A practical and cost-effective synthesis of 6,7-dimethoxy-2-tetralone

Article abstract of DOI:10.1055/s-1999-3638

The cyclic ketone, 6,7-dimethoxy-2-tetralone, a versatile starting material for many dopaminergic compounds, can be prepared practically, cost- effectively and in good overall yield. The synthesis starts from readily available 3,4-dimethoxyphenylacetic ac

Full text of DOI:10.1055/s-1999-3638

SHORT PAPER
2033
A Practical and Cost-Effective Synthesis of 6,7-Dimethoxy-2-tetralone
Amjad M. Qandil, David W. Miller, David E. Nichols*
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West
Lafayette, IN 47907, USA
Received 26 June 1999; revised 1 September 1999
In this paper we report a practical, very cost-effective and
Abstract: The cyclic ketone, 6,7-dimethoxy-2-tetralone, a versatile
overall high yielding methodology to prepare the desired
tetralone. The method utilizes easily available and inex-
pensive starting material and reagents. The synthesis
starting material for many dopaminergic compounds, can be pre-
pared practically, cost-effectively and in good overall yield. The
synthesis starts from readily available 3,4-dimethoxyphenylacetic
acid. Ring iodination gave the 2-iodo-4,5-dimethoxy acid, which starts with the high-yielding iodination of 3,4-dimethoxy-
was converted to its methyl ester. Palladium (II)-catalyzed Heck
cross coupling afforded the expected unsaturated diester, which was
phenylacetic acid (2) with iodine monochloride to afford
the iodoacid 3 that was then esterified to yield methyl 2-
then catalytically hydrogenated. Dieckmann condensation, fol-
iodo-4,5-dimethoxyphenylacetate (4). These two interme-
lowed by careful decarboxylation led to the desired 2-tetralone. Re-
diates have been reported in the literature,20-22 but our se-
agents used in subsequent reactions are inexpensive and readily
quence affords a better overall yield using less expensive
reagents. This ester was subjected to Heck cross coupling
conditions23-28 using only 1 mole% of dichlorobis-(triphe-
nylphosphine)palladium(II), a highly stable low-cost
form of palladium(II).29 The cinnamate 5, obtained in ex-
cellent yield, was catalytically reduced with hydrogen
over 10% palladium on carbon. This reaction was ex-
tremely fast, and after filtration of the catalyst and evapo-
ration of the solvent afforded analytically pure propionate
6 in quantitative yield. The diester was then treated with
potassium tert-butoxide in Et2O, and the precipitated po-
tassium salt was filtered, dried and then decarboxylated
using a DMSO/H2O/LiCl reagent system.30,31 The H2O
was added in the form of concentrated HCl to neutralize
the potassium salt from the previous reaction. The 2-te-
tralone was purified as its bisulfite adduct, which upon
treatment with sodium carbonate liberated to the ketone.
The overall yield when starting from intermediate 5 is
59.5% while when starting from intermediate 2 is 47%.
This methodology provides the option of synthesizing the
tetralone and storing it either as the ketone or the bisulfite
adduct, or accumulating the very stable cinnamate inter-
mediate 5 in large quantities and synthesizing the tetral-
one from it on demand, in a fast and practical way.
available. This method appears practical for large-scale synthesis of
the target tetralone, compared with other procedures reported in the
literature.
Key words: 6,7-dimethoxy-2-tetralone, esterification, Heck cross
coupling, Dieckmann condensation, decarboxylation
The cyclic ketone, 6,7-dimethoxy-2-tetralone (1) is a key
starting material for the synthesis of the full dopamine ag-
onist dihydrexidine and its derivatives.1,2 It has also been
used to synthesize various aminotetralins,3-7 isoquinoline
derived dopaminergic agents,8 other catecholamine mim-
icking agents,9,10 natural alkaloids,11 and cyclic amino ac-
ids.12 The accessibility of this material is hampered by
high cost ($131/500 mg, Aldrich), and tedious and/or ex-
tremely low yielding synthetic pathways when prepared.
There have been several syntheses reported for this com-
pound, the most widely employed perhaps being the reac-
tion of 3,4-dimethoxyphenylacetyl chloride with ethylene
gas in the presence of aluminum chloride as a cata-
lyst.6,13,14 This method suffers from difficulty in optimiz-
ing reaction parameters (e.g. ethylene gas flow), a very
tedious workup, and despite numerous reactions in our
laboratory where we attempted to optimize each variable,
always afforded yields of less than 30%. Ketone
transposition13-16 of the corresponding 1-tetralone has
found limited success, but it is a multi-step synthesis that
requires the preparation of the 1-tetralone starting materi-
al. Other reported methods employ silylenol ethers,17
rhodium catalyzed cyclization of diazoketones,18 or Pum-
merer rearrangement of a β-keto sulfoxide.7,19 Based on
our own experience with virtually all of these approaches,
we concluded that no really efficient synthesis of this im-
portant material had been developed.
Mps were determined with a Thomas-Hoover apparatus and are un-
corrected. 1H NMR spectra were obtained with a Varian VXR500
(500 MHz) or a Bruker AXR300 (300 MHz) NMR instrument in
CDCl3 and chemical shifts are reported in d values (ppm) relative to
an internal reference of CHCl3 (d 7.24). Chemical ionization (CI)
mass spectra were obtained with a Finnegan 4000 quadrupole mass
spectrometer. The ionization gas for CIMS was isobutane, unless
otherwise noted. Elemental analyses were performed by the mi-
croanalysis laboratory in the Chemistry Department at Purdue Uni-
versity.
2-Iodo-4,5-dimethoxyphenylacetic Acid (3)
To a soln of 3,4-dimethoxyphenylacetic acid (100 g, 0.51 mol) in
CH2Cl2 (600 mL) and HOAc (100 mL), iodine monochloride (27.6
mL, 87.76 g, 0.54 mol) in CH2Cl2 (500 mL) was added dropwise via
a dropping funnel. The reaction mixture was stirred overnight and
was then quenched with sat. sodium thiosulfate, and the organic lay-
Synthesis 1999, No. 12, 2033–2035 ISSN 0039-7881 © Thieme Stuttgart · New York

