Scheme 1
* Correspondent. E-mail: abanerje@ivic.gob.ve

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244 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 2
Mass spectra (MS) were determined on a Dupont 21-492B. Column
chromatography was carried out on silica gel 60 (Merck).The expres-
sion “workup” indicates that the solution was diluted with water,
extracted with ether or chloroform, washed with brine, 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 carried out in the Chemistry Department, IVIC,
Caracas.
1-Methoxy-5,8-dimethyl-1,2,3,4-tetrahydronaphthalene (3): To a
solution of tetralone 1 (2g, 0.011 mmol) in ethanol (30 mL) was added
dropwise a solution of the sodium borohydride (560 mg, 0.014 mol)
in ethanol (60 mL). The mixture was stirred for 20 h at room tempera-
ture, diluted with cold water and extracted with chloroform. The
workup afforded alcohol 2 as oil (1.96g, 97%); IR υmax (cm−1): 3406
(OH); MS (m/z): 158 (M+-H2O) (100%).
A solution of the alcohol 2 (2g, 0.011 mol) in THF (40 mL) was
added dropwise to a suspension of sodium hydride (4.31 g, 0.17 mole)
(60%, m/v) under nitrogen. The mixture was warmed for 10 min,
followed by the addition of methyl iodide (15 mL, 0.24 mol) and then
heated under reflux for 6 h. The mixture was cooled, diluted with
water and extracted with ether. The workup followed by chromato-
graphic purification (hexane:ether 8:2) yielded the product 3 (1.91,
88%); IR υmax (cm−1): 2973, 1082; MS(m/z): 158 (M+-MeOH) (100%).
143 (M+-MeOH-Me) (38%); 1H δ(ppm): 2.55 (s,3H), 2.63 (s,3H) (H-5,
H-8), 3.71 (s, 3H, OMe), 4.58 (s,1H) (H-1), 7.06 (s,1H), 7.15 (s,1H)
(H-6, H-7); 13C δ(ppm): 17.79 (Me-5), 18.90 (Me-8), 21.20 (C-4),
26.44 (C-3), 30.18 (C-2), 56.02 (OMe), 73.40 (C-1), 127.58 (C-6),
129.22 (C-7), 130.07 (C-5), 137.63 (C-8), 138.43 (C-9, C-10) (Found:
C, 82.32; H, 9.71. C13H18O requires C, 82.06; H, 9.54%).
(DDQ) in dioxane. To our surprise instead of the expected
ester 7, a phenol was obtained in 32% yield as pale yellow
solid, the spectroscopic data of which led to the assignment of
structure 8. The rest of the material, which contained several
products as shown by TLC, could not be identified.
As the phenol 8 is not an appropriate intermediate for the
synthesis of emmotin-H 13 attempts were made to transform
it to ar-occidol 11 which is an aromatic analogue of naturally
occurring bicyclic sesquiterpene occidol. An alternative syn-
thesis of ar-occidol has already been reported5. In order
to achieve the synthesis of ar-occidol (Scheme 3) the phenol 8
was converted to its mesyl derivative 9 which was hydroge-
nated10 with Pd-C (10%) in diethylamine and ethylacetate at
room temperature and atmospheric pressure to obtain the ester
10. This was identified by comparison of its spectra (IR and
NMR) with the literature data.5 Reaction of the ester 10 with
methyllithium furnished ar-occidol 11 whose spectra (IR and
NMR) when compared with the data reported5 confirmed its
structure.
In conclusion a new approach for the synthesis of ar-occidol
11 has been developed.
Experimental
Unless otherwise stated, all melting points are uncorrected and were
determined on an Electrothermal melting point apparatus. IR spectra
were taken on a Nicolet Fourier transform (FT) instrument and NMR
spectra were recorded on a Bruker AM-300 spectrometer in CDCl3.
