USE OF THE KAISER OXIME RESIN IN THE SOLID-PHASE SYNTHESIS OF 3-AMINOBENZISOXAZOLES

In connection with our efforts to identify ligands for a variety of biological targets, we have been interested in the synthesis of 3-aminobenzisoxazoles.1 To take advantage of parallel synthesis techniques,2 we sought to develop a method for the solid-phase synthesis of these interesting heterocycles. Two methods for the preparation of 3-aminobenzisoxazoles have been reported. Palermo describes a one-pot procedure involving an SNAr reaction of an activated ortho-halobenzonitrile with hydroxamate ion.3 Alternatively, Shutske uses a two-step process involving acetone oxime addition to 2-fluorobenzonitrile followed by a subsequent acid-mediated cyclization (Figure 1).4 We found the two-step approach using polymerbound oxime particularly attractive, because in theory, one could use the aryl oxime intermediate as a linker. Acid-mediated cyclization would then effect a cyclorelease5 from the resin, leaving no apparent residual functionality from linkage to the solid phase. To implement this strategy, we obtained the oximecontaining resin 1 (Scheme 1), which was originally developed by Kaiser and Degrado for solid-phase peptide synthesis6 and subsequently used in the synthesis of cyclic peptides,7 ureas,8 and hydroxamic acids.9 An attractive feature of the Kaiser resin is the incorporation of the nitro substituent on the benzophenone oxime, which enhances the stability of acylated intermediates to anhydrous acid. We hypothesized that aryl oxime adducts (3) would be at least as stable as acylated oxime intermediates, providing chemical compatibility of this linkage for library generation. Therefore, we sought to demonstrate that the Kaiser resin could serve as a nucleophile in SNAr reactions and that the resulting aryl oxime could be used as a linking group in the solid-phase synthesis of 3-aminobenzisoxazoles. In preliminary solution-phase studies, the oxime derived from p-nitrobenzophenone was treated with 2-fluorobenzonitrile and potassium tert-butoxide in DMF to give the SNAr product in quantitative yield. Treatment of this intermediate with anhydrous trifluoroacetic acid (TFA) for 24 h showed no reaction, whereas the addition of 20% water gave 50% conversion to 3-aminobenzisoxazole (4a) after 24 h. Although these conditions for acid-promoted cyclization are not optimized, the stability of the intermediate to anhydrous acid and the lability under aqueous conditions suggested that the desired transformations could be achieved on resin. Therefore, we moved on to optimize the conditions for these reactions on the solid phase, where we examined the influence of both steric and electronic factors on the loading and cyclitive removal steps. The effect of solvent on the loading reaction was explored in the case of 4-bromo-2-fluorobenzonitrile (2e, Table 1), with DMF, N-methylpyrrolidinone, DMSO, and THF giving 58%, 58%, 52%, and 90% yield, respectively.10 Although DMF is the solvent of choice for the solution phase reaction, THF is preferred on solid phase, presumably as a result of its superior resin-swelling ability. Column 3 of Table 1 gives loading yields for a variety of 2-fluorobenzonitriles. The presence of an electronwithdrawing group facilitates loading at room temperature. These electron-poor aryl fluorides can also be loaded equally well at 55 °C, except in the case of 2f, which (1) Suh has recently incorporated this heterocycle in the design of potent LTB4 receptor antagonists. Suh, H.; Jeong, S.; Han, Y. N.; Lee, H.; Ryu, J. Bioorg. Med. Chem. Lett. 1997, 7, 389. (2) Backes, B. J.; Ellman, J. A. Curr. Opin. Chem. Biol., 1997, 1, 86. Kaldor, S. W.; Siegel, M. G.; Curr. Opin. Chem. Biol. 1997, 1, 101. (3) Palermo, M. G. Tetrahedron Lett. 1996, 37, 2885. (4) (a) Shutske, G. M.; Kapples, K. J. J. Heterocycl. Chem. 1989, 26, 1293. (b) For the addition of other nucleophiles to aryl fluorides, see: Idoux, J. P.; Gupton, J. T.; McCurry, C. K.; Crews, A. D.; Jurss, C. D.; Colon, C.; Rampi, R. C. J. Org. Chem. 1983, 48, 3771. (5) For a recent example of cyclorelease to give a heterocycle, see: Smith, R. A.; Bobko, M. A.; Lee, W. Bioorg. Med. Chem. Lett. 1998, 8, 2369. Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahedron Lett. 1996, 37, 937. For other examples of cyclitive removal, see: Nicolaou, K. C.; Pastor, J.; Winssinger, N.; Murphy, F. J. Am. Chem. Soc. 1998, 120, 5132 and references therein. (6) Degrado, W. F.; Kaiser, E. T. J. Org. Chem. 1980, 45, 1295. (7) Osapay, G.; Profit, A.; Taylor, J. W. Tetrahedron Lett. 1990, 31, 6121. (8) Scialdone, M. A. Tetrahedron Lett., 1996, 37, 8141. (9) Golebiowski, A.; Klopfenstein, S. Tetrahedron Lett. 1998, 39, 3397. (10) The % loading determinations of entries a-h in Table 1 are an average of 3 experiments and were calculated on the basis of weight difference. IR spectra for these loaded resins showed the requisite nitrile absorptions from 2225 to 2235 cm-1. In addition, % loading was also calculated for entries a and c-f on the basis of nitrogen combustion analysis (n ) 12) and were found to be in close correspondence with yield determinations based on weight. See ref 8 for discussion of weight versus elemental analysis for yield determination. Figure 1. Shutske’s Synthesis of 3-Aminobenzisoxazoles.