Clean six-step synthesis of a piperidino-thiomorpholine library using polymer-supported reagents

Abstract

References

1. (a) L. A. Thompson and J. A. Ellman, Chem. Rev., 1996, 96, 555; (b) A. Akelah and D. C. Sherrington, Chem. Rev., 1981, 81, 557; (c) S. J. Shuttleworth, S. M. Allin and P. K. Sharma, Synthesis, 1997, 1217; (d) S. W. Kaldor and M. G. Siegel, Curr. Opin. Chem. Biol., 1997, 1, 101.
2. (a) M. J. Suto, L. M. Gayo-Fung, M. S. S. Palanki and R. Sullivan, Tetrahedron, 1998, 54, 4141; (b) L. M. Gayo and M. J. Suto, Tetrahedron Lett., 1997, 38, 513; (c) J. J. Parlow, Tetrahedron Lett., 1996, 37, 5257; (d) S. W. Kaldor, M. G. Siegel, J. E. Fritz, B. A. Dressman and P. J. Hahn, Tetrahedron Lett., 1996, 37, 7193; (e) D. L. Flynn, R. V. Devraj and J. J. Parlow, Curr. Opin. Drug Discovery Dev., 1998, 1, 41.
3. M. Bessodes and K. Antonakis, Tetrahedron Lett., 1985, 26, 1305; J. J. Parlow, Tetrahedron Lett., 1995, 36, 1395; G. Cainelli, M. Contento, F. Manescalchi and R. Regnol, J. Chem. Soc., Perkin Trans. 1, 1980, 2516.
4. D. L. Flynn, J. Z. Crich, R. V. Devraj, S. L. Hockerman, J. J. Parlow, M. S. South and S. Woodward, J. Am. Chem. Soc., 1997, 119, 4874; M. W. Creswell, G. L. Bolton, J. C. Hodges and M. Meppen, Tetrahedron, 1998, 54, 3983.
5. (a) B. Hinzen and S. V. Ley, J. Chem. Soc., Perkin Trans. 1, 1998, 1; (b) F. Haunert, M. H. Bolli, B. Hinzen and S. V. Ley, J. Chem. Soc., Perkin Trans. 1, 1998, 2235; (c) S. V. Ley, M. H. Bolli, B. Hinzen, A.-G. Gervois and B. J. Hall, J. Chem. Soc., Perkin Trans. 1, 1998, 2239; (d) M. H. Bolli and S. V. Ley, J. Chem. Soc., Perkin Trans. 1, 1998, 2243.
6. See for example: M. R. Barbachyn, D. K. Hutchinson, S. J. Brickner, M. H. Cynamon, J. O. Kilburn, S. P. Klemens, S. E. Glickman, K. C. Grega, S. K. Hendges, D. S. Toops, C. W. Ford and G. E. Zurenko, J. Med. Chem., 1996, 39, 680.
7. M. J. Frechet, M. J. Farrel and L. J. Nuyens, J. Macromol. Sci. Chem., 1977, 11, 507.
8. A. Bongini, G. Cainelli, M. Contento and F. Manescalchi, Synthesis, 1980, 143.
9. R. O. Hutchins, N. R. Natale and I. M. Taffer, J. Chem. Soc., Chem. Commun., 1978, 1088.
10. Y.-S. Liu, C. Zhao, D. E. Bergbreiter and D. Romo, J. Org. Chem., 1998, 63, 3471.
11. Diethylaminomethyl polystyrene was prepared by heating a suspension of chloromethylpolystyrene in N,N-dimethylformamide with diethylamine in the presence of a catalytic amount of tetra-N-butylammonium iodide at 75 °C for 20 h.
12. R. W. Murray and R. Jeyaraman, J. Org. Chem., 1985, 50, 2847; W. Adam, Y.-Y. Chan, D. Cremer, J. Gauss, D. Scheutzow and M. Schindler, J. Org. Chem., 1987, 52, 2800; R. W. Murray, Chem. Rev., 1989, 89, 1187.
13. Yield for reaction from precursor compound.
14. Masses given are obtained in positive mode and are M + H or in some cases M + NH₄. No mass ions were observed for compounds 2b and 2d under ES-MS conditions.
15. cis:trans ratio by separation was determined to be ∼1∶2.
16. Quantitative on 40 mg scale, 74% on 200 mg scale.
17. About 60% conversion after 2 days, but reaction does not go to completion on extended reaction time.