SHORT PAPER 2033 Synthesis 1999, No. 12, 2033–2035 ISSN 0039-7881 © Thieme Stuttgart · New York 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 Abstract: The cyclic ketone, 6,7-dimethoxy-2-tetralone, a versatile 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 was converted to its methyl ester. Palladium (II)-catalyzed Heck cross coupling afforded the expected unsaturated diester, which was then catalytically hydrogenated. Dieckmann condensation, fol- lowed by careful decarboxylation led to the desired 2-tetralone. Re- agents used in subsequent reactions are inexpensive and readily 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 transposition 13-16 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. In this paper we report a practical, very cost-effective and overall high yielding methodology to prepare the desired tetralone. The method utilizes easily available and inex- pensive starting material and reagents. The synthesis starts with the high-yielding iodination of 3,4-dimethoxy- phenylacetic acid (2) with iodine monochloride to afford the iodoacid 3 that was then esterified to yield methyl 2- iodo-4,5-dimethoxyphenylacetate (4). These two interme- diates have been reported in the literature, 20-22 but our se- quence affords a better overall yield using less expensive reagents. This ester was subjected to Heck cross coupling conditions 23-28 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 Et 2 O, and the precipitated po- tassium salt was filtered, dried and then decarboxylated using a DMSO/H 2 O/LiCl reagent system. 30,31 The H 2 O 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. Mps were determined with a Thomas-Hoover apparatus and are un- corrected. 1 H NMR spectra were obtained with a Varian VXR500 (500 MHz) or a Bruker AXR300 (300 MHz) NMR instrument in CDCl 3 and chemical shifts are reported in d values (ppm) relative to an internal reference of CHCl 3 (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 CH 2 Cl 2 (600 mL) and HOAc (100 mL), iodine monochloride (27.6 mL, 87.76 g, 0.54 mol) in CH 2 Cl 2 (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-