A Practical Synthesis of 3-Diethoxyphosphoryl-1,2-pyridazine Derivatives

Abstract

Under microwave (MW) heating, 1-diethoxyphosphorylbuta-1,3-diene cycloadds to diethyl, diisopropyl and di-tert-butyl azodicarboxylates leading to the corresponding hetero Diels-Alder (HD-A) cycloadducts in excellent yields. Cycloaddition to the di-tert-butyl derivative is conveniently scaled up using a six-entry parallel synthesis rotor (>10 g scale). B3LYP/6-31G** calculations confirmed the concerted, but highly asynchronous character of this reaction. The di-tert-butyloxycarbonyl cycloadduct is compatible with orthogonal deprotection (i.e., selective N-deprotection without degradation of the phosphonate ester). Thus, reduction and dihydroxylation of the C=C bond of this cycloadduct, followed by TFA deprotection, gave 3-diethoxyphosphorylhexahydro-1,2-pyridazine and 3-diethoxyphosphoryl-4,5-dihydroxyhexahydro-1,2-pyrida­zine, respectively. This HD-A strategy offers a convenient entry towards phosphonate bioisosters of cyclic α-hydrazino acid and azafagomine derivatives in racemic series.

Key words

azo compounds - cycloadditions - Diels-Alder reactions - heterocycles - phosphorus

