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Preparative Methods: by metalation of anisole in anhydrous ether with 2 equiv of n-Butyllithium and 2 equiv of N,N,N�,N�-Tetramethylethylenediamine at 25 °C for 1-2 h.1a Under these conditions a >95% conversion is obtained. If no excess of BuLi or other impurities can be tolerated, then the reagent can be prepared by metal halogen exchange of o-bromoanisole and purified by crystallization.1b Isolated o-lithioanisole is a pyrophoric white powder.
Form Supplied in: the reagent is prepared in situ as needed.
Handling, Storage, and Precautions: must be prepared and handled in an inert atmosphere, as for other organolithium reagents.
Several factors influence the site and extent of metalation of an aromatic system containing a substituent group (DMG) that directs metalation.2 The methoxy group of anisole was the earliest such group to be identified.3 The important factors affecting the intrinsic (structural) effectiveness of such groups are: (1) the coordinating ability of the heteroatom in the DMG, (2) the electron-withdrawing (o-hydrogen-acidity enhancing) ability of the DMG,4 and (3) the size of the ring structure resulting from the formation of the coordinated o-lithio intermediate.5 The methoxy group occupies an intermediate position in the ranking of DMGs to direct metalation.
Early investigations of this reaction reported conversions of only 50-65% to the o-lithio intermediate.6,7 Later work revealed that the reaction could be accelerated by sonication,9 and by addition of a stoichiometric amount of N,N,N�,N�-Tetramethylethylenediamine (TMEDA),8 with a yield of 73% of the o-trimethylsilyl derivative being reported. A better procedure, that affords 95% (GC yield) of the o-trimethylsilyl derivative,1 involves use of 2 equiv each of n-Butyllithium and TMEDA. Concentration also plays a role; solutions of anisole in the 1M range appear to be best. Significantly lower amounts of TMEDA are nearly as effective in promoting the metalation. For highest yields the reaction is run at 25 °C in ether solvent for about one hour.
A number of other monosubstituted anisoles have been metalated. Varying yields of product derived from metalation ortho to the methoxy group have been obtained from p-F,24-27 p-Cl,24,28 p-Br,24 and p-I24 anisole. The best yields that can be obtained from these systems lie in the 50-60% range because of the opportunities for various side reactions involving the halogens. p-Methylanisole has been metalated in about 30% yield29 and 1,4-dimethoxybenzene in about 75% yield.8 The latter compound, by the addition of TMEDA to the metalation system, can be made to form a 2,5-dilithio intermediate.
A number of directing groups related to the methoxy group also provide good yields of the o-lithio intermediate. These include the methoxymethoxy group (OCH2OMe),39 the carbamate group (OC(O)NEt2)2,40 the methoxyethoxy group (OCH2CH2OMe),41,44 the 2-(trimethylsilyl)ethoxymethoxy system (OCH2OCH2CH2SiMe3),42 and the dimethylaminoethoxy group (OCH2CH2NMe2).43,44 Some of these derivatives can be transformed into the phenol upon hydrolysis or other suitable treatment. Lastly, phenol itself can undergo o-lithiation.45 For the first three of the above-named directors the yields of o-lithiation are good.
1. (a) Slocum, D. W.; Moon, R.; Thompson, J.; Coffey, D. S.; Li, J. D.; Slocum, M. G.; Siegel, A.; Gayton-Garcia, R. TL 1994, 35, 385. (b) Glaze, W. H.; Ranade, A. C. JOC 1971, 36, 3331.
2. (a) Gschwend, H. W.; Rodriquez, H. R. OR 1979, 26, 1. (b) Snieckus, V. CRV 1990, 90, 879.
3. (a) Gilman, H.; Bebb, R. L. JACS 1939, 61, 109. (b) Wittig, G.; Fuhrmann, G. CB 1940, 73, 1197.
4. A determination of the acidity of a number of o-H's in certain substituted benzenes has been published: (a) Fraser, R. R.; Bresse, M.; Mansour, T. S. CC 1983, 620. (b) Fraser, R. R.; Bresse, M.; Mansour, T. S. JACS 1983, 105, 7790.
5. The o-lithio intermediate formed from the metalation of anisole contains, formally, a four- or a pseudo five-membered ring. For an initial proposal of a pseudo five-membered ring intermediate, see: (a) Slocum, D. W.; Sugarman, D. I. In Polyamine-Chelated Alkali Metal Compounds; Langer, A. W., Ed.; American Chemical Society: Washington, 1974; p 232. For a more recent consideration of the question of ring size, see: (b) Bauer W.; Schleyer, P. v. R. JACS 1989, 111, 7191.
6. Finnegan, R. A.; Altschuld, J. W. JOM 1967, 9, 193.
8. Crowther, G. P.; Sundberg, R. J.; Sarpeshkar, A. M. JOC 1984, 49, 4657.
9. Einhorn, J; Luche, J. L. JOC 1987, 52, 4124.
10. Harder, S.; Boersma, J.; Brandsma, L. van Mier, G. P. M.; Kanters, J. A. JOM 1989, 364, 1.
11. Harder, S.; Boersma, J.; Brandsma, L.; Kanters, J. A. JOM 1988, 339, 7.
12. Wehman, E.; Jastrzebski, J. T. B. H.; Ernsting, J-M; Grove, D. M.; van Koten, G. JOM 1988, 353, 133.
13. Lai, A.; Monduzzi, M.; Cabiddu, S.; Floris, C.; Melis, S. G 1987, 117, 759.
14. van Eikema Hommes, N. J. R.; Schleyer, P. v. R. AG(E) 1992, 31, 755.
