T3P: A Convenient and Useful Reagent in Organic Synthesis

Introduction

T3P is a highly reactive n-propyl phosphonic acid cyclic anhydride (II, Scheme 1) originally designed as a coupling agent. [1] T3P works both as coupling and as water removal reagent, offering several advantages over traditional reagents, such as high yields and purity, low toxicity, broad functional group tolerance, low epimerization tendency without any additives, and easy work-up (only water-soluble by-products, eliminating the need of chromatographic columns). [1] [2] It can be prepared from the reaction of propyl phosphonic acid (I, Scheme 1) with acetic anhydride at a temperature preferably in the range of 70-110 °C; then the oligomeric phosphonic acid anhydride intermediate is distilled at 0.01-50 mbar and a temperature range of 200-350 °C. The cyclic anhydride II is immediately dissolved in an inert organic solvent. [3] [4]

Scheme 1 Preparation of T3P

Although T3P has been mainly used as an effective and mild condensation reagent in peptide and peptidomimetic synthesis, [1-3] [5] new applications have recently been developed for this reagent, which include direct conversion of carboxylic acids into nitriles, [6] dehydrations of amides to nitriles, [6] formation of Weinreb amides, [7] β-lactam synthesis, [8] ester formations, [9] thiohydroxamic acid anhydride syntheses, [10] preparation of heterocycles, [11] alcohol ­oxidations, [12] and acylations. [13] The diverse advantages and applications of T3P show its potential as a reagent in or­ganic synthesis.

References

• 1a Wissmann H. Kleiner H.-J. Angew. Chem., Int. Ed. Engl.  1980,  19:  133 
• 1b Escher R. Bünning P. Angew. Chem., Int. Ed. Engl.  1986,  25:  277 
• 2 Glauder J. Speciality Chemicals Magazine  2004,  24:  30 ; and references cited therein
• 3 Wehner M, Kirschbaun B, Deutscher L, Wagner HJ, and Hoessl H. inventors; PCT Int. Appl.  WO 2005014604.  ; Chem. Abstr. 2005, 142, 198208
• 4 T3P is a trade name and it is commercially available as a 50% (w/w) solution in DMF, EtOAc, or BuOAc
• 5a Zadmard R. Schrader T. J. Am. Chem. Soc.  2005,  127:  904 
• 5b Rzepecki P. Gallmeier H. Geib N. Cernovska K. König B. Schrader T. J. Org. Chem.  2004,  69:  5168 
• 5c Davies JS. J. Pept. Sci.  2003,  9:  471 
• 6 Meudt A, Scherer S, and Nerdinger S. inventors; PCT Int. Appl.   WO 2005070879.  ; Chem. Abstr. 2005, 143, 172649
• 7 Burkhart F. Hoffmann M. Kessler H. Angew. Chem., Int. Ed. Engl.  1997,  36:  1191 
• 8 Crichfield KS. Hart JE. Lampert JT. Vaid RK. Synth. Commun.  2000,  30:  3737 
• 9a Wedel M. Walter A. Montforts F.-P. Eur. J. Org. Chem.  2001,  1681 
• 10a Hartung J. Schwarz M. Synlett  2000,  371 
• 10b Schwarz M. Synlett  2000,  1369 
• 11 Holla W, Napierski B, and Rebenstock H.-P. inventors; Ger. Offen.   DE 19802969.  ; Chem. Abstr. 1999, 131, 131507
• 12 Meudt A, Scherer S, and Böhm C. inventors; PCT Int. Appl.   WO 2005102978.  ; Chem. Abstr. 2005, 143, 440908
• 13 Hermann S. inventors; Ger. Offen.  DE 10063493.  ; Chem. Abstr. 2002, 137, 47003
• 14 Meudt A, Scherer S, and Böhm C. inventors; PCT Int. Appl.   WO 2005123632.  ; Chem. Abstr. 2005, 144, 69544
• 15a Ech-Chahad A. Minassi A. Berton L. Appendido G. Tetrahedron Lett.  2005,  46:  5113 
• 15b Appendido G. Minassi A. Berton L. Moriello AS. Cascio MG. De Petrocellis L. Di Marzo V. J. Med. Chem.  2006,  49:  2333