Highly Stereoselective and Flexible Synthesis of 6-Alkoxy-5,6-dihydro-4H-1,2-oxazines by Conjugate Addition of Organolithium Compounds to 6H-1,2-Oxazines Followed by Trapping with Electrophiles

Abstract

Conjugate additions of reactive organolithium compounds such as phenyllithium, n-butyllithium, tert-butyllithium, and 2-propenyllithium to 6H-1,2-oxazines 1, 24, and 25 followed by trapping of the intermediates with electrophiles gave a variety of highly substituted 6-alkoxy-5,6-dihydro-4H-1,2-oxazines 2-15 and 27-30 generally in very good yields. Most interestingly, this reaction sequence proceeds with high stereocontrol producing in large excess or exclusively the trans,trans-diastereomers. Using benzaldehyde as the electrophile, only compound 8, which is one of eight possible diastereomers, was formed. Methyllithium or lithiated methoxyallene as the nucleophilic component provide expected addition products 17 and 19, but formation of bis-1,2-oxazines 18 and 20 seems to be inevitable with these less reactive organolithium compounds.

asymmetric synthesis - conjugate addition - organolithium compounds - 1,2-oxazines - alkylation

References

1a Chrystal EJT. Gilchrist TL. Stretch W. J. Chem. Res., Synop.  1987,  180 

1b Chrystal EJT. Gilchrist TL. Stretch W. J. Chem. Res., Miniprint  1987,  1563 

2 Henning R. Lerch U. Urbach H. Synthesis  1989,  265 

3 Hippeli C. Reissig H.-U. Liebigs Ann. Chem.  1990,  475 

4 Zimmer R. Hoffmann M. Reissig H.-U. Chem. Ber.  1992,  125:  2243 

5 Angermann J. Homann K. Reissig H.-U. Zimmer R. Synlett  1995,  1014 

6 Zimmer R. Angermann J. Hain U. Hiller F. Reissig H.-U. Synthesis  1997,  1467 

7 Zimmer R. Homann K. Angermann J. Reissig H.-U. Synthesis  1999,  1223 

8 Homann K. Dissertation   Technische Hochschule; Darmstadt: 1994. 

9 Angermann J. Dissertation   Technische Universität; Dresden: 1997. 

10 Homann K. Angermann J. Collas M. Zimmer R. Reissig H.-U. J. Prakt. Chem.  1998,  340:  649 

11 Schmidt E. Dissertation   Technische Universität; Dresden: 2001. 

12 Zimmer R. Hiller F. Reissig H.-U. Heterocycles  1999,  50:  393 

13 Hartl H. Brüdgam I. Reissig H.-U. Buchholz M. Z. Kristallogr.  2001,  216:  591 

14 Paulini K. Gerold A. Reissig H.-U. Liebigs Ann. Chem.  1995,  667 

15 Mander LN. Sethi SP. Tetrahedron Lett.  1983,  24:  5425 

16 Winn M. von Geldern TW. Opgenorth TJ. Jae H. Tasker AS. Boyd SA. Kester JA. Mantei RA. Bal R. Sorensen BK. Wu-Wong JR. Chiou WJ. Dixon DB. Novosad EI. Hernandez L. Marsh KC. J. Med. Chem.  1996,  39:  1039 

17 For a review see: Zimmer R. Synthesis  1993,  165 

18 For experimental and theoretical investigations on regioselective additions of organolithium compounds to α,β-unsaturated imines see: Tomioka K. Shioya Y. Nagaoka Y. Ymada K. J. Org. Chem.  2001,  66:  7051 ; and references cited therein

19

Buchholz, M.; Hiller, F.; Reissig, H.-U. Eur. J. Org. Chem., in press.

20 Trost BM. Jungheim LN. J. Am. Chem. Soc.  1980,  102:  7910 

21 Paquette LA. Kuo LH. Tae J. J. Org. Chem.  1998,  63:  2010 

22 Reissig H.-U. Hippeli C. Arnold T. Chem. Ber.  1990,  123:  2403 

23 Zimmer R. Homann K. Reissig H.-U. Liebigs Ann. Chem.  1993,  1155