Scheme 3

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JOURNAL OF CHEMICAL RESEARCH 2010 245
4-Methoxy-5,8-dimethyl-1-tetralone (4): To a solution of the com-
pound 3 (200 mg, 1 mmol) in acetonitrile (25 mL) was added potas-
sium permanganate (1 g, 6.3 mmol) portionwise during a period of
5 min. The mixture was stirred vigorously at room temperature for
24 h. The reaction mixture was filtered and the residue was washed
with chloroform. To the combined extract was added hydrazine
hydrochloride, diluted with water and extracted with chloroform. The
organic extract was washed, dried and evaporated to obtain a viscous
oil which on chromatographic purification (hexane:ether 9:1) afforded
purification by preparative TLC over silica gel (eluant hexane-ether
8:2) yielded the mesylate 9 (55mg, 84%), m.p. 78–79 °C; IR υmax
(cm−1) 1724 (CO); MS (m/z): 308 (45%), 229 (M+-SO2Me) (100%);
1H δ(ppm): 2.51 (s,3H), 2.64 (s, 3H) (5-Me, 8-Me), 3.42 (s, 3H,
MeSO3-), 3.95 (s, 3H, OMe), 7.91–7.85 (st. 2H, J = 9.06 Hz) (4-H,
3-H), 7.28 (s, 1H), 8.01 (s, 1H) (H-7) (H-6); 13C δ(ppm): 19.35 (5-Me),
22.04 (8-Me), 39.6 (1-SO3Me), 120.98 (C-4), 121.06 (C-2), 123.11
(C-7), 124. 86 (C-6), 128.71 (C-9), 131.94 (C-3), 134.15 (C-5), 134.34
(C-8), 137.54 (C-10), 144.92 (C-1), 165.76 (C-11) (Found: C, 58.72;
H, 5.36. C15H16O5S requires C, 58.94; H, 5.19%).
5,8-Dimethyl-2-methoxycarbonylnaphthalene (10): To the mesyl-
ate 9 (28.2 mg, 0.092 g, mmol) dissolved in ethyl acetate (10 mL) and
diethylamine (0.1 mL, 0.19 mmol) was added 10% Pd-C (10 mg). The
mixture was hydrogenated for 10 h at room temperature and under
atmospheric pressure. The catalyst was removed by filtration and
the filtrate was extracted with ether, washed, dried and evaporated
to obtain a brown oil which on purification by preparative TLC over
silica gel (eluant hexane-ether 1:1) yielded the ester 10 (19.4 mg,
99%); IR υmax (cm−1) 1720 (CO); MS (m/z): 214 (M+) (100%);
1H δ(ppm): 2.46 (s, 3H), 2.65 (s, 3H) (5,8-Me), 3.95 (s, 3H, OMe), 7.25
(s,1H), 7.55 (s,1H) (6-H), (7-H), 8.01–7.93 (d, 2H, qAB, J = 8.8 Hz)
(3-H, 4-H), 8.48 (s, 1H) (1-H); 13C δ(ppm): 19.11 (5-Me), 21.47 (8-Me),
52.05 (2-OMe), 124.17 (C-3, C-4), 126.24 (C-2), 126.50 (C-6), 127.05
(C-9), 130.84 (C-1), 131.26 (C-7),132.99 (C-5), 134.03 (C-10), 135.97
(C-8), 167.38 (C-11) (Found: C, 78.72; H, 6.75. C14H14O2 requires C,
78.48; H, 6.59%).
the oily tetralone 4 (128 mg, 63%); IR υmax(cm−l): 1685 (CO), 1080;
1
MS (m/z): 205 (M+)+1 (11%), 173 (M+-MeOH)+1 (100%); H δ(ppm)
:
2.24 (s, 3H), 2.32 (s, 3H) (5-Me, 8-Me), 3.39 (s,3H, OMe), 4.49
(s, 1H, H-4), 7.16 (s, 1H), 7.63 (s, 1H) (H-6,H-7); 13C δ(ppm): 18.51
(5-Me), 20.91 (8-Me), 24.67 (C-2), 32.41 (C-3), 56.68 (OMe), 71.76
(C-4), 124.88 (C-7), 131.92 (C-10), 136.52 (C-6), 137.28 (C-8, C-9);
138.08 (C-5), 198.59 (C-1) (Found: C, 76.67; H, 8.04. C13H16O2
requires C, 76.44; H, 7.90%).
5,8-Dimethyl-4-methoxy-2-methoxycarbonyl-α-tetralone (5): To a
solution of the ketone 4 (600 mg, 2.3 mmol) in dimethoxyethane
(10 mL) was added sodium hydride (340 mg, 60% dispersion in min-
eral oil), and dimethyl carbonate (3.91 g, 0.044 mol). The resulting
mixture was subjected to microwave irradiation apparatus with a
power 280W for 1h, cooled, acidified with acetic acid, diluted with
water and extracted with ether. The ether extract was washed, dried
and evaporated to give a pale yellow oil which on chromatographic
purification (hexane:ether 9:1) afforded ketoester 5 (308mg, 40%);
IR υmax (cm−1): 1744 (ester CO), 1683 (CO); MS (m/z) 261 (M+-1)
(100%), 229 (M+-1-MeOH) (50%), 197 (M+-1-2MeOH) (30%);
1H δ(ppm): 2.33 (s, 3H), 2.37 (s, 3H) (5,8-Me), 3.29 (s, 3H,OMe), 3.81
(s, 3H, OMe) (4,8-OMe), 4.51–4.48 (dd, 1H, J = 2 Hz) (C-2),7.09
(s, 1H), 7.59 (s,1H) (C-6, C-7), 12.34 (s, 1H, C-1); 13C δ(ppm) (keto
form 5): 18.38 (5-Me), 24.92 (8-Me), 28.09 (C-3), 51.59 (11-OMe),
52.21 (C-2), 55.75 (4-OMe), 69.99 (C-4), 133.80 (C-6), 136.42 (C-7),
136.62 (C-9), 137.12 (C-5), 138.11 (C-10), 138.65 (C-8), 173.02
(C-11), 193.60 (C-1); (enol form 6): 18.58 (8-Me), 21.11 (5-Me),
48.86 (C-3), 51.59 (11-OMe), 55.75 (4-OMe), 69.99 (C-4), 93.23
(C-2), 123.06 (C-6), 125.37 (C-5), 129.39 (C-7), 130.88 (C-9), 132.17
(C-8), 137.44 (C-10), 164.52 (C-1), 170.99 (C-11) (Found: C, 68.99;
H, 7.16. C15H18O4 requires C, 68.68; H, 6.92%).
