Processing Aids for the Pharmaceutical and Fine Chemical Industries

The strong affinity of tertiary alkylphosphine oxides to accept oxygen and form tertiary alkylphosphine oxides provides the driving force for their use as processing aides in Wittig, Staudinger, Mitsunobu and disulfide reactions.

Normally one associates TPP as a precursor for non-stabilized Wittig reagents. However when stabilized or semi-stabilized Wittig reagents are required, then trialkylphosphines such as triethyl, tripropyl or tributylphosphines perform very well and provide high E:Z product ratios (Aqueous Wittig reagents references).

Recently, the group of McNulty has developed novel aqueous Wittig chemistry which employs trialkylphosphines and simple inorganic bases such as LiOH or NaOH to prepare highly stereoselective (E) stilbenes, 1,3 dienes, 1,3,5-trienes and sesquiterpenes. In addition to the “green” aqueous chemistry with inorganic bases, the reaction mixture work up was greatly simplified by using triethyl or tripropylphosphine as the Wittig reagent precursor because the resulting tertiaryphosphine oxide byproducts are extremely water soluble. The aqueous phase containing the inorganic salts and tertiaryphosphine oxides is simply decanted from the hydrophobic product layer. Read more. (Aqueous Wittig reagents references).

The Staudinger reaction is another common procedure used by the pharmaceutical and fine chemical industries to convert azides to amines. A well know example is in the synthesis of oseltamivir phosphate (Tamiflu). Read more. (Staudinger reaction references)

The Mitsunobu reaction is used to prepare esters under relatively mild conditions. Novel Mitsunobu reagents, derived from dimethylmalonate/Bu₃P by McNulty et al, and from cyanomethylbromide/Bu₃P by Tsunoda et al, are highly effective reagents as compared to those derived from TPP and azides. McNulty et al have elucidated the mechanism by which the esterification can proceed with or without stereochemical inversion depending on the choice of acid, alcohol and solvent (Mitsunobu publication references).

Trialkylphosphines are powerful reducing agents and thus find utility for disulfide reductions which are also commonly carried out by the pharmaceutical industry. In some cases, milder reducing phosphines such as tris(2-cyanoethyl)phosphine or the very water soluble tris(3-hydroxypropyl)phosphine are preferred (Disulfide reduction references).

Tributylphosphine is also used in a catalytic mode in Michael addition reactions, in the Morita-Baylis-Hillman reaction Read more. (CYTOP^® 340 reaction references), and in the oligomerization of isocyanates (Isocyanate oligomerization references).