Mechanistic evidence for an α-oxoketene pathway in the formation of β-ketoamides/esters via Meldrum's acid adducts

Journal of the American Chemical Society

Volumn 126, Issue 40, 2004, Pages 13002-13009

  Xu, Feng ^a   Armstrong III, Joseph D ^a   Zhou, George X ^a   Simmons, Bryon ^a   Hughes, David ^a   Ge, Zhihong ^a   Grabowski, Edward J J ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINES; CARBOXYLIC ACIDS; REACTION KINETICS;

AMIDES; HIGH YIELDING PROCESS; MELDRUM ACIDS; OXOKETENE;

ETHERS;

ALPHA OXOKETENE; AMIDE; BETA KETO AMIDE DERIVATIVE; BETA KETO ESTER DERIVATIVE; CARBOXYLIC ACID DERIVATIVE; KETENE DERIVATIVE; UNCLASSIFIED DRUG;

ADDITION REACTION; ARTICLE; ELIMINATION REACTION; ONLINE MONITORING; REACTION ANALYSIS; SYNTHESIS;

EID: 5644289358     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja046488b     Document Type: Article

References (52)

1. For reviews, see: (a) Far, A. D. Angew. Chem., Int. Ed. Engl. 2003, 42, 2340-2348.
2. (b) Gaber, A. E. M.; McNab, H. Synthesis 2001, 2059-2074.
3. (c) Chen, B. C. Heterocycles 1991, 32, 529-597.
4. (d) Huang, X. Youji Huaxue 1986, 329-334.
5. Emtenas, H.; Alderin, L.; Almqvist. F. J. Org. Chem. 2001, 66, 6756-6761.
6. Emtenas, H.; Soto, G.; Hultgren, S. J.; Marshall, G. R.; Almqvist, F. Org. Lett. 2000, 2, 2065-2067.
7. The mechanism involving acyl Meldrum's acids in solution was never clarified. It is often to have several proposed reaction pathways in the same publication.
8. For examples, see: (a) Pak, C. S.; Yang, H. C.; Choi, E. B. Synthesis 1992, 1213-1214.
9. (b) Svetlik, J.; Goljer, I.; Turecek, F. J. Chem. Soc., Perkin Trans. 1 1990, 1315-1318.
10. (c) Sato, M.; Yoneda, N.; Katagiri, N.; Watanabe, H.; Kaneko, C. Synthesis 1986, 672-674.
11. (d) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J. Org. Chem. 1978, 43, 2087-2088.
12. For additional examples, see: (a) Yamamoto, Y.; Watanabe, Y.; Ohnishi, S. Chem. Pharm. Bull. 1987, 35, 1860-1870.
13. (b) Sato, M.; Ogsawara, H.; Yoshizumi, E.; Kato, T. Chem. Pharm. Bull. 1983, 31, 1902-1909.
14. (c) Sato, M.; Ogsawara, H.; Yoshizumi, E.; Kato, T. Heterocycles 1982, 17, 297-300.
15. (a) Hamilakis, S.; Kontonassios, D.; Sandris, C. J. Heterocycl. Chem. 1996, 33, 825-829.
16. (b) Sato, M.; Takayama, K.; Abe, Y.; Furuya, T.; Inukai, N.; Kaneko, C. Chem. Pharm. Bull. 1990, 38, 336-339.
17. (c) Yamamoto, Y.; Watanabe, Y. Chem. Pharm. Bull. 1987, 35, 1871-1879.
18. For recent reviews, see; (a) Tidwell, T. T. Ketenes; John Wiley & Sons: New York, 1995.
19. (b) Wentrup, C.; Heilmayer, W.; Kollenz, G. Synthesis 1994, 1219-1249.
20. (c) Tidwell, T. T. Acc. Chem. Res. 1990, 23, 273-279.
21. Cassis, R.; Tapia, R.; Valderrama, J. A. Synth. Commun. 1985, 15, 125-133.
22. Gordon, H. J.; Martin, J. C.; McNab, H. J. Chem. Soc., Chem. Commun. 1983, 957-958.
23. Bibas, H.; Kappe, C. O.; Wong, M. W.; Wentrup, C. J. Chem. Soc., Perkin Trans. 2 1998, 493-498.
24. It is known that acyl Meldrum's acids are not always stable. For example, see ref 5b.
25. Measured by titration in water at ambient temperature.
26. One-pot process procedure: 2,4,5-Trifluorophenylacetic acid (5, 2.5 kg, 13.15 mol), Meldrum's acid (2.09 kg, 14.46 mol), and DMAP (128.5 g, 1.052 mol) were charged into a 50 L three-neck flask. Acetonitrile (7.5 L) was added in one portion at room temperature. N,N-Diisopropylethylamine (4.92 L, 28.27 mol) was added in portions at room temperature while maintaining the temperature below 50 °C. Pivaloyl chloride (1.78 L, 14.46 mol) was added dropwise over 1-2 h while maintaining the temperature below 55 °C. The reaction was aged at 45-50 °C for 2-3 h. Triazole hydrochloride 7 (3.01 kg, 13.2 mol) was added in one portion at 40-50 °C. Trifluoroacetic acid (303 mL, 3.95 mol) was added dropwise, and the reaction solution was aged at 50-55 °C for 6 h. 90% solution assay yield of 8. This process has been successfully and reproducibly demonstrated in 300 kg scales.
