Triphenylphosphine is widely used in organic synthesis, but the post-treatment and purification of triphenylphosphine oxide produced after the reaction is very difficult. This shortcoming limits the application of many reactions, such as the following reactions will produce triphenylphosphine oxide by-products, Mitsunobu reaction, Corey-Fuchs alkyne synthesis reaction, Appel reaction, Wittig reaction, Cadogan - Sundberg indole synthesis, Staudinger reduction, aza-Wittig reaction, Criegee ozonation reaction quenching, triphenylphosphine/imidazole/iodine system iodine reaction, the use of triphenylphosphine bromide to prepare aliphatic bromide, and triphenylphosphine condenser to prepare amide. If the post-treatment and purification of triphenylphosphine oxide is not solved, the process cannot be scaled up.
In 2017, Daniel Weix et al. reported a method of precipitating triphenylphosphine oxide and zinc chloride to form TPPO-Zn complexes in polar solvents and removing them by filtration. The above method is effective in using ethanol, isopropyl alcohol, ethyl acetate and isopropyl acetate as solvents, but some basic nitrogen atom functional groups that can complex with triphenylphosphine oxide and zinc chloride are not effective.
Recently, Antonio Rodríguez Hergueta of the Eli Lilly Research Center reported in the latest Org. Process Res. Dev. A new method for the convenient removal of triphenylphosphine oxide by co-precipitation of CaBr2 with triphenylphosphine oxide. This method can easily form a co-precipitation of triphenylphosphine and calcium bromide in solvents such as ethers and toluene, eliminating the need for column chromatography, which can greatly save costs.
The triphenylphosphine oxide/calcium bromide complex in the following table can be precipitated efficiently in various solvents, such as THF, 2-methyltetrahydrofuran, MTBE, toluene, isopropyl acetate, acetonitrile, etc. The solubility of this complex is significantly different from that of the TPPO-Zn complex, and the effect is not good in ethanol and isopropanol. The two methods can be used as complementaries and can be comprehensively considered in process development.
After the equivalent number of calcium bromide is higher than 2 equivalents, the precipitation effect basically reaches the peak.
The lower the concentration of triphenylphosphine oxide, the worse the removal effect. When the concentration is reduced to 40 mL/g, only 86% can be precipitated in tetrahydrofuran.
Stirring at room temperature for more than 3 hours basically achieves a good precipitation effect.
The author has conducted experiments on the tolerance of functional groups and found that ether, aldehyde, amide, aramid, fatty amine, alcohol, phenol, benzoic acid and other functional groups are not affected and can be precipitated smoothly. However, the previous TPPO-Zn complex precipitation method has poor effect on basic nitrogen atom groups, and this method overcomes this shortcoming.
Org. Process Res. Dev. 2022; https://doi.org/10.1021/acs.oprd.2c00104
Reactions involving the generation of triphenylphosphine oxide by-products, click on the title for details:
Using azodicarboxylate (usually diethyl azodicarboxylate, DEAD) and trisubstituted phosphonide (usually triphenylphosphine), nucleophilic test agent and alcohol undergo SN2 reaction configuration flipping to obtain the opposite configuration of the substituted product.
The reaction of aldehyde with carbon tetrabromide and triphenylphosphine to produce dibromoolefin, which is then treated with n-butyl lithium to obtain terminal alkynes is called Corey-Fuchs alkyne synthesis reaction.
The conversion of triphenylphosphine, carbon tetrahalides (CCl4, CBr4) and alcohols to the corresponding halogenated alkanes under mild conditions is called the appel reaction. The yield of this reaction is high, and the reaction is carried out under neutral conditions, so it is very useful for the synthesis of alcohols that are unstable to acid and base.
In the early 1950s, G. Wittig and G. Geissler reported studies on pentavalent phosphine, where they found that the reaction of methyltriphenylphosphine (Ph3P = CH2) and benzophenone can yield 1,1-diphenylethylene and triphenylphosphine oxygenate (Ph3P = O) in equivalent amounts. Wittig realized the importance of this phenomenon and systematically studied the reaction of phosphoranes (phosphoranes) and aldones to form olefins. Therefore, the reaction of phosphoranes and carbonyl compounds to prepare olefins is called the Wittig reaction.
Cadogan reaction refers to the reaction of o-nitrostyrene 1 or o-nitrostilbene compounds with triphosphite or trialkylphosphine to form azine 2, followed by cyclization to form indole 3. Sundberg indole synthesis is the reaction of o-azidostyrene 4 synthesizing indole 3 through azine intermediate 2.
A reaction in which azido compounds react with tertiary phosphines (e.g., Ph3P) to obtain intermediates of azo-azo compounds (e.g., phosphinimines), and hydrolyze to obtain corresponding amines. Imino phosphines can be used as intermediates in a variety of chemical reactions, and can also react with carbonyl groups to form imines (aza-Wittig reaction).
In 1919, H. Staudinger and J. Meyer prepared PhN = PPh3, the first preparation of azaWittig reagent, an azaYlide. The reaction of azaYlide (imidophosphine) with various carbonyl compounds to obtain Schiff base is called the azaWittig reaction.
Triphenylphosphine is widely used in the reduction of hydrogen peroxide or internal peroxides. The reaction is related to the substrate and can form alcohols, carbonyl compounds or epoxides. The main driving force for this type of reaction is that triphenylphosphine can form a strong P = O bond with a relatively weak O-O bond (188-209 kJ/mol). For example, the use of triphenylphosphine can reduce the decomposition of odorous oxides and selectively prepare ketones and alters.
Triphenylphosphine, imidazole, and iodine systems are iodized, and the three are generally 1eq-1.5eq. Solvents are used: dichloromethane, toluene, tetrahydrofuran, acetonitrile, and ether. It is best to avoid light during the reaction, and the reaction requires no water. Usually, the reaction temperature is low, the reaction time is short, and the yield is high. In addition, some substrates need to be heated to react.
In metal-catalyzed reactions, there are many reactions that use triphenylphosphine as a ligand. In such reactions, the amount of by-product triphenylphosphine oxide is small, so this method is not necessary. For some cases where triphenylphosphine oxide happens to have similar polarities to the product and cannot be purified by column chromatography, this method can be considered.
