Microwave-Assisted Combinatorial Chemistry. Examples of High-Speed Solid-Phase Organic Synthesis

1. MW Group Graz Institut für Chemie  Microwave Equipment  Conclusion  Esterification of Polymer-Supported Alcohol H N O DMAP (cat.) O + N C N DCM / DMF 9:1 O N O P h P h H O Ar-CO2H (1.5 eq) C l O Ar Cs2CO3 (2.0 eq) P P O H NMP, 700 W, 5-10 min P (Merrifield) H N O O O N P h O P h P 58 % thermodynamically more stable O N C N + P h H O shielded thermocouple (1:2) DCM / DMF 0°C, 30 min T (°C) Time (PhCO)2O Conversion O O 50 10 min 3 eq 27 %  Acid Attachment to Merrifield Resin (NMP, 200°C) P h P h O 80 10 min 3 eq 39 % 120 10 min 3 eq 48 % NMP, 200°C 150 10 min 3 eq 53 % DMAP (cat.) O H P 200 10 min 3 eq 74 % sealed vessel open vessel O 200 10 min 5 eq 99 % O P h P T (°C) Time Conversion 68 (50W) 15 min 48 % 89 (100W) 15 min 73 % 132 (200W) 15 min 53 % 153 (400W) 15 min 50 % O O O Ph TFA/DCM = 1:1 P h H O P Employing microwave irradiation, acidolysis of the Merrifield linker can furthermore be carried out quantitatively using a conventional TFA/DCM mixture under elevated pressure. 500 W, 30 min (Merrifield) >99% 120°C, 7 bar 99 % 500 W, 10 min Stadler A., Kappe C.O., Eur. J. Org. Chem., 2001, 919-925 Acknowledgement: This work was supported by the Austrian Science Fund (FWF, Project P-11994-CHE) The 12th European Symposium on Organic Chemistry (ESOC-12), July 13-18, 2001, Groningen, The Netherlands Institut für Chemie Microwave & Combichem C. Oliver Kappe,* Alexander Stadler, Gernot A. Strohmeier Institute of Chemistry, Organic and Bioorganic Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria email: oliver.kappe@uni-graz.at Microwave-Assisted Combinatorial Chemistry.Examples of High-Speed Solid-Phase Organic Synthesis Introduction: One of the most common solid-phase reactions in combinatorial synthesis involves the coupling of an acid (i.e. an amino acid) to polystyrene solid supports (i.e. Wang or Merrifield resin). A number of publications have reported the coupling of carboxylic acids to Merrifield resin via the cesium salt method and the esterification of Wang resin using carbodiimide either via the isourea method or the symmetrical anhydride method. Since the reaction times using conventional conditions have been reported to be rather long (16-48 h) we have investigated the effects of microwave irradiation towards both of these reactions using benzoic acid derivatives. Milestone MLS 1600 Multimode Batch Reactor (A) Isourea-Method „open vessel“ system http://www.milestonesci.com (B) Anhydride-Method Stadler A., Kappe C.O., Tetrahedron, 2001, 3915-3920 • Esterifications to solid support in 3-15 min instead of 24-72 hours l Isourea method causes byproduct due to rearrangement of the thermolabile intermediate l Significant rate enhancement for coupling of benzoic anhydride derivatives using microwave flash heating