A Simple and Efficient Method for the Preparation of Hindered Alkyl-Aryl Ethers

Antimitotic natural products that bind to cellular microtubules can be used as anticancer agents, and we are studying the cellular mechanisms of these compounds.1 The fungal metabolite phomopsin A is a key structure in these studies, and we are currently pursuing its synthesis.2 Our retrosynthetic analysis of phomopsin A targeted the chiral tertiary alkyl-aryl ether as a key disconnection within the molecule. Accordingly, we have investigated nucleophilic aromatic substitution (SNAr) as a mild method to synthesize tertiary alkyl-aryl ethers. In general, alkoxides can serve as bases or nucleophiles, and alkoxides have also been shown to engage in single electron transfer (SET) processes.3 Increasing steric congestion close to oxygen generally decreases nucleophilicity, leading to an increase in basic or SET mechanistic manifolds. Tertiary alkoxides are rarely used as nucleophiles and are more often utilized as nonnucleophilic bases. Nevertheless, we have recently observed that hindered tertiary alkoxides are effective nucleophiles in SNAr reactions with activated aryl fluoride electrophiles. A number of methods exist for the synthesis of alkylaryl ethers. Our initial search of the literature suggested that copper-mediated displacements of aryl halides with alkoxides might be promising.4 Preliminary reactions using potassium tert-butoxide were successful; however, attempts with more complex alkoxides proved to be lowyielding. We also investigated SNAr reactions between alkoxides and aryl halides complexed with either chromium tricarbonyl5 or cationic cyclopentadienyl ruthenium,6 as well as the recently reported palladiumcatalyzed cross-coupling reactions with alkoxides as nucleophiles.7 None of these methodologies proved to be suitable for synthesizing the ether linkage found in phomopsin A. Nucleophilic aromatic substitution of nitroactivated aryl halides with phenoxide and primary alkoxide nucleophiles has been shown to be an effective strategy for ether synthesis.8 However, there are far fewer examples of sterically hindered alkoxides being utilized as nucleophiles in this reaction, with most reports describing forcing conditions and moderate-to-low isolated yields of the desired ethers.9 Our studies demonstrate that tertiary alkoxides react quickly and efficiently with activated aryl halides to provide the desired tertiary alkyl-aryl ethers under mild conditions and in good yield. Initial experiments explored the reaction between potassium tert-butoxide and a variety of aryl halide electrophiles (Table 1). Treatment of 1-fluoro-2-nitrobenzene with potassium tert-butoxide at 0 °C using THF, 1,4dioxane, or toluene as the solvent led to complete conversion within 5 min (entry 1).10 The isolated yield was highest using THF, and subsequent experiments used THF as the solvent. We next investigated alternative methods for generating potassium alkoxides. Generation of the alkoxide in THF from tert-butyl alcohol and a solution of potassium bis(trimethylsilyl)amide (KHMDS) worked well. With the majority of substrates, the alcohol and aryl fluoride are dissolved in THF, and the alkoxide is generated in situ by treatment with KHMDS. With tert-butyl alcohol, this protocol provides results identical to those obtained using commercially available KOtBu. As anticipated from previous reports, aryl fluorides are significantly more reactive in SNAr reactions than either aryl chlorides or aryl bromides, and good levels of selectivity are observed when reacting aromatic substrates containing several potential halogen leaving groups (entry 2). Para-substituted aryl fluorides serve as good electrophiles (entry 3), and meta-substituted aryl fluorides, as expected, do not produce the desired ether (entry 4). The presence of an electron donating group on the electrophile is tolerated (entry 5), and nitrile* To whom correspondence should be addressed. Phone: (650) 7234005. Fax: (650) 725-0259. Email: [email protected]. (1) (a) Hamel, E. Med. Res. Rev. 1996, 16, 207. (b) Wilson, L.; Jordan, M. Chem. Biol. 1995, 2, 569. (2) (a) Culvenor, C. C. J.; Edgar, J. A.; Mackay, M. F.; Tetrahedron 1989, 45, 2351. (b) Lacey, E.; Edgar, J. A.; Culvenor, C. C. J.; Biochem. Pharm. 1987, 36, 2133. (3) (a) Guthrie, R. D.; Nutter, D. E.; J. Am. Chem. Soc. 1982, 104, 7478. (b) Buncel, E.; Menon, B. C. J. Am. Chem. Soc. 1980, 102, 3499. (4) (a) Whitesides, G. M.; Sadowski, J. S.; Lilburn J. J. Am. Chem. Soc. 1974, 96, 2829. (b) Lindley, J. Tetrahedron 1984, 40, 1433. (c) Aalten, H. L.; van Koten, G.; Grove, D. M.; Kuilman, T.; Piekstra, O. G.; Hulshof, L. A.; Sheldon, R. A.; Tetrahedron 1989, 45, 5565. (d) Keegstra, M. A.; Peters, T. H. A.; Brandsma, L. Tetrahedron 1992, 48, 3633. (5) (a) Hamilton, J.; Mahaffy, C. A. L. Synth. React. Inorg. Met. Org. Chem. 1986, 16, 1363. (b) Fukui, M.; Endo, Y.; Oishi, T.; Chem. Pharm. Bull. 1980, 28, 3639. (6) (a) Pearson, A. J.; Park, J. G. J. Org. Chem. 1992, 57, 1744. (b) Pearson, A. J.; Bignan, G.; Zhang, P.; Chelliah, M. J. Org. Chem., 1996, 61, 3940. (c) Janetka, J. W.; Rich, D. H. J. Am. Chem. Soc. 1995, 117, 10585. (7) (a) Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413. (b) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 3395. (c) Widenhoefer, R. A.; Zhong, H. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 6787. (8) (a) Beugelmans, R.; Singh, G. P.; Bois-Choussy, M.; Chastanet, J.; Zhu, J. J. Org. Chem., 1994, 59, 5535. (b) Evans, D. A.; Watson, P. S. Tetrahedron Lett. 1996, 37, 3251. (c) Boger, D. L.; Borzilleri, R. M.; Nukui, S.; Beresis, R. T. J. Org. Chem. 1997, 62, 4721. (d) Zhu, J.; Laib, T.; Chastanet, J.; Beugelmans, R.; Angew. Chem., Int. Ed. Engl. 1996, 35, 2517. (9) (a) Day, C. E.; Schurr, P. E.; Emmert, D. E.; TenBrink, R. E.; Lednicer, D. J. Med. Chem. 1975, 18, 1065. (b) DeVries, V. G.; Moran, D. B.; Allen, G. R.; Riggi, S. J.; J. Med. Chem. 1976, 19, 946. (c) Lednicer, D.; Heyd, W. E.; Emmert, D. E.; TenBrink, R. E.; Schurr, P. E.; Day, C. E. J. Med. Chem. 1979, 22, 69. (d) Masada, H.; Oishi, Y. Chem. Lett. 1978, 57-58. (10) All new compounds were fully characterized by spectroscopic and analytical methods. Chart 1 9594 J. Org. Chem. 1998, 63, 9594-9596