Triphenylphosphine is a versatile reagent in organic synthesis; reactions that use it to reduce functional groups, convert carbonyls to olefins, or effect substitution of an alcohol for another nucleophile are among the most common in organic chemistry. (1) In transformations that employ triphenylphosphine (TPP) as a reductant, the triphenylphosphine is converted to triphenylphosphine oxide (TPPO). Although in some cases separation of TPPO from the reaction product is easily achieved, the difficulty of the separation is often cited as a barrier to using TPP as a reductant or reagent. This has inspired research on improved removal methods for TPPO, the development of alternative phosphines whose oxides are easier to remove, and reactions that are catalytic in phosphine. Although substantial progress continues to be made using insoluble phosphine reagents or catalytic strategies, triphenylphosphine is unlikely to be completely replaced in the near term. For this reason, additional methods for the removal of TPPO are still needed. We report here that TPPO is efficiently precipitated as ZnCl(TPPO)in polar solvents and demonstrate how this discovery can be used to precipitate TPPO from reactions that would otherwise require purification by column chromatography.

All of these physical separation strategies were described using low-polarity solvents, such as hexanes, toluene, cyclohexane, and diethyl ether. To our knowledge, there are no methods for the precipitation of TPPO from more polar solvents (i.e., ethanol, ethyl acetate, tetrahydrofuran, etc.) that are commonly used in organic synthesis. Such a method would provide an additional tool in complex molecule synthesis.

Lewis acid TPPO adducts are also well-known and have been used in the extraction of metal salts but have been less frequently applied to the removal of TPPO. For example, crystals of ZnCl(TPPO)have been known for over 100 years, (15) yet we could only find one report where ZnClwas used to precipitate TPPO from ethereal reaction mixtures (16) and one patent where precipitation was mentioned, without examples, alongside more detailed methods using MgCl (17) Although the magnesium chloride method has been utilized on scale, it is notable that a switch to a less polar solvent was required for efficient separation. (17b)

When direct precipitation cannot be used and reactive conversion is not possible, addition of a co-crystallization agent has been employed. TPPO has been demonstrated to co-crystallize with a wide variety of organic molecules with acidic protons in nonpolar solvents. (12) For example, researchers at Shin-Etsu Chemical Co. removed TPPO by adding acetic acid to an-hexane mixture of product and TPPO to form an immiscible TPPO–AcOH fluid phase that was separated from the product solution. (13) As another example, chemists at Squibb found that, in toluene, they could remove TPPO and diisopropylurea as a 1:1 complex. (14)

In cases where these strategies cannot be applied, several groups have described methods to convert TPPO into a more easily separated species. For example, Lipshutz demonstrated the removal of TPPO by alkylative trapping on Merrifield resin, (10) and Gilheany described the use of oxalyl chloride to convert TPPO to triphenylphosphonium chloride, which is easily precipitated from cyclohexane. (11)

The separation of TPPO byproducts from reaction products has generally been accomplished by chromatography, but this can be tedious on a larger scale. (1, 6) Separation by distillation is useful for cases where the reaction product is sufficiently stable and low-boiling, (7) but a liquid–liquid or liquid–solid phase separation would be more generally useful. TPPO can be precipitated in cases where the reaction product is soluble in very nonpolar solvents, such as cold hexanes and diethyl ether mixtures. (8) Product precipitation or crystallization is also a common strategy, but success depends greatly upon the identity of the product. (9)

Reports on solutions to the problem of separating triphenylphosphine oxide (TPPO) byproducts in organic reactions fall into three broad categories: (1) improved methods for TPPO removal; (2) avoiding TPPO by using alternative phosphines (2) with more easily separated phosphine oxides, (3) and (3) avoiding stoichiometric phosphine oxide waste by developing reactions that are catalytic in phosphine (4) or do not require phosphine at all. (5) This report is focused on methods of TPPO removal, so strategies (2) and (3) will not be discussed further.

