Scavenging simplified with Fluorous Reagents

Scavenging has become a powerful synthetic protocol for the improvement of reaction yield and the simplication of the separation process. A typical scavenging procedure involves the use of excess reagent to drive the reaction to completion, followed by a quenching of the unreacted reagent with a scavenger. Scavengers usually contain a phase tag which can be removed from the reaction mixture by filtration, liquid-liquid extraction or solid phase extraction (SPE).

Fluorous chemistry has now been adapted to solution phase scavenging. Fluorous scavengers have the following advantages:

Fluorous tags are inert and thermally stable
Solubility in organic systems can be controlled by the fluorine content of the tag, increasing options available for separation
Homogeneous scavenging reactions are fast
Reaction process can be monitored by F-TLC, F-HPLC and NMR
Unlike resins, a large excess amount of scavenger is not needed

FTI offers three types of fluorous scavengers: Nucleophilic (F-Propylamine, F-Benzylamine, F-Thiol), Electrophilic (F-Isatoic Anhydride, F-Ethyl Isocyanate, F-Oxybenzyaldehyde) and Metal Scavengers (F-TMT, F-Methylthiourea, F-Methylaminodiol products are in developmental stage). If you have specific product questions, please contact Kris Mikulan, our technical support specialist by clicking here.

Fluorous Scavengers Outperform Solid-Bound Scavengers

Polymer-bound scavenging has become a popular synthetic technique for the removal of excess reagents or by-products. However, it can be slow due to the heterogenous reaction conditions, and often a large amount (> 3-5 equivalents) of the solid-supported scavenger is required. Fluorous scavengers, have solution phase nature of chemistry, react more efficiently than their solid-supported counterparts and only require a stochiometric amount of a scavenger (or a slight excess) to complete the reaction in a shorter amount of time. During application research on fluorous scavenging, we conducted an experiment to compare the performance of polymer-bound and fluorous isatoic anhydride as amine scavenger[8].

Under the same reaction conditions using 1.5 equiv of each scavenger, after 60 minutes 84% of the target amine remains by polymer scavenging (pink line) whereas fluorous scavenging (green line) removes nearly all. In this case, fluorous scavenging is about eight times more efficient than polymer scavenging. After doubling the amount of polymer scavenger to 3.0 equiv (purple line), we still found 44% of amine left after 60 min. Octyl-alkylated isatoic anhydride was prepared to compare the fluorous and the non-fluorous reaction (blue line). Interestingly, we found that the use of a fluorous scavenger gives reaction times that are about 10% faster than with the non-fluorous scavenger, which probably resulted from the favorable electronic-inducing effect of the fluorous tag. In another case using thiols as nucleophilic scavengers, despite the (now) negative electronic-inducing on the nucleophilicity of the thiol, we still found that the fluorous scavenging is about ten times faster than polymer[1]. In each case cited the desired product was easily recovered using fluorous solid phase extraction (F-SPE).

Separation options

Light fluorous: Solid-phase extraction

FTI[1,2], the Lindsley group at Merck [3,4] and Professor Curran[5] at University of Pittsburgh have each developed various light fluorous scavengers. In these reactions the scavenger usually has less than 40% fluorine content by molecular weight, which eliminates the need for fluorous solvents. Separation is done on a fluorous stationary phase. Light fluorous scavenging includes electrophilic scavengers such as fluorous isocyanate and fluorous isatoic anhydride to remove primary and secondary amines in the synthesis of urea, thiourea and beta-hydroxyamine analogs.

Light nucleophilic scavengers include fluorous thiol and fluorous benzylamine. In this example, fluorous thiol is been used to remove alpha-bromoketone in the parallel synthesis of a tertiary amine library.

Heavy fluorous: Liquid-liquid extraction

"Heavy" fluorous scavengers are usually >60% fluorine content by molecular weight and are separated using liquid-liquid extractions. This type of scavenger usually contains multiple fluorous chains for efficient partitioning in a fluorous solvent such as FC-72 or HFE-7100. The quenched reaction mixture is separated to yield pure product in the organic phase and the fluorous scavenged product will remain in the fluorous solvent phase. An example of this type of reaction is illustrated by the Curran group, which first developed a fluorous amine as a nucleophilic scavenger to remove excess isocyanate in parallel synthesis of aryl ureas[6]. The Curran group also introduced the use of fluorous trialkyltin hydride in Giese reactions[7]. In this example the fluorous trialkyltin hydride is used for scavenging excess alkenes. The reaction mixture is separated in a triphasic extraction where there are aqueous, organic (containing desired product) and fluorous layers. The trialkyltin hydride has also been used for scavenging of alkenes in nitrile oxide cycloadditions and alkynes in Diels-Alder reactions[7].

It should be noted that there are a variety of options available for heavy fluorous scavenging depending on the molecule that you are seeking to recover and the solvent system that you are using. Please contact FTI for further details.

References Cited in June 2004 Technical Bulletin:

[1] Zhang, W.; Curran, D.P.; Chen, C.H.-T. Tetrahedron 2002, 58, 3871

[2] Zhang, W.; Chen, C.H.-T.; Nagashima, T. Tetrahedron Letters 2003, 44, 2065

[3] Lindsley, C.W.; Zhao, Z.; Leister, W.H. Tetrahedron Letters 2002, 43, 4225

[4] Lindsley, C.W.; Zhao, Z.; Leister, W.H. Tetrahedron Letters 2002, 43, 6319

[5] Werner, S.; Curran, D.P. Organic Letters 2003, 3293

[6] Linclau, B.; Singh, A.K.; Curran, D.P. J. Organic Chemistry. 1999, 64, 2835

[7] Curran, D.P.; Hadida, S.; Kim, S.Y.; Luo, Z.Y. J. American Chemical Society. 1999, 121, 6607

[8] Zhang, W. Chemical Reviews, Vol 104, No 5, 2531-2566