Synthesis of 1,2,4-Oxadiazolines on Soluble Polymer Support

Abstract

A general method for the liquid-phase syntheses of 1,2,4-oxadiazolines through a 1,3-dipolar cycloaddition is described. The poly(ethylene glycol) (PEG)-supported imines reacted with nitrile oxides generated in situ from aldoximes, and then the adducts were cleaved from the PEG, to give 1,2,4-oxadiazolines in high yields and excellent purities.

Key words

poly(ethylene glycol) (PEG) - oxadiazolines - imines - cycloaddition - liquid-phase

References

• 1a Fruchtel JS. Jung G. Angew. Chem., Int. Ed. Engl.  1996,  35:  17 
• 1b Thompson LA. Ellman JA. Chem. Rev.  1996,  96:  555 
• 2 Han H. Wolfe MM. Brenner S. Janda KD. Proc. Natl. Acad. Sci. U.S.A.  1995,  92:  6419 
• 3a Wentworth J. Janda KD. Chem. Commun.  1999,  1917 
• 3b Geekeler KE. Adv. Polym. Sci.  1995,  121:  31 
• Reviews on liquid-phase organic synthesis (LPOS):
• 4a Gravert DJ. Janda KD. Chem. Rev.  1997,  97:  489 
• 4b Harwig CW. Gravert DJ. Janda KD. Chemtracts: Org. Chem.  1999,  12:  1 
• 4c Gravert DJ. Janda KD. In Molecular Diversity and Combinatorial Synthesis: Libraries and Drug Discovery   Chaiken IM. Janda KD. ACS Symp. Ser., American Chemical Society; Washington D.C.: 1996.  p.118-127  
• 4d Vandersteen AM. Han H. Janda KD. Mol. Diversity  1996,  2:  89 
• 4e For a recent example of LPOS, see: Annunziata R. Benaglia M. Cinquini M. Cozzi F. Chem.-Eur. J.  2000,  6:  133 
• 5 MeOPEG is not soluble in THF or CH₂Cl₂ at -78 °C. To circumvent this problem Janda et al have successfully used noncross-linked chloromethylated polystyrene (NCPS) as a soluble polymer support. See: Chen S. Janda KD. J. Am. Chem. Soc.  1997,  119:  8724 
• 6 Zhao XY. Metz WA. Sieber F. Janda KD. Tetrahedron Lett.  1998,  39:  8433 
• 7a Shang YJ. Wang YG. Tetrahedron Lett.  2002,  43:  2247 
• 7b Shang YJ. Wang YG. Synthesis  2002,  1663 
• 8 Xia M. Wang YG. Tetrahedron Lett.  2002,  43:  7703 
• 9 Messer S. Abuh YF. Liu Y. Periyasamy S. Ngur DO. Edgar MAN. El-Assadi AA. Sebeih S. Dunbar PG. Roknich S. Rho T. Fang Z. Ojo B. Zhang H. Huzl JJ. Nagy PI. J. Med. Chem.  1997,  40:  1230 
• 10 Watjen F. Baker R. Engelstoff M. Herbert R. Macleod A. Knight A. Merchant K. Moseley J. Swain CJ. Wong E. Springer JP. J. Med. Chem.  1989,  32:  2282 
• 11 Clitherow JW. Beswick P. Irving WJ. Scopes DIC. Barnes JC. Clapham J. Brown DJ. Hayes AG. Bioorg. Med. Chem. Lett.  1996,  6:  833 
• 12 Diana GD. Volkots DL. Nitz TJ. Bailey TR. Long MA. Vescio N. Aldous S. Pevear DC. Dutko FJ. J. Med. Chem.  1994,  37:  2421 
• 13 Andersen KE. Lundt BF. Joergensen AS. Braestrup C. Eur. J. Med. Chem.  1996,  31:  417 
• 14 Chiou S. Shine HJ. J. Heterocycl. Chem.  1989,  26:  125 
• 15 Liang GB. Feng DD. Tetrahedron Lett.  1996,  37:  6627 
• 16 Deegan TL. Nitz TJ. Cebzanov DE. Porco JA. Bioorg. Med. Chem. Lett.  1999,  9:  209 
• 17 Christian KS. Jesper L. Tetrahedron Lett.  1999,  40:  9359 
• 18 Normand H. Amy H. Scott CS. Tetrahedron Lett.  1999,  40:  8547 

19

The polymer supported aldehyde was characterized by 500 MHz ¹H NMR analysis in CDCl₃:δ = 8.19 (s, 1 H), 8.12 (d, J = 8.3 Hz, 2 H), 7.71 (d, J = 8.3 Hz, 2 H), 4.53 (t, J = 4.7 Hz, 2 H, -PEGOCH₂CH ₂CO), 3.70-3.90 (m, PEG) ppm. The polymer supported imine 2c (R = p-FC₆H₄) was characterized by 500 MHz ¹H NMR analysis in CDCl₃: δ = 8.51 (s, 1 H), 8.15 (d, J = 8.1 Hz, 2 H), 7.96 (d, J = 8.1 Hz, 2 H), 7.26 (m, 2 H), 7.11 (m, 2 H), 4.51 (t, J = 4.7 Hz, 2 H, -PEGOCH₂CH ₂CO), 3.50-3.78 (m, PEG) ppm.

20

Typical Procedure for the Synthesis of 1,2,4-Oxadiazolines: N-Chlorosuccinimide (NCS, 2 mmol) was stirred in a flask containing dry CH₂Cl₂ (5 mL). The oxime (2 mmol) was added at 25 °C in one portion.The polymer-supported acrylate (0.25 mmol) was added in one portion after the chlorination was over. Usually after ca 30 min, Et₃N (0.14 mL in 2 mL of CH₂Cl₂) was added drop by drop over ca 2 h. The reaction mixture was stirred overnight at r.t. To this was added a five fold excess of dry benzene and the resulting triethylamine hydrochloride was removed by filtration. The solution was concentrated and Et₂O was added to afford the polymer-supported 1,2,4-oxadiazolines 3. The resin 3 is then cleaved with CH₃ONa/CH₃OH at r.t. to give the desired 1,2,4-oxadiazolines 4. Compound 3a:
¹H NMR (500 MHz, CDCl₃): δ = 8.13 (d, J = 8.0 Hz, 2 H), 7.67 (d, J = 8.0 Hz, 2 H), 7.53 (d, J = 8.5 Hz, 2 H), 7.18 (d, J = 8.4 Hz, 2 H), 6.80-7.10 (m, 5 H), 6.54 (s, 1 H), 4.25 (t, J = 4.7 Hz, 2 H, -PEGOCH₂CH ₂CO), 3.80 (s, 3 H), 3.50-3.78 (m, PEG) ppm. Compound 4a: ¹H NMR (500 MHz, CDCl₃): δ = 8.11 (d, J = 8.0 Hz, 2 H), 7.67 (d, J = 8.0 Hz, 2 H), 7.53 (d, J = 8.5 Hz, 2 H), 7.18 (d, J = 8.4 Hz, 2 H), 6.80-7.10 (m, 5 H), 6.54 (s, 1 H), 4.11 (s, 3 H), 3.88 (s, 3 H) ppm. GC/MS: m/z = 388 (M⁺).