A new method for expeditious ketone synthesis from acids via acyl hemiacetals

Journal of Organic Chemistry

Volumn 61, Issue 17, 1996, Pages 6071-6074

  Mattson, Matthew N ^a   Rapoport, Henry ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0000024772     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo9607471     Document Type: Article

References (60)

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8. (c) Wakefield, B. J. Organolithium Methods in Organic Synthesis; Academic Press: San Diego, 1988.
9. (d) Use of lithium carboxylates with Grignard reagents has effectively formed ketones from substituted α-amino acids: Knudsen, C. G.; Rapoport, H. J. Org. Chem. 1983, 48, 2260.
10. S-(2-Pyridyl) thioates and 2-pyridyl esters: (a) Araki, M.; Sakata, S.; Takei, H.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1974, 47, 1777. (b) Reviewed in: Kim, S. Org. Prep. Proc. Int. 1988, 20, 145. Other heterosubstituted esters are noted in ref 1a, p 422.
11. S-(2-Pyridyl) thioates and 2-pyridyl esters: (a) Araki, M.; Sakata, S.; Takei, H.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1974, 47, 1777. (b) Reviewed in: Kim, S. Org. Prep. Proc. Int. 1988, 20, 145. Other heterosubstituted esters are noted in ref 1a, p 422.
12. (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. Reviewed in: Sibi, M. P. Org. Prep. Proc. Int. 1993, 25, 15.
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15. (c) Acyl isoxazolidides: Lubell, W. D.; Jamison, T. F.; Rapoport, H. J. Org. Chem. 1990, 55, 3511.
16. (d) Acyl imidazolides: Staab, H. A.; Jost, E. Liebigs Ann. Chem. 1962, 655, 90.
17. Sibi, M. P.; Stessman, C. C.; Schultz, J. A.; Christensen, J. W.; Lu, J.; Marvin, M. Synth. Commun. 1995, 25, 1255 and references cited therein. N,O-Dimethylhydroxamates have also been efficiently made from the methyl or ethyl esters: ref 2.
18. N,O-Dimethylhydroxylamine hydrochloride, an expensive commercial reagent, can be easily prepared: Goel, O. P.; Krolls, U. Org. Prep. Proc. Int. 1987, 19, 75.
19. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; Wiley: New York, 1991; Chapter 5.
20. (b) Kocienski, P. J. Protecting Groups; Thieme Verlag: New York, 1994.
21. Mild acidic quench of the reaction mixture, followed by washing with mild aqueous base, removes the starting carboxylic acid. The more stable dialkylhydroxamates remain after quenching and washing.
22. A procedure employing iodomethyl methyl ether was used: (a) Pankowski, J.; Winiarski, J. Org. Prep. Proc. Int. 1994, 26, 327. See also: (b) Dardoize, F.; Gaudemar, M.; Goasdoue, N. Synthesis 1977, 567.
23. A procedure employing iodomethyl methyl ether was used: (a) Pankowski, J.; Winiarski, J. Org. Prep. Proc. Int. 1994, 26, 327. See also: (b) Dardoize, F.; Gaudemar, M.; Goasdoue, N. Synthesis 1977, 567.
24. Wade, L. G., Jr.; Gerdes, J. M.; Wirth, R. P. Tetrahedron Lett. 1978, 731.
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27. (c) Ho, T.-L. Synth. Commun. 1979, 9, 267.
28. 1-Methyl-1-methoxyethyl ether formation: Klug, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc. 1972, 94, 7827.
29. THP ester formation: Bernady, K. F.; Floyd, M. B.; Poletto, J. F.; Weiss, M. J. J. Org. Chem. 1979, 44, 1438.
30. (a) THF-esters from 2-chloro-tetrahydrofuran or 2-(diphenylacetyl)tetrahydrofuran: Kruse, C. G.; Jonkers, F. L.; Dert, V.; van der Gen, A. Recl. Trav. Chim. Pays-Bas 1979, 98, 371.
31. (b) THF ethers from 2,3-dihydrofuran: Eliel, E. L.; Nowak, B. E.; Daignault, R. A.; Badding, V. G. J. Org. Chem. 1965, 30, 2441.
