O-Pyrazolylpropynyl-Hydroxylamines as Versatile Intermediates in the Synthesis of Compounds of Pharmacological Interest

Abstract

Through an optimised Pd/Cu-catalysed cross-coupling reaction of 4-iodopyrazoles with 2-propyn-1-ol, followed by Mitsunobu transformation with N-hydroxyphthalimide and subsequent hydrazinolysis, O-[(pyrazol-4-yl)-prop-2-ynyl]-hydroxylamines were obtained in good yields. Their usefulness as intermediates in the synthesis of pharmaceuticals is exemplified by the first reported intramolecular cyclization of O-(2-propynyl)-hydroxylamines to yield 4,5-dihydro-isoxazoles.

Key words

O-pyrazolylpropynyl-hydroxylamines - 3-pyrazolyl-4,5-dihydro-isoxazoles - cross-coupling - Mitsunobu reaction - intramolecular cyclisation

References

• 2 Tecle H. Barrett SD. Lauffer DJ. Augelli-Szafran C. Brann MR. Callahan MJ. Caprathe BW. Davis RE. Doyle PD. Eubanks D. Lipiniski W. Mirzadegan T. Moos WH. Moreland DW. Nelson CB. Pavia MR. Raby C. Schwarz RD. Spencer CJ. Thomas AJ. Jaén JC. J. Med. Chem.  1998,  41:  2524 
• 3 Inglesi M. Nicola M. Magnetti S. Farmaco  1990,  45:  1327 
• 4a Peixoto C. Laurin P. Klich M. Dupuis-Hamelin C. Mauvais P. Lassaigne P. Bonnefoy A. Musicki B. Tetrahedron Lett.  2000,  41:  1741 
• 4b Tsubouchi H. Tsuji K. Yasumura K. Ishikawa H. Chem. Pharm. Bull.  1994,  42:  2084 
• 4c Ternansky RJ. Draheim SE. Pike AJ. Counter FT. Eudaly JA. Kasher JS. J. Med. Chem.  1993,  36:  3224 
• 5 Sawaikar DD. Sinha B. Hebbalkar GD. Sharma RN. Patwardhan SA. Indian J. Chem., Sect. B  1995,  34:  832 
• 6 Kocur J. Mildenberger H. Sachse B. Z. Naturforsch., B.: Chem. Sci.  1982,  37:  902 
• 7a Rodríguez-Franco MI. Dorronsoro I. Martínez A. Pérez C. Badía A. Baños JE. Arch. Pharm., Pharm. Med. Chem.  2000,  333:  118 
• 7b Rodríguez-Franco MI. Dorronsoro I. Castro A. Martínez A. Tetrahedron  2000,  56:  1739 
• 8a Rodríguez-Franco MI. San Lorenzo P. Martínez A. Navarro P. Tetrahedron  1999,  55:  2763 
• 8b Rodríguez-Franco MI. Fierros M. Martínez A. Navarro P. Conde S. Bioorg. Med. Chem.  1997,  5:  363 
• 9 Sonogashira K. Tohda Y. Hagihara N. Tetrahedron Lett.  1975,  50:  4467 
• 10 Mitsunobu O. Eguchi M. Bull. Chem. Soc. Jpn.  1971,  44:  3427 
• 11 Pitts WJ. Wityak J. Smallheer JM. Tobin AE. Jetter JW. Buynitsky JS. Harlow PP. Solomon KA. Corjay MH. Mousa SA. Wexler RR. Jadhav PK. J. Med. Chem.  2000,  43:  27 
• 12 Rodríguez-Franco MI. Dorronsoro I. Hernández-Higueras AI. Antequera G. Tetrahedron Lett.  2001,  42:  863 
• 13 Tolf B.-R. Dahlbom R. Theorell H. Åkeson Å. Acta Chem. Scand., Ser. B  1982,  36:  101 
• 14a Tretyakov EV. Knight DW. Vasilevsky S. J. Chem. Soc., Perkin Trans. 1  1999,  3713 
• 14b Alami M. Ferri F. Linstrumelle G. Tetrahedron Lett.  1993,  34:  6403 
• 15 Brandsma L. Vasilevsky SF. Verkruijsse HD. Application of Transition Metal Catalysts in Organic Synthesis   Springer-Verlag; Berlin: 1999.  p.179 
• 16 Mitsunobu O. Synthesis  1981,  1 
• 17 Grochowski E. Jurczak J. Synthesis  1976,  682 
• 18 Xu R. Sim M.-K. Go M.-L. J. Med. Chem.  1998,  41:  3220 
• 19 March J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure   3rd ed.:  John Wiley; New York: 1985.  p.689 
• 20a McGrane PL. Jensen M. Livinghouse T. J. Am. Chem. Soc.  1992,  114:  5459 
• 20b McGrane PL. Livinghouse T. J. Org. Chem.  1992,  57:  1323 
• 20c Fukuda Y. Utimoto K. Synthesis  1991,  975 
• 20d Fukuda Y. Matsubara S. Utimoto K. J. Org. Chem.  1991,  56:  5812 
• 21 Li Y. Marks TJ. J. Am. Chem. Soc.  1996,  118:  9295 
• 22a Sheradsky T. Nov E. Segal S. Frank A. J. Chem. Soc., Perkin Trans. 1  1977,  1827 
• 22b Blatt AH. J. Am. Chem. Soc.  1939,  61:  3494 
• 23a Pradhan SK. Akamanchi KG. Divakaran PP. Pradhan PM. Heterocycles  1989,  28:  813 
• 23b Pradhan SK. Akamanchi KG. Divakaran PP. Tetrahedron Lett.  1983,  24:  5017 
• 24a Olson RE. Sielecki TM. Wityak J. Pinto DJ. Batt DG. Frietze WE. Liu J. Tobin AE. Orwat MJ. Meo SVD. Houghton GC. Lalka GK. Mousa SA. Racanelli AL. Hausner EA. Kapil RP. Rabel SR. Thoolen MJ. Reilly TM. Anderson PS. Wexler RR. J. Med. Chem.  1999,  42:  1178 
• 24b Quan ML. Ellis CD. Liauw AY. Alexander RS. Knabb RM. Lam G. Wright MR. Wong PC. Wexler RR. J. Med. Chem.  1999,  42:  2760 
• 25a Kleinman EF. Campbell E. Giordano LA. Cohan VL. Jenkinson TH. Cheng JB. Shirley JT. Pettipher ER. Salter ED. Hibbs TA. DiCapua FM. Bordner J. J. Med. Chem.  1998,  41:  266 
• 25b Khalil MA. Soliman R. Farghaly AM. Bekhit AA. Arch. Pharm.  1994,  327:  27 
• 26a Hara R. Itahana H. Sakamoto K. Hiusamichi H. Nagano N. J. Antibiot.  1996,  49:  1182 
• 26b Burton G. Clarke GJ. Douglas JD. Eglington AJ. Frydrych CH. Hinks JD. Hird NW. Hunt E. Moss SF. Naylor A. Nicholson NH. Pearson MJ. J. Antibiot.  1996,  49:  1266 
• 27 Rodríguez-Franco MI. Dorronsoro I. Martínez A. Castro A. J. Heterocycl. Chem.  2001,  38:  435 
• 28 Morgan GT. Ackerman I. J. Chem. Soc.  1923,  123:  1304 

1

This paper comprises a part of Isabel Dorronsoro’s Ph.D. thesis.