Simultaneous Deprotection and Purification Based on Ionic Resin Capture: Application to Amide Formations and Grignard and Mitsunobu Reactions

Abstract

Products containing Boc- or Tr-protected amines were caught directly out of reaction mixtures by simultaneous cleavage of the protecting group. By releasing the products with ammonia the corresponding free amines were obtained in high yields and purities. The broadly applicable method of simultaneous deprotection and purification based on ionic resin capture was applied for Grignard and Mitsunobu reactions as well as amide formations and show a high potential for multiparallel synthesis.

Key words

ion exchange - facile purification - Boc deprotection - Tr deprotection - combinatorial chemistry

References

• 1a Eames J. Watkinson M. Eur. J. Org. Chem.  2001,  1213 
• 1b Parlow JJ. Devraj RV. South MS. Curr. Opin. Chem.  1999,  3:  320 
• 2 Siegel MG. Hahn PJ. Dressman BA. Fritz JE. Grunwell JR. Kaldor SW. Tetrahedron Lett.  1997,  38:  3357 
• 3a Ley SV. Baxendale IR. Brusotti G. Caldarelli M. Massi A. Nesi M. Farmaco  2002,  57:  321 
• 3b Van den Eynde I. Van Rompaey K. Lazarro F. Tourwé D. J. Comb. Chem.  2004,  6:  468 
• 4 Bhattacharyya S. Curr. Opin. Drug Discovery Dev.  2004,  7:  752 
• 5a Thompson LA. Curr. Opin. Chem. Biol.  2000,  4:  324 
• 5b Rademann J. In Highlights in Bioorganic Chemistry. Polymer Supported Synthetic Methods - Solid-Phase Synthesis (SPS) and Polymer-Assisted Solution-Phase (PASP) Synthesis   Wiley-VCH; Weinheim: 2004.  p.290 
• 5c Dolle RE. J. Comb. Chem.  2005,  7:  739 
• 6a Gray CJ. Khoujah AM. Tetrahedron Lett.  1969,  31:  2647 
• 6b Seto H. Mander LN. Synth. Commun.  1992,  22:  2832 
• 6c Liu Y.-S. Zhao C. Bergbreiter DE. Romo D. J. Org. Chem.  1998,  63:  3471 
• 6d Baxendale IR. Ernst M. Krahnert W.-R. Ley SV. Synlett  2002,  1641 
• 6e Mukade T. Dragoli DR. Ellman JA. J. Comb. Chem.  2003,  5:  590 
• 9 Magdolen P. Vasella A. Helv. Chim. Acta  2005,  88:  2454 

7

Bondesil SCX (purchased from Varian Deutschland GmbH, Darmstadt, Germany) was used since this silica-based scavenger has a high density that facilitates the settling after shaking in multiparallel fashion. The solvent can be removed therefore faster and more easily than with an organic-polymer-based ion-exchange resin.

8

Grignard reagents were purchased from Rieke Metals Inc. (NE, USA; 2a) or Fluka Chemie GmbH (CH; 2b, 2c, 2c, 2d) as solutions in THF. Compound 1 and the alcohols 5b and 5d were supplied by ABCR GmbH & Co KG (Karlsruhe, Germany). All other reagents, Dowex 2X8-200 and solvents were purchased from Fluka Chemie GmbH (Buchs-CH).