32. These AHA esters are hygroscopic and readily hydrolyze at 20 °C; therefore, they should be used directly; if storage is required, it should be cold and dry.
33. A partial explanation may lie in the stronger σ-donor character of the sulfur in thioether 2 versus the oxygen in ether 1. As donation from Z to Mg in intermediate C increases (Scheme 1); the magnesium alkoxide bond is destabilized, and the electronegativity/leaving group ability of the ester is increased.
34. The ratio of ketone/tertiary alcohol products may be increased by using less Grignard reagent, and the yield of ketones may be optimized by adjustment with a small excess of Grignard reagent. Our study, however, is a comparison of the relative performance of several Grignard reagents under fixed conditions.
35. In the reaction of ester 5 with phenyl Grignard reagent, control of optimal monoaddition required fine tuning of the reaction temperature. The ratio of ketone/tertiary alcohol products is generally sensitive to the temperature and concentration.
36. Authentic samples of ketone and tertiary alcohol products, 9 and 10, respectively, were prepared from the corresponding N,O-dimethyl hydroxamate and methyl ester, respectively, of 3-phenylpropionic acid. As an example, phenyl Grignard reagent gave ketone 9f to tertiary alcohol 10f ratios of 32/1 and 1/49 with the hydroxamate and methyl ester, respectively.
37. Zook, H. D.; McAleer, W. J.; Horwin, L. J. Am. Chem. Soc. 1946, 68, 2404. In our hands, these Grignard reagents gave significant enolization with the methyl 3-phenylpropionate.
38. In no reaction was any product of Claisen (or aldol) condensation recovered.
39. Watanabe, S.; Suga, K.; Fujita, T.; Saito, N. Aust. J. Chem. 1977, 30, 427.
40. 2-Tetrahydrofuranyl substitution is exclusive in 2-tetrahydrofuranyl phenyl sulfone in the presence of the appropriate Lewis acids: Brown, D. S.; Bruno, M.; Davenport, R. J.; Ley, S. V. Tetrahedron 1989, 45, 4293.
41. (a) Imamoto, T. Organocerium Reagents. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, Chapter 1.8, p 231.
42. (b) Mudryk, B.; Shook, C.; Cohen, T. J. Am. Chem. Soc. 1990, 112, 6389.
43. Lipshutz, B. H. Tetrahedron Lett. 1983, 24, 127.
44. Certain heteroatom-substituted esters can yield ketones with lower-order cuprates: Humphrey, S. A.; Herrmann, J. L.; Schlessinger, R. H. J. Chem. Soc., Chem. Commun. 1971, 1244. Ester 8, however, was inert to the heterocuprate, BuCu(CN)Li, at 20 °C.
45. 1 group of the acid becomes more electronrich (11d versus 11c), the intermediate Mg-chelate eliminates to ketone slower relative to the rate of Grignard reagent addition to the THF ester.
46. Cf. ref 4a.
47. Further work is necessary to fully understand the nature and degree of the ester's participation. Nevertheless, aqueous washes easily remove most of the 2-hydroxytetrahydrofuran and other byproducts. For byproducts of 2-hydroxytetrahydrofuran, see ref 15a.
48. Normally the 1,10-phenanthroline method was used: Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165.
49. When the carboxylic acid was not completely soluble at -40 or -20 °C, addition of the methanesulfonic acid to the suspension catalyzed a slow clarification to form a solution of the more soluble THF ester.
50. 3).
51. Quenching by bolus addition of the quench into the vigorously stirred reaction mixture gave similar results. The ketone 9g was quenched with pH 7, 0.1 M phosphate buffer.
52. 2 solution is stirred with methanesulfonic acid and methanol (e.g., 5 μL and 1 mL, respectively), at 20 °C until hydrolyzed (1 h).
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