Unexpected Migration and Oxidative Cyclization of Substituted 2-Acetophenone Triflates under Basic Conditions: Synthetic and Mechanistic Insights

Journal of Organic Chemistry

Volumn 68, Issue 26, 2003, Pages 9964-9970

  Coe, Jotham W ^a   Bianco, Krista E ^a   Boscoe, Brian P ^a   Brooks, Paige R ^a   Cox, Eric D ^a   Vetelino, Michael G ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIZATION;

ESTERS; SUBSTITUTION REACTIONS; THERMAL EFFECTS;

AROMATIC COMPOUNDS;

2 ACETOPHENONE TRIFLATE; ACETOPHENONE DERIVATIVE; BENZOFURAN 3 ONE; BENZOFURAN DERIVATIVE; N,N DIMETHYLFORMAMIDE; TRIFLUOROMETHANESULFONIC ACID; UNCLASSIFIED DRUG;

ARTICLE; CYCLIZATION; GAS CHROMATOGRAPHY; LOW TEMPERATURE; MASS SPECTROMETRY; NUCLEAR OVERHAUSER EFFECT; OXIDATION; PROTON NUCLEAR MAGNETIC RESONANCE; REACTION ANALYSIS; SUBSTITUTION REACTION; SYNTHESIS; THIN LAYER CHROMATOGRAPHY;

EID: 0347624001     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo0352023     Document Type: Article

References (64)