2034
A. M. Qandil et al.
SHORT PAPER
tration to remove carbon, cooling afforded 67.24 g (96%) of a white
crystalline solid, mp: 95−97 °C.
IR (film): v = 2951, 1735, 1714, 1602, 1518, 1436, 1272, 1170 cm-1.
1H NMR: d = 3.65 (s, 3H, OCH3), 3.69 (s, 2H, ArCH2CO), 3.75 (s,
3H, OCH3), 3.85 (s, 6H, OCH3), 6.24 (d, 1H, ArCH = CHCO,
J = 15 Hz), 6.7 (s, 1H, ArH), 7.03 (s, 1H, ArH), 7.84 (d, 1H,
ArCH = CHCO, J = 15 Hz).
13C NMR (CDCl3, 75 MHz): d = 37.9, 51.6, 52.1, 55.8, 108.7,
113.4, 117.4, 125.9, 127.2, 141.3, 148.4, 150.7, 167.4, 171.5.
CIMS: 294/295 (47/13%), 263/264 (100/15%).
Anal. Calcd for C15H18O6: C, 61.22, H, 6.16. Found: C, 61.31, H,
6.13.
Methyl 3-[4,5-Dimethoxy-2-(2-methoxy-2-oxoethyl)phenyl]-
propanoate (6)
Cinnamate 5 (50 g, 0.17 mol) was dissolved in hot EtOH (1 L) and
to it was added 10% palladium on carbon (5 g). The reaction mix-
ture was shaken in a Parr hydrogenator at 50 psi until H2 uptake
ceased. The suspension was filtered over a thick pad of Celite and
the solvent was evaporated to afford a colorless oil in quantitative
yield.
IR (film): v = 2952, 1731, 1609, 1520, 1436, 1276, 1197 cm-1.
1H NMR: d = 2.52 (t, 2H, ArCH2CH2, J = 7 Hz), 2.86 (t, 2H,
ArCH2CH2CO, J = 7 Hz), 3.56 (s, 2H, ArCH2CO), 3.62 (s, 3H,
OCH3), 3.64 (s, 3H, OCH3), 3.80 (s, 6H, OCH3), 6.65 (s, 1H, ArH),
6.67 (s, 1H, ArH).
13C NMR (CDCl3, 75 MHz): d = 27.3, 34.9, 37.5, 51.2, 51.7, 55.5,
112.0, 113.3, 123.6, 131.0, 147.0, 147.8, 171.8, 172.9.
Scheme
CIMS: 297 (100%), 265 (17%), 237 (53%).
Anal. Calcd for C15H18O6: C, 60.80, H, 6.80. Found: C, 60.91, H,
6.88.
er was washed with brine (3 ¥ 150 mL), dried (MgSO4) and filtered.
The solvent was then evaporated and the residue was triturated with
Et2O to yield 142.2 g (86%) of a light-orange solid, mp: 161-164 °C
(Lit.21 mp: 164−165 °C).
6,7-Dimethoxy-2-tetralone (1)
Potassium tert-butoxide (Aldrich, 20 g, 0.178 mol) was stirred in
dry Et2O (1 L) under an Ar atm. To the suspension a solution of 6
(48 g, 0.162 mol) in anhyd Et2O (500 mL) was added dropwise via
a dropping funnel. After stirring for 30 min, the resulting suspen-
sion was filtered. The cake was washed repeatedly with Et2O and
dried under high vacuum to afford a quantitative yield of the potas-
sium enolate as a tan solid. This potassium salt (10 g, 33.11 mmol)
and LiCl (1.684 g, 39.73 mmol) were dissolved in DMSO (23 mL).
While stirring, conc. HCl (3.3 mL, 40 mmol) was added rapidly and
the flask was placed in an oil bath preheated to 125 ∞C and stirred
under Ar for 5 h. The reaction mixture was cooled and diluted with
EtOAc (500 mL). The organic layer was washed with H2O (3 ¥ 200
mL), dried (MgSO4), filtered, and the solvent evaporated. The resi-