References

• 1a Lewkowsi J. Focus on Organometallic Chemistry Research   Nova Science Publishers; New York: 2005. 
• 1b Kudzin Z. H. Depczynski R. Kudzin M. H. Drabowicz J. Amino Acids  2008,  34:  163 
• 1c Hu D.-Y. Wan Q.-Q. Yang S. Song B.-A. Bhadury PS.
  Jin L.-H. Yan K. Liu F. Chen Z. Xue W. J. Agric. Food Chem.  2008,  56:  998 
• 2 Kukhar V. Hudson H. Aminophosphonic and Aminophosphinic Acids: Chemistry and Biological Activity   Wiley; New York: 2000. 
• 3a Berlicki L. Rudzinska E. Mlynarz P. Kafarski P. Curr. Org. Chem.  2006,  10:  2285 
• 3b Bhadury PS. Song B.-A. Yang S. Zhang Y. Zhang S. Curr. Org. Synth.  2008,  5:  134 
• 3c Lesch B. Thomson DW. Lindell SD. Comb. Chem. High Throughput Screening  2008,  11:  36 
• 3d Guliaiko IV. Kolodiazhnyi OI. Phosphorus, Sulfur Silicon Relat. Elem.  2008,  183:  677 
• 3e Han L. Hiratake J. Kamiyama A. Sakata K. Biochemistry  2007,  46:  1432 
• 3f Wardle NJ. Bligh SWA. Hudson HR. Curr. Org. Chem.  2007,  11:  1635 
• 4a Ogita T. Gunji S. Fukazawa Y. Terahara A. Kinoshita T. Nagaki H. Tetrahedron Lett.  1983,  24:  2283 
• 4b Kang I. Kim Y. Bull. Korean Chem. Soc.  1994,  15:  595 
• 4c Paquette LA. Duan M. Konetzki I. Kempmann C. J. Am. Chem. Soc.  2002,  124:  4257 
• 5 Heydari A. Mehrdad M. Schaffie M. Abdolrezaie MS. Hajinassirei R. Chem. Lett.  2002,  1146 ; and references cited therein
• 6 Ciufolini MA. Xi N. Chem. Soc. Rev.  1998,  27:  437 
• 7a Liang X. Bols M. J. Org. Chem.  1999,  64:  8485 
• 7b Sivertsen AC. Gasior M. Bjerring M. Hansen SU. Lopez OL. Nielsen NC. Bols M. Eur. J. Org. Chem.  2007,  1735 
• 7c Helligs H. Lyngbye JL. Jensen A. Bols M. Chem. Eur. J.  2002,  8:  1218 
• 8 Rachon J. Wasielewski CR. Rocz. Chem.  1976,  50:  477 
• 9 Kang IJ. Kim YJ. Bull. Korean Chem. Soc.  1994,  15:  595 
• 10 Yuan C. Chen S. Xie R. Feng H. Maier L. Phosphorus, Sulfur Silicon Relat. Elem.  1995,  106:  115 
• 11 Yuan C. Li C. Synthesis  1996,  507 
• 12 Heydari A. Javidan A. Schaffie M. Tetrahedron Lett.  2001,  42:  8071 
• 13 Stevens CV. Van Meener E. Masschelein KG. Moonen K. De Blieck A. Drabowicz J. Synlett  2007,  2549 
• 14a Kaname M. Yoshinaga K. Arakawa Y. Yoshifuji S. Chem. Pharm. Bull.  2004,  52:  160 
• 14b Kaname M. Arakawa Y. Yoshifuji S. Tetrahedron Lett.  2001,  42:  2713 
• 14c Kaname M. Yoshinaga K. Arakawa Y. Yoshifuji S. Tetrahedron Lett.  1999,  40:  7993 
• 15a Monbaliu J.-C. Marchand-Brynaert J. Tetrahedron Lett.  2008,  49:  1839 
• 15b Monbaliu J.-C. Tinant B. Marchand-Brynaert J. J. Mol. Struct.  2008,  879:  113 
• 15c Robiette R. Defacqz N. Peeters D. Marchand-Brynaert J. Curr. Org. Synth.  2005,  2:  453 
• 15d Robiette R. Cheboub-Benchaba K. Peeters D. Marchand-Brynaert J. J. Org. Chem.  2003,  68:  9809 ; and references cited therein
• 16a Tietze LF. Kettschau G. Top. Curr. Chem.  1997,  189:  1 
• 16b Fringuelli F. Taticchi A. The Diels-Alder Reaction   Wiley; New York: 2002. 
• 16c Makino K. Henmi Y. Terasawa M. Hara O. Hamada Y. Tetrahedron Lett.  2005,  46:  555 
• 17a Streith J. Defoin A. Synthesis  1994,  1107 
• 17b Vogt PF. Miller MJ. Tetrahedron  1998,  54:  1317 
• 17c Yamamoto H. Kawasaki M. Bull. Chem. Soc. Jpn.  2007,  80:  595 
• 17d Comins DL. Kuethe JT. Miller TM. Fevrier FC. Brooks CA. J. Org. Chem.  2005,  70:  5221 
• 18a Al Badri H. About-Jaudet E. Collignon N. Tetrahedron Lett.  1996,  37:  2951 
• 18b Wyatt P. Villalonga-Barber C. Motevalli M. Tetrahedron Lett.  1999,  40:  149 
• 19 Pudovik AN. Konovalova IV. Zh. Obshch. Khim.  1961,  31:  1693 
• 20 Pudovik AN. Konovalova IV. Ishmaevan EA. Zh. Obshch. Khim.  1963,  33:  2509 
• 21a Claibourne E. Griffin C. Daniewski W. J. Org. Chem.  1970,  35:  1691 
• 21b Darling S. Subramanian N. J. Org. Chem.  1975,  40:  2851 
• 21c Darling S. Muralidharan F. Muralidaharan V. Tetrahedron Lett.  1979,  30:  2757 
• 21d Yamana K. Nakano H. Tetrahedron Lett.  1996,  37:  5963 
• 21e Evans D. Johnson J. Burgey C. Campos K. Tetrahedron Lett.  1999,  40:  2879 
• 21f Al-Badri H. Maddaluno J. Masson S. Collignon N. J. Chem. Soc., Perkin Trans. 1  1999,  2255 
• 21g Al-Badri H. Collignon N. Maddaluno J. Masson S. Tetrahedron  2000,  56:  3909 
• 22a Lidström P. Tierney J. Wathey B. Westman J. Tetrahedron  2001,  57:  9225 
• 22b Perreux L. Loupy A. Tetrahedron  2001,  57:  9199 
• 25a Langa F. de la Cruz P. de la Hoz A. Espildora E. Cossio F. Lecea B. J. Org. Chem.  2000,  65:  2499 
• 25b Diaz-Ortiz A. Carrillo J. Cossio F. Gomez-Escalonilla M. de la Hoz A. Moreno A. Prieto P. Tetrahedron  2000,  56:  1569 
• 25c Loupy A. Maurel F. Sabatie-Gogova A. Tetrahedron  2004,  60:  1683 
• 26 Tang M. Pyne SG. J. Org. Chem.  2003,  68:  7818 
• 27 Gorenstein D. Phosphorus-31 NMR, Principles and Applications   Academic Press; New York: 1984. 
• 28a Perez P. Garcia-Moreno M. Mellet C. Fernandez J. Eur. J. Org. Chem.  2005,  2903 
• 28b Grein F. J. Mol. Struct. (Theochem)  2001,  536:  87 

23

In this case, we supposed that the Lewis acids were quenched by the phosphonate moiety of diene 1, preventing any activation of DTAD. Higher conversion yields observed for the blank than for the Lewis acid activated samples supported this hypothesis. Acids could also contribute to the decomposition of 2c by Boc deprotection.

24

A few drops of toluene were added to guarantee sufficient fluidity of the reaction mixture. Indeed, the cycloadduct 3c is a viscous oil that precludes stirring of the mixture.