1. For leading references to benzofuran-3-one syntheses, see: (a) Jung, M. E.; Abrecht, S. J. Org. Chem. 1988, 53, 423-425.
2. (b) Smith, A. B., III; Koft, E. R. J. Am. Chem. Soc. 1982, 104, 2659-2661.
3. (c) Kanvinde, M. N.; Kelkar, R. M.; Paradkar, M. V. Synth. Commun. 1993, 23, 961-969.
4. (d) Garanti, L.; Zecchi, G.; Pagnoni, U. M. J. Heterocycl. Chem. 1977, 14, 445-448.
5. (e) Prakash, O.; Goyal, S. Synthesis 1992, 628-629.
6. (f) Pirrung, M. C.; Werner, J. A. J. Am. Chem. Soc. 1986, 108, 6060-6062.
7. (g) Powers, L. J.; Mertes, M. P. J. Med. Chem. 1970, 13, 1102-1105.
8. Results to be published at a later time.
9. (a) Louie, J.; Driver, M. S.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1997, 62, 1268-1273 and references therein.
10. (b) Gilbertson, S. R.; Fu, Z.; Xie, D. Tetrahedron Lett. 2001, 42, 365-368 and references therein.
11. Interestingly, 1.1 equiv of LiBr/1.5 equiv of TEA/DMF catalyzes the migration, whereas TEA alone does not. This catalysis is consistent with previous results involving closely related starting materials under similar conditions. See: (a) Ciattini, P. G.; Mastropietro, G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1993, 34, 3763-3766.
12. (b) Farina, V.; Baker, S. R.; Benigni, D. A.; Hauck, S. I.; Sapino, C., Jr. J. Org. Chem. 1990, 55, 5833-5847. The role of LiBr is unclear, but it presumably facilitates ketone ionization by triethylamine.
13. We have detected product of the same mass as starting material if with t-BuOK in DMF at 0 °C by GC-MS. This material has been preliminarily assigned the structure 3f, but it has eluded isolation.
14. Both mono- and dialkyl-substituted examples become brown upon treatment with DBU in DMF and darken slightly on warming. Success of these reactions is unimpaired when performed in the absence of light.
15. The conversion of 1b to salicylic acid is facile (3 equiv of KOAc, DMF, air, 90 °C, 18 h, 69%). Compound 3b is also converted to salicylic acid under these conditions in an air atmosphere.
16. See: (a) Doering, W. von E.; Chanley, J. D. J. Am. Chem. Soc. 1946, 68, 586-589.
17. (b) Doering, W. von E.; Haines, R. M. J. Am. Chem. Soc. 1954, 76, 482-486.
18. (c) Sawaki, Y.; Ogata, Y. J. Am. Chem. Soc. 1977, 99, 5412-5416.
19. For a discussion of photooxygenation of 2-methylbenzofuran-3-one silyl ethers, see: (d) Adam, W.; Kades, E.; Wang, X. Tetrahedron Lett. 1990, 31, 2259-2262.
20. While it might be unnecessary in some cases, as such it is advisable to deoxygenate all of these reactions.
21. For sulfonate to sulfinate conversions, see: (a) Ley, S. V.; Lygo, B.; Wonnacott, A. Tetrahedron Lett. 1985, 26, 535-538.
22. (b) Netscher, T.; Bohrer, P. Tetrahedron Lett. 1996, 37, 8359-8362.
23. (c) Creary, X. J. Org. Chem. 1985, 50, 5080-5084.
24. (d) Creary, X. J. Org. Chem. 1980, 45, 2727-2729.
25. (e) Binkley, R. W.; Ambrose, M. G. J. Org. Chem. 1983, 48, 1777-1779.
26. Syntheses of substrates 1 follow straightforward methods. For Weinreb amide formation conditions, see: (a) Nitz, T. J.; Volkots, D. L.; Aldous, D. J. ; Oglesby, R. C. J. Org. Chem. 1994, 59, 5828-5832.
27. (b) For halogen metal exchange conditions, see: Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300-305.
28. (c) For demethylation of 2-methoxyacetophenones, see: Nagaoka, H.; Schmid, G.; Iio, H.; Kishi, Y. Tetrahedron Lett. 1981, 22, 899-903.
29. (d) For triflate formation, see: Su, T. M.; Sliwinski, W. F.; Schleyer, P. v. R. J. Am. Chem. Soc. 1969, 91, 5386-5389.
30. (e) For a review of the Fries rearrangement, see: Blatt, A. H. in Organic Reactions; Wiley: New York, 1942; Vol. 1, pp 342-369. March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New York, 1992; pp 555-556. See the Experimental Section and Supporting Information.
31. (e) For a review of the Fries rearrangement, see: Blatt, A. H. in Organic Reactions; Wiley: New York, 1942; Vol. 1, pp 342-369. March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New York, 1992; pp 555-556. See the Experimental Section and Supporting Information.
32. For examples of cyclopropanes as mechanistic radical probes, see: (a) He, M.; Dowd, P. J. Am. Chem. Soc. 1997, 119, 1133-1137.
33. (b) Corey, E. J.; Nagata, R. J. Am. Chem. Soc. 1987, 109, 8107-8108.
