Chemical Synthesis

Phosphazene Bases

Activation of an organic substrate with an acidic C-H bond by strong bases is a key process in organic synthesis. Many of the most common organic reactions such as elimination, alkylation, Michael addition, silylation, and aldol condensation are base-catalyzed, and the determination of the appropriate base is therefore key for successful process development. Non-ionic nitrogen bases like Hünig’s Base (DIEA), DBN and DBU have found wide applications in today’s chemical processes. Nevertheless, the lower basicity and the instability of DBN, DBU, and other amidine and guanidine bases toward O2, hydrolysis, and electrophilic attack (e.g. carbonyls) limit their use.

Phosphazene bases represent a family of extremely strong, non-ionic, non-charged nitrogen–bases with an impressive list of advantages. Highly reactive “naked” enolates produced by phosphazene bases proved to be more stable towards side reactions than lithium enolates gained from conventional lithium dialkylamides. Additionally, the very low Lewis-acidity of the BH+ cation (compared to Li+) enables alkylations of otherwise unaccessible “naked” anions that would either decompose via ß-eliminations, or undergo Lewis acid-catalyzed side reactions (e.g. ß-alkoxyester, ß-lactones). Such enolates are alkylated with higher yields and very often better diastereoselectivity.

The particular ability of phosphazene bases to produce highly reactive anions together with their low nucleophilicity and inertness towards the electrophilic component enables reactions of very weak C-H acidic substrates via deprotonation in excellent yields. High solubility in nonpolar to moderately polar organic solvents (i.e. hexane, toluene, THF) and the ability of phosphazene bases to solubilize hydrophilic substrates in such solvents generates new alternatives to run base-catalyzed processes in organic media. Finally, the overall excellent chemical and thermal stability of phosphazene bases allows for facile and clean isolation of the salts of these bases from the reaction mixtures by precipitation or filtration over silica or alumina. Recovery of the free bases from the salts is a straightforward and efficient process.

Sigma-Aldrich has developed manufacturing processes for a series of mono-, di-, and tetrameric bases, polymer-bound reagents, as well as “naked” phosphazene fluoride salts. Below is a list of phosphazene bases available from Sigma-Aldrich.

Product Name/Description Structure Product #
BTPP
MeCNpKBH+ 28.4
79432
P1-t-Bu
MeCNpKBH+ 26.9
445363
BEMP
MeCNpKBH+ 27.6
360007
BEMP on PS, ~2.2mmol/g 536490
P1-t-Oct
MeCNpKBH+ 26.5
79412
P2-Et
MeCNpKBH+ 32.9
420425
P2-t-Bu
MeCNpKBH+ 33.5
79416
P2-t-Bu on PS, ~1.6 mmol/g 71477
P2-F
MeCNpKBH+~50
52585
P4-t-Bu
MeCNpKBH+41.9
79421
P4-t-Oct
MeCNpKBH+42.7
79422
P5-F
MeCNpKBH+ >50
87652