Synthesis and application of a new polymer-supported anhydride as scavenger resin for solution-phase chemistry
		Monica Sanna, Peter D. White,¶ BarrieW. Bycroft and Weng C. Chan*  School of Pharmaceutical Sciences,University of Nottingham, University Park, Nottingham NG7 2RD, UK and ¶CN Biosciences (UK) Ltd., Boulevard Industrial Park, Beeston, Nottingham NG9 2JR, U.K.  mailto:[email protected] Received: 20 August 2001 / Uploaded 21 August 2001 Introduction Following the successful introduction and extensive development of solid-phase peptide and organic syntheses,1 attention is focused in recent years in the development of robust polymer-supported reagents for use in traditional solution-phase reactions. These polymer-supported reagents typically function either as catalysts or scavengers.2 This combination of solution-phase with solid-phase reagents allow the removal of excess reagents and by-products by simple filtration methods without the need for chromatographic purification.  Results & Discussion We herein report a new high-loading carboxy-anhydride scavenger resin, and its properties and applications in solution-phase chemistry are described. The new reagent 1 display the advantages of combining a polymer-supported structure with a high substitution level (4.0-4.32 mmol g-1). In addition, the macroporous structure of the resin results in low swelling properties (1.8-3.4 ml g-1 in CH2Cl2, MePh, THF, DMF, i-PrOH, MeOH) and compatibility with most solvents used in organic chemistry. Such physical properties, together with its high substitution level, make this resin an effective and robust scavenger for solution-phase synthesis.  Polymer-supported reagent 1 was characterised by IR spectroscopy (nmax: 1759, 1805 cm-1), whilst its loading (4.32 mmol g-1) was determined by exposure to excess n-propylamine followed by elemental analysis of the resultant resin product 2 (Scheme 1). Scheme 1. Reaction of anhydride resin 1 with propylamine As illustrated in Scheme 1, nucleophilic attack of the amine at the cyclic anhydride results in amide bond formation via ring opening of the anhydride 1. The reactivity of the resin 1 towards primary, secondary and aromatic amines was then further investigated, which established the efficient scavenging properties of the resin (Table 1). Typically, a two-fold excess of resin over a 2-4 hour reaction period was required for the complete removal of non-hindered primary and secondary amines. In contrast, scavenging of substituted anilines was effected with longer reaction times at elevated temperatures (18 h at 60C). As anticipated, the resin 1 was found to be inefficient for the complete removal of severely hindered amines, e.g. N, N-diisopropylamine.

	A representative experimental procedure for the scavenging of a primary amine is as follows: A solution containing isobutylamine (1.0 eq.) and DMSO (1.0 eq., internal standard) in CDCl3 was analysed by 1H NMR: dH (250 MHz) 0.89 (6 H, d, J 6.7), 1.50-1.63 (1 H, m), 2.49 (2 H, d, J 1.8) 2.62 (6 H, s; DMSO). Scavenger resin 1 (2.0 eq.) was then added and the reaction mixture was vigorously stirredat room temperature for 2 h. Following removal of the resin, the supernatant was re-analysed by 1H NMR: dH (250 MHz) 2.62 (6 H, s; DMSO).  Figure 1. 1H NMR spectra for isobutylamine scavenging reaction before (top spectrum) and after treatment with polymer 1 (bottom spectrum).

	Figure 1 clearly shows the near-complete disappearance of the isobutylamine signals following treatment with resin 1 (bottom spectrum). The detectable quantity of isobutylamine after 2 h scavenging reaction at room temperature was less than 0.1%. Another example is shown in Figure 2, for the scavenging of the secondary amine piperidine. The experiment was conducted under the same conditions as described for isobutylamine using a two-fold excess of the resin 1. The 1H NMR spectrum showed no detectable amine after 4 h reaction at room temperature. Figure 2. 1H NMR spectra of piperidine scavenging experiments before (top spectrum) and after treatment with polymer 1 (bottom spectrum). The resin was also tested for the removal of amines in a series of model solution-phase reactions. An array of urea-derivatives were thus synthesised by the reaction of isocyanates with a range of amines. The unreacted excess amines were then scavenged using the resin-bound anhydride 1, affording each time the desired compounds in pure and high yields. In a typical procedure: allyl isocyanate (1.0 eq.) was reacted with benzylamine (1.2 eq.) in CDCl3. The reaction was stirred overnight (16 h) at room temperature, and analysed by 1H NMR. Resin 1 (5.0 eq.) was then added and the reaction was vigorously stirred overnight. The resin was filtered off and the supernatant analysed by 1H NMR (Figure 3). The required 1-allyl-3-benzylurea was isolated in high yield (89%) and purity (Figure 4): mp 91C; calcd. for C11H14N2O, C 69.44, H 7.41, N 14.72%; found C 69.28, H 7.29, N 14.30%; RP-HPLC: 5-100% B in 40 min, solvent A 0.06% v/v TFA(aq) , solvent B 0.06% v/v TFA(aq) in 90% v/v aqueous acetonitrile, tR 12.0 min

	Figure 3. 1H NMR spectra of the allyl urea-derivative before (top spectrum) and after scavenging (bottom spectrum). * = benzylamine CH2.  Figure 4. RP-HPLC chromatogram of allyl urea-derivative after purification using anhydride 1. Following the successful utilisation of the carboxy-anhydride resin 1, further studies on the application of the resin for solution-phase chemistry are currently in progress, particularly for the synthesis of peptidomimetics. In conclusion, a new high-loading resin-bound scavenger for solution-phase reactions has been successfully developed and its application has been comprehensively demonstrated.  References 1. (a) Lorsbach, B.A. & Kurth, M.J., Chem. Rev., 1999, 99, 1549-158; (b) Sammelson, R.E. & Kurth, M.J.,  Chem.Rev., 2001, 101, 137-202. 2. Ley, S.V., Baxendale, I.R., Bream, R.N., et al., J. Chem. Soc., Perkin Trans 1, 2000, 3815-4195. Acknowledgement