Holzapfel-Meyers-Nicolaou Modification of the Hantzsch Thiazole Synthesis

Abstract

Modified conditions for Hantzsch thiazole synthesis provides valine- and threonine-derived thiazoles without significant loss of optical purity. This two- or three-step procedure proceeds by the cyclocondensation of the corresponding thioamide under basic conditions, according to modified methods of Meyers and Holz­apfel. The hydroxythiazoline intermediate is then dehydrated by treatment with trifluoroacetic anhydride-pyridine, followed by triethylamine, according to Nicolaou’s procedure. Solvolysis of the trifluoroacetamide derivative produced in this process can be affected with sodium ethoxide in ethanol to give a reliable method for the stereoselective synthesis of functionalised thiazole building blocks in high yield.

Key words

Hantzsch - thiazoles - heterocycles - amino acids

References

• 1 Bagley MC. Dale JW. Merritt EA. Xiong X. Chem. Rev.  2005,  105:  685 
• 2 McDonald LA. Ireland CM. J. Nat. Prod.  1992,  55:  376 
• 3 Todorova AK. Jüttner F. Linden A. Plüss T. von Philipsborn W. J. Org. Chem.  1995,  60:  7891 
• 4a Bredenkamp MW. Holzapfel CW. van Zyl WJ. Synth. Commun.  1990,  20:  2235 
• 4b Aguilar E. Meyers AI. Tetrahedron Lett.  1994,  35:  2473 
• 5a (+)-Nostocyclamide: Moody CJ. Bagley MC. J. Chem. Soc., Perkin Trans. 1  1998,  601 
• 5b Promothiocin A: Bagley MC. Bashford KE. Hesketh CL. Moody CJ. J. Am. Chem. Soc.  2000,  122:  3301 
• 5c Lissoclinum cyclic peptide analogues: Bertram A. Blake AJ. Gonzàlez-López de Turiso F. Hannam JS. Jolliffe KA. Pattenden G. Skae M. Tetrahedron  2003,  59:  6979 
• 5d GE2270 A: Müller HM. Delgado O. Bach T. Angew. Chem. Int. Ed.  2007,  46:  4771 
• 6 Boden CDJ. Pattenden G. Ye T. Synlett  1995,  417 
• 7a Nicolaou KC. Safina BS. Zak M. Lee SH. Nevalainen M. Bella M. Estrada AA. Funke C. Zécri FJ. Bulat S. J. Am. Chem. Soc.  2005,  127:  11159 
• 7b Nicolaou KC. Zak M. Safina BS. Estrada AA. Lee SH. Nevalainen M. J. Am. Chem. Soc.  2005,  127:  11176 
• 8 Merritt EA. Bagley MC. Synlett  2007,  6:  954 
• Concurrent heating and cooling has been shown to improve the synthesis of compounds that are inherently thermally unstable, see:
• 9a Strauss CR. Trainor RW. Aust. J. Chem.  1995,  48:  1665 
• 9b Roberts BA. Strauss CR. Acc. Chem. Res.  2005,  38:  653 
• 10 Our previous studies showed that concurrent heating and cooling had a small but significant effect on pyrazole synthesis, see: Bagley MC. Lubinu MC. Mason C. Synlett  2007,  704 
• 11 Bagley MC. Buck RT. Hind SL. Moody CJ. J. Chem. Soc., Perkin Trans. 1  1998,  1:  591 
• 12 Nakamura Y. Shin C.-G. Umemura K. Yoshimura J. Chem. Lett.  1992,  1005 
• 13 Tavecchia P. Gentili P. Kurz M. Sottani C. Bonfichi R. Selva E. Lociuro S. Restelli E. Ciabatti R. Tetrahedron  1995,  51:  4867