Results and Discussion ARTICLE SECTIONS Jump To

2 from 4,4′-dibromo-2-nitrobiphenyl 1 by reductive cyclization with triphenylphosphine, 2 (TPPO) 2 from ethanol solutions has been reported previously but never applied to TPPO removal from reaction mixtures. In the course of large-scale (>50 g) preparation of 2,7-dibromocarbazolefrom 4,4′-dibromo-2-nitrobiphenylby reductive cyclization with triphenylphosphine, (18) one of us noted that triphenylphosphine could be conveniently separated from the carbazole product by precipitation from ethanolic zinc chloride ( Scheme 1 ). This approach was inspired by the use of phosphine oxides to selectively extract metal ions from mixtures during the enrichment of uranium ores. (19) In addition, the synthesis of pure crystals of ZnCl(TPPO)from ethanol solutions has been reported previously but never applied to TPPO removal from reaction mixtures. (15b, 15d)

Scheme 1 Scheme 1. Removal of Triphenylphosphine Oxide by ZnCl 2

The reaction procedure was simple: a 1.8 M solution of ZnCl 2 in warm ethanol was added to an ethanolic solution of the product/TPPO mixture at room temperature. After stirring and scraping to induce precipitation, the ZnCl 2 (TPPO) 2 adduct precipitated from solution. The solution was filtered to remove the precipitate, and the filtrate concentrated to remove ethanol. Finally, the residue was slurried with acetone to separate the soluble product from any insoluble excess zinc chloride. The filtered solution was completely free of triphenylphosphine oxide by TLC analysis without the need for chromatography.

2 to TPPO for complete precipitation of TPPO from solution ( 2 to promote precipitation. After precipitation, the amount of TPPO remaining in solution was quantitated by GC analysis. We found that 90% of the TPPO was removed from solution with an equimolar ratio of ZnCl 2 and TPPO. Increasing the ratio of ZnCl 2 to TPPO increased TPPO precipitation; at a 3:1 ratio TPPO could no longer be detected in the filtered solution. Considering the diminishing returns on TPPO removal with higher equivalents of ZnCl 2 , a 2:1 ratio was selected as optimal for further studies. It should be noted that this precipitation is robust and the ratio of ZnCl 2 to TPPO can be tuned to minimize TPPO or excess ZnCl 2 depending on the requirements for reaction purification. Elemental analysis of several different precipitates suggested that the complex formed is ZnCl 2 (TPPO) 2 but might contain a small amount of additional TPPO. The stoichiometry and literature precedent are consistent with ZnCl 2 (TPPO) 2 as the precipitate. Given this promising initial result, we sought to examine the molar amount of zinc chloride added and find the optimal ratio of ZnClto TPPO for complete precipitation of TPPO from solution ( Table 1 ). This study was accomplished by dissolving a fixed quantity of commercial TPPO in ethanol and adding various equivalents of ZnClto promote precipitation. After precipitation, the amount of TPPO remaining in solution was quantitated by GC analysis. We found that 90% of the TPPO was removed from solution with an equimolar ratio of ZnCland TPPO. Increasing the ratio of ZnClto TPPO increased TPPO precipitation; at a 3:1 ratio TPPO could no longer be detected in the filtered solution. Considering the diminishing returns on TPPO removal with higher equivalents of ZnCl, a 2:1 ratio was selected as optimal for further studies. It should be noted that this precipitation is robust and the ratio of ZnClto TPPO can be tuned to minimize TPPO or excess ZnCldepending on the requirements for reaction purification. Elemental analysis of several different precipitates suggested that the complex formed is ZnCl(TPPO) (15) but might contain a small amount of additional TPPO. The stoichiometry and literature precedent are consistent with ZnCl(TPPO)as the precipitate.

2 Equivalents on Precipitation Efficiency Table 1. Effect of ZnClEquivalents on Precipitation Efficiency a

2 to TPPO. After filtration, GC analysis demonstrated that precipitation proceeds in solvents ranging from THF to iPrOH. EtOAc, iPrOAc, and iPrOH stood out as excellent solvents for this method (<5% TPPO), whereas THF, 2-MeTHF, and methyl ethyl ketone were tolerated (<15% TPPO). MeOH, MeCN, acetone, and DCM (no precipitate formed) did not allow for efficient precipitation (>15% TPPO) either due to increased solubility of the TPPO/ZnCl 2 adducts or increased solvation of ZnCl 2 reducing the equilibrium constant for adduct formation. Solvent mixtures were explored to determine if combinations of solvents could improve precipitation. Only the combination of DCM/iPrOH improved TPPO removal. Finally, the addition of excess EtOH can assist in precipitation of ZnCl 2 (TPPO) 2 (vide infra). Next, a systematic investigation of polar solvents frequently used in organic synthesis was undertaken to determine the general utility of this procedure ( Table 2 ). TPPO was dissolved in each solvent and precipitated with a 2:1 ratio of ZnClto TPPO. After filtration, GC analysis demonstrated that precipitation proceeds in solvents ranging from THF toPrOH. EtOAc,PrOAc, andPrOH stood out as excellent solvents for this method (<5% TPPO), whereas THF, 2-MeTHF, and methyl ethyl ketone were tolerated (<15% TPPO). MeOH, MeCN, acetone, and DCM (no precipitate formed) did not allow for efficient precipitation (>15% TPPO) either due to increased solubility of the TPPO/ZnCladducts or increased solvation of ZnClreducing the equilibrium constant for adduct formation. Solvent mixtures were explored to determine if combinations of solvents could improve precipitation. Only the combination of DCM/iPrOH improved TPPO removal. Finally, the addition of excess EtOH can assist in precipitation of ZnCl(TPPO)(vide infra).

