5,6-Dihydro-4H-1,2-oxazines in Organic Synthesis: Catalytic Hydrogenation of [(5,6-Dihydro-4H-1,2-oxazin-3-yl)methyl]malonates to Methyl 7-Oxo-1-oxa-6-azaspiro[4.4]nonane-8-carboxylates

Abstract

[(5,6-Dihydro-4H-1,2-oxazin-3-yl)methyl]malonates undergo a cascade transformation into substituted methyl 7-oxo-1-oxa-6-azaspiro[4.4]nonane-8-carboxylates under catalytic hydrogenation conditions over Raney nickel. A mechanistic scheme involving initial N-O bond cleavage with the formation of imines as key intermediates is suggested.

Key words

5,6-dihydro-4H-1,2-oxazines - reduction - oxaazaspirononanones - imines

References

• 1a Angermann J. Homann K. Reissig H.-U. Zimmer R. Synlett  1995,  1014 
• 1b Buchholz M. Reissig H.-U. Eur. J. Org. Chem.  2003,  3524 
• 1c Gallos JK. Sarli VC. Stathakis CI. Koftis TV. Nachmia VR. Coutouli-Argyropoulou E. Tetrahedron  2002,  58:  9351 
• 2a Gallos JK. Sarli VC. Varvogli AC. Papadoyanni CZ. Papaspyrou SD. Argyropoulos NG. Tetrahedron Lett.  2003,  44:  3905 
• 2b Gallos JK. Sarli VC. Massen ZS. Varvogli AC. Papadoyanni CZ. Papaspyrou SD. Argyropoulos NG. Tetrahedron  2005,  61:  565 
• 3a Best WM. MacDonald JM. Skelton BW. Stick RV. Tilbrook MG. White AH. Can. J. Chem.  2002,  80:  857 
• 3b Humphrey AJ. Parsons SF. Smith MEB. Turner NJ. Tetrahedron Lett.  2000,  41:  4481 
• 3c Joubert M. Defoin A. Tarnus C. Streith J. Synlett  2000,  1366 
• 4 Tsoungas PG. Heterocycles  2002,  57:  915 
• 5a Lyapkalo IM. Ioffe SL. Russ. Chem. Rev.  1998,  67:  467 
• 5b Francotte E. Merenyi R. Vandenbulcke-Coyette B. Vieche H.-G. Helv. Chim. Acta  1981,  64:  1208 
• 6a Sukhorukov AYu. Klenov MS. Ivashkin PE. Lesiv AV. Khomutova YuA. Ioffe SL. Synthesis  2007,  97 
• 6b Klenov MS. Lesiv AV. Khomutova YuA. Nesterov ID. Ioffe SL. Synthesis  2004,  1159 
• 6c Eliseev OL. Ivashkin PE. Ostapenko AG. Lesiv AV. Khomutova YuA. Ioffe SL. Lapidus AL. Synlett  2006,  2239 
• 7 Sukhorukov AYu. Lesiv AV. Eliseev OL. Khomutova YuA. Bondarenko TN. Lapidus AL. Ioffe SL. Mendeleev Commun.  2007,  122 
• 10a Curran DP. Brill JF. Rakiewicz DM. J. Org. Chem.  1984,  49:  1654 
• 10b Rylander PN. Catalytic Hydrogenation in Organic Synthesis   Academic Press; New York: 1979.  p.153 
• 10c Nishimura S. Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis   Wiley; New York: 2001.  p.290-291  
• 11a Hippeli C. Zimmer R. Reissig H.-U. Liebigs Ann. Chem.  1990,  469 
• 11b Nakanishi S. Otsuji Y. Itoh K. Hayashi N. Bull. Chem. Soc. Jpn.  1990,  63:  3595 
• 11c Nakanishi S. Shirai Y. Takahashi K. Otsuji Y. Chem. Lett.  1981,  869 
• 11d Amarnath V. Anthony DC. Amarnath K. Valenyine WM. Watterau LA. Graham DG. J. Org. Chem.  1991,  56:  6924 ; and references cited therein
• 12a Chrystal EJT. Gilchrist TL. Stretch W. J. Chem. Res., Synop.  1987,  180 
• 12b Henning R. Lerch U. Urbah H. Synthesis  1989,  265 
• 12c Hippeli C. Reissig H.-U. Liebigs Ann. Chem.  1990,  475 
• 12d Tishkov AA. Reissig H.-U. Ioffe SL. Synlett  2002,  863 
• 13a Chlenov IE. Salamonov YuV. Tartakovsky VA. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.)  1976,  25:  1788 
• 13b Harada K. Kaji E. Takahashi K. Zen S. Chem. Pharm. Bull.  1994,  1562 
• For hydrolysis of imines see:
• 14a Pickard PL. Vaughan DJ. J. Am. Chem. Soc.  1950,  72:  5017 
• For hydrolysis of oximes see:
• 14b Buhler DR. Schroeter LC. Wechter WJ. J. Med. Chem.  1965,  8:  215 
• For reductive hydrolysis of oximes see:
• 14c Monti D. Gramatica P. Speranza G. Tagliapietra S. Manitto A. Synth. Commun.  1986,  16:  803 
• 14d Timms GH. Wildsmith E. Tetrahedron Lett.  1971,  12:  195 
• For reductive hydrolysis of 5,6-dihydro-4H-1,2-oxazines see:
• 14e Zimmer R. Collas M. Roth M. Reissig H.-U. Liebigs Ann. Chem.  1992,  709 
• 15 Meyers AI. Fray AH. Bull. Soc. Chim. Fr.  1997,  134:  283 
• 16 Kende AS. Hernando IJ. Milbank JB. Tetrahedron  2002,  57:  61 
• 17 Koseki Y. Sato H. Watanabe Y. Nagasaka T. Org. Lett.  2002,  4:  885 
• 18 Martin A. Perez-Martin I. Suarez E. Org. Lett.  2005,  7:  2027 
• 20 Treatment of the mixture of oxaazaspirononanones 6c ^III and 6c ^IV (1:1) with some bases (Et₃N, t-BuOK in THF at r.t.) does not influence the ratio of isomers
• 21 Gottlieb HE. Kotlyar V. Nudelman A. J. Org. Chem.  1997,  62:  7512 

8

Hydrogenolysis of oxazine 4b with Pd/C (70 bar H₂, MeOH, 80 °C, 2 h) resulted in low conversion of starting material (40%) and the formation of two major products: oxaazaspirononanone 6b (yield: 20%) and lactam 9 (Scheme [11] , yield: 17%). When the reaction is performed under more robust conditions [H₂ (150 bar), MeOH, 100 °C, 6 h] in addition to products 6b and 9 the corresponding dihydrofuran 5b was obtained in 11% yield [Scheme [2] , R¹ = Ph, R² = H, R³ = R⁴ = Me, FG = CH(CO₂Me)₂].

9

When the hydrogenation is carried out in the presence of undried Raney nickel the yields of target spirononanones decrease by 10-25% for the whole series of oxazines 4a-h.

19

CCDC 642140 contains the supplementary crystallographic data for 6b ^III . These data can be obtained free of charge via http://www.ccdc.cam.ac.uk, by e-mailing or faxing a request to [e-mail] or [phone], respectively, or by writing to the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK.