[57598-33-1]  · C12H15NO2  · 2-(o-Methoxyphenyl)-4,4-dimethyl-2-oxazoline  · (MW 205.28)

(electrophilic arylation of Grignard reagents, lithium reagents, and lithium amides by methoxy displacement; synthesis of o-substituted benzoic acids, o,o-biphenyls, and o-aminobenzoates3,4)

Alternate Name: 2-(2-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole.

Preparative Method: prepared from o-anisic acid and 2-amino-2-methyl-1-propanol in two steps.3,4

Handling, Storage, and Precautions: no special precautions are warranted.

General Considerations.

The title reagent, upon treatment with Grignard and organolithium reagents, undergoes displacement of the methoxy group (2-oxazolines are quite resistant to nucleophilic attack; Table 1).4,5

Many nucleophiles have been used for this methoxy displacement reaction, and a wide array of substitution on the aryl group of the oxazoline is also tolerated. Thus, this method allows facile preparation of unsymmetrical biphenyls as their ortho carboxylic acids and esters, after hydrolysis of the oxazoline (eqs 1-3).6-8

Moreover, the oxazoline can be directly converted to a variety of other functional groups, including ketones, alcohols, aldehydes, and nitriles.1,2 Similar arylations occur by nucleophilic aromatic substitution of 2-(o-fluoroaryl)9-11 and 2-(o-aminonaphthyl)oxazolines with Grignard and organolithium reagents. An extension of this methodology incorporates the lithio salts of primary and secondary amines as nucleophiles12,13 (eq 4).

2-(o-Methoxyaryl)oxazolines derived from amino alcohols other than 2-amino-2-methyl-1-propanol can also participate in the above described methodology. For example, o-anisic acid and ethanolamine combine to form the corresponding oxazoline (75%), and on treatment with a Grignard reagent, the o-alkylated aryl oxazoline is obtained (eq 5).14

Optically active biphenyls and binaphthyls can be prepared by using the appropriately substituted chiral oxazoline precursors (eqs 6 and 7).15-18

The same process is applicable to methoxy displacement from enantiomerically pure 2-(o-methoxyaryl)oxazolines. Optically active biphenyls can be rapidly accessed in this manner.19 For example, an enantiomerically pure (S)-valinol-derived oxazoline reacts with Grignard reagents to form C2-symmetric biaryls after further elaboration (eq 7).20

A similar transformation of o-methoxybenzaldehydes to o-substituted benzaldehydes has been accomplished by conversion of the benzaldehyde to N-(2,4-dimethyl-3-pentyl)imine, which is resistant to nucleophilic attack at the C=N bond.21 Similar methodology has been utilized to prepare enantiomerically enriched binaphthyls.22 Likewise, bulky esters ortho to a methoxy group can be substituted for the oxazoline group in the above mentioned protocol, thus affording biaryls23 and binaphthyls.24 In addition, ortho-substituted fluoroaryl oxazoles undergo nucleophilic aromatic substitution reactions.25

Related Reagents.

(4S,5S)-4-Methoxymethyl-2-methyl-5-phenyl-2-oxazoline; 2,4,4-Trimethyl-2-oxazoline.