due was dissolved in a minimum amount of Et2O, a freshly prepared
soln of sodium bisulfite (10.33 g, 10 mL of H2O) was added and the
biphasic mixture was vigorously stirred overnight. The precipitate
was filtered, air dried, and then dissolved in H2O. Excess solid
Na2CO3 was added to the soln to precipitate 1. The crystals were fil-
tered and washed with H2O to afford 4.23 g (62%) of white crystals,
mp: 84−86 °C (Lit.6 mp: 85.5−86.5 °C).
1H NMR: d = 3.74 (s, 2H, ArCH2CO), 3.81 (s, 6H, OCH3), 6.76 (s,
1H, ArH), 7.2 (s, 1H, ArH).
Methyl 2-Iodo-4,5-dimethoxyphenylacetate (4)
Thionyl chloride (75 mL) was added dropwise to a solution of 2-
iodo-4,5-dimethoxyphenylacetic acid (3) (138.2 g, 0.43 mol) dis-
solved in anhyd MeOH (1 L). The reaction mixture was stirred over-
night at r.t., then concentrated and the residue was taken up into
CH2Cl2 and washed with H2O and sat. aq NaHCO3. The organic lay-
er was dried (MgSO4), filtered and the solvent was evaporated. The
residue was crystallized from EtOAc:hexane to afford 132.2 g
(92%) of a white solid, mp: 76−78 °C (Lit.21 mp: 72−73 °C).
1H NMR: d = 3.66 (s, 3H, OCH3), 3.67 (s, 2H, ArCH2CO), 3.79 (s,
6H, OCH3), 6.76 (s, 1H, ArH), 7.15 (s, 1H, ArH).
Methyl (E)-3-[4,5-Dimethoxy-2-(2-methoxy-2-oxoethyl)phen-
yl]prop-2-enoate (5)
Methyl 2-iodo-4,5-dimethoxyphenyl acetate (4) (80 g, 0.238 mol)
was dissolved in MeCN (300 mL) and placed under an Ar atm. To
the solution was added Et3N (99.50 mL, 72.25 g, 0.714 mol), methyl
acrylate (85.91 mL, 81.96 g, 0.952 mol) and dichlorobis(tri-
phenylphosphine)palladium(II) (1 g, 1 mol%). The reaction mixture
was heated at reflux for 6 h. The cooled mixture was then concen-
trated and the residue was taken up into EtOAc (1 L) and washed
twice with H2O, several times with 2N HCl until the aqueous layer
remained acidic, and finally with H2O. The organic layer was dried
(MgSO4), filtered and the solvent was evaporated. The residue was
dissolved in boiling EtOH and decolorized with charcoal. After fil-
1H NMR: d = 2.56 (t, 2H, ArCH2CH2, J = 7 Hz), 3.00 (t, 2H,
ArCH2CH2CO, J = 7 Hz), 3.51 (s, 2H, ArCH2CO), 3.86 (s, 3H,
OCH3), 3.88 (s, 3H, OCH3), 6.62 (s, 1H, ArH), 6.74 (s, 1H, ArH).
Acknowledgement
This work was supported by NIH grant MH42705 and by the Bri-
stol-Myers Squibb Company.
Synthesis 1999, No. 12, 2033–2035 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
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A Practical and Cost-Effective Synthesis of 6,7-Dimethoxy-2-tetralone
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Article Identifier:
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Synthesis 1999, No. 12, 2033–2035 ISSN 0039-7881 © Thieme Stuttgart · New York