27. -] as described in the text. (Diagram presented) To have more focused discussion in the text, detailed kinetic analyses of all other possible mechanisms, which can be done as described in the text, are not listed here.
28. For leading references, see: (a) Gong, L.; McAllister, M. A.; Tidwell, T. T. J. Am. Chem. Soc. 1991, 113, 6021-6028.
29. (b) Lien, M. H.; Hopkinson, A. C. J. Org. Chem. 1988, 53, 2150-2154.
30. (c) Armitage, M. A.; Higgins, M. J.; Lewars, E. G.; March, R. E. J. Am. Chem. Soc. 1980. 102, 5064-5068.
31. (a) Birney, D. M. J. Org. Chem. 1994, 59, 2557-2564.
32. (b) Tortajada, J.; Berthomieu, D.; Morizur, J.-P.; Audier, H.-E. J. Am. Chem. Soc. 1992, 114, 10874-10880.
33. (c) Leung-Toung, R.; Peterson, M. R.; Tidwell, T. T.; Csizmadia, I. G. J. Mol. Struct. 1989, 183, 319-330.
34. (d) Bouchoux, G.; Hppilliard, Y. J. Phys. Chem. 1988, 92, 5869-5874.
35. +H. See: (a) Nobes, R. H.; Bouma, W. J.; Radom, L. J. Am. Chem. Soc. 1983, 105, 309-314.
36. (b) Vogt, J.; Williamson, A. D.; Beauchamp, J. L. J. Am. Chem. Soc. 1978, 100, 3478-3483.
37. Malinowski, E. H.; Howery, D. G. Factor Analysis in Chemistry; John Wiley & Sons: New York, 1980.
38. Cameron, M.; Zhou, G. X.; Hicks, M. B.; Antonucci, V.; Ge, Z.; Lieberman, D. R.; Lynch, J. E.; Shi, Y.-J. J. Pharm. Biomed. Anal. 2002, 28, 137-144.
39. The obtained online IR kinetic profiles of the combination of anion and free acid form of 6 as well as the formation of the product matched very well with the HPLC kinetic profile as shown later on in Figure 7.
40. A stepwise formation of the oxo-ketene by loss of acetone to form intermediates such as 4, followed by decarboxylation, cannot be ruled out. The fact that the reaction rate is unaffected by the increasing concentration of acetone formed during the reaction provides some evidence against the pathway via intermediates such as 4, if reversible formation6a of these intermediates is the rate-determining step.
41. Sorensen, U. S.; Falch, E.; Krogsgaard-Larsen, P. J. Org. Chem. 2000, 65, 1003-1007.
42. Yamamoto, Y.; Ohnishi, S.; Azuma, Y. Chem. Pharm. Bull. 1982, 30, 3505-3512.
43. Mohri, K.; Oikawa, Y.; Hirao, K.-I.; Yonemitsu, O. Chem. Pharm. Bull. 1982, 30, 3097-3105; Heterocycles 1982, 19, 515-520, 521-524.
44. Mohri, K.; Oikawa, Y.; Hirao, K.-I.; Yonemitsu, O. Chem. Pharm. Bull. 1982, 30, 3097-3105; Heterocycles 1982, 19, 515-520, 521-524.
45. Similar yields were reported in the literature for other substrates.
46. Shelkov, R.; Nahmany, M.; Melman, A. J. Org. Chem. 2002, 67, 8975-8982.
47. For more detailed discussions, see "Kinetic profile in the 'real' one-pot solution" section.
48. Hydration, aminolysis, and alcoholysis of ketenes are fast reactions. In comparison of the reaction rate constants the self-decomposition of 6 with reported k for hydration, or aminolysis, or alcoholysis of ketenes, the reaction rate difference could be up to 10 orders of magnitude, (a) Chiang, Y.; Guo, H.-X.; Kresge, A. J.; Tee, O. S. J. Am. Chem. Soc. 1996, 118, 3386-3391.
49. (b) Alien, A. D.; Andaos, J.; Kresge, A. J.; McAllister, M. A.; Tidwell, T. T. J. Am. Chem. Soc. 1992, 114, 1878-1879.
50. (a) Piettre A.; Chevenier, E.; Masardier, C.; Gimbert, Y.; Greene, A. Org. Lett. 2002, 4, 3139-3142.
51. (b) Plazuk, D.; Zakrzewski, J. J. Org. Chem. 2002, 67, 8672-8674.
52. See ref 6a. Yamamoto et al. confirmed oxazin-4-ones are formed if acyl Meldrum's acids are subjected to the same reaction conditions.