1. Gant, T. G.; Meyers, A. I. T 1994, 50, 2297.
2. Reuman, M.; Meyers, A. I. T 1985, 41, 837.
3. Meyers, A. I.; Mihelich, E. D. JACS 1975, 97, 7383.
4. Meyers, A. I.; Gabel, R.; Mihelich, E. D. JOC 1978, 43, 1372.
5. (a) Meyers, A. I.; Hutchings, R. H. TL 1993, 34, 6185. (b) Castedo, L.; Cid, M. M.; Seijas, J. A.; Villaverde, M. C. TL 1991, 32, 3871. (c) Comber, M. F.; Sargent, M. V. CC 1991, 190. (d) Ellefson, C. R.; Prodan, K. A.; Brougham, L. R.; Miller, A. JMC 1980, 23, 977. (e) Findlay, J. A.; Daljeet, A.; Murray, P. J.; Rej, R. N. CJC 1987, 65, 427. (f) Ladd, D. L.; Weinstock, J.; Wise, M.; Gessner, G. W.; Sawyer, J. L.; Flaim, K. E. JMC 1986, 29, 1904. (g) Patel, H. A.; MacLean, D. B. CJC 1983, 61, 7. (h) Perchonock, C. D.; Uzinskas, I.; McCarthy, M. E.; Erhard, K. F.; Gleason, J. G.; Wasserman, M. A.; Muccitelli, R. M.; DeVan, J. F.; Tucker, S. S.; Vickery, L. M.; Kirchner, T.; Weichman, B. M.; Mong, S.; Scott, M. O.; Chi-Rosso, G.; Wu, H.-L.; Crooke, S. T.; Newton, J. F. JMC 1986, 29, 1442. (i) Rizzacasa, M. A.; Sargent, M. V. JCS(P1) 1991, 841. (j) Saha, A.; Nasipuri, D. TL 1991, 32, 3213. (k) Chew, R.; Hynes, R. C.; Harpp, D. N. JOC 1993, 58, 4398.
6. Gschwend, H. W.; Hamdan, A. JOC 1982, 47, 3652.
7. Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A. L.; Pierce, M. E.; Price, W. A.; Santella, J. B.; Wells, G. J.; Wexler, R. R.; Wong, P. C.; Yoo, S.-E.; Timmermans, P. B. M. W. M. JMC 1991, 34, 2525.
8. Patten, A. D.; Nguyen, N. H.; Danishefsky, S. J. JOC 1988, 53, 1003.
9. Avila, W. B.; Crow, J. L.; Utermoehlen, C. M. J. Chem. Educ. 1990, 67, 350.
10. Cram, D. J.; Katz, H. E.; Dicker, I. B. JACS 1984, 106, 4987.
11. Meyers, A. I.; Williams, B. E. TL 1978, 223.
12. Gant, T. G.; Meyers, A. I. JACS 1992, 114, 1010.
13. Watthey, J. W. H.; Gavin, T.; Desai, M.; Finn, B. M.; Rodebaugh, R. K.; Patt, S. L. JMC 1983, 26, 1116.
14. (a) Levin, J. I.; Weinreb, S. M. JOC 1984, 49, 4325. (b) Levin, J. I.; Weinreb, S. M. JACS 1983, 105, 1397.
15. O'Malley, S.; Kodadek, T. JACS 1989, 111, 9116.
16. Wilson, J. M.; Cram, D. J. JACS 1982, 104, 881.
17. Wilson, J. M.; Cram, D. J. JOC 1984, 49, 4930.
18. Meyers, A. I.; Lutomski, K. A. JACS 1982, 104, 879.
19. (a) Meyers, A. I.; Himmelsbach, R. J. JACS 1985, 107, 682. (b) Warshawsky, A. M.; Meyers, A. I. JACS 1990, 112, 8090. (c) Rizzacasa, M. A.; Sargent, M. V. JCS(P1) 1991, 845. (d) Rizzacasa, M. A.; Sargent, M. V. CC 1991, 278.
20. Meyers, A. I.; Meier, A.; Rawson, D. J. TL 1992, 33, 853.
21. Flippin, L. A.; Carter, D. S.; Dubree, N. J. P. TL 1993, 34, 3255.
22. Shindo, M.; Koga, K.; Tomioka, K. JACS 1992, 114, 8732.
23. Hattori, T.; Suzuki, T.; Miyano, S. CC 1991, 1375.
24. Hotta, H.; Suzuki, T.; Miyano, S. CL 1990, 143.
25. Cram, D. J.; Bryant, J. A.; Doxsee, K. M. CL 1987, 19.

Todd D. Nelson & Albert I. Meyers

Colorado State University, Fort Collins, CO, USA

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