Phosphonate Diester and Phosphonamide Synthesis. Reaction Coordinate Analysis by 31P NMR Spectroscopy:  Identification of Pyrophosphonate Anhydrides and Highly Reactive Phosphonylammonium Salts1

• Published in: Journal of the American Chemical Society Vol. 119; no. 35; pp. 8177 - 8190
• Main Authors: Hirschmann, Ralph, Yager, Kraig M, Taylor, Carol M, Witherington, Jason, Sprengeler, Paul A, Phillips, Barton W, Moore, William, Smith, Amos B
• Format: Journal Article
• Language: English; Japanese
• Published: American Chemical Society 03.09.1997
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja962465o

A series of phosphonochloridates was prepared from the corresponding phosphonate monoesters, and their reactions with alcohols, amines, and the bisnucleophile 4-aminobutan-1-ol have been investigated using 31P NMR spectroscopy. In the conversion of phosphonate monoesters to phosphonochloridates via the addition of thionyl chloride or oxalyl chloride, pyrophosphonate anhydrides were found to be formed readily as byproducts. The anhydrides reacted readily with alcohols, but more slowly than the corresponding phosphonochloridates, and only sluggishly, if at all, with amines. Therefore, when phosphonamides are prepared, anhydride formation must be suppressed. This is accomplished when the monoester is added to the chloridating agent. Unhindered phosphonochloridates reacted predominantly with the amino function of 4-aminobutan-1-ol to furnish the phosphonamidates, whereas a sterically hindered phosphonochloridate demonstrated a preference for O-coupling. This result indictes that the energy gained during P−O bond formation surmounts the kinetic barrier resulting from steric hindrance more effectively than formation of the weaker P−N bond. Importantly, treatment of the phosphonochloridates with tertiary amines prior to addition of the nucleophile resulted in the formation of hitherto unrecognized phosphonylating agents, which we formulated as phosphonyltrialkylammonium salts. The latter, unlike the anhydrides, are more reactive than the phosphonochloridates toward both alcohols and amines, affording improved yields of phosphonate esters and amides. These improved yields are not obtained when triethylamine is added simultaneously with the nucleophile merely to neutralize acid rather than as a deliberate step to generate the phosphonyltrialkylammonium salts. Use of these novel phosphonylating agents proceeded without concomitant racemization at stereogenic centers α to phosphorous. Interestingly, reaction of even an unhindered phosphonyltriethylammonium salt with 4-aminobutan-1-ol favored O-phosphonylation over N-phosphonylation by a factor of 8, demonstrating that both the charge transfer in the transition state and steric hindrance affect the propensity for P−O vis a vis P−N bond formation. In marked contrast, simultaneous addition of this bisnucleophile and triethylamine, like coupling in the absence of tertiary amine, afforded the phosphonate and phosphonamide in nearly equal amounts.