2 a Table 2. Solvent Effect on TPPO Precipitation with ZnCl

2 adduct or by co-precipitating with TPPO and ZnCl 2 . 2 through basic nitrogen atoms: aniline, 4-methoxypyridine, and quinidine (entries 2, 7, and 10). We next sought to assess the functional group compatibility of the method. While no brief survey could reveal all potential incompatibilities, we conducted several precipitations in the presence of small molecules bearing a representative array of functional groups ( Table 3 ). We anticipated that some functional groups would prevent efficient separation by either solubilizing the ZnCladduct or by co-precipitating with TPPO and ZnCl (12) Removal of TPPO occurred efficiently (<5% TPPO) with alcohol, aldehyde, and amide functional groups in iPrOH (20) with only a slight decrease in the recovery of benzaldehyde (78%) (entries 1, 3, and 4). A protected amino acid, Boc-Gly-OMe (entry 9), was also tolerated with minimal loss. Less positive results were obtained with substrates that appeared to co-precipitate with TPPO and ZnClthrough basic nitrogen atoms: aniline, 4-methoxypyridine, and quinidine (entries 2, 7, and 10). (21) A more hindered pyridine, 2,6-lutidine, worked well (entry 8), consistent with the coordination hypothesis. It may be possible to avoid coprecipitation by further modification of the conditions (solvent, amount of zinc used), but this was not investigated further.

Table 3. Functional Group Compatibility of TPPO Precipitation a

4 ( 2 O 2 to convert any remaining phosphine and phosphonium species to TPPO, allowing efficient removal with a single precipitation with ZnCl 2 (4 could be obtained on multigram scale in 82% yield without the need for column chromatography. In addition to the initial carbazole-forming reaction (see Scheme 1 ), two classic organic reactions, the Corey–Fuchs (22) and the Mitsunobu reaction, (23) were explored to examine the new method in situations where TPPO separation often requires column chromatography. (24) In the Corey–Fuchs reaction to synthesize Scheme 2 ), we found that precipitation of TPPO worked well. The crude reaction mixture was washed with Hto convert any remaining phosphine and phosphonium species to TPPO, allowing efficient removal with a single precipitation with ZnCl Scheme 2 ). (25) Compoundcould be obtained on multigram scale in 82% yield without the need for column chromatography.

Scheme 2 Scheme 2. Corey–Fuchs Reaction with Removal of TPP and TPPO by Oxidation and Precipitation

6 from l -menthol and 5 was similarly successful (5 and oxidize any remaining TPP to TPPO. Simple solvent evaporation followed by dilution with EtOH and precipitation with ZnCl 2 (twice) removed the majority of TPPO and allowed for the crystallization of the product directly from the ethanol solution with no further manipulation; 6 was isolated in 68% yield without purification by column chromatography. The Mitsunobu reaction to formfrom-menthol andwas similarly successful ( Scheme 3 ). (23) The crude reaction mixture was washed with sodium bicarbonate and peroxide to remove excess acidand oxidize any remaining TPP to TPPO. Simple solvent evaporation followed by dilution with EtOH and precipitation with ZnCl(twice) removed the majority of TPPO and allowed for the crystallization of the product directly from the ethanol solution with no further manipulation;was isolated in 68% yield without purification by column chromatography.

Scheme 3 Scheme 3. Mitsunobu Reaction with Precipitation of TPPO by ZnCl 2

2, 4, and 6, we did find several limitations to the method. Besides the potential for co-precipitation (vide supra), we also found, in one case, that an acid-sensitive β-lactone 2 means that, in cases where zinc contamination would be a concern, additional washes or manipulations could be required (i.e., distillation, extraction with water). While the procedure worked well for the synthesis of, and, we did find several limitations to the method. Besides the potential for co-precipitation (vide supra), we also found, in one case, that an acid-sensitive β-lactone (26) reacted with solvent under these Lewis acidic conditions. In addition, the use of an excess of ZnClmeans that, in cases where zinc contamination would be a concern, additional washes or manipulations could be required (i.e., distillation, extraction with water).