Triphenylphosphonium 3,3-dimethyl-1,2, 5-thiadiazolidine 1,1-dioxide

[155632-33-0]  · C22H23N2O2PS  · (MW 428.494)

(reagent for mediating Mitsunobu-like processes;1 a convenient alternative to DEAD-triphenylphosphine system)

Physical Data: mp 169-172 °C (CH2Cl2-MeCN; decomposition).

Solubility: soluble in DMSO, CH2Cl2, CHCl3; limited solubility in THF, toluene, Et2O.

Form Supplied in: not commercially available. White solid.

Analysis of Reagent Purity: 1H-NMR, 31P-NMR, elemental analysis.

Preparative Methods: the title reagent can be prepared in quantitative yield by addition of DEAD (1 equiv) to a solution of 3,3-dimethyl-1,2,5-thiadiazolidine-1,1-dioxide (1 equiv)2 and triphenylphosphine (1 equiv) in THF at room temperature.1 3,3-Dimethyl-1,2,5-thiadiazolidine-1,1-dioxide can be prepared in high yield by reaction of sulfamide and 1,2-diamino-2-methylpropane in anhydrous pyridine.

Purification: preparation of the reagent as above affords material of high purity with no need for further purification. Recrystallization can be achieved from CH2Cl2-MeCN.

Handling, Storage, and Precautions: the compound is hydrolytically unstable to acid, decomposing on silica gel to triphenylphosphine oxide and 3,3-dimethyl-1,2,5-thiadiazolidine-1,1-dioxide, but can be stored in the solid state at room temperature, under nitrogen, for several months without significant degradation. 1H-NMR experiments in CDCl3 may be misleading for purity check due to presence of DCl/HCl/H2O.

Mitsunobu-like Processes

Triphenylphosphonium 3,3-dimethyl-1,2,5-thiadiazolidine 1,1-dioxide (1) can be conveniently utilized as a stable source of [Ph3P+] in the promotion of Mitsunobu-like processes. By analogy with the betaine generated by reaction of DEAD and triphenylphosphine, protonation of zwitterionic species 1 by an acidic component HX generates ion pair 2 which on subsequent reaction with an alcohol (ROH) affords oxyphosphonium species (3) and 3,3-dimethyl-1,2,5-thiadiazolidine-1,1-dioxide (4). Finally, SN2 displacement reaction, occurring with Walden inversion of the alcohol stereochemistry, leads to the coupled product R-X and triphenylphosphine oxide (TPPO) (1).

Reagent 1 has been utilized to promote the couplings of alcohols and carboxylic acids,1 phenols,3-7 phthalimide,1 thiazolidinedione,8 and sulphonamides.9 The compound has gained popularity as a preparatively useful reagent on Mitsunobu-like reactions on solid support, where advantages over conventional methodology have unfolded (e.g. convenient addition of one reagent rather than two, cleaner products).3-5,8,9 Suitable solvents for the reaction include dichloromethane and toluene, and although the reagent is not usually soluble at the start of the process, a homogenous solution is obtained as the reaction proceeds (excluding resin in solid-phase syntheses). Cyclic sulfamide (4) is not extracted into Et2O facilitating the isolation of coupled products. Illustrative examples of the above mentioned utilities are shown in 1.

Related Reagents.

Triphenylphosphine; diethyl azodicarboxylate.10

1. Castro, J. L.; Matassa, V. G.; Ball, R. G., J. Org. Chem. 1994, 59, 2289.
2. Castro, J. L.; Baker, R.; Guiblin, A. R.; Hobbs, S. C.; Jenkins, M. R.; Rusell, M. G. N.; Beer, M. S.; Stanton, J. A.; Scholey, K.; Hargreaves, R. J.; Graham, M. I.; Matassa, V. G., J. Med. Chem. 1994, 37, 3023.
3. Swayze, E. E., Tetrahedron Lett. 1997, 38, 8465.
4. Pavia, M. R.; Cohen, M. P.; Dilley, G. J.; Dubuc, G. R.; Durgin, T. L.; Forman, F. W.; Hediger, M. E.; Milot, G.; Powers, S. P.; Sucholeiki, I.; Zhou, S.; Hangauer, D. G., Bioorg. Med. Chem. 1996, 4, 659.
5. Daluge, S. M.; Jurgensen, C. H.; Martin, M. T.; Osterhout, M. H., World Patent Appl. WO 00/09707, 2000.
6. Dodge, J. A.; Glasebrook, A. L.; Lugar, C. W., European Patent Appl. EP 895989, 1999.
7. Carniato, D.; Gadek, T. R.; Gourvest, J. F.; Knolle, J.; Peyman, A.; Ruxer, J. M.; Bodary, S. C., World Patent Appl. WO 00/31036, 2000.
8. Brummond, K. M.; Lu, J., J. Org. Chem. 1999, 64, 1723.
9. Swayze, E. E., Tetrahedron Lett. 1997, 38, 8643.
10. Mitsunobu, O., Synthesis 1981, 1.

José L. Castro

Merck Sharp & Dohme Research Laboratories, Harlow, Essex, UK

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.