Versatile and efficient solid-phase syntheses of pyrazoles and isoxazoles

Organic Letters

Volumn 2, Issue 18, 2000, Pages 2789-2792

  Shen, Dong Ming ^a   Shu, Min ^a   Chapman, Kevin T ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ISOXAZOLE DERIVATIVE; PYRAZOLE DERIVATIVE;

ARTICLE; SYNTHESIS;

ISOXAZOLES; PYRAZOLES;

EID: 0034618340     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol006197h     Document Type: Article

References (12)

1. For example, there are 2292 pyrazoles and 906 isoxazoles in the MDL Drug Report (MDDR-3D, 99.2), representing 3.0% of entries. They are 1.6% of entries in Comprehensive Medicinal Chemistry (CMC-3D 99.1). Both databases are from MDL Information Systems.
2. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40, 1347.
3. (a) Marzinzik, A. L.; Felder, E. R. Tetrahedron Lett. 1996, 37, 1003.
4. (b) Cody D. R.; DeWitt, S. H.; Hodges, J. C.; Roth, B. D.; Schroeder, M. C.; Stankovic, C. J.; Moos, W. H.; Pavia, M. R.; Kiely, J. S. WO 94/08711, 1994.
5. No regioisomers were observed as a result of the condensation step for aromatic esters. Lower aliphatic esters, especially formates, gave both regioisomers at this step as was observed in similar reactions in solution.
6. 3OD, 500 MHz): δ7.77 (d, 2.6 Hz, 1H), 7.73-7.76 (m, 2H), 7.70 (d, 8.4 Hz, 1H), 7.50 (dd, 8.6 and 2.4 Hz, 1H), 6.95-6.98 (m, 2H), 6.67 (s, 1H), 4.65-4.70 (m, 1H), 4.03-4.09 (m, 1H), 3.82 (s, 3H), 3.42 (tt, 3.7 and 12.1 Hz, 1H), 3.04-3.10 (m, 1H), 2.84 (s, 6H), 2.81 (t. 7.6 Hz, 2H), 2.56-2.62 (m, 1H), 2.43-2.47 (m, 2H), 2.05-2.09 (m, 2H), 1.89-1.98 (m, 2H), 1.55-1.63 (m, 1H), 1.46-1.54 (m, 1H). COSY and NOESY spectra unambiguously assigned the isomers.
7. These isomers have characteristic UV profiles. 1,4-Diaryl-3-alkyl pyrazoles 5a have a peak at about 260-265 nm while the 1,3-diaryl-5-alkyl isomers 5b have a peak at 275 nm or above.
8. Willoughby, C. A.; Chapman, K. T. Unpublished results.
9. We used 20 equiv each of pentafluorobenzyl alcohol, triphenylphosphine, and diisopropyl azodicarboxylate in 1:1 DCM/THF at 0.4 M and ambient temperature for 3 h.
10. Hutchins, S. M.; Chapman, K. T. Unpublished results.
11. Isoxazoles were not stable under these conditions.
12. 1·2HCl (91%).