Brian M. Glass, Andrew P. Combs*
DuPont Pharmaceuticals Company, Chemical and Physical Sciences Department,
Experimental Station, P.O. Box 80500, Wilmington, DE 19880-0500, USA.
Email: [email protected]

Received: 15 August 2001 / Uploaded 22 August 2001

Abstract: Many solid phase reactions require high temperatures and/or long reaction times to drive the reactions to completion. Microwave irradiation provides a useful, expedient, and inexpensive solution to facilitate the rapid parallel synthesis of large combinatorial libraries. Here we utilize microwave irradiation and the safety-catch linker to rapidly produce large libraries of diverse amide and urea products.

Safety-Catch Linker Background Initially developed by Kenner1 for peptide synthesis Must be activated prior to nucleophillic displacement from support Stable to both strongly acidic and basic conditions Cleaved with hydroxide or nucleophillic amines to form acid and primary amide products Activation step and linker adapted by Ellman, et.al.2 to form more reactive acylsulfonamide linkage Cleavage with sterically hindered amines and non-nucleophillic amines possible with heating 1 Kenner, G. W.; McDermott, J. R.; Sheppard, R. C. "The Safety Catch Principle in Solid Phase Peptide Synthesis",Chemical Communications 1971, 636-637. 2 Backes, J. B.; Virgilio, A. A.; Ellman, J.A. J. Am. Chem. Soc. 1996, 118, 3055-3056.

Basics of Microwave Chemistry Microwave region of electromagnetic spectrum lies between 1cm and 1m Commercial microwaves operate at 2.45GHz Heating effect primarily due to dielectric polarization Molecular rotation is similar to frequency of radiation and therefore molecule continually attempts to rotate to align itself with the applied field and absorb energy Larger the dielectric constant, the greater the coupling with microwaves S. Caddick, "Microwave Assisted Organic Reactions",Tetrahedron 1995, 51, 10403-10432.  Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48, 1665-1692.

Safety Catch Strategy Scaffold attached to safety-catch resin Resin compatible with both BOC and FMOC protecting group strategies Resin is activated for cleavage by alkylating the sulfonamide nitrogen Compound cleaved from resin with nucleophillic displacement Only libraries of amide products have been shown in literature. Here we show that urea products are also possible.

Ureas Synthesized Using Safety-Catch a Purity of product based on crude 1H NMR. b Purified yields based on initial loading (0.73 mmol/g) of alkyl safety-catch linker.

Biaryl Ureas on Safety-Catch a Purity of product based on crude 1H NMR. b Purified yields based on initial loading (0.73 mmol/g) of alkyl safety-catch linker.

Microwave Assisted Library Production Scaffold attached to resin Resin activated and split into filter plates Cleavage run in DMSO solution with limiting amine concentration Microwaving drives reactions with weaker nucleophiles to completion Resin washed with DMSO to bring filtrate to 10mM for assaying (no solvent evaporation necessary) 88 Diverse Amines

Rates of Cleavage for Poor Nucleophiles   Rates of cleavage of resin in 0.01M amine solutions in DMSO Cleavage is sluggish at room temperature, heating accelerates rate Microwaving does not further accelerate rate over traditional heating Microwaving to higher temperatures can drive reactions to completion within 15 minutes

Microwaving Plates - Temperature Gradients Continuous microwaving for 1 minute in commercial oven (1100 watts) Polyfiltronics PKP 2mL Filter Plate - holds DMSO solution in plate until vacuum is applied 20 Degree Celsius Gradient in Plates for DMSO and DMF

TLC Analysis of Library Synthesis Convenient way to rapidly determine library purity Sensitive detection of the presence of leftover amine (ninhydrin stain) TLC of identical amines cleaving 2 different resins shows relative Rf pattern.

Concluding Comments 10 plates (880 compounds) synthesized per chemist in two weeks Libraries of amides and ureas can be synthesized in high purity >95% Identified by LCMS Proprietary amine inputs and scaffolds Source of large novel compound libraries for general high throughput screening No expensive equipment needed No special reaction vessel needed