34. (c) Waldemar, A.; Finzel, R. J. Am. Chem. Soc. 1992, 114, 4563-4568.
35. (d) Nonhebel, D. C. Chem. Soc. Rev. 1993, 347-359.
36. Structures from these crude reactions remain to be determined.
37. Structure 5 was prepared by alkylation of 3c (NaH, DMF, MeI, 0-20 °C).
38. For cyclopropanes designed for ready ionization, see: Carpino, L. A.; Chao, H. G.; Ghassemi, S.; Mansour, E. M. E.; Riemer, C.; Warrass, R.; Sadat-Aalaee, D.; Truran, G. A.; Imazumi, H.; El-Faham, A.; Ionescu, D.; Ismail, M.; Kowaleski, T. L.; Han, C. H.; Wenschuh, H.; Beyermann, M.; Bienert, M.; Shroff, H.; Albericio, F.; Triolo, S. A.; Sole, N. A.; Kates, S. A. J. Org. Chem. 1995, 60, 7718-7719.
39. For a discussion of radical chain mechanisms and substituent effects, see: March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New York, 1992; pp 186-195 and 683-686.
40. RN1 mechanism, see: (a) Kim, J. K.; Bunnett, J. F. J. Am. Chem. Soc. 1970, 92, 7466-7464.
41. (b) Rossi, R. A.; Pierini, A. B.; Palacios, S. M. J. Chem. Educ. 1989, 66, 720-722.
42. (c) Bunnett, J. F. Tetrahedron 1993, 49, 4477-4484.
43. 2 and leading references, see: Miyabe, H.; Ueda, M.; Maito, T. J. Org. Chem. 2000, 65, 5043-5047.
44. Yamada, K.; Fujihara, H.; Yamamoto, Y.; Miwa, Y.; Taga, T.; Tomioka, K. Org. Lett. 2002, 4, 3509-3511.
45. 2), see: Gong, J.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118, 4486-4487.
46. Xiang, J. S.; Mahadevan, A.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118, 4284-4290.
47. Pattenden, G.; Teague, S. J. J. Chem. Soc., Perkin. Trans. 1 1988, 1077-1083 and references therein. (diagram presented)
48. N2 displacement mechanisms, see: March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New York, 1992; pp 294-298.
49. An examination of models suggests that ideal 180° alignment of an enol(ate) nucleophile and sulfinate leaving group cannot be achieved.
50. For extensive discussion regarding related transition structures, see: Perkins, C. W.; Wilson, S. R.; Martin, J. C. J. Am. Chem. Soc. 1985, 107, 3209-3218 and references therein.
51. In enol triflate 3a, the triflate is not destabilized by a neighboring and cis substituent. We postulate that in highly substituted cases the equilibrium favors the starting ketones (1f, 1g) due to severe steric interactions encountered in the corresponding fully substituted enolic forms. The enol form, however, appears to be thermodynamically favored in the mono- and unsubstituted examples at low temperature.
52. The phenolsulfonate O-S cleavage is similarly stabilized; however, alkyl substitution in intermediates derived from this cleavage stabilize the phenol radical through extended vinylogous conjugation.
53. 5) take a different course and generate complex mixtures but do not produce benzofuranones. Migration occurs in 42% yield (t-BuOK/THF, 0-20 °C).
54. For studies of SET mechanisms, see: (a) Newcomb, M. Act. Chem. Scand. 1990, 44, 299-310.
55. (b) Newcomb, M.; Curran, D. P. Acc. Chem. Res. 1988, 21, 206-214.
56. (c) Ashby, E. C. Acc. Chem. Res. 1988, 21, 414-421.
57. In an attempt to trap an intermediate of this type, the reaction of 1g was carried out in the presence of triethylsilane (1 equiv). It proceeded as without triethylsilane. See ref 15.
58. (a) Crandall, J. K.; Conover, W. W.; Konim, J. B.; Machlender, W. H. J. Org. Chem. 1974, 39, 1723-1729.
59. (b) Camp, R. O.; Greene, F. D. J. Am. Chem. Soc. 1973, 90, 7349.
60. (c) Crandall, J. K.; Conover, W. W. J. Chem. Soc., Chem. Commun. 1973, 10, 340-341.
61. Hess, B. A., Jr.; Smentek, L.; Brash, A. R.; Cha, J. K. J. Am. Chem. Soc. 1999, 112, 5603-5604.
62. Myers, A. G.; Barbay, J. K. Org. Lett. 2001, 3, 425-428.
63. The solvolysis rate for trifluoromethane sulfonates has been demonstrated to be 40 000 times greater than that of tosylates. See: Crossland, R. K.; Wells, W. E.; Shiner, V. J., Jr. J. Am. Chem. Soc. 1971, 88, 4217-4220. Also see: Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85-126.
64. The solvolysis rate for trifluoromethane sulfonates has been demonstrated to be 40 000 times greater than that of tosylates. See: Crossland, R. K.; Wells, W. E.; Shiner, V. J., Jr. J. Am. Chem. Soc. 1971, 88, 4217-4220. Also see: Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85-126.