Ar-Occidol [1-Methyl-1-(5,8-dimethyl-2-naphthyl)ethanol] (11): A
solution of the ester 10 (20 mg, 0.09 mmol) in THF (3 mL) was added
over a period of 5 min to a stirred methyl-lithum solution (1.38 M,
2 mL) under an argon atmosphere. The resulting solution was then
heated for 2 h, cooled, diluted with water and extracted with ether. The
extract was washed, dried, evaporated and purified by preparative
TLC over silica gel (eluant ether:hexane 2:8) to afford ar-occidol 11
(14 mg, 72%); IR υ(max) (cm−1): 3601–3150 (OH), 1600 (aromatic);
MS (m/z): 214 (M+) (86%), 199 (M+-CH3) (67%), 196 (M+-H2O)
1
(69%), 181 (M+-H2O-CH3); H δ(ppm): 7.91–7.89 (d, 1H, J = 8.8 Hz,
4-H), 7.82–7.81 (d, 1H, J = 1.9 Hz, 1-H), 7.57–7.53 (dd, 1H, J = 1.9
Hz, 8.8 Hz, 3-H), 7.45 (s, 1H, 6-H), 7.12 (s, 1H, 7-H), 2.63 (s, 3H,
5-Me), 2.44 (s, 3H, 8-Me), 1.65 (s, 6H, 11-Me); 13C δ(ppm): 19.12
(Me-5), 21.59 (Me-8), 31.68 ( 2xMe-11), 72.67 (C-11), 122.35 (C-4),
122,40 (C-3), 124.05 (C-1), 125.49 (C-7), 128.80 (C-6), 129.75 (C-8),
133.67 (C-5), 133.77 (C-10), 135.38 (C-9), 146.16 (C-2).
5,8-Dimethyl-2-methoxycarbonyl-1-hydroxynaphthalene (8): To a
suspension of DDQ (332 mg, 1.3 equiv) in dry dioxane (20 mL) was
added the keto-enol ester 5 and 6 (260 mg, 1 mmol) and the mixture
was heated under reflux for 50 h. under an inert atmosphere. The solu-
tion was cooled and filtered. The filtrate was washed with a solution
of sodium bicarbonate (5%), brine, dried and evaporated. The result-
ing material on chromatographic purification (hexane:ether 9:1)
afforded the naphthol 8 (74 mg, 32%), m.p. 71–72 °C IR (film)
Received 17 March 2010; accepted 1 April 2010
Paper 1000002 doi: 10.3184/030823410X12724713859947
Published online: 9 June 2010
υ
max (cm−1): 3419 (OH), 1662 (CO); MS (m/z): 230 (M+) (72% ), 198
(M+-MeOH) (100%); 1H δ(ppm) 2.48 (s,3H), 2.61 (s, 3H) (Me at C-8 and
C-5), 3.97 (s, 3H, OMe), 7.26 (s,1H), 8.05 (s, 1H) (H-6, H-7); 7.34
(d, 1H, J = 9.03 Hz ), 7.69 (d, 1H, J = 9.03 Hz) (H-3, H-4), 11.89
(s, 1H, OH); 13C δ(ppm): 19.36 (s, 3H), 21.31 (s, 3H) (5-Me, 8-Me),
52.17 (OMe), 105.35 (C-2), 114.74 (C-4), 120.85 (C-7), 122.93 (C-3),
124.90 (C-5), 132.34 (C-6), 133.83 (C-9), 134.48 (C-8), 135.12
(C-10), 160,63 (C-1), 171.50 (C-11) (Found: C, 73.24; H, 6.31.
C14H14O3 requires C, 73.02; H, 6.13 %).
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