15. Klumpp, G. W.; Sinnige, M. J. TL 1986, 27, 2247.
16. Beak, P.; Siegel, B. JACS 1974, 96, 6803.
17. Slocum, D. W.; Koonsvitsky, B. P. JOC 1973, 38, 1675.
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19. Harmon, T. E.; Shirley, D. A. JOC 1974, 39, 3164.
20. Slocum, D. W.; Jennings, C. A. JOC 1976, 41, 3653.
21. Beak, P.; Brown, R. A. JOC 1979, 44, 4463.
22. Meyers, A. I.; Lutomski, K. JOC 1979, 44, 4464.
23. Cabiddu, S.; Melis, S.; Piras, P. P.; Secci, M. JOM 1977, 132, 321.
24. Eaborn, C.; Walton, D. R. M. JOM 1965, 3, 169.
25. Furlano, D. C.; Calderon, S. N.; Chen, G.; Kirk, K. L. JOC 1988, 53, 3145.
26. Katsoulos, G.; Takagishi, S.; Schlosser, M. SL 1991, 731.
27. Slocum, D. W.; Coffey, D. S.; Siegel, A.; Grimes, P. TL 1994, 35, 389.
28. Fitt, J. J.; Gschwend, H. W.; Hamdan, A.; Boyer, S. K.; Haider, H. M. JOC 1982, 47, 3658.
29. Letsinger, R. L.; Schnizer, A. W. JOC 1951, 16, 869.
30. Slocum, D. W.; Book, G.; Jennings, C. A. TL 1970, 3443.
31. (a) Adejare, A.; Miller, D. D. TL 1984, 25, 5597. (b) For a theoretical discussion, see: Saa, J. M.; Deya, P. M.; Suner, G. A.; Frontera, A. JACS 1992, 114, 9093.
32. Morey, J.; Costa, A.; Deya, P. M.; Suner, G; Saa, J. M. JOC 1990, 55, 3902.
33. Shirley, D. A.; Cheng, C. F. JOM 1969, 20, 251.
34. Sunthankar, S. V.; Gilman, H. JOC 1951, 16, 8.
35. Trecourt, F.; Mallet, M.; Marsais, F.; Queguiner, G. JOC 1988, 53, 1367.
36. Jen, K.-Y.; Eckhardt, H.; Jow, T. R.; Shacklette, L. W.; Elsenbaumer, R. L. CC 1988, 215.
37. Wada, A.; Yamamoto, J.; Hamaoka, Y.; Ohki, K.; Nagai, S.; Kanatomo, S. JHC 1990, 27, 1831.
38. Slocum, D. W.; Koonsvitsky, B. P.; Ernst, C. R. JOM 1972, 38, 125.
39. (a) Ronald, R. C.; Winkle, M. R. T 1983, 39, 2031. (b) Furukawa, Y.; Yamagiwa, Y.; Kamikawa, T. CC 1986, 1234. (c) Townsend, C. A.; Bloom, L. M. TL 1981, 22, 3923. (d) Harvey, R. G.; Cortez, C.; Ananthanarayan, T. P.; Schmolka, S. JOC 1988, 53, 3936.
40. Sibi, M. P.; Snieckus, V. JOC 1983, 48, 1935.
41. Ellison, R. A.; Kotsonis, F. N. JOC 1973, 38, 4192.
42. Sengupta, S.; Snieckus, V. TL 1990, 31, 4267.
43. Hanson, R. N.; Tonnesen, G. L.; McLaughlin, W. H.; Bloomer, W. D.; Seitz, D. E. J. Labeled Comp. Radiopharm. 1981, 18, 128.
44. Wada, A.; Kanatomo, S.; Nagai, S. CPB 1985, 33, 1016.
45. Posner, G. H.; Canella, K. A. JACS 1985, 107, 2571.
46. Grunewald, G. L.; Arrington, H. S.; Bartlett, W. J.; Reitz, T. J.; Sall, D. J. JMC 1986, 29, 1972.
47. Parker, K. A.; Koziski, K. A. JOC 1987, 52, 674.
48. Ng, G. P.; Dawson, C. R. JOC 1978, 43, 3205.
49. Meyers, A. I.; Reuman, M.; Gabel, R. A. JOC 1981, 46, 783.
50. Wikstrom, H.; Elebring, T.; Hallnemo, G.; Andersson, B.; Svensson, K.; Carlsson, A.; Rollema, H. JMC 1988, 31, 1080.
51. Yamada, K.; Yazawa, H.; Uemura, D.; Toda, M.; Hirata, Y. T 1969, 25, 3509.
52. Cram, D. J.; Carmack, R. A.; deGrandpre, M. P.; Lein, G. M.; Goldberg, I.; Knobler, C. B.; Maverick, E. F.; Trueblood, K. N. JACS 1987, 109, 7068.
53. Hasseberg, H.-A.; Gerlach, H. HCA 1988, 71, 957.
54. Reed, J. N.; Snieckus, V. TL 1984, 25, 5505.
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